Endemic Mycoses for Pulmonary Clinicians

Abstract

Topic Importance

Endemic fungal infections are increasingly recognized as important causes of community-acquired pneumonia. Despite this, diagnosis is often delayed or misattributed, resulting in significant morbidity and mortality.

Review Findings

Histoplasma capsulatum, Blastomyces species, and Coccidioides species are the most common endemic fungal infections in the United States. These infections share commonalities in modes of transmission and pathogenicity where regional climates, weather patterns, and certain exposures play a key role in infectivity. However, changes in climate and human migration patterns have altered and expanded the traditional maps of endemicity. Antigen- and antibody-based testing have improved diagnostic efficiency but are limited by host immune status. Understanding the proper use and limitations of antigen- and antibody-based testing is key to appropriate diagnosis. We also discuss the management of disseminated infection, recent developments in treatment modalities, and areas of active research.

Summary

Our results indicate that a greater number of patients are at risk of endemic fungal infections due to climate change, human migration patterns, and increased use of immunosuppressive medications. Pulmonary manifestations of these infections are similar and typically mild in immunocompetent patients, but clinical presentations can be highly variable, especially in those with disseminated infection. Azole therapy is used for most patients, with liposomal amphotericin B used in the most severe infections.

Patient 1

A 63-year-old farmer from Western Minnesota presents to the pulmonary clinic with an incidentally discovered 10-mm right lower lobe nodule. PET-CT scan demonstrated fluorodeoxyglucose (FDG) uptake in the nodule and station 4r, 11r, and 7 lymph nodes. The nodule’s standardized uptake value was less than that of the lymph nodes.

Patient 2

A 27-year-old hairstylist presents to the ICU after failing 2 courses of outpatient antibiotics with fevers and progressive hypoxemic respiratory failure. She went camping in Northern Wisconsin 3 weeks before presentation. Her dog has been sick as well. She requires immediate intubation and mechanical ventilation. CT scan of the chest shows dense left lower lobe necrotizing pneumonia with bilateral ground glass opacities and nodules.

Patient 3

A 40-year-old business executive, who moved from the Midwest to Arizona 4 years ago, developed a rash 3 weeks ago that resolved in 2 days. He then developed polyarticular joint pain and a persistent cough. He received a 7-day course of oral amoxicillin-clavulanate without improvement in his symptoms. He subsequently presented to the emergency department for worsening cough and chest pain; a CT scan of the chest showed a large left lower lobe cavitary lesion abutting the pleura, with associated pleural effusion.

Although these cases have disparate presentations, they represent a spectrum of diseases caused by endemic mycoses. These are increasingly recognized as significant causes of community-acquired pneumonia (CAP) and are also associated with extrapulmonary infections, potentially involving the skin, bone, central nervous system, digestive tract, and genitourinary system.

Herein, we review 3 of the most common endemic mycoses affecting North America: Histoplasma capsulatum, Blastomyces species, and Coccidioides species. We focus on the evolving geographic maps, pathogenicity, clinical characteristics, current understanding of appropriate diagnostic testing, and treatment strategies for these infections.

Literature Search

A professional librarian searched MEDLINE and Embase databases using the following terms: histoplasmosis, blastomycosis, coccidioidomycosis, endemic mycosis, pneumonia, and pulmonary infection. Articles were restricted to those written in the English language within the last 5 years and included primary references (meta-analyses, randomized controlled trials, retrospective case-control or cohort studies, case series, and case reports) and society guidelines. Articles outside of these parameters were included only if considered practice-changing by the authors. Primary references were preferred when available.

Changing Endemic Maps

Historical patterns of regional extent are changing for the endemic mycoses (Fig 1). Alterations in soil environments due to climate change, increasing land use, and urbanization are expanding the areas of endemicity.¹ Other factors include increased rates of human migration and travel, an aging global population, increasing comorbid disease burden, and increased use of immunosuppressive medications.² Heightened recognition by clinicians is also leading to increases in rates of diagnosis.

Figure 1.

Maps reflecting the global burden of common endemic mycoses.

