on 27-Nov-2022 (Sun)

Pulmonary infections are among the most common types of tissue-invasive infections in immunocompromised individu

Immunocompromised hosts are defined by susceptibility to infection with organisms of little virulence in normal individuals or with increased severity of common infections

All immunosuppressive treatments, including those used intermittently (eg, biologic agents targeting inflammatory mediators), should be reviewed when assessing a patient's risk for infection

Multiple simultaneous processes are common. These may include dual infection with Pneumocystis jirovecii (PCP; formerly Pneumocystis carinii) and cytomegalovirus (CMV) or superimposition of another process (lung injury or drug toxicity). Sequential infections (eg, viral infection preceding bacterial or fungal infection) are common

Patients with humoral immune defects are at risk for bacteremia, sinopulmonary infections, meningitis, and skin infections caused by encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis) [9]. In addition, humoral immune defects prevent the development of fully protective antibody responses to pneumococcal vaccination, although pneumococcal infections appear to be less severe in vaccinated versus nonvaccinated immunocompromised patients [10,11]. Patients treated with anti-CD20 antibodies are also at risk for hepatitis B virus reactivation; those treated with proteasome inhibitors have an increased risk of varicella-zoster reactivation [12].

T cell impairment. In these individuals, infection due to intracellular organisms (eg, Mycobacteria, Legionella, Nocardia, Strongyloides) and infection due to Pneumocystis, yeasts (eg, Cryptococcus), dimorphic mycoses (eg, Histoplasma), molds (eg, Aspergillus), and herpes viruses (eg, cytomegalovirus [CMV]) are increased. CMV is also a predisposing factor in subsequent opportunistic infections (eg, Pneumocystis pneumonia, Aspergillus).

Pulmonary infections due to molds, Nocardia, and metastatic staphylococcal infections are more common in patients with neutrophil dysfunction (chronic granulomatous disease) in addition to neutropenia and also occur in patients receiving glucocorticoids and/or T cell suppression.

The immunocompromised patient is also more likely to present with dissemination of pulmonary disease to the skin or central nervous system (eg, Aspergillus species, mycobacterial or Nocardia infections). When disseminated disease is being considered, careful skin examination with biopsy of concerning skin lesions, magnetic resonance imaging of the central nervous system, sampling of the cerebrospinal fluid, and bone imaging (eg, bone scan) may be helpful in diagnosis and determining response to therapy.

Pulmonary infections can be divided into the following general categories:

● Community acquired

● Nosocomial

● Reactivation

● Environmental exposure

Bacterial pneumonia frequently follows a viral respiratory tract infection, infection with atypical pathogens, or cytomegalovirus [2,16].

The potential for antimicrobial resistance in the compromised host population exceeds that in the general population, in part because of exposures to the hospital environment and to antimicrobial agents for treatment and prophylaxis and, frequently, ongoing microbial replication [17-19]. Inadequate initial (empiric) therapy of pneumonia has been linked to increased mortality [18].

Hospital-acquired (nosocomial) or health care-associated pneumonias arise most commonly in patients with preexisting lung injury (eg, chronic obstructive pulmonary disease, bronchiectasis), during intubation, or following aspiration [20].

The ESKAPE pathogens (ie, Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter spp, Pseudomonas aeruginosa, and Enterobacter spp) commonly colonize the airways, skin, intravascular catheters, endotracheal tubes, wounds, and tracheal anastomoses (in lung transplant recipients). As such, these pathogens are common causes of nosocomial pulmonary infections and are frequently multidrug resistant [20,21]. Gram-positive organisms including streptococci resistant to fluoroquinolones used for prophylaxis and methicillin-resistant S. aureus may also be implicated in pneumonia in these hosts

Major sources of environmental pathogens that lead to pulmonary infection in immunocompromised hosts are air, soil, and potable water. Clues to such exposures may be obtained with careful histories of patient travel (mycobacteria, parasites, endemic viruses, and fungi), home conditions (molds), occupation, and hobbies (eg, garden, farm, or animal exposures). As examples, gram-negative pneumonia (due to organisms such as Legionella pneumophila and P. aeruginosa) occurs in patients due to a contaminated water or air supply. NTM are commonly found in water supplies.

