103: Surgical Treatment of Thoracic Fungal Infections

Thoracic fungal infections have a complex and variable presentation, ranging from benign self-limited processes, which spontaneously resolve, to severe life-threatening infections associated with disabling morbidity and high mortality. Persistent fungal infections in normal individuals may either resolve without producing symptoms, or worsen leading to severe complications of hemoptysis, mediastinal fibrosis, empyema, and meningitis. Immune-compromised hosts demonstrate greater susceptibility to fungi than normal individuals and have more severe outcomes including vascular invasion, septicemia with fungal dissemination, organ infarction, and death. Adding to this complexity, the epidemiology of fungal disease is constantly changing as species emerge or relocate or increase in virulence. Early intervention can improve survival and in some cases obviate the necessity of surgery. It is critical therefore to recognize the clinical manifestations of thoracic fungal infection early in its clinical course. Fortunately, recent advances in knowledge concerning fungal biology including the functional genome, the structure of the cell wall and membrane, and the use of molecular and epidemiologic techniques have led to rapid identification of pathogens and the institution of effective, less toxic antifungal agents.¹

Fungi that are implicated in pulmonary pathology consist primarily of dimorphic organisms. They begin as airborne spores and later convert to yeast forms after entering the pulmonary system. The lung is a common portal of entry and represents the primary portal and site of infection in both immune-competent and immune-suppressed individuals. Opportunistic hospital-acquired infections generally arise in ICU patients with indwelling vascular or catheter instrumentation or following solid organ or hematopoietic stem cell transplantation.² Occasionally, infection may occur by nonpulmonary portals such as cutaneous inoculation, for example, sporotrichosis. Human-to-human transmission is extremely rare and primarily occurs in the organ transplant population.

Opportunistic fungal organisms may also persist in a chronic latent state, allowing possible future activation and infection if there is compromise of the immune system. As humans are often colonized with fungal organisms, the distinction between colonization and infection may be diagnostically challenging, and outcomes from fungal infection may vary depending on the degree and extent of fungal invasion based on a balance of factors between the host and organism.

The presence of endemic fungal infection in at-risk individuals may initially be suspected by a history of travel to niche areas of fungal prevalence (Fig. 103-1).³ However, with current global travel opportunities, latent fungal reactivation can occur following distant past travel which may require extensive individual interrogation as to possible fungal exposure from prevalent areas. It is also important to remain vigilant as fungal infections can resemble or coexist with malignant disease.

The epidemiology of thoracic fungal infections is constantly changing. The pace of this change has accelerated in recent decades, and four factors have been identified to account for this rapid change: an increasingly mobile world population, the aging population in Western countries, climatic environmental changes, and increased immune suppression for organ transplantation. The recognition and treatment of fungal infection is also dependent on microbiologic reclassification patterns. Actinomycosis and nocardia, for example, are no longer classified as fungal infections, since the source of infection recently has been identified as bacterial.⁴ Emerging and opportunistic infections undergo epidemiologic changes associated with climactic changes which alter current endemic fungal niches allowing for the emergence of new pathogens. In addition, alterations in immune pharmacologic management with new biologic immunosuppressant agents (e.g., TNF-alpha inhibitors), potent transplant rejection drugs, or chronic steroid use for chronic pulmonary conditions influence host predisposition for fungal infections.⁴

Thoracic fungal infections are categorized by host factors (immune competence and host defenses) or by invading organisms which are based on geography and virulence factors. Host defense categories include the following subpopulations: immune-competent or immune-deficient individuals with or without defective pulmonary defenses. Fungal invasion factors involve endemic versus opportunistic fungal organisms. Opportunistic fungi serve as common pathogens primarily for immune-suppressed individuals who also remain susceptible to endemic fungi. These individuals are additionally at risk of infection by saprophytic fungi (i.e., fungi that grow on dead organic matter) and emerging (mostly opportunistic) fungi.

