Diagnosis and Management of Systemic Endemic Mycoses ...

Review

Respiration

Diagnosis and Management of Systemic Endemic Mycoses Causing Pulmonary Disease

Helmut J.F. Salzer

a, b Gerd Burchard

c Oliver A. Cornely

d

Christoph Lange

a, b, e, f Thierry Rolling

c, g Stefan Schmiedel

g Michael Libman

h

Domenico Capone

i, j Thuy Le

k, l Margareth P. Dalcolmo

m Jan Heyckendorf

a, b a

Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany; b German Center for Infection Research, Clinical Tuberculosis Center, Borstel, Germany; c Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; d Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (ZKS Köln), University of Cologne and Department I of Internal Medicine, ECMM Excellence Center of Medical Mycology, University Hospital of Cologne, Cologne, Germany; e International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany; f Department of Medicine, Karolinska Institutet, Stockholm, Sweden; g Section of Infectious Diseases and Tropical Medicine, 1st Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; h J.D. MacLean Centre for Tropical Diseases, McGill University, Montreal, QC, Canada; i Pulmonology and Radiology Services, Rio de Janeiro State University, Rio de Janeiro, Brazil; j Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; k Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, USA; l Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; m Helio Fraga Reference Center, FIOCRUZ, Rio de Janeiro, Brazil

Received: April 23, 2018Accepted: April 23, 2018Published online: June 28, 2018

Helmut J.F. Salzer, MD, MPHDivision of Clinical Infectious Diseases, Research Center BorstelLeibniz Lung Center, Parkallee 35DE–23845 Borstel (Germany)E-Mail hsalzer @ fz-borstel.de

© 2018 S. Karger AG, Basel

E-Mail [email protected]/res

DOI: 10.1159/000489501

KeywordsEndemic mycoses · Pulmonary disease · Diagnosis · Management · Treatment

AbstractSystemic endemic mycoses cause high rates of morbidity and mortality in certain regions of the world and the real im-pact on global health is not well understood. Diagnosis and management remain challenging, especially in low-preva-lence settings, where disease awareness is lacking. The main challenges include the variability of clinical presentation, the fastidious and slow-growing nature of the fungal pathogens, the paucity of diagnostic tests, and the lack of options and toxicity of antifungal drugs. Coccidioidomycosis and para-coccidioidomycosis are restricted to the Americas only, and

while histoplasmosis and blastomycosis also occur predom-inantly in the Americas, these mycoses have also been re-ported on other continents, especially in sub-Saharan Africa. Talaromycosis is endemic in tropical and subtropical regions in South-East Asia and southern China. Systemic endemic mycoses causing pulmonary disease are usually acquired via the airborne route by inhalation of fungal spores. Infections can range from asymptomatic or mild with flu-like illnesses to severe pulmonary or disseminated diseases. Skin involve-ment is frequent in patients with paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis and mani-fests as localized lesions or diffuse nodules in disseminated disease, but can also occur with other endemic mycoses. Cul-ture and/or characteristic histopathology from clinical sam-ples is the diagnostic standard for endemic mycoses. Immu-nological assays are often not available for the diagnosis of

Salzer et al.Respiration2DOI: 10.1159/000489501

most endemic mycoses and molecular amplification meth-ods for the detection of fungal nucleic acids are not stan-dardized at present. The first-line treatment for mild to mod-erate histoplasmosis, paracoccidioidomycosis, blastomyco-sis, sporotrichosis, and talaromycosis is itraconazole. Severe illness is treated with amphotericin B. Patients with severe coccidioidomycosis should receive fluconazole. Treatment duration depends on the specific endemic mycosis, the se-verity of disease, and the immune status of the patient, rang-ing between 6 weeks and lifelong treatment.

© 2018 S. Karger AG, Basel

Introduction

Systemic endemic mycoses include a group of dimor-phic fungi that are found in distinct geographical regions. Paracoccidioidomycosis and talaromycosis are found in tropical and sub-tropical regions, while coccidioidomy-cosis is found in warm and dry climates of semi-deserts and blastomycosis in temperate climates. Histoplasmosis occurs under variable conditions ranging from tropical to temperate climates. The impact of climate change and changes due to migration is uncertain and the real global burden of endemic mycoses is not well understood [1].

Inhalation of fungal spores may cause infection. Clini-cal presentation can vary from asymptomatic to dissemi-nated fatal disease and depends on the immune status of the host and the infectious dose from the environmental exposure. Most endemic mycoses, including histoplasmo-sis, coccidioidomycosis, blastomycosis, and sporotricho-sis, are capable of causing large outbreaks. Diagnosis of

systemic endemic mycoses causing pulmonary disease is challenging, because mycoses may resemble other diseas-es (e.g., pulmonary tuberculosis, bacterial or viral pneu-monia, lung cancer) (Fig. 1), and physicians in low-prev-alence settings may not be familiar with the disease mani-festations. Establishing a diagnosis is further complicated by the difficulty in growing these organisms and by the paucity of nonculture-based diagnostic assays, specifically the lack of standardization of serological and molecular tests. Pathologists may not be familiar with the histopath-ological features. Furthermore, disease management is of-ten complex, including long-term antifungal treatment, drug-drug interactions, therapeutic drug monitoring (TDM), frequent follow-ups to monitor for antifungal side effects, and disease relapse and complications.

The aim of this review is to guide physicians in the di-agnosis and management of systemic endemic mycoses causing pulmonary disease. It should raise awareness about important disease characteristics (Tables 1, 2), diag-nostic tests (Table 3), and antifungal treatment (Table 4).

Disease Characteristics

HistoplasmosisHistoplasmosis caused by the dimorphic fungus His-

toplasma capsulatum is found worldwide, but particular-ly in North, Central, and South America (Table 1). It has been reported from parts of southern and eastern Europe, Africa, Asia, and Australia; however, reports are usually limited to a few cases [2]. It has the potential to cause larger outbreaks [3].

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Fig. 1. a Chest X-ray showing macronodular infiltrates in both upper lobes. b Corresponding CT scan of the chest showing two macronodular consolidations on the right side, smaller nodules, and traction bronchiectasis mim-icking pulmonary tuberculosis in a patient with histoplasmosis.

