Notes On Virology PDF

VIRAL INFECTIOUS DISEASES What are viruses ? Viruses appear to infect all living things – yet are not quite alive themselves. They are particles of genetic material ( strands of DNA or RNA ) – the essence of life, that carry the blue prints for all life. They lie as inert as the dea...

VIRAL INFECTIOUS DISEASES What are viruses ? Viruses appear to infect all living things – yet are not quite alive themselves. They are particles of genetic material ( strands of DNA or RNA ) – the essence of life, that carry the blue prints for all life. They lie as inert as the dead until an opportunity arises to invade a host. In other words , a virus is pure information encoded in molecules of DNA or RNA. In living organisms, these molecules or genes, contain the instructions for building and maintaining cells. Viruses are obligate intracellular infectious agents , smaller than bacteria (10-300 nm, bacteria are approximately 1000 nm and erythrocytes are 7500 nm in diameter), and are therefore seperable by filtration, and unable to multiply outside a living host. Viruses are not just harmful infectious agents, today, in experiments that herald a new age in medicine, viruses are being harnessed to save lives. Viruses can target specific cells, slip inside, and carry new genetic information. In the future, viruses will be an important tool for many other forms of gene therapy. Pathogenesis of Viral Infections A- Cellular responses to viral infections Cells respond in three ways; no apparent change, cytopathic effect and death (lytic infection) and hyperplasia (non-lytic infection). The nature and degree of these responses depend upon the specific viral agent and the species of the host cell that is infected. B- Patterns of disease Three basic patterns of viral infection may occur; localized, disseminated, and inapparent. 1- Symptoms may not accompany virus replication at the site of entry and this causes inapparent infection. The factors involved in such infection are; moderate or attenuated viruses (as in live vaccines), high resistance when the host’s defense mechanisms are effective including the host’s immunity, or failure of the virus to reach the target organ. In poliomyelitis; one paralytic case occurs every 100-200 inapparent infections. 2- The virus may replicate and remain at the primary site i.e. viral multiplication and cell damage remain localized near the site of entry thus causing localized infection.  In the skin virus spreads from the infected cells to the neighbouring cells by cell contact or diffusion across intercellular spaces causing a single lesion or a group of lesions e.g. Warts. In the respiratory and gastrointestinal tracts virus spreads by excretions or secretions causing diffuse involvement of an organ eg. influenza, common cold and viral gastroenteritis. 3- The virus may replicate and disseminate to other tissues by way of the blood stream, blood and tissue macrophages, the lymphatic system or through neurons. Transport of virus in the blood is termed a viremia. In disseminated infections, the virus enters the body and multiplies locally at the portal of entry. It then spreads rapidly to the regional lymph nodes where it also multiplies. The virus then enters the lymphatics and blood stream – primary viremia – causing dissemination of the virus to other susceptible organs as the liver and spleen where viral multiplication occurs causing necrotic lesions. The virus is then transferred to the blood causing more intense secondary viremia which disseminates the virus to the target organ where the virus multiplies producing symptoms. Now, the incubation period terminates and the clinical disease begins. The overt disease begins only after the virus becomes widely disseminated in the body and has attained maximum titers in blood and spleen. The target organ is the skin in case of smallpox and measles, the central nervous system in poliovirus and salivary glands in case of mumps. C- Effect of viruses on embryonic development Some viruses produce mild disease in adults, but produce extensive infection and severe malformations in the embryo. Of all the viral infections that may occur during the first trimester of pregnancy (first three months), rubella is the major cause of fetal death and congenital malformations such as improper development, small size of the infected baby and teratogenic effects, which may lead to ocular infections as cataracts, mental retardation, microcephaly, deafness and heart defects. Other viruses that cause embryonic malformations include; cytomegalovirus which induces a low incidence of microcephaly, motor disability and chorioretinitis, group B coxsackie viruses lead to congenital heart lesions and type2 herpes simplex virus causes microcephaly and other central nervous system malformations. D- Latent infections in animal hosts Latent infections are persistent invivo inapparent infections. The overt disease is not produced but the virus is not eradicated. Examples are herpes simplex virus which is both latent and recurrent, and adenovirus which causes latent infection of the tonsils and adenoids. 1 2  Herpes simplex virus infects humans between six and eighteen months of age. The virus persists but cannot be found except during recurrent acute episodes e.g. herpes labialis (fever blisters). The latent virus is undetectable, it remains latent in human sensory ganglia. Primary infection is followed by formation of neutralizing antibodies which neutralize the extracellular virus but the latent virus remains undetected. Recurrence of infection occurs because certain stimuli activate viral replication such as; change in level of immunity (low resistance), physical and physiologic factors such as fever, intense sunlight, wind, fatigue and menstruation. E- Slow viral infections These infections are caused by viruses that require prolonged periods of infection – often years – before the disease appears. Examples are : 1- Subacute sclerosing panencephalitis SSPE It follows several years after measles and perhaps after measles immunization. The causative virus is identical with or closely related to measles. 2- Progressive encephalitis PE It is similar to but more rapidly progressive than SSPE. It develops in a rare child who previously had congenital or early childhood rubella. 3- Kuru It is a degenerative disease of the cerebellum. It is manifested by ataxia, disturbed balance, tremors and progresses to death in less than a year after onset. 4- Creutzfeldt – Jacob disease A fatal disease which shows a spongyform encephalopathy and also appears to be a chronic disease. 3  RESPIRATORY TRACT INFECTIONS Respiratory infections are, numerically, the greatest problem in community health. Most respiratory infections are due to viruses that infect both upper and lower respiratory tracts- often simultaneously. Respiratory tract infections are transmitted by inhalation of respiratory secretions from an infected person. Viruses which affect the respiratory tract: Virus Disease Influenza viruses Acute localized upper and / or lower respiratory disease. Parainfluenza viruses Croup; colds, lower repiratory infections in children Respiratory syncytial virus Bronchiolitis and pneumonia in infants, colds. Rhinoviruses Colds: major cause of common cold. Adenoviruses Pharyngitis and conjunctivitis. Corona viruses Colds: 5-15% of colds in the community. SARS: Severe acute respiratory syndrome: lower respiratory infection. Influenza virus Infection Influenza A, B and C are the only members of the Orthomyxovirus group. Influenza virus is an RNA enveloped virus having two spike glycoproteins, the hemagglutinin-HA-, and neuraminidase-N- and an inner membrane-M-protein layer. It also contains the “S” or soluble antigen, the protein in the ribonucleoprotein core of the virus particle : all influenza A viruses share a common S antigen which is different from that shared by all influenza B viruses. There are three types of influenza: A, B and C, and many subtypes. Type A is the principal cause of epidemic influenza, type B causes a milder disease. Influenza virus causes an acute localized respiratory disease lasting from 3 to 7 days. Unique Features of Influenza A and B: Enveloped virion has a genome of 8 different RNA nucleocapsid segments. The hemagglutinin – HA – glycoprotein is the viral attachment protein, fusion protein, and elicits neutralizing, protective antibody responses. 4  The segmented genome promotes genetic diversity caused by mutation and reassortment of segments upon infection with two different strains. Pathogenesis The incubation period is 1 to 4 days. The virus enters the nasopharynx and spreads to susceptible cells. It multiplies in the upper respiratory tract and infects and destroys the cells lining the upper respiratory tract, trachea and bronchi. Viral multiplication is followed by necrosis of infected cells. Disease Mechanisms of Influenza A and B: Virus can establish infection of upper and lower respiratory tract. Systemic symptoms are due to interferon and lymphokine response to the virus. Local symptoms are due to epithelial cell damage, including ciliated and mucous secreting cells. Infected individuals are predisposed to bacterial superinfection because of the loss of these natural barriers and induction of bacterial adhesion to epithelial cells. Antibody is important for future protection against infection. Clinical Symptoms Fever, chills, generalized aching (muscular), headache, cough, prostration and anorexia. Three to seven days later, recovery is complete unless a complication occurs: In young children complications may be bronchitis, croup, otitis media or primary viral pneumonia. In adults and children secondary bacterial pneumonia (due to Streptococcus pneumonia, Haemophilus influenza or Staphylococcus aureus) is the major cause of death. Myositis, cardiac involvement and CNS involvement may also occur. Circulating antihemagglutinin and antineuraminidase antibodies are present for many years after infection, and the disease is usually mild when reinfection occurs by a subtype similar to the previously experienced one. Reye’s syndrome: It is a rare complication sometimes seen in children after influenza (and also other virus infections); that strikes the brain, liver and kidney and causes fatty degeneration of these organs, resulting in mortality in around 20-35%. Aspirin predisposes to the syndrome and children with influenza should therefore not be treated with this drug. Laboratory Diagnosis 1- Isolation of virus from nasal and throat washings i.e. nasopharyngeal washings. 2- Cultivation of virus by inoculation into the amniotic sac of 10 to 12 day chick embryos or onto primary monkey kidney cells. 3- Identification of the virus by hemadsorption (adherence of guinea pig erythrocytes or human group O erythrocytes to infected cells in cell culture), but since the test is nonspecific to influenza virus, the specific test is immunofluorescence of fluorescent conjugated antibodies in the acute stage from the nasopharynx (cells obtained from patient – containing virus - + specific fluorescent Ab, incubate for a few hours and examine for the detection of influenza viral Ags). Hemagglutination-inhibition reaction is also used for the indentification of influenza virus, while hemagglutination- inhibition titration is used for the demonstration of antibodies against influenza virus in the patient serum (serological test). 