Approach to the immunocompromised patient with fever and pulmonary infiltrates

INTRODUCTION — The spectrum of immunocompromised hosts has expanded with prolonged survival of solid organ and hematopoietic cell transplant recipients, patients with immune deficiencies (including congenital disorders and HIV/AIDS), and autoimmune disorders, as well as the development of novel cancer therapies including immunotherapies and checkpoint inhibitors. Novel immunosuppressive therapies create a diverse set of immune deficits that create the substrate for opportunistic infections. Compared with immunologically normal hosts, these patients are defined by susceptibility to infection with organisms of otherwise low native virulence or by increased severity of common infections. Survival has improved with the availability of newer antimicrobial agents but is threatened by the emergence of antimicrobial resistance.

The approach to the immunocompromised patient with fever and pulmonary infiltrates will be reviewed here. The epidemiology of these infections is discussed separately (see "Epidemiology of pulmonary infections in immunocompromised patients"). An overview of pulmonary infections in immunocompromised hosts is presented separately. Empiric therapy for adult patients with fever and neutropenia is also discussed separately.

●(See "Epidemiology of pulmonary infections in immunocompromised patients".)

●(See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

●(See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

●(See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

GENERAL PRINCIPLES — Pulmonary infection is the most common tissue-invasive infection in immunocompromised patients [1-7]; early diagnosis and directed treatment are the cornerstones of successful management. 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. Invasive diagnostic techniques are often required.

Several general principles are useful for the evaluation of immunocompromised patients presenting with fever and pulmonary infiltrates.

●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 or sequential pulmonary processes occur often. These include infectious (eg, viral, bacterial, fungal, parasitic) and noninfectious (eg, pulmonary edema, hemorrhage, 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.

●In some patients, radiographic evidence of pneumonitis may appear or intensify with immune reconstitution, notably engraftment after neutropenia. In such patients, there are few data to guide decisions regarding empiric antimicrobial therapies [8].

●After obtaining microbiologic samples, empiric antimicrobial therapy is initiated and is continued until specific microbiologic data are available to guide therapy. If anticipated invasive studies are delayed, empiric therapy should be instituted promptly after blood, urine, and sputum samples are obtained. Immediate empiric therapy is also appropriate for individuals who are clinically unstable, notably for those with hypotension, hypoxemia or progressive pulmonary processes, altered mental status or meningitis, evolving skin lesions, bleeding diathesis, or severe hyperglycemia. 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. (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".)

EPIDEMIOLOGY AND RISK OF PNEUMONIA — The incidence and severity of pneumonia vary with the characteristics of the affected individual, including the nature and duration of any immune deficits (table 1) and epidemiologic exposures . The epidemiology and risk for pneumonia in immunocompromised hosts have shifted with the increased variety and intensities of chemotherapeutic and/or immunosuppressive regimens and with patterns of antimicrobial use. Predisposition to certain specific pulmonary pathogens or syndromes based on specific therapies (coupled with individual risks) is worth consideration:

Routine prophylaxis and lack of antimicrobial stewardship have 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. Infectious risk is related to epidemiologic exposures both in the community, endogenous (microbiome of the host), and in the clinical center. Risk is altered (but not completely eliminated) by antimicrobial prophylaxis.

ETIOLOGY OF PULMONARY INFILTRATES — Infectious and noninfectious causes of pulmonary infiltrates may coexist in immunocompromised hosts.

Infection — The etiology of infectious pneumonitis in immunocompromised patients, when documented, is diverse [2,3,11-21]. The spectrum of infection is altered by antimicrobial prophylaxis. The frequency of identification of common organisms varies with the nature of the host and with the aggressiveness of diagnostic approach. In one series using invasive diagnostic approaches for pulmonary infiltrates in immunocompromised hosts, a specific diagnosis was obtained in 162 of the 200 cases evaluated (81 percent) [22]. An infectious etiology was found in 125 patients (77 percent) and a noninfectious etiology in 37 (23 percent); 38 (19 percent) remained undiagnosed. Among infectious causes, bacteria were documented in 24 percent, fungi in 17 percent, and viruses in 10 percent. In 7 percent, the etiology was polymicrobial. There were no statistically significant associations between the specific underlying immunosuppressive state and the etiology of the pulmonary infiltrates. Overall, including both invasive and noninvasive approaches to diagnosis, approximate rates of infection include [22-24]:

●Conventional bacteria – 37 percent (higher with neutropenia and mucositis and early after lung transplantation)

●Fungi – 14 percent (higher with prolonged neutropenia)

●Viruses – 15 percent (common with T cell suppression)

●P. jirovecii (formerly P. carinii) – 5 to 15 percent (without prophylaxis)

●Nocardia spp – 7 percent (including sulfa-resistant strains)

●Mycobacterium tuberculosis – 1 percent (higher in endemic regions)

●Mixed infections – 20 percent

The spectrum of pulmonary fungal infection includes infection with non-fumigatus Aspergillus spp, Fusarium spp, Scedosporium spp, and the Mucorales in patients with neutropenia and/or in association with graft-versus-host disease (GVHD) [25-27]. Azole-resistant mold infection may emerge during therapy (image 1). (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections" and "Mucormycosis (zygomycosis)".)

