Fungal Pneumonia Overview of Fungal Pneumonia

Fungal pneumonia is an infectious process in the lungs caused by 1 or more endemic or opportunistic fungi. Fungal infection occurs following the inhalation of spores, after the inhalation of conidia, or by the reactivation of a latent infection. Hematogenous dissemination frequently occurs, especially in an immunocompromised host.

Endemic fungal pathogens (eg, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis) cause infection in healthy hosts and in immunocompromised persons, in defined geographic locations of the Americas and around the world.

Opportunistic fungal organisms (eg, Candida species, Aspergillus species, Mucor species, Cryptococcus neoformans) tend to cause pneumonia in patients with congenital or acquired defects in their host defenses.

The individual prognosis ultimately is linked to the severity and outcome of the underlying disease and to whether the reversal of factors affecting the patient's immune status is possible.

Pulmonary nodules resulting from fungal infection are seen below.

Complications of fungal pneumonia

Complications of fungal pneumonia include (1) disease dissemination to other sites (ie, brain, meninges, skin, liver, spleen, kidneys, adrenals, heart, eyes) and sepsis syndrome and (2) blood vessel invasion, which can lead to pulmonary hemoptysis, infarction, myocardial infarction, cerebral emboli, cerebral infarction, or blindness. (See Effects of Disseminated Fungal Disease and Patient History.)

Other complications may include the following:

• Bronchopleural or tracheoesophageal fistulas
• Chronic pulmonary symptoms
• Mediastinal fibrosis (histoplasmosis)
• Broncholithiasis (histoplasmosis)
• Pericarditis and other rheumatologic symptoms

Treatment of fungal infection

The mainstay of therapy for fungal pneumonias must include antifungal agents. The type of antifungal drug to be used must be tailored based on the particular pathogen that has been isolated or that is clinically suspected. Many classes of antifungal agents are now available, including the classic antibiotics; first-, second-, and third-generation triazoles; and the echinocandins.

Go to Mycoplasma Pneumonia, Bacterial Pneumonia, and Viral Pneumonia for more complete information on these topics.

Workers or farmers with heavy exposure to bird, bat, or rodent droppings or other animal excreta in endemic areas are predisposed to acquire any of the endemic fungal pneumonias.

C immitis, because of its virulence, is also a threat among laboratory personnel working with this fungus.

Conditions that predispose patients to any of the opportunistic fungal pathogens are as follows:

• Acute leukemia or lymphoma during myeloablative chemotherapy
• Bone marrow or peripheral blood stem cell transplantation
• Solid organ transplantation on immunosuppressive treatment
• Prolonged corticosteroid therapy
• Acquired immunodeficiency syndrome
• Prolonged neutropenia from various causes
• Congenital immune deficiency syndromes
• Postsplenectomy state
• Genetic predisposition

With regard to predisposition through stem cell transplants, certain toll-like receptor (TLR) polymorphisms (eg, TLR 4 haplotype S4) in an unrelated stem cell donor can increase the risk of invasive aspergillosis in the transplant recipient.^[1] Similarly, TLR1 and TLR6 polymorphisms in the recipient have been associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation.^[2]

Distribution endemic fungi in the United States

Endemic fungi are prevalent in the Mississippi River Valley and the Ohio River Valley (eg, H capsulatum, B dermatitidis), the southwestern United States, and northwestern Mexico (eg, C immitis).

International distribution and incidence of fungal infection

These fungi have caused several pneumonia outbreaks in Argentina and other areas of Central and South America. P brasiliensis is restricted to Central and South America. African histoplasmosis, which is caused by H capsulatum duboisii, is limited to equatorial Africa between 20° N and 10° S, which includes Gabon, Uganda, and Kenya.

The other opportunistic organisms are ubiquitous, are usually found worldwide, and tend to cause disease in hosts with abnormal immune defenses. For instance, C neoformans can affect people with intact immune systems at a rate of 0.2 cases per million population per year. Prior to the advent of highly active antiretroviral therapy (HAART), approximately 80-90% of patients with acquired immunodeficiency syndrome (AIDS) developed cryptococcosis.^[3]

Morbidity and mortality in fungal infection and pneumonia

The endemic fungal pneumonias are generally self-limited in healthy hosts. C immitis is the most virulent, yet 90% of patients recover without treatment. However, patients with fungal pneumonias may develop chronic pulmonary (eg, cavitation, pleural effusions, bronchopleural fistulas) or extrapulmonary complications. In patients with AIDS, the mortality rate is as high as 70%.

