688

Practice Guidelines for the Management of Patients with Histoplasmosis

Joe Wheat,1,2,3 George Sarosi,1,3 David McKinsey,4 From the Departments of 1Medicine and 2Pathology, Indiana
Richard Hamill,5 Robert Bradsher,7 Philip Johnson,6 University School of Medicine, and 3Department of Veterans’ Affairs
James Loyd,8 and Carol Kauffman9 Hospital, Indianapolis, Indiana; 4Infectious Disease Associates of
Kansas City, Missouri; 5Department of Medicine, Houston Veterans
Affairs Medical Center, Baylor College of Medicine, and 6University
of Texas Medical School at Houston, Texas; 7Department of
Medicine, University of Arkansas School of Medicine, Little Rock;
8
Department of Medicine, Vanderbilt University School of Medicine,
Nashville, Tennessee; and 9Department of Medicine, Veterans Affairs
Medical Center, University of Michigan, Ann Arbor

Executive Summary forms of histoplasmosis, such as chronic pulmonary or dissem-

inated infection. It remains unknown whether treatment im-
Objective. The objective of this guideline is to provide rec-
proves the outcome for patients with the self-limited manifes-
ommendations for treating patients with the more common
tations, since this patient population has not been studied.
forms of histoplasmosis.
Other chronic progressive forms of histoplasmosis are not re-
Participants and consensus process. A working group of 8
sponsive to pharmacologic treatment.
experts in this field was convened to develop this guideline. The Treatment options. Options for therapy for histoplasmosis
working group developed and refined the guideline through a include ketoconazole, itraconazole, fluconazole, amphotericin
series of conference calls. B (Fungizone; Bristol-Meyer Squibb, Princeton, NJ), liposomal
Outcomes. The goal of treatment is to eradicate the infec- amphotericin B (AmBisome; Fujisawa, Deerfield, IL), ampho-
tion when possible, although chronic suppression may be ad- tericin B colloidal suspension (ABCD, or Amphotec; Seques,
equate for patients with AIDS and other serious immunosup- Menlo Park, CA), and amphotericin B lipid complex (ABLC,
pressive disorders. Other important outcomes are resolution of or Abelcet; Liposome, Princeton, NJ).
clinical abnormalities and prevention of relapse.
Evidence. The published literature on the management of
histoplasmosis was reviewed. Controlled trials have been con- Introduction
ducted that address the treatment of chronic pulmonary and
disseminated histoplasmosis, but clinical experience and de- Histoplasma capsulatum is endemic in certain areas of North
scriptive studies provide the basis for recommendations for and Latin America, but cases have also been reported from
other forms of histoplasmosis. Europe and Asia. In the United States, most cases have oc-
Value. Value was assigned on the basis of the strength of curred within the Ohio and Mississippi River valleys. Precise
the evidence supporting treatment recommendations, with the reasons for this endemic distribution pattern are unknown but
highest value assigned to controlled trials, according to con- are thought to include moderate climate, humidity, and soil
characteristics. Bird and bat excrement enhances the growth of
ventions established for developing practice guidelines.
the organism in soil by accelerating sporulation. These unique
Benefits and costs. Certain forms of histoplasmosis cause
growth requirements explain, in part, the localization of his-
life-threatening illnesses and result in considerable morbidity,
toplasmosis into so-called microfoci. Activities that disturb such
whereas other manifestations cause no symptoms or minor self-
sites are associated with exposure to H. capsulatum. Air currents
limited illnesses. The nonprogressive forms of histoplasmosis,
carry the spores for miles, exposing individuals who were un-
however, may reduce functional capacity, affecting work ca-
aware of contact with the contaminated site. Furthermore, en-
pacity and quality of life for several months. Treatment is
vironmental sites that are not visibly contaminated with drop-
clearly beneficial and cost-effective for patients with progressive
pings may harbor the organism, making it difficult to suspect
histoplasmosis in most cases.
Received 10 May 1999; revised 9 July 1999; electronically published 20 Severity of illness after inhalation exposure to H. capsulatum
April 2000.
This guideline is part of a series of updated or new guidelines from the
varies, depending on the intensity of exposure and the immunity
IDSA that will appear in CID. of the host. Asymptomatic infection or mild pulmonary disease
Reprints or correspondence: Dr. Joe Wheat, Histoplasmosis Reference follows low-intensity exposures in healthy individuals, whereas
Laboratory, 1001 West 10th St., OPW 430, Indianapolis, IN 46202 (lwheat
@iupui.edu).
heavy exposure may cause severe diffuse pulmonary infection.
Hematogenous dissemination from the lungs to other tissues
Clinical Infectious Diseases 2000; 30:688–95
q 2000 by the Infectious Diseases Society of America. All rights reserved.
probably occurs in all infected individuals during the first 2
1058-4838/2000/3004-0011$03.00 weeks of infection before specific immunity has developed, but
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 histoplasmosis with hypoxemia Acute self-limited syndromes
Acute pulmonary histoplasmosis for 11 month Acute pulmonary histoplasmosis, mildly ill
Chronic pulmonary histoplasmosis Rheumatologic
Esophageal compression and/or ulceration Pericarditis
Granulomatous mediastinitis with obstruction and/or invasion of tissue Histoplasmoma
Disseminated histoplasmosis Broncholithiasis
a
Fibrosing mediastinitis
a
Antifungal 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 fixation titers >1 : 32.