Mixed infections with combinations of respiratory viruses, cytomegalovirus (CMV), Aspergillus spp, and/or gram-negative bacilli are common in neutropenic hosts and hematopoietic cell transplant (HCT) recipients [28-32]. Pneumocystis pneumonia (PCP) is most common in patients receiving glucocorticoids as a part of a chemotherapeutic or maintenance regimen [33].

Invasive CMV disease may be difficult to distinguish from viral shedding (or activation in the setting of severe systemic illness) in the immunocompromised host with pulmonary infiltrates. Confirmation of invasive CMV pneumonitis can be achieved using assays from blood samples (eg, CMV viral load by nucleic acid testing) and/or tissue histology (image 2). In HCT recipients, CMV pneumonitis occurs most commonly in seropositive individuals (CMV donor seronegative, recipient seropositive; CMV D-/R+) after the completion of prophylaxis (late infection) [34,35]. This contrasts with the risk profile of CMV pneumonitis in solid organ transplantation, which is greatest in seronegative recipients of seropositive organs (CMV D+/R-). Antiviral resistance may allow CMV infection to break through antiviral prophylaxis. (See "Overview of infections following hematopoietic cell transplantation" and "Infection in the solid organ transplant recipient" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Approach to the diagnosis of cytomegalovirus infection".)

The lungs in systemic infections — Some infections, especially those due to tuberculosis, Nocardia spp, and Cryptococcus spp, generally enter via the lungs but metastasize to other sites. These other sites may be more accessible than the lungs for establishing a microbiologic diagnosis. (See 'Skin and CSF sampling' below.)

The lungs can also be a site for hematogenous spread of infection (eg, septic emboli due to Staphylococcus aureus or gram-negative bacteremia). Peripheral pulmonary lesions in the lungs can be a clue that there is important disease elsewhere (eg, line sepsis, hepatosplenic candidiasis, infective endocarditis) (image 3).

Noninfectious — Noninfectious etiologies for pulmonary infiltrates are common in immunocompromised patients, including pulmonary embolus, tumor, radiation pneumonitis, cancer, fibrosis, atelectasis with pulmonary edema, drug allergy or toxicity, and pulmonary hemorrhage [36-38]. Often, the resolution of fever in response to a trial of antibiotics is the only evidence suggesting that infection was present.

In an older series of patients who underwent open lung biopsy at Memorial Sloan Kettering Cancer Center, inflammatory processes (such as bronchiolitis obliterans organizing pneumonia [BOOP] or drug toxicity) and malignancy accounted for 67 percent of the specific diagnoses made; the remaining 33 percent were due to infection [39]. Drug toxicities (bleomycin, cyclophosphamide, and sulfonamides), leukoagglutinin reactions, radiation injury, pulmonary emboli, pulmonary hemorrhage, and cancer metastases may coexist with opportunistic infections.

Radiation-induced injury — Clinically apparent injury due to radiation therapy can occur acutely (typically 4 to 12 weeks following irradiation) or more than six months after the initial exposure to a dose of >2000 rads. Vascular damage, mononuclear infiltrates, and edema are seen histologically at 3 to 12 months. The severity of lung injury due to drugs or radiation appears to correlate with the rapidity of the withdrawal of glucocorticoid therapy. However, this timing may also reflect the emergence of the underlying inflammatory response rather than enhanced injury. Radiation fibrosis may occur (usually after six to nine months) and will amplify radiologic findings with other processes; lung function may not stabilize for up to two years. (See "Radiation-induced lung injury".)

Drug-induced injury — Acute, drug-induced lung disease may reflect hypersensitivity to chemotherapeutic agents, sulfonamides, or other agents.

●Methotrexate, bleomycin, and procarbazine can cause a syndrome of nonproductive cough, fever, dyspnea, and pleurisy with skin rash and blood eosinophilia. Chest radiographs generally demonstrate diffuse reticular infiltrates. (See "Methotrexate-induced lung injury" and "Bleomycin-induced lung injury".)

●Cyclophosphamide may cause a syndrome of pulmonary disease with interstitial inflammation and pulmonary fibrosis that occurs subacutely over weeks to months. (See "Cyclophosphamide pulmonary toxicity".)

●Sirolimus (rapamycin) used for immune suppression may be associated with a form of interstitial pneumonitis in transplant recipients [40]. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Rapamycin and analogs'.)

●Other common drugs causing lung injury include cytarabine, but fever is less often associated with these other drug-induced forms of pneumonitis.

Drug toxicity may be related to the cumulative dose of the agent (eg, bleomycin over 450 mg, carmustine [BCNU], lomustine [CCNU]) and to the age of the patient. Synergistic pulmonary toxicity is seen when certain chemotherapeutic agents are used in combination with radiation therapy (eg, bleomycin, mitomycin, busulfan) or oxygen (bleomycin).

Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS) is an important noninfectious complication of HCT, which typically occurs within the first several weeks following transplant [41]. IPS is less common following nonmyeloablative HCT. IPS is a clinical syndrome characterized by widespread alveolar injury plus signs and symptoms of pneumonia plus evidence of abnormal pulmonary physiology (an increased alveolar-arterial oxygen gradient or the need for supplemental oxygen) in the absence of lower respiratory tract infection. IPS may represent a heterogeneous group of disorders that result in the common pathologic findings of interstitial pneumonitis and/or diffuse alveolar damage. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Idiopathic pneumonia syndrome' and "Pulmonary complications after autologous hematopoietic cell transplantation", section on 'Early complications (first month)'.)