Histoplasmosis, most often caused by Histoplasma capsulatum var capsulatum in North America, has historically been endemic to the lower Midwest and Southeast regions of the United States including the Mississippi and Ohio River Valleys.^3,4 This region remains hyperendemic, but the number of identified cases of histoplasmosis has significantly increased, and the map of endemicity now stretches from the upper Midwest and Great Plains to the Western slopes of the Appalachian Mountains.^1,5 Molecular studies show increasing genetic diversity and proliferation of Histoplasma species globally, with much of South America, Central America, the Caribbean, subequatorial Africa, and Southeast Asia affected.⁶

Blastomyces dermatitidis and Blastomyces gilchristii are hyperendemic to the upper Midwest regions of the United States and Canada and endemic to areas surrounding major eastern waterways including the Great Lakes, Mississippi River, Ohio River, and St Lawrence River.^7,8 The map of Blastomyces species infection and the national burden of infection have significantly expanded. A 4-fold increase in incidence has been noted as westward as the Mohawk River Valley in New York State.^9,10 Insurance claims data suggest increasing endemicity in the state of Vermont, a region not previously considered to be endemic for B dermatitidis infection.¹¹ Blastomyces species have emerged in other countries as well including the Democratic Republic of Congo, South Africa, and Zimbabwe.¹²

Coccidioides immitis and Coccidioides posadasii are hyperendemic to the San Joaquin Valley of California and Southern Arizona in the United States, and adjacent regions of Mexico.⁵ Other areas with endemic Coccidioides species include the greater Southwest United States, parts of southeastern Washington State, and localized regions of Central and South America.^13,14 Coccidioides species germinates after rainfall, and the infectious arthroconidia are dispersed under dry conditions. As such, the area of Coccidioides species endemicity is expected to expand with increasing rainfall and periods of prolonged dryness in Western North America. By 2100, Coccidioides species endemicity could extend as far east as Western Minnesota and include the entire Western United States.¹⁵ The growing population of the Southwestern United States also contributes to this increased incidence due to the presence of previously unexposed patients, desert urbanization, and an older and more immunocompromised population.

Evidence Review

Clinical Presentation and Diagnosis

Histoplasmosis

Histoplasma capsulatum is transmitted by inhalation of conidia (Table 1). Histoplasma conidia are found deposited in soil and in high concentrations in bird or bat guano. After inhalation, conidia transform from the mold to the yeast form in respiratory tissue and express virulence factors that target respiratory phagocytes.¹⁶ Immunocompetent patients exposed to low inocula are typically asymptomatic.¹⁷ Exposure to higher inocula may lead to isolated pulmonary disease. Such patients may develop acute pulmonary histoplasmosis marked by a dry cough, chest pain, malaise, and headache occurring 1 to 2 weeks after exposure. Subacute pulmonary histoplasmosis presents more insidiously with milder respiratory symptoms lasting < 3 months.

Table 1.

Unique Features of Histoplasmosis

Feature	Details
Causative organism	•Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var duboisii
Clinical history/findings	•Pulmonary infection may present as acute pneumonia, subacute pneumonia, chronic pneumonia (classically in COPD), and mediastinal lymphadenitis/lymphadenopathy •Pleural effusions occur in < 10% •Disseminated infection most commonly includes liver, spleen, bone marrow, skin (papules, plaques, erythema nodosum), and CNS •90% of patients are asymptomatic
Diagnostic testing	•Culture and histopathology are highly specific but insensitive • Can use EIA, CF, or ID for serologic testing (sn: 98%, sp: 97%) o EIA: most sensitive o CF: positivity based on titer > 1:8 o ID: H band suggests acute infection •Serum antigen (sn: 82%, sp: 97%) •Urine antigen is cross reactive with Blastomyces species
Treatment	•Immunocompetent patients with asymptomatic or mild infection can be monitored without therapy •All others receive itraconazole (6-12 mo) •Induction with amphotericin B if severe pulmonary/disseminated infection

CF = complement fixation; CNS = central nervous system; EIA = enzyme immunoassay; ID = immunodiffusion; sn = sensitivity; sp = specificity.

Chronic pulmonary histoplasmosis, occurring classically in people with active tobacco use with COPD, is marked by cough and fevers but also by weight loss, anorexia, and hemoptysis. Pulmonary histoplasmosis may be isolated to the mediastinum and presents with lymphadenitis or granulomas. Rarely, such patients develop fibrosing mediastinitis in which inflamed lymph nodes grow and impinge on neighboring structures, resulting in debilitating symptoms or death from compression of bronchi, pulmonary vasculature, or the superior vena cava.

Disseminated histoplasmosis occurs most often in immunocompromised patients with defects in cell-mediated immunity leading to ineffective granuloma formation. The most vulnerable populations are patients receiving tumor necrosis factor-alpha inhibitors, recipients of hematopoietic stem cell and solid organ transplants, and people living with advanced HIV infection.¹⁸ Disseminated histoplasmosis may result from either primary inoculation or reactivation of prior latent disease and has a high mortality rate.¹⁹ Shock may result from either primary septic shock or from dissemination to the adrenal glands with resulting adrenal insufficiency. Pancytopenia, lymphadenopathy, and hepatosplenomegaly occur in up to 80%, 70%, and 40% of patients with disseminated histoplasmosis, respectively.20, 21, 22 The presence of watery diarrhea may indicate colonic involvement. Skin findings are variable and include papules, erosions, and ulcers.