5 6 Antigenic Variation Influenza A undergoes two distinct forms of antigenic variation: Antigenic drift: is due to spontaneous mutations in the hemagglutinin gene, causing minor antigenic changes in the hemagglutinin protien, but the hemagglutinin protein basically remains the same. Antigenic shift: major antigenic changes: it involves the replacement by genetic reassortment of the RNA segment which codes for hemagglutinin, by one from a different virus strain. This occurs when two different influenza viruses infect and replicate in the same cell. As a result, a new virus emerges with a novel hemagglutinin. The antigenic shift may involve either the hemagglutinin alone or the neuraminidase as well. The HA and NA of Influenza A can undergo major (reassortment, shift) and minor (mutation, drift) antigenic changes. Influenza B undergoes only minor antigenic changes. Epidemiology - Virus is transmitted by inhalation of infected respiratory droplets by sneezing, talking, breathing and coughing. - Virus likes cool less humid atmosphere (winter). - Virus spreads extensively by school children. - Incidence is highest in the young 5 to 9 years and above 35 years of age. - The very young and very old suffer highest mortality. - High risk groups: elderly, immunosuppressed individuals with cardiac or repiratory problems: asthma and smokers. Treatment, Prevention and Control Influenza virus is enveloped and is inactivated by detergents. - Reduce interpersonal contact with sick people. - Antiviral chemotherapy: Specific treatments for influenza A include four prescription drugs: amantadine, rimantadine, zanamivir (Relenza) and oseltamivir (Tamiflu) for prophylaxis or early treatment in the first 24 to 48 hours of illness. Their primary effects include reduction of symptoms, shortened disease duration and slowed virus transmission. Relatively high rates of resistance to the first two drugs have been reported. Nonspecific treatments are mainly to control the symptoms and include fluids, bed rest and nonaspirin pain relievers and anti-inflammatory drugs. Therapy includes antibiotics for bacterial complications. - Vaccination is currently recommended for the elderly and those with cardiac or respiratory problems. Vaccination is not aimed at preventing transmission. The standard formalin-inactivated whole-virus vaccine is grown in chick embryos and requires nearly a year to prepare. Current vaccine contains 3 strains: Influenza A, H1N1 (Swine influenza strain), H3N2 (Hong Kong flu) and Influenza B. The three virus variants are selected on the scientific evidence that predicts the most prominent strains to circulate that year. The vaccine is administered intramuscularly annually, and produces protection for a few months (around 60% protection). It is contraindicated in people allergic to egg protein. A new vaccine, FluMist, is a nasal mist vaccine consisting of the three strains of influenza virus in the live attenuated form. It is designed to simulate secretory immunity in the upper respiratory tract. Its efficacy and safety have so far been demostrated only 7  for persons between the ages of 5 and 49. It is not advised for immunocompromised individuals, and is significantly more expensive than the injected vaccine. Guillain-Barré syndrome: a neurological condition (polyneuritis) with ascending paralysis usually starting in the legs leading to weakness and sensory loss, is a rare complication of influenza vaccine: It clears up spontaneously in most patients, although it may cause paralysis of the respiratory muscles (therefore positive pressure respiration may be required) and may be debilitating and fatal.. Coronaviruses Coronaviruses probably cause from 5 – 15% of colds in the community. They are the second most prevalent cause of the common cold (Rhinovirus is first). Coronaviruses are enveloped RNA virions, named for their solar corona-like appearance when viewed with the electron microscope because of the surface projections on the virion. The glycoproteins of the envelope appear as club-shaped projections: the E1 glycoprotein is a transmembrane matrix protien, the E2 glycoprotein is responsible for viral attachment, membrane fusion, and is the target of neutralizing antibodies. Coronaviruses infecting the respiratory tract, remain localized to the upper respiratory tract. Serum antibodies do not prevent reinfection. The virus is most likely spread by aerosols and in large droplets (e.g. sneezes). The infection of the upper respiratory tract with coronaviruses, although mild, may cause chronic pulmonary disease such as asthma and bronchitis, and may be followed by pneumonia in children and adults. Laboratory diagnosis of coronaviruses is not routinely done, because the virus is difficult to isolate. Severe Acute Respiratory Syndrome SARS SARS virus is a mutated coronavirus with modified surface glycoproteins. The virus causes a severe life-threatening acute respiratory disease affecting the lower respiratory tract causing atypical pneumonia: inflamed lungs with many necrotic areas making it difficult to transfer oxygen to the blood and body organs. The virus enters the eyes, nose or mouth by inhalation or ingestion of respiratory droplets or by ingestion of meat infected with the virus (wild civet cats). The virus spreads to the upper respiratory tract and then infects the lower respiratory tract. The illness appears to infect the lower lobes of the lungs (unlike common cold viruses that typically attack the throat and nasal passages). Human Rhinoviruses HRV Rhinoviruses are naked RNA picornaviruses. At least 100 serotypes of rhinovirus have been identified. Being different from picorna viruses, rhinoviruses are sensitive to acidic environments such as that of the stomach, and their optimum temperature of multiplication is not normal body temperature but 33oC, the average temperature of the human nose (nasal mucosa). Infection 8 can be initiated by as little as one infectious particle. During the peak of illness, concentrations of 500 to 1000 infectious virions per ml are reached in the nasal secretions. The virus enters through the nose, mouth or eyes and initiates infection of the upper respiratory tract, including the throat. Infected cells release bradykinin and histamine, which causes the runny nose. Infected ciliated epithelial cells may be sloughed from the nasal mucosa. The patient can experience headache, chills, fatigue, sore throat, and cough. Incubation period ranges from 1 to 3 days. Both nasal secretory (IgA) and serum (IgG) antibody are induced by primary rhinovirus infection. Immune protection is transient and cannot compensate for the large number of serotypes. Immunity begins to wane approximately 18 months after infection. No specific therapy has been found to be effective for treatment of common cold. Nasal vasoconstrictors may provide relief but their use may be followed by rebound congestion and worsening symptoms. The usual therapy is to force fluids and relieve symptoms with various cold remedies and cough syrups that contain nasal decongestants, antihistamines and analgesics. Adenoviruses Adenoviruses were first isolated in 1953 from the adenoids. Adenovirus is a non-enveloped DNA virus with at least 42 types of human adenovirus. It causes acute respiratory and ocular infections primarily in children, less common in adults. Other types of adenovirus (group F types 40 - 42) cause acute gastroenteritis and diarrhea. Infection by reactivated virus (latent) occurs in immunocompromised children and adults. Infection with the virus is either inapparent or self-limited illness followed by complete recovery and persistent immunity. However, low grade chronic infection rather than true latency are observed since adenoviruses have a tendancy to persist for long periods in tissues as the tonsils and adenoids. Pathogenesis The virus enters by feeding or is swallowed in respiratory secretions. It multiplies in the gastrointestinal tract and is excreted in the faeces (infectious), but does not produce gastrointestinal disease (except Gp F adenovirus). No viremia and, therefore, no involvement of distant organs (Gp F). Infection mostly occurs before the age of fifteen. 50 to 80 % of tonsils and adenoids removed surgically contain adenovirus. Disease Mechanisms of Adenovirus: * Virus spreads by aerosol, close contact or fecal-oral means to establish pharyngeal infection. Fingers spread virus to eyes. *Virus infects epithelial cells of mucous membranes in the respiratory tract, gastrointestinal tract and conjunctiva / cornea causing cell damage directly. * Virus persists in lymphoid tissue (eg. Tonsils, adenoids, Peyer’s patches). * Viral DNA may persist in the nucleus of non-lysed cells. * Antibody is important for prophylaxis and resolution. Clinical Syndromes 9 In acute respiratory disease, fever, acute rhinitis, cough, pharyngitis, (laryngitis and bronchiolitis may occur) and enlarged cervical lymph nodes are clear symptoms. In ocular disease, follicular conjunctivitis occurs and both conjunctivae become inflammed: watery exudate, redness and partial closure. Other forms of adenoviruses cause gastroenteritis and diarrhea (enteric adenoviruses Gp F types 40 - 42) but do not cause fever or respiratory symptoms. They cause episodes of diarrhea in infants.. Epidemiology Direct person-to-person contact, by means of respiratory and ocular secretions in occular and respiratory infections, swimming pools, dusty working places, unsterilized optical instruments, and fecal material on hands to eyes and towels in ocular infections. Fecal-oral route in gastrointestinal infections. Many healthy carriers exist. The capsid virus is resistant to inactivation by the gastrointestinal tract and drying. Prevention and Control An inactivated polyvalent vaccine prepared from viral antigens is an effective preventive measure used often in military recruits. Laboratory Diagnosis 1- Isolation of virus from respiratory (throat or mouth washings) and occular secretions and faeces. 2- Cultivation of virus on human embryo kidney cells. A characteristic cytopathic effect – intranuclear inclusion bodies : clusters of large rounded cells like bunches of grapes – is observed. 