AIDS-related Opportunistic Infections Research Articles

Prophylaxis against Mycobacterium avium-intracellulare complex infections in human immunodeficiency virus-infected patients.

Infection due to the Mycobacterium avium complex (MAC) accounts for the most frequent AIDS-related opportunistic infections, but MAC infection is usually not the first AIDS-defining event that a patient infected with HIV experiences. The incidence increases linearly over time, at a rate of 20 to 25% per year, after a patient's first AIDS-defining event, and the incidence increases exponentially as the CD4+ cell count approaches zero. There is evidence that MAC may eventually infect most if not all HIV-infected patients who do not die from another HIV-related event. Since MAC infection contributes substantially to the morbidity and mortality of AIDS patients, prophylaxis appears to be mandatory. Rifabutin was the first drug which was shown to be effective in preventing MAC infection, and, recently, prophylaxis with clarithromycin was also found to prevent the disease. The optimal approach to prophylaxis still needs to be defined. Since a large majority of MAC infections occur in patients with CD4+ cell counts below 50/microliter, recommendations regarding the prophylaxis of patients with a history of an AIDS-defining opportunistic event and a CD4+ cell count between 50 and 200/microliter can be individualized, depending for example on how well the patient seems to be responding to antiretroviral treatment. Prophylaxis against MAC should be provided for any HIV-infected patient with a CD4+ cell count less than 50/microliter.

Alveolar macrophages as a cell source of cytokine hyperproduction in HIV-related interstitial lung disease.

Pulmonary macrophages play an important role in the pathogenesis of the acquired immunodeficiency syndrome (AIDS). They are known to be discrete target cells for human immunodeficiency virus (HIV), and compelling evidence is accumulating that alveolar macrophages (AMs) from HIV-infected patients behave as versatile secretory cells that, acting as antigen-presenting cells, release a great variety of cytokines. The secretory products of AMs, pivotal to their immune effects, may contribute to localized immune dysregulation as well as to primary lung damage and clinical disease. Pulmonary macrophages are also thought to facilitate retroviral spread by their direct infection, by presenting HIV antigens to uninfected T cells, and by secreting cytokines that transactivate HIV expression. This review briefly considers the events underlying the role of AMs in the pulmonary defense mechanisms against HIV and AIDS-related opportunistic infections. Following a brief overview of immune mechanisms taking place in the lungs of HIV-infected subjects, we describe the specific role of AMs in the immune mechanisms devoted to recognizing and removing HIV-infected cells and controlling the local growth of opportunists. The pathogenetic role envisaged for macrophages in lung damage are also reviewed in the context of the known biology of these cells. Finally, this review examines the relevance of the retroviral infection of AMs in terms of pathogenesis of the HIV-related interstitial lung disease.

Microsporidiosis as an AIDS-Related Opportunistic Infection

The clinical manifestations of AIDS-related microsporidiosis range from mild or asymptomatic infections to debilitating illness involving the gastrointestinal, respiratory, or urogenital tracts or the eyes. Intestinobiliary infections with Enterocytozoon bieneusi are the most common microsporidial diseases, but disseminated infections with Encephalitozoon hellem, Encephalitozoon cuniculi, and Septata intestinalis are being increasingly recognized. The isolation of infective microsporidial spores from urine and respiratory secretions and the presence of spores in stool and duodenal aspirates suggest that person-to-person transmission may occur. Primary infection may also occur by inhalation or ingestion of spores from environmental sources or by zoonotic transmission. Development of guidelines for prevention of microsporidiosis will require that sources of infection and modes of transmission be more clearly elucidated. The presence of infective spores in bodily fluids, however, suggests that precautions when handling body fluids in clinical settings and personal hygiene measures such as hand washing may help to prevent primary infections.

