Histoplasmosis

Kenneth S. Knox
1
and Chadi A. Hage
2
1
University of Arizona College of Medicine and Southern Arizona VA HealthCare System, Tucson, Arizona; and
2
Indiana University School of
Medicine and Roudebush Veterans Administration Medical Center, Pulmonary Critical Care Medicine, Indianapolis, Indiana
Histoplasmosis is the most prevalent endemic fungal infection in
North America. The clinical spectrum ranges from asymptomatic,
self-limited illness to a life-threatening progressive disseminated
disease. Chronic manifestations of healed infection can also be
problematic. Clinical presentation depends on the infectious load,
underlying immune status, and lung function. The preferred
diagnostic methods and treatment options vary with clinical sce-
nario and severity of illness. New diagnostic tools and treatment
options arenowavailableinclinical practice. Wepresent anoverview
of this important endemic mycosis with emphasis on diagnosis and
treatment recommendations for the different clinical syndromes of
histoplasmosis.
Keywords: histoplasmosis; diagnosis; treatment
EPIDEMIOLOGY AND PATHOGENESIS
Although histoplasmosis is reported worldwide, Histoplasma
capsulatum is endemic to North, Central, and South America as
well as parts of Europe and Africa. Most cases result from
sporadic exposures. Several outbreaks have been reported and
provide the foundation for our understanding of this disease.
The best-characterized outbreaks have occurred in the United
States, surrounding the Ohio and Mississippi River valleys (1).
In most instances, outbreaks can be tied to major construction
projects or demolition of old buildings.
Histoplasma is a soil dweller and thrives in areas contami-
nated with bird or bat excrement. Activities that have classically
led to high inoculum exposure include cleaning chicken coups,
cleaning attics and barns, caving, construction, and other soil-
disrupting activities (2, 3). The populations most at risk for
symptomatic acute disease are those with large inoculum expo-
sure or who are immunosuppressed. Other risk factors include
underlying emphysema and the extremes of age (4).
Infection occurs after infectious microconidia of Histoplasma
capsulatum are aerosolized and inhaled into the lower airways.
In the alveolar space conidia are recognized and phagocytized
by resident macrophages. Inside the macrophages, conidia
convert to yeasta necessary step in the pathogenesis of
histoplasmosis. During the rst couple of weeks, Histoplasma
yeasts multiply inside alveolar macrophages and spread
throughout the reticuloendothelial system (5). Dendritic cells
ingest and kill the yeast and are able to present Histoplasma
antigen to and stimulate naive T-lymphocytes (6, 7). Dendritic
cells line the airway and are thus involved early in uptake and
processing of Histoplasma (8). Within 2 to 3 weeks, a potent T
cellmediated immune response is generated and is responsible
for halting dissemination by assisting intracellular killing of the
yeast by effector macrophages (5). This orchestrated response
seems to depend on a number of cytokines such as tumor
necrosis factor-a (TNF-a) (9, 10), interferon-g (11), and in-
terleukin (IL)-12 (12). Regulatory cytokines IL-10, IL-17, and
IL-23 also appear to play a major role in coordinating an
effective immune response to Histoplasma infection (13). If
cellular immunity is defective, the fungus is left to proliferate
and disseminate throughout the body, causing tissue destruction
and multi-organ failure, leading to progressive dissemination
that can be fatal if left untreated.
CLINICAL MANIFESTATION AND TREATMENT
The vast majority of patients exposed to Histoplasma experi-
ence an asymptomatic or minimally symptomatic infection and
do not seek medical attention. If tested for epidemiological
study, these individuals are likely to have a serological antibody
response or positive skin test. However, histoplasmin skin tests
are no longer used clinically and are not commercially available.
Years later, radiographs may show splenic or pulmonary
calcications, lung nodules, or mediastinal abnormalities (14).
Symptomatic histoplasmosis is self-limiting in the majority of
cases and may be dismissed as a common viral syndrome or
bacterial community-acquired pneumonia. In the case of the
patient with suspected bacterial community-acquired pneumonia,
antibiotics are often given empirically. Serendipitously, histoplas-
mosis runs its course just as antibacterial treatment is completed.
Despite being well-characterized with known manifestations
of acute and chronic disease, histoplasmosis can be difcult to
diagnose. Failure to establish the diagnosis in immunosuppressed
patients can be fatal. Resection of benign nodules mistaken for
lung cancer is often performed in the endemic areas and is
associated with cost and morbidity.
