This document from the American Thoracic Society provides treatment guidelines for fungal infections in adult pulmonary and critical care patients. It was approved by the ATS Board of Directors in May 2010. The document focuses on 3 areas: endemic mycoses like histoplasmosis; fungal infections in immunocompromised patients like cryptococcosis and aspergillosis; and rare/emerging fungal infections. It reviews antifungal drug classes, provides treatment recommendations graded by evidence quality, and offers guidance for challenging clinical situations. The goal is to provide a concise clinical summary of current therapeutic approaches for fungal infections relevant to pulmonary and critical care practice.

1. American Thoracic Society Documents
An Official American Thoracic Society Statement:
Treatment of Fungal Infections in Adult Pulmonary
and Critical Care Patients
Andrew H. Limper, Kenneth S. Knox, George A. Sarosi, Neil M. Ampel, John E. Bennett, Antonino Catanzaro,
Scott F. Davies, William E. Dismukes, Chadi A. Hage, Kieren A. Marr, Christopher H. Mody, John R. Perfect,
and David A. Stevens, on behalf of the American Thoracic Society Fungal Working Group
THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS,
MAY 2010
CONTENTS immune-compromised and critically ill patients, including crypto-
coccosis, aspergillosis, candidiasis, and Pneumocystis pneumonia;
Introduction and rare and emerging fungal infections.
Methods
Antifungal Agents: General Considerations Keywords: fungal pneumonia; amphotericin; triazole antifungal;
Polyenes echinocandin
Triazoles
Echinocandins The incidence, diagnosis, and clinical severity of pulmonary
Treatment of Fungal Infections fungal infections have dramatically increased in recent years in
Histoplasmosis response to a number of factors. Growing numbers of immune-
Sporotrichosis compromised patients with malignancy, hematologic disease,
Blastomycosis and HIV, as well as those receiving immunosupressive drug
Coccidioidomycosis regimens for the management of organ transplantation or
Paracoccidioidomycosis autoimmune inflammatory conditions, have significantly con-
Cryptococcosis tributed to an increase in the incidence of these infections.
Aspergillosis Definitive diagnosis of pulmonary fungal infections has also
Candidiasis increased as a result of advances in diagnostic methods and
Pneumocystis Pneumonia techniques, including the use of computed tomography (CT)
Treatment of Other Fungi and positron emission tomography (PET) scans, bronchoscopy,
Glossary of Terms mediastinoscopy, and video-assisted thorascopic biopsy. At the
same time, the introduction of new treatment modalities has
With increasing numbers of immune-compromised patients with significantly broadened options available to physicians who
malignancy, hematologic disease, and HIV, as well as those receiving treat these conditions. Once largely limited to the use of
immunosupressive drug regimens for the management of organ
amphotericin B, flucytosine, and a handful of clinically available
transplantation or autoimmune inflammatory conditions, the in-
azole agents, today’s pharmacologic treatment options include
cidence of fungal infections has dramatically increased over recent
potent new azole compounds with extended antifungal activity,
years. Definitive diagnosis of pulmonary fungal infections has also
been substantially assisted by the development of newer diagnostic
novel lipid forms of amphotericin B, and a new class of antifungal
methods and techniques, including the use of antigen detection, drugs known as echinocandins. In light of all these developments
polymerase chain reaction, serologies, computed tomography and in the incidence, diagnosis, and treatment of pulmonary fungal
positron emission tomography scans, bronchoscopy, mediastino- infections, the American Thoracic Society convened a working
scopy, and video-assisted thorascopic biopsy. At the same time, the group on fungi to develop a concise clinical summary of the
introduction of new treatment modalities has significantly broad- current therapeutic approaches for those fungal infections of
ened options available to physicians who treat these conditions. particular relevance to pulmonary and critical care practice. This
While traditionally antifungal therapy was limited to the use of document focuses on three primary areas of concern: the
amphotericin B, flucytosine, and a handful of clinically available endemic mycoses, including histoplasmosis, sporotrichosis, blas-
azole agents, current pharmacologic treatment options include tomycosis, and coccidioidomycosis; fungal infections of special
potent new azole compounds with extended antifungal activity, concern for immune-compromised and critically ill patients,
lipid forms of amphotericin B, and newer antifungal drugs, including including cryptococcosis, aspergillosis, candidiasis, and Pneumo-
the echinocandins. In view of the changing treatment of pulmonary cystis pneumonia; and rare and emerging fungal infections.
fungal infections, the American Thoracic Society convened a working
group of experts in fungal infections to develop a concise clinical
statement of current therapeutic options for those fungal infections METHODS
of particular relevance to pulmonary and critical care practice. This
document focuses on three primary areas of concern: the endemic For each fungal infection evaluated, the available literature has
mycoses, including histoplasmosis, sporotrichosis, blastomycosis, been thoroughly reviewed and interpreted by the experts in-
and coccidioidomycosis; fungal infections of special concern for volved in this statement. In the search for published evidence,
workgroup members reviewed journal articles and previously
published guidelines, and conducted an evaluation of electronic
Am J Respir Crit Care Med Vol 183. pp 96–128, 2011
DOI: 10.1164/rccm.2008-740ST databases, including PubMed and MEDLINE. In general, only
Internet address: www.atsjournals.org articles written in English were used in the final recommenda-

2. American Thoracic Society Documents 97
TABLE 1. CATEGORIES INDICATING THE STRENGTH OF EACH TABLE 2. GRADES OF EVIDENCE QUALITY ON WHICH
RECOMMENDATION FOR OR AGAINST ITS USE IN THE RECOMMENDATIONS ARE BASED
TREATMENT OF FUNGAL INFECTIONS
Grade Definition
Category Definition
I Evidence from at least 1 properly randomized, controlled trial
A Good evidence to support a recommendation for use Evidence from at least 1 well-designed clinical trial without
B Moderate evidence to support a recommendation for use randomization, from cohort or case-controlled analytic studies
C Poor evidence to support a recommendation for or against use (preferably from . 1 center), from multiple patient series studies,
D Moderate evidence to support a recommendation against use II or from dramatic results of uncontrolled experiments
E Good evidence to support a recommendation against use Evidence from opinions of respected authorities, that is based on clinical
III experience, descriptive studies, or reports of expert committees.
tions. The most relevant literature references are included in this
publication. Discussion and consensus among workgroup mem- mend that patients with any degree of renal insufficiency be more
bers formed the basis for the recommendations made in this closely monitored. Many experienced clinicians pre-medicate
statement. The authors reviewed the evidence base for each patients with antipyretics, antihistamines, anti-emetics, or me-
major recommendation of this consensus statement and graded peridine to decrease the common febrile reaction and shak-
according to an approach developed by the U.S. Preventive ing chills associated with infusion (BIII). Meperidine is
Services Task Force (Tables 1 and 2). Although the American most effective for ameliorating the severe rigors. Rapid in-
Thoracic Society (ATS) and Infectious Disease Society of travenous administration of amphotericin B has been observed
America (IDSA) have recently adopted the GRADE approach to precipitate life-threatening hyperkalemia and arrhythmias
to grading the quality of evidence and strength of recommenda- (5); therefore, the daily dose of amphotericin B deoxycholate
tions for clinical guidelines, the current project was initiated and should be infused over 2 to 6 hours. Hypotension and shock
much of the work was completed prior to the official adoption of have also occasionally been observed during amphotericin B
GRADE. The recommendations included were, therefore, infusion. Amphotericin B should not be administered simulta-
graded according to the system used in prior guidelines (1–3). neously with leukocytes, as this may possibly precipitate pul-
Each section also includes expert interpretations regarding the monary toxicity (6). There appears to be an additive, and
best approach for challenging clinical situations that have not possibly synergistic, nephrotoxicity with other nephrotoxic
been well studied in the literature, but that are the basis for agents such as aminoglycoside antibiotics (7). Adequate intra-
frequent consultation of the members of the ATS working group venous fluid hydration has been shown to reduce the risk of
on fungal infections. For convenience, a glossary of definitions of nephrotoxicity (8). In complicated patients, consultation with an
uncommon terms is also included at the end of the document. experienced clinical pharmacist or use of tools such as software
Each member of the writing committee has declared any programs that delineate drug interactions, particularly those
conflict of interest, and every effort was made by the Chair as with suspected synergistic nephrotoxicity or those requiring
adjudicator to ensure that recommendations were free of any real renal clearance, is recommended. Additional side effects are com-
or perceived conflict of interest; however, it should be noted that mon, and may include hypokalemia, phlebitis/thrombophlebitis,
the process predates the official development and adoption of the anorexia and weight loss, fever and chills, headache and malaise,
revised ATS Conflict of Interest guidelines in 2008 (4). and cardiac dysrhythmias. Liver toxicity may also occur, but its
incidence is rare compared with renal toxicity. Nephrotoxicity
ANTI-FUNGAL AGENTS: GENERAL CONSIDERATIONS and other untoward side effects of amphotericin B deoxycholate
are largely dose-dependent. In clinical situations that require
In most cases, treatment of fungal infections must be based on doses of amphotericin B deoxycholate greater than or equal to
the causative fungus, the severity of disease, and the clinical 1.0 mg/kg/day, strong consideration should be given to using
features of each patient. Specific guidelines for therapy, in- lipid formulations of amphotericin to avoid the potentially high
cluding dosing recommendations, are included in subsequent incidence of toxic side effects (see below) (BIII).
