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AIDS and the anaesthetist
12 AIDS and the anaesthetist CHARLES
ANTHONY
HART
The acquired immune deficiency syndrome (AIDS) was first described in homosexual men in New York and California (Centers for Disease Control, 1981). These patients presented with Kaposi's sarcoma and Pneumocystis carinii pneumonia, but it soon became apparent that other opportunist pathogens (e.g. Cryptosporidiumparvum, Candida albicans, Cryptococcus neoformans, cytomegalovirus and Mycobacterium spp) and tumours (e.g. lymphomata) do occur in patients with AIDS. Since then it has become clear that probable cases of AIDS had been encountered as long ago as the 1950s (Huminer et al, 1987) and that the numbers of cases of AIDS are increasing at a remarkable rate worldwide. For example, it has been estimated that there have been 250000 cases of AIDS in the Americas, 50 000 in Europe, 300 000 in Africa and 3000 in Australasia (Quinn, 1990). The number of individuals asymptomatically infected with human immunodeficiency virus (HIV) exceeds the number of cases of AIDS by a factor of 10-100. Although the assumption has been questioned by some (Duesberg, 1989), it is generally agreed that a retrovirus is responsible for AIDS. In this chapter the nature of the virus and its pathogenesis are discussed, together with the secondary pathogens that lead to the clinical manifestations of AIDS. In addition the risks of transmission, methods for containment and control and prospects for effective chemotherapy and immunotherapy are assessed.
THE VIRUSES Taxonomy
The first indication that AIDS had a viral aetiology came with the isolation of retrovirus from a French patient with persistent generalized lymphadenopathy. The virus was called lymphadenopathy-associated virus (LAV) (Barr6-Sinoussi et al, 1983). Subsequently isolates were made from patients with AIDS. These isolates were termed immunodeficiency-associated virus (IDAV), human T-cell lymphotrophic virus (HTLV-III) (Gallo et al, 1984) and AIDS-related virus (ARV) (Table 1). All were subsequently shown to Baillibre's Clinical Anaesthesiology-Vol. 5, No. 1, June 1991 ISBN 0-7020-1524-5
243 Copyright 9 1991, by Bailli6re Tindall All rights of reproduction in any form reserved
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C.A. HART Table 1. Viruses associated with AIDS. LAV IDAV HTLV-III ARV HIV-1 HIV-2 HTLV-IV SIV FIV EIAV BIV
Lymphadenopathy-associatedvirus Immunodeficiency-associatedvirus Human T-cell lymphotrophicvirus III AIDS-related virus Human immunodeficiencyvirus 1 (synonymouswith above' Human immunodeficiencyvirus 2 Human T-cell lymphotrophicvirus IV. Simian immunodeficiencyvirus Feline immunodeficiencyvirus Equine infectious anaemia virus Bovine immunodeficiencyvirus
be variants of the same virus and were given the name human lmmunodeficiency virus (HIV). A second retrovirus was isolated from patients with AIDS in West Africa (Clavel et al, 1987). This isolate was significantly different from the original isolate in terms of antigenic and genomic structure; it was therefore termed HIV-2 and the original isolate was renamed HIV-1. Another retrovirus, H T L V - I V , was isolated from healthy prostitutes in Senegal (Kanki et al, 1986). This, it is thought, does not produce immunodeficiency, although it is not clear that this is entirely true (Molbak et al, 1986). Diseases very similar to AIDS have been encountered in other animal species; these include macaques, due to simian immunodeficiency virus (SIV); cats, due to feline immunodeficiency virus (FIV); and cattle, due to bovine immunodeficiency virus (BIV) (Narayan and Clements, 1989). Of these, SIVmac is the only one to exhibit sequence homology to the human viruses (McLure and Schulz, 1989). HIV-2 and SIV are approximately 75% homologous, and HIV-1 and SIV about 40%. This raises the possibility that HIV may have moved from monkey to human, perhaps with H T L V - I V as the 'missing link'. Structure
H u m a n immunodeficiency viruses 1 and 2 are both retroviruses of the Lentivirinae or slow subfamily. They have a single-stranded R N A genome, a cuboidal symmetry, a lipid envelope and are 100-150nm in diameter (Figures 1 and 2). The genome is about 10 kilobases long, consisting of the three main open reading frames (off) Gag, Pol and Env, together with at least seven other minor orfs that control replication. Gag stands for group specific antigen and encodes four structural or core proteins: p7, p9, p17 and p24, where p stands for protein and the number its molecular weight in thousands. The Pol region encodes three enzymes: a protease, a polymerase complex and an endonuclease/integrase. Env encodes two glycoproteins (gp), gp120 and gp41, which are exposed on the surface of the virus (Figure 2).
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Figure 1. A thin-section electron micrograph showing HIV-1 being released from an infected lymphocyte (scale bar 500 nm).
Trimericspike(9-10nm) containing3 molecules of gp 120 \ andgp41 'opp~
Lipid bilayerenvel
Coreprotein (p24)
~////~ (p17)Matprotein rix
~-~
Lateralbody
Corecontaining ribonucleoprotein (RNA,p7 and p9) and reverse transcriptase (p66) Figure 2. A diagrammatic representation of human immunodeficiency virus.
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A key feature of HIV and all other retroviruses is that they possess an RNA-dependent DNA polymerase or reverse transcriptase. This enzyme catalyses the conversion of the viral RNA genome back (hence 'retro') to a double-stranded DNA copy. This so-called proviral DNA uses the viral endonuclease/integrase enzyme to insert itself into the chromosomal DNA o f the cell it has infected. It thus becomes part of the genome of that particular cell and remains latent. This means that once individuals have been infected by the virus they will carry the virus for life and remain a potential infective risk for others. Following an as yet ill-defined signal, the proviral DNA is reactivated to produce the viral RNA genome. This is translated to produce the various gene products. Morphogenesis occurs at the cell surface; core components are assembled with two copies of the RNA viral genome inside the shell of p24. This then buds through an area of the host cell membrane which has gp41 and gp120 inserted in it, and mature virus particles are released into the surrounding medium (Gelderblom et al, 1987). Physical properties Because HIV is an enveloped virus it is relatively fragile. Nevertheless HIV is able to survive following drying on surfaces for over 7 days (Barr6-Sinoussi et al, 1985). This means that it is imperative that all spillages of body fluids should be cleaned with appropriate disinfectants. Hypochlorite-releasing disinfectants are rapidly virucidal (Spire et al, 1984); for example, sodium hypochlorite (2500p.p.m. available chlorine) and sodium dichlorisocyanurate (50 p.p.m, available chlorine) produced a 3-4 log reduction in HIV titre within 2 minutes (Bloomfield et al, 1990). However, much greater concentrations (5000 p.p.m.) were required to produce total kill within 2 minutes of virus in blood spillages. For blood spillages, use of chlorinereleasing powder formulations provides an effective alternative, especially since they will also be active against hepatitis B virus. However, chlorinereleasing disinfectants do corrode stainless steel and may damage instruments. Alternative disinfectants include glutaraldehyde (2% v/v), ethanol, methanol and isopropanol (70% v/v), and nonoxynol (Spire et al, 1984; Hicks et al, 1985; Hanson et al, 1989a). Although alcohols produce a rapid antiviral effect, their activity is less effective against cell-associated virus or virus suspended in high-protein media such as serum (Hanson et al, 1989a). Therefore fresh alkaline glutaraldehyde (2% v/v) is probably the most effective disinfectant for delicate instruments such as endoscopes (Hanson et al, 1989b). Care must be taken, since glutaraldehyde is a powerful allergen and can also stain the skin. HIV can be inactivated by heat when in liquid suspension (56~ for 30 minutes), but like other retroviruses it is relatively radioresistant (Spire et al, 1985). Virus replication Human immunodeficiency virus has a tropism for T lymphocytes and in
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particular for lymphocytes expressing the T4 antigen. This antigen defines a subpopulation of T lymphocytes called helper cells. The T4 antigen acts as the receptor for gp120 which forms the spikes on the HIV envelope (Dalgleish et al, 1984; Lifson et al, 1988). The T4 receptor is present on macrophages, monocytes and some brain cells (Wood et al, 1985; Maddon et al, 1986). However, it is now clear that HIV can infect cells that do not express the T4 receptor. Such cells include glial cells, some colonic carcinomas and HEp-2 (human laryngeal carcinoma) cells (Adachi et al, 1987; Cheng-Meyer et al, 1987; Morrison, 1989). The significance of such observations for human infection is as yet unclear. Unlike the transforming retroviruses, HIV is cytopathic; it both kills infected cells and causes cells to fuse together. This latter mechanism involves a reaction between T4 and gp120 on infected and uninfected cells and allows virus to pass intracellularly from cell to cell. Specific diagnosis of HIV infection Following infection with HIV most patients produce antibody, although this can take over a year to develop in a minority of patients. Detection of antibody has been the mainstay of specific diagnosis up to now. Most types of antibody detection systems have been employed including indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA), competitive radioimmunoassay and latex particle agglutination (LPA). Because of problems with antigen purity, confirmation of antibody positivity used western blotting as the 'gold standard'. However, many HIV antigens have now been 'genetically engineered' and large quantities of pure antigen (gp120, gp41, p24, etc.) are available for use in commercial ELISA and LPA tests. Thus western blottiffg is being replaced by a combination of ELISA and LPA tests (Dalgleish and Weiss, 1990). ELISA tests for detection of HIV antigenaemia, in particular the Gag p24, are available, and it is considered that development of antigenaemia was a marker for onset of AIDS. Virus cultures utilizing lymphoblastoid cell lines such as HT/H9, C8166 or HeLa CD4 + are available, but this can be an expensive and time-consuming exercise. Finally, methods of detection involving gene probing have been developed. These include in situ hybridization, genome isolation and amplification using the polymerase chain reaction (PCR). Of these, PCR is the most sensitive and easily performed, but because of its great sensitivity (it can theoretically detect just one copy of the viral genome) false positives can be a problem if cross-contamination of samples occurs. PATHOGENESIS AND NATURAL HISTORY Information on the acute manifestations of HIV infection can only be obtained from those cases in which the time of infection can be ascertained. In general, more than 50% of those infected have no acute clinical illness
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(Editorial, 1984; Cooper et al, 1985; Pedersen et al, 1989). After an incubation period of 2-3 weeks approximately half of those infected develop a 'glandular fever-like' illness with fever, lymphadenopathy and a macular erythematous rash. A smaller proportion develop other features such as meningoencephalitis (5%), arthralgia or myalgia (19%) or glomerulonephritis (1%). The median duration of illness was 16 (range 4-56) days (Pedersen et al, 1989). This initial phase, it is presumed, is due to replication of HIV in T4 lymphocytes, monocytes, macrophages and other cell types combined with the immune response to such infection. At the same time as this initial infection is occurring, viral genome is back-transcribed to proviral DNA to become latent. It was thought that this was a firm latency and that the only HIV present was cell-associated. Recently, however, it has become apparent that viraemia occurs in HIV-infected patients whether symptomatic or not (Baltimore and Feinberg, 1989). Thus HIV is continually replicating in infected patients and is continually mutating (Sang et al, 1988). During this period the patient is generally asymptomatic. The incubation period for AIDS varies according to the group of patients infected. For example, of intrauterine or perinatally infected New York infants, 20% will develop AIDS in the first year of life and at a rate of 8% yearly thereafter (Auger et al, 1988). In a cohort of male homosexuals in San Francisco, 48% had developed AIDS or AIDS-related conditions within 3 years (Moss et al, 1988), and 49% of a cohort of patients infected via blood transfusion developed AIDS within 7 years (Ward et al, 1989). However, as might be expected, there are considerable individual variations in rates of progression (Burger et al, 1990). The presentation of AIDS includes Table 2. Micro-organisms causing opportunistic infections in AIDS. Oropharynx
