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A C inical Manifestations of HIV Infection OPPORTUNISTIC INFECTIONS The deleterious effects inflicted on the immune system following HIV infection result in life-threatening opportunistic infections characterized by an aggressive clinical course, resistance to therapy, and a high rate of relapse. Opportunistic infections are the most common presenting clinical manifestations that ultimately lead to a diagnosis of AIDS (see Appendix E). The clinical recognition of these infections requires a high degree of suspicion, a familiarity with the many complexities of AIDS-related infections, and expert microbiological assistance. Treatment of the varied AIDS-related opportunistic infections is as complex as their diagnosis. The duration of therapy is frequently long, and drug toxicities are seen much more often than when the same anti- biotics are used in other patient populations. Protozoal Infections Pneumocystis carinii Pneumonia Pneumocystis carinii pneumonia (PCP) is the most common AIDS- related opportunistic infection in U.S. patients, accounting for over 50 percent of all initial AIDS diagnoses. Patients with PCP typically com- plain of fever, cough (usually nonproductive or productive of clear to white sputum), shortness of breath and dyspnea on exertion, and chest 281
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282 APPENDIX A tightness. Some or all of these symptoms are seen in approximately 80 percent of patients at the time of diagnosis. The time course between onset and medical evaluation is variable, ranging from several days in some cases to as long as two or more months in others (Kovacs et al., 1984). At the time of PCP diagnosis, the chest X-ray is usually abnormal. More than 95 percent of cases show some increase in bronchovascular/ interstitial markings. These infiltrates are typically diffuse. Pleural effu- sions are distinctly uncommon, and if seen suggest a secondary process. Similarly, mediastinal adenopathy is uncommonly associated with PCP alone (Catterall et al., 19851. Identification of the organism is required before a diagnosis of PCP can be made. Tissue diagnosis can be made using several techniques. Initially, transbronchial biopsies were performed in most individuals, but broncho- alveolar ravage either with or without bronchoscopy is nearly as sensitive and is less invasive (Broaddus et al., 1985; Ognibene et al., 19841. In addition, induced sputum has been increasingly used to make a diagnosis. Sputum must be examined with particular care to find PCP organisms, but this procedure avoids more than 50 percent of invasive procedures (Bibgy et al., 19861. Serologic testing is not sufficient for the diagnosis, and empiric therapy should be avoided in most cases because of frequent drug toxicity. The treatment of PCP consists of either trimethoprim-sulfamethoxazole or pentamidine isothianate (Hughes et al., 19781. However, toxicities are common with these drugs (Gordin et al., 1984), therapy must be longer than in other settings, and there is a high rate of relapse (Haverkos, 19841. Because conventional therapy is only partially elective with PCP, and because PCP is the most common direct cause of death in AIDS, there is currently a great deal of interest in identifying additional effective therapies. Trials are being conducted with dapsone (Hughes and Smith, 1984) and difluoromethoornithine (DEMO). Trials of prophylaxis using trimethoprim-sulfamethoxazole are also being conducted (Kaplan et al., 19861. Toxoplasma gondii Toxoplasmosis is one of the most common causes of central nervous system (CNS) disease in AIDS (Luft et al., 1984; Navia et al., 1986; Wong et al., 19844. It is also one of the most treatable AIDS-related opportu- nistic infections. Clinical features of CNS infection with Toxoplasma gondii include seizures, focal necrologic deficits, and encephalopathy. Because serologic testing for Toxoplasma is insensitive and nonspecific, diagnosis requires tissue confirmation. However, the morbidity of brain
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APPENDIX A 283 biopsy dictates that this is often not performed. Instead, many clinicians attempt empiric therapy in patients strongly suspected of having CNS toxoplasmosis. A diagnosis of T. gondii infection of the CNS can be suspected when a patient with AIDS or in an AIDS risk group complains of seizures or focal necrologic deficits (Luft et al., 19841. Although encephalopathy can be seen with toxoplasmosis, it is more suggestive of HIV-related encepha- lopathy. The diagnosis of Toxoplasma CNS infection can be confirmed by computerized tomography (CT) scanning or magnetic resonance imaging (MRI) procedures. These typically show multiple lesions deep in the brain tissue with ring enhancement. These lesions are nearly diagnostic for toxoplasmosis in this population, and the only common alternative diagnosis considered is CNS lymphoma. Therapy for toxoplasmosis is currently limited to a combination of pyramethamine and sulfadiazine with folinic acid. Response to therapy is generally prompt, with improvement on radiologic imaging seen within two weeks in most cases. However, relapses at some point after therapy are nearly universal. Also, drug toxicity is common and includes skin rashes, neutropenia, and thrombocytopenia. There is no standard second- line drug for the treatment of toxoplasmosis, but clindamycin is occasion- ally attempted. After a two- to three-week course of sulfadiazine-pyramethamine, CT or MRI scanning can be repeated. If substantial regression of previously noted lesions has occurred, this is taken as presumptive evidence of the diagnosis. If, on the other hand, the disease is stable or worse, a brain biopsy can be performed to evaluate the possibility of other problems, including CNS lymphomas. Cryptosporidium Cryptosporidium is a unicellular coccidian parasite that produces a self-limited diarrhea in animals, travelers, and veterinarians. In AIDS patients, infection instead produces sustained, profuse diarrhea, often associated with malnutrition, malabsorption, and significant weight loss (Soave et al., 1984~. Organisms are occasionally found in the lungs or gallbladder. Recognition of Cryptosporidium in stool requires special techniques. No effective therapy for Cryptosporidium infection has been found in animal studies or human clinical trials to date. Drugs found ineffective include trimethoprim-sulfamethoxazole, iodoquinol, metronidazole, quin- acrine, pentamidine, paramomycin, and tetracycline. Occasional clinical or parasitologic response to furazolidone have been encountered, but relapse occurs. Spiramycin, a macrolide antibiotic not commercially
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284 APPENDIX A available in the United States with an antimicrobial spectrum similar to that of erythromycin, has been reported to be effective in uncontrolled trials (Collier et al., 1984), but this was not substantiated in one controlled trial. Further controlled studies of this agent are under way. DEMO has been used with differing results (Soave et al., 1985), though bone marrow toxicity, especially thrombocytopenia, has been commonly noted (Rolston et al., 19851. Isospora belli Isospora bell), another invasive coccidian parasite, produces a severe diarrhea clinically indistinguishable from that caused by Cryptosporidium in patients with AIDS (Whiteside et al., 19841. Oocysts are large but may evade detection in stool examination, even with special techniques. Trimethoprim-sulfamethoxazole or furazolidone were reported to be effective in a few cases, but relapse occurred after discontinuation (Westerman and Christensen, 19791. Fungal Infections Candida Oral candidiasis (also known as thrush) is a very common infection in people with AIDS and at high risk for AIDS. The presence of thrush in high-risk patients without AIDS is strongly predictive of the subsequent development of a serious opportunistic infection (i.e., the development of AIDS) (Klein et al., 19841. However, only invasive esophageal candi- diasis meets the Centers for Disease Control (CDC) surveillance defini- tion of AIDS (see Appendix E). There have been no treatment trials for either thrush or Candida esophagitis in AIDS, so treatment recommendations must be based on clinical experience and the results of treatment trials in other im- munocompromised populations. Clotrimazole is commonly used to treat oral candidiasis in immunosuppressed non-AIDS patients and has been shown to be superior to placebo. Nystatin, the agent most commonly employed in patients who are not immunocompromised, has been only marginally effective in immunocompromised hosts. Candida esophagitis may be asymptomatic, and most, but not all, patients will have thrush. Treatment options include nystatin and keto- conazole. Candidemia is rarely encountered, but treatment would be no different than that for other populations, using amphotericin B for disseminated disease.