sections under specific organisms and infection site(s). This In addition to amphotericin B deoxycholate, two different
section will provide general comments about the major classes lipid-associated formulations have been developed and are in
of available antifungal agents, including novel agents such as current use: liposomal amphotericin B and amphotericin B lipid
extended-spectrum triazoles and echinocandins. complex. These agents have variable dosing schedules and
toxicities, but, in general are significantly less nephrotoxic than
Polyenes amphotericin B deoxycholate. Data concerning the improved
The prototype of the polyenes is amphotericin B deoxycholate efficacy of any amphotericin lipid formulation over amphotericin
(amphotericin B), which continues to be a fundamental treat- B deoxycholate are limited. So far, the clearest indication for use
ment option for severe fungal infections, particularly life- of a lipid formulation is to reduce renal toxicity (AII), which is an
threatening illnesses, including aspergillosis, cryptococcosis, especially important consideration in patients who have under-
systemic candidiasis, and severe cases of histoplasmosis, blasto- lying nephrotoxicity or in those who are receiving multiple
mycosis, coccidioidomycosis, and zygomycosis. Polyenes act by concomitant nephrotoxic drugs. For diseases where dosing of
binding to sterols in the fungal cell membrane, forming a trans- amphotericin B at 1.0 mg/kg/day or higher is standard, the
membrane channel that precipitates cell leakage and death. intrinsic nephrotoxicity of amphotericin B itself dictates pre-
Amphotericin B is administered intravenously, and is associated ferred use of lipid formulations. As with standard amphotericin B
with a broad range of side effects. Careful monitoring during formulations, monitoring for side effects during therapy should
therapy should focus on serum creatinine, blood urea nitrogen, include measurement of serum creatinine, blood urea nitrogen,
serum electrolytes (particularly potassium and magnesium), and serum electrolytes (particularly potassium and magnesium),
complete blood counts, and liver function tests, and monitoring complete blood counts, and liver function tests which should be
should be conducted at least weekly during therapy, or even performed at least weekly during therapy, or even daily in the
daily in the presence of renal insufficiency. Because the renal presence of renal insufficiency. Theoretically, lipid formulations
toxicity of amphotericin B can develop precipitously, we recom- of amphotericin might have some benefit of higher central

3. 98 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011
nervous system (CNS) penetration, especially when given in or other body fluids. The report usually provides the concen-
higher doses, although conclusive clinical data to support this tration of the parent compound and its active metabolites, but
approach in treatment of fungal meningitis are lacking. does not take into account binding of active drug, because of the
Recommendation. Among patients with renal insufficiency extraction process, used before the assay. Thus, the target range
or among those individuals who are receiving multiple concom- provided by the lab for each particular assay should be followed
itant nephrotoxic drugs, we suggest a lipid formulation of when making dose adjustments. Dosage adjustments of orally
amphotericin B to reduce renal toxicity (DII). administered itraconazole are not required in patients with
Remark. In certain clinical situations that require doses of am- renal impairment, and do not appear to be required during
photericin B deoxycholate greater than or equal to 1.0 mg/kg/day, hemodialysis. Itraconazole is extensively metabolized in the
the incidence of such toxicities is high, and lipid formulations liver, and caution should be employed in patients with signif-
of amphotericin are associated with fewer adverse effects, and icant liver insufficiency (12).
therefore may be preferred. Contraindications to itraconazole use include previous hy-
persensitivity to itraconazole or co-administration of cisapride,
Triazoles dofetilide, midazolam, pimozide, levacetylmethadol, quinidine,
The azole antifungal agents contain three nitrogen atoms within statin medications, triazolam, and other agents. Precaution
the basic ring. Triazoles in clinical use include ketoconazole, should be used in patients with severe congestive heart failure
itraconazole, fluconazole, voriconazole, and posaconazole. Tri- (CHF), achlorhydria, hepatic dysfunction, or hypersensitivity to
azoles target the 14-a-demethylase enzyme, which mediates the other azoles. Side effects of itraconazole are rare and may
conversion of lanosterol to ergosterol in the fungus. Interactions of include rash, diarrhea, and nausea. Serious, though uncommon,
azole drugs with human P450 cytochromes have been well side effects include worsening of CHF, Stevens-Johnson syn-
documented (9). Therefore, azole-related drug interactions are drome, and hepatotoxicity. As with other azole compounds,
especially problematic in immunocompromised hosts, particularly interactions occur with many such drugs, particularly cyclospor-
transplant patients and those infected with HIV. In these popula- ine, benzodiazepines, statins, certain anti-HIV drugs, and many
tions, decreased plasma concentration of the azole may occur as other agents related to its metabolism by the P450 cytochrome
a result of increased metabolism, or of increases or decreases in system (10). Pharmacy and medication cross-reference re-
concentrations of co-administered drugs. With most of the azole sources should be consulted whenever instituting treatment.
compounds, interactions occur with many such drugs, particularly Fluconazole. In the 1990s, fluconazole joined this class of
cyclosporine, benzodiazepines, statins, and certain anti-HIV drugs, antifungals, offering a reduced lipophilicity that allows for easier
as a result of altered rates of drug metabolism and induction of the administration. This agent has been shown to have good activity
relative P450 enzymes (10). The use of azoles is contraindicated against Candida albicans, and is used for prevention and treat-
during pregnancy; in these patients, amphotericin is preferred, ment of both mucosal and invasive diseases. Fluconazole also has
as amphotericin B and its lipid derivatives are rated class B for significant activity in cryptococcosis and coccidioidomycosis.
pregnancy. By contrast, fluconazole, itraconazole, and posacona- Dose adjustments are recommended in renal impairment, and
zole are class C drugs, while voriconazole is a class D drug. Earlier dosages are reduced by 50% when the creatinine is less than 50
generation azoles such as ketoconazole also have adverse effects ml/minute. Patients on hemodialysis require replacement of the
on steroid hormone levels and adrenal function (11). entire dosage after each dialysis session (14). Contraindications to
Itraconazole. Modifications to the azole structure have led to fluconazole therapy include known hypersensitivity to the agent.
additional extended spectrum antifungals. For instance, itraco- Side effects are generally uncommon, but can include skin rash
nazole contains a four-ring lipophilic tail that enhances its and pruritus, nausea and vomiting, increased liver enzymes, and
interactions with the CYP51 cytochrome, rendering it active headache. Anaphylactic reactions are generally rare for all azoles.
against molds. Itraconazole is effective for some Aspergillus Compared with other azole antifungal agents, such as itracona-
infections, mucosal candidal infections, histoplasmosis, blasto- zole, voriconazole, and posaconazole, drug–drug interactions are
mycosis, coccidioidomycosis, and other fungal infections (12). relatively less common with fluconazole, as the drug is a relatively
Unfortunately, due to itraconazole’s high protein binding and less active inhibitor of P450. Prescribing physicians should
poor CNS penetration, it is not an optimal choice for CNS generally consult pharmacy and medication cross-reference re-
infections. Itraconazole is available as either oral capsules or an sources when initiating treatment.
oral solution. The oral capsules require gastric acid for absorp- Voriconazole. Voriconazole is a newer azole antifungal that
tion, and so are usually taken with food or acidic beverages. In is increasingly being used for invasive aspergillosis and other
addition, concurrent use of proton pump inhibitors and antacids mold infections. As with most other azoles, the drug is contra-
should be avoided. To overcome problems with variable drug indicated in patients receiving co-administration of P450–CYP3A4
absorption, particularly in settings in which proton pump in- substrates, including fexofenadine, astemizole, pimozide, or
hibitors must be administered concurrently, itraconazole has quinidine, as these interactions may lead to increased plasma
been solubilized in a cyclodextrin solution, resulting in sub- concentrations of these drugs, electrocardiographic Q to T wave
stantial improvement in absorption (13). In contrast to the interval (QT) prolongation and, rarely, torsades de pointes. In
capsule form, the oral solution requires an empty stomach. addition, coadministration of rifampin, carbemazapine, barbi-
Because of the widespread use of antacids, H2 blockers, and turates, ritonavir, and efavirenz should be avoided. Voriconazole
proton pump inhibitors, the committee recommends thoughtful should be used with caution in patients with hypersensitivity to
consideration of the optimal form to use. When using oral other azole antifungal agents, or with hepatic cirrhosis. Due to
itraconazole, it is important to routinely assure that adequate the cyclodextrin component, intravenous preparations of vor-
levels of itraconazole are present in serum (AII). The bioassays iconazole should be used with caution in patients with renal
used to measure the antifungal activity of serum reflect all insufficiency (creatinine clearance ,50 ml/min), as the cyclo-
active antifungal substances that are present in the serum at the dextrin vehicle may accumulate. Although there are no direct
time of testing, and therefore may not specify the level of the data that indicate that the cyclodextrin in intravenous vorico-
unique agent of interest. In contrast, the high-performance nazole is in fact nephrotoxic, the oral form can be used instead.
