68 Pulmonary Infections in the Immunocompromised Patient
Improvements in solid-organ and hematopoietic stem cell transplantation (SOT and HSCT) techniques, expanded use of chemotherapeutic treatments and glucocorticoids, and the appearance of new immunomodulatory therapies contribute to the increasing numbers of immunocompromised patients.1 Recognizing and managing pulmonary complications, particularly infections that result from immunosuppression, are challenging tasks for clinicians. Despite the introduction of potent broad-spectrum antimicrobial agents, complex supportive care modalities, and the use of preventive measures, pulmonary infections continue to be the most frequent complications in these patients and have a high associated mortality, especially when intubation and mechanical ventilation are required.2 In a prospective study of 200 immunocompromised patients with lung infiltrates, infectious agents were isolated from more than three-fourths of patients.3 Early diagnosis and intervention are essential to improving outcomes.
Evaluating the Net State of Immunosuppression
Proper assessment of factors involving the patient’s net state of immunosuppression is of paramount importance (Table 68-1). Most important among them are the specific type of underlying immune deficiency, the immunosuppressive therapy received, and the epidemiologic exposures the patient has encountered in both the community and hospital. A timetable with intervals during which each type of infection and noninfectious pulmonary complication tend to be most prevalent have also been adapted for SOT and HSCT patients (Table 68-2). Knowledge of these time-related complications, as well as the individual characteristics of each patient, will help guide diagnostic tests and allow implementation of appropriate empirical therapy.
TABLE 68-1 Variables to Be Considered in Evaluating the Net State of Immunosuppression
TABLE 68-2 Timetable of the Most Likely Pulmonary Complications in Immunocompromised Transplant Patients
| First 30 Days After Transplant |
| 2 to 6 Months After Transplant |
| More Than 6 Months After Transplant |
Etiology of Pneumonia in Intensive Care Patients
Bacterial Infections
Bacteria are the most frequent cause of pulmonary infections in immunocompromised patients. Jain et al., in a study evaluating 104 intensive care unit (ICU) patients with lung infiltrates, found that 49% of episodes were bacterial infections.4 The specific bacterial etiology of pulmonary infections in immunocompromised patients differs in frequency depending on underlying immune defects. Encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae are particularly common in patients with immunoglobulin defects, such as those suffering from multiple myeloma or in patients with chronic lymphocytic leukemia. Infections caused by penicillin-resistant S. pneumoniae are on the rise,5 and prophylactic use of antibiotics against gram-negative bacteria in patients with neutropenia has favored the emergence of Staphylococcus aureus infections (including methicillin-resistant [MRSA]) and multi-resistant gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia.)6 Epidemiologic studies have shown that Legionella pneumonia is more prevalent in the ICU host, particularly in renal transplant recipients and patients with lymphoma. It is important to consider that 15% to 30% of cases of bacterial pneumonia are mixed bacterial/opportunistic infections,1 a finding of particular therapeutic importance in patients who do not respond to what was initially considered to be appropriate specific antibiotic treatment.
Fungal Infections
Aspergillus spp. are some of the most common microorganisms causing pneumonia in the ICU patient. Since neutrophils are the key cells in defense against Aspergillus, neutropenic patients, particularly HSCT recipients, are at special risk for this infection. Among recipients of solid-organ transplants, the incidence of invasive pulmonary aspergillosis (IPA) is highest after lung transplantation. A steady increase in documented cases of IPA after organ transplantation has been reported.7 It is estimated that aspergillosis is found in 30% of patients with protracted severe neutropenia.8
Although mortality associated with IPA in IC patients has historically been as high as 80%, during the past 2 decades, the outcome of this infection seems to be changing. Early detection of infection using antigen-specific diagnostic techniques based on serum detection of either galactomannan or beta-D-glucan, two constituents of fungal cell walls, may improve diagnosis, particularly in patients with leukemia and HSCT recipients. Recent reports suggest that detection of galactomannan in bronchoalveolar lavage fluid might be more sensitive than detection in serum.9 Diagnosis of invasive fungal diseases with the use of polymerase chain reaction (PCR) assay, although promising, is currently investigational.10 Implementation of thoracic computed tomography (CT) scan in patients at high risk for invasive pulmonary aspergillosis may improve outcome.11 Prompt institution of azoles appears to have resulted in improved survival.12
Candida species colonize the respiratory tract and are often recovered from pulmonary specimens in ICU patients, but are only considered truly pathogenic if fungemia occurs or lung tissue invasion can be demonstrated. With expanded use of new antifungal therapies, an increased incidence of infections due to Candida krusei and Candida glabrata has been reported. Other fungi that can infect immunocompromised patients as a result of environmental exposures (e.g., Penicillium purpurogenum,13 Scedosporium prolificans14) can cause lethal infections.
