EMERGING AND REEMERGING DISEASES
Dr. Egidia Miftode
Table 1. Emerging infectious diseases
Emerging infections
Bartonella henselae
Ehrlichia caffeensis/equi
Fakeeh virus
Hepatitis G virus
Human herpesvirus-8
Andes virus, Bayou virus
Laguna negra virus, New
York virus, Oran virus
Nipah virus
Helicobacter pilory
Nontuberculous
mycobacteria
Prion protein
Cryptosporidium,
Cyclospora, Microsporidia
Associated diseases
Cat-scratch disease
Human monocytic/granulocytic ehrlichiosis
Haemorrhagic fever in Saudi Arabia
Uncertain significance
Kaposi’s sarcoma
Hantavirus
pulmonary
syndrome
in
South/North America
Encephalitis
Gastritis/ulcer
Infections in HIV patients
New variant Crewtzfeld-Jacob disease
Gastroenteritis
Table 2. Resurgent infectious diseases
Disease agent
Borrelia burgdorferi
Dengue virus
Ebola
Echerichia coli O157:H7
Japanese encephalitis
Leishmania donovani
Machupo virus
Marburg virus
Rift valley fever virus
Toscana virus
Yersinia pestis
Associated disease
Lyme disease
Dengue haemorrhagic fever/shock
Haemorrhagic fever in Gabon/Congo
Gastroenteritis/haemolytic
uraemic
syndrome
Encephalitis in Nepal
Visceral leishmaniasis
Haemorrhagic fever
Haemorrhagic fever
Haemorrhagic fever
Encephalitis in Italy
Plague
Infectious diseases will continue to emerge, reemerge and submerge, but
continuing advances in diagnostics, surveillance, therapeutics and vaccines
may be very important in prevention and control.
Finally, we must be prepared for the unpredictable and unexpected, as was
the case with the emergence of AIDS.
PATHOGENESIS OF BACTERIAL INFECTION
Egidia Miftode
The virulence of pathogen
The fitness of a pathogen can be defined as its ability to multiply within a
host, disseminate from that host, translocate to a new host, colonize the new
host, and cause infection. This can be distinguished from the virulence from
a pathogen, which refers to the severity of clinical illness resulting from
infection.
Characteristics of bacteria that are pathogens include:
1. Transmissibility: from animal to humans/from human to human
 By food products to humans: Salmonella, Campylobacter
 By the fleas to humans: Yersinia pestis
 By animal products(raw hair): bacillus anthracis
 By ingestion: C. botulinum
 When wounds are contaminated by soil:C. perfringens and C. tetani.
 From one person to another by hands: S. aureus
The most frequent portal of entry of pathogenic bacteria are:
- respiratory
- gastrointestinal
- genital
- urinary tracts
2. Adherence to host cells
Once in the body bacteria must attach to host cells, usually epithelial cells
They multiply and spread directly through tissues or via the lymphatic
system to the blood stream
Adherence factors:
 Surface hydrophobicity and net surface charge (the more hydrophobic the
bacterial cell surface, the greater the adherence to the cell surface
 Specific surface molecules
-pili( eg. E. coli)
-fimbriae (group A Streptococci); lipoteichoic acid and M protein are
found on the fimbriae.
3. Invasion of host cells and tissues
This is a term commonly used to describe the entry of bacteria into host
cells.
Examples:
- Shigella adhere to host cells, induces the formation of pseudopods and
engulfment of the bacteria. Once inside the cells, the shigellae either
are released, or escape from the phagocytic vesicle, where they
multiply in the cytoplasm (similar for Yersinia enterocolitica.
- Legionella pneumophila - infects pulmonary macrophages and cause
pneumonia. The agent induces formation of a thin pseudopod, that
coils around the bacteria forming a vesicle. Phagolysosome fusion is
inhibited and the bacteria multiply within the vesicle.
4. Toxigenicity
Table 1. Characteristics of exotoxins and endotoxins
EXOTOXINS
ENDOTOXINS
 Excreted by living cells; high  Part of the cell wall of gramconcentrations in liquid medium
negative bacteria. May not need
to be released to have biologic
activity;
 Produced by both GP and GN
 Only in gram negative bacteria;
bacteria;
 Polypeptides;
 Lipopolysacharide complexes;
 Relatively unstable; toxicity often  Relatively stable, without loss of
destroyed rapidly by heating(>60
toxicity for hours if >60 C;
C);
 Highly
antigenic;
stimulate  Weakly immunogenic; antibodies
formation of antitoxin. Antitoxin
are antitoxic and protective;
neutralizes toxin;
 Non converted to toxoids
 Converted to antigenic, nontoxic
toxoids by formalin, acid, heat.
Toxoids
are
used
to
immunize(tetanus toxoid);
 Highly toxic(fatal in microgram  Moderately toxic;
quantities);
 Usually bind to specific receptors  Specific receptors not found in
on cells;
cells;
 Usually do not produce fever
 Produce fever by release of IL1
and other mediators
 Controled by extrachromosomal  Synthesis
directed
by
genes (plasmids)
chromosomal genes
5. Ability to evade the host’s immune system
Enzymes: coagulase, beta-lactamases, streptokinases
METHODOLOGIES USED IN THE DIAGNOSIS OF INFECTIOUS
DISEASES
Egidia Miftode
The methods of diagnosis used for the diagnosis of infectious diseases are as
follows:
I.





II.
1.
Serology: requires a diagnostic titer or evidence of conversion by
four-folds increase in titer of antibodies:
Complement fixation (CF) –
Neutralizing antibody titer (NA) -;
Hemagglutination inhibition (HI) –
Precipitating reaction (when soluble antigen comes in contact with its
corresponding antibody in solution, antigen-antibodies complexes result,
which are insoluble) -.
Immunofluorescence
and
immunoenzyme
procedures
–
Radioimmunoassay and enzyme immunoassay –
Direct detection by:
Special stains: Gram stain, acridine orange, mycobacterial stains (ZiehlNeelsen, fluorochrome stain),.
2. Antigen detection by:
a. latex agglutination – for CSF specimens, fungal antigens
b. enzyme immunoassay (ELISA)– for bacterial antigens (group A
sterptococcus, Legionella), bacterial toxins (toxins of E.coli, Clostridium
difficile), fungal antigens, parasitic antigens (Giardia lamblia,
Cryptosporidium), viral antigens (Herpes simplex, influenza A,
adenovirus, respiratory syncitial virus), chlamydial antigens.
c. Counter immune electrophoresis (CIE)
3. Molecular based assays:
a. Hybridization with DNA probe (detect specific ribosomal DNA)
b. Amplification assays such as those using PCR (polymerase chain
reaction) or ligase chain reaction.
III. Detection by culture and:
a. identification by biochemical reactions (ex. coagulase test)
b. identification by specific antisera by agglutination or fluorescent
antibody test
c. identification using molecular-based methods (specific probes, restriction
enzyme pattrern, DNA sequencing)
 antimicrobial susceptibility testing.
Specific susceptibility testing procedures
a. Disk diffusion susceptibility testing
b. Minimal inhibitory concentration testing
c. Testing for bactericidal activity
d. Serum bactericidal test
e. Synergy testing.
IV. Skin tests
1. Toxin neutralization
2. Delayed hypersensitivity –.
ANTI-INFECTIVE THERAPY
Egidia Miftode
Antibiotics are bacterial or fungal products, or are obtained by synthesis,
which are capable of inhibition or destruction of some microbiological
species.
The modern era of chemotherapy begins with the discovery of
sulphonamides in 1936, followed immediately, in the 1940s, by the
discovery of the therapeutic properties of penicillin and streptomycin.
Principles of anti-infective therapy
Choice of the proper antimicrobial agent
1. Identification of the infecting organism, or, if it is impossible to
determine the exact nature of the organism, may be useful to use
bacteriologic statistic (application of knowledge of the etiology most
likely to cause an infection in a given clinical setting);
2. Determination of antimicrobial susceptibility of etiological agent
(sensitive, intermediate sensitive, resistant);
3. Identifying host factors that may influence the efficacy and toxicity of
antimicrobial agents:
a. History of previous adverse reactions to antimicrobials
b. Age (ex. creatinine clearence may be reduced in elderly)
c. Genetic or metabolic abnormalities
d. Pregnancy
Table 1. Antimicrobials in pregnancy
Antibiotic
Penicilline
Cephalosporins
Macrolides
Polipeptides
Tetracyclines
Aminoglycosides
Phenicoles
Rifampicine
Sulphonamides
Quinolones
Nitrofurantoin
Imidazoles
I-st trimester
+
+
+
+
-
II-nd trimester
+
+
+
+
+
+
+
III-rd trimester
+
+
+
+
+
+
e. Renal and hepatic function (the major routes of drugs elimination)
Creatinine clearence (ml/min)=(14—Age in years) x weight in kg/serum
Creatinine in mg/dlx72.
f. Site of infection..
4. Antimicrobial combination may be justified in the following situations:
 When suspected polymicrobial infections (intraperitoneal, pelvic
infections, etc)
 To prevent emergence of resistance (tuberculosis, with antibiotics such as
vancomycin, aminoglycosides, fosfomycin)
 To obtain synergism (ex. penicillin + aminoglycosides for enterococci
infections)
 Initial therapy in neutropenic patients, or, when exact nature of infection
is not clear)
 To decrease toxicity
5. Choice of appropriate route of administration for antimicrobials:
- intravenous therapy
- oral absorption may be decreased
6.
7.
-
Pharmacologic properties of antimicrobials.
Monitoring the response of the patient to antimicrobial therapy:
determination of serum concentration of antimicrobial agents
determination of serum bactericidal titer
PENICILLINS
Classification of penicillins:
1.Natural penicillins
2.Penicillinase resistant penicillins (Methicilline group)
3.Aminopenicillins (“A” Group)
4.Antipseudomonal penicillins (carboxipenicillins and ureidopenicillins)
NATURAL PENICILLINS
Table 1. Doses of natural penicillins
DRUG
PENICILLINE G
PENICILLINE V
EXTENCILLINE
(BENZATHINE PEN G)
DOSE-ADULT/DAY
1-20 mil.UI, im/iv, 4/6/12h
3-4 mill. U, po , 6/8h
1,2 mill. U/15 days or
2,4 mill.U/month
DOSE-CHILD/DAY
50000-200000 U/kg
50000-100000 U/kg
600000 U/15 days or
1,2 mill.U/month
Table 2. Antimicrobial spectra and therapeutical indications of natural
penicillins
ANTIMICROBIAL SPECTRA
INDICATIONS
1. Streptococcus group A, B, C, D
2. Str. pneumoniae
3. Str. viridans
4. N. meningitidis
5. C. diphteriae
6. B. anthracis
7. Clostridium (ex. C. difficile)
8. Peptostreptococcus sp
9. Treponema pallidum
10. Leptospira
11.Borrellia
12.Listeria monocytogenes
( )-etiologic agent
Tonsillitis, Scarlet fever(1)
Pneumonia , meningitis, sepsis (2)
Endocarditis(3)
Sepsis, meningitis (4)
Anthrax (6)
Diphteria (5)
Syphillis (9)
Leptospirosis (10)
Lyme disease(11)
Meningitis, sepsis (12)
PENICILLINASE-RESISTANT PENICILLINS
Antibacterial spectra: Staphylococcus aureus (Methicillin-sensitive)
Indications: localised / generalised staphylococcal infections
Table 3. Doses of penicillinase - resistant penicillins
DRUG
OXACILLIN / NAFCILLIN
CLOXACILLIN
DICLOXACILLIN
DOSE-ADULT
2-4 g/d (po:6/8h;im,iv:4-12h)
4-12 g/d (im,iv: 4-6h)
1-4 g/d (6-8h)
DOSE-CHILD
50-100 mg/day
100-200 mg/kg/day
50-100 mg/kg
AMINOPENICILLINS
Table 4. Doses of aminopenicillins
DRUG
AMPICILLIN
AMOXICILLIN
BACAMPICILLIN
METAMPICILLIN
PIVAMPICILLIN
AMOXICILLIN-clavulanic acid
AMPICILLIN-sulbactam
DOSE-ADULT
Po: 2-4 g/day
Im, iv: 4-12 g/day
Po,im,iv: 1-8 g/d
0,8-2,4 g/d
2-12 g/d
1-3 g/d
2-3 g/d
3-4,5 g/d
DOSE-CHILD
100 mg/d
100-300 mg/d
25-200 mg/kg
50-100 mg/kg/d
50-200 mg/kg/d
50-100 mg/kg/d
30-40 mg/kg/d
30-40 mg/kg/d
The antimicrobial spectra and indications:
Enterococcus  endocarditis
Streptococcus gr. A,B,C,G  prophylaxis of stomatologic infections
S. pneumoniae  pneumonia, meningitis, sepsis
N. meningitis meningitis, sepsis
L. monocytogenes  meningitis, sepsis
Borrellia meningitis.
ANTIPSEUDOMONAL PENICILLINS (CARBOXY AND UREIDOPENICILLINS)
Table 5. Doses of antipseudomonal penicillins
DRUG
TICARCILLINE
TICARCILLINE+clavulanic acid
MEZLOCILLINE
PIPERACILLINE
PIPERACILLINE+tazobactam
DOSE-ADULT
250 mg/kg/d
12,4-18,6g/d
6-15 g/d
6-15 g/d
4,5-13,5 g/d
DOSE-CHILD
75-100 mg/kg/d
150-300mg/kg/d
100-300 mg/kg/d
100-300 mg/kg/d
100-300 mg/kg/d
Table 6. Antimicrobial spectra and indications of antipseudomonal
penicillins
ANTIMICROBIAL
SPECTRA
OF
ANTIPSEUDOMONAL PENICILLINS
TICARCILLINE:
Proteus
Enterobacter
Serratia
Pseudomonas
PIPERACILLINE: “AMPI” spectra +
Serratia marcescens
Enterobacte cloacae
Citrobacter
Bacteroides fragilis
Pseudomonas
Proteus
INDICATIONS
Severe infections with sensitive germes
Plurimicrobial infections: biliary, digestiv,
genito – urinary tract
MONOBACTAMS
AZTREONAM
Dose: 1g/day, i.v. in Gram negative cocci and bacilli infections.
Adverse reactions: allergies, hepatotoxicity, disulfiram-like syndrome.
CARBAPENEMS
Table 7. Doses of carbapenems
DRUG
IMIPENEM
MEROPENEM
ADULT
2 g/d
3 g/d
CHILD
30-60 mg/kg/d
40 mg/kg/d
Table 8. Antimicrobial spectra and indications of carbapenems
ANTIMICROBIAL SPECTRA
*GP COCCI (except Methicillin-Resistant-S. aureus)
*GN BACILLI (Ps. aeruginosa, Acinetobacter)
*GP ANAEROBES
*GN ANAEROBES (Bacillus fragilis)
INDICATIONS



Severe inf. with multi - resistant
germs
nosocomial infections
Pluribacterial infections
GP=gram positive, GN=gram negative
CEPHALOSPORINS
1st GENERATION CEPHALOSPORINS
Table 9. Doses of 1st generation cephalosporins
DRUG
CEFACLOR
CEFADROXYL
CEFALEXINE
DOSE-ADULT
2-4 g/d po
2-4 g/d po
2-4 g/d po
DOSE-CHILD
50-100 mg/kg/d
50-100 mg/kg/d
50-100 mg/kg/d
Table 10. Antimicrobial spectra and indications of 1 st generation
cephalosporins
ANTIMICROBIAL SPECTRA
S. pneumoniae
Streptococcus (except enterococcus)
Meti-S Staphylococcus
INDICATIONS
Respiratory infections
Urinary infections
Skin infections
2nd GENERATION CEPHALOSPORINS
Table 11. Doses of 2nd generation cephalosporins
DRUG
CEFAMANDOLE
CEFUROXIME
DOSE-ADULT
3-6 g/d
1,5-4 g/d
DOSE-CHILD
50-100 mg/kg/d
50mg/kg q8h iv, 10-15mg/kg bid po
CEFPROZIL
Cephamycines
CEFOTETAN
CEFOXITIN
500 mg/d, po
10-15mg/kg bid (max 1 g/d)
2-6 g/d, iv
3-6 g/d, iv
30-60 mg/kg/d
50-100 mg/kg/d
Table 12. Antimicrobial spectra and indications of 2nd generation
cephalosporins
ANTIMICROBIAL SPECTRA of 2nd gen. CS
1st gen. cephalosporins – spectra + :
 H. influenzae
 N. gonorrhoeae
 E. coli, Klebsiella
For cefoxitine: GN anaerobes
INDICATIONS
Otitis
Sinusitis
Tonsilitis (if failure with penicillin G, or
reccurences)
3rd GENERATIONS CEPHALOSPORINS
Table 13. Doses of 3rd generation cephalosporins
DRUG
CEFOPERAZONE
CEFOTAXIME
CEFTAZIDIME
CEFTRIAXONE
CEFTIZOXIME
LATAMOXEF
Oral
CEFIXIME
CEFPODOXIME
CEFTIBUTEN
CEFDINIR
DOSE-ADULT
4 g/d
4-6 g/d
3-6 g/d
2-3 g/d
3-12 g/d
2-6 g/d
DOSE-CHILD
30-60 mg/kg/d
50-100 mg/kg/d
50-100 mg/kg/d
50-75 mg/kg/d
30-60 mg/kg q8h
400 mg/d po
200-400 mg/d
400 mg/d
600mg/d
8 mg/kg/d div bid
10mg/kg div bid
4,5 mg/kg bid
Table 14. Antimicrobial spectra and indications of 3 rd generation
cephalosporins
ANTIMICROBIAL SPECTRA of 3rd gen. CFS
Enhanced activity vs. AEROBIC GN BACTERIA:
E. coli, Shigella, Proteus, Salmonella
Inconsistant activity vs.:
Serratia,
Pseudomonas,
Acinetobacter,
Enterobacter
Modest activity against ANAEROBES (only for
CEFTIZOXIME)
Antipseudomonal activ.: CEFTAZIDIME
Less active than 1st G.CFS. vs. GP COCCI
INDICATIONS
SEVERE INFECTIONS :
Sepsis
Broncho-pneum.
Nosocomial infections
Surgery antibioprophylaxis
GN=gram negative; GP=gram positive
4th GENERATION CEPHALOSPORINS
CEFEPIME: 1-2 g q12h, i.v. activity vs. Gram positive cocci  3rd
Generation CFS
CEFPIROME: enhanced activity vs. Enterobacteriaceae and P. aeruginosa.
LINCOSAMIDES
Table 15. Doses of lincosamides
DRUG
CLINDAMYCINE
LINCOMYCINE
DOSE-ADULT
DOSE-CHILD
0,6-2,4 g/d, po, im, iv 8-25 mg/kg, po
(every 6-8h)
15-40mg/kg, parenterally
0,6-1,8g im., iv po (8h)
30-60 mg/kg/d, po
10-20 mg/kg/d, im/iv
THE ANTIMICROBIAL SPECTRA is represented by:
 Anaerobic bacteria (Gram positive and gram-negative)
 Staphylococcus
 Streptococcus (excepting enterococcus)
THERAPEUTICAL INDICATIONS are:
 Bone and joint infections
 Infections with anaerobes (without meningitis!)
 Prophylaxis of infective endocarditis (if allergy to Penicillin is present).
AMINOGLYCOSIDES
Table 16. Doses of aminoglycosides
DOSE-ADULT
DRUG
1. AMIKACINE
2. DIBEKACINE
3. GENTAMYCINE
4. NETILMYCINE
5. SISOMYCINE
6. TOBRAMYCINE
7. KANAMYCINE
15 mg/kg/d (12-24h)
3 mg/ kg/d (12-24h)
3 mg/kg/d (8, 12, 24h)
4-7 mg/ kg/d (8, 12, 24h)
3 mg/ kg/d (8, 12, 24h)
3-5 mg/ kg/d (8, 12, 24h)
15 mg/kg/d (12h)
DOSE-CHILD
15 mg/kg/d
2-4 mg/kg/d
6-9 mg/kg/d
3-5 mg/kg/d
3 mg/kg/d
15mg/kg/d
8. STREPTOMYCINE
9. ISEPAMYCINE
0,5-1 g/d (24h)
15 mg/kg q24h
30-50 mg/kg/d
-
Table 17. Antimicrobial spectra and indications of aminoglycosides
ANTIMICROBIAL SPECTRA of
aminoglycosides
NETIL.,GENTA.,TOBRA.,SISO.,DIBEKA:
- Staphylococcus
- E.coli
- Listeria monocytogenes
Inconstantly:
Proteus,
Klebsiella,
Enterobacter, Serratia
AMIKA:
- Staphycoccus
-Aerobes GN bacilli: E.coli,Serratia
Enterobacter,
Proteus,
Pseudomonas,
Klebsiella
Acinetobacter
STREPTOMYCINE: My. tuberculosis,
Brucella
KANA: M. tuberculosis
INDICATIONS
! IN ASSOCIATION !







-URINARY INFECTIONS.
-INFECTIVE ENDOCARDITIS
-SEVERE INFECTIONS WITH STAPH/GN
BACILLI
-INFECTIONS WITH LISTERIA
-INFECTIONS WITH MULTIRESISTANT
GERMS
-BRUCELLOSIS
-TUBERCULOSIS
TETRACYCLINES
Table 18. Doses of tetracyclines
DRUG
1st Generation:
TETRACYCLINE
OXYTETRACYCLINE
ROLITETRACYCLINE
2nd Generation:
LYMECYCLINE
METACYCLINE
3rd Generation:
DOXICYCLINE
MINOCYCLINE
DOSE-ADULT
DOSE-CHILD
25-30 mg/kg (6-8h), po
250-500 mg (12-24h),im
300mg,im
50 mg/kg
10-20 mg/kg
10-30 mg/kg (12h)
10-30 mg/kg (12h)
10-15 mg/kg
200 mg (1st day),then 100 mg
200 mg (1st day),then 100 mg
2-4 mg/kg
2-4 mg/kg
Table 19. Antimicrobial spectra and indications of tetracyclines
ANTIMICROBIAL
tetracyclines
SPECTRA
N. gonorrhoeae, Yersinia
Brucella
of
INDICATIONS
Pasteurella
Legionella pneumophila
Vibrio cholerae
Erlichia canis
Mycoplasma pneumoniae
Rickettsiae
Chlamydia
Treponema
Borrelia
BRONCHO-PULMONARY INFECTIONS,
BRUCELLOSIS,
CHOLERAE,
GENITAL INFECTIONS WITH CHLAMYDIA.
MACROLIDES
Table 20. Doses of macrolides
DRUG
“old” macrolides:
ERYTHROMYCINE
SPIRAMYCINE
JOSAMYCINE
“new” macrolides:
CLARITHROMYCINE
DIRITHROMYCINE
ROXITHROMYCINE
Azalides:
AZITHROMYCINE
SINERGISTINES:
PRISTINAMYCINE
VIRGINIAMYCINE
DOSE-ADULT
DOSE-CHILD
2-3 g/d po, iv
2-3 g/d; 4,5-9 mil.UI/d
1-2 g/d
25-50 mg/kg/d
50000 UI/k/d
30-50 mg/k/d
0,5-2 g/d, po
0,5 mg/d, po
300 mg/d
300-600 mg/d
5-8 mg/k/d
500 mg/d, po
10 mg/kg/d
3 g/d, po
3g
50-100 mg/kg
50-100 mg/kg
Table 21. Antimicrobial spectra and indications of macrolides
ANTIMICROBIAL SPECTRA OF
MACROLIDES
Streptococcus A,C,G
Staphilococcus methicillin-Sensitive
Moraxella catarrhalis
Bordetella pertussis
Corynebacterium diphteriae
Erysipelotrix
Campylobacter
Treponema
Legionella
Mycoplasma
Chlamydia
INDICATIONS








BRONCHITIS
ATYPICAL PNEUMONIA,
PNEUMONIA WITH LEGIONELLA,
SKIN INFECTIONS,
ENTERAL INFECTIONS (YERSINIA,
CAMPYLOBACTER,
CRYPTOSPORIDIUM),
GENITAL INFECTIONS,
TOXOPLASMOSIS (pregnancy),
BACILLARY
ANGIOMATOSIS,
Rickettsia
GN cocci
Toxoplasma gondii ( SPIRAMYCINE,
ROXITHRO, CLARITHROMYCINE)
Atypical Mycobacteria
Bartonella
SINERGISTINS:
 Methicillin-resistant
Staphylococcus
 Penicillin-resistant Pneumococcus
 GP anaerobes
GP=gram-positive; GN=gram-negative

HEPATIC PELIOSIS
INFECTIONS IN STOMATOLOGY.
GLYCOPEPTIDES
Table 22. Doses of glycopeptides
DRUG
VANCOMYCIN
ADULT
1,5-2 g iv (12h)
TEICOPLANIN
200-400 mg/d
CHILD
0-30 days (age): 15 mg/kg/d
> 30 days (age): 10 mg/kg/d
10 mg/kg/d
The spectra includes:
- Methicillin-resistant Stafilococcus aureus (MRSA)
- Penicillin-resistant Streptococcus pneumoniae (PRP)
- Enterococcus
- Clostridium difficile
CHLORAMPHENICOL
The drug is bacteriostatic for the majority of organisms listed in the
following table, but it is bactericid for the germes involved in meningitis: N.
meningitidis, S. pneumoniae, H. influenzae.
Doses:
 >28 days old: 12,5-25 mg/kg q6h;
 older children and adults: 50 mg/kg/day (in 6 hourly intervals);
 older children and adults with meningitis: 100mg/kg/day (in 6 hourly
intervals).
Table 23. Antimicrobial spectra and indications of chloramphenicol
ANTIMICROBIAL SPECTRA
GP cocci:
S. aureus
S. epidermidis
S. pneumoniae
Peptococcus-Peptostreptococcus
GN cocci and coccobacilli:
N. gonorrhoeae
Pasteurella multocida
H. influenzae
Brucella spp
Bordetella pertussis
GP bacilli:
Corynebacterium diphteriae
Listeria monocytogenes
Clostridium spp
Prpionibacterium acnes
Actinomyces israelii
Actinobacillus actinomycetemcomitans
GN bacilli:
E. coli, S. typhy, and Proteus mirabilis (the other
Enterobacteriaceae have varying sensitivities)
Chlamydia, Mycoplasma, rickettsies
INDICATIONS
BRAIN ABSCESS
SUBDURAL EMPIEMA
MENINGITIS
TYPHOID FEVER
RICKETSIAL INFECTIONS

