OR
Culture positive for acid-fast bacilli but negative sputum smear by direct microscopic
examination.
Confirmed case of extra-pulmonary tuberculosis
A patient with culture positive specimens from an extra pulmonary site, or histological
evidence consistent with active extra-pulmonary tuberculosis followed by a decision by
medical officer to treat with a full course of antituberculosis therapy.
DESCRIPTIVE EPIDEMIOLOGY: (PERSON – PLACE – TIME)
Person
Some personal characteristics increase the risk of tuberculosis. The risk of the
disease increases with the increase of age. In early childhood, both male and female are
equally susceptible. However, with the advance in age, it becomes a disease of elderly
men.
Poor health status and morbid conditions increase the risk of the disease. A latent
infection may be converted into a tuberculous case after an attack of measles,
uncontrolled diabetes mellitus, malignancies, renal failure, major surgeries, mental strain,
HIV/AIDS and the prolonged intake of immunosuppressive drugs. Malnourished
individuals are more prone to tuberculosis because of poor immune system. Also,
tuberculosis may precipitate malnutrition in patients with border line nutrition.
Increased physical activity with heavy work leads to increase in respiration and
circulation enhances the extension of the infection.
Certain occupations increase the risk of contracting the infection and the
development of the disease as healthcare workers and workers exposed to silica dust.
Persons living under low socioeconomic conditions are more prone to the disease.
Illiteracy, unemployment, poor housing condition, overcrowding, and low quality of life are
interrelated factors. These factors contribute to the occurrence and spread of the disease
among the population.
2
The clustering of cases of tuberculosis in families is attributed to the risk of
exposure and not to genetic predisposition or hereditary tendency. The Mycobacteria are
not transferred across the healthy placenta.
Place
Tuberculosis is more prevalent in developing countries. Nowadays it is an
emerging problem in many developed countries. Within countries, it is uniformly
distributed in urban and rural areas. In urban areas, it is found more frequently among
slum dwellers and lower socioeconomic groups.
Time
Since the middle of the 20th century, morbidity and mortality from tuberculosis
showed a declining secular trend due to the improvement of living conditions and the
advancement in antimicrobial chemotherapy (figure1 shows an example).
Figure 1 Declining death rate from respiratory Tuberculosis in England and Wales
over 150 years. Most deaths occurring before antibiotic therapy was available.
(Adapted from McKeown T. 1976)
3
In the 90’s of the previous century, tuberculosis has re-emerged for the following reasons:
1.
Poor performance of tuberculosis control program
•
The program is neglected by governments, leading to the spread of the disease.
•
The poor management of the program contributed to the emergence of drug
resistant strains of Mycobacterium tuberculosis which increases the burden of the
disease.
•
Difficulty and high expenses of treating multi-drug resistant cases is a contributing
factors.
2. Demographic factors
•
The rapid population growth and its sequences such as malnutrition, housing
problems (overcrowding and bad ventilation), and lack of healthcare facilities has
contributed to the increase in the number of cases of tuberculosis.
•
Increase in life expectancy of the population which led to the increase opportunity
for the conversion of a latent infection into clinically evident case.
3. Emerging disease
The emerging problem of HIV/AIDs and its link with tuberculosis led to the increase of
cases of tuberculosis in HIV/AIDS endemic areas. HIV/AIDS destroys the immune
system and activate the disease in previously infected individuals.
CYCLE OF INFECTION
Causative agent
Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis that
belongs to the genus Mycobacteria. The organism commonly affects the lungs causing
pulmonary tuberculosis and less commonly affects other body sites causing
extrapulmonary tuberculosis.
The Mycobacteria are aerobic rod-shaped non-spore forming organisms. Although
they do not stain readily, once stained they resist decolorization by acid and are therefore
called “acid fast” bacilli. The high lipid content (mycolic acid) of their cell wall makes
Mycobacteria acid and alcohol fast.
4
The commoner species are classified into two groups:
1.
Typical Mycobacteria includes human type (M. tuberculosis) and bovine type
(M. bovis) and closely related species in the M. tuberculosis complex. They cause
chronic diseases producing lesions of the infectious granuloma type that affect man.
They are acid fast and alcohol fast. Another form of Mycobacteria that is pathogenic to
man is Mycobacterium leprae.
2.
Atypical Mycobacteria (Nontuberculous Mycobacteria (NTM)): Mycobacteria
other than typical tubercle bacilli (MOTT bacilli) include
2.1. Commensals as smegma bacilli (M. smegmatis) which are normally present
around the urethra in males and females. They are acid fast but not alcohol fast.
2.2. Saprophytic which are normally found in soil and water, but occasionally cause
opportunistic infections in man.
Morphology
Mycobacterium tuberculosis are thin straight or slightly curved rods which may
show beading. They are non-motile, non-spore forming and non-capsulated. They are
acid fast (25% H2SO2) and alcohol fast bacilli. Stained by either Ziehl Neelsen stain (ZN)
or fluorochrome stain (figure 2a).
Figure 2a: Acid Fast bacilli by
ZN stain
Figure 2b: Colonies of
M. tuberculosis on L.J. media
5
Cultural characters
Mycobacteria are obligate aerobes. Optimum temperature for growth is 37°C
incubated for 2 to 8 weeks (they grow slowly) with weekly inspection for growth (figure
2b). They can grow on media containing complex organic substances including:
•
Dorset egg and egg saline media; are enriched egg media.
•
Selective media as Lowenstein Jensen media (L.J.) containing malachite green to
inhibit bacteria other than Mycobacteria.
Sensitivity to physical and chemical agents
Mycobacteria are killed by moist heat at 60°C for 15-20 min. So, pasteurization
renders milk safe. They are susceptible to sunlight and ultraviolet rays. Mycobacteria tend
to be more resistant to chemical agents than other bacteria as malachite green and
antibiotics as penicillin so they can be incorporated into the media to inhibit bacteria other
than tubercle bacilli. Also, they can resist acid and alkali (used for decontamination of the
specimen). Tubercle bacilli are resistant to drying for long periods and 5% phenol for
several hours.
Reservoir of infection
In human type, the reservoir of infection are cases of pulmonary tuberculosis with
positive sputum for acid fast bacilli. In bovine type, the reservoir is infected cattle.
Source of Infection
The source of infection is respiratory secretions of a case of pulmonary
tuberculosis who excrete large numbers of tubercle bacilli. Unpasteurized milk of cattle
affected by tuberculosis is the source of infection in bovine tuberculosis.
Portal of exit
The portal of exit for the human type is the respiratory tract where organisms leave
the body via the nose and mouth. For the bovine type, the exit is the udder of infected
cattle where organisms are liberated with the milk.
Portal of inlet
The portal of entry is the nose and mouth in case of human tuberculosis. In the
bovine type the organisms enter through the mouth.
6
Mode of transmission
1. Contact transmission: droplet transmission and less commonly indirect contact
with contaminated articles (fomites or dishes)
2. Airborne transmission: droplet nuclei and dust nuclei
3. Common vehicle: the vehicle of transmission is unpasteurized milk and dairy
products
Period of communicability
Tuberculosis is a disease of moderate communicability as measured by the
secondary attack rate (48%). Patients are infective as long as they remain untreated;
effective treatment reduces infectivity by 90% within 48 hours. Communicability is
affected by the characteristics of the case and contacts as well as environmental factors.
•
Characteristics of the case: clinical type, frequency of cough, amount of sputum
and level of personal hygiene.
•
Characteristics of contacts: resistance, age, and closeness with the case.
•
Environmental
factors: level of crowdedness, ventilation
and
measures
of
disinfections.
Susceptibility
Susceptibility is general
but
higher among individuals with personal
characteristics favoring acquiring the infection and developing the disease. The immunity
is cell mediated depending on cellular proliferation. Immunity is either a natural active
immunity
following
infection
or
artificial
active
immunity
following
vaccination. Newborns do not acquire passive natural immunity from their mothers.
7
BCG
PATHOLOGY & PATHOGENESIS
Pathogenesis and immunity
1. At the time of exposure, organisms in droplets of 1-5 u are inhaled and reach the
alveoli.
2. Tubercle bacilli spread in the host by direct extension, and through the lymphatic
channels and blood stream (in case of infection by M. bovis, it is transmitted by ingestion
of milk from infected cows and causes intestinal tuberculosis).
3. The organism acquires intracellular location inside macrophages and cells of
reticuloendothelial system.
4. Once M. tuberculosis enters the respiratory airways, they are phagocytized by
alveolar macrophages. In a large percent of macrophages M. tuberculosis prevents
fusion of the phagosome with lysosomes protecting itself from intracellular killing. In
response, macrophages secrete interleukin (IL)-12 and tumor necrosis factor (TNF)-α,
that induce cell mediated immune response, with recruitment of T cells and natural killer
(NK) cells into the area of the infected macrophages, inducing T-cell differentiation into
TH1 cells (T-helper cells), with subsequent secretion of interferon (IFN)-γ.
5. Primary infection (the first contact with tubercle bacilli) results in an acute exudative
lesion in the lung which spreads to the lymphatics and regional lymph nodes (Gohn’s
complex).
6. Granuloma formation: Alveolar macrophages, epithelioid cells, and Langhans
giant cells (fused epithelioid cells) with intracellular Mycobacteria become organized to
form the central core of a necrotic mass that is surrounded by a dense wall of
macrophages and T cells. This structure is called granuloma. It prevents further spread
of the bacteria. If a small antigenic burden is present at the time the macrophages are
stimulated, the granuloma is small and the bacteria are destroyed with minimal tissue
damage. However, if many bacteria are present, the large necrotic or caseous
granulomas become encapsulated with fibrin.