Systemic Endemic Mycoses Causing Pulmonary Disease

3RespirationDOI: 10.1159/000489501

Table 1. Disease characteristics

Species Endemic areas Reservoir Route oftransmission

Populationsat risk

Prevention Commentary

Histoplasmosis Histoplasma capsula-tum sensu latu – Histoplasma capsu-latum var. capsulatum– Histoplasma capsula-tum var. duboisi (= African histoplasmo-sis)– Others

North and Central America, Africa (Central, South, West)

Soil, animal drop-pings (bats), caves, caverns, abandoned buildings

Aerogenic Local population, travelers to endemic regions (visit-ing caves, abandoned buildings, construction works)

Immunocompromised individuals should avoid activities with disturbing material/soil in regions of high prevalence

Disease severity partly depends on amount of inoculum and host im-mune status

Paracocci-dioidomycosis

Paracoccidioides brasil-iensis,Paracoccidioides lutzii

South America (Brazil, Peru, Argentina, Colombia, Ecuador, Venezuela)

Soil Aerogenic Local population, especially smokers with COPD, work-ers in rural areas (e.g., farmers), few cases in trav-elers

Human infections are not contagious

In some endemic (rural, humid) areas of Brazil incidence close to 40 cas-es/100,000 inhabitants;very high male to female ratio

Coccidioido-mycosis

Coccidioides immitis, Coccidioides posadasii

Southwestern USA – Arizona (66% of cases), central and southern California (31% of cases), New Mexico, Texas, few cases from Washington, Utah – Mexico, Central and South America

Soil of certain arid areas

Aerogenic, inhala-tion of dust (con-struction, landscap-ing, farming, ar-chaeology, excavation, recre-ational pursuits) or from dust clouds (earthquakes, wind-storms)

Persons after exposure in endemic regions (highest in dry periods following a rainy season), often associ-ated with outdoor activities and dust; very rare cases in travelers

Residents can avoid ac-tivities that expose them to dust or desert soil and stay indoors during dust storms. Laboratory per-sonnel handling the or-ganism should practice biosafety level 3 precau-tions

Approximately 2/3 of persons experience few or no symptoms

Blastomycosis Blastomyces dermatiti-dis,Blastomyces gilchristii

South-Eastern and South-Cen-tral states of the USA and Ca-nadian provinces bordering the Great Lakes, and New York state and Canada along the St. Lawrence River and the Nelson River

Soil containing de-caying vegetation or decomposed wood, associated with wa-terways

Aerogenic, skin inoculation

No special population, often seen in children, can be opportunistic in immu-nocompromised hosts

Human infections are not contagious, immunocom-promised individuals should avoid activities with disturbing material/soil in regions of high prevalence

Sporotrichosis Sporothrix schenckii,Sporothrix brasiliensis,Sporothrix globose,Sporothrix mexicana

Found worldwide from tem-perate to tropical climate, en-demic in Peru

Soil, moss, decaying wood and vegetation

Skin inoculation, aerogenic

No special population, higher risk for immuno-compromised patients

Skin protection in people working in gardening or landscaping

Talaromycosis Talaromyces marneffei(formally Penicillium marneffei)

Southeast Asia, northeastern India, and southern China

Bamboo rats, soil in bamboo rat burrows, soil enriched with animal excreta

Aerogenic, skin inoculation

Residents and travelers in endemic regions who are immunocompromised, especially patients with advanced HIV infection

Transmission has been reported

AIDS, acquired immune deficiency syndrome; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency syndrome.

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Fig. 2. Diffuse small nodules in both lungs on chest X-ray (a) and axial CT scan of the chest (b) mimicking mil-iary tuberculosis in a patient with histoplasmosis.


Table 2. Symptoms and radiological patterns of systemic endemic mycoses causing pulmonary disease

Clinical presentation Most frequentsymptoms

Organ involvements Chest radiological pattern Commentary

Histo-plasmosis

– Acute diffuse pulmonary disease (infiltrates)– Acute localized pulmonary disease (localized infiltrates, mediastinal lymphadenopathy)– Chronic cavitary– Mediastinal syndromes (e.g., medi-astinitis, fibrosis)– Broncholithiasis– Nodules

Asymptomatic or mild “flu-like symptoms”

Pulmonarydissemination to any organ (e.g., eye)

Diffuse infiltrates, opacities, small or large nodules, mediastinal mass, cavities (in chronic pulmonary disease), lymph node enlargement

Immunosuppression as risk factor for severe disease with dissemination (e.g., advanced HIV infection)

Paracoccidio-idomycosis

Acute/subacute form (juvenile) (5–25%)– Lymphadenopathy, hepatospleno-megaly– Cutaneous lesions, fistula formation– Rarely pulmonary involvementChronic form (adult) (74–96%)– Pulmonary (77%) – Other organs (skin, etc.)

Respiratory symptomsSkin lesions

Lymphatic system (lymph nodes, liver, spleen, bone marrow, skin, and mucous membranes (45–65%), organ abscess formations, fever (50–80%), pulmonary (84%), bone (5%), CNS (menin-gomyelitis) (2–3%), and adrenal gland

Consolidations (75%), multiple nodules, interlobar septal thickening, lymph node enlargement (hilar), (very) rarely pleural effusion, nodule predominance towards the inferior pulmonary lobes.Nodule diameters from 0.5 to 3 cm with ill-defined contour cavitation, miliary pat-tern (rare), diffuse interstitial infiltration, posttreatment fibrosis, and scars

More severe in immunocom-promised patients; HIV-infect-ed patients more often present with fever, lymphadenopathy, hepatosplenomegaly, and cuta-neous lesionsRelapses usually occur within 3 years after initial treatment

Coccidio-idomycosis

Primary infection: mostly with pul-monary involvementExtrapulmonary infection: indolent course

Estimated 2/3 of patients are asymp-tomaticFever, cough, chest pain, and arthal-gias in primary infectionErythema nodosum

Primary infection: lung, pleura, skin, and musculoskeletal Extrapulmonary: skin and soft tis-sue, skeleton, CNS (meninges and spinal cord), eye, heart, liver, kidneys, prostate

Primary infection: unilateral infiltrate with hilar adenopathy, parapneumonic effusion, thin-walled cavities or nodulesChronic infection:coccidioidal cavities (in 2–8% of patients), complicated by CPA or abscess formation, fistulae, persistent pneumonia, chronic fi-bro-cavitary changes (mixtures of infiltrates, cavitation, and hilar adenopathy), diffuse reticulonodular (miliary) pneumonia

Radiographic findings may persist for years Residual pulmonary nodules and thin-walled cavities usually have no clinical consequencesRarely cavity ruptures after years with broncho-pleural fistulaMore severe in immunocom-promised, elderly, diabetes mellitus, pregnancy

Blastomycosis Pulmonary disease (90%) Extrapulmonary disease

Pulmonary: nonspecific, cough, fever, night sweats, weight loss, chest pain, and hemoptysis

Mostly pulmonary, but frequent-ly skin involvement, sometimes bone and joints, CNS, and geni-tourinary

Consolidations, interstitial infiltrations, nodules and masses, involvement of mul-tiple or single lobes, less adenopathy

Sporotrichosis Lymphocutaneous: most commonPulmonary infection mainly in COPD and alcohol useOsteoarticular infection: in particular jointsCNS: meningitis is rareDissemination: in patients with ad-vanced HIV infection

Lymphocutaneous: ulcerative or nodular lesions, lymphangitisPulmonary: fever, cough night sweats, weight lossOsteoarticular: pain, swelling, de-creased range of motion, draining sinuses in affected joints

Skin and lymphatic, pulmonary, osteoarticular, CNS

Talaromycosis Localized disease: seen in non-HIV-infected personsDisseminated disease most common in patients with advanced HIV infec-tion

Localized disease: depends on organ involvedDisseminated disease: fever, fatigue, weight loss, lymphadenopathy, hepa-tosplenomegaly, skin lesions (primar-ily on the face)

Reticuloendothelial system (liver, spleen, lymph nodes, bone mar-row), skin, pulmonary, gastroin-testinal, osteoarticular, CNS

Interstitial to alveola infiltrates, reticulo-nodular pattern, nodules, miliary pattern

CNS, central nervous system; CPA, chronic pulmonary aspergillosis; TB, tuberculosis.

