HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND THE ACQUIRED HUMAN IMMUNODEFICIENCY SYNDROME
During 1981, cases of a rare neoplasm, Kaposi's sarcoma, and Pneumocystis carinii pneumonia (an unusual opportunist infection only seen in severely immunocompromised patients-for example, chemotherapy patients and those with severe malnutrition) were reported in the USA in previously healthy homosexual men. This was the beginning of an epidemic eventually termed the acquired immunodeficiency syndrome (AIDS). In 1984 the association between infection with the human immunodeficiency virus (HIV) and the development of AIDS was established. The subsequent global AIDS pandemic has stimulated an unprecedented biomedical research effort which has resulted in a major expansion of knowledge in many aspects of this infection, and in recent years the understanding of the pathogenesis management and control of the disease has greatly expanded.
The World Health Organization estimated that by the year and 2000 there would be 26 million persons infected with HIV, the cumulative total since the beginning of the epidemic being 40 million. Around 90% of cases are in developing countries unable to afford the expensive medical care required to control progress of the disease. The current global pandemic of HIV consists of many different regional epidemics in different countries, each with its own dynamics and different on clinical pattern of evolution. HIV probably originated from remote rural areas where it was endemic at low levels but then spread amongst sexually active populations in cities, initially in the early 1980s amongst homosexual men in the developed countries of Europe, North America and Australia. Recent serological tests have demonstrated HIV seropositivity in an African male in a blood sample taken in 1947. This series of epidemics was then followed by a further wave with predominant heterosexual spread in sub-Saharan ses Africa and South America and, more recently, the Indian subcontinent and South-east Asia, where the epidemics were late in developing but are accelerating at an alarming rate. The early dissemination of HIV was facilitated by travel and migration. Later epidemics have been facilitated by female sex workers and their clients, whereas intravenous drug use and use of HIV-infected blood and blood products have been important risk factors for spread throughout. The epidemics in Europe, North America and Australia have now apparently stabilised, although cases contracted heterosexually and through vertical transmission continue to increase. So far, sub-Saharan Africa has been hardest hit in clinical and sociological terms by the HIV epidemic and rapid spread continues in South-east Asia. The economic and demographic impact of HIV infection is profound as the disease is prevalent between 15 and 50 years of age, the most economically productive age group in most countries, and indeed HIV is now the most common cause of death in this age group in some parts of the world. A consequence of heterosexual transmission of HIV is the increase in the number of paediatric cases, which will greatly influence the expectation of life in many regions.
The characteristics of HIV disease in each region are determined by many different microbiological, cultural, social and behavioural aspects. For example, HIV infection in many parts of the USA remains rare, the highest density being seen in the major cities amongst homosexual men and intravenous drug users, whereas in Uganda, where heterosexual spread is predominant, it is estimated that 10% of the general populations are now infected . Such relatively high seroprevalence are seen in rural areas and may be more tha double in the cities.
Modes of transmission of HIVThere are three possible modes of transmission:
Infection with HIV essentially requires exchange of semen, vaginal or other body secretions, milk, or blood or blood products infected by the virus. The main mode of transmission world-wide is via the heterosexual route, accounting for over 75% of global cases. In the early 1980s, homosexual transmission was predominant but this has now been eclipsed by heterosexual transmission. The risk of HIV transmission is greatest with vaginal and anal intercourse and greater for the recipient of penetrative sex. The risk of transmission during intercourse is considerably increased if there is concomitant presence of sexually transmitted diseases, particularly if genital ulceration is present. As a control measure for the spread of HIV it has been shown that if sexually transmitted diseases can be controlled and reduced in incidence this is accompanied by a fall in HIV transmission rates.
Perinatal transmission is of increasing importance globally as a direct result of the increase in numbers of women with HIV infection who are of childbearing age. HIV infection may occur in utero, during delivery or postnatally as a result of breastfeeding. There is now good evidence that acquisition of HIV during parturition on contact with HIV-containing fluids in the vagina accounts for around 80% of vertical transmission. Neonates of HIV-infected women have a 13-52% chance of acquiring HIV from the mother. There is a wide regional variation in the risk. The risk is increased if the mother has advanced HIV disease with high viral titres. In utero the virus may infect the fetus by crossing the placenta. During delivery infection may result from fetomaternal blood interchange or transmission of HIV across fetal mucous membranes and finally, the virus may be present in breast milk so that breastfed babies have an additional risk of between 10 and 20%. This is a major problem in developing countries where switching to bottle-feeding carries high risks of infection due to poor sanitation. Use of pre-partum and postnatal antiretroviral agents (zidovudine) has been shown to reduce the risk of transmission to the fetus, in one series from 26% to 8%, a 68% reduction in risk. This emphasises the importance of prenatal screening of mothers for HIV infection.
Intravenous drug users (IVDUs) are at risk of HIV infection as a result of the practice of needle sharing, which allows transmission of HIV-infected blood from one individual to another. Transfusion of HIV-infected blood or blood products is an extremely efficient way of transmitting the virus and resulted in many haemophiliac patients acquiring the infection in the 1980s. Transmission via blood and blood products has now been virtually eliminated in many parts of the world following the introduction of routine screening for HIV and needle exchange programmes for IVDUs have helped, to reduce transmission in this group. It is estimated that with screening of donated blood using serodiagnosis the risk of single unit of blood transmitting HIV is 1 in 10 range to power 6 . The screening test will not pick up blood in patients incubating HIV prior to seroconversion.
Transmission to health-care workers
Studies of many thousands of health-care workers have shown that transmission of HIV following occupational exposure is a rare event. In these cases the major risk factor is needlestick injury with HIV-contaminated blood from an infected patient. Overall, the risk of transmission following needlestick injury has been calculated to be 0.3% (1 case per 300 needlestick incidents). Generally, the greater the size and depth of the blood inoculum, the greater the risk. Transmission of HIV has also been postulated through the conjunctiva and open lesions on the skin when in contact with HIV-containing body fluids.
HIV belongs to the Lentivirinae subfamily of retrovirus which have an RNA genome. The viral enzyme reverse transcriptase has the property of transcribing a DNA copy of the RNA genome following viral penetration of the host cell . This DNA copy then randomly integrates into the host cell genome for a variable and sometimes long period of time. This DNA copy can then be usedas a template to transcribe new RNA viral copies and this can occur under a number of circumstances, including activation of the host cell. This process thus led to the term 'retrovirus'. Following production of new viral RNA copies in the host cell, translation results in the production of viral proteins. These precursor polyproteins are then cleaved by the viral protease enzyme to form new viral structural proteins and viral enzymes such as the viral reverse transcriptase and protease. (There are currently two classes of antiretroviral drug in clinical practice: the reverse transcriptase inhibitors and the protease inhibitors, both of which block viral replication.) Lentiviruses, including HIV, cause brisk T cell and cellular responses but cause persistent infections which are not naturally eliminated in a number of species. HIV has a core consisting of the RNA genome and core protein surrounded by an envelope with high lipid content, rendering it sensitive to organic solvents. HIV gains entry to host cells by binding to the CD4 receptor using the viral surface membrane glycoprotein gp120. Host target cells of preference, therefore,.carry the CD4 molecule which is recognised by the virus, but in addition other cell surface molecules act as receptors and coreceptors for the virus. Many of these are chemokine receptors-for example, the CCR5 receptor. Following productive HIV infection new virions bud from the cell surface incorporating the host cell membrane as their own lipid bilayer coat and cell lysis occurs. New virions are then available to infect new uninfected cells and repeat the process.
There is a huge diversity amongst HIVs, which occur in two main types: HIV I and HIV 2. Disease caused by HIV 2 is similar to disease caused by HIV I but is generally milder, slower to progress and poorly transmitted vertically. HIV I is responsible for most of the disease seen world-wide. Until recently, HIV 2 was confined to West Africa but it is now being detected in India. HIV I is divided into several subtypes (see Fig. 2.8); there are at least five subtypes of HIV 2. HIV 1 subtype B is predominant in Europe and North America, whereas subtype E predominates in Central Africa. Now mixed patterns are being seen. For example, in India HIV 1 subtypes A, B, C and E have been identified along with HIV 2. Within each subtype there are huge strain variations and indeed many different strains may be identified within one individual.