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APPENDIX A 285 Cryptococcus The meninges are the sole site of cryptococcal infection in 75 percent of the cases seen in AIDS patients, though simultaneous or isolated infec- tions of the blood, lungs, or other sites occur (Zuger et al., 19861. Cryptococcal antigen and/or culture are positive at the site of infection in over 90 percent of patients. In meningitis, cerebrospinal fluid (CSF) is otherwise normal in more than 50 percent of AIDS patients (Kovacs et al., 1984), a much higher percentage than with non-AIDS patients with cryptococcal meningitis. There are no comparative trials of treatment for cryptococcal infections in patients with AIDS. However, in small series evaluated retrospectively, clinical failure and relapse are more frequent than in other immunosup- pressed populations. In large, multicenter series evaluating treatment of cryptococcal meningitis in non-AIDS patients, amphotericin B in combina- tion with 5-fluorocytosine achieved a better rate of cure and faster CSF sterilization than did amphotericin B alone given for a longer time. Intravenous amphotericin B in combination with 5-fluorocytosine is the standard initial therapy for cryptococcal infection in patients with AIDS. Total doses administered vary widely, and dose does not appear to correlate with outcome. A convenient oral therapy for suppression after initial treatment and also for the treatment of isolated pulmonary Cryptococcus infection is much needed. Ketoconazole alone or in combination with other antifungal agents is efficacious in the laboratory and in animal studies. However, prospective trials are needed to establish the role of ketoconazole in the treatment of cryptococcal infection in patients with AIDS. Bacterial Infections Mycobacterium tuberculosis Tuberculosis is seen with increasing frequency in groups at risk for AIDS, typically preceding the actual diagnosis of AIDS by several months (Louie et al., 19851. In Haitian patients infected with Myco- bacterium tuberculosis, disseminated disease was found in 80 percent of patients with AIDS, whereas it was found in 20 percent of infected Haitians without AIDS (Pitchenik et al., 19841. Response to standard antituberculosis therapy is usually good. Mycobacterium avium-intracellulare Mycobacterium avium-intracellulare is a frequent isolate in blood, sputum, urine, and feces of AIDS patients and is found at multiple sites in
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2SS6 APPENDIX A about half of AIDS patients in whom postmortem evaluation is done (Zakowski et al., 19821. This infection is usually identified late in the course of AIDS, in association with fever, wasting, and fatigue, but often without the failure of specific organ systems despite their involvement. Many other AIDS-related infections and/or neoplasms are often present simultaneously. In non-AIDS patients with Mycobacterium avium-intracellulare, dis- semination is rare and treatment of pulmonary disease with multiple drugs or surgery is sometimes elective. Most strains of the bacterium are resistant to standard antituberculosis drugs. However, most isolates from AIDS patients have demonstrated in vitro sensitivity to two experimental agents: ansamycin, a rifamycin S derivative, and clofazimine, a dye derivative used to treat leprosy. Various combination therapies are also under evaluation, but further investigation of therapeutic agents is sorely needed. Since Mycobacterium tuberculosis is a treatable disease in patients with AIDS and ARC, disseminated mycobacterial disease is probably best treated initially with triple drug therapy until cultures are available. If the patient has shown amelioration of systemic symptoms, some physicians would maintain that fame regimen even if infection with Mycobacterium avium-intracellulare is documented. Others would treat with ansamycin with or without clofazimine, and still others would try four to six drugs chosen from INH, rifampin, ethambutol, an injectable aminoglycoside, ethionamide, and cycloserine. More specific recommen- dations cannot be made at this time. If the patient is premorbid or is asymptomatic, many would recommend no treatment to avoid drug toxicity. Pulmonary colonization alone does not necessitate treatment, but close observation for potential disseminated infection is warranted. Salmonella Infections Several recent reports have disclosed 14 cases of bacteremic Salmo- nella infections in AIDS and ARC patients. In the cases in New York and Washington, D.C., all were due to Salmonella typhimurium, an infre- quent cause of Salmonella sepsis in other populations. Infections were severe, with sustained stool carriage and recurrent septicemia in some patients, despite therapy with antibiotics to which the organisms were sensitive in vitro (Glaser et al., 1985; Jacobs et al., 1985; Smith et al., 1985). In California, five cases of Salmonella dublin, a Salmonella species closely linked to dairy cattle products such as raw milk, have been reported in AIDS patients. Recurrent bacteremia has been the rule with this infection as well.