7. The bacteria can remain dormant (latent tuberculosis) in this stage or can be
reactivated years later when the patient’s immunologic responsiveness wanes as the
result of old age or immunosuppressive disease or therapy (reactivation).
8
Extra pulmonary tuberculosis can occur as the result of the hematogenous spread of
the bacilli during the initial phase of multiplication.
CLINICAL PICTURE
Incubation period
The incubation period is 4 to 12 weeks from infection until the appearance of the
primary lesion. The period between the infection to the development of progressive
pulmonary or extra-pulmonary tuberculosis is about 6- 12 months or may be longer.
Signs and symptoms
Tuberculosis is called general simulator, so it can present with any symptom or
sign, and these symptoms and signs are different according to the site of infection and
according to the immune status of the patient.
Symptoms
1. General symptoms
1.1. Asymptomatic discovered accidentally.
1.2. Tiredness and malaise.
1.3. Loss of weight, appetite, night fever and sweating.
1.4. Recurrent colds.
1.5. Amenorrhea.
2. Chest symptoms
2.1. Persistent cough
2.2. Sputum production of different quantity or color
2.3. Hemoptysis; yet never diagnostic or specific for tuberculosis
2.4. Chest pain varies from a dull ache, chest tightness to pleuritic pain
2.5. Wheezes and dyspnea may occur in patients with endobronchial tuberculosis
Signs
1. Chest examination
1.1. No signs.
1.2. Signs localized to the upper zones of chest: crepitation
1.3. Signs of cavitation, or fibrosis.
9
1.4. Localized or generalized wheezes.
1.5. Signs of consolidation, collapse or fibrosis.
2. General examination
2.1. Pallor and cachexia.
2.2. Fever, increase in heart rate and respiratory rate.
2.3. Clubbing is unusual.
DIAGNOSIS
Radiologic diagnosis
Chest x-ray is a very important tool for increasing the sensitivity of the diagnosis
of tuberculosis and is considered part of the local examination of chest in suspected cases
of tuberculosis.
In chest x-ray, tuberculosis can be presented as consolidation, fibrosis, cavitary
changes, pleural effusion or even as miliary pattern (figure 3). Other modalities of
radiology like CT, MRI and ultrasound give more information and help more in the
diagnosis of extra pulmonary tuberculosis.
Figure 3: Chest radiographs of pulmonary tuberculosis
10
Laboratory diagnosis
1. Laboratory diagnosis of active tuberculosis
Diagnosis is generally done by demonstrating the presence of tubercle bacilli in a
clinical specimen.
1.1. Specimens
The specimen depends on the site of infection. The specimen in pulmonary
tuberculosis is early morning sputum for three successive days. When sputum is not
expectorated, gastric lavage or bronchial lavage could be done. The specimen in extrapulmonary tuberculosis is urine, pleural fluid, cerebrospinal fluid, joint fluid, biopsy
material, or any other suspected material depending on the site of infection.
1.2. Direct smear for microscopy of collected specimens
Specimens are stained by Z.N. stain or fluorochrome stain. Microscopy is cheap
and has high specificity but low sensitivity. A positive acid-fast stain reaction corresponds
to higher infectivity.
1.3. Culture
Sputum culture is required to confirm the diagnosis in suspected cases whose
sputum smear is negative and to detect the sensitivity of bacilli to drugs especially in drug
resistant cases.
Specimens such as sputum are initially treated with a decontaminating reagent
(e.g. 2-4% sodium hydroxide) to eliminate colonizing organisms. Mycobacteria can
tolerate brief alkali treatment that kills the rapidly growing bacteria and permits selective
isolation of Mycobacteria.
•
Conventional culture: specimens inoculated onto egg-based (e.g. Löwenstein-
Jensen) and agar-based (e.g. Middlebrook) media generally take from 2- 8 weeks for
M. tuberculosis to be detected.
•
Automated culture systems: different automated culture systems are available that
offer continuous monitoring of Mycobacterial growth in broth media; through the
detection of bacterial metabolism as oxygen consumption and pH changes in the media
(e.g. BacT/ALERT shown in figure 4).
11
Figure 4: BacT/ALERT automated system
1.4. Identification from culture
Identification of the organism from culture is by Z.N. stained film, colonial
morphology from solid media and biochemical reactions including ability to grow on media
containing PNBA. Both human and bovine types do not grow on paranitrobenzoic acid
medium (PNBA).
1.5. Molecular diagnosis
A variety of molecular techniques were developed to rapidly detect specific
mycobacterial nucleic acid sequences present in clinical specimens (e.g. PCR and
probes).
Gene expert is an example of commercial molecular assays currently used for
screening for tuberculosis. It can detect M. tuberculosis in clinical specimens as well as it
can determine the susceptibility to rifampin; a marker for multidrug resistant (MDR)
strain.
N.B; MDR-TB:- Tuberculosis strains that are resistant to both rifampicin and isoniazid.
1.6. Susceptibility testing of Mycobacteria
Susceptibility of Mycobacteria to different antituberculosis drugs is important for
selection of effective therapy.
12
2. Laboratory diagnosis of latent tuberculosis
These tests assess the patient’s immunological response to exposure to M.
tuberculosis. Following the primary infection, a state of hypersensitivity (allergy) develops
to tubercle bacilli and the patient has sensitized T-cells to the tubercle bacilli.
2.1. Tuberculin test
•
Type of test: Tuberculin test is an intradermal test that is used to detect the state
of cell mediated hypersensitivity to tubercle bacilli.
•
Materials used: Purified protein derivative (PPD which is mycobacterial antigens.
•
Methods of tuberculin test: Mantoux test
-
This is the standard method with which all other methods are compared. A test
dose of PPD 5 tuberculin units is injected intradermally into the skin of the anterior
aspect of the forearm.
•
The site is examined and palpated 48-72 hours later. The development of an area
of palpable, firm induration equal or greater than 10 mm in diameter is recorded as
positive. A positive reaction usually develops 4 to 6 weeks of the exposure to M.
tuberculosis.
•
Interpretation of tuberculin test: A positive tuberculin test indicates that the
individual has been infected. It does not imply that active disease or immunity to the
disease is present; but there is a risk of developing reactivation from the primary latent
infection. Latent tuberculosis is a condition in which a person is infected with
Mycobacterium tuberculosis bacilli but does not currently have active disease.
• Value of tuberculin test is
-
The study of the epidemiology of tuberculosis in surveys. It is the only mean of
estimating the prevalence of infection in a population especially among children (in
countries where BCG vaccination is not obligatory).
-
Before BCG vaccination to identify tuberculin negative who are eligible for
vaccination
-
Evaluate the effectiveness of BCG vaccine as BCG vaccine converts tuberculin
negative persons to tuberculin positive.
- The test eliminates tuberculosis from the differential diagnosis of any disease.
13
- The test is capable of detecting latent tuberculosis
• Limitations of tuberculin testing are
-
Tuberculin test is of little value as a diagnostic tool for case finding of
tuberculosis because it cannot differentiate between active and latent infection as well
as the presence of false negative and false positive results.
-
Causes of false negative results include; early in the infection (incubation period)
and immunosuppression as in HIV/AIDS patients.
-
Causes of false positive results include; BCG vaccination and infection with
atypical Mycobacteria.
2.2. Interferon-gamma release assays for detection of latent tuberculosis (IGRAs)
If an individual was previously infected with M. tuberculosis, exposure of sensitized T
cells, present in whole blood, to M. tuberculosis specific antigen results in IFN-γ
production. Thus, on stimulation of these sensitized cells by specific M. tuberculosis
antigens (absent from atypical Mycobacteria and BCG strain), they produce interferongamma in high amounts. This interferon-gamma can be measured using the interferongamma release assays (IGRAs) which are used to detect latent tuberculosis.
Advantages over tuberculin skin test are: results are not affected by prior BCG
vaccination or atypical mycobacterial infection (i.e. more specific) and it requires only
one patient visit.
DRUGS USED FOR THE TREATMENT OF TUBERCULOSIS
Drugs used for the treatment of tuberculosis are categorized into first line drugs
and second line drugs.
1. First line drugs are for drug susceptible tuberculosis. These drugs combine
the greatest level of efficacy with an acceptable degree of toxicity. First line drugs
include isoniazid, rifampin, pyrazinamide, and ethambutol. The large majority of
patients with tuberculosis can be treated successfully with those drugs.
2. Second line drugs are for drug resistant tuberculosis.
14
Antituberculosis drugs are used in combination to produce the following effects:
1. Rapid reduction in the number of actively growing bacilli in the patient, thereby
decreasing severity of the disease, preventing death and halting transmission of M.
tuberculosis.
2. Eradicate persistent bacilli in order to achieve durable cure (prevent relapse) after
completion of therapy
3. Prevent of emergence of drug resistance strains of M. tuberculosis
1. FIRST-LINE DRUGS
1.1. ISONIAZID (INH)
Anti-mycobacterial activity
Isoniazid is a first-line agent for treatment of all forms of tuberculosis. It has profound
early bactericidal activity against rapidly growing bacilli. It also penetrates cells with ease
and thus is able to act on intracellular bacteria. It is very effective against rapid
multipliers.
Pharmacokinetics
Isoniazid is readily absorbed from the gastrointestinal tract. It diffuses into all body
fluids and tissues including cerebrospinal fluid. It is rapidly diffuse inside the cell, thus
intracellular and the extracellular levels are similar. Isoniazid undergoes N-acetylation
and hydrolysis, resulting in inactive products.
Mechanism of action
Isoniazid is a prodrug that is activated by the mycobacterial catalase-peroxidase. It
inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell
walls.