Recently, the dynamics of viral replication have become better defined using indirect studies in humans which employ potent combinations of antiretroviral agents to determine the change in viral populations within different cell compartments and plasma. These studies have also been made possible following the advent of the polymerase chain reaction to make quantitative measures of viral load (copies of viral RNA per ml of plasma). The half-life of free HIV in plasma is only 6 hours. Such free virus then infects predominantly uninfected CD4+ T-helper lymphocytes, the majority of which become productively infected with a half-life of about 1.6 days, resulting in the release of more free virus which is then available to infect another cohort of uninfected cells. Each generation of virus has been estimated to take 2.6 days, allowing approximately 140 generations of virus per year within one individual.It has been calculated that each day as many as 10 billion virions are produced and 2 billion CD4+ cells are infected and destroyed. When these facts are considered together with the infidelity of the reverse transcriptase enzyme in making accurate copies of the virus, the reason for the enormous genetic diversity of different strains of virus produced becomes apparent. Such high mutation rates have relevance for the rapid generation of drug-resistant mutants. Some of the viruses, probably less than 1%, infect CD4+ cells, which then enter a latent phase and do not become productively infected, whereas a further relatively small amount of virus infects long-lived cell populations such as monocytes, macrophages, microglial cells in the central nervous system and dendritic cells throughout the body. Such permanent incorporation of viral genome into host cells is common for retroviruses throughout the animal kingdom and makes eradication therapy exceedingly difficult.
As mentioned above, HIV infects CD4+ helper T lymphocytes (T cells) which are
responsible for the initiation of nearly
all immunological responses to pathogens. Following infection by HIV there
is gradual attrition of the CD4 cell population, resulting in gradual and
increasing failure of most aspects of immune function but particularly
cell-mediated immunity. The predominant opportunist infections seen in
HIV disease are intracellular parasites (e.g. Mycobacterium tuberculosis)
or are pathogens susceptible to cell-mediated rather than antibody-mediated
immune responses. HIV infects other cell lineages, including cells of the
monocyte/macrophage lineage, microglial cells in the central nervous
system and dendritic cells. The main immunological abnormalities in
HIV infection are listed in the information box. Much of the damage
done to the immune system is a result of primary damage inflicted by
HIV 1 replication within these cells. However, the exact mechanism of
immunopathology remains undetermined; direct infection and damage by
HIV to T
|IMMUNOLOGICAL ABNORMALITIES IN AIDS|
|T-helper (CD4) lymphocytes|
|Monocytes/macrophages and dendritic cells|
During the course of HIV disease there is a gradual reduction in the number of CD4 cells circulating in peripheral blood. Routine clinical measurement of the CD4 cell count is used in patients as a measure of disease progression. HIV load can be measured using the polymerase chain reaction.
HIV copy number in plasma is regarded as a measure of disease progression and is useful in monitoring therapy. The various complications of HIV disease and survival correlate well with the HIV copy number and to a lesser extent with the CD4 count. Both these measures are used as a guide as to when to institute antiretroviral therapy.
The major abnormality of immune function caused by HIV 18 in cell-mediated immunity, which particularly protects against intracellular parasites (e.g. viruses, protozoa and mycobacteria), whereas failure of appropriate neo and recall antibody responses also occurs, resulting in infection with encapsulated bacteria. HIV also indirectly affects cells of the central nervous system. This is probably due to migration of HIV-infected monocytes to the brain, where they become microglial cells, resulting in damage to the central nervous system. Most disease induced by HIV infection is, however, a consequence of immune system failure resulting in opportunist infections and secondary neoplasms. It is now clear that following infection with HIV in addition to antibody responses to various viral components, CD8+ cytotoxic T lymphocytes are generated; it is thought that these have a protective role in containing infection in the initial stages.
Testing for HIV and counselling
Although HIV infection may be suspected on clinical grounds, HIV infection is confirmed by demonstrating the presence of antibodies to HIV in serum. The current enzyme-linked immunosorbent assay (ELISA) test used for detecting such antibodies is simple and cheap and has the advantage of a very low false negative rate so that infected cases are unlikely to be missed. However, all positive results are normally confirmed by the more precise immunoblot (western blot) test, which also detects the presence of antiHIV antibodies. Following HIV infection, seroconversionthat is, the production of detectable antibodies to various components of the virus, including antibody to the gag protein, integrase and reverse transcriptase—may not occur for 6-12 weeks and sometimes much longer. This means that serial testing may be required following a high risk of exposure to HIV to exclude infection. In special circumstances-for example, in neonates who may be infected— antibody detection tests are unhelpful or misleading because of the presence of transplacentally acquired maternal antibody. The polymerase chain reaction can be used in this situation to detect the presence of viral genome in peripheral blood lymphocytes. In special circumstances direct viral culture from peripheral blood lymphocytes can confirm infection. However, ELISA remains the routine screening test and is used by centres offering rapid (same-day) testing services.
The diagnosis of HIV infection depends on being clinically astute, having a clear knowledge of the clinical manifestations of HIV disease, asking the patient about relevant risk factors and maintaining a high index of suspicion. The importance of HIV testing for the patient is related to the serious consequences, both social and medical, of having a positive test. Before a test is performed it is important that adequate counselling of the patient is undertaken, including a discussion of the way in which the virus is spread, the effects of the virus, the psychological stress that a positive test will exert, and the effects on the individual's social, work and medical life. Issues relating to confidentiality need to be discussed in the event of the test being positive. Other disadvantages of a positive test for the patient, apart from the medical consequences, include feelings of guilt, social stigma and the fact that some countries will not admit HIVpositive persons. However, the advantages of knowing that an individual is HIV-seropositive include appropriate medical care and prophylactic measures which will benefit health, prolong life and avoid infection of others. When an HIV test is negative the patient should be advised to practise safe sex and to abstain from other avoidable risk factors, such as sharing needles for intravenous drug use. When giving a positive HIV test result, clinicians should remember that this is a major event for the patient. Adequate time must be set aside for this without interruption and, if possible, a partner, close friend or family member should be available to provide immediate support once the news has been broken.
Therapeutic approaches to HIV infection
Many programmes in different parts of the world have been implemented in an attempt to prevent the spread of HIV infection since early in the epidemic (see the information box). The overall success of these programmes is difficult to estimate but the fact that currently reported numbers of AIDS cases and HIV-infected individuals in many countries fall far short of epidemiological predictions of a few years ago must be attributed in part to success of these strategies. However, there is an urgent need for major education campaigns and implementation of other measures in parts
|PREVENTION MEASURES FOR HIV TRANSMISSION|
of the world where the epidemic is proceeding unchecked.
Hopes for an effective vaccine remain highbut elusive at the moment despite an enormous research effort. Reasons for the failure of vaccine programmes include our incomplete understanding of the components of the immunological response to HIV which are protective, the inability of antibody to neutralise the virus, and the enormous ability of the virus to mutate rapidly and produce new strains capable evading the immune response.
The major therapeutic effort at present is directed at individuals already infected with HIV. There are now numerous agents in regular clinical use which interfere with HIV replication , and more agents will be available soon following further trials. Reverse transcriptase inhibitors prevent the spread of infectious virus into uninfected cells but do not affect replication of the HIV genome once integrated into the host cell. Protease inhibitors prevent post-translational cleavage of polypeptides into functional virus proteins. The first agent to be used clinically was the reverse transcriptase inhibitor, zidovudine.