Aspergillosis in patients who are neutropenic (from either leukemia chemotherapy or bone marrow transplantation) has a mortality rate of 50-85%. More often, in the case of aspergillosis and candidal infections or meningoencephalitis in the case of cryptococcosis, the cause of mortality in patients who are immunocompromised is disseminated disease.^[4]

The mortality rate for untreated disseminated histoplasmosis is 80%, but with treatment, the rate is reduced to 25%.

Race-associated characteristics

Although no race predilection is described, C immitis causes more severe disease in patients of African American or Philippine descent.

Sex predilection

Endemic fungal disease affects men (75-95%) more often than women; estrogen-mediated inhibition of mycelium-to-yeast transformation may be responsible for the male predominance. Estrogen seems to have a protective effect against cryptococcal infection. Cryptococcosis has a male-to-female ratio of 2-3:1.

Endemic mycoses with associated dissemination can effect skin (eg, papules, pustules, plaques, ulcers, abscesses, proliferative lesions; may mimic skin cancer as in B dermatitidis infection), bone and joints, and the brain and meninges (meningitis with poor prognosis [10-20%], brain abscess in infection with Aspergillus and Mucor species).

Other effected sites include the following:

• Kidneys
• Liver and spleen (hepatosplenic candidiasis)
• Muscle (Candida species)
• Eye (endophthalmitis; in Candida species infection)
• Nasal passages and sinuses (Aspergillus and Mucor species)
• Bloodstream and bone marrow (septicemia or sepsis syndrome)

History findings in persons with fungal pneumonia may include the following:

• Fever
• Cough, usually nonproductive
• Pleuritic chest pain or dull discomfort
• Dyspnea leading to respiratory failure
• Obstructive symptoms from enlarged mediastinal adenopathy in the endemic mycoses
• Hemoptysis (in invasive aspergillosis or mucormycosis)
• History of travel to or exposure in areas containing endemic mycoses
• Symptoms from involvement of extrapulmonary systems (may suggest disease)
• Rheumatologic syndromes (common among endemic mycoses) - Arthritis and arthralgia, erythema nodosum, erythema multiforme, and pericarditis
• Endemic mycoses with associated dissemination
• Hypersensitivity or allergic reactions
• Extrapulmonary sites in individuals who are immunocompromised
• Meningoencephalitis in patients with AIDS and cryptococcosis

In individuals who are neutropenic or immunocompromised, persistent fever (even before pulmonary findings) may be an early sign of infection, especially if the fever is unresponsive to broad-spectrum antibiotics.

Hypersensitivity or allergic reactions include allergic bronchial asthma (Aspergillus species, Candida species), allergic bronchopulmonary mycoses (Aspergillus species, Candida species), bronchocentric granulomatosis (necrotizing granulomatous replacement and eosinophilic infiltration of bronchial mucosa in infection with Aspergillus species), and extrinsic allergic alveolitis (malt worker's lung, farmer's lung).

Physical examination findings in patients with fungal pneumonia may include the following:

• Temperature elevation
• Tachycardia
• Respiratory distress
• Rales
• Signs of pulmonary consolidation
• Pleural rub

Important possible extrapulmonary findings include the following:

• Meningitis (neck stiffness, headaches, mental status change)
• Skin lesions (pustules, papules, plaques, nodules, ulcers, abscesses, hemorrhagic lesions)
• Rheumatologic and allergic findings

Conditions that can mimic the symptoms of fungal pneumonia include the following:

• Acute respiratory distress syndrome
• Chemical worker's lung
• Chlamydial pneumonias
• Coal worker's pneumoconiosis
• Eosinophilic pneumonia
• Pneumocystis carinii pneumonia
• Aspiration pneumonia
• Bacterial pneumonia
• Viral pneumonia
• Cardiogenic pulmonary edema
• Neurogenic pulmonary edema
• Idiopathic pulmonary fibrosis
• Interstitial pulmonary fibrosis (nonidiopathic)
• Tuberculosis

The total white blood cell (WBC) count may be elevated in normal hosts with endemic mycoses.

Eosinophilia can be observed in the differentials, particularly in persons with coccidioidomycosis.

If the patient presents with neutropenia or leukopenia, the possibility of an opportunistic infection with Candida or Aspergillus organisms is increased.

This study may show fungal hyphae or yeasts. However, the results must correlate with the clinical situation, because saprophytic colonization occurs in the oropharyngeal or respiratory tract of some patients and may not necessarily indicate invasive infection.