is nonprogressive in the majority of cases, which leads to the dicated in the typical patient with acute pulmonary histoplas-
development of calcified granulomas in the liver and/or spleen. mosis because the illness is self-limited and associated with min-
Progressive dissemination occurs primarily in those with un- imal morbidity (EIII; see article by Sobel [2] for definitions of
derlying immunosuppressive disorders or those at the extremes categories reflecting the strength of each recommendation for
of age. Progressive pulmonary infection is common in patients or against its use and grades reflecting the quality of evidence
with underlying centrilobular emphysema. A variety of acute on which recommendations are based).
and chronic manifestations of histoplasmosis appear to result Treatment with itraconazole, 200 mg once daily for 6–12
from unusual inflammatory or fibrotic responses to the infec- weeks, should be considered for patients who have shown no
tion, including rheumatologic syndromes and pericarditis dur- clinical improvement after 1 month of observation (BIII). Blood
ing the first year after exposure, and chronic mediastinal concentrations of itraconazole obtained 2–4 h after adminis-
inflammation or fibrosis, broncholithiasis, and enlarging pa- tration of a dose could be monitored in selected situations:
renchymal granulomas occurring later. A variety of treatment suspected treatment failure, concern about compliance or ab-
options are available, but first the decision must be made to sorption, use of medications that may reduce the solubility of
treat or to observe, since most patients with histoplasmosis itraconazole or accelerate its metabolism, and desire to reduce
recover without therapy (table 1). the dose from 200 mg twice daily to 200 mg once daily. Al-
though the “therapeutic” concentration has not been defined,
Specific Treatment Recommendations the MIC90 of itraconazole for H. capsulatum is .02 mg/mL, which
suggests that serum concentrations of 1 mg/mL measured by
Specific treatment recommendations for the more common bioassay should be therapeutic. Among AIDS patients, the me-
types of histoplasmosis are reviewed below and in table 2. dian plasma concentration was about 6 mg/mL for patients
receiving a dosage of 200 mg twice daily and ∼3 mg/mL for
Acute Pulmonary Histoplasmosis those receiving 200 mg once daily [3].
Diffuse pulmonary histoplasmosis in an immunocompetent
Fever, chills, headache, myalgia, anorexia, cough, and chest
host. Amphotericin B, 0.7 mg/kg/d (or 1 of the lipid prepa-
pain characterize this form of histoplasmosis and are seen in
rations at a dose of 3 mg/kg/d for patients with renal impair-
85%–100% of cases. Patients may experience pleuritic pain. The
ment) should be used initially in those patients with more severe
findings on examination are usually unremarkable, except for
fever, but may include rales or pleural friction rubs. manifestations who require ventilatory supportive therapy
The course after low-level exposure is benign in immuno- (AIII). If amphotericin B is used exclusively because the patient
competent patients. Symptoms usually abate within a few weeks cannot be treated with oral medications, a total course of <35
of onset [1]. Therapy may be helpful in symptomatic patients mg/kg is recommended, but this situation is expected to be rare
whose conditions have not improved during the first month of (AIII).
infection. Fever persisting for 13 weeks in acute histoplasmosis The inflammatory response may contribute to the pathogen-
may indicate that the patient is developing progressive dissem- esis of the respiratory compromise; thus, corticosteroids may
inated disease, which may be aborted by therapy. Whether an- be helpful, and prednisone could be administered at a dosage
tifungal therapy hastens recovery or prevents complications is of 60 mg daily for 2 weeks [4] (CIII). The role of corticosteroids
unknown, since it has never been studied in prospective trials. for treating extensive pulmonary histoplasmosis in the immu-
Patients with diffuse radiographic involvement following nocompromised host is less clear. Patients with AIDS and con-
more intense exposure often experience more severe disease. current disseminated histoplasmosis and Pneumocystis carinii
They may become hypoxemic and even require ventilatory sup- pneumonia who received corticosteroids in conjunction with
port. Without treatment, recovery is usually slow and the out- treatment for both microbial pathogens did not appear to do
come may be fatal. more poorly than other patients treated with antifungal therapy
Localized pulmonary histoplasmosis. Treatment is not in- only.
690 Wheat et al. CID 2000;30 (April)

