Fungal Infections (including PCP)

What every physician needs to know:

Fungal organisms are ubiquitous in the environment and humans inhale them almost constantly. In some settings, especially in patients with impaired clearance and immunity, these organisms can cause invasive pulmonary infection, with the potential for extra-pulmonary dissemination.

Fungi typically exist as yeasts and molds. Organisms that exhibit a temperature-dependent switch between yeast and mold forms are referred to as “dimorphic.”

The most common yeasts that cause disease are the Candida species. These organisms, which are commonly cultured from skin and mucosal sites, can cause bloodstream infection with involvement of other organs; however they rarely cause disease in the lungs. Other yeasts, namely the Cryptococcus species, can cause invasive pulmonary disease in both immunocompromised and immunocompetent hosts.

Molds, which are typically found in the environment, cause invasive pulmonary disease and can trigger allergic manifestations in a variety of hosts. The most common cause of infection is members of the Aspergillus genus. Other molds that rarely cause infection include the agents of mucormycosis (Rhizopus, Mucor, Rhizomucor).

The fungi that exhibit a dimorphic switch between yeasts and molds are also typically those that are distributed in endemic geographies. The agents of histoplasmosis, blastomycosis, sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, and chromoblastomycosis are caused by fungi that are dimorphic in nature, existing as yeast in the host and as a mold in the environment. Histoplasmosis, blastomycosis, and cocciodioidomycosis are the most common dimorphic fungi to cause pulmonary disease in endemic regions, especially in North America, Central America, and South America.

Pneumocystis jirovecii is another pathogen recently renamed and reclassified as a fungus that can cause pulmonary infection in humans.

Classification:

This review will focus primarily on pulmonary manifestations, pathogenesis, clinical features, and treatment of endemic mycoces (histoplasmosis, blastomycosis, coccidioidomycosis), cryptococcal disease, Pneumocystis pneumonia, and aspergillosis.

Histoplasmosis

Histoplasma capsulatum, the causative agent of histoplasmosis, is a member of the Ascomycetes family and is a soil inhabitant found worldwide. In the U.S., it is particularly endemic to the Ohio and Mississippi River valleys. H capsulatum is also endemic to certain areas in Mexico, Canada, Central/South America, Africa and Asia.

Blastomycosis

Blastomyces dermatitidis is another dimorphic fungus that is endemic to areas bordering the Mississippi, Ohio and St Lawrence River basins, as well as the Great Lakes. Blastomyces is rarely reported outside of North America, though some cases do occur in Africa.

Coccidioidomycosis

Coccidioides immitis and C. posadasii are the dimorphic fungi that cause coccidioidomycosis. These organisms are endemic to the arid regions in southern California, southern Nevada, Arizona, New Mexico, Utah, western Texas, northern Mexico, parts of Central America (Guatemala, Honduras, Nicaragua), and parts of South America (Argentina, Paraguay, Venezuela, Colombia, and Brazil).

Cryptococcosis

Cryptococcus neoformans and Cryptococcus gattii are two encapsulated yeast species that cause cryptococcosis and are found in soil. C. neoformans is found worldwide and associated with pigeon dropping and rotting vegetation, while C. gattii is found in tropical areas including Northern Australia and Papua New Guinea. There have been reports of C. gattii outbreaks in Northwest United States and around Vancouver in Canada.

Pulmonary Aspergillosis

Aspergillus is a filamentous fungus ubiquitous in the environment and has no known geographic predilection. The most common members of the Aspergillus genus that cause invasive infections are A. fumigatus, A. niger, A. terreus and A. flavus.

Pneumocystis Pneumonia (PCP)

The organism causing PCP in humans is Pneumocystis jirovecii, recently named to distinguish it from P. carinii, the organism that causes disease in rodents. While Pneumocystis jirovecii was previously thought to be protozoan, genetic evaluation has definitively identified it as a fungus. The organism is difficult to grow in the laboratory.

Are you sure your patient has a fungal infection? What should you expect to find?

Histoplasmosis: Infection from H capsulatum can result in a wide spectrum of clinical manifestations depending on host immunity and exposure intensity.

1. Asymptomatic infection

Occurs in up to 99% of those infected.

2. Acute and subacute pulmonary histoplasmosis

Acute infection presents with flu-like symptoms (myalgias, dry cough, fevers, chills, malaise, chest discomfort) for <1 month. Patients may have associated pulmonary infiltrates with focal, diffuse or multinodular pattern. Milder cases may resolve spontaneously but severe cases can progress to respiratory failure or disseminated extrapulmonary infection and are often associated with large exposures.

Subacute form is associated with milder symptoms for more than 1 month. Radiographic findings include focal nodular or patchy infiltrates, and mediastinal/hilar lymphadenopathy.