Therapeutic uses
Isoniazid is used for treatment of tuberculosis in combination with other
antituberculosis drugs. It is also used as chemoprophylaxis, to prevent the disease
among exposed individuals and contacts of newly diagnosed case of tuberculosis.
Duration of chemoprophylaxis is 6-9 months.
15
Adverse drug reactions
Isoniazid is well tolerated; incidence of side effects is 5.4 %. Adverse effects include:
•
It interferes with pyridoxine metabolism by inhibiting the formation of the active form
of the vitamin. Pyridoxine output in urine is increased. The principal effect is peripheral
neuropathy with numbness and tingling of the feet.
•
Liver injury ranges from moderate elevation of hepatic enzymes to severe hepatitis
with fatal outcome. The risk of hepatitis is greater in older age groups and in
alcoholics. Routine monitoring is not necessary. However, for patients who have
preexisting liver disease, liver function tests should be done monthly.
•
Mental disturbances, and ataxia may also occur.
•
Hemolysis in glucose-6-phosphate dehydrogenase deficiency.
•
Systemic lupus erythematosus-like syndrome.
•
Hypersensitivity reactions.
Drug interactions
▪
Isoniazid may precipitate convulsions in epileptic patients
▪
Isoniazid inhibits the metabolism of some antiepileptic drugs e.g., carbamazepine and
ethosuximide, which causes symptoms of overdosage; (excessive sedation).
1.2. RIFAMPIN (RIF)
Anti-mycobacterial activity
•
Rifampin (RIF) has activity against organisms that are rapidly multiplying (early
bactericidal activity), slowly multiplying (dormant) and intermittently multiplying (semidormant) bacterial populations, thus accounting for its sterilizing activity.
N.B. RIF inhibits the growth of most gram-positive (Staphylococcus aureus) and
many gram-negative micro-organisms, such as E. coli, Neisseria meningitidis, and
Haemophilus influenzae.
Pharmacokinetics
•
The drug is well absorbed after oral administration. It is partly metabolized in the
liver. Rifampin and its metabolites are eliminated in mainly bile and feces
•
It is a cytochrome P450-inducer and increases its own metabolism (as well as that
of several other drugs).
16
•
Rifampin crosses cell membranes and so can attack intracellular bacilli. The drug
penetrates well into most tissues including the meninges and reaches CSF in effective
concentration, particularly if they are inflamed.
•
Rifampin metabolites may impart an orange-red color to the urine, feces, saliva,
sputum, sweat, tears, and contact lenses; thus the patients should be warned.
Mechanism of action
Rifampin acts by inhibiting RNA synthesis. It binds strongly to bacterial DNAdependent RNA polymerase, thus inhibits RNA synthesis in bacteria. Human RNA
polymerase is not affected.
Adverse drug reactions
•
An influenza-like syndrome (The flu-syndrome) with fever, chills, and myalgias may
develop in 20 % of patients on an intermittent schedule (less than twice weekly) due to
sensitization, this may extend to acute renal failure.
•
Hepatotoxicity may occur. It is more common when the drug is given in
combination with INH. Liver functions monitoring should be performed when the drug is
used in old patients and those with underlying liver disease.
•
Cutaneous reactions, such as pruritis, may occur in some persons taking
rifampin. They are generally self-limited and may not be a true hypersensitivity;
continued treatment may be possible.
•
Rarely, rifampin can be associated with hypersensitivity reactions and
thrombocytopenia; associated with the presence of circulating IgG and IgM antibodies.
Drug interaction
•
Rifampin is a powerful inducer of hepatic drug metabolizing enzymes
(cytochrome P450). It interacts with a number of drugs (including warfarin and hormonal
contraceptives). Women using hormonal contraceptives should be advised to consider
an alternative method of contraception.
17
1.3. ETHAMBUTOL
Anti-mycobacterial activity
Ethambutol is included in the initial treatment regimens primarily to prevent emergence
of resistance to rifampin when primary resistance to isoniazid may be present.
Pharmacokinetics
•
Over 75% of the drug is absorbed from GIT after oral administration. It enters most body
tissues.
•
Insignificant amounts of ethambutol crosses into the CSF if the meninges are not
inflamed, but in tuberculous meningitis sufficient amounts may reach the CSF to inhibit
mycobacterial growth. It is eliminated mainly unchanged in urine. It needs dose
adjustment in renal impairment.
Mechanism of action
Ethambutol inhibits mycobacterial synthesis of arabinoglycan, an essential component
of mycobacterial cell wall.
Adverse drug reactions
•
Optic neuritis: The main problem is ocular damage with diminished visual acuity
and red-green color blindness. These effects are dose related and occur in less than 1
% of patients. Recovery usually occurs when ethambutol is withdrawn. If the drug is not
stopped the patient may go into blindness. Patients should have baseline visual acuity
testing and testing of color discrimination. At each monthly visit, patients should be
questioned regarding possible visual disturbances including blurred vision or visual field
defect.
•
Elevation of plasma uric acid (due to inhibition of renal tubular secretion of uric acid).
•
Peripheral neuritis is frequent.
Ethambutol is not recommended for children under 13 years of age because of concern
about the ability to test their visual acuity reliably.
18
1.4. PYRAZINAMIDE (PZA)
Anti-mycobacterial activity
Pyrazinamide is believed to exert greatest activity against the population of dormant or
semidormant (slow multiplier) organisms which might cause relapse.
Pharmacokinetics
Pyrazinamide is well absorbed from GIT after oral administration. It is widely distributed
throughout the body and CSF. It is partly metabolized in the liver. Parent drug and
metabolite are excreted in urine
Mechanism of action
Pyrazinamide is a prodrug, which is converted to the active form “pyrazinoic acid” by
the enzyme pyrazinamidase that is found in Mycobacterium tuberculosis. The product
pyrazinoic acid lowers intracellular pH, inactivates a vital enzyme in fatty acid synthesis
and destroys the Mycobacteria.
Adverse drug reactions
•
Liver injury: Liver functions monitoring should be performed when the drug is used
in patients with underlying liver disease
•
Non-gouty
polyarthralgia:
This
rarely
requires
dosage
adjustment
or
discontinuation of the drug. The pain usually responds nonsteroidal antiinflammatory agents.
•
Asymptomatic hyperuricemia: This is an expected effect of the drug and is
generally without adverse consequence.
•
Acute gouty arthritis: Acute gout is rare except in patients with pre-existing gout,
generally a contraindication to the use of the drug.
Regimens for treatment of drug –susceptible tuberculosis
➢
Empiric treatment with a 4-drug regimen should be initiated promptly even before
the results of acid-fast bacilli (AFB) smear microscopy, molecular tests, and
mycobacterial culture are known. The preferred regimen is a regimen consisting of an
intensive phase of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol
followed by a continuation phase of 4 months of INH and RIF.
19
➢
During the initial phase, the majority of tubercle bacilli are killed, symptoms resolve
and the patient usually becomes non-infectious.
➢
The continuation phase is required to eliminate the dormant bacilli.
➢
Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (e.g.
pregnant women, breastfeeding infants, persons infected with human immunodeficiency
virus; patients with diabetes, alcoholism, malnutrition, or chronic renal failure, or those
who are of advanced age).
➢
With respect to administration schedule, the preferred frequency is once daily for
both the intensive and continuation phases.
2.
SECOND-LINE DRUGS
Second-Line anti-Tuberculosis drugs are less effective but more toxic than isoniazid
and rifampicin. They are used in different combinations for drug resistant tuberculosis.
These drugs are also used in the case of patient’s intolerance to first line agents
(hypersensitivity or toxicity). They include the following:
2.1. Oral agents
2.1.1.
Fluoroquinolones - Moxifloxacin - Levofloxacin
2.1.2.
Thioamides - Ethionamide - Prothionamide
2.1.3.
Linezolid
2.1.4.
Cycloserine
2.1.5.
Para-aminosalicylic acid
2.1.6.
Clofazimine
2.1.7.
Delamanid
2.1.8.
Bedaquiline
2.2. Parenteral agents
2.2.1. The second-line injectable agents: they are collectively referring to the
aminoglycosides: amikacin, kanamycin, and the cyclic polypeptide capreomycin. These
are administered intravenously or by intramuscular injection.
2.2.2. Carbapenems:
Imipenem/cilastatin and meropenem.
lactam/carbapenems are only given intravenously
20
These
beta-
TREATMENT STRATEGY - DOTS
The direct observation therapy with short course chemotherapy (DOTS) is the
recommended strategy for the control of tuberculosis.
Criteria of potent DOTS
•
Short course therapy for a duration of six months under the observation of a
healthcare worker at home or in a specialized healthcare facility.
•
The use of four drugs (INH, rifampin, pyrazinamide, ethambutol) for an initial period
of two months followed by two drugs (INH, rifampin) for four months as a continuation
phase.
•
The priority for treatment with DOTS are smear positive pulmonary case.
•
The treatment should be monitored with sputum smear examination at the end of the
initial phase and at the end of the course.
The basis of the use of the four drugs
In cases of pulmonary tuberculosis, the causative agent is present in three forms and
their sensitivity to antituberculosis drugs are variable.
•
Rapid multipliers, found near the walls of pulmonary cavities, are sensitive to
isoniazid.
•
Slow multipliers, the intracellular form, are sensitive to pyrazinamide
•
Intermittent multipliers or persisters, responsible for the relapse, are sensitive to
rifampin.
Advantages of DOTS
•
Rapid cure i.e. elimination of both rapid and slow multipliers from the patient’s body.
•
Low failure rate.
•
Reduce the emergence of drug resistant strains.
•
Improve patient’s compliance
The only disadvantage of DOTS is the high cost.