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

Severe manifestation Moderately severe or mild manifestation
Type of histoplasmosis Treatment Class Treatment Class
a
Acute pulmonary AmB with corticosteroids, then Itr for 12 w AIII Symptoms !4 w: none; persistent symptoms EIII; BIII
for 14 w: Itr for 6–12 w
b
Chronic pulmonary AmB, then Itr for 12-24 mo AII Itr for 12–24 mo AII
b c
Disseminated in non-AIDS AmB, then Itr for 6–18 mo AII Itr for 6–18 mo AII
b
Disseminated in AIDS AmB, then Itr for life AII Itr for life AII
Meningitis AmB for 3 mo, then Flu for 12 mo BIII Same as for severe because of poor outcome BIII
Granulomatous mediastinitis AmB, then Itr for 6–12 mo BIII Itr for 6–12 mo BIII
d
Fibrosing mediastinitis Itr for 3 mo CIII Same as nonsevere CIII
e
Pericarditis Corticosteroids or pericardial drainage BIII Nonsteroidal anti-inflammatory agents BIII
for 2–12 w
Rheumatologic Nonsteroidal anti-inflammatory agents BIII Same as for severe BIII
for 2–12 w
NOTE. See article by Sobel [2] for definitions of categories reflecting the strength of each recommendation for or against its use and grades
reflecting the quality of evidence on which recommendations are based. AmB, amphotericin B; Flu, fluconazole; Itr, Itraconazole.
a
Effectiveness of corticosteroids is controversial (CIII)
b
If amphotericin B is used for the entire course of treatment, 35 mg/kg should be given over 3–4 months.
c
Therapy should continue until Histoplasma antigen concentrations are !4 units in urine and serum.
d
Therapy is controversial and probably ineffective except in cases of granulomatous mediastinitis that are misdiagnosed as fibrosing mediastinitis.
e
If corticosteroids are administered; concurrent antifungal therapy is recommended (CIII).