Fig. 3. Axial CT scan of the chest showing bipulmonary, solid nod-ules (white arrows) in a 27-year-old female biology student with cough and fever lasting for several weeks after returning from a field trip exploring bat caves in Central America. Diagnosis of pul-monary histoplasmosis was established by positive culture and Histoplasma capsulatum var. capsulatum-specific PCR from lung tissue as well as positive H. capsulatum antibody detection. Histo-pathology from lung tissue showed noncaseating granulomas with giant cells, but without evidence of fungi (Grocott’s methenamine silver stain). Cytology and routine microbiological cultures from bronchoalveolar lavage fluid revealed no evidence of fungi.



Table 3. Diagnostic tests to establish diagnosis of endemic mycoses and histological appearance

Culture Histopathology Antigen detection Serology Molecular methods

Histoplasmosis Isolation from clinical specimens remains gold standard (cave: dan-ger of laboratory infection by Histo-plasma capsulatum in mycel phase)

Tuberculoid granuloma with intracellular yeast cells (can be mistaken for trypano-soma, leishmania amastigotes, or Talaromy-ces marneffei yeast cells)

A polyclonal antibody-based antigen test in urine is commercially available in the USA; cross-reactivity with other fungal infections, including Blastomyces dermatiti-dis, CPA may occur;a monoclonal antibody-based lateral flow antigen detection assay is currently under evaluation

Antibody detection by ID, CF, or Western blot available, high specificity, however, results may be falsely negative in immuno-suppressed patients and in those who present with acute disease

PCR assays available in reference laboratories, not standardized

Paracoccioido-mycosis

Cultures are diagnostic, but can take up to a month to grow

Tuberculoid granuloma with multipolar budding yeast cells (“ship-pilot´s wheel” or “Mickey Mouse head”)

Antigen detection in BAL has been de-scribed (gp43, not expressed in Paracoc-cidioides lutzii), but not standardized

DID, CIE, ELISA, and immu-noblotting; utility is hampered by cross-reactivity with other endemic fungi; inaccuracies in the diagnosis in P. lutzii infec-tion.

PCR assays available in reference laboratories, but are not standardized

Coccidioido-mycosis

Culture confirms the diagnosis; Cultures must be manipulated in a biosafety level III laboratory

Tuberculoid granuloma with spherules (60–100 µm with endospores of 2–5 µm)

Coccidioides galactomannan antigen test available in reference laboratories; low sensitivity (70%)

ID and CF; Most clinical infec-tions diagnosed serologically in the setting of a compatible clini-cal syndrome

PCR assays are being evaluated

Blastomycosis Culture confirms the diagnosis; diagnostic yield is high for both bronchoscopy and sputum samples, but takes 1–4 weeks

Tuberculoid granuloma with unipolar broad-based budding yeast cells

EIA for polysaccharide cell wall antigen commercially available; high sensitivity (93%) but low specificity (79%) due to cross-reaction with other fungi

ID and CF have no role in diag-nosis because poor sensitivity and significant cross reactivity

PCR assays have not been tested in large studies

Sporotrichosis Isolation from clinical specimens remains gold standard; clinical specimens should be inoculated on Sabouraud agar and incubated at room temperature for 1–4 weeks

Necrotizing granulomas, paucity of yeasts Not available One EIA has been developed, but is not available

PCR‐based assays have been developed, yet to be evaluated

Talaromycosis T. marneffei can be cultured from blood and other clinical samples, but can take up to 14 days for iden-tification

Binary fission yeasts within histiocytes or extracellularly; T. marneffei may be con-fused with H. capsulatum, but has a central transverse septum unlike any other com-mon pathogenic yeasts

EIAs detecting mannoprotein in the fungal cell wall in blood and urine, have high sensitivity and specificity but are not com-mercially available yet;over 80% of patients with disseminated talaromycosis are galactomannan antigen (“Aspergillus spp.”) positive in sera

Antibody detection by ID, EIA, or Western blot available; low sensitivity in HIV-infected patients

PCR‐based assays have been developed, low sensitivities (60–70%), not standardized

BAL, bronchoalveolar lavage; CF, complement fixation; CIE, counterimmunoelectrophoresis; CPA, chronic pulmonary aspergillosis; DID, double immunodiffusion technique; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; ID, immunodiffusion; PCR, polymerase chain reaction.

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Fig. 4. a Chest X-ray showing bipulmonary diffuse pulmonary micronodules sparing the periphery in a 50-year-old HIV-positive male presenting with cough and dyspnea. b Corresponding axial CT scan of the chest showing diffuse, confluent perihilar pulmonary nodules. Biopsy from ulcerative lesions of the larynx and the anus dem-onstrated Histoplasma capsulatum.


The clinical manifestations vary depending on the im-mune status of the host and the infectious dose (Table 2). The disease is usually asymptomatic or manifests as an acute respiratory illness that is self-limiting in immuno-competent persons, but it can result in severe illness with progressive pulmonary disease or disseminated infec-tion, especially in immunocompromised persons. In most cases histoplasmosis presents with various pulmo-nary symptoms, often as a subacute pulmonary infection 3–21 days after exposure. Symptoms are usually mild. Fever, chills, headache, myalgia, anorexia, cough, and chest pain may occur in the more heavily exposed indi-viduals. Pulmonary histoplasmosis is generally classified according to radiographical appearance and includes (1)

acute diffuse pulmonary disease with diffuse infiltrates on chest imaging, (2) acute localized pulmonary disease with localized infiltrates and mediastinal lymphadenop-athy, (3) chronic cavitary pulmonary histoplasmosis, and (4) mediastinal syndromes (e.g., mediastinitis, fibrosis), broncholithiasis, or pulmonary nodules (Fig. 1–4) [2, 4]. Disseminated histoplasmosis occurs primarily in pa-tients with underlying immunocompromising disorders, in particular those with impairment of T-cell immunity such as in HIV infection, in patients who are treated with TNF-α inhibitors, and in patients with IFN-γ receptor deficiency [5, 6]. In endemic areas or in travelers with an appropriate travel history, pulmonary histoplasmosis should be considered as an important differential diag-

Table 4. Treatment regimens for pulmonary endemic mycoses based on available guidelines

