histoplasmosisguiasde manejo

8/8/2019 histoplasmosisguiasde manejo

1/8

688

Practice Guidelines for the Management of Patients with Histoplasmosis

Joe Wheat, 1,2,3 George Sarosi, 1,3 David McKinsey, 4

Richard Hamill, 5 Robert Bradsher, 7 Philip Johnson, 6

James Loyd, 8 and Carol Kauffman 9

From the Departments of 1 Medicine and 2 Pathology, IndianaUniversity School of Medicine, and 3 Department of Veterans Affairs

Hospital, Indianapolis, Indiana;4

Infectious Disease Associates of Kansas City, Missouri; 5 Department of Medicine, Houston Veterans

Affairs Medical Center, Baylor College of Medicine, and 6 Universityof Texas Medical School at Houston, Texas; 7 Department of

Medicine, University of Arkansas School of Medicine, Little Rock;8 Department of Medicine, Vanderbilt University School of Medicine,Nashville, Tennessee; and 9 Department of Medicine, Veterans Affairs

Medical Center, University of Michigan, Ann Arbor

Executive Summary

Objective. The objective of this guideline is to provide rec-ommendations for treating patients with the more commonforms of histoplasmosis.

Participants and consensus process. A working group of 8experts in this eld was convened to develop this guideline. Theworking group developed and rened the guideline through aseries of conference calls.

Outcomes. The goal of treatment is to eradicate the infec-tion when possible, although chronic suppression may be ad-equate for patients with AIDS and other serious immunosup-pressive disorders. Other important outcomes are resolution of clinical abnormalities and prevention of relapse.

Evidence. The published literature on the management of histoplasmosis was reviewed. Controlled trials have been con-ducted that address the treatment of chronic pulmonary and

disseminated histoplasmosis, but clinical experience and de-scriptive studies provide the basis for recommendations forother forms of histoplasmosis.

Value. Value was assigned on the basis of the strength of the evidence supporting treatment recommendations, with thehighest value assigned to controlled trials, according to con-ventions established for developing practice guidelines.

Benets and costs. Certain forms of histoplasmosis causelife-threatening illnesses and result in considerable morbidity,whereas other manifestations cause no symptoms or minor self-limited illnesses. The nonprogressive forms of histoplasmosis,however, may reduce functional capacity, affecting work ca-pacity and quality of life for several months. Treatment isclearly benecial and cost-effective for patients with progressive

Received 10 May 1999; revised 9 July 1999; electronically published 20April 2000.

This guideline is part of a series of updated or new guidelines from theIDSA that will appear in CID .

Reprints or correspondence: Dr. Joe Wheat, Histoplasmosis ReferenceLaboratory, 1001 West 10th St., OPW 430, Indianapolis, IN 46202 ([email protected]).

Clinical Infectious Diseases 2000;30:688952000 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2000/3004-0011$03.00

forms of histoplasmosis, such as chronic pulmonary or dissem-inated infection. It remains unknown whether treatment im-proves the outcome for patients with the self-limited manifes-tations, since this patient population has not been studied.

Other chronic progressive forms of histoplasmosis are not re-sponsive to pharmacologic treatment.

Treatment options. Options for therapy for histoplasmosisinclude ketoconazole, itraconazole, uconazole, amphotericinB (Fungizone; Bristol-Meyer Squibb, Princeton, NJ), liposomalamphotericin B (AmBisome; Fujisawa, Deereld, IL), ampho-tericin B colloidal suspension (ABCD, or Amphotec; Seques,Menlo Park, CA), and amphotericin B lipid complex (ABLC,or Abelcet; Liposome, Princeton, NJ).

Introduction

Histoplasma capsulatum is endemic in certain areas of Northand Latin America, but cases have also been reported fromEurope and Asia. In the United States, most cases have oc-curred within the Ohio and Mississippi River valleys. Precisereasons for this endemic distribution pattern are unknown butare thought to include moderate climate, humidity, and soilcharacteristics. Bird and bat excrement enhances the growth of the organism in soil by accelerating sporulation. These uniquegrowth requirements explain, in part, the localization of his-toplasmosis into so-called microfoci. Activities thatdisturbsuchsites are associatedwith exposure to H. capsulatum. Air currentscarry the spores for miles, exposing individuals who were un-aware of contact with the contaminated site. Furthermore, en-

vironmental sites that are not visibly contaminated with drop-pings may harbor the organism, making it difcult to suspecthistoplasmosis in most cases.

Severity of illness after inhalation exposure to H. capsulatumvaries, depending on the intensity of exposure and the immunityof the host. Asymptomatic infection or mild pulmonary diseasefollows low-intensity exposures in healthy individuals, whereasheavy exposure may cause severe diffuse pulmonary infection.Hematogenous dissemination from the lungs to other tissuesprobably occurs in all infected individuals during the rst 2weeks of infection before specic immunity has developed, but


2/8

CID 2000;30 (April) Treatment of Histoplasmosis 689

Table 1. Indications for antifungal treatment in patients with histoplasmosis.