Carefully transport, process, and culture specimens that may be contaminated by bacteria, may be saprophytic yeasts endogenous to the oral cavity, and may be airborne Conidia of saprophytic fungi.

Obtain a blood culture to identify Candida species (lysis centrifugation) or B dermatitidis if the patient has disseminated disease.

Obtain a urine fungal culture in men after a prostatic massage, to identify Cryptococcus species.

These provide a more rapid and sensitive test when compared with culture methodology. Various antigen detection assays, such as galactomannan enzyme immunoassay for detection of Aspergillus invasive infections, are now in clinical use. Polymerase chain reaction (PCR)–based assays are also available for detecting various pathogens, including Aspergillus, Histoplasma, and Candida species.^{[5, 6, 7]}

Comparison of these assays (antigen detection using enzyme-linked immunosorbent assay [ELISA] or latex agglutination and molecular detection with PCR) show equal specificities for all 3 assays (≥97%) in the detection of Candida species. PCR-based assays are most sensitive compared with ELISA and latex agglutination (95%, 75%, and 25%, respectively).

For Aspergillus species antigen, galactomannan ELISA assay findings may be positive in the blood very early prior to clinical suspicion of invasive fungal infection and may be of use in monitoring and preemptive treatment in high-risk populations.^{[8, 9, 10]}

Using a galactomannan platelia Aspergillus enzyme immunoassay approved by the US Food and Drug Administration (FDA), investigators showed that 2 consecutive samples with an optical index of 0.5 provided the highest test accuracy (specificity, 97.5%; sensitivity, 92.1%; positive predictive value, 87.5%; negative predictive value, 98.5%).^[11] Testing in bronchoalveolar lavage (BAL) fluid increased the sensitivity compared with serum galactomannan assay from 71-100%.^[12] Care should be taken, however, because false-positive results have been reported in patients taking piperacillin-tazobactam antibiotics and certain intravenous fluids, such as plasmalyte.^[13]

Beta-glucan testing is also available and may be comparable or more sensitive than galactomannan assays in diagnosing invasive aspergillosis; several kits are available worldwide. False-positive results have also been reported in patients receiving fungal-derived antibiotics and cross-reactions have been reported with Pseudomonas aeruginosa infections.^[14]

Aspergillus PCR is most sensitive (100%) when performed on the bronchial lavage fluid of patients with invasive pulmonary aspergillosis, but it is only 40-66% sensitive when performed on the blood. No standardized protocols have been established among laboratories that re performing this assay.^{[14, 6, 4]}

ELISA or latex agglutination is 70-80% sensitive for identifying H capsulatum and C immitis. PCR for H capsulatum from the bronchoalveolar lavage fluid aids in the rapid detection within 24 hours in a patient with AIDS, and this has been confirmed 10 days later based on the growth and culture isolation of the organism from various tissues.

The utility of serology depends on the individual fungal infectious agent. Antibody detection for the identification of C immitis is highly useful, but these tests are of less utility if the pulmonary infection is due to other fungi. Serology testing for blastomycosis provides little clinical diagnostic help because of the insensitivity of testing for this fungus and the antibody cross-reactivity that occurs with other fungal infections.

Patchy infiltrate, nodules (seen in the image below), consolidation, cavitation, or pleural effusion may be observed.

Mediastinal adenopathy is common in patients with endemic fungal pneumonias. The adenopathy may be either unilateral or bilateral.

Miliary infiltration occurs in patients with disseminated disease.

Chest CT scanning

This imaging study plays a role in the early diagnosis of nonspecific infiltrates in patients who are immunocompromised.

High-resolution chest computed tomography (CT) scanning allows observation of the halo sign in patients with aspergillosis. This is a nodular lesion usually surrounded by a ground-glass opacity or halo. As many as 61% of 235 patients with invasive aspergillosis were found to have the halo sign in one study.^[15] Lung lesions from aspergillosis are shown below.

Obtaining a CT scan of the abdomen and brain may reveal sites of dissemination.

MRI of lung lesions

Magnetic resonance imaging (MRI) may reveal the hemorrhagic content of Aspergillus lesions.

Fiberoptic bronchoscopy (procedure of choice) is used to obtain bronchial lavage specimens for staining and culture techniques and transbronchial biopsy specimens for identification of fungal tissue invasion. This procedure reveals positive results in 75-90% of endemic mycoses, shows a 50-90% yield in cryptococcal disease, and shows varying yields in Aspergillus and Candida infections, for which clinical correlation is still important.