Engraftment syndrome — The engraftment syndrome is generally suspected when a patient develops fever and rash approximately 9 to 16 days following autologous HCT (and more rarely following allogeneic HCT) [42]. The engraftment syndrome is associated with increased systemic capillary permeability that occurs during the neutrophil recovery phase. It is attributed to release of proinflammatory cytokines that precedes neutrophil engraftment. Clinical manifestations include fever without infection, maculopapular rash mimicking acute GVHD, diffuse pulmonary opacities, and/or diarrhea. (See "Pulmonary complications after autologous hematopoietic cell transplantation", section on 'Engraftment syndrome and PERDS' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Engraftment syndrome'.)

Other mimics of infection — A variety of other noninfectious processes can mimic infection in immunocompromised patients:

●Pulmonary edema, pulmonary emboli, or hemorrhage. (See "Pathophysiology of cardiogenic pulmonary edema" and "Noncardiogenic pulmonary edema" and "The diffuse alveolar hemorrhage syndromes".)

●Alveolar proteinosis may be associated with hematologic malignancies or can coexist with infection due to S. maltophilia, Nocardia, PCP, or less often with cryptococcosis, aspergillosis, tuberculosis, or histoplasmosis [43]. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults".)

●Pulmonary infarction can also resemble infection; chest radiographs tend to have segmental pleural-based infiltrates.

●In patients with primary connective tissue/collagen vascular diseases, infection may be difficult to distinguish from the effects of the primary disease or toxicities of therapy. Systemic lupus erythematosus and rheumatoid arthritis are associated with a variety of pulmonary infiltrates. The pulmonary-renal syndromes (Goodpasture syndrome and granulomatosis with polyangiitis) may present with pulmonary hemorrhage, consolidation, nodular lesions, and patchy infiltrates and may progress to cavitation. Sarcoidosis is generally associated with hilar lymph node enlargement and interstitial infiltrates, but nodular disease and superinfection are common. Histology may be required to differentiate infection from noninfectious pulmonary processes. (See "Pulmonary manifestations of systemic lupus erythematosus in adults" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Clinical manifestations and diagnosis of sarcoidosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

●Older therapies for rheumatic disease (eg, penicillamine, gold salts, antiinflammatory agents) may cause acute or chronic reticulonodular pulmonary infiltrates associated with fever, dyspnea, and cough. Anti-tumor necrosis factor-alpha therapy has been associated with the reactivation of latent intracellular infections including tuberculosis and histoplasmosis. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

●Acute respiratory distress syndrome (ARDS) is usually the result of severe pneumonia or ongoing systemic infectious or inflammatory processes. Systemic inflammation syndromes associated with CAR-T cells or immunotherapy, severe acute respiratory syndrome coronavirus 2 infection, or sepsis are indistinguishable as a prelude to ARDS. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

●Transfusion-associated leukoagglutinin reactions (transfusion-related lung injury [TRALI]) are uncommon, but transient pulmonary infiltrates may occur following transfusions. Virtually all blood products have been implicated in TRALI. Infusions of whole blood, platelets, packed red blood cells, and fresh frozen plasma are the most commonly identified precipitating causes, but case reports have also implicated transfusions of allogeneic stem cells, cryoprecipitates, intravenous immunoglobulin, and granulocytes. (See "Transfusion-related acute lung injury (TRALI)".)

●Allograft rejection, chronic lung allograft dysfunction (CLAD), or primary graft dysfunction in lung transplant recipients can also mimic pulmonary infection. (See "Primary lung graft dysfunction".)

●Posttransplant lymphoproliferative disorders may present with pulmonary nodules or lymphadenopathy. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

●Bronchiolitis obliterans (BOS) following allogeneic HCT is associated with GVHD, antecedent respiratory viral infections, advanced age, methotrexate exposure, and low immunoglobulin levels. BOS is also observed in CLAD. Pulmonary venoocclusive disease after HCT may present with dyspnea, elevated pulmonary arterial pressures, and the appearance of pulmonary edema.

●Checkpoint inhibitor therapy may cause pneumonitis in up to 6 percent of patients receiving programmed cell death receptor 1 (PD-1) or PD-1 ligand (PD-1L) antagonists and up to 12 percent with combined PD-1/PD-1L and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade [44-46]. Pneumonitis may progress to acute respiratory distress syndrome. Pulmonary immune-related adverse events (irAEs) following immune checkpoint inhibitor therapy have a median onset of three months but may occur within a week [47,48]. PD-1/PD-1L therapies are more often associated with pneumonitis (or thyroiditis) than CTLA-4 antibodies. Pneumonitis may occur with or without other irAEs including mild skin, endocrine, or autoimmune manifestations or severe inflammatory processes including colitis, myocarditis, or shock. Immune activation may also unmask subclinical infections, and combinations of immune and infectious etiologies may occur (eg, allergic bronchopulmonary aspergillosis). A grading system exists for lung toxicities based on symptoms and radiologic data [49].