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APPENDIX A 287 Pyogenic Bacteria Pyogenic infections are relatively uncommon in AIDS patients but do contribute to morbidity and mortality. Serious pneumococcal infections may be more common in AIDS patients than in the hospital population at large, and failure to respond to pneumococcal vaccine has been docu- mented. Viral Infections Herpes Simplex Virus A severe cutaneous herpes simplex virus (HSV) infection that persists for more than four weeks is considered diagnostic of AIDS. Such an infection may occur initially or be an ongoing problem throughout the course of an AIDS illness. Other identified types of herpes infections include severe orofacial herpes, encephalitis, myelitis, and pneumonia. There are neither studies of the natural history nor comparative treatment trials of these viral infections in AIDS or ARC. Acyclovir used topically, intravenously, and orally reduces viral shedding and enhances the healing of cutaneous lesions in other immunocompromised popula- tions (Epstein, 19831. Oral and intravenous acyclovir are also effective prophylaxes against recurrence in immunocompromised patients. Herpes Zoster Localized cutaneous zoster (shingles) is frequently encountered in patients with AIDS and ARC. However, there are no natural history studies of the relative severity of disease, the frequency of dissemination, or the incidence of postherpetic neuralgia. Disseminated disease and zoster encephalitis have been encountered. Since most AIDS patients with herpes zoster are not sick enough to warrant hospitalization, treatment with intravenous acyclovir is best reserved for patients with cutaneous or visceral dissemination or systemic symptoms. Cytomega1/ovirus Serologic evidence of cytomegalovirus (CMV) infection is almost universal in homosexual men with AIDS and ARC. At bronchoscopy, more than one-third of patients have evidence of colonization by CMV, although histologic evidence of invasive disease is rare. In a small prospective study, the presence of CMV had no effect on the survival of
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288 APPENDIX A AIDS patients with Pneumocystis carinii. CMV can be associated with symptomatic retinitis, adrenalitis, colitis, and encephalitis. To date no commercially available therapies are effective. A nucleoside analog, dihydroxymethyl propoxymethylguanine, has excellent in vitro activity against replication of CMV. The drug is currently undergoing clinical trials in AIDS patients, and preliminary results are encouraging (Bach et al., 1985; Felsenstein et al., 1985; Masur et al., 19861. Other Infections in Members of Risk Groups Given the large number of people in the United States infected with HIV, infections other than those considered diagnostic of AIDS are certain to occur. It can be very difficult to establish a direct relationship between these other medical problems and HIV-induced immune defi- ciency. This is especially so with certain infectious diseases that were well known to occur in members of AIDS risk groups prior to the introduction of HIV in those communities. In the case of IV drug users, these diseases are principally hepatitis B virus infection and endocarditis from a variety of organisms. So far, clinical or laboratory patterns of these infections and their response to conventional therapy do not seem to have changed. Like IV drug users, homosexual and bisexual men have frequently been affected by infectious diseases. For example, they have a high incidence of sexually transmitted diseases (Rein, 1986), including gonorrhea, syph- ilis, genital herpes virus infections, genital warts, and bacterial and parasitic infections of the large bowel (Quinn, 19861. Although changes in life-styles of homosexual men in response to the AIDS epidemic have reduced the frequency of new diagnoses of sexually transmitted diseases in this group in recent years, they remain common. Apart from sexually transmitted diseases such as persistent genital HSV infection, the relationship of other common infections to underlying cellular immune deficiency is unclear. In some instances, however, the features of such infections are suspected of having changed in people infected with HIV. Salmonellosis, for example, while not previously uncommon in homosexual men, is nonetheless being seen with increased incidence. In contrast to previous experience, it is increasingly resistant to drug therapy and typified by frequent relapses. Although evidence is still lacking, the fear remains that the delta agent may spread more readily in both homosexual men and IV drug users, given established chronic cases of hepatitis B and cellular immune deficiency. Because infectious diseases are a common feature of at least two of the major AIDS risk groups independent of the AIDS epidemic, it may be extremely difficult to establish any direct connection between HIV
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APPENDIX A 289 i] nfection and these other infections. Nevertheless, surveillance mecha- nisms should continue to record these other infections, particularly to find any evidence suggesting alterations in their clinical presentation or response to therapy. MALIGNANCIES AND OTHER NEOPLASTIC DISEASES Kaposi's Sarcoma Before 1981, Kaposi's sarcoma was a distinctly uncommon cancer in the United States, and it had not previously been seen in healthy young adults. Its recognition in young homosexual men in mid- 1981 was therefore an early and obvious alert that a new disease had arrived. Today, Kaposi's sarcoma remains a common and vie reminder of AIDS. ~.. ~ I-~1A _;- ~+ Throughout the AIDS epidemic, Kaposi's sarcoma has played an important role as an easily monitored clinical marker of the underlying immune deficiency. For this reason, plus the fact that Kaposi's sarcoma patients are frequently less severely immunocompromised than other AIDS groups, Kaposi's sarcoma has been the focus of many clinical therapy trials. Kaposi's Sarcoma in Non-AIDS Populations Prior to 1981, Kaposi's sarcoma, when seen, was limited to several groups, including elderly American men (especially those of Mediterra- nean descent), black Africans, and individuals with severe exogenous immunosuppression such as renal allograft recipients. While reports of Kaposi's sarcoma therapy in the elderly and African groups have little relevance to current cases in AIDS patients, Kaposi's sarcoma in renal transplant patients mimics the disease in AIDS patients. In both, Kaposi's sarcoma is often, though not always, an aggressive malignancy with extensive visceral spread; in both, opportunistic infections are common. Perhaps the most striking observation, however, is that in renal allograft patients Kaposi's sarcoma often regresses completely after the with- drawal of immunosuppressive drugs. This suggests that in AIDS-related Kaposi's sarcoma, drug-induced immune restoration might control the cancer. It also implies that Kaposi's sarcoma may, in the future, be useful as a clinical marker of the response to immunologic therapy. Not all groups of AIDS patients are at equal risk of developing Kaposi's sarcoma. For reasons as yet unclear, Kaposi's sarcoma is much more frequent in homosexual men than in other AIDS patients (Cohn and Judson, 1984; Des Jarlais et al., 19841. Infection of homosexuals with