Perform transthoracic fine-needle aspiration of nodules to access lesions that are short of an open lung biopsy.

Occasionally, performing an open lung biopsy is the only way to prove invasive disease for Aspergillus or Candida organisms; however, this procedure may be difficult to perform in patients with severe neutropenia and thrombocytopenia who are in respiratory failure.

Perform a lumbar spinal puncture in patients with suspected cryptococcosis or disseminated disease with central nervous system (CNS) symptomatology.

Conduct a bone marrow aspiration and biopsy if the patient has persistent fever or suspected disseminated disease or if the patient has hematologic findings, such as thrombocytopenia or neutropenia.

Biopsy specimens show the following:

• Caseating or necrotizing granulomas with intracellular organisms inside macrophages (eg, H capsulatum, C immitis)
• Fungal hyphae in infection with Aspergillus and Mucor species
• Intracellular yeast organisms in Candida species infections

In persons with endemic mycoses, spontaneous recovery usually occurs without treatment, especially in patients who are mildly affected and immunocompetent without dissemination; otherwise, administer treatment as outlined in the table below.

In cases in which aspergillosis, mucormycosis, and candidiasis occur in an immunocompromised host, reversing the factors affecting the patient's immune status is linked to successful recovery from the infection. Attempt ancillary events that may help to promote recovery from the opportunistic infection. These include (1) ensuring, with the use of growth factors, neutropenia recovery in patients receiving chemotherapy and bone marrow transplants; (2) withdrawing or tapering immunosuppressive drugs and steroids; and (3) removing infected or highly colonized catheters in patients with candidiasis.

Table. Medical and Surgical Fungal Therapy (Open Table in a new window)

Pharmacologic treatment

When treatment is indicated, initiate antifungal agents as appropriate. Amphotericin B is the mainstay of initial therapy in many cases, especially for patients who are acutely ill. More expensive liposomal preparations of amphotericin B offer equal efficacy with less toxicity. In patients with invasive aspergillosis, including pulmonary aspergillosis, voriconazole is the new standard of care, based on its superiority over amphotericin B as primary therapy.^{[17, 18, 19, 4]} Vary the dose and treatment duration depending on the underlying pathogen causing the pneumonia.

Amphotericin B is available in a variety of formulations. Conventional amphotericin B injection contains amphotericin B and sodium deoxycholate as the solvent vehicle.

Amphotericin B cholesteryl sulfate complex (ABCD, Amphotec) consists of a 1:1 molar ratio of amphotericin B to cholesteryl sulfate in a colloidal dispersion, forming a bilayer in microscopic, disk-shaped particles that have a diameter of approximately 115 nm and a thickness of 4 nm.

Amphotericin B lipid complex (ABLC, Abelcet) is composed of amphotericin B and phospholipid complex, with a microscopic, ribbonlike structure having a diameter of approximately 2-11 µm.

Liposomal amphotericin B (L-AmB, AmBisome) contains amphotericin B intercalated in a unilamellar bilayer liposomal membrane; has a liposomal membrane diameter of less than 100 nm; and consists of hydrogenated soy phosphatidylcholine, cholesterol, distearoyl phosphatidylglycerol, and alpha tocopherol.

Some clinicians offer empiric therapy with conventional amphotericin B or liposomal amphotericin B for presumed fungal infections in patients who are febrile and neutropenic (eg, cancer, bone marrow transplantation, solid organ transplantation) and whose febrile state persists after receiving broad-spectrum antibiotics for a few days. Other agents that could be used in this setting are itraconazole and an echinocandin, namely, caspofungin.^[20] The therapy is continued until the neutropenia resolves and the patient does not show a documented fungal infection or radiographic infiltrate.

Prophylactic therapy (suppressive therapy) with amphotericin B is used against recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in individuals infected with the human immunodeficiency virus (HIV) who have received adequate treatment for the infection.

Other formulations, however, are starting to replace amphotericin B because of their ease of use (oral formulations) and lower toxicity for more long-term suppression. Posaconazole is used in the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients receiving hematopoietic stem cell transplants who have graft-versus-host disease and in patients with hematologic malignancies who have chemotherapy-induced neutropenia.^[21]

Other antifungal agents used in the treatment of fungal pneumonia are fluconazole (Diflucan), itraconazole (Sporanox), flucytosine (Ancobon), and ketoconazole (Nizoral). Newer antifungal agents, such as the third-generation triazoles or the echinocandins, are more tolerable than amphotericin B or its liposomal preparations are and may even be more effective in first- or second-line treatment.

