Overview

The respiratory tract is continually exposed to a range of microorganisms that normal immune responses generally prevent from causing infection. Hence, it is not surprising that patients with significantly impaired immunity frequently develop lung infections. Immunodeficient patients also frequently have several other risk factors that contribute to an increased risk for development of pneumonia, including low-level microaspiration of oropharyngeal contents, mucosal damage caused by cytotoxic therapy, underlying lung damage, and poor nutrition. As a consequence, lung infections are a common and frequently serious complication in patients with significant impairment of the immune system. Pulmonary infiltrates occur in 25% of patients with neutropenia developing after chemotherapy, and up to 5% of patients undergoing hematopoietic stem cell transplantation (HSCT) will die as a result of pneumonia. The range of potential pathogens causing lung infections in immunocompromised patients is much broader than for the usual pathogens causing community-acquired pneumonia and includes organisms such as Aspergillus fumigatus and human cytomegalovirus (CMV); the diagnosis of infections due to these microbes can be difficult, and the required therapies frequently are toxic. The large number of potential pathogens and the background disease together make management of lung infection in immunocompromised patients considerably more complex, and the use of invasive diagnostic tests such as bronchoscopy frequently is necessary. This chapter focuses on the common causative pathogens and the clinical approach to pulmonary infections in patients who have been severely immunocompromised by chemotherapy, organ transplantation, or hematologic disease (Box 28-1) but not human immunodeficiency virus (HIV) infection (discussed in Chapter 29). Pneumonia in patients with milder degrees of immunosuppression due to myeloma, low-dose cytotoxic therapy, or disease-modifying agents administered for rheumatologic conditions generally should be managed as community- or hospital-acquired pneumonia, but with recognition that the disease could be due to various opportunistic pathogens, as discussed in this chapter.

General Principles of the Clinical Approach

Potential pathogens causing lung infection in the immunocompromised patient are listed in Table 28-1. Empirical therapy that is active against all these possible pathogens is not feasible, especially given the potential toxicity of some treatments. Hence, the challenge in managing these patients is to (1) reduce the scope of the differential diagnosis to include the most likely problems and thus allow relatively targeted empirical therapy and (2) identify when and which type of invasive diagnostic test(s) should be used to provide the most useful data. The likely potential causative pathogens can be defined by ascertaining the following:

Table 28-1 Range of Pathogens Commonly Associated With Pneumonia in the Non–HIV-Infected Immunocompromised Patient

Modified from Rañó A, Agustí C, Jimenez P, et al: Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures, Thorax 56:379–387, 2001.

The exact type of immune defect is determined by a combination of the disease and the treatment received and, fortunately, can generally be predicted (Table 28-2). The three main categories of immune defect are absolute or functional neutropenia, defects in cell-mediated immunity, and deficiencies in antibody responses (a clinically less severely affected category). Each is associated with a particular range of pathogens (see Table 28-2). Patients with neutropenia are mainly at risk for infection with extracellular pathogens such as pyogenic bacteria and filamentous fungi. Defects in cell-mediated immunity tend to predispose affected patients to development of infections with intracellular pathogens such as viruses and mycobacteria, as well as some unusual extracellular infections such as Pneumocystis pneumonia (PCP). Deficiencies in antibody responses result in a high incidence of infections due to encapsulated bacteria such as Streptococcus pneumoniae and to herpesviruses. Individual patients may have a combination of these immune defects; for example, lymphoma can cause impairment of cell-mediated immunity that can be combined with neutropenia if the patient receives chemotherapy.

Table 28-2 Type of Immune Defect According to Disease/Treatment and Range of Pathogens Commonly Associated With Infections in Patients with Such Immune Defects

HSCT, hematopoietic stem cell transplantation.

* Allografts up to 1 month, autografts usually less than 14 days.

† Patients usually have a normal neutrophil count but have defects in their function and/or a poor response to infection.

HSCT, especially for allograft recipients, is particularly associated with lung complications, including infections with a daunting range of pathogens. The immune defects associated with HSCT depend on the conditioning regimen and type of graft, and evolve with time. In phase I, the preengraftment phase (15 to 45 days after transplantation), prolonged neutropenia and breaks in the mucocutaneous barrier increase the risk of bacterial and fungal infections. Herpes simplex virus reactivation also can occur during this phase. In phase II, the immediate post-engraftment phase at around 30 to 100 days after transplantation, infections relate primarily to impaired cell-mediated immunity and include those due to herpesviruses (particularly CMV) and PCP unless the patient is given prophylaxis. During phase III, the late phase (beyond 100 days), common pathogens again include herpesviruses, but there is also a marked increased incidence of infection with encapsulated bacteria such as S. pneumoniae, perhaps relating to impaired humoral immunity. Graft-versus-host disease also is associated with ongoing susceptibility to Aspergillus during phases II and III. For recipients of nonmyeloablative hematopoietic stem cell transplants, substantial differences may be observed during phase I, but susceptibility to infections during phases II and III is about the same. The risk of disease from community-acquired respiratory viruses is elevated in all three phases.

