Infecciones Cerebrales En Vih

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Cerebral Infections in AIDS: Coccidioidomycosis, Histoplasmosis, and Other Fungal Infections Michael J.G. Harrison, DM, FRCP, Justin C. McArthur, MBBS, MPH Infect Med 15(7):474-478, 1998. © 1998 Cliggott Publishing, Division of SCP Communications

Abstract and Introduction Abstract AIDS patients are at risk for CNS fungal infections in addition to cryptococcal meningitis. Amphotericin B is the drug of choice for treating most of these infections. Introduction In addition to cryptococcal meningitis, patients with AIDS are susceptible to other central nervous system (CNS) fungal infections. These include coccidioidal meningitis, extrapulmonary histoplasmosis, blastomycosis, nocardiosis, and even candidal meningitis.

Coccidioidal Meningitis Coccidioides immitis is a dimorphic fungus that is common in soil. It is endemic in low-altitude, warm, arid areas. In the US, this includes the Southwest (California, New Mexico, and Texas). Infection is acquired through the respiratory route, and meningitis occurs early, with higher risk among non-Caucasians.[1] Ampel and colleagues[2] followed 170 HIV-infected patients in an endemic area (Tucson, Ariz.). Thirteen developed active coccidioidomycosis, with an estimated cumulative incidence of 25% after 41 months. A CD4 count below 250/mm3 and a diagnosis of AIDS predicted active infection. Prior infection, a positive skin test, and long-term residence in the area did not appear to be risk factors. This suggests that AIDS patients are at risk for primary, rather than reactivated, infection. Coccidioidal meningitis can present as either an acute or chronic granulomatous meningitis with fever, headache, weight loss, and in about 50% of patients, encephalopathy. Meningismus (neck stiffness) is less common than with cryptococcal meningitis and is seen in one third of patients. Papilledema, cranial nerve signs, and other focal findings are seen in approximately 10%. Skin and lung lesions are fairly frequent. Polymorphonuclear leukocytes predominate early in the infection, but mononuclear cells predominate later. Cerebrospinal fluid (CSF) shows an elevated protein and hypoglycorrhachia, and culture is positive in one half of cases. The CSF pleocytosis is variable, from 50 to 200 cells/mm3, and occasionally several thousand cells/mm3 are seen in late stages. The diagnosis is established by serologic tests. A positive CSF titer, a complement fixation titer, or a serum titer of 1:16 suggests active infection. Approximately 75% of patients with coccidioidal meningitis have detectable antibody in their CSF. The sensitivity of detection can be increased to 95% with an overnight binding complement fixation (CF) assay and to 100% with radioimmunoassay (RIA).[3] Rising CF titers in serum or CSF are associated with disease progression, while falling titers parallel clinical improvement. Enzyme immunoassay (EIA) using a combination of coccidioidal antigens is the method of choice for diagnosing infection. In CSF it yields a sensitivity of 100% and a specificity of 96%, as well as providing information about

disease stage.[3] False-negative serologic reactions appear to be uncommon. Imaging may reveal enhancement of the meninges or hydrocephalus due to ependymitis. Multiple abscesses may develop. The recommended treatment is amphotericin B 1.5mg/kg/day IV and amphotericin B 0.5mg intrathecally, 2 doses per week, or intraventricular amphotericin B. C immitis is not sensitive to 5flucytosine.[4] Treatment should be continued for several months, until the CSF has returned to normal.[5,6] Therapeutic responses should be monitored by lumbar puncture, not by analysis of CSF obtained from a ventricular reservoir, because ventricular fluid may be relatively normal even when lumbar fluid is markedly abnormal.[7] Fluconazole has been used in coccidioidal meningitis.[8,9] Trials using 400mg/day showed efficacy in suppressing coccidiodal meningitis.[10]