Caspofungin is approved for the treatment of invasive Aspergillus infections in patients unresponsive to or unable to receive amphotericin B. Combinations of a triazole with an echinocandin with or without amphotericin B have been anecdotally reported to be effective in some cases of resistant organisms, such as Mucor or Zygomycetes species.^[20]

Echinocandins such as caspofungin, micafungin, and anidulafungin^{[22, 23, 24]} offer a broad spectrum of activity for the many Candida species, including fluconazole-resistant strains. They also show effectiveness in Aspergillus infections alone or in combination with an azole.

Because of the introduction of these safer and (possibly) more potent agents, and owing to the ability to combine them together, the outlook for patients with invasive pulmonary infections, especially immunocompromised hosts, may be improving.

The role of combination therapy has been studied only in small retrospective trials with very unclear results. Combination therapy is usually not indicated in first-line treatment. In rare cases, it might be offered with a great deal of caution as second-line or salvage treatment.^[25]

The establishment of neutrophil recovery or engraftment and the reduction of immunosuppression in certain patients who are at risk for fungal infections are likely to improve the chances of a successful treatment outcome. Granulocyte-macrophage colony-stimulating factor can theoretically augment pulmonary host defenses against A fumigatus infection .

Surgical care

Indications for surgery in invasive aspergillosis are as follows^[26] :

Surgery is indicated in patients with documented invasive aspergillosis who have been treated with antifungal agents but who have residual lesions. The surgery is performed to prevent disease relapse when additional immunosuppression is required.

Surgery is also indicated as a means to prevent or treat massive bleeding, especially when the lung lesion is contiguous with a large blood vessel.

Watch for rapidly progressive respiratory failure in patients who are neutropenic; patients may need ventilatory support. In patients who are severely neutropenic, rapid progression of fungal pneumonia and dissemination of fungal infection (eg, aspergillosis) necessitate a high degree of suspicion, early empiric antifungal therapy, and corrective measures (if possible) to reverse neutropenia or other causes of immunosuppression.

Consider rapidly reducing or withdrawing immunosuppressive therapy (eg, corticosteroids), if feasible.

Correct hyperglycemia and acidosis.

Consider the correction of neutropenia via the administration of growth factors (eg, filgrastim [Neupogen], pegfilgrastim [Neulasta], sargramostim [Leukine]) or leukocyte transfusions.

Offer maintenance therapy to suppress disease reactivation or recurrent disease in patients infected with HIV or in other individuals who are immunocompromised.

Ensure appropriate follow-up care to monitor for possible recurrence.

Patients with ongoing immune deficiencies may require prolonged or lifelong maintenance therapy with triazole agents to prevent recurrences.

A pulmonologist may perform diagnostic procedures (eg, bronchoscopy, lavage).

Interventional radiologists can perform needle aspirations, when necessary, for diagnosis.

Patients who are severely ill and progressively hypoxic may require intensive care, ventilatory support, and pressor support in the ICU under the care of a critical care intensivist.

Rheumatologists can assist with the rheumatologic syndromes manifesting with the endemic mycoses.

Infectious disease consultants may assist with the intricacies of antifungal treatment, especially with respect to the exact drugs, dose, duration, therapy length, maintenance treatment, and even follow-up studies.

Instruct patients to avoid travel to and exposure in endemic areas.

Patients undergoing bone marrow transplantation or any period of prolonged neutropenia are advised to avoid activities (eg, gardening, cleaning, agitating debris) or objects (eg, potted plants, flowers, fresh fruits, vegetables) that may unduly cause exposure to spores of Aspergillus species or other ubiquitous fungi.

For patients undergoing bone marrow transplantation, solid organ transplantation, or antileukemic chemotherapy, use air filtration systems in the treatment units to minimize patient risk of exposure to Aspergillus spores.

Administer prophylactic antifungal therapy (ie, treatment with intranasal or intravenous amphotericin B or its other formulations) in patients at high risk for opportunistic fungal infection, including patients with a history of fungal infection.^[27]

In a study, posaconazole was shown to be superior to fluconazole in reducing invasive aspergillosis incidence (1% vs 5.9%, respectively) in allogeneic hematopoietic stem cell transplant recipients with clinically significant graft-versus-host disease.^[28]

In another trial, conducted using neutropenic patients undergoing chemotherapy for acute leukemia or myelodysplasia, posaconazole again reduced the incidence of invasive aspergillosis to 1%. The incidence in patients in the study who received either fluconazole or itraconazole was 7%.^[29]