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APPENDIX A 293 Toxoplasmosis, which was previously a rare opportunistic infection of the brain, is frequently seen in AIDS patients, where it appears as multiple abscesslike lesions. Cryptococcal meningitis is the second most common opportunistic infection of the central nervous system in AIDS and is most commonly seen in Africa. Disseminated herpesvirus infections of the nervous system (herpes simplex, varicella poster, and cytomegalovirus) are seen less commonly. Progressive multifocal leukoencephalopathy, an otherwise rare demyelinating disease caused by papovavirus infection of oligodendrocytes, has occurred in patients with unprecedented fre- quency. A variety of other bacterial, viral, and fungal infections have also been reported (Snider et al., 19831. Tumors of the central nervous system in patients with AIDS have largely been primary CNS lymphomas. Secondary lymphomas and met- astatic Kaposi's sarcoma have occurred much more rarely. Metabolic encephalopathies associated with pulmonary, hepatic, and renal failure are found postmortem in approximately 10 percent of AIDS patients (Navia et al., 19861. Although many of these infections and tumors have unusual presenta- tion, five years of experience with AIDS have sharpened clinical evalu- ations and diagnoses and have allowed more timely and effective treat- ments, particularly for toxoplasmosis and cryptococcal meningitis. Aseptic Meningitis Healthy seropositive persons and ARC patients sometimes experience a self-limited aseptic meningitis. Though of minor clinical importance, this illness may have major significance in relation to disease pathogen- esis. On several occasions, it has been noted at the time of seroconver- sion, and the virus has been isolated from cerebrospinal fluid (Cooper et al., 1985; Ho et al., 1985~. Symptoms include fever, headache, meningeal signs, and in some cases cranial nerve palsies. Cerebrospinal fluid shows a mononuclear cell pleocytosis and protein elevation. This may represent HIV's initial invasion of the central nervous system. The frequency of its subclinical occurrence in HIV-infected persons is not known. Subacute Encephalitis Dementias that are sufficient to be detected by objective psychological tests and that are associated with subacute encephalitis appear to occur in over 50 percent of patients with AIDS. In a New York study, after excluding patients with metabolic encephalopathies and opportunistic infections, 46 of 70 AIDS patients had clinical evidence of dementia. This
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294 APPENDIX A correlated with the severity of the subacute encephalitis found at autopsy in over 80 percent of the cases (Navia et al., 19861. In the majority of cases, the cerebrospinal fluid shows an elevation of protein and mild pleocytosis with a striking reversal of the CD4 to CD8 ratio. Computerized tomography shows cortical atrophy and enlarged ventricles. Magnetic resonance imaging, which has been limited, may show remarkable white matter abnormalities. Multiple abnormal signals from white matter have been seen even in ambulatory, minimally affected patients. A diffuse abnormal signal in white matter may be present in patients with full-blown dementia. Despite the severity of clinical disease and the dramatic findings on imaging studies, histopathologic changes are remarkably subtle. There is a diffuse pallor of white matter, perivascular infiltrations of lymphocytes and macrophages, and, in more advanced cases, multinucleated cells. These pathologic changes have been noted to be most striking in the white matter, basal ganglia, and temporal areas (Navia et al., 1986~. The dementia in children born with lIIV infection frequently shows a more striking clinical course and pathology. During early development, they fail to thrive, develop microcephaly, and suffer from seizures, blindness, and abnormal movements. Their brains show decreased vol- ume with gross atrophy, many microglial nodules and multinucleated cells in the white matter, and vascular calcifications (Epstein et al., 1985b; Sharer et al., 19861. Myelopa thy Vacuolar myelopathy is found in approximately 20 percent of patients with AIDS. Clinically, this correlates with the development of progres- sive paraparesis accompanied by ataxia, spasticity, and incontinence. Pathologic vacuolar degeneration of myelin is found in the dorsal and lateral columns without inflammation (Petito et al., 19851. Peripheral tieuropathies Involvement of the peripheral nervous system takes three forms in AIDS. Many patients develop a severe painful sensory neuropathy with electrophysiologic characteristics indicative of axonal degeneration. The pathology of this neuropathy is undefined but may involve dorsal root ganglia. A second painful, less common multifocal neuropathy appears to be related to a vasculitis with multifocal nerve infractions. This has been found in patients with both AIDS and ARC. Third, a group of patients, none with AIDS but seropositive and often with various signs of ARC, have developed acute or subacute demyelinat
