29. EMERGING HEPATITIS VIRUSES Other hepatitis viruses, non-A, non-B, non-C G. L. Davis Evidence that agents other than the commonly described hepatotrophic viruses can cause hepatitis comes from the observation of multiple distinct episodes of serologically uncharacterized hepati tis in some patients and the persistence of some cases of post-transfusion hepatitis despite elimination of hepatitis B and C from the donor pool. Additionally, most cases of non-A, non-B hepatitis are also due to HCV. THE AGENTS Several viral agents have been identified recently but these are unlikely to cause clinical liver disease. The ‘‘Hepatitis G’’ or ‘‘Hepatitis GB’’ is another flavivirus-like virus with 20–30% sequence homologous to HCV. Though probably transfusion transmitted, it is not felt to result in clinical disease and is no longer felt to be a hepatitis virus. The SEN and TT viruses are common in patients with hepatitis B and C, as well as the general population. Although solid evidence that they cause hepatitis is lacking, it does appear that they may be responsible for some cases. TRANSMISSION/INCUBATION PERIOD/CLINICAL FEATURES All 3 of the above-mentioned agents are common in trans fusion recipients and patients with other forms of parenterally transmitted hepatitis, suggesting that the routes of transmission may be similar. It still remains unclear how prevalent these infections are and whether they account for an appreciable proportion of patients, if any, with cryptogenic hepatitis and cirrhosis. THERAPY Interestingly, retrospective testing of HCV co-infected subjects has shown that all 3 agents respond to interferon. Nonetheless, since liver disease as a result of these infections has not been proven, treatment should not be considered. LABORATORY DIAGNOSIS The lack of widely available serological markers for these infections has prevented identification of patients outside of research surveys. The studies reported to date have screened serum samples with either RT-PCR amplification of the viral RNA or an immunoperoxidase test to detect antibody. 201 FIFTH DISEASE? A Practical Guide to Clinical Virology. Edited by L. R. Haaheim, J. R. Pattison and R. J. Whitley Copyright  2002 John Wiley & Sons, Ltd. ISBNs: 0-470-84429-9 (HB); 0-471-95097-1 (PB) 30. PARVOVIRUS B19 Human parvovirus, human serum parvovirus. Erythema infectiosum. Slapped cheek disease. Fifth disease. J. R. Pattison Parvovirus B19 is a moderately contagious virus. The common result of infection is erythema infectiosum (EI). When the virus infects individuals with chronic haemolytic anaemia, aplastic crisis results. TRANSMISSION/INCUBATION PERIOD/CLINICAL FEATURES Transmission occurs by droplet inhalation. The interval between exposure and EI is 2.5–3 weeks. Patients are infectious for approximately 7 days, commencing 1 week after acquiring infection. Patients with EI are rarely infectious. SYMPTOMS AND SIGNS Systemic: Prodromes: Fever, Chills Local: Rash, Arthropathy Other: See Complications The rash persists for up to 1 week, but may recrudesce. Arthropathy and arthralgia may persist for weeks. COMPLICATIONS Aplastic crisis, fetal infection, chronic infection in the immuno- compromised. THERAPY AND PROPHYLAXIS Intravenous immunoglobulin to control chronic infection in immuno- compromised individuals. No vaccine. 203 LABORATORY DIAGNOSIS In erythema infectiosum most patients have detect able IgM antibody at presentation. Aplastic crisis patients present towards the end of the period of viraemia. Virus is detectable in 60% of patients at presentation. In the remainder IgM is detectable. In fetal infection, damage may not be apparent until some weeks after maternal infection, thus detection of IgM in maternal blood is infrequent. Fetal infection may only be diagnosed by detection of virus in fetal blood or tissues. 204 Figure 30.1 PARVOVIRUS B19 (APLASTIC CRISIS, ERYTHEMA INFECTIOSUM) CLINICAL FEATURES SYMPTOMS AND SIGNS Transmission is commonly by droplet inhalation. Rarely, the transfusion of blood or blood products may lead to infection. At the peak of the viraemia, 1 week after exposure, there may be a mild flu-like illness with fever, chills and malaise, lasting 2–3 days. In many cases infection occurs without further symptoms. In erythema infectiosum the first sign is often marked erythema of the cheeks (slapped cheek appearance). A faint pink macular or maculopapular rash then develops on the trunk and limbs. As the rash fades a lacy or reticulate pattern may emerge. Recrudescence is common, especially after bathing or exposure to sunlight. In adult women symmetrical arthropathy is common (80% of cases), involving ankles, knees, wrists and fingers. This is normally resolved within 2–4 weeks. Low-grade fever may be present, and the