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ЕРСИТЕТ
НИВ
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ЬКОВСКИЙ
ХАР
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ЬНЫ
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Kharkiv National Medical
University
Department of Infectious
Diseases
Typhoid fever.
Paratyphoid fevers
TYPHOID FEVER
Acute infectious disease caused by
Salmonella enterica typhi and
characterized with bacteriemia,
severe intoxication, continuous
fever and affection of lymphatic
formations of small intestine with
formation of ulcers.
HISTORY
460-377 y. BC
Beginning of
ХІХ c.
Hippocrates epoch
Bretonio and Charle Loue
Typhoid – all “feverish” diseases
(by Greek smoke).
Typhoid fever first described as separated
disease
1868
S.P. Botkin
1874
Borovich, I. Sokoliv
1880
Ebert
Extracted S. typhi from sections of spleen of
patients, described pathogen
1884
Gaffki
Extracted S. typhi in pure culture
1896
Geuber and Vidal
ХХ c.
different years
I.S. Kildushevsky,
N.I. Rogoza, J. Padalka,
К.V. Bunin and other
Made classical description of clinical
symptoms and complications.
Was discovered Salmonella typhi
Implemented reaction of agglutination
(Vidal test).
Detailed description of clinical symptoms,
methods of diagnostics, treatment and
prophylaxis.
Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per
1,000 population) and kills an estimated 200,000 people every year
ETIOLOGY
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•
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•
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•
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Pathogen – Salmonella enterica Typhi
Family – Enterobacteriacae
Genus – Salmonella, Sp. – enterica
Gram-negative non-sporing, motile rods (2-4X0.5µm), do not
have capsules.
Antigenic structure: О – somatic, Н – flagellar,
Vi – virulence antigen
Serogroup D (classification by Kauffman-White).
PATHOGENIC FACTORS
Endotoxin (LPS)
Gialuronidase, fibrinolsysin, hemolysin, catalase and other
enzymes
«pathogenic isles»: SPI-1, SPI-2, SPI-7 и др.
ETIOLOGY
• Resistance in an environment is
rather high
• Can survive several months away from the host (in
water and soil).
• Can survive refrigeration, freezing and dry conditions.
• Can survive in the stuff-foods (milk, meat) from 1-2 till
25-30 days.
• Boiling or chlorination of water immediately destroy
the bacilli
• The bacilli are killed at 55ºC in one hour or at 60ºc in
15 minutes.
EPIDEMIOLOGY
• Anthroponosis
• Source of infection –
sick person or carriers
• Mechanism of transmission – fecal-oral
• Routs of transmission – alimentary, watery, contact
• Outbreaks – alimentary and watery routs
• Sporadic cases – contact rout
• Susceptibility is high
• Season: summer, autumn
• Immunity – strong, steady
Environmental and behavioral risk factors that are
independently associated with typhoid fever
• eating food from street vendors,
• living in the same household with someone
who has new case of typhoid fever,
• washing the hands inadequately,
• sharing food from the same plate,
• drinking unpurified water,
• living in a household that does not have a
toilet
In 1906, Irish immigrant Mary Mallon worked as a cook in the
home of New York banker Charles Henry Warren and his family.
By the end of the summer,
Mary Mallon
six members of the household
(wearing glasses)
photographed
had contracted typhoid fever.
with
The Warrens hired sanitary engineer, bacteriologist
Emma Sherman
on North Brother
George Soper, to determine
Island in 1931 or
1932, over 15
years after she
the source of the disease. Soper
had been
there
concluded that Mallon, while immune quarantined
permanently.
herself to the disease, was its carrier.
For three years, she was isolated on
North Brother Island, near Rikers Island, earning the nickname
"Typhoid Mary." Instructed not to cook for others upon her release,
she nevertheless changed her name and became a cook at a
maternity hospital in Manhattan. At least 25 staff members
contracted typhoid.
"Typhoid Mary" returned to North Brother Island, where she lived
alone for 23 years in quarantine, until her death of a stroke in 1938.
PATHOGENESIS
1.
2.
3.
4.
5.
6.
7.
8.
Invasion. Penetration of the pathogen into GI
tract
Invasion of the pathogen into mesentherial
lymph nodes (regional lymphogenic reaction)
Bacteriemia
Endotoxinemia
Parenchymatous diffusion (bone marrow, liver,
spleen, kidneys, other organs)
Excretory allergic phase. Morphologic changes.
Immunologic reactions
Convalescence
MORPHOLOGICAL CHANGES IN INTESTINE
IN TYPHOID FEVER
1-week
2- week
3- week
4- week
5- week
“cerebral-like swelling” of solitary follicules
and Peyer's patches – proliferation of
typhoid cells
Massive secondary entrance of S. typhi on
background of hyperreactivity leads to
formation of local necrosis of follicles
Seizure of necrotic masses and formation
of ulcers. Perforation of intestinal wall or
bleeding are possible.
