AQUIRED IMMUNODEFICIENCY SYNDROME

(AIDS/HIV INFECTION)

Secondary immunodeficiency syndrom is caused by a virus and characterized by severe immune deficiency resulting in opportunistic infections, malignancies, and neurologic lesion in individuals without prior history of immulogic abnormality.

Historic reference

In June 1981 the "Morbidity and Mortality Weekly Report" carried a report of five deaths due to overwhelming Pneumocystis carinii pneumonia in Los Angeles, California. P. carinii has been recognized for many years as a human opportunist infection,infrequently causing life threatening pneumonia in patients with naturally occurring or iatrogenic immunosuppression. Since the development of immunosuppressive regimens for overcoming transplantation rejection, Pneumocystis has been seen in patients with compromised cellular immunity. All of the five patients reported had been homosexual men with no prior illness or history of congenital immunodeficiency, and none had taken know immunosupresive drugs. In December 1981 three reports in the "New England Journal of Medicine" described the medical presentation and laboratory characterisation of a further 20 homosexual men who had died of unexplained immunodeficiency. In every case previously healthy young men ( mean 35 years) had developed overwhelming opportunist infections associated with profound cellular immunodeficiency, or Kaposi's sarcoma, a tumor previously associated with immunosupresion. All the patients had an absolute decrease in the number and proportion of CD-4 T-lymphocytes, and a specific loss of T-cells immunity. The syndrome was initially termed "gay-related immune deficiency" (GRID), but by the end of 1982,cases of this acquired immunodeficiency had been reported in intravenous drug users, female sexual partner of index cases, children of affected women and in heterosexual men and women from Haiti resident in the US. As this disease was clearly not linked exclusively to homosexuality, the term acquired immunodeficiency syndrome (AIDS) was adopted.

The disease was described in homosexual men and intravenous drug users through Europe, South Africa and Australia by the end 1982. Subsequently in 1984 it was reported that heterosexual cases of AIDS were occurring in large numbers in West, Central and Eastern Africa, involving minimally the countries of Zaire, Uganda and Ruanda. The global distribution of cases and the occurrence suggested strongly that the infections agent was responsible for epidemic and, as blood-born transmission was common, it was most likely to be a virus. Two distinct patterns of transmission were observed: pattern 1 was that the blood-

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born agent which was transmitted in a similar manner to the hepatitis  virus and was prevalent in homosexual men, intravenous drug users, their sexual partners and recipients throughout the western world, and had turned the US cases into a pandemic over a very short period. Pattern 2 transmission was more similar to a classical sexually transmitted disease,and approximately equal number of male and female cases were found; pattern 2 transmission predominated in the developing world, in particular in sub-Sahar Africa.

From early 1982 onwards, efforts to identify the causative agent intensified and in may 1983 group from the institute Pasteur in Paris, reported about the isolation and propagation of a T-lymphotropic retrovirus, lymphoadenopathy associated virus, LAV from the lymph node of a patients with persistent lymphoadenopathy, a syndrome know to be assotiated with, and preceding the development of AIDS.

This virus had been fully characterized by 1984 and formally termed the human immunodeficiency virus type 1 (HIV-1) in 1986. Serological assays for antibodies to HIV-1 were widely commercially available by 1985 allowing large-scale sero-epidemiology and screening to be undertaken. Examination of stored sera revealed that HIV-1 had been introduced into homosexual men in the US during 1978,and had not existed in the US priori to that time. Subsequently,a serological variant HIV-2 was identified in West Africa. HIV-2 leads to persistent lifelong infection, and is also associated with the clinical development of AIDS, many years after infections. However, there are reproducible data which show that the likelihood of AIDS developing after HIV-2 infection are lower at 10 years post infection than with HIV-1, and that HIV-2 is generally less pathogenic, and less transmissible, than HIV-1. These epidemiological observation are matched by an apparent lower HIV-2 viral load in peripheral blood than seen in the corresponding time from infection in HIV 1 infected subject, the full-lenght sequencing of HIV-1 and HIV-2 isolates revealed that these viruses were lentiviruses of the retrovirus family, and that all isolated shared a common tropism for T-lymphocytes, through the use of the CD 4 receptor. The emergence of a new infections agent in a human population can have only a limited range of explanation; either the infection was previously in an isolated human population from which it had been exported though some societal change, or else it might have been a zoonosis newly exposed to human transmission. A third line of explanation, that of an extraterrestrial or even a man-made origin, has been popular with conspiracy theorists, but will not be furthers discussed. The natural history of HIV-1 infection is marked by the long period of time between infection and disease.

Etiology

The cause is a retrovirus that has been termed the human T-lymphotrophic virus Type III (HTLV-III), lymphadenopathy-associated virus (LAV), and the AIDS-

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associated retrovirus (ARV) by different laboratories. More recently, it has also been referred to as the human immunodeficiency virus (HIV), the term that will be used here.

Retroviruses are very small viruses composed of a single strong of RNA, the intermediate nucleic acid in the production of proteins. Normally, the flow genetic information starts with a piece of DNA, which makes a piece of RNA, which in turn codes for, protein. Everything flows in that direction.