rash may be pruritic. Leukopenia, reticulocytopenia and thrombocytopenia occur. Differential diagnosis. Other exanthems, especially rubella, also scarlet fever, echovirus and coxsackievirus infections, and allergy. The diagnosis can only be made with certainty by laboratory tests. CLINICAL COURSE The rash persists for 4–5 days, although recrudescence may occur over 1 month. Arthropathy in adults resolves in the majority within 2–4 weeks, although in some arthralgia may persist for 2 months or so. Where arthritis occurs in children it is rarely symmetric, and may be severe for 1–2 months. COMPLICATIONS Aplastic crisis. The cell receptor for parvovirus B19 is the P antigen present on red blood cells, vascular endothelium and fetal myocytes. During all B19 infections, red blood cell precursors are infected in the bone marrow, causing a transient arrest of erythropoiesis for 7–10 days. In patients whose red cells have a shorter lifespan than normal, this arrest causes a rapid decrease in haemoglobin to very low, sometimes life-threatening, levels. Such aplastic crises occur in patients with hereditary haemolytic anaemias (e.g. sickle-cell anaemia). Aplastic crisis is treated by transfusion of packed red cells to raise haemoglobin levels. Fetal infection. If infection occurs during pregnancy, the virus may cross the placenta. This occurs in just under one-third of cases of maternal B19 infection. In 90% of cases of maternal infection the pregnancy proceeds to term and to date no defects have been noted in such ba bies. However, about 10% end in spontaneous abortion in the second trimester (a 10-fold increase compared 205 with controls). Occasionally infection during pregnancy manifests as hydrops fetalis. Immunocompromised patients. Anaemia due to persistent infection may occur in patients who are immunocompromised due to acute lymphatic leukaemia, and HIV positivity. THE VIRUS Parvovirus B19 (Figure 30.2) is a single-stranded DNA virus of the genus Parvovirus, family Parvoviridae. The cap sid is a naked icosahedron, 21 nm in diameter for which the full three-dimens ional structure has been elucidated. It is composed of two structural proteins VP1 and VP2, the latter constituting approximately 80% of the total protein mass of the virus. The genome of B19 is a single-stranded DNA 5.5 kb long. It ha s a characteristic parvovirus structure with a linear coding region bounde d at each end by terminal palindromic sequences that fold into hairpin duplexes. The virus packages plus and minus DNA strands into separate virio ns in approximately equal proportions, but the coding regions of B19 are confined to the plus strand. There are two open reading frames both driven by a single promotor at map position 6. There appears to be a single stable antigenic type of B19 so that infection is followed by long-lasting immunity in an individual. However, genomic variants do occur and these have been classified into a number of groups. The groups do not correlate with the variety of clinical manifestations of B19, but individual viruses in the groups cluster in time and geographically. The virus cannot easily be propagated in tissue culture, although replication occurs in primary cultures of human bone marrow. Virus replication requires host-cell function(s) found in late S phase of cell division. EPIDEMIOLOGY B19 virus is transmitted by droplet inhalation. Patients are infectious for about 1 week, coinciding with prodromal illness. Case-to-case intervals vary between 7 and 14 days. Infection is most common in primary school children aged 5–13 years, among whom outbreaks may occur. Evidence of past infection is present in 60–70% of adults. The virus is most common in the late winter and spring months. Epidemics occur every 3–5 years. The virus occurs throughout the world. 206 Figure 30.2 PARVOVIRUS B19. Bar, 50 nm (Electron micrograph courtesy of M. J. Anderson) THERAPY AND PROPHYLAXIS Due to difficulty in propagating the virus in vitro, there is no vaccine. During local epidemics, transfusion of packed erythrocytes or the administration of normal human immunoglobulin may afford some protection to individuals at risk of aplastic crisis. There is no indication for termination of pregnancy if maternal infection occurs, since no abnormalit ies have been noted in babies born to mothers whose pregnancy has been c omplicated by B19 infection. The symptoms of B19 infection may be treated as appropriate: erythrocyte transfusion for aplastic crisis, calomine lotion for pruritic rash, anti- inflammatory agents for arthritis. Intravenous immunoglobulin is effective in controlling chronic infection in the immunocompromised. LABORATORY DIAGNOSIS Erythema infectiosum. In the majority of cases specific IgM is present at the onset of