Candida albicans Herpes simplex virus Epstein-B arr virus Papillomavirus Fusobacteria
Cutaneous
Candida albicans Cryptococcus neoformans Pityrosporum orbiculare Varicella-zoster virus Herpes simplex virus Molluscum contagiosum virus
Central nervous system
Toxoplasma gondii Cryptococcus neoformans Mycobacteria HIV Cytomegalovirus Gastrointestinal tract
Cryptosporidium parvum Giardia larnblia Isospora belli Entamoeba histolytica Microsporidia Cytomegalovirus HIV Salmonellae Mycobacteria
Disseminated infection Capsulate bacteria
(e.g. Streptococcus pneumoniae) Salmonellae Mycobacteria Respiratory tract Mycobacteria Cytomegalovirus
Pneurnocystis carinii Genital tract Herpes simplex virus Papillomavirus
Haemophilus ducreyi Chlamydia trachomatis
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infection with a large variety of opportunistic pathogens (Table 2) as well as other conditions such as Kaposi's sarcoma and non-Hodgkin's lymphomata. Some features of AIDS, e.g. AIDS dementia complex (Wigdahl and Kunsch, 1990) and enteropathy (Editorial, 1989), are due to HIV itself. Antibody response
In general, antibodies to HIV antigens appear within 3-6 weeks of infection. However, it can take up to a year for antibody to be produced. With intrauterine or perinatal infection the IgM anti-HIV response is often delayed and transient, and it has been suggested that measurement of IgA anti-HIV is the best marker for neonatal infection (Weiblen et al, 1990). Three patterns of antibody/antigen response have been described (Haseltine, 1989). In pattern 1, which is the most common, there is prolific replication of HIV within 3-6 weeks of infection with virus and viral antigen readily detectable in blood and cerebrospinal fluid. Antibodies to viral antigens (particularly gp120 and gp41) appear and rise to high levels. They persist throughout infection. In pattern 2, which is rare, the initial phase occurs but then viral antigen and antibody become undetectable. HIV infection is only detectable by PCR. In pattern 3, there is prolonged HIV infection without antibody production (Imagawa et al, 1989). Clearly, measurement of anti-HIV antibody will not detect all HIV-infected individuals. Cellular responses
Although cells of monocyte/macrophage lineage may be reservoirs of HIV, most of the cell-associated virus in blood is in T4 lymphocytes (Baltimore and Feinberg, 1989). As disease progresses the proportion of T4 lymphocytes infected with HIV increases until as many as 1 in every 100 are infected in patients with AIDS. HIV is cytolytic and in AIDS the absolute numbers of T4 lymphocytes falls precipitately. This means both that antibody production by B lymphocytes is less than optimal and that cell-mediated immunity is impaired. Thus opportunistic infections and tumours become manifest. Sites of virus excretion
The most important sites of virus excretion in terms of transmission are seminal fluid and female genital secretions. HIV has been detected in cervical secretions of asymptomatic women (Vogt et al, 1986) and HIV has been transmitted by artificial insemination by donor sperm (Stewart et al, 1985). Sexual transmission is facilitated by the presence of mucosal ulceration produced by other genital tract pathogens, although this is not an absolute prerequisite (Clumeck et al, 1989). HIV can be found in saliva both cell-free and cell-associated (Groopman et al, 1984). However, there is little evidence that HIV has been transmitted by saliva; indeed there appear to be components of saliva that inhibit HIV (Fultz,
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1986), and experimental transmission of H I V in saliva to chimpanzees has not been achieved. H I V has been found in tears (Fujikawa et al, 1985) but there is no evidence that this site has contributed to spread of infection. HIV has also been found in urine (Levy et al, 1985), and since it can cause an enteropathy may also be found in faeces. Again, there is no evidence to support spread of infection from these sites. Similarly, H I V can be isolated from cerebrospinal fluid (Wigdahl and Kunsch, 1990) and from skin and mucous membrane biopsies (Rappersberger et al, 1988), but these are unlikely to transmit infection. H I V can be found in breast milk and there is circumstantial evidence to suggest that this can be a mode of transmission from mother to baby (Ziegler et al, 1985). In contrast, H I V is found in blood, and there is a large body of evidence demonstrating that blood-to-blood contact can cause transmission of HIV. Infection has been documented following blood transfusion, organ transplantation and infusion of blood products.
RISKS OF TRANSMISSION OF HIV
In order to assess the risk of transmission of HIV, factors that must be considered are the amount of virus being released from a particular site, its survival outside the body, the infective dose and the presence of a portal of entry. Both the frequency at which various sites contain H I V and the number of virus particles present vary according to the site tested (Levy, 1989). Although H I V is present in plasma of infected individuals at all stages, the amount of virus present increases as the patient develops AIDS. On average there are between 10 and 50 infectious particles of H I V per ml of plasma. Saliva is less frequently positive and contains fewer than 1 particle per ml. Semen is more frequently positive and has 10-50 particles per ml, while female genital tract secretions have fewer than 1 particle per ml. Once outside the body H I V will survive relatively well in liquid media (over 7 days with no loss of titre) and even on drying (Barr6-Sinoussi et al, 1985). There is no information on the infective dose of H I V for humans. There is a theoretical possibility that H I V can gain access through unbroken skin via Langerhans' cells (Rappersberger et al, 1988) or through oral and intestinal mucosa via M cells, and at least one such case has been reported (Centers for Disease Control, 1987a). Nevertheless all the epidemiological evidence points to inoculation of virus into blood being the main portal of entry. In addition to the above four considerations, the risk is also related to the chance of being exposed to a biological fluid from a patient who is infected by HIV. Since population serosurveys are not possible and anonymous testing of serum for anti-HIV antibody has only just begun, we have grossly incomplete information on the prevalence of H I V seropositivity. There are, however, some data available. In Baltimore it was found that 5.2% of 2302 adult patients attending an emergency department were H I V seropositive
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(Kelen et al, 1988), and in neonatal blood (and hence in their mothers' blood) rates of 2% and 0.75% seropositivity were observed in New York and Massachusetts respectively (Editorial, 1988). In contrast, in certain parts of Africa and among certain groups of individuals, seropositivity rates of between 20% and 50% have been reported. Transmission by casual contact There is no evidence that casual contact either within a social context or within a family results in transmission of H I V (Friedland et al, 1986; Fischl et al, 1987). Indeed, in a French boarding school that was attended by some HIV-infected haemophiliac children, it was found that H I V was not transmitted to any of the other children at the school, whereas there was evidence of transmission of hepatitis B virus (Berthier et al, 1986). Sexual transmission There is little doubt that this is the major mode of transmission worldwide. The estimated rates of transmission for males to females vary from 3% to 73%, for females to males from 8% to 71%, and for males to males from 10% to 60% (Anderson and May, 1988). Rates vary according to mode of intercourse and concomitant venereal diseases. The rates of homosexual transfer seem to be falling, but unfortunately heterosexual transfer appears to be unaffected by exhortations to practise 'safe sex' (Quinn et al, 1989). Transmission by blood and blood products The numbers of individuals who have acquired H I V infection through transfusion of infected blood, blood products or by organ transplantation (Centers for Disease Control, 1987b) are relatively small (about 3% of cases) (Friedland and Klein, 1987; Wofsy, 1990). The number of new cases should also decline. All donated blood is screened for antibodies to H I V as is blood from those donating organs. However, as can be appreciated from the foregoing discussion, it is possible for an individual to be infected by HIV yet be seronegative. For example, in the USA it has been estimated that the odds of a patient contracting H I V infection from any HIV-antibody screened transfusion were 1 : 153 000 per unit transfused (Cumming et al, 1989). In the U K the risk is assessed as even lower, at less than 1 : 1000 000 per unit transfused. However, with improvement of donor recruitment practice and with tests for viral genome or antigen the risk should decrease further (Zuck, 1988). Perinatal transmission Transmission of H I V can occur in utero, during delivery or postnatally, possibly through breast-feeding. Precise figures on the risk of perinatal
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transmission are lacking since the IgM anti-HIV response in neonates is often delayed or transient, and all those born to infected mothers will have maternally derived transplacental IgG anti-HIV. For the future, the use of IgA anti-HIV measurement (Weiblen et al, 1990) or PCR will provide a more accurate figure for risk of transmission. Current figures suggest a risk of between 25% and 40% for babies born to HIV-infected mothers (Quinn, 1990), Transmission among injecting drug abusers The rise in rate of transmission of HIV among this group is one of the most rapid. Spread is both by sharing of needles and syringes and by sexual contact. In the USA serosurveys of over 18 000 drug abusers have shown very high prevalence rates of 50-60% (Friedland and Klein, 1987; Quinn, 1990). Transmission may not only be associated with drug abuse; there is one example of transmission of HIV from child to child following use by a mother of the same needle and syringe to administer a vitamin injection (Koenig et al, 1986). Insects There is no evidence to suggest that biting insects can transmit HIV (Friedland and Klein, 1987). RISKS TO HEALTH-CARE WORKERS The risk of acquisition of HIV infection by health-care workers or by patients nursed in proximity to HIV-infected symptomatic or asymptomatic patients is very low. However, the risk is not non-existent (Centers for Disease Control, 1987a, 1988). The risk is related to the chance of treating an HIV-infected individual but is also highly dependent upon the procedures involved. Procedures that involve the risk of blood-to-blood transmission such as surgery, blood taking or insertion of long-term venous access give the greatest risk. Anecdotal evidence seems to show that the risk of transmission following mouth-to-mouth resuscitation is low (Saviteer et al, 1985), unless there is fresh blood in the airways. Needle-stick injuries appear to occur at an alarming rate in most hospitals. In a Virginia University Hospital, 326 injuries were reported over a 10month period (Jagger et al, 1988). Disposable syringes accounted for the highest percentage of injuries (35%) but had the lowest rate of needle-stick (6.9 per 100 000 units purchased).~Intravenous tubing and needle assemblies accounted for 26% of the injuries and had the highest rate of injury per 100 000 units (36.7). One-third of the injuries were related to recapping needles. There have been several prospective surveys of needle-stick and bloodsplash exposure to HIV-infected blood (Table 3). The overall risk of HIV infection following needle-stick is 4.2 per 1000 episodes. This is much lower