●CAR-T cell therapies may induce toxicities including cytokine-release syndrome with fevers and multiorgan dysfunction, CAR-T cell-related encephalopathy syndrome with altered mental status and neurologic dysfunction, or hemophagocytic lymphohistiocytosis-macrophage-activation syndrome [50].

INITIAL EVALUATION — Recognition of infection in immunocompromised hosts is often delayed because the usual signs of infection are missing due to the muted inflammatory response. As an example, sputum production and radiographic changes may be reduced or absent in the neutropenic patient with pneumonia. In one series of cancer patients with pneumonia, neutropenic patients produced purulent sputum far less often than those without neutropenia (8 versus 84 percent) [18]. Many infections are recognized only when fever, clinical symptoms (eg, cough, pleurisy, confusion), unexplained hypotension, or radiologic abnormalities develop after immune suppression or neutropenia is reversed. Blood, urine, and sputum cultures (and cerebrospinal fluid if relevant) should be obtained before starting antimicrobial therapy.

Hospital admission — The need for hospitalization is among early management decisions regarding immunocompromised patients with pneumonitis and possible infection. Any sign of invasive infection in immunocompromised patients requires at least a brief hospitalization. Localizing signs (eg, headache, altered mental status, rash, dyspnea, chest pain, redness or pain over an indwelling catheter site, pulmonary infiltrates) merit consideration for emergency admission. While symptoms may be muted, a low threshold for hospitalization must exist if the patient “looks sick.” Immunocompromised patients with fever without a clear etiology are at high risk for rapid progression.

Certain subgroups of immunocompromised patients are highly susceptible to infection. Symptoms may continue to evolve despite therapy. These include patients with:

●Aggressive tumors (eg, new or relapsed leukemia or lymphoma or uncontrolled metastatic cancer) with initiation of chemotherapy

●Recent hematopoietic cell transplant recipients, especially those with, or at risk for, severe graft-versus-host disease or delayed engraftment, such as after umbilical cord blood transplantation

●Recent infections, especially due to cytomegalovirus (CMV) or respiratory viruses, or with known colonization with fungi or resistant bacteria [51,52]

●Absolute neutrophil count (ANC) below 500/microL, and especially those below 100/microL, or those in whom the ANC is falling rapidly or expected to fall below 100/microL

●High-dose glucocorticoid therapy or recent intensification of immunosuppression (eg, in solid organ transplant recipients being treated for graft rejection)

These patients are best managed as inpatients until clinically stable. Patients with frank rigors or hypotension should be admitted. A very low threshold should also exist for admission of splenectomized patients with fever. Patients with a history of recent or recurrent infection after organ transplantation (eg, Pseudomonas spp or S. maltophilia infections in lung transplant recipients or CMV infection in any solid organ transplant recipient) or with anatomic predisposition to infection (eg, bronchiectasis) merit consideration for hospitalization. Patients with pneumonitis following checkpoint inhibitor therapy may progress over hours to days.

DIAGNOSIS — Given the broad differential diagnosis of pulmonary infiltrates in the immunocompromised host, historical (eg, epidemiologic) and radiologic clues may be useful in narrowing the possibilities (table 2) (see "Epidemiology of pulmonary infections in immunocompromised patients"). Molecular diagnostics and whole genome sequencing tools are valuable adjuncts to culture-based and antigen-based detection tools. Nevertheless, sampling of tissues is frequently required to make a definitive diagnosis, especially in distinguishing infectious from noninfectious causes.

Historical clues — Historical features are often useful in making a preliminary diagnosis and in selecting the initial empiric antimicrobial regimen. Some of these include:

●Travel and occupation – Exposures to tuberculosis, endemic fungi (eg, H. capsulatum, Coccidioides spp), Rhodococcus equi (horse breeders), Cryptococcus neoformans (eg, pigeon breeders and cave explorers), Strongyloides stercoralis (residence in or prolonged travel to endemic areas, even quite distant in time), or exposure to soil (eg, Aspergillus spp or Nocardia spp in landscapers and gardeners)

●Prolonged duration of neutropenia (higher risk for gram-negative infections, Aspergillus spp, and Fusarium spp)

●Past history of frequent antimicrobial exposure (increased risk for organisms with resistance to antimicrobials used previously)

●Recent intensification of immunosuppression for graft rejection (cytomegalovirus [CMV], Pneumocystis) or graft-versus-host disease (Aspergillus or molds) or change in prophylaxis

●Potential or witnessed aspiration (risk for anaerobic infection)

●Presence of potential pulmonary pathogens in prior cultures, particularly molds (Aspergillus spp, Fusarium spp), Pseudomonas spp, or Stenotrophomonas spp

●Cardiac abnormalities (endocarditis), indwelling catheters, or intravascular clot (bacteremic seeding of the lungs)

●Obstructing metastatic tumors, particularly intrathoracic malignancies (which can lead to postobstructive pneumonia)

●Diabetes mellitus with sinopulmonary infection (mucormycosis) (see "Mucormycosis (zygomycosis)")

●The specific immune defects and their associated infections (table 1)

Diagnostic approach — The initial evaluation for immunocompromised patients with fever with or without pulmonary findings, at a minimum, should include:

●Rapid assessment of vital signs, including oxygen saturation

●Complete blood count with differential

●Electrolytes, blood urea nitrogen, and creatinine

●Blood cultures (minimum of two sets, with at least one peripheral set and one set from any indwelling catheter)

●Urine sediment examination and culture with susceptibility testing

●Sputum for Gram stain, fungal smears, and cultures (aerobic, anaerobic, fungal, as well as specific cultures for mycobacteria, Nocardia spp, and Legionella spp) and susceptibility testing

●Imaging of the lungs (chest radiography or, if possible, chest computed tomographic scanning) and imaging of any symptomatic site (eg, abdomen)

●Skin examination, looking for evidence of metastatic infection

●CMV quantitative molecular testing is often valuable; other viral polymerase chain reaction (PCR) assays as appropriate to the individual (adenovirus, parvovirus B19, severe acute respiratory syndrome coronavirus 2)

●Consideration of sample collection for nonculture-based diagnostic tools (eg, specific molecular and antigen tests such as Aspergillus or Pneumocystis PCR, cryptococcal antigen), Aspergillus galactomannan, beta-1,3,-glucan, metagenomic sequencing) [53]

Hypoxemia — The presence or absence of hypoxemia can assist in the differential diagnosis of pulmonary infiltrates in immunocompromised patients. In PCP, hypoxemia with an elevation in lactic dehydrogenase or beta-1,3-glucan and minimal radiographic findings are common. In contrast, presence of pulmonary consolidation with the absence of hypoxemia is more common in nocardiosis, tuberculosis, and fungal infections; hypoxemia often does not occur until later in the course.

Radiologic clues

Chest radiography — The presence or absence of pulmonary infiltrates should be defined by chest radiography or computed tomography (CT) scan since the pattern of involvement can be helpful in establishing the etiology of the process [54,55]. A chest radiograph is insufficient to exclude pulmonary involvement if there are respiratory symptoms or historical features that suggest a possible pulmonary process. The threshold for obtaining a chest CT is very low. The initial findings and evolution of the chest radiograph provide important clues to both the differential diagnosis of pulmonary infection and the appropriate diagnostic evaluation (table 2) [56]. The following radiographic parameters are useful in developing clinical-radiographic-pathologic correlations [5]:

●Time of appearance, rate of progression, and time to resolution of pulmonary radiographic abnormalities in relation to clinical events. Comparison with prior imaging results is essential.

●Distribution of radiologic abnormalities – An abnormality confined to one anatomic area is considered focal, whereas widespread lesions are considered diffuse. Abnormalities that are present in more than one area but are discrete are termed multifocal. Findings may be located centrally, peripherally, or both, particularly on CT scans.

Three types of pulmonary infiltrates are common:

●Consolidation, with a substantial replacement of alveolar air by tissue density material, typically with air bronchograms and a peripheral location of the abnormality (image 4)

●Peribronchovascular (or interstitial) distribution, in which the infiltrate is predominantly oriented along the peribronchial or perivascular bundles (image 5)

●Nodular space-occupying nonanatomic lesions with well-defined, more or less rounded edges surrounded by aerated lung

Other findings may include pleural fluid, atelectasis, cavitation (image 6), lymphadenopathy, and cardiac enlargement. The location of pleural fluid can be a clue; bilateral effusions are more common in congestive heart failure and fluid overload, and unilateral in necrotizing or granulomatous infection (especially in association with lymphadenopathy or cavitation).

This classification system for radiographs can be combined with information about the rate of progression of the illness to generate a differential diagnosis. Several examples are illustrative:

●A focal or multifocal consolidation of acute onset will probably be caused by a bacterial infection. In contrast, similar multifocal lesions with a subacute to chronic progression are more commonly due to fungal, tuberculous, or nocardial infections.

●Large nodules are usually a sign of fungal or nocardial infection in this patient population, particularly if they are subacute to chronic in onset.

●Subacute disease with diffuse abnormalities, either of the peribronchovascular type or miliary micronodules, are usually caused by viruses (especially CMV or respiratory viruses), P. jirovecii, or, in the lung transplant recipient, rejection (image 7).

●The presence of cavitation suggests a necrotizing infection, which can be caused by filamentous molds, Nocardia spp, mycobacteria, certain gram-negative bacilli (most commonly Klebsiella pneumoniae and Pseudomonas aeruginosa), and anaerobes [5].

●The appearance of invasive pulmonary aspergillosis is heterogeneous [57]. The most common features include patchy infiltrates, nodules, cavitation, and pleural-based wedge-shaped lesions with associated pleurisy [32]. In some patients, including those with neutropenia, the initial appearance may be nodules with surrounding hypoattenuation (the "halo sign") followed by cavitation (the "air-crescent sign") following the return of neutrophils. The halo sign may also be observed with other infections that cause infarction (eg, other angioinvasive fungi, Nocardia spp, P. aeruginosa) and malignancies. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Imaging'.)

The depressed inflammatory response of the immunocompromised transplant patient may modify or delay the appearance of a pulmonary lesion on radiography, especially if neutropenia is present. As an example, fungal invasion, which causes a less exuberant inflammatory response than does bacterial infection, will often be very slow to appear on conventional chest radiography. By contrast, immune reconstitution (eg, leukocytes after hematopoietic cell transplantation or chemotherapy or HIV therapy) or immune stimulation (with checkpoint inhibitors) may reveal previously unrecognized pulmonary infiltrates.

