Thoracic fungal infections can be divided into two basic categories that are based on a balance between the virulence of the invading fungal organism and the immune status of the individual. Endemic fungi develop pathogenic infections when by sheer number of organisms they defeat the host's normal immune mechanism. Conversely, opportunistic fungal organisms possess lesser degrees of virulence; only rarely can they infect a normal immune system, but they are capable of establishing infections in immunoincompetent hosts (Figs. 90-1 and 90-2). Since the portal of entry for all fungal spores is through the airways, the pulmonary system is uniquely at risk for fungal infection compared with other visceral organs. The need for T-cell modulation to prevent graft rejection in organ transplant recipients places these individuals at particular risk for fungal infections. The proliferation of surviving transplant recipients has been accompanied by a rising incidence of fungal infections with novel yeast organisms that carry various degrees of antibiotic resistance.¹

FUNGAL INFECTIONS IN IMMUNOCOMPETENT INDIVIDUALS

Endemic fungal infections typically occur in regions specific to certain fungi. Denizens of these areas are at risk for the following infections: histoplasmosis, coccidioidomycosis, blastomycosis, and paracoccidioidomycosis (South American blastomycosis). Surgical treatments for these fungal infections have been well reviewed by Bethlem and colleagues,² Robinson,³ and Johnson and Sarosi⁴ and are outlined below.

Histoplasmosis

Histoplasma capsulatum is endemic in the midwestern region of the United States. Cases arise in a bandlike distribution along both sides of the Mississippi and Ohio River valleys. It is also found in certain regions of Central and South America, Africa, India, and Southeast Asia. The symptomatic infection usually is heralded by flulike symptoms, including fever, cough, headaches, and myalgias. The acute infection resolves spontaneously in 99% of individuals who have an immediate polymorphonuclear (PMN) and macrophage response, which isolates but does not destroy the fungus. If the inoculum is sufficiently large, the initial immune response may create a clinical scenario of acute respiratory distress syndrome. The initial response is followed by a chronic phase in which there is granuloma formation with fungal destruction by a delayed cell-mediated response. If the cell-mediated response is muted or absent, there may be progressive dissemination affecting mucosal surfaces, liver, spleen, adrenal gland, and meninges with multiorgan system failure.

The fungus is found in soil that has been contaminated with bird or bat droppings. Approximately 80% of populations in areas of endemic disease skin-test positive for exposure to the fungus.⁵ The mode of transmission is by airborne inhalation of spores.

In normal individuals, several conditions may require surgical treatment for histoplasmosis:

1. A solitary pulmonary nodule that may need to be removed in an individual "at risk" for malignancy. Histoplasmoses are difficult to biopsy by fine-needle aspiration, thus leading to removal by either video-assisted thoracic surgery (VATS) or thoracotomy with wedge resection of the lesion. Solitary pulmonary nodules that demonstrate the characteristic calcification pattern of a granuloma may be observed in "good risk" patients.

2. Pericarditis that may complicate a Histoplasma infection because of neighboring infection and may require percutaneous drainage. Rarely is a pericardial window required.

3. Cavitary disease that may occur occasionally as a long-term complication of the fibrotic reaction created in response to primary Histoplasma infection. However, surgical intervention is rarely required because these cavities respond to antifungal medications.

4. Mediastinal granuloma formation with obstruction of mediastinal and hilar structures. In this form of the disease, progressive granuloma development with surrounding fibrosis can impinge on mediastinal structures, such as the superior vena cava, the esophagus, and the bronchus. Resection of these granulomata to relieve any obstruction may be attempted, although this is uncommon. Venous bypass has been performed in the past with varying degrees of graft patency.

Coccidioidomycosis

Coccidioides immitis is the etiologic agent of coccidioidomycosis. This fungus is endemic in the southwest region of the United States and in certain areas of Mexico and South America. The infection is symptomatic in 40% of cases and causes flulike symptoms, including fever, cough, headaches, rash, and myalgias.⁶ The infection incites a PMN exudative reaction with macrophage recruitment for phagocytosis of the fungal spores and eventual development of granulomata, signifying cell-mediated immunity. However, some individuals develop a chronic pulmonary infection or widespread disseminated infection that can affect the meninges, soft tissues, joints, and bone.

The fungus is found in the soil in areas with a semiarid climate. A specific incidence of 15 cases per 100,000 population was reported in Arizona in 1995.⁶ The infection may lead to meningitis and permanent neurologic damage with chronic disease. The route of transmission is airborne and occurs usually by inhalation of segmented spores (arthroconidia) in dust as a consequence of natural disasters, such as dust storms or earthquakes.