Disseminated histoplasmosis can occur in patients who may not be considered overtly immunosuppressed. In this group, histoplasmosis tends to be subacute and milder than in the immunocompromised. Manifestations may include skin ulceration, lymphadenopathy, colonic ulceration, and adrenal gland infiltration.²³ Such symptoms can make differentiation from TB, malignancy, or inflammatory bowel disease difficult.²⁴

Radiographic findings of patients with pulmonary histoplasmosis may correlate with the subtype of disease. Nodules occur in > 50% of patients from endemic areas and are often asymptomatic.²⁵ They may be solitary or multiple and rarely have internal cavitations. Calcified nodules are often indicative of prior resolved infection.

Lung nodules in patients from a Histoplasma-endemic region may be indeterminate and are easily misconstrued as malignant, especially when lymphadenopathy is present. PET-CT scan may be used in such cases. The elucidation of mediastinal and ipsilateral hilar lymph nodes with increased FDG uptake compared with that of the nodule is a reassuring feature called the fungal flip-flop sign, which has nearly 100% specificity when combined with positive serologic or antigen testing for Histoplasma species or Blastomyces species²⁶ (Fig 2).

Figure 2.

A 34-y-old woman without significant medical history was evaluated for progressive fatigue, drenching night sweats, and unintentional 20-kg weight loss. Her workup included a chest CT scan which showed mediastinal and hilar lymphadenopathy and a left lower lobe lung nodule. Imaging findings and clinical history were highly suspicious of lymphoma. However, workup included positive Histoplasma serology by complement fixation at a dilution of 1:32 and a PET-CT scan showing thoracic lymph nodes with more intense fluorodeoxyglucose avidity than in the single pulmonary nodule as previously seen, results consistent with the fungal flip-flop sign. Endobronchial ultrasound-guided transbronchial needle aspiration of thoracic lymph nodes revealed granulomas, and a concurrent bronchial washing grew Histoplasma capsulatum complex. Symptoms resolved with initiation of itraconazole.

Other radiographic manifestations include consolidations, broncholithiasis, and mediastinal lymphadenopathy. Parenchymal mass-like cavitations occur in up to 39% of patients with chronic histoplasmosis.²⁷ Pleural effusions are rare. In disseminated disease, a miliary pattern can be present.

Histoplasmosis is diagnosed using a combination of microbiologic and serologic testing in patients with suitable exposure histories, characteristic symptoms, and compatible imaging. The criterion standard of histoplasmosis diagnosis is fungal culture of sputum, blood, cerebrospinal fluid, or other tissues. Culture is limited by variable sensitivity and a lengthy time to diagnosis, often requiring > 2 weeks for adequate incubation.²⁸ Histopathology (eg, from tissue obtained by transbronchial biopsy) allows for direct visualization of organisms. Unfortunately, sensitivity is low and is operator-dependent, limiting its utility.²⁹

Serologic testing involves the evaluation of antibodies to Histoplasma antigens but is dependent on the host immune response.³⁰ Antibody titer is determined by enzyme immunoassay (EIA), complement fixation (CF), or immunodiffusion (ID). EIA is used to measure IgG and IgM antibodies to Histoplasma EIA is the most sensitive serologic test for acute histoplasmosis. CF involves the endogenous formation of antibody-antigen complexes that interact with erythrocytes coated with antibodies through complement activation. Serial dilutions are performed until endogenous complexes are unable to fix complement, resulting in a quantitative titer. Positivity is based on a titer ≥ 1:8; a titer of ≥ 1:32 is suggestive of active infection.³⁰ ID involves the interaction between serum-derived Histoplasma antibodies and an agar plate embedded with Histoplasma H and M antigens. The presence of an H band is consistent with acute disease, whereas the presence of an M band suggests recent acute or chronic disease.

Serum and urine antigen testing is a common means of diagnosing active histoplasmosis and is not limited by immune status. Serum and urine antigen testing are sensitive (81%) and highly specific (99%), depending on clinical context.³¹ Studies assessing the sensitivity of antigen testing often include large populations of people living with HIV; thus, sensitivity and specificity for antigen testing in patients without HIV infection or disseminated infection is lower. Urine antigen testing is highly sensitive in the case of severe acute pulmonary and disseminated infection (92%) but significantly less sensitive in subacute and chronic pulmonary infections (30%).³² Antigen testing is limited by cross reactivity with other fungal antigens, most notably Blastomyces species.¹⁷

Histoplasmosis Case

Patient 1 (a 63-year-old farmer from Western Minnesota with an incidentally discovered right lower lobe nodule) was diagnosed with histoplasmosis. PET-CT scan was indicative of the fungal flip-flop sign. Serology by EIA was equivocal. After risk-benefit discussion, he elected to proceed with fine needle aspiration of the nodule and avid lymph nodes. Pathology from the nodule showed small yeasts resembling Histoplasmosis with a background of granulomatous inflammation. The patient was not treated with antifungal therapy and underwent serial surveillance chest imaging showing decreased size of the pulmonary nodule.

