Epidemiology of pulmonary infections in immunocompromised patients

INTRODUCTION — Pulmonary infections are among the most common types of tissue-invasive infections in immunocompromised individuals. The spectrum of potential pathogens known to cause pulmonary infections in immunocompromised individuals has grown as a result of intensified immunosuppression, prolonged patient survival, the emergence of antimicrobial-resistant pathogens, and improved diagnostic assays. Immunocompromised hosts are defined by susceptibility to infection with organisms of little virulence in normal individuals or with increased severity of common infections. Susceptibility to specific pathogens varies based on the underlying immune defects (eg, hematopoietic stem cell transplantation, solid organ transplantation, neutropenia). All immunosuppressive treatments, including those used intermittently (eg, biologic agents targeting inflammatory mediators), should be reviewed when assessing a patient's risk for infection.

Common pulmonary infections in the immunocompromised host will be reviewed here. The evaluation of an immunocompromised patient with pulmonary infiltrates is discussed separately. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Infectious risks associated with specific immunomodulating agents are discussed separately. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Secondary immunodeficiency induced by biologic therapies".)

GENERAL CONSIDERATIONS — Pulmonary infection is the most common form of documented tissue-invasive infection observed in immunocompromised patients [1-5]. The specific approach to management of pulmonary infection is determined by the clinical status of the patient, the type and degree of immunosuppression, and the availability of a specific microbiologic diagnosis. General considerations include:

●The importance of obtaining specific microbiologic diagnoses in the care of immunocompromised individuals cannot be overemphasized. Antimicrobial susceptibility testing, quantitative molecular testing, and immunohistology are essential components of the diagnostic evaluation. Newer molecular techniques (eg, broad-range polymerase chain reaction, whole-genome sequencing) are increasingly used; the clinical value of these tests remains under investigation [6-8].

●Early imaging (eg, computed tomography scan) is an important part of the diagnostic evaluation. Invasive procedures (biopsies and/or bronchoscopy) are often necessary to establish a microbiologic diagnosis.

●Empiric antibiotic therapy should be started as soon as possible after initial sample for cultures are obtained. Antimicrobial selection should be based on available data (eg, epidemiologic exposures, sputum Gram stain/special stain, prior microbiologic data, recent antibiotic use). Loading doses should be administered when appropriate, with subsequent adjustment for renal or hepatic dysfunction. Initial broad empiric regimens can be modified as new microbiologic data are obtained.

●Reduction of the overall level of immune suppression may be a component of care. However, immune reconstitution may be detrimental with the risk of exuberant inflammatory responses, allograft rejection, and graft-versus-host disease.

●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.

●Laboratory assay results must be interpreted cautiously and must consider the clinical context of each patient. As examples, detection of galactomannan or CMV in bronchoalveolar lavage fluid do not necessarily represent invasive disease. (See "Diagnosis of invasive aspergillosis", section on 'Bronchoalveolar lavage fluid' and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Clinical manifestations'.)

HOST SUSCEPTIBILITY — A patient's risk for infection with specific pathogens is influenced by the nature of their underlying immune defect (eg, innate or adaptive immunodeficiency). In practice, most patients have mixed immune defects.

Humoral — Humoral immune defects, including hypogammaglobulinemia, are common among patients with hematologic malignancies, HIV infection, nephrotic syndrome, impaired splenic function, or certain congenital disorders (eg, common variable immune deficiency) and can result from chemotherapy, biologic therapy, or chimeric antigen receptor-modified T (CAR-T) cell therapy or following organ transplantation. Among organ transplant recipients, increased attention to the role of antibody (donor-specific antibody) in allograft injury has led to increased use of plasmapheresis, proteasome or eculizumab therapies, CAR-T cell therapies, or B cell depletion with anti-CD20 therapy, all of which can induce hypogammaglobulinemia.

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]. Whether antibody repletion offsets these defects is unclear as studies evaluating antibody repletion outside of the congenital deficiency syndromes are lacking.