Surgical options for coccidioidomycosis infection are

1. Wedge resection of a solitary pulmonary nodule to distinguish it from a malignancy in the absence of other less invasive methods of diagnosis

2. Possible wedge resection for either cavitary lung disease to prevent rupture into the pleural cavity or for hemoptysis secondary to cavity infection

3. Pleural drainage for rupture of lung cavities

Blastomycosis

Blastomyces dermatitidis, the inciting fungus in blastomycosis, is endemic to the Mississippi and Ohio River valleys, as well as parts of southeastern United States. The fungus also can be found in certain regions of Canada and Central and South America, as well as parts of Africa. The disease often occurs in persons exposed to forested areas, including farmers, forestry works, hunters, and campers. It occurs in a regional distribution similar to histoplasmosis. The infection is symptomatic in approximately 50% of cases. The presenting symptoms include fever, chills, productive cough, myalgia, arthralgia, and pleuritic chest pain. In patients who fail to recover from the acute illness, a chronic pulmonary infection may ensue, or the disease may spread systemically to involve the skin, bones, or genitourinary tract and occasionally the meninges.⁷

The fungus is found in moist soil that is enriched with decomposing organic debris, such as along riverbeds. The incidence is 1–2 cases per 100,000 population in regions where the illness is endemic. The mortality rate is approximately 5%, and chronic forms of the disease can be associated with permanent lung damage. The mode of transmission is by airborne inhalation of spores. Surgical involvement is usually relegated to establishing or confirming the diagnosis because of the susceptibility of the fungus to antifungal antibiotics.

Paracoccidiodomycosis (South America Blastomycosis)

The fungus that causes paracoccidioidomycosis, Paracoccidioides brasiliensis, is specific to Latin America. Surgical involvement is uncommon other than for diagnosis to identify the cause of the interstitial pattern of lung involvement.

FUNGAL INFECTIONS IN IMMUNOCOMPROMISED INDIVIDUALS

Opportunistic fungal infections are distributed ubiquitously throughout the world, and these organisms depend on reduced immune resistance in the host to accommodate for a lesser degree of virulence compared with the endemic fungi. Immune compromise is common to many disease states. However, organ transplantation in particular is extremely permissive to the possibility of fungal infections, with varying infectivity rates depending on the organ transplanted. Among solid-organ transplant recipients, the risk of fungal infections is 11% after heart-lung or bowel transplantation versus 0.4% after renal transplantation. Lung transplant recipients are uniquely susceptible to Aspergillus infections, which manifest as airway colonization (26%), isolated tracheobronchitis (4%), and invasive pneumonia (5%). Liver transplantation carries a 7–42% risk of fungal infection depending on underlying risk factors. The mortality of invasive mycoses is high: 60–80% for either bone marrow transplantation or solid-organ transplantation.⁸ Most fungal infections in the immunocompromised population are attributable to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans; however, there are increasing numbers of emerging novel fungal infections.¹

Candidiasis

Candidal infections are commonly attributable to C. albicans, although there are increasing numbers of infections by C. tropicalis and C. parapsilosis. Candida pneumonia occurs commonly in individuals who are severely ill, often with multi-organ system failure. This disease is difficult to diagnose antemortem because pulmonary involvement is usually not apparent, and radiographs of individuals with Candida pneumonia may range from normal to signs of infiltrates or cavitating masses. Treatment is with antifungal medication.

Aspergillosis

Aspergillosis is the most common fungal infection in lung transplant recipients.⁹ A. fumigatus and A. flavus represent the most common forms. Lesser forms include A. terreus and A. nidulans, both of which are resistant to amphotericin B, and A. niger. These fungi give rise to several pulmonary conditions: invasive pulmonary aspergillosis (IPA), chronic necrotizing aspergillosis, aspergilloma, allergic bronchopulmonary aspergillosis, and anastomotic infections (similar to Candida).

Invasive pulmonary infection usually presents with fever, cough, and chest pain. It may progress to involve other organs (i.e., brain, skin, and bone). The fungus can be found in soil, decomposing plant matter, dust, building materials, ornamental plants, items of food, and water. Since the infection is opportunistic, it is fairly rare (estimated in some instances at 1–2 per 100,000).⁵ The mode of transmission is by inhalation of airborne spores. Solid-organ transplantation is more commonly associated with aspergillosis than with HIV infection. Patients who experienced prolonged granulocytopenia are at highest risk.

IPA is the most serious form of Aspergillus infections, and it manifests with pulmonary infarction, cavitation with hemoptysis, and nodule formation. On x-ray (Fig. 90-3) or CT scan (Fig. 90-4), it is identified initially by a halo sign and later by the air crescent sign, which indicates recovery. It is especially virulent in the post-lung transplant population, where the mortality rate approaches 60%.⁹ The risk of IPA varies with organ type. Stem cell transplantation is associated with the highest incidence of infection. The degree of genetic compatibility with the transplanted cells also affects incidence. The incidence with autologous stem cell transplantation is 0.5–4%; allogenic stem cell transplant is higher at 2.3–15%. The highest risk of IPA is found in patients with severe graft-versus-host disease who have undergone allogenic stem cell transplantation.¹⁰

