Pulmonary Medicine

Fungal Infections (including PCP)

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What every physician needs to know:

Fungal organisms are ubiquitous in the environment; we inhale them almost constantly. In some settings, especially when a patient has impaired clearance and immunity, these organisms can cause invasive pulmonary infection, with the potential for extra-pulmonary spread.

Fungi typically exist as yeasts and molds. Organisms that exhibit a temperature-dependent switch between yeast and mold forms are typically 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 invade to cause bloodstream infection with involvement of other organs, but 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. There are many types of molds, but only a few are the most prevalent cause of pulmonary infection.

The fungi that exhibit a dimorphic switch between yeasts and molds are also typically those that are distributed in endemic geographies. The organisms, pathogenesis, clinical features, and treatment are discussed here.

Pneumocystis carinii (PCP) is also referred to as Pneumocystis jirovecii, as the organism that causes disease in humans has been renamed. It is also now considered a fungal pathogen.

Classification:

The agents of histoplasmosis, blastomycosis, sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, and chromoblastomycosis are caused by fungi that are dimorphic in nature, existing as a yeast in the host and 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.

Histoplasmosis

Histoplasma capsulatum (var. capsulatum), a member of the Ascomycetes family, is a soil inhabitant that is particularly endemic to part of the Ohio and Mississippi River valleys and part of Latin and Central America. Another variety, H. capsulatum var. duboisii, is also present in Africa and causes disease.

Blastomycosis

Blastomyces dermatitidis is another dimorphic fungus that is found in a geography similar to that where histoplasmosis is found but with some extension into southern US states like North Carolina, north-central US states like Wisconsin, and Canadian provinces that border the Great Lakes.

Coccidioidomycosis

Coccidioides immitis and C. posadasii are the dimorphic fungi that cause coccidioidomycosis. These organisms are found endemic to the arid regions in southern California, southern Nevada, Arizona, New Mexico, 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 primary human and veterinary pathogens that cause disease worldwide. They are yeasts, and although previously considered to be one species, they are now considered to be sufficiently different to warrant separate species status.

Filamentous fungal infections: Aspergillosis and Mucormycosis

Filamentous fungi that grow in the environment are a common cause of pulmonary infection, particularly in people who are immunosuppressed because of treatment for a hematological malignancy or receipt of transplantation. These organisms, especially the Aspergillus species, are also implicated in several allergic manifestations, including sinusitis, asthma, and allergic bronchopulmonary aspergillosis (ABPA), but these are not discussed in depth here. Aspergillus fumigatus is by far the most common species to cause invasive pulmonary aspergillosis (IPA), although numerous other species also cause disease.

Pneumocystis Pneumonia (PCP)

The organism that causes PCP in humans is Pneumocystis jirovecii, recently so named to distinguish it from P. carinii, the organism that causes disease in rodents (rats). While Pneumocystis jirovecii were previously thought to be parasites, genetic evaluation has definitively identified them as fungi. The organism is not cultivatable.

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

Histoplasmosis

Acute primary infection

The majority of primary infections are medically unrecognized and are dismissed as flu-like syndromes that self-resolve. In some cases, patients can present with fever, malaise, cough, and chest pain. Indications include concurrent mediastinal and hilar lymphadenopathy, pericarditis, arthralgias, and skin lesions, such as erythema nodosum and erythema multiforme.

Chronic pulmonary histoplasmosis

Nodular lesions can progress, patchy infiltrates that can evolve with dense consolidation can appear, and cavitation can occur (Figure 1). Cavitary lesions are found in people with chronic histoplasmosis, especially in the upper lobes of the lungs. Presentation is variable and is associated with immune response. Cavities can fibrose or expand. Patients who present with chronic pulmonary histoplasmosis typically have fever, weight loss, and cough, and they often have a positive antibody to H. capsulatum (75-95%) and antigenuria (40%).

Figure 1.

Nodular lesion confirmed by biopsy to be H. capsulatum

Progressive disseminated histoplasmosis (PDH)

In some cases, the infection can be characterized by relentless growth of yeasts and uncontrolled pulmonary inflammation, which is especially common in older people and in those who are immunosuppressed (e.g., because of AIDS or organ transplant). Dissemination can occur because of reactivation or re-exposure or after acute exposure, and disseminated disease can be acute, sub-acute, or chronic.