Histoplasmosis Histoplasmosis occurs in 2% to 5% of AIDS patients from endemic areas of the central US, Latin America, and the Caribbean. Cases may also occur outside endemic areas. Outdoor workers who have contact with spores in soil, such as those in construction or farming, are at particularly high risk. The majority of AIDS-related histoplasmosis occurs with a CD4 count lower than 100/mm3. Histoplasma capsulatum is a typical dimorphic yeast present in soil and in bird and bat feces in endemic areas—usually river valleys such as the Ohio, Mississippi, and St. Lawrence. Infection develops after inhaling airborne spores. Although histoplasmosis remains a common cause of deep-seated fungal infections in North America, CNS abscesses or histoplasmoma are unusual.[11,12] A more common neurologic manifestation is meningitis, which is seen in up to 8% of all cases and in one quarter of those with disseminated disease. In 1987, extrapulmonary histoplasmosis was added to the Centers for Disease Control (CDC) list of AIDS-defining illnesses.[13] Histoplasmosis in AIDS is usually a severe disseminated infection (Table I), often resembling septicemia. In the largest review to date,[14] 72 patients with AIDS and histoplasmosis were reviewed (Table II). Fifty-three percent had pulmonary involvement, 13% a septicemia-like syndrome, 26% hepatomegaly, and 18% CNS involvement. These included encephalopathy, meningitis, and focal abscesses. Eight of 13 patients with CNS histoplasmosis died of the infection. The diagnosis of histoplasmosis was made by positive fungal cultures for H capsulatum in over 90% of the cases, and in the remainder by detecting histoplasma polysaccharide antigen (HPA) in body fluids (detected in 97%). An increase of HPA in serum or urine of >/=2 units detected relapse in 6 of 9 cases in this series. The organism can be cultured from bone marrow, lymph nodes, or ulcers. CSF culture is often negative. The most sensitive tests to detect H capsulatum polysaccharide antigen in body fluids are RIA or EIA. Results are expressed as HPA units, and values of 1 or more are considered positive. Sensitivity is 90% to 97%.[15] Serologic diagnosis by antibody detection is not reliable because of high false-positive rates in patients from endemic areas and in patients with other fungal or bacterial infections. In patients with AIDS and histoplasmosis, the appearance of antigen in blood or urine heralds a relapse.[16] Treatment of histoplasmoma requires a combination of surgical drainage and intravenous amphotericin B 0.6 to 1.0mg/kg/day until there is radiologic evidence of improvement. In the largest review to date,[14] 80% of cases improved after induction therapy with amphotericin B, the majority defervescing within 1 week. Ketoconazole was effective in preventing relapse.

Blastomycosis Blastomyces dermatitidis is another dimorphic yeast that is endemic in the south and south central US and in the Great Lakes area. Seeding of the CNS can occur after dissemination from a respiratory focus. Meningitis occurs in about 5% of cases, and mass lesions or blastomycomas

can develop occasionally. CSF culture is rarely positive. An EIA using purified antigen A has a high sensitivity for blastomycosis and good specificity, and distinguishes blastomycosis from coccidioidomycosis. False-positive results occur in some cases of histoplasmosis and sporotrichosis.[17] Experience is limited, but the recommended treatment at this time is intravenous amphotericin B, at least 2g.[4]

Nocardiosis Nocardia asteroides is an aerobic saprophytic actinomycete that exhibits fungal characteristics (true aerial hyphae) but is considered to be a higher bacterium because its cell wall contains peptidoglycans. It is a thin (0.5-1.0mcg), branching, and often beaded, gram-positive rod. It is found ubiquitously in soil, and infection is usually acquired through inhalation. Hematogenous dissemination occurs in immunosuppressed HIV-positive patients. Nocardiosis is an uncommon opportunistic infection in AIDS. One clue to its presence is an acute necrotizing pneumonia that is associated with cavitation. Patients are usually systemically ill, with fever, cough, and weight loss. Dissemination to the brain commonly presents with focal cerebritis and contrast-enhancing mass lesions (Fig. 1). The differential diagnosis includes neoplasms, tuberculosis, and fungal disease.