Cell mediated — T lymphocyte-mediated immunity is impaired in most individuals with AIDS, immunosuppression for organ transplantation, and graft-versus-host disease prophylaxis and in many with hematologic malignancies. Individuals with impaired antigen presentation by monocytes and dendritic cells may also manifest relative 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). Such infections are also prominent in patients receiving ongoing T lymphocyte immunosuppressive or immunomodulatory therapies for rheumatologic diseases or inflammatory bowel disease. (See "Infection in the solid organ transplant recipient" and "Overview of infections following hematopoietic cell transplantation".)

Neutrophils — Neutropenia predisposes to infection with endogenous bacterial flora and candidemia, particularly in the presence of mucositis and indwelling intravenous catheters. 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. (See "Overview of neutropenic fever syndromes" and "Diagnostic approach to the adult cancer patient with neutropenic fever".)

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. (See "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis" and "Central nervous system tuberculosis: An overview".)

Genetic polymorphisms in various immune-response genes predispose to specific infections such as Aspergillus or CMV infections [13,14]. Genetic mutations have also been described for some immunodeficiencies recognized in patients with recurrent infections. In general, such individuals present with chronic or recurrent bacterial, fungal, or viral infections of the skin, sinuses, respiratory, and/or gastrointestinal tract. Many develop autoimmune conditions, malignancies, atypical rashes, paucity of lymphoid tissue or lymphadenopathy, and unusual reactions or unresponsiveness to common vaccines. These disorders may affect both humoral and cellular immune functions as well as defects in innate immunity, complement, and/or phagocytosis. The evaluation of such individuals is described elsewhere. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Risk factors' and "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

PATTERNS OF INFECTION — Epidemiologic exposures combined with the patient's immune defect determine the pattern of pulmonary infection. Pulmonary infections can be divided into the following general categories:

●Community acquired

●Nosocomial

●Reactivation

●Environmental exposure

Community-acquired infection — Bacterial pneumonia in the immunocompromised host most often involves the same pathogens acquired in the community by immunocompetent hosts [7,15]. Bacterial pneumonia frequently follows a viral respiratory tract infection, infection with atypical pathogens, or cytomegalovirus [2,16]. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults".)

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 infection — Colonization of patients with hospital-acquired microbes occurs early in hospitalization. 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]. This is common in patients who are debilitated or have hepatic or renal dysfunction, diabetes, encephalopathy, or mucositis and who may be unable to protect their airways. Lung transplant recipients with prior colonization with antimicrobial-resistant organisms, disrupted lymphatic drainage, abnormal pulmonary clearance mechanics, and immunosuppression are at particular risk. Hematogenous seeding of the lungs (septic emboli) in association with bacteremia or fungemia is common in neutropenic hosts, often in association with vascular access catheters, and may also present with skin or gastrointestinal lesions.

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.

In patients with recurrent lung infections including those with cystic fibrosis and lung and liver transplant recipients, Stenotrophomonas and Burkholderia spp as well as nontuberculous mycobacteria (NTM) may carry or develop antimicrobial resistance following exposures to multiple courses of antimicrobial therapy. Once established, such infections often require prolonged courses of bactericidal therapy and, in some cases, surgery to achieve cure [22]. It is unclear whether these should be considered nosocomial or simply relapsed, progressively drug-resistant infections. Although NTM infection rates are low compared with other types of infection, NTM infections in transplant and other immunocompromised hosts cause significant morbidity. (See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

Infections in lung transplant recipients are discussed in greater detail separately. (See "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Viral infections following lung transplantation".)

Environmental exposures — 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]. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection" and "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection" and "Epidemiology of nontuberculous mycobacterial infections" and "Epidemiology and clinical manifestations of Talaromyces (Penicillium) marneffei infection" and "Epidemiology and clinical manifestations of invasive aspergillosis" and "Nocardia infections: Clinical microbiology and pathogenesis" and "Bacterial infections following lung transplantation" and "Bacterial infections following lung transplantation", section on 'Burkholderia cepacia'.)