Treatment indicated Treatment not indicated

Acute pulmonary his toplasmosis with hypoxemia Acute self -l imited syndromesAcute pulmonary histoplasmosis for 1 1 month Acute pulmonary histoplasmosis, mildly illChronic pulmonary histoplasmosis RheumatologicEsophageal compression and/or ulceration PericarditisGranulomatous mediastinitis with obstruction and/or invasion of tissue HistoplasmomaDisseminated histoplasmosis Broncholithiasis

Fibrosing mediastinitisa

aAntifungal therapy has not been proven to be effective for this form of histoplasmosis but should be considered,

especially in patients with elevated erythrocyte sedimentation rates or complement xation titers 1 : 32.

is nonprogressive in the majority of cases, which leads to thedevelopment of calcied granulomas in the liver and/or spleen.Progressive dissemination occurs primarily in those with un-derlying immunosuppressive disorders or those at the extremesof age. Progressive pulmonary infection is common in patientswith underlying centrilobular emphysema. A variety of acuteand chronic manifestations of histoplasmosis appear to resultfrom unusual inammatory or brotic responses to the infec-tion, including rheumatologic syndromes and pericarditis dur-ing the rst year after exposure, and chronic mediastinalinammation or brosis, broncholithiasis, and enlarging pa-renchymal granulomas occurring later. A variety of treatmentoptions are available, but rst the decision must be made totreat or to observe, since most patients with histoplasmosisrecover without therapy (table 1).

Specic Treatment Recommendations

Specic treatment recommendations for the more common

types of histoplasmosis are reviewed below and in table 2.

Acute Pulmonary Histoplasmosis

Fever, chills, headache, myalgia, anorexia, cough, and chestpain characterize this form of histoplasmosis and are seen in85%100% of cases. Patients may experience pleuritic pain. Thendings on examination are usually unremarkable, except forfever, but may include rales or pleural friction rubs.

The course after low-level exposure is benign in immuno-competent patients. Symptoms usually abate withina fewweeksof onset [1]. Therapy may be helpful in symptomatic patientswhose conditions have not improved during the rst month of

infection. Fever persisting for 1 3 weeks in acute histoplasmosismay indicate that the patient is developing progressive dissem-inated disease, which may be aborted by therapy. Whether an-tifungal therapy hastens recovery or prevents complications isunknown, since it has never been studied in prospective trials.

Patients with diffuse radiographic involvement followingmore intense exposure often experience more severe disease.They may become hypoxemic and even require ventilatory sup-port. Without treatment, recovery is usually slow and the out-come may be fatal.

Localized pulmonary histoplasmosis. Treatment is not in-

dicated in the typical patient with acute pulmonary histoplas-mosis because the illness is self-limited and associated with min-imal morbidity (EIII; see article by Sobel [2] for denitions of categories reecting the strength of each recommendation foror against its use and grades reecting the quality of evidenceon which recommendations are based).

Treatment with itraconazole, 200 mg once daily for 612weeks, should be considered for patients who have shown noclinical improvement after 1 month of observation (BIII). Bloodconcentrations of itraconazole obtained 24 h after adminis-tration of a dose could be monitored in selected situations:suspected treatment failure, concern about compliance or ab-sorption, use of medications that may reduce the solubility of itraconazole or accelerate its metabolism, and desire to reducethe dose from 200 mg twice daily to 200 mg once daily. Al-though the therapeutic concentration has not been dened,the MIC 90 of itraconazole for H. capsulatum is.02 mg/mL,whichsuggests that serum concentrations of 1 mg/mL measured bybioassay should be therapeutic. Among AIDS patients, the me-

dian plasma concentration was about 6 mg/mL for patientsreceiving a dosage of 200 mg twice daily and 3 mg/mL forthose receiving 200 mg once daily [3].

Diffuse pulmonary histoplasmosis in an immunocompetenthost. Amphotericin B, 0.7 mg/kg/d (or 1 of the lipid prepa-rations at a dose of 3 mg/kg/d for patients with renal impair-ment) should be used initially in those patients with more severemanifestations who require ventilatory supportive therapy(AIII). If amphotericin B is used exclusively because the patientcannot be treated with oral medications, a total course of 35mg/kg is recommended, but this situation is expected to be rare(AIII).

The inammatory response may contribute to the pathogen-esis of the respiratory compromise; thus, corticosteroids maybe helpful, and prednisone could be administered at a dosageof 60 mg daily for 2 weeks [4] (CIII). The role of corticosteroidsfor treating extensive pulmonary histoplasmosis in the immu-nocompromised host is less clear. Patients with AIDS and con-current disseminated histoplasmosis and Pneumocystis carinii pneumonia who received corticosteroids in conjunction withtreatment for both microbial pathogens did not appear to domore poorly than other patients treated with antifungal therapyonly.


3/8

690 Wheat et al. CID 2000;30 (April)

Table 2. Summary of treatment recommendations for treatment of patients with histoplasmosis.