3- Electron microscopy : for the detection of fastidious adenovirus in the faeces (types 40 and 41) as they do not grow in routine cell cultures and are serologically distinct from respiratory strains. Antigens could be detected in stools by ELISA. Treatment No known treatment for adenovirus infection. Treatment of enteric adenovirus infection is symptomatic: rehydration with care to correct sodium loss (hyponatremia) if rehydrating salt solutions are used too liberally. In ocular infection the use of local corticosteroids may be useful. Antibiotics may also be used to prevent secondary bacterial infection. VIRAL GASTROENTERITIS 10 Viruses are an important cause of acute diarrhea in young children. In developing countries, viral gastroenteritis plays a major role in the high infant mortality. Several viruses are responsible, but most do not grow in cell culture: electron microscopy is, therefore, necessary for their diagnosis. These viruses mainly affect infants aged between 6 months and 2 years, but older children and more rarely adults can also be affected. The main viruses associated with acute diarrhea are: Rotavirus, Adenovirus, Astrovirus, and Caliciviruses. Endemic infection is common in young children (especially group A rotaviruses and group F adenoviruses). Epidemics or outbreaks of infection are associated with some viruses (e.g. Norwalk-like viruses) than others. Treatment of viral gastroenteritis is symptomatic: rehydration with care to correct sodium loss (hyponatremia). Rotaviruses Rotaviruses are non-enveloped RNA viruses. Rotaviruses cause infantile gastroenteritis; a childhood diarrhea. Approximately 50% of all the cases of diarrhea in children requiring hospitalization (because of dehydration) are caused by rotavirus infections. In underdeveloped countries one million deaths in children due to rotavirus occur each year. Rotavirus survives in acidic environment, in a buffered stomach or in a stomach after a meal. Pathogenesis The incubation period of rotavirus is 48 hrs. The virus enters the gastrointestinal tract by ingestion, passes through the stomach and adsorbs to the epithelial cells on the villi of the upper small intestine and the virus replicates. Virus infection prevents absorption of water. This causes secretion of water from the gastrointestinal tract and the loss of ions causing watery diarrhea. The loss of fluids together with electrolytes causes severe dehydration, which could lead to death if the lost electrolytes are not replaced. Rotavirus infections are symptomatic in infants, while in adults the rotavirus infections are usually asymptomatic. Clinical Symptoms The symptoms of rotavirus infection are watery diarrhea, fever, vomiting and loss of fluids and electrolytes may lead to dehydration and shock. Infection due to rotavirus is a self-limited disease and recovery is complete, but if untreated, dehydration may lead to death. Epidemiology Rotavirus infections are transmitted from person-to-person by the fecal oral route, through ingestion of the virus. 11 It is a world-wide disease and children are usually infected at an early age usually under four years. Viruses survive on objects such as hands, furniture and toys since viruses can withstand drying. Actively or passively acquired antibody (including antibody in the colostrum and mother’s milk) lessen the severity of the disease but it does not prevent reinfection. Babies from 6 to 24 months of age lacking maternal antibodies have the greatest risk for fatal disease. Immunity to infection requires the presence of secretory IgA in the lumen of the gut. Laboratory Diagnosis Clinical findings make laboratory diagnosis unnecessary. The virus is found in the stools in large quantities in most infections, making the direct detection of viral antigen by the use of enzyme immuoassay. Treatment, Prevention and Control Mortality in patients with rotavirus diarrhea result from dehydration and electrolyte imbalance. The purpose of supportive therapy is to replace fluids so that blood vloume and electrolyte and acid-base imbalance are corrected. Acquisition of rotaviruses occurs very early in life. Once hospitalized, however, diseased patients must be identified and isolated to limit spread of infection to other susceptible patients. Vaccination: Two vaccines (Rota Teq, Rotarix) based on various versions of live attenuated viruses are currently available. They reduce serious illness by 85% to 95% in infants.They are both orally administered but are rather costly. ENTEROVIRUS INFECTIONS 12 Enteroviruses are naked RNA picornaviruses. Enteroviruses confer chemical stability to acid, bile and detergents. Enteroviruses primarily infect the gut, they rarely cause intestinal symptoms. Enterovirus diseases are the result of spread of the viruses to other sites of the body - particularly the CNS. Enteroviruses have the following properties: Enter the body via ingestion by mouth. Primary site of mutiplication is the lymphoid tissue of the alimentary tract - including the pharynx. Spread from gut is in two directions: 1- Outwards into the blood (viremia) to other tissues and organs. 2- Inwards into the lumen of the gut then excretion into feces. Most infections are confined to the alimentary tract and are symptomless: enteroviruses do not cause diarrhea. A small proportion of infections cause febrile illness due to viremia. Still fewer cases progress to aseptic meningitis or paralysis after spread of virus to CNS. The Enteroviruses family includes various groups: polioviruses, coxsackie viruses, echoviruses and unclassified enteroviruses. Enterovirus diseases: Syndrome Main viruses responsible 1. Neurological (i) Paralysis (i) polioviruses (ii) Aseptic meningitis (ii) most enteroviruses 2. Febrile illness most enteroviruses 3. Herpanginas; hand, foot coxsackie A viruses and mouth disease 4. Myocarditis, pericarditis coxsackie B viruses 5. Bornholm disease: coxsackie B viruses Inflammation of the intercostal muscles 6. Acute haemorrhagic enterovirus 70, conjunctivitis coxsackie virus A 24 Poliomyelitis Infantile paralysis 13 Poliomyelitis is an acute enteroviral infection of the spinal cord that can cause neuromuscular paralysis. There are three types of polioviruses; type 1, 2 and 3. Poliomyelitis is a severe crippling and paralytic occasionally fatal disease. Pathogenesis Incubation period of the disease is 1-35 days. The virus enters by ingestion and it multiplies in the lymphoid tissue of the tonsils and pharynx, and later infect the lymphoid cells of Peyer’s patches underlying the intestinal mucosa which leads to primary viremia (transient viremia).Primary viremia spreads the virus to susceptible tissues: brown fat (axillary, paravertebral and suprasternal) and viscera (reticuloendothelial cells). The virus replicates in these tissues, resulting in symptoms and a secondary viremia (persistant viremia).Since the virus is neurotropic and is in blood now: blood is the major pathway to the CNS by direct invasion through capillary walls. Clinical Symptoms Asymptomatic illness; virus is limited to the oropharynx and gut: 90% of infections. Abortive poliomyelitis; minor illness: 5% of infections. It is a non-specific febrile illness: fever, headache, malaise, sore throat and vomiting and lasts for 3-4 days. Nonparalytic poliomyelitis; aseptic meningitis in 1-2% of infections. The virus progresses into the CNS causing back pain and muscle spasms together with symptoms of minor illness but no paralysis. Virus invades the CNS but no destruction of the nervous tissue. Paralytic poliomyelitis; major illness in 0.1 – 2% of infections. Three to four days after the minor illness subsides, the virus spreads from the blood to the CNS leading to destruction of the nervous tissue and paralysis. The CNS lesions that cause paralysis may occur in: 1- Spinal cord leading to spinal poliomyelitis (paralytic poliomyelitis involves one or more limbs).Because motor function, but not sensation, is compromised, the crippled limbs are often very painful. 2- Cranial nerves and medullary respiratory center leading to bulbar poliomyelitis which involves muscles of pharynx, vocal cords and respiration causing respiratory or cardiac failure. 3- Motor cortex leading to encephalitic poliomyelitis. 2 is fatal, 1 and 3 survive with residual patterns of paralysis. Post-polio syndrome: A sequele of poliomyelitis in 20 to 50% of the patients later in life; 30 to 40 years. Poliovirus is not present, but there is progressive deterioration of the originally affected muscles due to loss of neurons. Laboratory Diagnosis 1- Isolation of virus from pharynx during the first few days or from faeces for as long as 30 days after onset, but rarely from the cerebrospinal fluid (CSF). 2- Cultivation of virus on cell culture and identification by cytopathic effect. 3- Serological tests: test could be done for identification using standard antisera for each of the 3 types. 14 15  Epidemiology - Transmission by fecal-oral route since virus remains 5 weeks in faeces after infection. - Pharyngeal excretions contain the virus and therefore person-to-person contact leads to spread in families and schools. - Poor sanitation and crowded living conditions. - Sewage contamination of water supplies which leads to epidemics. - Flies are accidental vectors. - Summer is the major season for enterovirus disease. - After infection with the virus, the gut becomes resistant to reinfection due to production in the gut of virus-specific neutralizing IgA antibody. Treatment During the acute phase: Pain-relieving drugs. Respiratory failure may require artificial ventillation maintenance. Prompt physical therapy to diminish crippling deformities and to retain muscles is recommended after the acute febrile phase subsides. Prevention and Control 1- Hygenic sanitary conditions. 2- Vaccination: - Inactivated poliovaccine: IPV (Salk vaccine). It contains the 3 types and is formalin- inactivated. It is given in 3 intramuscular or subcutaneous doses over a 3-6 month period. - Live attenuated poliovaccine: TOPV (Sabin vaccine). It contains the 3 - types after passage in human or monkey cell cultures: type 1 in highest quantity, type 2 in least quantity to decrease interference. It is given orally at 2,4,6,18 months of age and a booster dose at 3-5 years. - Live attenuated virus replicates in the oropharynx and intestinal tract producing s-IgA. Unfortunately one per 4 million cases of vaccination may lead to paralytic disease. Besides an unvaccinated family member may acquire infection and disease from a vaccinated child. Both vaccines are effective but one may be favored over the other. Hand-Foot-and-Mouth disease This disease is a vesicular exanthem caused by an enterovirus, usually coxsackie virus A16. The main features of this infection are vesicular lesions of the hands, feet, mouth and tongue. The patient is mildly febrile, and the illness subsides in a few days. Transmission by : (1) Fecal-oral route (2) Ingestion via contaminated food and water. (3) Contact with infected hands. (4) Inhalation of infectious aerosols. This virus infects sheep, cows, goats, and pigs causing foot-and-mouth disease with very painful vesicles and then leads to death. Herpangina is the painful eruption of vesicles in the mouth and throat, and is a part of the syndrome of hand- foot- and- mouth disease. CHILDHOOD FEVERS 16 Mumps, Measles and Rubella are, with Varicella, the common childhood fevers. Most cases occur in children under the age of 15. Measles has been partially controlled by vaccination since 1968. In the year 1988, infant immunization with a combined, live, attenuated measles, mumps and rubella (MMR) vaccine was introduced. Erythema infectiosum is another childhood fever due to human parvovirus. Mumps and measles viruses are enveloped RNA paramyxoviruses.The envelope contains an inner layer of membrane protein and an outer layer containing two spike glycoproteins: hemagglutinin-neuraminidase –HN- and cell fusion –F- proteins. Rubella virus is an enveloped RNA rubi-togavirus. Mumps Mumps virus causes an acute benign viral parotitis (swelling of one or both glands). Immunity is permanent, second attacks are very rare. Pathogenesis Incubation period is 16 to 18 days, an average of 2 to 3 weeks. The virus enters the upper repiratory tract and infects the parotid gland(s). It multiplies there and then spreads throughout the body by viremia to the testes, ovaries, kidneys, pancreas, thyroid and other organs like the heart and CNS (meninges). Cell-mediated immunity is essential for control of infection and is responsible for some symptoms. Antibody is not sufficient due to mumps ability to spread from cell to cell. Clinical Symptoms Acute onset of fever, nasal discharge, muscle pain and malaise followed by parotitis (painful swelling of the salivary glands) almost always bilateral. Most infections are followed by complete, uncomplicated recovery,with permanent immunity. Complications: Four to seven days later it may be followed by orchitis which may cause sterility in 20-30% of males past puberty, oophoritis in adult females, nephritis, and meningitis (aseptic meningitis). Laboratory Diagnosis 1- Isolation of virus from saliva and secretions from parotid duct or spinal fluid and urine. 