Full ablution of ulcers (“clear ulcers”).
Perforation of intestinal wall or bleeding are
possible.
Healing of ulcers without formation of scars.
CLINICAL CLASSIFICATION
I. Typical forms
- mild
- moderate
- severe
- very severe
II. Atypical forms
- oblitereted
- abortive
- ambulatory
III. Masked forms
 pneumotyphus,
 nephrotyphus,
 meningotyphus,
 encephalotyphus,
 colonotyphus
IV. Bacteria carrying
- acute (about 3 month)
- chronic (long time, sometimes
lifelong).
- transitional (singular detection of
the pathogen,without specific
changes in immune system).
Periods
I.
Incubation
9-14 days (3-60)
II. Initial
Stadium incrementi
1st week
III. Climax
Stadium fastigii
2-4th week
IV. Decreasing of symptoms.
Cjnvalescence
Stadium decrementi
5th week
.
Initial period Stadium incrementi
1st week of the disease
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Moderate increasing of temperature,
Constant headache,
Disorders of sleeping, insomnia (from the 5th day)
Increasing weakness, loss of apetite
Skin is pale.
Abdominal distension. Constipation.
Relative bradicardia, decreasing of BP.
Presence of Padalka symptom.
Hepatosplenomegaly (from the 5th day).
TYPHOID FEVER. TYPES OF TEMPERATURE CURVES
DAY OF DISEASE
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
41
43
45
47
49
51
1
53
41
42
40
41
4
7
10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73
40
39
39
38
38
37
37
36
36
35
35
Botkin, 1868
Wunderlich, 1856
1
3
5
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55
42
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
38
41
40
37
39
38
36
37
36
35
35
Kildushevsky
Irregular
41
43
45
47
49
51
53
55
57
59
Climax period (Stadium fastigii )
(2-4th week of the disease)
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Fever is maximal and stable.
Constant headache, insomnia.
Patient is adynamic, apathetic. Skin is pale.
Rose spots (from the 8-10 d of the disease).
Relative bradycardia and dicrotic pulse (double beat, the second
beat weaker than the first)
Fuliginous “typhoid” tongue.
Severe abdominal distension.
Some patients experience foul, green-yellow, liquid diarrhea
(pea soup diarrhea), some – constipations.
Hepatosplenomegaly. Padalka sign. Philippovich sign.
“Typhoid state” - prolonged apathy, lethargy, confusion,
delirium, hallucinations, disorientation.
Possibility of intestinal bleeding and perforation.
.
Characteristics of exanthema
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Rose spots,
Rash is monomorphic
salmon-colored,
blanching,
truncal (abdomen and
lower part of thorax),
• usually 1-5 mm wide
• not abundant (3-10 elem.);
• generally resolve
within 2-5 days
Convalescence period (Stadium decrementi)
5th week of the disease.
• Gradual decreasing of temperature and
intoxication.
• Decrease of headache.
• Better sleep, appetite.
The clinical course of typhoid fever may deviate
from the description of classic disease.
• The timing of the symptoms and host response may
vary based on geographic region, race factors,
and the infecting bacterial strain.
• The stepladder fever pattern that was once the
hallmark of typhoid fever now occurs in as few as
12% of cases.
• In most contemporary presentations of typhoid
fever, the fever has a steady insidious onset.
• Young children, individuals with AIDS, and one third
of immunocompetent adults who develop typhoid
fever develop diarrhea rather than constipation.
COMPLICATIONS OF TYPHOID FEVER
Specific
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Intestinal bleeding;
Intestinal perforation;
Toxic shock;
Status typhosus;
Nonspecific
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pneumonia;
parotitis;
abscesses;
otitis;
pyelitis;
trombophlebitis;
• exacerbation;
• relapse
INTESTINAL BLEEDING (1-8%)
Paleness of skin
 Dryness of mucous membranes
 Dizzines, tinnitus, severe weakness
 Decreasing of temperature
 Tachycardia
 “Cross” or
“scissors” sign
 Hypotonia
 Meteorism and
hyperperistalsis
 Detection of blood
in feaces
(blobs or “melena”)

PERFORATION OF INTESTINE (0,3-8%)


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Abrupt pain in abdomen (nonsevere)
Local muscular defense in right iliac region,
Depression of peristaltic
Abdomen does not take part in breathing
Absence of hepatic dullness
Peritonitis with increasing of intoxication,
enteroparesis,
 dryness of a tongue,
 tachycardia
 meteorism without wind
 peritoneal signs
 Leucocytosis in blood test
PERFORATION OF INTESTINE (0,3-8%)
Relapse
• 5-20% of typhoid fever cases that have
apparently been treated successfully.