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Needle-stick No. No. exposed infected
Hirsch et al, 1985 Weiss et al, 1985 Henderson et al, 1986 Gerberding et al, 1987 McEvoy et al, 1987 Marcus et al, 1988 Overall
30 42 40 129 76 860 1177
0 1 0 0 0 4 5
Mucous membrane (%)
(0) (2.4) (0) (0) (0) (0.47) (0.42)
No. No. exposed infected
3 0 110 213 24 103 453
0 0 0 0 0 0 0
(%)
(0) (0) (0) (0) (0) (0)
than the 6-23% risk reported for transmission of hepatitis B. However, it is clear that the larger the amount of blood transferred the greater is the risk. For example, one case of seroconversion followed a deep intramuscular injection of a substantial quantity of blood (Stricof and Morse, 1986). The mean volume of blood inoculated during needle-stick injuries is about 1.4 txl (Napoli and McGowan, 1987). Although, in prospective surveys, no case (risk less than 2 per 1000) of infection via skin or mucous membranes exposed to HIV-infected blood was observed (Table 3), at least two cases have been reported where infection occurred via intact skin or mucous membranes (Hughes et al, 1988). Exposure to blood and body fluids does also occur during surgery. In one survey in San Francisco, accidental exposure to blood occurred parenterally in 1.7% of procedures and cutaneously in 4.7% of procedures (Gerberding et al, 1990). Furthermore it was found that 17.5% of gloves examined after surgery had some form of perforation. If surgeons 'double-gloved', 17.4% of the outer gloves showed perforations but only 5.5 % of the inner gloves. It has been estimated that emergency department surgeons in the USA have a 2% annual risk of contracting an H I V infection by performing surgery, but that an orthopaedic surgeon working within a high HIV prevalence area might have a risk as great as 12% per year (Emanuel, 1988).
RISKS TO ANAESTHETISTS There is little information directly relating to anaesthetists, but both administering anaesthesia and managing patients in intensive care units may give rise to transmission of HIV.
Administering anaesthesia During such procedures the risks from blood splash and needle-stick injury apply. In addition, intubation might be expected to expose anaesthetists to the same risk of infectidn as dentists. There is no evidence that saliva can transmit infection even when inoculated intravenously, intraorally or intravaginally into chimpanzees (although chimpanzees are infectable by HIV). Thus unless there is blood in the mouth, transmission of infection is unlikely.
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In surveys of dentists working with HIV-infected patients there seems to be little to no risk of acquisition of infection (Klein et al, 1987; Gerberding, 1990).
Intensive care units
Increasing numbers of AIDS patients and HIV-infected patients will be admitted to intensive care units. Following an initial report in which the need for acute respiratory support for AIDS patients with acute respiratory failure was defined (Murray et al, 1984), there is increasing experience of managiag AIDS patients in the intensive care unit (ICU) and the survival rates of such patients are improving greatly (Rogers et al, 1989; Singer et al, 1990). Clearly the management of AIDS patients in the ICU produces both medical and psychological (for the staff) problems. By definition, ICU patients will have numerous invasive procedures and there is ample opportunity for splashes of blood and other biological fluids to reach the skin and mucous membranes of staff members. Indeed, in a report from a medical ICU in Pittsburgh, a total of 25 needle-stick injuries and 56 mucosal splashes from HIV-infected material affected 76 members of staff over a 3-year period (Rogers et al, 1989). Fortunately, none seroconverted to being HIV antibody positive. No transfer of HIV has been noted in medical personnel providing dialysis for HIV-infected patients (Centers for Disease Control, 1986). Risk of HIV infection may not come only from those with AIDS. In a survey of 203 critically ill patients in the USA, it was found that 3% had antibody to HIV (Baker et al, 1987). In a larger survey of 2275 patients presenting to an emergency department, 5.2% had antibody to HIV; most of these did not have AIDS or AIDS-related complex, and penetrating trauma was associated with a higher seropre ,alence rate (Kelen et al, 1988). Of the HIV-infected patients, only 29% were considered to be at high risk of having been infected. Thus, especially in geographical areas with a high prevalence of HIV infection, it would be wise to ensure that the needle-stick and mucous splash are minimized. Currently there is a debate over whether some or all patients about to undergo major surgery should be screened for HIV antibody. Some say 'at risk' patients should be screened, and some say all should be screened prior to such surgery (Porteous, 1990). Leaving aside the major ethical problems of such a policy, there are other problems. If only 'at risk' patients are tested then it is probable that HIV-infected individuals will be missed. The 'at risk' activities for HIV include sexual promiscuity (homosexual or heterosexual) and injecting drug abuse. To determine whether an unconscious ICU patient falls into an 'at risk' group could be difficult, as evidenced by the survey showing that only 29% of conscious HIV-infected patients admitted to an emergency department were considered by staff to be 'at risk' patients. Secondly, to rely on serological testing will inevitably lead to a false sense of security, since anti-HIV antibodies are not present in the serum of all HIV-infected patients.
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Well-defined recommendations are therefore needed for dealing with patients and their body fluids in the ICU and other areas where procedures are undertaken that might lead to transmission of HIV, hepatitis B or other blood-borne infections. INFECTION C O N T R O L MEASURES
It is not the purpose of this chapter to review the excellent infection control advice given both in the USA (Centers for Disease Control, 1987c) and the UK (Hospital Infection Society, 1990). Both recommend universal precautions (i.e. assume that all samples of blood and certain body fluids are infectious). The majority of the 21 cases of transmission of HIV to hospital staff have involved a needle-stick injury (Wofsy, 1990). Clearly, great care must be taken in handling needles and other sharp instruments. Resheathing of needles is a particularly dangerous activity. Blood and other body fluid spillages should be cleaned up immediately using various chlorine-releasing powders. Adequate barrier precautions must be available, e.g. gloves, masks and eye protection, and double-gloving for high-risk procedures is a useful practice. Health-care workers with exudative lesions or weeping dermatitis should not be allowed to participate in procedures likely to result in release of infected blood or body fluids. Endoscopy equipment (bronchoscopes, etc.) must be cleaned and effectively sterilized (Hanson et al, 1989b). The most effective measure is to educate all staff on the risks and modes of transmission, the epidemiology of HIV infection and methods of prevention. If accidental contamination occurs the site should be washed with soap and water immediately and the infective status of the patient and recipient explored. Under certain circumstances (Wofsy, 1990) chemoprophylaxis with zidovudine might be offered. However, it must be recognized that such chemoprophylaxis is not uniformly successful (Lange et al, 1990). The measures described are aimed at decreasing the very low risk of transmission of HIV to hospital staff (there is no evidence to suggest th at other patients in the hospital are at risk). However, it must be remembered that patients with AIDS may be infected with a series of pathogens of varying virulence (Table 2). These may infect both hospital staff and other patients. Some of these infections are treatable (Glatt et al, 1988), but others are not. For example, the protozoan Cryptosporidiumparvum causes gastroenteritis, lower respiratory tract infection, cholangitis and conjunctivitis in AIDS patients; it can cause a severe gastroenteritis in the immunocompetent, is easily spread in hospitals, and there is no effective therapy (Hart and Baxby, 1987). C H E M O T H E R A P Y AND VACCINES
Because HIV is able to become latent inside the host cell's chromosome it is unlikely that any chemotherapeutic intervention will completely ablate
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infection. The chemotherapeutic strategy is to damp down viral replication and thus prevent T4 and other cells being killed. The first antiviral agent used successfully to treat AIDS patients was zidovudine. There is now a plethora of alternative chemotherapeutic agents at various stages of development. These include nucleoside analogues such as dideoxycytidine, protease inhibitors and soluble CD4 (the T4 antigen) to act as a false receptor (Hirsch, 1990). Zidovudine can be marrow toxic in patients with AIDS, making them transfusion-dependent. Thus patients are now being treated just before it is predicted they will develop AIDS or AIDS-related complex (Editorial, 1990). This seems a promising strategy and will improve the survival of HIV-infected patients. Prevention is always better than a cure. However, the prospects for a vaccine to prevent HIV infection are not entirely hopeful. Not all patients infected with HIV will produce neutralizing antibody, and when such antibody is produced it is often of low titre. The major envelope glycoprotein of HIV (gp120) is highly variable and mutations have been noted during the infection of individual patients. Thus, at present, we must rely upon education and public health and infection control measures to prevent the spread of HIV infection. SUMMARY
Manifestation of AIDS follows a loss of T4 helper cells. This results in impaired humoral and cell-mediated immunity, and allows the development of opportunistic infections and tumours. Human immunodeficiency virus (type 1 or 2) is responsible for this suppression of immune function. The virus principally infects cells bearing the T4 receptor, although other cell types are infectable. HIV is a slow retrovirus. Following infection, viral R N A is back-transcribed to proviral DNA; this means that once infected with HIV an individual is infected for life. Patients are often asymptomatically infected with HIV for years prior to the development of AIDS. Although most HIV-infected individuals produce antibody, some do not. There is as yet no evidence of nosocomial spread of HIV from patient to patient. However, it must be remembered that patients with AIDS will be infected with pathogens of varying virulence which can be transferred nosocomially. They are also immunoincompetent and may be at risk of nosocomial acquisition of pathogens from other patients. The risk of acquisition of HIV by health-care personnel from infected patients is tow. Thus far, only 21 such cases have been documented in developed countries. This risk of transfer is linked to types of procedure rather than to particular risk occupations in hospitals. Those who undertake procedures in which it is possible that HIV-infected blood or other body fluids such as cerebrospinal fluid might be directly inoculated into the circulation via needle-stick or other 'sharps' injury are at greatest risk. The majority of cases of transfer of HIV to hospital staff have involved this route. In prospective surveys the risk of HIV infection via needle-stick injury is less
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t h a n 0 . 5 % ( c o m p a r e d w i t h 5 - 2 5 % for h e p a t i t i s B v i r u s i n f e c t i o n ) . T h e risk o f t r a n s f e r by s k i n o r m u c o u s m e m b r a n e c o n t a c t w i t h H I V - i n f e c t e d b l o o d is e v e n l o w e r (less t h a n 0 . 2 % ) , b u t t w o s u c h c a s e s h a v e b e e n r e c o r d e d . T h e r e is n o e v i d e n c e t h a t c a s u a l c o n t a c t will s p r e a d H I V i n f e c t i o n . P r o c e d u r e s h a v e b e e n d e v i s e d to d e c r e a s e t h e risk o f H I V i n f e c t i o n o f h e a l t h - c a r e personnel.