Retroviruses contain an enzyme called reverse transcriptase that can convert viral RNA in the cytoplasm into DNA, which may replicate from extrachromosomal sites or move into the cell nucleus where it becomes part of the host cell DNA. These integrated viral genes are duplicated with normal cellular genes, and all progeny of the originally infected cell will contain the viral genes. Expression of the viral genes for some retroviruses may be oncogenic, converting the cell into a cancer, or may have other pathologic effects which may alter normal cell function or produce cell death. Retroviruses have been known to cause malignant and nonmalignant diseases, and the same virus may cause different diseases in different animals; e.g., bovine leukemia virus causes à Â cell lymphoma in cows, a T cell lymphoma in sheep, and an immunodeficiency disorder similar to AIDS in rabbits.

There are 3 groups of retroviruses that affect humans, and all have a remarkable affinity for lymphocytes, particularly for T4 lymphocytes. HIV preferentially infects the major subset of T-cells, defined phenotypically as T4 and functionally as "inducer/helper" cells, which are then depleted, resulting in a reduced ratio of T4 helper (Th) to T8 suppressor (Ts) cells. However, the virus also is capable of infecting some nonlymphoid cells, such as macrophages and nervous tissue cells, and presumably remains present for life.

Epidemiology

The major transmission routes of human immunodifficiency virus are sexual contact, parenteral exposure to blood and blood products and perinatal transmission. Early in the AIDS epidemic, epidemiological studies establish that receptive rectal intercourse was the predominant mode of HIV-1 acquisition by homosexual man. Other practices that could traumatize the rectal mucosa appeared to increase further the infection risk for the receptive partner. Insertive rectal sex could also place a men at risk for HIV-1 infection, although the insertive partner would be at lower risk than the receptive partner.

On a world-wide basis sex between man and women apparently is the most common mode of acquiring HIV-1 infection heterosexual transmission accounts for the vast majority of cases. In other country where AIDS cases attributed to heterosexual transmission, although still a small percentage of the total number of reported cases comprise the most rapidly growing category. Therefore an understanding of the rate at which HIV-1 is transmitted between heterosexual couples and of the factors that may impede or enhance heterosexual transmission is important in slowing the worldwide HIV-1 epidemic.

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In the country, where HIV-1 infection is more common in men than women, studies of female-to-male transmission of HIV-1 infection are both fewer and smaller than studies of male-to-female transmission. Available date suggest female-to-male transmission may be less efficient than male-to-female transmission.

Overall these American and European studies suggest that heterosuxual transmission from HIV-infected persons to their regular sex partner is relatively inefficient, especially female-to-male transmission. Furthermore, the risk of heterosexual transmission is not related simply to the number of episodes of sex with HIV-infected person because some people' have remained uninfected after hundreds of such contacts whereas others have become infected after a single episode of intercourse.

Infectivity may be higher during early infection before the development of antibodies to HIV-1, also genital ulcer diseases and inflammation of the genital tract lead to increased susceptibility to HIV infection.

Perinatal or vertical transmission. Mother-to-infant transmission of HIV apparently is relatively efficient; without treatment approximately one in the four infants born to seropositive mothers is infected. With one rapid spread of infection to women of reproductive age perinatal transmission is now a major consequence of HIV epidemic. The precise rate of perinatal transmission in a given setting has been difficult to define because of problems in the infant and the difficulties in maintaining long-term follow-up. Uninfected children born to seropositive mothers may retain passively aquired maternal antibody for 6 to 18 months.

The timing mechanisms, and risk factors for perinatal transmission might occur and guiding the development of effective interventions. These factors include maternal stage of disease maternal antibody response to infection, viral titer, variations in viral genotype and phenotype, and obstetric factors such as preterm birth, mode of delivery, and maternal or placental coinfection. Perinatal HIV transmission can occur both in utero or at birth. Several lines of evidence support the occurrence of human placenta tissue express CD4 receptors and are suseptible to HIV infection. Virus has been isolated from amniotic fluid and has been identified in fetal abortus tissue by culture, PCR and in situ hybridization. However, other investigators have not found HIV in fetal tissue and it is difficult to exclude contamination of these tissues by maternal blood. Clinically, the fact that subsets of infected infants have detectable virus at birth immunologic abnormalities in the neonatal period and rapid progression to AIDS in the first four months of life suggest in the utero transmission. The proportion of infants actually infected in utero and the time during gestation when this is most likely to occur, however, are not known.

Intraportum transmission, analogous to the vertical transmission of hepatitis B, likely occurs through direct contact with maternal blood secretions as the infant is delivered through the birth canal. HIV has been isolated from cervical secretions. Also the virus might be able to pass directly through maternal-fetal

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transfusions, particularly during placental separation at birth. The fact that many infected children are born without detectable virus or immunologic abnormalities supports the likelihood that delivery represents a high risk for HIV transmission. Interestingly there has not been strong evidence that that delivery by caesarean section is protective. However, a recent report based on an international twin registry suggests that being the first of two twins delivered and vaginal delivery are risk factors for infection in twin births. This hypothesis and its relevance for singleton births warrant further study. Although it has not been shown that intrapartum fetal scalp monitoring facilitates transmission, avoiding invasive of the fetus whenever possible, seem prudent.

Postpartum perinatal transmission of HIV through breast-feeding has been reported. Free virus has been found in the cellfree fraction of breast milk and might directly penetrate the infant's gastrointestinal mucosa. However, data from several cohort studies suggest that the additional risk of postpartum transmission is low in pregnant mother already infected with HIV. These finding may result from low viral titers in breast milk of previously infected women, concomitant IgA antibody or some other factor.

Extensive laboratory research and epidemiological studies indicate that HIV is not transmitted by shaking hands, hugging, kissing, contacting bodily secretion such as sweat, mucus (as in sneezing or coughing) or salive. Nor is HIV transmitted by food, swimming at a pools, drinking at a water fountain and also bloodsucking mosquitoes or other arthropods.