• A relapse is heralded by the return of fever
soon after the completion of antibiotic
treatment.
• The clinical manifestation is frequently
milder than the initial illness.
• Cultures should be obtained and standard
treatment should be administered.
MOST FREAQUENT REASONS AND SIGNS
OF RELAPSES
• Reasons:
•
– genetic peculiarities;
•
– immunodeficiency;
•
– faults of treatment (insensibility of antibiotics
or low dosage, early cancellation).
• Signs:
•
– prolonged subfebrile temperature;
•
– prolonged hepatosplenomegaly;
•
– stable meteorism (wind);
•
– Low titers of serum antibodies;
•
– aneosinophilia.
Differential diagnosis of typhoid fever
Paratyphoid А and В, generalized
Influenza, ARVI, pneumonia.
Sepsis.
Louse – borne typhus.
Brucellosis.
Viral Hepatitis
Malaria
Tuberculosis.
salmonellosis.
DIFFERENTIAL DIAGNOSIS OF PARATYPHOID A AND B
PARATYPHOID А
- anthroponosis (sick persons or carriers)
- incubation period - 8-10 days
- acute onset (50%);
- fever is remittent, sometimes – hectic;
- affection of respiratory system from the
beginning of disease (cough, sore throat,
dysphonia);
- dyspepsia;
- hyperemia of skin and sclera, signs of
pharyngitis;
- chills and sweating are possible;
- rash appears on 5-7 day, polymorphic,
plentiful, on trunk, upper extremities;
- status typhosus is rare
- in blood – normal WBC or leucocytosis;
- relapses more frequent, perforation or
bleeding are rare;
- rather mild, moderate course.
PARATYPHOID В
-Zooanthroponosis (sick persons,
livestock, poultry) ;
-- incubation period is shorter (5-8 days);
- acute onset,
-- fever is subfebrile or remittent, continue
during 1-5 days
- Gastrointestinal syndrome – nausea,
vomiting, diarrhea
-hyperemia of skin and sclera
-Chills, sweating
- Rash appears on 4-5 day, polymorphic,
plentiful, sometimes on skin of face;
- status typhosus is rare
in blood leucocytosis, ESR increasing;
- Clinical course can be severe,
accompanied with meningitis, sepsis.
- rather mild, subclinical course (1-3 days)
CLINICAL CLASSIFICATION OF PARATYPHOID FEVER
• Typhoid form
Paratyphoid А – 50 – 60%
Paratyphoid В – 10 – 12%
• Catarrhal form
Paratyphoid А – 20 – 25%
Paratyphoid В – 10 – 12%
• Gastrointestinal form
Paratyphoid В – 60 – 65%
• Mixed forms
Diagnostics
• CBC: Initial period – moderate leucocytosis or
normocytosis , shift to the left, an elevated ESR
• Climax period – leucopenia, aneosinophilia,
lymphomonocytosis, thrombocytopenia, an
elevated ESR.
• Urine test – no specific changes.
• Additional methods
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X-ray of lungs
X-ray of abdomen
ECG
USI
Specific diagnostics
• Culture: blood, urine, bile, faeces, bone marrow, rose spots.
• Hemoculture is positive during all feverish period. Most
frequent positive hemoculture on a first week.
• Coproculture and urinoculture are positive from the second
week.
• Bone marrow culture is 90% sensitive until at least 5 days
after commencement of antibiotics. However, this
technique is extremely painful, which may outweigh its
benefit
• Bile culture – is obligatory component of diagnostics of
convalescents. Duodenal intubation must be performed not
earlier then 5th week of the disease (threat of perforation or
bleeding).
Wilson and Blair bismuth sulphite medium
jet black colony with a metallic sheen
Serologic tests
• Widal test – was the traditional method for decades.
Diagnostic titer - 1:200. It is not specific, due to O –
antigen can be positive for other Salmonella groups.
• Indirect hemagglutination is more specific.
• Latex agglutination or coagglutination tests for
antibody to the Vi antigen (sensitivity to 95%).
• Indirect enzyme-linked immunosorbent assay (ELISA)
for immunoglobulin M (IgM) and IgG antibodies to S
typhi polysaccharide
• Reaction of immune fluorescence - 100 times more
specific then Widal test.
• Polymerase chain reaction (PCR)
PRINCIPLES OF TREATMENT OF
TYPHOID FEVER
• Strict bed rest up to 5-10th day of normal
temperature;
• Diet N 2 up to 5th week of disease;
• Antibacterial treatment up to 10th day of normal
temperature;
• Pathogenic treatment:
• Desintoxication (40 ml/kg per day) PO, IV;
• Vitamins B, C;
• Desensibilisation;
• Glucocorticoids (shock, delirium).