Traditionally, the clinical classication of disease includes
the following acute entities that may require antifungal therapy
due to recent symptomatic infection:
d Acute pulmonary histoplasmosis
d Chronic-cavitary pulmonary histoplasmosis
d Progressive disseminated histoplasmosis
d Mediastinal lymphadenitis
Other entities that may require treatment, but not anti-
fungal therapy, include:
d Pulmonary nodule
d Mediastinal granuloma
d Mediastinal brosis
d Broncholithiasis
d Inammatory syndromes (pericarditis, arthritis, erythema
nodosum)
Manifestations Requiring Antifungal Therapy
Manifestations of acute pulmonary histoplasmosis: immuno-
competent host. Acute pulmonary histoplasmosis occurs 2
weeks after a relatively large inoculum exposure in immuno-
(Received in original form July 17, 2009; accepted in nal form August 19, 2009)
Supported by VA-Career Development Award-2 (to C.A.H.).
Correspondence and requests for reprints should be addressed to Chadi A. Hage,
M.D., Assistant Professor of Medicine, Pulmonary-Critical Care and Infectious
Diseases, Indiana University School of Medicine, Roudebush VA Medical Center,
1481 W. 10th St., 111P-IU, Indianapolis, IN 46202. E-mail: chage@iupui.edu
Proc Am Thorac Soc Vol 7. pp 169172, 2010
DOI: 10.1513/pats.200907-069AL
Internet address: www.atsjournals.org
competent patients. Symptoms are nonspecic and include
fever, chills, cough, dyspnea, and chest pain. Most often, lobar
or patchy pulmonary inltrates are seen on chest imaging.
Frequently, mediastinal adenopathy is present. Some patients
with heavy exposure will have severe dyspnea and hypoxemia
with diffuse pulmonary inltrates, mimicking hypersensitivity
pneumonitis. These patients are likely to undergo testing and
receive a course of antifungal treatment. Although not well
dened, patients who are hypoxemic with diffuse inltrates may
receive a short course of corticosteroids once antifungal treat-
ment is initiated. Valuable testing strategies for patients with
this larger burden of disease include Histoplasma antigen
testing in urine and serum. Direct examination of respiratory
secretions, often obtained by bronchoalveolar lavage (BAL),
are extremely useful (15). Individuals with severe acute pulmo-
nary histoplasmosis are more likely to have signs of dissemi-
nated disease. Findings compatible with dissemination include
hepatosplenomegaly, extrapulmonary lymphadenopathy, oral
or skin lesions, adrenal or intestinal masses. Laboratory abnor-
malities suggesting dissemination include anemia, leukopenia,
thrombocytopenia, hepatic enzyme elevation, and/or adrenal
insufciency. Self-limited disease is the rule after infection with
a relatively small inoculum. In those cases of minimally
symptomatic disease, testing for histoplasmosis is rarely un-
dertaken.
Serology is often used to make the diagnosis of localized
pulmonary histoplasmosis. Complement xation (CF) and im-
munodiffusion are the most widely used methods. About 4 to
6 weeks is required to mount an antibody response in histo-
plasmosis. Therefore, serology is typically negative during the
rst month after infection, which limits its usefulness in the
management of patients with suspected acute histoplasmosis. If
serological tests are negative, follow-up testing 1 or 2 months
later can detect sero-conversion. In addition, antibodies may
persist for several years after the infection has healed. There are
no prospective studies to guide antifungal treatment in acute
pulmonary histoplasmosis in an immunocompetent host. Anti-
fungal therapy is not recommended unless symptoms are severe
and persist for weeks. Itraconazole therapy for up to 3 months is
recommended (16). Acute or subacute adenopathy can com-
press vital structures or promote stula formation. In such cases
of symptomatic mediastinal lymphadenitis or granulomatous
mediastinitis, antifungal therapy is recommended.
Chronic pulmonary histoplasmosis: immunocompetent host.
Patients with underlying structural lung disease such as emphy-
sema are at risk for a progressive entity termed chronic-cavitary
pulmonary histoplasmosis (17, 18). Patients typically have pro-
ductive cough, fever, night sweats, and weight loss. Radiographs
show upper lobe brocavitary disease resembling reactivation
tuberculosis. The disease progresses over months and is not
usually self-limiting. Because the acute infection smolders and
provides continuous antigenic stimulation for antibody forma-
tion, compliment xation titers are often positive and provide
very useful clues to diagnosis. Serum and urine antigen tests are
usually negative due to low fungal burden, but antigen testing is
rarely performed in this clinical scenario. Sputum fungal stain
and culture may be useful in this instance. BAL is frequently
performed for cytological analysis and culture. Histoplasma
antigen can be detected in the BAL providing a rapid diagnosis
in some instances (19). Prolonged treatment with itraconazole
for 1 to 2 years duration is recommended (16).
