Pulmonary Tuberculosis - Macro PDF

PULMONARY TUBERCULOSIS Tuberculosis is a major global cause of disability and death especially in developing countries. Tuberculosis is a social disease with medical aspects and is an indicator of social welfare. In Egypt the disease is an important public health problem with an annual incidence o...

PULMONARY TUBERCULOSIS Tuberculosis is a major global cause of disability and death especially in developing countries. Tuberculosis is a social disease with medical aspects and is an indicator of social welfare. In Egypt the disease is an important public health problem with an annual incidence of nearly 12 new cases per 100,000 populations as of the year 2019; half of them were smear positive. However, annual incidence was 20 per 100,000 in 2000. STANDARD CASE DEFINITION Suspected case of pulmonary tuberculosis Any patient with any type of cough for more than two weeks associated with fever, loss of weight and night sweating. Confirmed case of pulmonary tuberculosis  Pulmonary tuberculosis, smear positive cases are those with positive sputum for acid-fast bacilli by direct microscopic examination of two initial specimens. OR Positive sputum for acid fast bacilli by direct microscopic examination of a single specimen and radiologic abnormalities consistent with active pulmonary tuberculosis as determined by the treating medical officer. OR Positive sputum for acid-fast bacilli by direct microscopic examination of a single smear specimen and, culture positive for acid fast bacilli.  Pulmonary tuberculosis, smear negative cases are those with suggestive symptoms of pulmonary tuberculosis; with at least three negative sputum smear specimens for acid fast bacilli by direct microscopic examination; and with radiographic abnormalities consistent with active pulmonary tuberculosis determined by a medical officer followed by decision to treat the patient with full course of anti-tuberculosis therapy. 1  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. 6  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. 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 BCG vaccination. Newborns do not acquire passive natural immunity from their mothers. 7  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 9  1.3. Signs of cavitation, or fibrosis. 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. 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 extra- pulmonary 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. Figure 4: BacT/ALERT automated system 11   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). 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  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 interferon- gamma in high amounts. This interferon-gamma can be measured using the interferon- gamma 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 (semi- dormant) 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 DNA- dependent 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 anti- inflammatory 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. These beta- lactam/carbapenems are only given intravenously 20  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 MDR-TB 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 (N1- N11), 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 self- aggregation 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 Figure 3: Human-avian-swine flu viruses epidemic. reassortment in pigs  2009 (H1N1pdm09); formerly known as swine flu 29  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 designation of the hemagglutinin 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 designation A/Turkey/Wisconsin/1/66 (H5, N2). 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 virus- contaminated 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 mucus- secreting, ciliated, and other epithelial cells of the respiratory tract, thus paving the way 32 for secondary bacterial infection. For virulence, both neuraminidase and hemagglutinin 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 for 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 single- dose 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 cation- containing 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. 36  5. Avoiding touching one’s eyes, nose or mouth. 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 4- week 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 38oC 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 laboratory- confirmed 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. 39  Figure 1: Structure and electron microscopic picture of coronavirus 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). 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. 40  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  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. 41 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. 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 42  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. 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 (ILI) OR 43  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 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 44  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. 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. Research is therefore ongoing to identify alternative 45 animal reservoirs and potential intermediate hosts of SARS-CoV-2 like snakes and turtles. 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. 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 46 transmitted over longer distances. However, more studies are needed to investigate the significance of this mode of transmission in the spread of COVID-19. Period of Communicability Beginning of contagious period Viral load in the upper respiratory tract is highest one day before and the days immediately after the onset of symptoms. Evidence is still accumulating on pre- symptomatic transmission. Pre-symptomatic transmission is thought to account for 48- 62% of all transmission. Contact tracing guidelines therefore consider all potential contacts of a case from 48h before symptom onset. In the absence of containment measures, the highest transmission potential seems to be for symptomatic individuals. End of contagious period The ending of the contagious period is not known yet. After the first week of the illness, the virus load drops considerably however, some patients may continue to shed the virus for a long period of more than 30 days. Virus shedding is not equated with contagiousness and infectious virus has not been isolated after 8 days of the symptoms. The