Reactivation infection — 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. (See "Evaluation for infection before solid organ transplantation" and "Evaluation for infection before hematopoietic cell transplantation".)

Screening for tuberculosis by tuberculin skin test or interferon-gamma release assay prior to immunosuppression is particularly important and discussed in detail separately. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Tuberculosis in solid organ transplant candidates and recipients" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)

PATHOGENS — The differential diagnosis of pulmonary infections in the immunocompromised host is broad. The following discussion addresses some of the most common pathogens that should be considered in the differential diagnosis.

Bacteria — Community-acquired pathogens include S. pneumoniae, Haemophilus influenzae, Mycoplasma, Legionella, Chlamydia, and others. Distinction between community-acquired and nosocomial pathogens may be less meaningful as antimicrobial resistance increases [21]. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults".)

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 nature and time course of immunosuppression is also an important factor to consider. Acute neutropenia may provoke the rapid onset of infection due to invasive nosocomial or colonizing organisms (eg, Pseudomonas, Aspergillus). Successful empiric therapy generally includes agents active against organisms previously identified in the individual. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

Fungi — 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.

Pneumocystis jirovecii — 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]. The natural reservoir of infection remains unknown. Aerosol transmission of infection has been demonstrated in animal models [36,37]. Clusters of infections have been documented in HIV-infected patients, renal transplant recipients, and patients with hematologic malignancies; one genotyping study showed that person-to-person transmission could occur in these settings but is uncommon [38]. Both new exposures and reactivation of undertreated prior infections remain significant factors in the incidence of disease in immunocompromised hosts. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)

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. Prophylaxis against Pneumocystis should be administered for at-risk patients unless there are contraindications. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

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. In lung transplant recipients, the rate of asymptomatic isolation of P. jirovecii approaches two-thirds of the total in some series. Of these, up to one-half are expected to develop symptomatic disease without treatment. 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. The risk of PCP has declined in patients with HIV infection since the advent of antiretroviral therapy.

Aspergillus — 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 risk of invasive pulmonary aspergillosis appears to be high once the respiratory tract, sinuses, or trachea are colonized and the intensity of immunosuppression is maintained or increased. Preemptive antifungal therapy may be indicated when colonization is noted, or, alternatively, prophylaxis can be given to the highest risk patients (eg, patients with acute leukemia undergoing chemotherapy and/or allogeneic hematopoietic cell transplantation [HCT] with graft-versus-host disease). 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]. (See "Prevention of infections in hematopoietic cell transplant recipients".)

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. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Treatment and prevention of invasive aspergillosis".)

Cryptococcus species — 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]. (See "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus gattii infection: Clinical features and diagnosis".)

Candida species — 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. (See "Candida infections of the abdomen and thorax", section on 'Pneumonia'.)

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). Other Candida species (eg, Candida glabrata and Candida krusei) have become more frequent pathogens in these hosts, possibly as a result of nosocomial exposures and prior exposure to prophylactic agents including fluconazole. C. auris is an uncommon pulmonary pathogen that more frequently involves the bloodstream and is often multidrug resistant [47]. (See "Management of candidemia and invasive candidiasis in adults".)

Agents of mucormycosis — 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.

Invasive disease is more common in diabetic patients often with exogenous immune suppression and neutropenia and may follow CMV infection. In the lungs, these molds cause rapidly progressive single or multiple pulmonary nodules and may produce lung infarction and necrosis, hemorrhage, and empyema. Metastatic spread to the skin is common. Surgical excision is generally required in addition to antifungal therapy. (See "Mucormycosis (zygomycosis)".)

Other fungi — 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. Failure to respond to therapy may suggest the need for antifungal susceptibility testing. (See "Treatment of Scedosporium and Lomentospora infections" and "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Antifungal susceptibility testing".)

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.

Viruses — 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].