Blastomycosis

Blastomycosis is caused by the dimorphic fungus B dermatitidis or, more rarely, B gilchristii, Blastomyces helicus, or other Blastomyces species.^33,34 The pathogenesis of blastomycosis resembles that of histoplasmosis: Blastomyces conidia are inhaled near areas of recent or ongoing soil disturbance (Table 2). After inhalation, the increased temperature surrounding respiratory epithelium promotes transformation from mold to yeast form.³⁵ The yeast forms reproduce and either remain isolated to the lungs or hematogenously spread to distant sites, with a predilection for skin, bone, genitourinary, and nervous tissue. A rarer route of infection involves direct inoculation of extrapulmonary tissue, usually in the setting of trauma.³⁶

Table 2.

Unique Features of Blastomycosis

Feature	Details
Causative organism	• Blastomyces dermatitidis • Blastomyces gilchristii • Blastomyces helicus
Clinical history/findings	•Thoracic adenopathy and pleural effusions are rarer (occur in up to 20% of cases) •Skin lesions (pustules or ulceration) and bone lesions (typically osteolytic) usually suggest disseminated infection •50% of patients are asymptomatic
Diagnostic testing	•Culture is quite sensitive (86%) •EIA is preferred serologic test (sn: 88, sp: 99%) •Serum antigen (sn: 95%, sp: 100%) •Urine antigen is cross reactive with Histoplasma species
Treatment	•Itraconazole monotherapy often given for immunocompetent patients with mild to moderate disease •Amphotericin B (2 wk) followed by itraconazole (6-12 mo) for all patients with severe pulmonary and disseminated disease

EIA = enzyme immunoassay; sn = sensitivity; sp = specificity.

Infections may occur in isolation from a single exposure but can also present as localized outbreaks, often among families with shared exposure histories.^33,37 Dogs are highly susceptible to blastomycosis, and dog owners may relate a history of diarrhea, lethargy, anorexia, or dyspnea in their pets, suggesting a shared exposure to Blastomyces spores.³⁸ Risk factors for blastomycosis include male sex and outdoor occupations.³⁹ Obesity, diabetes mellitus, immune suppression, and multilobar involvement at time of diagnosis portend worse prognosis.⁴⁰ Key historical risk factors for blastomycosis include outdoor activities (eg, fishing, hiking) and close contact with disturbed soil or rotting plant materials (eg, gardening, gathering wild plants, cutting wood, soil excavations).³⁷

Up to one-half of patients with pulmonary blastomycosis are asymptomatic. Symptoms are often nonspecific, including cough, fever, and malaise. Nonresolving pneumonia in patients exposed to endemic regions should raise the index of suspicion for blastomycosis. Delayed recognition and treatment are highly associated with mortality. An estimated 15% of patients with pulmonary infection develop ARDS, with mortality rates of up to 75%.^41,42 Unfortunately, there are no clear distinguishing features of ARDS caused by Blastomyces species to support a more rapid diagnosis.⁴³ Over one-quarter of patients either lack respiratory symptoms or have coexisting nonrespiratory symptoms after pulmonary dissemination, most commonly a verrucous skin rash or bone pain due to osseous lesions.³⁷ Isolated cutaneous or osseous blastomycosis without lung involvement is a rare presentation, usually due to direct inoculation.^36,44

Radiographic findings in patients with pulmonary blastomycosis can include lobar or multilobar consolidations, pleural effusion (Fig 3), reticulonodular alveolar and interstitial infiltrates, and solitary pulmonary nodules or masses.⁴⁵ Patients who undergo PET-CT scan for characterization of pulmonary nodules or masses may be found to have a fungal flip-flop sign similar to histoplasmosis.

Figure 3.

A 75-y-old man who had previously undergone kidney transplant and was on immunosuppressive therapy developed dyspnea and hypoxemia over 2 wk. Workup revealed a right Enterobacter cloacae empyema and multiple indeterminate pulmonary nodules (note here in the left and right upper lobes). He had only minimal improvement with chest tube placement and antibacterials. Additional workup including urine histoplasma antigen, urine Blastomyces antigen, and serum histo/blasto antigen were strongly positive. A biopsy of the right pleura showed yeast with broad-based budding suggestive of Blastomyces species. The patient improved after receiving liposomal amphotericin B for 2 wk and treatment dose of itraconazole for 12 mo followed by itraconazole chronic suppressive therapy.