2- Cultivation of virus on cell culture shows a cytopathic effect: characteristic multinucleated giant cells. 3- Serologic Tests Test the serum by a direct fluorescent or ELISA method. Compement-fixation test : Two antigens are used : i- “S” or soluble antigen (in nucleoprotein core) ii- “V” or viral antigen (on the surface of the viral particle) Antibody to “S” antigen tends to diminish sooner than antibody to “V” antigen. “V” antibody usually persists for years. 17 18  Epidemiology - Mumps is a childhood disease. - The virus is transmitted in the saliva and respiratory secretions. - Salivary secretions contain infectious virus 6 days before and 9 days after appearance of glandular swelling. - The disease appears most often during winter and early spring in temperate climates, and 40% of the cases are subclinical. Treatment, Prevention and Control Symptomatic treatment to relieve fever, dehydration and pain is usually adequate. Immunization by live, attenuated vaccine (Jeryl Lynn vaccine) administered as part of the MMR vaccine given subcutaneously to children 12 to 15 usually 14 months of age followed by at least one booster. Vaccination produces persistant immunity almost similar to that following the natural disease or for at least a decade. A separate single vaccine is available for adults who require protection. In women, pregnancy must be avoided for 3 months after vaccination, and vaccination is contraindicated during pregnancy. Measles Rubeola Morbillivirus infection Measles virus produces a highly contagious, acute, febrile, exanthematous disease, with maculopapular rash. Immunity is permanent following infection. Pathogenesis Incubaction period is 7 to 13 days, nearly 2 weeks. The virus enters in the respiratory tract, multiplies in the mucosal lining, and in the regional lymph nodes, then primary viremia occurs and virus is disseminated into distant organs and causes infection of the conjunctiva, respiratory tract, urinary tract, small blood-vessels and the CNS. Cell-mediated immunity is essential to control infection, antibody is not sufficient due to measles ability to spread from cell to cell. Sequale in the central nervous system may result from immunopathogenesis (postinfectious measles encephalitis) or development of defective mutants (subacute sclerosing panencephalitis, SSPE). Clinical Symptoms In the prodrome there is high fever, sore throat, dry cough, coryza, headache, conjunctivitis; photophobia and lymphadenitis. At this time the patient is most infectious. After 2 days of illness: typical mucous membrane lesions-Koplik’s spots- appear in mouth, conjunctiva and vagina. These spots last 24 to 48 hours and their appearance in the mouth establishes with certainty the diagnosis of measles. An exanthem of measles follows starting below the ears and spreads over the head, face, then to the trunk and extremities. The rash is maculopapular and it takes 1 to 2 days to cover the body and then fades in the same order it appeared. The fever is highest and patient is sickest on the first day of the rash. 19 20 Complications Frequent complications: Bronchopneumonia and otitis media or sinusitis with or without bacterial involovement. Most serious complications : - Encephalitis begins 7 to 10 days after the rash, it may be fatal, and occurs in 1:2000 cases of measles infection. - Giant cell pneumonia without rash and with bacterial infection. It occurs in immunodeficient patients and malnourished infants (in Africa). - Subacute sclerosing panencephalitis SSPE is an extremely serious very late neurological sequale of measles in approximately 7 per one million cases. Defective measles virus remains in the brain and acts as a slow virus. Months or even years after measles infection the patient develops progressive neurological degeneration manifested by profound intellectual and neurological impairment, followed by coma and death. Laboratory Diagnosis Measles virus is difficult to isolate and grow. 1- Isolation of virus from nasal or pharyngeal secretions, blood, urine and brain tissue. 2- Cultivation of virus on cell cultures. 3- Identification by direct demonstration of specific viral antigen by immunofluorescence in nasopharyngeal aspirates. Characteristic cytopathic effect: multinucleated giant cells with cytoplasmic and nuclear inclusion bodies. Epidemiology: - It is a highly contagious disease. - The virus is transmitted by respiratory secretions before and after the onset of symptoms: during the periods of incubation, prodromium and the skin rash. - It is predominantly a childhood disease occuring in winter and spring. Treatment, Prevention and Control: Treatment relies on reducing fever, suppressing cough and replacing lost fluid. Complications require additional remedies to relieve neurological and respiratory symptoms and to sustain nutrient, electrolyte and fluid levels. Therapy includes antibiotics for bacterial complications and doses of immune globulin. - Active immunization with a live, attenuated measles vaccine given alone at 9 months of age or together with MMR at 12-15 months subcutaneously followed by a booster dose a few years later. The administered vaccine (Schwartz or Moraten attenuated strain) achieves immunity that persists for about 20 years. In women, pregnancy must be avoided for 3 months after vaccination and vaccination is contraindicated in pregnant women. - A single antigen vaccine (Meruvax) is also available for older patients who require protection against measles alone. - Exposed susceptible individuals who are immunocompromised should be given measles immune serum globulin. It is most effective when given within 6 days of exposure: large doses prevent the disease while smaller doses reduce its severity. Rubella 21  German measles Rubella virus is an RNA, enveloped, (Rubi) Togavirus. It contains the spike glycoproteins hemmagglutinin - HA - , and neuraminidase - N -. Unlike togaviruses, rubella is a respiratory virus. The disease resembles measles but is milder, with a macular rash and does not have serious consequences in the very young. Maternal rubella infection is the major cause of fetal death and congenital malformation in the first 16 weeks of pregnancy; after that rubella does not damage the fetus. Two forms of rubella can be distinguished: 1-Postnatal Rubella: Pathogenesis Incubation period is approximately 2 to 3 weeks. The virus enters the upper repiratory tract, spreads to local lymph nodes, followed by viremia which spreads the virus throughout the body. Infection of the other tissues and the characteristic mild rash result. The prodrome period lasts for 2 weeks, and the virus is shed in the respiratory tract 2 weeks before and 2 weeks after the onset of the rash. Clinical Syndrome In children : fever, malaise, sore throat, a 3-day rash and swollen glands. The rash of pink macules first appears on the face and progresses down the trunk and towards the extremities. In adults: it is more severe and is often accompanied by joint inflammation and pain; arthritis, and rarely postinfectious encephalitis (similar to postinfectious measles encephalitis). 2-Congenital Rubella: Rubella infection in a pregnant woman can result in serious congenital abnormalities – fetus is at major risk in the first trimester of pregnancy. If the mother does not have antibodies, the virus can replicate in the placenta and spread to the fetal blood supply and throughout the fetus. Rubella can replicate in most tissues of the fetus. This can lead to improper development, small size of the infected baby and teratogenic effects. The virus may persist in the tissues, and may be shed for up to one year after birth. The most common manifestations of congenital rubella infection include; cataracts and other ocular defects, physical and mental retardation due to microcephaly, deafness and heart defects. Mortality in-utero and within the first year of birth is high for these babies as a result of intrauterine growth retardation. Less drastic sequelae that usually resolve in time are anemia, hepatitis, pneumonia, carditis and bone infection. Laboratory Diagnosis Rubella is often asymptomatic, so it should not be diagnosed on clinical grounds alone. Diagnosis is mainly used to confirm suspected rubella in a pregnant woman or congenital rubella. Serological diagnosis: is confirmed by the presence of anti rubella-specific IgM in a single sample of blood by ELISA or by immunofluorescence, which indicates recent infection. A rising antibody titer in the sera by hemagglutination-inhibition, complement-fixation, ELISA or fluorescent assay, is an indication of continuing rubella infection. Latex-agglutination card is a simple, more rapid, miniaturized test for IgM assay. 22 Infants with the rubella syndrome have IgM antibody to rubella virus (the maternal antibody wich crosses the placenta is IgG antibody). Isolation of the virus: for diagnosis of congenital rubella in the fetus, is done by sensitive molecular techniques using PCR to detect rubella virus genetic material. Epidemiology - It is a highly contagious, endemic disease. - It spreads by respiratory droplets. - It may produce many inapparent infections in children and adults. - Transmission occurs by nasal or respiratory droplets and direct contact during the prodromal phase and up to 1 to 2 weeks after the rash appears. - Nonimmune women of childbearing age are the greatest concern, raising the prospect of congenital rubella. - The normal infant excreting the virus acquired in-utero is the most dangerous carrier, because infection is not recognized and comes in contact with nurses, doctors and hospital visitors including future mothers early in pregnancy. Treatment, Prevention and Control Postnatal rubella is generally benign and requires only symptomatic treatment. - Immunization by live, attenuated vaccine which is administered in conjunction with the measles and mumps vaccine – MMR, at 12 to 15 months and a booster at 4 or 6 years of age. - Passive immunization of pregnant women after exposure with rubella immune serum globulin is recommended. - There is good immunity after both naturally and vaccine-acquired rubella but reinfections could occur, as the vaccine does not always provide lasting immunity. - Rubella vaccine contains live, attenuated rubella virus given to non-immune, non- pregnant women; one dose given subcutaneously or intramuscularly. Pregnancy must be avoided for 3 months after vaccination. HUMAN HERPES VIRUS INFECTIONS 23 Herpes viruses are enveloped DNA viruses. They costitute a large family whose members include: Herpes simplex 1 and 2 (HSV); the cause of fever blisters and genital infections, Varicella-zoster virus (VZV); the cause of chickenpox and shingles, Epstein-Barr virus (EBV); associated with infection of the lymphoid tissue, Cytomegalovirus (CMV); infects