QUINUPRISTIN AND DALFOPRISTIN
Dose: 7,5 mg/kg i.v. (q 8h)
Table 23. Antimicrobial spectra and indications of quinupristin and
dalfopristin
INDICATIONS
ANTIMICROBIAL
SPECTRA
of
Quinupristin and dalfopristin
E. faecium
Skin infections
S. aureus (including MRSA)
Hospital aquired pneumoniae
S. pneumoniae (including PRP)
Urinary tract infections
Lactobacillus spp,
Bone and joint infections
Leukonostoc spp
Endocarditis
Bacteroides spp
Catheter-related bacteremia
Moraxella
L. monocytogenes
Prevotella
My. pneumoniae
Adverse reactions: local pain, inflammation, phlebitis, gastrointestinal
manifestations.
METRONIDAZOLE AND OTHER NITROIMIDAZOLES
Dose depends upon the infection:
Giardiasis: 250 mg bid 5-7 days, or 2g/day 3 days.
Susceptible anaerobic infection:
 i.v. - 15 mg/kg then 7,5 mg/kg q6h
 p.o. – 1-2 g/d in 2-4 doses .
Antimicrobial activity: Bacteroides fragilis, B. melaninigenicus, Prevotella,
Fusobacterium spp, anaerobes gram-negatives cocci and gram-positive
cocci, Cl. perfringens, Giardia lamblia, Entamoeba histolytica,
Trichomonas vaginalis
Tinidazole is effective as single dose regimen for treatment of
trichomoniasis and giardiasis.
Other nitroimidazole compounds are ornidazole, carnidazole and
secnidazole.
FOSFOMYCINE
Fosfomycine is active against Staphylococcus (even the methicillin-resistant
Staphylococcus) and Gram negative bacilli.
Recommended doses:
- 8-12 g/d, iv (adults)
- 100-200 mg/kg/d (child)
FLUOROQUINOLONES
Table 24. Classification and antimicrobial spectra of fluoroquinolones
Biologic classification of fluoroquinolones
GroupI: Limited spectrum
Nalidixic acid
Flumequine
Oxolinique acid
Piromedique acid
Pipemidique acid
Cinoxacine
Group II: Large spectrum
Pefloxacin
Enoxacin
Norfloxacin
Ciprofloxacin
Fleroxacin
Lomefloxacin
Ofloxacin
Group III: Extended spectrum
Temafloxacin
Tosufloxacin
Moxifloxacin
Grepafloxacin
Clinafloxacin
Gemifloxacin
Trovafloxacin
Levofloxacin
Gatifloxacin
Sitafloxacin
Microbiologic classification
ENTEROBACTERIACEAE
Enterobacteriaceae and:
H. influenzae
Neisseria spp
Coagulase negative staphylococcus
Intracellular pathogens
Mycoplasma spp
P. aeruginosa
Acinetobacter spp
Vibrio holerae
M. tuberculosis
M. leprae
Gpoup II spectra
+
S. pneumoniae
Streptococcus spp
+/ANAEROBES
 Caution for the use of FQ in children
KETOLIDES
The most prominent member of ketolides used in therapy is
TELITHROMYCINE.
The antibiotic spectrum includes:
 Gram – positive cocci , including: Macrolides – resistant -Streptococcus
pyogenes, S. aureus, S. pneumoniae
 Gram – negative pathogens: H. influenzae, Moraxella catarralis
 Legionella pneumophila
 Mycoplasma pneumoniae
 Chlamydia pneumoniae
OXAZOLIDINONES
Oxazolidinones belongs to a new family of antimicrobial agents.
The first compound introduced in therapy is LINEZOLID.
The spectrum of activity is mainly represented by
GRAM – POSITIVE BACTERIAL PATHOGENS:
 Methicillin – resistant S. aureus (MRSA)
 S. epidermidis
 Penicillin – resistant pneumococci (PRP)
 Vancomycin – resistant enterococci (VRE)
 Vanco – intermediate strains (VISA)
Indications:
 Community and hospital – acquired pneumonia
 Skin infections
 Other infections with gram positive – resistant germs.
Dose: 600 mg. x 2 / day, or 25 mg/kg/day
Excretion: Liver 70% + Renal 30%.
SULFONAMIDES AND TRIMETHOPRIM
Table 25. Antimicrobial spectra of sulfonamides
DRUG
ANTIMICROBIAL ACTIVITY
Sulfadiazine
Gram positive organisms (S. aureus, S.
Sulfisoxazole
pneumoniae,
S.
pyogenes,
Sulfametoxazole
Enterococcus fecalis, Corynebacterium
Sulfadoxine
diphteriae, Listeria monocytogenes,
Bacillus antracis)
Gram negative organisms (E. coli,
Klebsiella,
Salmonella,
Serratia,
Shigella,
H.
influenzae,
N.
meningitidis)
Other:
Chlamydia
Nocardia asteroides.
trachomatis,
TRIMETHOPRIM is a dihydrofolate reductase inhibitor, which is
available as a single agent and in combination with sulfamethoxazole
(trimethoprim 80 mg; sulfamethoxazole 400 mg).
Clinical use:
- urinary tract infections
- respiratory tract infections (acute bronchitis)
- gastrointestinal infections (typhoid fever, diarrhea cased by ETEC)
- gonorrhea, brucellosis, periodontal infections, nocardiosis.
- Pneumocystis carinii infections
ANTIVIRAL DRUGS
Table 26. Characteristics of antiviral drugs
ANTIVIRAL
DRUG
ACYCLOVIR
MECHANISM
VIRUS
DOSES
OF ACTION
AFFECTED
Acycl. triphosphate inhibits
H. simplex, varicella-zoster, 10 mg/
viral DNA polymerase.
cytomegalovirus
kg/d,po/iv.
!ADVERSE EFFECTS: reversible nephropathy, GI disturbances, phlebitis, headache, encephalopathy.
Same as Acyclovir
Same as Acyclovir
VALACYCLOVIR
! A.E: Same as for Acyclovir + Thrombotic microangiopathy.
Ganciclovir triph.inhibits
Cytomegalovirus,
5 mg/kg/d
GANCICLOVIR
viral DNA polymerase.
possible:HS, VZ, HHV8
! A.E: Bone marrow suppression (granulocytopenia) – common, renal insufficiency, fever, headache, phlebitis,
rash, encephalopathy
Pencicl.triph inhibits
PENCICLOVIR
viral DNA polymerase.
Only available topically, with no appreciable systemic absorbtion!
! A.E: None.
Same as Penciclovir.
Herpes simplex, varicellaFAMCICLOVIR
zoster
! A.E: Headache, nausea, diarrhea, interactions with drugs inhibiting or requiring hepatic oxidation –
uncommon.
Inhibits viral DNA polymerase,
Cytomegalov, acyclovir
60mg/kg/d
FOSCARNET
reverse transcriptase.
resistant HSV, VZV
every 8h
! A.E: Renal failure, electrolyte imbalance ( esp. hypocalcemia) , nausea, vomiting – common, anemia, genital
ulcers, seizures – uncommon.
Interference with viral
Lassa fever, hantavirus,
0.5/0.6 g
RIBAVIRIN
messanger RNA.
hepatitis C (chronic)
x2 /d, po
! A.E: Anemia – common, skin, eye and upper airway irritation, bronchospasm – common
Inhibition of viral DNA and
Hepatitis B (chronic cases), 100 mg/d,
reverse transcriptase.
HIV type 1
po
! A.E.: Lactic acidosis and severe hepatomegaly with steatosis – rare.
Blocks a protein ion channel, Influenza A virus
100mg/d,
AMANTADINE
altering the intracellular pH.
2.2mg/k/d
! A.E.: Nausea and anorexia – common, CNS dysfunction – uncommon, death from overdose – rare.
As amantadine
As amantadine
200mg/d,
RIMANTADINE
5mg/kg/d
! A.E.: Nausea and anorexia, CNS dysfunction – less frequent than with amantadine.
Interference with viral
Hepatitis B and C (possible
INTERFERON ALFA
protein synthesis.
D), HHV8, Papillomavirus
DOSES: B hepatitis: 5 millions units/d or 10 mill U 3 times/week, sc /im for 16-24 wks;
C hepatitis: 3 mill.U 3 times weekly, subcutaneously /im, for 24-48wks
! A E.: Influenza-like symptoms, GI disturbances, CNS dysfunction (including depression) bone marrow
suppression – common, autoimmune phenomena – uncommon.
LAMIVUDINE
SYSTEMIC ANTIFUNGAL AGENTS
DRUG
Polyenes
-Amphotericin B
Flucytosine
Imidazoles
-Ketoconazole
-Itraconazole
-Fluconazole
DOSE
1mg/kg (T=2-2,5g)
INDICATIONS
Deep mycosis: Candida spp,
Cryptococcus
neoformans,
Aspergillus,
hystoplasma,
blastomyces
150 mg/kg/d (in 4 doses) Cryptococcosis,
candidiasis
(renal,
CNS,
eye),
chromomycosis
400 mg/d qd(>400mg/d Chronic cutaneous candidiasis,
if meningitis)
coccidioidomycosis,
histoplasmosis, blastomycosis
200 mg/d bid
 Candidiasis vaginitis
200mgx3/d the first 3  Deep mycosis
days
50-100 mg once daily
 Oropharyngeal candidiasis
100-400 mg
 Esophagial candidiasis
400 mg/d-2 mo (after the  Cryptococcal meningitis
initial
therapy
with
Ampho B+flucytosine)
T= total dose.
STREPTOCOCCAL INFECTIONS
Egidia Miftode
Morphology and identification
Table 1: Characteristics of medically important streptococcus
Name
Streptococcus
pyogenes
Streptococcus
agalactiae
Group
specific
substance
A
Hemo
-lysis
Habitat
Beta
Throat
Skin
B
Beta
Female
genital
tract
Colon
Enterococcus faecalis D
(and other enterococci)
None,
alpha
Streptococcus
bovis D
(non enterococcus)
None
F (A,C,G) Beta
Streptococcus
anginosus
(S.inter- and
medius, S.constellatus, untypable
S milleri group)
Usually not Alpha
typed
or none
untypable
Viridans streptococci
Usually not Alpha
typed
or none
untypable
Streptococcus
None
Alpha
Colon
Throat,
colon,
female
genital
tract
Throat
colon,
female
genital
tract
Mouth
throat,
colon,
female
genital
tract
Throat
Common
and
important
Diseases
Pharyngitis,
impetigo,
rheumatic
fever,
glomerulonephritis
Neonatal
sepsis
and meningitis
Abdominal
abscess,
urinary
tract
infection,
endocarditis
Endocarditis,
common
blood
isolate in colon
cancer
Pyogenic
infections,
including
brain
abscesses
Not well defined
Dental
caries
(S.mutans),
endocarditis,
abscesses
(with
many
other
bacterial species)
Pneumonia,
pneumoniae
Peptostreptococcus
(many species)
None
None.
Alpha
Mouth,
colon,
female
genital
tract
meningitis,
endocarditis
Abscesses
(with
multiple
other
bacterial species)
Classification of streptococci of
particular medical interest
Streptococcus pyogenes.
Streptococcus agalactiae.
Groups C and G
Enterococcus faecalis (E. faecium, E. durans)..
Streptococcus bovis.
Streptococcus anginosus.
Groups E, F, G, H and K-U streptococci..
Streptococcus pneumoniae..
Viridans streptococci. Include S. mitis, S. mutans, S. salivarius, S.
sangius and others. -genesis of dental caries.
Peptostreptococcus. in mixed anaerobic infections in the abdomen,
pelvis, lung or brain.
Functional Classes of Fitness Determinants
a) Adherence and colonization
Possible virulence and transmissibility determinants of group A streptococci:
 M and M-like protein (binds to membrane cofactor protein on
keratinocytes and fibronectin);
 Hyaluronic acid capsule (fibronectin and fibrinogen binding, invasion)
 Streptokinase (converts plasminogen to plasmin)
 Cysteine protease (cleaves fibronectin and degrades vitronectin)
b) Avoidance of host defenses
Antiphagocytic properties (M proteins)
Anticomplementary properties
Cysteine protease function.
Cytolysins.
Streptolysin O
Streptolysin S is a potent cytolytic toxin.
Superantigens. Group A streptococci secrete a variety of other
biologically active proteins referred to as superantigens because of their
profound effects on the immune system
In group A streptococci there are six known superantigens:
 SPE A, B and C;
 SPE F (mitogenic factor)
 Streptococcal superantigen
 Str.pyogenes mitogen.
The SPEs share many biological properties, including: fever induction,
enhance susceptibility to endotoxic shock.
Diseases attribuable to invasion by beta-hemolytic group A streptococci
Group A streptococci may be classified clinically as the agents of
pharyngitis (throat strains), pyoderma (skin strains), rheumatic fever,
glomerulonephritis (pharyngeal or skin strains), and erythema (pharyngeal or
skin strains).
Erysipelas.
Puerperal fever.
Sepsis.
.
Fulminant, invasive group A streptococcal infections, with
streptococcal toxic shock syndrome are characterized by shock, bacteremia,
respiratory failure, and multiorgan failure. Death occurs in about 30% of
patients.
Group B streptococci are part of the normal vaginal flora in 5 – 25% of
women. Group B streptococcal infection during the first month of life may
present as fulminant sepsis, meningitis, or respiratory distress syndrome.
Poststreptococcal diseases (rheumatic fever, glomerulonephritis)
Following an acute group A streptococcal infection, there is a latent
period of 1 – 4 weeks, after which nephritis or rheumatic fever occasionaly
develops
Acute glomerulonephritis.
Rheumatic fever.
SCARLET FEVER
Egidia Miftode
Epidemiology
The mortality has declined from 72% in the preantibiotic era to 7 to
27%.
Pathogenesis
There are three mechanisms involved in the production of scarlet fever:
toxic, septic and immunologic.
1. The streptococcal erythrogenic toxin.
2. As a result of soft tissue infections may occurs otitis, sinusitis,
adenitis and bacteremia.
3. Immune mechanism: antibodies against different streptococcal
antigens (
Clinical manifestations
Incubation period is usually 3-6 days.
The onset is abrupt with fever, headache, dysphagia, vomiting, with
approximately 3 days duration.
Exanthem –
Characteristic:
 Filatov’s mask:
 Pastia’s lines:
 The erythema abates in 7-9 days.
Enanthem consists of:
 Characteristic appearance of tongue
 Exudative or erythematous pharyngitis and tonsillitis, and very rarely,
ulcerative aspect of tonsillitis.
Descuamation period starts after 7-14 days of illness
Laboratory features
1. Throat culture - positive for group A streptococci;
2. Rapid antigen detection tests in throat swab;
3. White blood cell count reveals leukocytosis, hypereosinophilia,
neutrophilia;
4. Increased ESR
5. Intracutaneous administration of erythrogenic toxin elicits local erythema
(positive Dick test – not used at the present time).
Differential diagnosis
1. Other infectious causes of tonsillitis: ..
2. Different eruptive disease: …
Kawasaki
Complications of scarlet fever
 Suppurative complications:
 Nonsuppurative complications:
glomerulonephritis.
acute
rheumatic
fever,
acute
Treatment
To prevent primary attacks of rheumatic fever, treatment should
ensure penicillin levels for at least 10 days. This can be achieved by 7 days
of penicillin G (2-4 million IU/day) followed by 3 administration of
benzathine penicillin (every 7 days).
If penicillin allergy is suspected, the drug of choice is erythromycin (30-40
mg/kg/day).
MEASLES
Egidia Miftode
Measles is a contagious disease characterized by a prodrome of fever,
cough, coryza, and conjunctivitis, followed by an erythematous,
maculopapular, confluent rash and a pathognomonic enanthem (Koplik
spots).
Etiology
measles virus, member of the genus Morbillivirus (family
Paramyxoviridae). Measles virus is a spherical, enveloped RNA virus,
Infected cells may also develop intranuclear and intracytoplasmic inclusion
bodies (a frequent pathologic feature of persistent CNS infections).
Pathogenesis
Infection is spread between individuals by the respiratory route.
In the second day, primary viremia occurs
On the 5th to 7th day after inoculation, secondary viremia occurs
Between the 11th and 14th days after inoculation the greatest viral content is
noted; this is the moment when prodrome starts followed by the occurrence
of exanthema.
Clinical manifestations
Incubation period is 10-14 days.
The prodromal stage (lasts for 3-4 days) - is characterized by:
 fever, malaise,
 cough, coryza
 conjunctivitis photophobia
 diarrhea.
 Koplik spots are the pathognomonic lesions of the measles:
 Sore throat and gingivitis are another two manifestations of enanthem.
The rash (persists for 6-7 days)
 appears 3-4 days after the onset
 the lesions are light, pink at the beginning (lesions blanched with
pressure), then, they become confluent;
 maculopapular eruption begins behind the ears, involves the upper part of
the neck;
 spreads centrifugally,
 the exanthem begins to fade after 3 days of evolution
 the end of the exanthem is marked by a fine
 in the same period physical examination can reveals pharyngitis,
enlargement of cervical lymph nodes and fever
Clinical syndromes of measles
1. Atypical measles
It’s a form of measles that occurs in children with a previous administration
of measles vaccine.
Measles virus can not be isolated, but antibody levels are very high.
2. Modified measles
Modified measles is a mild form that occurs in partially immune persons:
The distinguishing features are: a longer incubation period and a minimal
prodromal period.
3. Measles in pregnant women
In a pregnant woman, measles can lead to spontaneous abortion and
stillbirth.
4. Measles in immunocompromised patients
In immunocompromised patients measles infection evolves as a severe,
frequently fatal disease..
Complications
Complications may be consequences of viral infection or secondary to
bacterial infections:
1. Otitis media, mastoiditis, laryngitis, laryngotracheitis;
2. Pulmonary involvement:
3. Neurologic complications:
a. Post infectious encephalomyelitis
b. Measles inclusion-body encephalitis
c. Subacute sclerosing panencephalitis.
Laboratory diagnosis
Serological exams: ELISA and hemagglutination-inhibition assay. Virus
isolation from nasopharyngeal secretions is not a routine technique.
Differential diagnosis









rubella,
scarlet fever
erythema infectiosum
roseola infantum
enteroviral infection
Epstein-Barr virus exanthema
viral hepatitis
drug-induced exanthema
trichinosis.
Treatment
Bed rest must continue at least 8-10 days after the appearance of rash.
Infection is contagious 5 days before and another 5 days after the appearance
of rash.
Treatment consists, primary, of symptomatic relief.
If bacterial superinfection occurs antibiotics are indicated.
Prevention
Passive immunization with human immune globulin, intramuscularly, within
6 days after exposure, is recommended in children under 1 year of age, in
chronically ill patients, pregnant women, immunosuppressed patients.
Active immunization
Two doses of vaccine are recommended for all the children.
RUBELLA
Egidia Miftode
Rubella (German measles or 3-days measles) is an acute febrile illness
characterized by a rash and posterior auricular and suboccipital
lymphadenopathy that affects children and young adults. Infection during
early pregnancy may result in serious abnormalities of the fetus, referred to
as the congenital rubella syndrome.
Rubella virus, a member of the Togaviridae family, is the sole
member of the Rubivirus genus.
Acquired rubella
Pathogenesis
Infection occurs through the mucosa of the upper respiratory tract.
Clinical Findings
Incubation takes 2-3 weeks.
The rash starts on the face, extends over the trunk and extremities and
lasts 1-5 days.
Ocasionally, an enanthem consisting of small, red macules on the soft palate
precedes/accompanies the rash.
 Posterior auricular and suboccipital adenopathy
 Rare complications include thrombocytopenic purpura, myocarditis,
Guillain-Barre syndrome, bone marrow aplasia and encephalitis.
Laboratory diagnosis
isolation of virus  evidence of seroconversion.
 Differential diagnosis: scarlet fever, enterovirus infection, measles,
adenovirus infection, human parvovirus B19 disease, sunburn, allergic
rash, infectious mononucleosis.
Treatment
Rubella is a mild, self-limited illness and no specific treatment is
given. Laboratory-proved rubella in the first 3-4 months of pregnancy is
almost uniformly associated with foetal infection; therapeutic abortion is the
only means of avoiding the risk of malformed infants in such cases.
Prevention
Attenuated live rubella vaccines have been available since 1969 as a
single antigen or combined with measles and mumps vaccine. Vaccinated
children pose no threat to mothers who are susceptible and pregnant. The
vaccine induces immunity in at least 95% of recipients and will endure at
least 10 years.
Congenital Rubella Syndrome
Pathogenesis
Maternal viremia associated with rubella infection during pregnancy
may result in infection of the placenta and fetus. Mother may be either
symptomatic or asymptomatic.
Clinical Findings
1. Transient effects in infants
2. Permanent manifestations
 congenital heart diseases
 total or partial blindness
 growth retardation; failure to thrive,
 hepatosplenomegaly,
 thrombocytopenic purpura, anemia,
 osteitis and meningoencephalitis.
3. Developmental abnormalities that appear and progress during
childhood and adolescence:
4. Laboratory diagnosis: Demonstration of rubella antibodies of the
IgM class
5. Differential diagnosis includes other congenital infections:
syphilis, toxoplasmosis, CMV and herpes simplex virus infection.
Treatment: There is no specific treatment for congenital rubella. Many
abnormalities can be corrected by surgery or may respond to medical
therapy. Specific lesions are managed clinically without regard to their
etiology.
Prevention: To eliminate rubella and the congenital rubella syndrome, it is
necessary to immunize women of childbearing age, as well as all school-age
children.
VARICELLA
Egidia Miftode
Varicella (chickenpox) is a contagious, benign, acute illness
characterized by a generalized vesicular rash, which results from primary
infection with varicella-zoster virus (VZV).
Etiology
VZV belongs to the family Herpesviridae. The VZV genome consists
of a double-stranded DNA molecule.
Pathogenesis
VZV is spread by air droplets from nasopharyngeal secretions.
Pathology
In the skin, VZV produces ballooning degeneration of epithelial cells
in the malpighian layer of the epidermis.
Clinical manifestations
Incubation period: 15 days (10-20 days)
Prodrome symptoms (last for 1-2 days):
Exanthem is represented by pink macular (at the beginning) that quickly
become papular and develop into vesicle 1 to 4 mm in diameter surrounded
by a zone of erythema. The lesions become pustules as inflammatory cells
migrate into the vesicular fluid.
Enanthem: vesicles also involve mucosal surfaces, and rapidly evolve into
shallow ulcerations.
Varicella occurring during the first trimester of pregnancy has been
associated with congenital abnormalities
Neonatal varicella may occur when the mother develops the disease within a
period of 5 days before to 2 days after delivery.
- Varicella in immunocompromised persons is a serious and
potentially fatal infection.
Complications
1. Bacterial superinfection,
2. Varicella pneumonia –
3. Neurologic complications:
a. Reye’s syndrome
b. Cerebellar ataxia
c. Encephalitis
d. Transverse myelitis
e. Aseptic meningitis
4. Other rare complications:
pancreatitis.
hepatitis,
arthritis,
Lyell
syndrome,
Laboratory tests
1. Culture of VZV
2. By electron microscopy and histopathology
3. Detection of VZV antigens in a scrapping obtained from the base of a
vesicle;
4. Direct fluorescent antigen detection;
5. PCR
6. Serologic techniques (a fourfold rise in antibody titers is considered
diagnostic)
Diagnosis
1. The history of exposure/no prior history of chickenpox and the clinical
appearance of the exanthem (diffuse vesicular rash);
2. The presence of virus, viral antigens, or virus associated cytopathic effect
within the lesions;
3. Documentation of VZV - antibody production.
Differential diagnosis
Differential diagnosis includes vesicular exanthems caused by:
coxackievirus, disseminated HSV infection, diffuse impetigo, or
rickettsialpox.
UPPER RESPIRATORY TRACT INFECTIONS
Egidia Miftode
The classification of upper respiratory tract infections includes:
1. The common cold
2. Pharyngitis
3. Epiglotitis
4. Acute laryngitis
5. Acute laryngotracheobronchitis
6. Sinusitis
7. Otitis externa, otitis media and mastoiditis
1. The common cold
Viruses associated with the common cold are adenoviruses, parainfluenza
virus, influenza virus, rhinoviruses and respiratory syncytial virus.
2. Pharyngitis
Table 1. Etiology of pharyngitis
Viral:
- Rhinoviruses
- Adenoviruses
- Herpes simplex virus (type 1 and 2)
- Parainfluenza virus
- Influenza virus
- Coxsackievirus A
Bacterial:
- Streptococcus pyogenes (Group
A and C beta-hemolytic
streptococcus)
- N. gonorrhoeae
- Corynebacterium diphteriae
- Yersinia enterocolitica
- Epstein Barr virus
- Cytomegalovirus
- HIV-1
- Treponema
Chlamydia pneumoniae
Mycoplasma pneumoniae and
hominis
Mixed anaerobic bacterial
infection (Vincent’s angina)
Clinical manifestations
Streptococcal pharyngitis
Streptococcal pharyngitis - is characterized by:
 High fever
 Severe pharyngeal pain
 Odynophagia
 Headache, chills
 Edema and hyperemia of the tonsills/uvula
 A patchy, grayish-yellow exudate on the tonsils
 Tender, enlarged cervical lymph nodes.
Complications of streptococcal pharyngitis
 Suppurative complications:
 Nonsuppurative complications: acute rheumatic fever, acute
glomerulonephritis.
Anaerobic pharyngitis (Vincent’s angina)
The etiology is represented by mixture of anaerobic bacteria (Fusobacterium
necrophorum) and spirochetes.
Pharyngoconjunctival fever
Adenoviruses are involved in etiology and the manifestations include:
malaise, myalgia, sore throat, headache, chills, dizziness, conjunctivitis,
erythema and inflammatory exudate. Evolution of temperature is usually 5-6
days.
Herpetic pharyngitis
It is characterized by the presence of:
- vesicle and shallow ulcers on the palate
- inflammation and inflammatory exudate
- cervical adenopahy.
Herpangina
Herpangina is primarily seen in children. The etiologic agent are
coxsackieviruses.
Clinical features consist of:
- marked sore throat, dysphagia, anorexia
- small vesicles (1-2 mm) on the soft palate, uvula, and anterior tonsilar
pillars; after the rupture of vesicles, small and white ulcers appear.
Infection with Mycoplasma pneumoniae occurs primarily in collectivities of
children and young.
Differential diagnosis
Infectious pharyngitis must be distinguished from noninfectious conditions:
1. Bullous pemphigoid
2. Systemic lupus erythematous
3. Behcet’s disease
4. Kawasaki disease
Laboratory diagnosis
 Throat culture
 Rapid antigen detection tests in throat swab
 Specific serologic tests for infectious mononucleosis
 Serologic tests for My. pneumoniae, herpes simplex, adenoviruses, etc.
Treatment of sterptococcal pharyngitis:
1. The current recommended treatment for this infection is penicillin V 2550 mg/kg/day divided into a 4-dose-per-day schedule for 10 days.
2. Benzathine penicillin (penicillin G) 50,000 u/kg intramuscular
3. If a patient is penicillin-allergic: erythromycin 30 mg/kg/day or
azithromycin (given once daily for 5 days only) or clarithromycin (twice
daily for 10 days)
First-generation cephalosporins
Second-generation cephalosporins
3. Epiglottitis
Acute epiglottitis is defined as a cellulitis of the epiglottis and
adjacent structures that may produces complete airway obstruction.
The most frequently etiologic pathogen is H. influenza type B, and
occasionally pneumococcus, staphylococcus, streptococcus. H. influenzae
epiglottitis may be associated in a large proportion of cases with bacteremia
and sepsis, with different secondary location of infection.
Clinical manifestations
Onset is abrupt, marked by fever, irritability, dysphonia, dysphagia,
followed by respiratory distressLaryngoscopy reveals a “cherry-red”
epiglottis.
Laboratory features
 Leukocytosis with neutrophilia
 Positive cultures of blood and epiglottis
 Radiograph of the lateral neck shows enlarged
 Differential diagnosis includes: croup, dyphteria, angioneurotic edema,
foreign body aspiration, etc..
Therapy:
- intravenous therapy with antibiotics such as: cefotaxime (100180mg/kg/day), ceftriaxone (80-100mg/kg/day) or amocicillin-clavulanic
acid(200mg of amoxicillin/kg/day) for 7-10 days.
4. Acute laryngitis
Etiology:
- viruses –
- bacteria –
- fungi –.
Clinical manifestations: recent onset of hoarsness or episodes of aphonia.
Examination of larynx reveals hyperemia of vocal folds.
Differential diagnosis: croup, acute epiglottitis, supraglottitis, bacterial
tracheitis, voice abuse, gastroesophageal reflux disease, laryngeal
malignancy.
Antibiotics are not routinely recommended.
5. Acute laryngotracheobronchitis (croup)
Acute laryngotracheobronchitis is a viral infection that consists of
inflammation in the subglottic area.
Etiology: parainfluenza viruses, influenza A, B viruses, respiratory syncitial
virus, adenovirus, rhinovirus, enterovirus, and rarely, Mycoplasma
pneumoniae.
Clinical manifestations
The croup is preceded by an upper respiratory tract infection.
.
Laboratory findings:
Differential diagnosis
- Non infectious causes of stridor:
- Bacterial epiglottitis
Complications:
Therapy: humidification devices of the airway, good supportive care,
corticosteroids.
6. Sinusitis
The most common bacteria are: Streptococcus pneumoniae, Haemophilus
influenzae, Moraxella catarrhalis, Streptococcus pyogenes, and
Staphylococcus aureus. Anaerobic bacteria ,Fungal sinusitis ,
Viruses may also cause sinusitis.
Diagnostic modalities include fiberoptic nasal endoscopy, CT scans, and
plain x-rays.
 Amoxicillin-clavulanic acid, trimethoprim/sulfametoxazole, amocillin
 Azithromycin/Clarithromycin (if penicillin allergy);
 Levofloxacin/moxifloxacin (when Penicillin-Resistant Pneumococcus is
suspected);
7. Otitis Media
Etiological agents the most frequently seen are: S. pneumoniae, H.
influenzae, M. catarrhalis, viruses (respiratory syncitial virus, rhinoviruses)
Diagnosis is suggested by:
 Hearing loss
 Ear pain
 Fever
 Delayed speech development in children
Therapy
 Amoxillin or amoxicillin-clavulanic acid
 Cefuroxime, ceftriaxone (50 mg/kg/day)
 Clindamycin (if failure of treatment after 3 days).
INFLUENZA
V. Luca, Egidia Miftode
The Orthomyxoviridae (influenza viruses
are known:
 Type A;
 Type B –
Type C
Three immunologic types
Etiology
 The HA protein.
The antigenicity of NA,
The standard nomenclature system for influenza virus isolates
includes the following information:
 type,
 host of origin,
 geographic origin,
 strain number,
 year of isolation (example: A/Hong Kong/03/68(H3N2).
So far, 14 subtypes of HA (H1-H14) and nine subtypes of NA (N1-N9) in
many different combinations have been recovered.
Antigenic drift and antigenic shift
.
 Minor antigenic changes are termed antigenic drift;
 Major antigenic changes in HA or NA, called antigenic shift,
 Influenza virus replication
Epidemiology
The three types of influenza vary in their epidemiologic patterns.
Influenza C is least significant: it causes mild, sporadic respiratory disease,
but not epidemic.
Influenza B sometimes causes epidemics,
Influenza type A can causes around the world massive epidemics called
pandemics.
Pathogenesis
Influenza virus spreads from person to person by airborne droplets or by
contact with contaminated hands or surfaces.
Clinical findings
Uncomplicated Influenza
Incubation period: 1-4 days.
Symptoms usually appear abruptly and include:
 chills,
 headache,
 dry cough- respiratory symptoms typically last another 3-4 days.
The cough and weakness may persist for 1-3 weeks.
 high fever- lasts 3 days
 generalised muscle aches,
 malaise and anorexia
Complications
Pneumonia Reye’s Syndrome :.
Early signs:
 persistent/continuous vomiting
 loss of energy
 irritability
 fluctuating personality changes
 confusion
As the encephalopathy becomes more severe, extreme irritability, agitation,
delirium, convulsions, and coma may develop.
Laboratory findings
 hyperammoniemia
 elevated levels of alanin aminotransferase and aspartat
aminotransferase
 prolonged prothrombin time
 hypoglycemia
 hyperlactatemia
 acid-base disorders
 CSF – with <8cells/mmc, and normal level of protein and glucose
Differential diagnosis

Treatment
- Glucose administration
- Antiedematous drugs, diuretics
- Fresh frozen plasma/fresh blood (if bleeding occurs)
- Corticosteroids
- The mortality rate is high (10-50%).
Other complications: sinusites, myocarditis, pericarditis, cardiac failure,
renal failure, neurological complications.
Immunity
Immunity to influenza is long-lived and subtype-specific.
Laboratory Diagnosis
Diagnosis of influenza relies on:
1. isolation of the virus;
2. identification of viral antigen or viral nucleic acid in the patient’s cells, or
3. demonstration of a specific immunologic response.
Other tests are: ELISA and RIA. Paired acute and convalescent sera are
necessary, because normal individuals usually have influenza antibodies. A
fourfold or greater increased in titer must occur to indicate influenza
infection.
Treatment
Amantadine and rimantadine,
Zanamivir and Oseltamivir
A. All people at risk in whom influenza develops
B. Persons with severe influenza
C. For persons who wish to shorten the duration of illness.
Prevention
Inactivated viral vaccines
The vaccine is usually a cocktail containing two influenza A subtypes
(H1N1, H3N2) and a type B virus of the strains isolated in the previous
winter’s outbreaks.
Annual influenza vaccination is recommended for high-risk groups.:
 Persons >50 years old
 those with either chronic heart or lung disease,
 adult and children with asthma, or metabolic or renal disorders,
immunossuppression, hemoglobinopathy
 residents of nursing homes;
 persons who might transmit influenza to high-risk groups :
- medical personnel,
- employees in chronic care facilities,
- household members.
MUMPS
Dr. Egidia Miftode
Mumps is an acute viral disease characterized by nonsuppurative
swelling and tenderness of the salivary glands.
Etiology
Mumps virus belongs to paramyxoviridae family.
Epidemiology
The virus is spread by infectious saliva or by urine. Neonates are protected
by transplacental maternal antibodies.
Clinical manifestations
Incubation period: 14-25 days.
Prodromal symptoms (3 days): fever, headache, malaise.
Glandular involvement:
- The onset of parotitis:
 Submandibular/sublingual glands involvement (10% of cases)
- Epididymo-orchitis
 Oophoritis –
Neurologic manifestations
1. CSF pleoocytosis
- Meningitis
2. Encephalitis
3. Other features in mumps are:
 Renal function abnormalities (>60%);
 ECG abnormalities (5-15%);
 Pancreatitis –
 Thyroid inflammation:
Complications
1. Myocarditis – is very rare
2. Arthritis.
3.
4.
5.