Acute and progressive disseminate histoplasmosis: immuno-
supressed host. Progressive disseminated histoplasmosis (PDH)
occurs in immunosuppressed patients after initial exposure.
Whereas immunocompetent individuals develop protective im-
munity in the rst 2 weeks of infection, immunosuppressed
patients lack the cellular immune response necessary to clear
the infection. The prototypical patient with progressive dissem-
inated disease is one with AIDS. The majority of the studies
relating to the efcacy of treatment have been studied in this
population (20, 21). Recently, patients treated with biologics,
particularly antitumor necrosis factor (TNF) agents, have
become the population of concern for PDH (22, 23). Antigen
testing in blood and urine is positive in 90% of patients with
PDH and is the initial test of choice (16). Clinically, the
differential diagnosis of PDH is quite large and includes
histoplasmosis, pneumocystis pneumonia, invasive fungal in-
fections, and mycobacterial and other opportunistic pathogens.
Concomitant infection with two or more opportunistic patho-
gens is common. Thus BAL is often performed for cytopathol-
ogy and microbiology. Antigen testing of BAL can be done and
is often positive in patients with PDH. However, careful
cytological examination of BAL is recommended and has high
sensitivity and specicity in this patient population (15). Cyto-
logical examination and culture of biopsy specimens of affected
organs (bone marrow, lung) provides rapid diagnosis as well.
Serology may be negative due to inefcient coordination of the
immune response. Amphotericin B, preferably the liposomal
formulation, is the treatment of choice in severe cases and is
followed by itraconazole once clinical improvement is secure
(usually after 2 weeks). Those with mild to moderate disease
can be successfully treated with itraconazole (21).
The choice of antifungal agent depends on the immune
status of the host, severity of illness, and toxicity prole. ATS
guidelines are forthcoming and the IDSA has issued an update
in 2007 (16). The duration of treatment varies with clinical
scenario. Mild to moderate acute pulmonary histoplasmosis and
mediastinal granuloma requiring antifungal therapy can be
treated with itraconazole 200 mg once to twice daily for 6 to
12 weeks. Similarly, chronic cavitary histoplasmosis can be
treated with itraconazole alone for a 12- to 18-month duration,
sometimes longer, as chronic upper lobe disease is prone to
recurrence. In brief, the sickest patients and those requiring
hospitalization will require amphotericin B preparation (lipid
formulation amphotericin B, 35 mg/kg/d intravenously or
deoxycholate 0.71 mg/kg/d intravenously) initially as induction
therapy. These patients have either severe acute pulmonary
histoplasmosis or progressive disseminated histoplasmosis.
Once clinical improvement occurs (typically after 12 wk of
treatment), itraconazole is recommended for the remainder of
the therapeutic course. Progressive disseminated disease should
be treated for at least 12 months and needs secondary pro-
phylaxis if immunosuppression persists. Maintenance itracona-
zole can be safely discontinued in patients with PDH after they
have received at least 1 year of itraconazole therapy, have
negative results of blood cultures, have cleared their Histo-
plasma serum and urine antigen level to less than 2 ng/ml, and
are receiving HAART with a sustained immunological response
as evidenced by CD4 T cell count greater than 150 cells/mm
3
(24). Mild and moderate cases of progressive disseminated
histoplasmosis may be treated with itraconazole alone with
close clinical follow up (21). Urine and serum antigen levels
should be measured during therapy and for 12 months after
therapy is ended to monitor for relapse. Patients treated with
itraconazole should have itraconazole blood levels monitored to
ensure adequate drug exposure (16).
Newer triazoles, voriconazole and posaconazole, are active
in vitro against H. capsulatum and appeared to be clinically
effective in fewcase reports and small series (2527). Prospective
studies are required to better dene their role in the treatment of
histoplasmosis. Echinocandins demonstrated limited in vitro
activity against H. capsulatum and variable efcacy in animal
170 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010
models of histoplasmosis (28, 29). None of the echinocandins is
recommended for the treatment of histoplasmosis.