Individuals presenting with clinical disease due to fungal infection are categorized by their immune status: immune-competent versus immune-suppressed. The latter group is comprised of transplant recipients, patients receiving biologic immunosuppressive agents, and patients with malignant and/or hematologic conditions or acute debilitating injuries which suppress the individual's immune state. Most fungal infections that afflict immune-suppressed hospitalized patients occur in the ICU setting or in the immediate post-transplant recipient. Therefore, early determination of the patient's immune status will help to establish the individual's exposure risk for well-defined geographically prevalent areas of fungal infection (see Fig. 103-1).³

Radiography has an important role in diagnosing fungal disease since the radiographic abnormalities observed with fungal infection overlap with the radiographic signs of thoracic malignancy. For example, both entities may exhibit signs of patchy parenchymal infiltrates, pulmonary nodules, consolidation, cavitation, and pleural effusion. In addition, patients with endemic fungal disease may have unilateral or bilateral mediastinal adenopathy. The presence of a halo or a reversed halo sign on a lung CT, often seen in thoracic malignancy, is also a common sign of mucormycosis and may suggest fungal parenchymal disease (Fig. 103-2). Chest CT along with a heightened index of clinical suspicion has a prominent role in the diagnosis and separation of fungal infections. Marom and Kontoyiannis⁵ demonstrated a survival advantage when early CT was performed in immune-compromised patients with neutropenic fever.

A fungal infection may also be multicentric, having the appearance of a metastatic process. For example, a case of disseminated aspergillosis, shown in Figure 103-3, was initially mistaken for a metastatic cancer. An incidental pulmonary nodule arising in a patient who resides in or has recently traveled to a niche area of endemic fungal infection needs to be differentiated from a solitary pulmonary malignant nodule as shown in Figure 103-4.

Special consideration for rapid diagnosis of fungal infections is given to immune-suppressed individuals who are predisposed to opportunistic infection. Moreover, there are clear differences in disease severity and survival between groups of transplant recipients, for example, solid organ transplant recipients (SOT) versus hematologic stem cell transplant (HSCT) recipients, with the latter exhibiting greater susceptibility and mortality to fungal infections.⁶ Subgroup differences also may be found within these subpopulations.

Although surgical therapy for fungal lung disease is uncommon, given the development of effective antimicrobial agents, the thoracic surgeon may be called upon to perform diagnostic lung biopsies, and occasionally for the primary treatment of complications of fungal infections (see Table 103-1).⁷

The endemic fungal infections that affect immune-competent individuals in areas of geographic fungal prevalence are histoplasmosis, coccidioidomycosis (Fig. 103-4), blastomycosis (Fig. 103-5), paracoccidioidomycosis (previously identified as South American blastomycosis), and penicilliosis. Sporotrichosis is found chiefly in tropical and subtropical areas. Immune-suppressed individuals in endemic areas may be more susceptible to endemic fungal infections, which if acquired are more virulent with higher mortality in this at-risk population. Immune-competent individuals generally experience subclinical disease and often are able to deal with these organisms independent of antifungal therapy. One exception is the organism, Cryptococcus gattii, which has recently emerged in the Pacific Northwest. This pathogen can cause severe pulmonary and central nervous system infection even in individuals with normal immune systems.^3,8,9

Histoplasmosis

The most common endemic fungal infection worldwide, histoplasmosis, may be caused by one of the two organisms: Histoplasma capsulatum or Histoplasma duboisii. The H. capsulatum variety has a worldwide distribution. In the United States it is found primarily in the Ohio and Mississippi Valley regions. The H. duboisii variety coexists with H. capsulatum in central and Western sub-Sahara and has a special tropism for cutaneous and skeletal structure but lacks the ability for thoracic diseases associated with H. capsulatum. Histoplasmosis is primarily a soil dweller and arises from bird and bat droppings. Inhalation of the microconidia from this fungus is a classic model for endemic fungal dissemination and infection within the pulmonary system. The clinical presentation and disease severity following fungal inoculum exposure is entirely dependent on the balance between the number of inhaled organisms and the immune status of the individual.

Inhalation of spores of this fungus into the lower respiratory tract leads to phagocytosis by alveolar macrophages with internal macrophage conversion of the organism to yeast forms and subsequent spread throughout the reticuloendothelial system. Dendritic airway cells limit disease progression by both ingesting and killing yeast organisms and then presenting histoplasma antigens to stimulate naïve T lymphocytes which activate macrophages to destroy intracellular yeast infections. This orchestrated response occurs 2 to 3 weeks following histoplasma inoculation, and in the majority of patients will limit the disease process. Less than 1% of immune-competent patients may develop the following complications: Pericarditis, granulomatous mediastinitis, histoplasmoma, broncholithiasis, and mediastinal fibrosis. Chronic cavitary disease may occur in older patients with COPD. This condition is both progressive and life threatening without treatment.³

Immune-suppressed individuals who are exposed to histoplasmosis generally present with acute, severe pneumonia which manifests with the radiographic appearance of diffuse pulmonary infiltrates and hilar lymphadenopathy. If the immune response is inadequate to deal with the organisms, further progressive dissemination may lead to organ failure and death.