The following table reviews the radiographic appearances of pulmonary disorders in immunocompromised patients (table 2).

Chest CT — Computed tomography (CT) frequently reveals abnormalities even when the chest radiograph is negative or has only subtle findings. CT can also help to define the extent of the disease. Knowledge of the extent of infection at the time of diagnosis allows for subsequent assessment of the response to therapy. This is especially relevant for opportunistic fungal and nocardial infections. Therapy should be continued until evidence of infection is eliminated; reversal of immunosuppression may accelerate radiologic progression (immune reconstitution) while enhancing clinical recovery. (See "Treatment of nocardiosis" and "Treatment and prevention of invasive aspergillosis", section on 'Duration'.)

The morphology of the abnormalities found on CT scan can be useful in developing a differential diagnosis; few lesions are sufficiently specific to obviate the need for microbiologic diagnosis [58]:

●Cavitary CT lesions are suggestive of infections with mycobacteria, Nocardia spp, Cryptococcus spp, Aspergillus spp, and some gram-negative bacilli (P. aeruginosa, Klebsiella spp).

●Rapidly expanding pulmonary lesions with cavitation and/or hemorrhage are associated with the Mucorales, especially in diabetics, and Scedosporium spp.

●Opacified secondary pulmonary lobules in the lung periphery are suggestive of bland pulmonary infarcts or septic or hemorrhagic Aspergillus infarcts (especially if cavitary).

●Opacities in a peribronchial (or interstitial) distribution are suggestive of fluid overload, viral infection such as CMV (image 8), or P. jirovecii infection (image 9), and, in the lung transplant recipient, allograft rejection.

●Dense regional or lobar consolidation on CT is usually seen in bacterial pneumonia or invasive fungal infection.

●Lymphadenopathy is not a common finding in immunosuppressed patients other than in those with lymphoma or posttransplant lymphoproliferative disorder associated with Epstein-Barr virus. Lymphadenopathy may be observed with some acute viral infections (CMV), sarcoidosis, and infections due to mycobacteria and Cryptococcus spp and with drug reactions (eg, trimethoprim-sulfamethoxazole). Positron emission tomography-CT (PET-CT) may differentiate infection from tumor.

In contrast with conventional radiographs, CT scans will frequently detect multiple patterns simultaneously, which can raise the possibility of dual processes (eg, fibrosis and infection) or sequential infections of the lungs. In a patient being treated for PCP, for example, the appearance of acinar, macronodular, or cavitary lesions is highly suggestive of a complicating infection, such as Aspergillus invasion of lung tissue compromised by the primary process.

Another important use of the CT scan is to identify the site for optimal sampling and assist in defining the most appropriate invasive procedure [59]. Thus, CT can provide precise guidance for needle biopsy or for thoracoscopic or open lung excision [59-65]. CT can also help to predict whether bronchoscopy is likely to be useful. As an example, the demonstration of a feeding bronchus that communicates with a pulmonary nodule greatly increases the diagnostic yield when bronchoscopy is performed (60 versus 30 percent when the feeding bronchus is not visible). If CT demonstrates centrally located diffuse opacities, a bronchoscopic approach is the procedure of choice.

Invasive procedures — Invasive procedures are frequently required to obtain tissue or respiratory samples for specific diagnoses. Decisions regarding invasive procedures are best made early in the course; patients may become too ill or develop contraindications (eg, coagulopathy, hypoxemia) that prevent procedures [22,24,66,67].

Skin and CSF sampling — As discussed above, several infections, especially those due to M. tuberculosis, Nocardia spp, and Cryptococcus spp, generally enter via the lungs but metastasize to other sites. These other sites may be more accessible than the lungs for establishing a microbiologic diagnosis. Thus, skin lesions or cerebrospinal fluid (CSF) may demonstrate Cryptococcus spp or mycobacterial infection before microbiologic data from sputum or lung biopsy specimens are available. (See 'The lungs in systemic infections' above.)

Lung sampling — An invasive diagnostic procedure such as bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy, percutaneous needle biopsy, video-assisted thorascopic biopsy (VATS), or open lung biopsy is frequently required to obtain a sample of sputum or lung tissue [60-64,66-73]. The selection of the optimal procedure is determined both by the nature (ie, focal or diffuse) and location of the pulmonary lesion and the skills available locally. Diffuse lesions may be sampled by transbronchial biopsy, whereas nodules are better located by CT-guided percutaneous needle biopsy, VATS, or open lung biopsy. VATS is also very useful for sampling of peripheral pulmonary lesions. The sensitivity of BAL is improved by early (days 1 to 2) over later sampling and is reduced by antimicrobial treatment [66,73,74]. The yield of invasive procedures varies between 25 and approximately 60 percent depending on the patient population studied. In 199 patients with hematologic malignancy and fever, BAL was performed 246 times and produced a microbiologic diagnoses in 118 patients [75].