A number of recent reports observed paradoxical worsening
in patients with AIDS and PDH early during treatment despite
effective antifungal therapy and clearance of the infection,
suggesting the possibility of an immune reconstitution inam-
matory syndrome (IRIS) (30, 31). Such worsening could be
misinterpreted as signs of treatment failure or a result of
incorrect diagnosis, thus leading to unnecessary changes in
therapy.
Chronic Manifestations that Do Not Require
Antifungal Therapy
Pulmonary nodules. Although not treated with antifungal
agents, asymptomatic pulmonary nodules due to recent or
remote histoplasmosis are common and can be diagnostically
challenging, as they mimic malignancy. Often these nodules are
biopsied or excised and may stain positive for the organism.
Serology is not useful to discriminate from malignancy and, due
to small burden of residual disease antigen testing, is universally
negative and not performed. When Histoplasma cannot be
cultured, antifungal treatment is not recommended. The time
to calcication is variable and cannot be used alone to distin-
guish from malignancy. Many nodules never calcify and PET
scans can show increased uptake in these lesions (32). The
decision to pursue diagnosis in this patient population depends
on many factors, including smoking status, chronicity, and
patient preference. Repeat CT scan at 3- to 6-month intervals
to document stability is often preferred to an invasive strategy
for those who live in endemic areas. Needle biopsy may also be
pursued in lieu of resection up front. Diagnostic strategies are
highly individualized based on patient preference and size of
nodule(s). In patients who are symptomatic with multiple
pulmonary nodules and associated chest adenopathy, recent
infection is presumed and treatment with antifungal agents may
be warranted depending on disease severity and duration of the
illness, as discussed above for acute pulmonary histoplasmosis.
Broncholithiasis. Broncholithiasis occurs when calcied me-
diastinal lymph nodes erode into the airway causing symptoms
of dyspnea, wheezing, or hemoptysis. Many times these are
managed conservatively and the patient spontaneously coughs
the broncholith out of the airway. In instances in which the
patient requires intervention, bronchoscopic evaluation is rst
recommended. Removing a partially or completely eroded
broncholith can usually be safely performed at the time of
bronchoscopic evaluation (32, 33), but surgical intervention may
be required if broncholithiasis is complicated by obstructive
pneumonia, stula formation, or massive hemoptysis (34, 35).
Antifungal treatment is not generally recommended.
Fibrosing mediastinitis. Fibrosing mediastinitis is uncom-
mon, but is often progressive, with distortion and compression
of major vessels and central airways. The etiology is unknown
and not likely related to presence of mediastinal disease during
acute infection. It must be differentiated from the granuloma-
tous mediastinitis related to more recent infections or malig-
nancy. Patients may experience symptoms for years before
diagnosis. Fibrosing mediastinitis can be fatal and, despite lack
of proven therapy, a 12-week course of itraconazole, 200 mg
twice daily may be considered, but will be ineffective if the
diagnosis of brosing mediastinitis is correct (36, 37). If
radiographic or physiological improvement is obvious, a granu-
lomatous component from recent infection may exist and
therapy should be considered for 12 weeks. The use of
corticosteroids is not recommended and the role of antibrotics
(for example, tamoxifen) is unclear (38). Intravascular stents
may be useful in appropriately selected patients with typically
bilateral disease, open airways, and severe manifestations of
vascular compromise (39). The algorithm for compressive
disease of the airway is complicated. Balloon bronchoplasty,
followed by consultation with a surgeon specializing in medias-
tinal disease and endobronchial stenting, is prudent. Stenting of
the airway in benign disease is reserved for those with no other
options and when performed, a removable silicone stent is
initially preferred. Endobronchial laser therapy has been used
for hemoptysis related to brosing mediastinitis and hyperemic
airways (40). Surgical resection of the brotic tissue is not
recommended. Surgical treatment should be reserved for those
with severe disease and performed by experienced surgeons
(34). The procedure can be technically challenging and brosis
can recur after surgery.
Conict of Interest Statement: K.S.K. owns stocks of Alpha Med ($10,001
$50,000) and received grant support from the National Institutes of Health
($1,000,000). C.A.H. served on the Board or Advisory Board for OrthoMcNeal
($1,001$5,000) and received grant support from MiraVista Diagnostics-
MiraBella Technologies ($5,001$10,000). He is an employee of, and has
received grant support from, the VA ($100,001 or more), and his spouse/life
partner is an employee of the VA ($50,001$100,000).
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