Recommended regimen Duration Alternative treatment Commentary

Histoplasmosis Mild to moderate: Itraconazole 200 mg p.o. t.i.d. for 3 days (loading dose) followed by 200 mg p.o. once daily or b.i.d.Severe: Liposomal amphotericin B 3–5 mg/kg/day IV (pre-ferred) for 2 weeks or until clinical improvement followed by itraconazole (see above)or Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV for 1-2 weeks or until clinical improvement followed by itraconazole (see above)

6–12 weeks Posaconazole 400 mg (oral suspension) b.i.d. [58] Voriconazole 200 mg p.o. b.i.d. [59]Isavuconazole 200 mg t.i.d. for 2 days, fol-lowed by 200 mg once daily [60]

– No treatment recommended for mild symptoms <4 weeks or for pulmonary nodules or broncholithiasis or mediastinal fibrosis only– Oral solution has a better absorption – 12-month treatment duration is recommended in patients with chronic (cavitary) histoplasmosis– Surgery (e.g., lobectomy) should be discussed in pa-tients with residual pulmonary cavities (CAVE: risk of relapse or long-term complications such as CPA)– Echinocandins are not effective

Paracoccidio-idomycosis

Mild to moderate: Itraconazole 200 mg p.o. once dailySevere: Liposomal amphotericin B 3–5 mg/kg/day IV (pre-ferred) until clinical improvement followed by itraconazole (see above)orDeoxycholate amphotericin B 0.5–0.7 mg/kg/day IV until clini-cal improvement followed by itraconazole (see above)

12 months(9–18 month)

Cotimoxazole 960 mg p.o. b.i.d. or t.i.d. – Cotrimoxazole increases treatment duration to 18–24 months

Coccidio-idomycosis

Mild: No treatment recommendedSevere: Fluconazole 400 mg p.o. once dailySevere disease in immunocompromised hosts: Liposomal am-photericin B 4–6 mg/kg/day plus fluconazole 400 mg daily until clinical improvementorDeoxycholate amphotericin B 0.7–1.0 mg/kg/day IV plus fluco-nazole 400 mg daily until clinical improvement

3–6 months

12 months

Itraconazole 200 mg p.o. b.i.d.

Liposomal amphotericin B 3–5 mg/kg/day IV

– Patients with a mild disease usually recover without antifungal treatment– Fluconazole has fewer side effects and drug interac-tions compared to itraconazole– Liposomal amphotericin B as an alternative for more severe cases– Treatment duration of 6–12 months in immunocom-promised patients

Blastomycosis Mild to moderate: Itraconazole 200 mg p.o. t.i.d. for 3 days (loading dose), followed by 200 mg p.o. b.i.d. Severe: Liposomal amphotericin B 3-5 mg/kg/day IV (pre-ferred) for 1–2 weeks or until clinical improvement followed by itraconazole (see above)orDeoxycholate amphotericin B 0.7–1.0 mg/kg/day IV until clini-cal improvement followed by itraconazole (see above)

6–12 months Fluconazole 400–800 mg p.o. per dayVoriconazole 200 to 400 mg p.o. b.i.d. after amphotericin B therapy for CNS disease

– Alternative treatment with ketoconazole or flucon-azole less effective– CAVE: higher toxicity of ketoconazole– Voriconazole or posaconazole may also be effective, but lack of evidence

Sporotrichosis Mild to moderate: Itraconazole 200 mg p.o. b.i.d.Severe: Liposomal amphotericin B 3–5 mg/kg/day IV until clinical improvement followed by itraconazole (see above)or Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV until clini-cal improvement followed by itraconazole (see above)

≥12 months Fluconazole 400–800 mg p.o. daily – Surgical resection should be discussed– Alternative treatment less effective

Talaromycosis Regardless of disease severity: Liposomal amphotericin B 3–5 mg/kg/day IV for 1–2 weeks followed by itraconazole (see above)orDeoxycholate amphotericin B 0.7–1.0 mg/kg/day IV for 2 weeks or until clinical improvement followed by itraconazole (see above)

12 weeks Voriconazole 400 mg b.i.d. on day 1 followed by 200 mg b.i.d. for 12 weeksItraconazole 200 mg p.o. t.i.d. for 3 days, followed by 200 mg p.o. b.i.d. for 12 weeks for patients unable to tolerate or have no access to amphotericin B

– Initial treatment with amphotericin B deoxycholate reduces mortality by 50% compared to itraconazole at 6 months in HIV-associated talaromycosis in the IVAP trial [52]

CPA, chronic pulmonary aspergillosis; b.i.d., twice a day; p.o., per os; t.i.d., three times a day; IV, intravenously.



nosis to pulmonary tuberculosis, malignancy and sar-coidosis. Extrapulmonary manifestations such as peri-carditis, arthritis/arthralgia, or erythema nodosum are also reported.

CoccidioidomycosisPulmonary coccidioidomycosis (i.e., valley fever) re-

fers to pulmonary infection by the dimorphic fungi Coc-cidioides immitis and Coccidioides posadasii (Table 1). It is endemic in the southwestern parts of the USA (Califor-nia, Arizona, New Mexico, Utah, and Nevada) and parts of Central and South America (Mexico, Brazil, Argenti-na). Outbreaks have been reported in military trainees, in archeological workers, or have been associated with dust storms, as well as laboratory-acquired infection [7–11].

Approximately two-thirds of infected persons re-main asymptomatic or develop self-limiting respiratory symptoms. When symptomatic, pulmonary involve-ment is common (> 95% of all cases). The most common clinical manifestations are chest pain, cough, fever, weight loss, and fatigue, often associated with dermato-logical manifestations including erythema nodosum (Fig. 5) or erythema multiforme and rheumatological manifestations including myalgia and arthralgia. Ra-diological presentation can vary considerably (Table 2) (Fig. 6, 7). The disease can spread from the lungs hema-togenously to bones, joints, skin, and the central ner-vous system. Some patients have persistent pulmonary complications including residual pulmonary nodules (coccidioidomas), fibrosis and cavities, with the con-

current risks of developing chronic pulmonary asper-gillosis or pulmonary abscesses, or fistulae as long-term sequelae [7, 12, 13].

ParacoccidioidomycosisParacoccidioidomycosis caused by the dimorphic

fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii is found in certain parts of South America, espe-cially in Brazil, but also in Argentina, Colombia, Ecua-

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Fig. 5. Erythema nodosum in a patient with coccidioidomycosis.

Fig. 6. a Chest X-ray of a 30-year-old man with coccidioidomycosis showing bilateral large confluent infiltrates predominantly located in the lower lung fields. b Corresponding axial CT scan of the chest shows multiple large nodules. The patient presented with intense asthenia, cough, and chest pain. Clinical symptoms started 7 days after having participated in armadillo hunting in northeastern Brazil.