Hemolytic anemia, trombocytopenia;
Deafness with uni, or bilateral involvement;
In pregnant women (with gestational viral infection):
fetal death is common during the first trimester.
low birth weight
endocardial fibroelastosis
juvenile diabetes mellitus.
Laboratory features
Diagnosis is based on: history of exposure, parotid swelling and tenderness,
constitutional symptoms.
Differential diagnosis
Parotid swelling must be differentiated by:
 Other infectious causes:
 Noninfectious causes:
 Extraparotid causes:
Prognosis is generally good, except severe forms of encephalitis,
myocarditis, glotic edema. Lethality is approximately 0,01%.
Treatment
Treatment is entirely symptomatic: analgesics for orchitis or pancreatitis,
drugs against vomiting, etc. Patients should avoid acid food, the diet must be
light, with a good hydration.
The vaccine contains a live mumps, virus and may be administrated alone or
in combination with measles and rubella vaccines.
INFECTIOUS MONONUCLEOSIS
Egidia Miftode
Infectious mononucleosis is an acute illness characterized by fever,
pharyngitis, lymphadenopathy, and mononuclear leukocytosis with atypical
lymphocytes.
Etiology
The Epstein-Barr virus (EBV)
Pathogenesis
EBV infects B lymphocytes and epithelial cells in the oropharynx and
cervix.
During primary infection, EBV-infected B-cells undergo lytic infection with
production of virus or express the full complement of latent viral proteins.
The latter cells are kept in check by natural killer and cytotoxic T cells,
which may appear as “atypical lymphocytes” on the peripheral blood smear.
Some latently infected cells undergo lytic replication in the oropharynx,
resulting in production of virus with shedding the virus into the saliva.
Clinical manifestations
Incubation period: 30-50 days.
 Characteristic triad consists of: fever (75% of cases), pharyngitis (84%),
and lymphadenopathy (94%).
 Other common signs and symptoms are: splenomegaly (50%),
hepatomegaly (10%), palatal petechiae (10%), rash (10%), jaundice
(10%) associated with sore throat, headache, anorexia, abdominal pain,
nausea, chills, myalgia.
A morbilliform rash
As a result of congenital infection an embriopathy may occasionally result:
Complications
Neurologic complications.
1. Haematologic complication:
2. Hepatitis, myocarditis, splenic rupture, genital ulcers.
Laboratory tests
a. Hemoleucogram shows a mononucleosis syndrome:
 Leukocytosis
 an absolute increase in the number of peripheral mononuclear cells
 atypical lymphocytes (>10%) which are primary T cells responding to the
EBV-infected cells.
b. Elevated serum aminotransferase levels
c. Serological tests.
The humoral immune response to EBV infection involves both viral-specific
and nonspecific antibodies.
Nonspecific antibodies:
Paul-Bunnell-Davidson test –
Three specific antibodies to EBV antigens are diagnostically important, and
the antigens are:
 VCA – viral capsid antigen
 EA – early antigen
 EBNA – EBV nuclear antigen(table 1)
Table 1. Diagnostic tests in infectious mononucleosis
Antibody
Heterophil
Onset
Before or at time of symptoms
Duration
Weeks to months
VCA-IgM
VCA-IgG
EBNA
EA
Before or at time of symptoms
Before or at time of symptoms
3-4 weeks after onset
peaks 3-4 weeks after onset
4-8 weeks
Lifelong
Lifelong
Months to years
d. Isolation of the pathogen
-EBV culture is not a routine method
-demonstration of EBV genoma by PCR and of EBV antigen by
immunoblot techniques.
Other clinical syndromes produced by EBV infection
Chronic active EBV infection - is a rare disorder
X-Linked Lymphoproliferative Disease -.
Cancers associated with EBV
1.Nasopharyngeal carcinoma –
3.Hodgkin’s disease.
4.Lymphoproliferative disease –
5.Other tumors:
Treatment
No specific therapy is indicated for most patients with infectious
mononucleosis.
Corticosteroid therapy is recommended for patients with severe
complications:
DIPHTHERIA
Egidia Miftode
Diphtheria is an acute disease manifested by both local infection of
the upper respiratory tract and the systemic effects of a toxin, which are
most notable in the heart and peripheral nerves.
Etiology
The etiologic agent is the principal human pathogen of the Corynebacterium
group, C. diphtheriae, an aerobic gram-positive bacillus with irregular
shape.
Pathology
All human tissues may suffer by the toxin because all human cells have
receptor sites.
The diphtheria bacilli within the membrane continue to produce toxin
actively. This is absorbed and leads to distant toxic damage, particularly
parenchymatous degeneration, fatty infiltration and necrosis in heart muscle,
liver, kidneys (tubular necrosis), adrenals, sometimes accompanied by
important hemorrhage. The toxin also produces nerve damage (neuronal
demyelination), resulting often in paralysis of the soft palate, eye muscles, or
extremities.
There are 2 phases of diphtheria: the initial local presentation as a
severe pharyngitis with tough membranes that can cause suffocation and a
late systemic phase caused by the effects of the circulating exotoxin on
tissues of the host.
Nondiptheria corynebacteria produce localized or systemic diseases
Clinical Findings
Incubation period is usually less than 1 week.
Pharyngitis.
Laryngeal diphtheria.
Nasal diphteria
Cutaneous infection
Other organ involvement includes: ears, conjunctiva, cornea.
Complications
1. Cardiovascular
complications
Myocarditis
Late myocarditis –
2. Neurologic complications
a. Palatal paralysis –
b. Oculomotor paralysis –
c. Peripheral polyneuritis
Laboratory Tests
1. Isolation of C. diphteriae
2. Stained smears show beaded rods in typical arrangement.
Diagnosis
Differential diagnosis
 Other pharyngeal diseases:
 Retropharyngeal and peritonsillar abscesses.
 A foreign body in the larynx, viral laryngitis
Treatment
Note: specific treatment must never be delayed for laboratory reports
if the clinical picture is strongly suggestive of diphtheria.
1. The imperative in diphtheria treatment is to administer the
antitoxin as soon
as possible, as it is the only mean to neutralize toxin that has not
already bound to cells. The mainstay of therapy is prompt
administration of equine diphtheria antitoxin: 20000-100000 IU, i.v.
the test for hypersensitivity consists of administration of one drop of
antitoxin diluted 1:10 in one eye.
If the antitoxin is administrated in the first day of illness, the mortality is less
than 1%.
Antibiotics PENICILLIN or ERYTHROMYCIN
2. Supportive care and maintenance of an airway
3. Strict bed rest during the acute phase of diphteria.
Prevention
Diphtheria was the first bacterial disease for which toxic cause was
demonstrated and the first to be treated successfully with an antitoxin. In
1913 a vaccine was created, composed of treated diphtheria toxin, called
anatoxin, later transformed in diphtheria toxoid. In 1940 a combined vaccine
appeared: DTP = Diphtheria toxoid + Tetanus toxoid + Pertussis vaccine.
Active immunization in childhood with diphtheria toxoid
In the most developing countries, immunization with diphteria and tetanus
toxoids and pertussis vaccine was introduced by the late 1970s; in countries
with low immunization coverage, diphteria continues to be endemic.
WOOPING COUGH
Egidia Miftode, Carmen. Corcaci
Whooping cough is presently one of the ten most common causes of
death from infectious diseases worldwide.
Despite a high vaccine uptake, resurgences of this disease have been
observed in several countries.
Etiology
The genus Bordetella consists of the following species:
 B. pertussis-infects only humans
 B. parapertussis-cause a similar but milder disease in humans (also
isolated from sheeps)
 B. bronchiseptica-infect pigs rabbits, dogs, and rarely humans.
 B. avium-is similar with B. bronchiseptica and cause turkey coryza and
rare human infection
 B. hinzii, B. holmesii and B. trematum rarely cause human infections. The
human pathogens are small aerobic, nonmotile gram-negative
coccobacilly. All species are piliated, aerobic and oxidize aminoacids but
do not ferment carbohydrates. The organisms require nicotinamide for
growth at an optimal temperature of 35-37°C. B. parapertussis grows
slightly faster,produces larger colonies and in peptone agar or in liquid
medium produces a characteristic brownish pigment.
Virulence factors
1. Agglutinogens.
2. Fimbriae (three major-2, 3, X, and one minor-Y) –
3. Pertussis toxin (PT)
4. Pertactin
5. Filamentous haemagglutinin (FHA)
6. Tracheal cytotoxin (TCT).
7. Dermonecrotic toxin Lipopolysaccharide - produces endotoxin-like
effects, sensitisation to histamine, and is pyrogenic.
8. Tracheal colonisation factor
9. Serum resistance factor. B. pertussis.
Phisiopathology
Roles for these multiple factors in the pathophysiology of pertussis can be
considered in the context of a generic sequence of events for an infectious
disease:
Epidemiology
The organism is transmitted by respiratory droplets, with attack rates of 50100%.
Clinical manifestations
The incubation period is 5-7 days.
The catarrhal phase (lasting 7 days) is characterized by nonspecific
symptoms: rhinorrhea, mild conjunctival congestion, lacrimation and normal
temperature.
Paroxysmal phase (last at least 2 weeks): a dry, nonproductive cough with
vomiting develops. Rarely, signs of encephalopaty may be seen.
The convalescent phase begins with a decrease in intensity of the cough and
the frequency of paroxysms.
The disease may be atypical in the adult age group and in partially
immunized children and adults.
Complications
Complications of pertussis include:
1. Secondary infections.
2. Physical sequelae of paroxysmal cough.
3.CNS complications. The pertussis encephalopathy may occur in 0,9%, and
convulsions in 3%.
.
Laboratory features
 The total white blood cell count exceeds 50000 cells/mmc with
lymphocytosis.
 hypoglicemia.
 Pulmonary consolidation is seen on the chest radiograph of more than
20% of hospital patients.
 Isolation of organism by culture
 Another method is direct fluorescein-labeled antibody to detect B.
pertussis in nasopharingeal smears.
 Serological tests
 DNA hybridization enzyme assay or antibodies
Diagnosis
The WHO definition of pertussis is based on both a minimum of 21 days of
paroxysmal cough and confirmation of infection by laboratory tests.
Treatment
 erythromycin,(and also azithromycin, clarithromycin) – is the drug of
choice; aful 2 weeks course should be performed to prevent the relapse.
 tetracycline
 trimethoprim-sulfamethoxazole.
 Chloramphenicol.
Corticosteroids should be limited in infants with life-threatening disease.
Prevention
The vaccine currently recommended by the World Health Organization
Acellular vaccine: various pertussis virulence factors have been shown to be
more or less protective when used in acellular vaccine (pertussis toxoid,
filamentous haemagglutinin, pertactin and fimbriae).
ACUTE BACTERIAL MENINGITIS
Egidia Miftode
Acute meningitis is a medical emergency that requires the utmost in
diagnosis and therapeutic skills.
The death rate, about 30% have changed little in the last 25 years.
Pathogenesis
Bacteria reach the meninges through one of the following pathways:
1. hematogenous dissemination from a distant site (nasopharynx, skin, lung,
etc)
2. spread from an adiacent suppurative focus of infection (otitis, sinusitis,
mastoiditis)
3. a congenital or an acquired structural defect
The pathogenic sequence of bacterial neurotropism is as follows:
 colonization or mucosal invasion
 intravascular survival
 crossing of blood-brain-barrier
 survival within CSF:.
Production of the disease in the meninges and brain.
Table 1: Factors involved in the pathogenesis and pathophysiology of
bacterial CNS infections
FACTORS INVOLVED IN THE PATHOGENESIS AND
PATHOPHYSIOLOGY OF BACTERIAL CNS INFECTIONS
Bacterial factors
 Fimbriae
 Capsule
 Outer-membrane proteins
 Lipopolysaccharide
 Cell wall
 Peptidoglycan
 Slime
Host factors
 Blocking IgA antibody
 Decreased CSF immunoglobulin concentrations
 Decreased CSF complement concentrations
 Impaired phagocytosis
 Production of inflammatory cytokines (interleukin –1 , tumor necrosis
factor, interleukin-6, interleukin-8, interleukin-10)
 Production of arachidonic acid metabolites (e.g., prostaglandin E2)
 Production of platelet-activating factor
 Production of reactive oxygen species (nitric oxide, superoxide,
peroxynitrite)
 Production of excitatory amino-acids (glutamate, aspartate, glycine,
taurine, alanine)
Table 2: Pathophysiologic consequences of subarachnoid space
inflammation
Pathophysiologic consequences of subarachnoid space inflammation
 Increased blood brain barrier permeability
 Cerebral edema (vasogenic; interstitial, cytotoxic)
 Cerebral vasculitis
 Increased CSF outflow resistance
 Increased intracranial pressure
 Altered cerebral blood flow; loss of autoregulation of cerebral blood
flow;
 Cerebral cortical hypoxia;
 CSF acidosis secondary to glucose utilization by anaerobic glycolysis
 Increased CSF lactate
 Decreased CSF glucose
 Neuronal injuries
 Cranial and spinal nerve dysfunction
 Encephalopathy
Pathology
On gross examination there is purulent exudate which is most
abundant in the cisterns, at the base of the brain, and over the convexities of
the hemispheres.
Etiology
Table 3 Etiology related to history/physical examination
Historical data/ physical examination
 Hospital acquired
 Contact with rodents/domestic
animals
 Upper respiratory infections
 Brain abscess
 Trauma
-closed skull fracture
-open skull fracture
-CSF othorrhea and rhinorrhea
 Neurosurgery
 Underlying conditions
 Complement deficits
Microorganisms
GNB, Staphylococci
Leptospires
Pneumococci, meningococci
Anaerobes
-pneumococcus, GNB
-GNB, staphylococci
-pneumococcus, GNB,
staphylococcus
Staphylococci, GNB
Pneumococcus
Meningococci
Clinical manifestations
Initial symptoms could be: fever, headache, lethargy or altered level of
consciousness, irritability, vomiting, photophobia, respiratory symptoms.
The altered mental state may range from simple irritability to confusion,
obtundation, or coma.
In elderly, meningitis should be suspected if presence of: fever,
disorientation, headache, stupor, or coma.
Physical examination
A. Signs of meningeal irritation:
 Nuchal rigidity neck stiffnes
 Brudzinski’s signs:
- the nape –of –the – neck sign:
- the reciprocal controlateral reflex sign
- Kernig’s signs:
 -first sign-;
 second signB. Presence of skin eruptions: petechiae, purpura;
C. Cardiovascular manifestations: bradycardia, hypertension or low blood
pressure
D. Respiratory features: respiratory failure of central cause
E. Focal neurologic signs:
 cranial nerve palsies with abnormalities of ocular motility
 hemiparesis
 visual fiel defects
 ataxia.
In neonates and infants the signs and symptoms of meningitis may be very
subtle: fever, irritability, lassitude, confusion, seizures, diarrhea, full
fontanella, Lesage sign
Complications
1. Subdural effusions (empyema)2. Obstructive or communicating hydrocephalus:
Brain abscess, cerebritis, cortical infarction, ventricular empyema,
superior sagital sinus thrombosis:
3. Cranial nerve dysfunction:.
4. Neurosensorial abnormalities:
5. Hemiparesis, quadriparesis
Sequelae
Neonates and infants more frequently have long-term sequelae:
 Permanent sensorineural hearing loss
 Blindness
 Hemiparesis
 Quadriparesis
 Mental retardation
 Late-onset epilepsy
 Diabetes insipidus
 Seizure disorders
Diagnosis of meningitis
White blood cell count
 The normal WBC count in the CSF is 0-10 per cubic mm (does not
contain PMN).
 In bacterial meningitis there are > 100 WBC/ mm3 (frequently
>1000WBC/mm3) (table 3).
 Differential count shows a predominance of PMN
Table 4. Typical CSF findings in bacterial versus aseptic meningitis
CSF parameter
 WBC
 Glucose
 Protein
 Lactate
 Gram’s stain
 Opening pressure
Bacterial meningitis
>10 to <10000/mm3
PMN predominate
<40 mg/dl
>50 mg/dl
Aseptic meningitis
50-2000/mm3
Lymphocytes predominate
>45 mg/dl
Normal or slightly
elevated
Normal
Negative
>3,8mmol/l
+ in 70-90% of untreated
cases
Normal or slightly
>180mmH2O
elevated
.
Microbiological data for the etiological diagnosis of bacterial meningitis
Different approaches for the diagnosis of bacterial meningitis:
1. Classical bacteriologic diagnosis:
Gram stain
Cultures
2. Detection of bacterial components metabolites:
a).physico-chemical
-gas –cromatographie
-mass-spectrometrie
b).biochemical:
-detection of an endotoxin by limulus test
-detection of the genome(hybridation , polymerase chain reaction)
c).immunological- detection of antigens in CSF, serum, urine by:
-counter-imunoelectrophorese
-latex agglutination/coagglutination
-ELISA, RIA
d).Detection of an immune-response
3. Non specific biochemical reactions .
Direct examination
The cultures
The cultures-are performed at 37 C with a daily follow up of cultures at lest
Determination of bacterial genoma:
Immunological tests
Differential diagnosis
1.
2.
3.
4.
Meningeal reaction
Brain abscess, subdural empyema)
Subarachnoid hemorhage
Noninfectious conditions:
 Systemic lupus erythematosis, sarcoidosis
 Non-steroidal anti-inflammatory drugs, cotrimoxazole
 Spinal trauma/spinal tap, myelography
 Increased level of blood ureea
 Neoplasms: glioma, leukemia, craniopharyngioma
5. Bacterial endocarditis
6. Spirochetoses
7. Viral meningitis
8. Fungal meningitis
9. Protozoan and parasitic meningitis
10.Brucellosis
Treatment
Table 4: Antibiotics recommended for empirical therapy in patients with
suspected bacterial meningitis who have a nondiagnostic Gram's stain of
cerebrospinal fluid
Group of patients
Immunocompetent
With impaired cellular
immunity
With head trauma,
neurosurgery,
or
cerebrospinal
fluid
shunt
Likely Pathogen
Choice of antibiotic
S.agalctiae, E.coli,
L.monocytogenes
N.meningit.,
S.pneum.,
H.influenzae
S.pneum.,
N.meningit.
S.pneum.,L.monocyt
.,
gram neg.bacilli
L.monocyt./gramneg bacilli
Staphylococci, gramneg.bacilli,
S.pneumoniae
Ampicillin (2) + broadspectrum cephalosporin
Broad-spectrum
cephalosporin (3)
Broad-spectrum
cephalosporin (4)
Ampicillin (5) + broadspectrum cephalosporin
(4)
Ampicillin + Ceftazidime
Vancomycin
Ceftazidime
+
Treatment of increased intracranial pressure:
- head of the bed elevated
- mannitol
- phenobarbital
Glucocorticoids: dexametasone is indicated in children more than two
months of age who have bacterial meningitis, in Haemophilus influenzae
meningitis,
Meningococcal meningitis
The meningococcus is a gram-negative diplococcus which lives only in the
human orofarynx
Fulminating meningococcemia (Waterhouse-Friederichsen syndrome)
This syndrome is characterized by the following:
 Sudden onset of a febrile illness
 Extensive petechial hemorrhages in the skin and mucous membranes
 Cardiovascular collapse
 Disseminated intravascular coagulation
Table 5. Prognosis score in fulminating meningococcemia







Clinical/laboratory features
WBC count in CSF <20/mm3
Cardiovascular collapse
Petechial hemorrhages appeared within the first 12
hours of the disease
Absence of blood leukocytosis
ESR=normal
High rectal temperature
Thrombocytopenia
Score
1
1
1
1
1
1
1
1
Haemophilus influenzae meningitis
Haemophilus species are small, gram-negative pleomorphic
coccobacilli. Almost all invasive infections are caused by H. influenzae
serotype b (Hib).
Hib is the most common cause of bacterial meningitis between the neonatal
period and age 6 years.
In older patients Hib meningitis occur when predisposing factors exist:
 Otitis media
 Other parameningeal focci of infection
 CSF leak
 Head trauma
 An immunocompromised disease.
Hib meningitis are seen more frequently in winter, following an influenzalike syndrome.
Onset could be:
 acute (like in other forms of meningitis)
 with coma
 seizures
 respiratory abnormalities
 purpuric/petechial skin eruptions
Children with Hib meningitis usually present with an illness that have been
progressive over 24-72 hours; some children may have a fulminant illness
that develops over several hours.
A common complication of Hib meningitis is subdural empyema.
Treatment
First-intention therapy: third generation cephalosporins (cefotaxime,
ceftriaxone) or ampicillin with chloramphenicol.
If H. influenzae is not a beta-lactamases producer strain: Ampicillin
200-400mg/kgc/day.
Duration of therapy is 2-3 weeks (a condition being CSF protein<0,4g/l).
Pneumococcal meningitis
Streptococcus pneumoniae, a gram-positive diplococcus is the major
cause of meningitis in adults over 15 years of age, accounting for 30-50% of
cases.
Predisposing factors are:
 Pneumonia, sinusitis, endocarditis
 Old or recent head trauma,
 CSF leak
 Splenectomy
 Sickle hemoglobinopathy
 Bone marrow transplant
 alcoholism
Treatment
Penicillin G: 300 000-400 000U/kgc/day, for children and 15 mil U/day in
adults
Ampicillin: 400 mg/kgc/day for children and 8-12 g/day in adults
For S. pneumoniae with low sensitivity to PG: third generation
cephalosporins (cefotaxime-100mg/kgc/day in children and 3-5g/day in
adults, ceftriaxone)
For Penicillin –resistant-Pneumococcus:
 Vancomycin: 30-40 mg/kgc/day
 Rifampin: 10-20mg/day
 Chloramphenicol (usually, a PRP is also chloramphenicol-resistant): 75100mg/kgc/day in children and 3g/day in adults
Duration of treatment is 14 days, but depend also on clinical (absence of
fever and other clinical manifestations) and CSF evolution
(pleocytosis<30/mm3, and 0% PMN).
Staphylococcus aureus
Staphylococcus aureus- commonly the result of spread from a site
outside the CNS:
 various abscesses (abdominal, cerebral, epidural, oral),
 cellulitis, sinusitis, osteomyelitis,
 decubitus ulcer,
 infected intravascular grafts.
Since the decades of antimicrobial therapy, staphylococcal meningitis has
been seen most frequently in patients with underlying CNS pathology:
trauma, craniotomy, CSF shunts.
The issues of treatment and outcome make for an interesting analysis.
Patients with Staphylococcal aureus meningitis should be treated with:
 high doses of Cefotaxime/Ceftazidime with/without a
fluoroquinolone or Rifampin.
 Vancomycin is reserved for patients who are either allergic to
penicillin or have methicillin-resistant organisms as the cause of
the meningitis. In this situation must be done a close monitoring of
CSF concentrations during therapy.
 Cefotaxime or Vancomycin could be associated with rifampin in
the treatment of S.aureus meningitis, as it may synergistically
enhance the activity of the first two agents in vitro.
Epidural abscess
An epidural abscess represents localized infection between the outermost
layer of the meninges, the dura mater, and the overlying skull or vertebral
column.
Sources of infection are numerous and include:
 bacterial endocarditis,
 infected indwelling catheter,
 urinary tract infection,
 peritoneal and retroperitoneal infection
 direct extension of infection from vertebral osteomyelitis occurs in
adults and rarely in children.
Clinical manifestations
A four phase sequential evolution has been described with:
(1) localized spinal pain,
(2) radicular pain and paresthesias,
(3) muscular weakness, sensory loss, and sphincter dysfunction, and
(4) paralysis.
Positive diagnosis
Headache is a common additional complaint. Nuchal rigidity and
focal tenderness to percussion are almost universal.
 The white blood cell count and the erythrocyte sedimentation rate are
elevated.
 CSF evaluation.
 X-ray films of the spine may show osteomyelitis.
 Computerized tomography may be helpful,
 Myelography is the diagnostic procedure of choice. Blood and abscess
aspirate should be submitted for aerobic and anaerobic culture.
Meningitis due to Listeria monocytogenes
This organism is an important cause of neonatal and elderly
meningitis. For the neonates the source is the genital tract or subclinical
infection of the mother.
Early neonatal disease usually presents as sepsis rather than
meningitis.
L. monocytogenes may causes meningitis in normal adults, which are:
diabetic, alcoholic, or immunosuppressed.
Clinical presentation includes:
 fever and headache ,
 increased tendency for focal neurologic deficits and seizures during the
initial presentation.
 clinical picture suggestive of an acute brain-stem disorder or
rhombencephalitis, with signs of ataxia, cranial nerve deficits, and
nystagmus
CSF are characterized by wide ranges for WBC count
Tratament
Ampicillin is the drug of choice (often combined with gentamicin.
For treatment of L.monocytogenes meningitis in patients allergic to
ampicillin, intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) is
recommended.
Meropenem
Meningitis with Cryptococcus neoformans
Most frequently this type of meningitis occur in AIDS patients (incidence of
2-11%).
On pathologic examination is seen a basilar, chronic meningitis that is
typically neither thick nor exudative.
Classic features are: headache, photophobia, mental status changing and
neck stiffness, although they may be absent in many patients with AIDS.
Treatment
 Amphotericin B (0,6-1 mg/kg/day) iv, at least 6 weeks, associated or not
with 5-flucytosine (100-150mg/kg\day)-2 weeks followed by oral
fluconazole (400mg/day)-8-10 weeks.
 If, at the end of this period , the CSF culture is negative, the fluconazole
doze may be reduced to 200mg/day and continued as secondary
prophylaxis.
Recurrent bacterial meningitis
Table 5: Conditions predisposing to recurrent bacterial meningitis
 Defects of the stapes footplate,
oval window, cohlear aqueduct
 Giant apical air cell syndrome
 Basietmoidal or cribriform plate
defect
 Cranial or spinal dermal sinus
 Meningocele
 Encephalocele
 Neurenteric cyst
Traumatic or surgical CSF fistulae  skull fracture involving paranasal
sinuses, cribriform plate or
petrous bone
 postoperative
(particularly,
following nasal surgery)
Immunodeficiency
 immunoglobulin/complement
component deficiency
 hemoglobinopathy
 congenital or acquired asplenia
 leukemia
 lymphoma
Congenital CSF fistulae
Meningitis produced by Gram Negative bacilli
Approximately 80% of cases of Gram-negative bacillary meningitis
occur in conjunction with head trauma or neurosurgical procedures.
Meningitis with organism such as E.coli, Klebsiella and Pseudomonas
occur later in the hospital course after the use of antibiotics for treatment of
other infection or an initial episode of meningitis. It could appear that the
overall use of prophylactic antimicrobial agents does not change the
incidence of most postoperative bacterial meningitis and may in fact result in
the selection of highly resistant gram-negative organisms.
Approximately 20% of shunt infections are due to a variety of gramnegative organisms such as: E.coli, Klebsiella pneumoniae and
Pseudomonas.
Another GNB that is involved more and more in nosocomial
meningitis in the presence of instrumentation is Acinetobacter. Many of
bacteriaemia due to Acinetobacter are polimicrobial.
Meningitis caused by P.aeruginosa represents a special situation because
reported mortality rates are approximately 84%.
Treatment
 Third generation cephalosporins (ceftiaxone, cefotaxime, ceftazidime)
associated with an aminoglycoside or a fluoroquinolone
 Piperacillin/Azlocillin with fluoroquinolones
 Meropenem alone or in association
 Aztreonam.
HYDROCEPHALUS SHUNT INFECTION
Hydrocephalus, a condition caused by accumulation of cerebrospinal
fluid (CSF) within the cerebral ventricular system, is commonly seen in
neurosurgical practice. The usual cause of the accumulation is obstruction to
the flow of CSF or failure to absorb it.
The incidence of shunt infections varies considerably between centers, from
over 30% to less than 1% of operations.
Etiology
Clinical manifestations
In VA shunts, the organism from the lumen of the colonized
Treatment
The three main goal of treatment of any CNS prosthetic device infection are:
1. minimizing the mortality and morbidity of the infection and it’s treatment
2. maintaining a functioning device if it is still needed
3. resolving the infection; the drug of choice is vancomycin associated with
rifampin. The third generation cephalosporins have good anti-gram-negative
coverage.
Table 5: Recommendations for antibiotic therapy in patients with bacterial
meningitis who have a positive Gram's stain or culture of cerebrospinal
fluid
TYPE OF BACTERIA
On Gram's staining
Cocci
- negative
CHOICE OF ANTIBIOTIC
Ampicillin
Vancomycin + broad-spectrum cephalosporin
Broad-spectrum
cephalosporin
+/aminoglycoside
Bacilli
-positive
-negative
Ampicillin/Penicillin G + aminoglycoside
Broad-spectrum
cephalosporin
aminoglycoside
+
On culture
S.pneumoniae
Ampicillin/Penicillin
Vancomycine + broad-spectrum cephalosporin
H.influenzae
Ceftriaxone/ Ampicilin+Chloramphenicol
N.meningitidis
Penicillin G
L.monocytogenes
Ampicillin + Gentamicin
S. agalactiae
Penicillin G
Enterobacteriaceae
Broad-spectrum
cephalosporin
+
aminoglycoside /Fluoroquinolones
Meropenem
Pseudomonas aeruginosa, Ceftazidime
+
Acinetobacter
aminoglycoside/Fluoroquinolones
Meropenem
Neonatal bacterial meningitis
Many factors are considered to be risk factors for newborn meningitis:
 Low birth weight (<2500g)
 Resuscitation at birth
 Premature rupture of the membrane
 Mother infection
The most frequently agents are: Streptococci group A, B, D (45%), Gramnegative bacilli (Klebsiella, Enterobacter, Echerichia, Pseudomonas) (44%),
Listeria monocytogenes (5%), Staphylococcus epidermidis and aureus.
Clinical manifestations
Early onset disease (onset within 48 hours after delivery)
-infants present with symptoms and signs of sepsis: fever,
gastrointestinal manifestations (abdominal distension, vomiting) respiratory
distress, and lethargy;
-CNS specific symptoms are often not detected
Late-onset disease (onset later than 7 days after birth and up to 6 weeks of
age): fever and presence of CNS dysfunction (seizures).
Treatment
 Ampicillin and cefotaxime/ceftriaxone
 Ampicillin and an aminoglycoside
VIRAL MENINGITIS
Egidia Miftode
Acute meningeal inflammation produced by viruses is usually
characterized by moderate signs and symptoms, low level of WBC in CSF,
with lymphocytic predominance, and a benign evolution.
Etiology
Common causes:
 Enteroviruses
 Arboviruses
 Herpes simplex virus type 2
Uncommon causes:
 Mumps
 Human herpes virus type 6
 Lymphocytic choriomeningitis virus
 Human immunodeficiency virus
Rare causes:
 Herpes simplex virus type 1
 Varicella-zoster virus
 Cytomegalovirus
 Epstein-Barr virus
 Influenza viruses A and B
 Measles virus
 Rotavirus
 Encephalomyocarditis virus
 Parvovirus B19.
Clinical manifestations
ENTEROVIRUSES
Pathogenesis
The virus traverses the intestinal lining cells, A minor viremia, seeding
numerous organ systems: CNS, liver, lungs and heart.
The characteristic rash caused by an enterovirus consist of erythematous
macules and papules on the face, neck, trunk, and to a lesser degree the
extremities.
Neonates are at risk for severe systemic illness:
For other cathegories of age the symptoms and signs are:
-the fever pattern may be biphasic
-photophobia, headache, vomiting
-rash, diarrhea, myalgias, cough.
Meningitis with certain serotypes of EV is associated with particular signs:
-hand-foot-mouth syndrome (EV71)(vesicular eruption);
-nonspecific rashes (echovirus 9)
The duration of illness is usually less than 1 week
Laboratory findings
 low level of WBC count in CSF(100-1000/mm3);
 PMN may predominate early in the meningeal infection;
 Lymphocytic profile (>50%) over the first 8 to 48 hours;
 Glycorachia is normal or slightly decreased;
 CSF protein is normal or slightly elevated;
 Interferon- gama level is increased in viral meningitis;
 Isolation of virus from CSF, blood, throat, feces;
 Serology: neutralizing reaction and complement fixation
 PCR-based detection of EV.
LYMPHOCYTIC CHORIOMENINGITIS VIRUS
The virus is a member of the family Arenaviridae; it is transmitted by
rodents (rats, mice).
Infected persons could remain asymptomatic or present mild clinical
manifestations;
Less frequently severe neurologic disease could occur: meningoencephalitis,
encephalitis.
The course of meningitis is often prolonged.
HERPES VIRUS MENINGITIS
Aseptic meningitis may be produced by almost all the member of this
family: Herpes simplex virus type1 and 2 (HSV-1 and HSV-2), varicellazoster virus, Epstein-Barr virus, cytomegalovirus (CMV), and human
herpesvirus 6 (HHV-6).
MOLLARET’S MENINGITIS
Mollaret’s meningitis is a rare disease characterized by recurrent, benign
episodes of aseptic meningitis, most commonly seen in young adults.
Clinical manifestations
Acute onset with fever, headache, nuchal rigidity; these symptoms resolve
spontaneously within 2-5 days.
Recurrent attacks appear weeks to months later.
Laboratory diagnosis
 CSF exam reveal a mixed lymphocytic and PMN pleocytosis.
 An early finding are large, fragile, mononuclear cells (“endothelial cells”
which are monocytes).
 After 24 hours Mollaret’s “endotelial” cells and PMN cells have
disappeared. By 1 week CSF has completely normalized.
Viruses of the herpesvirus family have now been strongly implicated in
numerous cases; this association has potential therapeutic importance
(acyclovir might prevent recurrences).
Laboratory diagnosis of viral meningitis
1. CSF exam (presented above)
2. Cultures of the virus
3. Serological exams(become positive after 2-8 weeks from the onset)
4. Other tests:
-leucogram ( leucopenia with lymphocytosis)
-X-ray for paranasal sinuses
-CT, MRI, funduloscopic exam for the exclusion of empyema, tumors,
abscesses, etc.
Differential diagnosis
For the differential diagnosis of viral meningitis must be rule out other
causes of aseptic meningitis syndrome:
Bacteria:
 Leptospira species, Borrelia burgdorferi
 Mycobacterium tuberculosis
 Brucella species
 Mycoplasma hominis, pneumoniae
 Partially treated bacterial meningitis and other parameningeal infections
(sinusitis, otomastoiditis).
Fungi:
 Cryptococcus neoformans (ususlly in immunocompromised patients)
 Coccidioides imitis
 Histoplasma capsulatum
 Candida sp.
Other
 Autoimmune disorders (systemic lupus erytematosus)
 Bechet’s syndrome is a systemic inflammatory disease characterized by:
 Aseptic meningitis, meningoencephalitis, seizures, cranial nerves palsies,
hemiparesis (10-30%)
 Recurrent aphtous stomatitis: genital aphtae, uveitis, skin lesions
(erytema nodosum, acneiform lesions).
Treatment: glucocorticoid and immunosuppressive therapy
 Drugs(immunomodulators, antibiotics, AINS)
 Malignancies
 Kawasaki disease (aseptic meningitis develops in 25-70% of patients
with Kawasaki disease)
 Vogt-Koyanagy-Harada syndrome
TUBERCULOUS MENINGITIS
Egidia Miftode
Tuberculous meningitis (TB) is the most life-threatening form of
tuberculosis.
Pathogenesis
. Following primary infection, there is a lymphatic and hematogenous
dissemination to a multitude of sites, including the kidneys, bone marrow,
liver, spleen, CNS
The initial pathologic events in TB meningitis are secondary to a
hypersensitivity recation to the bacilli within the subarachnoidian space.
 There is a resultant exudative inflammatory reaction;
 Exudative reaction can become extensive, and by consequence CSF
absorption and circulation become impaired leading to progressive
hydrocephalus;
 As hydrocephalus progress, the increase in intracranial pressure can lead
to brain stem herniation;
 Vasculitis contribute to the neurologic sequelae.
Clinical manifestations
I.
Stage I (first week-10 days) is characterized by nonspecific early
signs (related to the increase in intracerebral pressure): emesis,
decreased activity, lethargy, no neurologic deficits;
II.
Stage II (second week of evolution): signs of meningeal irritation,
lethargy, minor neurologic deficits (cranial nerves palsies);
III. Stage III (after three weeks of evolution ) seizures, severe neurologic
deficits (pareses/paralysis), abnormal movement (chorea myoclonus,
cerebellar ataxia), stupor or coma.
Diagnostic tests
CSF examination
-clear CSF
-several hundred WBCs, with the predominance of lymphocytes
-low CSF chloride
-increased level of protein concentration
-low level of glucose( CSF/serum glucose ratio=20-25%)
-acid fast staining with positive results
-definitive diagnosis of TB meningitis depend on the growth of M.
tuberculosis from CSF sample (that may require 4-6 weeks)
-rapid diagnosis methods: adenosine deaminase level, mycobacterial
antigen, mycobacterial antibody, PCR.
Other diagnostic mesures
Erytrocyte sedimentation rate is elevated
-extraneural cultures: sputum, gastric culture, urine, lymph node,
pleura, marrow and liver culture, flexible bronchoscopy with
bronchoalveolar lavage
-tuberculin test (almost 80% rate of positivity); malnutrition,
debilitation and general immunosuppression could explain negative results;
-funduloscopic exam;
-chest X-ray
-brain CT scan
-MRI
Complications
-Hydrocephalus
-Tuberculoma (can developed after 10 days until 9 years): papilledema and
neurologic deficits. CT scan have demonstrated resolution of lesions as early
as 12 weeks after the beginning of treatment.
Sequelae
 Psychiatric sequelae:
 Neurologic sequelae.
 Endocrinologic abnormalities:,
Mortality is near 20-30%.
Prognostic factors corelated with poor prognosis are: advanced stages of the
disease (two fold increase in mortality), extreme of youth or old age,
coexistence of miliary disease, pregnancy or puerperium markedly elevated
protein in CSF, spinal block, markedly decreased CSF glucose.
Differential diagnosis
I.
Early in the disease: otitis media, gastroenteritis, influenza.
II.
CSF lymphocytic pleocytosis may be similar to that seen in:
-viral meningoencephalitis (herpes simplex, etc)
-fungal meningitis: cryptococcal meningitis, coccidiodomycosis.
III. Brain abscess, malignancy, hemorrhage (see chapter encephalitis).
IV.
V.
Chronic meningitis with infectious causes: Cryptococcus neoformans,
Coccidioides immitis, Histoplasma capsulatum, Borrelia burgdorferi,
Treponema palidum;
Chronic meningitis with noninfectious causes: sarcoid, carcinoma,
granulomatous angiitis, systemic lupus erytematosus, Behcet’s
disease, Vogt-Koyanagi-Harada syndrome.
Diagnosis
1. Fever, vomiting, progressive neurologic deterioration over several weeks
2. Family history of TB (in 70% of cases)
3. CSF lymphocytic pleocytosis, CSF/serum glucose reatio<0,25
4. Concurrent pulmonary TB (in 50% of cases)
5. Initial PPD >10mm induration (in 50% of cases)
6. Hydrocephalus(in infants).
Treatment
Table 1. Treatment with four antimycobacterial agents
Drug
First-line drugs
Izoniazid
Rifampin
Pyrazinamide
Ethambutol
Streptomycin
Second-line drugs
Cycloserine
Paraaminosalicylic acid (PAS)
Kanamycin
amikacin
Ciprofloxacin
Ethionamide
Dose (mg//kg/day)
Max. dose
10-20 mg/kg/day
10mg/kg/day
20-40mg/kg/day
15-25mg/kg/day
20-40mg/kg/day
300mg
600mg
2g
2,5g
1g
1-15 mg/kg/day
150 mg/kg/day
15 mg/kg/day
7,5 mg/kg/day
15-30 mg/kg/day
15 mg/kg/day
500mg
12
1g
1g
1,5g orally
1g
Treatment must be continued:
 for 2 months with 4 drugs(first-line drugs).
And for 7 months with rifampin+isoniazid
Corticosteroids (Dexametasone or prednisone) are recommended if
hydrocephalus, spinal block, cranial nerve palses, or coma is present.
VIRAL ENCEPHALITIS
Egidia Miftode
Encephalitis is defined as an inflammation of parenchymal brain
tissue clinically expressed by fever, consciousness impairment, seizures,
focal neurologic deficits.
Definitions
Acute encephalitis is the brain inflammation that occurs over a relatively
short period of time.
Chronic encephalitis presents over weeks to months.
Slow viral infections of the CNS (kuru, Bovine spongiforme
encephalopathie)
Classification upon the mechanism of the disease:
1. Primary encephalitis2. Postinfectious encephalitis -.
Etiology
 Togaviridae-Alphavirus (arbovirus): Western, Eastern, Venezuelean
encephalitis virus
 Flaviviridae-Flavivirus (arbovirus):
-West Nile fever virus,
-Japanese encephalitis virus
-St. Louis encephalitis virus,
-Tickborne encephalitis virus (TBE complex: louping ill, Powassan,
TBE Western and Eastern subtype, Omsk hemorrhagic fever),
-Murray Valley virus.
 Bunyaviridae (arbovirus)
 Herpesviridae:
-Herpes simplex virus type 1 and 2
-Cytomegalovirus
-Epstein –barr virus
-Varicella –zoster virus
-human herpes virus -6
 Picornaviridae: echovirus
 Paramyxoviridae: mesles virus, mumps virus
 Orthomyxoviridae: influenza viruses
 Rhabdoviridae: rabies virus
 Retroviridae: HIV-1
 Arenaviridae: lymphocytic choriomeningitis virus
 Adenoviridae: Adenovirus.
Pathogenesis
 Enteroviruses and arboviruses have a viremic spread to the CNS.
 Rabies and HSV infection are prototypes of viral CNS infection.
 Poliovirus and reovirus infect CNS by viremia and neuronal spread.
Clinical manifestations
1. General symptoms: fever, headache chills;
2. Symptoms of cortical involvement: trouble of consciousness (obtundation,
somnolence, delirium, confusion, coma), seizures, motor deficit,
sleepness, dysphasia;
3. Symptoms of cerebral peduncles involvement: paresis of cranial nerves,
respiratory and cardiovascular dysfunction, hemiparesis;
4. Spinal symptoms: paraparesis and tetraparesis;
5. Meningeal signs and symptoms
Laboratory features
CSF:
 Glucose level is normal/slightly elevated
 Protein level is moderately raised
 Pleocytosis: usually <500/mm3, with a predominance of mononuclear
cells (early in the disease could be as high as 1000/mm3, with a
predominance of neutrophils); persists for 3-6 weeks (may lasts for as
long as 3-4 months).
Specific diagnosis
 Viral culture or antigen detection in brain
 Serologic titers: hemagglutination inhibition (HI), complement fixation
(CF), neutralizing antibody titer (NA), immunofluorescent antibody
(IFA), counterimmunoelectrophoresis (CIE),
 CSF IgM (ELISA)
 PCR
Tick-borne encephalitis
The Western subtype virus produces a biphasic febrile illness:
 First phase lasts 2-7 days without signs/symptoms of
meningoencephalitis.
 An afebrile and relatively asymptomatic period lasts 2-10 days
 Second phase (in 1/3 of patients): fever and symptoms of meningitis and
meningoencephalitis.
The Eastern subtype virus is characterized by a monophasic course:
flushing of the face and neck, conjunctival injection, headache, somnolence,
nausea, vomiting, dizziness, myalgia, hyperestesia.
The main clinical neurological syndromes associated with TBE are:
A. Febrile headache, with myalgia,.
B. Aseptic meningitis:
C. Meningoencephalitis: y.
D. Meningoencephalomyelitis:
Differential diagnosis
 Infection with other tick-borne pathogens: tularemia, spotted fever group
of rickettsioses, babesiosis;
 Other febrile headache: infectious mononucleosis, influenza, typhoid
fever, shigellosis, legionellosis, relapsing fever, erlichiosis, brucellosis;
 Infections causing meningitis meningoencephalitis or encephalomyelitis:
 Syndromes mediated by bacterial toxins: botulism, tetanus, Bordetella
pertussis infection
 Noninfectious encephalopathies:
 Neoplastic lesions
 Guillain – Barre syndrome is an acute inflammatory demyelinating
polyneuropathy
 Behcet’s disease
 Vogt-Koyanagi-Harada syndrome is an autoimmune disease:
-Meningitis: Severe anterior and posterior uveitis
-Vitiligo, alopecia
-Dysacousia and tinnitus
Treatment
There is no curative therapy for TBE. Treatment is supportive
(antiedematous drugs, parenteral hydration, symptomatics).
Bed rest for up to 2 weeks improves outcome.
In severe cases corticosteroids could be administrated.
Herpes Simplex virus encephalitis