21
MULTIDRUG RESISTANT TUBERCULOSIS (MDR-TB)
Multidrug resistant strain of tuberculosis is an organism that is resistant to at least
isoniazid and rifampin, the two most potent drugs.
Magnitude of the problem
In 2015, an estimated 480,000 people worldwide developed MDR-TB, and an additional
100,000 people with rifampin-resistant tuberculosis were also newly eligible for MDRTB treatment. India, China, and the Russian Federation accounted for 45% of these
580,000 cases. It is estimated that about 9.5% of these cases were extensively drug
resistant tuberculosis (XDR-TB); a rare type of MDR-TB that is resistant to isoniazid and
rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs
(i.e. amikacin, kanamycin, or capreomycin).
Patients at risk of MDR-TB are those who
•
Do not take their antituberculosis medications regularly
•
Do not take all of their antituberculosis medications as instructed by the treating
physician
•
Develop tuberculosis again, after having taken antituberculosis medications in the
past
•
Come from areas of the world where drug-resistant tuberculosis is common
•
Have spent time with someone known to have drug-resistant tuberculosis
Prevention of MDR-TB
The most important measure to prevent the spread of MDR-TB is full compliance with
the prescribed regimen; patients should not miss a dose or stop the treatment
prematurely. Patients should discuss with the treating physician the reason of their poor
compliance such as drug side effects, cost of medications or unavailability of
medications.
Healthcare providers can help prevent MDR-TB by quickly diagnosing cases, following
recommended treatment guidelines, monitoring patients’ compliance and response to
treatment.
Infection with MDR-TB can be prevented by avoiding the exposure to a known MDR-TB
patient in closed or crowded places such as hospitals, prisons, or homeless shelters.
22
Personnel working in hospitals or healthcare settings where cases of tuberculosis are
likely to be seen, should consult infection control team or occupational health experts
for the suitable respiratory protective devices.
Control measures for drug-resistant tuberculosis
•
Cure cases of tuberculosis the first time they are around
•
Provide access to diagnosis
•
Ensure adequate infection control in facilities where patients are treated
•
Ensure the appropriate use of recommended second-line drugs.
PREVENTION OF TUBERCULOSIS
1. Community development is highly needed to overcome the socioeconomic factors
that contribute to the occurrence and spread of the disease.
2. Health education of the public regarding the modes of transmission, methods of
control and the importance of early diagnosis and compliance with treatment.
3. Pasteurization of milk is a preventive measure of public health importance to
prevent bovine tuberculosis.
4. Immunization of eligible population using BCG vaccine; a live attenuated variant
vaccine prepared from bovine tubercle bacilli. In developing countries, including Egypt,
the vaccine is compulsory for infants and children. It could be administered immediately
after birth since cell mediated maternal immunity cannot be transferred to the fetus. In
countries with low prevalence rate of tuberculosis, BCG vaccine is restricted to the high
risk groups as tuberculin negative contacts of a sputum positive case of pulmonary
tuberculosis, industrial workers exposed to silica and healthcare personnel.
BCG efficacy is more than 80% in preventing tuberculous meningitis and miliary
tuberculosis in children. Among adults, BCG does not prevent infection but it possibly
decreases the probability of progression of the infection to active disease.
BCG could be kept frozen in dark bottles to prevent its damage by direct sunlight. In
health center, it is stored between +2°C and +8°C. The vaccine is in a freeze dried form
and is reconstituted in saline and used within six hours after reconstitution. Cleaning the
23
site of injection with local antiseptic is not recommended as it may damage BCG
vaccine.
Adverse event associated with BCG vaccine include local reaction characterized by
severe, unhealed and prolonged ulceration and lymphadenitis. The risk of local
reactions is related to the BCG strains produced by the manufacturer, the high dose
of the inoculum and the accidental subcutaneous administration of the vaccine.
Disseminated infection and death is rare and are associated with defects in cellular
immunity.
BCG vaccine should not be given to immuno-compromised individuals as HIV/AIDS
patients, patients suffering eczema, and malignancies as well as those on
immunosuppressive therapy.
CONTROL OF TUBERCULOSIS
1.
Report of cases to local public health authorities of cases meeting the standard
case definition of tuberculosis.
2.
Isolation of cases at home, if the home condition is suitable, is cost effective.
Hospitalization is necessary only for patients with severe illness and for those whose
medical and social circumstances make treatment at home impossible.
3.
Treatment of cases promptly using first-line drugs and preferably following the
DOTS strategy. Case finding and treatment is considered the best measure for the
control of tuberculosis.
4.
Concurrent and terminal disinfections of patient’s sputum are recommended.
Decontamination of air may be achieved by ventilation; this may be supplemented by
ultraviolet light. Hand washing and good housekeeping should be maintained.
5.
Enlistment and investigation of contacts of cases of tuberculosis: Prompt contacts
investigation is essential to identify any other TB cases. Contacts should be screened
by clinical manifestations, TST, chest X-ray and sputum examination if required. For
adult household contacts who have persistent cough for more than 2 weeks or more,
collect 3 sputum samples for examination. Asymptomatic contacts should be managed
24
as shown in Figure (5). Children household contacts aged < 5 years who are not active
TB on clinical evaluation should receive chemoprophylaxis.
Figure 5: Algorithm for the investigation and management of contacts of a case of
pulmonary tuberculosis
25
INFLUENZA
Influenza is an acute infection of the respiratory tract different from common cold;
influenza is caused by a different virus and usually more severe. The World Health
Organization estimates that nearly one billion people are infected and up to 500 000 die
from influenza each year. The greatest burden of the illness is usually among children,
while the highest burden of severe disease (hospitalization and death) is among those
with medical problems, infants, children, and elderly.
STANDARD CASE DEFINITION: NOVEL INFLUENZA A
Suspected case
A case meeting the clinical criteria of influenza virus infection (fever > 37.77 o C, with
cough and/or sore throat) pending laboratory confirmation.
Probable case
A case meeting the clinical criteria and epidemiologically linked to a confirmed case,
but for which no confirmatory laboratory testing for influenza virus infection has been
performed or test results are inconclusive for a novel influenza A virus infection.
Confirmed case
A case of human infection with a novel influenza A virus confirmed by the CDC
influenza laboratory or using methods agreed upon by CDC.
OCCURRENCE
Influenza occurs as pandemics, epidemics and seasonal or sporadic cases. Influenza
epidemics occur almost every year but pandemics are rare. Epidemics are caused
mainly by type A virus and occasionally by type B virus or both. Epidemics occur without
any regular periodicity and last, generally, for 3 to 6 weeks but the virus remains for a
variable numbers of weeks before and after the epidemic. Epidemics are more likely to
occur during the winter in temperate areas and during the rainy seasons in the tropics
but outbreaks or sporadic cases may occur in any month.
26
During epidemics, the attack rates range from 10% to 20% in the general community
to more than 50% in closed communities (such as nursing homes and schools).
Preschool and school age children are predominantly affected during the initial phase
of the epidemic while adults are affected during a subsequent phase.
CYCLE OF INFECTION
Causative agent
The causative agent is influenza viruses (orthomyxoviruses). The viruses receive their
name from their special affinity to mucous containing surfaces with no viremic spread.
Four antigenic types of influenza viruses are known, designated as A, B, C and D based
on different ribonucleoprotein antigens. Antigenic changes continually occur within type
A and to a lesser degree in type B, whereas type C is antigenically stable.
Morphology (figure 1)
•
Spherical in shape (filamentous
forms occur).
•
Helical nucleocapsid with a core of
segmented ss RNA to which protein
capsomeres
are
attached.
RNA
genome of influenza A and B viruses
occurs as eight separate segments.
Each of the RNA eight segments
Figure1: Orthomyxovirus
encodes a certain viral protein.
•
The segmented nature of the genome is an important cause of the high
reassortment frequency exhibited by these viruses.
•
The nucleocapsid is surrounded by a lipid-containing envelope derived from the
host cell. Two virus encoded glycoproteins, hemagglutinin (HA) and neuraminidase (NA)
are inserted into the envelope and are exposed as spikes on the surface of the particle
(figure 1). These two surface glycoproteins determine antigenic variation of influenza
viruses and host immunity.
27
•
Influenza A viruses are divided into subtypes based on hemagglutinin (HA) and
neuraminidase (NA). So far, 18 subtypes of HA (H1-H18) and 11 subtypes of NA (N1N11), in different combinations have been recovered from humans and animals. Current
subtypes of influenza A virus that routinely circulate in humans include: A(H1N1) and
A(H3N2).
Hemagglutinin spikes (HA)
The HA protein derives its name from its ability to agglutinate erythrocytes. The HA
protein binds viral particles to susceptible cells and is the major antigen against which
neutralizing (protecting) antibodies are directed. Variability in HA is primarily responsible
for the continual evolution of new strains and subsequent influenza epidemics.
Neuraminidase spikes (NA)
They are mushroom shaped protrusions, antigenically distinct from hemagglutinins. NA
functions at the end of the viral replication cycle to facilitate the release of viral particles
from the surface of infected cell during the budding process and thus helps prevent selfaggregation of virions. It is possible that NA helps the virus negotiate through the mucin
layer in the respiratory tract to reach the target epithelial cells.
Antigenic drift and antigenic shift
Mutability and high frequency of genetic reassortment and resultant antigenic changes
in the viral surface glycoproteins are characteristic of influenza viruses. The two surface
antigens undergo antigenic variation independent of each other. Two types of antigenic
changes occur in influenza viruses: minor antigenic change and major antigenic change
(figure 2).