A marked decrease in the incidence of Pneumocystis jiroveci pneumonia has been found recently, primarily owing to use of specific prophylaxis in patients at risk and the use of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients. In a recent report, P. jiroveci infection was documented in 2.5% of patients undergoing allogeneic HSCT. The majority of cases occurred late in the course following HSCT (median 14.5 months)15 and with a CD4+ count less than 200 cells/mm3.
Mycobacterium Infections
There has been a marked decrease in pulmonary tuberculosis in HIV-infected patients with the introduction of HAART.16 However, remarkable geographic differences in the incidence of pulmonary tuberculosis in such patients have been reported.17 A high level of suspicion is necessary to diagnose pulmonary tuberculosis in ICU patients; tuberculosis should be particularly considered in patients with T-cell defects (see Table 68-1). The typical radiologic pattern is often replaced by diffuse, basal, or miliary infiltrates as well as mediastinal lymph nodes. Although sputum analysis is a good noninvasive test for mycobacterium staining, most patients will undergo bronchoscopy, with a diagnostic yield of more than 90%.
Viruses
Cytomegalovirus (CMV) is the most prevalent and lethal virus causing pneumonia in ICU patients. The incidence of CMV infection will depend on several factors: the type of transplant (highest in allogeneic HSCT recipients), degree of immunosuppression (highest when graft rejection is present and/or additional immunosuppressive treatment is required), and serologic status. The risk for CMV pneumonia without prophylaxis is greater in allogenic (20%-35%) than autologous transplantation (1%-6%). Patients receiving heart/lung or lung transplants are at high risk for CMV infections, probably because the lung harbors latent CMV, and therefore CMV can be transmitted into the allograft. The introduction of HAART has resulted in a drastic decrease in the number of cases of CMV disease in HIV-infected patients. CMV infection is extremely rare in patients with cancer.18
Since a third of patients with serologic evidence of previous CMV infection will develop CMV pneumonia, emphasis must be placed on the prevention of CMV disease in high-risk patients. In addition, reactivation of CMV probably contributes to the net state of immunosuppression, resulting in increased susceptibility to other infectious agents. CMV antigenemia based on the detection of the pp65CMV antigen in peripheral blood leukocytes, and quantitative PCR for early detection of viral DNA/RNA in serum, are used for early detection of active infection. Both assays have a sensitivity and specificity for the diagnosis of active infection of greater than 80% and diagnose active infection 1 to 3 weeks before conventional methodologies.19 As a rule, symptomatic CMV infection will not develop before 2 to 3 weeks after transplantation. However, widespread use of anti-CMV prophylactic therapy has resulted in significantly delayed appearance of CMV among transplant recipients.20
The clinical and radiologic findings of CMV pneumonia are nonspecific. Occasionally, involvement of other organ systems with hepatitis, ulcerative gastroenteritis, hemorrhagic colitis, or retinitis may be a clue to the etiology of the pulmonary disease. Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. New treatment options for CMV are urgently needed and may be critical for the management of drug-resistant CMV disease, which will probably become more prevalent with increased use of antiviral drugs in ICU patients.21 Before the development of surveillance and prophylactic measures, CMV pneumonia had a high mortality that reached 85%. Currently, mortality is between 30% and 50%.
Recent developments in molecular-based diagnostic tools have shown that conventional respiratory viruses (influenza, parainfluenza, RSV, adenoviruses, enteroviruses, rhinoviruses) are frequent causes of respiratory illnesses and are associated with high rates of morbidity and mortality among ICU patients.22
Diagnostic Approaches
Evaluation of pulmonary infiltrates in the ICU host remains a diagnostic challenge (Table 68-3). A confident diagnosis can seldom be made based on clinical and conventional radiology. Sputum cultures have a low sensitivity but are indicated because organisms isolated in the upper respiratory tract are likely to be the cause of the pneumonia. Since ICU patients with pulmonary infection are at risk for rapid dissemination of the disease with accompanying acute respiratory failure, fiberoptic bronchoscopy (FOB) should be considered early after the appearance of pulmonary infiltrates. Early use of FOB may add to prompt identification of the specific etiologic agent, facilitating an etiology-guided treatment and avoiding unnecessary and potentially harmful additional treatment. It has been shown that early diagnosis of both viral and fungal infections decreases mortality.23 Fiberoptic bronchoscopy is a low-risk procedure that can be safely performed in most patients, including those with hypoxemia who are treated with supplemental oxygen or during noninvasive ventilation. In ICU patients, it provides a specific diagnosis in 50% to 80% of cases.3,24,25
TABLE 68-3 Variables Related to Mortality in Different Groups of Immunocompromised Patients
Bronchoalveolar lavage (BAL) is a reliable technique for detecting opportunistic infections such as P. jiroveci, CMV, and fungi but also bacteria, mycobacteria, and other pathogens. It can still recover resistant pathogens even after several days of empirical treatment, thereby allowing modifications of the primary regimen. This bronchoscopic technique also provides useful information in diagnosing noninfectious etiologies such as diffuse alveolar hemorrhage or alveolar proteinosis that can occur in ICU patients.26 The protected specimen brush (PSB) does not seem to add diagnostic information to BAL. By contrast, a simple, safe, and cost-effective technique such as tracheobronchial aspirate may complement BAL in diagnosing pneumonia in ICU patients.32
Rarely, an open lung biopsy will be needed for diagnostic purposes. Although its diagnostic yield is high and often leads to changes in therapy,27 the indications and proper moment must be selected carefully, owing to potential morbidity and mortality.
