102: Lung Infections and Interstitial Lung Disease: Overview and General Approach

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).

The total duration of neutropenia and the short time interval between neutropenic episodes increase the risk of invasive aspergillosis.²⁹ The mortality rate associated with invasive pulmonary aspergillosis is high (in the range of 60%).^30,31 Thus, early diagnosis and prompt antifungal treatment are essential in reducing mortality. Other encountered invasive pulmonary fungal infections in neutropenic patients include zygomycetes, fusarium, dematiaceous mold, and other fungi.

The role of the thoracic surgeon in the management of suspected fungal infection is important since radiographic characteristics of the lung lesions in most cases are nonspecific. Differential diagnosis of a lung nodule includes malignancy, various bacterial pathogens including Nocardia sp., mycobacterial infection, as well as a variety of fungal pathogens that all may exhibit nodular and/or halo signs (Fig. 102-4). Empiric antimicrobial treatment often is not feasible because of the wide range of pathogens possibly involved and its associated adverse side effects including hypersensitivity reactions, nephrotoxicity, hepatotoxicity, and drug–drug interaction. Different fungal pathogens have different antifungal susceptibility patterns. Obtaining tissue for definitive diagnosis is consequently of utmost importance. This can be done through different approaches including fine-needle aspiration, biopsy, or wedge resection via video-assisted thoracoscopic surgery (VATS). In some instances, resection of the pulmonary lesion when feasible allows for both diagnostic and therapeutic purposes and may significantly reduce the duration of antimicrobial therapy and its associated toxicity. Early surgical intervention also could be life saving, since fungal infections are often angioinvasive and depending on location and proximity to great vessels could erode through vessel walls and cause hemoptysis or exsanguination.

Infections in Hematopoietic Stem Cell Transplant Recipients

Hematopoietic stem cell transplant (HSCT) recipients are at increased risk for severe infectious complications as a result of a combination of factors including underlying disease, the type of conditioning regimen (myeloablative versus nonmyeloablative), the type of HSCT (autologous transplantation versus allogeneic transplantation), and its associated risk of graft versus host disease (GVHD), and its treatment. The timing of infection post-HSCT and the type of pathogens involved vary depending on the type of HSCT and the way it was performed.

In autologous stem cell transplantation, the patient's own stem cells are collected prior to transplantation and cryopreserved to permit intense chemotherapy targeting the underlying disease and then reinfused after conditioning—as stem cell rescue. The time to engraftment (blood counts recovery) in autologous HSCT is relatively short and thus the risk of infection is less compared to allogeneic HSCT.

In allogeneic HSCT, stem cells are collected from family members, volunteers, or from banked cord blood cells. HLA matching is required to decrease the risk of GVHD. To decrease the risk of infectious complications after HSCT, prophylactic or pre-emptive antimicrobials using antibacterials, antivirals, and sometimes antifungal agents are often used but the type and duration of prophylactic strategies vary between procedures and institutions based upon patient risk profile for infection.

GVHD occurs when the donor cells (graft) recognize the recipient (host) as “non-self” and attempt to reject it. The treatment of acute GVHD requires the use of intense immunosuppression including high-dose steroids, monoclonal antibodies, or TNF-receptor blockers, all of which increase significantly the risk of opportunistic infections. To decrease the risk of GVHD after allogeneic HSCT, prophylaxis using immunosuppressive regimens targeting T cell activation is often employed.

Pneumonic syndromes are common after HSCT and could be due to either an infectious or noninfectious etiology depending on the timing of onset of signs and symptoms and the nature and duration of antimicrobial prophylaxis.³² Imaging of the chest using high-resolution CT scan is a very sensitive method to detect and characterize pulmonary infiltrates.^33,34 When evaluating HSCT recipients with lung infiltrates or a focal lung lesion, it is important to note the type of HSCT, the timing of onset of the lung infiltrates or lesion, its radiologic appearance (diffuse, focal, nodular), the current immunosuppressive regimen, whether GVHD is present or absent, and the prophylactic regimen that the patient is taking.