Both forms may be associated with other inflammatory manifestations such as pleuritis, pericarditis, erythema nodosum, erythema multiforme and polyarthritis.

3. Chronic pulmonary histoplasmosis

Patients with underlying lung disease are at risk for developing a chronic form of the infection with productive cough, dyspnea, chest pain, weight loss, hemoptysis, fevers and sweats with symptoms lasting >3 months. Radiographic findings include fibrotic and cavitary apical infiltrates. TB can present similarly and should be excluded.

4. Progressive disseminated histoplasmosis

Acute pulmonary histoplasmosis can progress to disseminated infection in patients with immune deficiency (HIV/AIDS, organ transplant, TNF-alpha inhibitor therapy), malignancy, advanced age, and rarely in healthy hosts. Disseminated disease can be life threatening with multiorgan involvement. Findings include pulmonary interstitial or reticulonodular infiltrates, mucosal and skin lesions, lymphadenopathy, cytopenias, transaminitis, hepatosplenomegaly, endocarditis, and meningitis/encephalitis.

5. Other pulmonary manifestations

• Lung nodules (Figure 1)

• Broncholithiasis – Calcified pulmonary granulomas and lymph nodes can erode into adjacent bronchi resulting in cough, hemoptysis and expectoration of small stones.

• Mediastinal granuloma – Enlarged caseous lymph nodes can cause compression of adjacent structures such as pulmonary vasculature, trachea and pulmonary vessels.

• Fibrosing mediastinitis – Results from excessive fibrotic reaction to histoplasmosis that can lead to compression of mediastinal vessels, esophagus and airways.

Figure 1.

Blastomycosis

Blastomycosis can have a wide variety of clinical presentations from asymptomatic to disseminated infection. The most common manifestation is pulmonary disease since the vast majority of exposures occur through an inhalational route. Extrapulmonary disease occurs from hematogenous spread from the primary pulmonary source and can involve, in order of decreasing frequency: skin, bone (osteomyelitis), genitourinary system (prostatitis and epididymoorchitis) and CNS (meningitis, intracranial and epidural abscesses). A characteristic skin finding is an ulcerated or verrucous lesion with irregular borders and purulent discharge. Extrapulmonary manifestations will not be discussed in detail in this review.

Pulmonary Manifestations:

• Acute pneumonia – patients present with symptoms similar to community-acquired pneumonia with productive cough, fevers, weight loss, shortness of breath, and night sweats. CXR findings include alveolar and mass-like infiltrates, though reticulonodular and miliary patterns can also be seen. CT scans can show tree-in-bud opacities, pleural effusions, nodular lesions, or consolidation occasionally with cavitation. Unlike histoplasmosis, significant hilar lymphadenopathy is not present, which can help distinguish between the two endemic mycoses.

• Chronic pneumonia – patients may present with a chronic form that may be in distinguishable from other fungal infections, TB, and malignancy. Symptoms include fevers, weight loss, chest pain, productive cough, and hemoptysis. Common radiographic findings are fibronodular infiltrates, mass-like opacities than can mimic bronchogenic carcinoma, and alveolar infiltrates. Upper lobe lesions are more frequent and pleural effusion and pleural thickening may also be present.

• ARDS – In rare cases, patients may present with diffuse pulmonary infiltrates and ARDS, associated with a very high mortality. It is unclear whether this form occurs due to high fungal burden or poor host immune response.

Coccidioidomycosis

The majority of coccidioidomycosis infections are thought to be subclinical. A fraction of patients with pulmonary infection develops extrapulmonary disseminated infection with the most common sites involving skin (granulomatous lesions, abscess), bones, joints, and meninges. An LP should be performed on all patients with primary infection and headache, blurry vision, or any other neurologic symptoms.

Pulmonary Manifestations:

• Primary infection – aka Valley fever; accounts for up to 1/3 of community-acquired pneumonia in endemic areas, and presents with cough, fatigue, fevers and chills. Patients may have accompanying erythema nodosum and exanthem similar to erythema multiforme, both of which usually indicate a favorable prognosis. Radiographic findings may be unremarkable in up to 1/2 of patients or show lobar infiltrate and ipsilateral hilar adenopathy. Up to 15% may develop pleural effusions with lymphocytic and eosinophilic predominance. Rare cases of acute respiratory failure and ARDS have been reported. This may occur in patients with underlying immune compromise such as HIV/AIDS or those with massive fungal exposure.

• Residual pulmonary nodules – in a small fraction of patients with primary infection, infiltrates do not resolve completely, and they are left with solitary pulmonary nodules often in the peripheral lung. Malignancy should be considered in the differential.