It is reasonable to obtain an induced sputum for certain studies (eg, acid-fast bacilli, Pneumocystis, cytology, and routine stains and cultures) while awaiting more invasive procedures [76]. Positive results may allow for more invasive procedures to be avoided. The yield of induced sputum samples is higher than routine sputum samples only for mycobacteria, PCP, and cytology [76].

The diagnostic yield of BAL is greatest in untreated HIV-infected patients due to the large numbers of organisms (eg, P. jirovecii, mycobacteria) compared with other compromised individuals [77]. Conversely, transbronchial biopsy may be considered with BAL in HIV-uninfected immunocompromised hosts without specific contraindications to avoid the need for multiple sequential procedures. BAL alone is less often useful for the diagnosis of invasive fungal infection than for PCP or bacterial processes [20]. BAL samples should be coupled to microbiologic studies (cultures, polymerase chain reaction, Aspergillus galactomannan antigen) to improve sensitivity [78-80]. Biopsy allows distinction between colonization and invasion of fungal or viral infections and may detect underlying processes such as bronchiolitis obliterans and drug-induced lung injury. Bronchial brushings do not generally add much information in immunocompromised patients. Post-BAL sputum samples are often revealing.  

In patients in whom transbronchial biopsy is not feasible, VATS or open lung biopsy will often provide the best means for establishing a diagnosis [73,81]. One study from Memorial Sloan Kettering Cancer Center evaluated the results of lung biopsy (either via thoracotomy or VATS) in 63 patients with hematologic malignancies: 40 percent of patients had active malignancy at the time of the procedure [39]. Only 6 percent of patients were neutropenic at the time of the biopsy. Open lung biopsy resulted in a specific diagnosis in 62 percent of these cases and in a change of therapy in 57 percent. Patients with focal abnormalities by chest radiography were more likely than those with diffuse findings to obtain a specific diagnosis following biopsy (79 versus 32 percent). Forty-six percent of patients who underwent bronchoscopy with BAL, 50 percent of the eight patients who underwent transbronchial biopsy, and 50 percent of patients who underwent needle aspiration had specific diagnoses made after lung biopsy. The procedure resulted in complications in 13 percent of cases, including two with major complications. However, the mortality was improved at 30- and 90-days post-procedure for those in whom a specific diagnosis was made compared with those without a specific diagnosis, especially in patients who had undergone hematopoietic cell transplantation (8 versus 62 percent 90-day mortality).

Microbiologic assays — Routine sputum samples should be collected for cultures and staining whenever possible. Induced sputum specimens are most useful for diagnosing mycobacterial infections and PCP and for cytologic evaluation [76]. In many cases, bronchoscopy with BAL is required to obtain adequate specimens (table 3) [72].

In addition to microbiologic testing of sputum samples, non-culture-based assays can be performed on a variety of other types of samples and can be used as adjuncts to culture-based techniques, although negative assays may not definitively exclude specific diagnoses:

●Nasal washings or swabs (direct fluorescent antibody, PCR-molecular testing, and viral cultures for resistance testing) may be used for the diagnosis of community-acquired viral infections due to influenza, parainfluenza, adenovirus, metapneumovirus, SARS-CoV-2, and respiratory syncytial virus.

Testing for coronavirus disease 2019 (COVID-19) is discussed separately. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

●Urinary antigen tests may be used to diagnose Legionella pneumophila, H. capsulatum, Blastomyces dermatitidis, and Streptococcus pneumoniae infections.

●Various antigen detection and nucleic acid-based assays can be performed using blood samples as well as CSF and BAL fluid. Examples include CMV viral loads (nucleic acid testing [NAT]) or antigenemia, serum cryptococcal antigen (particularly if any signs of meningitis), syphilis serology, human herpesvirus 6 NAT, Aspergillus galactomannan antigen [79,82], Histoplasma antigen, and 1,3-beta-D-glucan. The A. galactomannan antigen assay can also be performed on BAL samples.

●Molecular diagnostic techniques including nucleic acid amplification and unbiased (next-generation) metagenomic sequencing may be applied to tissue and respiratory specimens to identify some unculturable pathogens [53,83].

●Newer molecular diagnostic techniques may be applicable to BAL fluid.

Detection of certain common organisms (eg, Aspergillus spp, CMV) in respiratory tract specimens may represent colonization rather than infection. Thus, it is important to interpret positive test results in clinical context (eg, whether there is a compatible clinical syndrome and radiographic findings). The presence of CMV viremia may indicate CMV reactivation; viremia in the context of a compatible pulmonary syndrome is suggestive of invasive disease. The absence of CMV viremia may mitigate against the diagnosis of invasive CMV pneumonitis. (See "Diagnosis of invasive aspergillosis" and "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" and "Approach to the diagnosis of cytomegalovirus infection".)

The decision of which studies to obtain depends upon the individual patient's clinical findings and on availability at clinical laboratories.

Serologic techniques are generally of little use in the diagnosis of active infection in immunocompromised patients because such patients may be unable to generate an adequate immune response to a new pathogen or they may have made a response to a previous infection before they became immunocompromised. Blood transfusions or immunoglobulin infusions may also complicate interpretation of serologic testing. Thus, both a negative and a positive result may be uninterpretable.