Culture of sputum or bronchoalveolar lavage fluid is highly specific and sensitive (about 85%-90% in cases of Blastomyces pneumonia) but is limited by an incubation time of up to 5 weeks.²⁹ Blastomyces species is reliably identified on histopathologic testing with fungal staining. Culture and histopathologic testing can be obtained after bone or skin biopsy. Direct microscopy of respiratory fluid is a rapid means of identifying broad-based budding yeast that is characteristic of Blastomyces species. Serology is optimally obtained by EIA, which is both sensitive and specific in immunocompetent patients, whereas CF and ID have limited sensitivity and specificity.⁴⁶ Blastomyces antigen testing can be performed on serum, urine, sputum, or cerebrospinal fluid; however, its sensitivity and specificity are dependent on organism burden like Histoplasma species. The sensitivity and specificity of urine antigen testing are approximately 80% but are limited by cross reactivity with other endemic mycoses including Histoplasma species.⁴⁷

Diagnosis is often delayed. Even in hyperendemic regions, the median duration between onset of symptoms and diagnostic test positivity is 3 to 4 weeks despite initial medical contact within 5 days of symptom onset.^37,48 A review of 20 patients with blastomycosis in New York, an area of emerging endemicity, showed that diagnosis was delayed by an average of 53 days, with up to 60% of patients initially suspected to have had malignancy.¹⁰

Blastomycosis Case

Patient 2 was diagnosed with ARDS due to blastomycosis, which can occur even in immunocompetent hosts. In this patient, a tracheal aspirate showed broad-based budding yeast on fungal smear consistent with Blastomyces species, and urine Blastomyces antigen testing was positive. The patient was treated with liposomal amphotericin B (LAmB) plus itraconazole. LAmB was continued until therapeutic itraconazole serum levels were achieved. The patient made a complete recovery.

Coccidioidomycosis

Coccidioidomycosis, colloquially known as Valley fever, is caused by Coccidioides immitis, the species endemic primarily to California, or Coccidioides posadasii, the species endemic outside of California. C immitis and C posadasii cause similar disease and can only be distinguished by genetic testing of isolates. Almost all patients who develop coccidioidomycosis have exposure to an endemic region; however, the duration of exposure required for infection is uncertain (Table 3). Isolated cases of infection have been identified after < 5 days of exposure. Seroconversion with new anti-Coccidioides antibodies among US Navy servicemembers assigned to a military base in the San Joaquin Valley occurred in 0.5 patients per 100 person-years over 12 months of exposure.⁴⁹

Table 3.

Unique Features of Coccidioidomycosis

Feature	Details
Causative organism	• Coccidioides immitis • Coccidioides posadasii
Clinical history/findings	•Chest pain and rash (nodules, ulcers) are more common than in other mycoses •Progressive headache suggests coccidioidal meningitis •Lung nodules on chest imaging frequently cavitate but do not calcify •Up to 20% have thoracic adenopathy, and 5% to 15% have pleural effusion •60% of patients are asymptomatic
Diagnostic testing	•Serologic testing involves EIA followed by ID (sn: 92, sp: 94%) •Use CF to assess response to treatment
Treatment	•Fluconazole or itraconazole monotherapy for symptomatic patients, those with risk factors for severe disease, or with elevated CF titer (≥ 1:32) •Posaconazole, voriconazole, and isavuconazole are options for disease not responding to fluconazole or itraconazole •Amphotericin B can be added for those with severe disease

CF = complement fixation; EIA = enzyme immunoassay; ID = immunodiffusion; sn = sensitivity; sp = specificity.

Patients develop infection by inhaling Coccidioides arthroconidia present in the soil of endemic areas. In lower respiratory epithelium, endospores (2-4 μm in size) mature into spherules (120 μm) and multiply in host tissues.⁵⁰ Immunocompetent patients may be asymptomatic or develop mild symptoms of fatigue, cough, fever, joint pains, enlarged or inflamed lymph nodes, and more rarely dyspnea which appears 1 to 3 weeks after exposure. Skin involvement is common and may be due to (1) direct inoculation or dissemination of fungi to the skin (seen as plaques, verrucous lesions, and ulcers), or (2) an immunologic response to infection (seen as erythema nodosum or erythema multiforme). Many patients with mild symptoms recover without treatment. However, even immunocompetent patients can develop disseminated disease, most often including bone, skin, or central nervous system. Coccidioidal meningitis is a particularly severe manifestation, and neuroimaging followed by lumbar puncture is mandatory for patients with significant headache or other neurologic manifestations. Risk factors for severe disease include HIV infection, diabetes mellitus, Black race, male sex, Filipino ancestry, and COPD. Cirrhosis has the highest risk for mortality among patients with severe coccidioidomycosis.⁵¹