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APPENDIX A 295 ing neuropathies resembling Guillain-Barre syndrome. These patients have been found to recover spontaneously or may respond to plasma- pheresis. This has been postulated to represent an autoimmune phenom- enon during a time of immunologic deregulation occurring prior to the onset of clinically apparent immunosuppression as manifested in clinical AIDS. In addition to the demyelination normally seen in the Guillain- Barre syndrome, this disease shows a strikingly greater degree of inDam- mation and vacuolar changes in cells than is the case with usual demy- elinating neuropathies (Cornblath et al., in press). HIV Infection of the Nervous System HIV has been isolated from the nervous systems of AIDS and ARC patients with necrologic syndromes with remarkable consistency. Levy et al. (1985) recovered virus from the spinal fluid of 13 of 14 AIDS or ARC patients, including one without necrologic symptoms. Ho et al. (1985) recovered virus from at least one spinal fluid or tissue specimen from 24 of 33 AIDS patients. These specimens included spinal fluid isolates from 6 of 7 patients with chronic meningitis, the brains of 6 patients with dementias, the spinal cord of one patient with myelopathy, the spinal fluid from one patient who had an acute meningitis at the time of seroconver- sion, and a peripheral nerve of one patient with demyelinating neu ropathy. Further evidence for the direct replication of HIV in the brain comes from the demonstration of intrathecal antibody synthesis in patients. Comparisons of antibody levels in serum and in cerebrospinal fluid indicate antigenic stimulation within the nervous system (Resnick et al., 1985). Initial in situ hybridization studies have also demonstrated that cells within the microglial nodules contain the RNA from HIV. Viral DNA sequences have also been found in brains by Southern blot analysis, where they occurred in greater quantities than in the spleen, lymph nodes, liver, or lung (Straw et al., 19851. These findings establish that the virus is present in the nervous system and that its presence correlates to some degree with necrologic disease. They fail to identify, however, whether the virus is in neural cells or in cells of hematogenous origin within the brain (Johnson and McArthur, 19861. Cellular Localization of HIV Electron microscope studies have demonstrated apparent virus parti- cles within multinucleated cells, probably of macrophagic origin. In one
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296 APPENDIX A case, particles resembling virus were also seen within astrocytes, but the failure to find budding particles leaves open the possibilities that these were phagocytosed (Epstein et al., 1985a). A variety of studies have now been done with immunocytochemical staining for viral antigen, followed by double staining to identify cells with cell markers or in situ hybridization. In summary, all have shown low numbers of infected cells and a predominance of viral antigens and viral nucleic acids in macrophages within perivascular inflammatory responses (Gabuzda et al., in press; Koenig et al., 1986; Pumarola-Sune et al., in press; Wiley et al., in press). Several of these studies note that the presence of the virus in perivascular cells is more prominent in the white matter. Most of these studies have also found some infected parenchymal cells. The most interesting and disparate findings are those of Wiley et al. (in press), who used immunocytochemistry together with in situ hybridiza- tion to find involvement in 9 of 12 cases of capillary vascular endothelial cells of the brain. This finding could be of major importance in terms of the virus's mode of entry, the potential pathogenesis of the diffuse white matter lesions, and the development of future therapeutic strategies. Studies by Pert (1986) have attempted to map CD4 cell receptors in the brain of humans, monkeys, and rats. She has found the antigen to be predominantly in the outer layers of the cortex and in the hippocampus. The presence of these receptors is interesting, but their location fails to correlate with that of the histopathologic distribution of the viral antigens. Unsolved Problems The timing and frequency of nervous system infection by HIV is not known. The isolations of HIV with aseptic meningitis at the time of seroconversion raise the grim possibility that the virus may invade the nervous system very early in many patients. This is reminiscent of syphilis, where pathogenic organisms may invade the nervous system early but remain latent until disease develops up to 30 years later. How much time elapses between involvement of the central nervous system and the development of the subacute encephalitis with dementia also remains unknown. Clearly, this has broad implications for the use of therapeutic immunomodulators, which could improve hematologic pa- rameters and clear systemic infections but have little effect on an ongoing or latent infection within the central nervous system. It also has major implications for the use of drug therapies. If vascular endothelial cells are the primary site of infection, the systemic administration of drugs may be effective; if rare neurons or glial cells are involved, it may not. The pathogenesis of the CNS lesions is also mysterious. Imaging
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APPENDIX A 297 studies suggest widespread severe white matter disease, but the histologic findings are subtle and the number of cells with evidence of HIV infection is very small. This does not appear to be analogous either to acute infections such as poliomyelitis, where selective infection of specific cells (the motor neurons) leads to paralysis, or to chronic infections such as progressive multifocal leukoencephalopathy, where oligodendrocytes harbor vast amounts of replicated papovavirus and are lysed, causing demyelinating disease. Instead, complex and indirect pathogenic mecha- nisms may be involved. For instance, recent studies of visna virus (Kennedy et al., 1986; Narayan et al., 1985) suggest that small amounts of visna virus in rare macrophages can cause the induction of a novel interferon, which in turn induces the expression of an Ia antigen on neural cells. This then evokes an inflammatory and demyelinating disease, despite a paucity of virus. PEDIATRIC AIDS Clinical Features and Diagnosis The clinical manifestations of AIDS in children are significantly dif- ferent from those in adults. In one series they included failure to thrive (65 percent), recurrent bacterial infections (43 percent), persistent candidiasis (70 percent), generalized lymphadenopathy (74 percent), recurrent (31 percent) or protracted (33 percent) diarrhea, hepatosplenomegaly, lymphadenopathy, parotitis (14 percent), interstitial pneumonitis (59 percent), chronic otitis media (48 percent), and encephalopathy. Kaposi's sarcoma (19 percent) and B-cell lymphoma occur but are less frequent than in adults (Parks and Scott, 19861. In a minority of infants the same types of infections are seen that have been described in adults. Almost a third (32 percent) of AIDS cases in children have Pneumocystis carinii pneumonia. Candida esophagitis occurs in 22 percent of cases, and disseminated cytomegalovirus infection is found in 24 percent. On the other hand, disseminated cytomegalovirus was a well-known perinatally acquired infection before the emergence of HIV and, therefore, is not very specific evidence of AIDS. Even though Kaposi's sarcoma is found in some pediatric cases, the lesions are located in lymph nodes as opposed to the skin in adults. The lesions are usually found only at autopsy and thus are not of diagnostic help in caring for the patient. In general, pediatric AIDS is characterized by the occurrence of unusually severe infections in a child without the presence of predispos- ing factors, such as congenital immunodeficiency or antineoplastic che- motherapy. Recurrent infection is by far the most frequent AIDS-related