Decreasing level of consciousness with focal neurologic findings
Sometimes presence of skin vesicles
CSF pleocytosis and proteinosis
The absence of bacterial and fungal pathogens in CSF
Focal electroencephalographic (focal slowing, spiking, and paroxysmal
lateralizing epileptiform discharges), CT and MRI findings.
Treatment
Acyclovir - at a dose of 10mg/kg every 8 hours (30mg/kg/day), for a period
of 10-14 days.
West Nile encephalitis
The disease incidence was 12.4 per 100.000 inhabitants.
Epidemiology
The virus multiplies in various species of birds, some of which get
severely sick, like humans, whereas others harbor the virus without signs of
disease.
Humans, and occasionally cats and horses, get infected
Clinical manifestations
After an incubation period of 3 to 6 days, disease starts without any
prodromal stage with:
- fever, joint pains and headache;
- temporary skin rash
- lymph node swelling.
-a typical biphasic fever progression is observed with West Nile virus: after
a few days of normal body temperature, fever increases again strongly.
The diagnosis detection of specific antibodies and/or the detection of viral
RNA by PCR.
The lethality of this form of disease is between 3 and 15%.
POLIOMYELITIS
Egidia Miftode
Poliomyelitis is a clinicopathologic syndrome characterized by
transient or permanent paresis of one or more extremities and aseptic
meningitis.
Etiology
Polioviruses belong to the genus Enterovirus (family Picornaviridae).
Three polioviruses serotypes are recognized: type 1-Brunhilde, type 2Lansing and type 3-Leon.
- single –stranded RNA genome approximately 7500 bases in length.
Epidemiology
The possible routes for polioviruses transmission are:
 Fecal-oral transmission is the most important route
 Spread through upper respiratory tract secretions are favored by
crowding, water quality, levels of hygiene
Risk factors
 Recent intramuscular injections
 Injuries
 Exercise during the early stages of the major illness.
Pathogenesis
After ingestion, polioviruses implant in the oropharynx and small
bowel (Payer’s patches).
“Minor” viremia occurs as a consequence of spread to the regional lymph
nodes and to bone marrow, liver and spleen.
-“major” viremia, which coincides with the onset of the clinical symptoms
associated with the “minor” illness 3 to 7 days after infection.
Immunity to poliovirus infection is type-specific.
.
Clinical manifestations
Approximately 95% of poliovirus infections are inapparent.
Acute clinical poliomyelitis has 2 phases (” dromedary “ pattern):
Minor illness (coinciding with viremia); has a duration of 1-5 days
-incubation period is 3-7 days
-consists of nonspecific symptoms:
-frequently resolves within 1-2 days
B. Asymptomatic period: 3-5 days
C. Major illness
-incubation period is 9-12 days
 Nonparalytic poliomyelitis:
-abrupt onset of headache, vomiting, meningeal signs
-CSF pleocytosis at an early stage,;
-hypotonia
 Paralytic stage (within 2-3 days):
-fever
-prodromal myalgias;
-paresis, paralysis (asymmetric, flaccid, involves proximal muscles of the
limbs), progress for 1-7 days after onset;
-deep tendon reflexes become absent;
-cranial nerve involvement (the 9-th and the 10-th are the most
commonly involved).
Evolution
Recovery of patients with limb paresis takes weeks to months after acute
disease. Paralysis improves slowly as follows: 60% of eventual recovery is
achived by 3 months and 80% by 6 months. Minimal further improvements
continue over almost 2 years.
Classification:
A. Nonparalytic poliomyelitis: “minor” illness, meningitis (normal value of
proteins in CSF in the early stage, and increased level of proteins after 2
weeks of evolution)
B. Paralytic poliomyelitis: spinal forms, “bulbar poliomyelitis”
Meningomyeloencephalitis:
C.
Complications
1.
2.
3.
4.
5.
Respiratory:
Cardiovascular:;
Gastrointestinal: paralytic ileus, gastric dilatation;
Urinary: ileus of the bladder, urinary tract infection;
Decubitus ulcers
Laboratory findings
Virus can be grown in tissue culture from pharyngeal swab, (in the first
week of the illness), from the feces (for at least 3 weeks), from blood and
CSF (less frequently).
Serological tests: complement fixation reaction and neutralizing reaction
(neutralized antibodies are life-long persistent).
Differential diagnosis
 Paralytic diseases caused by nonpolio enteroviruses;
 Guillain-Barre syndrome: paralysis is classically ascending, symmetric,
and accompanied by sensory abnormalities.
 Other conditions with acute paralysis: transverse myelitis, botulism,
encephalitis, epidural abscess, intramedullary abscess, cord tumors,
brucellosis, syphilis.
Prognosis
Nonparalitic poliomyelitis has a complete recovery, and only 50-55% of
paralysis has the same good evolution.
Overall mortality for spinal pliomyelitis is about 4%-6% and for bulbar
poliomyelitis is 25-75%.
Treatment
Treatment consists of supportive therapy and reduced physical activity for 710 days in nonparalitic poliomyelitis and for 10-14 days in paralitic forms.
Mechanical ventilation is sometimes required in severe cases.
Prevention
1. Live, attenuated poliovaccine (OPV)
2. Inactivated poliovirus vaccine (IPV).
ENTEROVIRUSES INFECTIONS
Daniela Leca
As members of the genus Enterovirus, the group A coxsackieviruses, group
B coxsackieviruses, echoviruses, and newer enteroviruses
Epidemiology
The enteroviruses have a worldwide distribution. The proportion of infected
individuals who will develop illness varies from 2 to 100 percent
Pathogenesis and pathology
After primary replication in the epithelial cells and lymphoid tissues in the
upper respiratory and gastrointestinal tracts, viremic spread to other sites can
occur.
Illnesses caused by Enteroviruses
Acute Aseptic Meningitis
Acute aseptic meningitis is a syndrome characterized by signs and
symptoms of meningeal irritation and cerebrospinal fluid (CSF) pleocytosis
in the absence of bacteria or fungi.
Encephalitis
Frank encephalitis is an unusual manifestation of CNS infection with
coxsackieviruses and echoviruses that sometimes complicate the course of
aseptic meningitis.
The differential diagnosis includes: encephalitis due to other viruses
(arboviruses, herpes simplex virus -especially in focal encephalitis, mumps);
postinfectious encephalitis after measles, rubella, varicella, or pertussis;
Reye’s syndrome; Lyme disease; toxic encephalopathies.
Paralysis and other neurologic abnormalities
Sporadic cases of flaccid motor paralysis have been associated with several
coxsackievirus (A7, A9, B1-5) and echovirus (6,9) serotypes, and with
enterovirus 71.
Guillain-Barré syndrome is caused by coxsackievirus serotypes A2, A5, and
A9, and with echovirus serotypes 6 and 22.
Systemic coxsackievirus B2 disease
Reye syndrome.
Exanthems
Coxsackieviruses and echoviruses cause a variety of exanthems:
rubelliform or morbilliform, roseoliform, vesicular, and petechial.
 Roseoliform exanthems.
 Exanthem subitum (roseola infantium).
 Hand-foot-and-mouth (HFM) disease or vesicular stomatitis.
 Generalized vesicular eruptions are caused by coxsackievirus A9 and
echovirus 11.
 Petechial and purpuric rashes
Acute Respiratory Disease
 Undifferentiated febrile illnesses ("summer grippe").
 Coxsackieviruses A21 and A24 produce illness resembling the common
cold.
 Coxsackieviruses B have been associated with a variety of respiratory
illnesses,.
Herpangina
Herpangina primarily affects children between the ages of 3 and 10
years.
Coxsackieviruses A (types 1–10, 16, 22) are the etiologic agents in most
cases.
The illness begins with fever of 37.7–40.5 0C. Sore throat and pain on
swallowing precede the appearance of the enanthem that begins as punctate
macules,.
Epidemic Pleurodynia
Epidemic pleurodynia is an acute infectious disease characterized by
fever and sharp, spasmodic pain in the chest or upper abdomen.
Pain in the chest may mimic pneumonia, pulmonary infarction, myocardial
ischemia, and the preeruptive phase of zoster.
Myopericarditis
Enteroviral myocarditis occurs at all ages but has a special predilection for
adolescents and active young adults
Most children and adults recover uneventfully. The complications consist in
persistent electrocardiographic abnormalities, cardiomegaly, chronic
congestive heart failure. Chronic constrictive pericarditis occurs after 5
weeks to 1 year.
Differential diagnosis include: others viral myopericarditis
Coxsackievirus and Echovirus Disease in the newborn Infant
Many enterovirus serotypes causes the same self-limited clinical
syndromes in neonates as they do in older persons (e.g., aseptic meningitis,
exanthems, hand-foot-and-mouth syndrome), but some serotypes are capable
of producing fulminant, frequently fatal disease (group B coxsackievirus
serotypes 2–5 and echovirus 11).
Acute hemorrhagic conjunctivitis is a contagious ocular infection
characterized by pain, swelling of the eyelids, and subconjunctival
hemorrhages .
Laboratory diagnosis
The diagnosis is established by:
 virus isolation from throat, swabs, stool or rectal swabs, body fluids, and
occasionally tissues;
 polymerase chain reaction, enhancing and speeding detection in tissue
and CSF, but is not currentlly available
 serodiagnosis -;
 White blood cell counts and erythrocyte sedimentation rates are usually
mildly elevated; Hyperbilirubinemia and elevated transaminase and
alkaline phosphatase levels.
Prophylaxis and treatment
Glucocorticoids are contraindicated.
GASTROINTESTINAL INFECTIONS
Dr. E Miftode
Etiology
The microorganisms that cause infectious gastroenteritis are:
Bacteria
- Shigella
- E. coli (enteroinvasive, enterohemorrhagic E.coli, entero toxigen E. coli)
- Salmonella spp
- Vibrio cholerae
- Vibrio parahaemolyticus
- Clostridium difficile
- Clostridium perfringens
- Campylobacter jejuni
- S. aureus
- Bacillus cereus
- Yersinia enterocolitica
Viruses
- Rotavirus
- Astrovirus
- Caliciviruses
- Adenoviruses
- Parvoviruses (Norwalk,Hawaii, agents, etc)
- Coronaviruses
Parasites
- Entamoeba histolytica
- Giardia lamblia
- Cryptosporidium
Pathogenesis
There are three types of enteric infections:
Type I - is a noninflammatory (enterotoxin or adherence/superficial
invasion) mechanism
Etiology of this type of diarrhea:
- S. aureus
- Vibrio cholerae
- Bacillus cereus
- E. coli (ETEC-entero toxigen E. coli)
- Clostridium perfringens
- Rotavirus Norwalk-like viruses
- Giardia lamblia
- Cryptosporidium
Type II. Characterized by inflammatory destruction of the ileal or colonic
mucosa (by invasion, cytotoxin), producing dysentery illness. Stool
examination reveal fecal polymorphonuclear leukocytes and a high level of
lactoferrin.
Etiology:
- Shigella
- E. coli (enteroinvasive and enterohemorrhagic E.coli)
- Salmonella enteritidis
- Vibrio parahaemolyticus
- Clostridium difficile
- Campylobacter jejuni
- Entamoeba histolytica
Type III. Characterized by penetration through an intact mucosa to the
reticuloendothelial system.
Stool examination reveals fecal mononuclear leukocytes.
Etiology:
- Salmonella typhi
- Yersinia enterocolitica
The intestinal host factors that may help prevent the acquisition of
diarrheal disease are:
1. Host species, genotype and age
2. Personal hygiene..
3. Gastric acidity4. Intestinal motility,
5. -Normal bacterial flora
6. Intestinal immunity is represented by phagocytic, humoral and cellmediated elements..
7. Human milk is protective.
Microbial factors involved in producing disease are:
1. Toxins:
a. Neurotoxins:(Clostridium botulinum, S. aureus, B. cereus)
b. Enterotoxins (V. cholerae, E. coli, Salmonella, Shigella dysenteriae, B.
cereus)
c. Cytotoxins (Shigella, C. perfringens, V. parahemolyticus, S. aureus,
EHEC, Helycobacter pylori, Campylobacter jejuni)
2. Attachment
3. Ivasiveness
4. Other virulence factors: motility, chemotaxis, mucinase production
General aspects and diagnosis
Viral diarhea
The principal presentation of rotavirus infection is acute voluminous watery
diarrhea with or without vomiting
Diagnosis can be made by electron microscopy, antigen detection or
genome detection (RT-PCR)-the latter is the most sensitive and can also be
adapted to genotype of the virus.
The human astrovirusis are the second commonest cause of diarrhea in
hospitalized children. The clinical features are similar to these of rotavirus
but in general are less severe.
The human Caliciviridae have the typical “star of David” morphology and
small round-structured viruses. Epidemic and sporadic diarrhea and
vomiting can result from calicivirus infection. Diagnosis has improved
greatly with the application of antigen detection and RT-PCR.
ACUTE DISENTERY
Egidia Miftode
Shigella spp. are the main cause of dysentery worldwide and have also
been related to hemolytic uremic syndrome.
Dysentery is defined as frequent, small bowel movements accompanied by
blood and mucus with tenesmus or pain on defecation.
There is a substantial risk of person-to person transmission.
.
Pathogenesis
Invasion of Shigella in the colon produces an inflammatory colitis.
Clinical manifestations
The incubation period ranged from 6 hours to 9 days (usually <72)
The onset is manifested by fever, followed by small amounts of watery and
then bloody diarrhea with mucus.
Patients present abdominal pain, tenesmus and pain on defecation.
Extraintestinal manifestations.
Complications
 Hemolytic-uremic syndrome
 Pseudomembranous colitis
 Arthritis (10%) - 2 to 5 weeks after the dysenteric illness.
 Rectal prolapse
 Reiter syndrome (arthritis, urethritis and conjuntivitis)
 Toxic megacolon
 Protein-loosing enteropathy.
Differential diagnosis
I. Specific infectious processes:
II. Proctitis:
III. Other syndromes:
- Necrotizing enterocolitis
- Enteritis necroticans
- Pseudomembranous enterocolitis (Clostridium difficile)
- Diverticulitis
- Typlitis
IV. Heavy metal poisoning (As, Sn, Fe, Cd, Hg, Pb)
V. Syndromes without known infectious causes:
- Idiopathic ulcerative colitis
- Chron’s disease
- Ischemic colitis
- Radiation enteritis.
VI. Noninfectious endocrine causes:
VII. Impaired small bowel absorption: tropical sprue, enzymes
deficiencies, solute loads.
VIII. Noninfectious chronic noninflammatory diarrhea:
IX Tumors, polyposis
Principles of treatment in infectious diarrhea
Treatment consists of:
 Correcting and maintaining hydration
 Eliminating the etiological agent if possible
 Maintaining adequate nutrition
Rehydration therapy
Clinical findings to estimate fluid volume depletion in diarrhea
Findings