In a large controlled study, it was shown to prolong survival of patients with advanced HIV disease. It has, however, subsequently been shown that zidovudine given in early HIV disease has little benefit in delaying the onset of AIDS or in improving survival (Concorde trial). It is now known that zidovudine quickly loses its efficacy as an anti-HIV agent due to the emergence of drug-resistant strains of the virus. Controlled studies have now shown improved survival with combinations of two or three antiretroviral agents taken together. Many different combinations of two or three antiretroviral agents taken together . Many different combinations of drugs are effective and monotherapy is no longer used.In mild disease two-drug combination(e.g. zidovudine and
|* Multiple drug interactions as metabolised by hepatic cytochrome P450 system.|
|Indications for antiretroviral drug treatment of HIV disease|
|HIV copy number (PCR plasma measurement)||5000-30 000/ml||10 000-50 000/ml|
|CD4+ (TH count in peripheral blood)||< 500/mm>3||< 300/mm3|
lamivudine, or lamivudine and stavudine) are used, whereas in more severe HIV disease triple therapy, a combination of two nucleoside reverse transcriptase inhibitors together with a protease inhibitor, is effective. These new combination drug therapies (HAART; highly active antiretroviral therapy) have been highly effective in delaying the progress of HIV disease and have brought about major changes to clinical practice where these drugs are available. Unfortunately, due to cost this is not the case for the vast majority of HIV-infected individuals in developing countries. The indications for starting antiretroviral therapy are listed in Table . Some authorities advocate early intervention on the grounds that this will prevent or delay extensive damage to the immune system, whereas others advocate starting much later in the natural history of HIV disease on the grounds that many patients have a long asymptomatic phase of many years during which treatment is unnecessary and expensive, and will induce morbidity through drug toxicity, raising problems with compliance, and through increasing drug resistance. Even with potent combinations of three antiretroviral drugs, drug resistance inevitably develops and following a period of clinical improvement HIV disease will relapse. This raises further problems relating to the sequence in which the antiretroviral drugs are used in an individual. All antiretroviral drugs are toxic; for example, side-effects of zidovudine include nausea, vomiting, headaches and myalgia, anaemia, macrocytosis, neutropenia and occasionally leucopenia and thrombocytopenia.
Prophylactic use of anti-HIV drugs is recommended for health-care workers who have had percutaneous exposure to HIV-infected blood following needlestick injury or injury with surgical instruments. Such an injury carries the risk of HIV transmission of around 0.3%. The risk of percutaneous injury can be reduced by adopting universal precautions and taking care in handling sharps--for example, by not resheathing needles. A case control study demonstrated that zidovudine administered shortly after exposure reduced the risk of seroconversion by 80%. However, protection is not absolute and health-care workers have been reported to seroconvert despite taking zidovudine. The risk of seroconversion is raised with the increase in size of blood inoculum and the disease stage of the patient from which the infected blood was taken. Following needlestick injury, a rapid decision must be taken as to whether prophylaxis is desired or not. The drugs must be readily available as, to be effective, they must be started within an hour or two. Current recommendations are that zidovudine, lamivudine and indinavir should be taken for a 4-week period. In developed countries HIV seroconversion due to occupational exposure may be subject to industrial compensation and many health-care workers store their serum at regular
intervals for subsequent HIV testing.Clinical features of HIV disease
Following infection with HIV there is a latent period of a few (classically 8-12) weeks during which there may be intense viraemia. This period is followed by seroconversion when detectable antibodies to HIV and HIV-specific cytotoxic T lymphocytes appear in serum . At this time there is a rapid fall in viraemia, suggesting that the immunological response has contained the infection. At this stage approximately one-third of individuals have a brief illness lasting about 2 weeks. Symptoms include fever, malaise, headache, fleeting arthralgia, maculo-papular rash, tender lymphadenopathy, and occasionally encephalitis, diarrhoea and mouth ulcers. There then follows an asymptomatic phase of variable duration. Some individuals have quite rapid progression to symptomatic disease over a year or two, whereas others remain asymptomatic and completely well for many years. An early study from San Francisco of patients infected with HIV 11 years previously showed that 50% had died of AIDS; of the survivors, 20% had AIDS and 40% had symptoms attributable to HIV infection, whereas 40% remained completely free of symptoms. AIDS is thus the long-term consequence of chronic infection with HIV. The average time to developing AIDS from infection in most developed countries is 10-11 years but there is a considerable variation. Some will develop AIDS in less than 5 years but it is thought that eventually all HIV-infected individuals will develop AIDS in due course.
Some, but not all, HIV-infected patients develop persistent generalised lymphadenopathy (PGL), which is defined as the presence of enlarged lymph nodes greater than 1 cm in diameter in two anatomically distinct sites for more than 3 months in the absence of other detectable causes of lymphadenopathy. Most of these patients are asymptomatic although a few have fever and weight loss. The diagnosis of PGL is usually made clinically; biopsy of lymph nodes shows reactive hyperplasia. The prognosis for patients who develop PGL is the same as for those who do not. Asymmetric lymphadenopathy suggests alternative diagnoses such as lymphoma or tuberculosis. Percutaneous fine-needle aspiration of lymph nodes is a very useful test to differentiate causes of lymphadenopathy under these conditions.
Classification of HIV-associated conditions
Patients with acute HIV infection, or who are asymptomatic, fall into group A of the Centers for Disease Control (CDC) classification of HIV-associated conditions. Group B patients have symptoms but do not have an AIDS-defining condition. This group is sometimes referred to as the AIDS-related complex (ARC) and is characterised by conditions not exclusively confined to immunocompromised individuals (see the information box). As these patients are relatively immunosuppressed, they are also more prone to develop ordinary infections such as herpes zoster and bacteria pneumonia. Group C includes patients who have AIDS a therefore have one of the conditions meeting the CDC case
|CLINICAL FEATURES OF SYMPTOMATIC HIV DISEASE|
|General symptoms||General signs|
|CONDITIONS THAT MEET THE 1987 CDC/WHO* CASE DEFINITION FOR AIDS|
|Lymphocytic interstitial pneumonia (mainly children)|
|CDC = Centers for Disease Control, Atlanta, Georgia; WHO = World Health Organization|
definition for AIDS . As HIV disease progresses and patients become symptomatic, the peripheral blood CD4 count declines and the viral load increase. These two measures now offer the opportunity of precise clinical staging of HIV disease and are important in deciding when to commence antiretroviral chemotherapy . Taken together, they are useful surrogate markers for clinical progression. The lower the CD4 count and the higher the viral load, the greater the likelihood of opportunist infections and secondary neoplasms. Survival for patients once AIDS is established used to be poor, with only 50% of patients still alive by 18 months. However, the situation has improved since the introduction of combination antiretroviral therapy, more intense clinical surveillance with rapid diagnosis and treatment of opportunist infections, and effective antimicrobial prophylaxis for many recurrent and relapsing opportunist infections. The major opportunist infections and other conditions that characterise AIDS will be described in the rest of this chapter.
Disseminated disease in AIDS
A logical approach to describing opportunist infections and neoplasms of AIDS is not straightforward as many affect ore than one organ or site. These will be described first, hereas conditions that have a particular organ predilection
|DISSEMINATED DISEASE IN AIDS|
will be described under appropriate organ headings. Conditions seen in AIDS which tend to be disseminated at presentation are listed in the information box.
CMV is a herpesvirus, and infection is extremely common in HIV disease. Approximately 50% of the general population and 90% of homosexual men are seropositive and harbour the virus. Clinical disease results from reactivation of latent CMV infection in the face of severe immunosuppression. This is seen when the CD4 count is normally below 50/mm and the HIV load is high. Diagnosis of CMV disease is based on the clinical picture and histology. Many organs can be involved including eyes, central nervous system, liver, gut, adrenals, mouth, oesophagus and lung. The most common and dramatic problem is CMV choroidoretinitis , which can lead very rapidly to blindness and is characterised by fundal perivascular haemorrhages and exudates. Overt adrenal involvement is uncommon but can occasionally present with lassitude, postural hypotension, dehydration and hyponatraemia which respond to corticosteroid therapy. CMV encephalitis usually presents subacutely in contrast to the more gradual progression of HIV-related encephalopathy, with personality change, poor concentration, headaches and insomnia. CMV may also cause transverse myelitis and polyradiculopathy. It can also cause colitis senting with diarrhoea, weight loss, anorexia and fever, but is a less common cause of colitis than other pathogens which include cryptosporidia, microsporidia and Mycobacterium avium intracellulare, Shigella and Campylobacter. Sigmoidoscopy reveals diffuse submucosal haemorrhages and ulcerations. CMV may also cause oesophagitis. Unlike the other sites where CMV undoubtedly does cause disease, in the lungs CMV is a rare cause of pneumonia although it is frequently isolated from the lung of AIDS patients. Treatment of CMV is with ganciclovir or, alternatively, foscarnet. Originally, both drugs had to be given intravenously and permanent venous access via a Hickman line or similar device was normally required. However, ganciclovir can now be given orally and intra-ocular implants are available for localised eye disease. A favourable clinical response is normally obtained but maintenance therapy at lower dose may be required. Drug resistance may develop, necessitating a switch to alternative therapy, and occasionally dual therapy is required.