• Cavities – Residual thin walled cavities may develop from primary infection and are often asymptomatic. Rarely these cavities can rupture into the pleural cavity forming a bronchopleural fistula and pneumothorax. A ruptured cavity can present as the initial manifestation of Coccidioides in some patients with chest pain and dyspnea, and are not associated with immunosuppression. In some patients, especially diabetics, primary infection can remain unresolved and evolve into chronic fibrocavitary pneumonia.

• Diffuse reticulonodular pneumonia – develops in patients with cellular immune deficiency or large exposures. It results from fungemia leading to septic emboli and patient presents with severe dyspnea, fevers and night sweats.

Cryptococcosis

The most common and serious manifestation of cryptococcosis is meningitis but this review will focus on pulmonary manifestation. Additional sites of infection include skin (Figure 2), prostate, bone and eyes. The spectrum of clinical manifestations ranges from colonization to asymptomatic infection to severe pneumonia and respiratory failure.

Figure 2.

• Colonization may be seen in patients with underlying structural lung disease.

• In immune competent hosts with exposure, subclinical infections are common and most are asymptomatic. Infections often are found incidentally with diagnostic evaluation of pulmonary nodules. Symptomatic infection is associated with cough, chest pain, fevers, malaise, sputum production, and hemoptysis. Radiographic findings include non-calcified pulmonary nodules, masses, consolidation, cavities, mediastinal/hilar lymphadenopathy, and interstitial pneumonitis.

• Immunocompromised patients are generally more symptomatic, have more severe radiographic findings, and are more likely to present with extrapulmonary disease. The majority of these infections are likely from reactivation of latent disease. ARDS is most likely to occur with organ transplant recipients and is associated with high mortality.

• The severity and extent of disseminated infection in HIV patients correlates inversely with CD4 counts. The majority of HIV patients with pulmonary cryptococcosis will have CNS involvement.

Aspergillosis

Aspergillus causes a wide spectrum of clinical manifestation based on host immune status. In the U.S., it is the most common cause of mortality from invasive mycosis. Extrapulmonary disease can occur and manifests as invasive sinus disease, tracheobronchial aspergillosis, endocarditis and myocarditis, osteomyelitis and septic arthritis, endopthalmitis and keratitis, cutaneous disease, peritonitis and CNS aspergillosis (Figure 4).

Figure 4.

Below lists the pulmonary disease presentations in order of increasing invasiveness in the setting of increasing immune suppression.

• Allergic bronchopulmonary aspergillosis (ABPA) – hypersensitivity reaction in response to airway colonization with Aspergillus. Most commonly seen in patients with asthma and cystic fibrosis (see separate section on ABPA).

• Aspergilloma – formation of fungal ball composed of Aspergillus hyphae, mucous, fibrin and cellular debris within a prior cavity from COPD, sarcoidosis or TB. The typical radiographic finding is a freely moving solid mass within a cavity. Aspergillomas are often asymptomatic but may present with cough and rarely life threatening hemoptysis.

• Chronic necrotizing and chronic cavitary aspergillosis – semi-invasive form in patients with normal to some degree of immune deficiency, associated with cavitary lung lesion. Cavities may be thin walled or may be a consolidation with areas of cavitation.

• Invasive pulmonary aspergillosis (IPA) – commonly presents with fevers, hemoptysis and pleuritic chest pain. Aspergillus fumigatus is the most common species in IPA. The classic presentation is a pulmonary nodule that develops in a neutropenic patient. This lesion can expand and evoke localized inflammation and hemorrhage, creating a radiographic “halo sign” before ultimately cavitating, which largely occurs after resolution of neutropenia concurrent with tissue necrosis forming an air-crescent sign. Radiographic findings are variable and include nodules +/- cavitation, patchy or segmental consolidation, tree-in-bud opacities and ground glass opacities (Figure 3).

Figure 3.

Pneumocystis Pneumonia (PCP)

Clinical manifestations of PCP in HIV differ from that of patients with other immune deficiencies. PCP in HIV usually presents with an insidious onset of dry cough, progressive dyspnea, weight loss, and fever. Acute dyspnea and chest pain should raise suspicion for a pneumothorax. Immunocompromised patients without HIV typically present with acute and fulminant respiratory failure usually in the setting of a change in immunosuppression. Most patients have hypoxemia and increased alveolar-arterial (A-a) oxygen gradient on presentation.

CXR may be unremarkable in early mild disease and chest CT may be helpful in these cases. Most common findings are bilateral diffuse ground glass and interstitial infiltrates +/- consolidation, extending from the perihilar region (Figure 5). Less common findings are nodules that may cavitate, lobar infiltrates, pneumatocele, and occasionally pneumothorax.

Figure 5.

