Size and duration of zidovudine benefit in 1003 HIV-infected patients: U.S. Army, Navy, and Air Force natural history data. Military Medical Consortium for Applied Retroviral Research.

OBJECTIVES: The study's objectives were to determine the size and duration of benefits of early versus delayed versus late treatment with zidovudine (ZDV) on disease progression and mortality in HIV-infected patients, and whether patients rapidly progressing before ZDV treatment had a different outcome from those not rapidly progressing before ZDV. DESIGN: The design was an inception cohort of 1003 HIV-infected patients. One hundred and seventy-four of the 1003 patients were treated before CD4 counts fell to <400 x 10(9)/L, ("early treatment"); 183 of 1003 patients were treated after CD4 counts fell to <400 x 10(9)/L but before clinical disease developed ("delayed treatment"); and 646 of the 1003 patients had either been treated after clinical disease developed or had not been treated at all by the end of follow-up ("late treatment"). Outcomes were progression to clinical HIV disease and mortality. RESULTS: The relative risk (RR) of progression for early versus delayed treatment was 0.58 (p < .03), and durability of ZDV benefits on progression was estimated at no more than 2.0 years; however, this estimate had wide confidence intervals. The RR of progression for delayed versus late treatment was 0.54 p < .0001, and durability of ZDV benefits was estimated at 1.74 years; this estimate had narrow confidence intervals. Survival was better for the early versus delayed treatment (RR = 0.55), but this difference was not statistically significant. In the subgroup of patients with more rapid CD4 decline prior to ZDV therapy, significant benefits on progression were observed for early versus delayed ZDV therapy (RR = 0.42, p = .02) and delayed versus late ZDV therapy (RR = 0.51; p = .0004). Duration of benefit was estimated to be 4.5 years (early versus delayed) and 1.7 years (delayed versus late). For patients with less rapid pre-ZDV decline in CD4 levels, a significant progression benefit was observed for delayed versus late therapy (RR = 0.50; p = .02). Duration of benefit in this subgroup was estimated to be 1.8 years. No significant benefit was found for early versus delayed treatment (RR = 1.12) in the less rapid pre-ZDV CD4 cell decline subgroup. CONCLUSIONS: Early treatment compared with delayed treatment was associated with a sizable reduction in HIV progression, but the duration of benefits was estimated to last only about 2 years. Delayed treatment compared with late treatment with ZDV was associated with substantial reduction of progression, but this reduction was also clearly limited in duration. Benefits on progression and mortality for the early treatment group were heavily dependent on the pre-ZDV CD4 slope. In the subgroup of patients with the most rapid pre-ZDV CD4 cell declines, the duration of benefit was much longer, possibly as long as 4 years.

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.

OBJECTIVE: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. DESIGN AND METHODS: PBMC from HIV-1 infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-gamma, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. RESULTS: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiment indicated that antigen-stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. CONCLUSIONS: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Cytomegalovirus polyradiculopathy in HIV-infected patients.

Cytomegalovirus polyradiculopathy, a late complication of HIV infection, is characterized by lower extremity weakness, urinary retention, and sacral dysesthesias. We describe four patients (mean CD4 T-cell count = 25 cells/mm3) who developed this "infectious cauda equina syndrome." The characteristic cerebrospinal fluid (CSF) findings, notably atypical for a viral infection, included polymorphonuclear leukocytosis (mean white blood cell count = 1512 cells/mm3, 72% polymorphonuclear leukocytes), elevated protein level (mean = 370 mg/dl), and hypoglycorrhacia (mean = 28 mg/dl). Physicians who treat patients with HIV should be familiar with this syndrome because early intervention, prior to microbiologic confirmation, provides the best hope for improving neurologic function.

The significance of hematuria in patients infected with the human immunodeficiency virus.

PURPOSE: We determined the importance of hematuria in patients infected with the human immunodeficiency virus (HIV). MATERIALS AND METHODS: The records of 1,326 HIV infected patients with yearly evaluations were reviewed for hematuria and evaluation results. Mean followup was 2.1 years. RESULTS: A total of 331 patients (25.0%) had 1 episode of hematuria and 67 were evaluated with 5 significant diagnoses made. Management was affected in only 3 of these patients. No occult genitourinary tumors were found. CONCLUSIONS: In young, asymptomatic, HIV infected patients with microscopic hematuria a urological evaluation can be safely omitted in the presence of normal renal function and a benign urological history.

Presence of neutralizing antibodies to heterologous human immunodeficiency virus type 1 isolates in sera of infected individuals is not predictive of rate of disease progression.

These studies were undertaken to examine whether the presence of human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies in sera of infected individuals would alter the rate of disease progression. HIV-1-infected individuals (n = 87) were initially examined for neutralizing activity in vitro against both laboratory and tissue culture-adapted clinical heterologous HIV-1 isolates. The neutralizing activities of sera were determined by a 90% or greater reduction in HIV-1 p24 levels in vitro. In a cross-sectional analysis of all infected individuals, we observed that sera from asymptomatic individuals neutralized a significantly greater number of heterologous HIV-1 isolates than sera from symptomatic patients. Patients who could be followed up longitudinally (n = 24) were then studied to determine the impact of neutralizing antibodies on the rate of disease progression. We observed no significant difference between the numbers of HIV-1 isolates neutralized in vitro by sera from patients who remained clinically stable and by those from patients who progressed rapidly. Our data indicated that the presence or absence of neutralizing antibodies to heterologous HIV-1 isolates was not associated with the rate of disease progression.

In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus.

Human immunodeficiency virus type 1 (HIV-1)-infected patients (n = 335) in the US Air Force HIV Natural History Program were followed for 3 years (mean) after skin testing, immunophenotyping of CD4+ cell subsets, and measurement of in vitro interleukin-2 production after stimulation by phytohemagglutinin, alloantigens, tetanus toxoid, and influenza A virus. The T cell functional assay predicted survival time (P < .001) and time for progression to AIDS (P = .014). Skin testing for tetanus, mumps, and Candida antigen and the total number of positive tests (P < .001 for each) stratified patients for survival time. In a multivariable proportional hazards model, the T cell functional assay (P = .008), the absolute number of CD4+ T cells (P = .001), the percentage of CD4+ CD29+ cells (P = .06), and the number of reactive skin tests (P < .001) predicted survival time. Thus, cellular immune functional tests have significant predictive value for survival time in HIV-1-infected patients independent of CD4+ cell count.

Rates of p24 antigenemia and viral isolation in comparable white and black HIV-infected subjects. Military Medical Consortium for Applied Retroviral Research.

OBJECTIVE: To determine the relative frequencies of HIV-1 p24 antigen and culture positivity in white and black patients. DESIGN: Volunteers in the US military's HIV natural history study were 46% white, 44% black, 7% Hispanic and 3% other. Focusing on the comparable groups of whites and blacks, a retrospective analysis was performed of the results of virologic assays collected over a 2-year period. METHODS: p24 antigen was quantitated in sera with and without immune complex dissociation (ICD); viral isolation was performed by coculture of peripheral blood mononuclear cells. RESULTS: Results of the two virologic assays were very similar in the two racial groups, both overall and after stratification by CD4 cell count. As reported previously, the concentration of serum immunoglobulin G was found to be greater in black than white subjects. In contrast to results with ICD, sera tested without ICD resulted in differing (higher) rates of antigenemia in whites than blacks (P = 0.002). CONCLUSIONS: The frequencies of p24 antigen and culture positivity were found to be independent of race. Previously observed racial differences in antigen positivity were likely to be due to more extensive antibody binding in blacks than in whites.

Multivariate models for predicting progression to AIDS and survival in human immunodeficiency virus-infected persons.

Nine hundred thirty persons enrolled in the US Air Force Human Immunodeficiency Virus (HIV) Natural History Study were evaluated with a standard battery of 30 potential surrogate markers of disease progression. A risk score for predicting progression to AIDS was then calculated for each patient in the cohort by using the four highest-ranking variables from multivariate analysis: percentage of CD4 CD29 cells, anergy status, age, and hemoglobin. For predicting survival, beta 2-microglobulin replaced age in the Cox model. Stratification according to the risk score demonstrated that rates of progression to AIDS and survival were significantly different between risk groups (P < .0001). The novel combination of these markers results in extremely accurate risk scores, which may serve as the basis for the development of true surrogate markers of disease progression.

Serologic evaluation of human immunodeficiency virus type 1-infected individuals from Argentina and the United States indicates a similar distribution of subgroup B isolates.

Utilizing peptides based on the V3 region of gp120, we undertook a serologic examination of human immunodeficiency virus type 1 (HIV-1)-infected individuals from Argentina to determine if prevalent HIV-1 isolates could be identified in this population. Our findings suggest that a similar pool of HIV-1 subgroup B isolates exists in both Argentina and the United States.

PIP: This study examined serum specimens from HIV-1 infected individuals from Argentina (n = 50) and the United States (n = 38) for antibody reactivity to a panel of V3-based synthetic peptides. Serum specimens were further analyzed for the ability to neutralize laboratory and clinical isolates of HIV-1 in vitro. Patterns of antibody reactivity to these V3 peptides, together with neutralizing activity, indicated that infected individuals from both Argentina and the US have been exposed to HIV-1 isolates belonging to subgroup B. Serum specimens from the United States (37 males and 1 female) were obtained from military personnel and their dependents. Of these patients, 35 were asymptomatic and 3 were symptomatic. Specimens from Argentina were obtained from HIV-1-infected individuals examined in Buenos Aires, Argentina (37 males and 13 females). Half of the infected individuals from Argentina were symptomatic. Serum specimens were screened for antibody reactivity to HIV-1 gp160 synthetic peptides by an enzyme-linked immunosorbent assay. Examination of V3 peptide recognition indicated that a higher percentage of Argentinean serum specimens reacted with peptide RP189 than serum specimens from the United States (34% and 5%, respectively). A higher percentage of serum specimens from the United States reacted with peptide RP135 (LAI) than was observed with serum specimens from Argentina (47% vs. 16%, respectively). Neutralization assays again indicated a similar pattern of antibody reactivity with serum specimens from infected individuals from Argentina and the United States. Nucleotide sequence analysis of clinical isolates has demonstrated that the HIV-1 subgroup B is predominant in the United States. Serologic reactivity to V3-based peptides in this study suggests that isolates commonly found in the US (i.e., MN, SF2, and NY-5) are also frequently observed in Argentina. These results suggest that there is similar distribution of HIV-1 subgroup B isolates among infected individuals from Argentina and the United States.

Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis.

In vitro T-cell receptor-induced programmed cell death in both activated T cells from human immunodeficiency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines. Addition of exogenous recombinant "type 1" lymphokines interferon gamma and interleukin 2 (IL-2), as well as the macrophage-produced IL-12, which favor cell-mediated T-cell responses, blocks both systems of T-lymphocyte programmed cell death. In contrast, the "type 2" lymphokines IL-4 and IL-10, which favor antibody responses, either had no effect or enhanced these systems of in vitro T-cell programmed cell death. A role for endogenously produced cytokines was suggested by the inhibition of T-cell receptor-mediated death by antibodies against IL-4 and IL-10 and its enhancement by anti-IL-12 in cultures containing monocytes. These results demonstrate that the functional properties of type 1 and type 2 cytokine classes may be further extended to include their effects on T-cell programmed cell death and their possible role in the pathogenesis of HIV infection.

Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.

In vitro activation of PBLs from HIV+ individuals resulted in programmed cell death (PCD) within 2 days in 58 of 95 HIV+ blood donors, in contrast to only two of 30 control HIV- donors. CD4+ and CD8+ T cells from HIV+ donors died under these conditions, and these cells showed apoptotic nuclear morphology and DNA fragmentation. To test the hypothesis that this cell death shares a common biochemical pathway with that induced by TCR cross-linking in normal dividing T cells, inhibitors of the calcium-activated cysteine protease calpain were tested for their ability to block the activation-induced PCD of HIV+ donors. The E-64 (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60% inhibition of HIV+ PCD responses, while the aldehyde inhibitors, leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The involvement of this calpain-dependent death pathway in HIV-induced functional T helper cell deficiency was tested by examining the effect of calpain inhibitors on the defective Ag- and mitogen-dependent proliferative responses of HIV+ donors. Twenty to fifty percent of such defective responses were significantly restored toward normal levels by calpain inhibitors, whereas control responses by normal donors were largely unaffected. These data suggest that a calpain-dependent PCD pathway contributes to HIV-associated immunodeficiency and suggest the use of calpain inhibitors as a possible route to therapy of HIV infection.

False-positive rapid plasma reagin tests in human immunodeficiency virus infection and relationship to anti-cardiolipin antibody and serum immunoglobulin levels.

The incidence of biologic false-positive rapid plasma reagin (RPR) tests may be increased in human immunodeficiency virus (HIV) infection; however, injecting drug use has not been excluded as the cause. Review of 3371 periodic syphilis serology results from 1077 HIV-seropositive patients in the United States Air Force HIV Natural History Study between January 1986 and June 1992 revealed a cumulative biologic false-positive RPR rate of 1%. Most (6/9) were transient low-titer results associated with a recent acute infectious process. False-positive RPR tests did not appear to correlate with anticardiolipin antibody levels or serum IgG or IgA levels, which are increased in HIV infection. Although not statistically significant, there was a trend toward higher IgM levels in patients with biologic false-positive tests. Thus, the incidence of false-positive RPR in an HIV-infected population with a low risk of injecting drug use is similar to that in the general population, and the mechanism may correlate with elevated serum IgM levels.

A case of Pott's disease in a 20-year-old military dependent.

Tuberculous spondylitis (Pott's disease) is an uncommon complication of Mycobacterium tuberculosis infection that may have serious consequences if the diagnosis is missed or delayed. A case of tuberculous spondylitis in a military dependent is presented. Clinical presentation, radiologic findings, laboratory findings, and treatment are discussed.

Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus.

The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-10-specific mRNA would be upregulated in PBMC from asymptomatic, HIV-infected (HIV+) individuals; (b) PBMC from these same individuals would produce increased levels of IL-10 when stimulated in vitro with phytohemagglutinin; and (c) defective antigen-specific TH function could be restored by anti-IL-10 antibody. We observed that IL-10-specific mRNA was marginally upregulated, and increased levels of IL-10 were produced by PBMC from HIV+ individuals compared with PBMC from uninfected individuals. Those individuals whose TH function was more severely compromised produced higher levels of IL-10. Additionally, defective antigen-specific TH function in vitro could be reversed by anti-IL-10 antibody, including the response to HIV envelope synthetic peptides. Furthermore, the antigen-specific TH responses of HIV-uninfected PBMC could be reduced with IL-10, a process reversed by anti-IL-10. These results confirm that the early loss of TH function in HIV+ individuals is due at least in part to cytokine-induced immune dysregulation, and support the hypothesis of a switch from a predominant type 1 state to a predominant type 2 condition in HIV infection.

Legionnaires' disease in human immunodeficiency virus-infected patients: eight cases and review.

Despite being a well-known pathogen for immunocompromised patients, Legionella pneumophila has infrequently been described in persons with infection due to human immunodeficiency virus (HIV). Since 1986, we have identified eight cases of legionella pneumonia among seven HIV-infected persons enrolled in the HIV Natural History Study of the U.S. Air Force. The median CD4+ T cell count for these patients was 83/mm3; 50% of the cases occurred in persons for whom AIDS was previously diagnosed, and five of the cases were nosocomial. Six of the patients had coexistent pulmonary infections. None of the cases occurred among persons receiving prophylactic therapy with trimethoprim-sulfamethoxazole. Therapeutically, all patients appeared to respond well to standard antilegionella therapy or high doses of trimethoprim-sulfamethoxazole. Overall, these seven patients represent 1.7% of the patients with late-stage HIV infection (Walter Reed stage 5 or 6) in this cohort. L. pneumophila, although remaining an uncommon pathogen for HIV-infected patients, may produce serious disease in this population. HIV-infected persons should be considered at risk for legionnaires' disease, particularly in institutions where potable water supplies have become contaminated.

Longitudinal analysis of the humoral immune response to human immunodeficiency virus type 1 (HIV-1) gp160 epitopes in rapidly progressing and nonprogressing HIV-1-infected subjects.

Antibody response to conserved human immunodeficiency virus type 1 (HIV-1)IIIB gp160 epitopes was longitudinally examined in HIV-1-infected persons. Twelve hundred individuals were evaluated, and sequential sera from 25 rapidly progressing (RP) and 30 nonprogressing (NP) subjects collected over an average of 4 years were examined. Initial sera from the RP group contained greater reactivity to a gp120 epitope defined by peptide 503-528 than did sera from the NP group (P < .001). Reactivity declined with sequential sera for the RP group, paralleling disease progression. Conversely, antibody recognition to this site developed in 23% of the NP group with time. However, 60% of the NP group never developed a response to this epitope. This suggests sequential examination of antibody response to an epitope within the gp120 carboxyl-terminus may have prognostic significance. No association between antibodies directed against the gp160 epitopes and in vitro neutralizing activity against HIV-1IIIB was observed.

Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro.

Peripheral blood mononuclear cells (PBMCs) from many asymptomatic individuals infected with human immunodeficiency virus-type 1 (HIV) are unresponsive as measured by in vitro T cell proliferation and interleukin-2 (IL-2) production to influenza virus and synthetic peptides of HIV envelope (Env). Strong influenza virus- and Env-stimulated IL-2 responses and T cell proliferation were restored when cultures were stimulated in the presence of IL-12. Interferon-gamma production by PBMCs from HIV seropositive (HIV+) patients was also restored with IL-12. Furthermore, in vitro antigen-specific production of IL-2 and proliferation of PBMCs from HIV- donors were suppressed by antibody to IL-12, but were not enhanced by addition of exogenous IL-12. Thus, IL-12 may be limiting in PBMCs from HIV+ but not HIV- individuals. These findings demonstrate that IL-12 can restore HIV-specific cell-mediated immunity in vitro in HIV-infected individuals and suggest a potential use of IL-12 in augmenting the diminished immunologic functions associated with HIV infection.

Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients.

OBJECTIVE: To evaluate the prognostic significance of cutaneous delayed-type hypersensitivity (DTH) skin testing in persons infected with HIV. DESIGN: Cohort study. SETTING: United States Air Force (USAF) Medical Center. PATIENTS: Consecutive sample of 889 HIV-infected USAF personnel or dependents undergoing their first staging evaluation from 1985 through August 1990 in the USAF HIV Natural History Study. MEASUREMENTS: All patients were evaluated with DTH skin testing including purified protein derivative and four control skin test antigens: mumps, candida, tetanus toxoid, and trichophyton. In addition, all patients underwent CD4+ T-cell surface marker determinations. The relation between DTH skin test response at first evaluation and progression to Walter Reed stage 6 (presence of an AIDS-defining opportunistic infection) was evaluated using Kaplan-Meier survival analysis. RESULTS: Patients with more than 400 CD4+ T cells/mm3 are more likely than those having fewer than 400 CD4+ T cells per mm3 to respond to at least one (94% compared with 67%, P < 0.001) or at least two (86% compared with 45%, P < 0.001) DTH skin tests. Mean CD4 counts are lower for anergic compared with nonanergic patients and for patients responding to a single control skin test compared with those responding to two or more skin tests (P < 0.05). The DTH skin test response at first evaluation was also found to predict progression to AIDS; the relative risk at 5 years of follow-up was 2.5 (95% CI, 1.2 to 5.2) for anergy compared with a single positive skin test and 3.0 (CI, 1.4 to 6.2) for a single compared with two or more skin test responses. The DTH skin test response at first evaluation was a predictor of progression (P < 0.001) when controlling for initial CD4 count and Walter Reed stage in a Cox proportional hazards regression analysis. CONCLUSIONS: The DTH skin test response, a functional measure of cellular immunity, is an independent predictor of progression to AIDS in persons with HIV.

Nosocomial Legionnaires' disease: aspiration as a primary mode of disease acquisition.

PURPOSE: Nosocomial Legionnaires' disease remains a significant problem with many unresolved questions regarding transmission of legionella organisms to patients. We performed a case-control and environmental study to identify risk factors and modes of transmission of Legionella infection during an outbreak of nosocomial Legionnaires' disease in a military medical center. PATIENTS AND METHODS: During the calendar year 1989, 14 cases of nosocomial Legionnaires' disease were identified by active surveillance following the discovery of 2 culture-proven cases among organ transplant recipients. Four control patients were matched to each case by age, sex, and date of admission. Cases and controls were compared with respect to past medical history and hospital exposure variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for matched variables. Environmental culturing of air and water supplies in and around the medical center was also performed. RESULTS: The case-control study revealed the following significant risk factors for the acquisition of nosocomial Legionnaires' disease: immunosuppressive therapy (OR = 32.7, CI = 4.5 to 302.6), nasogastric tube use (OR = 18.4, CI = 2.6 to 166.2), bedbathing (OR = 10.7, CI = 2.2 to 59.0), and antibiotic therapy (OR = 14.6, CI = 2.9 to 84.4). Shower use (OR = 0.1, CI = 0 to 0.4) appeared to be a negative risk factor. Water cultures revealed Legionella pneumophila serogroup 1, monoclonal antibody subtype Philadelphia (identical to all patient isolates) in the ground-water supply to the hospital, 1 hot-water tank, and 15% of 85 potable water sites tested. Air sampling of cooling towers, hospital air intakes, and medical air and oxygen supplies were negative for Legionella organisms. CONCLUSIONS: This study confirms the importance of potable water in transmitting nosocomial Legionnaires' disease and suggests that the organism gains access to the hospital via external water supplies. The risk factors identified in this case-control study provide evidence that Legionnaires' disease may act as a superinfection in a nosocomial setting and is likely acquired by aspiration, similar to other nosocomial pneumonias.

Coccidioidomycosis: a persistent threat to deployed populations.

The world-wide deployability of aircrew members exposes them to a peculiar array of medical problems. Non-immune populations, upon deployment to endemic areas, may present to the deployed flight surgeon with acute, poorly recognizable syndromes, such as acute coccidioidomycosis. Alternatively, the acquisition of the chronic progressive form of coccidioidomycosis in endemic areas may be a problem for the flight surgeon, who may be faced with a poorly recognizable syndrome which first manifests itself weeks to months after the crewmember's return from deployment. We describe three cases of coccidioidomycosis in service members that highlight the difficulty in the diagnosis of this disease. These cases prompted an epidemiologic survey of recent cases of coccidioidomycosis among Air Force beneficiaries, presented here, to better define the impact of this disease on personnel assigned to endemic areas. A brief discussion of the epidemiologic and clinical features of the disease and of the aeromedical disposition of the aviator is presented.