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CliniCal Case of the Month

A 31-Year-Old Man With AIDS, Fever, and a Rash

Faisal Musa, MD; Jorge A. Martinez, MD, JD; Raisa Martinez, MD; Catherine Hebert, MD; Matthew Safley, DO; David Smith, MD;

Fred A. Lopez, MD (Section Editor)

CASE PRESENTATION

A 31-year-old man came to the emergency department complaining of two-week history of intermittent subjective fevers, night sweats, chills, and nonpruritic rash, which started over his right upper extremity and spread to the rest of the body. Watery diarrhea developed four days prior to admission. He complained of headache and photophobia, but denied neck pain. He also complained of poor appetite, fatigue, and unintentional weight loss of approximately 15 to 20 pounds over a period of three months. He denied shortness of breath, cough, or chest pain.

He had a past medical history of acquired immunode-ficiency syndrome (AIDS) with a CD4 cell count of 37cells/mm3 one year prior, cryptococcal meningitis, and pulmonary tuberculosis. He had not been seen in the human immuno-deficiency virus (HIV) outpatient clinic for one year and had stopped taking antiretroviral treatment and opportunistic infection prophylaxis. He moved to New Orleans from Hon-duras seven years ago, and he works currently as a painter.

In the emergency department, the patient was ill-ap-pearing with diaphoresis, tachycardia, and a rapid respira-tory rate that was not labored. His temperature was 106˚F, heart rate was 130 beats/minute, blood pressure 100/67 mm Hg, respiratory rate 24/min, and oxygen saturation at 100% on room air. He weighed 80 kilograms and was 165 centi-meters tall; the body mass index was 21.3. Physical exam was remarkable for a purple, non-blanching, maculopapular on his face, trunk, and arms lesions. There was no central clearing, blistering, vesicles, or desquamation (Figure 1).

An arterial blood gas revealed a pH 7.46, PCO2 28 mm Hg, PaO2 69 mm Hg, bicarbonate 21 mmol/L, and O2 saturation 97%. The alveolar-arterial gradient (A-a gradient) was 99.5 torr. His complete blood count and comprehensive metabolic profile were normal except for an elevated LDH of 561 U/L (Reference Range <201 U/L). His CD4 cell count was 104 cells/mm3 (Reference Range is 228-2290), and the CD4% was 10.8 % (Reference Range is 37-63 %). His lumbar puncture was negative for evidence of blood or infection.

His chest X-ray showed a patchy nonhomogeneous opacity consistent with pneumonia in the lingular division of the left upper lobe (Figure 2).

He was placed in respiratory isolation and empiri-cally administered trimethoprim-sulfamethoxazole and prednisone for Pneumocystis jiroveci pneumonia (PJP); fluconazole for possible fungal infection; and vancomycin, cefepime, and azithromycin for bacterial pneumonia. Three acid-fast bacillus (AFB) smears were negative. Cryptococcal

Figure 1: Purple, non-blanching, maculopapular rash on the back.

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antigen studies of the blood and cerebrospinal fluid were negative. The skin biopsy and urine antigen tests were positive for histoplasmosis (Figures 3, 4). The patient was initially treated with liposomal amphotericin and was later switched to itraconazole. Antiretroviral therapy was to be initiated in outpatient clinic setting.

DISCUSSION

Epidemiology and EtiologyHistoplasma capsulatum is a thermally dimorphic

fungus, growing as a mold in the environment and as a yeast at 37oC. Infection develops when Histoplasma micro-conidia are inhaled into the lungs, where they change from a filamentous to a yeast form. Neutrophils, macrophages, lymphocytes, and natural killer (NK) cells are attracted in response to the infection. As in tuberculosis, macrophages assist in dissemination of the organism via lymphatics and the blood to the adjacent lymph nodes and throughout the reticuloendothelial system (liver, spleen, lymph nodes, adrenal glands, and bone marrow).1 T cell immunity plays the predominant role in recovery from Histoplasma infec-tion. Once cellular immunity to Histoplasma develops, macrophages become activated to kill the organism. Cyto-kines, including interleukin (IL)-12 and interferon-gamma (IFN-gamma), assist macrophages in eradicating the fungus and halting progression of disease.2-4 Histoplasmosis is an important infectious disease among patients with advanced AIDS and continues to cause severe morbidity and mortality in endemic areas such as Mississippi, Ohio, the St. Lawrence River valleys, the Caribbean, southern Mexico, certain parts