By combining the clinical pattern of presentation with knowledge of the patient’s immune defect, a differential diagnosis of likely pathogens can be suggested. For example, infections developing rapidly over 1 to 3 days with a marked rise in serum inflammatory markers such as C-reactive protein (CRP), pronounced fever, and focal radiologic changes are very likely to be due to infection with pyogenic bacteria. In a patient with a defect in cell-mediated immunity, however, widespread ground glass infiltrations in both lungs developing over several days could represent CMV pneumonitis or PCP. In general, the more severe and prolonged the immune defect, the greater the range of possible causative pathogens and the less typical the clinical presentation for a particular pathogen, prompting the need for early invasive investigation if the initial therapy is failing to effect improvement. Furthermore the character of the disease can be dictated by the severity of the immune defect. For example, infections due to filamentous fungi such as Aspergillus progress faster with increasing severity of neutropenia, but may regress and become more focal when the neutrophil count recovers. Table 28-3 shows the common conditions that should be considered for different presentations of lung complications in immunocompromised patients. Many patients will be found to have dual pathologic processes, either involving two separate pathogens or with simultaneous noninfective (fluid overload being the most common) and infective problems, which will be responsible for separate elements of the clinical picture.

Previous results of microbiologic tests need to be reviewed, because these may provide a strong indication of the cause of the present lung infection. For instance, infected indwelling vascular and urinary catheters can form foci of infection that can metastasize to the lungs, and previous Aspergillus infection may recur during new episodes of immunosuppression. Knowledge of previous and present CMV status identifies patients at risk for development of CMV pneumonitis, and positive sputum surveillance cultures for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa may indicate likely causes of a new pneumonia. In addition, positive samples from other patients also may be helpful, because local epidemics of respiratory virus infections are not uncommon in hospitals, and more rarely, clusters of nosocomial Aspergillus, Nocardia (both of which may be associated with ongoing construction on the hospital site), or Legionella infection can occur.

Other important factors that need to be taken into account include the patient’s present antibiotic prophylaxis regimen, travel history, and ethnic background. A patient compliant with co-trimoxazole prophylaxis will rarely develop PCP, and fluconazole prophylaxis predisposes to non-albicans Candida infection. Patients with certain ethnic backgrounds or a pertinent travel history are more at risk of TB, endemic mycoses such as histoplasmosis, or parasitic diseases such as disseminated strongyloidiasis. Finally, the patient’s background lung structure and function should be considered, because existing structural abnormalities may make certain pathogens more likely. For example, bronchiectasis could predispose affected persons to pneumonia caused by P. aeruginosa (Figure 28-1), and preexisting lung cavities to Aspergillus infection.

Figure 28-1 A, Computed tomography (CT) scan of thorax shows dilated, thick-walled bronchi, characteristic of bronchiectasis. The patient, who had a long history of chronic lymphatic leukemia and immunoglobulin deficiency, produced purulent sputum daily, culture of which grew Pseudomonas aeruginosa. B, A chest radiograph obtained in the same patient, whose clinical presentation included high fever, productive cough, and marked hypoxia, shows consolidation (most marked in the left middle zone) due to P. aeruginosa pneumonia.

Clinical Assessment and Diagnostic Protocols

The combination of new respiratory symptoms and/or new radiologic findings with pyrexia suggests lung infection, although incidental radiologic or microbiology results may also identify active lung infection in an asymptomatic patient. The patient should undergo careful clinical assessment, including a review of previous laboratory and radiologic findings; the high mortality associated with lung infections in immunocompromised patients requires that this is initiated rapidly. The level of oxygenation will characterize the immediate risk to the patient and can also suggest likely pathogens as severe hypoxia is more likely with a bacterial lobar pneumonia, extensive PCP or viral infections. Chest radiographs are an essential first line investigation and are useful for monitoring progress. However, with the exception of lobar consolidation chest radiographs may not be sufficiently sensitive to make an accurate assessment of the pattern of lung shadowing. Ultimately a computed tomography (CT) scan of the thorax often is required. CT scans are approximately 20% more sensitive than chest radiographs at identifying lung involvement and also define whether new changes on a chest radiograph represent consolidation, nodules, ground glass infiltrates, or “tree-in-bud” changes.