Figure 2: Antigenic shift and antigenic drift
28
Minor antigenic change (antigenic drift)
Antigenic drift occurs as a result of the accumulation of a single mutation in the gene,
resulting in amino acid amino acid changes in the protein. Sequence changes can alter
antigenic sites on the glycoprotein, thus a new strain showing minor differences from
the strain of the previous year emerges and can escape recognition by the host’s
immune system. These drifts which occur gradually from season to season, allow some
degree of infection to continue. Infectivity persists because type-specific immunity is not
entirely protective against drifting strains. It results in smaller epidemics at intervals of
2–3years.
Major antigenic changes (antigenic shift)
Antigenic shift occurs at a longer period of 10–40 years, usually causing worldwide
pandemics. It reflects drastic changes in the sequence of a viral surface protein, caused
by genetic reassortment between human, swine and avian influenza viruses, resulting
in the appearance of an entirely new subtype. Only influenza A undergoes antigenic
shift, presumably because types B and C are restricted to humans.
The epidemiologic pattern of influenza viruses varies: Influenza virus type A and B
cause seasonal epidemics; only type A can sweep across continents causing
pandemics. Influenza virus type C cause mild, sporadic respiratory illness.
Pandemics related to influenza type A antigenic shift
•
1918 (H1N1) Spanish flu
•
1957 (H2N2) Asian flu
•
1968 (H3N2) Hong Kong flu
•
1977 (H1N1) Russian flu; reemerged without epidemic.
•
2009 (H1N1pdm09); formerly known as swine flu.
29
Figure 3: Human-avian-swine
flu viruses reassortment in
pigs
The 2009 H1N1
The 2009 H1N1 virus was a novel virus of swine-origin. It was a quadruple reassortant
virus containing genes from North American and Eurasian swine viruses as well as from
avian and human influenza viruses (figure 3). The currently circulating influenza A(H1N1)
viruses are related to the virus of the 2009 N1H1 pandemic. These H1N1 viruses have
undergone relatively small genetic changes and antigenic changes over time. Influenza
A (H3N2) viruses, also currently circulating, tend to change more rapidly, both
genetically and antigenically.
Avian influenza
The first documented infection of humans by avian influenza A virus (H5N1) occurred
in Hong Kong in 1997. The source was domestic poultry. Isolates from human cases
contained all RNA gene segments from avian viruses indicate that the virus jumped
directly from birds to humans across the species barrier. To-date, evidence indicates
that close contact with diseased birds was the source of human H5N1. The virus does
not appear to be transmissible among humans.
A pandemic can occur following the emergence of new influenza virus capable of
infecting humans causing serious illness and spread from person to person without any
contact with birds.
Influenza virus strain designation
It has become necessary to design a system of nomenclature to compare the nature
of the virus strains as they mutate year by year. The standard nomenclature system for
influenza virus isolates includes the following information (figure 4):
30
1. The antigenic type (A, B, C or D).
2. Host of origins swine, equine, avian, etc. For human isolates, designation is not
given for the host of origin.
3. Geographical origin.
4. Strain number and year of isolation.
5. Antigenic
hemagglutinin
designation
of
the
and neuraminidase i.e.
subtype (for type A).
Examples:
A/ Hong Kong/ 1/68 (H3, N2).
A/Swine/New Jersey/8/76 (H1, N1).
Figure 4: Influenza virus strain
A/Turkey/Wisconsin/1/66 (H5, N2).
designation
A/Poultry/Hong Kong/1/97 (H5, N1); Avian
flu
B/USSR/100/83.
Reservoir of the infection
•
Influenza A: Human are the primary reservoir. Influenza A strains also affect
aquatic birds, ducks, turkeys, chickens, geese, pigs, horses and seals.
•
Influenza types B and C: They circulate only in humans.
•
Influenza D: Primarily affect cattle and are not known to infect or cause illness in
men.
Source of infection
The source of infection is the discharges from nose, throat.
Portal of exit and inlet
The portal of exit is the respiratory system where organisms leave via the mouth and
nose. The inlet is the mouth and nose.
31
Mode of transmission
1. Person to person transmission primarily through large-particle respiratory droplet;
e.g. when an infected person coughs or sneezes near a susceptible person at
approximately 6 feet or less.
2. Indirect contact transmission via hand transfer of influenza virus from viruscontaminated surfaces or objects to mucosal surfaces of the face (e.g. nose, mouth).
3. Airborne transmission via small particle aerosols in the vicinity of the infectious
individual may also occur.
The relative contribution of the different modes of influenza transmission is unclear.
Period of communicability
In adults, communicability is 3-5 days starting from the onset of clinical manifestations.
In children, viral shedding may continue for a longer period extending up to 7 or 10 days.
Susceptibility and resistance
All people are susceptible with the appearance of a new subtype except those who
lived through earlier epidemics or pandemics caused by a related subtype. Post infection
immunity is specific against the infecting virus, but its extent and duration vary widely. It
depends, partly, on host factors, the degree of antigenic drift in the virus and the period
of time since the previous infection.
PATHOGENESIS & CLINICAL PICTURE
Influenza is an acute disease that targets the upper respiratory tract and causes
inflammation of the upper respiratory tree and trachea. The incubation period from
exposure to the virus to the onset of clinical illness varies from 1 to 4 days. Symptoms
persist for seven to ten days, and the disease is self-limited in most of
healthy individuals. Viral shedding starts the day preceding the onset of symptoms,
peaks within 24 hours then declines within 5 days.
The virus replicates in the upper and lower respiratory passages targeting the mucussecreting, ciliated, and other epithelial cells of the respiratory tract, thus paving the way
for secondary bacterial infection. For virulence, both neuraminidase and hemagglutinin
32
are vital as they are the key targets by the neutralizing antibodies. The immune reaction
to the viral infection and the interferon response are responsible for the viral syndrome
that includes high fever, coryza, and body aches.
High-risk groups who have chronic lung diseases, cardiac disease, and pregnancy are
more prone to severe complications such as primary viral pneumonia, secondary
bacterial pneumonia, hemorrhagic bronchitis, and death.
LABORATORY DIAGNOSIS
Laboratory tests do not need to be done on all patients and the diagnosis would depend
on the signs and symptoms. For individual patients, tests are most useful when they are
likely to give results that will help with critical diagnosis and treatment decisions, or
during a respiratory illness outbreak in a closed setting (e.g. hospitals, nursing home, or
boarding schools) to assure the diagnosis of influenza.
Collection of samples
Proper collection, storage and transport of respiratory specimens is the essential first
step for laboratory detection of influenza virus infections. Samples for influenza testing
include nasopharyngeal swabs, nasal swabs, and nasal aspirate or lavage fluid.
Samples should be collected within 3 days of the onset of symptoms.
Available diagnostic tests
Rapid influenza antigen detection tests (RIDTs)
These can identify the presence of influenza A and B viral antigens in respiratory
specimens and provide results within 15 minutes or less. However, RIDTs have limited
sensitivity to detect influenza virus infection and negative test results should be
interpreted with caution.
Polymerase chain reaction (PCR)
Reverse transcription-polymerase chain reaction (RT-PCR) assays are preferred for
the diagnosis of influenza as they are rapid (< 1day), sensitive and specific.
Multiplex molecular assays that can detect influenza viral nucleic acids and distinguish
influenza virus infection from other respiratory pathogens are available.
33
Rapid molecular assays detect influenza virus nucleic acids in upper respiratory tract
specimens with high sensitivity (90-95%) and specificity giving results in approximately
15-30 minutes. They can be used as point-of-care tests (bed side).
Isolation and identification of the virus
Conventional viral cultures provide results in 3-10 days, while rapid cell cultures (on
cover slips in shell vials) give the results usually at 48 hours. Viral isolates can be
identified by hemagglutination inhibition and by RT-PCR.
Serology
Routine serodiagnosis tests are based on hemagglutination inhibition and enzyme
linked immunosorbent assay. Paired acute and convalescent sera are necessary and a
fourfold or greater increase in titer must occur to indicate influenza infection.
The reference standards for laboratory confirmation of influenza virus infection are
reverse transcription-polymerase chain reaction (RT-PCR) or viral culture.
TREATMENT
Antiviral agents are used for the prevention or the treatment of influenza virus.
They are recommended as soon as possible in the following conditions:
•
Influenza patients at an early stage of infection (within 48 hours of illness onset).
Early treatment can reduce illness duration, speed functional recovery, and
reduce the risk of complications.
•
Influenza patients who are at higher risk of developing serious influenza-related
complications (e.g., patients with asthma, chronic lung disease, diabetes, heart
disease, morbid obesity, advanced age [≥65 years].
•
Influenza patients who require hospitalization (patients with severe progressive,
or complicated illness).
34
Antiviral drugs for influenza
Neuraminidase inhibitors
The neuraminidase inhibitors:
oseltamivir, zanamivir and peramivir are effective
against influenza A and influenza B viruses. Oseltamivir is an orally administered
prodrug that is activated by hepatic esterases and widely distributed throughout the
body. Zanamivir is administered directly to the respiratory tract via inhalation. Peramivir
is used as a single intravenous dose.
Mechanism of action
Neuraminidase inhibitors competitively and reversibly inhibit the enzymatic action of
influenza neuraminidase which is essential for the release of the virus from infected
cells. Inhibition of neuraminidase leads to viral aggregation at the cell surface and the
prevention of the spread of infection within the respiratory tract.
Therapeutic uses
•
The neuraminidase inhibitors are indicated for the treatment of acute
uncomplicated influenza A or B virus infections.
•
Oral oseltamivir and inhaled zanamivir are effective in the prevention of influenza
A and B virus infections.
•
Oral oseltamivir is the recommended antiviral for patients with severe complicated
illness.