secondary attack rates are significantly higher among contacts whose exposure to the index case started within 5 days of the onset of symptoms compared with those exposed later. Spread of covid-19 in the community The basic reproductive number (R0; written R “zero” and pronounced R nought) is defined as “the expected number of secondary cases produced by a single infection in a totally susceptible population”. R0 value of less than 1 means that the infection is spreading slowly among the population. R0 greater than 1 means that the infection is spreading exponentially, and an epidemic is likely to occur. R 0 is not constant for any disease, and it is estimated when the immunity of the population is zero (hence the term R0). R0 depends on the infectiousness of the organism, the proportion of susceptible population and population density, and the rate by which cases are eliminated by death 47 or recovery. Higher population density, larger number of susceptible and highly infectious organism result in a larger R0. Rapid rate of elimination of infected persons results in a smaller R0. This applies to SARS-CoV2 where estimates for R0 vary widely, particularly as newer strains emerge. 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. 48  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.  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 49 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 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 50  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. 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. 51  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. Authorized and approved COVID-19 vaccines up to May 2022 Vaccine Type (technology) Doses and intervals Pfizer COVID-19 vaccine 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 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) 2 doses COVID-19 vaccine 4–12 weeks Johnson & Johnson Adenovirus vector (recombinant 1 dose COVID-19 vaccine Ad26) 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/ 52 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. 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. 53  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. 54  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). 55  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: (Figure 1) 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. 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. 56  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. 57  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. 58  Susceptibility Susceptibility is general and the disease is usually milder and anicteric in children and infants. (Protective immunity follows infection if anti HBsAb develops and HBsAg disappears). Susceptibility is general for individuals having lower level of antibodies to HBs Ag (less than 20 IU/ ml). Population subgroups at higher risks of the infection are  Health care workers especially those performing invasive procedures as dentists and surgeons.  Laboratory technicians working in blood banks.  Recipients of blood transfusion and its products in countries using unscreened blood.  Hemodialysis patients.  Recipients of solid organ transplant.  Household contacts and sex partners of HBV infected persons.  Infants of mothers who are carrier of HBV.  Injection drug abusers.  Heterosexuals with multiple partners and men who have sex with men. CLINICAL PICTURE Incubation period The incubation period ranges from 45 to 180 days with an average of 120 days. Signs and symptoms Acute hepatitis B Hepatitis B infection causes a wide spectrum of liver diseases, from a subclinical carrier state to severe hepatitis or acute liver failure (fulminant hepatitis), particularly in the elderly, in whom mortality can reach 10 to 15%. Most patients have typical manifestations of viral hepatitis including:  Anorexia, malaise, fever, nausea, and vomiting, followed by jaundice.  Symptoms persist from a few weeks up to 6 months. 59   5 to 10% of all patients with HBV develop chronic hepatitis B or become inactive carriers. The younger the age when acute infection occurs, the higher the risk of developing chronic disease. Chronic hepatitis B Hepatitis lasting for more than 6 months is generally defined as chronic hepatitis, although this duration is arbitrary. Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Without treatment, cirrhosis often develops; risk of hepatocellular carcinoma is increased. Antiviral drugs may help, but liver transplantation may become necessary. Clinical picture of chronic hepatitis includes:  Malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nonspecific upper abdominal discomfort. Jaundice is usually absent.  Often, the first findings are signs of chronic liver disease or portal hypertension (e.g. splenomegaly, spider nevi and palmar erythema) or complications of cirrhosis (e.g. portal hypertension, ascites and encephalopathy)  Few patients with chronic hepatitis develop manifestations of cholestasis (e.g. jaundice, pruritus, pale stools, steatorrhea).  Extrahepatic manifestations may include polyarteritis nodosa and glomerular disease. Symptoms of chronic hepatitis B vary depending on the degree of underlying liver damage. Many patients, particularly children, are asymptomatic. Prognosis (outcome) of hepatitis B infection  Outcomes of HBV infection are age-dependent. Acute hepatitis B occurs in nearly 1% of perinatal, 10% of early childhood (1-5 years of age) and 30% of late infections (> 5years of age).  The development of chronic HBV infection is inversely related to the age and occurs in approximately 80-90% of persons infected perinatally, in 30% infected in early childhood (1-5 years) and in 5% infected later (> 5 years of age). 60   Without treatment, chronic hepatitis B can resolve (uncommon), progress rapidly, or progress slowly to cirrhosis over decades.  Resolution often begins with a transient increase in disease severity and results in seroconversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (anti-HBe).  Coinfection with hepatitis D virus (HDV) causes the most severe form of chronic HBV infection; without treatment, cirrhosis develops in up to 70% of patients.  Chronic HBV infection increases the risk of hepatocellular carcinoma. The case fatality rate is about 1%; it is higher in those over 40 years of age. Fulminant HBV infection occurs in pregnancy and among newborns of infected mothers. Figure 2: Serological course of acute HBV infection with recovery Virologic and serologic events 1. Acute hepatitis B virus infection with recovery (figure 2)  HBV DNA and HBeAg, wh