Preventing Toxoplasmic Encephalitis in Persons Infected with Human Immunodeficiency Virus

Toxoplasmic encephalitis (TE) is the second most common AIDS-related opportunistic infection of the CNS. It occurs in 10%-50% of patients with AIDS who are seropositive for antibodies to Toxoplasma gondii and have CD4+ T lymphocyte counts of < 100/mm3. Primary toxoplasmic infection usually is acquired by ingestion of T. gondii oocysts from soil contaminated by cat feces or by ingestion of tissue cysts present in undercooked red meats. In patients with AIDS, TE probably results from the reactivation of Toxoplasma tissue cysts that remained latent after the primary infection. Detection of IgG antibodies to Toxoplasma indicates prior infection and the possible presence of tissue cysts and, thus, risk for developing TE. A regimen of trimethoprim-sulfamethoxazole or dapsone plus pyrimethamine with leucovorin is recommended for persons infected with the human immunodeficiency virus (HIV) and who are seropositive for IgG to Toxoplasma after their CD4+ T lymphocyte counts fall to < 100/mm3. HIV-infected persons who are seronegative for IgG to Toxoplasma should be counseled to protect themselves from primary toxoplasmic infection by eating only well-cooked meats and washing their hands after outdoor activities involving soil contact; if they have a cat, they should feed it only commercial or well-cooked foods, keep it indoors, and make sure that the litter box is changed daily. HIV-infected persons who are Toxoplasma seropositive may also be advised about these preventive behavioral practices.

Intensive treatment of AIDS‐related non‐Hodgkin's lymphomas with the MACOP‐B protocol

The usefulness of intensive chemotherapy with the MACOP-B protocol was evaluated in 8 patients with AIDS-related non-Hodgkin's lymphoma (NHL). Four patients had a prior AIDS diagnosis. The median CD4+ lymphocyte count was 0.079 cells x 10(9)/l (range 0.016-0.330). All patients responded to treatment. Four patients finished chemotherapy, all with complete remission, while another 3 patients deteriorated prior to finishing treatment and died. The median survival was 4 months (range 1 to 86 months). Major causes of the poor outcome were AIDS-related opportunistic infections and meningeal CNS involvement by NHL developing during or after chemotherapy. Patients with AIDS-related NHL usually do not appear to benefit from treatment with MACOP-B protocol. Advanced immunodeficiency is associated with poor tolerance to treatment and inability to finish this chemotherapy protocol. MACOP-B chemotherapy does not prevent meningeal spread of lymphoma in spite of using repeatedly systemic methotrexate crossing the blood-brain barrier. CNS prophylaxis with repeated application of intrathecal methotrexate may lower the risk of meningeal spread of lymphoma, which developed in 1 of 5 patients given CNS prophylaxis as compared to 2 of 3 patients without CNS prophylaxis.

NIH conference. Recent advances in the management of AIDS-related opportunistic infections.

Secondary infections remain the leading cause of death in patients with the acquired immunodeficiency syndrome (AIDS). Dealing with the rapidly evolving spectrum of infectious problems seen in patients with AIDS requires knowledge of current therapeutic and prophylactic strategies. Through an extensive preclinical trials network supported by both industry and government, an increasing number of new agents are being identified and rapidly moved into clinical trials. Several agents are now available to treat diseases caused by Pneumocystis carinii, and corticosteroids have become a useful adjunct to antimicrobial agents in the treatment of P. carinii pneumonia. Although the treatment of toxoplasmosis remains a challenge, alternatives to sulfadiazine and pyrimethamine are now available. Mycobacterial infections, particularly with Mycobacterium tuberculosis, have become an increasing problem for patients with AIDS, and both old and new combination drug regimens are being used. Cytomegalovirus disease, until recently an untreatable problem, can now at least be partially managed with antiviral agents. The use of more complete prophylactic regimens may decrease the morbidity and mortality from opportunistic infections.

Copyrine alkaloids: synthesis, spectroscopic characterization, and antimycotic/antimycobacterial activity of A- and B-ring-functionalized sampangines.

Several A- and B-ring-substituted sampangines were synthesized and evaluated for antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens. Electrophilic halogenation provided a channel for structural elaboration of the sampangine B-ring at position 4, while the synthesis of A-ring 3-substituted sampangines and benzo[4,5]sampangine (24) were achieved from the corresponding functionalized cleistopholines. Two-dimensional NMR spectroscopy was used to rigorously characterize the A- and B-ring substituent patterns. Structure-activity relationship studies revealed the activity of the sampangines was enhanced by the presence of a substituent at position 3 or by a 4,5-benzo group.