Herpes zoster infection, usually in the form of multidermatomal shingles, is seen in HIV-infected patients, usually belonging to group B of the CDC classification. Rarely, herpes zoster may cause pneumonitis or encephalitis in AIDS patients. Chronic mucocutaneous herpes simplex infection is an AIDS-defining diagnosis and infection may be extensive but disseminated infection is rare. In addition, both Kaposi's sarcoma and B-cell lymphomas associated with AIDS are now known to result from herpesvirus 8 infection and will be discussed later.
Bacterial infections in HIV
Although many of the serious opportunist infections in AIDS are due to viruses, fungi or protozoa, bacterial infections are very common in these patients. It is important to recognise that such infections are often not contained within a particular organ and septicaemia is common. These infections will be discussed further in later sections. Neurosyphilis should be considered in the differential diagnosis of neurological disease in AIDS and, conversely, HIV infection should be considered in patients presenting with syphilis.Mycobacterium tuberculosis. Tuberculosis (TB) is probably the most important opportunist infection related to HIV in global terms and HIV is now regarded as the most important risk factor for the development of TB (see the information box). The relationship between HIV and TB is closely determined by the prevalence of the two separate infections, which geographically is extremely variable. If TB is prevalent in a community, the incidence of clinical TB is greatly increased by the presence of HIV infection within that population. This is particularly the case in developing
|MAIN FEATURES OF TUBERCULOSIS IN HIV INFECTION|
countries such as those in sub-Saharan Africa, where both infections are very common. In Uganda, for example, it is estimated that 10% of the population are now infected with HIV. As a result, the incidence of TB since the early 1980s has increased dramatically. In the USA, the annual decline in TB that had been occurring since the beginning of the century ceased in 1986 and numbers began to increase, This increase was directly related to cases of HIV disease in major American cities such as New York, Miami and San Francisco, whereas the decline overall continues in the general (HIV-negative) population in the USA. In the countries of Europe, increases in the number of TB cases have been observed since the beginning of the HIV epidemic in HIVinfected individuals. In sub-Saharan Africa TB is the most common opportunist infection seen in HIV disease.
The association between HIV and TB relates to the decline in cell-mediated immunity, allowing reactivation to occur in previously infected individuals. It has been estimated that people previously infected with TB who do not develop clinical disease at the time of infection have a 5% lifetime chance of developing clinical disease as a result of reactivation at some later stage in their lives. In HIV-infected individuals this risk is increased to 8% per year. TB in HIV-infected individuals generally follows a more rapid clinical course al course with a higher mortality than in individuals with TB who are not HIV-infected. This is because the TB itself accelerates HIV disease by increasing HIV production in macrophages. It has now been determined that recent infection with TB is as important as, if not more important than, reactivation, and TB is unique amongst opportunist infections in HIV disease in being pathogenic to normal individuals. Tuberculosis may occur at any stage of HIV infection. When immunity is still relatively well preserved, pulmonary disease alone is seen, often resembling post-primary disease in normal individuals. When severe immunosuppression is present, extra-pulmonary disease involving lymph nodes, bone, pericardium, peritoneum, central nervous system, liver and marrow may occur, as well as miliary TB. Overall, 60–70% of TB cases with HIV infection have extra-pulmonary disease, compared to about 15% in those who are HIV-negative. Non-specific features of fever, weight loss and fatigue may also be present. In overwhelming mycobacterial infection HIV-infected patients may present with a classical septicaemia and mycobacteria can be cultured directly from blood.
The diagnosis of TB classically relies on sputum examination and culture, tuberculin testing and the chest radiovraph. However, in HIV infection the tuberculin test is often negative because of the defect in cell-mediated immunity. As TB may be disseminated, pulmonary disease may be minimal and there may be no sputum for examination. If there is, this is frequently negative on smear and culture. Thirdly, the chest radiograph appearances may be atypical (see Fig. 2.12). Diagnosis therefore relies on a high index of clinical suspicion and remembering that the clinical presentation may be unusual.
Clinical response to standard treatment with isoniazid, rifampicin, pyrazinamide and ethambutol is generally good, with rapid improvement in symptoms. However, overall survival is poor due to acceleration of HIV disease. Drug reactions are generally more common in HIV-infected individuals than in HIV-seronegative individuals and this may be a particular problem in the treatment of TB. For example, thioacetazone, a drug used in developing countries for TB, can cause life-threatening side-effects and is now generally contraindicated. Also, numerous drug interactions can occur. Due to these features, compliance may be a problem and in some cases supervised or directly observed therapy may be appropriate to ensure compliance. To prevent TB developing in HIV disease due to reactivation, chemoprophylaxis with isoniazid for a period of 1 year is effective, particularly in individuals who are tuberculin-positive and who either live in or have come from areas of the world with a high prevalence of TB. Not only does chemoprophylaxis prevent development of TB but it has also been shown to delay progress to AIDS and death.
Over the last few years there has been increasing concern following the emergence of multidrug-resistant TB (MDRTB). These strains of tuberculosis are resistant to both isoniazid and rifampicin and may also be resistant to other first- and second-line drugs. MDR-TB is at best extremely difficult to treat and at worst may be resistant to all antituberculosis drugs. The prognosis is generally very poor. The development of MDR-TB relates to poor compliance, and inappropriate and incomplete treatment. The prevention of the development of MDR-TB is a strong argument in favour of supervised or directly observed therapy. A further hazard is that MDR-TB can be transmitted to health-care workers and fatalities have been described. There is great concern regarding outbreaks of MDR-TB in hospitals and other health-care facilities. The technique of restriction fragment length polymorphism analysis (DNA fingerprinting) has confirmed that MDR-TB can be spread rapidly amongst HIV-positive patients and health-care workers.Atypical mycobacteria.
Of the non-tuberculous mycobacteria Mycobacterium avium intracellulare (MAI) is the most common to cause disease in AIDS patients. M. kansasii can also produce disseminated infection. Unlike TB, MAI is a pathogen of very low virulence and is commonly found in the environment, being present in soil, water and food. MAI usually causes clinical disease when the CD4 count is very low (less than 50/mm). The portal of entry is thought to be the gut. The most common presenting features are persistent fever, night sweats, anaemia and weight loss, in addition to non-specific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painful lymphadenopathy.
On examination hepatomegaly is frequently present, and the chest radiograph and CT scan often reveal widespread intrathoracic and intra-abdominal lymphadenopathy. The diagnosis is generally easy, provided it is considered, as clinical specimens from affected organs contain numerous acid-fast bacilli. Unlike TB, MAI is universally resistant to most first-line antituberculosis drugs. It has now been shown in several clinical trials that clarithromycin, azithromycin, rifabutin, ethambutol and amikacin are effective and these drugs are used in combination. Clarithromycin, rifabutin and ethambutol in combination are probably the most effective. Toxicity may be a problem but this is outweighed by clinical benefits in most cases. Monotherapy, usually with clarithromycin, is now used for prophylaxis.
Fungal infectionsCandidiasis. Oral candidiasis is almost universal at some stage of HIV infection and if seen unexpectedly in the mouth of a young patient should prompt consideration of significant immunodeficiency and HIV infection. Lesions
in the mouth may initially respond to topical antifungal agents such as nystatin or amphotericin but when more advanced, systemic therapy is required, normally with ketoconazole or fluconazole. When Candida spreads beyond the mouth to the oesophagus or, more rarely, the lung it becomes an AIDS-defining diagnosis with oesophageal involvement; painful dysphagia is frequent and barium swallow may reveal a ragged-looking mucosal surface. Once Candida infection is firmly established, antifungal therapy often needs to be continuous and liver function tests should be closely monitored if ketoconazole is used. Fluconazole has now replaced ketoconazole as it is much less hepatotoxic. Continuous use of azole drugs in the long term often leads to resistance developing. Widely disseminated disease is generally rare but can become a problem in patients with neutropenia, intravenous drug users and patients with indwelling central venous lines.Cryptococcal infection.