Antibacterial treatment
• Chloramphenicol was used universally to treat
typhoid fever from 1948 until the 1970s, when
widespread resistance occurred.
• Ampicillin and trimethoprim-sulfamethoxazole
(TMP-SMZ) then became treatments of choice.
However, in the late 1980s, some S typhi and S
paratyphi strains developed simultaneous
plasmid-mediated resistance to all three of these
agents.
Antibacterial treatment
• Fluoroquinolones (ciprofloxacin, ofloxacin,
levofloxacin, gatifloxacin) are now
recommended by most authorities for the
treatment of typhoid fever.
• Unfortunately, resistance to first-generation
fluoroquinolones is widespread in many parts
of Asia.
Antibacterial treatment
• Therefore, for strains that originate outside of
south or Southeast Asia, the WHO
recommendations are:
• uncomplicated disease should be treated
empirically with oral ciprofloxacin and
• complicated typhoid fever from these regions
should be treated with intravenous
ciprofloxacin
Guideline for the treatment of typhoid fever in south Asia
(Indian Association of Pediatrics)
• For empiric treatment of uncomplicated typhoid fever, the
IAP recommends cefixime and, as a second-line agent,
azithromycin.
• For complicated typhoid fever, they recommend
ceftriaxone.
Aztreonam and imipenem are second-line agents for
complicated cases.
There is opinion, if the origin of the infection is unknown,
the combination of a first-generation fluoroquinolone and
a third-generation cephalosporin should be used.
the combination of azithromycin and fluoroquinolones is not
recommended because it may cause QT prolongation and is
relatively contraindicated.
PRINCIPLES OF TRATMENT OF TYPHOID FEVER
Drug
Dosage
Duration
Course
Levomycetin
(Chloramfenicol)
Ampicillin,
amoxicillin
Co-trimoxazol
(Biseptol)
Azitromicin
50-75 mg/kg 4 td
14-21
Uncomplicated
75-100 mg/kg 3 td
14
Uncomplicated
8 mg/kg 2 td
14
Uncomplicated
10 mg/kg 1 td
7
Uncomplicated
Ceftriaxon
60 mg/kg 1 td
10-14
Cefotoxim
80 mg/kg 2-3 td
10-14
Cyprofloxacin
20 mg/kg 2 td
10-14
severe,
complicated
severe,
complicated
severe,
complicated
Treatment of GI complication
• Patients with intestinal haemorrhage need intensive care,
monitoring and blood transfusion. Surgical intervention is not
needed unless there is significant blood loss.
• Strict bed rest
• Cold compress on a stomach
• Fasting on 10 – 12 hours
• Further begin feeding by broths, jelly, mousse, kissel
• For stoppage of bleeding – dicinonum, calcium chloride,
vicasolum, aminocapronic acid, plasma
• In the absence of effect – surgical intervention – an intestinal
resection
• Surgical consultation for suspected intestinal perforation is
indicated.
• If perforation is confirmed, surgical repair should not be
delayed longer than six hours.
Prevention
 For travelers
 Buy bottled drinking water or bring it to a rolling boil for one minute before








drinking it.
Ask for drinks without ice, unless the ice is made from bottled or boiled
water. Avoid Popsicles and flavored ices.
Eat food that have been thoroughly cooked and that are still hot and
steaming.
Avoid raw vegetables and food that cannot be peeled like lettuce.
When eat raw fruit and vegetables that can be peeled, peel yourself. Don’t
eat the peelings.
Avoid foods and beverages from street vendors.
Be vaccinated against typhoid while traveling to a country where typhoid is
common.
Need to complete your vaccination at least one week before travel.
Typhoid vaccines lose their effectiveness after several years so check with
your doctor to see if it is time for a booster vaccination.
Indications for Vaccination
1.Travelers going to endemic areas who will be
staying for a prolonged period of time,
2. Persons with intimate exposure to a
documented S. typhi carrier
3. Microbiology laboratory technologists who
work frequently with S. typhi
4. Military personnel
Travelers should be vaccinated at least one
week prior to departing for an endemic area.
Typhoid fever vaccines
• injected Vi capsular polysaccharide (ViCPS;
Typhim Vi, Pasteur Merieux) antigen,
• enteric Ty21a (Vivotif Berna, Swiss Serum
and Vaccine Institute) live-attenuated
vaccine,
• an acetone-inactivated parenteral vaccine
(used only in members of the armed forces).
The efficacy of both vaccines available to the
general public approaches 50%.