Shift in focus for treating AIDS-related opportunistic infections

Shift in focus for treating AIDS-related opportunistic infections

Invasive Aspergillosis in AIDS

Invasive pulmonary aspergillosis was diagnosed in two patients with HIV infection, one with prolonged neutropenia and another receiving corticosteroid therapy. We found 17 additional cases in the literature. A known predisposing risk factor for invasive aspergillosis, eg, neutropenia, corticosteroid use, or intravenous drug abuse, was present in 79% of the cases. That the known immunologic defect of AIDS is not a major host defense against Aspergillus is supported by the empiric observation of the relative rarity of aspergillosis in patients with AIDS. The lung was the most common site of Aspergillus infection (75%), and transbronchial biopsy is diagnostically useful. Central nervous system involvement was seen in 55% and appears to be more frequent in HIV-infected patients than in other immunosuppressed patients with invasive aspergillosis. Prognosis is grim. Despite early institution of amphotericin B therapy in a few cases, the disease was uniformly fatal. Efficacy of therapy with amphotericin B plus rifampin or itraconazole remains to be evaluated. We conclude that aspergillosis is not an AIDS-related opportunistic infection.

Hodgkin's Disease and AIDS: Twenty-Three New Cases and a Review of the Literature

Despite numerous reports suggesting an association of Hodgkin's disease (HD) with the acquired immunodeficiency syndrome (AIDS), HD in an individual seropositive for the human immunodeficiency virus (HIV) still is not considered a criterion for the diagnosis of AIDS. The authors report 23 new cases of HD in individuals at risk for AIDS and review the literature. As a group, individuals at risk for AIDS who develop HD have a more aggressive form of the illness (82% with stage III or IV), have or develop AIDS-related opportunistic infections (54%), second neoplasms (10%), and /or profound cytopenias (32%), and 85 to 90% are HIV positive when tested. More than two thirds die within 1 year of the diagnosis of HD. The authors conclude that HIV infection alters the clinical course of HD, that advanced or high-grade HD in HIV-infected individuals should be considered indicative of AIDS, and all patients with HD should be tested for HIV.

Living With AIDS

The image of acquired immunodeficiency syndrome (AIDS), for the past 9 years, has been the image of death. The devastation that the AIDS epidemic has wreaked on individuals, families, communities, and nations is imponderable. From the earliest case reports of AIDS,^1-3the case-fatality rate has been high and survival short. Of the 112 241 persons with AIDS reported to the Centers for Disease Control as of October 31, 1989, fifty-nine percent are known to have died.⁴In a study of the first 505 patients with AIDS in San Francisco, Calif, Bacchetti and coworkers⁵found a median survival of 11 months. Patients diagnosed with<i>Pneumocystis carinii</i>pneumonia, the most common AIDS-related opportunistic infection, had a median survival of 10 months, and virtually all had died within 2 years of diagnosis. Survival for other opportunistic infections was shorter, and persons with Kaposi's sarcoma, although initially living longer than other

AIDS and the lung. Introduction.

Damage to the immune system induced by the human immunodeficiency virus (HIV) leads to a spectrum of opportunistic infections of which the lung is the most common site. In Europe and North America, pneumocystis carinii pneumonia is the presenting symptom in 64% of cases of acquired immunodeficiency syndrome (AIDS) and occurs at some point in 80% of AIDS victims. This infection is less common in Africa, where tuberculosis is the predominant opportunistic infection. Other AIDS-related lung infections that are gaining in prevalence include pneumonia due to pyogenic bacteria, pulmonary infection with Mycobacterium tuberculosis, and lymphoid interstitial pneumonitis. In addition, there is evidence that the lung may be extensively involved in Kaposi's sarcoma. Given the importance of the lung as a site for AIDS-related opportunistic infections, respiratory physicians will be required to become more involved in the diagnosis and management of AIDS cases.

Otologic disease in patients with acquired immunodeficiency syndrome.