Type of histoplasmosis

Severe man ifestation Moderately severe o r mild manifestat ion

Treatment Class Treatment Class

Acute pulmonary AmB with cort icosteroids,a

then Itr for 12 w AIII Symptoms ! 4 w: none; persistent symptoms

for 1 4 w: Itr for 612 w

EIII; BIII

Chronic pulmonary AmB,b

then Itr for 12-24 mo AII Itr for 1224 mo AIIDisseminated in non-AIDS AmB,

bthen Itr for 618 mo

cAII Itr for 618 mo AII

Disseminated in AIDS AmB,b

then Itr for life AII Itr for life AIIMeningitis AmB for 3 mo, then Flu for 12 mo BIII Same as for severe because of poor outcome BIIIGranulomatous mediastinitis AmB, then Itr for 612 mo BIII Itr for 612 mo BIIIFibrosing mediastinitis Itr for 3 mo

dCIII Same as nonsevere CIII

Pericarditis Corticosteroidse

or pericardial drainage BIII Nonsteroidal anti-inammatory agentsfor 212 w

BIII

Rheumatologic Nonsteroidal anti-inammatory agentsfor 212 w

BIII Same as for severe BIII

NOTE. See article by Sobel [2] for denitions of categories reecting the strength of each recommendation for or against its use and gradesreecting the quality of evidence on which recommendations are based. AmB, amphotericin B; Flu, uconazole; Itr, Itraconazole.

aEffectiveness of corticosteroids is controversial (CIII)

bIf amphotericin B is used for the entire course of treatment, 35 mg/kg should be given over 34 months.

cTherapy should continue until Histoplasma antigen concentrations are ! 4 units in urine and serum.

dTherapy is controversial and probably ineffective except in cases of granulomatous mediastinitis that are misdiagnosed as brosing mediastinitis.

e If corticosteroids are administered; concurrent antifungal therapy is recommended (CIII).

After discharge from the hospital, itraconazole, 200 mg onceor twice daily, should be used to complete a 12-week course(BIII).

Itraconazole alone, 200 mg once or twice daily for 612weeks, could be used for patients who are not sufciently ill torequire hospitalization (BIII).

Chronic Pulmonary Histoplasmosis

Patients with underlying lung disease may develop chronic

pulmonary infection after exposure to H. capsulatum. The clin-ical and radiographic ndings resemble those seen in reacti-vation tuberculosis [5]. Without treatment, the illness is pro-gressive, causing loss of pulmonary function in most patientsand death in up to half [5, 6]. In 1 study, although only 30%of cases progressed after 1 year, 79% progressed with longerobservation [5]. Although some patients improve spontane-ously, they remain at risk for recrudescence.

Treatment is indicated in all patients with chronic pulmonaryhistoplasmosis. Studies have shown amphotericin B to be ef-fective in 59%100% of cases [614] (table 3). Ketoconazoleand itraconazole are effective in 75%85% of case patients, buttheir use is also complicated by high relapse rates [1113]. Flu-

conazole, 200400 mg daily, appears to be less effective (64%response) than ketoconazole or itraconazole [14].

Itraconazole, 200 mg once or twice daily for 1224 months,is the treatment of choice for chronic pulmonary histoplasmosis(AII).

Amphotericin B, 50 mg daily, or about 0.7 mg/kg/d, is rec-ommended for patients who are judged to require hospitali-zation because of ventilatory insufciency or general debilita-tion, inability to take itraconazole because of drug interactionsor allergies, inability to absorb itraconazole, inability to achievedetectable concentrations of itraconazole in the blood, or fail-

ure to improve clinically after at least 12 weeks of itraconazoletherapy (AII). Some patients may not be able to tolerate thatdosage of amphotericin B, which justies reducing the dosageto 0.50.6 mg/kg/d or to use of 1 of the lipid formulations. If amphotericin B is administered for the full course of therapy,at least 35 mg/kg should be given at doses of 50 mg 3 timesweekly, if tolerated. In most patients, however, treatment canbe changed to itraconazole, 200 mg once or twice daily.

Fluconazole, 200400 mg daily, is less effective than ampho-tericin B or itraconazole and yielded a response rate of 64% in1 study [14]. Fluconazole could be used in patients who cannotreceive itraconazole or are unable to achieve detectable bloodconcentrations with itraconazole, but the dose should be in-creased to 400800 mg daily (BII). In a study of patients withAIDS who had disseminated histoplasmosis, 800 mg daily wasused for histoplasmosis [15].

Ketoconazole (200 mg, 400 mg, or 800 mg daily) is reason-ably effective but less well-tolerated than itraconazole or u-conazole [12, 13]. Toxicity is more common in patients receivingthe 800 mg daily dosage, which is discouraged.

Disseminated Histoplasmosis

Underlying immunosuppressive conditions and extremes of age are risk factors for dissemination, and illness is more severein immunocompromised individuals. Fever and weight loss arethe most common symptoms, and hepatomegaly or spleno-megaly are common physical ndings of disseminated histo-plasmosis. Other frequent sites of dissemination include theoropharyngeal or gastrointestinal mucosa, the skin, and theadrenal glands. Shock, respiratory distress, hepatic and renalfailure, and coagulopathy may complicate severe cases [16].CNS involvement occurs in 5%20% of cases, presenting aschronic meningitis or focal brain lesions. Histoplasma rarely


4/8


Table 3. Outcome of antifungal therapy for patients with chronicpulmonary histoplasmosis.

ReferenceAntifungal

agent

No. of patientstreated

Treatment outcome,% of patients

Responded Relapsed Died

Furcolow [6] Amphotericin B 89 59 10 16Putnam [9] Amphotericin B 32 100 NR NRSutliff [8] Amphotericin B 16 81 12 6Baum [10] Amphotericin B 56 96 9 NRParker [7] Amphotericin B 238 99 15 NRDismukes [11] Itraconazole 20 80 15 5Dismukes [12] Ketoconazole 23 74 4 NRSlama [13] Ketoconazole 7 86 NR NRMcKinsey [14] Fluconazole 11 64 29 NR

NOTE. NR, not reported.

infects the spinal cord. The mortality without treatment is 80%but can be reduced to ! 25% with antifungal therapy [6, 1122](table 4). Treatment is indicated for all patients with progressivedisseminated histoplasmosis.