Diagnostic tests for histoplasmosis include culture testing (may be too slow for fungus recovery), antibody assays in immune-competent individuals, and urine antigen testing. Treatment includes antifungal therapy for both acute and progressive disease states (i.e., acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis, progressive disseminated histoplasmosis, and mediastinal lymphadenitis). Routine antifungal therapy in the absence of steroid therapy is not recommended for delayed complications, such as pulmonary nodules, mediastinal granuloma, mediastinal fibrosis, broncholithiasis, and inflammatory syndromes (i.e., pericarditis, arthritis, and erythema nodosum). Surgery is rarely required other than for differentiation of malignancy from histoplasmoma and to deal with complications from broncholithiasis or cavitary disease.^3,10 Mediastinal disease with recurrent pericardial effusions or vascular fibrosis rarely requires surgical treatment.⁷

Coccidioidomycosis

The coccidioidomycosis (see Fig. 103-4) organism occupies a geographic area within the southwest of the United States and Northwestern Mexico. Sixty percent of infected patients are asymptomatic with subclinical disease that is detectable only by a cellular reaction to coccidioidal antigen.¹¹ The remaining 40% of patients primarily demonstrate three varieties of pulmonary clinical syndromes (described below) other than the disseminated form of the disease which is more likely to occur in immune-compromised individuals, Filipinos, and African Americans.^3,12

The pulmonary disease states due to this organism consist of two syndromes. The first is acute pulmonary coccidioidomycosis with lung infiltrates or consolidation, hilar adenopathy, and possibly pleural effusion. The extent of disease from coccidioidomycosis, much like histoplasmosis, is dependent upon the balance between the numbers of invading organisms and the immune status of the individual. The second is the chronic form of pulmonary coccidioidomycosis, which affects less than 5% of patients. These patients may experience pulmonary nodules or cavities or a chronic progressive pneumonia which may be associated with either diabetes mellitus or preexisting pulmonary fibrosis. This entity, like the above clinical states, may resemble tuberculosis both radiographically and clinically.

Diagnostic tests for coccidioidomycosis include culture testing, antibody serology testing for immune-competent individuals, and antigen testing. Treatment for chronic fibro-cavitary medically refractory disease or pleural space infection may include surgical resection which may also be performed for the diagnosis of nodular disease.⁷ Prophylaxis for immune-suppressed individuals is controversial, but transplant candidates and recipients visiting or living in endemic areas may benefit from targeted prophylactic therapy.^3,12

Blastomycosis

Similar to coccidioidomycosis, blastomycosis (see Fig. 103-5) is clinically silent in greater than 50% of individuals. Symptomatic patients often present late after exposure (30–45 days).¹³ Acute pulmonary involvement in immune-competent individuals resembles bacterial pneumonia with lobar consolidation. The disease is often identified in the chronic phase with lung masses, cavities, or infiltrates which may be accompanied by cutaneous and subcutaneous lesions.^3,13 Immune-suppressed individuals, who may acquire this infection either from new acquisition or reactivation, suffer disease consequences with greater severity and higher mortality.^3,13

Culture results may be delayed for 4 to 6 weeks following testing which may complicate treatment in severe disease states that require immediate treatment.^3,13 Treatment guidelines for all individuals recommend antifungal therapy to prevent extrapulmonary dissemination.¹⁴ Surgical involvement is for nodular disease identification or pleural space infections.⁷

Paracoccidioidomycosis

This organism has a Latin American geographic distribution, although Brazil is primarily affected, and the organism Paracoccidioides brasiliensis includes at least three species distinguished by nationally based infection which occurs primarily in agricultural workers. Chronic disease leads to systemic symptoms of a febrile illness with bilateral infiltrates leading to fibrotic lung disease.³ As with blastomycoses, positive culture returns may be delayed and the diagnosis may depend on serologic tests. Immune-suppressed individuals may experience more severe forms of the disease and have increased risk because of diagnostic delays due to slow culture growth of this organism. Surgical therapy is rare other than differentiation from malignancy and for reconstructive therapy for chronic disease.⁷

Penicilliosis

Penicillium marneffei is an emerging opportunistic endemic mycosis located primarily in tropical Asia. Immune-competent individuals may suffer subclinical infection. HIV patients with low CD4 counts are more commonly affected in comparison with other immune-suppressed individuals. Chronic disease manifests with diffuse pulmonary infiltrates and generalized lymphadenopathy and cutaneous lesions. Without treatment it is progressive and fatal.³