Radiographic findings of patients with coccidioidomycosis are also variable. Nodules may be solitary, multiple with satellite nodularity, or mass-like with cavitation (Fig 4). Calcification, as occurs with resolved histoplasmosis, is less common. Pleural effusions are rare but may result from rupture of a peripheral cavity or from direct pleural infection. Differentiating lung lesions due to Coccidioides species from those due to malignancy is challenging. In patients at high risk for both coccidioidomycosis and malignancy, the presence of satellite nodularity with a primary cavitary nodule suggests infection but is not confirmatory.⁵² Unlike Histoplasma species and Blastomyces species, Coccidioides species are not associated with the fungal flip-flop sign on PET-CT scan. FDG-avid lesions due to Coccidioides species tend to have lower standardized uptake value maximum than those due to malignancy; however, PET-CT scan is a poor differentiator between coccidioidomycosis and malignancy on its own, and up to 5% of FDG-avid lung nodules in highly endemic areas may be due to Coccidioides species.⁵³

Figure 4.

A, A 50-y-old patient who does not smoke who had a CT scan obtained in the emergency department for subjective shortness of breath, showing an incidentally discovered solid coccidioidomycosis nodule. Subsequent serology testing including IgM and complement fixation were positive at follow-up pulmonary office visit. Follow-up imaging at 3 mo showed almost complete resolution of nodule. B, A 40-y-old patient who does not smoke and who was immunocompetent, had CT scan performed for cough and pleuritic chest pain showing a large cavitary lesion in the left lower lobe. Patient needed surgical removal of biopsy-confirmed coccidioidal cavity and was placed on 6 mo of fluconazole and made complete recovery. Although pulmonary coccidioidomycosis can present like an incidentally discovered solidary pulmonary nodule, it can also present as locally aggressive disease even in otherwise immunocompetent individuals.

As with the other endemic mycoses, the criterion standard for diagnosis is isolation of Coccidioides species on fungal culture or histopathologic specimen. However, most infections are diagnosed by a combination of positive serum testing, characteristic symptoms, and exposure to a Coccidioides-endemic region.⁵⁴ Serologic testing typically includes an initial or screening EIA. If EIA is positive, CF is useful for infection confirmation and guiding treatment initiation and maintenance. Coccidioides serum or urine antigen testing can be used in tandem with serologic testing to improve the sensitivity of diagnosis; however, its isolated sensitivity is low except in disseminated infection.⁵⁵ Diagnosis of Coccidioides meningitis is typically by cerebrospinal fluid CF serologic testing, but culture and antigen testing can also be used.

Coccidioidomycosis Case

Patient 3 was diagnosed with pulmonary coccidioidomycosis complicated by pleural effusion. Serologic testing positive for anti-Coccidioides IgG and IgM by EIA and CF showed a titer of 1:64. He was placed on high-dose fluconazole and required surgical decortication and resection of a pulmonary cavity that was likely seeding the pleural space. Antifungals were continued for 6 months, and the patient made a complete recovery.

Treatment of Endemic Mycoses

Histoplasmosis and Blastomycosis

Treatment strategies for most endemic fungal infections are based on disease severity, organ involvement, and host immune status. For histoplasmosis, immunocompetent hosts who are asymptomatic or mildly symptomatic typically do not require antifungal treatment. In practice, many infectious disease specialists do treat such patients to reduce the risk of disease progression and the development of latent disease.56, 57, 58 Although immunocompetent patients with mild pulmonary blastomycosis can also be monitored without treatment,⁵⁹ it is our practice to treat all patients with blastomycosis with antifungal therapy because of the risk of progressive, multiorgan infection.

Itraconazole forms the backbone of treatment for mild and moderate histoplasmosis and blastomycosis. Itraconazole has complex pharmacokinetics with significant interpatient variability in absorption and multiple drug interactions. For these reasons, therapeutic drug monitoring should be used to measure trough plasma concentrations 7 to 14 days after initiation of itraconazole with a goal plasma concentration of at least 1.0 μg/mL.^56,59 Absorption of itraconazole capsules is reduced with decreased gastric acidity; therefore, holding acid-lowering medications and having patients take the medication with an acidic beverage can improve absorption.⁶⁰ Itraconazole solution has better absorption compared with capsules but is often cost prohibitive. Super-bioavailability itraconazole is a new capsule formulation of the drug available in the United States, Australia, and some European countries that demonstrates improved and more uniform bioavailability compared with traditional itraconazole. Adverse effects of itraconazole range from mild (nausea, hypokalemia, and hypertension) to worrisome or severe (new or worsening heart failure, QT interval prolongation, and hepatotoxicity). Posaconazole is a reasonable alternative to itraconazole.^60,61 Echinocandins and flucytosine are not appropriate treatments due to intrinsic resistance to these antifungals.