Pathogenesis

Following infection across a genital surface, involving infection of CD-4 bearing cells in the mucosa or submucosa, the virus presumably migrates to a regional lymph node, where viral replications occurs. A number of rounds of viral replication than occur within the bounds of the regional lymph node as no detectable virus or immune respons occurs for up to 42 days post infection. When the quantity of infected cells exceeds a threshold,viremia occurs,and the symptoms of an acute non-specific viral illness with tende adenopathy, sore throat, diffuse macular rash, arthralgia and fever. Following the acute viremia, when up to 107 viral particles/mL plasma can be found, a primary immune response develops with antibodies to viral proteins and a cytotoxic T-cells response, which limit viral replication and clear viral particles from the plasma. The reduction the viral load in plasma is not matched by a clearance of provirus in peripheral blood mononuclear cells, and cellular viremia continues in the face persistent and sustained cellular and humoral immune response for the duration of the infection. Even while plasma viral load is suppressed by the immune response, CD-4 T-Iymphocyte number foil in linear manner over time. The most plausible explanation for the pathogenesis of AIDS over time is the sustained less CD-4 cells by ongoing HIV viral replication in nature peripheral blood T-cells

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and by a slight failure of production of match peripheral destruction of HIV CD-4 cells. However, recent controversy over the pathogenic mechanisms and homestasis of T-cells has revealed that simple viral cytopathic effect on CD-4 cells may be overly simplistic model.

During the course of HIV infection, CD-4 cells continue to decline in peripheral blood and plasma viral load slowly rises. Over a definite period CD-4 cells number declines from 800 to 200 mL; at this level, the probability of the cellular immune system containing latent or environmental infections such as P. carinii falls and clinical opportunist infection becomes* increasingly possible. As the viral 1 retrovirus load rises. HIV isolates with altered co-receptor usage appear which can use the CXCR-4 chemocine receptor rather than CCR-5; these isolates are more cytopathic in vitro, and may lead to wider tissue distribution of HIV in later disease, AIDS is therefore, the clinical condition of an immune system which is sufficiently compromised by HIV infection that there is an inability to protect against the growth of low grade pathogenes or viral indeced tumors.

The fact that this virus, after infection of the host, besides destroyed strong immune system also can spread to many body tissues. The ultimate outcode of the infection depends on the host's immune reaction to the virus either through suppression of HIV replicationor through killing of the infected cell. In some individuals an active immune system has prevented development of the disease for years. The factors important in maintaining this immune response are not yet know and merit close attention. The immune deficiency produced by HIV infection makes patients suseptible to infection by a variety of organisms, including viryses, bacteria, fungi and parasites that are of low pathogenecity in the normal individual and of variable prevalence in different part of the world. In some individuals the immune system appears to make enhancing antibodies to HIV and this phenomenon occurs particularly with progression of disease. It is related to change to antibodies made and in some cases to modifications in the virus so that is more sensitive to enhancing antibodies. Moreover, the immune system can hyperreact, with production of antibodies that might also hasten the development of disease. Clearly changes in the virus and the immune response of the host play important roles in the ultimate steps leading to AIDS.

Anatomic pathology

Forty to sixty percent of AIDS patients develop neurologic dysfunction and up to 90 % have neuropathology changes at autopsy. HIV itself can cause brain disease manifested as meningoencephalitis, mild cognitive dysfunction, or frank dementia. It is felt that the pathogenesis of this neurologic damage is related to the presence of infected tissue macrophages that may release viral proteins or cytokines that result in brain dysfunction, inflammation, and tissue destruction. In this regard, studies of brain tissue from AIDS patients have shown that the predominant cell type infected with HIV is the monocyte/macrophages (M/M).

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Infected M/M m'ay release factors resulting in reactive glial cell growth, and, because glial cells have been shown to be infectable with HIV in vitro, infected brain M/M may provide a source of infectious HIV to these glial cells. The HIV envelope protein can inhibit neuronal growth in vitro; this may be due to competition between neuroleukin and gpl20 for binding to the neuroleukin receptor, because there is partial sequence homology between these two proteins. It is possible, but not yet demonstrated, that infected M/M in the brain may release large quantities of gpl20 resulting in the inhibition of neuronal growth.

A wide variety of hematologic abnormalities occur in HIV-infected individuals including pancytopenia and myelodysplasia. Although the etiology of these multiple abnormalities has not been completely delineated, it has been shown that the CD34+ bone marrow myeloid progenitor cell can be infected with HIV in vitro with the resultant production of large amounts of predominantly intracellular virus and minimal cytopathic effects. More recently, CD34+ cells isolated from the bone marrow of some infected individuals have been shown to be infected with HIV. Whether these precursor cells produce large amounts of virus in the bone marrow in vivo and the potential contribution of these cells to the hematologic abnormalities observed are currently unknown. Infected macrophages within the bone marrow have been reported to produce factors, presumably cytokines, which appear to suppress hema-topoiesis through their effects on the CD34 + precursor cell. Whether bone marrow macrophages are an important reservoir of HIV has not been definitively determined.