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Adachi A, Koenig S, Gendelman H et al (1987) Productive persistent infection of human colorectal cell lines with human immunodeficiency virus. Journal of Virology 61: 209-213. Anderson RM & May RM (1988) Epidemiological parameters of HIV transmission. Nature 333: 514-518. Auger I, Thomas P, De Gruttola V et al (1988) Incubation periods for paediatric AIDS patients. Nature 336: 575-577, Baker JL, Kelen GD, Silvertson KT et al (1987) Unsuspected human immunodeficiency virus in critically ill emergency patients. Journal of the American Medical Association 257: 2609-2611. Baltimore D & Feinberg MB (1989) HIV revealed: toward a natural history of infection. New England Journal of Medicine 321- 1673-1675. Barr6-Sinoussi F, Chermann JC, Rey F et al (1983) Isolation of a T-lymphotrophic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220." 868-871. Barr6-Sinoussi F, Nugeyre MT & Chermann JC (1985) Resistance of AIDS virus at room temperature. Lancet ii: 721-722. Berthier A, Chamaret S, Fauchet et al (1986) Transmissibility of human immunodeficiency virus in haemophiliac and non-haemophiliac children living in a private school in France. Lancet ii: 598-601. Bloomfield SF, Smith-Burchnell CA & Dalgleish AG (1990) Evaluation of hypochlorite releasing disinfectants against the human immunodeficiency virus (HIV). Journal of Hospital Infection 15: 273-278. Burger H, Belman AL, Grimson R et al (1990) Long HIV-1 incubation periods and dynamics of transmission within a family. Lancet 336: 134-136. Centers for Disease Control (1981) Kaposi's sarcoma and pneumocystis pneumonia among homosexual men--New York City and California. Morbidity and Mortality Weekly Report 30: 305-308. Centers for Disease Control (1986) Recommendations for providing dialysis treatment to patients infected with human T-lyanphotropic virus. Journal of the American Medical Association 256: 703-704. Centers for Disease Control (1987a) Update: human immunodeficiency virus infections in health care workers exposed to blood of infected patients. Morbidity and Mortality Weekly Report 36: 285-289. Centers for Disease Control (1987b) Human immunodeficiency virus infection transmitted from an organ donor screened for HIV antibody. Morbidity and Mortality Weekly Report 36: 306-308. Centers for Disease Control (1987c) Recommendations for prevention of HIV transmission in health-care settings. Morbidity and Mortality Weekly Report 36 (supplement 2S): 1-44. Centers for Disease Control (1988) Acquired immunodeficiency syndrome and human immunodeficiency virus infection among health care workers. Morbidity and Mortality Weekly Report 37: 229-239. Cheng-Meyer C, Rutka JT, Rosenblum ML et al (1987) Human immunodeficiency virus can productively infect cultured human glial cells. Proceedings of the National Academy of Sciences of the USA 84: 3526-3530. Clavel F, Mansinho K, Chamaret Set al (1987) Human immunodeficiency virus type 2 infection associated with AIDS in West Africa. New England Journal of Medicine 316:1180-1185.
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Clumeck N, Taelman H, Hermans Pet al (1989) A cluster of HIV infection among heterosexual people without apparent risk factors. New England Journal of Medicine 321: 1460-1462. Cooper DA, MaClean P, Finlayson R et al (1985) Acute AIDS retrovirus infection: definition of a clinical illness associated with seroconversion. Lancet i: 537-540. Cumming PD, Wallace EL, Schorr JB & Dodd RY (1989) Exposure of patients to human immunodeficiency virus through the transfusion of blood components that test antibody negative. New England Journal of Medicine 321: 941-946. Dalgleish AG & Weiss RA (1990) Human retroviruses. In Zuckerman AJ, Banatvala JE & Pattison JR (eds) Principles and Practice of Clinical Virology, 2nd edn, pp 573-602. Chichester: John Wiley. Dalgleish AG, Beverley PCL, Clapham PR et al (1984) The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312: 763-767. Duesberg PH (1989) Human immunodeficiency virus and acquired immunodeficiency syndrome: correlation but not causation. Proceedings of the National Academy of Sciences of the USA 86: 755-764. Editorial (1984) Needlestick transmission of HTLV-III from a patient infected in Africa. Lancet ii: 1376-1377. Editorial (1988) HIV infection: obstetric and perinatal issues. Lancet i: 806-807. Editorial (1989) HIV-associated enteropathy. Lancet ii: 77%778. Editorial (1990) Zidovudine for symptomless HIV infection. Lancet 335: 821-822. Emanuel EJ (1988) Do physicians have an obligation to treat patients with AIDS? New England Journal of Medicine 318: 1686-1690. Fischl MA, Dickinson GM, Scott GB et al (1987) Evaluation of heterosexual partners, children and household contacts of adults with AIDS. Journal of the American MedicalAssociation 257: 640-644. Friedland GH & Klein RS (1987) Transmission of the human immunodeficiency virus. New England Journal of Medicine 317: 1125-1135. Friedland GH, Saltzman BR, Rogers MF et al (1986) Lack of transmission of HTLVIII/LAV infection to household contacts of patients with AIDS or AIDS related complex with oral candidiasis. New England Journal of Medicine 314" 344-349. Fujikawa LS, Salahuddin SZ, Palestine A G et al (1985) Isolation of human T-lymphotropic virus type Ill from the tears of a patient with the acquired immunodeficiency syndrome. Lancet ii: 529-530. Fultz PN (1986) Components of saliva inactivate human immunodeficiency virus. Lancet ii: 1215. Gallo RC, Salahuddin SZ, Popovic M e t al (1984) Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224: 500-503. Gelderblom HR, Hausmann EHS, Ozel M, Pauli G & Koch MA (1987) Fine structure of human immunodeficiency virus (HIV) and immunolocalization of structural proteins. Virology 156: 171-176. Gerberding JL (1990) Occupational HIV transmission. In Sande ME & Volberding PA (eds) The Medical Management ofA1DS, pp 57-67. Philadelphia: WB Saunders. Gerberding JL, Bryant-Le Blanc CE, Nelson K et al (1987) Risk of transmitting the human immunodeficiency virus, cytomegalovirus and hepatitis B virus to health care workers exposed to patients with AIDS and AIDS related conditions. Journal of Infectious Diseases 156: 1-8. Gerberding JL, Littell C, Tarkington A, Brown A & Schecter WP (1990) Risk of exposure of surgical personnel to patients' blood during surgery at San Francisco General Hospital. New England Journal of Medicine 322: 2788-2793. Glatt AE, Chirgwin K & Landesman SH (1988) Treatment of infections associated with human immunodeficiency virus. New England Journal of Medicine 318: 1439-1448. Groopman JE, Salahuddin SZ, Sarngadharan MG et al (1984) HTLVIII in saliva of people with AIDS related complex and healthy homosexual men at risk for AIDS. Science 226: 447-449. Hanson PJV, Gor D, Jeffries DJ & Collins JV (1989a) Chemical inactivation of HIV on surfaces. British Medical Journal 298: 862-864. Hanson PJV, Gor D, Clarke JR et al (1989b) Contamination of endoscopes used in AIDS patients. Lancet ii: 86-88.