PDH is usually characterized by prominent pulmonary disease with diffuse infiltrates, which can progress to ARDS. Skin lesions, involvement of the CNS and bone marrow, and organomegaly (hepatic and spleen) are particularly common in people with advanced disease.

Blastomycosis

Disease usually presents in a chronic progressive form, with acute pulmonary infection often going unrecognized. Chronic pneumonia can present with weight loss, cough, and lobar alveolar infiltrates or mass-like lesions, with or without cavitation. Unlike histoplasmosis, hilar lymphadenopathy and post-infection calcification of lymph nodes and pleura is unusual. Skin lesions and bone lesions, especially those involving the face, mucosa, and long bones, are relatively common. Blastomycosis is one of the infections that disseminates frequently to the genitourinary tract in men, presenting as prostatitis or epididymal disease. It can also disseminate to the CNS, where it typically presents as ring-enhancing, mass-like lesions.

Coccidioidomycosis

Infection occurs by inhaled arthroconidia, which transform in vivo into spherules, forming focal pulmonary lesions. Infection can propagate either from the fungus' invading vasculature or by transport via infected macrophages that travel into local hilar and mediastinal lymphatics, much like histoplasmosis. Most primary infections are never documented, and the presence of characteristic pulmonary calcifications, nodules, or cavities, often indicates that the patient has been affected previously.

Acute pulmonary infection with Coccidioides spp. is difficult to distinguish from other community-acquired pneumonias, except some people with this infection develop a triad fever, migratory arthralgias, and erythema nodosum, or "desert rheumatism." A fine, transient papular rash and abrupt onset of pleuritic pain can also be indications of potential coccidioidomycosis. An acute and rapid progression of severe pneumonia that can lead to respiratory failure is an uncommon presentation that usually occurs with underlying immunocompromise. Immunocompromised patients and certain ethic groups, especially those of African and Filipino ancestry, have higher risks for extrapulmonary spread, which usually manifests as joint and bone infection, skin lesions, and meningitis.

Cryptococcosis

With as many as a million cases recognized in Africa annually, C. neoformans is a common cause of death in people with advanced AIDS. Although infection originates in the lungs, most cases are not recognized until it disseminates into the CNS with symptoms of meningoencephalitis, and relatively poor overall outcomes result. Disease that is limited to pulmonary infection also occurs, especially in people who are relatively less immunosuppressed, such as those who are post-organ transplantation. In this setting, it is also more common to observe C. neoformans as a cause of extra-pulmonary, non-CNS dissemination to, for instance, the skin and joints (Figure 2), prostate, and eye.

Figure 2.

Cryptococcus neoformans cellulitis of elbow in renal transplant recipient

C. gattii is a related species, but while C. neoformans is found in a ubiquitous distribution, C. gattii has been limited to tropical areas, especially parts of Australia, New Zealand, South America, and Africa. Recently, however, an outbreak has been recognized on Vancouver Island, British Columbia, and areas of endemicity are now recognized in the western U.S. This spread is important, as this species commonly infects people who have relatively "healthy" immune systems, with up to half of cases now recognized in people who have no known immunodeficiency.C. gattii causes both focal pulmonary disease and disease disseminated to the CNS, with outcomes impaired by CNS pressure management and many pressure complications.

Cryptococcal pulmonary disease caused by either of these species can present with varied types of pulmonary infiltrates, but it usually presents with lobar or segmental consolidations or mass-like lesions, commonly referred to as cryptococcomas. Several cases have come to light after biopsy when concern about lung cancer reveals the yeasts by histopathology.

Filamentous fungal infections: Aspergillosis and Mucormycosis

The classic presentation of invasive pulmonary aspergillosis (IPA) is a pulmonary nodule that develops in a neutropenic patient. This lesion can progress to expand in volume and evoke localized inflammation and bleeding, creating a radiographic "halo" before ultimately cavitating, which largely occurs after resolution of neutropenia concurrent with tissue necrosis. However, radiographic presentation can be highly variable, with focal or multifocal alveolar infiltrates the most common finding in non-neutropenic patients, such as post-engraftment stem cell transplant recipients and organ transplant recipients (Figure 3).

Figure 3.

Pulmonary aspergillosis in a BMT recipient

Invasive pulmonary disease that is caused by other organisms, such as agents of mucormycosis, occur with typical patterns and have no clearly pathognomic features. Mucormycosis should be suspected in specific hosts, especially diabetics and people who have received long courses of steroids and/or voriconazole.