Finally, cells of the monocytic lineage that populate other organs are susceptible to infection with HIV and may contribute to pathogenesis of disease at these sites. Specifically, lung alveolar macrophages, Kopffer cells of the liver, and peritoneal macrophages are infectable in vitro with HIV, and alveolar macrophages from HIV-infected individuals are clearly infected in vivo. It is currently unknown whether these cells contribute to tissue-specific disease, such as the diffuse pulmonary fibrosis that occurs frequently in pediatric AIDS patients

Clinical manifestations

The time from exposure to HIV until the onset of the acute clinical illness is typically 2 to 4 weeks, although longer incubation period have been reported. The clinical illness is acute in onset and lasts from 1 to 2 weeks. It can be associated with an appreciable degree of morbidity and patient may require hospitalization. The main clinical features of primary HIV infection reflected both the lymphocytopatic and neurologic tropism of HIV. Patients report fever, lethargy, fatigue, headaches, retro-orbital pain, sore throat, muscular pain, occasional diarrhea, maculopustular rash and the onset of swollen lymph nodes (swollen glands). Meningoencephalitis may also occur. Lethargy and malaise are frequent, often severe and may persist for several months after resolution of the other clinical manifestations of primary HIV infection. Lymphoadenopathy (Fig. 15) develops

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in approximately 70 % of persons, generally in the second week of the illness and usually concomitant with the development of peripheral lymphocytosis,reflects the fact that HIV has activated B-lymphocytes to become plasma cells and secrete HIV antibodies.

The lymphoadenopathy may be generalized, but the occipital, axillary and cervical nodes are most commonly involved. The lymph node enlargement persist after the acute illness bat tend to decrease with time. Splenomegaly has also been reported. The mechanism for this splenomegaly is not apparent; it may be related to increased clearance of virally infected lymphocytes. The most frequently reported dermatologic evidence of primary. HIV infection is an erythematous, nonpruritic maculopapular rash. This rash is generally simmetric, with lesions 5 to 10 mm in diameter, and affects the face or trunk, but it can also affect the extremities including the palms and soles, or can be generalized. Other skin lesions noted during primary HIV infection include a roseola-like rash, diffuse urticaria,vesicular,pustular exanthema and enanthema,desquamation of the palms and soles and alopecia. Mucocutaneous ulceration is a distinctive feature of primary HIV infection. Ulcer have been reported on the buceal mucosa, gingiva, or palate, esophagus, anus, and penis. They are generally round or oval and sharply demarcated, with surrounding mucosa that appears normal. The tongue of patient showing the characteristic symptoms of thrush. Note the milk-white flakes of C. albicans on the tongue surface. An unexplained incident of thrush is often considered an early sign that HIV infection is present. Patients also experience weight loss of as much as 10 % of baseline body weight or more. Constant low-grade fever at about 37.3-37.8 °Ñ and diarrhea extending over several weeks. In addition, the fatigue may be so overwhelming that patients cannot lift their heads from the pillow on waking in the morning. One of the most troublesome aspects is the night sweats. Individuals perspire so heavily at night that the bed linens and nightwear become drenched with sweat. Saturation can be extensive enough to require linen changes,and sleep is fitful at best. Few other microbial diseases are accompanied by such heavy sweating.

The isolation of HIV from cerebrospinal fluid (CSF) during primary HIV infection indicates that infection of the central nervous system (CNS) occurs soon after exposure. Elevated neopterin and p2-microglobulin levels have also been found in CSF during primary HIV infection both in individuals with and without clinical meningitis, suggesting that the cellular immune system in the CNS may be activated during this stage even without the development of overt neurologic symptoms or signs. The most common neurologic symptoms are headaches, retro-orbital pain (particularly during eye movement) and photophobia. Several cases of aseptic meningoencephalitis during primary HIV infection have been reported.

Prolonged infection with HIV is often completely asymptomatic; however, a minority of patients complain of nonspecific constitutional symptoms in the month or years after primary infection. Patients commonly complain of being

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easily fatigued and report the need to reduce their normal activities somewhat. In patients with more advanced HIV disease and severe de pletion of CD4 cells, constitutional disease may primarily reflect immunosupression or may herald the onset of opportunistic infections or malignancies. Patients with progressive constitutional symptoms should be evaluated carefully for opportunistic pathogens. A history of respiratory, neurologic, gastrointestinal and dermatological symptoms should be elicited and a thorough physical examination completed.

In the late stages of HIV infection when immune defenses have been severely compromised and systemic complications have begun to accumulate, the nervous system becomes highly susceptible to a wide array of disorders involving all levels of the neuraxis, including meninges, brain, spinal cord, peripheral nerve, and muscle.

Several disorders may involve the leptomeninges in patients with advanced HIV disease, with symptomatology ranging from mild headache to severe disability with hydrocephalus and cranial nerve palsies. Among the true meningitides a syndrome of aseptic meningitis, presumably relating to direct HIV infection of the meninges, can occur acutely in the setting of seroconversion as described above, but it is more common in patients with advanced HIV infection. The cerebrospinal fluid (CSF) shows mild mononuclear pleocytosis, usually with normal or mildly depressed glucose and slightly elevated protein levels. The presumption that this conditions is due to direct HIV infection of the meninges related to two observations: the virus can be isolated from the CSF, and no other cause has been identified.

The most important meningeal infection in HIV infected patients is caused by seemingly uncommon in HIV infected patients. Meningeal involvement by syphilis in HIV infected individuals may take form of acute meningitis or meningovascular syphilis.

Systemic lymphoma complicating HIV infection may secondarily to the central nervous system involving the meninges, clinical manifestation may be cryptic but usually include cranial nerve palsies, head aches, or increased intracranial pressure.