Sporotrichosis

Infection with Sporothrix schenckii occurs in tropical and temperate zones worldwide, but unlike the other endemic mycoses, the infection occurs by a cutaneous route through contact with the organism in the soil and in moss. Exposure by this route leads to cutaneous or lymphatic disease with later progression to the lungs and systemic dissemination. Significant spore aeration can result in disseminated pulmonary disease leading to cavitary fibrotic lung disease or hilar or mediastinal adenopathy for which surgery may be required.⁷ Culture results for Sporotrichosis are returned reasonably rapidly and serology testing is helpful for diagnosis.¹⁵

There are three main groups of important molds in this category: Zygomycosis, Hyaline septated molds, and dematiaceous molds.

Zygomycosis

This term zygomycosis (used interchangeably with mucormycosis) (Fig. 103-6) includes saprophytic molds that occur in a worldwide distribution in decaying plants and animals. Mucorales infection occurs by spore inhalation and the disease is progressive in individuals with diabetes, hematologic malignancy with transplantation, solid organ transplantation, treatment of iron overload states, AIDS, and immune-compromised patients using voraconazole or posaconazole, a new class of drugs with broad antifungal activity.¹

The most common species associated with angio-invasion are organisms of the rhizopus species which infect the sinuses, brain, lung, GI tract, and kidneys. This is a lethal infection that may lead to massive and fatal hemoptysis from pulmonary vessel invasion.¹⁶ Surgical treatment for this highly aggressive organism may include extensive debridement and resection of involved tissues.⁷

Hyalohyphomycosis

The most common form of disease from molds in this group include Fusariosis and Scedosporium infections which are responsible for an increased pneumonia presence in transplant recipients and patients with hematologic malignancies.¹

Fusariosis organisms resemble aspergillus on histologic examination; differentiation depends on culture speciation. These organisms are unique in their ability to sporulate in vivo leading to vascular invasion with yeast dissemination.^3,17,18 Transplant recipients manifest differences in disease response and outcome between SOT and HSCT recipients. These differences are likely causally associated with neutropenia in HSCT recipients who experience disseminated infections (commonly with pulmonary involvement) as compared to localized disease in SOT recipients. Immune reconstitution is important for treatment, since prolonged neutropenia with infection has a high mortality.^3,17

Scedoporium is the second most common mold after aspergillus to colonize the airway of cystic fibrosis patients, and like Fusariosis, has the ability to undergo adventitious sporulation. Moreover, the disease severity is worse for HSCT recipients as compared to SOT recipients. Surgical excision for localized disease may be a component of therapy given the poor response of this organism to antifungal therapy.^3,17

Phaeohyphomycosis

This disease is caused by inhalation or inoculation of species of black molds leading to allergic bronchopulmonary disease (ABPD) associated with eosinophil elevations. Nonallergic pulmonary disease occurs in immune-compromised individuals and represents tissue invasion of this fungus which is a common airway colonizer. Invasive phaeohyphomycosis may manifest as pneumonias or parenchymal or endobronchial nodules.

Opportunistic Fungal Infections

Opportunistic fungal infections are caused by the following organisms: Candida, Aspergillus, emerging fungal organisms (noted above), Cryptococcus, and Pneumocystis jirovecii (previously Pneumocystis carinii). Infections from these fungal organisms occur primarily in immune-compromised individuals and fall into several easily recognizable groups (infections are worsened by the presence of diabetes in all groups) (see Table 103-1): transplant recipients, cancer patients, immune-suppressed populations, and patients with other debilitating disease, including Lupus and Crohn disease.

Differences occur between the above groups and are accentuated in the transplant recipients as noted in a recent report using data from the Transplant Associated Infections Surveillance Program (TRANSNET)¹⁹: Invasive aspergillosis has replaced Candida as the most common invasive fungal infection in the HSCT population. There is a low 1-year survival for invasive fungal infections in HSCT recipients (6% for Fusarium infections, 25% for invasive aspergillus, 28% for zygomycosis, and 34% for invasive candidiasis). Invasive fungal infections in HSCT recipients increase as the donor match differs from the recipient (increasing infection rates for autologous and allogenic [matched, unrelated, mismatched]). Candida is still the most common infection of SOT recipients except for lung transplant recipients where Aspergillus infections predominate.¹⁸

