The respiratory tract (Fig. 102-1) is in constant contact with the environment and exposed to direct inoculation by infectious and noninfectious agents. To defend itself against these agents, the respiratory tract is equipped with several types of defense mechanisms including both mechanical and immune-mediated mechanisms. Large size airborne particles (>5 microns) are filtered by the nose and are trapped by the nasal cilia. Intermediate size (1–5 microns) particles are deposited in the trachea and bronchi, and small size particles (0.01–1 microns) and infectious agents often are deposited in the bronchioles and the alveolar space (Fig. 102-2).

The respiratory tract from the trachea to the bronchioles is lined with ciliary cells and goblet cells that secrete a thin layer of mucus. The rhythmic beat of the cilia move the mucus-trapped material upward, which is then cleared externally by the cough mechanism or swallowed interiorly and eliminated by the gastrointestinal tract. This mechanism is called the mucociliary escalator (Fig. 102-3) and is a very important defense mechanism that plays a major role in clearing infectious and noninfectious particles from the respiratory tract.

The alveolar macrophages are another important line of defense. Macrophages clear bacteria and nonliving particles that reach the alveolar space through phagocytosis and digestion by cellular lysosomes. Opsonization, which involves coating of the invading agents by antibodies secreted by lymphocytes present in the mucosa, can further enhance phagocytosis. The alveolar macrophages also secret cytokines upon interaction with foreign particles that help recruit and activate neutrophils, lymphocytes, and other inflammatory cells to clear the foreign material.

The lungs and pleura are also richly supplied by an extensive lymphatic drainage system that helps transport phagocytosed particles and infectious agents out of the lungs to the regional lymph nodes where certain infectious agents (mycobacteria, fungi) can remain in a latent phase potentially for prolonged periods of time.

The interaction between host and pathogen factors determines if an infection is established or cleared. Certain host factors or conditions like altered mental status and alcoholism, for example, may predispose to the development of aspiration pneumonia as a result of the absence of protective gag reflexes. Other factors like endotracheal intubation or chest tube placement may predispose to ventilator-associated pneumonia and surgical wound infection, respectively, by bypassing normal host defenses. Infection could also be initiated when pathogen virulence factors overwhelm the host defense mechanisms.

In this chapter, we discuss lung infections associated with impaired host defense mechanisms and the important role of the thoracic surgeon in the approach to and management of these infections either through procurement of tissue specimens that help establish histopathological and/or microbiological diagnosis or through curative surgical resection of the infected tissue.

Infections Associated with Mucociliary Clearance Dysfunction

The importance of the mucociliary clearance as a key host defense mechanism is highlighted in patients with primary ciliary dyskinesia where failure of the mucociliary escalator function (see Fig. 102-3) leads to chronic suppurative lung disease.¹ Inhibition of the mucociliary clearance mechanism plays a significant role in allowing certain pathogens to establish persistent and recurrent infections in patients with cystic fibrosis (CF), bronchiectasis, and chronic obstructive pulmonary disease (COPD). The course of the disease in these patients is often marked by frequent and recurrent exacerbations due to the intense inflammatory response associated with the infectious process that results in parenchymal destruction and ultimately respiratory failure.

Cystic Fibrosis

CF is an autosomal recessive multisystem disease that was first described as a clinical syndrome in 1938.² Inadequate hydration of luminal secretions due to abnormal ion transport leads to accumulation of viscous mucus which compromises the mucociliary clearance mechanism.^3–5 At the base of this defect is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.^3–5 The concentrated mucus present in CF airways favors bacterial colonization and persistence. There is also intense neutrophilic inflammation in the airways of CF patients associated with the presence of bacterial pathogens.^6–8 Initial colonization of the airways of CF patients occurs early and is followed by persistent infection. Pseudomonas aeruginosa and Staphylococcus aureus are common bacterial pathogens that cause colonization and infection in CF patients.^9–12 Biofilm production by these pathogens makes eradication difficult.^13–15 Other important pathogens include Burkholderia cepacia complex,^16,17 Stenotrophomonas maltophilia,¹⁸ respiratory viral infections, and nontuberculous mycobacteria.^19,20 Various species of fungi also may cause infection and allergy in the airways. Frequent exacerbations in CF patients due to recurrent infections are associated with intense inflammation which results in airway wall damage and lung parenchymal destruction, ultimately leading to respiratory failure.^10,21 Aggressive treatment of pulmonary bacterial infections is an important and effective intervention in the treatment of CF patients. Antimicrobial resistance is common and varies between institutions. Antimicrobial treatment of CF exacerbations could be challenging because of drug resistance and should be guided by antimicrobial susceptibility data.