From an early stage it become clear that the nervous system was frequently involved in HIV infected patients. Among the severe and life-threatening infections experienced by those with immune deficiency were brain abscesses due to toxoplasmsis. As other neurologic manifestations emerged without signs of recognizable opportunistic infection it became clear that HIV was probably directly neurotropic as well as lymphotropic.

Toxoplasma gondii is an obligate intracellular parasite for which the primary host is the cat. Humans may acquire it from the cat by the fecal-oral route in man primary infection is usually asymptomatic unless congenitally acquired. The organism forms cysts in all tissues which persist for life and are the source of recrudescent infection in the compromised host. Infection in the brain is usually multifocal as old encysted parasites become actively pathogenic again. The clinical

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presentation may be focal or diffuse but is a cerebrovascular accident, but is more usually progressive aver a few days or a week or two.

Peripheral neuropathies of several types can complicate the various stages of HIV infection. Early in the course of HIV infection a Guillain-Barre type of neuropathy may be seen. The clinical picture is the same as the familiar acute inflammatory or postinfectious neuropathy, with weakness of limb and facial muscles, minor sensory symptoms and loss of tendon reflexes. The weakness tends to be both proximal and distal. There may be backache and limb pains. There is evidence that the axonal neuropathy in the late stages of the disease

correlated with the presence of dementia. Its ethnology is unknown, but it has been suggested that it may be a direct effect of HIV.

The most prevalent opportunistic disease among persons with HIV in late stage is Pneumocystis carinii pneumonia. Chagas initially in 1906 considered P. carinii with trypanosome. Subsequently it was reclassifiedby the Delanoes as parasite. Recently, however, studies of ribosomal RNA of P. carinii have shown that phylogenetically the organism is most closely related to the Ascomycetes (yeasts): thus P. carinii should probably be considered a fungus rather than a parasite. This reclassification has little clinical relevance but may suggest new therapeutic approaches and culture techniques. P. carinii is thought to have a life cycle consisting of three stages: cyst, whish are spherical or crescent-shaped form 5 to 8 mm in diameter; sporozoites or intracystic bodies, found only within the cyst; and tropozoites, found outside the cyst and believed intermediate between the sporozoite and the cyst. The Giemsa stain is taken up by both the intracystic sporozoites and extracystic tropozoites; cyst are not pozitively stained and cannot be seen except as negative images within the matrix of a clump of tropozoites. Infection with P. carinii is common early in the life and dose not generally results in symptomatic disease in immunocompetent hosts. Until the occurrence of the epidemic of infection with the HIV P. carinii pneumonia was an uncommon, sporadic disorders that occurred primary in patient with leukemia or other recognized causes of impairment of host defences and in patients who were given immunosuppressive therapy. Several studies in the United States have shown that circulating antibodies to P. carinii develop in most children by age 2 to 3 years, leading to the conclusion that asymtomatic infection with P. carinii is nearly universal at least in the areas where these studies were conducted. Patients with P. carinii pneumonia usually have had non-specific symptoms such as fever, fatigue, and weight loss for weeks to months before developing respiratory symptoms and often have other HIV-related disorders that indicate severe immunosupression. The most common presenting symptoms of P. carinii pneumonia are fever, nonproductive cough, and progressive shortness of breath. In patient with P. carinii pneumonia chest radiographs most often show diffuse interstitial infiltration involving all portions of the lungs. Several variations may be seen. The infiltration may be heterogenously distributed throughout the lung, or it may be miliary in appearance.

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Diffuse or local air-space consolidation may also be noted. In patients who are being given aerosol pentamidine prophylaxis, focal upper lole infiltration are relatively common. Cystic changes or pneumatoceles may occur, especially during the healing process, and cavitation withing pre-existing nodular lesions has been described. Probably as a result of the cystic or cavitary processes, spontaneous pneumothorax may occur. Pleural effusion and intrathoracic adenopathy are very uncommon with P. carinii pneumonia.

Since the beginning of the HIV epidemic an increasing association of Mycobacterium tuberculosis infection with HIV infection has been noted. Between 1978 and 1985 the yearly rate of tuberculosis more than doubled at one New York City hospital. Although the pathogenesis of most HIV associated tuberculosis appears to involve reactivation of latent M. tuberculosis infection, the clinical presentation is generally typical of reactivation tuberculosis only for those patients whose immune function is still relatively intact, whereas that of patients with HIV is much more typical of progressive primary tuberculosis. Only one-third to one halt of HIV-associated tuberculosis is confined to the lungs. The most frequent radiographic manifestations of pulmonary tuberculosis in patients with HIV are (1) hilar or mediastinal adenopathy or both and (2) localized infiltrates limited to the middle or lower lung fields. Pulmonary cavitation is rarely seen. The classic radiographic picture of apical infiltrates in the absence of hilar or mediastinal adenopathy has been reported in less than 10 % of HIV-associated cases. One half to two thirds of HIV-related tuberculosis involves extrapulmonary sites (with or withoutpulmonary involvement). Peripheral lymph nodes and bone marrow are the extrapulmonary biopsies but rarely in pulmonary biopsies. Other extrapulmonary sites that have revealed M. tuberculosis include urine, blood, bone, joint, cerebrospinal fluid, liver, spleen, skin, gastrointestinal mucosa and ascites fluid. Two extrapulmonary tuberculosis syndromes described in HIV patients are of particular interest: M. tuberculosis bacteremia and central nervous system mass lesions. On the other hand, tuberculosis in patients with otherwise asymptomatic HIV infection usually is clinically similar to tuberculosis in immunocompetent hosts.