Candida

This organism is the most common opportunistic fungal infection in ICU patients and SOT recipients (excluding lung transplants due to tracheobronchial or anastomotic Aspergillus infections).^2,18,20 Other patient groups that may be affected by this organism are patients with solid tumors and hematologic malignancies at risk for neutrophil defects as opposed to T-cell deficiencies. As compared to the other fungal infections noted above, infections from this organism typically arise from endogenous sources, and the majority of infections occur in the presence of vascular access devices (Fig. 103-7). Candida nonalbicans infections as compared with Candida albicans are rising rapidly in frequency and carry a higher mortality.^2,18,20 Pulmonary consolidation may be difficult to diagnose as candida pneumonia owing to candida colonization of the airway. Furthermore this organism may predispose to pulmonary bacterial infections.²⁰ Surgery is rarely required for this organism other than to deal with pleural or pericardial space infections.

Aspergillus

Aspergillus is ubiquitous in nature and is the most common opportunistic mold to cause pulmonary infection. Host factors allowing aspergillus hyphae invasion include prior structural lung disease or defects in immune resistance. However, severe infection most often arises in immune-deficient patient populations comprising two groups: Patients with chronic neutropenia and nonneutropenic patients secondary to steroids or SOT recipients with chronic pulmonary damage.

Patients with normal immune systems are at risk for any of the following Aspergillus infections as shown in Figure 103-8. Aspergillus colonization is common in all patients (50% of cystic fibrosis patients are colonized with aspergillus); the presence of this organism may lead to recurrent episodes of hemoptysis.

Immune-suppressed patients differ with respect to this organism related to the individual suppression type. In SOT, specifically lung transplant patients, aspergillus colonization rarely leads to invasion, whereas in HSCT recipients or patients with hematologic malignancies it has a high predictive value for invasion.¹⁸ With respect to lung transplantation, the following clinical Aspergillus infections can occur: Standard colonization, pseudomembranous necrotizing tracheobronchilitis, invasive aspergillosis, and ABPA.

Bronchial mucosa disruptions occurring in lung transplant patients and aspergillus colonization has made aspergillus the most common fungal infection in lung transplant recipients in comparison with other SOT recipients, suggesting the use of routine antifungal therapy until bronchial remodeling is complete (Fig. 103-9).^18,21 Aspergillus anastomotic infections carry significant mortality as does invasive aspergillosis as seen in Table 103-2.

Surgical therapy for Aspergillus infections is indicated for immune-competent symptomatic medically refractory patients with adequate pulmonary reserve; lung resection is required for parenchymal disease and possibly thoracoplasty for pleural disease. Immune-suppressed patients have a high mortality (30%–80%) from invasive pulmonary aspergillosis owing to massive hemoptysis. Lobectomy is indicated in these high risk individuals with radiographic suggestions of pulmonary artery involvement.²²

Cryptococcus Neoformans

This organism (Fig. 103-10) is ubiquitous in the environment and infection may lead to neurologic infection and involvement with pathologic processes. Inhalation of spores from this organism with subsequent macrophage internalization may lead to yeast germination inside host macrophages. These infected macrophages may then disseminate yeast infections according to a Trojan horse model of infection of distant organs.²³ The groups at risk with this organism are HIV individuals and transplant recipients.⁹

Pneumocystis Jirovecii

This organism previously named P. carinii is thought to be transmitted via an airborne route leading to either colonization or clearance depending on the status of host T lymphocytes. Certain at-risk groups suffer higher colonization rates by this organism: HIV infected patients, COPD patients, diabetes, myeloma, chronic lymphocytic leukemia (CLL), and sarcoidosis. With the introduction of highly active antiretroviral therapy (HAART) medications and Pneumocystis pneumonia (PCP) prophylaxis, patients without HIV now constitute the majority of current PCP infections. This patient population includes immune-deficient states, malignancies (hematologic and solid organ), and transplant recipients.

The disease presentation includes symptoms of pneumonia and respiratory distress without physical signs of pneumonia. The organism is not easily cultured and diagnosis relies on microscopic visualization in pulmonary secretions. Mortality is still high for all infected groups revealing the value of prevention.

Thoracic fungal infections are an important clinical consideration, not because the diseases are common, but because they are commonly confused with thoracic malignancy. As more effective antifungal therapies are developed, it will be increasingly important to recognize the clinical and radiologic features of thoracic fungal infections to avoid unnecessary surgical intervention.