Figure 1. Cranial MRI of nocardiosis showing multiple scattered contrast-enhancing lesions. Serologic diagnosis is limited because of cross-reactivity with other related organisms, including

other Nocardia species and mycobacteria. Histologic confirmation from tissue and culture is the diagnostic gold standard. Species identification can be accomplished by a combination of biochemical tests. Cultures grow slowly, so plates should be incubated for at least 10 days. Nocardia is extremely sensitive to sulfonamides; clinical improvement should begin within 7 to 10 days of treatment. Trimethoprim-sulfamethoxazole (1 double-strength tablet bid) can be used and should be continued lifelong. In patients who are allergic to sulfa drugs or in whom Nocardia is resistant, an alternative is minocycline 200mg bid. For severely ill patients, the combination of cefotaxime 2g IV every 8 hours with imipenem/cilastatin (500mg IV every 6 hours) may be effective. This particular combination has shown in vitro synergism. Amikacin, an aminoglycoside, also has very good activity against Nocardia.

Other Fungal Infections Despite the frequency of oropharyngeal and esophageal candidiasis in AIDS, candidal brain abscess is relatively rare, and candidal meningitis even rarer. Several AIDS patients with candidal microabscesses have been reported.[18] Diagnosis should be suspected when multiple microabscesses develop in the setting of candidal septicemia. Diagnosis is confirmed by culture of biopsied tissue. Similarly, despite the relative frequency of Aspergillus infections in patients with hematologic neoplasms or neutropenia, or in those receiving immunosuppressive drugs, CNS infections with Aspergillus species are rare in patients with AIDS. Like other molds, Aspergillus has a predilection for invading blood vessel walls and causing thrombosis, infarction, and hemorrhage. Meningitis without cerebritis is uncommon. Because of the vasocentric nature of the infection, the neurologic presentation is often one of stroke or subarachnoid hemorrhage. Generally, infection is spread hematogenously with multiple small abscesses and microabscesses (Fig. 2). The CSF is nonspecifically abnormal, and CSF culture is usually negative.[19] Current serologic tests are insensitive, although immunoassays based on Aspergillus fumigatus antigens are being developed.[20]

Figure 2. Postmortem appearance of cerebellum showing multiple aspergillus abscesses. The diagnosis of aspergilloma should be strongly suspected in an immunosuppressed HIVpositive patient who presents with a stroke or an intracranial hemorrhage and has single or multiple contrasted enhancing lesions. As with candidal infection, treatment consists of a combination of surgery and amphotericin B. Concomitant therapy with rifampin or 5-flucytosine has been tried.

Management of Fungal Meningitis AIDS patients with overt meningitis or with a short history of headaches, confusion, or fever may have a fungal infection of the CNS. After imaging studies have been performed to rule out unexpected mass lesions, a lumbar puncture should be done. The pressure should be noted, and the fluid should be screened with appropriate stains, including india ink, and cultured on appropriate media. Cryptococcal antigen titers should be measured. MRI may show dilated Virchow-Robin spaces or cryptococcomas. If any of these investigations point to a cryptococcal infection, amphotericin B should be prescribed, to which 5-flucytosine may have to be added. After a satisfactory clinical response, prophylaxis against relapse requires continuing treatment with fluconazole. Some cases respond poorly and need intensified antifungal treatment as well as management of raised intracranial pressure. In endemic areas, CSF coccidioidomycosis antibody and blood and urine histoplasma antigen should be measured. Amphotericin B is the mainstay of treatment.

Tables Table I. Clinical Findings of Severe Histoplasmosis in AIDS

Hypotension Hypoxia Altered mentation Rhabdomyolysis Coagulopathy Pancytopenia Hepatic enzyme elevation Renal failure

Table II. Clinical Findings of Histoplasmosis

Finding

Wheat series (n = 72) Literature (n = 51) No.

%

No.

%

Respiratory system

38

52.8

8

15.7

Hepatomegaly

19

26.4

15

29.4

Splenomegaly

9

12.5

18

35.3

Lymphadenopathy

12

16.7

19

37.3

Central nervous system

13

18.0

7

13.7

Skin

1

1.4

9

17.6

Septicemia-like syndrome

9

12.5

5

9.8

Gastrointestinal tract

2

2.8

6

11.8

Mucosa

1

1.4

0

0

Adapted from N Engl J Med (1986; 314:83-88), Copyright © 1986, Massachusetts Medical Society.[15]

References

1. Bouza E, Dreyer JS, Hewitt WL, et al: Coccidioidal meningitis. An analysis of 31 cases and review of the literature. Medicine 60:139-172, 1981.

