Chapter 242. Fungal Respiratory Infections

Fungi are ubiquitous in our environment and uncommon respiratory pathogens in the immunocompetent host; they usually present with no or mild symptoms that are self-limiting. In an immunocompromised host these infections can be associated with significant morbidity and mortality.Given that most symptomatic fungal infections present with nonspecific findings, early diagnosis requires a high index of suspicion, close attention to a patient’s clinical course, and interpretation of the patient’s findings within the context of host immune status. They are categorized into two groups—those that cause endemic mycoses and those classified as opportunistic pathogens (Table 242-1). Included under endemic mycosis are two fungi, Sporothrix schenckii and Penicillium marneffei, that are not always thought of in this category but that share some similarities with others in this group. Included as an opportunistic pathogen is Pneumocystis jirovecii, an organism previously called Pneumocystic carinii and at one time thought to be protozoa.

Endemic mycoses are geographically clustered1 as shown in Table 242-2. In cases of suspected infection, past history, including travel, is important because the organisms can remain dormant for many years. Outbreaks and clusters of cases of histoplasmosis associated with soil-disrupting activity have been described. Respiratory infections caused by opportunistic fungi generally do not occupy a geographical or ecological niche but are clustered in centers that care for the immunocompromised host. There seems to be an increase in the incidence of these infections, likely related to an increase in number of immunocompromised patients given intensive antineoplastic and immunosuppressive therapy, related improved survival, increased clinical awareness for these infections, and improved diagnostic ability. The incidence of these infections varies among centers because of factors such as differences in immunosuppressive regimens, transplants, and use of antifungal prophylaxis. For example, the incidence of pulmonary zygomycosis has been reported to be increasing in association with the increased use of voriconazole prophylaxis.2-5 Whether this increase is a result of the selective inactivity of voriconazole against zygomyces and hence the related breakthroughs, improved patient survival related to its efficacy against other known pathogens such as Aspergillus species or simply due to increasing susceptibility of the immunocompromised population is unclear.

The period of highest risk for invasive fungal infections varies based on the organ transplanted. Whereas the risk is highest within the first 4 weeks after liver transplant, it is highest several months after lung transplant.6 Hematopoietic stem cell transplant recipients are at highest risk for fungal infections during the first 4 weeks posttransplant when awaiting engraftment. Even postengraftment, the risk for fungal infection is associated with graft-versus-host disease (GVHD) and its management with steroids and other immunosuppressive drugs. Invasive aspergillosis has been increasingly reported in patients with neutropenia, impaired cellular immunity, or GVHD.7,8

Infection is the result of the interplay between host susceptibility, virulence of the pathogen, and inoculum of exposure. Clinical manifestations of infection are in part related to the pathogen and in part the immune system reacting to it. In some sense the organisms causing endemic mycosis are more virulent than those classified as opportunistic pathogens, given their ability to cause disease in the otherwise immunocompetent host.

Deficits in the host defense system that make patients susceptible to fungal respiratory infections can be categorized as (1) neutropenia (as in hematological malignancy, chemotherapy), (2) deficits in cell-mediated immunity (as in AIDS, lymphoma, corticosteroids), (3) deficits in the phagocytic system (as in chronic granulomatous disease), and (4) disruption of the mucosal and cutaneous barriers (as with radiation, chemotherapy, indwelling catheters). The latter allows resident or colonizing fungal flora (specifically Candida species) access into the bloodstream with dissemination and end organ disease (including the lungs). These physical barriers are further compromised by related depletion of mucosa-associated lymphoid tissue (MALT) and reduced antimicrobial peptides secreted by epithelial cells such as lysozymes, phospholipase A2, and defensins.9,10 Inhalation of airborne fungal conidia is the main route of acquiring most other fungal respiratory infections. The phagocytic response of the respiratory tree and alveolar macrophages acts as the first line of defense. The alveolar macrophages, activated by different interleukins secreted by T lymphocytes, play a major role in cell-mediated immunity against fungal pathogens. Conidia that are not contained by phagocytes and start mycelial growth trigger a neutrophil response. If these defense systems are impaired, the conidia germinate into the hyphal form in the sinuses or lung tissue (molds) or into yeastlike cells or spherules (dimorphic endemic mycoses).