In studies that mostly included immunocompetent hosts andspecically excluded those with AIDS, amphotericin B was ef-fective in 68%92% of patients [6, 17, 18], itraconazole (200400mg daily) in 100% (only 10 patients studied) [11], ketoconazole(200400 mg daily) in 56%70% [12, 13], and uconazole(200400 mg daily) in 86% [14] (table 4).

Among patients with AIDS, therapy with amphotericin Bwas effective in 74%88% of patients [19, 20], itraconazole (400mg daily for 12 weeks) in 85% [21], ketoconazole (200400 mgdaily) in 9% (only 11 cases) [16], and uconazole (800 mg dailyfor 12 weeks) in 74% [15] (table 4). Of note, patients with severe

or moderately severe clinical manifestations wereexcluded fromthe prospective studies that used itraconazole [21] and ucon-azole [15] but not from the retrospective reviews of patientstreated with amphotericin B. Of patients with severe disease,nearly half died despite treatment with amphotericin B, whereas98% of those with less severe illness responded to therapy [20].

There are no published reports about the use of the newerlipid preparations of amphotericin B for treating histoplasmosis[16]. Most patients respond to therapy rapidly, with resolutionof fever in 12 weeks. Therapy is not curative for patients withAIDS. Lifelong maintenance therapy is needed to prevent re-lapse in patients with AIDS and disseminated histoplasmosis.Amphotericin B, 50 mg given weekly or twice weekly, is highly

effective (81%97%) but inconvenient and not well-tolerated[16, 23]. Itraconazole, 200400 mg daily, was effective in atleast 90% of cases [22]. Fluconazole, 100400 mg daily waseffective maintenance therapy in 88% of patients with AIDSwho received amphotericin B induction therapy [24]. However,in a prospective study, relapse occurred in nearly one-third of patients who received uconazole, 400 mg daily, after successfulinduction therapy with uconazole, 800 mg a day [15]. In vitroresistance to uconazole developed in isolates from about half of those patients who relapsed [15].

Immunocompetent hosts and immunocompromised hosts with-

out AIDS. Amphotericin B, 0.71.0 mg/kg/d is recommendedfor patients who are sufciently ill to require hospitalization(table 2) (AII). Experience using the lipid formulations of am-photericin B for treating histoplasmosis has not been reported.

Most patients respond quickly to amphotericin B and can thenbe treated with itraconazole. The transition from amphotericinB to itraconazole therapy could occur after the patient becomesafebrile, no longer requires blood pressure or ventilatory sup-port or iv uids or nutrition, and is able to take oral medi-cations. If amphotericin B is to be used for the full course, thetotal dosage should be 35 mg/kg given over 24 months.

Itraconazole, 200 mg once or twice daily for 618 months,is the treatment of choice for patients with mild or only mod-erately severe symptoms who do not require hospitalization,and for continuation of therapy in those whose condition hasimproved in response to amphotericin B (AII).

Fluconazole should be used only in patients who cannot take

itraconazole (BII). The uconazole dosage should be at least400 mg daily in nonimmunocompromised individuals and 800mg daily in those with severe immunosuppressive conditions.H. capsulatum may develop resistance to uconazole duringtherapy, leading to relapse [25] and thus necessitating carefulfollow-up assessment, including measurement of H. capsulatumantigen concentration in blood and urine (BIII).

Ketoconazole, 200 mg once or twice daily, is also reasonablyeffective (56%70% response rate) but less well-tolerated thanitraconazole or uconazole [12, 13]. Ketoconazole could beused in some situations where itraconazole is contraindicated(BII).

Antigen testing may be useful for monitoring therapy in pa-tients with disseminated histoplasmosis. Most of the data onthe use of the antigen test for monitoring therapy are derivedfrom studies of patients with AIDS. Antigen concentrationsdecrease with therapy [16, 22] and increase with relapse [3, 26].Some investigators recommend that treatment should be con-tinued until antigen concentrations revert to negative or at leastreach low levels of 4 units. If treatment is stopped beforeantigen concentrations in urine and serum revert to negative,patients should be followed closely for relapse, and antigenlevels should be monitored every 36 months until they becomenegative (BIII).

Patients with AIDS as the cause of immunosuppression.

Therapy is divided into an initial 12-week intensive phase toinduce a remission in the clinical illness and then followed bya chronic maintenance phase to prevent relapse. A similar ap-proach may be appropriate in other patients without AIDSwho have relapsed after appropriate courses of therapy.

For induction therapy, amphotericin B is recommended forpatients who are sufciently ill to require hospitalization (table2) (AII). Amphotericin B can be replaced with itraconazole,200 mg twice daily (when the patient no longer requires hos-pitalization or iv therapy), to complete a 12-week total courseof induction therapy.


5/8


Table 4. Outcome of antifungal therapy for patients with disseminatedhistoplasmosis.