These organisms can disseminate hematogenously, usually to the brain or skin, producing ring-enhancing mass-like lesions on MRI (Figure 4) and skin lesions that usually contain some degree of central necrosis.

Figure 4.

Pneumocystis Pneumonia (PCP)

PCP usually presents with an insidious onset of nonproductive cough, shortness of breath, and fever. Signs of cyanosis can be present on exam, and radiographs usually demonstrate bilateral diffuse infiltrates extending from the perihilar region (Figure 5). PCP can cause focal nodular infiltrates that are sometimes even buried in granulomatous inflammation; radiographic presentation, fungal burden, and inflammation appear to differ based on the immune response of the host.

Figure 5.

PCP in a BMT recipient

This organism can also disseminate to extra-pulmonary sites, including the lymph nodes, spleen, liver, bone marrow, eyes, thyroid, and adrenal glands.

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

Not applicable.

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

Histoplasmosis

After infecting propagules of the organism are inhaled, they convert to the yeast form, which is phagocytosed by macrophages, where the yeast can remain dormant. Infection in the lungs and elsewhere in the body is characterized by the production of chronic granulomatous inflammation that develops after the organism is processed in the lungs and drained through hilar lymph nodes and the reticuloendothelial system, much like M. tuberculosis. As such, people who resolve acute pulmonary infection (the majority), typically demonstrate signs of pleural, lymph node, hepatic and splenic calcifications, much like TB. Disease may occur acutely, especially in immunosuppressed people, but most cases involve reactivation of latent infection.

Pneumocystis Pneumonia (PCP)

Pneumocystis inhaled into the respiratory tract attaches to alveolar epithelial cells, which promotes persistence and possibly replication. Most clinicians now agree that humans become infected at a young age, and disease is usually the result of reactivation of latent infection. However, reports of PCP transmitted from person to person have increased recently, and outbreaks--or "epidemic" PCP--are known to occur.

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

Not applicable.

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

Histoplasmosis

Acute primary infection

Acute infection is difficult to diagnose and does not usually require antifungal therapy. In the absence of disseminated disease, antibody levels will be variably positive (25-85%), and antigen levels will usually be undetectable in serum and in urine. Subsequent development of calcifications in this distribution is suggestive of acute pulmonary histoplasmosis, but disease is usually self-limited.

Chronic pulmonary histoplasmosis

Patients with chronic pulmonary histoplasmosis often have a positive antibody to H. capsulatum (75-95%) and antigenuria (40%).

Progressive disseminated histoplasmosis (PDH)

Diagnosis relies on cultivation of the fungus from tissues, direct visualization on histopathology, and detection of antigens and/or antibodies from serum.

Blastomycosis

Diagnosis relies on direct cultivation of the organism, visualization of the "broad-based" budding yeast on histopathology, and detection of fungal antigens in the blood or urine. The antigen can also be detected in other fluids, such as bronchoalveolar lavage. Serologic tests are available to measure antibody levels, but the utility of these tests is variable, as there is a good deal of false negativity and false positivity.

Coccidioidomycosis

Diagnosis of coccidioidomycosis relies on direct visualization of spherules in tissues, cultivation of the organism, and detection of antibodies in serum or other infected fluids. Antigen tests are commercially available, but they exhibit some cross-reactivity with antigens of other endemic fungi.

Cryptococcosis

While histopathology and/or cultivation provide a definitive diagnosis of cryptococcosis, antigen tests are increasingly used as accurate and relatively sensitive indicators of pulmonary and CNS disease. These widely available tests detect the presence of a polysaccharide antigen that is contained on and secreted from the yeasts' capsule. Although there may be pulmonary disease without a positive antigen, this test is useful and should be obtained when a mass-like or focal alveolar infiltrate is suggestive of a cryptococcoma.

A positive antigen does not distinguish between species, as both C. neoformans and C. gattii can be detected with available commercial assays. Similarly, most laboratories do not distinguish between species even with culture, and they automatically report " C. neoformans," even though easy assays that rely on growth on chromogenic media are now used in large laboratories in C. gattii-endemic regions. Clinicians should keep in mind that disease caused by C. gattii is currently under-reported because of these laboratory standards.