Geographically restricted infections causing significant pulmonary infection in immunocompromised hosts include endemic bacteria (eg, tuberculosis), viruses (eg, Middle East respiratory syndrome coronavirus), and fungi (eg, Histoplasma or Coccidioides spp). Exposure to soil has been linked to infections with Aspergillus and Nocardia spp and, in Southeast Asia, with Penicillium marneffei and Burkholderia pseudomallei. Caves and bird excrement carry Cryptococcus neoformans. Burkholderia cepacia strains from soil have been demonstrated to match clinical isolates in cystic fibrosis patients using genotyping techniques [23]

Latent infections may reactivate in immunocompromised hosts many years after the initial exposure. Those that can affect the lung include but are not limited to herpes viruses (eg, cytomegalovirus, varicella-zoster virus), strongyloidiasis, Chagas disease, cryptococcosis, histoplasmosis, toxoplasmosis, or mycobacterial infections. Prior to starting immunosuppressive medications, patients should be screened for pertinent latent infections.

In a retrospective review of patients diagnosed with tuberculosis at Memorial Sloan-Kettering Cancer Center, patients with hematologic neoplasms and head and neck cancer had rates of tuberculosis 40 and 20 times greater than the rate among the United States population, respectively [24]. Thus, tuberculosis must be considered in these patients with pulmonary infiltrates

The three most important causes of fungal pulmonary infection are Pneumocystis jirovecii, Aspergillus species (especially A. fumigatus), and C. neoformans [2,25-34]. These agents require early targeted therapy for successful outcomes.

P. jirovecii pneumonia is one of the most common pulmonary infections in immunocompromised patients. Risk is greatest during the first six months after organ transplantation, with prolonged neutropenia, during periods of intense immunosuppression, and with systemic glucocorticoid use [25-28,35].

In patients not receiving prophylaxis, the occurrence of Pneumocystis infection is highly associated with cytomegalovirus (CMV) infection, possibly because of the inhibitory effect of CMV on alveolar macrophages and T lymphocyte function. Risk of infection is strongly associated with immunosuppression that includes chronic glucocorticoid administration (usually 15 to 20 mg prednisone equivalent daily for more than two weeks) or T lymphocyte depletion; bolus glucocorticoids and calcineurin inhibitor use contribute to the risk of infection and increased mortality.

The hallmark of infection due to P. jirovecii is the presence of marked hypoxemia, dyspnea, and cough with a paucity of physical or radiologic findings. In transplantation and neutropenia, Pneumocystis pneumonia (PCP) is generally an acute or subacute infection.

For other immunocompromised patients without HIV infection, 5 to 12 percent of patients who are not receiving prophylaxis will develop pneumocystosis [26].

In patients with untreated HIV, PCP is a more rapidly progressive process with a greater organism burden than in non-HIV-infected immunocompromised hosts.

Invasive pulmonary aspergillosis may result from primary infection acquired from a nosocomial or environmental source or may occur following immunosuppression in a patient who is chronically colonized. Infection due to non-fumigatus strains of Aspergillus and other molds with differing antimicrobial susceptibility patterns generally result in similar clinical presentations; hence, specific microbial diagnosis with susceptibility testing is essential for guiding therapy [39]

The incidence of Aspergillus infections in HCT recipients is 3 to 14 percent [40-42]. Ibrutinib has a unique cellular target (Bruton’s tyrosine kinase in B cell malignancies) and has been associated with an excess incidence of invasive mold infection [43].

The clinical course is determined by the timing of recognition and treatment of infection. Necrotizing bronchopneumonia with vascular invasion is a worrisome complication, characterized by hemoptysis, hemorrhage, and/or pulmonary infarction. Extrapulmonary dissemination most often occurs in persistently neutropenic and immunosuppressed hosts. Some patients manifest extrapulmonary disease at the time of diagnosis; the brain and skin are the most common sites involved. Other molds (eg, Scedosporium spp, Mucorales) also cause rapidly progressive, disseminated infection but manifest different antifungal susceptibility patterns, which highlight the importance of obtaining a microbiologic diagnosis.