Reference(s)Antifungal

agent

No. of patientstreated

Treatment outcome,% of patients

Responded Relapsed Died

Furcolow [6] Amphotericin B 22 68 9 23Sathapatayavongs [19] Amphotericin B 43 74 7 16Reddy [17] Amphotericin B 17 76 NR 23Sarosi [18] Amphotericin B 24 91 20 8Wheat [16, 20]

aAmphotericin B 73 88 19 12

Dismukes [11] Itraconazole 10 100 NR NRWheat [21, 22] Itraconazole 59 85 5 NRDismukes [12] Ketoconazole 31 56 10 NRSlama [13] Ketoconazole 10 70 40 NRWheat [16]

aKetoconazole 11 9 50 NR

Wheat [15] Fluconazole 49 74 31b

2McKinsey [14] Fluconazole 14 86 14 7

NOTE. NR, not reported.a

These studies were done in patients with AIDS.b

Relapses occurred in patients who responded to induction therapy and continued themedication chronically for maintenance, although some of the relapses occurred in patientswho were not compliant with therapy or in those who were receiving rifampin.

Itraconazole, 200 mg 3 times daily for 3 days and then twicedaily for 12 weeks is the treatment of choice for patients whohave mild or moderately severe symptoms who do not requirehospitalization (AII).

Fluconazole, 800 mg daily, is an alternative for patients whocannot take itraconazole (BII). Patients who are receiving u-conazole should be followed closely clinically for relapse, andantigen concentrations in urine and blood should be monitoredquarterly and at the time of suspected relapse (BIII).

For maintenance therapy, the treatment of choice is itracon-

azole 200 mg once or twice daily for life (AII). Antigen con-centrations in serum and urine should be monitored every 36months to provide evidence that maintenance therapy is con-tinuing to suppress the progression of infection (BIII).

Amphotericin B, 50 mg iv once weekly, is an alternative butis not as well-tolerated or accepted by patients and should bereserved for patients who cannot take itraconazole (BII).

Fluconazole, 400800 mg daily, could be used for patientswho cannot tolerate or do not absorb itraconazole and prefernot to be treated with amphotericin B, but uconazole therapyis discouraged because of its reduced efcacy as chronic main-tenance therapy for histoplasmosis (DII). Patients receiving u-conazole should be followed closely clinically for relapse, and

antigen concentrations in urine and blood should be monitoredquarterly and at the time of suspected relapse.

For prophylaxis in immunocompromised subjects, itracon-azole is recommended. A trial comparing itraconazole, 200 mgdaily, versus placebo in patients with CD4 counts ! 150/ mLshowed a 2-fold reduction in the incidence of histoplasmosisin the itraconazole group, compared with the placebo group(6.8%2.7%) during a median follow-up period of 1 year [27].

In regions experiencing high ratesof histoplasmosis( 1 5 cases/100 patient-years), prophylaxis with itraconazole is recom-mended (200 mg once daily) (BI). Fluconazole is not an ac-ceptable alternative because of its inferior activity against H.

capsulatum , and lower efcacy for treatment of histoplasmosis[15].

CNS Histoplasmosis

Manifestations include meningitis, focal brain or spinal cordlesions, cerebrovascular accident caused by vascular involve-ment or cerebral emboli, and diffuse encephalitis [28]. Symp-toms usually have been present for months to years beforediagnosis. Fever, headache, confusion, mental status changes,

seizures, or focal neurological decits may be seen. CSF ab-normalities include lymphocytic pleocytosis, protein elevation,and hypoglycorrhachia in patients with meningitis. Single ormultiple enhancing lesions may be seen by CT scan or MRIin the brain or spinal cord of those with parenchymal involve-ment [28].

The course of the disease is progressive and fatal if nottreated, although the speed of clinical deterioration is highlyvariable [28]. The response to therapy is inferior to that in othertypes of histoplasmosis: 20%40% of patients with meningitissuccumb to the infection, despite treatment with amphotericinB, and up to half of responders relapse after therapy is dis-continued [28].

The optimal treatment for Histoplasma meningitis is un-known, but an aggressive approach is recommended becauseof the poor outcome.

Amphotericin B, 0.71 mg/kg/d to complete a 35 mg/kg totaldose over 34 months has been used most often (BIII). Flu-conazole, 800 mg daily, might be continued for another 912months after completion of amphotericin B, to reduce the riskfor relapse (BIII).

Liposomal amphotericin B (AmBisome), 35 mg/kg/d orevery other day given over a 34 month period might be con-sidered for patients who have failed therapy with amphotericinB followed by uconazole (CIII). In animal studies, liposomal


6/8


amphotericin B achieved higher concentrations in the bloodand brain than did amphotericin B or the other lipid formu-lations [29], which provides a theoretical basis for its use inmeningitis. However, neither the lipid preparation nor ampho-

tericin B achieve detectable concentrations in CSF [2931], andnone have been evaluated in cases of Histoplasma meningitis.Chronic uconazole maintenance therapy, 800 mg daily,

should be considered for patients who relapse, despite fullcourses of therapy, as described elsewhere (CIII).

Itraconazole, although more active than uconazole againstH. capsulatum, does not enter the CSF, which makes it a less-appealing choice for treatment of meningitis and discouragesits use for this indication (DIII). Of note, however, the role of CSF concentrations of antifungal agents in the outcome of treatment of fungal meningitis is unclear.