2. Ampel NM, Dols CL, Galgiani JN: Coccidioidomycosis during human immunodeficiency virus infection: Results of a prospective study in a coccidioidal endemic area. Am J Med 94:235-240, 1993.

3. Gade W, Ledman DW, Wethington R, et al: Serological responses to various coccidioides antigen preparations in a new enzyme immunoassay. J Clin Microbiol 39:1907-1912, 1992.

4. Tucker T, Ellner JJ: Chronic meningitis, in Scheld WM, Whitley RJ, Durack DT (eds): Infections of the Central Nervous System. New York, Raven Press, 1991, pp 703-728.

5. Zealear DS, Winn WA: The neurosurgical approach in the treatment of coccidioidal meningitis: Report of ten cases, in Allejo L (ed): Coccidioidomycosis. Tucson, University of Arizona Press, 1967, pp 43-53.

6. Post MJ, Kursunoglu SJ, Hensley GT, et al: Cranial CT in acquired immunodeficiency syndrome: Spectrum of disease and optimal contrast enhancement technique.

Roentgenology 145:929-940, 1985.

7. Goldstein E, Winship MS, Pappagianis D: Ventricular fluid and the management of coccidioidal meningitis. Ann Intern Med 77:243-246, 1972.

8. Tucker RM, Galgiani JN, Denning DW, et al: Treatment of coccidioidal meningitis with fluconazole. Rev Infect Dis 12(suppl 3): S380-S389, 1990.

9. Tucker RM, Denning DW, Dupont B, et al: Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 112:108-112, 1990. 10. Galgiani JN, Catanzaro A, Cloud GA, et al: Fluconazole therapy for coccidioidal meningitis. Ann Intern Med 119:28-35, 1993.

11. Goodwin RA, Shapiro JL, Thurman GH, et al: Disseminated histoplasmosis: Clinical and pathological correlations. Medicine (Baltimore) 59:1-33, 1980.

12. Walpole HT, Gregory DW: Cerebral histoplasmosis. South Med J 80:1575-1577, 1987. 13. Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 36(suppl 1S):S3-S15, 1987.

14. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al: Disseminated histoplasmosis in the acquired immune deficiency syndrome: Clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 69(6):361-374, 1990.

15. Wheat LJ, Kohler RB, Tewari RP: Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med 314:83-88, 1986.

16. Wheat TT, Connolly-Stringfield PA, Blair P, et al: Histoplasmosis relapse in patients with AIDS: Detection using Histoplasma capsulatum variety capsulatum antigen levels. Ann Intern Med 115:936-941, 1991.

17. Green JH, Harrell WK, Johnson JE, et al: Isolation of an antigen from blastomyces

dermatitidis that is specific for the diagnosis of blastomycosis. Curr Microbiol 4:293-296, 1980.

18. Snider WD, Simpson DM, Neilsen S, et al: Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neurol 14:403-418, 1986.

19. Boon AP, O'Brien D, Adams DH: Ten-year review of invasive aspergillosis detected at necropsy. J Clin Pathol 44:452-454, 1991. 20. Kurup VP, Kuamar A: Immunodiagnosis of aspergillosis. Clin Microbiol Rev 4:439-456, 1991.

Sidebar: Drugs Mentioned in This Article Amikacin

Amikin, generic

Amphotericin B

Generic

Cefotaxime

Claforan

5-flucytosine

Ancobon

Fluconazole

Diflucan

Gentamicin

Generic

Imipenem/cilastatin

Primaxin

Itraconazole

Sporanox

Ketoconazole

Nizoral

Minocycline

Dynacin

Rifampin

Generic

Trimethoprim/ sulfamethoxazole Bactrim, Cotrim, generic

Dr. Harrison is Professor of Neurology, Reta Lila Weston Institute of Neurological Studies, University College London, School of Medicine, London, UK. Dr. McArthur is Professor of Neurology and Epidemiology, Johns Hopkins University School of Medicine, Baltimore, Md.