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dor, Peru, and Venezuela [14, 15]. It is usually seen in individuals working in rural areas (e.g., farmers). Out-breaks of paracoccidioidomycosis have been reported [16, 17].

Infection is often asymptomatic. Symptomatic disease is divided in an acute/subacute form and a chronic form. The acute form occurs in children and young adults (ju-venile form), develops more rapidly, usually within 45 days after exposure, is progressive and more severe. Pa-tients present with infection of the lymphatic system,

manifested by enlarged lymph nodes that can develop into abscesses or draining fistulae. Important differential diagnoses such as visceral leishmaniasis or tuberculosis should be considered. The disease can disseminate through the reticuloendothelial system manifested as hepatosplenomegaly and bone marrow dysfunction.

The chronic (adult) form represents reactivation of the primary infection and develops over months to years. Pulmonary involvement is the most frequent manifesta-tion, but the disease may affect any other organs (Fig. 8–10). Patients usually present with dry cough and dyspnea and can have extensive radiographic findings varying from localized consolidations, nodules, cavities, and bilateral infiltrates to chronic findings of septal or interlobular thickening consistent with fibrosis. Hema-togenous dissemination to the oropharynx area occurs over 50% of the time and is manifested as granulomatous ulcerative oropharyngeal lesions called “mulberry-like” stomatitis (Fig. 11). Infection by P. brasiliensis occurs mainly by inhalation. Patients often present with pulmo-nary symptoms associated with fever, leukocytosis with hypereosinophilia, and radiological signs of apical pleural and pulmonary lesions (Fig. 12). Enlarged lymph nodes are not a common finding, except in children. Immuno-compromised patients such as those with HIV infection, cancer, malnutrition, alcoholism, or drug abuse are at risk for the development of disseminated disease with a more rapid progression with involvement of the lung, liver, lymph nodes, and skin. Occasionally it is found in travel-ers [18].

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Fig. 7. A 50-year-old female traveled for 1 week on a retreat to a lodge in the Arizona desert. Eleven days after return, she presented with cough, dyspnea, and fever. She was diagnosed as having coc-cidioidomycosis. Soon afterwards, she developed typical erythema nodosum lesions on her legs. Her chest X-ray showed faint reticu-lar opacities in the right upper lobe, as well as a nodular opacity in the right apex. A CT scan shows a cavitating nodule in the right apex. Mediastinal images revealed multiple enlarged lymph nodes.

Fig. 8. Axial CT scans of the chest showing various types of lesions of paracoccidioidomycosis in a 42-year-old farmer presenting with fever, asthenia, severe weight loss, dysphagia, and cough. Physical examination showed diffuse enlarged lymph nodes, notably in the mid and posterior cervical chains and a small ulcerated lesion in the pharynx. Microscopy of bronchoalveolar lavage showed Paracoccidioides brasiliensis. a Axial CT scan of the chest shows nodules associated with ground-glass opacities and consolidations beside cavities with irregular walls. b The larger cavity on the left side shows a small round mass inside. Basal parts of the lung show peripheral con-fluent opacities without cavities, some displaying the reverse halo sign.



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a b

c d

Fig. 9. a Fistulated and enlarged cervical lymph node in a 60-year-old farmer from Brazil presenting with cough, dysphagia, and hoarseness since 6 months. Microscopy of lymph node material revealed Paracoccidioides brasil-iensis. b Axial CT scan of the chest at the carina level shows nodules and consolidation with a thickened bron-chovascular bundle (white arrows) in addition to areas of cicatricial emphysema.

Fig. 10. a Chest X-ray showing diffuse micronodular interstitial infiltrates predominantly in the lower fields of the lung in a 35-year-old farmer in the interior of the state of Rio de Janeiro. He presented with fever for about 40 days, asthenia, and severe weight loss. Immunodiffusion was positive for Paracoccidioides brasiliensis. b For-ty days later the X-ray showed a progression of the pulmonary lesions with volumetric reduction and hypertrans-parent images. c Axial CT scan of the chest showing extensive areas of cicatricial emphysema in the left upper lobe. The patient developed respiratory insufficiency and died. d Postmortem biopsy revealed budding cells of P. brasiliensis (silver stain).

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BlastomycosisThe causative pathogens for blastomycosis are the di-

morphic fungi Blastomyces dermatitidis and Blastomyces gilchristii, which are found in humid soil containing de-caying vegetation or decomposed wood and are associ-ated with freshwater drainage basins [19]. It is reported mainly in North America and in Africa, but occasionally has also been reported in Central and South America, Mexico, India, and the Middle East. Blastomycosis has caused a number of outbreaks [20].

After inhalation of the fungus, the most commonly af-fected organ is the lung followed by the skin, genitouri-nary tract, and central nervous system (Fig. 13) [21]. Lung involvement is classified as acute or chronic pneumonia. Acute blastomycosis pneumonia cannot be readily distin-guished from viral or bacterial pneumonia [21], and has

very diverse radiological findings, which include alveolar infiltrates, consolidation with or without cavitation, mili-tary or reticulonodular patterns, and small pleural effu-sions. Acute pneumonia can potentially lead to acute re-spiratory distress syndrome with multiorgan failure and mortality rates of 50%. The clinical appearance of chron-ic blastomycosis pneumonia is similar to tuberculosis, lung cancer, or histoplasmosis. The radiological pattern is often described as alveola or fibronodular infiltrations, mainly with an upper lobe distribution [21]. The absence of mediastinal lymph node involvement can be helpful in distinguishing blastomycosis from histoplasmosis.

SporotrichosisThe dimorphic fungus Sporothrix schenckii causes

sporotrichosis, a chronic infection mainly found in

a b

c d

Fig. 11. a “Mulberry-like” stomatitis in a 44-year-old female patient from Brazil with paracoccidioidomycosis. She was admitted with the suspicion of oral pharyngeal cancer. b X-ray of the chest showed localized infiltrates in the lower and middle fields of both lungs (left > right). c Corresponding CT scan of the chest shows localized consolidations with bounded ground-glass opacities. d After 1 year of antifungal treatment with itraconazole radiological findings were resolved.

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healthy individuals with outdoor activities that involve inoculation of soil through the skin or subcutaneous tis-sues such as gardening and landscaping [22, 23]. It is found worldwide in temperate, but also tropical and sub-tropical areas. Larger outbreaks of sporotrichosis have been reported [24].

Disseminated disease involving the central nervous sys-tem may occur in immunosuppressed patients (e.g. HIV/AIDS, alcoholism, diabetes) [25]. Infection is either due to inhalation of spores or through skin inoculation. The most common form is the lympho-cutaneous manifestation, which has only mild systemic involvement (Fig. 14). Pul-monary involvement usually occurs in patients with chron-ic obstructive pulmonary disease and alcohol use, and pro-gresses to death if untreated. Symptoms and radiographic appearance are similar to pulmonary tuberculosis and oth-er chronic fungal infections (Fig. 15) [26].