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Hart CA & Baxby D (1987) Cryptosporidiosis in children. Pediatric Reviews and Communications 1: 311-341. Haseltine WA (1989) Silent HIV infection. New England Journal of Medicine 320: 148%1489. Henderson DK, Saah A J, Zak BJ et al (1986) Risk of nosocomial infection with human T-cell lymphotropic virus type III/lymphadenopathy-associated virus in a large cohort of intensively exposed health care workers. Annals of Internal Medicine 104: 644--647. Hicks DR, Martin LS, Getchell JP et al (1985) Inactivation of HTLV III/LAV infected cultures of normal human lymphocytes by nonoxynol-9 in vitro. Lancet it: 1422-1423. Hirsch MS (1990) Chemotherapy of human immunodeficiency virus infections: current practice and future prospects. Journal of Infectious Diseases 161: 845-857. Hirsch MS, Wormser GP, Schooley RT et al (1985) Risk of nosocomial infection with human T-cell lymphotropic virus III (HTLV-III). New England Journal of Medicine 312: 1-4. Hospital Infection Society (1990) Acquired immune deficiency syndrome: recommendations of a working party of the Hospital Infection Society. Journal of Hospital Infection 15: 7-34. Hughes JM, Garner JS, Marcus R & Jaffe HW (1988) AIDS: epidemiological lessons from the health care setting. Journal of Hospital Infection 11 (supplement A): 209-217. Huminer D, Rosenfeld JB & Pitlik SD (1987) AIDS in the pre-AIDS era. Review of Infectious Diseases 9:1102-1108. Imagawa DT, Lee MH, Wolinsky SM et al (1989) Human immunodeficiency virus type-1 infection in homosexual men who remain seronegative for prolonged periods. New England Journal of Medicine 320: 1458-1462. Jagger J, Hunt EH, B rand-Elnaggar J & Pearson RD (1988) Rates of needle-stick injury caused by various devices in a university hospital. New England Journal of Medicine 319: 284-288. Kanki PJ, Barin F, M'Boup S e t al (1986) New human T-lymphotropic virus related to Simian T-lymphotropic virus type III (STLV III). Science 232: 238-243. Kelen GD, Fritz S, Qaqish B et al (1988) Unrecognized human immunodeficiency virus infection in emergency department patients. New England Journal of Medicine 318: 1645-1650. Klein RS, Pholan J, Friedland GH et al (1987) Low occupational risk for HIV infection for dental professional. Abstracts' of the 3rd International Conference on AIDS, Washington, p 53. Koenig RE, Gautier T & Levy JA (1986) Unusual intrafamilial transmission of human immunodeficiency virus. Lancet it: 627. Lange JMA, Boucher CAB, Hollak CEM et al (1990) Failure of zidovudine prophylaxis after accidental exposure to HIV-1. New England Journal of Medicine 322: 1375-1377. Levy JD (1989) Human immunodeficiency viruses and the pathogenesis of AIDS. Journal of the American Medical Association 261: 29973005. Levy JA, Kaminsky LS, Morrow WJW et al (1985) Infection by the retrovirus associated with the acquired immunodeficiency syndrome. Annals of Internal Medicine 103: 694-699. Lifson JD, Hwang KM, Nava PL et al (1988) Synthetic CD4 peptide derivatives that inhibit HIV infection and cytopathicity. Science 241: 712-716. Maddon PJ, Dalgleish AG, McDougal'JS et al (1986) The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47: 333-348. Marcus R & CDC Cooperative Needlestick Surveillance Group (1988) Surveillance of health care workers exposed to blood from patients infected with the human immunodeficiency virus. New England Journal of Medicine 319: 1118-1123. McEvoy M, Porter K, Mortimer P, Simmons N & Shanson D (1987) Prospective study of clinical laboratory and ancillary staff with accidental exposures to blood or other body fluids from patients infected with HIV. British Medical Journal 294: 1595-1597. McLure MO & Schulz TF (1989) Origin of HIV. British Medical Journal 298: 1267-1268. Molbak K, Lauritzen E, Fernandes et al (1986) Antibodies to HTLV-IV associated with chronic, fatal illness resembling 'slim' disease. Lancet it: 1214.1215. Morrison NK (1989) In vitro studies on HIV. PhD thesis, University of Liverpool. Moss AR, Bacchetti P, Osmond D et al (1988) Seropositivity for HIV and the development of AIDS or AIDS related condition. British Medical Journal 296: 745-750. Murray JF, Felton CP, Garay SM et al (1984) Pulmonary complications of the acquired immunodeficiency syndrome. New England Journal of Medicine 310: 1682-1688. Napoli VM & McGowan JE (1987) How much blood is in a needlestick? Journal oflnfectious Diseases 155: 828.
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Narayan O & Clements JE (1989) Biology and pathogenesis of lentiviruses. Journal of General Virology 70" 1617-1639. Pedersen C, Orskov Lindhardt B, Lakke Jensen B e t al (1989) Clinical course of primary HIV infection: consequences for subsequent course of infection. British Medical Journal 299: 154-i57. Porteous ML Le (1990) Operating practices of and precautions taken by orthopaedic surgeons to avoid infection with HIV and hepatitis B during surgery. British Medical Journal 301: 167-169. Quinn TC (1990) Global epidemiology of HIV infections. In Sande ME & Volberding PA (eds) The Medical Management of AIDS, pp 3-22. Philadelphia: WB Saunders. Quinn TC, Zacrias FRK & St John RK (1989) AIDS in the Americas: an emerging public health crisis. New England Journal of Medicine 320: 1005-1007. Rappersberger K, Gartner S, Schenk G e t al (1988) Langerhans' cells are an ~ictual site of HIV-1 replication. Intervirology 29: 185-194. Rogers PL, Lane C, Henderson DKJ, Parillo J & Masur H (1989) Admission of AIDS patients to a medical intensive care unit: causes and outcome. Critical Care Medicine 17" 113-117. Sang MS, Hahn BH, Gibbons J e t al (1988) Extensive variation of human immunodeficiency virus type-1 in vivo. Nature 334: 440-444. Saviteer SM, White GC, Cohen MS & Jason J (1985) HTLV-III exposure during cardiopulmonary resuscitation. New England Journal of Medicine 313: 1606-1607. Singer P, Askanazi J, Akiva L, Bursztein S & Kvetan V (1990) Reassessing intensive care for patients with the acquired immunodeficiency syndrome. Heart and Lung 19: 387-394. Spire B, Barr6-Sinoussi F, Montagnier L & Chermann JC (1984) Inactivation of lymphadenopathy associated virus by chemical disinfectants. Lancet ii" 899-901. Spire B, Dormont D, Barr6-Sinoussi F, Montagnier L & Chermann JC (1985) Inactivation of lymphadenopathy-associated virus by heat, gamma rays and ultraviolet light. Lancet i: 188-189. Stewart GL, Tyler JPP, Cunningham AL et al (1985) Transmission of human T-cell lymphotropic virus type III (HTLV-III) by artificial insemination by donor. Lancet ii: 581-584. Stricof RL & Morse DL (1986) HTLVIII/LAV seroconversion following a deep intramuscular needlestick injury. New England Journal of Medicine 314: 1115. Vogt MW, Witt D J, Craven DE et al (1986) Isolation of HTLV-III/LAV from cervical secretions of women at risk for AIDS. Lancet i: 525-529. Ward JW, Bush TJ, Perkins HA et al (1989) The natural history of transfusion-associated infection with human immunodeficiency virus. New England Journal of Medicine 321: 947-952. Weiblen B J, Lee FK, Cooper E R et al (1990) Early diagnosis of HIV infection in infants by detection of IgA HIV antibodies. Lancet 335: 988-990. Weiss WH, Saxinger WC, Rechtman C et al (1985) HTLV-III infection among health care workers: association with needle-stick injuries. Journal of the American Medical Association 254: 2089-2093. Wigdaht B & Kunsch C (1990) Human immunodeficiency virus and neurologic dysfunction. In Melnick JL (ed.) Progress in Medical Virology, 37, pp 1-46. Basel: Karger. Wofsy CB (1990) Prevention of HIV transmission. In Sande MA & Volberding PA (eds) The Medical Management ofA1DS, pp 38-56. Philadelphia: WB Saunders. Wood GS, Warner NL & Warnke R A (1985) Anti Leu3/T4 antibodies react with cells of monocyte/macrophage and Langerhans lineage. Journal of Immunology 131: 212-216. Ziegler JB, Cooper DA, Johnson RD & Gold J (1985) Postnatal transmission of AIDSassociated retrovirus from mother to infant. Lancet i: 896-897. Zuck TF (1988) Transfusion-transmitted AIDS reassessed. New England Journal of Medicine 318: 511-512.
ANTHONY
HART
The acquired immune deficiency syndrome (AIDS) was first described in homosexual men in New York and California (Centers for Disease Control, 1981). These patients presented with Kaposi's sarcoma and Pneumocystis carinii pneumonia, but it soon became apparent that other opportunist pathogens (e.g. Cryptosporidiumparvum, Candida albicans, Cryptococcus neoformans, cytomegalovirus and Mycobacterium spp) and tumours (e.g. lymphomata) do occur in patients with AIDS. Since then it has become clear that probable cases of AIDS had been encountered as long ago as the 1950s (Huminer et al, 1987) and that the numbers of cases of AIDS are increasing at a remarkable rate worldwide. For example, it has been estimated that there have been 250000 cases of AIDS in the Americas, 50 000 in Europe, 300 000 in Africa and 3000 in Australasia (Quinn, 1990). The number of individuals asymptomatically infected with human immunodeficiency virus (HIV) exceeds the number of cases of AIDS by a factor of 10-100. Although the assumption has been questioned by some (Duesberg, 1989), it is generally agreed that a retrovirus is responsible for AIDS. In this chapter the nature of the virus and its pathogenesis are discussed, together with the secondary pathogens that lead to the clinical manifestations of AIDS. In addition the risks of transmission, methods for containment and control and prospects for effective chemotherapy and immunotherapy are assessed.