liquid chromatography (HPLC) method measures the actual Dose adjustments are not necessary for oral voriconazole in
concentration of the specific compound in question in the serum patients with mild to moderate renal impairment. If intravenous

4. American Thoracic Society Documents 99
voriconazole is absolutely necessary in patients with moderate Caspofungin. Caspofungin exhibits fungicidal activity against
or severe renal insufficiency (creatinine clearance , 50 ml/min), Candida species and fungistatic activity against Aspergillus
serum creatinine should be monitored closely. For patients species. Caspofungin has been used primarily for candidiasis,
receiving hemodialysis, the removal of the drug by hemodialysis treatment of febrile neutropenia, and for salvage therapy of
is not sufficient to warrant dosage adjustment. Voriconazole invasive aspergillosis. Laboratory studies support activity against
should not be used in patients with severe hepatic insufficiency, Pneumocystis species and some other fungal infections, although
unless the benefits outweigh the risk of liver problems. Patients clinical data are lacking (21, 22). Caspofungin is only adminis-
also need to avoid direct sunlight, since photosensitivity re- tered via intravenous infusion, with dosage adjustment being
actions can occur. Side effects include peripheral edema, rash, required in the case of hepatic impairment. The medication is
nausea, vomiting, and liver dysfunction. Severe liver dysfunc- contraindicated in patients with hypersensitivity, and precaution
tion and failure have rarely occurred (15). Visual disturbance should be exercised in patients with liver impairment, those who
(scotomata) occurs in approximately one-third of patients, but are pregnant, and those concomitantly receiving cyclosporine.
the condition is rapidly reversible, and will abate within minutes Common side effects include increased liver enzymes, nausea,
to hours following discontinuation of the agent (16). Some facial swelling, headache, and pruritus. Notably, caspofungin and
reports suggest that cutaneous malignancies have been asso- the other echinocandins are not inhibitors or inducers of the
ciated with voriconazole use. Metabolism of the drug can be cytochrome metabolism enzymes. However, drug–drug interac-
variable, and recent experience indicates a potential need for tions may still be observed, especially with cyclosporine and
monitoring of serum levels. Again, drug interactions are com- tacrolimus, rifampin, and certain anti-HIV drugs.
mon, and medication cross-reference resources should be con- Micafungin. Like caspofungin, micafungin also has activity
sulted when instituting therapy. against Candida and Aspergillus species. This agent has been
Posaconazole. Posaconazole has received FDA approval for approved for treatment of invasive candidiasis, for prophylaxis of
use as prophylaxis against invasive fungal infections in severely stem cell transplantation patients against Candida, and for
immunocompromised patients and for treatment of oropharyn- Candida esophagitis (23). Precaution should be used in patients
geal candidiasis that is refractory to fluconazole and itracona- with prior hypersensitivity to other echinocandins. Serious hyper-
zole. In addition, this agent has proven effective when used as sensitivity reactions, including anaphylaxis and shock, have rarely
salvage therapy in severely immunocompromised patients with occurred. Side effects include phlebitis; rash; abdominal discom-
refractory infection with Aspergillus species (17), and as a treat- fort with nausea, vomiting, or diarrhea; and hyperbilirubinemia.
ment for coccidioidomycosis (18). The agent also displays Anidulafungin. Anidulafungin is the most recently approved
activity against zygomycetes (19) and a variety of other fungi. echinocandin, and has received approval for use in candidemia,
Posaconazole is contraindicated in patients receiving ergot candidiasis, and candidal esophagitis, with additional activity
alkaloids, and in those receiving terfenadine, astemizole, pimo- exhibited against Aspergillus species (22). Studies of its relative
zide, or quinidine, as these interactions may lead to increased activity in comparison to other agents are underway. This agent
plasma concentrations of these drugs with QT prolongation is generally well tolerated, but should be infused slowly.
(20). Common adverse effects include diarrhea and abdominal Common side effects include diarrhea and hypokalemia. Seri-
discomfort, and serious side effects include occasional hepatic ous adverse reactions include deep vein thrombosis and, rarely,
dysfunction, in addition to long QT syndrome. Posaconazole has liver toxicity. The drug should be used cautiously in patients
saturable absorption, requiring adequate dietary fat that limits with liver dysfunction, and appropriate clinical monitoring
oral dosing to approximately 800 mg per day. The optimal way should be implemented in these patients. At present, all three
to provide the drug is 200 mg four times per day, and with fatty of the currently licensed echinocandins should be viewed as
meals when possible. Dose adjustments for posaconazole are not equally effective for candidemia.
necessary in patients with mild to severe hepatic insufficiency or
renal impairment. Dose adjustments are also not necessary after TREATMENT OF HISTOPLASMOSIS
dialysis. Appropriate clinical monitoring is indicated, including
liver function tests at the start and during the course of therapy, Histoplasma capsulatum is a dimorphic fungus that is endemic
and assessment of serum potassium, magnesium, and calcium to the Ohio, Missouri, and Mississippi River valleys in the
levels, with rigorous correction of levels as needed before United States, as well as some river valleys in Central America.
initiating therapy. As additional drug interactions may emerge, Severity of illness after inhalational exposure to Histoplasma
medication cross-reference resources should be consulted when capsulatum depends on the intensity of exposure, as well as the
instituting treatment. immune status and underlying lung architecture of the host, and
Recommendations. In patients receiving itraconazole, vori- plays a major role in treatment decisions (Table 3). The chronic
conazole, or posaconazole, we recommend measurements of manifestations of healed histoplasmosis will be briefly men-
drug levels in serum to be certain that the drug is being tioned and, as a rule, do not require specific antifungal therapy.
absorbed and to guide treatment (AII). In all instances, severe progressive disseminated disease, as well
In patients with renal insufficiency (creatinine clearance as CNS involvement, require initial treatment with amphoter-
,50 ml/min), we suggest reducing the dose of fluconazole by 50% icin B, while mild to moderate disease can usually be treated
(BIII). with itraconazole (AII).
Remark. Patients undergoing hemodialysis require redosing
after each dialysis session. Pulmonary Nodules
Although not treated with antifungal agents, asymptomatic
Echinocandins pulmonary nodules due to recent or remote Histoplasma
The echinocandins are an entirely novel class of antifungal exposure are common and diagnostically challenging, as they
agents that disrupt fungal cell walls through inhibition of the mimic malignancy. Often these nodules are biopsied or excised,
1,3-b-glucan synthase complex. Thus, they have been referred and may on occasion stain positively for Histoplasma. Univer-
to as the ‘‘penicillins of the antifungal armamentarium.’’ sally, when Histoplasma cannot be cultured, antifungal treat-
Currently, three agents are available: caspofungin, micafungin, ment is not recommended (EIII). The time to calcification is
and anidulafungin. variable and cannot generally be used alone to absolutely

5. 100 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011
TABLE 3. TREATMENT RECOMMENDATIONS FOR HISTOPLASMOSIS
Disease Manifestation Treatment Recommendations Comments
Mild pulmonary histoplasmosis; Itraconazole (200 mg twice daily for 12 wk) Liposomal amphotericin is preferred in patients
therapy deemed necessary with renal insufficiency.
Moderately to severely ill Amphotericin B (0.7 mg/kg/day) 6 corticosteroids Consider itraconazole serum level at 2 wk of therapy.
pulmonary histoplasmosis for 1–2 wk, then itraconazole Monitor renal and hepatic function.
(200 mg twice daily for 12 wk)
Chronic pulmonary histoplasmosis Itraconazole (200 mg twice daily for 12–24 mo) Continue treatment until no further radiographic improvement.
Monitor for relapse after treatment is stopped.
Itraconazole serum level at 2 wk, then every 3–6 mo recommended.
Progressive disseminated Lipid formulation amphotericin B (3–5 mg/kg/d) or Chronic maintenance therapy may be necessary
histoplasmosis amphotericin B (0.7–1.0 mg/kg/d for 1–2 wk), if immunosuppression cannot be reduced.
then itraconazole (200 mg twice daily for 12 mo)* Monitoring antigen levels may be useful.
Monitor renal and hepatic function.