Overall, although qualitative and quantitative defects in the phagocytic system, especially neutrophil and macrophages, seem to make patients especially vulnerable to opportunistic fungi and defects in cell-mediated immunity to endemic mycosis, this predisposition is not absolute. For example, CD4-depleted HIV-infected patients are at high risk for developing Pneumocystis jirovecii pneumonia (PCP). This T-cell depletion also predisposes them to disseminated histoplasmosis, which is an AIDS-defining condition.

Early diagnosis of respiratory fungal infections is a challenge in both immunocompetent and immunocompromised patients. The initial clinical findings are nonspecific and are similar to other more common bacterial and viral infections. Critical to an early diagnosis is a clinician’s index of suspicion, which is influenced by recognition of the host’s immune status and vulnerability for fungal infections. Patient location and travel history aids suspicion of endemic mycosis.

Persistent fever in an immunocompromised host while on broad-spectrum antibiotics, with or without skin lesions and clinically apparent pneumonia or sinusitis, is a common presentation of invasive fungal infection as discussed in Chapter 229. Even when not clinically apparent, infection of the sinuses, lungs, and abdominal organs such as the liver and spleen should be looked for using radiological studies such as computed tomography.

Although classic clinical findings of inflammation may sometimes be less pronounced in a profoundly neutropenic host, presence of pain (face or chest pain) in a patient with persistent fever on broad-spectrum antibiotics should raise concern about an underlying fungal infection. Neutropenic patients may not produce sputum, and typical signs of consolidation upon physical examination may not be appreciated.

The more immunocompromised the host is, the higher the urgency of establishing an accurate diagnosis to identify the infectious organism and initiate appropriate therapy. Disseminated fungal infections that can be detected in blood cultures include Candida species, Histoplasma species, Fusarium species, Trichosporon species, and P. marneffei. A biopsy of a suspicious lesion such as a lung nodule, a pneumonic patch, or a sinus aspirate is often the quickest way to establish a diagnosis and confirm the organism.

A thorough skin exam can be very helpful for the diagnosis of deep-seated invasive fungal infections. Skin lesions are often seen in disseminated candidiasis, aspergillosis, and fusariosis and when present are readily accessible to skin biopsy.

In a profoundly neutropenic host suspected of invasive fungal disease, absence of radiological findings in the chest or abdomen does not necessarily mean absence of disease. Findings may become apparent when the patient’s absolute neutrophil count increases and an inflammatory reaction at the involved sites becomes more apparent.

Finally, putting together a differential diagnosis of likely pathogens involves taking into consideration the degree of immunosuppression of the host, constellation of clinical findings, previous history of fungal infections if known, and type of antifungal coverage if the patient is on it at the time of presentation.

Clinical Diagnosis

Sinusitis

None of the endemic mycosis are typically present with sinusitis. Invasive fungal sinusitis in immune-compromised patients is most frequently associated with mold infections. Aspergillus species are the most common fungal pathogen involving the nose and paranasal sinuses. Other emerging fungal pathogens such as Fusarium species,Scedosporium species, and zygomycosis have been increasingly reported; the latter can especially be a problem in a patient with uncontrolled diabetes. Indolent sinus aspergilloma is a localized disease without bone erosion and without predisposing factors of immunodeficiency. Patients present with symptoms of chronic nasal congestion and obstruction or chronic rhinorrhea. On the other hand, aspergillus sinusitis can be an invasive disease with bone erosion. It usually affects immunocompromised patients, being more common in stem cell than solid organ transplant recipients, and most commonly caused by A fumigatus and A flavus. Symptoms and signs include fever, facial pain and tenderness, epistaxis, headache, nasal congestion. and periorbital swelling. Clinical exam of the nares for fungal lesions and a nares fungal culture can help in the diagnosis. Infection is often complicated by hyphal invasion into contiguous structures such as the blood vessels, brain, and orbits, leading to mental status changes, focal neurologic signs, infarction, hemorrhage, or proptosis.

Pulmonary Nodules and Cavities

Pulmonary nodules or cavities may be found on radiological studies in otherwise asymptomatic patients or associated with general systemic symptoms such as persistent fever or findings of pneumonia. A pulmonary nodule detected as a chance radiological finding in an otherwise asymptomatic host may be a presentation of some of the endemic mycosis such as histoplasmosis, a setting in which no treatment is necessary. In contrast, aggressive mold infections in immunocompromised hosts start as a small localized nodule detected only on a chest CT and rapidly progress to more classic findings of pneumonia and related morbidity and mortality if left untreated. In contrast again is an aspergilloma, a solid rounded mass within a pulmonary cavity containing intertwined aspergillus hyphae matted together with fibrin, mucus, and cellular debris. (See Chapter 295.), congenital pulmonary cysts, fibrocystic sarcoidosis, cavitary tuberculosis or histoplasmosis, or fibrotic lung disease. Although an aspergilloma can remain indolent, related complications can include life-threatening hemoptysis if the mass erodes into a bronchial artery.