Cryptococcus neoformans is the most common cause of meningitis in AIDS patients and may also cause pulmonary disease. Although clinically disseminated infection is rare, the organism may be cultured from blood, urine, gut or bone marrow. Initial symptoms of cryptococcal meningitis are fatigue, fever and weight loss, followed by headache, nausea, vomiting and photophobia. Diagnosis may be delayed because the poor inflammatory response often masks the classic symptoms and signs of meningitis. Diagnosis is made by Indian ink staining of CSF to identify the organism, and culture and measurement of cryptococcal antigen both in serum and CSF. The CT scan of the brain is usually normal and CSF examination may show a monocytosis and raised protein. Standard therapy has traditionally been amphotericin with or without flucytosine. However, because of the toxicity associated with amphotericin use, fluconazole or liposomal amphotericin is now often used, with satisfactory clinical responses Relapse is common, so long-term suppressive therapy i required with high-dose oral fluconazole. Commonly such treatment merely arrests the meningitis and after several months clinical escape occurs, resulting in papilloedema blindness and severe headache.
Endemic fungal infection in AIDS. Disseminated infection with Histoplasma capsulatum and Coccidioidomyces immitis is seen in AIDS patients who have been exposed to these fungi in endemically restricted areas such as occur in certain parts of the USA and Africa. It is therefore vital to take a good travel history from anyone with HIV infection. Amphotericin is the treatment of choice, although azole drugs, such as fluconazole, may be useful.
Toxoplasma gondii infection is very common in humans and, following severe immunosuppression with AIDS, clinical disease may emerge, with fever, lymphadenopathy and headache. The brain is the most common site for lesions, which usually present with focal neurological symptoms, convulsions, cognitive impairment, confusion, lethargy or coma. Other organs including the retina may be involved. Diagnosis is usually made by cranial CT scan which shows characteristic ring-enhancing lesions surrounded by cerebral oedema . Magnetic resonance imaging is more sensitive. Serological tests may be unreliable in this context and definitive diagnosis requires demonstration of the organism in brain biopsy material. However, such biopsy is hardly ever necessary, the diagnosis being made on clinical grounds and radiological and clinical response to treatment in 2-4 weeks. If Toxoplasma serology is completely negative, a space-occupying lesion in the brain of an AIDS patient is unlikely to be due to toxoplasmosis. Treatment of toxoplasmosis employs folate antagonists, usually pyrimethamine and sulphadiazine given with folinic acid. A combination of clindamycin and pyrimethamine is also effective. Pyrimethamine plus either clarithromycin or azithromycin are alternatives. Dexamethasone may be necessary to relieve cerebral oedema and anticonvulsants to control convulsions. Relapse is likely to occur if treatment is stopped completely and therefore maintenance is recommended with lower doses of similar drug combinations taken twice weekly. Routine prophylaxis of patients with cotrimoxazole (three times weekly) when the peripheral blood CD4 count falls below 200 offers good protection against toxoplasmosis and Pneumocystis carinii .
Nematode infectionsStrongyloides stercoralis is acquired as an endemic infection in certain parts of the world , normally resulting in latent infection which very rarely becomes disseminated in AIDS patients. The diagnosis is made by identifying larvae in the faeces and treatment is with ivermectin. Albendazole or thiabendazole are alternatives.
Neoplasms associated With AIDS
Kaposi's sarcoma is an unusual neoplastic condition which was rare before AIDS. It is the most common secondary neoplasm seen in North American and European AIDS cases. It is unusual in that although it has many features of malignant disease it invariably arises at multiple sites within a short space of time, the cell of origin being the venular capillary endothelium. AIDS-associated Kaposi's sarcoma is closely linked with a new herpesvirus, human herpesvirus 8 (HHV 8). Kaposi's sarcoma is most common in homosexual male AIDS patients in Europe and North America (up to 25% of cases) and also occurs in sexually transmitted HIV infection in sub-Saharan African patients; it is rare in AIDS patients with haemophilia who acquired HIV from blood products. Histologically, the tumour consists of spindle cells and small blood vessels. Some authorities regard it as a hyperplastic rather than a true neoplastic condition. The most common site of involvement is the skin. The mouth, hard palate, tip of the nose, penis and lower legs are favoured sites . Lesions are red or violaceous, well circumscribed, and flat or raised. In darkskinned individuals lesions may appear brown or even black. When multiple skin lesions are present they tend to develop along skin flexures. The prognosis for skin disease is very variable, although as the CD4 count falls, Kaposi's sarcoma tends to become more aggressive. Lymph nodes are the second most common site and, along with extranodal visceral disease, lymph node involvement indicates a poor prognosis compared to isolated skin disease. The gastrointestinal tract may be involved at any point and such patients may present with abdominal pain, bleeding or obstruction. Liver and spleen involvement causes hepatosplenomegaly, and pulmonary involvement may result in cough and breathlessness due to bronchial and parenchymal involvement or the development of pleural effusions. Patients with visceral involvement nearly all have mucocutaneous or lymph node involvement. In patients with a few skin lesions the disease may follow an indolent course, whereas extensive disease tends to be more aggressive. Skin lesions, particularly on the face, are unsightly and single lesions can be treated by local radiotherapy. Satisfactory palliation of disseminated disease can be achieved by combination chemotherapy with vincristine or vinblastine and bleomycin, often with the addition of doxorubicin. More recently, treatment with a single agent, with liposome encapsulated daunorubicin or doxorubicin, has produced good results comparable to combination therapy, with far lower drug toxicity. Treatment reduces morbidity but does not improve survival. It is noteworthy that Kaposi's sarcoma virtually never involves the brain. Restoration of immune function with combination antiretroviral therapy (HAART) has been associated with regression of Kaposi's sarcoma. The mechanism is not yet clearly elucidated but is thought to involve enhanced immune recognition associated with restoration of immune function and destruction of cells expressing HHV 8 antigens.
This group of lymphomas arises from B lymphocytes in 80% of cases, with the remainder arising from T lymphocytes. Of the B-cell tumours the majority are high-grade B-cell lymphomas of various histological types, including immunoblastic lymphoma and Burkitt-type lymphoma. The development of one of these lymphomas in an HIV-positive individual constitutes an AIDS-defining diagnosis and, in contrast to their development in normal individuals, these tumours tend to arise largely at extranodal sites, most frequently the CNS, bone marrow, gastrointestinal tract and liver. They are often advanced at the time of diagnosis, producing B symptoms (fever, constitutional symptoms and weight loss). Diagnosis is by tissue biopsy of affected sites and histological examination. Treatment is with combination chemotherapy and various regimens produce useful response. Primary lymphoma of the brain, however, is particularly difficult to treat, although short-term responses have been reported following cranial irradiation. Overall survival, irrespective of location or initial response to therapy, is poor and usually less than 1 year.
There is an increased incidence of cervical dysplasia and neoplasia in HIV-infected women and of anal carcinoma, particularly in HIV-infected homosexual men. Women with HIV infection should have regular cervical smears. The association between these carcinomas and HIV is thought to be due to a greater incidence of infection by the human papillomavirus in HIV-infected patients rather than a consequence of immunodeficiency.