Although rare, dissemination to extra-pulmonary sites, including the lymph nodes, spleen, liver, and bone marrow may occur in patients on aerozolized pentamidine prophylaxis or those with advanced HIV not on prophylaxis.

Beware: there are other diseases that can mimic a fungal infection:

In general, alternative causes of pneumonia, malignancy, TB, sarcoidosis etc. should be considered in the differential.

How and/or why did the patient develop a fungal infection?

Histoplasmosis

H capsulatum proliferates in soil rich in bird and bat droppings, and exposure may occur with activities such as spelunking in caves contaminated with bat guano, construction, excavation, or working in chicken coops, abandoned buildings, wood lots etc.

After H capsulatum microconidia are inhaled, they convert to the yeast form and spread to adjacent alveoli, hilar and mediastinal lymph nodes. Yeast is then phagocytosed by macrophages where it can remain dormant. Hematogenous dissemination occurs through these infected macrophages and is usually self-limited, resulting in often incidentally found granulomas in lung, lymph nodes, liver and spleen. Only a small fraction of those exposed develop symptomatic infection. Risk for disseminated and progressive infection is associated with heavy exposures, impaired cellular immunity, HIV/AIDS, treatment with TNF-alpha inhibitors, organ transplant, and extremes of age.

Blastomycosis

Blastomyces enters the body by inhalation of conidia, which are then phagocytosed and killed by alveolar macrophages, monocytes and polymorphonuclear leukocytes. Clinical infection occurs if these conidia are able to convert to the pathogenic yeast form, which induces expression of certain virulence factors. Unlike other fungal infections, blastomycosis occurs in immune competent patients, though patients with diabetes may have an increased risk. Though cellular immunity plays a major role in controlling infection, it is not clear whether blastomycosis has increased rates in immunocompromised patients. However, immunocompromised patients are more likely to have severe and disseminated disease with higher mortality rates.

Outbreaks have been associated with activities with exposures to waterways and moist soil with decaying vegetation. Of note, primary cutaneous Blastomyces infections also have been rarely reported with dog bites and accidental inoculations in lab settings and autopsies.

Coccidioidomycosis

Infection occurs by inhalation of arthroconidia, which are ingested by pulmonary macrophages. The anthroconidia subsequently transforms into a round cell that enlarges into a spherule with internal septations forming hundreds of endospores. Mature spherules rupture after several days releasing endospores that can disseminate by hematogenous or lymphatic drainage.

Risk of infection is high in people exposed to aerosolized soil e.g., archaeologists, excavators, construction workers, and agricultural workers. Coccidioidomycosis is also noted to have increased incidence in patients with compromised cell mediated immunity. A small fraction of patients with primary infection develop disseminated disease. Risk factors for disseminated disease include HIV with reduced CD4 counts, solid organ transplant, use of TNF-alpha antagonists, and comorbidities such as diabetes, underlying lung, heart and kidney diseases. Additionally, African American and Filipino patients and pregnant women in their third trimester are also at risk for severe and disseminated disease.

Cryptococcosis

Similar to the endemic mycoses, infection occurs through inhalation of spores, which may be phagocytosed by alveolar macrophages or lead to disseminated or latent infection. Cryptococcus can cause infection in both immune competent and immunocompromised patients. C. gattii more commonly infects normal hosts and C. neoformans commonly infects compromised hosts.

Risk factors include HIV, chronic steroid therapy, diabetes, hematologic malignancy, solid organ transplant, sarcoidosis and impairment in cell-mediated immunity e.g., anti-TNF-alpha therapy.

Aspergillosis

Aspergillus hyphae in the environment produce conidia that enter the host via inhalation. In immune competent hosts, alveolar macrophages clear the conidia by phagocytosis with minimal to no inflammatory response.

Patients with underlying lung disease such as asthma and cystic fibrosis can develop non-invasive manifestation including ABPA (reviewed elsewhere). Risk factors for chronic and semi-invasive pulmonary aspergillosis include COPD, diabetes, mycobacterial disease, fibrocavitary sarcoidosis and prior pneumothorax.

Risk factors for IPA include severe and prolonged neutropenia, use of high dose steroids, organ transplant, advanced AIDS and chronic granulomatous diseases. IPA has also been recognized in critically ill patients without classic risk factors as well as patients with other diseases such as COPD, cirrhosis, and alcoholism.

Pneumocystis Pneumonia (PCP)

Pneumocystis is found in the lungs of healthy individuals worldwide and a clear environmental source has not been identified. Although it was previously thought that infection remains latent unless the host is immunosuppressed, this mechanism does not account for all PCP cases. Pneumocystis is transmitted by the airborne route and person-to-person transmission is also suspected from hospital outbreaks.