the rash. This may be detected by antibody capture RIA or ELISA. Where the acute serum contains no detectable IgM, either a second sample taken 10 days later should be simila rly examined, or the acute sample examined for virus (see below). Aplastic crisis. Sera taken within 3 days of the onset of symptoms are likely to contain virus. Virus antigen may be detected by RIA or ELISA. Virus may also be detected by hybridization to cloned viral DNA labelled with biotin or 32 P. RIA, ELISA and DNA hybridization give positive results in 60% of acute sera from cases of aplastic crisis; this figure falls to 30% if CIE and/or electron microscopy are used. Fetal infection. Diagnosis can only be made by examination of fetal material. It is most useful to test fetal blood for virus antigen or DNA, since the fetus may be too immature to synthesize IgM. DNA extracted from fetal tissue is tested by DNA hybridization for viral genome. Alternatively, formalin-fixed paraffin- embedded tissue may be examined for viral DNA by in situ hybridization. 207 A STEP IN THE WRONG DIRECTION? A Practical Guide to Clinical Virology. Edited by L. R. Haaheim, J. R. Pattison and R. J. Whitley Copyright  2002 John Wiley & Sons, Ltd. ISBNs: 0-470-84429-9 (HB); 0-471-95097-1 (PB) 31. RETROVIRUSES re ¼ reverse; tr ¼ transcriptase. A. B. Dalen Retroviruses are widely distributed throughout the vertebrates and perhaps the invertebrates. The main characteristics of this group of viruses is the presence in all infectious virions of an enzyme, reverse transcriptase, which catalyses the formation of a complementary DNA strand to an RNA template. A double- stranded DNA copy of the viral RNA genome (proviral DNA) may then be integrated and propagated in the host-cell genome. The chemical, physical and structural properties of the retroviruses from different species are essentially similar. Retroviruses are enveloped RNA viruses, 80–100 nm in diameter. Most retroviruses carry surface glycoprotein spikes, anchored to the interior by a transmembrane protein or glycoprotein. The loosely arranged interior core contains a major and several minor proteins (the gag proteins). The viral genome consists of two identical strands of RNA to which reverse transcriptase is bound. The plasticity of the genome readily allows retroviruses to adapt to selective pressure. Point mutations occur with the same frequency as in other RNA viruses, but retroviral genomes recombine at an exception al rate with other viral genes or host-cell sequences. Endogenous retroviruses or retrovirus genomic material (retrogenes) are normal constituents of cells and are inherited as Mendelian elements. They may be expressed under certain circumstances as complete, infectious virus particles (exogenous retroviruses). Mostly, however, the gene sequence contains deletions and therefore remains unexpressed or gives rise to incomplete particles. Endogenous retroviruses are mostly animal viruses which may be ‘rescued’ when the cell is stressed in some way. Exogenous retroviruses comprise three subfamilies: . Oncovirinae (RNA tumour virus group). These are further subdivided on morphological criteria into: (a) intracellular A-particles, (b) B-type retroviruses (mouse mammary tumour virus), (c) C-type retroviruses (leukaemia viruses HTLV-1 and 2) and (d) D-type retroviruses (associated with primate neoplasias). . Lentivirinae (slow virus group). Lentiviruses are non-oncogenic and cause chronic, inflammatory disorders in the host. HIV-1 and 2 are related to this group. . Spumavirinae (foamy virus group). Spumavirus has been isolated from many species, including man, and has no known pathogenic potential. 209 MODE OF INFECTION AND DISEASE MECHANISMS Retroviruses have generally low infectivity, and transmission under natural conditions usually requires intimate contact with blood, sperm, milk or sputum. Retrovirus infections are often but not invariably permanent, and the immune defence is in many systems inadequate to cope with the infection. Many cell types may be infected within the host. Some cells propagate virus without impairment of cellular function, while others may undergo malignant transformation or present other signs of cellular dysfunction. The latent period before disease develops is usually very long in retroviral infections. Numerous organ systems may be afflicted, but the virus has a predilection for lymphocytes (leukaemias and lymphocyte destruction) and the central nervous system (chronic inflammatory diseas e). The mechanisms underlying cellular dysfunction caused by retroviral infections are poorly understood with the exception of acute transforming retroviruses. Endogenous retroviruses have an aetiological role in certain neoplasias and inflammatory disorders in animals. A similar function has not been clearly demonstrated in the human counterpart. 