Organ-specific HIV disease
In this section infections and other conditions which tend to be more organ-specific than the conditions already discussed will be described.Skin
Skin disease is extremely common in HIV-infected patients. Some of these diseases are also seen in the normal population but less frequently and less severely (e.g. molluscum contagiosum (see Fig. 2.16) and seborrhoeic dermatitis), whereas others are specific to HIV infection (e.g. Kaposi's sarcoma). The common skin diseases seen in HIV-infected patients are listed in the information box. In Africa, Slim disease consists of weight loss, diarrhoea (due to either HIV itself or enteric tuberculosis) and dermatitis, and is an AIDS
|COMMON SKIN DISEASES IN HIV INFECTION|
defining diagnosis. Management of the various skin infections observed in these patients is identical to the treatment given to non-HIV-infected patients. Pruritus is the most common skin problem in African patients and is exceedingly difficult to treat.Drug eruptions
Drug-induced skin eruptions are very common and more severe in HIV disease than in the general population. This is thought to be as a result of the immune dysregulation induced by HIV. Drug eruptions are a very important aspect of the care of AIDS patients, as the majority will develop a major drug eruption at some stage. Many drugs produce these reactions but particular culprits are co-trimoxazole, which frequently induces a widespread, intensely itchy, maculopapular rash and Fansidar (pyrimethamine. sulfadoxine combination), sometimes used in prophylaxis against Pneumocystis pneumonia, which may induce erythema multiforme and the Stevens-Johnson syndrome. The drugs used to treat tuberculosis may result in skin eruptions, as may dapsone. Itchy drug reactions may respond to antihistamines such as chlorpheniramine, although it may be necessary to stop the drug.Oral disease
Oral disease is prominent in HIV infection and maintenance of good dental and oral hygiene is hence very important in these patients. As mouth lesions are so common in HIV and may be present early in HIV disease, a very careful inspection of the mouth during clinical examination is mandatory. Oral disease may cause disabling symptoms but most conditions are responsive to appropriate therapy. The most common condition is oral candidiasis and initially local therapy with amphotericin lozenges, nystatin pastilles or clotrimazole may control the infection. More extensive disease will require a systemic azole (fluconazole, itraconazole or ketoconazole); however, resistance to azoles may occur. Oral hairy leucoplakia may occur in HIV infection and presents as serrated white areas, normally along the sides of the tongue. These plaques are adherent and cannot be pushed off with a spatula like Candida. They are usually painless, are due to the Epstein-Barr virus and
|Oral diseases in HIV|
|Bacterial periodontal disease Gingivitis Hairy leucoplakia||Dental hygiene Penicillin/metronidazole Aciclovir|
|CMV/herpes simplex/herpes zoster stomatitis||Ganciclovir/aciclovir|
|Aphthous ulcers||Orabase triamcinolone Benzocaine lozenges Thalidomide|
|Kaposi's sarcoma||Local radiotherapy/chemotherapy|
usually respond to aciclovir or ganciclovir. It should be noted from table that for refractory aphthous ulceration thalidomide produces useful relief, but if used, the dose should be kept to a minimum to prevent the development of peripheral neuropathy; it is vital that female patients take contraceptive measures while on thalidomide.Gastrointestinal disease
Weight loss is a marked feature of AIDS and much morbidity and death in late AIDS is due to gastrointestinal disease. Many of the pathogens which cause diarrhoea and marked weight loss in advanced AIDS are essentially untreatable. For example, microsporidia and cryptosporidia cannot be eradicated; they cause damage to the small bowel villous
architecture, leading to malabsorption, maldigestion, diarrhoea and weight loss. Weight loss is a major contributor to cause of death in many AIDS patients and is commonly due to protozoal gut infection with microsporidia and cryptosporidia, producing a picture of starvation clinically which can be ameliorated with additional calories by the enteral route. This is in distinction to the weight loss and cachexia seen in systemic infections such as MAI and CMV which do not respond to simple refeeding. Parenteral nutrition has been successfully used in severe intestinal failure of AIDS but is very expensive. Salmonellosis with septicaemia is often seen in AIDS and is a particular problem requiring antibiotic treatment and constant surveillance of the patient after recovery, as return of bacteraemia is common.
The oesophagus. Painful dysphagia is common in HIV disease due to oesophagitis. The most common cause is candidiasis and the majority of patients also have oral candidiasis. Barium swallow appearances are characteristic but endoscopy provides definitive diagnosis. Initial response to a systemic azole such as fluconazole is normally good and rapid. CMV is a quite common cause of oesophagitis, either causing diffuse disease or discrete ulcers. Pain on swallowing and intermittent retrosternal pain may be present. Mucosal biopsy reveals characteristic inclusion bodies, confirming the diagnosis. Response to ganciclovir or foscarnet is normally satisfactory but maintenance therapy is normally required to prevent relapse. In up to 10% of cases no specific diagnosis of oesophageal ulceration is made. Some of these respond to thalidomide. Occasionally, primary lymphoma and Kaposi's sarcoma are found in HIV patients with dysphagia. Finally, HIV patients are not immune from ordinary diseases and gastro-oesophageal reflux may result in oesophagitis and ulceration. Tablet-induced ulceration may be seen. In view of the wide differential diagnosis, all AIDS patients with dysphagia refractory to antifungal agents should be considered for endoscopy.
Gastric disease. Nausea and vomiting are very common in AIDS and are frequently the result of drug therapy, in particular, high-dose co-trimoxazole in the treatment of Pneumocystis pneumonia. Alternatively, they may result from intrinsic gastric disease due to Kaposi's sarcoma, lymphoma or gastric ulcer. Mallory-Weiss tears and variceal bleeding are also seen as many AIDS patients belonging to the homosexual IVDU risk group have high alcohol intake, and hepatitis B and C are also common in this group. Nausea and vomiting in AIDS, from whatever cause, can be a major management problem but usually respond to either metoclopramide, domperidone, prochlorperazine or ondansetron.
Small bowel disease. Weight loss, high-volume diarrhoea and colicky para-umbilical pain are suggestive of small bowel disease which may be due to a wide range of infections (see the information box). Diagnosis depends on microscopic examination and culture of stools to allow for specific therapy with appropriate antimicrobial agents.
|SMALL BOWEL DISEASE IN HIV|
Three sequential stool examinations and cultures will result, in a diagnosis in 80% of cases. Small bowel biopsy is some, times required, which may demonstrate subtotal villous atrophy in addition to specific pathogens. HIV itself produces minor changes in the small gut, termed HIV enteropathy and this damage may be immunologically mediated. It is thought not to be severe enough of itself to cause diarrhoea Similarly, bacterial overgrowth and hypochlorhydria are found quite commonly in advanced AIDS but are not thought to have an important role in villous atrophy. Overall, the most common causes of diarrhoea in AIDS are protozoal gut infections with cryptosporidia and microsporidia, leading to malabsorption, maldigestion and malnutrition, resulting in diarrhoea which can present a major management problem in AIDS. Fluid and electrolyte replacement, nutritional supplements and antidiarrhoeal agents such as loperamide, diphenoxylate and codeine are first steps in management. Some patients with secretory diarrhoea will respond to the somatostatin analogues, octreotide and vapreotide.
Cryptosporidiosis, which is an AIDS-defining diagnost if chronic, is a parasitic infection which affects the brush the border of the gastrointestinal tract and normally presents with profuse watery diarrhoea accompanied by abdominal pain, fever, anorexia, malaise, malabsorption and Wasting. In one-third of cases spontaneous resolution occurs. Prophylactic measures involve boiling tap water before drinking; for established infection, paromomycin may be weakly effective. Cryptosporidiosis may also involve the biliary tract, causing biliary tract pain, the pancreatic duct and gallbladder. Microsporidium may respond to albendazole whereas Isospora belli sometimes responds to cotrimoxazole. Bacterial gut infections such as salmonella and shigella are often accompanied by signs of disseminated infection and septicaemia. Response is normally good to appropriate antibiotics.