Clinically apparent PCP is almost never seen in immune competent hosts, and if diagnosed, should prompt an investigation into underlying occult immune deficiency. The prevalence of PCP increased dramatically in the 1980s with the AIDS epidemic. This incidence has since declined in the Western Hemisphere with PCP prophylaxis and highly active antiretroviral therapy (HAART). PCP is an AIDS defining condition and the most common respiratory opportunistic infection in HIV patients. It typically occurs when CD4 counts drop <200/μL without appropriate HAART or PCP prophylaxis.

In non-HIV infected patients, risk factors for PCP include immunosuppressive medications (glucocorticoids, anti-TNF-alpha agents, cytotoxic agents), cancer (especially hematologic malignancy), and defects in cell-mediated immunity, hematopoietic or solid organ transplant, rheumatologic diseases, severe malnutrition and severe combined immune deficiency.

Which individuals are at greatest risk of developing a fungal infection?

See previous section.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Histoplasmosis

In patients with clinical and radiographic suspicion for histoplasmosis, diagnosis can be supported with Histoplasma antigen and antibody detection, fungal cultures and histopathology. Cultures and antigen tests are usually negative in those with broncholithiasis, lung nodules, mediastinal granuloma, and fibrosing mediastinitis.

• Histoplasma antigen – can be detected in blood, urine, CSF, or bronchoalveolar lavage (BAL) fluid. Highest diagnostic yield results from testing both urine and serum. Up to 83% with acute pulmonary histoplasmosis have positive antigens. BAL antigen also improves diagnostic yield in pulmonary histoplasmosis though antigen cross reactivity can be seen with other endemic mycoses.

• PCR assays – less sensitive than microscopic examination or antigen detection and of uncertain utility.

• Serum antibodies – peak about a month after infection and often negative earlier in the course of the disease. Sensitivities are up to 89% for localized pulmonary infection, up to 90% for chronic pulmonary histoplasmosis and up to 80% for disseminated disease. Antibodies can be falsely negative in immunosuppressed patients. It can also remain positive for several years and may not represent active disease.

• Fungal cultures – from sputum, tissue or BAL and most helpful in patients with chronic pulmonary histoplasmosis though may require up to 6 weeks for growth. Blood cultures can be also positive in patients with disseminated disease.

• Histopathology and cytology (BAL) – findings include caseating granulomas and yeast with narrow-based budding.

Blastomycosis

Diagnosis of blastomycosis involves high index of clinical suspicion and definitive diagnosis requires clinical specimen with growth of B dermatitidis.

• Cultures – a positive culture result is the gold standard. Sputum and BAL cultures are associated with high diagnostic yield.

• Direct examination – though of relatively low diagnostic yield, KOH preparation of clinical specimens (skin scraping/drainage, sputum, BAL, CSF, urine, etc) can show characteristic broad-based budding yeast. Direct visualization in the appropriate clinical setting can justify starting empiric antifungals while awaiting culture confirmation. Serologic testing – not helpful in diagnosis because of low sensitivity and specificity as well as cross-reactivity with other endemic mycosis.

• Antigen testing – has limited utility in diagnosis of blastomycosis.

Coccidioidomycosis

Diagnosis of symptomatic coccidioidomycosis relies on a history of exposure and appropriate clinical and radiographic presentation. Several tests can assist with establishing a diagnosis including culture, histopathology, or serologic testing. Antigen testing has poor sensitivity but may be useful in immunocompromised patients or to monitor response to therapy.

• Serologic testing – EIA for IgG or IgM are ordered as screening tests, and if positive, confirmatory immunodiffusion assay can be completed. A complement fixation titer can also be obtained which can help in determining the severity of disease.

• Culture – Coccidioides growth does not require special media and can be isolated from sputum, skin lesions, and rarely blood samples. When clinically suspected, laboratory staff should be alerted since exposure can lead to infection in laboratory personnel.

• Histopathology – Coccidioides spherules are the common form seen in tissue samples.

• Other findings – peripheral eosinophilia may be seen in up to 1/4 of patients.

Cryptococcosis

Diagnosis of cryptococcosis relies on isolation of the pathogen from a respiratory specimen in the appropriate clinical setting. Diagnostic tools in addition to imaging includes fungal cultures, histopathology and serum cryptococcal antigen. Immunocompromised patients with pulmonary disease should be evaluated for disseminated disease with blood and CSF cryptococcal antigen and fungal cultures.

• Fungal culture and histology – isolation and growth of encapsulated yeast form in sputum, BAL fluid, blood, and tissue samples are diagnostic in the appropriate setting. Biopsy of asymptomatic nodules can show yeast form but cultures may be negative.