THE VIRUSES Taxonomy
The first indication that AIDS had a viral aetiology came with the isolation of retrovirus from a French patient with persistent generalized lymphadenopathy. The virus was called lymphadenopathy-associated virus (LAV) (Barr6-Sinoussi et al, 1983). Subsequently isolates were made from patients with AIDS. These isolates were termed immunodeficiency-associated virus (IDAV), human T-cell lymphotrophic virus (HTLV-III) (Gallo et al, 1984) and AIDS-related virus (ARV) (Table 1). All were subsequently shown to Baillibre's Clinical Anaesthesiology-Vol. 5, No. 1, June 1991 ISBN 0-7020-1524-5
243 Copyright 9 1991, by Bailli6re Tindall All rights of reproduction in any form reserved
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Lymphadenopathy-associatedvirus Immunodeficiency-associatedvirus Human T-cell lymphotrophicvirus III AIDS-related virus Human immunodeficiencyvirus 1 (synonymouswith above' Human immunodeficiencyvirus 2 Human T-cell lymphotrophicvirus IV. Simian immunodeficiencyvirus Feline immunodeficiencyvirus Equine infectious anaemia virus Bovine immunodeficiencyvirus
be variants of the same virus and were given the name human lmmunodeficiency virus (HIV). A second retrovirus was isolated from patients with AIDS in West Africa (Clavel et al, 1987). This isolate was significantly different from the original isolate in terms of antigenic and genomic structure; it was therefore termed HIV-2 and the original isolate was renamed HIV-1. Another retrovirus, H T L V - I V , was isolated from healthy prostitutes in Senegal (Kanki et al, 1986). This, it is thought, does not produce immunodeficiency, although it is not clear that this is entirely true (Molbak et al, 1986). Diseases very similar to AIDS have been encountered in other animal species; these include macaques, due to simian immunodeficiency virus (SIV); cats, due to feline immunodeficiency virus (FIV); and cattle, due to bovine immunodeficiency virus (BIV) (Narayan and Clements, 1989). Of these, SIVmac is the only one to exhibit sequence homology to the human viruses (McLure and Schulz, 1989). HIV-2 and SIV are approximately 75% homologous, and HIV-1 and SIV about 40%. This raises the possibility that HIV may have moved from monkey to human, perhaps with H T L V - I V as the 'missing link'. Structure
H u m a n immunodeficiency viruses 1 and 2 are both retroviruses of the Lentivirinae or slow subfamily. They have a single-stranded R N A genome, a cuboidal symmetry, a lipid envelope and are 100-150nm in diameter (Figures 1 and 2). The genome is about 10 kilobases long, consisting of the three main open reading frames (off) Gag, Pol and Env, together with at least seven other minor orfs that control replication. Gag stands for group specific antigen and encodes four structural or core proteins: p7, p9, p17 and p24, where p stands for protein and the number its molecular weight in thousands. The Pol region encodes three enzymes: a protease, a polymerase complex and an endonuclease/integrase. Env encodes two glycoproteins (gp), gp120 and gp41, which are exposed on the surface of the virus (Figure 2).
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Figure 1. A thin-section electron micrograph showing HIV-1 being released from an infected lymphocyte (scale bar 500 nm).
Trimericspike(9-10nm) containing3 molecules of gp 120 \ andgp41 'opp~
Lipid bilayerenvel
Coreprotein (p24)
~////~ (p17)Matprotein rix
~-~
Lateralbody
Corecontaining ribonucleoprotein (RNA,p7 and p9) and reverse transcriptase (p66) Figure 2. A diagrammatic representation of human immunodeficiency virus.
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A key feature of HIV and all other retroviruses is that they possess an RNA-dependent DNA polymerase or reverse transcriptase. This enzyme catalyses the conversion of the viral RNA genome back (hence 'retro') to a double-stranded DNA copy. This so-called proviral DNA uses the viral endonuclease/integrase enzyme to insert itself into the chromosomal DNA o f the cell it has infected. It thus becomes part of the genome of that particular cell and remains latent. This means that once individuals have been infected by the virus they will carry the virus for life and remain a potential infective risk for others. Following an as yet ill-defined signal, the proviral DNA is reactivated to produce the viral RNA genome. This is translated to produce the various gene products. Morphogenesis occurs at the cell surface; core components are assembled with two copies of the RNA viral genome inside the shell of p24. This then buds through an area of the host cell membrane which has gp41 and gp120 inserted in it, and mature virus particles are released into the surrounding medium (Gelderblom et al, 1987). Physical properties Because HIV is an enveloped virus it is relatively fragile. Nevertheless HIV is able to survive following drying on surfaces for over 7 days (Barr6-Sinoussi et al, 1985). This means that it is imperative that all spillages of body fluids should be cleaned with appropriate disinfectants. Hypochlorite-releasing disinfectants are rapidly virucidal (Spire et al, 1984); for example, sodium hypochlorite (2500p.p.m. available chlorine) and sodium dichlorisocyanurate (50 p.p.m, available chlorine) produced a 3-4 log reduction in HIV titre within 2 minutes (Bloomfield et al, 1990). However, much greater concentrations (5000 p.p.m.) were required to produce total kill within 2 minutes of virus in blood spillages. For blood spillages, use of chlorinereleasing powder formulations provides an effective alternative, especially since they will also be active against hepatitis B virus. However, chlorinereleasing disinfectants do corrode stainless steel and may damage instruments. Alternative disinfectants include glutaraldehyde (2% v/v), ethanol, methanol and isopropanol (70% v/v), and nonoxynol (Spire et al, 1984; Hicks et al, 1985; Hanson et al, 1989a). Although alcohols produce a rapid antiviral effect, their activity is less effective against cell-associated virus or virus suspended in high-protein media such as serum (Hanson et al, 1989a). Therefore fresh alkaline glutaraldehyde (2% v/v) is probably the most effective disinfectant for delicate instruments such as endoscopes (Hanson et al, 1989b). Care must be taken, since glutaraldehyde is a powerful allergen and can also stain the skin. HIV can be inactivated by heat when in liquid suspension (56~ for 30 minutes), but like other retroviruses it is relatively radioresistant (Spire et al, 1985). Virus replication Human immunodeficiency virus has a tropism for T lymphocytes and in
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particular for lymphocytes expressing the T4 antigen. This antigen defines a subpopulation of T lymphocytes called helper cells. The T4 antigen acts as the receptor for gp120 which forms the spikes on the HIV envelope (Dalgleish et al, 1984; Lifson et al, 1988). The T4 receptor is present on macrophages, monocytes and some brain cells (Wood et al, 1985; Maddon et al, 1986). However, it is now clear that HIV can infect cells that do not express the T4 receptor. Such cells include glial cells, some colonic carcinomas and HEp-2 (human laryngeal carcinoma) cells (Adachi et al, 1987; Cheng-Meyer et al, 1987; Morrison, 1989). The significance of such observations for human infection is as yet unclear. Unlike the transforming retroviruses, HIV is cytopathic; it both kills infected cells and causes cells to fuse together. This latter mechanism involves a reaction between T4 and gp120 on infected and uninfected cells and allows virus to pass intracellularly from cell to cell. Specific diagnosis of HIV infection Following infection with HIV most patients produce antibody, although this can take over a year to develop in a minority of patients. Detection of antibody has been the mainstay of specific diagnosis up to now. Most types of antibody detection systems have been employed including indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA), competitive radioimmunoassay and latex particle agglutination (LPA). Because of problems with antigen purity, confirmation of antibody positivity used western blotting as the 'gold standard'. However, many HIV antigens have now been 'genetically engineered' and large quantities of pure antigen (gp120, gp41, p24, etc.) are available for use in commercial ELISA and LPA tests. Thus western blottiffg is being replaced by a combination of ELISA and LPA tests (Dalgleish and Weiss, 1990). ELISA tests for detection of HIV antigenaemia, in particular the Gag p24, are available, and it is considered that development of antigenaemia was a marker for onset of AIDS. Virus cultures utilizing lymphoblastoid cell lines such as HT/H9, C8166 or HeLa CD4 + are available, but this can be an expensive and time-consuming exercise. Finally, methods of detection involving gene probing have been developed. These include in situ hybridization, genome isolation and amplification using the polymerase chain reaction (PCR). Of these, PCR is the most sensitive and easily performed, but because of its great sensitivity (it can theoretically detect just one copy of the viral genome) false positives can be a problem if cross-contamination of samples occurs. PATHOGENESIS AND NATURAL HISTORY Information on the acute manifestations of HIV infection can only be obtained from those cases in which the time of infection can be ascertained. In general, more than 50% of those infected have no acute clinical illness
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(Editorial, 1984; Cooper et al, 1985; Pedersen et al, 1989). After an incubation period of 2-3 weeks approximately half of those infected develop a 'glandular fever-like' illness with fever, lymphadenopathy and a macular erythematous rash. A smaller proportion develop other features such as meningoencephalitis (5%), arthralgia or myalgia (19%) or glomerulonephritis (1%). The median duration of illness was 16 (range 4-56) days (Pedersen et al, 1989). This initial phase, it is presumed, is due to replication of HIV in T4 lymphocytes, monocytes, macrophages and other cell types combined with the immune response to such infection. At the same time as this initial infection is occurring, viral genome is back-transcribed to proviral DNA to become latent. It was thought that this was a firm latency and that the only HIV present was cell-associated. Recently, however, it has become apparent that viraemia occurs in HIV-infected patients whether symptomatic or not (Baltimore and Feinberg, 1989). Thus HIV is continually replicating in infected patients and is continually mutating (Sang et al, 1988). During this period the patient is generally asymptomatic. The incubation period for AIDS varies according to the group of patients infected. For example, of intrauterine or perinatally infected New York infants, 20% will develop AIDS in the first year of life and at a rate of 8% yearly thereafter (Auger et al, 1988). In a cohort of male homosexuals in San Francisco, 48% had developed AIDS or AIDS-related conditions within 3 years (Moss et al, 1988), and 49% of a cohort of patients infected via blood transfusion developed AIDS within 7 years (Ward et al, 1989). However, as might be expected, there are considerable individual variations in rates of progression (Burger et al, 1990). The presentation of AIDS includes Table 2. Micro-organisms causing opportunistic infections in AIDS. Oropharynx
Candida albicans Herpes simplex virus Epstein-B arr virus Papillomavirus Fusobacteria
Cutaneous
Candida albicans Cryptococcus neoformans Pityrosporum orbiculare Varicella-zoster virus Herpes simplex virus Molluscum contagiosum virus
Central nervous system