The distribution of factors associated with IPA is bone marrow transplantation (32%), hematologic malignancy (29%), and solid-organ transplantation (9%). For lung infections, the surgical treatment of aspergillosis depends on the form of the infection, with IPA requiring the most urgent attention. The surgical involvement for IPA may commence with a lung biopsy by either VATS or open lung biopsy to confirm a suspected diagnosis. A transbronchial biopsy is not recommended because of the higher risk of bleeding. Medical treatment alone for IPA has a very high mortality but is improved with surgical resection for localized disease. Possible indications for surgical resection in localized IPA are continued toxicity despite antifungal treatment, an enlarging fungal mass despite antifungal treatment, hemoptysis, a mass located near a major vessel, the need for either further chemotherapy or a bone marrow transplant in a patient with quiescent IPA, and evidence of metastatic fungal disease from a localized cavity.^3,10,11

The indications for surgical resection for chronic necrotizing Aspergillus infections or for an aspergilloma are confined to patients with localized disease and good pulmonary reserve who are intolerant of antifungal therapy. Surgery is also indicated for patients who have residual localized but active disease despite adequate antifungal therapy.¹⁰

Cryptococcosis

C. neoformans has been isolated in soil samples from pigeon and chicken droppings on all continents. The initial infection is usually asymptomatic. Therefore, most patients present with widespread disseminated infection often involving cryptococcal meningitis owing to the neurotropic nature of the fungus. Pulmonary involvement requires immediate assessment of the CNS. The treatment of this fungus is primarily medical, with antifungal antibiotics.

C. neoformans is found in the soil, usually in association with bird droppings. Its incidence is 0.4–1.3 cases per 100,000 in the general population. However, among patients with HIV infection, the annual incidence is 2–7 cases per 1000 population. In the United States, 85% of cases are associated with HIV infection.¹²

CNS involvement may lead to permanent neurologic damage or death at a rate of approximately 12%. The infection is transmitted by inhalation of airborne yeast cells or basidiospores.

Pulmonary Mucormycosis

Mucormycosis is the third most common fungal lung infection after Candida and Aspergillus. The organism responsible is saprophytic, that is, primarily pathogenic to humans who are immunosuppressed. Like Aspergillus,the spores manifest a tropism for vascular invasion and cause thrombosis, infarction, necrosis, and eventually, abscess and aneurysm development with hemoptysis.³ The presence of an air crescent sign on x-ray denotes a higher possibility of massive hemoptysis and sudden death.

The surgical resection of areas of the lung, in combination with antifungal antibiotics for localized fungal disease, results in a much better patient survival rate than medical treatment only. The indications for surgery are similar to those for IPA.^4,13

Monosporiosis

This is an opportunistic infection of previously damaged lung tissue, which may develop into a fungus ball; particularly susceptible are immunocompromised patients. Localized resection of cavitary disease with antifungal treatment in "good risk" patients is recommended.³

EMERGING FUNGAL PULMONARY PATHOGENS

Fusarium

Fusarium spp. are common plant pathogens typically isolated from soil and water. They typically affect immunoincompetent individuals, and they are second to Aspergillus as causes of fungal infections in immunosuppressed individuals. Antifungal medication is the most effective treatment.

Pseudallescheria Boydii (Scedosporium Apiospermum)

This species accounts for 25% of all non-Aspergillus fungal infections in organ transplant patients. Localized forms of this disease may respond to surgery and antifungal therapy; disseminated disease has a mortality rate of 60–90%.

Paecilomyces

This species is rare; patients not responding to antifungal medication may require resection.¹

Scopulariopsis

This species is associated with fungus balls and pneumonic infiltrates and subpleural nodules in immunocompromised individuals. Patients have a high resistance to antifungal therapy and may require surgical resection of fungal cavities.

Penicillium Marneffei

This fungus is endemic in Southeast Asia and has been reported primarily in association with HIV infection. Soil exposure with subsequent pulmonary inhalation of the fungus leads to reticular nodular or ground glass lower lobe infiltrates or diffuse cavitary disease. Treatment is with systemic and oral antifungal therapy for proven infections with oral lifelong prophylaxis.

Pneumocystis Carinii

This organism is now considered a fungus; the presentation is one of diffuse lung infiltrates. Investigation is with a bronchoscopy and bronchoalveolar lavage.¹⁴

Actinomyces and Nocardia

These organisms are nonfungal anaerobic gram-positive non-spore-forming bacteria that are either commensals of the oropharynx or soil saprophytes that can cause chronic lung infiltrates or cavities. If left untreated, they may lead to metastatic sites of infection or become fatal. Both are treated with chronic antibiotic usage and occasional surgical drainage of abscesses or empyema.¹⁵

SUMMARY

Fungal lung infections can occur in endemic areas in both immunocompetent and immunosuppressed individuals. Surgery for endemic fungal infections is indicated primarily to exclude malignancy or to treat the inflammatory sequelae of these infections. Opportunistic fungal infections are ubiquitous and occur primarily in immunocompromised individuals, for example, in recipients of solid-organ transplants. Surgery for these organisms is used primarily to avert the consequences of further invasion, which may be life-threatening, or to remove localized foci of resistant organisms.

EDITOR'S COMMENT

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 anti-fungal therapies are developed, it will be increasingly important to recognize the clinical and radiologic features of thoracic fungal infections to avoid unnecessary surgical interventions.

–SJM

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