Central pulse
Peripheral pulse
Skin turgor
Eyes
Muscles
Appearance
Urine flow
Depletion (percentage of body weight)
0-5
5-10
10-15
Full
Full
Weak
“
Weak
Absent
N
Decreased
Poor
N
Slightly sunken
Sunken
N
Some cramps
Severe cramps
Alert/thirst
Alert/thirsty
Restless/+thirsty
N
reduced
absent
A. Replacement of fluid loss
Deficit of body weight
<5%
5-10%
10-15%
Volume of fluids
50 ml/kg
50-100 ml/kg
100-150 ml/kg
B. Supply of metabolic necessities
Body weight
Volume of fluids
1-10 kg
100 ml/kg
11-20 kg
1000 ml+(50 ml/kg x nr of kg>10 kg)
21-80 kg
1500 ml+(20 ml/kg x nr of kg > 20 kg)
Composition of oral electrolyte solutions in Who solution (1 packet) is as
follows: 3,5 g NaCl, 1,5 g K, 2,9 G trisodium citrate dihydrate and 20 g of
glucose. The solution is made by addign 1 packet of electrolyte to one liter
of water.
FOOD BORNE DISEASES
Dr. Egidia Miftode, Dr. C. Corcaci
Food borne disease is defined as an acute illness with gastrointestinal
or neurologic manifestations that results from ingestion of contaminated
foods (with microorganisms or microbial toxins).
Table 1. Etiology and pathogenic mechanism of food borne diseases
Preformed toxin Toxin produced in
vivo
S. aureus
Bacillus cereus
C. botulinum
C. perfringens
Bacillus cereus
ETEC
V. cholerae
Shiga-toxinproducing E. coli
C. botulinum (in
Tissue
invasion
EIEC
Salmonella
Shigella
Campylobacter
jejunii
Toxin production
and/or tissue
invasion
V. parahemoliticus
Yersinia
enterocolitica
infants)
Staphylococcal food poisoning – occurs after consumption of ham, milk,
eggs, salads, poultry.
Characteristics:
 Short incubation period (1-6 hours)
 Manifested by nausea and vomiting (rarely diarrhea)
 Fever is uncommon
Enterotoxins produced by S. aureus are heat-stable protein (A-E)
B. cereus
Occurs after ingestion of fried rice, meats, vegetables
C. perfringens
Food borne disease occurs after ingestion of meat (beef and poultry),
gravies.
E. coli
Enteroaggregative E. coli (EAEC), Enterohemorrhagic (EHEC),
Enteropathogenic(EPEC), Enterotoxigenic(ETEC). E. coli remains the most
common bacterial enteric pathogen reported worldwide.
Enterohemorragic E. coli and especially strain O157:H7 has emerged as a
cause of serious gastrointestinal disease since its recognition 20 years ago.
Clinical manifestations:
 fever, abdominal cramps and diarrhea
bloody diarrhea without fever-when Shiga toxin-producing strains of E. coli
are involved. complications are: hemolytic –uremic syndrome, thrombotic
thrombocytopenic purpura.
Salmonella
Food poisoning occurs after comsumption of: poultry, eggs, beef, dairy
products, fresh produce (tomatoes, melons).
Clinical manifestations (frequently within 16-48 hours): fever, abdominal
cramps, watery diarrhea.
Yersinia enterocolitica
Yersinia enterocolitica serogroup O:3 is the predominant strain in acute
enterocolitis, primarily affecting children younger than 5 years of age.
In young children the disease is a febrile diarrhea.
In older children and in adults Y. enterocolitica mimics acute appendicitis.
Yersinia enterocolitica septicemia is less common and is most often reported
in patients with diabetes mellitus, severe anemia, cirrhosis, malignancy and
in elderly patients. Erythema nodosum and reactive polyarthritis
Vibrio parahaemolyticus
V. parahaemolyticus is a gram-negative, halophilic,marine organism that
causes a self-limited gastroenteritis. Diarrhea, cramps, weakness, chills,
headache, fever and vomiting
Campylobacter jejuni
Campylobacter spp.-the cytolethal distending toxin of
Diagnosis: fever, abdominal cramps, diarrhea within 16-72 hours after the
ingestion; fecal blood, and polymorphonuclear leukocytes.
Duration of illness is < 1 week with relapse in untreated patients.
Complications: Guillain-Barre syndrome occurs 1-3 weeks after diarrheal
illness.
Treatment: erythromycin.
Differential diagnosis
1. Heavy metal food borne disease (Copper, zinc, Cadmiu)
2. Fish poisoning evolves with symptoms resembling those of a histamine
reaction:
3. Mushroom poisoning (onset within 2 hours).
Laboratory diagnosis
 Culture of different specimens: feces, vomitus, serum, blood and food
handlers
 Isolation and serotyping of organism from the feces:.
 Rectal swab
 Toxin testing of food
 Serology for Y. enterocolitica, V cholerae, Shiga toxin producing E. coli.
Therapy
Antibiotics should be avoided in uncomplicated gastrointestinal infections
caused by non-typhoidal Salmonella, C. perfringens, B. cereus or
staphylococcal food poisoning.
Doxycycline and TMP-SMZ have been shown to reduce the incidence of
traveler’s diarrhea-is not recommended universal use of doxycycline.
TYPHOID FEVER
Dr. Egidia Miftode
Typhoid fever is caused by Salmonella typhi, but, other Salmonellae
(S. paratyphi, S. schottmulleri, S. hirschfeldii, and S. choleraesuis) may
cause similar clinical syndrome.
Etiology
S. typhi, a gram-negative rod, possesses two O antigens (surface
polysaccharide) and one H (flagellar) antigen; the envelope antigen, Vi
(virulence antigen) is not constant.
Pathogenesis
S. typhi are ingested with food/water pass from the stomach into the
duodenum. In the distal small bowel they penetrate the intestinal epithelium,
over Payer’s patches. They multiply in the intestinal lymphoid tissue and
then disseminate via lymphatic circulation or hematogenous route.
Local concentration of endotoxin are responsible for cytotoxic and
ischemic damage, and circulating endotoxin is responsible of septic shock.
Inflammation of the epithelial cells and the subsequent release of chemical
mediators, which can stimulate the secretion of fluid into the gut lumen may
explain the diarrhea.
Clinical manifestations
Incubation period is 7-14 days.
Clinical features are:
1. Fever: begins as a remittent feverduring the first 72 hours, rising in a
stepwise fashion after this period associated with chills.
2.
3.
4.
5.
6.
Diarrhea is present in 40-50% of cases, and, sometimes constipation.
Headache
Diffuse or localized abdominal pain (often in the right upper quadrant)
Relative bradicardia
Rose spots: maculopapular lesions on the abdominal wall and chest (in
the first few days of illness).
7. Splenomegaly
8. Pharingitis is infrequent.
Laboratory findings
For definitive diagnosis
1. Isolation of S. typhi/another Salmonella spp from:
 Blood (positive for about 2 weeks in untreated patients)
 Bone marrow
 Stool (positive for several months in untreated patients)
 Urine
 Duodenal contents
2. Serology
 Widal test-detect anti-S.typhi antibodies
 ELISA using a cell envelope antigen or lipopolysaccharide of S. typhi or
purified Vi antigen.
 PCR.
Additional laboratory tests:
- leukopenia
- absence of eosinophils on peripheral smears
- mildly elevated bilirubin/transaminase level
- urinalysis: proteinuria, piuria, casts.
- Chest radiographic films reveale infiltrate
- Mononuclear cells in fresh stool specimens.
Differential diagnosis
1. Enteric fever-like syndrome causing by other bacteria : Yersinia
enterocolitica, Y. pseudotuberculosis, Campylobacter (manifested by
fever, headache, abdominal pain).
2. Systemic infection that may mimic typhoid fever:
 Bacterial infections:
 Parasitic infections:
 Viral infections:.
 Mycotic infections: disseminated histoplasmosis.
 Rickettsial infections: epidemic/endemic typhus, Q fever, erlichiosis,
Rocky Mountain spotted fever.
Complications
Major complications are:
- hemorrhage from ulcerating lesions –late in the course of disease (2% of
untreated patients)
- perforations of the terminal ileum or proximal colon.
Other complications are: psychosis, cholecystitis, hepatitis, meningitis,
pericarditis, pneumonitis, nephritis.
Treatment
Antibiotic therapy can eliminate the fever over 3 to 5 days.
1. Ampicillin:
2. Chloramphenicol3. Trimethoprim-sulfamethoxazole;
4. Fluoroquinolones: ciprofloxacin and ofloxacine
5. Third generation cephalosporins;
6. Monobactam.
Evolution
Untreated patients maintain a constant temperature pattern for 3 to 4
weeks.
Relapses occur in about 10-15% of treated patients, usually about 2 weeks
after the therapy was stopped. These patients need another short course of
therapy.
Prevention: Typhoid vaccine is recommended for travelers in endemic areas
where the water supply is suspect.
BOTULISM
Dr. Egidia Miftode
Botulism is a paralytic illness caused by the neurotoxin produced by
the bacterium C. botulinum.
Etiology
Members of genus Clostridium are gram-positive, anaerobic bacilli.
C. botulinum and closely related organisms produce toxins designated as
types A, B, C, D, E, F, and G. The toxins causing this disease are among the
most potent bioactive substances known (the oral lethal dose for humans is
0.05-0,5 microg).
Pathogenesis
There are four clinical type of botulism
Foodborne botulismWound botulism
Infant.
“Infectious“ botulismClinical manifestations
The latent period is typically 12-36 hours, but can range from 6 hours to 10
days. Patients are afebrile in the absence of complications.
The symptoms are:
 gastrointestinal-nausea, vomiting, abdominal cramps,
diarrhea/constipation, dryness of mucous membranes;
 neurologic, which are manifestations of cranial nerve dysfunction:
 muscle weakness;
 manifestations of parasympathetic nervous system dysfunction: pupils
may be dilated or nonreactive.
Complications include otitis media, aspiration pneumonia, respiratory
distress syndrome.
Laboratory diagnosis
 Detection and identification of botulinum toxin in blood, feces and in the
food consumed before onset of illness. Isolation of C. botulinum from the
stool.
 CSF is normal
Differential diagnosis
The diseases that may be confused with botulism are: tick-borne
encephalitis, diphtheria, poliomyelitis, Guillain-Barre syndrome, myastenia
gravis, food poisoning of other etiology.
For infant botulism differential diagnosis includes: sepsis, dehydration,
pneumonia, Epstein-Barr infection, diphtheria, congenital myastenia gravis,
muscular dystrophy, hypothyroidism, metabolic and toxic conditions which
may produce weakness and hypotonia.
Mortality is 25-30%.
Therapy
1. Supportive care, nutritional support;
2. Prevention of nosocomial pulmonary and urinary tract infection.
3. Trivalent botulinum antitoxin (neutralize only circulating toxin)-must be
administrated as early as possible, with a test for the hypersensitivity.
Antitoxin must be given intravenously, in one vial (if there are no signs
of hypersensitivity).
Hypersensitivity reactions must be averted through the use of human
botulism immune globulin.
Botulism antitoxin desensitization: with serial subcutaneous injections of
antitoxin in 20-minutes intervals
.
4. Guanidine hydrochloride
5. High-dose penicillin therapy is generally given
6. Antibiotics if there are complications
7. Debridement of the wound
C. botulinum spores are not killed by boiling at 100 C. The toxin is heatlabile, so it may be inactivated by boiling of foods before consumption.
Mortality is 25-30%.
CHOLERA
Daniela Leca
An acute infection involving the entire small bowel, characterized by
profuse watery diarrhea, vomiting, muscular crumps, dehydration, oliguria
and collapse.
Etiology
V. cholerae is not invasive, short (1.5-3 mm by 0.5 mm), curved,
motile, gram negative, aerobic rod, oxidase-positive, grows luxuriantly in
alkaline media in the presence of bile salts, and produces a neuraminidase
that has the property of degrading gangliosides to the monosialosyl form,
which is the specific receptor for cholera toxin.
Antigenic structure include:
- flagellar (H) antigens; antisera prepared against them do not distinguish the
vibrio causing human epidemic disease from water vibrios.
- somatic (O) antigens do distinguish V. cholerae Ogawa, Inaba, and
Pathophysiology
V. cholerae is swallowed either with water or food. It must survive passage
through the stomach to colonize the small intestine even though it is
extremely acid sensitive.
Epidemiology
Cholera is spread by ingestion of water, sea foods and other foods
contaminated by the excrement of persons with symptomatic or
asymptomatic infection.
Clinical manifestations
Cholera may be present:
 in an asymptomatic state,
 mild diarrhea, or
 the typical "full-blown" syndrome.
 The first symptoms of cholera are an increase in peristalsis.
 There is little abdominal pain in cholera, most of the anxiety, muscle
cramps, thirst, and faintness being related in their prominence to the rate
of fluid loss.
 Rarely, ileus may occur at the onset of illness with profound -"Cholera
Sicca".
 Altered consciousness.
 Electrolyte
 Uncomplicated cholera is self- limited; recovery occurs within 3 to 6
days. The fatality rate can be > 50% in untreated severe cases but is < 1%
with prompt and adequate fluid and electrolyte therapy.
Diagnosis
Clinical diagnosis rests on the history of acute onset and the watery stool in
the absence of high fever or much abdominal pain.
Laboratory diagnosis
1. The stool, microscopically, will show limited numbers of white cells and
rarely red cells.
2. darkfield or phase microscopy,.
3. Cultures
4. Antibodies to the specific somatic O antigens:
 direct agglutination of heated V. cholerae,
 the agglutination of chicken red blood cells that have been coated with
antigens,
 a vibriocidal test
Treatment
. The water and salts lost in the cholera stool must be replaced in
comparable amounts and concentrations.
The replacement can, except in severe cases, be accomplished by
mouth (see chapter “Diarrheal diseases”).
Intravenous replacement therapy is needed when:
 the volume of stool output exceeds 100 ml/kg/24 hour,
appropriate oral rehydration has not been given
Antimicrobials will shorten the duration of diarrhea and, thereby, reduce
fluid losses in cholera. These includes:
1. Tetracycline:
2. Ampicillin,
3. Trimethoprim-sulfamethoxazole
4. Furazolidone:,
5. doxycycline:)
6. fluoroquinolones:
7. The most important reversible life-threatening complication of cholera
after fluid and electrolyte loss is hypoglycemia..
Prevention
Prompt prophylaxis with tetracycline 500 mg orally q 6 h in adults (12
mg/kg q 6 h in children < 8 years of age
TRICHINOSIS
Egidia Miftode
Trichinella spiralis was first seen in human tissue at autopsy in the
early 1800s. By the 1900s, trichinosis was definitely recognized as a public
health problem.
Table 1. Trichinella spiralis: life cycle stages
Time after infection
first 2-4 hours
30 h
Day 6
Day 10
Day 14
Day 21
Day 23
Month 1
Stage in life cycle
Excysted larvae enter intestinal mucosa
Worms mature and mate
Females deposit larvae/muscle, invasion
begins
Heaviest muscle invasion
Decrease in larval deposition
Encapsulation of larvae
Intestine free of adult worms
Encapsulation almost complete
Month 3
Month 6
Year 1
Year 6
Adult worms die
Cyst calcification begins
Cyst calcification usually complete
Most larvae still viable within calcified cyst
Clinical disease
Incubation has a 1-30 days duration
I.
Intestinal effects.
II.
Muscle penetration and larva encapsulation (invasion phase) –
 fever,
 facial (periorbital) edema,
muscle pain, swelling, and weakness; conjunctivitis, subconjunctival
hemorrhages,
 pruritus.
 Skin rashes include:
Less frequent manifestations are:
 Myocarditis Central nervous system involvement (10-20%):
 Pneumonitis: pulmonary infiltrates, pleural reaction
III. Convalescent phase (after 2 months): fever subsides, improvement in
muscular symptoms.
Laboratory abnormalities
A. Peripheral eosinophilia (of at least 20%, and possibly up to 90%) is
present during the muscle invasion phase of the infection.
B. Leukocytosis
C. Hypoproteinemia
D. Hypokalemia
E. Elevated cretinphosphokinase
F. Mild elevation of alaninaminotransferase level (ALAT)
Diagnosis
1. The history may suggest possible trichinosis (consumption of rare or raw
infected meat).
2. Eosinophilia
3. Serologic tests:
4. Muscle biopsy (gastrocnemius, deltoid, and biceps)- does not provide
positive results until 2 to 3 weeks after the onset of the illness.
5. Larvae or adult worms are rarely recovered during the intestinal phase
(diarrhea).
6. Examination of suspect meat may reveal larvae (artificial digestion
procedure).
Differential diagnosis
During the intestinal phase:
 Viral gastroenteritis,
 Food poisoning
During the visceral phase:
 Typhoid fever
 Dermatomiositis,
 Serum sickness
 Polyarteritis nodosa,
 Periorbital cellulitis, angioneurotic edema
 Rheumatic fever
 Trypanosomiasis
 Neurologic involvement may mimic: polyneuritis, acute anterior
poliomyelitis, myastenia gravis, meningitis, viral encephalitis
 Cardiac involvement may mimic: viral or bacterial myocarditis,
endocarditis, ischemic cardiomyopathy.
Tretment
Albendazole: 400mg po bid, 14 days.
Mebendazole: 5mg /kg po bid, 10-13 days.
Concomitant prednisone: 40-60 mg po qd; it is indicated in severe disease
VIRAL HEPATITIS
Egidia Miftode
Table 1. Characteristics of hepatitis viruses
Property
Family
Nucleic acid
type
Transmission
Maximum titer
Fulminant
disease
Chronicity
Malignancy
Serologic tests
Antigen
Antibody
HAV
Picornaviridae
RNA
HEV
?
RNA
HBV
Hepadnaviridae
DNA
HCV
Flaviviridae
RNA
Fecal-oral
109/ml
Rare
Parenteral-sexual
109-10/ml
Rare
Parenteral
106/ml
Rare
No
No
Fecal-oral
?
Pregnant
women
No
No
1-10%
Yes
50-90%
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Genotypes
7
3
5
Vaccination
Yes
No
Yes
>6weeks
Types 1-6
with
subtypes a,
b, c
No
HEPATITIS A
Hepatitis A virus (HAV) is a member of picornaviridae family (which
includes poliovirus and rhinoviruses, agents of the common cold).
The virus particle
 is of 27nm in diameter
 is not enveloped
 has an outer capsid which surrounds a single-stranded RNA.
Risk factors for acquisition:
 contact with acutely ill individuals
 travel to endemic areas
 homosexual activity
 contact with children attending day care centers
 illicit drug use
Among the persons under 18 years old, 50% in France, 90% in Portugal and
>95% in Romania present antibodies against HAV.
Pathogenesis
During acute HAV infection, there is an initial viremia and fecal shedding of
viruses; viremia persists for up to 3 weeks.
Histopathological aspects include the existence of:
 hepatocellular necrosis
 centrilobular cholestasis
 periportal infiltration of the liver with mononuclear inflammatory cells
Clinical manifestations
Only 10% of A-hepatitis are clinically manifested.
The incubation period: the symptoms of HA usually appear about 4 weeks
after exposure, but the interval may range from 2-6wks.
The clinical manifestations are different in adults and young children
(children of less than 2 years old experience asymptomatic infection or
develop other symptoms than those suggestive for hepatic inflammation.
A. Prodromal (preicteric) phase lasts for 4-10 days could be very variable:
1. Gastrointestinal symptoms: anorexia, nausea and vomiting, right
upper-quadrant pain,
2. diarrhea (in children –20% of cases ), distaste for cigarettes (in
smokers only);
3. Influenza-like - syndrome: fever /chills, muscle pain, headache;
4. Rheumatic syndrome: arthralgias (usually disappear after onset
of jaundice);
5. Eruptions: petechiae, measles/scarlet fever-like exanthema;
6. Fatigability;
7. Pruritus;
8. Jaundice
9. Acute abdomen (mimicking an appendicitis)
B. Icteric phase – is ushered by the appearance of dark, golden-brown urine
due to bilirubinuria, followed one to several days later by pale stools
yellowish coloration of the mucous membranes, conjunctivae, sclerae and
skin.
The physical examination
2 special forms of evolution may be encountered:
 Cholestatic hepatitis A - >12 weeks of jaundice
 Relapsing hepatitis A
Diagnostic
1. AST (Aspartate Aminotransferase) or SGOT (Serum Glutamic-Oxalacetic
Transaminase) (N = 5 – 54 U/L).
2. ALT (Alanine Aminotransferase) or SGPT (Serum Glutamic-Piruvic
Transaminase): (N = 0 – 36 U/L).
3. Alkaline Phosphatase (N = 40 –120 U/L).
4. GGT (Gamma Glutamyltransferase) (N = 3 – 59 U/L).
5. LDH (Lactose DeHydrogenase) (N = 135 – 225 U/L)..
6. Total bilirubin
7. Direct bilirubin (conjugated) (N = 0 – 5 μmol/L).
8. Albumin (N = 35 – 50 g/L)9. PT (Prothrombin Coagulation Time) (N = 10 – 12 sec.) or QUICK Index
(N≥80%).
10. Urine tests: bilirubin appears in the urine in the prodromal phase and
may lead to the diagnosis
11. Peripheral blood:
12. Serological confirmation is always required, by the specific
detection of IgM anti HAV.
Complications
 Neurological complication: encephalitis, meningoencephalitis, GuillainBarre syndrome, mononeuritis affecting cranial or peripheral nerves.
 Myocardial involvement: myocarditis and electrocardiographic changes
 Pancreatitis
 Pleural effusions and ascites
 Aplastic anemia
Differential diagnosis of jaundise
I Abnormalities of bilirubin metabolism
1. Increased bilirubin production (unconjugated bilirubinemia):
 Hemolysis
 Ineffective erythropoiesis: megaloblastic anemias, myeloproliferative
diseases, protoporphyria etc
 Blood transfusions
 Resorbtion of haematomas
2. Decreased hepatic clearence:
a. decreased uptake and/or conjugation of bilirubin
- Gilbert syndrome, Crigler Najjar syndrome
- Rifampin
- Physiologic jaundice of neonate
b. Decreased canalicular excretion of bilirubin: Dubin-Johnson and Rotor
syndromes
II. Hepatocellular jaundice
1. Acute/subacute hepatocellular damage
 Acute hepatitis: viral (CMV, Epstein-Barr virus, herpes), bacterial
(leptospirosis, brucellosis, staphylococcal, gram-negative bacillary
sepsis, tuberculosis, salmonellosis), amoebiasis, giardiasis
 Hepato-toxines: alcohol, Amanita, acethaminophen;
 Drugs: isoniazide, macrolides, sulfonamides, metildopa, valproic acid,
paracetamol, non steroidal anti-inflammatory drugs, halothane and
derivatives, antidepressants, anti-HIV, ketoconazole
 Chemical agents: carbon tetrachloride, tetrachloroethylene
 Metabolic disorders: Wilson’s disease, Reye’s syndrome
 During pregnancy: acute liver steatosis
2.Chronic hepatocellular diseases
 Chronic active hepatitis
 Cirrhosis
 Neoplasia
 Neonatal hepatitis
 Autoimmune hepatitis
 Alfa1-antitripsin deficiency
III. Biliary obstruction
Extrahepatic
 Gallstones
 Neoplasia
 Sclerosing colangitis
 Biliary stricture
 Pancreatitis
 Parasites
Intrahepatic
 Cholestatic viral hepatitis
 Postoperative cholestasis
 Benign recurrent cholestasis
 Primary biliary cirrhosis
 Chronic inflammatory bowel disease
 Biliary atresia
Treatment
The aim of the treatment is to maintain comfort and nutritional
balance.
Bed rest is indicated.
A high-calorie, high-protein diet has been shown to reduce the length of time
in hospital.
The adequate calories must be provide: 30-35 kcal/kg, mostly from
carbohydrates.
Low-fat diet is frequently advised. Avoidance of alcohol is recommended
for some months after acute infection.
Patients with severe anorexia, nausea or vomiting occasionally need
nutritional support.
Meat can be introduced when urine exam for bilirubin and urobilinogen are
back to normal. In cholestatic hepatitis hypertonic glucose is used.
Prevention
Now, there is available a double vaccine against A and B hepatitis viruses
(Twinrix)
HEPATITIS B
The hepatitis B virus (HBV), discovered in 1966, infects more than 400
million people world-wide.
Epidemiology
Areas with high prevalence Areas with low level of endemicity The distribution of hepatitis B infection varies greatly throughout the
world.
Modes of trasmission
 Contact transmission through body secretions: semen, vaginal secretions,
blood, saliva
 Maternal-neonatal transmission: 5 –10 % of neonatal HBV infections
result from in utero infection
 Percutaneous transmission: drug abusers, health care workers
 Blood transfusions.
Virologic characteristics
HBV belongs to Hepadnaviruses (DNA-woodchuck hepatitis virus,
the duck hepatitis virus and other avian and mammalian variants).
The hole VIRION – the Dane particle is a 42 nm sphere, which contains:
 the core enclosing the DNA and
 an envelope material , which is found abundantly in the circulation,
shaped as small spheres and rods with an average width of 22 nm.
The viral genome is represented by a double – stranded circular DNA of
approximately 3200 pairs of bases that encodes 4 overlapping open reading
frames:
1.
2.
3.
4.
S, for the surface or envelope gene
C, for the core gene
X, for the X gene
P, for the polymerase gene
HBV replication cycle
The replication cycle of HBV begins with attachment of the virion to
the hepatocyte.
Inside the hepatocyte nucleus the viral genome is converted into a covalently
closed circular DNA (cccDNA).
The cccDNA is
Serologic makers of importance in HBV infection
Hepatitis B core antigen (HBcAg) - represents the nucleocapsid that
encloses the viral DNA.
Hepatitis B ″e″ antigen( HBeAg). It is a circulating peptide derived from
the core gene and then modified and exported off the liver cells and serves
as a maker of active viral replication.
DNA polymerase (encoded by the P gene) – also serves as a witness of
reserve transcriptase activity.
Antibodies against HBsAg (anti – HBs) are produced as a response to the
presence of the envelope (surface) Ag:
Antibodies against HBcAg (HBcAb)
 are detected virtually in all patients who have ever been exposed to HBV: they are not
protective
 IgM subtype antibodies are associated with acute infection; usually they
disappear within 4-8 months after acute infection.
Antibodies against HBeAg (HbeAb) appear once the antigen has been
cleared
Immune response
A. Immune response to acute HBV infection
Recovery from acute HBV infection is dependent on:
- B cell response with production of antibodies to pre-S and S
antigens
- T cell response.
B. Immune response to chronic HBV infection
In patients with chronic HBV infection the HBV-specific CTL response is
weak and limited to one or a few epitopes.
Immune tolerance in perinatally acquired HBV infection
Immune tolerance to HBV is manifested by:
 A high rate of progression to chronic infection
 Lack of disease activity in the presence of very high level of virus
 Very low rate of spontaneous or interferon-induced HBeAg
seroconversion.
Pathogenesis
1. Immune-mediated liver injury
HBV-related liver injury is related to:
a. CTL-mediated lysis of infected hepatocytes;
b. Non-cytolytic pathways via the release of cytokines.
2. Direct cytopatic effects
HBV is in general not a cytopatic virus. Direct cytopathic liver injury can
occur when the viral load is very high (as in fibrosing cholestatic hepatitis).
Hepatocarcinogenesis
Life cycle of HBV in the human host
 95% of infected neonates become asymptomatic chronic HBV carriers
 30% of children of 3months – 6years become asymptomatic chronic
HBV carriers
 only 3 –5% of adults become asymptomatic chronic HBV carriers.
The Four Stages of Hepatitis B Infection are:
1. First Stage (Immune Tolerence) is defined as incubation period
2. Second stage (period of symptomatic hepatitis):
 In patients with acute HBV infection - it lasts 3 – 4 wks;
 In patients with chronic disease, stage 2 may persist for > 10 years
possibly leading to cirrhosis.
3. Third stage (end of active viral replication)
 HBeAg is no longer present.
 HBeAb become detectable.
 There is a marked decrease in viral DNA.
 ALT becomes normal.
 The patient remain + for HBsAg.
4. Fourth stage (immune stage)
 HBsAg is absent;
 HBV DNA is absent
 HBsAb is positive testifing the development of full immunity.
Some factors can affect the evolution through the four stages, like:
 the genetic predisposition of the host,
 the presence of other viruses,
 the treatment with immunosuppressive agents,
 sex,
 infections with HBV mutants.
HBV variants
HBV mutant that are detected clinically confer survival advantage over the
wild type virus by:
- evading host immune response
- enhancing virus replication.
Mutations in the precore, S and P genes have been most extensively studied.
Precore mutants
S mutants
Mutations in the HBV gene have been reported in infants born to carrier
mother who developed HBV infection despite vaccination, and in liver
transplant recipients who developed HBV reinfection despite prophylaxis
with hepatitis B immune globuline (HBIG).
Clinical manifestations
I. Asymptomatic hepatitis
A. Subclinical infection: abnormal blood tests, without jaundice and
symptoms;
B. Inapparent infection: no symptoms or biochemical abnormalities are
present, but serologic tests are positive
II. Symptomatic hepatitis
A. Anicteric hepatitis –
B. Icteric hepatitis
 Icteric phase:
- dark urine, lightening of stool color – a few days before onset of jaundice,
- as jaundice progress the constitutional symptoms become less severe,
- duration of jaundice is 1 – 2 months after its onset.
The physical findings are similar to those described in HAV, adenopathy,
small spider angiomata.
Extrahepatic manifestations of viral hepatitis
a. transient serum-sickness like syndrome:
b. polyarteritis nodosa:
c. glomerulonephritis
d. mixed cryoglobulinemia
e. acrodermatitis of childhood (Gianotti’s disease):.
Laboratory features
Blood chemistry was shown above. Minor elevation of ALT values may
persist for a few months, even if the bilirubin level turned normal.
Serologic Tests
 HBsAg is the first identifiable marker (before the level of ALT start to
Increase) by ELISA, RIA. It’s persistence beyond 6 months suggests the
development of HBV carrier state.
 HBeAg it will be detectable in the next days to weeks after the
appearance of HBsAg and in uncomplicated HBV infections it will
disappear priory to the HBsAg.
 HBeAb become detectable shortly after the disappearance of HBeAg.
They may persist for long periods.
 DNA- HBV: is detectable during the early phase of infection and →
 undetectable several wks later.
 HBcAb (anti - HBc) are detectable in serum shortly after the HBsAg′s
 discovery and before the appearance of anti-HBs.
 IgM anti – HBc peak in several weeks from the onset of infection; is the
most sensitive test for acute HBV infection. They persist for 4 to 8
months after their appearance.
 IgG anti – HBc are synthetised in late convalescence and are found
thereafter for years, but levels decline slowly.
 Anti – HBs. As the titer of HBsAg declines, corresponding antibodies
become detectable and reach a peak level in a few months. They are
- neutralizing,
0
1
2
3
4
5
6
7
8
9
10
Evolution of HBV infection
1.
2.
3.
4.
5.
6.
Full recovery
Fulminant hepatitis
Persistence of HBsAg
Chronic hepatitis B
Cirrhosis
Hepatocellular carcinoma
1. Full recovery is assumed if the ALT reaches normal or close to normal
levels and if HBsAg becomes negative in EIA. This takes more than 6
months in some cases.
2. Fulminant hepatic failure (FHF) was defined as a potentially
reversible condition, the consequence of severe liver injury, in
which encephalopathy developed within 8 weeks of the appearance
of the first symptoms, in the absence of pre-existing liver disease
Pathophisiology
Pathophisiologically, the terminal event in this illness is injury and/or death
of hepatocytes. Although the actual pathogenesis is not well understood, this
damage is probably due to liberation of chemical and immunological
mediators.
FHF is announced by some signs, such as:
 severe jaundice (> 15 mg% in adults or > 7 mg% in infants); mild
jaundice does not excluded the fulminant hepatitis;
 persistence of vomiting and anorexia after the jaundice have installed;
 presence of bleedings
 persistence of fever in the presence of jaundice
 quickly decreased in size of liver;
 tachicardia instead of bradicardia in an icteric and afebrile patient
 foetor hepaticus.
In stage I coma, mild mental changes are present, but asterixis
is minimal or absent. Stage II coma is marked by worsening of mental
changes and definite asterixis. In stage III coma, the patient develops stupor
and semicoma, but can still be roused. With stage IV coma, the patient no
longer is arousable, and there may or may not be a response to deep pain
stimuli. Patients with hepatic failure, may demonstrate other neurologic sign
- flapping of the tongue, involuntary movements, long-tract signs, and
decerebrate posturing.
Biological data that announced the FHF are:
 decreased of Prothrombin - time (Quick index < 30%)
 decreased of plasminogen (<20%)
 raised blood ammonia (>120 mg%)
 leukocytosis with increased level of neutrophils
 sudden decreased of ALT.
Table 2. Complications of FHF and their treatment:
Cerebral oedema
*Monitor intracranial pressure (extradural monitor) if
encephalopathy reaches grade III or IV
*Avoid manoeuvres that increase intracranial pressure
*Control restlessness
*If intracranial pressure > 20-30 mm Hg, apply:
1.Hyperventilation (PaCO2 25 -3- mm Hg) then
2.Mannitol 0,5 g/kg in bolus then
3.Haemodialysis or haemofiltration then
4.Barbiturate coma
Renal failure
Bacterial
infection
Circulatory
dysfunction
Haemorrhagic
complications
Hypoglicemia
Other
complications
*Avoid arterial hypotension, nephrotoxic drugs,
control infection
*Dopamine 2 - 4 microgm/min
*Haemodialysis or haemofiltration
*Careful hygienic measures
*High index of suspicion of infection
*Daily cultures of blood, urine, and other biological
fluids
*Start empiric antibiotic therapy
*Possible selective intestinal decontamination
*Possible parenteral antibiotic prophylaxis
*Insert pulmonary-artery catheter and measure
indicators of tissue hypoxia frequently
*Avoid vasoconstrictors
*Possibly treat with N-acetylcysteine
*Upper gastrointestinal bleeding; ranitidine or
sucralfate
*Fresh frozen plasma only in cases of bleeding and
before invazive procedures
*Measure blood glucose concentration every 1 hour
*Intravenopus hypertonic glucose
*Pulmonary oedema, respiratory alkalosis,
hyponatremia, hypophosphatemia, pancreatitis,
aplastic anaemia
Persistence of HBsAg for more than 6 months after onset in high
concentrations (>100 PEI units/ml) means that:
(1) the acute hepatitis B evolved to chronicity;
(2) a pre-existing chronic HBV infection was superimposed by an acute
hepatitis of another etiology; or
(3) the acute disease may actualy be an exacerbation of chronic hepatitis B.
Full recovery is assumed if the ALT reaches normal or close to normal
levels and if HBsAg becomes negative in EIA. Chronic hepatitis B
Clinical manifestations of chronic hepatitis are mild and non-specific : lack
of energy, malaise, ease fatigability, myalgias, arthralgias, and skin rash.
The evolution is usually intermittent with acute exacerbations consisting on:
abdominal discomfort, nausea, weight loss, dark urine, jaundice, loss of
appetite.
Cirrhosis
The above mentioned symptoms are more important, associated or not with
signs of hepatic encephalopathy, blood coagulation is decreased, serum
albumin is decreased; the ALT levels are only moderately enhanced, and
often fluctuate. The liver status can be assessed by histology, liver function
tests, and determination of serum proteins with liver metabolism.
Hepatocellular carcinoma
In highly epidemic areas, persons positive for HbsAg are 100 times more
likely to develop HCC compared to those who have anti-HBs.
Abdominal imaging by ultrasound of HbsAg-positive patients with liver
cirrhosis is advisable at intervals of 3-4 months.
Complications
 Neurological complication: encephalitis, meningoencephalitis, GuillainBarre syndrome, mononeuritis affecting cranial or peripheral nerves.
 Myocardial involvement: myocarditis and electrocardiographic changes
 Pancreatitis
 Pleural effusions and ascites
 Aplastic anemia
 Polyarteritis nodosa
 Membranoprolipherative glomerulonephritis
 Leucocytoclastic vasculitis
Treatment
The main aims of treatment of chronic HBV infection are:
 Viral suppression (as shown by loss of HBeAg with or without
seroconversion to anti-HBe) and a decrease in HBV DNA;
 Reduction in liver damage (return to normal values of serum
aminotransferases, histological improvement on liver biopsy samples;
 Complete eradication of the virus (as shown by loss of HBsAg, with
seroconversion to anti-HBs) and the absence of HBV DNA detection.
Agents for the treatment of chronic hepatitis B
Interferon alfa – it is given parenterally either 5 MU daily or 10 MU three
times per week with loss of HBeAg and HBV DNA in only 20% of cases,
and loss of HBsAg in only 6% of cases.
Lamivudine
Entecavir
Telbivudina
Adefovir
Tenofovir
Hepatitis B vaccines
Long-term immunity against HBV infection is conferred by the
presence in the blood of adequate levels of anti-BHs, the antibody to the
surface antigen. It is generaly accepted that the threshold anti-HBs titre for
protection is 10mIU/ml.
It is significant to note that a 3-dose schedule of Engerix-B
(10microg/dose) alone gives protective efficacy rates of 94,8%- not
significantly different from the efficacy rates of 97,6% and 97,4% for
vaccinees who also received HBIG.
Passive immunization
A special immunoglobulin is produced from donors who are naturally
immune and boosted with plasma-derived vaccine. Passive immunization is
recommended together with active immunization to prevent HBV infection
in newborns from HBsAg and HBeAg mothers, and after proven accidental
exposure of a non-immune person.
HEPATITIS D
Hepatitis D virus is a defective RNA virus that uses HBsAg to
produce delta hepatitis.
Transmission is similar to that of HBV.
A high prevalence of HDV infection is seen in South America, Central
Africa, southern Italy and Eastern European countries.
Acute HDV infection occurs in two forms depending on the state of HBV
infection:
1) Co-infection-acute delta hepatitis occurs simultaneously with acute
hepatitis B. Most patients in this situation recover. The rate of fulminant
infection is higher than in superinfection.
2) Superinfection- acute delta hepatitis developed on a chronic hepatitis B.
Laboratory data
Delta antigen can sometimes be detected in serum during the early
phase of acute delta hepatitis.
HDV RNA can be detected in the serum and liver using molecular
hybridization technology.
Anti-HDV arises with the disappearance of the Delta antigen.
HBsAg is present concomitantly with IgM anti-HBc in early phases of coinfection and with IgG anti HBc in superinfection.
Diagnosis of chronic HDV infection involves:
 High titers of anti HDV (>1:100 by radioimmunoassay)
 Detection of HDV antigen
 Persistence of IgM anti HDV in serum.
Evolution
Chronic delta hepatitis is more severely than chronic hepatitis B alone or
chronic hepatitis C, and 60-70% of patients develops cirrhosis.
0
2
4
6
8
10
12
24
32
0
2
4
6
8
10
12
24
32
0
2
4
6
8
10
12
24
32
HEPATITIS C
It is a small single-stranded RNA virus that is distantly related to
members of the Flaviviridae family (e.g., Dengue viruses, Yellow fever
virus, and the Japanese encephalitis virus).
According to WHO data, it is estimated that 3% of the world population has
been infected with hepatitis C virus.
Therefore, there may be more than 170 million chronic carriers in the
world
Modes of transmission
1. Blood products
2. Intravenous drug users
3. Donor organs (4. The importance of sexual transmission is controversial.
The frequency of HCV transmission to female sexual partners was 5 times
higher when HIV was also transmitted, possibly because co-infection with
HIV leads to higher levels of HCV in serum.
5. The risk of developing hepatitis following needle-stick exposure is
6. Vertical transmission of this virus –the risk of transmission is much lower
than for hepatitis B infection.
Nosocomial risk is a major point of concern, as documented in
oncology units.
Pathogenesis
Hepatitis C virus is a member of the Flaviviridae family, which
includes the flaviviruses and pestiviruses.
that encodes a large single polyprotein of 3000 amino-acids:
 the N-terminal one third harbors the structural proteins;
 the C-terminal two thirds contains the nonstructural proteins:
C22-3
Antiviral immune response
 Th1: interferon-gamma and interleukin-2, which are important stimuli for
the development of the host antiviral immune responses, including
cytotoxic T-lymphocyte (CTL) generation and NK-cell activation
 Th2: interleukin-4, interleukin-5 and interleukin-10, which enhance
antibody production and downregulate the Th1 response.
The imbalance between the Th1 and the Th2 responses is implicated in
disease progression and the inability to clear the infection.
Humoral immune response
Cellular immune response
The cellular immune response has the ability to recognize and eliminate
Clinical manifestations
HCV infection is infrequently diagnosed during the acute phase of infection.
Incubation period is usually 7 to 8 weeks (range 2 to 26).
The majority of persons have either no symptoms or only mild symptoms.
Symptoms of acute hepatitis usually consist of: jaundice, malaise and
nausea.
A characteristic feature of all these patients is marked fluctuation of
aminotransferase level. Although the aminotransferase level (ALT) may
occasionally peak as high as 1000 to 2000IU/L,
Extrahepatic manifestations of HCV infection are associated with
autoimmune or lymphoproliferative states
Lymphoproliferative disorders
1. Mixed cryoglobulinemia..
2. Lymphoma.
Other extrahepatic diseases
 Autoimmune thyroiditis
 Dermatological manifestations- apart from the palpable purpura due to
leukocytoclasic vasculitis (the most frequently seen dermatological
manifestation of HCV-related EMC) other cutaneous disorders are:
sporadic porphyria cutanea tarda and cutaneous/mucosal lichen planus
 Sjogren’s syndrome
 Idiopatic pulmonary fibrosis
 Mooren corneal ulcers.
Tests for HCV
There are still no tests for antigens of hepatitis C virus in serum.
Infection is usually diagnosed by detecting hepatitis C virus antibodies based
on immunoassay detection.
1. HCV antibody testing
2. Detection of serum HCV RNA
 Detection of serum HCV RNA by PCR is the best test for early diagnosis
of acute HCV infection (it is positive as soon as 1 week after exposure).
3. HCV genotypes.
HCV was classified into 6 types (1 to 6) each including subtypes (a, b, c...)
4. Quasispecies
There is a correlation between a high quasispecies heterogeneity an a more
severe liver disease and a poor response to interferon therapy.
0
1
2
3
4
5
6
12
24
36 48
60
120
Evolution
The infection becomes chronic in most cases (80%), and chronic infection is
typically characterized by a prolonged period in which there are no
symptoms.
.
At the cirrhotic stage, about 3-5% of patients per year develops
hepatocarcinoma, which may develop in up to 50% within 10 years.
Chronically infected individuals generally have fluctuating or continuously
abnormal levels of ALT and are viraemic.
Treatment of Hepatitis C infection
-
Prior to treatment, the investigation should:
ascertain that chronic hepatitis C virus infection (HCV) is present;
exclude contraindication of treatment;
evaluate histological findings
determine the viral genotype, and for genotype 1 patients, also, the viral
load.
Exclude contraindication for treatment
Contraindications for interferon (IFN) and IFN/ribavirin combination
therapy are:
- Pregnancy or no optimal contraception(ribavirin)
- Severe heart disease
- CNS dysfunction/epilepsy
- Decompensated liver disease(interferon)
- Organ transplant, except liver transplant
- Severe renal failure(ribavirin)
- Untreated severe anemia(ribavirin)
- Hemoglobinopathies(ribavirin)
- Autoimmune hepatitis(interferon)
- Ongoing or recent drug or alcohol abuse
- Leukopenia(WBC<1500/mm3, neutrophols<750/mm3)
- Thrombocytopenia(<50000/mm3)
Relative contraindications:
-Psychiatric disease/depression
-Not well controlled thyroid disease or diabetes melitus
-Autoimmune disease
-Mild bone marrow suppression.
Evaluation of the histological damage
Patients with mild histological inflammation without fibrosis will
probably not develop serious liver disease, not even with prolonged followup. A second histological evaluation after 2-5 years is therefore
recommended for this patient cathegory.
Cirrhotic patients, with manifest disease, should only be treated if they are in
compensated phase, while those with decompensated cirrhosis should be
evaluated and considered for possible liver transplantation.
Recommend treatment if:
- HCV-RNA is detectable
- ALT above the upper normal reference level
- No contraindications for treatment
- Liver biopsy showing fibrosis stage >=2 and ongoing inflammation or/
fibrosis stage 1 and inflammation grade >2
Treatment with:
-alfa-IFN 3MU s.c., 3 times a week + ribavirin 1000-1200 mg /day.
Non-responders to previous IFN monotherapy:
-Lack of sufficient information - no recommendation given.
Table 1. Treatment recommendations
Patients
Previously untreated patients
-Genotype other than 1 or genotype 1 and
viral load < 2-3 million genome copies/ml
-Genotype 1 and viral load > 2-3 million
genome copies/ml
Previous relapse after IFN monotherapy
-All genotypes
-If contraindication for ribavirin
Treatment length
-Treatment for 24 weeks
-Treatment for 48 weeks.
-24 weeks treatment
-IFN monotherapy
weeks
for
48
Pegylated Interferon
Indication of pegylated interferon (with ribavirin):
- first intention therapy of patients with: fibrosis-stage 3 (Knodell or
Metavir score), necroinflamatory score>9, hemophilia/thalasemia,
age<55 years
- recurrences /absence of response after the standard therapy with
interferon and ribavirin, coinfections.
Inhibition of viral replication might also be achieved by:
 Antisense oligonucleotides that bind to specific sequences in the HCV
RNA.
 Ribozymes that catalyze cleavage of HCV RNA.
 Gene transfer of interfering proteins, that specifically interrupt virion
assembly in the hepatocyte.
HEPATITIS E
Hepatitis E virus was identified by Balayan et al. (1983) in human
fecal samples. In 1995 this virus has been classified within the Caliciviridae.
HEV is a non-enveloped, RNA virus with single-stranded genome
Epidemiology
Hepatitis E could be a sporadic disease or may evolve in outbreaks
with contaminated drinking water as the source of infection. The most
frequently involved regions are: India, China, Pakistan, Egypt, Algeria,
Sudan, Ethiopia, Mexico.
HEV infections generally occurred after the age of 16 years
Pathogenesis
Pathological changes in the liver include hepatocyte necrosis and
inflammatory cell infiltration
Clinical manifestations
Incubation period has an average of 40 days.
HEV produces an acute, self-limited disease without progression through
chronic hepatitis.
The prodromal symptoms include: malaise, anorexia, abdominal discomfort.
In women infected during the third trimester of pregnancy was noted a high
rate of fulminant disease and a 15-20% case-fatality rate.
Diagnosis
1. Detection of HEV-RNA by PCR
2. Detection of HEV-Ag by electronic immunomicroscopy
3. Detection of HEV-antibody:
- immunofluorescence inhibition
- ELISA (IgM, IgG)
- Immunotransfert (IgM, IgG)
GB VIRUS-C/HEPATITIS G VIRUS
Virology and tissue tropism
GBV-C/HGV is an enveloped RNA virus which belongs to the
Flaviviridae family. The envelope 2 (E2) region encodes a glycoprotein
which is located on the outer surface of the virion. At least 4 major
genotypes exists.
GBV-C/HGV may replicate in human peripheral blood mononuclear cells
and endotelial cells, in liver tissue, spleen and bone marrow.
Prevalence and transmission
There is a high prevalence of viremia in healthy persons in Europe and
North America (1-4%) and a higher prevalence rate in South America and
Africa (10-33%).
GBV-C/HGV may be transmitted via blood/blood products, by sexual
contacts, by close social contact, and from mother to infant.
Clinical features
The majority of adults have a transient infection with clearence of
viremia and development of E2 antibodies.
GBV-C/HGV viremia after vertical or perinatal transmission may persist for
at least 36 months.
Diagnostic
1. Reverse transcription polymerase chain reaction (RT-PCR) –
2. PCR is used to diagnose ongoing infections and does not give any
information on a resolved infection (may underestimate the
prevalence/occurrence of these infections).
3. EIA
4. In situ hybridization to detect GBV-C RNA
5. Immunofluorescence.
6. Liver biopsy
Infection with TT Virus
TTV is a unenveloped, single stranded, circular DNA virus that was
isolated from a Japanese patient with post-transfusion hepatitis of unknown
etiology.
Although TTV DNA titers have been shown to be closely correlated with
aminotransferase levels in the sera of some patients during post-transfusion
hepatitis, no clear association between TTV infection and human liver
disease has been establish at this time. TTV is a parenterally transmissible
virus
TTV DNA was detected in 10% of normal population in England, in 34% of
voluntary US blood-donors and in 47% of patients with acute and chronic
non A-G hepatitis. Very high prevalences of viremia (>50%), observed in
healthy populations in different countries, indicate that persistent infection is
common and that routes of transmission other than the parenteral route do
exist. However, the main mode of TTV transmission remains to be
determined.
RICKETTSIAL DISEASES
Egidia Miftode
The family Rickettsiaceae comprises a group of small, gram-negative,
obligate intracellular bacteria that normally infect animals and sometimes
cause disease in humans. Human rickettsial diseases are zoonoses.
The definitive hosts for most rickettsia are rodents or other mammals,
whereas vectors are ticks, mites, fleas or lice.
The rickettsial diseases that affect humans fall into four divisions:
1. the spotted fever group
2. the typhus fever group
3. the scrub typhus group
4. a group of conditions including:
- Q fever
- ehrlichiosis and
- acute febrile cerebro-vasculitis (with presumed but unproven
rickettsial etiology).
- Infections caused by Bartonella (formerly Rochalimaeae), organisms
which were formerly grouped with the rickettsiae, are described
separately.
Pathogenesis
Rickettsia are introduced into the human body in various ways:
 Directly by the bite of vectors (ticks or mites);
 Contamination of the skin by infective faeces from the vectors (fleas or
lice);
 Contamination of the oropharyngeal mucous membranes by inhalation of
aerosolized faeces from fleas or lice
Table 1. The major rickettsial diseases
Disease
Organism
Vector
Host
Geographic
distribution
Ticks
Rodents
Ticks
Rodents
-North Asian tick R. sibirica
typhus
-Queensland
tick R. australis
typhus
-Rickettsialpox
R. akari
Ticks
Rodents
N,
C., S
America
Africa, Asia,
Medit.basin
Asia
Ticks
Rodents,
marsupials
Mouse
-Oriental
spotted R. japonica
fever
Typhus group
-Epidemic typhus
R prowazeki
unknown unknown
Spotted fever group
-Rocky Mountain Rickettsia
spotted fever
rickettsii
-Boutonneuse fever R. conorii
-Murine typhus
Scrub typhus group
-Scrub typhus
Other genra
-Q fever
Mite
Body
louse
R. typhy
Rat flea
R. tsutsuga- Larvae
mushi
of mites
Coxiella
burnetii
-Human monocytic Ehrlichia
Ehrlichiosis
chafensis
-Human
granulo- Ehrlichia sp
cytic Ehrlichiosis
None
Humans
N Australia
Possibly
wordwide
Japan
Wordwide
rodents
wordwide
Rodents/bir Asia, Pacific
ds
island, Austr.
Cattle,
Worldwide
goats,sheep
Unknown
Possibly
worldwide
Amblyo
mma
american
um
ticks
unknown
ROCKY MOUNTAIN SPOTTED FEVER
Possibly
worldwide
RMSF is caused by Rickettsia rickettsii the vector for this pathogen
being the wood tick or the common dog tick.
The disease is found throughout the Western hemisphere.
Clinical features
Laboratory findings
 Blood: normal or low total white blood cell count with a market left shift,
thrombocytopenia, hyponatremia, elevated liver enzyme concentrations,
and increased level of bilirubin;
 CSF can be normal or there is a mild CSF pleocytosis (<200/mmc), CSF
protein concentration is elevated;
 Electroencephalography is usually abnormal, but nonfocal;
 Serologic confirmation: immunofluorescence, PCR, ELISA.
Treatment
- Tetracycline in children over 8 years of age (20-50 mg/kg/day) or in
adults (500 mg four times daily)
- Chloramphenicol (50 mg /kg/day in four doses) for children under 8
years of age
- Ciprofloxacin
OTHER SPOTTED FEVER GROUP RICKETTSIOSES
These infections include: boutonneuse fever (Mediterranean spotted
fever), East African tick typhus and South African tick-bite fever, all caused
by R. conorii; North Asian tick typhys (by R sibirica), Queensland tick
typhus (R. australis) and Oriental spotted fever (R. japonica).
Infections caused by R. conorii
Laboratory findings
- normal/low white blood count (with granulocytosis in elderly and
lymphocytosis in young)
- thrombocytopenia
- abnormal liver function tests
- CSF: lymphocytic pleocytosis, hyperglycorrachia
- Histology: cerebral/cerebellar perivascular mononuclear infiltrates
- Identification of ricketsia by immunofluorescence, PCR
Treatment:
EPIDEMIC TYPHUS
Laboratory findings
- leucocytosis with neutrophilia
- abnormal level ofliver enzymes
- CSF pleocytosis
Clinical manifestations of epidemic typhus and the pathology of typhus in
the CNS resemble that of RMSF.
Treatment: tetracycline or chloramphenicol need to be continued for 2 to 3
days after defervescence.
If a recurrent illness occurs after early treatment a second course of therapy
are needed.
Mortality rate ranges from 15 - 20% to as high as 60% in debilitated
patients in severe epidemics.
BRILL-ZINSSER DISEASE
This is a late recurrence of epidemic typhus associated with a wanning
immunity to a past infection to R. prowazekii.
Clinical manifestations are less prominent that in the primary disease: onset
with fever, headache, and rash; milder neurological complaints.
Differentiation of Brill-Zinsser disease from primary epidemic typhus can
be made by: antibody analysis (IgM antibodies are present in primary
disease and IgG in Brill-Zinsser disease), CSF analysis (usually normal in
Brill-Zinsser disease).
The treatment is the same as in primary typhus.
Q FEVER
Coxiella burnetti is the etiologic agent of Q fever. It is most often a
non specific, self limited febrile illness, but it may present as: atypical
pneumonia, endocarditis, granulomatous hepatitis, osteomyelitis or a variety
of neurological syndromes.
Human acquires C.burnetti from infected animals or animal products,
probably by direct inhalation.
Clinical features
Incubation is about 20 days.
The patient develops fever, chills, myalgias, headache, fatigue.
Laboratory features
 There is a normal WBC count. Liver function tests are normal. CSF is
normal. CT and MRI scans of the head in patients with Q fever
meningoencephalitis have been normal.
 Specific immunofluorescence in tissues or serology can establish this
diagnosis.
 In chronic Q fever, granulomatous inflammation occurs. Focal
accumulations of mononuclear cells, giant cells and neutrophils with a
central clearing have been described on the liver and bone marrow.
Treatment
Acute Q fever is typically a self-limited illness, but, for Q fever with
pneumonia, hepatitis or CNS disease are recommended:
 tetracycline or chloramphenicol for 2 weeks
 erythromicin, trimetoprim-sulfametoxazole, and rifampin are also
effective.
EHRLICHIOSIS
The genus Ehrlichia includes species of intraleukocytic rikettsiae
which are primarily animal pathogens; some also cause human diseases.
There are two leading ehrlichial diseases:
1. Human monocytic ehrlichiosis (HME) is caused by E. chaffensis,
which infects mononuclear leukocytis and causes a febrile illness
resembling RMSF: fever, chills, myalgias, headache and a history of a
tick bite.
2. Human granulocytic ehrlichiosis (HGE) is caused by an as yet
unnamed species that causes high fever, chills, headache, myalgias.
Laboratory features
Treatment: atients with HME or HGE usually respond well to tetracycline
or doxycycline given in the same doses used for RMSF.
Human disease caused by Bartonella species
I. Bacillary angiomatosis (BA) and bacillary peliosis hepatis
A. Bacillary angiomatosis (BA)
Cutaneous lesions of BA are the most frequently identified form of BA, but
these vascular proliferative lesions also occur in other organs including:
bone, brain, lymph nodes, gastrointestinal and respiratory tracts.
B. Bacillary peliosis hepatis (BP)
Treatment
The drugs of first choice in the treatment of BA or BP are:
1. erythromycin or
2. doxycycline;
3. rifampin may have clinical efficacy as adjunctive therapy in patients who
have CNS disease.
II. CAT scratch diseases (CSD)
CSD occurs almost exclusively in immunocompetent individuals.
Before B. henselae was documented as the causative agent, diagnosis of
CSD was made when three of four clinical criteria were met:
1) a history of cat contact and the presence of a primary inoculation
site,
2) development of lymphadenopathy approximately 2 weeks after
the primary inoculations,
3) a positive CSD skin test result and
4) histopathological findings characteristic of CSD in biopsied
lymph node tissue.
Treatment
Treatment of immunocompetent patients with uncomplicated CSD is
Azithromycin 500 mg p.o. x 1, then 250 mg/d x 4 (children 10 mg/kgc).
In
immunocompromised
patients,
the
treatment
is
Clarithromycin/Azithromycin,
Ciprofloxacin,
Erythromycin
or
Doxycyclin.
Relapsing Bacteremia and Endocarditis
Bartonella bacteremia and endocarditis have been reported to occur in
both immunocompromised and immunocompetent hosts in the absence or
presence of focal Bartonella infection.
TETANUS
Egidia Miftode
Tetanus is a disease of the nervous system characterized by persistent tonic
spasm, with violent brief exacerbations. The onset is acute and the spasm
almost always commences in the muscles of the neck and jaw, causing
trismus, and involves the muscles of the trunk more than those of the limbs.
Microbiology and Pathophysiology
Clostridium tetani is an obligate anaerobic rod
Two exotoxins, tetanospasmin and tetanolysin, are released by some strains
of the organism while it is actively dividing.
Pathophysiology
Tetanospasmin act at three levels: central motor control, autonomic function
and neuromuscular junction.
The 150-kD peptide tetanospasmin inhibits release of inhibitory
neurotransmitters g-aminobutyric acid (GABA) and glycine. The resulting
imbalance in the central nervous system predisposes the patient to reflex
spasms.
The process involves three steps:
1. binding to the presynaptic membrane,
2. translation of the toxin to the active site
3. induction of paralysis
Clinical manifestations
Tetanus can occur in patients with gangrene, burns, decubitus ulcers, septic
abortions, intramuscular injections, dental infections, penetrating eye
injuries, and umbilical stump infections.
The incubation period range from 3 to 30 days (11 days).
The disease has four forms:
 Generalized tetanus.