The association of disseminated Mycobacterium avium complex (MAC) infection with HIV was recognized early in the HIV epidemic. Disseminated MAC infection has been reported only rarely in patients without HIV. Disseminated MAC infection occurs exclusively in patients with very advanced HIV disease essentially only in patients with CD4 lymphocyte counts<100/mL. MAC is a ubiquitous soil and water saprophyte. The source of MAC invasion in HIV patients may be gastrointestinal or respiratory. The presence of large clusters of mycobacterium within macrophagas of the small bowell lamina propria suggests the bowel wight be the portal of entry. However, respiratory isolation of the MAC also frequently precedes disseminated infection, suggesting MAC infection may begin in the lungs as well. Since most HIV patients with disseminated MAC

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infection have other concomitant infections or neaplasms and since MAC appears to cause little histopathologic evidence of inflammatory response or tissue destruction,the relationship between constitutional symptoms,organ dysfunction, and MAC infection has been uncertain.

Four clinical syndromes often overlapping, have been associated with disseminated MAC infection.

- Systemic symptoms. Fever, malaise, weight loss often associated with anemia, neutropenia.

- Gastrointestinal symptoms.

- Chronic diarrhoea and abdominal pain (MAC infection of colon often observed at autopsy).

- Chronic malabsorbtion (histopatologic changes in small intestine similar to those with Whipple's disease often observed at autopsy).

- Extrabiliary obstructive jaundice secondary to peri portal lymphadenopathy.

Cryptococcus neaformans and tuberculosis are the major opportunistic

infection complicating the HIV epidemic world-wide. Although other pathogens may dominate on individual continents or in specific regions, no other major pathogen poses as great a global threat to those immunocompromised by HIV infection. The high mortality and morbidity rates associated with cryptococcal infection and the toxicity of traditional therapy have sparred intense interest in new treatment alternatives. A better understanding of the natural history of HIV-mediated immunodepression has seen the emergence of debate about the use and advisability of fungal prophylactic. This organism a common resident of the lung, is often inhaled from the air. It grows actively in the droppings of pigeons and enters the air in wind borne particles. The fungus is generally noninfectious,but in patients with HIV it multiplies in the lungs,spreads to the blood and localized on the brain and its coverings. The clinical presentation of cryptococcal disease in HIV patient is often subtle and nonspecific. A prolonged febrile prodrome, indistinguishable from that accompanying other opportunistic infections is common. Frequently no localizing signs or symptoms are present to guide the physician toward the diagnosis of cryptococcal disease. Although the portal of entry for C. neoformans is the lung. Pulmonary cryptococcosis is usually clinically. Most cases of pulmonary cryptococcal infection are discovered serendipitously, not because of organ specific signs or symptoms. Occasionally, however, pulmonary symptoms dominate the clinical presentation and progression to respiratory failure and death are not unknown. However, among those HIV-infected patients with cryptococcal disease and without CNS involvement, fully two thirds had cough and shortness of breath. In contrast only 18 % of those patients with culture-proven CNS disease had respiratory symptoms. These numbers add weight to the argument that all patients with CNS involvement have or have had antecedent pulmonary infection. Blood-borne spread to any organ, but the organism has a predilection for the CNS. It causes a granulomatous

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meningitis with or without clinically evident pulmonary or disseminated infection. In addition, there may be small cysts in the cerebral cortex. The clinical presentation is usually with headache, fever, and constitutional upset; neck stiffness, photophobia and focal neurologic signs are present.

Skin disease is an extremely common complication of HIV infection, affecting up to 90 % of persons. Some of the skin conditions also are commonly seen in uninfected persons (e.g. seborrheic dermatitis) but are of increased severity in the HIV infected person. Other skin diseases are relatively unique to HIV infection (Kaposi's sarcoma). The average HIV infected patient has at least two and often more different skin conditions simultaneously. It is useful to classify the cutaneous disorder seen with HIV disease as either infectious disorder, hypersensitivity disorders and drug reactions, or neoplasms.

Oral lesions have been recognized as prominent features of HIV infection since the beginning of the epidemic. Some of these changes are reflections of reduced immune function manifested as oral opportunistic conditions, which are often the earliest clinical features of HIV infection. Some, in the presence of known HIV infection are highly predictive of the ultimate development of the full syndrome, whereas others represent the oral features of AIDS itself. The particular susceptibility of the mouth to HIV disease is a reflection of a wider phenomenon. Oral opportunistic infections occur in a variety of conditions in which the teeming and varied microflora of the mouth take advantage of local and systemic immunologic and metabolic imbalances.

They include oral infections in patients with primary immunodeficiency, leukemia, and diabetes, and those resulting from radiation therapy, cancer chemotherapy and bone marrow supression. In the prospective cohorts of HIV infected homosexual and bisexual men hairy leukoplakia is the most common oral lesion, and pseudomembranous candidiasis is next most common.

Kaposi's sarcoma (KS) in patients with AIDS produces oral lesions in many cases. The lesions occur as red or purple macules, papules, or nodules. Occasionally the lesions are the same color as the adjoining normal mucosa. Although frequently asymptomatic, pain may occur because of traumatic ulcerisation with inflammation and infection. Bulky lessions may be visible or may interfere with speech and mastication. Diagnosis involves biopsy. Lesions at the gingival margin frequently become inflamed and painful because of plaque accumulation.