Adverse drug reactions
•
Oseltamivir: nausea and vomiting (can be prevented by administration with food),
fatigue, and headache.
•
Zanamivir: cough, wheezing, and bronchospasm. Zanamivir administration is not
recommended for patients with underlying airway disease.
•
Serious skin reactions and neurologic abnormalities (delirium and abnormal
behavior) have been reported with neuraminidase inhibitors.
35
Cap-dependent endonuclease inhibitor (baloxavir)
Baloxavir is an antiviral drug that is effective in the treatment of influenza A and
B virus infection.
Mechanism of action
Baloxavir inhibits the endonuclease activity of the polymerase acidic protein (an
influenza virus-specific enzyme in the viral RNA polymerase complex required for viral
gene transcription). Inhibition of polymerase acidic protein leads to inhibition of mRNA
synthesis and inhibition of influenza virus replication.
Therapeutic uses
Baloxavir is indicated as a single, oral, weight-based dose for treatment of:
1. Treatment of Acute uncomplicated influenza in adults and children aged 5 years or
more who have been symptomatic for less than 48 hours. This marks the first singledose oral influenza medicine approved for children in this age group.
2. Prevent influenza following contact (postexposure prophylaxis of adults and
children older than 5 years) with an infected person.
Adverse drug reactions
Common
adverse
drug
reactions
include
nausea,
diarrhea,
bronchitis,
nasopharyngitis, and headache.
Drug interactions
Some drugs may decrease plasma concentrations of Baloxavir: polyvalent cationcontaining laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium,
selenium, or zinc).
PREVENTION
Personal protective measures
1.
Regular washing and proper drying of the hands.
2.
Maintaining respiratory hygiene including covering of the mouth and nose when
coughing or sneezing, using tissues and the sanitary disposal of the used tissues.
3.
Early self-isolation of those feeling unwell or feverish or having other symptoms of
influenza.
4.
Avoiding close contact with sick persons.
5.
Avoiding touching one’s eyes, nose or mouth.
36
Immunization
Because of the antigenic changes which occur in influenza viruses, a suitable seasonal
vaccine must be used. The WHO Global Influenza Surveillance and Response System
(GISRS) monitors the appearance of new strains to be used for vaccine preparation.
Surveillance also extends to animal population (birds, pigs and horses).
According to the circulating strain, seasonal influenza vaccine includes one influenza
A (H1N1), one influenza A (H3N2), and one or two influenza B viruses (trivalent or
quadrivalent vaccine).
Controlled trials indicate that influenza vaccine confers a
moderate degree of protection ranging between 50% and 80%.
Types of influenza vaccine
1. Inactivated vaccine
It is a tetravalent vaccine including 2 subtypes of influenza A virus (H3N2 and H1N1)
and 2 strain of influenza B virus. In adults, the vaccine is given as a single dose of 0.5ml
by intramuscular injection in the deltoid region. In children, it is given in two doses at 4week interval in the anterior lateral aspect of the thigh.
The WHO recommends the vaccine for population subgroups at high risk of the
disease or at high risk of severe disease including:
•
Pregnant women; at any stage of pregnancy
•
Persons aged ≥ 65 years
•
Children and adolescents (6 months to 18 years) on long term aspirin therapy
•
Persons with chronic medical conditions.
•
Immunocompromised persons including those living with HIV
•
Healthcare workers
2. Live attenuated vaccine
It is a tetravalent vaccine including two subtypes of influenza A virus and two subtypes
of influenza B virus. The vaccine is cold adapted; allowing the efficient replication of the
vaccine virus at 25oC however, it is temperature sensitive; a property that limits the
replication of the vaccine virus at 38 oC and thus, restricts its replication in the lower
respiratory tract of humans.
37
The vaccine is given as intranasal spray in a dose of 0.5 ml. Following the
administration, the vaccine virus replicates in the nasopharynx and stimulates the
production of local and systemic immunity. The administration of the vaccine by
intranasal spray makes it more acceptable to the public. It is given before the peak of
influenza season (October and November) for persons in the age group of 5 to 49 years.
CONTROL
1. Reporting cases to local health authority. Reporting outbreaks or laboratoryconfirmed cases assists disease surveillance.
2. Isolation of cases is not practical because of the delay in the diagnosis. Ideally all
hospitalized cases with a respiratory illness including suspected influenza should be
placed in a single room.
3. Disinfection entails the concurrent and terminal disinfection.
4. Treatment: as stated previously.
5. Measures towards contacts: surveillance of contact for the incubation period.
Prophylaxis using antiviral drugs may be considered.
EPIDEMIC MEASURES
The response to influenza epidemic is planned at the national level. Measures
undertaken are
1. Health education of the general public addressing the principles of reducing the
spread of respiratory tract infection.
2. Surveillance by health authorities of the progress of the epidemic or the outbreak
and reporting of the findings to the population.
3. Maintain a continuous supply of antiviral drugs for the treatment of high-risk group
of the population and medical personnel if vaccine against the circulating strain is not
available.
As healthcare workers are likely to be affected during an epidemic as a result of higher
exposure to cases attending healthcare facilities, their immunization against the
circulating strain is essential during the initial wave of the epidemic to meet the
increasing demands on healthcare.
38
CORONAVIRUS INFECTIONS
Human coronavirus infections were until recently upper respiratory tract infections
causing common cold. They were a major cause (15-30%) of respiratory illness in adults
during winter months and the lower respiratory tract was rarely involved. Antibodies to
coronaviruses appear in early childhood, increase in prevalence with age and are found in
90% of adults.
CLASSIFICATION
There are four main genera of Coronaviridae, known as alpha, beta, gamma, and delta.
There are seven species that infect humans.
•
Common human coronaviruses causing upper respiratory tract infections:
229E, NL63, OC43 and HKU1.
•
Other human coronaviruses causing lower respiratory tract infections:
SARS-CoV (the beta coronavirus that causes severe acute respiratory syndrome, or
SARS), MERS-CoV (the beta coronavirus that causes Middle East Respiratory
Syndrome, or MERS) and SARS-CoV-2 (the novel coronavirus that causes coronavirus
pandemic 2019, or COVID-19).
Some members of Coronaviridae cause cross species infections and this was
responsible for major epidemics as SARS and MERS in the last decade. The last three
viruses are zoonotic in origin.
STRUCTURE OF THE VIRUS
Large enveloped single stranded RNA viruses with linear non-segmented genome (the
largest among RNA viruses). They have a helical nucleocapsid with club or petal shaped
protein spikes, widely spaced on the outer surface of the envelope, suggestive of a solar
corona (figure 1).
39
Figure 1: Structure and electron microscopic picture of coronavirus
PATHOLOGY & PATHOGENESIS
Coronaviruses cause disease in humans and domestic animals. They were considered
to be highly species specific. In their natural hosts they used to exhibit marked tissue
tropism to epithelial cells of the respiratory tract. Coronavirus infections in humans used
to remain limited to the upper respiratory tract.
In contrast, the outbreaks of SARS-CoV, MERS-CoV and SARS-CoV-2, were
characterized by serious respiratory illness including pneumonia and progressive
respiratory failure. The virus was also detected in other organs including kidney, liver
and small intestine and in stool.
RECENT EPIDEMICS CAUSED BY CORONAVIRUS
1. Severe acute respiratory syndrome (SARS)
It is a life-threatening respiratory disease that originated in southern China late in 2002
and was known then as the mystery pneumonia resulting in progressive respiratory
failure.
SARS epidemic started when infected animals (strains from a cat like mammal) in live
animal markets in Southern China transmitted the virus to humans. Humans became
infected as they raised and slaughtered the animals. Person to person spread occurred
by close contact through respiratory droplets.
Structure and characteristics of SARS-CoV are the same as coronaviruses except that
40
•
It is not species specific.
•
It can be grown easily on tissue culture cells resulting in a cytopathic effect.
•
It has a tropism to the lower respiratory tract and so is considered the first
coronavirus that causes severe lower respiratory tract disease in humans.
2. Middle East respiratory syndrome corona virus (MERS-COV)
The MERS-CoV is a novel corona virus that was first identified in 2012 as the cause of
respiratory failure in a patient from Saudi Arabia. The virus appears to have an animal
reservoir (bats and camels). It has been associated with severe acute pneumonia (fatal
outcome) and renal failure.
3. Severe acute respiratory syndrome-related coronavirus (SARS-COV-2)
The latest outbreak of a coronavirus-associated acute respiratory disease, originating in
Wuhan China from bats in December 2019, is the third documented spillover of an
animal coronavirus to humans in only two decades resulting in a major pandemic. The
spectrum of the illness is wide, ranging from asymptomatic infection to life-threatening
cytokine storm and respiratory failure. Acute respiratory distress syndrome (ARDS) is
the leading cause of death, followed by sepsis, cardiac complications, and secondary
infections.
Evolution of SARSCoV-2 produces numerous viral variants (example Delta and
Omicron) as a mechanism of immune escape, reduction in effectiveness of treatments or
vaccines, or diagnostic detection failures. These variants continue to be closely monitored
by the Center for Disease Prevention and Control to identify changes and new data are
continually being analyzed.
COVID-19 LABORATORY DIAGNOSIS
Specimen collection:
Upper respiratory tract samples: Nasopharyngeal swabs, Oropharyngeal (throat) swabs
and nasal swabs.
Lower respiratory tract samples: Bronchoalveolar lavage, tracheal aspirate, pleural fluid,
lung biopsy and sputum.
41
1. NAAT (Nucleic acid amplification tests):
RT-PCR can be useful starting from the first week of infection.