Filamentous fungal infections: Aspergillosis and Mucormycosis

Establishing a diagnosis requires histopathology or cultivation of these organisms from sterile tissue. That said, most diagnoses are made by culturing the implicated organism from lavage fluid obtained for evaluation of pulmonary infiltrates in at-risk hosts. However, these organisms are difficult to culture, as sensitivity is only 50 percent at best, so a negative culture does not rule out any filamentous fungal infection.

Use of antigen assays, especially the galactomannan enzyme immunoassay, assists diagnosis greatly. This antigen can be detected in both serum and in lavage fluid, and when it is present in the appropriate context, it can be highly predictive of disease. Studies have shown that the GM EIA increases sensitivity beyond culture by about 30 percent when it is applied to BAL fluid; this approach should be taken routinely in settings in which culture is set up for Aspergillus species or when the disease is being considered.

Twice-weekly screening of serum assays for galactomannan assist in early detection of disease in high-risk hosts, although these preventative strategies have not been tested in large studies. Multiple factors can lead to false-negative results (e.g., antifungal therapy) and false-positive results, so findings should be interpreted in context. Other antigen assays that detect glucan in serum have been used more widely for other fungal infections, such as candidiasis (and PCP, below), but there is an indication that these assays may also assist in the diagnosis of IPA.

Pneumocystis Pneumonia (PCP)

Establishing a definitive diagnosis of PCP requires histopathologic demonstration of the organism using fungal stains like Gomori methenamine silver, Wright-Giemsa, or monoclonal antibodies more specific to Pneumocystis. The organism cannot be grown in culture, but tissue and soluble antigens can be detected using several commercial products. Some laboratories also use molecular testing with PCR. The sensitivity of detection of the organism using BAL is better than that of induced sputum, and sensitivity differs based on the host, with sensitivity highest in people with AIDS-related PCP. A negative BAL antigen assay does not rule out disease, especially in hosts with underlying conditions.

Blood-based assays that detect antigens present on Pneumocystisspp. are being evaluated, with recent studies showing optimism for use of serum beta-glucan levels as a predictor of PCP.

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

Not applicable.

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

Not applicable.

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

Cryptococcosis

People with documented cryptococcal infection in the lungs should be assessed for CNS infection even in the absence of clear meningeal symptoms. While there are some people in whom LP may be deferred, most people should have a CT scan followed by LP to determine whether there is any CNS disease, as it frequently requires aggressive pressure management.

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

Not applicable.

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

Histoplasmosis

Acute primary infection

Treatment should be considered in the setting of severe disease and when timely symptom resolution is lacking; itraconazole 200 mg oral three times daily or administration of the better-absorbed liquid solution is usually sufficient. Severe disease may warrant treatment with an amphotericin B formulation.

Chronic pulmonary histoplasmosis

Antifungal therapy is indicated in symptomatic patients. Itraconazole (dosed to achieve adequate levels in capsular or liquid oral form) and amphotericin B formulations (3-5 mg/kg/day equivalents) are both acceptable, with the latter reserved for people with particularly severe disease. Duration of therapy, which is typically long and variable (12 weeks to 24 months), depends on the extent of disease and the immune response.

Progressive disseminated histoplasmosis (PDH)

Treatment of acute PDH should include an amphotericin B formulation followed by itraconazole after stabilization. Some people with mild symptoms and a more chronic presentation can be treated successfully with the azole drug up front. Duration of therapy is long and can be life-long, as people who are particularly immunosuppressed have a high recurrence rate without resolution of their immune risk.

Blastomycosis

Itraconazole has been the mainstay therapy for blastomycosis, with outcomes probably better than those with fluconazole. Those with severe disease may warrant therapy with amphotericin B formulations instead, especially in the setting of CNS dissemination or relapse despite azole therapy. New azole drugs, such as voriconazole and posaconazole, have excellent in vitro activity but have not been widely tested or used clinically.

Coccidioidomycosis

The decision to treat with antifungal therapy is based on the risk of dissemination (for instance, in the presence of immunocompromised state and pregnancy) and in the setting of severe pneumonia and/or high risks for pneumonic complications (fibrosis, cavitation). Both amphotericin B formulations and a wide array of azole antifungals are active, and the decision to use these agents should be based on the severity of disease and other variables, such as tolerability.

Pregnant women should receive amphotericin. People who have severe pulmonary infection benefit and have more rapid resolution from early treatment with amphotericin B. Given its tolerability and efficacy, high-dose fluconazole (400 mg/day) is usually appropriate for most other infections and maintenance therapy, including CNS infection.