the salivary glands and other viscera, Human herpesviruses-6 and -7 (HHVs); cause roseola, and Herpesvirus-8 (KSHV); implicated in Kaposi’s sarcoma. Herpes viruses are morphologically identical and have the important property of being latent, in a potentially viable form, within the cells of the host after primary infection. This involves the entry of viral DNA into the nucleus, where it becomes an extrachromosomal particle called an episome. Latent virus persists for long periods of time, probably throughout life: some reactivate from time to time from the latent state to produce recurrent infection. Herpes Simplex viruses HSV Herpes simplex viruses – HSV – cause latent infections with recurrent infections at irregular intervals. There are two serotypes: HSV type1 responsible for the familiar fever blisters and cold sores found around the mouth and lips; herpes labialis, in the eyes causing herpetic keratitis (corneal lesions in the eye) and on the fingers; herpetic whitlow. HSV type 2 is characterized by lesions found on and around the genital organs. Pathogenesis Incubation period is 2 to 12 days. Initial infection tends to be age specific: HSV-1 frequently occurs in infancy and childhood (6-18 months) through the mucous membranes e.g. eye, mouth, throat and genitals, or through the skin (cuts or cracks) where local multiplication occurs in the basal and epithelial cells, and the virus is then transferred to the regional lymph nodes then by the blood to the distant organs. By adulthood, most people exhibit some serological evidence of infection. Primary infection with HSV-2 occurs, most frequently between the ages of 14 and 29, which reflects the sexual route of transmission. Virus causes direct cytopathology and avoids antibody by cell-to cell spread (syncytia). In 20 to 50% of primary infections,virus multiplies in the distal regions of sensory neurons and is carried to the ganglia. Virus establishes latency in neurons (hides from immune response).Virus reactivates from latency by stress or immune suppression. Cell-mediated immunity (CMI) contributes to symptoms and is required for resolution with limited role for antibody. Clinical Syndromes Oral Herpes: 10 to 15 % of primary infections are herpetic gingivostomatitis which is multiple vesicles in oral mucous membranes, gums and mucocutaneous border. Lesions 24 begin as clear vesicles and then become ulcerated. Vesicles may be produced on the head or neck due to kissing. Herpetic whitlow: due to implantation of virus into fingers. Infection is acquired through contamination of hands by virus in saliva or respiratory secretions (occupational hazard of doctors and nurses). Conjunctivitis and keratitis: primary herpes can involve the eye – both conjunctiva and cornea: the eyelids are swollen and have vesicles and ulcers on them. Recurrent infection may be induced naturally by stress, heat, cold, wind, sunlight (UV light), fever, pituitary and adrenal hormones and emotional disturbances. The clinical picture is much the same with each episode. If the primary infection is gingivostomatitis, the recurrent infection will be herpes labialis i.e. fever blisters in the lips. If the primary infection is herpetic keratitis (limited to one eye), the recurrent infection will be keratitis which could lead to corneal scarring, corneal damage and blindness. Genital herpes: Primary infection is usually asymptomatic with symptoms of transient viremia as fever and malaise. Lesions are usually painful and itching. HSV-2 becomes latent in the lumbosacral ganglion. Recurrence is short and less severe. Before erruption of vesicles, a burning sensation occurs in the place where the lesions will errupt. Neonatal infection: severe generalized infection in the neonate and fetus are very destructive and can be fatal. It is usually acquired when infants are contaminated by a genital infection in the mother immediately before or during birth, or hand transmission from the mother’s lesions to the baby. HSV-2 is more frequently involved, however, HSV-1 infection has similar complications. If disease is confined to mouth, skin or eyes, mortality rate is 30%. Disease affecting the CNS, has a 50 to 80% mortality rate. Generalized infection: is a rare manifestation in adults with primary infection with type 1 virus which dissiminates into the viscera and other body organs e.g. herpes hepatitis. Life-Threatening complications Herpes simplex encephalitis is a rare case due to HSV-1. Infection disseminates along the nerves to the CNS or the spinal cord, causing headache and stiff neck and can progress to mental disturbances and coma. If untreated, fatality rate is 70%. Immunodeficient, transplant, cancer and AIDS patients are more prone to disseminated infections. Herpes simplex meningitis is a complication of HSV-2. Epidemiology Infection is most common in childhood and adolescence. HSVs are relatively sensitive to the environment. Transmission of HSV usually involves direct exposure to secretions containing the virus. HSV1 is transmitted in oral and respiratory secretions. HSV2 is transmitted through sexual contact and from mother to newborn. Person-to person contact e.g. kissing (type1), sexual intercourse (type2). Secretions from lesions around the mouth and genitalia are the most frequent sources (contain live virus). Contaminated eating and drinking utensils. People with herpetic lesions or carriers of latent virus from time to time secrete virus in their saliva without any symptoms (source of undetected infection). Mothers with genital herpes are the primary source of neonatal infections with HSV-2 In women HSV-2 infection may lead to cervical carcinoma. In men HSV-2 infection may lead to prostatitis. Transplant patients may develop severe or self limiting herpes reactivations. 25 Laboratory diagnosis 1- Isolation of virus from scrapings from the base of the vesicles (swab or fluid), from skin, saliva, conjunctiva, corneal scrapings, stained with Giemsa, Wright or Papanicolaou (Pap) methods, or brain biopsy. 2- Direct demonstration of virus or antigen in fluids or tissues, or cell culture by electron microscopy or immunofluorescence or DNA detection by PCR. 3- Cultivation of virus on cell culture. Identification of virus by cytopathic effect: intranuclear inclusion bodies in round giant mutinucleated epithelial cells (syncytia) within 24 to 48 hours. Type of HSV is detected by immunofluorescence. Treatment, Prevention and Control Acyclovir is used for treatment and prophylaxis. It is non-toxic and is adminstered intravenously, orally or topically. Famciclovir and valacyclovir are alternate drugs. Topical medication is applied to oral and genital lesions. Oral valacyclovir (Valtrex) is effective for genital herpes. Systemic therapy is available for herpes keratitis and disseminated infections. - Prevent contact between infants and herpetic adults during presence of lesions (contact only after reepithelialization completely). - Prevent sexual intercourse during presence of lesions – only after being completely reepithelialized. - Pregnant women with active genital HSV should deliver with cesarean section to prevent contact of the infant with virus-infected lesions. Sometimes the virus is present in genital secretions and the child could be exposed to it during delivery. Varicella-Herpes Zoster virus VZV Human Herpes virus 3 Varicella virus causes chicken pox. Herpes zoster virus causes shingles. The two viruses are indistinguishable , and there is a consideration that chicken pox is the primary infection , while shingles is the recurrent infection of varicella-herpes zoster virus VZV. Chicken pox is a disease of young children, a febrile, exanthematous illness with a vesicular maculopapular rash. Shingles is a disease of adults: a severe painful disease with chickenpox-like lesions (recurrent infection of varicella virus). Attack by varicella is followed by solid and long-lasting immunity to varicella but not to zoster. Pathogensis Varicella (chicken pox) The virus spreads by respiratory secretions, enters the respiratory tract & multiplies. The virus then goes to the regional lymph nodes, to the blood causing viremia, then to the internal organs and the skin. The incubation period is 14 to 16 days. Herpes zoster (shingles) It infects mostly adults who were previously infected with chicken pox. The virus goes from the skin (acute Varicella) through the nerves to the sensory ganglia, then to the ganglionic 26 nerve cells (latent virus), then through the nerves again to the skin causing Shingles. The virus is latent in the dorsal root or cranial nerve ganglia. Shingles develops abruptly after reactivation by stimuli as X-ray treatment, immunosuppressive and other drug therapy, surgery, developing malignancy or declining immune function and is more common in older patients. VZV can escape antibody clearance, and cell-mediated immune response is essential to control infection. Clinical Syndromes Varicella (chicken pox) Varicella is characterized by fever, maculopapular rash more severe on trunk than on extremities and notably present on scalp, also present on mucous membrane. The lesions pass through the stages of macule, papule, vesicle and pustule. The lesions are itching but not painful. Successive crops of lesions occur for 3 to 5 days so that lesions of different age are present together. Pocking only occurs if lesions are scratched seriously due to bacterial infection and scarring occurs. In adults primary infection is infrequent but if it occurs, it is more severe and may cause interstitial pneumonia in 20 to 30% of patients and may be fatal. Herpes zoster (shingles) Shingles causes mild fever and severe pain in the area innervated by the nerve which is followed by the appearance of chicken-pox-like lesions: small closely spaced maculopapular lesions on an erythematous base, very painful vesicles. Zoster is more common in the elderly. Dorsal root ganglia: a segmental rash extends from the middle of the back in a horizontal strip round the side of the chest – a belt of roses from hell. Cranial zoster involving the ophthalmic nerve: a sharply demarkated area of lesions down one side of the forehead or scalp: in about half the patients there are lesions in the eye. Ramsay Hunt syndrome: a rare form of zoster: eruption is on the tympanic membrane and external auditory canal and there is often a facial nerve palsy. Postherpetic neuralgia: a chronic pain syndrome due to inflammation of ganglia and pathways of nerves, can persist for months, usually lasts for 2 to 4 weeks. If inflammation spreads to the cranial nerve, it may cause eye inflammation and neurological signs as facial paralysis. Laboratory Diagnosis 1- Isolation of virus from the base of the vesicle. Direct demonstration of virus in vesicle fluid (or scrapings) by electron microscopy. 2- Identification is best done with fluorescent antibody detection of viral antigen in skin lesions, DNA probe analysis or culture. 3- Cultivation of virus on cell culture shows a cytopathic effect: multinucleated giant cells with large intranuclear inclusion bodies, also seen in stained smears prepared from vesicle scrapings. This cytopathic effect is indistinguishable from that produced by Herpes simplex virus. 