A 5-year retrospective study evaluating otologic disease in patients with acquired immunodeficiency syndrome (AIDS) was conducted at the New York University Medical Center-Bellevue Hospital Center. Twenty-six patients with documented otologic disease who met the Centers for Disease Control criteria for AIDS were identified and their charts were analyzed according to presenting complaints, physical examination, diagnostic modalities, pathologic condition, management, and outcome. A marked diversity of otologic diseases of varying severity was noted. The majority of patients complained of hearing loss and otalgia during their hospitalization for treatment of AIDS-related opportunistic infections. The most frequent diagnoses were otitis externa, acute otitis media, and otitis media with effusion. Sensorineural hearing loss frequently appeared to be related to ototoxic medications and neurologic infections.

Gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus.

Gastrointestinal viruses, predominantly rotaviruses and adenoviruses, were detected by enzyme-linked immunosorbent assay, electron microscopy, or cell culture in >50% of two groups of homosexual men with symptomatic human immunodeficiency virus (HIV) infection, who did (54%) or did not (50%) have diarrhea. Lower detection rates were observed in HIV-seronegative (15%) and asymptomatic HIV-seropositive (16%) men. In the patients with diarrhea, 95% of the isolates of virus were found in the most immuno suppressed patients, those patients with AIDS-related complex or opportunistic infections associated with AIDS. High excretion rates of these viruses are probably associated with both anal-oral transmission and immunosuppression. These viruses apparently cause acute episodes or relapses of diarrhea in some patients but may be co-pathogens or noncontributory to chronic diarrhea in others.

Mycobacterial Diseases: Tuberculosis and Mycobacterium avium Complex

Pulmonary or extrapulmonary tuberculosis occurs in 5 to 35 per cent of AIDS patients, frequently precedes the diagnosis of AIDS, and is increasing in incidence. Clinically, AIDS-associated tuberculosis is similar in presentation to progressive, primary tuberculosis and can be treated effectively with standard antituberculous therapy. Disseminated Mycobacterium avium complex (MAC) infection, one of the most common AIDS-related opportunistic infections, is best diagnosed by special mycobacterial blood culture techniques. The relationship between MAC infection and constitutional symptoms as well as the value of antimycobacterial therapy for disseminated MAC is controversial.

AIDS-related lymphoid neoplasia. The Memorial Hospital experience.

The clinical features and laboratory results of 63 patients with or at risk for AIDS with lymphoid neoplasias seen from November 1980 through November 1986 are reviewed. Forty-three had systemic non-Hodgkin's lymphoma (NHL), nine had primary large cell lymphomas of the brain, 11 had Hodgkin's disease (HD), and one had plasmacytoma evolving to myeloma. Those with systemic NHL included 40 (93%) with intermediate or high-grade histologies, 35 (81%) with advanced stage (III, IV), and 28 (65%) with extranodal disease at presentation (predominantly marrow and meninges). Overall survival was short (median, 10.5 months from diagnosis) with the majority of deaths attributable to AIDS-related opportunistic infections (OI). However, 17 patients with diffuse NHL achieved a complete clinical remission, and nine now have been disease-free for more than 1 year (median follow-up, 28 months; range, 12 to 73 months). Early stage and lack of systemic symptoms were features associated with prolonged disease-free survival. Primary brain NHL was a uniformly lethal manifestation of AIDS, being diagnosed at postmortem in seven of nine severely immunosuppressed homosexual men. As with NHL, a propensity towards advanced disease and extranodal involvement was also observed in HD, suggesting that the atypical clinical behavior of HD may be an additional epiphenomenon of AIDS. This experience tends to argue for the use of intensive therapy in at least some patients with AIDS-related systemic NHL since it has resulted in a proportion of long-term disease-free survivors.

Bacterial infections in AIDS patients.

Bacterial infections cause a substantial burden of disease in the HIV-infected population. Like the opportunistic infections associated with AIDS, they are often usually severe. Unlike many AIDS-related opportunistic infections, however, many can be eradicated by therapy with the appropriate antibiotic, although some, like Salmonella sepsis, require prolonged suppressive therapy to prevent recurrences. Most importantly, the possibility of a bacterial infection should be kept in mind when evaluating any acutely ill HIV-infected patient, as therapy of bacterial disease is often curative while untreated infection can lead to severe morbidity and premature death.