Cryptococcal infection is often detected as an asymptomatic pulmonary nodule or lymph node enlargement on a routine chest radiograph. However, in one retrospective review of patients (the majority of whom were solid organ transplant recipients) with pulmonary cryptococcosis, clinical symptoms were present in 74 percent of 38 patients [44]. The most frequent symptoms were shortness of breath, cough, and fever. The presence of a pleural effusion was a poor prognostic factor by multivariate regression analysis, and overall mortality was 24 percent. Subacute consolidation with influenza-like symptoms may occur and may progress in the immunocompromised host to acute respiratory distress syndrome. Our own clinical experience suggests that asymptomatic infection remains common [45]

The major importance of cryptococcal pulmonary infection is that the lung is the portal of entry for disseminated infection, which frequently involves the central nervous system. Presenting symptoms of the central nervous system can be subtle and nonspecific (eg, headache with or without fever). Thus, an aggressive diagnostic evaluation must be initiated even for asymptomatic pulmonary infection. Among solid organ transplant recipients, cryptococcal infection is most common in liver transplant recipients [46].

Although Candida species are frequently isolated from sputum, cases of pulmonary invasion are extremely rare even in immunocompromised hosts. Thus, a positive sputum culture for Candida albicans should not lead to specific therapy against Candida spp; other processes should be sought to explain pulmonary symptoms.

By contrast, hematogenous seeding of the lungs during fungemia can occur with Candida species. Fungemia commonly results from infection of indwelling vascular access catheters and infection related to transplant surgery (particularly of the pancreas or liver).

C. auris is an uncommon pulmonary pathogen that more frequently involves the bloodstream and is often multidrug resistant [47]

Mucormycosis (previously called zygomycosis) is an infection caused by fungi that belong to the order Mucorales including Rhizopus spp, Mucor spp, Lichtheimia (previously Absidia) spp, Cunninghamella, Rhizomucor, and Apophysomyces spp [47]. The lung is a common site of infection along with the sinuses, rhinocerebral spaces, skin, and gastrointestinal tract

The spectrum of fungal pathogens in immunocompromised patients includes fungi with distinct antifungal susceptibility patterns. These include Scedosporium apiospermum complex and Lomentospora prolificans (formerly Scedosporium prolificans), Fusarium spp, Trichosporon spp, Geotrichum spp, and various dematiaceous or brown-black molds.

Dematiaceous molds, such as Aureobasidium, Alternaria, Curvularia, Phialophora, Wangiella, and Cladosporium, are increasingly implicated as causes of sinus, pulmonary, and central nervous system disease in transplant and leukemic patients [48]. These filamentous organisms pose special therapeutic problems because they may be resistant to multiple antifungal agents, including amphotericin B.

CMV is one of the most common viruses of concern in immunocompromised patients, especially transplant recipients. However, other viruses including community-acquired respiratory viruses are diagnosed commonly using either molecular screening tests or rapid antigen testing.

Most pulmonary viral infections in immunocompromised patients begin insidiously with constitutional symptoms including fever and a dry, nonproductive cough; some patients develop varying degrees of tachypnea, dyspnea, and hypoxemia [1-3].

In the absence of antiviral prophylaxis, CMV pneumonitis usually occurs one to four months post-solid organ transplantation [2,50].

The radiographic manifestations of CMV pneumonia can take many forms, but a bilateral, symmetrical, peribronchovascular, and alveolar process predominantly affecting the lower lobes is the most frequent. Less commonly, a focal consolidation more suggestive of a bacterial or fungal infection or even a solitary pulmonary nodule may be caused by CMV [2]. Mixed patterns on chest radiography should suggest dual infection; CMV and PCP or Aspergillus are common infections that may coexist

The immunocompromised patient is at increased risk for lower respiratory tract infection due to community-acquired respiratory viruses (RVI) compared with normal hosts. Influenza, parainfluenza, respiratory syncytial virus (RSV), metapneumovirus, and adenovirus infections are of special importance.

Human metapneumovirus (hMPV) is an increasingly recognized pathogen of immunocompromised children and adults [ 51]. In solid organ recipients, RVI may produce protracted symptoms and prolonged viral shedding with greater risk for progression from upper to lower respiratory tract infection.