Colorectal disease. Colonic disease normally results in frequent small-volume stools, left lower quadrant and suprapubic colicky pain, tenesmus and pain on defaecation. A number of infectious causes are seen, two important ones being cryptosporidiosis and CMV. In homosexual patients a sexual history should be taken and proctoscopy performed, swabs being taken for chlamydia and gonorrhoea. Warts and herpes simplex are common in this group and syphilis serology should be performed.Hepatobiliary disease
Abnormal liver function tests, right upper quadrant pain and hepatomegaly are extremely common findings in AIDS patients, as hepatic disease is extremely common. The main cause of hepatic disease in HIV-infected patients are: hepatitis A, B or C, hepatotoxic drugs, and CMV and MAL infections. Investigations should include hepatitis and syphilis serology ultrasound or CT of the upper abdomen, and liver biopsy if indicated. MAI and CMV are particularly common causes of hepatitis as part of disseminated disease and CMY Candida, cryptosporidia and microsporidia are recognised causes of acalculous sclerosing cholangitis. The liver may be involved in Kaposi's sarcoma and lymphoma.Respiratory disease
Respiratory disease is very common in AIDS and the spectrum of causes is listed in the information box. One of the most serious common opportunist infections in the lung is due to the atypical fungus Pneumocystis carinii in Europe and North America. Before the introduction of chemoprophylaxis, up to 80% of all patients with AIDS had one or more episodes of Pneumocystis pneumonia. In Africa, however, Pneumocystis pneumonia is unusual whereas tuberculosis is very common. Pneumocystis infection is largely confined to the lung, where the air spaces fill with
|SPECTRUM OF LUNG DISEASE IN AIDS|
|PNEUMOCYSTIS CARINII PNEUMONIA|
foamy exudate containing cysts and trophozoites of the organism. Pneumocystis pneumonia usually starts insidiously with an irritating dry cough and breathlessness. There is often a background of fatigue, weight loss and fever as well as other signs of HIV infection. Sputum production is unusual, and audible crackles in the chest are rare. An increased respiratory rate is common, with cyanosis indicative of severe disease (see the information box). Since the introduction of chemoprophylaxis, the incidence of Pneumocystis pneumonia has fallen dramatically; however, the infection remains common in individuals unaware of their HIV status , or individuals who are HIV-seropositive but are not taking prophylaxis. Risk factors for Pneumocystis pneumonia are: a low CD4 count—95% of cases occur when the CD4 count is < 200/mm'; or if symptoms such as fever, weight loss or oral Candida are present and the CD4 count is > 200/mm'; or failure of antibiotic prophylaxis. Typically the chest radiograph shows diffuse bilateral interstitial perihilar shadowing (see Fig. 2.19), although 10% of cases have a normal chest radiograph and 10% have atypical features such as focal consolidation or nodular shadows. A pleural effusion and mediastinal adenopathy are both rare in Pneumocystis pneumonia and suggest alternative diagnoses such as mycobacterial infection or Kaposi's sarcoma. Non-invasive investigations, such as arterial oxygen desaturation on exercise
determined by a pulse oximeter or pulmonary function testing lack diagnostic specificity but are helpful at a stage when the chest radiograph may be normal, to confirm that organic pulmonary disease is present. As Pneumocystis carinii does not grow in vitro and sputum production is rare, diagnosis usually requires bronchoscopy and broncho-alveolar lavage or nebulised hypertonic saline-induced sputum. The lung washings reveal cysts of Pneumocystis carinii with silver stain. Giemsa stain can be used to provide rapid provisional diagnosis whereas immunofluorescent techniques with specific monoclonal antibodies have improved sensitivity and specificity. Use of the polymerase chain reaction (PCR) to detect specific genomic sequences of Pneumocystis has extremely high diagnostic sensitivity and specificity but is expensive.
The treatment of choice for Pneumocystis pneumonia is high-dose co-trimoxazole, initially given intravenously. If the patient improves significantly a switch to oral therapy is appropriate and treatment should continue for 3 weeks. Alternative therapies are with dapsone and trimethoprim in combination or clindamycin and primaquine in combination. Intravenous pentamidine is also effective but is not used because of toxic side-effects. At least 90% of patients will respond to treatment. As a general rule, admission to intensive care units and intermittent positive pressure ventilation are avoided in these patients due to the high mortality. It has been shown that treatment with high-dose corticosteroids at the time of admission in patients with Pneumocystis pneumonia who are in respiratory failure reduces morbidity and mortality. Like many of the opportunist infections already discussed, Pneumocystis pneumonia is a relapsing condition and secondary prophylaxis should be offered. Oral treatment with co-trimoxazole or dapsone and pyrimethamine provides good protection against further attacks. Co-trimoxazole is the most effective agent, and primary prophylaxis to
prevent first episodes should be offered to all HIV seropositive patients with a CD4 count below 200/mm3 and all patients with AIDS. Dapsone and pyrimethamine in combination and co-trimoxazole have the added advantage of providing some protection against toxoplasmosis.It is increasingly recognised that respiratory tract infection generally are more common in HIV-seropositive individuals than seronegative, with an increased incidence of colds, sore throats, sinusitis and acute bronchitis. The incidence of bacterial pneumonia is also increased over and above the incidence in a normal population. Illness tends to be more severe but response to appropriate antibiotics is usually good. TB and MAI have been discussed in a previous section, as has CMV. Although frequently isolated from the lung, CMV does not seem to cause pneumonia very frequently.
It is important to make a specific microbiological diagnosis of serious respiratory disease in HIV to allow specific therapy. Attention to which HIV risk group the patient belongs to is important; for example, IVDUs have an increased incidence of pneumococcal infection, whereas homosexual men are at risk from Kaposi's sarcoma. A travel history is also important, particularly if the patient is from high-prevalence areas for TB, pathogenic fungi and Strongyloides. A chest radiograph may show characteristic appearances of Pneumocystis pneumonia but these appearances can be seen with other pathologies. If the CD4 lymphocyte count and HIV viral load measurements are available, these are helpful as, generally speaking, the lower the CD4 count and the higher the viral load, the wider the differential diagnosis.
Non-invasive tests, such as simple lung function tests, are of value in excluding the presence of serious organic pulmonary disease where the chest radiograph is normal, but if these are abnormal then bronchoscopy is frequently indicated.Neurological disease
HIV infects the central nervous system at an early stage in the disease and inflicts damage resulting in clinical diseas HIV can be readily isolated from brain tissue and CSF in high proportion of patients with HIV infection, and at postmortem pathological changes are present in the brain in about three-quarters of patients with AIDS. Neurological symptoms in HIV infection require careful investigation. which often includes CT or MRI, lumbar puncture and electrophysiological studies. Very occasionally, brain biopsy is required. Causes of nervous system disease are listed in Table. Direct effects of HIV infection. During seroconversion following HIV infection, encephalitis may occur with mood change, convulsions or altered level of consciousness. Meningitis may also occur. In late HIV disease, HIV itself can cause aseptic meningitis but, more importantly, causes a diffuse encephalopathy referred to as the AIDS dementia complex (ADC), characterised by cognitive, motor and
|Diseases of the nervous system in HIV infection and their presentation|
behavioural dysfunction. This is the most common neurological complication of HIV infection and affects the majority of AIDS patients to varying degrees. In late AIDS the majority of patients have some degree of dementia even if is mild. Zidovudine has been shown to be effective in cucing the prevalence of AIDS dementia complex. Onset is sually insidious with increasing forgetfulness, loss of entration and loss of cognitive skills, leading to con" apathy, agitation and social withdrawal with ural disturbance. Motor dysfunction normally starts with unsteadiness of gait, weakness of the legs and lack of coordination. Steady decline leads to global dementia with limb weakness and pyramidal tract signs, ataxia and incontinence. Convulsions may occur in late disease. Investigations often show cortical atrophy on CT scan and increased protein and lymphocyte count in the CSF. HIV can also cause myelopathy, contributing to the motor disturbance seen in the AIDS dementia complex. A variety of peripheral neuropathies occur in HIV infection, with the most common being a sensory neuropathy, probably directly due to HIV.