27 28 Epidemiology Varicella is an epidemic disease acquired by contact with cases of varicella or less commonly of zoster. Zoster unlike varicella is not acquired by contact with cases of either varicella or zoster. Epidemics of varicella occur in winter and spring. The virus is mainly transmitted by respiratory droplets but also by direct contact, since virus is also present in the fluid of active skin lesions. The dried scabs are not infectious. Treatment, Prevention and Control Varicella is self-limited and requires no therapy aside from alleviation of discomfort. Application of antimicrobial ointments in case of secondary bacterial infections that can cause dangerous complications (streptococcal and staphylococcal). Intravenous acyclovir and famciclovir and high-dose interferon are beneficial in systemic disease (immunocompromized). Acyclovir, corticosteroids, analgesics may be used in case of shingles. Varicella could be prevented by varicella zoster immunoglobulin (VZIG) in contacts within 72 hours of exposure in immunocompromized patients. A live, attenuated vaccine (Varivax: Oka strain) is effective. The vaccine is administered between 2 months and 12 years of age, and immunity will be longer lasting if 2 doses are given. The vaccine induces protective or ameliorating antibody and is effective as a prophylactic treatment even after exposure to VZV. Most significantly, it promotes protection in immunodeficient children. A vaccine (Zostavax) has been approved for prevention of shingles in patients over 60. Epstein-Barr virus EBV Human Herpes virus 4 Epstein-Barr virus (EBV) causes a disease known as infectious mononucleosis, and it is associated with African Burkitt’s lymphoma and nasopharyngeal carcinoma. It contains genes that, when expressed, transform certain lymphocytes into malignant cells. Childhood EBV infections are usually asymptomatic, but in young adulthood it is more symptomatic. Infectious mononucleosis is an acute infectious disease, primarily affecting lymphoid tissue throughout the body (glandular fever). Pathogenesis Incubation period is long from 4 to 7 weeks (30 to 50 days). The virus enters in the pharyngeal secretions and multiplies in the epithelial cells of the oropharynx during the primary infection. The virus then moves to the parotid gland (major area of viral replication and latency), and is shed in the saliva and salivary secretions and multiplies in the local lymphatic tissues. The virus then gets access to the B-lymphocytes in the lymphatic tissue, multiplies in the B-lymphocytes causing B cell proliferation (immortalization) and T cell activation. This leads to an increase in the number of WBCs and mononuclear cells (lymphocytosis). Lymphocytes (B & T cells) are atypical with enlarged misshapen nuclei and excess cytoplasm. It also causes swollen lymph glands, spleen and liver. 29 30 EBV persists in latent form within B-lymphocytes following primary infection. Cell-mediated immune response is responsible for controlling infection and preventing complications. Antibody role is limited. Clinical Symptoms Fever, malaise, sore throat, fatigue (major complaint), cervical lymphadenopathy. Many patients have hepatosplenomegaly, also abnormal lymphocytes in the blood. The disease lasts from 2 to 3 weeks and is rarely fatal but can result in complications as neurological disorder, laryngeal obstruction or rupture of the spleen. Laboratory Diagnosis : Virus isolation is not practical 1. Differential blood count: shows lymphocytosis, neutropenia and abnormal , large (atypical) lymphocytes , with vacuolated cytoplasm and fenestrated (lobulated) nuclei. Initially there is leukopenia but during the 2nd week, the count may rise to 10,000 – 80,000 cells per ml. 2. Serological assays: Indirect immunoflurescence with viral capsid antigen to detect EB virus-specific IgM is the most specific diagnostic method. 3. Presence of heterophile antibodies: nonspecific antibodies produced by EBV-infected B cells. Epidemiology This is a disease of teenagers and youg adults. The virus is present in the lymphoid tissue and salivary glands, the source of infecting virus is in the pharyngeal secretions of infected persons and saliva. It is a latent and recurrent disease and individuals with latent infection produce the virus in pharyngeal and oral secretions for prolonged periods after recovery. The disease is transmitted by direct oral contact (kissing disease) by kissing or sharing tooth brushes , cups , etc … EBV can be transmitted by blood transfusion. Generally, any person with an immune deficiency (specially of T cells) is highly susceptible to EBV. In children the disease is more benign than in adults; usually symptomless as in adults it could lead to glandular fever which may lead to tumor formation. EBV is suspected to be a trigger for multiple sclerosis (MS) and Hodgkin’s disease. Burkitt’s Lymphoma A highly malignant tumor of lymphoid tissue (B cell malignancy) that usually develops in the jaw and grossly swells the cheek. It is common in African children (4 to 8 years), and spreads rapidly with widespread metastases. Burkitt’s lymphoma is found in areas with holoendemic malaria. Malaria may act as a cofactor with EBV to produce malignant transformation in lymphoid tissue (as in Burkitt lymphoma). Nasopharyngeal carcinoma is a malignancy of the epithelial cells of the nasopharynx. It also shows a striking geographical distribution and is particularly common among older Chinese and African men. Hairy oral leukoplakia is an unusual presentation of EBV infection that causes lesions of the mouth (white adherent plaques on the tongue due to invasion of the epithelium). It is an opportunistic presentation in AIDS patients. 31 Treatment For infectious mononucleosis: symptomatic relief of fever and sore throat. For disseminated disease: specific antiviral measures are; intravenous gamma globulin, interferon, acyclovir and monoclonal drugs. For Burkitt’s lymphoma: systemic anticancer chemotherapy (cyclophosphamide or vincristine), along with surgical removal of the tumor. Screening blood and organ donors before blood transfusion and organ transplantation. Cytomegalovirus (Salivary gland virus) CMV Human Herpes virus 5 Cytomegaloviruses are named for their tendancy to produce giant cells with nuclear and cytoplasmic inclusions. They produce a primary infection followed by latency of the virus in white blood cells such as T cells, monocytes and other cells. Most healthy adults and children with primary CMV infection are asymptomatic. However, three groups that develop a more virulent form of the disease are fetuses, newborns and immunodeficient adults. CMVs are the most prevalent fetal infections. It is a severe disease often fatal, usually affecting salivary glands, brain, kidneys, liver and lungs. It is transmitted by infected cells including lymphocytes and leucocytes, which spread the virus throughout the body. Pathogenesis: Infection occurs either: (i) through transplacental transfer during pregnancy causing congenital infections, (the fetus can be damaged in any of the 3 trimesters of pregnancy), or (ii) by excreting the virus into the genital tract at the time of birth causing neonatal subclinical infections (acquired before or at birth by mother).Therefore the infant carrier is a source of dissemination. The virus produces latent infections which may be activated by pregnancy and multiple blood transfusion. Cell mediated immune response is required for resolution and contributes to symptoms. Antibody role is limited, and suppression of cell mdiated immunity allows recurrence. Clinical Syndrome The disease is usually asymptomatic in adults. Sometimes it may develop clinical illness: fever, malaise, pharyngitis, lymphadenopathy and hepatosplenomegaly. Congenital infections: Newborns with clinical disease, show signs and symptoms of cytomegalic inclusion disease: jaundice, hepatosplenomegaly, capillary bleeding, thrombocytopenia, hemolytic anemia, and the brain is almost always involved and some infants have microcephaly, motor disorders and ocular inflammation. In some cases, damage can be so severe and extensive that death follows within a few days or weeks. Many of the congenitally infected neonates who survive, develop normally, but some show neurological sequale later in life: deafness, visual disturbances and mental retardation. 32 Neonatal infections: Perinatal CMV infection is chiefly asymptomatic, although pneumonitis and a mononucleosis-like syndrome can develop during the first 3 months after birth. Post natal infections : In young children : Hepatitis with or without jaundice. In adults and older children: CMV mononucleosis, a syndrome characterized by fever and lymphocytosis, somewhat similar to the disease caused by EBV with negative test for heterophile antibodies. In immunodeficient patients: Disseminated CMV infection; a severe opportunistic infection of AIDS patients causing fever, severe diarrhea, hepatitis, pneumonia, retinitis which if untreated can lead to blindness. Most kidney transplants and half of those receiving bone marrow develop CMV life- threatening pneumonia, but almost any organ can be affected. Laboratory Diagnosis 1. Isolation of virus from virtually all organs and epithelial tissue; explants of apparently normal adenoids and salivary glands (saliva) i.e. throat swabs and from urine. 2. Cultivation of virus in cell culture and observation of characteristis cytopathic effect: cell enlargement (characteristic cytomegalic cells) with intranuclear (owl’s eye) and cytoplasmic inclusion bodies and both affected cells and nucleus are very much increased in size. 3. Indirect immuno fluorescence, direct ELISA and DNA probe analysis for virus indentification are also useful in diagnosis. 4. Serological Tests may fail to diagnose infection in neonates and the immunocompromized (less reliable). Epidemiology The virus is transmitted in saliva, respiratory mucous, milk, urine, semen and cervical secretions. Transmission usually involves oral , sexual routes, transplacental infection, vaginal birth, blood transfusion, organ transplantation. and by person-to-person spread in urine and respiratory secretions. The major routes of transmission are sexual route, tissue transplant and transfusion routes. CMV is commonly carried in a latent state in white blood cells. Treatment, Prevention and Control Drug therapy is reserved for immunocompromized patients. Ganciclovir and Foscarnet are active against CMV in immunocompromized patients administered by slow intravenous infusion. They have toxic side effects (renal impairment and toxicity), and cannot be administered for long periods. Avoid exposure of pregnant women to infected infants. Screening potential blood and organ donors before blood transfusion and tissue transplant 33  Human Herpes virus 6 ( HHV 6 ) Human B-lymphotropic virus It is a latent infection of lymphoid tissue, with characteristics similar to CMV. (i) Roseola ( also known as roseola infantum): a febrile, mild, faint facial and body rash in small babies 2 to 12 months of age associated with HHV-6 infection. (ii) Mononucleosis with cervical lymphadenopathy: has been described in a few adults undergoing primary infection with HHV-6. HHV-6 infections suppress the function of the grafted tissues and are possibly a factor in rejection. HHV-6 could play a role in multiple sclerosis (MS). HHV-6 has some role in cancer, such as Hodgkin’s lymphoma, oral carcinoma and certain T-cell leukemias. Human Herpes virus 7 ( HHV 7 ) HHV-7 is very closely related to HHV-6, and it causes similar diseases in children