Cryptococcosis

Severe pulmonary disease and disease documented to involve the CNS should be treated with lipid amphotericin B formulations provided in relatively high doses that at least exceed 3 mg/kg/day (and preferably start with 5 mg/kg/day). Data generated from randomized trials performed in people with AIDS demonstrated some improved outcomes in people in whom 5-FC was administered during the first two weeks of therapy.

Azole antifungals can be effective, and the preferred agent is fluconazole because of its good CNS penetration and ease of administration in high doses. Higher doses can be provided for early "consolidation" phases (400 mg to 800 mg), with suppressive management including lower doses (200 mg). Infection, especially that involving the CNS, should be treated for an extended period (months, depending on resolution of immune suppression).

Fluconazole may be used as monotherapy in some cases, and it is listed in guidelines as an alternative for treatment of isolated pulmonary infection in people with no defined immune suppression. However, there has been a good deal of failure in this approach, especially in people who have pulmonary infection caused by C. gattii, so amphotericin B -based induction therapy is still recommended for this infection, even in cases of isolated pulmonary disease. Studies show that some subtypes of C. gattii, including the strain in the Pacific Northwest outbreak, may exhibit a degree of fluconazole "resistance," which might explain clinical failure.

An integral component of effective management is control of inflammatory reactions, especially those that involve the CNS. Serial lumbar puncture for drainage is needed in all cases of cryptococcal meningitis that demonstrate high opening pressures. Some people who have severe disease go on to require longer-term manipulations, such as shunt placement. We have administered corticosteroids to control CNS inflammation, especially in the setting of CNS disease caused by C. gattii in immunologically competent people. Immune-reconstitution syndrome (IRIS) occurs with this infection, so it may be wise to back off pharmacologic immunosuppressants gradually.

Filamentous fungal infections: Aspergillosis and Mucormycosis

Identification of the microbial cause of pulmonary infiltrates has become critically important, as antifungals used today have differential activity toward Aspergillus species and agents of Mucormycosis. Specifically, voriconazole is currently considered a standard therapy for IPA, based on results of a randomized trial in which survival rate improved compared to conventional amphotericin B. Alternatively, lipid formulations of amphotericin B are preferred for mucormycosis, with voriconazole having no activity. Lipid formulations of amphotericin B are also acceptable alternatives for treatment of IPA, with studies demonstrating relatively equivalent outcomes, but no comparative data are available.

The Infectious Diseases Society of America recommends voriconazole over lipid formulations of amphotericin B for primary treatment of IPA based on existing data. Echinocandins, although evaluated for salvage therapy of IPA, may have some activity, but they generally do not kill the organisms and have not been studied as primary treatment options. Combination therapy regimens that include echinocandins appear to result in good outcomes; one randomized trial has recently completed enrollment, with results available soon.

A trick in administering voriconazole effectively in this setting is to provide enough of the drug to achieve adequate levels, an issue that is especially relevant in people who are receiving oral voriconazole. Some laboratories are making assays available to measure voriconazole levels; it is good practice to confirm a trough serum level greater than 2.0 ug/mL, especially in people who are receiving oral drug.

Adjunctive therapy with surgical resection is usually not needed for IPA, although such therapy may be wise in people with uncontrolled hemoptysis, encroachment on large vessels, or large lesions that contain abundant necrosis. However, infections that are caused by agents of mucormycosis should be evaluated closely for surgical resection, as these organisms tend to cause much more focally invasive disease and can grow readily in necrosis.

Several studies have evaluated the potential utility of combination therapies for mucormycosis using agents that include echinocandins or iron chelators that exhibit direct antifungal activity. The combined use of echinocandins is a relatively safe adjunct. Posaconazole is an azole drug that has good in vitro activity against these organisms, and it has been used for primary and "salvage" therapy of sinus and pulmonary disease. It provides a good option for maintenance therapy in people with prolonged immunosuppression.

Pneumocystis Pneumonia (PCP)

Although they are fungi, these organisms are not treated with antifungals. Trimethroprim-sulfamethoxazole (TMP-SMX) is the drug of choice for the treatment and prevention of PCP. The drug is dosed orally or via IV to achieve 15-20 mg/kg/day TMP and 75-100 mg/kg/day SMX, divided into 3-4 doses daily. In the setting of severe disease, IV drug should be given for at least three weeks, followed by continued oral maintenance.