• Serum cryptococcal antigen – associated with high sensitivity/specificity in immunocompromised hosts and disseminated disease but its utility is limited in immune competent patients with isolated pulmonary disease. Serum titers during therapy do not correlate with response to therapy. BAL and sputum antigen titers are not useful.

• LP – should be performed in all patients with disseminated disease, neurologic symptoms or positive serum antigen titers to evaluate for cryptococcal meningitis.

Aspergillosis

Definitive diagnosis of aspergillosis involves growth of Aspergillus species in culture, and in IPA, evidence of tissue invasion by fungal hyphae on pathology. Non-invasive modalities are available to aid in the diagnosis since biopsy may not be always feasible.

• Bronchoscopy with BAL should be performed in cases of suspected IPA. In general transbronchial biopsies are not recommended given their low yield and bleeding risk. BAL diagnostic yield varies with radiographic lesions and with consolidative opacities and tree-in-bud abnormalities, yields are close to 70%.

• Serum 1-3-beta-D-glucan (cell wall component) or Fungitell assay is recommended by guidelines for diagnosis of IPA in high-risk patients. This assay is not specific for Aspergillus and can be positive in other fungal infections. False positives can also occur with antibiotic use such as with ampicillin-sulbactam and carbapenems.

• BAL galactomannan (polysaccharide cell wall component) is also recommended as a marker for IPA in the appropriate clinical setting. False positives occur with certain antibiotics such as pipercillin-tazobactam and in patients with other invasive mycoses. BAL galactomannan sensitivities exceed 70%.

• PCR assays have showed mixed results and are currently not recommended.

• Histopathology in the setting of invasive disease will demonstrate characteristic septated fungal hyphae with 45° branching.

Pneumocystis Pneumonia (PCP)

Since Pneumocystis cannot be grown in culture, establishing a definitive diagnosis of PCP requires visualization of organism in cysts or trophic form from respiratory specimens or PCR.

• Induced sputum – variable sensitivity but sensitivity approaches 100%.

• BAL – next step if sputum nondiagnostic or unobtainable; has high sensitivity with yield increased with multiple lobes sampled; transbronchial biopsies can be considered (yields up to 100%) in patients receiving aerosolized pentamidine since this lowers BAL yield.

• Transthoracic or open lung biopsy – can be considered in patients with nondiagnostic sputum, BAL and transbronchial biopsies; up to 100% sensitivity and specificity but significant risks associated with the procedure should be weighed against the benefits.

• PCR assays – of respiratory secretions, BAL, blood or tissue samples can increase diagnostic yield especially in non-HIV immunocompromised patients.

• Other labs:

  1-3-beta-D-glucan – serum levels present in Pneumocystis cell wall and can be used with clinical findings to make a presumptive diagnosis of PCP when definitive diagnosis cannot be made; also elevated in histoplasmosis, candida infections, and aspergillosis.

  LDH – levels usually elevated but not useful in differentiating PCP from other diseases.

What imaging studies will be helpful in making or excluding the diagnosis of a fungal infection?

See previous section.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a fungal infection?

See previous section.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a fungal infection?

See previous section.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a fungal infection?

See previous section.

If you decide the patient has a fungal infection, how should the patient be managed?

Histoplasmosis

• Pulmonary nodules: no treatment recommended

• Acute pulmonary histoplasmosis

  Mild-moderate disease

  Treatment usually unnecessary

  If symptoms present for >1month: Itraconazole for 6-12 wks (200 mg 3 times daily for 3 days (itraconazole load) and then 200 mg 1-2 times daily)

  Severe disease

  1^st line: Amphotericin B (AmpB) lipid formulation (3-5 mg/kg/day for 1-2 wks), then Itraconazole for 12 weeks (200 mg load and then 200 mg twice daily)

  Alternate: Deoxycholate formulation of AmpB 0.7-1.0 mg/kg/day if low risk for nephrotoxicity followed by itraconazole as above

  Methylprednisolone 0.5-1.0 mg/kg/day for 1-2 wks along with antifungals if patient develops hypoxemia or respiratory distress

• Chronic cavitary pulmonary histoplasmosis

  Itraconazole load, then 200 mg 1-2 times daily for at least 1 year

• Mediastinal granuloma

  Asymptomatic: treatment unnecessary

  Symptomatic: Itraconazole load, then 200 mg 1-2 times daily for 6-12 wks

• Mediastinal fibrosis

  Treatment with antifungals not recommended

  Stenting is an option for pulmonary vascular obstruction

• Broncholithiasis

  Treatment with antifungals not recommended

  Broncholiths can be removed by bronchoscopy or by surgical intervention if complicated by fistula formation, massive hemoptysis or obstructive pneumonia