Toxoplasma gondii Cryptococcus neoformans Mycobacteria HIV Cytomegalovirus Gastrointestinal tract
Cryptosporidium parvum Giardia larnblia Isospora belli Entamoeba histolytica Microsporidia Cytomegalovirus HIV Salmonellae Mycobacteria
Disseminated infection Capsulate bacteria
(e.g. Streptococcus pneumoniae) Salmonellae Mycobacteria Respiratory tract Mycobacteria Cytomegalovirus
Pneurnocystis carinii Genital tract Herpes simplex virus Papillomavirus
Haemophilus ducreyi Chlamydia trachomatis
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infection with a large variety of opportunistic pathogens (Table 2) as well as other conditions such as Kaposi's sarcoma and non-Hodgkin's lymphomata. Some features of AIDS, e.g. AIDS dementia complex (Wigdahl and Kunsch, 1990) and enteropathy (Editorial, 1989), are due to HIV itself. Antibody response
In general, antibodies to HIV antigens appear within 3-6 weeks of infection. However, it can take up to a year for antibody to be produced. With intrauterine or perinatal infection the IgM anti-HIV response is often delayed and transient, and it has been suggested that measurement of IgA anti-HIV is the best marker for neonatal infection (Weiblen et al, 1990). Three patterns of antibody/antigen response have been described (Haseltine, 1989). In pattern 1, which is the most common, there is prolific replication of HIV within 3-6 weeks of infection with virus and viral antigen readily detectable in blood and cerebrospinal fluid. Antibodies to viral antigens (particularly gp120 and gp41) appear and rise to high levels. They persist throughout infection. In pattern 2, which is rare, the initial phase occurs but then viral antigen and antibody become undetectable. HIV infection is only detectable by PCR. In pattern 3, there is prolonged HIV infection without antibody production (Imagawa et al, 1989). Clearly, measurement of anti-HIV antibody will not detect all HIV-infected individuals. Cellular responses
Although cells of monocyte/macrophage lineage may be reservoirs of HIV, most of the cell-associated virus in blood is in T4 lymphocytes (Baltimore and Feinberg, 1989). As disease progresses the proportion of T4 lymphocytes infected with HIV increases until as many as 1 in every 100 are infected in patients with AIDS. HIV is cytolytic and in AIDS the absolute numbers of T4 lymphocytes falls precipitately. This means both that antibody production by B lymphocytes is less than optimal and that cell-mediated immunity is impaired. Thus opportunistic infections and tumours become manifest. Sites of virus excretion
The most important sites of virus excretion in terms of transmission are seminal fluid and female genital secretions. HIV has been detected in cervical secretions of asymptomatic women (Vogt et al, 1986) and HIV has been transmitted by artificial insemination by donor sperm (Stewart et al, 1985). Sexual transmission is facilitated by the presence of mucosal ulceration produced by other genital tract pathogens, although this is not an absolute prerequisite (Clumeck et al, 1989). HIV can be found in saliva both cell-free and cell-associated (Groopman et al, 1984). However, there is little evidence that HIV has been transmitted by saliva; indeed there appear to be components of saliva that inhibit HIV (Fultz,
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1986), and experimental transmission of H I V in saliva to chimpanzees has not been achieved. H I V has been found in tears (Fujikawa et al, 1985) but there is no evidence that this site has contributed to spread of infection. HIV has also been found in urine (Levy et al, 1985), and since it can cause an enteropathy may also be found in faeces. Again, there is no evidence to support spread of infection from these sites. Similarly, H I V can be isolated from cerebrospinal fluid (Wigdahl and Kunsch, 1990) and from skin and mucous membrane biopsies (Rappersberger et al, 1988), but these are unlikely to transmit infection. H I V can be found in breast milk and there is circumstantial evidence to suggest that this can be a mode of transmission from mother to baby (Ziegler et al, 1985). In contrast, H I V is found in blood, and there is a large body of evidence demonstrating that blood-to-blood contact can cause transmission of HIV. Infection has been documented following blood transfusion, organ transplantation and infusion of blood products.
RISKS OF TRANSMISSION OF HIV
In order to assess the risk of transmission of HIV, factors that must be considered are the amount of virus being released from a particular site, its survival outside the body, the infective dose and the presence of a portal of entry. Both the frequency at which various sites contain H I V and the number of virus particles present vary according to the site tested (Levy, 1989). Although H I V is present in plasma of infected individuals at all stages, the amount of virus present increases as the patient develops AIDS. On average there are between 10 and 50 infectious particles of H I V per ml of plasma. Saliva is less frequently positive and contains fewer than 1 particle per ml. Semen is more frequently positive and has 10-50 particles per ml, while female genital tract secretions have fewer than 1 particle per ml. Once outside the body H I V will survive relatively well in liquid media (over 7 days with no loss of titre) and even on drying (Barr6-Sinoussi et al, 1985). There is no information on the infective dose of H I V for humans. There is a theoretical possibility that H I V can gain access through unbroken skin via Langerhans' cells (Rappersberger et al, 1988) or through oral and intestinal mucosa via M cells, and at least one such case has been reported (Centers for Disease Control, 1987a). Nevertheless all the epidemiological evidence points to inoculation of virus into blood being the main portal of entry. In addition to the above four considerations, the risk is also related to the chance of being exposed to a biological fluid from a patient who is infected by HIV. Since population serosurveys are not possible and anonymous testing of serum for anti-HIV antibody has only just begun, we have grossly incomplete information on the prevalence of H I V seropositivity. There are, however, some data available. In Baltimore it was found that 5.2% of 2302 adult patients attending an emergency department were H I V seropositive
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(Kelen et al, 1988), and in neonatal blood (and hence in their mothers' blood) rates of 2% and 0.75% seropositivity were observed in New York and Massachusetts respectively (Editorial, 1988). In contrast, in certain parts of Africa and among certain groups of individuals, seropositivity rates of between 20% and 50% have been reported. Transmission by casual contact There is no evidence that casual contact either within a social context or within a family results in transmission of H I V (Friedland et al, 1986; Fischl et al, 1987). Indeed, in a French boarding school that was attended by some HIV-infected haemophiliac children, it was found that H I V was not transmitted to any of the other children at the school, whereas there was evidence of transmission of hepatitis B virus (Berthier et al, 1986). Sexual transmission There is little doubt that this is the major mode of transmission worldwide. The estimated rates of transmission for males to females vary from 3% to 73%, for females to males from 8% to 71%, and for males to males from 10% to 60% (Anderson and May, 1988). Rates vary according to mode of intercourse and concomitant venereal diseases. The rates of homosexual transfer seem to be falling, but unfortunately heterosexual transfer appears to be unaffected by exhortations to practise 'safe sex' (Quinn et al, 1989). Transmission by blood and blood products The numbers of individuals who have acquired H I V infection through transfusion of infected blood, blood products or by organ transplantation (Centers for Disease Control, 1987b) are relatively small (about 3% of cases) (Friedland and Klein, 1987; Wofsy, 1990). The number of new cases should also decline. All donated blood is screened for antibodies to H I V as is blood from those donating organs. However, as can be appreciated from the foregoing discussion, it is possible for an individual to be infected by HIV yet be seronegative. For example, in the USA it has been estimated that the odds of a patient contracting H I V infection from any HIV-antibody screened transfusion were 1 : 153 000 per unit transfused (Cumming et al, 1989). In the U K the risk is assessed as even lower, at less than 1 : 1000 000 per unit transfused. However, with improvement of donor recruitment practice and with tests for viral genome or antigen the risk should decrease further (Zuck, 1988). Perinatal transmission Transmission of H I V can occur in utero, during delivery or postnatally, possibly through breast-feeding. Precise figures on the risk of perinatal
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transmission are lacking since the IgM anti-HIV response in neonates is often delayed or transient, and all those born to infected mothers will have maternally derived transplacental IgG anti-HIV. For the future, the use of IgA anti-HIV measurement (Weiblen et al, 1990) or PCR will provide a more accurate figure for risk of transmission. Current figures suggest a risk of between 25% and 40% for babies born to HIV-infected mothers (Quinn, 1990), Transmission among injecting drug abusers The rise in rate of transmission of HIV among this group is one of the most rapid. Spread is both by sharing of needles and syringes and by sexual contact. In the USA serosurveys of over 18 000 drug abusers have shown very high prevalence rates of 50-60% (Friedland and Klein, 1987; Quinn, 1990). Transmission may not only be associated with drug abuse; there is one example of transmission of HIV from child to child following use by a mother of the same needle and syringe to administer a vitamin injection (Koenig et al, 1986). Insects There is no evidence to suggest that biting insects can transmit HIV (Friedland and Klein, 1987). RISKS TO HEALTH-CARE WORKERS The risk of acquisition of HIV infection by health-care workers or by patients nursed in proximity to HIV-infected symptomatic or asymptomatic patients is very low. However, the risk is not non-existent (Centers for Disease Control, 1987a, 1988). The risk is related to the chance of treating an HIV-infected individual but is also highly dependent upon the procedures involved. Procedures that involve the risk of blood-to-blood transmission such as surgery, blood taking or insertion of long-term venous access give the greatest risk. Anecdotal evidence seems to show that the risk of transmission following mouth-to-mouth resuscitation is low (Saviteer et al, 1985), unless there is fresh blood in the airways. Needle-stick injuries appear to occur at an alarming rate in most hospitals. In a Virginia University Hospital, 326 injuries were reported over a 10month period (Jagger et al, 1988). Disposable syringes accounted for the highest percentage of injuries (35%) but had the lowest rate of needle-stick (6.9 per 100 000 units purchased).~Intravenous tubing and needle assemblies accounted for 26% of the injuries and had the highest rate of injury per 100 000 units (36.7). One-third of the injuries were related to recapping needles. There have been several prospective surveys of needle-stick and bloodsplash exposure to HIV-infected blood (Table 3). The overall risk of HIV infection following needle-stick is 4.2 per 1000 episodes. This is much lower
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253 Table 3. Rates of infection following exposure to HIV infected blood.