It is considered to be the gold standard test for diagnosis of SARS-CoV-2 infection, but
its sensitivity is estimated to be approximately 70% and specificity, 95%.
2. Antigen detection tests:
ELISA and Chemiluminescence Immunoassay (CLIA) for antigen detection are useful
5-12 days of symptoms.
3. Serological tests:
Testing for humoral response to the virus by estimating IgM (starting from the 5-8th day
of symptoms onset) and IgG (starting from the 10-14th day of symptoms onset) in serum
using ELISA or CLIA. They are therefore not appropriate for early diagnosis.
Immune response to the virus is primarily cellular.
COVID-19 PANDEMIC
Since December 2019, COVID-19 has spread rapidly causing a pandemic that threatens
global health. Globally, as of 29 March 2023, there have been 761,402,282 confirmed
cases of COVID-19, including 6,887,000 deaths, reported to WHO. As of 28 March
2023, a total of 13,331,626,129 vaccine doses have been administered. The Ministry of
Health in Egypt reported 515,882 confirmed cases of COVID-19 with 24,613 deaths, to
the World Health Organization as of 31 March 2023. Given the developing nature of this
pandemic, numbers are continuously being updated. Figure 2 and 3 show global
distribution of confirmed cases and fatalities. However, it is important to note that
challenges related to limited testing and difficulty of attribution of cause of deaths,
particularly in low- and middle-income countries, influence the accuracy of these
estimates.
42
STANDARD CASE DEFINITION OF COVID-19
WHO COVID-19: Case Definitions Updated in Public health surveillance for COVID-19,
22 July 2022 According to the most recent WHO criteria (issued in December 2020):
Suspected case of SARS-CoV-2 infection (3 options)
A. Person who meets the clinical OR epidemiological criteria:
Clinical criteria:
Acute onset of fever AND cough, influenza-like illness (ILI)
OR
• Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever,
cough, general weakness/fatigue1, headache, myalgia, sore throat, coryza, dyspnoea,
nausea/diarrhoea/anorexia
OR Epidemiological criteria:
Contact of a probable or confirmed case, or linked to a COVID-19 cluster.
B. Patient with severe acute respiratory illness (SARI: acute respiratory infection with
history of fever or measured fever of ≥38 °C; and cough; with onset within the last 10
43
days; and requires hospitalization)
C. Person with no clinical symptoms OR meeting epidemiologic criteria with a positive
professional-use or self-test SARS-CoV-2 Antigen-RDT
Probable case of SARS-CoV-2 infection (2 options)
A. A patient who meets clinical criteria AND is a contact of a probable or confirmed case,
or linked to a COVID-19 cluster
B. Death, not otherwise explained, in an adult with respiratory distress preceding death
AND who was a contact of a probable or confirmed case or linked to a COVID-19 cluster
Confirmed case of SARS-CoV-2 infection (2 options)
A. A person with a positive Nucleic Acid Amplification Test (NAAT), A regardless of
clinical criteria OR epidemiological criteria
B. A person meeting clinical criteria AND/OR epidemiological criteria (suspect case A)
with a positive professional-use or self- test SARS-CoV-2 Antigen-RDT.
Definition of a contact
A contact is a person who has experienced any one of the following exposures during
the 2 days before and the 14 days after the onset of symptoms of a probable or
confirmed case:
1. Face-to-face contact with a probable or confirmed case within 1 meter and for
at least 15 minutes
2. Direct physical contact with a probable or confirmed case
3. Direct care for a patient with probable or confirmed COVID-19 disease without
the use of recommended personal protective equipment, or
4. Other situations as indicated by local risk assessments.
44
For confirmed asymptomatic cases, the period of contact is measured as the 2 days
before through the 14 days after the date on which the sample was taken which led to
confirmation.
CYCLE OF INFECTION
Causative agent
SARS-CoV-2 virus is a member of Coronaviridae family sharing same structure. The
physical and chemical resistance of SARS-CoV-2 include:
•
In the absence of any ventilation, the virus remains viable in aerosols for 3 hours.
•
It is most stable on plastic and stainless steel, with viable virus detected up to 72
hours in the absence of any intervention (e.g. no disinfection of surfaces).
•
It is very stable at 4°C but sensitive to ultraviolet rays and heat (inactivated within
10 minutes at 55°C).
•
It can be effectively inactivated by lipid solvents and common disinfectants
including ether (75%), ethanol, chlorine-containing disinfectant, and chloroform.
•
It is inactivated by soap which dissolves its lipid bilayer.
Reservoir of infection
SARS-CoV-2 is believed to have a zoonotic origin. Whole genome sequencing has
shown that SARS-CoV-2 is 96.2% identical to a bat coronavirus (Bat CoV RaTG13)
which suggests that bats are a possible reservoir for the virus. Nevertheless, the
common epidemiological link among the initial human cluster of COVID-19 in Wuhan
City (Hubei, China) was a wholesale fish and live animal market, in which bats were
apparently not available for sale.
Experimental studies indicate that animal species such as cats, ferrets, raccoon dogs,
Egyptian fruit bats, and Syrian hamsters are susceptible to SARS-CoV-2 infection, and
that cat-to-cat and ferret-to-ferret transmission can take place via contact and air.
45
Source of infection
In human-to-human transmission, respiratory droplets or aerosols is the main source of
infection.
Portal of exit and inlet
The virus exits from the nose and mouth of an infected human and enter through the
nose, mouth and the conjunctiva of a susceptible human host.
Mode of transmission
1. Contact transmission
•
Direct person-to-person respiratory transmission is the primary means of
transmission of SARS-CoV2. Mainly through close range contact via respiratory
particles Evidence indicates that SARS-CoV-2 is transmitted from human to human by
infectious droplets through coughing, sneezing or speaking. People in close contact
(within 1 meter) with an infected person can get the infection when those infectious
droplets get into their mouth, nose or eyes.
•
Indirect contact through touching objects or surfaces contaminated by respiratory
discharge such as tabletop and doorknobs then touching the eyes, nose or mouth.
2. Airborne transmission
Virus could exist in the air in poorly ventilated places for at least 30 minutes. Airborne
transmission occurs in closed places, such as restaurants, workplaces and places of
worship when these places are crowded, poorly ventilated and where an infected person
spend long time with others. Airborne transmission can also mean infection can be
transmitted over longer distances. However, more studies are needed to investigate the
significance of this mode of transmission in the spread of COVID-19.
46
Period of Communicability
Recommendations of CDC for isolation and precautions for people with COVID-19
Updated in 2022.
•
People who are infected but asymptomatic or people with mild COVID-19 should
isolate through at least day 5 (day 0 is the day symptoms appeared or the date the
specimen was collected for the positive test for people who are asymptomatic).
They should wear a mask through day 10. A test-based strategy may be used to
remove a mask sooner.
•
People with moderate or severe COVID-19 should isolate through at least day 10.
Those with severe COVID-19 may remain infectious beyond 10 days and may
need to extend isolation for up to 20 days.
•
People who are moderately or severely immunocompromised should isolate
through at least day 20. Use of serial testing and consultation with an infectious
disease specialist is recommended in these patients prior to ending isolation.
Susceptibility and immunity
Population at risk
Older age group has been identified as population subgroup at the highest risk for
severe COVID-19 disease. Children seem to be less affected by COVID-19 than adults.
Patients with chronic health problems are more susceptible to COVID-19. Among
hospitalized COVID-19 patients, the most prevalent diseases were hypertension,
cardiovascular diseases, diabetes mellitus, chronic obstructive pulmonary disease
(COPD), malignancies, and chronic kidney disease. Also, smokers were over-presented
among hospitalized COVID-19 patients.
Immunity
•
Immunity can occur naturally after developing COVID-19, from getting the
COVID-19 vaccination, or from a combination of both.
•
In June 2022, the CDC reported that BA.4 and BA.5 subvariants of Omicron
became the predominant subvariants in the U.S.
47
•
Infections with variants before Omicron or being fully vaccinated appear to be
less effective at preventing immunity against BA.4 and BA.5.
•
Scientists are learning more and more about the length of immunity after
developing COVID-19, getting the vaccine, or both.
PATHOLOGY & PATHOGENESIS
The pathology and pathogenesis are as previously described for Coronaviridae.
CLINICAL PICTURE
Incubation period
The mean incubation period (the period between infection and onset of symptoms) is
about 4 to 6 days with about 95% of individuals developing symptoms within 14 days
from infection.
Signs and symptoms
The possibility of COVID-19 should be considered primarily in patients with new-onset
fever and/or respiratory tract symptoms (e.g. cough, dyspnea). It should also be
considered in patients with severe lower respiratory tract illness without any clear cause.
Other consistent symptoms include myalgia, diarrhea, and smell or taste disturbances.
Although these syndromes can occur with other viral respiratory illnesses, the likelihood
of COVID-19 is increased if the patient:
•
Resides in or has traveled within the prior 14 days to a location where there is
community transmission of SARS-CoV-2 (i.e. large number of cases that cannot be
linked to specific transmission chains). In such locations, residence in congregate
settings or association with events where clusters of cases have been reported is a
particularly high risk for exposure. OR
•
Has had close contact with a confirmed or suspected case of COVID-19 in the prior
14 days, including contact through work in healthcare settings. Close contact includes
being within approximately six feet (about two meters) of the individual with COVID-19
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for more than a few minutes while not wearing personal protective equipment (PPE) or
having direct contact with infectious secretions while not wearing PPE.