* For mild to moderate disease in progressive disseminated histoplasmosis, itraconazole 200 g twice daily for 12 mo may be an option.
distinguish from malignancy, though some reveal typical central therapy has been used for hemoptysis related to fibrosing
and concentric calcification on CT imaging, which is suggestive mediastinitis and hyperemic airways (31).
of being benign. Moreover, many nodules never calcify. PET
scans can also show increased uptake in these histoplasma- Immunocompetent Hosts with Symptomatic Histoplasma
induced lesions (24). The decision to pursue diagnosis in this Pneumonia, or with Progressive or Severe Disease
patient population depends on many factors, including smoking Because healthy individuals with progressive disease are un-
status, chronicity, and patient preference. In patients who are common, recommendations for treatment of immunocompetent
symptomatic with pulmonary nodule(s) and associated chest patients are based primarily on expert opinion. In healthy
adenopathy, recent infection is presumed and treatment with individuals, asymptomatic infection follows low-intensity expo-
antifungal agents may be warranted depending on disease sures and typically requires no therapy (32). Because effective
severity, as discussed below for the immunocompetent host. and minimally toxic oral therapy is now available, 200 mg
itraconazole twice daily for up to 12 weeks is appropriate
Broncholithiasis therapy for patients who remain symptomatic after 3 weeks of
Broncholithiasis occurs when calcified lymph nodes erode into observation (BIII). In contrast, inhalation exposure to a large
the airway, causing symptoms of dyspnea, wheezing, or hemop- inoculum may cause severe pulmonary infection with massive
tysis. Many times these are managed conservatively and the mediastinal lymphadenopathy, hypoxemia, respiratory failure,
patient may spontaneously cough the broncholith out of the and acute respiratory distress syndrome (ARDS), even in
airway. In instances in which the patient requires intervention, healthy individuals. In patients with life-threatening pulmonary
bronchoscopic evaluation is first recommended (BIII). Remov- infections, including patients with severe gas-exchange abnor-
ing a partially or completely eroded broncholith can usually be mality, severe toxicity, and rapid progression, amphotericin B
safely performed at the time of bronchoscopic evaluation (25), deoxycholate (0.7 mg/kg/d) or a lipid formulation of amphoter-
but surgical intervention may be required if broncholithiasis is icin (5 mg/kg/d) should be used initially in these severely ill
complicated by obstructive pneumonia, fistula formation, or patients (AIII), followed by itraconazole 200 mg twice daily to
massive hemoptysis (BIII) (26). Antifungal treatment is not complete at least a 12-week course once the patient clinically
generally recommended (BIII). improves (BIII). Initiating therapy with itraconazole 200 mg
twice daily for 12 weeks is recommended for patients with mild
Fibrosing Mediastinitis or moderate disease (BIII). The role of corticosteroids in acute
Fibrosing mediastinitis is uncommon, but is often progressive infection is controversial. Patients with hypoxemia associated
with distortion and compression of major vessels and central with diffuse infiltrates and patients with massive granulomatous
airways. It must be differentiated from granulomatous media- mediastinitis may benefit as long as steroid therapy is used in
stinitis related to recent infections, malignancy, and chronic combination with antifungal therapy (CIII). The panel felt that
pulmonary thromboembolism. Patients may experience symp- prednisone 40–60 mg/day for 1 to 2 weeks was an appropriately
toms for years prior to diagnosis. Fibrosing mediastinitis can be conservative regimen (CIII).
fatal and, despite lack of proven therapy, some clinicians
recommend a 12-week course of itraconazole at 200 mg twice Immunocompromised Hosts
daily (CIII) (27, 28). If radiographic or physiologic improve- In immunosuppressed patients, progressive disseminated histo-
ment is obvious, therapy should be considered for 12 months. plasmosis occurs and amphotericin B (0.7–1.0 mg/kg/d to clin-
The use of corticosteroids is not routinely recommended (DIII), ical improvement or up to a total of 2 g), or a lipid formulation
and the role of antifibrotics (for example, tamoxifen) are of amphotericin (3–5 mg/kg/d), is the initial recommendation
unclear (CIII) (29). Intravascular stents may be useful in for patients who are sufficiently ill to require hospitalization.
appropriately selected patients—typically those with advanced This should be followed by itraconazole, 200 mg twice daily for
disease, open airways, and severe manifestations of vascular 12 months once clinical improvement is noted (AII). In one study,
compromise (BIII) (30). The algorithm for compressive disease initial treatment of patients with AIDS with liposomal ampho-
of the airway is complicated. The committee suggests consider- tericin B (AmBisome) showed a survival benefit (33) (BI).
ing balloon bronchoplasty, followed by consultation with a sur- However, patients treated with amphotericin B deoxycholate in
geon specializing in mediastinal disease, and endobronchial this study inadvertently had more severe disease activity, which
stenting (CIII). Stenting of the airway in benign disease is may have influenced the results in favor of liposomal ampho-
reserved for those with no other options, and a removable tericin B. Patients with mild to moderate disease can be treated
silicone stent is initially preferred (CIII). Endobronchial laser with itraconazole monotherapy. A loading dose of 200 mg three

6. American Thoracic Society Documents 101
times daily is recommended for the first 3 days of therapy, tolerated (DII). Voriconazole and posaconazole are active
followed by 200 mg twice daily for 12 months (AII) (34). against H. capsulatum and have been successfully used in
Monitoring of itraconazole levels is useful and should be salvage therapy (44–48). The echinocandins do not appear to
performed using either the bioassay or HPLC methods. Ther- be an effective treatment for Histoplasma infection (49).
apeutic reference ranges should be obtained from the local Recommendations. IMMUNOCOMPETENT HOSTS WITH HISTOPLASMA-
laboratory and testing method, since the effective range will RELATED PULMONARY NODULES, BRONCHOLITHIASIS, OR FIBROSING
vary with the method employed. In general, the bioassay MEDIASTINITIS. Among asymptomatic patients with pulmonary
therapeutic range is believed to be between 1 and 10 mg/ml. nodules in whom Histoplasma cannot be cultured, we recom-
The reference ranges for various HPLC assays vary by the mend that antifungal treatment not be used (DI).
methods used, though they are generally in ranges three to five In most patients with broncholithiasis, we recommend that
times lower than those obtained through bioassay methods. antifungals not be used (BIII).
Patients with HIV and AIDS may require prolonged itraco- In selected patients with broncholithiasis who require in-
nazole maintenance therapy (e.g., itraconazole 200 mg twice tervention, such as those with significant hemoptysis, we suggest
daily) after appropriate initial therapy (35). However, when bronchoscopic evaluation and removal of the broncholith either
effective immune reconstitution occurs, maintenance therapy bronchoscopically or surgically (BII).
generally can be safely discontinued when CD4 counts greater Among selected patients with broncholithiasis complicated
than 200/ml are achieved (36) (BII). In those patients who by obstructive pneumonia, fistula, or massive hemoptysis, we
remain immunosuppressed and require lifelong maintenance suggest surgical intervention (BII).
therapy, Histoplasma polysaccharide antigen levels, checked In patients with fibrosing mediastinitis, some clinicians rec-
several times a year, should be monitored in urine and serum, as ommend itraconazole 200 mg twice daily for 12 weeks (CIII). In
a rise in antigen levels may predict relapse (BIII). The use of patients with radiographic or physiologic improvement after an
glucocorticoids in immunocompromised patients with severe initial 12 weeks of therapy, we suggest longer treatment, up to
hypoxemia and diffuse infiltrates, such as in the setting of 12 months (CIII). In these patients, we also suggest that antifibrotic
immune reconstitution inflammatory syndrome which can occur agents and systemic glucocorticosteroids not be used (DII).
with histoplamosis, remains poorly studied and controversial (37). In selected patients with fibrosing mediastinitis and severe
However, the writing group felt that prednisone 40–60 mg/day vascular or airway compromise, we suggest placing intravascu-
for 1 to 2 weeks was an appropriately conservative regimen if lar stents (BII), bronchoplasty, and/or placing endobronchial
deemed useful on a patient-by-patient basis (CIII). Patients stents, if appropriate expertise is available (BIII). If a decision
with AIDS who live in endemic areas, particularly those who do is made to place a stent, we suggest initially using removable
not exhibit significant immune reconstitution through HAART stents (BIII).
reflected by CD4 cells greater than 200/ml, or those with a high IMMUNOCOMPETENT HOSTS WITH SYMPTOMATIC, PROGRESSIVE, OR
likelihood of occupational or recreational exposure, may be con- SEVERE PULMONARY HISTOPLASMOSIS. In asymptomatic patients,
sidered for prophylaxis with itraconazole 200 mg/day (38); we recommend that no antifungal treatment be used (BII).
however, whether the benefits outweigh the cost and risk is not In symptomatic patients with mild pulmonary histoplasmosis,
well established (BII). In addition, recent treatment with anti– who remain symptomatic after 3 weeks of observation, we suggest
tumor necrosis factor-a (TNF-a) agents has also been associated itraconazole 200 mg twice daily for up to 12 weeks (BIII).