TalaromycosisTalaromycosis is caused by the dimorphic fungus Ta-

laromyces marneffei (formally Penicillium marneffei) and is endemic in South-East Asia, southern China and north-eastern India [27]. Talaromycosis mainly affects immu-nocompromised patients living or traveling to these re-gions, in particular patients with advanced HIV infection, with hematological malignancy, and patients undergoing immunosuppressive therapy [28, 29]. Although bamboo rats are a natural reservoir, infection risk is not associated with exposure to bamboo rats but is associated with high humidity and exposure to plants and farmed animals in highland regions [30].

The infection has an insidious onset over weeks to months. The clinical symptoms range from mild to mod-erate infection with localized disease, to disseminated in-fection with multiple organ involvement, to severe dis-ease including respiratory failure and shock [31]. The most prominent clinical features in HIV-infected pa-tients are fever, weight loss, anemia, generalized lymph-adenopathy, hepatomegaly, and splenomegaly [31]. Typ-ical central umbilicated skin lesions are present in 70% of HIV-infected and up to 40% of non-HIV-infected pa-tients and aid in the rapid diagnosis [32]. Besides the skin and reticuloendothelial system involvement, talaromyco-sis often invade the gastrointestinal tract with oropharyn-geal ulcerations and diarrhea, the pulmonary system with progressive respiratory failure, and occasionally the cen-tral nervous system with meningoencephalitis. Arthritis and osteomyelitis are more commonly observed in non-HIV-infected patients. The radiological appearance is di-verse and includes interstitial to alveolar infiltrates, or both (Fig. 16), and reticulonodular consolidation, with occasionally a miliary pattern similar to tuberculosis (Fig. 17) [33].

Diagnosis

In low-prevalence settings the diagnostic workup for endemic mycoses is challenged by the availability of diag-nostic tests, and will differ widely from site to site. In ad-dition, the positive predictive values of some nonculture-based tests will be significantly lower than in endemic set-

cba

Fig. 12. Different radiological manifestations of paracoccidioidomycosis in patients coming from rural regions of Brazil. X-rays of the chest showing extensive consolidating infiltrates of both lungs (a), infiltrates predomi-nately located in the mid and lower fields of both lungs (b), and a more micronodular pattern of distribution mimicking miliary tuberculosis (c).


a

b c d

Fig. 13. a, b Chest X-rays of a 42-year-old male resident of Mon-treal, Canada, showing extensive consolidation mostly involving the superior segment (S6) of the right lower lobe. He was also a recreational hunter in the region of the St. Laurence river valley. He presented with a 2-month history of cough, mild hemoptysis, and intermittent fevers. Biopsy revealed budding yeast cells, and culture from a bronchoalveolar lavage grew Blastomyces derma-titidis. c, d Two male patients with slowly growing, minimally

painful skin lesions, unresponsive to several courses of antibacte-rial agents. Exposures were most like to be in rural regions of south-western Quebec (c) and central Manitoba (d), Canada. Bi-opsy specimens revealed noncaseating granulomatous changes, and cultures from biopsy specimens grew Blastomyces. There were no respiratory symptoms, but in both cases small nodular lesions were seen on pulmonary imaging, which resolved with antifungal treatment.

Fig. 14. Slowly progressive skin lesions in a 24-year-old male traveler returning from several months in India, where he partici-pated in gardening activities at his resi-dence. The initial ulcerating verrucous lesion appeared on the tip of 4th digit, followed by the appearance of popular/nodular lesions on the forearm. Culture from the fingertip ulcer grew Sporothrix schenkii.

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tings. As such, awareness of geographical distribution and exposure risks of endemic mycoses, along with case discussion involving an interdisciplinary team compris-ing infectious disease specialists, microbiologists, radiol-ogists, and pathologists are paramount to making the diagnosis [34]. Culture of most of these organisms (par-

ticularly for coccidioides) requires biosafety level 3 laboratory precautions, and the laboratory should be alerted when infection is suspected. Table 3 summarizes diagnostic tests to establish the diagnosis of endemic my-coses.

a

b

c

d e

Fig. 15. a Pyogenic and ulcerated cutaneous lesion of thighs of a 24-year-old male pig caregiver in Brazil, reported onset of the dis-ease about 4 months ago complaining of sporadic fever, cough, asthenia, and weight loss. Chest X-ray (b) and axial CT scans (c, d) show irregularly shaped thick-walled cavitations of different

sizes. c Small nodular cavities can be seen in both lungs, some par-tially occupied by material with soft tissue density. d A large thick-walled cavity of the left lung with an irregular wall can be seen. e Culture of biopsies harvested from the cutaneous lesion demon-strated growth of Sporothrix schenkii.

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HistoplasmosisWhile evidence is too scarce to recommend a specific

diagnostic scheme, a combination of at least two of the following diagnostic methods seems reasonable:

(a) Histology. Typically, biopsy specimens show tuber-culoid granulomas with many polymorphonuclear leuco-cytes and histiocytes with intracellular yeast cells. Differ-entiation from tuberculosis or sarcoidosis may be diffi-cult – especially in low-prevalence settings. Sensitivity and specificity of histology are highly dependent on the pathologist’s experience, but may be enhanced by fungal stains, e.g., Gomori methenamine silver and periodic acid–Schiff stains [35]. The tiny yeast forms (approx. 2 µm) are easily missed.

(b) Culture. Sensitivity depends on the clinical mani-festation, the immunity status of the host, and the fungal burden – it is low in patients with acute pulmonary his-toplasmosis [36]. Repeated sputum and/or bronchoalve-olar lavage (BAL) and/or bone marrow aspirate for cul-tures and a long incubation period of cultures (up to 6 weeks) may be necessary.

(c) Antigen test. An enzyme immunoassay (EIA) for detection of H. capsulatum galactomannan from blood, urine, and BAL is commercially available in the USA [37]. In a multicenter study with 111 patients with proven pro-gressive disseminated histoplasmosis, the EIA reached a sensitivity of 91% and a specificity of 99% in urine [38]. Sensitivity seems to be lower in immunocompetent hosts,

probably due to a lower fungal burden. Similarly, sensi-tivity is lower in localized pulmonary disease. Of note, there is strong cross-reactivity with other endemic myco-ses such as blastomycosis, paracoccidioidomycosis, and talaromycosis [38]. Histoplasma sp. contain galactoman-nan in the cell wall, and may give a positive result in galactomannan assays used for the diagnosis of asper-gillosis.

(d) Antibody test. Histoplasma-specific antibodies can be detected either by immunodiffusion, by complement fixation or by EIA, and a commercial assay is available in the USA. Due to the time needed for the development of specific antibodies (up to 3 months) a negative test does not always exclude histoplasmosis. In contrast to antigen testing, sensitivity is higher in immunocompetent hosts, and therefore antigen and antibody are often used togeth-er to maximize overall sensitivity [38]. The histoplasmin delayed-type hypersensitivity skin test is used mainly for epidemiological studies, and is not sufficiently accurate for use in individual case diagnosis

(e) PCR. Several protocols using a variety of molecular targets have been described in the literature, but the role for PCR in the diagnostic workup is not yet certain [34]. Fluorescence in situ hybridization (FISH) has also been described.