The combination of primaquine and clindamycin is an alternative to TMP-SMX when the drug is not tolerated or is otherwise contraindicated. This combination is the one used most frequently and is the preferred alternative regimen in the setting of established disease. Although atovaquone is another alternative, it has been shown to be less effective than TMP-SMX and is roughly equivalent to pentamidine as a third-line therapy.

Although resistance to TMP-SMX has been demonstrated, the significance of this resistance is unclear.

An important adjunct to antimicrobial therapy is corticosteroid administration, which is provided largely to minimize development of pneumonitis and progressive hypoxia. Studies have been done in the HIV-infected population that support its administration in the first seventy-two hours when O2 pressure is less than 70 mm HG or when it has high gradients. It is not clear that steroids help treatment of disease in non-HIV infected patients in whom corticosteroid administration frequently presents as the primary risk for disease. As hypoxia can worsen rapidly, sometimes with an IRIS-like progression, immunosuppression should not be withdrawn abruptly.

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

Not applicable.

What other considerations exist for patients with fungal infections?

Not applicable.

What’s the evidence?

Limper, AH, Knox, KS, Sarosi, GA, Ampel, NM, Bennett, JE, Catanzaro, A. "An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients.". Am J Respir Crit Care Med. vol. 183. 2011. pp. 96-128.

This is a comprehensive review of fungal infections, produced by the ATS.

Guo, YL, Chen, YQ, Wang, K, Qin, SM, Wu, C, Kong, JL. "Accuracy of BAL galactomannan in diagnosing invasive aspergillosis: a bivariate meta-analysis and systematic review". Chest. vol. 138. 2010. pp. 817-24.

Galactomannan testing on BAL has been shown to be useful addition to culture when Aspergillus species are suspected of causing disease; this meta-analysis reviews multiple studies.

Vergidis, P, Walker, RC, Kaul, DR, Kauffman, CA, Freifeld, AG, Slagle, DC. "False-positive Aspergillus galactomannan assay in solid organ transplant recipients with histoplasmosis". Transpl Infect Dis. vol. 1399. Sept. 26, 2011. pp. 3062.

This simple report illustrates the complexity of interpreting antigen assays.

Gupta, AO, Singh, N. "Immune reconstitution syndrome and fungal infections". Curr Opin Infect Dis. vol. 24. 2011. pp. 527-33.

A thoughtful review of the controversial clinical manifestation of IRIS.

Knox, KS, Hage, CA. "Histoplasmosis". Proc Am Thorac Soc. vol. 7. 2010. pp. 169-72.

A well-developed review.

Smith, JA, Kauffman, CA. "Blastomycosis". Proc Am Thorac Soc. vol. 7. 2010. pp. 173-80.

A well-developed review.

Perfect, JR, Dismukes, WE, Dromer, F, Goldman, DL, Graybill, JR, Hamill, RJ. "Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America.". Clin Infect Dis. vol. 50. 2010. pp. 291-322.

These practice guidelines summarize relevant therapeutic issues.

Harris, JR, Lockhart, SR, Debess, E, Marsden-Haug, N, Goldoft, M, Wohrle, R. "Cryptococcus gattii in the U.S.: clinical aspects of infection with an emerging pathogen.". Clin Infect Dis. vol. 53. 2011. pp. 1188-95.

Our understanding of the manifestations and treatment of C. gattii disease is evolving; this CDC-produced summary illustrates some of the most current findings.

Huang, L, Cattamanchi, A, Davis, JL, den Boon, S, Kovacs, J, Meshnick, S. "International HIV-associated Opportunistic Pneumonias (IHOP) Study; Lung HIV Study. HIV-associated Pneumocystis pneumonia". Proc Am Thorac Soc. vol. 8. 2011. pp. 294-300.

A comprehensive review of pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP.

Sax, PE, Komarow, L, Finkelman, MA, Grant, PM, Andersen, J, Scully, E. "AIDS Clinical Trials Group Study A5164 Team. Blood (1->3)-beta-D-glucan as a diagnostic tests for HIV-related Pneumocystis jirovecii pneumonia". Clin Infect Dis. vol. 53. 2011. pp. 197-202.

One of the best studies on the utility of beta-glucan as an adjunct to diagnose PCP in HIV-infected patients.
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