Patients who relapse despite chronic maintenance therapy arecandidates for administration of amphotericin B directly into

the ventricles, cisterna magna, or lumbar arachnoid space. Ex-perience using intrathecal or intraventricular therapy, however,has not been encouraging; this approach to therapy is dis-couraged except for patients for whom all other approaches totherapy have failed [28] (DIII).

Focal involvement of the brain or spinal cord in the absenceof meningitis may be more responsive to antifungal therapy.Of 6 such cases in persons without AIDS, all responded toamphotericin B therapy, but 2 relapsed [28]. Amphotericin Bis recommended for the initial therapy (BIII). Penetration of the CSF may not be required for successful therapy of paren-chymal lesions; thus itraconazole, 200 mg 2 or 3 times daily,may be appropriate after the patients conditions have im-

proved with amphotericin B (CIII).Parenchymal lesions rarely require surgical excision [28]

(DIII).

Granulomatous Mediastinitis

Symptoms that include chest pain, cough, hemoptysis, anddyspnea may be caused by compression of the airways, superiorvena cava, or pulmonary vessels in patients withgranulomatousmediastinitis. These syndromes represent active inammationof the mediastinal lymph nodes rather than brotic reactionsto past infection. Although symptoms are often mild and re-

solve over a few months, they may be more severe and pro-tracted. Antifungal therapy has been helpful in some cases [32,33]. Adjunctive treatment with corticosteroids appeared to havebeen benecial in 1 patient who had airway obstruction [34].Resection of obstructive masses is another approach that hasbeen helpful for patients with granulomatous mediastinitis[3538]

Amphotericin B, 0.71.0 mg/kg/d, should be considered asinitial therapy for patients with severe obstructive complica-tions of mediastinal histoplasmosis (BIII). Therapy could bechanged to itraconazole, 200 mg once or twice daily, after im-provement is sufcient for outpatient treatment.

Itraconazole, 200 mg once or twice daily for 612 months,is recommended for patients with milder manifestations thatpersist for 1 1 month (table 3) (BIII).

Prednisone, 4080 mg daily for 2 weeks, could be considered

in those with major airway obstruction (CIII).Surgical resection of the mediastinal mass should be reservedfor patients who remain symptomatic and continue to dem-onstrate obstruction of major mediastinal structures, despite atrial of antifungal therapy (BIII).

Fibrosing Mediastinitis

Fibrosing mediastinitis is a late complication of histoplas-mosis arising from nodal regions and ultimately invasion andocclusion of the central vessels and airways. Patients often re-port symptoms of several years duration at the time of diag-nosis. The course is progressive and often fatal [39, 40]. Al-though most authorities believe that neither antifungal noranti-inammatory treatment ameliorates the outcome of -brosing mediastinitis [39, 40], others have reported improve-ment after antifungal therapy [41].

Information is inadequate on which to make rm treatmentrecommendations. The progressive course of this syndrome,however, makes it difcult to withhold antifungal therapy. If the clinical ndings are consistent with a more acute inam-matory process rather than a chronic brotic process, especiallyif complement xation titers and the erythrocyte sedimentationrate are elevated, treatment may be helpful.

A 12-week trial of itraconazole, 200 mg once or twice daily,is suggested if clinical ndings do not differentiate brosingmediastinitis from granulomatous mediastinitis (CIII). Patientswho truly have brosing mediastinitis are not expected to re-spond to antifungal therapy. The only basis to prolong therapybeyond 12 weeks would be clearcut radiographic demonstrationof abatement of obstruction, in which case therapy could becontinued for 1 year.

Corticosteroid therapy has not been helpful when tried [39,42, 43] and is discouraged (DIII).

Surgery should be approached with great caution in patientswith severe complications of brosing mediastinitis and onlyin those who are expected to succumb from the condition with-out intervention. Surgeons experienced in the management of

brosing mediastinitis should be consulted (CIII).Placement of intravascular stents has been helpful in somepatients with superior vena cava, pulmonary artery, or pul-monary vein obstruction, and might be tried in patients withsevere manifestations (CIII).

Pericarditis

Pericarditis occurs in 5%10% of patients with acute histo-plasmosis and appears to be caused by the inammatory re-sponse to the infection rather than the infection per se. Thesemanifestations rarely may be a complication of disseminated


7/8


histoplasmosis [44]. Patients with pericarditis respond to non-steroidal anti-inammatory agents without antifungal therapy,but those with pericardial tamponade often require percuta-neous or surgical drainage of the pericardial uid [44]. Long-

term outcome is excellent, with only rare progression to con-strictive pericarditis [44].Antifungal therapy is not recommended (DIII).Therapy with nonsteroidal anti-inammatory agents is rec-

ommended for 212 weeks, on the basis of clinical resolutionof the symptoms and physical ndings of pericarditis (BIII).

Corticosteroids might be tried for 12 weeks in patients withhemodynamic compromise, followed by continued treatmentwith nonsteroidal anti-inammatory agents, until the clinicalndings and radiographic evidence of cardiomegaly resolved(CIII). Concurrent itraconazole, 200 mg once or twice daily for12 weeks, could be given along with corticosteroids, to reducethe concern that corticosteroids might promote progression of

the infection (CIII).Percutaneous or surgical drainage is recommended for pa-

tients with more severe ndings of pericardial tamponade orwith moderately severe evidence of hemodynamic compromisethat does not respond to corticosteroids (AIII).