From the very outset of the HIV epidemic, cliniciane everywhere noted a high prevalence of the gastrointestinal (GI) signs and symptoms. Some of these manifestation such as weight loss, dysphagia, anorexia, and diarrhoea are almost universally among patients with HIV. Early and complete invasive and noninvasive evulation of these patients should be undertaken with particular attention to treatable non-HIV-associated biliary tract disease. Hepatic parenchymal disease likewise is common in patient with HIV infection.

Cramping paraumbilical abdominal pain, weight loss (Fig. 16) and large-volume diarhea are common in patient with HIV disease. The majority of HIV

Aquired immunodeficiency syndrome

patients with these complaints has specific small bowel infection. Certainly routine colonic bacterial pathogens such us Salmonella, Shigella and Campylobacter, which may be persistent and mimic chronic inflammatory bowel disease, should be excluded by the adequate culture techniques. Likewise,routine and atypical parasitic infestation including that caused by Giardia lamblia, E. histolytica, Criptosporidium and /. belli must be excluded. Colonic diarrhea usually is associated with frequent small volume stools,left lower quadrant or suprapubic cramping, rectal urgency (tenesmus), and proctalgia and dyskenesia (painful defecation). On occasion a small amount of bright red blood may be noted. Once again, in the majority of these patient with diarfhea of colonic origin, specific bacterial and parasitic pathogens can and should be easily isolated by careful analysis of the stool. In addition some patient may have classic herpetic perianal ulceration which can be diagnosed by specific viral culture of swabs taken directly from the perianal area. CMV proctocolitis has been described as having sigmoidoscopic features suggestive of focal ishemic colitis that is submucosal hemorrhages and discrete shallow ulceration of distal colonic mucosa. Once again, obtaining specific biopsy specimens for histology and viral culture is indicated. Even in the absence of focal or diffuse colonic mucosal changes, biopsy specimens should be taken for histologic evaluation to look for the occasional patient with Cryptosporidium whose stools have been negative for this organism.

On occasion, patients with HIV may suddenly develop ascites. Since some HIV-infected patient may have underlying cirrhosis (caused by either alcohol consumption or viral hepatitis), a sizeable percentage of them will have transudative ascites related to their chronic liver disease. Careful evaluation of the ascites fluid, including performing cytology, and acid-fast stains should be done early to exclude patients with malignancy and tuberculosis peritonitis.

Malignancies as a complication of immunodeficiency have been well described in the literature, being recognized long before the advent of the HIV epidemic. The incidence of both Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) are marked by increased in immunosuppressed allograft recipients. It is therefore not suprising that patients with HIV infection, who also have proformed defects in cell-mediated immunity also develop these two malignancies. KS once a rarely reported malignancy is the most common neoplasm affecting HIV-infected individuals (Fig. 17, 18). It is seen primarily in homosexual men and has only rarely been reported in intravenous drug users or other risk groups. The pathogenesis of KS and HIV-infected patients remain uncertain. The natural history of KS associated with HIV infection more closely resembles that observed in immunosuppressed allograft patients. The disease tends to progress with time and is associated with the appearance of larger and more numerous cutaneous lesions. However, the course of the disease is unpredictable. A patient may have relatively few lesions that remain stable over time. New cutaneous lesions may not appear for many months but may be followed by a sudden and rapid increase

346 Infectious diseases

in disease activity. Visceral involvement with KS is extremely common and can involve almost any visceral site. Careful endoscopic examination will reveal gastrointestinal sites of disease in most patient. Athough KS is usually not a direct cause of death in HIV-infected, the morbidity associated with more advanced disease with more advanced disease can be significient.

Cutaneous lesions may become painful and if large cutaneous surfaces are involved can restrict movement. Lymphatic obstruction is common and can result in severe edema, most commonly involving the extremities or the face. Visceral spread of KS is rarely symptomatic, particularly when it involves the gastrointestinal tract. Careful examination of the skin and oral cavity at each clinic visit is the key to early diagnosis. Once lesions are identified, histologic confirmation should be obtained.

The non Hodgkin's lymphomas are a heterogenous group of malignancies. Their biologic behavior ranges from indolent requiring no therapy,to aggressive malignancies with few long-term survivors. In the most commonly used classification system for the NHL, these malignancies are divided into three major categories: low grade, intermediate grade, and high grade, according to pathologic characteristics of involved lymph nodes and morphologic criteria of the lymphoma cells.

The first cases of NHL in homosexual men were reported in 1982 and increasing numbers of cases have been reported since that time. The finding of an intermediate or high-grade B-cel! NHL in an HIV-infected individual constitutes an AIDS diagnosis as defined by the Centers for disease control. Advanced extranodal disease is commonly found at presentation, and median survival times have been short.

Infection with the HIV is associated with a wide spectrum of hematologic abnormalities. These abnormalities are found in all stages of HIV disease and involve the bone marrow,cellular elements of the peripheral blood and coagulation pathways. The cause of these abnormalities is multifactorial. A direct suppressive effect of HIV infection, ineffective hematopoiesis, infiltrative disease of the bone marrow,nutritional deficiencies,peripheral consumption secondary to splenomegaly or immune dysregulation, and drug effect all contribute to the variety of hematologic findings in these patients. Many of these abnormalities are clinically significant, whereas others are more of academic interest.