Pneumonia

Pneumonia can be a presenting finding of fungi typically listed under endemic mycosis as well as those listed under opportunistic pathogens. Patients with pneumonia due to endemic mycosis may have a wide spectrum of presentations ranging from being asymptomatic to typical symptoms of fever, cough, dyspnea, and pleuritic chest pain or prolonged pneumonia refractory to antibiotics or adult respiratory distress syndrome. To a large extent this depends on host immune status and the inoculum of organisms inhaled.

In the immunocompetent patient, the most common clinical presentation of coccidioidomycosis is primary pulmonary disease, which is self-limited acute or subacute community-acquired pneumonia 1 to 3 weeks after infection. Five to 10% of these infections result in residual pulmonary lesions such as nodules or cavities. Other clinical manifestations include chronic progressive pulmonary coccidioidomycosis and pulmonary manifestations of disseminated disease. Acute pulmonary infection by Blastomyces dermatitidis usually presents with mild flulike symptoms that resolve spontaneously. However, most patients diagnosed with blastomycosis present with acute or indolent onset chronic pneumonia that manifests as alveolar infiltrates, mass lesions that mimic malignancy, or fibronodular interstitial infiltrates. Most cases of histoplasmosis are asymptomatic, but clinical presentation can include acute pneumonia, mediastinal granulomatous inflammation and fibrosis, chronic progressive pulmonary cavitary disease, or disseminated disease.

A pulmonary presentation of an endemic mycosis in an immunocompromised host can be related to either a primary infection or reactivation of latent infection. Findings can include acute severe pulmonary infection and adult respiratory distress syndrome with or without dissemination.

All of the opportunistic fungi can present with a pneumonic picture that is clinically apparent or found on chest radiology in an immunocompromised host with persistent fevers. Once a clinician suspects a fungal infection, definitive diagnosis rests on getting a specimen from a biopsy or bronchoalveolar lavage. Hemoptysis is an ominous symptom because it could be related to fungal erosion or invasion into the pulmonary vasculature, causing pulmonary infarction and hemorrhage.

Other Pulmonary Presentations

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction in the respiratory tract to A fumigatus hyphae that become trapped in the thick mucus of patients with asthma or cystic fibrosis. The primary diagnostic criteria are: (1) episodic bronchial obstruction (asthma), (2) peripheral blood eosinophilia, (3) immediate scratch test reactivity to Aspergillus antigen, (4) precipitating antibodies to Aspergillus antigen, (5) elevated serum IgE concentrations, (6) history of pulmonary infiltrates, and central bronchiectasis. Presence of 6 diagnostic criteria makes the diagnosis highly likely, whereas the presence of all 7 criteria makes the diagnosis certain.11 Secondary diagnostic criteria include repeated detection of Aspergillus species in sputum by stain and/or culture, history of expectoration of brown plugs, elevation of specific IgE against Aspergillus antigen, Arthus reaction (late skin reactivity) to prick test with Aspergillus antigen, and characteristic defects on intrabronchial challenge with Aspergillus antigen.

Radiologic Diagnosis

Although the chest x-ray has the advantage of being quick, widely available, and inexpensive and having a low radiation dose, it has a low sensitivity in the early detection of pneumonia in immunocompromised hosts.12-14 In patients with chest symptomatology, a chest x-ray can help with the differential diagnosis. For example, although lobar pneumonia suggests bacterial or fungal pneumonia, a diffuse interstitial pattern may be due to Pneumocystis jirovecii pneumonia, cytomegalovirus pneumonia, pulmonary edema or hemorrhage, or drug or radiation-related toxicity.