of Central and South America, Africa, and Asia.5

Risk FactorsMost patients with disseminated histo-

plasmosis have underlying conditions that impair their ability to defend against intracel-lular pathogens. These conditions include HIV infection with CD4 count <100 cells/microL, primary immunodeficiency or other immu-nosuppressive disorders, use of immunosup-pressive medications such as glucocorticoids, antirejection therapies in solid organ transplant recipients, TNF-alpha inhibitor therapies, and extremes of age.6-8 A separate group of patients, most of whom are middle-aged to older men, have chronic progressive disseminated histo-plasmosis and have no known underlying im-munosuppression. In these patients, unidenti-fied defects in cellular immunity likely explain their inability to control the infection.9

Clinical PresentationIn the immunocompetent host, histo-

plasmosis can present as a mild self-limiting pulmonary illness.10 However, patients with advanced AIDS or immunosuppression may

develop progressive disseminated histoplasmosis (PDH). They may present with lymphadenopathy, mucocutaneous lesions, hepatosplenomegaly, pancytopenia, transaminitis, altered mental status, neurological abnormalities, nausea, vomiting, diarrhea, weight loss, and fever. Approximately 40%-50% of AIDS patients with PDH have pulmonary involvement, often presenting with cough and dyspnea. Isolated pulmonary involvement without dissemination occurs in less than 5% of cases. Ten to fifteen percent of pa-tients with disseminated histoplasmosis have skin lesions.7 Adrenal glands are affected in approximately 80%-90% of autopsied cases, but overt adrenal insufficiency is unseen in less than 10% of the cases.6 Central nervous system involve-ment may manifest as encephalitis, meningitis, focal brain, or spinal cord lesions.11

Characteristics of severe disease include a sepsis-like syndrome with multi-organ failure (including respiratory or renal failure) or concomitant meningitis. Despite ap-propriate therapy, mortality rates can be as high as 50% in patients with AIDS.8,13 Patients with chronic disseminated histoplasmosis are usually non-immunocompromised and often present with pancytopenia, hepatosplenomegaly, hepatic enzyme elevation, and oropharyngeal or gastroin-testinal lesions. Other sites of involvement may also include the skin, brain, and lungs, especially with underlying lung disease like emphysema and adrenal glands.12

Diagnostic EvaluationThere are multiple diagnostic tests for disseminated

Histoplasma capsulatum infection, including culture, serol-

Figure 2: A posteroanterior radiograph of the thorax demonstrates ill-defined, patching opacity in the lingula, partially obscuring the inferior left heart border. There is no evidence of dense consolidation or pleural effusion.

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ogy, antigen testing, and direct microscopy; the diagnostic yield will depend on the stage of disease.14 In HIV-associated disseminated disease, the most sensitive and specific test is detection of Histoplasma antigen.15,16 In one case report the Histoplasma antigen was detected in the following samples: urine (97%), blood (83%), and cerebrospinal fluid (67%).8 Direct microscopy can rapidly make the diagnosis by visu-alization of the organism within cells on a Wright’s stained smear of either peripheral blood or a buffy coat. This method allows rapid identification and is very inexpensive, although the sensitivity is low (less than 10%).15,17 Histopathologic examination of tissues has a sensitivity that is similar to direct microscopy; stains for fungi performed on skin biopsy specimens revealed the organism in 86%-100% of cases of HIV-associated disseminated histoplasmosis.18,20 Standard serology has limited value.8 Culture of blood, respiratory samples, or other tissues (eg. bone marrow) remains the “gold standard” for diagnosis.19

Treatment and ProphylaxisThe treatment for mild-to-moderate disseminated

histoplasmosis is oral itraconazole for at least 12 months.18 For moderately severe and severe disseminated disease, therapy should be initiated as soon as possible due to a high mortality rate. One or two weeks of induction therapy with daily intravenous liposomal amphotericin B (preferred over the other amphotericin formulations due to its greater efficacy, lower nephrotoxicity, and better overall survival) or until symptoms improve is recommended, after which time the patient can be switched to oral itraconazole.14,18,21 Suppressive therapy with daily oral itraconazole prevents relapse in up to ninety five percent of cases and should be administered continually after completion of one-year main-tenance therapy and can be discontinued safely if patients

fulfill the following criteria: completion of a minimum of one-year maintenance therapy, histoplasma antigen levels are negative or remain low (<2 ng/mL), blood cultures are negative, CD4 cell counts have increased to >150 cells/microL.18,22-25 The 2009 NIH/CDC/IDSA guidelines recom-mend consideration of prophylactic itraconazole for patients with a CD4 count below 150/microL who are at high risk because of occupational exposure or who live in hyperen-demic area with histoplasmosis.14