• Progressive disseminated histoplasmosis

  Mild to moderate disease

  Itraconazole load, then 200 mg 2 times daily for at least 1 year

  Severe disease

  1^st line: AmpB lipid formulation (3 mg/kg/day for 1-2 wks), then itraconazole for at least 12 months (200 mg load and then 200 mg 1-2 times daily)

  Alternate: Deoxycholate formulation of AmpB 0.7-1.0 mg/kg/day if low risk for nephrotoxicity followed by itraconazole as above

  In patients with relapse despite appropriate therapy and immunocompromised patients, lifelong suppressive therapy with itraconazole 200 mg daily may be required

  Histoplasma antigen levels can be measured during therapy and up to 12 months after therapy to assess for relapse

Blastomycosis

Unlike other mycoses where treatment is often unnecessary, antifungal therapy is required in most patients with blastomycosis. Untreated infection is associated with up to 60% mortality. Choice and duration of antifungal therapy depends on clinical manifestation and host immunity.

• Pulmonary blastomycosis

  Mild to moderate disease: Itraconazole 200 mg 1-2 times daily for 6-12 months

  Severe disease: AmpB lipid formulation (3-5 mg/kg/day) or deoxycholate AmpB (0.7-1.0 mg/kg/day) for 1-2 weeks, then itraconazole 200 mg twice daily for 6-12 months

• Disseminated disease

  Mild to moderate disease: Itraconazole 200 mg 1-2 times daily for 6-12 months

  Severe disease: AmpB lipid formulation (3-5 mg/kg/day) or deoxycholate AmpB (0.7-1.0 mg/kg/day) for 1-2 wks, then itraconazole 200 mg twice daily for 12 months

• Immunosuppressed hosts

  AmpB lipid formulation (3-5 mg/kg/day) or deoxycholate AmpB (0.7-1.0 mg/kg/day) for 1-2 wks, then itraconazole 200 mg twice daily for 12 months

• Pregnant women

  Azoles contraindicated in pregnancy

  AmpB lipid formulation (3-5 mg/kg/day)

Coccidioidomycosis

The decision to treat with antifungals is based on the risk of dissemination and the severity of disease. In immune competent hosts, most cases of primary pulmonary infection do not require treatment. Therapy should be considered in patients with severe disease, impaired cell mediated immunity (AIDS, solid organ transplant recipients), those on TNF-alpha inhibitors, and patients with comorbidities such as heart failure, chronic lung disease and renal failure. Patients with primary pulmonary coccidioidomycosis should be followed to ensure resolution and to assess for complications for ≥1 year.

• Primary pulmonary infection

  Normal host:

  No therapy is needed in most patients

  Fluconazole or itraconazole (400 mg daily) for 3-6 months if: severe symptoms, symptoms lasting >6 weeks, comorbidities as above, and in at risk demographic/ethnicities

  Immunocompromised host: fluconazole or itraconazole (400 mg daily) for 3-6 months or longer based on clinical response

  Empyema should be drained and managed appropriately

• Pulmonary nodule

  Normal host: no therapy needed

  Immunocompromised host: consider fluconazole or itraconazole (400 mg daily) during periods of intense immune suppression

• Coccidioidal cavity

  Normal host:

  No therapy needed in most patients

  Consider itraconazole or fluconazole for 3-6 months if: increasing cavity size, rising titer, persistent cough, pleuritic chest pain, or hemoptysis

  Immunocompromised host: Fluconazole or itraconazole for 12-18 months or longer until symptoms improve and cavity size stable

  Surgical intervention (resection, lobectomy, decortication) may be needed with persistent or ruptured cavities

• Diffuse pulmonary disease

  Normal host: Liposomal AmpB (5 mg/kg/day) or deoxycholate AmpB (0.7-1.0 mg/kg/day) until clinical response, then fluconazole or itraconazole for ≥1 year

  Immunocompromised host: same regimen as normal host; consider long term suppression with azole

• Disseminated disease (non-meningeal): normal host and immunocompromised host

  Fluconazole or itraconazole for ≥1 year and until clinical improvement and stability

  Severe disease: Liposomal AmpB (5 mg/kg/day) or deoxycholate AmpB (0.7-1.0 mg/kg /day) until clinical response, then fluconazole or itraconazole for ≥1 year

Cryptococcosis

Treatment decisions for cryptococcosis depend on clinical presentation and host immune status.