All patients with suspected new lung infection require blood and sputum cultures, as well as routine blood tests, and in many cases nasopharyngeal aspirate studies for identification of viruses, assessment of CMV status, and serum testing for fungal antigens (galactomannan or β-D-glucan). An important question for the respiratory physician is when to utilize more invasive investigations, either bronchoscopy with bronchoalveolar lavage (BAL) and possibly transbronchial biopsy, percutaneous radiologically guided biopsy, or, on occasion, surgical biopsy, usually video-assisted thoracoscopic surgery (VATS). Which test should be used and when will depend to a large extent on the type of radiologic presentation—consolidation, diffuse ground glass infiltrates, tree-in-bud changes, and nodules—in accordance with the algorithms for each provided in Figures 28-2, 28-4, 28-6, and 28-7, respectively. These suggested protocols balance the likelihood and necessity of a positive yield against the clinical probability that a particular disease will be identified with the potential complications of the investigations. These protocols are for general guidance; atypical presentations and dual pathology are not uncommon, and an individual patient often will require a modified approach. Immunocompromised patients are also at high risk for development of a range of noninfective causes of lung disease, including pulmonary edema, idiopathic pneumonia syndrome (IPS), and diffuse alveolar hemorrhage (see Chapter 59). These conditions should always be considered in the differential diagnosis for new lung disease. The protocols are discussed in detail next.

Investigation of Consolidation

Rapidly developing focal consolidation usually is due to bacterial pneumonia and initially can be treated empirically with broad-spectrum antibiotics (Figure 28-2). The most likely reason for a lack of improvement in the patient’s condition within 48 to 96 hours is infection with bacteria resistant to first-line antibiotics. At this point, treatment with second-line antibiotics effective against likely resistant organisms should be started. Consideration also should be given to starting antibiotics that are effective against MRSA and anaerobic pathogens if this has not been done already. In patients at high risk for invasive fungal infection, especially those with CT evidence of associated nodular disease or patchy or infarct-shaped consolidation, failure of first-line therapy warrants testing for fungal antigens (galactomannan or β-D-glucan) and either fiberoptic bronchoscopy (FOB) with BAL or percutaneous CT-guided biopsy (mainly for evaluation of dense consolidation adjacent to the pleura). These investigations also will be necessary in patients whose pneumonia fails to respond to second-line antibiotic therapy or those with subacute or chronic consolidation in whom sputum microbiologic or cytologic testing is nondiagnostic. With progressive disease and lack of a definitive diagnosis after the foregoing tests, surgical biopsy should be seriously considered.

Figure 28-2 Investigation of consolidation in the immunocompromised patient. AFBs, acid-fast bacilli; BAL, bronchoalveolar lavage; CRP, C-reactive protein; CT, computed tomography; FOB, fiberoptic bronchoscopy; MC+S, microbial culture and sensitivity [testing]; TBB, transbronchial biopsy; VATS, video-assisted thoracoscopic surgery.

Investigation of Diffuse Ground Glass Infiltration

The differential diagnosis for ground glass infiltrates and centrilobular nodules (Figures 28-3 and 28-4) is wide in scope and includes CMV infection, viral pneumonias, PCP, extensive bacterial infection, and noninfective causes such as acute respiratory distress syndrome (ARDS), drug toxicity, and IPS associated with HSCT (see Chapter 77). As a consequence, unless nasopharyngeal aspirate studies identify a respiratory viral infection, early FOB with BAL and, if possible, transbronchial biopsy should be attempted. Often, however, these patients are markedly hypoxic, increasing the risk associated with the procedure. Negative results on FOB do not exclude infective causes, and a decision then needs to be taken about empirical treatment versus VATS lung biopsy. CT-guided biopsy for investigation of diffuse lung disease carries a high risk of complications coupled with low diagnostic yield and therefore is not appropriate in this setting.

Figure 28-3 Computed tomography (CT) scan of thorax showing widespread bilateral ground glass infiltration in a hematopoietic stem cell transplant recipient. The differential diagnosis for this imaging appearance is broad in scope, including cytomegalovirus pneumonia, Pneumocystis pneumonia, drug reactions, and idiopathic pneumonia syndrome, and early invasive investigation typically is required even though with such widespread lung disease the patient is likely to have significant hypoxia.

Figure 28-4 Investigation of diffuse ground glass infiltrates in the immunocompromised patient. BAL, bronchoalveolar lavage; CMV, cytomegalovirus; FOB, fiberoptic bronchoscopy; MC+S, microbial culture and sensitivity [testing]; PCP, Pneumocystis pneumonia; VATS,

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