CoccidioidomycosisSerology is the main method for diagnosing Coccid-

iodes infection in the USA, where EIAs for specific IgM and IgG are commercially available [39]. A confirmatory immunodiffusion test should be ordered after a positive EIA due to higher specificity [40]. In contrast to most other infectious diseases, anti-coccidioidal antibodies will be positive only in the case of an ongoing or recent infection. A limitation is that antibodies will only form after a latency period of several weeks; therefore the ab-sence of antibodies does not exclude infection in the ear-ly course of illness. Direct microscopic examination of clinical specimens and/or culture may be a faster means of diagnosing Coccidiodes infections [39]. Fungal growth can be observed within 1 week, and identification is fol-lowed by a commercially available Genprobe with detects C. immitis-specific nucleic acid sequence. To assert dis-seminated coccidioidomycosis, it is usually necessary to visualize fungi in extrapulmonary biopsy specimens [39].

ParacoccidioidomycosisA definite diagnosis of paracoccidioidomycosis can be

made after direct microscopic examination of the charac-teristic yeast forms in tissue samples (sputum, ascites, bi-

Fig. 16. Progressive bilateral alveola and interstitial infiltrates with air bronchogram signs in the left lower lobe in a 32-year-old man who presented to the Hospital for Tropical Diseases in Ho Chi Minh City in 2015 with 2 weeks of fever, weight loss, fatigue, cough, difficulty breathing when laying down, abdominal pain, and diffuse central umbilicated nodules on his face, body, and ex-tremities. He was diagnosed with HIV and had a CD4 cell count of 3 cells/mm3. His skin culture grew Talaromyces marneffei, while sputum and blood culture showed no growth.



opsies, scraping of skin lesion, etc.) stained with fungal stains (large yeast cells surrounded with multipolar bud-ding daughter cells resembling a “Mickey mouse head” or a “steering-wheel”) or by culturing the organism [14]. Culture can take up to 1 month to grow; therefore direct microscopy remains the cornerstone in the diagnosis of paracoccidiodes infection. Serological methods, in par-ticular the quantitative immunodiffusion method, are widely available in the endemic regions. However, in most cases serology is not necessary for diagnosing para-coccidioidomycosis. While it can be a useful tool to mon-itor treatment success, so far serologic diagnosis is not standardized, and results from different laboratories may be conflicting [41]. There are no validated serological techniques for diagnosis of infection with P. lutzii.

BlastomycosisDirect proof of Blastomyces infection – either by cul-

ture or visualization of the yeast forms – is necessary for a definite diagnosis of blastomycosis and the method of choice [42]. Culturing Blastomyces organisms from respi-ratory samples of affected patients has a high sensitivity of around 90%, but takes 1–4 weeks. Direct microscopic examination of typical yeast organisms with broad-based buds is characteristic of Blastomyces; however, micros-copy has a low diagnostic yield of up to 40%. Serological tests for blastomycosis are hampered by their low sensi-tivities and their lack of specificity due to cross-reactivity

against other endemic mycoses, in particular against his-toplasmosis [43]. The utility of PCR assays for the detec-tion of B. dermatidis has not yet been validated in large clinical studies. Finally, similar to histoplasmosis, a single antigen detection assay is available in the USA [44]. The assay has a high sensitivity of around 90%, but also lacks specificity due to cross-reactivity – especially with histo-plasmosis.

SporotrichosisCulture is the best option in the diagnostic workup of

suspected sporotrichosis [45]. Culture is very sensitive, and visible growth can be seen within 1 week. S. schenckii is not considered a colonizer, thus a positive clinical sam-ple is diagnostic. While histopathology may help in show-ing a pyogenic and granulomatous picture, the organism can only rarely be visualized due to the paucity of or-ganisms [45]. No validated serology or PCR is currently available.

TalaromycosisT. marneffei can be cultured from blood and clinical

samples using standard media for bacteria culture (Fig. 18). As growth may take approximately 1 week, a presumptive diagnosis can be made based on the visual-ization of binary fission yeasts on fungal staining of skin scraping, sputum smear, or biopsies [46]. This enables the initiation of antifungal therapy before confirmation of

a b c

Fig. 17. a A 30-year-old man who presented to the Hospital for Tropical Diseases in Ho Chi Minh City in 2013 with 1 month of fever, weight loss of 12 kg, dry cough, shortness of breath, enlarged cervical lymph nodes, hepa-tosplenomegaly, and multiple central umbilicated nodules on his face and trunk. He was diagnosed with HIV and had a CD4 count of 12 cells/mm3. b X-ray of the chest showed a diffuse micronodular interstitial pattern consistent with miliary talaromycosis. Cultures from the lymph node, skin lesions, and blood were all positive for Talaromyces marneffei. c T. marneffei yeast cells obtained from a Giemsa-stained touch skin smear were seen under the microscope.

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culture results. Rapid diagnostic assays are being devel-oped including several monoclonal antibody-based anti-gen detection EIAs, which have high sensitivity and spec-ificity, and are being evaluated as rapid diagnostic tests [47, 48]. Real-time PCR assays have been developed but sensitivities are currently insufficient (60–70%) to be clinically useful.

Management

For most systemic endemic mycoses causing pulmo-nary disease including histoplasmosis, paracoccidioido-mycosis, blastomycosis, sporotrichosis, and talaromyco-sis, experts generally recommend antifungal treatment with itraconazole. It is the treatment of choice for mild to moderate disease manifestations (Table 4) [14, 22, 49–52]. Mild cases of histoplasmosis with symptoms less than 4 weeks usually do not require antifungal treatment, while paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis should be treated when diagnosed [14, 22, 50]. Disseminated talaromycoses should be treated as soon as possible to decrease mortality, and initial therapy with amphotericin B deoxycholate has been shown to be superior to itraconazole in the IVAP trial in Vietnam [53]. For all endemic mycoses with severe disease mani-festations, amphotericin B is recommended as initial

therapy followed by itraconazole consolidation therapy. Generally, lipid formulations of amphotericin B are pre-ferred due to their relatively lower toxicity (infusion re-lated reactions, renal failure, electrolyte disturbance, and anemia). High-dose fluconazole is recommended as the treatment of choice for severe coccidioidomycosis infec-tions, while patients with a mild disease usually recover without any antifungal treatment [39]. Little evidence ex-ists with alternative treatment strategies and the efficacy of different antifungal drugs can differ considerably be-tween endemic mycoses and between different manifes-tations within each endemic mycosis. Table 4 summa-rizes current antifungal treatment recommendations according to available guidelines.