Although there are no specific clinical features that can reliably distinguish COVID-19
from other viral respiratory infections yet, the development of dyspnea several days after
the onset of initial symptoms is suggestive of COVID-19. Presence of general symptoms
should raise suspicion as, among healthcare workers, constant mild symptoms of
anosmia, muscle ache, ocular pain, general malaise, headache, extreme tiredness and
fever were associated with a positive test. Other unusual findings, such as new-onset
pernio-like lesions (e.g. "COVID toes"), also increases suspicion for COVID-19.
However, none of these findings definitively establish the diagnosis of COVID-19 without
microbiologic testing.
Patients with suspected COVID-19 who do not need emergency care are advised to call
their healthcare provider before visiting a healthcare facility as guidance regarding the
need for testing can be done over the phone. For patients in a healthcare facility,
infection control measures should be implemented as soon as COVID-19 is suspected.
DIAGNOSIS
•
Antigen and nucleic acid detection
Coronavirus antigens in cells in respiratory secretions may be detected using the ELISA
test. PCR assays are useful to detect coronavirus nucleic acid in respiratory secretions.
•
Isolation and identification of virus
Isolation of human coronaviruses in cell culture has been difficult.
•
Serology
Serodiagnosis using acute and convalescent sera is the practical means of confirming
coronavirus infections, because of the difficulty of virus isolation. ELISA and indirect
immunofluorescent antibody assays may be used.
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TREATMENT
•
Isolation of patients at home or in a hospital
•
Supportive treatment to stabilize vital signs including intravenous fluids,
analgesics, antipyretics, vitamin C and D and zinc supplement
•
Prophylactic or therapeutic anticoagulation to prevent thrombus formation
•
Anti-viral drugs usually in combination e.g. remdesivir and favipiravir
•
Immune modulator drugs as corticosteroids or IL-6 blockers
•
Intravenous infusion of convalescent plasma serum to increase the immunity
against the virus
•
Support ventilation with supplemental oxygen or mechanical ventilation in case of
respiratory failure
PREVENTION
1. Limiting contact with people at higher risk like older adults and those with poor
health.
2. Practicing social distancing by avoiding crowded places and non-essential
gatherings, keeping a distance of at least 2 arms-length (approximately 1.5 meters) from
others, avoid greetings with handshakes.
3. Disinfection of surfaces using 0.1% hypochlorite sodium (diluted bleach) or ethanol
70% is effective against the virus within 1 minute.
4. Maintaining the highest possible level of personal hygiene including frequent hand
washing for 20 seconds with soap and water or alcohol-based hand rub, avoid touching
the face and surrounding surfaces, cover the nose and mouth with a disposable tissue
or flexed elbow when coughing or sneezing.
5. Wearing a face mask is universally recommended, not to protect the wearer but
mainly to prevent the spread of the infection from asymptomatic individuals. Droplets
are emitted not only when coughing or sneezing, but also when breathing or speaking.
6. Wearing surgical mask, gown, gloves, and goggles or face shield is recommended
for healthcare workers coming into close contact (less than 1.5 meter) with suspected
or confirmed case.
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Authorized and approved COVID-19 vaccines up to May 2022
Vaccine
Type (technology)
Doses and intervals
RNA (modRNA in lipid
2 doses
nanoparticles)
3–4 weeks
Moderna COVID-19
RNA (modRNA in lipid
2 doses
vaccine
nanoparticles)
4 weeks
Sinopharm
Inactivated SARS‑CoV‑2
2 doses
Pfizer COVID-19 vaccine
3–4 weeks
Sinovac
Inactivated SARS‑CoV‑2
2 doses
2-4 weeks
Sputnik Light
Adenovirus vector (recombinant
1 dose
Ad26)
Oxford–AstraZeneca
Adenovirus vector (ChAdOx1)
COVID-19 vaccine
2 doses
4–12 weeks
Johnson & Johnson
Adenovirus vector (recombinant
COVID-19 vaccine
Ad26)
1 dose
Source: London School of Hygiene and Tropical Medicine. COVID-19 vaccine tracker. [Online]. 2021 Mar 1 [cited
2021 Jun 25]; Available from: https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/
The Pfizer vaccine can be safely administered to children from 5 years of age.
Both Moderna and Pfizer vaccines are licensed for use in children from 12 years of age.
Contraindications and precautions
● History of severe allergic reactions/anaphylaxis to any of the ingredients of the
COVID-19 vaccine.
● Fever over 38.5ºC on the day of vaccination. Vaccination is postponed until
recovery.
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● Confirmed or suspected COVID-19 patients. Vaccination should be postponed until
the patient completes the mandated isolation period and the acute symptoms are
passed.
Side effects
Side effects after a COVID-19 vaccination tend to be mild, temporary, and like those
experienced after routine vaccinations. They include:
● Pain, swelling, and redness on the arm where the shot was given
● Tiredness
● Headache
● Muscle or joint pain
● Fever
● Chills
● Swollen lymph nodes
● Severe allergic reactions after COVID-19 vaccination are rare but can happen. For
this reason, everyone who receives a COVID-19 vaccine is monitored by their
vaccination provider for at least 15 minutes.
CONTROL
1. Reporting to local health authorities of cases meeting the standard case definition
of SARS-CoV-2
2.
Isolation of cases either at home (if the home conditions are suitable) or in a
hospital.
3. Treatment of cases in line with the recommended regimen should start
immediately.
4. Concurrent and terminal disinfection of patients’ discharge and contaminated
articles.
5. Individuals meeting the definition of “contacts” should be traced, enlisted and
quarantined (restriction of their activities at home or in a special place). Contacts should
be placed under observation for the maximum incubation period of the disease which
entails the daily recording of temperature and the inquiry into related symptoms.
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VIRAL HEPATITIS B
(HBV)
Viral hepatitis B (formerly known as serum hepatitis) is an acute systemic infection with
major pathology in the liver, caused by hepatitis B virus (HBV).
STANDARD CASE DEFINITION
Suspected case
A case having an acute illness of jaundice, dark urine, anorexia, extreme fatigue, and
right upper quadrant tenderness.
Confirmed case
A case with clinical description that is confirmed by laboratory investigations.
OCCURRENCE
The disease is endemic throughout the world especially in tropical and developing
countries and also in some regions of Europe. According to the prevalence of HBV, there
are three areas:
•
Areas of high endemicity where most infections occur during infancy and early
childhood and this leads to chronic infection.
•
Areas of intermediate endemicity where infections occur commonly in all age
groups.
•
Areas of low endemicity where most infections occur in young adults, especially
those belonging to known risk groups.
CYCLE OF INFECTION
Causative agent
HBV is a member of the Hepadnavirus family, the only DNA virus among hepatotropic
hepatitis viruses. It is a small, enveloped virion, with an icosahedral nucleocapsid
containing a partially double-stranded circular DNA genome (Figure 1).
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The genome shows compact organization with overlapping encoding sequences coding
for multiple proteins which include the following: (Figure 2)
1- HBe antigen which is a secreted protein (i.e not assembled within virions). It is
secreted in a soluble form and detected only in infected patient’s serum.
2- The core protein (HBcAg) or viral capsid protein which is only present inside
hepatocytes and detected in liver biopsies and not detected in serum.
3- Hepatitis B surface antigen (HBsAg) which is the outer shell or envelope. It is host
cell derived and contains small, medium and large surface proteins.
4- HBV polymerase.
5- HBx Ag which is a regulatory protein for transcription and is required for initiation of
infection. It can be detected only in the cells replicating the virus.
Electron microscopy of a patient’s serum reveals three different particles: (Figure1)
1- Spherical particles which are the most numerous.
2- Filamentous particles.
These two forms are made up exclusively of surface
antigens and result from over production of HBsAg during viral replication.
3- The complete virions containing the viral nucleocapsid.
Replication cycle
Virus replicates and assembles exclusively in hepatocytes and virions are released
through cell secretory pathways non-cytopathically.
Upon uptake into hepatocytes, the nucleocapsid is transported to the nucleus where the
partially circular DNA will be converted to covalently closed circular DNA, to serve as
template for viral transcripts that is translated to different viral proteins.
Viral genome can be integrated randomly in the host genome. This is not required for viral
replication but it is one of the important mechanisms for hepatocyte transformation and
HCC development.
Viral genome is subjected to frequent mutations leading to existence of distinct viral
species in infected individuals.
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Figure 1: Particles of hepatitis B virus identified by electron
microscopy
Figure 2: The overlapping genome organization of HBV
Reservoir of infection
Man is the only reservoir of infection in the form of cases (clinical and subclinical) and
chronic carriers.
Source of infection
1.HBV DNA is present in the blood; human blood, blood products and organs for
transplantation, transmit the infection if not screened for HBsAg.
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2.Contaminated needles, syringes and other intravenous equipment are source of
infection.
3.HBV DNA is found in low concentration in body fluids such as saliva, semen, vaginal
secretion and breast milk.
Mode of transmission
1. Per-cutaneous transmission including intramuscular, intravenous, subcutaneous
or intra-dermal injections, tattooing, ear piercing and needle stick.
2. Contamination of skin lesions (fresh cutaneous scratch, abrasion and burns).
3. Infected blood and blood products through transfusion or dialysis.
4. Sexual contact; (heterosexual or homosexual)
5. Perinatal transmission when mothers are HBsAg positive due to leak of maternal
blood to infant’s circulation during birth. Transplacental transmission is rare.
6. Organs for transplantation.
Period of communicability
All persons who are HBsAg positive are potentially infectious. Blood is infective many
weeks before the onset of first symptoms and remains infective through the acute clinical
course of the disease and during the chronic carrier state which may persist for life.
Occult HBV infection:
It is defined as detection of HBV DNA in blood, serum or liver biopsies in absence of
detectable HBsAg.
It has been shown that these patients are infectious by transfusion or organ
transplantation specially in immunocompromised patients.
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