Coronavirus disease 2019 (COVID-19) pneumonitis is discussed separately. Immunocompromised patients admitted with COVID-19 have an increased mortality compared with normal hosts. Patients receiving assisted ventilation for COVID-19 pneumonitis, and possibly also with intensive glucocorticoid therapy, have an increased incidence of superinfection with multidrug-resistant bacteria and fungi including Aspergillus and the Mucorales [52]

The clinical history is often suggestive of the possibility of superinfection of viral pneumonitis. Marked hypoxemia or purulence of sputum may develop acutely during the course of otherwise mild upper respiratory infection.

The seasonal variability of each respiratory virus in immunocompromised hosts reflects that seen in the general community. As a result, influenza, RSV, and hMPV generally cause disease from November through April in the northern hemisphere; rhinovirus typically circulates in the fall and spring; and adenovirus and parainfluenza circulate throughout the year [53]. Some cases may be observed earlier in immunocompromised hosts than in the general community as harbingers of an impending outbreak.

Respiratory viruses cause more severe disease with more frequent complications in immunocompromised individuals. The risk and severity of disease is greatest in individuals with significant T cell defects. The true incidence of respiratory viral infection is unknown, particularly as atypical presentations are common and may go unrecognized.

Progression from upper to lower tract disease occurs in 7 to 50 percent of HCT recipients and approximately 13 percent of solid organ transplant recipients infected with influenza [54]. Lung recipients are at greatest risk for complications of RVI [55]. Lower tract disease may occur in the presence of negative screening assays for respiratory viruses (eg, nasal swabs for antigen detection).

Primary varicella pneumonia may accompany chickenpox in normal adults and in the immunocompromised host [56]. Pulmonary involvement occurs within the first seven days of illness, with mortality approaching 18 percent [57,58]. Chest radiographs will reveal nodular or interstitial infiltrates in up to 16 percent of adults with chickenpox, while only 10 to 25 percent of these will have clinical symptoms [58]. Pulmonary involvement with HSV and VZV in the immunocompromised host should be considered a life-threatening emergency

In patients with cutaneous herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections, viral dissemination to liver, lungs, brain, or gastrointestinal tract can occur in up to 10 percent of patients. Nasal, oropharyngeal, or esophageal HSV or VZV infections may spread directly to the lungs with the development of vesicular lesions in the trachea

Parasitic pathogens are not a common cause of pulmonary involvement in immunocompromised hosts. However, infection with Strongyloides stercoralis and Toxoplasma gondii are important diagnostic considerations since they can lead to life-threatening infections

Hyperinfection strongyloidiasis is generally associated with conditions of depressed cellular immunity. Autoinfection within the gastrointestinal tract begins when rhabditiform larvae transform into filariform larvae, which penetrate the intestinal wall to enter the bloodstream, which can lead to polymicrobial bacteremia. Dissemination of filariform larvae and bacteria to the lungs, liver, heart, central nervous system, and endocrine glands induces inflammation that may result in symptomatic dysfunction of these organs. The chest radiograph reveals pulmonary infiltrates that consist of foci of hemorrhage, pneumonitis, and edema. Dual infections by CMV or PCP with Strongyloides may be observed.

Rapid reproduction occurs in certain individuals with appropriate exposure:

● Patients receiving glucocorticoids and calcineurin inhibitors

● Solid organ and hematopoietic cell transplant recipients

● Burn victims

● Individuals with an alcohol use disorder

● Individuals with hypogammaglobulinemia

T. gondii pneumonia is uncommon but, when it occurs, usually represents reactivation of latent infection. Patients at risk are typically seropositive for this pathogen (40 percent of adults in the United States and over 70 percent in Europe, South America, and Africa). Over 95 percent of clinical disease is restricted to the central nervous system, but T. gondii can cause chorioretinitis and pneumonia.

Heart and lung transplant recipients who are seronegative and receive an organ from a seropositive donor appear to be a high-risk group for T. gondii infection, with an incidence approaching 80 percent without prophylaxis [25]. Most infections affect only the transplanted organ including myocarditis or pneumonitis, but some cases are disseminated to the pleura and central nervous system.