and adults. Human Herpes virus 8 ( HHV 8 ) Kaposi’s sarcoma–associated herpesvirus (KSHV) KSHV is lymphotropic. KSHV is the cause of Kaposi’s sarcomas vascular tumors and is involved in the pathogenesis of body cavity-based lymphomas occuring in AIDS patients. KSHV is also linked to multiple myeloma, a relatively common cancer of the blood. KSHV appears to be sexually transmitted among men who have sex with men. Infections acquired by nonsexual routes include saliva, oral secretions, breast milk and organ transplants. POX VIRUS DISEASES 34 The poxviruses include the human viruses variola (smallpox) and molluscum contagiosum and poxviruses that naturally infect animals e.g. orf, cowpox and monkey pox, but can cause identical infection of humans (zoonosis). Many of these viruses share antigenic determinants with smallpox, allowing the use of an animal poxvirus for a human vaccine. Poxviruses are enveloped DNA viruses, they are the largest most complex viruses. Smallpox Variola Smallpox is a highly infectious and fatal disease. It is a visible pustular disease with characteristic vesicular rash involving the internal viscera. Two variants of smallpox existed: variola major, with a mortality of 15% to 40%, and variola minor, with a mortality of 1%. Smallpox is initiated by infection of the respiratory tract with subsequent involvment of local lymph glands, leading to viremia. Viremia is associated with fever, headache, backache, and later seeding of the skin with the development of a characteristic vesiculopustular virus- containing rash. The rash (pox) has two characteristics that distinguish it from other exanthems: (1) lesions are all at the same stage of development and they progress from macules to vesicles to pustules to crusting and healing, and (2) the rash is centrifugal i.e. begins centrally on the face, shoulders, chest, and later involves more distal sites. In addition to skin involvment, visceral organs (specially the spleen, liver and lungs) are also involved. Smallpox (variola) is a very contagious disease. It is spread primarily by respiratory transmission or, less efficiently, by close contact with dried virus on clothes or other materials. The virus used for vaccination is vaccinia virus (a laboratory altered poxvirus), which was probably derived from an animal poxvirus such as horsepox. Vaccination consists of breaking (scratching) the skin under a drop of live virus and observing for the development of vesicles and pustules to confirm effective vaccination. Revaccination at periodic intervals is necessary to maintain immunity. There are complications related to vaccination, several of which are severe and even fatal, including encephalitis and progressive infection specially in immunocompromized patients. Smallpox was one of the major infectious diseases that accounted for many deaths. Development of the first live vaccine in 1796 and a worldwide distribution program led to the eradication of smallpox by 1980. WARTS Human Papillomavirus Infections 35  (HPV) Warts are one of the commonest infections. Warts are caused by a group of small non- enveloped DNA papillomaviruses. They encode proteins that permit cell growth. Human papillomaviruses (HPV) cause benign outgrowth of cells into warts i.e. benign tumours of the skin with proliferation of keratinized and non-keratinized squamous epithelium, in both skin (cutaneous HPV) and mucous membranes (mucosal HPV). Warts are most common on hands and feet , genitalia and anus , and are also found in the larynx and oral cavity. Almost 100 HPV types have been identified and classified. Pathogensis : The virus infects and replicates in the squamous epithelium of skin and mucous membranes, to induce epithelial proliferation, a wart. Viral infection remains local and generally regresses spontaneously. The virus remains in the basal layer of the epithelium. The papillomavirus genome can persist in the cells and may cause recurrences. HPV viral DNA has been found in both benign and malignant tumors, especially mucosal papillomas. HPV-16 and HPV-18 cause cervical papillomas which contain integrated HPV- DNA. The mechanism by which papillomas resolve is not known. The importance of cell-mediated immunity is suggested since immunosuppressed individuals have recurrences and more severe presentations of papillomavirus infections. Clinical Syndromes Skin warts Most persons with infection have common HPV types 1 through 4, which infect keratinized surfaces usually hands and feet. Benign Head and Neck Tumours Single (solitary) oral papillomas are benign epithelial tumours of the oral cavity. They rarely recurr after surgical excision. Laryngeal papillomas Commonly associated with HPV-6 and HPV-11, are considered life-threatening in children. Occasionally, papillomas may extend down the trachea and into the bronchi. Anogenital warts Genital warts occur on the external genitalia and perianal areas. These are caused by HPV- 6 and HPV-11, the anogenital lesion infected with these HPV types rarely progress to malignancy in healthy individuals. Cervical Dysplasia, Neoplasia (Cervical carcinoma) It is recognized as a common sexually transmitted disease (STD). HPV infection causes cytologic changes (koilocytotic cells). HPV types 16 and 18 are associated with intraepithelial cervical neoplasia and cancer, and 85% of cervical carcinomas contain integrated HPV DNA. The E6 and E7 proteins of HPV-16 and HPV-18 have been identified as oncogenes i.e. can become immortalizing genes. The first neoplastic changes noted by light microscopy are termed dysplasia. 40% to 70% of the mild dysplasias undergo spontaneous regression. Precancerous lesions proceed through progressive cellular changes from mild cervical intraepithelial neoplasia (CIN): CIN I to moderate CIN ΙI to severe dysplasia and /or invasive carcinoma CIN III. This sequence of events progresses over a period of 1 to 4 years. 36 Epidemiology HPV is relatively stable to inactivation and can be transmitted by direct contact e.g. hand to hand or contact with contaminated surfaces, bathroom floors or towels. They can be transmitted via water in the surrounds of swimming pools (plantar warts on feet). HPV infections are also acquired through small breaks in the skin or mucosa. Plantar, common , and flat warts are most common in children and young adults. Genital warts are transmitted sexually, and asymptomatic shedding may promote transmission. Laryngeal papillomas may be transmitted via the infected mother’s birth canal with juvenile laryngeal papillomas. Laboratory Diagnosis Clinical diagnosis is reliable in most cases. In ambiguous cases, a biopsy and histological examination can be clarifying: They can be confirmed microscopically by: - Characteristic histological appearance consisting of hyperplasia of prickle cells and hyperkeratosis (production of excess keratin). - Presence of koilocytotic (vacuolated cytoplasm) squamous epithelial cells which are rounded and occur in clumps (a precancerous condition) identified by the Pap smear. DNA molecular probes (DNA probe analysis) for viral nucleic acid for establishing the presence of HPV infection in cervical swabs and in tissue. HPV (the virus itself) can be seen by electron microscopy in lesions as well as HPV antigens by immunofluorescent techniques. Treatment, Prevention and Control − Spontaneous disappearance of warts is the rule, but this may take months to years. − Painful or bulky lesions are removed by surgical cryotherapy (freezing), electrocautery, laser surgery, burning with acids or by chemical means as podofilox (podophyllin), but recurrences are common. − Topical application of drugs such as imiquimod (Aldara) is often effective. − Warts that do not respond to any other treatments can be treated with lasers or injected with bleomycin (anticancer drug). − Injection of interferon is also beneficial. − Surgery may be necessary for laryngeal papillomas. The best means for prevention is avoidance of direct contact with infected tissue. Two HPV vaccines: Gardasil and Cervarix have been developed to prevent cervical cancer, precancerous genital lesions and genital warts due to HPV. Both vaccines protect against HPV-16 and HPV-18 that can cause cervical cancer and some other genital cancers. Gardasil also protects against HPV-6 and HPV-11 and is a 3 dose (injection) vaccine with intial dose followed by additional shots given 2 and 6 months later. Gardasil 9, 9-valent recombinant vaccine covering 9 HPV types, approved for prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58 and for prevention of genital warts caused by HPV types 6 and 11. The vaccines are based on viral protein surface receptors made by recombinant DNA technology. Currently, the main target group is girls and young women between 9 and 26 years of age and males ages 9 to 15. Both vaccines have shown a nearly 100% efficacy and safety. 37  ZOONOTIC DISEASES Zoonoses are diseases acquired from animals or non-human primates; which are the reservoir of infection. Zoonotic diseases are endemic in certain areas, but travel the world through infecting people and animals. They cannot be eradicated as human pathogens. Examples of viral zoonotic diseases: Viral agent Animal reservoir Zoonotic disease Rabies virus Dogs, cats, cattle Encephalitis Ebola virus Monkeys, gorillas Hemorrhagic fever Marburg virus Chimpanzees Hemorrhagic fever Monkeypox virus Monkeys, rodents Pustular disease Hantavirus Rodents Hemorrhagic fever Hendravirus Horses Kidney & respiratory failure Nipah virus Pigs Brain inflammation SARS virus Civet cats Respiratory failure Avian influenza virus Birds Respiratory disease Human immunodeficiency Chimpanzees AIDS virus Mad cow disease Cattle, sheep Spongiform encephalopathy Rabies Rabies virus is an RNA enveloped cylindrical bullet-shaped rhabdovirus. It causes the disease known as Rabies which is a fatal meningoencephalitis with neuronal degeneration of the spinal cord and brain. The disease is a zoonosis i.e. acquired from animals which are reservoirs of infection. Host Range Rabies virus can infect all mammals. The primary reservoirs of the virus are wild mammals. These can spread infection to domestic animals as cats, dogs and cattle. 38 Pathogenesis Incubation period is 3 to 8 weeks, yet it can be as short as 6 days or as long as one year. The virus enters a wound or abrasion of skin caused by a rabid animal: virus entering with the animal’s saliva. The virus multiplies at the site of inoculation (striated muscle) and remains localized for a week at the trauma site. It then gradually enters nerve endings and advances to the peripheral nerves, to the ganglia and eventually to the spinal cord and CNS. The virus multiplies there, then disseminates via the afferent neurons to highly innervated sites as the skin, head, neck, eye, nasal mucosa, salivary glands and heart. Rabies is fatal once the clinical disease is apparent. The duration of incubation period depends upon; the size of viral inoculum, the severity of the wound, the length of the neuronal path from wound to the brain i.e. shorter following bites on face and head, and the host’s age and immune status. Clincal Symptoms 1- The Prodrome phase: (2 to 10 days) characterized by fever, malaise, vomiting headache, gastrointestinal symptoms, fatigue and anorexia. Some patients experience pain, burning sensations, or parasthesia at the site of the bite. 2- The Acute phase (neurological involvement): (2 to 10 days) and is characterized by the furious phase: agitation, disorientation, generalized seizures and twitching. Hydrophobia is the most characteristic symptom of rabies (associated with pain when swallowing water), the patient is fully coherent and alert. 