• Normal host

  Colonization: no therapy necessary

  Pulmonary disease: Fluconazole (or itraconazole) 400 mg daily for 6-12 months

  Disseminated or CNS disease:

  Deoxycholate AmpB (0.7-1.0 mg/kg/day) ± flucytosine (100 mg/kg/day) for 2 wks, then fluconazole (or itraconazole) 400 mg daily for 10 weeks OR

  Deoxycholate AmpB (0.7-1.0 mg/kg/day) ± flucytosine (100 mg/kg/day) for 6-10 wks

• Immunocompromised host

  Asymptomatic or mild pulmonary disease: Fluconazole (or itraconazole) 400 mg daily for 6-12 months, followed by secondary prophylaxis

  Disseminated or CNS disease:

  Deoxycholate AmpB (0.7-1.0 mg/kg/day) ± flucytosine (100 mg/kg/day) for 2 weeks, then fluconazole (or itraconazole) 400 mg daily for 8 wks followed by maintenance OR

  Deoxycholate AmpB (0.7-1.0 mg/kg/day) ± flucytosine (100 mg/kg/day) for 6-10 wks followed by maintenance OR

  Lipid AmpB (3-6 mg/kg/day) for 6-10 weeks followed by maintenance

  Maintenance or secondary prophylaxis: Fluconazole 200 mg/day; in HIV, may be discontinued after initiation of HAART therapy once disease free and if CD4>200

• Surgical resection for localized disease may be necessary in some cases unresponsive to antifungal therapy

Aspergillosis

Management of aspergillosis varies with the severity of disease. In general, voriconazole is the mainstay of IPA treatment. A newer triazole, isavuconazole is now also FDA approved for IPA and may have fewer drug related adverse effects compared to voriconazole.

• Aspergilloma

  Antifungal therapy not indicated

  If severe hemoptysis, consider bronchial artery embolization or surgical resection

• Chronic cavitary aspergillosis – same as IPA

• Invasive aspergillosis

  First line: voriconazole 6 mg/Kg IV every 12 hr on day 1, then 4 mg/kg IV every 12 hr; oral therapy with 200-300 mg every 12hr

  Alternative:

  Primary: Liposomal AmpB (3-5 mg/kg/day), isavuconazole 200 mg every 8 hrs for 6 doses, then 200 mg daily

  Salvage:

  AmpB lipid complex (5 mg/kg/day IV), Caspofungin (70 mg/day x1, then 50 mg/day IV), micafungin (100-150 mg/day IV), posaconazole (oral suspension 200 mg three times daily, tablet and IV 300 mg twice daily on day 1, then 300 mg daily)

  Surgical resection can be considered in refractory hemoptysis from a focal lesion, lesions eroding into bone, and in patients with lesions contiguous with large vessels or vital organs.

Pneumocystis Pneumonia (PCP)

All immunocompromised patients with PCP should be treated. Though many agents are available trimethoprim-sulfamethoxazole (TMP-SMX) remains the preferred agent. Adjunctive steroids should be given to HIV patients with moderate to severe PCP and hypoxia (A-a gradient >35 or PaO2 on room air <70 mmHg) and has been shown to reduce the risk of respiratory failure and death. Steroids can also be considered in non-HIV patients with moderate to severe PCP.

Primary PCP prophylaxis should be given to HIV patients when CD4 levels fall <200/μL. In non-HIV immunocompromised patients, prophylaxis can be considered when on prednisone doses exceeding 20 mg/day for >1 month, especially if on concurrent cytotoxic or anti-TNF therapy. Patients with prior PCP should receive lifelong secondary prophylaxis until CD4>200/μL for 3 months.

• Treatment Regimens:

  Preferred: TMP/SMX 15-20/75-100 mg/kg/day in divided doses for 3 wks (oral or IV)

  Alternates:

  Primaquine 30 mg/day + Clindamycin 600 mg three times/day for 3 wks (oral)

  Atovaquone 750 mg twice/day for 3 wks (oral)

  Pentamidine 4 mg/kg/day or 600 mg/day for 3 wks (IV or aerosol)

  Adjunctive steroids: Prednisone 40 mg twice daily (5days), 40 mg daily (days 6-11), then 20 mg daily (through day 21)

• Prophylaxis Regimens (all oral options except for pentamidine)

  TMP/SMX 1 DS tablet daily (preferred), 1 SS tablet daily, 1 DS tablet 3 times/week

  Dapsone 50 mg twice daily or 100 mg daily

  Dapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorin 25 mg weekly

  Dapsone 200 mg weekly + pyrimethamine 75 mg weekly + leucovorin 25 mg weekly

  Atovaquone 750 mg twice daily

  Pentamidine 300 mg monthly (rarely used)

What is the prognosis for patients managed in the recommended ways?

The prognosis varies widely depending on the organism, adequacy of treatment, and the ability of the host to restore their immune system. In general the prognosis for the endemic mycoses is favorable while invasive fungal infections such as IPA carry a high mortality especially if the patient remains immunocompromised.

What other considerations exist for patients with fungal infections?

Not applicable.

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