The general rule is to be aggressive in pursuing a specific microbiologic diagnosis in immunocompromised patients with pulmonary infiltrates to enable early therapy while avoiding overly broad antimicrobial therapy.

A specific diagnosis avoids the potential toxicities of broad-spectrum antimicrobial therapies, most notably nephrotoxicity, drug interactions, and Clostridioides difficile colitis

Most immunocompromised patients with any signs of possible invasive infection should be hospitalized for evaluation.

Awareness of the epidemiology of infection in the community (eg, respiratory viruses, tuberculosis) and the individual (eg, travel history, sexual history, prior infections, occupational exposures) provide helpful clues.

Multiple simultaneous pulmonary processes occur often. These include infectious (eg, viral, bacterial, fungal, parasitic) and noninfectious (eg, pulmonary edema, malignancy) etiologies. Routine chest radiography and sputum sampling may fail to detect these concomitant diseases.

Serologic testing is generally not useful in the acute management of immunocompromised patients. These patients often fail to generate an adequate or timely antibody response to infection. Microbiologic testing should include antigen detection and/or nucleic acid detection-based assays as well as cultures

The presence or absence of pulmonary infiltrates should be defined by chest imaging. A routine chest radiograph may be insufficient to exclude pulmonary involvement if there are respiratory symptoms or historical features that suggest a possible pulmonary process. Minor abnormalities on a chest radiograph in the immunocompromised host merit further evaluation, generally including computed tomography scanning. Comparison with prior imaging studies is essential.

Antimicrobial agents used for prophylaxis should be avoided in empiric therapy.

Specific guidelines such as those for fever and neutropenia must be modified based on physical and radiologic findings and past medical history, including exposures, previous infections, and prior antimicrobial therapies.

Routine prophylaxis has increased the risk for unusual pathogens that are resistant to prophylactic agents including fluoroquinolone-resistant streptococci, other multidrug-resistant bacteria, azole-resistant molds, and ganciclovir-resistant cytomegalovirus (CMV) [6,9,10]. As a result, empiric therapies for infection require use of agents not used for prophylaxis in the recent past and review of prior microbiology data from individual patients.

Whether due to underlying malignancy, chemotherapy, or the side effects of other drugs, the depth and duration of neutropenia are correlated with the risk for infection [11].

The originating site of infection frequently cannot be identified in febrile cancer patients [15-17]. When identified, common sources of infection in the febrile neutropenic patient are colonizing organisms from the upper and lower respiratory tract especially with mucositis and aspiration, the gastrointestinal tract (including the perineal and perirectal areas), the urinary tract, and the skin (including intravenous lines and wounds) [6,18,19].

Pulmonary infections are among the leading causes of morbidity and mortality in febrile neutropenic patients [ 20]. Many infections are detected only at autopsy, particularly disseminated fungal or combined fungal and bacterial infections [21-23].

Glucocorticoids — Glucocorticoids play an important role in the pathogenesis of pneumonia due to depression of phagocytic function of alveolar macrophages and neutrophils, decreased mobilization of inflammatory cells into areas of infection, and alterations in antigen presentation and lymphocyte mobilization. These effects increase the risk of bacterial and fungal infections (including those due to Pneumocystis jirovecii, Nocardia spp, and Aspergillus spp) and the risk for pulmonary involvement in the setting of certain herpes virus infections (eg, CMV, varicella zoster virus) [29]. A meta-analysis of 42 observational studies described a dose-dependent increase in serious infection risk of 1.5- to 4-fold for glucocorticoid doses of <5 mg to >20 mg/day [30].

The agents used to suppress T lymphocyte function include the calcineurin inhibitors (eg, cyclosporine, tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus, everolimus) used in organ and hematopoietic cell transplantation. These predispose to herpesvirus infections (CMV, herpes simplex, and varicella-zoster) and community-acquired respiratory viruses, fungal infections (including Cryptococcus, Pneumocystis, and Aspergillus spp), and parasites (eg, Strongyloides, Toxoplasma, and Trypanosoma cruzi) [7,33-37].