Peripheral cytopenias are common in HIV-infected individuals and are due to either decreased production in the bone marrow or accelerated destruction in the peripheral circulation. In general the cytopenias increase in frequency as HIV-disease progresses. Anemia is the most common hematologic abnormality noted in patients with HIV disease. The largest HIV infection affects the lymphocyte, neutrophil and macrophage monocyte cell lines. Despite the hyperhammahlobulinemia noted in these patients, they suffer complications from both defective cellular immunity and dysregulated humoral immunity. The hallmark of HIV infection is progressive depletion of the CD-4 lymphocytes. This decrement

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presumably occurs through direct viral invasion of these cells. Early in HIV infection an initial increase in the CD-4 population occurs before a decline in the number of CD-4 cells is noted. Granulocytopenia independent of drug use is noted in approximately 50 % of patients with HIV. Drug-induced neuthropenia is in the HIV-infected individual. Medication used to treat infection such as P. carinii pneumonia, toxoplasmosis and cytomegalovirus retinitis or colitis cause neuthropenia. Similarly, ridovudine is implicated as a cause of neuthropenia, often necessitating dose reduction or cessation of teraphy. As for the complication of neuthropenia, most documented infection involve gram-negative organisms. The most common platelet abnormality found in HIV-infected patients is thrombocytopenia have only minor submucosal bleeding, characterized by petechiae, echymoses and occasional epistaxis. Rare patients have gastrointestinal blood loss. Laboratory findings reveal that patients generally have isolated thrombocytopenia, which usually is not accompanied by anemia and leukopenia. Patients with HIV infection, including those being treated with antibodies for an AIDS-opportunistic infection and those being treated with cytotoxic chemotherapeutic agents for HIV-related malignancies, may also develop thrombocytopenia secondary to a therapeutic intervention. In these patients severe thrombocytopenia should be managed as it is in the non-HIV-infected individual. Medications causing thrombocytopenia should be discontinued and platelet transfusion should be administered when indicated.

Diagnosis

The first test developed to detected HIV infection was isolation of the virus through tissue culture. Unfortunately although sensitive for viral isolation the tissue culture procedure is expensive, time consuming and labor intensive. As a result soon after the initial discovery of HIV several tests were developed using protein products of the newly discovered virus to detect antibodies produced by the infected host. The two antibodi tests used most commonly are the enzyme-linked immunosorbent assay (ELISA) and the western blot. In addition to being less expensive, faster and easier to perform than viral culture, the ELISA and the Western blot test do not require working with like virus and therefore are safer. Over the best some years several novel techniques have been developed. The radioimmunoprecipitation assay (RIPA) is a more time consuming, and labor intensive test the Western blot, yet it provides much finer resolution of the high-molecular-weight envelope proteins than the western blot test. The RIPA is considered more sensitive and specific than the Western blot test, however, the time, expense, and need for active cell lines and radioactive materials make the RIPA a poor choice for routine testing in commercial laboratories. Rather its use is best reserved for difficult-to-diagnose cases. Like the RIPA the indirect immunofluorescence assay (IFA) requires preparation of HIV antigens that are expressed on infected cells and are stained subsequently. Infected cells are

348 Infectious diseases

placed on the glass slides in a fixed monolayer and are incubated with patient serum. Anti-HIV antibodies present within the serum bind to antigens expressed on the surface of cells, and these bound antibodies are then detected with anti-human antibody that has been labeled with fluorescein isothiocyanate an ultraviolet-activated dye compound, after appropriate processing, the slide is viewed under a fluorescent microscope and the number of cells the intensity of staining and the staining pattern are assessed. Polymerase chain reaction (PCR) technique, introduced in the late 1980s, represent a major advance in the diagnosis of many disorders, including HIV infection. This powerful technique can amplify DNA existing in very small quantities through a series of binary replicative cycles. The PCR procedure can also be applied to RNA.

The pool of human lymphocytes possesses specific glycoproteins of their surface that play an important role in the cells activity and function CD-4 positive lymphocytes are the primary target of HIV infection, and the CD-4 receptor is the primary binding site of HIV. Throughout the course of chronic HIV infection the number of CD-4 lymphocytes is depleted and the loss of these cells is associated with development of the characteristic opportunistic infection and malignancies of AIDS. Thus the measurement of CD-4 positive lymphocytes is one of the most impotent determinates for clinically staging the disease status of HIV infected patients. In uninfected controls normal values for the CD-4/CD-8 ratio are 2.0 to 1.0. Normal values for CD-4 counts are generally 500 to 1,000 cells/mL3 in adults.

Differential diagnosis

The differential diagnosis of the acute retroviral syndrome includes a number of other illnesses: infectious mononucleosis; other viral infections such as influenza, measles, rubella, and herpes simplex; and secondary syphilis. Evaluation of patients presenting with an illness consistent with acute retroviral infection should include a careful history to elicit risks for HIV infection, laboratory tests to rule out mononucleosis and syphilis, HIV antibody and antigen tests, and complete blood counts and differential. Sequential HIV antibody tests may need to be performed over several months to confirm the diagnosis.

The differential diagnosis of persistent generalized lymphadenopathy (PGL) includes HIV infection and a wide variety of other processes that are associated with generalized lymphadenopathy: sarcoid, secondary syphilis, and Hodgkin's disease, for example. In patients with HIV infection, lymphadenopathy may also be caused by mycobacterial infections, KS, and lymphoma. In patients with clinical findings suggesting opportunistic disease, needle aspiration of lymph nodes may help establish a specific diagnosis. Examination of aspirates with cytologic, acid-fast, and Gram stains is valuable in identifying infection or malignancy. If a specific diagnosis is not determined after staining and culture of node aspirates, then lymph node biopsy is indicated. Aspiration of lymph nodes in patients with PGL usually reveals

Date: 2014-12-21; view: 874