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298 APPENDIX A syndrome in the pediatric age group. In addition to oral and esophageal candidiasis resistant to the usual therapies and recurrent viral infections (including herpetic stomatitis, varicella/herpes poster, condyloma, and molluscum contagiosum), children frequently suffer from bacterial infec- tions. In this regard, infections in children are different from those in adults, in whom bacterial infections are much less frequent. Bacterial infections seen include recurrent pneumonia, bacterial sepsis (especially with Streptococcus pneumonias and Haemophilus influenzoe), and chronic draining otitis media. Infants who are born infected tend to be small for gestational age and are usually symptomatic by six months of age. Recently, a specific phenotypic appearance of young infants with AIDS has been described, which suggests early in utero spread (Marion et al., 19861. Infants who are transfused with contaminated blood during the first year of life may be clinically well from one to four years before developing clinical symptoms. Diagnostic Criteria The conditions that have been listed above are similar to many that are usual in the general pediatric practice. What is unusual is that these problems are extremely severe and persistent in patients with AIDS. Lymphadenopathy with associated failure to thrive appears to be the most common finding. Once the clinician's suspicion of the possible diagnosis of AIDS has been aroused, the appropriate laboratory tests should be ordered. The laboratory results will differ depending on whether they are performed early (before there are definitive clinical findings) or late (after one or more of the clinical findings previously described has occurred). The earliest finding is that of a positive test for HIV antibodies, usually made using the ELISA test. This result must be confirmed with the Western blot test. Where the antibody test is positive, there is a very good chance that the virus will be isolated. A common finding is a polyclonal hypergammaglobulinemia, which results from increased stimulation of B cells and/or decreased suppression by T lymphocytes. Usually this involves IgG, but sometimes also IgA and IgM. Some patients may have hypogammaglobulinemia. In the later stages of the disease, the laboratory findings are consistent with a deterioration of T-lymphocyte function along with one or more of the clinical syndromes already described and HIV positivity. Children tend to have levels of lymphocytes higher than those seen in adults or older patients, presumably because children normally have much higher levels of lymphocytes than do adults. Special testing may reveal that CD4 cells have been depleted relative to CD8 cells, producing an inverted
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APPENDIX A 299 T-lymphocyte subset ratio. This finding, in combination with polyclonal increase in IgG levels, is sufficient for laboratory confirmation of a tentative or presumptive diagnosis of AIDS in an infant. In addition to n~ v, a variety of other viruses are often present, including hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and DANA A4_~^~^V ~ ~ AN __ 7 _ J ~ ~ herpes simplex. When there is severe disease, there may oe a negative HIV antibody test. It is important to exclude other congenital immunodeficiency syn- drc~mes. such as the Nezelof syndrome or combined immune deficiency , my. .. .- ~ 1 ._ ~ _1~ 1 =_1:~ LEA 1~, syndrome. 'line combination OI selected cllnlt;~ ~;~ Beau ~a~l"~l, results provides the physician with a presumptive diagnosis of AIDS in infants. But it has become clear that it is impractical to try to make the diagnostic criteria for AIDS in children fit those of adults. It seems that grouping the clinical findings into different syndromes may be the most elective way to recognize clinical AIDS when Kaposi's sarcoma and opportunistic infections do not occur. Because most clinicians still try to use the adult diagnostic criteria to diagnose AIDS in small children, this disorder is underreported in the pediatric age group. Additional work is needed to further clarify the natural history of AIDS in children. REFERENCES Bach, M. C., S. P. Bagwell, N. P. Knapp, K. M. Davis, and P. S. Hedstron. 1985. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine for cytomegalovirus infections in patients with the acquired immunodeficiency syndrome. Ann. Intern. Med. 103:381-382. Bigby, T. D., D. Margolskee, J. L. Curtis, P. F. Michael, D. Sheppard, W. K. Hadley, and P. C. Hopewell. 1986. The usefulness of induced sputum in the diagnosis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Am. Rev. Respir. Dis. 133:515-518. Broaddus, C., M. D. Dake, M. S. Stulbarg, W. Blumenfeld, K. Hadley, J. A. Golden, and P. C. Hopewell. 1985. Bronchoalveolar ravage and transbronchial biopsy for the diagnosis of pulmonary infections in the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:747-752. Catterall, J. R., I. Potasman, and J. S. Remington. 1985. Pneumocystis carinii pneumonia in the patient with AIDS. Chest 88:758-762. Cohn, D. C., and F. N. Judson. 1984. Absence of Kaposi's sarcoma in hemophiliacs with AIDS. N. Engl. J. Med. 101:401. Collier, A. C., R. A. Miller, and J. D. Meyers. 1987. Cryptosporidiosis after marrow transplantation: Person-to-person transmission and treatment with spiramycin. Ann. Intern. Med. 101:205-206. (banner n A.. J. Gold P. Maclean, B. Donovan, R. Finlayson, T. G. Barnes, H. M. ~~~r~ Michelmore, P. I3rooke, and x. Penny. EYES. ACule Al~O r~-vV1tU~ i~il~tlvll. ~llill~lVI' of a clinical illness associated with seroconversion. Lancet 1:537-540. Cornblath, D. R., J. C. McArthur, and J. W. Griffin. In press. Inflammatory demyelinating peripheral neuropathies associated with AIDS retrovirus infection. Ann. Neurol. Des Jarlais, D. C., M. Marmor, P. Thomas, M. Chamberland, S. Zolla-Pazner, and D. J.