Thoracic CT scan is an important diagnostic tool in invasive pulmonary aspergillosis (IPA). The halo sign (hemorrhagic pulmonary nodule) and air-crescent sign (cavitation) are early radiologic signs typical of IPA. This technique is also valuable in detecting pneumonic infiltrates in febrile neutropenic patients, particularly in transplant recipients,28 since it can detect pulmonary infiltrates when the chest x-ray is normal and may provide a time gain of several days in diagnosis. On the other hand, neutropenic patients with fever and a normal HRCT scan have a very low risk of pneumonia. A potential drawback of the CT scan in evaluating pulmonary infiltrates in ICU patients is its incapacity to detect polymicrobial infections. The possibility of more than one etiologic agent can be as high as 15% in some groups of ICU patients.
Prognostic Factors for Pneumonia in Intensive Care Patients
Pneumonia in ICU patients carries a high mortality irrespective of the factors leading to the altered immune status. Those patients with the highest mortality rate are recipients of an HSCT. A number of additional prognostic factors have been identified that portend a poor prognosis.29 Some of these factors are common to the different groups of ICU patients, whereas others relate to specific groups. Particularly relevant is the requirement for mechanical ventilation, which is associated with a grim prognosis, particularly in HSCT recipients, where the mortality rate is higher than 90%; very few survive 6 months after the onset of this pulmonary complication. Another prognostic factor that has a decisive influence on outcome is inadequacy of empirical antimicrobial treatment. The difficulty of making an appropriate antibiotic selection in light of growing resistance and the wide spectrum of potential etiologic factors emphasizes the importance of designing strategies aimed at obtaining an early diagnosis. The impact of diagnostic delay on mortality is an important theme in the care of seriously ill patients, particularly as it affects the adequacy of initial therapy.29,30
Therapeutic Strategies
Noninvasive Ventilation
Patients requiring mechanical ventilation may have a worse prognosis than similar patients matched for general severity-of-illness scoring systems, such as APACHE II, because mechanical ventilation may be directly injurious to the lungs through increasing the risk for nosocomial pneumonia.30 Early implementation of noninvasive ventilation (NIV) is indicated in the early stage of hypoxemic acute respiratory failure in ICU patients, since it decreases the requirement for intubation and the incidence of nosocomial pneumonia.31 However, there are concerns with the nonselective use of NIV in immunocompromised patients, especially insofar as it may have a deleterious impact on clinical course by delaying the institution of conventional mechanical ventilation in patients who have acute lung injury.32
Empirical Treatment of Suspected Pneumonia
Empirical treatment of pneumonia in ICU patients will vary depending on factors influencing the net state of immunosuppression (see Tables 68-1 and 68-2) and local patterns of microbial resistance.33 For neutropenic patients with fever, administration of empirically chosen intravenous antibiotics is a widely accepted clinical practice.34 However, there is considerable controversy regarding this topic. Often there is an unwise combination of potent broad-spectrum antimicrobial drugs for long periods of time. Clearly this approach is highly cost-ineffective and can cause harm due to toxicity and potential interactions of the drugs administered.35
Novel antifungal and antiviral (mainly CMV) diagnostic tests not only provide earlier diagnosis and need for treatment, but negative tests may support withholding specific therapy, thereby avoiding the risk of severe side effects.35 Recently, considerable attention has been directed towards stratification of patients with febrile neutropenia according to their risk. Studies have shown that by using demographic and clinical data, as well as the evaluation of different inflammatory markers such as procalcitonin,36 interleukin (IL)-6, and IL-8,37 it is possible to identify patients at low risk for complication who might be safely managed with a more simplified antibiotic regime, even on an outpatient-monitored basis. These findings represent an important step forward in the rational use of antibiotic treatment, offering the potential for cost savings, reduction in adverse drug events, and decreases in antibiotic resistance and hospitalization.35
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