Duration of Itraconazole TreatmentDuration of itraconazole treatment strongly depends

on the specific endemic mycoses, clinical syndrome, and host immune factors (Table 4). Histoplasmosis and tal-aromycosis usually require a period of 2 weeks of induc-tion therapy followed by 6–12 weeks of consolidated treatment, while paracoccidioidomycosis and sporotri-chosis usually require long-term treatment of at least 12 months [14, 51, 52]. Generally, the duration should be guided by clinical improvement and radiological resolu-tion. For immunosuppressed persons, secondary pro-phylaxis is recommended to prevent disease relapse. In patients with advanced HIV infection, consolidation therapy with itraconazole is recommended until the CD4+ T-cell count increases and remains above 100 cells/mm3 for at least 3–6 months on antiretroviral therapy. Strategies to mitigate the underlying cause of immuno-suppression will dictate the duration of secondary pro-phylaxis (or consolidation therapy). In persons requiring immunosuppressive therapy, management requires a balance between strategies to mitigate immunosuppres-sion and lifelong antifungal prophylaxis.

The treatment duration for a specific endemic mycosis will differ depending on clinical syndrome and host fac-tors. Pulmonary histoplasmosis with its different clinical syndromes is an illustrative example. Asymptomatic pa-tients with pulmonary nodules usually do not benefit from antifungal treatment, while symptomatic patients do. Furthermore, patients with acute diffuse pulmonary histoplasmosis often require only 6 weeks of antifungal treatment, while in patients with chronic cavitary histo-plasmosis long-term treatment of at least 12 months is recommended. In AIDS patients with pulmonary histo-plasmosis who do not achieve immune reconstitution even lifelong treatment may be recommended [54].

25°C

SDA

med

ium

37°C

SDA

med

ium

a

d

b

c

Fig. 18. Morphology of Talaromyces marneffei colonies on Sab-ouraud agar (SDA) medium and the fungus under the microscope at 25 ° C (a, b) and at 37 ° C (c, d).

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Dosage of Itraconazole TreatmentThe commonly recommended dosage for itraconazole

consolidation treatment is 200 mg once to twice daily de-pending on the severity of disease (Table 4). Generally, the oral solution of itraconazole is preferred due to the improved absorption compared to capsules and tablets. However, the itraconazole solution is not well tolerated due to the osmotic effect of the co-formulated cyclodex-trin [54]. Gastric acid is required for adequate absorption of the capsules and tablets, so they should be taken im-mediately after meals or with an acidic drink. Antacids should be avoided or taken at least 4–6 h apart from itra-conazole tablets and capsules. The oral solution of itra-conazole, however, should be taken on an empty stom-ach. It is recommended to start itraconazole treatment with a loading dose of 200 mg 3 times a day for 3 days to attain adequate drug levels more rapidly. The manufac-turer labeling recommends a loading dose only for severe and life-threatening cases, but in these cases the guide-lines usually recommend initial therapy with amphoteri-cin B intravenously until clinical improvement before continuation with oral itraconazole. Because of the vari-able bioavailability and the potential for drug-drug inter-actions, TDM is recommended, especially for patients who have severe disease, critically ill patients in intensive care unit, patients on multiple drugs including rifampicin and antiretroviral therapy with nonnucleoside reverse transcriptase inhibitors and protease inhibitors, and pa-tients with infections of the central nervous system, eyes or bones. However, TDM is not universally available and several limitations have to be considered (e.g., assays are not standardized, optimal timing of sampling, sample transportation, unclear reference values) [55].

Amphotericin B TreatmentEarly intravenous amphotericin B treatment is recom-

mended for most severe cases of systemic endemic myco-ses (Table 4). Generally, lipid-formulated amphotericin B is preferred due to reduced toxicity. However, in many resource-constrained settings, lipid-formulated ampho-tericin B is not available or affordable. Deoxycholate am-photericin B still remains an effective alternative, but nephrotoxicity is common and should be closely moni-tored. Toxicity is significantly mitigated by daily saline and potassium supplementation. The commonly recom-mended duration of amphotericin B treatment is 1–2 weeks, but strongly depends on the severity of disease and the clinical condition of the patient. After clinical stabili-zation of the patient treatment should be changed to itra-conazole.

Follow-Up and ComplicationsAzoles strongly influence the enzymatic activity of cy-

tochrome P450 (e.g., CYP3A4), which can lead to consid-erable drug-drug interactions [56]. TDM can assist in de-tecting subtherapeutic drug concentrations due to mal-absorption and drug-drug interaction and in optimizing individual dosage regimes. Treatment monitoring and patient follow-up are essential to detect antifungal side effects, drug-drug interactions, treatment failure, and pulmonary sequelae. Long-term sequelae such as chronic pulmonary aspergillosis should be considered in patients with cavitary destruction of lung parenchyma [12, 57]. Symptoms may persist for several months and a lung function test (usually showing an obstructive pattern) may help to monitor the course of disease.

Conclusions

This review article should guide physicians in the di-agnosis and management of systemic endemic mycoses causing pulmonary disease. Several aspects have to be considered.

First, clinical presentation and radiological pattern of systemic endemic mycoses may mimic other diseases and are nonspecific. The medical history plays a central role, especially the travel history and information on risk fac-tors for potential environmental exposures. Having a clinical suspicion is critical as it facilitates specific myco-logical diagnostics and communication with laboratory personnel on potential biosafety risk (in particular for Coccidioides spp.). Physicians need to be aware of basic disease manifestations and the diversity of clinical and radiological patterns.

Second, even when an endemic mycosis is suspected, diagnoses may be hampered by the lack of availability of diagnostic tests, especially in low-prevalence settings. Consultation with a mycology reference laboratory is rea-sonable to discuss proper sample collection and available diagnostic tests. Test results should be interpreted with consideration for their performance and for the lower positive predictive values of some of these tests in com-parison to what are reported from endemic regions. Cul-ture or histology from clinical samples (e.g., BAL, lung tissue) is the method of choice for most endemic mycoses. A combination of different diagnostic methods is reason-able, and may increase the likelihood of establishing a di-agnosis.

Third, if antifungal treatment is indicated itraconazole (or fluconazole in the case of coccidioidomycoses) is the


treatment of choice in mild to moderate cases, except for talaromycosis, where amphotericin B should be the initial treatment. Early amphotericin B therapy (preferably lipid formulations) is recommended in severe cases until clin-ical stabilization of the patient before changing to itra-conazole consolidation therapy. Drug-drug interactions, adverse events, and possible long-term sequelae should be monitored. Duration of treatment differs significantly between endemic mycoses and depends on the specific mycoses, severity of disease, clinical syndrome, and the immune status of the hosts.

In low-prevalence settings it is advisable to discuss pa-tients with suspected endemic mycoses with an interdis-ciplinary team involving infectious disease specialists, microbiologists, radiologists, and pathologists.

Disclosure Statement

The authors have no conflicts of interest to declare.

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