with histoplasmosis, as well as other endemic and opportunistic In selected patients with mild to moderate pulmonary
fungal infections (39). Clinicians should be aware of this associ- histoplasmosis, we suggest initiating treatment with itraconazole
ation and have a high index of suspicion for this diagnosis in such 200 mg twice daily rather than with amphotericin B (BIII).
patients. In addition, adrenal insufficiency has been estimated to In patients with severe pulmonary histoplasmosis, such as
complicate disseminated histoplasmosis in 7% of cases, and this those with life-threatening pulmonary infections including pa-
possibility should be considered, particularly in patients who do tients with severe gas-exchange abnormality, severe toxicity, and
not respond well to therapy (40). rapid progression, we recommend amphotericin B 0.7 mg/kg/day
Patients with underlying structural lung disease (particularly until clinical improvement is observed or until a cumulative
emphysema) may develop ‘‘chronic pulmonary histoplasmosis.’’ dose of 2 g of amphotericin B is reached (BI). In patients who
This condition has been observed during histoplasmosis outbreaks improve clinically after initial treatment with amphotericin B,
when acute infection occurs in patients with centrilobular emphy- we suggest maintenance itraconazole 200 mg twice daily for at
sema or other forms of upper lobe structural disease. The clinical least 12 weeks (BII).
and radiographic findings may resemble those classically seen in In patients with severe pulmonary histoplasmosis with
reactivation tuberculosis, and infection is likely to progress if not diffuse pulmonary infiltrates or massive granulomatous media-
treated (41). However, it needs to be emphasized that current stinitis, we suggest adjunctive systemic glucocorticosteroid
concepts indicate that chronic pulmonary histoplasmosis does not therapy be used (CII).
represent reactivation of a prior infection (42). Treatment failures Remark. Prednisone 40–60 mg/day (or equivalent) for 1 to 2
commonly occur and provide a rationale for prolonged treatment weeks seems appropriate in these patients.
(43). Itraconazole given at 200 mg twice daily for 12 to 24 months is In patients with pulmonary histoplasmosis, we suggest
the current treatment of choice for chronic pulmonary histoplas- itraconazole rather than fluconazole or ketoconazole (CII).
mosis (AIII). Itraconazole levels should be monitored to verify Remark. In selected patients who do not tolerate itracona-
that the patient is absorbing the agent. Amphotericin B can zole, fluconazole or ketoconazole may still be used.
alternatively be used if clinical severity warrants (41). Histoplasma IMMUNCOCOMPROMISED HOSTS WITH PULMONARY HISTOPLASMO-
antigen testing, complement fixation titers, and gel diffusion tests SIS OR WITH PROGRESSIVE OR DISSEMINATED DISEASE, OR WITH
have no role in following treatment efficacy in patients with chronic CHRONIC PULMONARY HISTOSPLAMOSIS. In patients with mild to
pulmonary histoplasmosis. moderate histoplasmosis, we recommend itraconazole 200 mg
Although older studies suggest that fluconazole and ketoco- three times daily for 3 days followed by 200 mg twice daily for
nazole can be used to treat both acute and chronic pulmonary 12 months (CI).
histoplasmosis, they are inferior to itraconazole and should be In patients with severe progressive disseminated histoplas-
used only in special circumstances or when itraconazole is not mosis requiring hospitalization, we recommend amphotericin

7. 102 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011
B 0.7–1.0 mg/kg/day (or a lipid formulation of amphotericin TREATMENT OF BLASTOMYCOSIS
3–5 mg/kg/d) until clinical improvement is observed or until a cu-
mulative dose of 2 g of amphotericin B is reached (BII). In patients Introduction
who improve clinically after initial treatment with amphotericin B, Blastomyces dermatidis is a dimorphic fungus endemic in the
we suggest itraconazole 200 mg twice daily for 12 months (CI). central and southeastern United States. Blastomycosis is ac-
In patients with AIDS and progressive disseminated histo- quired by inhalation and can present as an acute, subacute, or
plasmosis who completed 12 months of initial itraconazole even chronic infection. A small number of cases present as an
therapy, we suggest itraconazole 200 mg twice daily until infectious ARDS with fulminant diffuse pneumonia (54). The
effective immune reconstitution occurs (i.e., CD41 T cell wide range of less severe pulmonary presentations includes
counts . 200/ml) (CII). lobar pneumonia, mass lesions, single or multiple nodules, and
In patients with AIDS who remain immunosuppressed and chronic fibronodular or fibrocavitary infiltrates. Dissemination
require lifelong maintenance therapy, we suggest monitoring from the lung is generally believed to occur in a minority of
Histoplasma polysaccharide antigen levels in urine and serum cases, either concurrent with the pulmonary infection or after
several times per year (BIII). resolution of a clinical or subclinical primary infection (usually
In patients with chronic pulmonary histoplasmosis, we within 1 or 2 yr) (55). It is unknown whether these delayed cases
recommend itraconazole 200 mg twice daily for 12 to 24 months represent a manifestation of reactivation of the primary in-
rather than no antifungal treatment (BI), and suggest that fection. The usual pattern of spread is to skin and bone. Less
Histoplasma antigen is not monitored (BIII). than 5% of disseminated cases involve the central nervous
In patients with severe chronic pulmonary histoplasmosis, we system, the meninges, or, less commonly, the brain itself. In
recommend initial treatment with amphotericin B over itraco- immunosuppressed patients, especially those with AIDS, the
nazole (BII). disease is more severe and the pace of illness is accelerated (56,
In selected immunocompromised patients with severe pul- 57). Considerations for treatment of blastomycosis have to be
monary histoplasmosis and diffuse pulmonary infiltrates, we viewed in the context of this wide spectrum of clinical illness
suggest adjunctive systemic glucocorticosteroid therapy (BII). (Table 4).
Remark. Prednisone 40–60 mg/day (or equivalent) for one to
Immunocompetent Hosts
two weeks seems appropriate in these patients.
The vast majority of clinically recognized cases are mild to
TREATMENT OF SPOROTRICHOSIS moderate in severity, involving the lung and/or the skin and
bones. For these infections, the usual treatment is itraconazole
Introduction 200 mg orally twice daily for 6 months (AII) (43, 58, 59). This
Sporotrichosis is an illness caused by the dimorphic fungus treatment is highly effective and is the same for pulmonary
Sporothrix schenkii. The organism is found throughout the world, infections and for nonmeningeal dissemination (accompanying
and is associated with various forms of vegetation. The most pulmonary disease or in isolation), except that treatment
common form of the infection is caused by inoculation of the duration is extended to 12 months when bones are involved
organism into skin and subcutaneous tissues. The usual pre- (BII) (59–63). Thus, a 6- to 12-month course of oral itraconazole
sentation of the disease is the characteristic lymphocutaneous or is appropriate treatment for most patients who present with
ulcerative skin form of sporotrichosis. Occasionally patients will blastomycosis. The challenge is to define the range of treatment
inhale the organism, leading to the development of pulmonary options for the small minority of patients with the most difficult
sporotrichosis, which may occasionally disseminate to various and life-threatening infections. Because patients with very
parts of the body, predominantly to large joints. The treatment severe infection, including all patients with CNS disease, were
recommendations for sporotrichosis are derived predominantly excluded by protocol from the large clinical trials that showed
from nonrandomized trials, case series, and case reports (50–52). itraconazole equal to amphotericin B deoxycholate, the latter
There have been no randomized controlled therapeutic trials. agent remains the gold standard for such patients. It should be
Itraconazole remains the drug of choice for most forms of noted, however, that subsequent case reports do suggest efficacy
sporotrichosis (53). Doses range from 200 mg/day for the of itraconazole for patients who are quite ill (63, 64).