After discharge from the hospital, itraconazole, 200 mg once ure to improve clinically after at least 12 weeks of itraconazole
or twice daily, should be used to complete a 12-week course therapy (AII). Some patients may not be able to tolerate that
(BIII). dosage of amphotericin B, which justifies reducing the dosage
Itraconazole alone, 200 mg once or twice daily for 6–12 to 0.5–0.6 mg/kg/d or to use of 1 of the lipid formulations. If
weeks, could be used for patients who are not sufficiently ill to amphotericin B is administered for the full course of therapy,
require hospitalization (BIII). at least 35 mg/kg should be given at doses of 50 mg 3 times
weekly, if tolerated. In most patients, however, treatment can
be changed to itraconazole, 200 mg once or twice daily.
Chronic Pulmonary Histoplasmosis Fluconazole, 200–400 mg daily, is less effective than ampho-
Patients with underlying lung disease may develop chronic tericin B or itraconazole and yielded a response rate of 64% in
pulmonary infection after exposure to H. capsulatum. The clin- 1 study [14]. Fluconazole could be used in patients who cannot
ical and radiographic findings resemble those seen in reacti- receive itraconazole or are unable to achieve detectable blood
vation tuberculosis [5]. Without treatment, the illness is pro- concentrations with itraconazole, but the dose should be in-
gressive, causing loss of pulmonary function in most patients creased to 400–800 mg daily (BII). In a study of patients with
and death in up to half [5, 6]. In 1 study, although only 30% AIDS who had disseminated histoplasmosis, 800 mg daily was
of cases progressed after 1 year, 79% progressed with longer used for histoplasmosis [15].
observation [5]. Although some patients improve spontane- Ketoconazole (200 mg, 400 mg, or 800 mg daily) is reason-
ously, they remain at risk for recrudescence. ably effective but less well-tolerated than itraconazole or flu-
Treatment is indicated in all patients with chronic pulmonary conazole [12, 13]. Toxicity is more common in patients receiving
histoplasmosis. Studies have shown amphotericin B to be ef- the 800 mg daily dosage, which is discouraged.
fective in 59%–100% of cases [6–14] (table 3). Ketoconazole
and itraconazole are effective in 75%–85% of case patients, but
Disseminated Histoplasmosis
their use is also complicated by high relapse rates [11–13]. Flu-
conazole, 200–400 mg daily, appears to be less effective (64% Underlying immunosuppressive conditions and extremes of
response) than ketoconazole or itraconazole [14]. age are risk factors for dissemination, and illness is more severe
Itraconazole, 200 mg once or twice daily for 12–24 months, in immunocompromised individuals. Fever and weight loss are
is the treatment of choice for chronic pulmonary histoplasmosis the most common symptoms, and hepatomegaly or spleno-
(AII). megaly are common physical findings of disseminated histo-
Amphotericin B, 50 mg daily, or about 0.7 mg/kg/d, is rec- plasmosis. Other frequent sites of dissemination include the
ommended for patients who are judged to require hospitali- oropharyngeal or gastrointestinal mucosa, the skin, and the
zation because of ventilatory insufficiency or general debilita- adrenal glands. Shock, respiratory distress, hepatic and renal
tion, inability to take itraconazole because of drug interactions failure, and coagulopathy may complicate severe cases [16].
or allergies, inability to absorb itraconazole, inability to achieve CNS involvement occurs in 5%–20% of cases, presenting as
detectable concentrations of itraconazole in the blood, or fail- chronic meningitis or focal brain lesions. Histoplasma rarely
CID 2000;30 (April) Treatment of Histoplasmosis 691