REFERENCES

1. Deepe, G. S., Jr, W. E. Bullock. 1992. Histoplasmosis: a granulomatous inflammatory response. J. I. Gallin, Jr, and I. M. Goldstein, Jr, and R. Snyderman, Jr, eds. Inflammation: Basic Principles and Clinical Correlates. New York: Raven Press, 1992:943-958.

2. Zhou P, Sieve MC, Tewari RP, Seder RA. Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum. Infect Immun 1997; 65:936-942.

3. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261-1265.

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5. Murray JF, Mills J. Pulmonary infectious complications of human immunodeficiency virus infection. Part II. Am Rev Respir Dis 1990; 141:1582-1598.

6. Goodwin RA Jr, Shapiro JL, Thurman GH, et al. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980; 59:1-31.

7. Assi MA, Sandid MS, Baddour LM, et al. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007; 86:162-169.

8. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome:

Figure 3: Periodic acid schiff stain demonstrating histoplasma yeast forms.

Figure 4: Grocott’s methenamine silver stain demonstrating yeast forms of histoplasma.

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clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990; 69:361-374.

9. Wheat LJ, Slama TG, Norton JA, et al. Risk factors for disseminated or fatal histoplasmosis. Analysis of a large urban outbreak. Ann Intern Med 1982; 96:159-163.

10. Goodwin RA Jr, Shapiro JL, Thurman GH, et al. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980; 59:1-33.

11. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system. A clinical review. Medicine (Baltimore) 1990; 69:244-260.

12. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007; 20:115-132.

13. Shelburne SA 3rd, Visnegarwala F, Adams C, et al. Unusual manifestations of disseminated Histoplasmosis in patients responding to antiretroviral therapy. Am J Med 2005; 118:1038-1041.

14. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009 Apr 10;58(RR-4):1-207.

15. Baddley JW, Sankara IR, Rodriquez JM, et al. Histoplasmosis in HIV-infected patients in a southern regional medical center: poor prognosis in the era of highly active antiretroviral therapy. Diagn Microbiol Infect Dis 2008; 62:151-156.

16. Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 2011; 53:448-454.

17. Nightingale SD, Parks JM, Pounders SM, et al. Disseminated histoplasmosis in patients with AIDS. South Med J 1990; 83:624-630.

18. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45:807-825.

19. Couppié P, Aznar C, Carme B, Nacher M. American histoplasmosis in developing countries with a special focus on patients with HIV: diagnosis, treatment, and prognosis. Curr Opin Infect Dis 2006; 19:443-449.

20. Jeannette Guarner and Mary E. Brandt. Histopathologic Diagnosis of Fungal Infections in the 21st Century. Clin Microbiol Rev. 2011 April; 24(2): 247–280.

21. Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002; 137:105-109.

22. Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore) 1997; 76:339-354.

23. McKinsey DS, Gupta MR, Riddler SA, et al. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 111:655-659.

24. Hecht FM, Wheat J, Korzun AH, et al. Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:100-107.

25. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004; 38:1485-1489.

Dr. Musa is a fourth-year Resident in Internal Medicine-Pediatrics at Louisiana State University School of Medicine in New Orleans. Dr. Jorge Martinez is a Professor and Program Director of the Internal Medicine and Emergency Medicine-Internal Medicine training programs at LSU Health Sciences Center in New Orleans. Dr. Raisa Martinez is a second-year Resident in Neurology at LSU School of Medicine in New Orleans. Dr. Hebert is an Associate Professor and Associate Program Director of the Internal Medicine training program at LSU Health Sciences Center in New Orleans. Dr. Safley is a fourth-year Resident in Pathology and Chief Resident at LSU School of Medicine in New Orleans. Dr. Smith is an Assistant Professor at LSU School of Medicine in New Orleans, Department of Radiology. Dr. Lopez is the Richard Vial Professor of Medicine and Vice Chair in the Department of Medicine at LSU School of Medicine in New Orleans, Louisiana.