lymphocutaneous form to 200 mg twice daily for pulmonary Life-threatening pulmonary infections include patients with
and osteoarticular disease (BIII). Conventional amphotericin B severe gas-exchange abnormality, severe toxicity, and rapid
deoxycholate or a lipid formulation of amphotericin is used for progression. The recommended treatment is intravenous
meningeal disease and may be used for severe pulmonary and amphotericin B deoxycholate (0.7–1.0 mg/kg/d) to a total
osteoarticular disease in a course of 1 to 2 g total dose (BIII). cumulative dose of 1.5–2.5 g (AII) (58, 65). Treatment can be
Relapse following therapy is unfortunately common. given daily until clinical improvement has been established, and
Recommendations. In patients with mild to moderately severe then three times weekly to completion (AIII) (65). Lipid
pulmonary sporotrichosis, based on the extent of radiographic formulations of amphotericin should be used for patients with
involvement and oxygenation status, we suggest itraco- pre-existing renal failure or with renal complications from am-
nazole 200 mg twice daily, with a total duration of therapy photericin B deoxycholate. The usual daily dosage is 5 mg/kg/day,
generally of 3 to 6 months based upon overall clinical response but even higher dosing has been used (BIII). Although there
(BIII). is a large positive experience in clinical practice, there are no
In patients with severe pulmonary sporotrichosis, such as disease-specific clinical trial data proving equivalency of lipid
those with life-threatening pulmonary infections including pa- formulations of amphotericin versus amphotericin B deoxycho-
tients with severe gas-exchange abnormality, severe toxicity, late in blastomycosis, and the total cumulative dose and
and rapid progression, we suggest amphotericin B 0.7 mg/kg/day duration of required treatment have not been studied. In
until clinical improvement is observed or until a cumulative current clinical practice, sequential therapy is often used after
dose of 1 to 2 g of amphotericin B is reached, followed by initial therapy with either agent. Amphotericin B deoxycholate
itraconazole 200 mg twice daily, with total duration of therapy (or lipid formulation amphotericin) is used until clinical im-
generally of 3 to 6 months based upon overall clinical response provement is achieved (500–1,000 mg of amphotericin B
(BIII). deoxycholate or 1–3 wk of lipid formulation amphotericin),

8. American Thoracic Society Documents 103
TABLE 4. TREATMENT RECOMMENDATIONS FOR BLASTOMYCOSIS
Disease Manifestation Treatment Recommendations Comments
Mild to moderately ill patients with pulmonary Itraconazole (200 mg twice daily for 24 wk) Monitor levels to insure absorption.
and nonmeningeal disseminated blastomycosis Consider liquid preparations.
Skin disease Itraconazole (200 mg twice daily for 24 wk) Monitor levels to insure absorption.
Consider liquid preparations.
Bone disease Itraconazole (200 mg twice daily for 12 mo) Monitor levels to insure absorption.
Consider liquid preparations.
Life-threatening severe blastomycosis, Liposomal amphotericin B (5 mg/kg/d) or Consider concurrent corticosteroids for
including ARDS amphotericin B (0.7–1.0 mg/kg/d) until severe gas-exchange abnormalities.
clinical improvement, then itraconazole For immune-suppressed patients, treat for a
(200 mg twice daily for 6–12 mo) minimum of 12 mo and indefinitely for
AIDS without immune reconstitution.
Meningeal infection Liposomal amphotericin B (5 mg/kg/d) or For immune-suppressed patients, treat for
amphotericin B (0.7–1.0 mg/kg/d) until a minimum of 12 mo and indefinitely for
clinical improvement, and concurrent or AIDS without immune reconstitution.
sequential itraconazole (400 mg/d) or
fluconazole (400-800 mg/d) for 6–12 mo
followed by itraconazole 200 mg orally twice daily for 6 months of amphotericin B deoxycholate) until clinical improvement,
(BIII) (58). Thus, it is difficult to gauge the optimal duration of followed by oral itraconazole 200 mg twice daily for a minimum
lipid formulation amphotericin B treatment, since it is seldom of 12 months. In mild to moderate clinical infections, itracona-
used for the entire treatment course. Six to eight weeks of zole from the onset of therapy may be adequate. For patients
amphotericin administration has been suggested depending on with AIDS, lifetime maintenance, such as with itraconazole, is
treatment response, only by comparison to the treatment of necessary unless immunity is fully restored, with CD4 lympho-
other fungal infections. cytes greater than 200/ml for 3 months (BII).
Meningeal infections are also treated differently due to high CNS involvement may also occur in immunosuppressed
protein binding and poor CNS penetration of itraconazole. The patients, either isolated or more likely as part of widespread
recommended treatment is amphotericin B deoxycholate at dissemination. Mortality is high and treatment should be aggres-
a dose of 0.7 mg/kg/day, to a total dose of at least 2 g (BIII) (58, sive. Combination therapy is often used, again without specific
65). Lipid formulations of amphotericin B may be used in supporting data. One option is amphotericin B deoxycholate (or
patients who cannot tolerate the standard deoxycholate formu- liposomal amphotericin B) together with high dose fluconazole
lation. Lipid formulations of amphotericin B have the theoret- (400–800 mg daily) from onset. The amphotericin B deoxycholate
ical benefit of higher brain tissue levels (versus amphotericin B (or liposomal amphotericin B) component is continued to clinical
deoxycholate) in animal models. There are case reports of suc- improvement and then fluconazole is continued for at least an
cessful retreatment of CNS blastomycosis with lipid formulation additional 12 months. Lifetime maintenance therapy, such as with
amphotericin B after failure of amphotericin B deoxycholate fluconazole, is recommended when AIDS without immune re-
(66, 67). Triazoles alone should not be used in blastomycotic constitution is the underlying immunosuppressive illness (AII).
meningitis (CIII). However, combination therapy may be use- As discussed previously, liposomal amphotericin B has the
ful. High-dose fluconazole (400–800 mg daily, either intrave- theoretical benefit of achieving higher brain tissue levels in
nous or oral) can be used together with amphotericin B animal models and voriconazole has some attraction as a potential
deoxycholate (or lipid formulation amphotericin B) from onset, triazole component, but there are no disease-specific data
or used in sequence after initial improvement. The time course comparing one regimen to another (CII).
of fluconazole treatment should be extended to at least 6 months. There are two other specific clinical circumstances that merit
Although fluconazole is less effective than itraconazole for comment. First, if CNS disease progresses on amphotericin B
pulmonary and nonmeningeal disseminated blastomycosis (68, deoxycholate therapy or develops while a patient is being treated
69), it has been used for meningitis because of better CNS with itraconazole for pulmonary or non–CNS-disseminated dis-
penetration (CIII). Voriconazole, a newer triazole, is interme- ease, then a change in strategy is warranted (64, 67, 69, 74). A
diate between itraconazole and fluconazole in terms of CNS reasonable but unproven regimen might be combination ther-
penetration, and in animal models has efficacy against blasto- apy with liposomal amphotericin B plus fluconazole 800 mg
mycosis (70, 71). It is attractive conceptually as the triazole daily to clinical improvement, followed by fluconazole for 6
component of a combination or sequential strategy for menin- months (immunocompetent), 12 months (immunocompromised/
gitis (CIII), but supporting clinical data is limited to individual non-AIDS), or indefinitely (AIDS without satisfactory immune
case reports and small series of patients (72, 73). reconstitution) (BIII). Voriconazole 200 mg twice daily might
be an alternative for fluconazole in the above regimen, based on
Treatment of Immunosuppressed Hosts pharmacokinetic properties and in vitro sensitivities (CIII).
Blastomycosis in immunosuppressed patients is another setting Surgical resection may play a role in some patients with fo-
in which the standard 6- to 12-month course of oral itraconazole cal CNS disease, in combination with aggressive antifungal
is often altered, again based on very limited specific data. The chemotherapy.
basic principle is that immunosuppressed patients have higher Second, patients with highly unstable pulmonary or dis-
mortality and likely require more aggressive and prolonged seminated blastomycosis who require advanced physiologic
therapy (56, 57). Recommended treatment for pulmonary and support (including mechanical ventilation, advanced oxygen-
nonmeningeal blastomycosis in moderately immunosuppressed ation techniques, and vasopressors) have a guarded prognosis.
patients, such as solid organ recipients, includes sequential Many have severe ARDS. A reasonable but unproven reg-
therapy with amphotericin B deoxycholate (or liposomal imen might be amphotericin B deoxycholate or liposomal
amphotericin B in cases of renal insufficiency or intolerance amphotericin B plus itraconazole 200 mg twice daily until clinical

9. 104 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011
improvement, followed by oral itraconazole for 6 months (im- amphotericin B, there is serious uncertainty about the relative
munocompetent), 12 months (immunocompromised/non-AIDS), efficacy of itraconazole compared with amphotericin.
or indefinitely (AIDS) (CIII). Voriconazole 200 mg twice daily In patients with pulmonary blastomycosis and bone involve-
might be substituted for itraconazole in the above regimen, ment, we suggest prolonging treatment with itraconazole to
based on pharmacokinetic properties and in vitro activity (CIII). 12 months (CII).
A role for corticosteroids for severe diffuse pulmonary disease In patients with pulmonary blastomycosis and concomitant
is not proven, but they are sometimes used to try to improve CNS involvement, we suggest:
severe hypoxemia during the initial and most unstable period,
together with mandatory appropriate antifungal therapy (75). In d liposomal amphotericin B 0.7 mg/kg/day until a cumulative
addition, the use of glucocorticoids in immunocompromised dose of 2 g is reached (BII);
patients with severe hypoxemia and diffuse infiltrates related to d triazoles should not used as monotherapy for meningeal
blastomycosis, such as in the setting of immune reconstitution blastomycosis (DII);
inflammatory syndrome, also remains poorly studied and con-
d high dose intravenous or oral fluconazole 400–800 mg
troversial. As discussed above for histoplasmosis, the writing
daily may be provided as an add-on therapy to intravenous
group felt that adjunctive corticosteroid doses in the range of
40–60 mg prednisone daily for 1 to 2 weeks was an appropriately amphotericin B in patients with severe or refractory
conservative regimen if deemed useful on a patient-by-patient disease, with the total duration of fluconazole therapy
basis (CIII). extended for at least 6 months (BIII).