Table 3. Outcome of antifungal therapy for patients with chronic out AIDS. Amphotericin B, 0.7–1.0 mg/kg/d is recommended
pulmonary histoplasmosis.
for patients who are sufficiently ill to require hospitalization
Treatment outcome, (table 2) (AII). Experience using the lipid formulations of am-
No. of
% of patients
Antifungal patients photericin B for treating histoplasmosis has not been reported.
Reference agent treated Responded Relapsed Died Most patients respond quickly to amphotericin B and can then
Furcolow [6] Amphotericin B 89 59 10 16 be treated with itraconazole. The transition from amphotericin
Putnam [9] Amphotericin B 32 100 NR NR
Sutliff [8] Amphotericin B 16 81 12 6
B to itraconazole therapy could occur after the patient becomes
Baum [10] Amphotericin B 56 96 9 NR afebrile, no longer requires blood pressure or ventilatory sup-
Parker [7] Amphotericin B 238 99 15 NR port or iv fluids or nutrition, and is able to take oral medi-
Dismukes [11] Itraconazole 20 80 15 5
Dismukes [12] Ketoconazole 23 74 4 NR
cations. If amphotericin B is to be used for the full course, the
Slama [13] Ketoconazole 7 86 NR NR total dosage should be 35 mg/kg given over 2–4 months.
McKinsey [14] Fluconazole 11 64 29 NR Itraconazole, 200 mg once or twice daily for 6–18 months,
NOTE. NR, not reported. 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 has
infects the spinal cord. The mortality without treatment is 80%
improved in response to amphotericin B (AII).
but can be reduced to !25% with antifungal therapy [6, 11–22]
(table 4). Treatment is indicated for all patients with progressive Fluconazole should be used only in patients who cannot take
disseminated histoplasmosis. itraconazole (BII). The fluconazole dosage should be at least
In studies that mostly included immunocompetent hosts and 400 mg daily in nonimmunocompromised individuals and 800
specifically excluded those with AIDS, amphotericin B was ef- mg daily in those with severe immunosuppressive conditions.
fective in 68%–92% of patients [6, 17, 18], itraconazole (200–400 H. capsulatum may develop resistance to fluconazole during
mg daily) in 100% (only 10 patients studied) [11], ketoconazole therapy, leading to relapse [25] and thus necessitating careful
(200–400 mg daily) in 56%–70% [12, 13], and fluconazole follow-up assessment, including measurement of H. capsulatum
(200–400 mg daily) in 86% [14] (table 4). antigen concentration in blood and urine (BIII).
Among patients with AIDS, therapy with amphotericin B Ketoconazole, 200 mg once or twice daily, is also reasonably
was effective in 74%–88% of patients [19, 20], itraconazole (400 effective (56%–70% response rate) but less well-tolerated than
mg daily for 12 weeks) in 85% [21], ketoconazole (200–400 mg itraconazole or fluconazole [12, 13]. Ketoconazole could be
daily) in 9% (only 11 cases) [16], and fluconazole (800 mg daily used in some situations where itraconazole is contraindicated
for 12 weeks) in 74% [15] (table 4). Of note, patients with severe (BII).
or moderately severe clinical manifestations were excluded from Antigen testing may be useful for monitoring therapy in pa-
the prospective studies that used itraconazole [21] and flucon- tients with disseminated histoplasmosis. Most of the data on
azole [15] but not from the retrospective reviews of patients the use of the antigen test for monitoring therapy are derived
treated with amphotericin B. Of patients with severe disease, from studies of patients with AIDS. Antigen concentrations
nearly half died despite treatment with amphotericin B, whereas decrease with therapy [16, 22] and increase with relapse [3, 26].
98% of those with less severe illness responded to therapy [20]. Some investigators recommend that treatment should be con-
There are no published reports about the use of the newer tinued until antigen concentrations revert to negative or at least
lipid preparations of amphotericin B for treating histoplasmosis reach low levels of <4 units. If treatment is stopped before
[16]. Most patients respond to therapy rapidly, with resolution antigen concentrations in urine and serum revert to negative,
of fever in 1–2 weeks. Therapy is not curative for patients with patients should be followed closely for relapse, and antigen
AIDS. Lifelong maintenance therapy is needed to prevent re- levels should be monitored every 3–6 months until they become
lapse in patients with AIDS and disseminated histoplasmosis. negative (BIII).
Amphotericin B, 50 mg given weekly or twice weekly, is highly Patients with AIDS as the cause of immunosuppression.
effective (81%–97%) but inconvenient and not well-tolerated Therapy is divided into an initial 12-week intensive phase to
[16, 23]. Itraconazole, 200–400 mg daily, was effective in at induce a remission in the clinical illness and then followed by
least 90% of cases [22]. Fluconazole, 100–400 mg daily was a chronic maintenance phase to prevent relapse. A similar ap-
effective maintenance therapy in 88% of patients with AIDS proach may be appropriate in other patients without AIDS
who received amphotericin B induction therapy [24]. However, who have relapsed after appropriate courses of therapy.
in a prospective study, relapse occurred in nearly one-third of For induction therapy, amphotericin B is recommended for
patients who received fluconazole, 400 mg daily, after successful patients who are sufficiently ill to require hospitalization (table
induction therapy with fluconazole, 800 mg a day [15]. In vitro 2) (AII). Amphotericin B can be replaced with itraconazole,
resistance to fluconazole developed in isolates from about half 200 mg twice daily (when the patient no longer requires hos-
of those patients who relapsed [15]. pitalization or iv therapy), to complete a 12-week total course
Immunocompetent hosts and immunocompromised hosts with- of induction therapy.
692 Wheat et al. CID 2000;30 (April)

Table 4. Outcome of antifungal therapy for patients with disseminated

histoplasmosis.
Treatment outcome,
No. of
% of patients
Antifungal patients
Reference(s) agent treated Responded Relapsed Died

Furcolow [6] Amphotericin B 22 68 9 23

Sathapatayavongs [19] Amphotericin B 43 74 7 16
Reddy [17] Amphotericin B 17 76 NR 23
Sarosi [18] Amphotericin B 24 91 20 8
a
Wheat [16, 20] Amphotericin B 73 88 19 12
Dismukes [11] Itraconazole 10 100 NR NR
Wheat [21, 22] Itraconazole 59 85 5 NR
Dismukes [12] Ketoconazole 31 56 10 NR
Slama [13] Ketoconazole 10 70 40 NR
a
Wheat [16] Ketoconazole 11 9 50 NR
b
Wheat [15] Fluconazole 49 74 31 2
McKinsey [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 the
medication chronically for maintenance, although some of the relapses occurred in patients
who were not compliant with therapy or in those who were receiving rifampin.