a. The most commonly presenting sign is trismus
b. risus
c. the typical generalized spasm
Other positions are orthotonus and pleurosthotonus
d. Generalized spasms can involve abdominal, diaphragmatic, and
laryngeal muscles,
e. Autonomic dysfunction is the leading cause of death in tetanus
patients.
Localized tetanus
Cephalic tetanus:
-Facial paresis is usually present
-Ophtalmoplegic tetanus when there is a paresis of the III rd, IV th and
VI th cranial nerves.
Neonatal tetanus
Rating scales for tetanus severity
Table 1. Veronesi scale
Veronesi scale
Incubation period<7 days
Period of onset*<48 hours
High-risk portal of entry (surgical, abortion,etc)
Generalized tetanus
Core temperature above 40 C
Tachycardia (heart rate >120 in adults, >150 in neonates)
Score one point for each:
*period from the first symptom to the first reflex spasm.
Table 2. Severity and prognosis
Score* Severity
Mortality
0-1
Mild
<10%
2-3
Moderate
10-20%
4
Severe
20-40%
5-6
Very severe
>50%
*Cephalic tetanus are always scored as sever or very severe
Neonatal tetanus are always scored as very severe.
Table 3. Modified Ablett scale of severity
Group
Mild
Moderate
Symptoms
 Mild rigidity and spasms
 More intense spasms and rigidity, accompanied by disphagia
Severe
 Marked rigidity, frequent generalized spasms, disphagia,
respiratory compromise/apnea
Diagnosis
The average annual incidence of tetanus in the world is about 1
million cases. Due to its rarity, the initial clinical symptoms may be missed
and the diagnosis may not be made until a generalized tetanic spasm occurs.
Diagnosis is established in the presence of a portal of entry, trismus, tonic
contraction, sudden spasms and a descending manner of contraction
progression.
Differential diagnosis
 Trismus in tetanus must be distinguished by: alveolar ridge abscess,
temporomandibular joint arthritis, tonsillitis;
 Spasms and rigidity must be distinguished by: generalized convulsive
status epilepticus, strychnine intoxication, tetany precipitated by
hypocalcemia, meningitis, encephalitis, brain hemorrhage;
 Local tetanus-with transverse myelitis.
Complications
1.
2.
3.
4.
5.
Respiratory dysfunction:
Cardiovascular complications: cardiomiopathy
Urinary tract infections and acute renal failure caused by rhabdomyolysis
Vertebral compression, fractures, hyperostoses
CNS and systemic consequences of hypoxia.
Management
Management of tetanus involves:
A. Neutralizing wound and circulating toxin,
B. Eradicating the source of toxin
C. Standard supportive care
D. Treating related complications
E. Treatment of the portal of entry
Mortality
Even with today's advanced level of care, during 1995-1997 the case fatality
ratio of tetanus was 11%.
LEPTOSPIROSIS
Egidia Miftode
Leptospirosis is a zoonotic disease that affects human on all
continents, in both urban and rural areas. Clinical presentation of this febrile
illness may include in severe forms liver involvement, renal failure,
meningitis, myocarditis, hemorrhagic pneumonitis, and hemodynamic
collapse.
The first description of the leptospirosis was done in 1886 by Weil.
Etiology
Etiologic agent is a spirochete of the genus Leptospira. Leptospires are
aerobic bacteria that appear as flexible, thin and motile, helicoidal rod (6-20
microm in lenght and 0,1-0,2 microm in diameter).
Epidemiology
The reservoir of Leptospira is represented by wild, domestic or peridomestic
animals and the spirochetes are excreted in urine, placenta or amniotic fluid
At risk to acquire Leptospira are occupational activities such as abattoir
workers, veterinarians, rice farmers, livestock workers, or recreational
activities (swimming in lakes etc).
Table 1. Serovars of Leptospira spp and the potential animal reservoir
Serovars
L. grippotyphosa and pomona
L. canicola, icterohemorrhagiae, pomona
L. australis, bataviae, hardjo, gryppotyphosa,
icterohemorrhagiae and pomona
L. pomona
Potential animal
reservoir
cattle and sheep
Pig
Rodents
Horse
Pathogenesis
Leptospira enter the body through skin lesions, water logged skin,
mucouse membrane or conjunctivae, aerosol inhalation.
Septicemic phase.
Leptospira are cleared from the circulation by the reticuloendothelial system.
Circulating antibodies are involved in the development of aseptic meningitis,
uveitis, iritis, iridocyclitis chorioretinitis.
Other mechanisms of leptospiral pathogenesis have been suggested to
Clinical manifestations
The disease may evolve as a subclinical illness, self-limited disease,
or as a severe disease.
Incubation period is 7-14 days (range 5-30 days).
The evolution of leptospirosis is biphasic:
1. The acute septicemic phase:
- the onset is abrupt with high fever, chills, headache, myalgia,
conjunctival suffusion, back pain, abdominal pain, nausea, vomiting,
cutaneous eruption (maculopapular/macular/urticarial rash), cough;
- physical examination reveals hepatomegaly, splenomegaly, muscle
tenderness;
2. Immune phase:
- lasts from 4 to 30 days
- recurrence of fever
- meningeal symptoms and signs
- rash, uveitis.
In severe form of the disease (Weil’s syndrome) symptoms and signs of the
initial phase progress to a life-threatening illness
 liver involvement);
 renal failure;
 circulatory collapse,;
 severe hemorrhagic pneumonitis
The convalescent period may have duration of several months.
Laboratory features
Nonspecific features
- Leukocytosis with neutrophilia, the sedimentation rate is elevated
- Thrombocytopenia
- Proteinuria, pyuria, microscopic hematuria, increased blood urea nitrogen
- Increased bilirubinemia and liver enzymes, hypoprothrombinemia
- CSF examination during the immune phase reveals pleocytosis
(<500/mmc), and elevated proteinorrachia;
- Chest x-ray abnormalities (opacities, pleural effusions)
- Electrocardiographic abnormalities even without evidence of heart
disease (inverted T waves, tachycardia, small QRS complexes).
Specific diagnosis
1. Isolation of leptospires
2. Direct detection using:
3. Seroconversion)
4. IgM ELISA assay).
5. The indirect hemagglutination test.
Differential diagnosis
A febrile illness associated with myalgia and headache (with or
without liver/renal involvement) must be differentiated from different
entities such as: meningitis, encephalitis, nephritis, influenza, hepatitis,
typhoid fever, septicemia, brucellosis, relapsing fever, malaria, toxic shock
syndrome etc.
Treatment
1. Supportive management: measures to manage the fever, pain, renal
failure, liver injury, fluid and electrolyte imbalances, hypotension;
2. Antibiotics:
- Penicillin i.v. for severe and late disease
- Ampicillin, amoxicillin, tetracycline orally-for mild to moderately severe
disease.
Prevention includes:
- maintaining hygiene,
- protective clothing
- immunization of animals with leptospira vaccine.
ANTHRAX
Egidia Miftode, Luminita Sabadis
The disease anthrax is produced by the sporulating bacterium Bacillus
anthracis, found in the soil in many parts of the world. The spores from
infected animal carcasses can contaminate the pasture for many decades and
lead to sporadic outbreaks.
Epidemiology
The disease is naturally one of animals, particularly herbivores, who
ingest spores on the grass and from the environment. Until the advent of an
effective vaccine, the disease was common in cattle, sheep, goats, horses and
pigs, but is now far rarer.
Etiology
C. anthracis is a large (1x3mm), Gram-positive, aerobic, rod-shaped, nonmotile, sporulating bacillus. The spores are central and thermostable.
Like many other members of the genus Bacillus, the spores are
remarkably resistant and long-lived in the environment.
Pathogenesis
Naturally acquired anthrax in humans is generally due to contact with
infected animals or their carcasses. Although fatal human disease may occur,
B. anthracis is not highly virulent, and in spite of its previous prevalence in
the environment and in animals, human infections were not common and are
now rare.
Three toxins are produced by B.anthracis all thermolabile proteins;
Clinical manifestations
 Cutaneous form is the commonest form of the disease, characteristic
black, painless eschar with surrounding oedema. In most cases cutaneous
anthrax is self-limited, the lesion resolving within 10 days.
In some cases systemic anthrax may develop (malignant edema
 Inhalation anthrax.
 Gastro-intestinal anthrax.
 Meningitis
Laboratory findings
 Gram stain examination of vesicle fluid, CSF, blood
 Culture of vesicle fluid, CSF, blood
 Immunofluorescence
 in those with negative blood cultures, PCR, immunohistochemical
staining or a four-fold rise in IgG can confirm anthrax.
 Electrophoretic immuno-transblot test
 Termoprecipitation reaction (Ascoli-Cornelson-Toma) (formation of an
opalescent ring at the interface between the mixture containing crust and
anti-anthrax serum)
 abnormal radiographs/mediastinal widening in inhalation anthrax
 total WBC normal or only slightly elevated
 increased % of neutrophils or band forms
Differential diagnosis
- Cutaneous anthrax: Staphylococcal lesions, cutaneous leishmaniasis,
herpes zoster, herpes simplex lesion, erysipelas, inflammatory edema of
the face;
- Gastrointestinal anthrax: food poisoning, acute abdomen, shigellosis,
yersiniosis
- Inhalation anthrax: other pneumopathies
- Anthrax meningitis: Listeria meningitis, tuberculous meningitis,
meningeal hemorrhage.
Treatment
Most strains of B. anthracis are susceptible to a wide range of
antibacterial agents. The organism was traditionally highly susceptible to
penicillins and, until recently, these were the drug of choise.
- the first choice is now generally a fluoroquinolone, (ciprofloxacin), although other FQ are probably also
effective.
Therapy of current inhalation cases: combination intravenous treatment with
Ciprofloxacin and Rifampicin plus Clindamycin/ Vancomycin/ Penicillin.
Current dosages recommended:
Penicillin G (procaine) – 600.000 U im. every 6 or 8 hours
Penicillin V – 500 mg orally 3 times a day
Doxycycline – 100 mg orally 3 times a day
Ciprofloxacin – 500 mg twice a day
Prevention
Vaccination is not a viable option currently for large numbers of
people and supplies are not plentiful.
BRUCELLOSIS
Dr. Egidia Miftode, Dr. Daniela Leca
Brucellosis is an infectious disease characterized by an acute febrile
stage with few or now localizing signs and by a chronic stage with relapses
of fever, weakness, sweats and vague aches and pains.
The pathogen
Brucella are smal, gram-negative coccobacilli that are nonmotile and
do not form spores. The major cell wall antigen of the brucellae is endotoxic
lipopolysaccharide (LPS).
Epidemiology
Brucellosis is a zoonosis and virtually derives directly or indirectly
from animal exposure.
Pathogenesis
Brucella spp. usually gain entry to the body through abrasions in the skin in
the course handling infected animals or their carcasses. Accidental
innoculation of the conjunctival sac of the eyes is another route of infection
that is especially common among veterinarians using live brucella vaccines.
Infection via the respiratory tract is a special risk for abattoir workers
engaged in the slaugther of infected animals. Brucella melitensis is generally
transmited via ingestion of unpasteurized dairy products.. Bacteria entering
lymphatics and hematogenous dissemination is then followed by localization
of bacteria in organs rich in elements of the reticuloendothelia system
(RES), including liver, spleen, lymph nodes, bone marrow, and kidneys.
Host immunity
Clinical manifestations
The incubation time from exposure to the onset of symptoms is
generally 2-3 weeks (range:2-8 weeks)
Brucellosis is a systemic infection that can involve many organs and tissues.
Symptoms are nonspecific:
 Fever, sweats, malaise, anorexia, headache, and back pains. An
“undulant” fever pattern is observed if patients go untreated for long
periods of time. Some patients complain of sweat and a peculiar taste in
their mouth.
 Depression is common, and physical abnormalities may be few.
 Mild lymphadenopathy occurs in 10-20 percent, and splenomegaly in
20-30 percent of cases.
 Hepatomegaly is reported in 20-60 percent.
Complications
 Gastrointestinal tract..