Needle-stick No. No. exposed infected
Hirsch et al, 1985 Weiss et al, 1985 Henderson et al, 1986 Gerberding et al, 1987 McEvoy et al, 1987 Marcus et al, 1988 Overall
30 42 40 129 76 860 1177
0 1 0 0 0 4 5
Mucous membrane (%)
(0) (2.4) (0) (0) (0) (0.47) (0.42)
No. No. exposed infected
3 0 110 213 24 103 453
0 0 0 0 0 0 0
(%)
(0) (0) (0) (0) (0) (0)
than the 6-23% risk reported for transmission of hepatitis B. However, it is clear that the larger the amount of blood transferred the greater is the risk. For example, one case of seroconversion followed a deep intramuscular injection of a substantial quantity of blood (Stricof and Morse, 1986). The mean volume of blood inoculated during needle-stick injuries is about 1.4 txl (Napoli and McGowan, 1987). Although, in prospective surveys, no case (risk less than 2 per 1000) of infection via skin or mucous membranes exposed to HIV-infected blood was observed (Table 3), at least two cases have been reported where infection occurred via intact skin or mucous membranes (Hughes et al, 1988). Exposure to blood and body fluids does also occur during surgery. In one survey in San Francisco, accidental exposure to blood occurred parenterally in 1.7% of procedures and cutaneously in 4.7% of procedures (Gerberding et al, 1990). Furthermore it was found that 17.5% of gloves examined after surgery had some form of perforation. If surgeons 'double-gloved', 17.4% of the outer gloves showed perforations but only 5.5 % of the inner gloves. It has been estimated that emergency department surgeons in the USA have a 2% annual risk of contracting an H I V infection by performing surgery, but that an orthopaedic surgeon working within a high HIV prevalence area might have a risk as great as 12% per year (Emanuel, 1988).
RISKS TO ANAESTHETISTS There is little information directly relating to anaesthetists, but both administering anaesthesia and managing patients in intensive care units may give rise to transmission of HIV.
Administering anaesthesia During such procedures the risks from blood splash and needle-stick injury apply. In addition, intubation might be expected to expose anaesthetists to the same risk of infectidn as dentists. There is no evidence that saliva can transmit infection even when inoculated intravenously, intraorally or intravaginally into chimpanzees (although chimpanzees are infectable by HIV). Thus unless there is blood in the mouth, transmission of infection is unlikely.
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In surveys of dentists working with HIV-infected patients there seems to be little to no risk of acquisition of infection (Klein et al, 1987; Gerberding, 1990).
Intensive care units
Increasing numbers of AIDS patients and HIV-infected patients will be admitted to intensive care units. Following an initial report in which the need for acute respiratory support for AIDS patients with acute respiratory failure was defined (Murray et al, 1984), there is increasing experience of managiag AIDS patients in the intensive care unit (ICU) and the survival rates of such patients are improving greatly (Rogers et al, 1989; Singer et al, 1990). Clearly the management of AIDS patients in the ICU produces both medical and psychological (for the staff) problems. By definition, ICU patients will have numerous invasive procedures and there is ample opportunity for splashes of blood and other biological fluids to reach the skin and mucous membranes of staff members. Indeed, in a report from a medical ICU in Pittsburgh, a total of 25 needle-stick injuries and 56 mucosal splashes from HIV-infected material affected 76 members of staff over a 3-year period (Rogers et al, 1989). Fortunately, none seroconverted to being HIV antibody positive. No transfer of HIV has been noted in medical personnel providing dialysis for HIV-infected patients (Centers for Disease Control, 1986). Risk of HIV infection may not come only from those with AIDS. In a survey of 203 critically ill patients in the USA, it was found that 3% had antibody to HIV (Baker et al, 1987). In a larger survey of 2275 patients presenting to an emergency department, 5.2% had antibody to HIV; most of these did not have AIDS or AIDS-related complex, and penetrating trauma was associated with a higher seropre ,alence rate (Kelen et al, 1988). Of the HIV-infected patients, only 29% were considered to be at high risk of having been infected. Thus, especially in geographical areas with a high prevalence of HIV infection, it would be wise to ensure that the needle-stick and mucous splash are minimized. Currently there is a debate over whether some or all patients about to undergo major surgery should be screened for HIV antibody. Some say 'at risk' patients should be screened, and some say all should be screened prior to such surgery (Porteous, 1990). Leaving aside the major ethical problems of such a policy, there are other problems. If only 'at risk' patients are tested then it is probable that HIV-infected individuals will be missed. The 'at risk' activities for HIV include sexual promiscuity (homosexual or heterosexual) and injecting drug abuse. To determine whether an unconscious ICU patient falls into an 'at risk' group could be difficult, as evidenced by the survey showing that only 29% of conscious HIV-infected patients admitted to an emergency department were considered by staff to be 'at risk' patients. Secondly, to rely on serological testing will inevitably lead to a false sense of security, since anti-HIV antibodies are not present in the serum of all HIV-infected patients.
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Well-defined recommendations are therefore needed for dealing with patients and their body fluids in the ICU and other areas where procedures are undertaken that might lead to transmission of HIV, hepatitis B or other blood-borne infections. INFECTION C O N T R O L MEASURES
It is not the purpose of this chapter to review the excellent infection control advice given both in the USA (Centers for Disease Control, 1987c) and the UK (Hospital Infection Society, 1990). Both recommend universal precautions (i.e. assume that all samples of blood and certain body fluids are infectious). The majority of the 21 cases of transmission of HIV to hospital staff have involved a needle-stick injury (Wofsy, 1990). Clearly, great care must be taken in handling needles and other sharp instruments. Resheathing of needles is a particularly dangerous activity. Blood and other body fluid spillages should be cleaned up immediately using various chlorine-releasing powders. Adequate barrier precautions must be available, e.g. gloves, masks and eye protection, and double-gloving for high-risk procedures is a useful practice. Health-care workers with exudative lesions or weeping dermatitis should not be allowed to participate in procedures likely to result in release of infected blood or body fluids. Endoscopy equipment (bronchoscopes, etc.) must be cleaned and effectively sterilized (Hanson et al, 1989b). The most effective measure is to educate all staff on the risks and modes of transmission, the epidemiology of HIV infection and methods of prevention. If accidental contamination occurs the site should be washed with soap and water immediately and the infective status of the patient and recipient explored. Under certain circumstances (Wofsy, 1990) chemoprophylaxis with zidovudine might be offered. However, it must be recognized that such chemoprophylaxis is not uniformly successful (Lange et al, 1990). The measures described are aimed at decreasing the very low risk of transmission of HIV to hospital staff (there is no evidence to suggest th at other patients in the hospital are at risk). However, it must be remembered that patients with AIDS may be infected with a series of pathogens of varying virulence (Table 2). These may infect both hospital staff and other patients. Some of these infections are treatable (Glatt et al, 1988), but others are not. For example, the protozoan Cryptosporidiumparvum causes gastroenteritis, lower respiratory tract infection, cholangitis and conjunctivitis in AIDS patients; it can cause a severe gastroenteritis in the immunocompetent, is easily spread in hospitals, and there is no effective therapy (Hart and Baxby, 1987). C H E M O T H E R A P Y AND VACCINES
Because HIV is able to become latent inside the host cell's chromosome it is unlikely that any chemotherapeutic intervention will completely ablate
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infection. The chemotherapeutic strategy is to damp down viral replication and thus prevent T4 and other cells being killed. The first antiviral agent used successfully to treat AIDS patients was zidovudine. There is now a plethora of alternative chemotherapeutic agents at various stages of development. These include nucleoside analogues such as dideoxycytidine, protease inhibitors and soluble CD4 (the T4 antigen) to act as a false receptor (Hirsch, 1990). Zidovudine can be marrow toxic in patients with AIDS, making them transfusion-dependent. Thus patients are now being treated just before it is predicted they will develop AIDS or AIDS-related complex (Editorial, 1990). This seems a promising strategy and will improve the survival of HIV-infected patients. Prevention is always better than a cure. However, the prospects for a vaccine to prevent HIV infection are not entirely hopeful. Not all patients infected with HIV will produce neutralizing antibody, and when such antibody is produced it is often of low titre. The major envelope glycoprotein of HIV (gp120) is highly variable and mutations have been noted during the infection of individual patients. Thus, at present, we must rely upon education and public health and infection control measures to prevent the spread of HIV infection. SUMMARY
Manifestation of AIDS follows a loss of T4 helper cells. This results in impaired humoral and cell-mediated immunity, and allows the development of opportunistic infections and tumours. Human immunodeficiency virus (type 1 or 2) is responsible for this suppression of immune function. The virus principally infects cells bearing the T4 receptor, although other cell types are infectable. HIV is a slow retrovirus. Following infection, viral R N A is back-transcribed to proviral DNA; this means that once infected with HIV an individual is infected for life. Patients are often asymptomatically infected with HIV for years prior to the development of AIDS. Although most HIV-infected individuals produce antibody, some do not. There is as yet no evidence of nosocomial spread of HIV from patient to patient. However, it must be remembered that patients with AIDS will be infected with pathogens of varying virulence which can be transferred nosocomially. They are also immunoincompetent and may be at risk of nosocomial acquisition of pathogens from other patients. The risk of acquisition of HIV by health-care personnel from infected patients is tow. Thus far, only 21 such cases have been documented in developed countries. This risk of transfer is linked to types of procedure rather than to particular risk occupations in hospitals. Those who undertake procedures in which it is possible that HIV-infected blood or other body fluids such as cerebrospinal fluid might be directly inoculated into the circulation via needle-stick or other 'sharps' injury are at greatest risk. The majority of cases of transfer of HIV to hospital staff have involved this route. In prospective surveys the risk of HIV infection via needle-stick injury is less
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t h a n 0 . 5 % ( c o m p a r e d w i t h 5 - 2 5 % for h e p a t i t i s B v i r u s i n f e c t i o n ) . T h e risk o f t r a n s f e r by s k i n o r m u c o u s m e m b r a n e c o n t a c t w i t h H I V - i n f e c t e d b l o o d is e v e n l o w e r (less t h a n 0 . 2 % ) , b u t t w o s u c h c a s e s h a v e b e e n r e c o r d e d . T h e r e is n o e v i d e n c e t h a t c a s u a l c o n t a c t will s p r e a d H I V i n f e c t i o n . P r o c e d u r e s h a v e b e e n d e v i s e d to d e c r e a s e t h e risk o f H I V i n f e c t i o n o f h e a l t h - c a r e personnel.
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