There is no evidence that antifungal, anti-inammatory, orsurgical therapy prevents constrictive pericarditis (DIII).

Rheumatologic Syndromes

The arthritis is polyarticular and symmetrical in half of casesand involves joints of the upper and lower extremities with

similar frequency. Nearly half of patients with rheumatologicmanifestations exhibit erythema nodosum and/or erythemamultiforme [45, 46]. The joint symptoms usually resolve in re-sponse to treatment with nonsteroidal anti-inammatoryagents.

Antifungal therapy is not recommended (DIII).Therapy with nonsteroidal anti-inammatory agents is rec-

ommended for 212 weeks, on the basis of resolution of thesymptoms and physical ndings of arthritis and erythema no-dosum (BIII). Relapse may occur after anti-inammatory ther-apy is stopped, thus requiring reinstitution for another 48weeks.

Histoplasmosis During Pregnancy

Pregnant women with histoplasmosis should not be treatedwith azole antifungal agents because of the potential of thisclass of drugs to cause teratogenic complications.AmphotericinB, however, is safe during pregnancy and is the treatment of choice for such cases. The safety of the lipid preparations of amphotericin B during pregnancy is unknown. There is no ev-idence that histoplasmosis is more severe during pregnancy orthat dissemination occurs to the fetus.

References

1. Brodsky AL, Gregg MB, Kaufman L, Mallison GF. Outbreak of histoplas-mosis associated with the 1970 Earth Day activities. Am J Med 1973 ;54:33342.

2. Sobel JD. Practice guidelines for the treatment of fungal infections. ClinInfect Dis 2000;30:652 (in this issue).

3. Hecht FM, Wheat J, Korzun AH, et al. Itraconazole maintenance treatmentfor histoplasmosis in AIDS: a prospective, multicenter trial. J AcquirImmune Dec Syndr Hum Retrovirol 1997 ;16:1007.

4. Kataria YP, Campbell PB, Burlingham BT. Acute pulmonary histoplasmosispresenting as adult respiratory distress syndrome: effect of therapy onclinical and laboratory features. South Med J 1981 ;74:5347.

5. Rubin H, Furcolow ML, Yates JL, Brasher CA. The course and prognosisof histoplasmosis. Am J Med 1959 ;27:27888.

6. Furcolow ML. Comparison of treated and untreated severe histoplasmosis.JAMA 1963 ;183:1217.

7. Parker JD, Sarosi GA, Doto IL, Bailey RE, Tosh FE. Treatment of chronicpulmonary histoplasmosis. N Engl J Med 1970 ;283:2259.

8. Sutliff WD, Andrews CE, Jones E, Terry RT. Histoplasmosis cooperativestudy: Veterans AdministrationArmed Forces Cooperative Study on his-toplasmosis. Am Rev Respir Dis 1964 ;89:64150.

9. Putnam LR, Sutliff WD, Larkin JC, et al. Histoplasmosis cooperative study:chronic pulmonary histoplasmosis treated with amphotericin B alone andwith amphotericin B and triple sulfonamide. Am Rev Respir Dis 1968 ;97:96102.

10. Baum GL, Larkin JC, Sutliff WD. Follow-up of patients with chronic pul-monary histoplasmosis treated with amphotericinB. Chest 1970 ;58:5625.

11. Dismukes WE, Bradsher RW Jr, Cloud GC, et al. Itraconazole therapy forblastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am JMed 1992 ;93:48997.

12. Dismukes WE, Cloud G, Bowles C, et al. Treatment of blastomycosis andhistoplasmosis with ketoconazole: results of a prospective randomizedclinical trial. Ann Intern Med 1985 ;103:86172.

13. Slama TG. Treatment of disseminated and progressive cavitary histoplas-mosis with ketoconazole. Am J Med 1983 ;74:703.

14. McKinsey DS, Kauffman CA, Pappas PG, et al. Fluconazole therapy forhistoplasmosis. Clin Infect Dis 1996 ;23:9961001.

15. Wheat J, MaWhinney S, Hafner R, et al. Treatment of histoplasmosis withuconazole in patients with acquired immunodeciency syndrome. Am JMed 1997 ;103:22332.

16. Wheat LJ, Connolly-Stringeld PA, Baker RL, et al. Disseminated histo-plasmosis in the acquired immune deciency syndrome: clinical ndings,diagnosis and treatment,and review of the literature.Medicine(Baltimore)1990 ;69:36174.

17. Reddy PA, Gorelick DF, Brasher CA, Larsh H. Progressive disseminatedhistoplasmosis as seen in adults. Am J Med 1970 ;48:62936.

18. Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histo-plasmosis: results of long-term follow-up. Ann InternMed 1971 ;75:5116.

19. Sathapatayavongs B, Batteiger BE, Wheat LJ, Slama TG, Wass JL. Clinicaland laboratory features of disseminated histoplasmosis during two largeurban outbreaks. Medicine (Baltimore) 1983 ;62:26370.