In early postengraftment period, diffuse bilateral pulmonary infiltrates (pneumonitis) could equally be due to infectious or noninfectious etiologies. Infectious etiologies include respiratory viruses (respiratory syncytial virus, influenza viruses, parainfluenza viruses, picornaviruses and adenoviruses),^28,35–38 legionella, CMV, or PCP. Knowledge of the type of prophylactic antimicrobial regimen that the patient is taking helps narrow the differential diagnosis. For example, it is unlikely for a patient on trimethoprim-sulfamethoxazole prophylaxis to develop PCP or for a patient on acyclovir prophylaxis to have herpes simplex virus or varicella zoster virus pneumonitis.

Focal pulmonary infiltrates in the postengraftment period often are due to bacterial or fungal infections. The risk of invasive fungal infections, mainly aspergillosis, increases significantly in the presence of GVHD.^39,40 However, noninfectious etiologies could also be a possibility. Idiopathic interstitial pneumonitis, alveolar hemorrhage, bronchiolitis obliterans, and cryptogenic organizing pneumonia are often encountered.

The paucity of symptoms often encountered in the context of immunosuppression, the broad differential diagnosis in this population, the likelihood of noninfectious etiologies of the lung infiltrate, the toxicity, and the potential for drug–drug interaction associated with empiric therapy, often mandate early and definitive diagnosis through procurement of clinical samples for microbiological diagnosis and preferably tissue samples for both histopathological and microbiological diagnosis from the affected area of the lungs. Samples can be obtained through bronchoscopy, bronchoalveolar lavage, fine-needle aspiration, lung biopsy, or wedge resection via VATS.

Thoracic surgeons should be involved early in the evaluation of cavitary or nodular lesions suspicious for invasive fungal infection. Local progression of fungal infections often involves angioinvasive features and a predilection to erode into adjacent vessels which can cause hemoptysis and in some instances life-threatening massive bleeding. Careful evaluation by thoracic surgeons should take into consideration the anatomic location and resectability of the lung lesion. Potential complications from surgery include inability to close the stump with stump breakdown and the risk of developing a bronchopleural fistula, bleeding due to thrombocytopenia, and wound nonhealing (neutropenia) (Fig. 102-5).

Infections after Lung Transplantation

Infectious complications account for up to 20% of all-cause mortality at 5 years after lung transplantation.⁴¹ Lung transplant recipients are at high risk for infectious complications because of constant exposure to the environment allowing direct pathogen inoculation, the high level of immunosuppression especially during the induction phase and subsequently with treatment of rejection, and the adverse effects on the local host defense mechanisms due to the surgical procedure itself. The lung transplantation procedure is associated with disruption of the lymphatics, the loss of mucociliary clearance, and lung denervation which results in decreased effective cough mechanism and lymphatic drainage. The risk and type of infection is a function of the nature and duration of prophylactic regimens employed, the degree of immunosuppression (presence or absence of rejection), and the timing after transplantation. The most commonly encountered pathogens are P. aeruginosa, CMV, community-acquired respiratory viruses, and Aspergillus sp.⁴² Colonization preceding transplantation, especially in CF and bronchiectasis patients, may play a major role in subsequent infections. Prophylactic regimens targeting known colonizing organisms administered peri-transplantation help decrease the rate of infections after transplantation.

During the early post-transplant period (<1 month after surgery), the most commonly encountered infections include donor and/or recipient-derived infections and nosocomial infections associated with hospitalization and surgery. Most of these infections are caused by bacterial pathogens, but Candida infection is also common in the absence of prophylaxis. The period between 1 and 6 months after transplantation is marked by the development of opportunistic infections, mainly CMV, PCP (in the absence of prophylaxis), Aspergillus pneumonia, as well as post-transplant lymphoproliferative disease (PTLD) induced by EBV.