Osteoarticular manifestations.
Neurologic
Respiratory symptoms
Genitourinary complications.
The hematologic manifestations:.
Cutaneous manifestations:.
Evolution
Brucellosis may evolve as:
1. Acute (typical form),
2. Subacute disease
3. Chronic brucellosis Symptoms in such patients resemble the “chronic
fatigue syndrome”.
Diagnosis
Because the symptoms of brucellosis are nonspecific, it is imperative that
the clinician obtain a detailed history, including occupation, exposure to
animals, travel to enzootic areas, and ingestion of high-risk foods (e.g.
unpasteurized dairy products).
Laboratory findings
 White blood cell (WBC) count is usually normal or depressed. Anemia,
leukopenia and thrombocytopenia are common.
 Diagnosis of brucellosis is made with certainty when brucellae are
recovered from blood, bone marrow, or other tissue.
 The Castaneda biphasic technique, lysis-concentration techniques,
polymerase chain reaction (PCR) are rapid diagnostic tests.
 Serological tests are very useful for diagnosis:
- Agglutination assay Rose-Bengal test is easily and rapidly performed
(used when there are acute manifestations).
- Coombs test and blocking antibodies are recommended in the diagnosis
of chronic brucellosis
- Immunofluorescence
- ELISA
- Counterimmunoelectrophoresis
Differential diagnosis
Brucellosis may be distinguished among many common illnesses that may
mimic the most frequent presentations: infectious mononucleosis,
septicemia, toxoplasmosis, tuberculosis, hepatitis, systemic lupus
erythematosus, thyphoid fever.
Treatment
 Doxycycline 100 mg orally bid (or tetracycline 500 mg orally qid) for 3
to 6 weeks plus streptomycin 1 g IM q 12 to 24 h for 14 days;
 Doxycycline 100 mg orally bid + Rifampicin 600-900 mg/day;
 In children < 8 years : thrimethoprim/sulphamethoxazol and either IM
streptomycin or oral rifampin for 3 to 5 weeks;
 Ciprofloxacin 1 g/day and rifampicin 600 mg/day for 30 days
Prevention
Live-attenuated brucella vaccines were used for human immunization in
some countries; however, they were restricted to high-risk personnel in areas
of high endemicity.
RABIES
Egidia Miftode
An important histopathologic observation was made by Negri in 1903, when
he discovered cytoplasmic inclusion bodies (“Negri bodies”) in the neuronal
cells of the brains of rabid dogs.
In 1912, Babes published a compendium of cases that defined the natural
history and clinical findings of human rabies, which remains one of the most
complete documents about this disease.
Etiology
Rabies virus belongs to the Rhabdoviridae family which includes
pathogens that infect a wide variety of mammals, fish, birds and plants.
The Rhabdoviridae family consists of two genera: Lyssavirus and
Vesiculovirus..
Pathogenesis
Most wild mammals can become infected with rabies, but
susceptibility varies according with species. Foxes, wolves, coyotes, and
jakals are the most susceptible; dogs, bats, raccoons, mangooses and
monkeys are intermediate; opossums are quite resistant.
There are two routes of rabies virus acquisition: most cases of human rabies
occur following animal bites, and nonbite routes of transmission include
aerosols, and person-to-person transmission following corneal transplants.
Clinical manifestations
 Incubation period for rabies is very variable – between days and years
(usually 30-90 days).
 Prodrome and early clinical symptoms have a duration of 2-10 days:
-paresthesia/pain at site of bite,
-malaise, fever, myalgias, headache,
-nausea, vomiting, abdominal pain, diarrhea
 Acute neurologic disease (2-7 days) can be classified in two forms:
1. “Furious rabies”(80%):
2. “Paralytic rabies” (20%):
 Coma can develop immediately after the onset of disease or it can occur
up to 14 days after the onset. Death occurrs an average of 18 days after
the onset.
Treatment
No specific therapy exists for rabies virus infections in humans or animals.
Prevention
The principles used to control rabies in domestic animals were restriction of
movement and mandatory vaccination. Since the early 1980s, orally
absorbed vaccines, distributed by hand and by aircraft, have controlled
rabies in foxes.
A. Pre-exposure prophylaxis
A pre-exposure regimen includes the administration of vaccine
intramuscularly over 28 days on days 0, 7, 21, and 28.
Post-exposure prophylaxis
The combination of local wound treatment, passive immunization, and
vaccination is uniformly effective.
Table 1. Post-exposure prophylaxis
Circumstances
1.Person not previously vaccinated
The animal was not captured
The animal is dead
Animal is alive and could be
observed
2. Person previously vaccinated
Management
 Immediate cleansing with soap
and water
 Rabies immune globulin (RIG):
20mg/kg of body weight
 Vaccine: 1 ml of vaccine i.m. in
the deltoid area on days 0, 3, 7, 14,
and 28.
 RIG+vaccine
 Start the prophylaxis and stop in
function of laboratory exam (direct
fluorescent antibody testing of the
animal brain)
 Start prophylaxis* and stopped if
the animal doesn’t present any
signs on days 0, 7, 14
 Local wound cleasing
 RIG should not be given
 Vaccine on days 0 and 3
*Type of exposure:
 Person licked on a normal skin: no prophylaxis necessary
 Superficial wounds: vaccination
 Bites or contamination with saliva of an open wound/mucous membrane:
RIG and vaccine.
MALARIA
Egidia Miftode
The four most common species that infect humans are:
1. Plasmodium vivax – may account for 80% of of the infections
2. Plasmodium falciparum - generally confined to the tropics
3. Plasmodium malariae – is sporadically distributed
4. Plasmodium ovale – is confined mainly to central West Africa.
The number of imported malaria cases increases. Infected mosquitoes can
reach different areas by airplanes.
Life cycle and morphology
The vector for malaria is the female anopheline mosquito.
 With the vector blood meal, sporozoites contained in the salivary glands
are discharged into the bite wound;
 Sporozoites are carried to the liver (via the blood), where they penetrate
hepatocytes, grow and initiate the preerythrocytic (primary
exoerythrocytic) cycle;
 The sporozoites begin dividing; this schizogony results in large numbers
of exoerythrocytic merozoites;
 After the merozoites leave the liver, they invade the red blood cells
(RBC), thus initiating the erythrocytic cycle;
 A dormant (secondary) schizogony may remain quiscent in the liver
resulting hypnozoites; this stage occurs only in P. vivax and P. ovale
organisms;
 Within the RBC, the merozoite (or young trophozoite) is vacuolated,
ring shaped, ameboid and uninucleate; malarial pigment is present inside
the RBC;
 Once the nucleus begin to divide, the trophozoite is called a developing
schizont;
 The mature schizont contains merozoites (whose number depend on the
species) which will be released into the blood stream;
 One part of the merozoites are destroyed by the immune system, and
others invade RBCs, in which initiate a new cycle of erythrocytic
schizogony;
 Some of the merozoites do not become schizonts, but, develop into the
male and female gametocytes;
 Gametocytes, ingested by mosquito, mature into gametes (in the
mosquito gut)
 The male microgametes penetrate the female microgametes resulting a
zygote;
 Zygote becomes motile and is called ookinete which secretes a thin wall
and grows into the oocyst;
 Within a few days to 2 weeks, the oocyst matures, with the formation of
hundreds of sporozoites; some of them reach the salivary glands.
Physiopathology
Mechanisms of anemia are:
 Direct RBCs lysis which occurs during the life cycle of the parasite
 Splenic removal of RBCs
 Autoimmune lysis of RBCs
 Decreased RBCs production from bone marrow
 Increased fragility of RBCs
Immunity
Some genetic alterations in the RBCs confer natural immunity to
malaria:
Infants are relatively immune to malarial infection during the first
year of life (presence of a large percentage of HbF).
Clinical manifestations
Incubation period varies between 8 to 40 days, depending on species (table
1). Sometimes may be prolonged for months to years.
- Classic paroxysm: cold stage, fever, and sweats; fever may be absent in
the early stages of the infection. Paroxysm begins with the cold stage and
rigors (lasting 1 to 2 hours) followed by high fever. The last hours body
temperature decreased to normal or subnormal. Periodicity of the cycle
may not be established during the early stages.
- Anemia
- Splenomegaly
- Other symptoms: lethargy, vomiting, diarrhea, headache.
Complications
1. Disseminated intravascular coagulation 2. Cerebral malaria;
Table 1. Clinical characteristics of different types of malaria
Characteristic
P. vivax
P. ovale
Incubation
period (days)
Prodromal
symptoms
-Severity
-Initial fever
pattern
10-17
10-17
P. malariae P.
falciparum
18-40
8-11
++
Irregular,
quotidian
+
Irregular,
quotidian
++
Regular, 72
h
Periodicity
Initial paroxysm
-Severity
-Avg duration
Duration of
untreated
primary attack
(wk)
Duration of
untreated inf
Anemia
CNS
involvement
Nephrotic
syndrome
Relapses
48
Moderate to
severe
10
3-8+
48
Mild
10
2-3
72
Moderate to
severe
Severe
11
16-36
3-24
2-3
5-7 yr
12 mo
20 yr
6-17 mo
++
+
+
+/-
++
+
++++
++++
+/-
+
++++
+
Yes
Possible, but
usually
spontaneous
recovery
No, but
long-term
recrudescen
ces are
recognized
No longterm relapses
3. Bilious remittent fever
4. Algid malaria
5. Blackwater fever –
Acute renal failure –
+
Continuous
remittent,
quotidian
36-48
Laboratory diagnosis
 Hemoleucograme shows: anemia, leukopenia/occasional leukocytosis,
and less frequently can be seen eosinophilia and thrombocytopenia.
 Microbiological exams:
1. Thick and thin blood smears –
2. The stain of choice is Giemsa
3. Another method uses fluorescent dye benzothiocarboxypurine P.
falciparum antigen detection
4. Dot blot assay
5. PCR amplification: high sensitivity, and rapidity.
Diagnosis
 Malaria is associated with patients having a history of travel within an
endemic area.
 Recent transfusion or intravenous drug addiction are, also, associated
with this disease
 Fever, chills, splenomegaly, anemia
 Positive thick and thin blood smears
Differential diagnosis
Malaria can mimic other diseases such as gastroenteritis, pneumonia,
hepatitis, meningitis, sepsis, encephalitis.
Treatment
Antimalarial drugs are classified by the stage of malaria against which they
are effective:
A. Erythrocytic cycle (schizonts): sulfonamides, sulfones, proguanil,
pyrimethamine, colchicine, amodiachine, quinine, quinidine, cloroquine
mefloquine, artemisinine;
B. Erythrocytic cycle (gametocytes): proguanil, primaquine
C. Exoerythrocytic cycle: primaquine, pyrimethamine.
Prophylaxis
It is indicated to persons who are going into areas where malaria is endemic.
For areas free of chloroquine resistant P. falciparum: chloroquine 500mg
po/week starting 1-2 wks before travel, during travel, and 4 wks post-travel;
for children-5mg/kg/wk once

-
For areas with chloroquine resistant P. falciparum:
mefloquine 250mg po/wk, the same schema or
doxycycline 100 mg po daily for adults and children>12 years
atovaquone 250mg – proguanil100mg
Treatment
 Cloroquine is the treatment of choice for P. vivax, P. ovale, P. malariae
and uncomplicated falciparum malaria (cloroquine sensitive), 1g po
(=600mg base), 0,5g at 12 h, 24 and 36 h + primaquine 26mg (15mg
base) x 14 days
 Treatment of cloroquine - resistant P. falciparum:
- oral: Quinine sulfate 600mg tid/day + doxicicline 100mg bid
x7days/pyrimethamine-sulfadoxine 3tb once on last day of quinine –
sulfate
- parenteral: Quinine gluconate 10 mg/kg iv over 1-2 h, then
0,02mg/kg/min until start of oral therapy (monitor EKG 72h) (drug used
in US)
-Quinine dihydrochloride 20mg/kg loading dose in 10-mg/kg
5% glucose over 4 h followed by 10 mg/kg over 2-4 h q8h (max
1800mg/day) until start of oral therapy.
TOXOPLASMOSIS
Dr. Daniela Leca
Toxoplasmosis describes the clinical or pathological disease caused
by T. gondii and is distinct from toxoplasma infection, which is
asymptomatic in the vast majority of immunocompetent patients. Chronic
(latent) infection ensues in all infected people after resolution of the acute
phase due to asymptomatic persistence of T. gondii in the cyst form.
Reactivation of the chronic infection with resultant toxoplasmosis occurs
almost exclusively in patients who are severely immunocompromised.
Etiology
Toxoplasma gondii is worldwide distributed. Cats (which maintain an
enteroepithelial sexual cycle of T. gondii) are the definitive hosts; all other
infected animals are secondary hosts (and have an extraintestinal asexual
cycle). Three life forms of T. gondii occur:
1. The oocyst
2. The tachyzoite (the asexual invasive form), is seen during the acute
infection;.
3. The tissue cyst contains bradyzoites and is able to persist in tissues
during the chronic or late phase of the infection.
Epidemiology
Toxoplasma infection is a worldwide zoonosis. The organism infects
herbivorous, omnivorous, and carnivorous animals. The prevalence of tissue
cysts in meat used for human consumption is high. Excretion of oocysts has
been reported in approximately 1 percent of cats.
Pathogenesis and Immunity
Pathology
The histopathology changes in toxoplasmic lymphadenitis are frequently
distinctive and often diagnostic. There is a typical triad of findings: a
reactive follicular hyperplasia, irregular clusters of epitheloid histiocytes and
focal distension of sinuses with monocytoid cells.
 Toxoplasma encephalitis (TE) in AIDS patients typically produces brain
abcesses with three characteristics zones. The central area is avascular.
Surrounding this is an intermediate hyperemic area with a prominent
inflammatory infiltrate and perivascular cuffing by lymphocites, plasma
cells, and macrophages. Edema, vasculitis, hemorrhage, and cerebral
infarction may also be observed. Diffuse TE (DTE) is characterized by
widespread microglial nodules without abcesses in the gray matter of the
cerebellum, and brain stem.
 Pulmonary toxoplasmosis may appear in the form of interstitial
pneumonitis, necrotizing pneumonitis, and/or consolidation.
 Chorioretinitis in AIDS patients - segmental panophtalmitis and areas of
coagulative necrosis.
 Myocarditis- focal necrosis with edema and an inflammatory infiltrate.
 Myositis- necrotic muscle fibers with a variable inflammatory reaction.
 Extensive involvement of the gastrointestinal tract may occur with
variation in the inflammatory response, hemmorhagic gastritis and colitis.
Other organs reported to be involved during toxoplasmosis include the
liver, pancres, seminiferous tubules, prostate, adrenals, kidneys, and bone
marrow.
Clinical manifestations
Toxoplasmosis is conveniently considered in four categories: (1) acquired in
the immunocompetent patient, (2) acquired or reactivated in the
immunodeficient patient, (3) ocular, and (4) congenital.
1. Acute acquired toxoplasma infection in the immunocompetent patient
2. Acute Toxoplasmosis in the immunodeficient host
3. Ocular toxoplasmosis in immunocompetent patients
4. Congenital toxoplasmosis
Diagnosis
Acute infection is diagnosed by:
 the isolation of Toxoplasma from blood or body fluids by inoculation of
specimens into the peritoneal cavities of mice;
 demonstration of trophozoites in histologic sections of tissue or in
cytologic preparations of body fluids;
 demonstration of characteristic lymph nodes histology;
 demonstration of Toxoplasma tissue cysts in the placenta, fetus, or
neonate.
 PCR amplification for detection of T. gondii DNA in body fluids and
tissues .
 demonstration of antigen in body fluids by the ELISA technique .
 Serologic tests for demonstration of antibody:
- Sabin-Feldman dye test, ELISA, the IFA test,
Differential diagnosis
Treatment
Chemotherapy of infection with Toxoplasma in pregnant women
 Chemotherapy through the end of the 15th week of pregnancy: spiramycin
3.0 g (9 mIU) per day in 3 divided doses
 Chemotherapy from the 16th week of pregnancy onwards - independent
of prior treatment with spiramycin, the following therapy should be
initiated for four weeks:
- Sulfadiazine: 50 mg/kg/d up to 4 g PO in 4 doses
- Pyrimethamine: 50 mg on the first day, 25 mg on the consecutive days,
PO o.d.
- Folinic acid: 10 to 15 mg/d, PO (prevention of inhibition of
haemopoiesis)
- For monitoring haemopoiesis, weekly blood counts are mandatory. In
case of allergic reactions, sulfadiazine administration should be replaced
by spyramicin.
Chemotherapy in neonates and infants:
First, administer for four weeks:
Sulfadiaazine: 50-100 mg/kg/d PO in 4 divided doses
Pyrimethamine: 2 mg/kg on the first day, 1 mg/kg on the consecutive days
PO, o.d.
Folinic acid: 5 mg twice a week
Corticosteroides: (in the presence of symptoms involving the CNS or the
eyes): 1-2 mg/kg/d PO, only until remission of symptoms
Thereafter, again for four weeks:
Spyramicin: 100 mg/kg/d (300.000 IU/d) in two divided doses
These therapy cycles, lasting four weeks each, have to be carried out in the
alternation for one year. Monitoring haemopoiesis are required every week.
Table 1. Guidelines for acute primary therapy of toxoplasmic encephalitis
in patients with AIDS
Drug
Dosage schedule
Standard regimens
Pyrimethamine
Folinic acid (leucovorin)
plus
Sulfadiazine
or
Clindamycin
Oral 200 mg loading dose then 50 to 75 mg daily
Oral, IV, or IM 10- 20 mg daily (up to 50 mg
daily)
Oral 1- 1,5 g every 6 hours
Oral or IV 600 mg q6h (up to IV 1200 mg q6h)
Possible alternative regimens
a. Trimethoprim/
sulfamethoxazole
b. Pyrimethamine and
folinic acid
c. Clarithromicyn
d. Azythromycin
e. Atovaquone
f. Dapsone
Oral or IV 5 mg (trimethoprim component)/ kg q6h
As in standard regimens plus one of the following
Oral 1 g q12h
Oral 1200- 1500 mg daily
Oral 750 mg q6h
0ral 100 mg daily
HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Egidia Miftode
Acquired immunodeficiency syndrome was first reported in 1981 in
the Morbidity and Mortality Weekly Report under the title “ Pneumocystis
pneumonia – Los Angeles”. In 20 years, the AIDS epidemic has grown from
a series of small outbreaks in several risk groups throughout the United
States and western Europe into a global public health calamity. Tremendous
advances have been made in understanding the molecular mechanisms, in
achieving of antiretroviral therapy and blood-supply safety.
Although the disease was first encountered in homosexual men andinjectiondrug users, the risk groups soon included transfusion recipients,
infants,female sexual contact of infected men, prisoners, Haitians and
Africans.
Structure of the HIV-1 virion
Table 1. Genes and gene products of HIV 1 and 2
Genes
Gag
Pol
Env
Vif
Vpr
Tat
Rev
Vpu
Nef
vpx
Proteins
p17, p24, p1, p2, p6, p7.
Protease, RT, integrase
gp120, gp41
virion infectivity protein
viral protein R
transactivator of of transcription
regulator of expression of virion protein
viral protein U (HIV-1 only)
negative regulatory factory
virion protein X (HIV-2 only).
The life cycle of HIV-1
The major steps in the HIV life are:
I.
Afferent functions
1. Binding and entry.
2. Reverse transcription, nuclear import, and integration of viral DNA

II.
Efferent functions
 Viral transcription (production of mRNA
 Production of viral regulatory factors
 Virion assembly.
 Virus budding and release
Pathogenesis of HIV disease
The main target of HIV infection is the CD4-positive-lymphocyte
population, although infection of tymocytes, macrophages and dendritic
cells, can occur.
Additional co-receptor which are used for virus entry into CD4-T cells are:
1. CC-chemokine receptor CCR5
2. CXC-chemokine receptor (CXCR4)-.








Acute HIV infection
Viral load levels in the blood rise;
Dissemination of the virions
CD4 T-cells count decrease
Appearance of HIV-specific CTL (cytotoxic T lymphocytes) which kill
infected cells and secrete antiviral cytokines and chemokines).
Chronic HIV infection
CD4 T-cells number and function continue to decline during the period
of clinical latency;
Defects in T-cell function/loss of specific responses to recall antigens;
Abnormalities in B-cell, natural killer, monocytes and dendritic cell
functions
Altered cytokine secretion with reduced production of IFN-gamma, IL-2
and IL-12 may occur
The virus continue to replicate at all stages of infection
Mechanisms of immune depletion are:
1.
2.
3.
4.
Direct cytopathic effect
Syncytium or multinucleated cell formation,
Apoptosis (programmed cell death).
Removal of infected CD4 T cells and dendritic cells by the
vigorous HIV-specific CTL responses
Clinical manifestations
Classification of HIV-1 disease into six stages is based on a combination of
clinical features and CD4 count:
1. Initial infection (acute seroconversion syndrome)
2. Early HIV-1 disease
3. Intermediate HIV-1 disease
4. Late HIV-1 disease
5. Advanced HIV-1 disease
6. Terminal HIV-1 disease.
1. Initial infection (acute seroconversion syndrome) – usually occurs
within 2 to 6 weeks (median=21 days) after exposure to the virus.
- may be asymptomatic or
- may evolve with symptoms of flu-like or mononucleosis-like illness
The most common symptoms are:
 fever,
 lymphadenopathy
 pharyngitis, esophagitis, aphthous ulcerations
 myalgias, arthralgias
 headache
 diarrhea
 morbilliform skin eruption
 neurologic manifestations: meningitis, peripheral neuropathy, myopathy,
cranial nerve palsies.
2. Early HIV-1 disease - is defined by a CD4 cell count greater than
500cells/mmc. Most persons are asymptomatic.
Among symptoms:
 lymphadenopathy (cervical, axillary and inguinal chains),
 dermatologic abnormalities: seboreic dermatitis, perifolliculitis,
eosinophilic folliculitis,
 oral lesions: aphtous ulcerations, hairy leucoplakia.
3. Intermediate stage of HIV-1 disease – is defined by a CD4 count
between 200 and 500 cells/mmc and could evolves without symptoms or
with mild disease manifestations:
 Recurrent herpes simplex infection
 Oropharyngeal/vaginal candidiasis
 Varicella zoster virus infection
 Weight loss
 Bacterial sinusitis, bronchitis, pneumonia
 Headache, myalgias, arthralgias
4. Late-stage disease – is defined by a CD4 cell count between 50 and 200
cells/mmc. These patients have a great risk of developing
 opportunistic infections such as Pneumocystis carini pneumonia,
Toxoplasma gondii infection, cryptosporidiosis, tuberculosis, Kaposi’s
sarcoma, esophagial candidiasis and
 hematologic abnormalities (anemia, neutropenia, idiopathic
thrombocytopenia).
5. Advanced HIV disease – is defined as a CD4 count of less than 50
cells/mmc. The most frequent conditions seen during this stage are: MAC
disease, cryptococcal meningitis, cytomegalovirus retinitis, progressive
multifocal leukoencephalopathy.
6. Terminal HIV disease – symptoms of disease cannot be controlled
because no treatment are available
The management includes psychological support, family support, and pain
management.
Classification
Table 2. Clinical categories
Clinical category A
Asymptomatic HIV
infection
Persistent generalized
lymphadenopathy
Primary (acute) HIV
illness
Clinical category B
Symptomatic, nonA or C
conditions
- Candidiasis,
oropharyngeal
- Candidiasis,
vulvovaginal(>1 mo)
- Bacillary angiomatosis
- Cervical displasia,
Clinical category C
Candidiasis:
esophageal, trachea,
bronchi
Coccidioidomycosis,
extrapulmonary
Cryptococcosis,
extrapulmonary
Cryptosporidiosis>1mo
severe, or carcinoma
in situ
- Constitutional
symptoms: fever,
diarrhea>1 month
CMV retinitis, or in
other than liver, spleen,
nodes
HIV encephalopathy
Histoplasmosis,
extrapulmonary,
disseminated
Isosporiasis>1 mo
Kaposi’s sarcoma
Lymphoma
M.avium/kansasii:
extrapulmonary
M. tuberculosis
infection
Pn.carinii pneumonia
Pneumonia, recurrent
Progressive multifocal
leukoencephalopathy
Salmonella bacteremia,
recurrent
Toxoplasmosis,
cerebral
Wasting syndrome
HIV encephalopathy
Table 3. Classification system
CD4 cell
category
1) >500/mmc
2) 200-499/mmc
3) <200/mmc
CLINICAL CATEGORY
A
B
A1
B1
A2
B2
A3
B3
Pulmonary diseases
Any CD4 level:

CD4<200/mmc

C
C1
C2
C3
CD4<100/mmc
 Cryptococcosis
 Coccidioidomycosis
 Histoplasmosis
CD4<50/mmc
 Aspergilosis
 M. avium
Neurologic manifestations
Brain involvement
A. Focal lesions
B. Nonfocal complications
Spinal cord
Meninges
Peripheral nerve and root
 lymphomatous meningitis;
Table 4. Classification of oral lesions:
Viral lesions
 Hairy leukoplakia
 Herpes simplex
 Herpes zoster
 Cytomegalovirus
Fungal lesions
 Candidiasis
 Histoplasmosis
 Cryptococcosis
Bacterial lesions
 Periodontal disease
 Necrotizing stomatitis
 Mycobacterium avium complex
 Bacillary angiomatosis
Neoplastic lesions
 Kaposi’s sarcoma
 Non-Hodgkin’s lymphoma
 Hodgkin’s lymphoma
Autoimmune/idiopathic lesions
 Salivary gland disease
 Aphtous ulcers
 Abnormal pigmentation
Dermatologic complications
Table 5. Skin lesions
Maculopapular lesions
 Moluscum contagiosum
 Syphilis
 Mycobacterial infection
 Kaposi’s sarcoma
Nodular, verrucous, and/or ulcerative
lesions
 Bacillary angiomatosis
 Cryptococcosis
 Sporotrichosis
 MAC infections
 Kaposi’s sarcoma
Vesicular, bulous or pustular lesions
 Herpes simplex virus
 Varicella-zoster
 Cytomegalovirus
 Staphylococcal impetigo
 Stevens-Johnson syndrome
Papulosquamous lesions
 Seborrheic dermatitis
 Dry-skin syndrome
 Psoriasis
 Norwegian scabies
 Staphylococcal folliculitis
 Eosinophilicfolliculitis
Table 6. Acute infectious diarrhea






Campylobacter jejuni
Clostridium difficile
Enteric viruses
Enteroadherent E. coli
Salmonella
Shigella
Spectrum of associated malignancies
 Kaposi’s sarcoma
 Primary CNS lymphoma
 Non-Hodgkin’s lymphoma
 Cervical carcinoma
 Hodgkin’s disease
 Seminoma






Cryptosporidia
Cytomegalovirus
Entamoeba histolytica
Isospora belli
Microsporidia
Mycobacterium avium
Laboratory tests
HIV antibody tests
Enzyme immunoabsorbant assay (EIA).
 Western-Blot (WB).
 Immunofluorescent assay
1. Rapid detection methods:
2. Home tests kits
Viral detection
Treatment
Table 7. Antiretroviral drugs
Antiretroviral drugs
Nucleoside reverse-transcriptase
inhibitors (NRTI)
Group A drugs
- Zidovudine (ZDV) - Retrovir
- Stavudine (D4T) - Zerit
Group B drugs
- Didanosine (ddi) – Videx
- Zalcitabine (ddC) - HIVID
- Lamivudine (3TC) - Epivir
Non-nucleoside reversetranscriptase inhibitors (NNRTI)
- Nevirapine-Viramune
- Delavirdine - Rescriptor
Protease inhibitors
- Saquinavir - Invirase
- Saquinavir - Fortovase
- Indinavir – Crixivan
- Ritonavir – Norvir
- Nelfinavir - Viracept
Doses
300 mg bid or 200 mg tid
40 mg bid (>60 kg), 30 mg bid
(<60kg)
200 mg bid (>60 kg), 125 mg bid
(<60kg)
0,75 mg tid
150 mg bid
200 mg qdx2 wks, then 200 mg bid
400mg tid
600 mg q8h with meals
1200 mg q8h with meals
800 mg q8h, empty stomach
300 mg q12 h-2 wks, then 600mg bid
750 mg q8h
Initial regimens
Preferred:
 2 nucleosides and a PI
 2 nucleosides and a NNRTI
Under evaluation:
 3 nucleosides
 In patients with CD4<50/mmc or viral load >100 000c/ml:
- 2NRTIs + 2 PI
- 2NRTIs + PI + NNRTI
HAART (highly active antiretroviral therapy) is an antiretroviral regimen
that can be expected to reduce the viral load to<50c/ml in treatment-naïve
patients.
Indications for Antiretroviral therapy
Table 8. Indications for the initiation of antiretroviral therapy (DHHS
Guidelines-2000)
Clinical category
Asymptomatic
Asymptomatic
Acute HIV, or <6 mo
after seroconversion
Symptomatic (AIDS,
unexplained fever)
CD4 cell count/HIV
RNA
CD4<500/mmc, or
RNA>10000 (bDNA),
or >20000 (RT-PCR)
Recommendation
CD4>500/mmc and
HIV RNA<10000
(bDNA), or
<20000 (RT-PCR)
All
Delay therapy and
observe , or treat
All
Treat
Treat
Treat
Table 9. Management of opportunistic infections in patients with HIV
infection
Preferred regimen(s)
Alternative regimen(s)
 Pentamidine
Pneumocystis carinii  Trimethoprim
-Acute infection
(TMP)15mg/kg/day +
4mg/kg/dayIVx21
sulfamethoxazole
days
75mg/kg/day x 21
 Clindamycin 600mg
days
IV + primaquine
30mg base/day
 Atovaquone 750mg
suspension po
 TMP + dapsone
100mg po/day
-Prophylaxis when
 Trimethoprim/sulfam  Dapsone
CD4<200mmc, or
etoxazole
 Atovaquone
unexplained fever>2
 Aerosolized
wks
pentamidine 300mg q
month
Candida
- Oropharyngeal  Clotrimazole 10 mg
 Fluconazole 100mgpo
5x/day
 Amphotericin B oral
 Nistatin 500000u
suspension
gargled 5x/day
 Itraconazole
Maintenance
 Fluconazole 100mg
200mg/day
po 3x/wk
- Esophagitis
 Fluconazole 200mg/d  Ketoconazole
x 2-3 wks
200mg/d po
 Itraconazole
Prophylaxis
Not recommended
Cryptococcal
meningitis
-Initial treatment
 Amphotericin 0,7-1
 Fluconazole 400-800
mg/kg/d IV +/mg/d po +/flucytosine 100
flucytosine 100
mg/kg/d po x 14 days
mg/kg/d x 6-10 wks
then fluconazole 400
mg/d x 8-10 wks
-Maitenance
 Fluconazole 200
 Amphotericin B 0,6-1
mg/d po
mg/kg/d 1-3 wks
-Prophylaxis
 when CD4<100/mmc
 Fluconazole 200
mg/d po
 Itraconazole 400 mg
po/d
Toxoplasma gondii
encephalitis
-Acute infection
-Suppressive therapy
-Prophylaxis when
positive toxo IgG +
CD4<100/mmc
Mycobacterium
tuberculosis
-Treatment
-Prophylaxis
(if PPD>5mm
induration, high-risk
exposure)
Mycobacterium
avium complex
(MAC)
-Treatment
-Prophylaxis
(if CD4<50/mmc)
 Pyrimethamine 100-  Pyrimethamidine +
200mg loading dose
clindamycin 900then 50-100 mg/d po
1200mg >6wks
+ sulfadiazine 4-8 g/d  Azithromycin 1800
at least 6 wks +
mg/d 1st day then
folinic acid
1200 mg/d x 6wks,
 Pyrimethamine 25-75
then 600mg/day
mg po + sulfadiazine
0,5-1 g/d
 TMP Dapsone 50mg/d+
sulfamethoxazole
pyrimethamine
50mg/wk
-no concurrent use of
PI/NNRTIs
 INH/RIF/PZA/EMB  INH/RIF daily or 2-3
daily x 2 mo
x/wk x 18 wks
-concurrent PI/NNRTIs
 INH/RFB/PZN/EMB  INH/RFB daily or
daily x 8 wks
2x/wk x 18 wks
 INH/SM/ PZN/EMB  INH/SM/PZA 2-3/wk
daily x 8wks
x30 wks
 INH 300 mg/d x 9mo
 Rif 600 mg/d + PZN
20 mg/kg/d x 2 mo
 FQ/PZN or
EMB/PZN (for
multiply-resistant
strain)
 Clarythromycin 500
 Azithromycin 600
mg bid + EMB+/mg/d + EMB+/rifabutin 300 mg/d
rifabutin
 Amikacin/ciprofloxac
in
 Rifabutin 300mg, po
 Clarythromycin 500
qd
mg bid
Cytomegalovirus
retinitis
-Treatment
Initial
Maintenance
-Prophylaxis
(when positive CMV
serology +
CD4<50/mmc)
Cryptosporidia
Isospora
Microsporidiosis
Herpes simplex
- mild
- severe
 Azithromycin
1200mg q wk
 Ganciclovir 5 mg/kg
IV bid x 14-21 days
 Foscarnet 60
mg/kgq8h x 14-21 d
 Cidofovir 5mg/kgIV
x 2 then 5mg/kgq
2wks
 Foscarnet 90-120
mg/kg/d
 Ganciclovir 5 mg/k/d
 Ganciclovir-oral 1g
tid
 Paromomycin 2 gx
14-28 days
 TMP/sulfametox. x 24wks
 Albendazole 400800mg >3wks
 Nitazoxanide 1 g
 Azithromycin
 Pyrimethamine 50-75
mg/d x 1 mo
 Metronidazole 1,5 g
 Acyclovir 400mg tid,
 Famciclovir
 Acyclovir 800 mgpo
5x/d >7 days
 Valacyclovir 1g tid
 Foscarnet 40 mg/kg
IV q 8h 3 wks
SEPTICEMIA, SEPSIS, SEPTIC SHOCK
Egidia Miftode
Definition
An expert consensus conference of the American College of Chest
Physicians and the Society of Critical Care coined the phrase systemic
inflammatory response syndrome (SIRS) to describe a clinical syndrome
believed to be the result of an overly activated inflammatory response. This
new definition recognized the important role that endogenous mediators of
systemic inflammation play in sepsis, which was no longer regarded as
being caused by microbial pathogenicity factors alone .
Septicemia is a dramatic clinical syndrome, which result from acute
invasion of the bloodstream by certain microorganism or their toxic
products. Fever, chills, tachycardia, tachypnea and altered mentation are
common acute manifestations of septicemia.
Bacteremia: is the presence of vivid bacteria in bloodstream
confirmed by the blood culture with the isolation of a pathogen.
Systemic inflammatory response syndrome (SIRS): contains two or
more of the following conditions:
1. fever, over the 38oC or hypothermia less than 36oC;
2. tachypneea more than 20 breaths/min;
3. tachycardia more than 90 beats/min.;
4. leucocytosis more than 12000/mmc;
5. leucopenia less than 4000/mmc or more than 10 percents immature
forms.
-
Sepsis means: SIRS plus a documented infection
Severe sepsis
Septic shock
Multiple organ dysfunction syndrome (MODS)
Respiratory: PaO2<80 mmHg, PaCO2>50mmHg, respiratory
rate<5/min, or >50/min;
 Renal system: increased serum creatinine, oliguria (<480ml/24h);
 Cardiovascular system: hypotension, heart rate<55/min, ph<7.25;