20. Wheat L. Histoplasmosis in the acquired immunodeciency syndrome. Cur-rent Topics in Medical Mycology 1996 ;7:718.

21. Wheat J, Hafner R, Korzun AH, et al. Itraconazole treatmentof disseminatedhistoplasmosis in patients with the acquired immunodeciency syndrome.AIDS Clinical Trial Group. Am J Med 1995 ;98:33642.

22. Wheat J, Hafner R, Wulfson M, et al. Prevention of relapse ofhistoplasmosiswith itraconazole in patients with the acquired immunodeciency syn-drome. NIAID Clinical Trials & Mycoses Study Group Collaborators.Ann Intern Med 1993 ;118:6106.

23. McKinsey DS, Gupta MR, Riddler SA, Driks MR, Smith DL, Kurtin PJ.Long-term amphotericin B therapy for disseminated histoplasmosis in


8/8


patients with the acquired immune deciency syndrome. Ann Intern Med1989 ;111:6559.

24. Norris S, Wheat J, McKinsey D, et al. Prevention of relapse of histoplasmosiswith uconazole in patients with the acquired immunodeciency syn-drome. Am J Med 1994 ;96:5048.

25. Wheat J, Marichal P, Vanden Bossche H, Le Monte A, Connolly P. Hy-pothesis on the mechanism of resistance to uconazole in Histoplasmacapsulatum. Antimicrob Agents Chemother 1997 ;41:4104.

26. Wheat LJ, Connolly-Stringeld P, Blair R, Connolly K, Garringer T, KatzBP. Histoplasmosis relapse in patients with AIDS: detection using His-toplasma capsulatum variety capsulatum antigen levels. Ann Intern Med1991 ;115:93641.

27. McKinsey DS, Wheat LJ, Cloud GA, et al, and NIAID Mycoses. Itracon-azole prophylaxis for fungal infections in patients with advanced humanimmunodeciency virus infection: randomized, placebo-controlled, dou-ble-blind study. Clin Infect Dis 1999 ;28:104956.

28. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum in-fections of the central nervous system: a clinical review. Medicine (Bal-timore) 1990 ;69:24460.

29. Groll A, Giri N, Gonzalez C, et al. Penetration of lipid formulations of amphotericin B into cerebrospinal uid and brain tissue [abstract A90].In: 37th Interscience Conference on Antimicrobial Agents and Chemo-therapy (Toronto), 1997 :19.

30. Dugoni B, Guglielmo BJ, Hollander H. Amphotericin B concentration incerebrospinal uid of patients with AIDS and cryptococcal meningitis.Clin Pharm 1989 ;8:2201.

31. Leenders A, Reiss P, Portegies P, et al. Liposomal amphotericin B (Am-Bisome) compared with amphotericin B both followed by oral uconazolein the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997 ;11:146371.

32. Savides TJ, Gress FG, Wheat LJ, Ikenberry S, Hawes RH. Dysphagia dueto mediastinal granulomas: diagnosis with endoscopic ultrasonography.Gastroenterology 1995 ;109:36673.

33. Maholtz MS, Dauber JH, Yousem SA. Fluconazole therapy in Histoplasmamediastinal granuloma. Am J Med Sci 1994 ;307:2747.

34. Greenwood MF, Holland P. Tracheal obstruction secondary to Histoplasmamediastinal granuloma. Chest 1972 ;62:6425.

35. Gilliland MD, Scott LD, Walker WE. Esophageal obstruction caused by

mediastinal histoplasmosis: benecial results of operation. Surgery 1984 ;95:5962.

36. Woods LP. Mediastinal Histoplasma granuloma causing tracheal compres-sion in a 4-year-old child. Surgery 1965 ;58:44852.

37. Garrett HE Jr, Roper CL. Surgical intervention in histoplasmosis. AnnThorac Surg 1986 ;42:71122.

38. Landay MJ, Rollins NK. Mediastinal histoplasmosis granuloma: evaluationwith CT. Radiology 1989 ;172:6579.

39. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal brosis com-plicating histoplasmosis. Medicine (Baltimore) 1988 ;67:295310.

40. Goodwin RA, Nickell JA, Des Prez RM. Mediastinal brosis complicatinghealed primary histoplasmosis and tuberculosis. Medicine (Baltimore)1972 ;51:22746.

41. Urschel HC Jr, Razzuk MA, Netto GJ, Disiere J, Chung SY. Sclerosingmediastinitis: improved management with histoplasmosis titer and keto-conazole. Ann Thorac Surg 1990 ;50:21521.

42. Mathisen DJ, Grillo HC. Clinical manifestations of mediastinal brosis andhistoplasmosis. Ann Thorac Surg 1992 ;54:10538.

43. Dines DE, Payne WS, Bernatz PE, Pairolero PC. Mediastinal granulomaand brosing mediastinitis. Chest 1979 ;75:3204.

44. Wheat LJ, Stein L, Corya BC, et al. Pericarditis as a manifestation of his-toplasmosis during two large urban outbreaks.Medicine(Baltimore) 1983 ;62:1109.

45. Ozols II, Wheat LJ. Erythema nodosum in an epidemic of histoplasmosis inIndianapolis. Arch Dermatol 1981 ;117:70912.

46. Sellers TF Jr, Price WN Jr, Newberry WM Jr. An epidemic of erythemamultiforme and erythema nodosum caused by histoplasmosis. Ann InternMed 1965 ;62:124462.

histoplasmosisguiasde manejo

Documents