Chest computed tomography (CT) scan is more useful for early detection of lung nodules suggestive of invasive fungal infection and for defining the location, type, and extent of pulmonary lesions to facilitate tissue sampling.15-18 In one study, a CT scan was shown to have 87% sensitivity and 88% negative predictive value as a screening method to exclude pneumonia.15 CT scan findings in pulmonary fungal infections can be variable, including diffuse interstitial infiltrates, discrete nodules, halo sign, air-crescent sign, cavitary lesion, and lobar pneumonia (eFig. 242.1).17,19,20 The halo sign is an area of low attenuation surrounding a nodule caused by edema or bleeding surrounding an ischemic area and has been shown to have high specificity (93%) but low sensitivity of 68% for invasive fungal infection. On follow-up CTs, especially with neutrophil count recovery, the more specific air-crescent sign caused by retraction of infected tissue appears.17 Although the halo sign and the air-crescent sign are seen with invasive pulmonary aspergillosis, these signs are not specific for this fungus and can be seen with other molds. CT scan findings commonly precede plain chest radiographic abnormalities.

Differential diagnosis of radiographic changes in the chest of an immunocompromised patient is often broad and, depending on whether it is a lung nodule or pneumonia, includes other nonfungal infectious etiologies such as Nocardia species, tuberculosis, and atypical mycobacteria in addition to noninfectious etiologies including graft-versus-host disease, radiation pneumonitis, drug toxicity, tumor recurrences, and pulmonary hemorrhage.

Laboratory Diagnosis

Microbiologic Testing

Although detectable fungemia occurs with some fungal pathogens such as Candida species, Histoplasma species, Fusarium species, Trichosporon species, and P marneffei, the yield of blood cultures is variable. In an immunosuppressed host, definitive diagnosis is often based on tissue histopathology and/or culture. Obtaining a specimen for these tests requires invasive procedures such as a sinus aspirate, bronchoalveolar lavage (BAL), or lung biopsy. In immunosuppressed patients, the reported diagnostic yield of BAL varies between 30% and 57% but this may improve with the use of fungal polymerase chain reactions and antigen tests such as galactomannan on BAL specimens. A negative BAL result does not exclude fungal infection. Depending on the location of a pulmonary lesion and available expertise, a biopsy can be transbronchial, percutaneous (fine-needle aspiration), or open lung. CT-guided fine-needle aspiration provided a diagnostic result in 62% to 79% of bone marrow transplant patients with suspected pulmonary infection21,22and for peripherally located lung nodules is sometimes the preferred first-line approach.23 Although histopathology (Gomori methenamine-silver [GMS] or periodic acid-Schiff [PAS]) may show characteristic morphology of an organism and narrow the differential diagnosis, a definitive diagnosis requires growth in cultures and subsequent identification. For example, Aspergillus species, Fusarium species, and Pseudallescheria boydii have similar tissue appearance (septate, branching hyphae) and can be differentiated only by culture.

Serologic Testing

Antigen detection assays are useful for the diagnosis of aspergillosis. These include enzyme immunoassay (EIA) for detection of galactomannan and (1→3)-β-d-glucan, fungal membrane polysaccharides (eTable 242.1). These assays have a wide range of the reported sensitivity and specificity due to differences in the selection of the cut-off values and number of positive tests that constitute a true positive, different definitions of invasive aspergillosis, and previous use of mold-active antifungal agent.24-26 These tests have been studied and used as serial assays in a high-risk host and not as a onetime diagnostic test in a patient with a suspected respiratory fungal infection. False-positive results are another limitation of these tests.

In the case of cryptococcosis, a positive serum cryptococcal antigen test has high sensitivity and specificity for the diagnosis of disseminated disease. Similarly, histoplasma antigen can be detected by enzyme immunoassay in the urine in > 90% of patients and in the serum in > 80% of patients with disseminated histoplasmosis, but it has much less sensitivity in localized diseases such as pulmonary or mediastinal disease.

Antibody detection assays play an important role in the diagnosis of endemic mycoses. However, titers are diagnostic weeks after infection and there may be cross-reacting antibodies that make test result interpretation difficult. A negative serologic test during the acute phase of symptoms does not exclude fungal infection, and repeating serologic tests in 3 to 4 weeks to document fourfold increase between the acute and convalescent titers is diagnostic (eTable 243.1). Additionally, the value of antibody detection tests in the diagnosis of endemic mycosis in an immunocompromised patient is limited, given the inability in many cases to mount an antibody response.