IMMUNOCOMPROMISED HOSTS. In patients with severe pulmo-
Additional Treatment Considerations
nary blastomycosis without CNS involvement, we recommend am-
1. Special consideration should be given for treating patients photericin B 0.7 mg/kg/day until clinical improvement is observed
with blastomycosis who are pregnant. In these patients, (BII). Once clinical improvement is observed, we recommend oral
amphotericin B is preferred over the azole agents. Ampho- itraconazole 200 mg twice daily for at least 12 months (BII).
tericin B and its lipid derivatives are rated class B for In patients with mild to moderate pulmonary blastomycosis
pregnancy, while fluconazole, itraconazole, and posacona- without CNS involvement, we suggest oral itraconazole 200 mg
zole are class C drugs, and voriconazole is a class D drug (76). twice daily for at least 12 months (BIII).
2. The high efficacy of itraconazole for the great majority of When AIDS is involved, we suggest oral itraconazole
200 mg/day indefinitely or until immunity is fully restored (BII).
blastomycosis cases has been proven in large clinical trials
In patients with pulmonary blastomycosis and concomitant
that will not likely be repeated with voriconazole or with
CNS involvement, we recommend:
newer triazoles such as posaconazole, despite some the-
oretical advantages for those newer agents in absorption d combined therapy with amphotericin B 0.7 mg/kg/day to-
and tissue penetration. Since there likely will be no gether with intravenous or oral fluconazole 400–800 mg daily
prospective studies comparing these agents to itracona- from the onset until clinical improvement is observed (BIII).
zole for either standard cases or in special situations such
d use of fluconazole for at least 12 months total after
as CNS disease, there also will likely be no strong
discontinuation of combined intravenous treatment with
evidence-based guidelines forthcoming that will advance
amphotericin B and high-dose fluconazole (BIII);
current preferences beyond those outlined above.
d use of liposomal amphotericin B rather than amphotericin
3. Echinocandins likely have no role (either alone, in B deoxycholate should be considered due to theoretic
combination, or sequentially) in treatment of blastomy- better CNS penetration (CIII);
cosis, even in situations warranting a nontraditional ap-
d triazoles are not used as monotherapy (DII);
proach (DIII). Although the echinocandins have some
activity in vitro, clinical efficacy of these agents against d patients with AIDS should continue to receive oral
Blastomyces has not been demonstrated (77). fluconazole 400 mg per day indefinitely or until immunity
is restored (AII).
4. The prostate, like the CNS, can serve as a sanctuary site
with respect to itraconazole with its high protein binding. In patients with pulmonary blastomycosis with new or
Lipid formulations of amphotericin B and newer triazoles progressing CNS involvement despite amphotericin B mono-
with less protein binding, sometimes in concert with therapy, we suggest:
surgery, have been used successfully in some cases (CII).
d combined therapy with liposomal amphotericin B 5 mg/kg/day
Recommendations. IMMUNOCOMPETENT HOSTS. In patients until clinical improvement is observed, together with intra-
with mild to moderate pulmonary blastomycosis, we recom- venous or oral fluconazole 800 mg/day (CIII);
mend oral itraconazole 200 mg twice daily for 6 months (AII).
In patients with severe pulmonary blastomycosis, we recom- d fluconazole is used for at least 6 months in immunocom-
mend amphotericin B 0.7–1.0 mg/kg/day daily until clinical petent patients, and at least 12 months in immunocom-
improvement is observed (BII), followed by continuation of promised patients, after discontinuation of combined
amphotericin B 0.7–1.0 mg/kg three times weekly, until a cumu- treatment with amphotericin B and fluconazole (CIII);
lative dose of 1.5–2.5 g is reached (BII). Once clinical improve- d patients with AIDS receive oral fluconazole 400 mg daily
ment is observed, we suggest oral itraconazole 200 mg twice indefinitely or until immunity is restored (AII).
daily for 6 months (BII).
Remarks. In patients with renal failure, lipid formulations of In some carefully selected patients with blastomycosis and
amphotericin are preferred. focal CNS lesions, consideration of surgical resection of the fo-
Because patients with very severe blastomycosis have been cal CNS lesions may occasionally be considered, if appropriate
excluded from clinical studies that compared itraconazole to expertise is available (CIII).

10. American Thoracic Society Documents 105
In critically ill patients with pulmonary blastomycosis, we TREATMENT OF COCCIDIOIDOMYCOSIS
suggest:
Coccidioidomycosis is caused by the soil-dwelling fungi Cocci-
d combined therapy with amphotericin B (0.7–1.0 mg/kg dioides immitis and Coccidioides posadasii that are localized to
amphotericin B deoxycholate or 5 mg/kg daily liposomal relatively arid regions of the Western hemisphere. The areas of
amphotericin B) until clinical improvement is observed, highest endemicity in North America are the San Joaquin
together with oral itraconazole 200 mg/day (CII); Valley of California, the south-central region of Arizona, and
northwestern Mexico. The vast majority of cases of coccidioi-
d following the initial intravenous therapy, oral itraconazole domycosis are acquired by inhalation. Approximately 60%
is used for at least 6 months in immunocompetent patients, of infections are asymptomatic (78). Many of the remainder
and at least 12 months in immunocompromised patients, are associated with a pulmonary syndrome resembling other
after discontinuation of combined treatment with ampho- community-acquired pneumonia (CAP) syndromes or an upper
tericin B and itraconazole (CII); respiratory tract infection. Acute pulmonary coccidioidomyco-
d after initial therapy is complete, patients with AIDS sis may be distinguished from CAP by its lack of response
to antibacterial therapy, and sometimes by hilar adenopathy,
should receive oral itraconazole 200 mg/day indefinitely,
peripheral blood eosinophilia, severe fatigue, night sweats, and
or until immunity is restored (CII). Voriconazole 200 mg
the presence of erythema multiforme or erythema nodosum.
twice daily may be used as an alternative to itraconazole The diagnosis can be established by the presence of anticocci-
(CIII). dioidal antibody in the serum, measurable by ELISA, immu-
nodiffusion, or by tube precipitin and complement fixation
In selected critically ill patients with severe pulmonary
assays. The diagnosis can also be established by the identifica-
blastomycosis, such as blastomycosis-associated ARDS, we
tion of coccidioidal spherules in tissue or by isolating the fungus
suggest consideration of adjunctive systemic glucocorticoste-
by culture from a clinical specimen. Because acute primary
roids (CIII). Prednisone 40–60 mg daily (or equivalent) for 1 to
pulmonary coccidioidomycosis is frequently self-limited, many
2 weeks seems appropriate in these patients. cases appear to respond to antibacterial antibiotics and are
In patients with pulmonary blastomycosis with new or consequently misdiagnosed as CAP. In endemic regions, coc-
progressing CNS involvement despite amphotericin B mono- cioidomycosis may be responsible for nearly one-third of
therapy, we suggest: patients presenting with lower respiratory tract symptoms (79).
d combined therapy with liposomal amphotericin B 5 mg/kg/ Immunocompetent Patients
day until clinical improvement is observed, together with
intravenous or oral fluconazole 800 mg/day (CIII); Most cases of primary pulmonary coccidioidomycosis in individ-
uals without identified risk factors are self-limited and do not
d fluconazole is used for at least 6 months in immunocom- require treatment (BIII) (Table 5) (78). Therapy of primary
petent patients, and at least 12 months in immunocom- pulmonary coccidioidomycosis should be considered when symp-
promised patients, after discontinuation of combined toms persist for more than 6 weeks or for especially severe acute
treatment with amphotericin B and fluconazole (CIII); disease (80). The principles of therapy in this group are identical
d patients with AIDS receive oral fluconazole 400 mg daily to those discussed next for treatment of immunosuppressed
indefinitely or until immunity is restored (AII). patients and other patients at risk for disseminated disease.
d Voriconazole 200 mg twice daily may be considered as an Immunosuppressed Patients and Others at Risk
alternative to fluconazole, though extensive disease-spe- for Disseminated Disease
cific data are currently lacking (CIII).
Therapy for primary pulmonary coccidioidomycosis should be
In some carefully selected patients with blastomycosis considered for patients with impaired cellular immunity, such as
and focal CNS lesions, consideration of surgical resection of the those with solid-organ transplants, those with HIV infection
focal CNS lesions may occasionally be considered, if appropri- with peripheral blood CD4 cell counts less than 200/ml, and in
ate expertise is available (CIII). those with co-morbidities likely to be adversely affected by
In critically ill patients with pulmonary blastomycosis, we ongoing primary infection, such as chronic lung disease, chronic
suggest: renal failure, or congestive heart failure (BIII) (Table 5).