Opportunistic central nervous system pathology in patients with AIDS.

Central nervous system disease related to the acquired immunodeficiency syndrome (AIDS) includes both those illnesses arising from primary human immunodeficiency virus infection and those secondary to opportunistic processes. Ten percent of AIDS patients present with neurological illness; nearly 40% have significant neurological symptoms and 75% have neuropathological abnormalities on autopsy. The frequency of multiple central nervous system pathological processes in the neurologically symptomatic AIDS patient may approach 30%, making the diagnosis and follow-up of these patients extremely difficult. Specific AIDS-related opportunistic infections of the central nervous system are discussed.

Tissue diagnosis of selected AIDS-related opportunistic infections.

Opportunistic infections are the most common initial manifestations of AIDS and, in many instances, are first encountered in surgical specimens. Pneumocystis carinii pneumonitis is by far the most frequent infection seen in biopsy specimens of AIDS patients. Most pathologists are familiar with its histopathologic presentations from previous experience. By contrast, many other opportunistic infections are either new or present clinically and pathologically in unfamiliar ways. Cytomegalovirus affects primarily the alimentary tract and lung. Colitis is the most common presentation. Penetrating ulcers may perforate. Most often, mesenchymal cells, endothelium in particular, show the typical intranuclear and intracytoplasmic inclusion bodies. The greater the number of inclusion bodies in tissues the shorter is the survival of the patient. Mycobacterium avium-intracellulare affects mainly small intestine and lymph nodes and produces a clinical and histologic picture similar to that of Whipple's disease. Diffuse infiltrates of histiocytes stuffed with acid-fast bacilli are characteristic. Cryptosporidiosis is the most ominous enteric opportunistic infection. Protozoa attach themselves to the epithelial surface and produce severe profuse, watery diarrhea. Cryptococcosis is seen in lung, lymph node, and brain biopsy specimens. Large numbers of organisms, sometimes with deficient mucinous capsules, and little or no inflammatory reaction, are notable. Toxoplasmosis is the most common cause of neurological complications in AIDS. Brain biopsy specimens show necrosis, microglial nodules, perivascular lymphocytic infiltrates, and, in 50% of cases, trophozoites.

Activation of tissue macrophages from AIDS patients: in vitro response of AIDS alveolar macrophages to lymphokines and interferon-gamma.

To test the hypothesis that tissue macrophages from AIDS patients have no intrinsic defects in either antimicrobial activity or in the capacity to respond to T cell-derived activating stimuli, alveolar macrophages from 11 patients were treated with crude lymphokines produced by healthy donors. After 72 hr of pretreatment with 10% mitogen- or antigen-induced crude lymphokines (which contained 300 U/ml of interferon-gamma [IFN-gamma]), AIDS alveolar macrophages generated twofold to threefold more H2O2 and readily inhibited the replication of the intracellular pathogens Toxoplasma gondii and Chlamydia psittaci. These responses were indistinguishable from those displayed by activated alveolar cells from 12 non-AIDS patients and three healthy volunteers. As judged by the abrogating effects of a neutralizing anti-human IFN-gamma monoclonal antibody, lymphokine-induced alveolar macrophage activation appeared to be largely IFN-gamma-dependent; thus, macrophages were also stimulated with recombinant (r)IFN-gamma alone. Seventy-two hours of treatment with 300 U/ml of rIFN-gamma resulted in both enhanced oxidative and antimicrobial activity comparable to that achieved by crude lymphokines, and the responsiveness of AIDS alveolar macrophages to rIFN-gamma was identical to control cells. These in vitro results suggest that tissue mononuclear phagocytes from AIDS patients a) are free of apparent defects in intracellular antimicrobial activity, b) are fully responsive to activating T cell products, and c) support the use of IFN-gamma as a potential macrophage-activating immunotherapeutic agent in AIDS-related opportunistic infections.