3- The Dumb phase: no hyperactivity but disorientation, hallucinations and paralysis. 4- The Comatose phase: where respiratory and cardiac arrest occur with other neurological complications and is followed by death. Laboratory Diagnosis Rabies is difficult to diagnose during life, but usually at autopsy. Specimens are often negative and serological results difficult to interpret if immunization has been undertaken. 1- Detection of viral antigens in specimens of brain, spinal cord or skin (back of neck) and corneal smears by immunofluorescence with rabies antiserum. 2- Isolation of virus from brain tissue and saliva, CSF and urine. 3- Identification of the virus by intracytoplasmic inclusion bodies: Negri bodies; characteristic cytopathic effect in affected neurons and brain tissue (postmortem). Negri bodies + Seller’s stain give red intracytoplasmic intrusions. 4- Serological Tests are impractical, only during later stages. in an unimmunized patient. 5- RNA detection by PCR now offers a sensitive and reliable method of confirming the diagnosis in the laboratory. Epidemiology - Dogs are the most dangerous source of infection to man, followed by cats (urban rabies), through bites, scratches and inhalation of droplets. - Contamination of an open wound or mucous membrane by saliva or brain tissue of suspected (infected) animal. - Forest (or sylvatic) rabies involves many species of wildlife e.g. racoons, skunks, foxes, bats …etc. - Infection of man from bats by inhalation of infected aerosols. 39 40 Prevention, Control and Treatment 1- Prophylaxis - Compulsory prophylactic immunization of dogs and cats with vaccines. - Registration of all dogs. - Destruction of stray dogs. 2- Long Term Prophylaxix for high risk groups e.g. veterinarians, laboratory workers, dog handlers, these should receive a course of vaccine followed in several months by a booster injection. Subsequent booster doses should be given every 2 to 3 years or following a suspected exposure. 3- Prophylactic Treatment: The goal of prophylactic treatment is to confine the virus to the site of entry. Patients should be given combined passive and active immunization. Active immunization should be started immediately after passive immunization. a) Local treatment of wound thorough cleansing of wound by washing immediately with soap or detergent and water, followed by debridement and application of antiseptic as alcohol or peroxide. Infiltration or infusion of the wound with human rabies immune globulin (HRIG). b) Simultaneous inoculation of hyperimmune serum (HRIG) and vaccine intramuscularly. The first provides antibody until the patient produces antibody in response to the vaccine (14 days), which in turn prevents the virus from reaching the CNS. Antiserum alone should never be used. Vaccines: Pasteur and Semple vaccines were the first rabies vaccines. - Inactivated, partially attenuated rabies vaccine: Rabies virus attenuated in embryonated duck eggs and inactivated by β- propiolactone, given intraperitoneally in 21 injections (daily) and booster doses 10 and 20 days later. - Human diploid cell vaccine HDCV: a potent inactivated vaccine cultured in human embryonic fibroblasts given intramuscularly into the deltoid area of the upper arm, or intradermally on days 1,3,7,14 and 28 (and day 60, with two boosters) following exposure. Three injections during 1 week are equal in antibody level to a full course of duck embryo vaccine. 41  HEMORRHAGIC FEVERS Viral hemorrhagic fevers are caused by a variety of viruses: by arthropod-borne viruses as yellow fever and rift valley fever, or by non-arthropod-borne viruses as marburg fever and ebola. Hemorrhagic fevers are characterized by localized bleeding, fever and shock. ELISA techniques may detect antigen in clinical specimens from patients with high levels of viremia. Treatment of such fevers relies completely on supportive measures to control fever, convulsions, dehydration, shock and edema. ARTHROPOD-BORNE VIRUS INFECTIONS Arboviruses Arboviruses are arthropod-borne viruses. They cause diseases transmitted by the bite of an arthropod vector. These viruses multiply in both vertebrates (e.g. mammals, birds, amphibians, reptiles); which serve as reservoirs, and arthropods (e.g. mosquitoes, ticks) which serve as vectors acquiring infection with a blood meal. The virus is propagated in the arthropod’s gut, attains a high titer in its salivary glands, and is transmitted when a fresh host is bitten. There are three groups of Arboviruses : Togaviruses, Bunyaviruses and Arenaviruses. Arboviruses can cause three types of diseases: encephalitis, fever and hemorrhagic fever. These disease syndromes may overlap: hemorrhages quite often complicate arbovirus fevers; the hemorrhagic forms of the disease may be due to formation of immune complexes due to abnormally large production of antibodies. Yellow Fever The virus causing yellow fever is an RNA enveloped flavi-togavirus. Yellow fever is a severe systemic disease involving the viscera such as liver and kidneys. It is known as a grave disease, with a mortality rate of approximately 10-50% during epidemics. Pathogenesis Incubation period is 3 to 7 days. The virus enters the blood or lymph following an infected mosquito bite. It multiplies in the lymph nodes. Primary multiplication is followed by extensive secondary viral mutiplication with cell destruction and degeneration in many viscera including the liver, spleen, kidneys, heart, bone-marrow and lymph nodes. These are accompanied by hemorrhages of blood vessels. Clinical Symptoms Fever, chills, headache, prostration, hepatitis, nephritis and hemorrhage of blood vessels leading to massive gastrointestinal hemorrhages (black vomit). Hepatitis causes jaundice which is the most striking feature of yellow fever. Toxic nephritis and protein urea are frequent complications. 42 43 Laboratory Diagnosis 1- Isolation of virus from blood or serum during the first 2-4 days of the disease. 2- Cultivation of virus in susceptible cell cultures. 3- Serologic Tests Complement-fixation assays are preferred since they are simple, fast, economic and lack cross reactivity. Enzyme-linked immunosorbent assay ELISA may also be used for IgM detection. Epidemiology There are two distinct epidemiologic types of yellow fever: urban and jungle yellow fever. Each has a different cycle but they may interact. The urban yellow fever is transmitted by the domestic mosquito Aedes aegypti. The jungle yellow fever is transmitted by various jungle mosquitoes, primarily to monkeys. Man becomes an accidental host when he enters the animal domain. Infection of man may initiate a cycle of urban yellow fever. Prevention and Control - Preventing the transmission of virus by eradicating or at least reducing the population of arthropod vectors. - Artificial immunization by live virus vaccine, prepared from 17D strain that was isolated and propagated in monkeys, mosquitoes embryonic tissue culture and embryonated chicken eggs for long periods (repeated passages): Dakkar vaccine. The vaccine is given intradermally or subcutaneously and elicits an immunity for 6 to 10 years. Dengue fever Dengue fever is a major health problem in many areas of the world, e.g. southeast Asia, India, the Pacific islands, the Caribbean etc. Monkeys are probably the main reservoir of infection and the main vector is the mosquito Aedes aegypti. Clinically, dengue is a severe febrile disease with pain in the limbs and rash; the infection is mild and the fatality rate of this type of dengue is low. However, another form called Dengue hemorrhagic shock syndrome; is a serious complication of dengue in young children and can be lethal. An attack of dengue progresses to a more severe disease characterized by hemorrhages and shock. Rift Valley Fever Rift valley fever virus was first discovered in Kenya in sheep, then infection was discovered in man. The virus causing rift valley fever is an RNA enveloped phlebo-bunyavirus Rift valley fever is a febrile hemorrhagic disease, with encephalitis and hepatic involvement. Humans are infected through contact with infected animals (sheep, cattle and domestic animals) as well as via infected mosquito bite or sand fly (phlebotomous fly) bite. In the primary stages of the disease patients have conjunctivitis and stiff neck, followed by hemorrhage in 50% of the patients. NON-ARTHROPOD-BORNE HEMORRHAGIC FEVERS 44 Ebola, marburg and hanta viruses cause diseases known as zoonoses. They cause non- arthropod borne hemorrhagic fevers. Monkeys may be the reservoir of the ebola and marburg viruses. However, the host species of hantavirus is rodents. Ebola and Marburg Fever Ebola and its german relative marburg virus are filamentous, enveloped, RNA filoviruses. Ebola virus causes severe or fatal haemorrhagic fevers and is endemic in Africa. The virus replicates efficiently and produces extensive tissue necrosis in the liver, spleen, lymph nodes and lungs. Widespread haemorrhage causes edema and hypovolemic shock followed by death in 10 days. The mechanism of natural transmission of Ebola virus is unknown. The disease is able to spread directly from case to case by accidental injection, and by the use of contaminated syringes. Ebola virus may also be passed by close contact and by body fluids. Viral antigens can be detected in the tissues (liver, spleen, lymph nodes and lungs) by direct immunofluorescence. Antibodies to Ebola virus in blood can be detected by ELISA or RIA, or by indirect immunofluoresance. Infected individuals should be quarantined, and contaminated animals should be sacrificed. Handling of the viruses or contaminated materials requires very stringent isolation procedures. The hospital should employ strict infection-control measures as wearing gloves, gowns and masks, since an ebola virus victim may be close enough to others to spread the infection, especially within the walls of a hospital. Marburg fever is a severe disease that has clinically the same signs and symptoms of Ebola. Hantaan fever Hanta virus is an RNA enveloped bunyavirus. Hantaan virus causes hemorrhagic fever with renal sydrome and adult respiratory distress syndrome. The primary lesions are leakage of plasma and erythrocytes through the vascular endothelium. These changes are most prominent in the kidney and are accompanied by hemorrhagic necrosis of the kidney. The Hantaan virus spreads from rodents to rodents and can spread directly to humans by aerosols or by rodent mites. The disease is a zoonosis. Rodent control minimizes transmission of Hantaan virus. ELISA or immunofluorescence technique detect antigens in patients with high levels of viremia. Ribavirin has been used intravenously to treat severe infections. VIRAL HEPATITIS 45 Hepatitis viruses primarily target the liver to cause the disease viral hepatitis. Infectious hepatitis caused by hepatitis A virus –HAV– transmitted by intestinal – oral route. Serum hepatitis caused by hepatitis B virus –HBV– transmitted by injection of infected blood or its products. Non A non B post-transfusion hepatitis caused by hepatitis C virus –HCV– transmitted by blood transfusion of infected blood or its products. Delta hepatit