Itraconazole, 200 mg 3 times daily for 3 days and then twice capsulatum, and lower efficacy for treatment of histoplasmosis
daily for 12 weeks is the treatment of choice for patients who [15].
have mild or moderately severe symptoms who do not require
hospitalization (AII).
CNS Histoplasmosis
Fluconazole, 800 mg daily, is an alternative for patients who
cannot take itraconazole (BII). Patients who are receiving flu- Manifestations include meningitis, focal brain or spinal cord
conazole should be followed closely clinically for relapse, and lesions, cerebrovascular accident caused by vascular involve-
antigen concentrations in urine and blood should be monitored ment or cerebral emboli, and diffuse encephalitis [28]. Symp-
quarterly and at the time of suspected relapse (BIII). toms usually have been present for months to years before
For maintenance therapy, the treatment of choice is itracon- diagnosis. Fever, headache, confusion, mental status changes,
azole 200 mg once or twice daily for life (AII). Antigen con- seizures, or focal neurological deficits may be seen. CSF ab-
centrations in serum and urine should be monitored every 3–6 normalities include lymphocytic pleocytosis, protein elevation,
months to provide evidence that maintenance therapy is con- and hypoglycorrhachia in patients with meningitis. Single or
tinuing to suppress the progression of infection (BIII). multiple enhancing lesions may be seen by CT scan or MRI
Amphotericin B, 50 mg iv once weekly, is an alternative but in the brain or spinal cord of those with parenchymal involve-
is not as well-tolerated or accepted by patients and should be ment [28].
reserved for patients who cannot take itraconazole (BII). The course of the disease is progressive and fatal if not
Fluconazole, 400–800 mg daily, could be used for patients treated, although the speed of clinical deterioration is highly
who cannot tolerate or do not absorb itraconazole and prefer variable [28]. The response to therapy is inferior to that in other
not to be treated with amphotericin B, but fluconazole therapy types of histoplasmosis: 20%–40% of patients with meningitis
is discouraged because of its reduced efficacy as chronic main- succumb to the infection, despite treatment with amphotericin
tenance therapy for histoplasmosis (DII). Patients receiving flu- B, and up to half of responders relapse after therapy is dis-
conazole should be followed closely clinically for relapse, and continued [28].
antigen concentrations in urine and blood should be monitored The optimal treatment for Histoplasma meningitis is un-
quarterly and at the time of suspected relapse. known, but an aggressive approach is recommended because
For prophylaxis in immunocompromised subjects, itracon- of the poor outcome.
azole is recommended. A trial comparing itraconazole, 200 mg Amphotericin B, 0.7–1 mg/kg/d to complete a 35 mg/kg total
daily, versus placebo in patients with CD41 counts !150/mL dose over 3–4 months has been used most often (BIII). Flu-
showed a 2-fold reduction in the incidence of histoplasmosis conazole, 800 mg daily, might be continued for another 9–12
in the itraconazole group, compared with the placebo group months after completion of amphotericin B, to reduce the risk
(6.8%–2.7%) during a median follow-up period of 1 year [27]. for relapse (BIII).
In regions experiencing high rates of histoplasmosis (15 cases/ Liposomal amphotericin B (AmBisome), 3–5 mg/kg/d or
100 patient-years), prophylaxis with itraconazole is recom- every other day given over a 3–4 month period might be con-
mended (200 mg once daily) (BI). Fluconazole is not an ac- sidered for patients who have failed therapy with amphotericin
ceptable alternative because of its inferior activity against H. B followed by fluconazole (CIII). In animal studies, liposomal
CID 2000;30 (April) Treatment of Histoplasmosis 693