Patients with severe blastomycosis and those with severe pulmonary or disseminated histoplasmosis should receive IV amphotericin B, preferably LAmB.^56,57,59 We usually continue LAmB for 1 to 2 weeks and overlap with itraconazole until therapeutic itraconazole levels are assured and the patient is no longer critically ill. Duration of azole therapy depends on host immune status and illness severity but is usually months-long. We do not use CF to assess treatment response or guide duration of therapy due to lag in quantitative improvement compared with symptomatic improvement. Immunocompromised patients are continued on itraconazole or an alternate triazole antifungal for the duration of their immunosuppression. For patients with HIV, itraconazole is continued until virologic suppression is achieved with antiretroviral therapy and with adequate CD4+ T-lymphocyte recovery.

Histoplasmosis may co-occur in patients with TB, most often described in patients living with advanced HIV infection (CD4+ T-lymphocyte count < 50 cells/mm³). Antimycobacterial and antiviral agents (ie, rifamycins, protease inhibitors) will affect itraconazole serum concentrations and vice versa. In such patients, we increase the frequency of itraconazole serum concentration monitoring, especially when dosages of these medications are altered. We typically wait at least 2 weeks after starting therapy for histoplasmosis before initiating antiretroviral therapy to reduce the likelihood of immune reconstitution inflammatory syndrome.

In patients with severe or disseminated disease (whether histoplasmosis, blastomycosis, or coccidioidomycosis), we recommend consultation with an infectious disease specialist with expertise in management of endemic fungal infections, due to overlap in infectious presentations, propensity for diagnostic uncertainty, risk of complications, and need for long-term follow-up and antifungal management.

Coccidioidomycosis

Coccidioides species cause up to 20% of CAP in patients from highly endemic areas. The question of whether empirical antifungal coverage should be offered to patients with CAP in endemic regions remains unanswered.⁶² Our practice for patients in highly endemic regions is to add antifungal therapy for patients hospitalized for CAP considered to be at elevated risk for severe infection.

In immunocompetent patients with confirmed coccidioidomycosis of at least moderate severity, a CF titer of ≥ 1:32 has been proposed as a cutoff for initiating antifungal therapy.⁶³ Antifungal treatment should be considered in all immunocompromised patients, patients with high-risk comorbidities (eg, diabetes mellitus), those with moderate or severe symptoms, and those with unresolving symptoms.

Like histoplasmosis and blastomycosis, triazoles are the mainstay of therapy. Fluconazole at a dose of at least 400 mg daily is the most common regimen due to favorable efficacy and side effect profile.^54,57 However, rising minimum inhibitory concentrations to fluconazole in Coccidioides isolates have led some experts to recommend other agents, including itraconazole and posaconazole, as reasonable alternatives,⁶⁴ especially in patients refractory to fluconazole. Itraconazole was found to be equivalent in efficacy to fluconazole in a randomized, double-anonymized trial in patients with progressive nonmeningeal coccidioidomycosis and may have advantages in osteoarticular infection.⁶⁵ Patients with severe or extrapulmonary disease may benefit from the addition of LAmB until critical illness has improved or resolved.^54,57

For coccidioidal meningitis, high-dose fluconazole starting at 800 mg/d is the mainstay of therapy, but some patients with severe or refractory disease may require intrathecal amphotericin B as salvage therapy. IV amphotericin B is not recommended; however, LAmB has been used as salvage in limited reports. Lifelong azole therapy is recommended for patients with confirmed coccidioidal meningitis.⁶⁶

Corticosteroids in Severe Disease

Patients with ARDS secondary to endemic mycoses may benefit from adjuvant corticosteroids; however, data are mixed. Corticosteroid regimens vary widely in terms of agent, when to initiate therapy, duration, and dosing and is most often based on institutional experience. We typically use IV methylprednisolone dosed at 0.5 to 1.0 mg/kg/d for at least 1 week in patients who require invasive mechanical ventilation due to hypoxemia. The duration of steroids is not standardized and is dependent on treatment response.