Other neurological disease The most common cause of meningitis is cryptococcal infection; other causes include bacterial infection, tuberculosis, syphilis, other fungal infections and HIV itself. A diffuse encephalopathy may be caused by metabolic disturbance, herpes zoster or simplex, and CMV. Toxoplasmosis is the most common cause of a space-occupying lesion in HIV disease (see p. 163). Less common causes of space-occupying lesions are primary cerebral lymphoma and tuberculosis. CMV most commonly causes choroidoretinitis, presenting with blurring and then loss of vision, which is often unilateral at first. Less commonly, CMV causes encephalitis or radiculopathy. Progressive multifocal loucencephalopathy (PMl) is relatively uncommon and is an opportunist infection caused by the JC papovavirus. This results in damage predominantly to the white matter; the clinical course is more protracted than that seen in toxoplasmosis or lymphoma and a definitive diagnosis can only be made by brain biopsy or at autopsy although specific appearances on gadoliniumenhanced MRI scans are reported. There is no effective treatment. Peripheral neuropathies of various types in addition to those caused by HIV may occur, including autonomic neuropathy. These may be secondary to herpes zoster or CMV infection, or drug-induced-in particular as a result of the use of antiretroviral agents. Finally, myopathy, polymyositis and a dermatomyositis- like illness of undetermined aetiology are seen. Myopathy may also be caused by zidovudine. Autonomic neuropathy is also well recognised in AIDS and may be manifest by postural hypotension and abnormal Valsalva manoeuvre.
The eye. Non-specific conjunctivitis is common in HIV disease. CMV is the most common cause of retinal disease in AIDS. CMV choroidoretinitis can rapidly lead to blindness. Treatment with ganciclovir or foscarnet is successful but maintenance therapy is usually required to prevent relapse. The exudates of CMV retinitis may be confused with the cotton wool spot exudates due to HIV itself. Other causes of retinal disease in AIDS include toxoplasmosis, candidiasis and syphilis.Psychiatric problems
A positive HIV test result can lead to a variety of psychological reactions ranging from anger, guilt and anxiety with panic attacks, through to depression. Patients with HIV infection may present with symptoms of organic brain syndrome due to HIV infection itself. The stress of having HIV infection or AIDS in terms of relationships, work and social life is likely to result in a wide range of affective disorders, with depression being common. Acute psychosis is relatively rare but does occur. More common are mood change, behaviour change and cognitive disorders that herald the AIDS dementia complex.Haematological complications
Idiopathic thrombocytopenic purpura (ITP) can complicate early HIV disease. This is thought to be related to HIV itself and is associated with antiplatelet antibodies. It is usually relatively mild and tends to resolve with the onset of AIDS. Treatment may be required and initially involves high-dose prednisolone or intravenous gammaglobulin. Progressive lymphopenia, in particular a progressive fall in the CD4 count, is the hallmark of HIV infection. Anaemia with or without other cytopenias is extremely common with the onset of AIDS and represents direct bone marrow suppression; it may arise from a wide variety of causes relating to both the infectious and neoplastic complications of AIDS. For example, anaemia may be associated with marrow infiltration due to MAI, M. tuberculosis or lymphoma, chronic blood loss from Kaposi's sarcoma of the stomach or B12 deficiency due to malabsorption as a result of chronic gastrointestinal infections. Finally, many drugs commonly used in AIDS are myelosuppressive-for example, antiretroviral agents, co-trimoxazole and ganciclovir.Renal, cardiac and endocrine disease
HIV-induced nephropathy characterised by glomerulonephritis has been described, but this is relatively uncommon. It is more common in AIDS patients who are intravenous drug users or Afro-Caribbean patients with intrinsic renal disease. However, a large number of nephrotoxic drugs (e.g. amphotericin B, foscarnet, pentamidine) are commonly used in AIDS patients. A variety of cardiac pathologies have been described from post-mortem studies but the most consistent finding is of myocarditis. Clinical cardiac disease is relatively rare in AIDS patients and usually presents as congestive cardiomyopathy or pericardial effusion. Diffuse endocrine gland pathology has been reported from autopsy studies and clinical endocrine abnormalities have been described; these are generally rare but adrenal insufficiency is extremely important to diagnose. CMV frequently causes adrenalitis but clinical adrenal insufficiency, although reported, is rare.Paediatric HIV
Paediatric infection is a direct consequence of heterosexual spread of HIV and of HIV-seropositive mothers. There are three routes of transmission from mother to fetus:
Overall, the risk of materno-fetal transmission of HIV is between 13% and 42% and is twice as common in Africa as in Europe. The risk of infection is increased if the mother has advanced HIV disease, or a low CD4 count and a high viral load, as may be the case if maternal seroconversion occurs during pregnancy or breastfeeding.
As the number of women with HIV infection increases, so will the number of children infected, and prevention is therefore crucial. Universal screening for HIV infection in antenatal clinics is one approach to identifying HIV-infected mothers-to-be. The risk of fetal infection from infected in mothers can be reduced with zidovudine during pregnancy, labour and delivery and for the neonate after delivery. This reduces the overall risk of infection from (in one series) 25% to 8%, a reduction of nearly 70% overall. Caesarean section also reduces the risk by a surprisingly small foctor and further reductions can be achieved by avoiding breast feeding. However, in the developing world this raises problems with the risk of bottle feeding-associated infections.
Early diagnosis of HIV infection in the neonate is complicated by the presence of maternal IgG antibodies which cross the placenta. These antibodies can persist for up to 18 months, making standard antibody tests unreliable Definitive diagnosis therefore relies on viral culture techniques or use of PCR. Generally, a diagnosis before 3 months of age is difficult but a firm diagnosis can usually be made at this time. Transient HIV infection in the neonate has been described and it appears that the virus can, in some rare situations, be cleared. Of infected neonates, about one-quarter develop rapid HIV disease and onset of AIDS within 1 year. The remainder progress more slowly and some children remain well until the age of 8–10 years. However, most have some signs of HIV disease by 6 months of age, and by 1 year 80% have evidence of disease. Age at onset of symptoms predicts for survival and there is a wide spectrum of clinical manifestations. Non-specific features may be present: hepatosplenomegaly, failure to thrive, fever without obvious cause and recurrent gastroen. Between 30 and 50% have early opportunist infections,of which Pneumocystis pneumonia is the most common,and first prophylaxis for this infection is therefore important.Other opportunist infections commonly seen in children are oral Candida, CMV, cryptosporidiosis, TB, MAI, toxoplasmosis and serious bacterial infections. Lymphoid interstitial pneumonitis is relatively common in children but rare in adults; this is due to lymphoid proliferation in the lung interstitium. Presentation is with tachypnoea, hypoxaemia and clubbing; the chest radiograph shows diffuse reticular nodular shadows with hilar adenopathy.Drug interactions
Many of the drugs used to treat AIDS patients are toxic in their own right and this must always be considered. Furthermore, many of these patients require large numbers of different drugs with complex interactions. Since small intestinal disease is relatively common, malabsorption of drugs has been demonstrated and this must be borne in mind.Terminal care
Despite all available treatment, AIDS remains a fatal disease and good support from a partner, family and friends can be of great help during this distressing time. During this phase, good symptom relief is vital and attention to the control of anorexia, nausea, vomiting, dry mouth, dysphagia, pressure areas and diarrhoea is important, as well as effective pain control if necessary. Many patients are anxious or depressed.Dysphagia can be a particular problem and some medications can be given rectally. Intramuscular injections should be avoided as, in addition to being painful, they are difficult to administer; these patients are often wasted with little muscle mass Syringe drivers for subcutaneous or intravenous delivery of antiemetics and opiates can be extremely useful.HUMAN T-CELL LYMPHOTROPIC VIRUS (HTLV) INFECTIONS
There are two other retroviruses, HTLV 1 and HTLV 2, associated with disease in humans.
HTLV 1 is endemic in Japan, the Caribbean and certain areas of West Africa. It is transmitted by blood transfusion, by drug users sharing needles and from mother to child, principally through breastfeeding. It can also be transmitted by sexual intercourse, especially from male to female.
HTLV 1 is associated with adult T-cell leukaemia/ lymphoma and with a degenerative neurological disease characterised by demyelination of the long motor neurons in the spinal cord, known as tropical spastic paraparesis in the Caribbean and HTLV 1-associated myelopathy in Japan. These diseases also occur in Europe and in North America in immigrants from areas of the world where HTLV 1 infection is endemic.
HTLV 2, a much more rarely isolated virus than HTLV 1, has been isolated from Native Americans and in Africa, and also from intravenous drug users in the USA. Its role in nuisease is uncertain: although it was first Isolattu om a case of hairy cell leukaemia, it is infrequently associated with this disease.