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300 APPENDIX A Sencer. 1984. Kaposi's sarcoma among four different AIDS risk groups. N. Engl. J. Med. 310:1119. Drew, W. L., R. C. Miner, J. C. Ziegler, J. H. Gullett, D. I. Abrams, M. A. Conant, E.-S. Huang, J. R. Groundwater, P. Volberding, and L. Mintz. 1982. Cytomegalovirus and Kaposi's sarcoma in young homosexual men. Lancet II:125-127. Epstein, E. 1983. Acyclovir for immunocompromised patients with herpes zoster. N. Engl. J. Med. 309:1254. Epstein, L. G., L. R. Sharer, E.-S. Cho, M. Myerhofer, B. A. Navia, and R. W. Price. 1985a. HTLV-III/LAV-like retrovirus particles in the brains of patients with AIDS encephalopathy. AIDS Res. 1:447-454. Epstein, L. G., L. R. Sharer, V. V. Joshi, M. M. Fojas, M. R. Koenigsberger, and J. M. Oleske. 1985b. Progressive encephalopathy in children with acquired immunodeficiency syndrome. Ann. Neurol. 17:488-496. Felsenstein, D., D. J. D'Amico, M. S. Hirsch, D. M. Cederberg, P. de Miranda, and R. T. Schooley. 1985. Treatment of cytomegalovirus retinitis with 9-[2-hydroxy-1-(hydroxy- methyl)ethoxymethyl]guanine. Ann. Intern. Med. 103:377-380. Gabuzda, D. H., D. D. Ho, S. M. de al Monte, M. S. Hirsch, T. R. Rota, and R. A. Sobel. In press. Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS. Ann. Neurol. Glaser, J. B., L. Morton-Kute, S. R. Berger, J. Weber, F. P. Siegel, C. Lopez, W. Robbins, and S. H. Landesman. 1985. Recurrent Salmonella typhimurium bacteremia associated with the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:189-193. Gordin, F. M., G. L. Simon, C. B. Wofsy, and J. Mills. 1984. Adverse reactions to trimethoprim-sulfamethoxazole in patients with AIDS. Ann. Intern. Med. 100:495-499. Haverkos, H. W. 1984. Assessment of therapy for Pneumocystis carinii pneumonia. Am. J. Med. 76:501-508. Ho, D. D., T. R. Rota, R. T. Schooley, J. C. Kaplan, J. D. Allan, J. E. Groopman, L. Resnick, D. Felsenstein, C. A. Andrews, and M. C. Hirsch. 1985. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N. Engl. J. Med. 313:1493-1497. Hughes, W. T., and B. C. Smith. 1984. Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonia. Antimicrob. Agents Chemother. 26:436. Hughes, W. T., S. Feldman, S. C. Chaudhary, M. J. Ossi, F. Cox, and S. K. Sanyal. 1978. Comparison of pentamidine isothionate and trimethoprim-sulfamethoxazole in the treat- ment of Pneumocystis carinii pneumonia. J. Pediatr. 92:285-291. Ioachim, H. C., M. C. Cooper, and G. C. Hellman. 1985. Lymphomas in men at high risk for acquired immune deficiency syndrome (AIDS). A study of 21 cases. Cancer 56:2831-2842. Jacobs, J. L., M. W. M. Gold, H. W. Murray, R. B. Roberts, and D. Armstrong. 1985. Salmonella infections in patients with the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:186-188. Johnson, R. T., and J. C. McArthur. 1986. AIDS and the brain. Trends Neurosci. 9:91-94. Kaplan, L. D., R. Wong, C. Wofsy, and P. A. Volberding. 1986. Trimethoprim-sulfa- methoxazole (TMP-SMZ) prophylaxis of Pneumocystis carinii pneumonia (PCP) in AIDS. P. 53 in Abstracts of the Second International Conference on AIDS, Paris, June 23-25, 1986. Kennedy, P. G. E., O. Narayan, Z. Ghotbi, J. Hopkins, H. E. Gendelman, and J. E. Clements. 1986. Persistent expression of Ia antigen and viral genome in visna-maedi virus-induced inDammatory cell s . J. . Exp . Med. . 162: 1970- 1982. Klein, R. S., C. A. Harris, C. B. Small, B. Moll, M. Lesser, and G. H. Friedland. 1984. Oral candidiasis in high risk patients as the initial manifestation of the acquired immunodefici- ency syndrome. N. Engl. J. Med. 311:354-358.
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APPENDIX A 30) Koenig, S., H. E. Gendelman, M. C. DelCanto, M. Yungbluth, G. H. Pezeskpour, T. Folks, M. Martin, H. C. Lance, and A. S. Fauci. 1986. Detection of AIDS retroviral RNA in nonlymphoid cells in the brain of an AIDS patient with encephalopathy. Clin. Res. 34:722A. Kovacs, J. A., J. W. Hiemenz, A. M. Macher, D. Stover, H. W. Murray, J. Shelhamer, H. C. Lane, C. Urmacher, C. Honig, D. L. Longo, M. M. Parker, C. Natanson, J. E. Parrillo, A. S. Fauci, P. A. Pizzo, and H. Masur. 1984. Pneumocystis carinii pneumonia: A comparison between patients with acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann. Intern. Med. 100:663-671. Levy, J. A., J. Shimabukuro, H. Hollander, J. Mills, and L. Kaminsky. 1985. Isolation of AIDS-associated retrovirus from cerebrospinal fluid and brains of patients with neuro- logical symptoms. Lancet II:586-588. Lou~e, E., L. B. Rice, and R. S. Holzman. 1985. Mycobacterium tuberculosis (Mtb) infection in patients with AIDS. P. 38 in Abstracts of the International Conference on AIDS, Atlanta, Gal, April 14-17, 1985. Luft, B. J., R. G. Brooks, F. K. Conley, R. E. McCabe, and J. S. Remington. 1984. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 252:913-917. Marion, R. W., A. A. Wiznia, G. Hutcheon, and A. Rubenstein. 1986. Human T-cell lymphotropic virus type III (HTLV-III/LAV) embryopathy. A new dysmorphic syndrome associated with intrauterine HTLV-III infection. Am. J. Dis. Child. 140:638-640. Marmor, M., A. E. Friedman-Kien, L. Laubenstein, R. D. Byrum, D. C. William, S. D'Onofrio, and N. Dubin. 1982. Risk factors for Kaposi's sarcoma in homosexual men. Lancet 1:1083-1087. Masur, M., H. C. Lane, and A. Palestine. 1986. Effect of 9-(1,3-dihydroxy-2-propoxy- methyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homo- sexual men. Ann. Intern. Med. 104:41-44. Mintzer, D. M., F. X. Real, L. Jovino, and S. E. Krown. 1985. Treatment of Kaposi's sarcoma and thrombocytopenia with vincristine in patients with the acquired im- munodeficiency syndrome. Ann. Intern. Med. 102:200-202. Mitsuyasu, R. T., and J. E. Groopman. 1984. Biology and therapy of Kaposi's sarcoma. Semin. Oncol. 11:53-59. Narayan, O., D. Sheffer, J. E. Clements, and G. Tennekoon. 1985. Restricted replication of lentiviruses: Visna viruses induce a unique interferon during interaction between lym- phocytes and infected macrophages. J. Exp. Med. 162:1954-1969. Nash, G., and S. Fligiel. 1984. Pathologic features of the lung in the acquired immune deficiency syndrome (AIDS): An autopsy study of seventeen homosexual males. Am. J. Clin. Pathol. 81:6-12. Navia, B. A., E.-S. Cho, C. K. Petito, and R. W. Price. 1986. The AIDS dementia complex: II. Neuropathology. Ann. Neurol. 19:525-535. Ognibene, F. P., J. Shelhamer, V. Gill, A. M. Macher, D. Loew, M. M. Parker, E. Gelmann, A. S. Fauci, J. E. Parrillo, and H. Masur. 1984. The diagnosis of Pneumocystis carinii pneumonia in patients with the acquired irnmunodeficiency syndrome using subsegmental bronchoalveolar ravage. Am. Rev. Respir. Dis. 129:929-932. Parks, W. P., and G. B. Scott. 1986. An Overview of Pediatric AIDS: Approaches to Diagnosis and Outcome Assessment. Background paper. Washington, D.C.: Committee on a National Strategy for AIDS. Pert, C. B. 1986. HTLV-III virus visualization of the OKT4 antigen in brain. Paper presented at the National Institute of Mental Health AIDS Conference. Bethesda, Md. Petito, C. A., B. A. Navia, E.-S. Cho, B. D. Jordan, D. C. George, and R. W. Price. 1985. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 312:874-879.