210 [...]... Mononucleosis-like, Erythematous Maculopapular Rash Canidida, Dermatological Symptoms, Varicella-Zoster Fever, Night Sweat, Fatigue Opportunistic Infections, Kaposi’s Sarcoma, Neuropathy, Dementia, Tuberculosis The average survival time after the diagnosis of AIDS has been made is about 1 year if no antiviral therapy is given 213 THERAPY AND PROPHYLAXIS Various antiretroviral combination therapies are beneficial... from a case of hairy cell leukaemia However, most hairy cell leukaemia cases are of B-cell phenotype HTLV-I has been associated with chronic neurological disease, tropic spastic paraparesis (TSP) or HTLVassociated myelopathy (HAM), and adult T-cell leukaemia virus (ATL) Most HTLV-I infections are subclinical ATL is a disease of early adulthood, mostly between the age of 20 and 30 years, appearing in approximately... the acidic environment of the stomach EPIDEMIOLOGY TBE is endemic to Northern, Central and Eastern Europe, Russia and the Far East Cases have been reported from Austria, Byelorussia, Bulgaria, China, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Japan, Kazakhstan, Latvia, Lithuania, Norway, Poland, Russia, Romania, Slovenia, Sweden and Switzerland With increasing... rare outside the endemic areas Clinical manifestations of early infection have not been delineated, although cutaneous manifestations and febrile disease have been reported A few infected individuals (1 in 2000 to 1 in 100) develop adult T-cell leukaemia (ATL) after an average interval of 30 years SYMPTOMS AND SIGNS HTLV-I: HTLV-II: Associated with Chronic Neurological Disease (HAM/TSP) and Adult T-Cell... retroviruses TRANSMISSION/INCUBATION PERIOD /CLINICAL FEATURES HTLV-I has a low infectivity and is transmitted vertically from mother to child and horizontally by blood transfusions, intravenous drug abuse or sexually Transmission by drug abuse of HTLV-I and HTLV-II is an increasing problem in many areas HTLV-I exists in striking clusters in Japan, central and South America, Africa and the Caribbean Islands The... infested areas such exposure will not always be recalled by the patient The prodromal phase of TBE lasts 2–12 days and has no pathognomic symptoms At this stage the disease will most commonly be diagnosed as a non-specific fever with headache and myalgia If an EEG is performed, pathological findings may, however, be detected The ‘major disease’ (secondary phase) may follow after a symptom-free period lasting... Leukaemia (ATL) Not Yet Associated with Disease in Man The typical aggressive form of ATL shows lymphadenopathy and frequent cutaneous and visceral involvement An atypical, more indolent form of the disease has recently been reported Chronic progressive myelopathy (tropical spastic paraparesis, HTLVassociated myelopathy) has been identified as another clinical manifestation appearing with a low prevalence... studies of HTLV-I and HTLV-II show a geographical clustering of cases with the highest prevalence in Southern Japan, the Caribbean, Central Africa and the Southeastern USA In Southern Japan, seroprevalence rates approach 35% In the USA and Europe the seroprevalence of both viruses appears to be increasing in association with injected drug abuse and blood transfusion In the USA HTLV-I and HTLV-II infect... HIV pandemic; 216 in particular contacts with prostitutes, bisexual men and intravenous drug users Sub-Saharan Africa, India, Thailand, the Russian Federation and China represent epidemic hot spots with rapidly increasing HIV prevalence HIV is also transmitted from mother to child, in utero, intrapartum or perinatally via breast feeding Transmission via whole blood or blood products has virtually ceased... HTLV-I should be counselled regarding their inadequacy as blood and organ donors THERAPY AND PROPHYLAXIS At present there is no therapy for HTLV-I and HTLV-II infections, nor are there currently any vaccines available Introduction of routine screening of blood and organ donors for antibody is decreasing seroconversion rates LABORATORY DIAGNOSIS Serological assays and molecular biological assays are . have an aetiological role in certain neoplasias and inflammatory disorders in animals. A similar function has not been clearly demonstrated in the human counterpart. 210 A GLOBAL CHALLENGE A Practical. SIGNS ‘Primary infection’: Influenza- or Mononucleosis-like, Erythematous Maculopapular Rash HIV-related symptoms: Canidida, Dermatological Symptoms, Varicella-Zoster Constitutional symptoms: Fever,. virions of an enzyme, reverse transcriptase, which catalyses the formation of a complementary DNA strand to an RNA template. A double- stranded DNA copy of the viral RNA genome (proviral DNA) may then