Patients receiving TNF-a inhibitor therapy are also at increased
d combined therapy with amphotericin B (0.7–1.0 mg/kg risk for developing symptomatic coccidioidomycosis (81). Pa-
amphotericin B deoxycholate or 5 mg/kg daily liposomal tients with diabetes mellitus are likely to develop chronic
amphotericin B) until clinical improvement is observed, pulmonary coccidioidomycosis, particularly cavitary disease,
together with oral itraconazole 200 mg/day (CII); and require close monitoring, with clinical assessment and
radiography every 1 to 2 months until the cavity resolves or
d following the initial intravenous therapy, oral itraconazole stabilizes (82). Cavitary disease can be complicated by hemop-
is used for at least 6 months in immunocompetent patients, tysis, which independently represents an indication for therapy.
and at least 12 months in immunocompromised patients, All patients with primary pulmonary coccidioidomycosis should
after discontinuation of combined treatment with ampho- be followed for at least 1 year to assure complete resolution and
tericin B and itraconazole (CII); absence of complications (BIII). A small fraction of patients
d after initial therapy is complete, patients with AIDS develop persistent pulmonary disease or dissemination. Patients
should receive oral itraconazole 200 mg/day indefinitely, with solid-organ transplants and those with HIV infection and
depressed CD4 cell counts are at particularly high risk for
or until immunity is restored (CII).
dissemination. African-American and Filipino-American men
d Voriconazole 200 mg twice daily may be considered as an are also at increased risk for developing disseminated coccidi-
alternative to itraconazole, though this is based largely on oidomycosis, as are pregnant women who experience coccidioi-
in vitro sensitivities and limited case based data (CIII). dal infection during the second or third trimester (83). The most

11. 106 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011
TABLE 5. RECOMMENDED INITIAL THERAPY FOR COCCIDIOIDOMYCOSIS
Disease Manifestation Nonimmunocompromised Host Immunocompromised Host
Primary pulmonary No therapy in most; fluconazole (400 mg/d) Fluconazole (400 mg/d) or itraconazole (400 mg/d)
or itraconazole (400 mg/d) for 3–6 mo for 3–6 mo or longer depending on clinical response.
in selected cases.*
Pulmonary nodule No therapy. Consider fluconazole (400 mg/d) or itraconazole (400 mg/d)
during periods of significant immune suppression.
Pulmonary cavity No therapy. Consider therapy in some cases†; Fluconazole (400 mg/d) or itraconazole (400 mg/d)
in those consider fluconazole (400 mg/d) or for 12–18 mo or longer until cavity and symptoms stabilize.
itraconazole (400 mg/d) for 3–6 mo or longer
until cavity and symptoms stabilize.
Diffuse pulmonary Liposomal amphotericin B (5 mg/kg/d) or Liposomal amphotericin B (5 mg/kg/d) or amphotericin
amphotericin B (0.7–1.0 mg/kg/d) until clinical B (0.7–1.0 mg/kg/d) until clinical improvement, followed
improvement, followed by fluconazole (400 mg/d) by fluconazole (400 mg/d) or itraconazole (400 mg/d)
or itraconazole (400 mg/d) for at least another year. for at least a year. ‡For ongoing immune suppression
consider long-term maintenance with azole.
Disseminated, nonmeningeal Fluconazole (400 mg/d) or itraconazole‡ (400 mg/d) Fluconazole (400 mg/d) or itraconazole‡ (400 mg/d)
(including bone disease) for at least a year and until clinical improvement for at least a year and until clinical improvement and stabilization.
and stabilization; in severe cases, liposomal In severe cases, liposomal amphotericin B (5 mg/kg/d)
amphotericin B (5 mg/kg/d) or amphotericin or amphotericin B (0.7–1.0 mg/kg/d) until clinical
B (0.7–1.0 mg/kg/d) until clinical improvement improvement followed by fluconazole (400 mg/d)
followed by fluconazole (400 mg/d) or itraconazole or itraconazole (400 mg/d) for at least another year.
(400 mg/d) for at least another year.
Meningitis Fluconazole (400–1,000 mg/d) or itraconazole Fluconazole (400–1000 mg/d) or itraconazole (400–600 mg/d)
(400–600 mg/d) for life; intrathecal amphotericin for life; intrathecal amphotericin B in some cases.
B in some cases.
* Moderate, severe, or prolonged infection (. 6 wk), or for patient factors including chronic obstructive pulmonary disease, chronic renal failure, congestive heart
failure, diabetes mellitus, and certain ethnicities and demographic factors as discussed in the text.
†
In cases in which persistent productive cough or hemoptysis, continued pleuritic chest pain, or increasing size of cavity occurs or rising serologic titer.
‡
Itraconazole preferred for bone disease.
common sites of disseminated coccidioidomycosis are the skin, B. The echinocandin class of antifungals has not been adequately
soft tissues, bones and joints, and the meninges. A lumbar assessed in coccidioidomycosis, but does not appear to possess
puncture with analysis of cerebrospinal fluid should be done in efficacy. Azole antifungals that are well studied in coccidioido-
any patient with primary coccidioidomycosis presenting with mycosis include ketoconazole, fluconazole, and itraconazole.
headache, blurry vision, photophobia, meningismus, or any There are small series and case reports suggesting efficacy of
other CNS symptom, and should be considered in any patient voriconazole and posaconazole in recalcitrant cases of coccidi-
who is severely ill or not likely to be subsequently followed. oidomycosis (18, 89–91). Ketoconazole has been largely sup-
Persistent pulmonary disease comprises nodules, cavities, planted by fluconazole and itraconazole, and the latter has
and chronic infiltrates. Coccidioidal nodules are usually asymp- greater efficacy than fluconazole for bone and joint coccidioido-
tomatic, presenting a problem only in distinguishing them from mycosis (AI) (87). When fluconazole and itraconazole are
malignancies, and generally require no treatment. Cavities may employed, the minimum dose is 400 mg/day (BII) (86–88).
occasionally be associated with pleuritic chest pain, productive Amphotericin B is currently reserved for the most severe
cough, or hemoptysis. Patients with cavities should be consid- cases of coccidioidomycosis or those that do not respond to
ered for therapy, especially when hemoptysis is present, or with azoles (AIII). Although there is no evidence that the newer lipid
progressive enlargement of the cavity (BIII). Chronic pulmo- formulations of amphotericin B possess any greater efficacy than
nary coccidioidomycosis, defined as symptoms ongoing for more the conventional amphotericin B deoxycholate preparation, the
than 3 months, frequently occurs in patients with underlying lipid formulations are better tolerated and allow treatment with
lung disease and should be treated (BIII). a reduction in renal and other toxicities (BIII).
All forms of disseminated coccidioidomycosis require anti- Recommendations. IMMUNOCOMPETENT HOSTS. In most immu-
fungal therapy (AIII). Meningitis represents a special situation nocompetent patients with primary pulmonary coccidioidomy-
because currently available azole antifungal therapy should be cosis and no additional risk factors for dissemination, we
continued throughout a patient’s lifetime (AII) (84), given the suggest no antifungal treatment (BII).
extremely high relapse rate. Intravenous amphotericin B deox- Remark. Additional risk factors for dissemination include
ycholate is considered ineffective for coccidioidal meningitis, COPD or other chronic structural lung disease, chronic renal
but intrathecal amphotericin B has a role in its management in failure, congestive heart failure, diabetes mellitus, pregnancy,
cases of azole therapy failure, or when a more rapid response is African-American or Filipino-American heritage, HIV, and
desired (AII) (85). Because of the risk of hydrocephalus and those patients receiving TNF-a antagonists.
other complications even in the face of appropriate antifungal In immunocompetent patients with primary pulmonary coccid-
therapy, an expert should be consulted in the management of ioidomycosis and moderate to severe symptoms, or those in whom
coccidioidal meningitis (BIII) (82). symptoms persist for more than 6 weeks, we suggest treatment
Antifungal therapy for chronic coccidioidomycosis is gener- with triazole antifungal drugs for at least 3 to 6 months or longer if
ally prolonged, with a minimum course of 12 to 18 months (AII) symptoms and radiographic abnormalities persist (BII).
(86–88). Courses beyond 18 months should be considered in IMMUNOCOMPROMISED HOSTS AND OTHERS AT RISK FOR DISSEM-
patients with underlying immunocompromising conditions. De- INATED DISEASE. Therapy for primary pulmonary coccidioido-
clining titers of serum anticoccidioidal antibody indicate treat- mycosis should be considered for patients with impaired cellular
ment effectiveness. Available agents for the treatment of immunity, such as those with solid organ transplants, those with
coccidioidomycosis include azole antifungals and amphotericin HIV infection with peripheral blood CD4 cell counts less than