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302 APPENDIX A Pitchenik, A. E., C. Cole, B. W. Russet, M. A. Fischl, T. J. Spira, and D. E. Snider, Jr. 1984. Tuberculosis, atypical mycobacteriosis and the acquired immunodeficiency syn- drome among Haitian and non-Haitian patients in south Florida. Ann. Intern. Med. 101: 641-645. Pumarola-Sune, T., B. A. Navia, C. Cordon-Cardo, E.-S. Cho, and R. W. Price. In press. LAV/HTLV-III antigen in the brains of patients with the AIDS dementia complex. Quinn, T. C. 1986. Clinical approach to intestinal infections in homosexual men. Med. Clin. North Am. 70:611-634. Rein, M. F. 1986. Clinical approach to urethritis, mucocutaneous lesions, and inguinal lymphadenopathy in homosexual men in AIDS and other medical problems in the male homosexual. Med. Clin. North Am. 70:587-609. Resnick, L., F. diMarzo-Veronese, J. Schupbach, W. W. Tourtellotte, D. D. Ho, F. Muller, P. Shapshak, M. Vogt, J. E. Groopman, P. D. Markham, and R. C. Gallo. 1985. Intra-blood-brain-barrier synthesis of HTLV-III specific IgG in patients with necrologic symptoms associated with AIDS or AIDS-related complex. N. Engl. J. Med. 313:1498- 1504. Rolston, K., V. Fainstein, P. Mansell, A. Sjoerdsma, and G. P. Bodey. 1985. Alpha- difluoromethylornithine (DEMO) in the treatment of cryptosporidiosis in AIDS patients: Preliminary evaluation. P. 77 in Abstracts of the International Conference on AIDS, Atlanta, Gal, April 14-17, 1985. Schoeppel, S. C., R. T. Hoppe, R. F. Dorfman, S. J. Horning, A. C. Collier, T. G. Chew, and L. M. Weiss. 1985. Hodgkin's disease in homosexual men with generalized lymphadenopathy. Ann. Intern. Med. 102:68-70. Sharer, L. R., L. G. Epstein, E.-S. Cho, V. V. Joshi, M. F. Myenhofer, L. F. Rankin, and C. K. Petito. 1986. Pathology of AIDS encephalopathy in children: Evidence for LAV/HTLV-III infection in brain. Human Pathol. 17:271-284. Shaw, G. M., M. E. Harper, B. H. Hahn, L. G. Epstein, D. C. Gajdusek, R. W. Price, B. A. Navia, C. K. Petito, C. J. O'Hara, E.-S. Cho, J. M. Oleske, F. Wong-Staal, and R. C. Gallo. 1985. HTLV-III infection in brains of children and adults with AIDS encephalop- athy. Science 227:177-182. Smith, P. D., A. M. Macher, M. A. Bookman, R. V. Boccia, R. G. Steis, V. Gill, J. Manischewitz, and E. P. Gelmann. 1985. Salmonella typhimurium enteritis and bac- teremia in the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:207-209. Snider, W. D., D. M. Simpson, G. Nielson, J. W. M. Gold, C. Metroka, and J. B. Posner. 1983. Neurologic complications of acquired immunodeficiency syndrome: Analysis of 50 patients. Ann. Neurol. 14:403-418. Soave, R., R. L. Danner, C. L. Honig, P. Ma, C. C. Hart, T. Nash, and R. B. Roberts. 1984. Cryptosporidiosis in homosexual men. Ann. Intern. Med. 100:504-511. Soave, R., A. Sjoerdsma, and M. J. Cawein. 1985. Treatment of cryptosporidiosis in AIDS patients with alpha-difluoromethylornithine. P. 77 in Abstracts of the International Conference on AIDS, Atlanta, Gal, April 14-17, 1985. Volberding, P. A., R. Valero, J. Rothman, and G. Gee. 1984. Alpha interferon therapy of Kaposi's sarcoma in AIDS. Ann. N.Y. Acad. Sci. 437:439-446. Westerman, E. L., and R. P. Christensen. 1979. Chronic Isospora belli infection treated with co-trimoxazole. Ann. Intern. Med. 91:413-414. Whiteside, M. E., J. S. Barkin, R. G. May, S. D. Weiss, M. A. Fischl, and C. L. MacLeod. 1984. Enteric coccidiosis among patients with the acquired immunodeficiency syndrome. Am. J. Trop. Med. Hyg. 33:1065-1072. Wiley, C. A., R. D. Schrier, J. A. Nelson, P. W. Lampert, and M. A. B. Oldstone. In press. Cellular localization of human immunodeficiency virus infection within the brains of acquired immunodeficiency syndrome (AIDS) patients. Proc. Natl. Acad. Sci. USA.
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APPENDIX A 303 Wong, B., J. W. Gold, A. E. Brown, M. Lang, R. Fried, M. Grieco, D. Mildvan, J. Giron, M. L. Topper, C. W. Lerner, et al. 1984. Central nervous system toxoplasmosis in homosexual men and parenteral drug abusers. Ann. Intern. Med. 100:36-42. Zakowski, P., S. Fligiel, G. W. Berlin, and L. Johnson, Jr. 1982. Disseminated Mycobac- terium avium-intracellulare infection in homosexual men dying of acquired immunodefici- ency syndrome. JAMA 248:2980-2982. Ziegler, J. L., J. A. Beckstead, P. A. Volberding, D. I. Abrams, A. M. Levine, R. J. Lukes, P. S. Gill, R. L. Burkes, P. R. Meyer, C. E. Metroka, J. Mouradian, A. Moore, S. A. Riggs, J. J. Butler, F. C. Cabanillas, E. Hersh, G. R. Newell, L. J. Laubenstein, D. Knowles, C. Odajnyk, B. Raphael, B. Koziner, C. Urmacher, and B. D. Clarkson. 1984. Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadeno- pathy and the acquired immunodeficiency syndrome. N. Engl. J. Med. 311:565-570. Zuger, A., E. Louie, R. S. Holtzman, M. S. Simberkoff, and J. J. Rahal. 1986. Cryptococcal disease in patients with acquired immunodeficiency syndrome. Ann. Intern. Med. 104: 234-240.
Representative terms from entire chapter: