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Factors Associated with Severe Manifestations of Histoplasmosis in AIDS

  1. L. Joseph Wheat1,2,4,5,
  2. Ploenchan Chetchotisakd7,
  3. Brian Williams3,
  4. Patricia Connolly1,5,
  5. Kathleen Shutt6, and
  6. Rana Hajjeh6
  1. 1Department of Medicine, Indianapolis, Indiana
  2. 2Department of Pathology and Laboratory Medicine, Indianapolis, Indiana
  3. 3Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana
  4. 4Department of Veterans Affairs Hospitals, Indianapolis, Indiana
  5. 5Department of Histoplasmosis Reference Laboratory, Indianapolis, Indiana
  6. 6Department of Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
  7. 7Department of Medicine, Khon Kaen University, Khon Kaen, Thailand
  1. Reprints or correspondence: Dr. L. Joseph Wheat, Histoplasmosis Reference Laboratory, 1001 West 10th Street, OPW 430, Indianapolis, IN 46202 (lwheat{at}iupui.edu; home page, www.iupui.edu/it/histodgn).
 
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Abstract

We report factors associated with severe manifestations of histoplasmosis (such as shock, respiratory failure, and death) in patients with AIDS during an outbreak. Severe disease was present in 28 of 155 patients (17.9%). The following factors were associated with severe disease: black race (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.2–6.2); hemoglobin level <9.5 g/dL (OR, 2.7; 95% CI, 1.2–6.4), partial thromboplastin time >45 s (OR, 3.1; 95% CI, 1.1–9.3); alkaline phosphatase level >2.5 times normal (OR, 3.4; 95% CI, 1.3–8.7); aspartate aminotransferase level >2.5 times normal (OR, 4.2; 95% CI, 1.7–10.0); bilirubin level concentration >1.5 mg/dL (OR, 9.2; 95% CI, 2.5–34.3); creatinine concentration >2.1 mg/dL (OR, 8.3; 95% CI, 2.2–31.9); and albumin concentration <3.5 g/dL (OR, 4.6; 95% CI, 1.3–16.4). Zidovudine use was associated with decreased risk of severe disease (OR, 0.3; 95% CI, 0.1–0.7). Multivariate analysis showed that a creatinine value >2.1 mg/dL (OR, 9.5; 95% CI, 1.7–52) and an albumin value <3.5 g/dL (OR, 4.8; 95% CI, 1.0–22) were associated with an increased risk of severe disease, and zidovudine therapy remained associated with a decreased risk (OR, 0.2; 95% CI, 0.1–0.6). Findings associated with severe histoplasmosis should be recognized early and the cases managed aggressively.

Histoplasmosis is the most common of the endemic mycoses in patients with AIDS, primarily affecting those who live in the Ohio and Mississippi river valleys of the United States and in Latin America. Histoplasmosis occurs in 2%–5% of persons from cities in the areas of endemicity and in up to 25% from some of these cities. During an outbreak of histoplasmosis that occurred in Indianapolis between June 1988 and June 1995, histoplasmosis was the AIDS-defining illness or a subsequent complication for nearly one-third of patients with AIDS [1, 2]. Although histoplasmosis typically is a subclinical illness or mild self-limited pulmonary infection in healthy individuals, 95% of cases involving patients with AIDS were manifested by signs of disseminated infection [1].

The outcome of treatment has been quite favorable for patients with AIDS who have milder manifestations of histoplasmosis: resolution of illness and clearance of cultures have occurred for 85% of patients treated with itraconazole and 98% of those treated with amphotericin B (AmB) [1–3]. However, the outcome has been poor for those with hypotension, respiratory failure, or neurological manifestations. In an earlier review of AIDS patients with histoplasmosis in Indianapolis who were treated with AmB, the outcome was fatal for 47% of those who developed shock that required vasopressors, respiratory failure that required mechanical ventilatory support, or mental-status impairment [2].

In view of the treatment options currently available, including oral therapy with itraconazole and iv therapy with AmB or one of the newer lipid formulations, identification of patients who are likely to be at increased risk for an unfavorable outcome is important. Failure to identify such cases before shock or respiratory failure develops precludes the opportunity to improve outcome through more aggressive management, including treatment with AmB or possibly with immunomodulating agents. Once shock or respiratory failure develops, the outcome of treatment with AmB is poor [2].

In this retrospective review of patients with histoplasmosis diagnosed during the 1988–1995 outbreak in Indianapolis, we identify 3 factors that correlate with severe manifestations of histoplasmosis: shock, respiratory failure, and death.

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Patients and Methods

Identification of cases. Cases of disseminated histoplasmosis were identified by review of the mycologic culture results and Histoplasmosis Reference Laboratory antigen test results at the Indiana University Medical Center hospitals (Indianapolis), Indianapolis Community Hospital, and Methodist Hospital of Indianapolis. Patients whose serological tests for HIV-1 infection were positive and who had laboratory evidence of histoplasmosis (histopathologic demonstration of the organism in tissues, positive cultures, or detection of Histoplasma antigen in urine and/or serum) were eligible for inclusion in this investigation.

Definition of severe histoplasmosis. For this analysis, severe disease was defined as shock that required treatment with vasopressors, respiratory failure that required mechanical ventilation, or death attributed to histoplasmosis.

Review of medical records of patients with AIDS and histoplasmosis. All reported cases met the 1987 AIDS case definition of the Centers for Disease Control and Prevention. Physicians caring for these patients were contacted, and consent was obtained to review medical records. The presence or absence of clinical and laboratory findings of pulmonary or disseminated disease was recorded for each case of histoplasmosis. Background data collected for the patients included their age, sex, race or ethnicity, the date of diagnosis of AIDS, the date of diagnosis of HIV infection, and whether they had previously received antiretroviral treatment. Data about histoplasmosis included date of diagnosis, clinical manifestations, chest radiographic findings, and selected laboratory test results at the time of diagnosis (for this analysis, we accepted data that were gathered from 3 days before through 3 days after diagnosis of histoplasmosis).

The results of laboratory tests used to establish the diagnosis of histoplasmosis also were recorded, including findings from serological tests for antibodies and for Histoplasma antigen in urine, serum, or CSF; fungal cultures; and histopathologic examination of tissue. The type of antifungal therapy that the patient received was recorded, as was the outcome of the illness.

Statistical analysis. We analyzed all variables using unconditional logistic regression with PROC LOGISTIC in SAS 6.12 (SAS Institute, Cary, NC). Variables were examined univariately to determine which risk factors were independently associated with severe disease. P≤.05 was considered significant. Continuous laboratory values were dichotomized with use of medically relevant breakpoints. For this analysis, laboratory parameters with conventional multiples above normal values were chosen for convenience. Confounding factors and variables with sufficient numbers of responses that were significant in the univariate analysis were included in a multivariate stepwise logistic regression. CD4 cell count was included in the univariate analysis but not in the multivariate analysis because data were missing for a large number of subjects, owing to the retrospective study design.

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Results

Description of cases. We reviewed the medical records of 155 patients with cases of histoplasmosis; 28 cases met the definition of severe disease. Table 1 summarizes the demographic characteristics of all the case patients. The median age of patients with severe disease was 37.5 years, versus 33 years for those with milder disease (P = .02). Although differences in sex were not observed, patients with severe disease were more likely to be black than were those with nonsevere disease (P = .01). In 81% of the severe cases, versus 61% of the nonsevere cases, the CD4 counts were <50 cells/µL, but this difference was not statistically significant.

Most case patients (53%) presented with disseminated manifestations only, and 41% of case patients presented with both disseminated and pulmonary disease manifestations (table 2). Although combined pulmonary and disseminated manifestations were more common in patients with severe manifestations (57%) than in those with nonsevere manifestations (45%), the differences were not statistically significant. Specific radiographic findings were not recorded, which precluded analysis of differences in patterns of pulmonary infiltrates in severe versus nonsevere cases.

Unusual manifestations included CNS involvement in 6 patients, mouth ulcers in 3, skin lesions in 2, and pancreatitis and pericarditis in 1 each. The laboratory basis for diagnosis of histoplasmosis is shown in table 2, which shows the proportions of positive results from the tests performed. The proportions of positive diagnostic tests showed no statistically significant differences between the patients with severe cases and those with nonsevere cases.

The diagnosis of histoplasmosis occurred within 1 month of the diagnosis of HIV infection in 44% of patients with severe cases and 53% of those with nonsevere cases (table 3). The duration of illness before hospitalization and the interval between onset of symptoms and initiation of evaluation for histoplasmosis were not noted in the chart review. Of the 28 patients with severe disease, 7 (25%) were hypotensive and required treatment with dopamine, 19 (68%) had respiratory failure and required mechanical ventilation, and 20 (71%) died during the hospitalization. The timing of these complications relative to the date of admission, date of diagnosis, and date of initiation of therapy was not recorded.

Twenty-four of the patients with severe disease received AmB, 1 received ketoconazole, and 3 received no therapy. Reasons for not administering AmB to these 4 patients included underlying renal failure in 2, terminal malignancy in 1, and lack of diagnosis before autopsy in 1. By definition, none of the nonsevere cases were fatal. Obtundation was more common in the patients with severe disease (21% vs. none of those with nonsevere cases). Similar proportions of patients from each group were hospitalized (100% and 90%, respectively). Intensive care unit admission was significantly more common among patients with severe cases (61%) than among those with nonsevere cases (2%), as was hospitalization for >3 weeks (32% vs. 11%, respectively).

Univariate analysis. The results of univariate analysis are summarized in table 3. The following factors were associated with increased risk of severe outcome: black race, hemoglobin level <9.4 g/dL, partial thromboplastin time > 45 seconds, alkaline phosphatase level >2.5 times normal, aspartate aminotransferase concentration >2.5 times normal, bilirubin concentration >1.5 mg/dL, creatinine level >2.1 mg/dL, and albumin concentration <3.5 g/dL. Patients with nonsevere disease were more likely to have received zidovudine treatment before diagnosis of histoplasmosis than were those with severe disease (62% vs. 32%; P = .01).

Factors that were not significantly different between patients with severe cases and those with nonsevere cases included sex, degree of fever, amount of weight loss, level of abnormality in leukocyte or platelet count, prothrombin time, lactic acid dehydrogenase value, creatine kinase value, and CD4 cell count. The median CD4 cell count was 20 cells/µL in the patients with severe cases (range, 6–386 cells/µL) versus 32 cells/µL in the patients with nonsevere cases (range, 2–638 cells/µL; P = .10). Furthermore, antigen concentrations were similar in the patients with severe cases and those with nonsevere cases. A similar proportion of patients in both groups had high antigen concentrations (>4 units or >10 units, respectively; data not shown). Median antigen concentrations in serum were 6.2 units (range, 0.4–27.4 units) among the patients with severe cases and 3.7 units (range, 0.3–33 units) among the patients with nonsevere cases.

Median antigen concentrations in urine also were similar in patients with severe and patients with nonsevere cases: 10.5 units (range, 0.4–27.4 units) and 8.7 units (range, 0.6–36 units), respectively. No statistically significant differences were observed in urine or serum antigen values between the severe and nonsevere groups. Although not significantly different, titers of complement-fixing antibodies to Histoplasma capsulatum antigen were slightly higher in patients with severe cases than in patients with nonsevere cases. Titers of antibodies to the mycelial-phase antigen above 1∶64 were present in 27% of the patients with severe cases versus 9% of the patients with nonsevere cases (P = .08). Titers of antibodies to the yeast-phase antigen above 1∶64 were present in 27% of the patients with severe cases versus 13% of the patients with nonsevere cases (P = .20).

Multivariate analysis. The final multivariate logistic regression model included the following variables: age, race, zidovudine therapy, creatinine concentration >2.1 mg/dL, and albumin level <3.5 g/dL. CD4 cell count was not included because of the large number of missing values. The multivariate analysis found that a creatinine value >2.1 mg/dL (OR, 9.5; 95% CI, 1.7–52) and an albumin level <3.5 g/dL (OR, 4.8; 95% CI, 1.0–22) were significantly associated with an increased risk of severe disease. In addition, zidovudine therapy was independently associated with a decreased risk of severe disease (OR, 0.2; 95 CI, 0.1–0.6]).

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Discussion

Disseminated histoplasmosis may have a severe outcome in a small proportion of patients with AIDS. In a retrospective review of patients with AIDS who received AmB as treatment for disseminated histoplasmosis, 12% died [2]. Only 2% of those with nonsevere manifestations died, versus 47% of those with shock, respiratory failure, or mental-status impairment [2]. Our study showed that 70% of those with severe disease died. Death was part of the definition of severe disease in this study but not in the earlier review, and mental-status impairment was part of the definition in the earlier report but not in the current study. These differences in definition of severe disease may partially explain the higher death rate in the current report.

Triazole therapy often is administered to patients who do not have manifestations of severe disease, and the mortality associated with such therapy is low (<5%) [2–4]. However, treatment with triazoles has failed for 10%–15% of patients with “nonsevere” manifestations, a circumstance emphasizing the need to identify such patients and offer them more effective therapies [3, 4]. In this study, detailed information about therapy was not collected since our objective was to identify predictors of severe disease, not response to therapy. Prospective trials have defined the response to treatment with itraconazole [3] and fluconazole [4], and the experience with AmB has been reviewed retrospectively [2].

Demographic and laboratory factors associated with a severe course that were identified by univariate analysis included older age, black race, no previous antiretroviral therapy, hemoglobin level <9.5 g/dL, partial thromboplastin time >45 seconds, aspartate aminotransferase value >2.5 times normal, bilirubin concentration >1.5 mg/dL, creatinine concentration >2.1 mg/dL, and albumin level <3.5 g/dL. With use of a multivariate logistic regression model controlling for age and race, only creatinine elevation and hypoalbuminemia remained predictive of an unfavorable outcome, whereas having previously received zidovudine therapy was protective.

There was considerable overlap in the frequency of predictors for severe disease between the 2 severity groups. Furthermore, the ability of the study to identify additional predictors of severe disease was limited by the small sample size, the retrospective study design, and the missing data. Patients with factors that are known to be associated with severe histoplasmosis, including those identified by univariate analysis, should receive therapy with AmB or one of its lipid formulations and should be hospitalized to ensure prompt recognition and aggressive management of the more severe complications that portend a poor outcome, even with AmB therapy. Having previously received zidovudine therapy appeared to protect against severe disease. An obvious reason for protection would be improvement in immunity to H. capsulatum, but since CD4 cell counts did not differ in the 2 severity groups in the univariate analysis, this explanation was less likely. Alternatively, previous zidovudine therapy could be a marker for greater access to medical care, permitting an earlier diagnosis of histoplasmosis, before progression to more severe disease.

The small size and retrospective design of this study did not allow us to differentiate between these 2 effects of previous therapy on the outcome of histoplasmosis. In addition, the effect of more potent antiretroviral therapy on outcome could not be examined, since such therapies were not available. An ongoing prospective trial will permit more careful assessment of the effect of potent antiretroviral therapy on the course of histoplasmosis in patients with AIDS.

It is interesting that high fever, extreme weight loss, CD4 cell count, anemia, leukopenia, thromboctyopenia, coagulopathy, concentration of Histoplasma antigen in urine or serum, and titer of antibodies to Histoplasma did not correlate with severity. Unfortunately, viral load testing was not available during this study, precluding assessment of its contribution to risk of histoplasmosis. Although we failed to show an adverse relationship between CD4 count and outcome, the analysis was not ideal because of missing data on many patients.

Because of the poor outcome of AmB treatment for AIDS patients with histoplasmosis once they have developed shock or ventilatory failure, improved treatments are needed. Renal impairment is common in patients with severe disease and may prevent aggressive therapy with AmB. The newer lipid formulations of AmB cause less nephrotoxicity [5], permitting more intense therapy for such patients. A study comparing liposomal AmB (AmBisome; Vestar, San Dimas, CA) to AmB deoxycholate for treatment of histoplasmosis in patients with AIDS showed the lipid preparation to be more effective and less nephrotoxic [6]. Antifungal prophylaxis is another strategy to prevent histoplasmosis in patients with AIDS; however, a prospective placebo-controlled evaluation of itraconazole showed no effect on survival despite impressive reduction in the incidence of histoplasmosis [7].

Can the results of our study in the era that preceded potent antiretroviral therapy be applied to patients under care today? One-half to three-quarters of cases occurred at the time of initial HIV diagnosis, before any antiretroviral therapy was prescribed [1]. Therefore, such patients would not benefit from potent antiretroviral therapy. Currently, in addition to cases occurring before the diagnosis of HIV infection, cases occur in patients who know their HIV serostatus but have declined medical care and in patients whose therapy has failed because of phenotypic resistance or nonadherence to medical regimens. Therefore, our findings are relevant in this era of more potent antiretroviral therapy.

In conclusion, recognition of clinical and laboratory findings that are associated with increased risk of severe outcome should assist the clinician in management of disseminated histoplasmosis in patients with AIDS. Hospitalization for aggressive management, including antifungal and supportive therapy, appears warranted for patients with any of the findings that were associated with a poor outcome in the univariate or multivariate analysis in this study. Prospective studies to assess risk factors are in progress.

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Figures and Tables

Table 1
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Table 1

Demographic characteristics and CD4 cell counts in patients with AIDS and severe or versus nonsevere histoplasmosis.

Table 2
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Table 2

Clinical classification and laboratory basis for diagnosis of histoplasmosis.

Table 3
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Table 3

Univariate analysis of baseline findings in severe and nonsevere cases of histoplasmosis.

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Footnotes

  • Financial support: This work was sponsored in part by research funding from the AIDS Clinical Trials Group (U01AI25859) and the Research Program of the Department of Veterans Affairs.

  • Received November 17, 1999.
  • Revision received December 1, 1999.
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References

  1. ↵
    1. Wheat LJ,
    2. Connolly-Stringfield PA,
    3. Baker RL,
    4. et al
    . Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine 1990;69:361-74.
    Medline
  2. ↵
    1. Wheat L
    . Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol 1996;7:7-18.
    Medline
  3. ↵
    1. Wheat J,
    2. Hafner R,
    3. Korzun AH,
    4. et al
    . Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med 1995;98:336-42.
    CrossRefMedlineWeb of Science
  4. ↵
    1. Wheat J,
    2. MaWhinney S,
    3. Hafner R,
    4. et al
    . Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. Am J Med 1997;103:223-32.
    CrossRefMedlineWeb of Science
  5. ↵
    1. Walsh TJ,
    2. Finberg RW,
    3. Arndt C,
    4. et al
    . Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-71.
    CrossRefMedlineWeb of Science
  6. ↵
    1. Johnson P,
    2. Wheat LJ,
    3. Cloud G,
    4. et al
    . Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. Alexandria, VA: Foundation for Retrovirology and Human Health; 2000. A multicenter randomized trial comparing amphotericin B (AmB) and liposomal amphotericin B (AmBisome, LAmB) as induction therapy of disseminated histoplasmosis (DH) in AIDS patients.
  7. ↵
    1. McKinsey DS,
    2. Wheat LJ,
    3. Cloud GA,
    4. et al
    . Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999;28:1049-56.
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  1. Clin Infect Dis. (2000) 30 (6): 877-881. doi: 10.1086/313824
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