Bacterial, viral, fungal, and mycobacterial infections all occur at an increased frequency after lung transplantation.⁴² Pleural effusions diagnosed within 3 months of transplantation could represent infection and warrant further investigation particularly if the patient has systemic signs of infection.⁴³ This often requires intervention by the thoracic surgeon to drain the empyema with placement of chest tubes, pleurodesis, and decortication.

Infectious complications after lung transplantation are important to manage adequately since they may be associated with the development of bronchiolitis obliterans and contribute to allograft loss of function.^44,45

Diagnostic evaluation of lung infection after lung transplantation includes early and aggressive evaluation. Bronchoscopy (with bronchoalveolar lavage) and transbronchial biopsy are warranted to establish a definitive microbiological and histopathologic diagnosis and to rule out rejection and malignancy (PTLD). Often the management differs significantly depending on the underlying etiology. An opportunistic infection (CMV pneumonia, fungal infection) or PTLD diagnosis, for example, requires decreasing immunosuppression, whereas rejection requires increasing immunosuppression. PTLD is often difficult to differentiate radiographically from an infectious process (bacterial, fungal infections) and a diagnostic procedure is often required (Fig. 102-6). Whenever significant rejection treatment is initiated, antimicrobial prophylaxis against CMV and PCP should be restarted.

Management of Lung Abscess

Lung abscess results from necrosis of the lung parenchyma caused by microbial infection. In most cases, the lung abscess is due to aspiration of oral flora into the lungs as a result of altered mental status, alcoholism, or dysphagia. In the case of multiple lung abscesses, septic emboli are usually suspected. Septic emboli could be due to S. aureus bacteremia secondary to tricuspid valve endocarditis or indwelling vascular catheter, or in the case of Lemierre's syndrome could arise from suppurative thrombophlebitis of the internal jugular vein due to an infection by Fusobacterium necrophorum.

Lung abscesses may be caused by polymicrobial infection predominantly involving oral anaerobes (Peptostreptococcus, Prevotella, Bacteroides, Fusobacterium) or microaerophilic streptococci (Streptococcus milleri).^46,47 Lung abscess could be also due to monomicrobial infection. The most common bacteria include S. aureus, Klebsiella pneumoniae, Streptococcus pyogenes, Haemophilus influenzae type B, Legionella, Nocardia, and Actinomyces.^48–50 In the immunocompromised host, infections due to P. aeruginosa, Enterobacteriaceae, Nocardia, Aspergillus are more common. Most patients with lung abscess present with indolent symptoms that evolve over weeks or months. Fever, night sweats, weight loss, and putrid sputum are the most common symptoms. The radiographic features of lung abscess include a cavity with air fluid level (Fig. 102-7).

The treatment of lung abscess in most cases is medical and involves prolonged administration of antimicrobials targeting anaerobes for several months and until radiologic resolution of the abscess. Bronchoscopy is often indicated in atypical cases where foreign body aspiration, underlying malignancy or mycobacterial infection is suspected. Bronchoscopy is also useful in obtaining clinical specimens for culture and allow for biopsy for histopathologic diagnosis in cases where malignancy is suspected. Surgical intervention is rarely required in patients with uncomplicated lung abscess. Indications for surgery include failure to respond to medical treatment, bleeding and suspected malignancy. In patients considered to be poor surgical candidates, placement of percutaneous drain with special care to prevent contamination of pleural space or endoscopic drainage could be attempted.^51,52

Thoracic surgeons play a pivotal role in the optimal management of lung infections. Surgical interventions are often required to help establish early and definitive diagnosis especially in immunocompromised patients. Surgical procedures are often curative and allow for reduced use of prolonged antimicrobial therapy. Surgery can also prevent life-threatening complications such as massive bleeding caused by erosion into major blood vessels by uncontrolled invasive fungal infections. When evaluating lung infections, a good understanding by the thoracic surgeon of the underlying medical conditions, the host–pathogen interaction, and the complex variables often at play are essential to the decision-making process and to assessing the risks associated with surgical intervention in a particular patient population.