Although concerns of fungal dissemination with use of high-dose corticosteroids in patients receiving antifungal therapy for severe disease exist, there is yet to be any evidence suggesting this is the case. Furthermore, current treatment guidelines recommend consideration of corticosteroids for ARDS secondary to endemic fungi.^56,57,59 Most evidence suggesting survival benefit comes from case series and retrospective cohort studies.^42,51,67

Other Global Endemic Fungi

Talaromycosis is an infection caused by Talaromyces marneffei, endemic to Southern and Southeast Asia, with a predilection for people living with HIV, especially those with CD4+ T-lymphocyte counts < 100 cells/mL.⁶⁸ Most patients experience fevers, weight loss, cough, and strikingly diffuse skin papules affecting the face and chest. Physical examination may be notable for hepatomegaly, splenomegaly, and generalized lymphadenopathy. Diagnosis is usually made by fluid culture or histopathologic evaluation.⁶⁹ Acute treatment includes amphotericin B and itraconazole, followed by extended courses of itraconazole in combination with antiretroviral therapy for those living with HIV.⁷⁰

Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis and Paracoccidioides lutzii and is endemic to regions of Central and South America. Uniquely, most patients are only symptomatic after reactivation of a prior infection. In the lungs, this is usually manifested by pulmonary fibrosis or emphysema.⁷¹ The adrenal glands are commonly affected, and patients with chronic infection may develop adrenal insufficiency.⁷² Oral and nasopharyngeal mucosa are also frequently affected. Diagnosis can be made by fluid or tissue culture, histopathologic evaluation, or by serology, specifically ID.⁷³ Treatment is usually with itraconazole, but other triazoles and trimethoprim-sulfamethoxazole are alternatives.⁷⁴

Sporotrichosis and cryptococcosis, caused by Sporothrix species and Cryptococcus species, respectively, are endemic to varying regions of Australasia and the Americas. Sporothrix species often cause a lymphangitic nodular skin rash for which itraconazole is the mainstay of treatment. Cryptococcus neoformans and Cryptococcus gattii infect the lungs (seen as large nodules called cryptococcomas) and meninges, often necessitating cerebrospinal fluid analysis. Cryptococcosis is treated with fluconazole; amphotericin and flucytosine are added in the case of central nervous system disease.

Future Directions

With factors such as climate change, increased global migration, and a growing population of immunocompromised individuals, we must broaden the maps and appreciate the growing population at risk for endemic fungal infections. There are several areas of near-term growth in the diagnosis and care of these patients: earlier clinical identification, improved diagnostic testing, and minimized antifungal toxicities.

Diagnostic delay is a major cause of morbidity. Expanding unified reporting systems outside of traditionally endemic areas may improve surveillance.⁷⁵ This has been successful for coccidioidomycosis, but no such large-scale system exists for histoplasmosis or blastomycosis. We must improve awareness that such fungal infections should be considered in patients with unexplained CAP, particularly if these infections are not improving with antibacterial therapy.

With the number of culture- and tissue-based, immunologic, and antigen-based testing platforms currently available, there are now more options for accurate diagnosis than in decades prior. Despite this, sensitivity and specificity of these tests are dependent on the burden of infection and immunocompetence of the patient. Culture-independent next-generation sequencing technologies may improve diagnostic speed and accuracy.⁷⁶ Improved rapidity and accuracy of diagnostic testing may also reduce inappropriate exposure to antibacterials and the rate of antibiotic resistance among bacteria.^77,78

These infections are well treated by current antifungal regimens, but future therapies must improve the efficacy and toxicity associated with treatment. A randomized controlled trial showed single-dose LAmB for disseminated histoplasmosis is safe and may be noninferior to the standard 1 to 2 weeks of therapy before initiation of azole therapy.⁷⁹ Newer antifungals (eg, olorofim, fosmanogepix) have activity against Histoplasma species and Coccidioides species and appear to be well tolerated.^80,81 An oral formulation of amphotericin B has shown efficacy with reduced side-effect profile in treatment of cryptococcal meningitis for certain patient populations.⁸²

Summary

Endemic fungal infections are a significant but underrecognized cause of CAP and extrapulmonary infection. As changes in weather patterns and increased soil disruption occur, the traditional maps of endemicity have expanded. The number of patients at risk for severe infection from these organisms is likely to continue increasing. Reduction in patient morbidity and mortality is dependent on clinicians’ awareness of clinical presentations, diagnostic testing options, and evidence-based treatment modalities. Improvement in surveillance of infection and reduction in the time from presentation to diagnosis will play a vital role in reducing the burden of disease.

Funding/Support

The authors have reported to CHEST Pulmonary that no funding was received for this study.

Financial/Nonfinancial Disclosures

None declared.