amphotericin B achieved higher concentrations in the blood Itraconazole, 200 mg once or twice daily for 6–12 months,
and brain than did amphotericin B or the other lipid formu- is recommended for patients with milder manifestations that
lations [29], which provides a theoretical basis for its use in persist for 11 month (table 3) (BIII).
meningitis. However, neither the lipid preparation nor ampho- Prednisone, 40–80 mg daily for 2 weeks, could be considered
tericin B achieve detectable concentrations in CSF [29–31], and in those with major airway obstruction (CIII).
none have been evaluated in cases of Histoplasma meningitis. Surgical resection of the mediastinal mass should be reserved
Chronic fluconazole maintenance therapy, 800 mg daily, for patients who remain symptomatic and continue to dem-
should be considered for patients who relapse, despite full onstrate obstruction of major mediastinal structures, despite a
courses of therapy, as described elsewhere (CIII). trial of antifungal therapy (BIII).
Itraconazole, although more active than fluconazole against
H. capsulatum, does not enter the CSF, which makes it a less-
appealing choice for treatment of meningitis and discourages Fibrosing Mediastinitis
its use for this indication (DIII). Of note, however, the role of Fibrosing mediastinitis is a late complication of histoplas-
CSF concentrations of antifungal agents in the outcome of mosis arising from nodal regions and ultimately invasion and
treatment of fungal meningitis is unclear. occlusion of the central vessels and airways. Patients often re-
Patients who relapse despite chronic maintenance therapy are port symptoms of several years’ duration at the time of diag-
candidates for administration of amphotericin B directly into nosis. The course is progressive and often fatal [39, 40]. Al-
the ventricles, cisterna magna, or lumbar arachnoid space. Ex- though most authorities believe that neither antifungal nor
perience using intrathecal or intraventricular therapy, however, anti-inflammatory treatment ameliorates the outcome of fi-
has not been encouraging; this approach to therapy is dis- brosing mediastinitis [39, 40], others have reported improve-
couraged except for patients for whom all other approaches to ment after antifungal therapy [41].
therapy have failed [28] (DIII). Information is inadequate on which to make firm treatment
Focal involvement of the brain or spinal cord in the absence recommendations. The progressive course of this syndrome,
of meningitis may be more responsive to antifungal therapy. however, makes it difficult to withhold antifungal therapy. If
Of 6 such cases in persons without AIDS, all responded to the clinical findings are consistent with a more acute inflam-
amphotericin B therapy, but 2 relapsed [28]. Amphotericin B matory process rather than a chronic fibrotic process, especially
is recommended for the initial therapy (BIII). Penetration of if complement fixation titers and the erythrocyte sedimentation
the CSF may not be required for successful therapy of paren- rate are elevated, treatment may be helpful.
chymal lesions; thus itraconazole, 200 mg 2 or 3 times daily, A 12-week trial of itraconazole, 200 mg once or twice daily,
may be appropriate after the patients’ conditions have im- is suggested if clinical findings do not differentiate fibrosing
proved with amphotericin B (CIII). mediastinitis from granulomatous mediastinitis (CIII). Patients
Parenchymal lesions rarely require surgical excision [28] who truly have fibrosing mediastinitis are not expected to re-
(DIII). spond to antifungal therapy. The only basis to prolong therapy
beyond 12 weeks would be clearcut radiographic demonstration
of abatement of obstruction, in which case therapy could be
Granulomatous Mediastinitis
continued for 1 year.
Symptoms that include chest pain, cough, hemoptysis, and Corticosteroid therapy has not been helpful when tried [39,
dyspnea may be caused by compression of the airways, superior 42, 43] and is discouraged (DIII).
vena cava, or pulmonary vessels in patients with granulomatous Surgery should be approached with great caution in patients
mediastinitis. These syndromes represent active inflammation with severe complications of fibrosing mediastinitis and only
of the mediastinal lymph nodes rather than fibrotic reactions in those who are expected to succumb from the condition with-
to past infection. Although symptoms are often mild and re- out intervention. Surgeons experienced in the management of
solve over a few months, they may be more severe and pro- fibrosing mediastinitis should be consulted (CIII).
tracted. Antifungal therapy has been helpful in some cases [32, Placement of intravascular stents has been helpful in some
33]. Adjunctive treatment with corticosteroids appeared to have patients with superior vena cava, pulmonary artery, or pul-
been beneficial in 1 patient who had airway obstruction [34]. monary vein obstruction, and might be tried in patients with
Resection of obstructive masses is another approach that has severe manifestations (CIII).
been helpful for patients with granulomatous mediastinitis
[35–38]
Pericarditis
Amphotericin B, 0.7–1.0 mg/kg/d, should be considered as
initial therapy for patients with severe obstructive complica- Pericarditis occurs in 5%–10% of patients with acute histo-
tions of mediastinal histoplasmosis (BIII). Therapy could be plasmosis and appears to be caused by the inflammatory re-
changed to itraconazole, 200 mg once or twice daily, after im- sponse to the infection rather than the infection per se. These
provement is sufficient for outpatient treatment. manifestations rarely may be a complication of disseminated
694 Wheat et al. CID 2000;30 (April)

histoplasmosis [44]. Patients with pericarditis respond to non- References

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