Hepatic system: serum bilirubin>60mg/l, TP<15%;
Gastrointestinal system: bleedings, pancreatitis, ileus, perforation;
CNS: Glasgow coma score <6;
Hematologic system: platelet count<20000/mmc, leucocytes<1000/mmc,
hematocrit<20%.
Etiology
Multiple components of the microbial structure may initiate the systemic
inflammatory response.
Gram positive:
 Streptococcus pneumoniae
 Staphylococcus aureus/epidermidis
 Streptococcus pyogenes
 Clostridium
Gram negative:
 Neisseria meningitidis
 Gram negative bacilli: E. coli, Salmonella, Klebsiella, Pseudomonas,
Yersinia pestis, Vibrio vulnificans, Aeromonas species
Rickettsia rickettsii
Capnocytophaga canimorsus
Erlichia species
Bartonella species
Dengue viruses
Viruses - causes of the hantavirus pulmonary syndrome
Plasmodium falciparum
Babesia microti
Anaerobes: peptococcus, microaerofili streptococci, Actimomyces
israelii.
Epidemiology
Predisposing factors include:
 diabetes mellitus,
 cirrhosis,
 alcoholism,
 leukemia, lymphoma or disseminated carcinoma,
 cytotoxic chemotherapy and immunosuppresive drugs which cause
neutropenia,
 total parenteral nutrition,
 a variety of surgical procedures and infections arising from the urinary,
biliary or gastrointestinal tracts.
Pathogenesis and pathology
Most of the bacteria causing gram-negative sepsis are normal
commensals in the gastrointestinal tract. From there they may spread to
contiguous structures (as in peritonitis after appendiceal perforation), or they
may migrate from the perineum into the urethra or bladder.
Gram-negative bacteremia follows infection in a primary forms, usually the:
 genitourinary tract,
 biliary tree,
 gastrointestinal tract or
 lungs and
 less commonly, the skin, bones and joints.
Metastatic abscess formation may complicate bacteremia.
The involved target organs are:
 lungs: pulmonary-edema, hemorrhage and hyaline membrane formation,
abscesses, bronchopneumonia
 kidney: tubular or cortical necrosis,
 myocardium: patchy necrosis, superficial ulceration or even hemorrhage
necrosis
 gastrointestinal tract, superficial ulceration or even hemorrhage necrosis
 capillaries in many tissues: leukocyte-platelet or fibrin thrombus
formation
 brain /meninges: abscesses, meningitis
Pathophysiology
Table 1: Virulence factors of Staphylococcus aureus and their proposed
pathogenic mechanism
VIRULENCE FACTORS OF STAPHYLOCOCCUS AUREUS AND
THEIR PROPOSED PATHOGENIC MECHANISM
 Twart host defenses




-
Microcapsule
Protein A
Coagulase
Fatty acid-metabolizing enzyme
Leukocidin and/or gama-toxin
Invade tissue
Proteases
Nucleases
Lipases
Hyaluronate lyase
Staphylokinase
Elicit sepsis syndrome
Toxic shock syndrome toxin
Enterotoxins
Cytolytic toxins (alpha, beta, gama and delta)
Induce specific toxinosis
Toxic shock syndrome toxin
Enterotoxin
Exfoliative toxin
Attach to endothelial cells and basement membrane
Binding proteins for fibrinogen, fibronectin, laminin, collagen,
vitronectin and thrombospondin
Clinical manifestations
Clinical manifestations are related to the following elements:
I.
Portal of entry
 Skin: erysipelas, staphylococcal skin infection, trauma, burns;
 Respiratory tract infections
 Gastrointestinal tract lesions: stomatitis, gingivitis, teeth extraction,
enterocolitis;
 Genito-urinary tract infections
II.
Lymphangitis and primary sites of infection
III. Positive blood cultures: hematogenous dissemination is manifested
with fever, chills, headache;
IV. Metastatic foci of infection:
 Cardiovascular system: infective endocarditis, myocarditis, pericarditis
 Central nervous system: brain abscess, epidural abscess, purulent
meningitis (confusion, obtundation, coma);
 Respiratory system: bronchopneumonia, pleural effusion (acute
respiratory distress syndrome, tachypnea, hypocapnea);
 Gastrointestinal: liver and spleen abscess, impaired gastrointestinal
motility, sterss related mucosal disease, hyperbilirubinemia, elevation of
liver enzymes.
 Renal system: renal abscess, nephritis
 Bone and joint involvement: osteitis, osteomyelitis, spondylodiscitis,
arthritis
 Cutaneous manifestations: cellulitis, flegmons, diffuse erythroderma
(caused by gram-positive organisms and by the action of pyrogenic or
erythrogenic toxins); colorful skin lesions such as ecthyma gangrenosum
(associated with P. aeruginosa septicemia), colorful vezicular or bullous
lesions, cellulitis, petechial lesions (may appear in gram negative
septicemia)
Toxic shock syndrome
Clinical manifestations
1. Hemodynamic changes:.
2. Dermatologic findings:
3. Severe myalgias, muscle tenderness, weakness
4. Diarrhea, nausea, vomiting]
5. Encephalopathy
6. Respiratory distress syndrome
7. Acute renal failure
8. Hepatic necrosis
9. Disseminated intravascular coagulation.
Table 4: Streptococcal Toxic Shock Syndrome
Streptococcal Toxic Shock Syndrome –
definition
Symptoms
Signs
An acute, febrile illness that begins with a
mild viral-like prodrome or minor softtissue infection and may progress to shock,
multiorgan failure and death
Early symptoms are vague:
 Viral-like prodrome
 Severe pain and erythema of an
extremity
 Mental confusion
 Hypotension, systolic




Laboratory features
Fever > 38 degree
Soft-tissue swelling
Tenderness
Respiratory failure, rales, cyanosis,
tachypneea
Hematologic:
 Marked left shift
 Decline in hematocrit
 Thrombocytopenia
- Renal azotemia (2,5 x normal on
admission) and hematuria
- Hypocalcemia
- Hypoalbuminemia
- Creatine phosphokinase elevation
- Pulmonary abnormalities:
-Pulmonary infiltrate on chest x-ray
-Hypoxia
Table 5. Laboratory investigations in sepsis
Complete blood count
Blood chemistry
Urinalysis
Chest radiography
Erythrocyte sedimentation rate
Blood cultures (3 or more separate
specimens)
Cultures from other biologic fluids
(pus, pleural effusion, joint effusion,
catheter, etc)
Differential diagnosis
Infectious diseases
Bacterial infections
Rickettsial infections:
Viral infections:,
Parasitic infections:;
Fungal infections:.
Non-infectious diseases
A. Neoplastic diseases:;
Antinuclear antibodies
Rheumatoid factor
Computed tomography of abdomen,
pelvis, other sites
Radionuclide scans
Venous duplex imaging of lower
limbs
Echocardiography
B.
C.
D.
E.
Autoimmune diseases:
Hypersensitivity;
Granulomatous diseases:
Other: CNS hemorrhage, CNS degenerative diseases, familial
Mediteranean fever, cholangitis.
Treatment
A. Initial therapy for the sepsis syndrome
Community-acquired infections
1. Suspected staphyloccocal etiology: oxacillin+aminoglycoside
2. Suspected genito-urinary source: a third generation cephalosporin (3GC);
a quinolone; ticarcillin/piperacillin with/without an aminoglycoside;
3. Non-urinary tract source: 3GC or ampicillin/ticarcillin/piperacillin – beta
lactamase-inhibitor (BLI)
Hospital-acquired infections:
 Non-neutropenic patients: 3GC with/without metronidazole, cefepime, a
beta lactam drug-BLI/imipenem with/without an aminoglycoside
 Neutropenic patients: ceftazidime + an aminoglycoside; ticarcillinclavulanat/piperacillin-tazobactam + an aminoglycoside;
imipenem/meropenem + an aminoglycoside.
Tabel 6.First intention treatment and alternative therapy for infective
endocarditis on native valve
Etiology
1. S.aureus meti-S
First intention treatment
1. (oxaciline 8g/d iv, every
4h)x4-6wks +gentax35days
2. S.aureus meti-R
2. (Vanco 2g/d iv, every
12h)x4-6wks
3. S.viridans, S. bovissensitive to Pen.
G(CMI<o,1microg/
ml)
3. Pen.G 12-18milU/d, iv,
cont/4hx2 wks + genta
3mg/kg/d x2wks or
Pen G x4wks or
Alternative
1. Cefazolin 6g
ivx46weeks+genta3mg/
kgx3-5d, OR 2.
Vanco 4-6wks
3. (Ceftriaxone +
genta)x2wks
Ceftriaxone 4g/d x4wks
4. S.viridans, S.bovis
with CMI PenG:0,10,5microg/ml
4. Pen G 18mil U/d
x4wks+genta 3mg/kg/d
x 2wks,
5. .S viridans, S.bovis
(CMI PenG>1),
enterococi sensitive
to ampi/Pen G,
vanco, genta
6. Enterococi (CMI
Pen G >16ng/ml)
7. Enterococi pen/ampi
R, high resistance to
genta, vanco-R
8. Difteroizi sensitive
to genta (MIC<4/ml)
9. Difteroizi resistent
to genta (>4/ml)
10.gram-negative
cocobacili from the
group HACEK*
5. Pen G 18milU/24h, 46spt+genta 4-6wks, or
5. (vanco+genta)
(AMP12g/zi iv cont or
x4-6wks
every 4h+genta)x4-6wks
11.Bartonella
11.Fluoroquinolone or RIF
or macrolide
12.Amfotericine B+/-an
azol (fluconazole)
13.Vanco+RIF+gentax6wks
12.Candida
4. vanco
30mg/kgc/d until la
2g/dx4wks
6. Vanco+gentax4-6wks
7. Quinupristin/dalfopristin
or linezolid 1200mg/zi iv 7.Vancox6wks
8. PenG+gentax6wks
9. Vancox6wks
10.Ceftriaxone 2-3g iv or
cefotaxime 3g ivx6wks
10.Ampi
12g/d+(strepto
15mg/kg-1g/d
or genta)x6wks
13.EI on valvular
prothesis with
negative
bloodcultures
Genta=gentamicine, RIF=rifampicine, HACEK include Haemophilus sp,
A.actinomycetemcomitans, Cardiobacteriu.hominis, Eikinella corrodens,
Kingella sp.
Table 7. Infective endocarditis on prosthetic valve
Etiology
First intention treatment Alternative
 S. epidermidis
 S.aureus meti-R
 S.aureus meti-S
 (Vanco 2g/d iv, every
12h+RIF 900mg/d,
every 8h)x6wks
+genta* 240mg/d
every 8 hx2wks
 “ “ “
 (oxaciline 8g/d iv,
every 4h+RIF)x6wks
+gentax2wks
 Vanco+Fluoroquin
olone+RIF
 “
“ “
Vanco+RIF+gentax6wks
EI on valvular
prothesis with
negative bloodcultures As for the native valve
For the other etiology- endocarditis.
B. Adjunctive measures in the treatment of sepsis syndrome
1. Maintenance of adequate tissue perfusion with volume replacement:
normal saline solution, fresh frozen plasma, albumin, dextran, crystaloid
solutions.
2. Sympatomimetic amines: dopamine, dobutamine
3. Corticosteroids for gram-negative rod septicemia-is controversed.
4. Diuretics for the early oliguric phases of schock.
LYME DISEASE (LYME BORRELIOSIS)
Dr. Daniela Leca
Lyme disease, originally called Lyme arthritis, was recognized in 1975
because of a close geographic clustering of affected children in Lyme,
Connecticut, who were thought to have juvenile rheumatoid arthritis. The
illness is now known to be a multisystem disorder caused by the ticktransmitted spirochete, Borrelia burgdorferi
Etiology
Borrelia burgdorferi grows best at 33 oC in Barbour-Stoenner-Kelly
medium.
Epidemiology
Lyme disease is now the most common vector-borne infection in the
USA and also occurs in Europe, Scandinavia, the former Soviet Union,
China, Japan, Australia.
Pathogenesis
B. burgdorferi may survive primarily in certain niches within the joints,
nervous system, or skin where may persist, latently or symptomatically, for
years.
Clinical manifestations
Stage 1 (localised infection, erythema migrans)
Erythema chronicum migrans (ECM) .
Stage 2 (disseminated infection)
ECM
Neurologic symptoms
- Within several weeks after the onset of illness, about 5 percent of
untreated patients develop cardiac involvement:
Stage 3 (persistent infection)
Frank arthritis occurs primarly in large joints, especially the knee, usually
one or two joints at a time. ECM, begins with red violacious lesions that
become sclerotic or atrophic. These lesions, may last for many years.
Sclerotic lesions may look like localized scleroderma.
-chronic neurologic manifestations as subacute encephalopathy (with
increasing cerebrospinal fluid protein levels or evidence of intrathecal
antibody production to B. burgdorferi), encephalomyelitis, encephalitis,
dementia, psychiatric syndromes, brain stem abnormalities, extrapyramidal
syndromes.
The Laboratory Diagnosis
1. Culture of the spirochete from patient specimens permits a definitive
diagnosis,
Serologic (ELISA), indirect immunofluorescence assay (IFA), antibodycapture immunoassay (EIA), Western blotting or immunoblotting.
In neuroborreliosis, comparison of the antibody response to B. burgdorferi in
CSF and serum by EIA is a helpful diagnostic test (a CSF/serum ratio of
specific antibody of greater than 1 is suggestive of intrathecal antibody
production).
The nonspecific laboratory abnormalities are:
- a high erythrocyte sedimentation rate,
- an elevated serum IgM level,
- an increased serum glutamic-oxaloacetic transaminase (SGOT) level,
glutamic-pyruvic transaminase (SGPT) and lactate dehydrogenase
(LDH).
- anemia early in the illness
- occasionally elevated WBC counts with shifts to the left in the
differential count
- microscopic hematuria, sometimes with mild proteinuria
- C3 and C4 levels are generally normal or elevated
- tests for rheumatoid factor or antinuclear antibodies are usually negative.
Treatment
Lyme disease can be treated with oral antibiotic therapy, except for
neurologic abnormalities, which require intravenous therapy.
 For patients with infection localized to the skin, 10 days of therapy is
generally sufficient.
 For patients with disseminated infection, longer courses of 20–30 days
are recommended. Approximately 15 percent of patients with early
disseminated infection experience a Jarisch-Herxheimer-like reaction
during the first 24 hours of therapy. In vitro, B. burgdorferi is sensitive to
tetracycline, penicillin, macrolides and to third-generation
cephalosporins, but it is resistant to rifampin, ciprofloxacin, and
aminoglycosides.
 Reinfection may occur in patients who are treated with antibiotics early
in the illness. With any of the recommended treatment regimens,
treatment failure may occur and retreatment may be necessary.
Prevention
The risk of tick bites in high-risk areas can be reduced by simple
measures, particularly by wearing long trousers tucked into socks and by
checking for ticks after exposure in wooded areas.
INFECTIONS CAUSED BY LISTERIA
MONOCYTOGENES
Daniela Leca
Human disease due to L. monocytogenes generally occurs in the
setting of pregnancy or immunosupression due to illness or medication and
is characterised by invasive syndromes such as meningitis, sepsis,
chorioamnionitis and stillbirth.
Epidemiology
Listeria monocytogenes has been isolated from soil, dust, food
products for humans, both animal and vegetable, animal feed, water, sewage,
and almost every type of animal cultured, including asymptomatic humans.
Pathogenesis
Listeria monocytogenes can invade the eye and the skin of humans
after direct exposure, or may cross the placenta during maternal bacteremia
and infect the placenta, amniotic fluid, and fetus.
Clinical Syndromes
The results of an infection with L. monocytogenes can be manifest in
a number of five different syndromes. The most common result of contact
with the organism appears to be a transient, asymptomatic carrier state.
Infections in Pregnancy
These infections may occur any time during pregnancy, but more
often in the third trimester. The patient usually complains of chills and fever
and back pain.
Granulomatosis Infantiseptica is caused by transplacental transmission
Sepsis of Unknown Origin
Meningoencephalitis
Cerebritis
Focal Infections
1. Skin infections
2.Ocular infections: purulent conjunctivitis, nonpurulent conjunctivitis, acute
anterior uveitis with isolation of the organism from the anterior chamber.
3. Lymph node infections
4. Subacute bacterial endocarditis
5.Other focal infections include arthritis, osteomyelitis, prosthetic joint
infection, spinal or brain abscess, peritonitis, cholecystitis, acute hepatitis.
Diagnosis
Treatment
 Ampicillin or penicillin appears to be the best drugs. Experimental
laboratory results show synergism between either ampicillin or penicillin
and aminoglycosides against L. monocytogenes.
 Trimethoprim-sulfamethoxazole (15/75mg/kg per day, intravenously, in
three divided doses) has been used in penicillin-allergic patients .
Vancomycin is a possible alternative,
Prognosis
Treatment of maternal bacteremia during pregnancy can prevent neonatal
infection. Antibiotic therapy for the newborn can limit sequelae, although
the widely disseminated disease characteristic of granulomatosis
infantiseptica is frequently fatal regardless of treatment. Mortality varies
considerably according to the syndrome. Granulomatosis infantiseptica and
meningitis in immunosuppressed patients have the highest mortality, ranging
in the former from 33 to 100 percent and in the latter from 12.5 to 43
percent.
HEMORRHAGIC FEVER
Hemorrhagic fever viruses are a group of RNA viruses, which have rodent
hosts, and, some of them have arthropod vectors, but other are transmitted
from person to person.
Yellow fever virus
Yellow fever virus is an RNA virus that belongs to the family Flaviviridae.
Epidemiology
The disease occurs in tropical America and in Africa in endemic
zones (15 degrees north latitude and 15 south latitude).
Epidemic (urban) Yellow fever is transmitted by Aedes aegypti mosquitoes
(after feeding on viremic humans, they may transmit infection for 1-2
weeks).
In South America - only the sylvatic cycle of transmission, involving forest
mosquitoes and monkeys-occurs.
Sporadic cases and outbreaks- occur during the late rainy season when
vector ( Hemagogus mosquitoare) is most abundant.
In yellow fever may occurs a cross-immunity to dengue and other
flaviviruses.
Pathophysiology
 necrosis of hepatocytes, Councilman bodies in the sinusoides
 degeneration/necrosis of the myocardium
 tubular necrosis on the kidney
 depletion of lymphocytes B (that may compromise the immune
response).
Clinical features
Incubation period is 3-6 days
Yellow fever evolves as a biphasic illness progressing through three stages:
1. Infection – is characterized by abrupt onset: fever chills, headache,
backache, myalgias, nausea and vomiting flushing of the face and
conjunctivae, relative bradicardia;
2. Remission – occurs after 3-4 days (duration of hours to 1-2 days)
3. Intoxication - symptoms recur and intensify:
 jaundice
 renal dysfunction
 hemorrhagic diathesis
 encephalopathy (because hepatic or renal failure).
Table 1. Transmission of viral Hemorrahagic Fever diseases agents
Transmitted by:
Disease
Mosquitoes
Dengue
hemorrhagic
Rift Valley fever
Yellow fever
Crimean-Congo
hg. Fever
Kyasanur and
Omsk hg fever
 Argentine
HF(Junin virus)
 Bolivian
HF(Machupo v)
 HF with renal
syndrome
 Lassa fever
Tick
Rodents
Unknown
Etiologic agent
family
Togaviridae
Etiologic agent
genus
Flavivirus
Bunyaviridae
Togaviridae
Bunyaviridae
Phlebovirus
Flavivirus
Nairovirus
Togaviridae
Togaviridae
Arenaviridae
Flavivirus
Flavivirus
Arenavirus
Arenaviridae
Arenavirus
Bunyaviridae
Hantavirus
Arenaviridae
Marburg and Ebola Filoviridae
virus diseases
Filoviridae
Arenavirus
Filovirus
Filovirus
Complications: bacterial infections
Laboratory diagnosis
 leukopenia
 albuminuria
 prolonged prothrombin time
 elevation of ALAT and bilirubin(direct and indirect)
 +/-thrombocytopenia
 hypoglycemia
 serological tests (fourfolds increases in dynamic) in hemagglutination
inhibition(HI), complement fixing(CF), neutralizing antibodies
 IgM (EIA)-rapid test
 histopatologic examination which reveals
Differential diagnosis:
 malaria, dengue, influenza, leptospirosis, typhoid fever, viral hepatitis
 hemorrhagic fevers produced by: Lassa, Ebola, Marburg, CongoCrimean, and Rift-Valley fever viruses
 certain intoxications.
Prevention: yellow fever vaccine for ages 9-12 months
Dengue
The dengue syndrome is an acute febrile viral disease characterized by
exanthem, headache, myalgia, anorexia, gastrointestinal disturbances, and
prostration caused by an RNA virus (transmitted by mosquitoes, principally
A. aegypti).
Epidemiology
Between 250000-500000 cases of dengue hemorrhagic fever, dengue
shock syndrome (DHF/DSS) occurs throughout the world annually.
Countries principally involved are China, the Philippines, Vietnam,
Laos Cambodia, Thailand Malaysia, Cuba, and, sporadically India,
Bangladesh, Sri Lanka.
Pathogenesis
Clinical manifestations
Dengue fever
Clinical features are different in children and in adults.
Infants/young children: pharyngeal inflammation, rhinitis, mild caugh (lasts
for 1-5 days);
In adults the disease is characterized by:
 incubation period: 1-7 days
 sudden onset with fever, back pain, macular, generalized rash, relative
bradicardia followed by: myalgia/ arthralgia, nausea, vomiting,
generalized lymphadenopathy, hyperesthesia, taste aberration
 after defervescence—a morbilliform, maculopapular rash appears (1-5
days duration), followed by descuamation.
Dengue hemorrhagic fever has a biphasic evolution:
-the first phase is mild: malaise, vomiting , headache
-the second phase (after 2-5 days) – with rapid clinical deterioration and
collapse, gastrointestinal bleeding, ecchymosis, flushed face, irritability,
hepatomegaly.
Laboratory findings
 increase in hematocrit value
 trombocytopenia
 leukocytosis
 prolonged bleeding time
 fibrin split products are elevated
 ALAT are moderately elevated
 metabolic acidosis
 increased urea nitrogen
 chest X ray shows pleural effusions in all patients
 Virus isolation-from blood
 Serologic diagnosis (ELISA, FA, CF, HI, N test)-I sample<5days of illness
-II sample >2weeks after the onset
Differential diagnosis
Dengue fever must be distinguished from:
 Influenza – like diseases, viral respiratory tract infections
 Early stage of malaria
 Hepatitis
 leptospirosis
 diseases Chikungunya virus (in Africa-arthralgia), West Nile virus
 four arboviral diseases with dengue-like courses, but without rash:
Colorado tick fever, Rift Valley fever, Ross River fever, sandfly fever;
Dengue hemorrhagic fever:
 rickettsial diseases,
 meningococcemia
 other hemorrhagic fevers, and other severe illness with hemorrhagic
manifestations
Treatment is supportive (bed rest, antipyretic drugs, etc)
If shock: replacement of fluid and electrolytes
Transfusions of fresh blood or of platelets suspended in plasma.
Simptomatics: cloral hydrate, diuretics, digitalis therapy.
Prophylaxis consists of avoiding mosquitoes bites and vaccination.
Arenaviruses and Hemorrhagic Fever (HF)
1. Lassa fever
Geographic repartition: Nigeria, Liberia, Sierra-Leone, Guinea;
Transmission: rodent urine; human-human via infected secretion
Incubation: 7-17 days;
Delay until major signs appear: 7 days after the onset;
Symptoms: fever, headache, joints pain, non-productive cough
Day 5: pain on deglutition, pharyngeal exudat, vomissment, diarrhea;
Day 7: face edema, purpuric and petechial eruption; bleeding is associated
with fatal outcome.
Complications: liver involvement, encephalopathy, pericarditis, pleural
effusion, ascites, MOD.
Laboratory diagnosis: Lymphopenia, proteinuria, elevated blood urea
nitrogen; specific IgM appear early
Treatment-Convalescent-phase plasma is effective for arenaviruses
hemorrhagic fever, and Ribavirin.
Fatality rate: 15-20%.
2. Junin virus and Machupo virus HF
Geographic repartition: Argentine (for Junin virus), and Bolivia (for
Machupo virus);
Transmission: rodent-human via urine
Clinical aspects are similar for both diseases:
-unlike Lassa fever, respiratory symptoms, sore throat and encephalopathy
are infrequent.
-among the most prominent manifestations are: conjunctivitis, erythema of
the face, neck and thorax.
The same treatment is indicated as for Lassa Fever.
Bunyaviridae and Hemorrhagic Fever
1. Rift Valley HF
Etiology: an ARN virus-Phlebovirus (belongs to Bunyaviridae)
Geographic repartition: W and S- Africa, Egypt
Incubation period: 3-4 days
Delai until major signs appear: 2-4days after the onset
Symptoms: like Dengue - abrupt onset, biphasic fever, headache, myalgia,
arthralgia, face congestion, chemosis;
Complications- blinding, encephalitis, convulsions, hemiplegia
Laboratory diagnosis-blood antigen, presence of IgM (ELISA),
funduloscopic examination is suggestive;
Reservoir: sheep, cows
Vector-mosquitoes
Inter-human contamination is possible.
Treatment: symptomatic, vaccination, Interferon, Ribavirin.
2. Crimean-Congo HF
Etiology: Nairovirus.
Geographic repartition: S-E Europe, Chine, S, E-Africa, W, Central Sahara
Transmission: tick bite, contact with blood of humans/domestic animals;
Incubation period - 5-12 days
Delai until major signs appear: 3-6 days after the onset
Symptoms - fever, headache, myalgia, edema of the neck, sleepness,
conjunctivitis, pharyngitis
Complications-cerebral bleeding, renal and liver failure,
Laboratory diagnosis – presence of IgM antibodies
Reservoir: like Rift Valey HF
Vector: Hyalomma tick
3. HF with renal syndrome
Etiology: Hantavirus (Hantaan, Seoul, Puumala, Dobrava)
Geographic repartition: worldwide (also in France)
Transmission: Aerosols from rodent excreta;
Incubation period: 7-15 days
Delai until major signs appear: 3-6 days after the onset
Symptoms: trouble of vision, abdominal pain, hypotension, bradicardia,
proteinuria, shock, renal failure, bleeding.
Complications: melena, thrombocytopenia
Laboratory diagnosis: presence of specific antibodies.
Vector: yellow neck mouse/or bankvole.
Treatment: specific anticorp, dialysis
4. Hantavirus with pulmonary syndrome
Etiology: Hantavirus sin nombre;
Symptoms: fever, shock, pulmonary edema;
Vector: deer mouse;
Filoviridae and HF
Marburg/Ebola virus diseases
Geographic repartition: S-Africa, Kenya, Zimbabwe, Sudan, Zaire, Congo,
Gabon;
Pathogenesis of Ebola virus infection
Incubation: 5-10 days
Delay until major signs appear: 5 days after the onset
Abrupt onset with: fever, chills, headache, lumbar pain, myalgia;
 abdominal pain, nausea, vomiting, diarrhea, ulcerations of the lips and
tongue, pharyngitis.
 rash of the face, trunk, arms; bleedings (>50% of patients)
 CNS involvement: somnolence, delirium, coma;
Complications: liver and kidney involvement, pancreatitis,
After a week of evolution: defervesces or death in shock;
Laboratory diagnosis: detection of antibodies by IF on infected cells, culture
of virus from blood, urine, or throat swab.
Only laboratories with the highest level of safety (P4 facilities) are allowed
to handle these viruses.
Reservoir/Vector: There is abundant circumstantial evidence to indicate that
the natural habitat of the two filoviruses is the tropical rain forest. It seems
that, in the wild, the virus circulates between small mammals and highly
specialized insects, both dwelling either predominantly or exclusively in the
canopy of the rain forest. According to this scenario, small arboreal
mammals would be the actual reservoir of the virus, and blood sucking
insects its vectors.
Route of transmission: blood exposure, or contact with body fluids possibly
by aerosols.
Treatment – is symptomatic.
Mortality in Marbourg infection is 25% and in Ebola infection is 80-90%.