Cytomegalovirus — Solid organ recipients at greatest risk for primary CMV infection are donor seropositive and recipient seronegative. In contrast, the greatest risk for CMV pneumonitis following HCT occurs in the seropositive recipient of seronegative stem cells. The incidence of CMV is related to the intensity of the immunosuppressive therapy, notably T lymphocyte-depleting therapies in organ and stem cell transplantation [49]. Much of the lung injury in the HCT recipient is due to immune responses to CMV antigens. Thus, a pneumonitis syndrome may not occur until after the reemergence of immune function with hematopoietic engraftment.

In the absence of antiviral prophylaxis, CMV pneumonitis usually occurs one to four months post-solid organ transplantation [2,50]. Late infection may occur following completion of antiviral prophylaxis or with treatment for graft rejection. The attack rate and severity of pneumonia is greater in recipients of lung allografts (approximately 50 percent) than in the other transplant groups. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

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.

CMV infection in transplant recipients is discussed in greater detail separately. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients".)

Community-acquired respiratory viruses — 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. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Parainfluenza viruses in adults" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Human metapneumovirus infections" and "Viral infections following lung transplantation".)

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]. (See "COVID-19: Clinical features" and "COVID-19: Diagnosis" and "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'COVID-19-associated infection' and "Mucormycosis (zygomycosis)", section on 'Coronavirus disease 2019-associated'.)

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. Data from retrospective studies allow some generalizations about respiratory viral infections in immunocompromised hosts.

●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). (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Human metapneumovirus infections" and "Parainfluenza viruses in adults", section on 'Clinical manifestations'.)

Herpes simplex and varicella-zoster viruses — 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.

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.

Parasites — 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.

Strongyloides — 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. (See "Strongyloidiasis".)

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

Toxoplasmosis — 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. (See "Toxoplasmosis in patients with HIV".)

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.

SUMMARY

●The differential diagnosis of pulmonary infections in the immunocompromised host is broad and includes bacteria, fungi, viruses, and parasites. The spectrum of potential pathogens known to cause pulmonary infections in immunocompromised individuals has grown as a result of intensified immunosuppression, prolonged patient survival, the emergence of antimicrobial-resistant pathogens, and improved diagnostic assays. (See 'Introduction' above and 'Pathogens' above.)

●Immunocompromised hosts are defined by susceptibility to infection with organisms of little native virulence in normal individuals. Each group of hosts (eg, solid organ or hematopoietic stem cell recipients, patients with neutropenia) has enhanced susceptibility to a subset of pathogens depending upon the nature of the underlying immune defects. The risk for severe pulmonary infection should be considered a reflection of the intensity, persistence, and nature of immune deficiencies. The impact of antibody-based therapies targeting T and B lymphocytes and inflammatory mediators should be considered in the assessment of risk. (See 'Introduction' above.)

●Patient exposures and the nature of the host immune defects influence the pattern of pulmonary infection. These infections can be divided into the following general categories (see 'Patterns of infection' above):

•Community acquired (common pathogens)

•Hospital acquired (nosocomial) or health care associated

•Reactivation (latent infections, often distant from initial exposures)

•Environmental exposures (patient-specific exposures)

●A number of general considerations apply in the immunocompromised patient with a pulmonary infection (see 'General considerations' above):

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

•Early imaging (computed tomography scan) and specific microbiologic diagnoses are essential. Invasive procedures (biopsies and bronchoscopy) are often necessary to establish a microbiologic diagnosis. Antimicrobial susceptibility testing and advanced diagnostic testing including immunohistology and molecular assays are important to the management of pneumonia in immunocompromised patient.

•Microbicidal therapy must be started as soon as possible. Empiric therapy should be based upon the data that are available (epidemiologic history, sputum Gram stain, special stains, prior microbiologic data, previous courses of antimicrobial agents). Overly broad initial antimicrobial therapy can be modified based upon more specific microbiologic data as it becomes available.

•Reduction of the overall level of immune suppression may be necessary to improve outcomes but can also lead to immune reconstitution syndromes.

•Laboratory assay results must be interpreted cautiously and must take into account the clinical context of each patient.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren A Marr, MD, who contributed to an earlier version of this topic review.