Molecular Testing

Molecular diagnostic techniques for fungal pathogens, such as polymerase chain reaction, are still experimental. In one study for invasive pulmonary aspergillosis as compared to galactomannan and β-glucan enzyme immunoassay tests, a fungal polymerase chain reaction (blood) was found to be faster, with better specificity (92%) but variable sensitivity.27

The principal and specific agents used for treatment of fungal diseases are discussed in detail in Chapter 247 and Table 247-1. Early diagnosis and treatment substantially improves the outcome. This is especially important in the severely immunocompromised host, where these infections are often disseminated and associated with significant morbidity and mortality. Exceptions to this rule are certain presentations of histoplasmosis and coccidioidomycosis, especially in an otherwise immunocompetent host, where treatment is felt to have no clear benefit and the natural course of the disease is spontaneous resolution.

Empiric antifungal therapy is considered the standard of care when managing a high risk host. The Infectious Diseases Society of America (IDSA) guidelines recommend adding empiric antifungal therapy in cancer patients with persistent fever and neutropenia and no identified focus of infection after 5 to 7 days of antibiotic therapy.28

Multiple factors influence the choice of the antifungal therapy, including the inherent or acquired resistance of some fungal pathogens to antifungal agents, comorbid conditions, drug interactions, and drug toxicities. Careful attention to dosing and drug interactions potentially influencing drug levels is especially important when treating an immunocompromised host with invasive respiratory fungal infections. Maximally tolerated doses are often given, and when available, drug levels are used to guide therapy.

Combination antifungal therapy is often used in clinical practice, especially in the high-risk host with opportunistic fungal infections such as aspergillosis. Evidence to unequivocally support the merit of such an approach is lacking; until such support is found, it remains an individual patient care and pathogen-specific decision.

Surgical resection is considered for invasive mold disease when efficacy of antifungal agents is in question, there is an opportunity to resect a relatively localized lesion, or close proximity of infection to vital organs such as the eye or vessels threatens their integrity.

In the immunocompromised, immune reconstitution and reversal of underlying predisposing factors maximizes chances of clearing infection and minimizes relapse. The use of colony-stimulating factors or granulocyte transfusions to actively or passively reverse neutropenia have also been investigated. Other immunomodulators such as interleukin or interferon-γ therapy have also been tried.

Further discussion of the treatment agents used for treatment of fungal infections is found in Chapter 247, Table 247-1. Specific fungal infections are discussed in Section 17, Part 6.

Invasive fungal infections in immunocompromised patients have a high morbidity and mortality. Fifty-eight percent to 88% mortality, despite antifungal therapy, has been reported for invasive aspergillosis.36,37 Greater than 80% mortality despite aggressive surgical and medical intervention has been reported with zygomycosis. On the other hand, endemic mycoses have a better prognosis in general. For example, blastomycosis has been reported to have a cure rate between 70% and 95%, depending on the severity of the disease, the immune competence of the patient, and the antifungal agent used.38-43 In general, the crude mortality rate associated with endemic mycosis in inpatients in the United States is estimated to be about 5% in children and 7% in adults.1

For prevention of histoplasmosis, especially in immunocompromised patients, exposure to soil and dust from areas with significant accumulations of bird and bat droppings should be avoided. Immunocompromised patients residing in or traveling to areas endemic for coccidioidomycosis should be counseled to avoid exposure to activities that may aerosolize spores in contaminated soil. No specific control measures are recommended to prevent blastomycosis or paracoccidiomycosis. Prevention efforts to reduce opportunistic respiratory fungal infections are largely focused on minimizing airborne exposure in the susceptible host. For high-risk hosts such as transplant patients, these include use of positive pressure and high-efficiency particulate air (HEPA)–filtered airflow, directed laminar airflow, high rates of room air exchange, and use of barriers between patient care and renovation or other construction areas. High-efficiency masks such as the N95 mask have also been used by high-risk patients when they are outside their hospital rooms.

The incidence of invasive fungal infections and the associated morbidity and mortality in some patient groups such as allogenic stem cell transplant recipients warrant antifungal prophylaxis. Agents such as fluconazole have been used with great success with reduction in rate of susceptible organisms such as many Candida species. Breakthrough fungal infections have been observed with various antifungal prophylaxis strategies. Relative increases in Candida krusei and C glabrata infections were seen with widespread fluconazole use, and there is concern of increasing zygomycosis with voriconazole prophylaxis. Selecting the patient population that deserves prophylaxis and choosing the antifungal agent for this purpose requires ongoing assessment of the risks and benefits of such an intervention and list of targeted fungi.