Thoracic surgeons often are involved in the care of CF patients when respiratory function deteriorates significantly and lung transplantation is considered (see Chapter 108 for an overview of lung transplantation). Eligibility for lung transplantation usually is reviewed by a multidisciplinary team prior to transplantation to optimize perioperative management and help improve transplantation outcome. Perioperative antimicrobials that target known pathogens isolated from the most recent respiratory cultures, guided by antimicrobial sensitivities, often are used to help prevent seeding of the pleural space upon explantation of the native lungs. Such treatment also helps to prevent infection of the anastomotic site, as well as surgical site infection and postoperative infectious complications. The choice of perioperative antimicrobials should be guided preferably by an infectious disease or pulmonary specialist experienced in the treatment of CF. Certain organisms pose increased risk in the lung transplant setting such as Burkholderia cenocepacia, thus requiring special consideration when transplantation is being considered in patients colonized pre-transplantation.^22,23

Infections Associated with Innate and Adaptive Immune System Dysfunction

The human immune system is a complex array of innate and adaptive processes geared toward defending the body against pathogens. The immune system has layered defense mechanisms against infections. Physical barriers (skin, mucosal surfaces) constitute the first line of defense against potential pathogens. The innate immune system is the second defense mechanism and provides an immediate but nonspecific immune response through several mechanisms including inflammation, complement system activation, macrophages, dendritic cells, neutrophils, and natural killer cell activation. On the other hand, the adaptive immune system is a highly sophisticated defense mechanism that has evolved over millions of years and involves an antigen-specific immune response capable of recognizing “non-self” antigens. It also has the ability to generate memory cells that permit a quick and tailored response to pathogens previously encountered. Both the innate and the adaptive immune systems are interconnected. The innate immune system plays an important role in the activation of the adaptive immune system.

Immunodeficiency could result from either a genetic abnormality (e.g., severe combined immunodeficiency) or could be acquired. The most common causes of acquired immunodeficiency syndromes are due to human immunodeficiency virus (HIV) infection or are secondary to immunosuppressive agents (chemotherapy, biological agents, monoclonal antibodies such as against T and B cells) administered after organ transplantation or for the treatment of chronic inflammatory disease or malignancy.

The resulting net state of immunosuppression can predispose the host to certain types of lung infections depending on the affected component of the immune system. Neutropenia, for example, will predispose the host to infections due to bacterial (S. aureus, P. aeruginosa) and fungal pathogens (Aspergillus, Zygomycetes, Candida), whereas T cell immunodeficiency (HIV, steroids, alemtuzumab, thymoglobulins) predisposes the host predominantly to viral infections (cytomegalovirus [CMV], Epstein–Barr virus [EBV], herpes simplex virus, varicella zoster virus) and fungal infections (Pneumocystis jirovecii pneumonia [PCP], Aspergillus, Zygomycetes, Candida). B cell immunodeficiency (rituximab, hypogammaglobulinemia) predisposes the host to infection by such pathogens as bacterial encapsulated organisms and some viral infections (such as hepatitis B). The use of tumor necrosis factor (TNF) inhibitors (etanercept, infliximab, adalimumab) is particularly associated with mycobacterial (including TB) and fungal infections.²⁴

Infections Associated with Chemotherapy-induced Neutropenia in Patients with Solid Tumors and Hematologic Malignancies

Patients with chemotherapy-induced neutropenia are at increased risk for a range of lung infections including bacterial, viral, and fungal infections. Up to 60% of patients with neutropenia develop pulmonary infiltrate at some point during the course of their disease and often with severe consequences.^25,26 Bacterial infections are the most common and are due mainly to gram-negative organisms (P. aeruginosa, Escherichia coli, and other gram-negative rods), S. aureus, and other bacterial pathogens.²⁷ Community respiratory viruses also are common and include respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses, picornaviruses, and adenoviruses.²⁸ Invasive pulmonary aspergillosis is an important fungal infection in neutropenic patients. Inhaled Aspergillus conidia are usually phagocytosed by lung macrophages, and the hyphal growth required for tissue invasion is prevented by neutrophils. In neutropenic patients, however, failure to control hyphal growth leads to angioinvasion with occlusion of tissue blood supply and subsequent ischemic necrosis of the lung parenchyma. This is manifested radiographically by the classic signs of invasive aspergillosis on computed tomography (CT) scan of the chest, that is, a dense nodule with a halo sign or cavitary lesions (Fig. 102-4).