Pursuit of a unifying diagnosis — While it is always appealing to make a single diagnosis and initiate therapy, it is important to remember that multiple simultaneous processes are common in the immunocompromised patient. The occurrence of multiple simultaneous infections or conditions can complicate and delay appropriate therapy (image 10). As an example, CMV infection may complicate the treatment of graft rejection or venoocclusive disease or contribute to the pathogenesis of PCP or Aspergillus pneumonia.

SELECTION OF INITIAL THERAPY — In practice, most initial therapy is empiric while awaiting diagnostic studies. However, with careful attention to individual patient characteristics, a limited differential diagnosis can be established, and empiric antibiotic therapy tailored to treat the most likely pathogens and minimize toxicity and cost. This may also avoid unnecessary broad-spectrum antimicrobial coverage. Antimicrobial agents used for prophylaxis should be avoided in empiric therapy as resistance may emerge.

The management of specific infections is discussed separately:

●Empiric treatment of patients with febrile neutropenia (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")

●Community-acquired pneumonia (see "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Treatment of community-acquired pneumonia in adults in the outpatient setting")

●Hospital-acquired, ventilator-associated, and health care-associated pneumonia (see "Treatment of hospital-acquired and ventilator-associated pneumonia in adults")

●Invasive aspergillosis (see "Treatment and prevention of invasive aspergillosis")

●Pneumocystis pneumonia (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV" and "Treatment and prevention of Pneumocystis infection in patients with HIV")

●Cytomegalovirus pneumonitis [84] (see "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients")

●Mucormycosis (see "Mucormycosis (zygomycosis)")

●Mycobacterial infections (see "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum" and "Tuberculosis in solid organ transplant candidates and recipients" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy")

●Infections in lung transplant recipients (see "Fungal infections following lung transplantation" and "Bacterial infections following lung transplantation")

SUMMARY AND RECOMMENDATIONS

●The spectrum of immunocompromised hosts has expanded with prolonged survival for solid organ and hematopoietic cell transplant recipients, patients with immune deficiencies (including congenital disorders and HIV/AIDS), cancers, and autoimmune disorders. (See 'Introduction' above.)

●Recognition of infection in immunocompromised hosts is often delayed because the usual signs of infection are missing due to the muted inflammatory response. The differential diagnosis of pulmonary infiltrates in immunocompromised patients is broad and includes both infectious and noninfectious conditions. (See 'Initial evaluation' above.)

●Novel immunosuppressive therapies create a diverse set of immune deficits that create the substrate for opportunistic infections. These patients are defined by their susceptibility to infection with organisms of low native virulence for immunologically normal hosts. Pulmonary infection remains the most common form of tissue-invasive infection in these hosts. (See 'Introduction' above.)

●Clinical presentations and radiologic findings may be amplified by immunomodulatory therapies (eg, checkpoint inhibitors or chimeric antigen receptor-modified T [CAR-T] cells) and immune reconstitution (highly active antiretroviral therapy in HIV, stem cell engraftment).

●Early diagnosis and specific therapy of opportunistic infections is the cornerstone of successful treatment. The general rule is to be aggressive in pursuing a specific microbiologic diagnosis in immunocompromised patients with pulmonary infiltrates to avoid overly broad antimicrobial therapy; invasive diagnostic techniques are often required. (See 'General principles' above and 'Diagnosis' above.)

●The incidence and severity of pneumonia vary with the characteristics of the affected individual, including the nature of the immune deficits (table 1) and epidemiologic exposures. Aspiration remains an important source of pulmonary infection in all immunocompromised patients. (See 'Epidemiology and risk of pneumonia' above.)

●Most immunocompromised patients with any sign of possible invasive infection including rigors or hypotension should be hospitalized for evaluation. The differential diagnosis of pulmonary infiltrates in immunocompromised patients is broad and includes both infectious and noninfectious conditions. (See 'General principles' above and 'Hospital admission' above.)

Certain subgroups of immunocompromised patients are highly susceptible to infection. These include patients with:

•Aggressive tumors (eg, new leukemia or lymphoma or uncontrolled metastatic cancer)

•Recent hematopoietic cell transplant (HCT), matched unrelated HCT (MUD), umbilical cord HCT, and allogeneic HCT recipients with significant graft-versus-host disease (GVHD)

•Recent infections, especially due to cytomegalovirus (CMV) or respiratory viruses, or with known colonization with fungi or resistant bacteria

•Absolute neutrophil count (ANC) below 500/microL, and especially those below 100/microL, or those in whom the ANC is falling rapidly or expected to fall below 100/microL

•High-dose glucocorticoid therapy or recent intensification of immunosuppression (eg, in solid organ transplant recipients being treated for rejection)

●The presence or absence of pulmonary infiltrates should be defined by chest radiography or computed tomography (CT) scan. The pattern of involvement can be helpful in establishing the etiology of the process. Routine chest radiograph is not sufficient to exclude pulmonary involvement if there are any respiratory symptoms or historical features that suggest a possible pulmonary process. The threshold for performing a chest CT should be low in immunocompromised hosts. (See 'Radiologic clues' above.)

●Invasive procedures are frequently required to obtain tissue or sputum in order to make a specific diagnosis. These are best considered early in the clinical course. (See 'Invasive procedures' above.)

●Most initial therapy is empiric while awaiting diagnostic studies. With attention to individual patient characteristics, a limited differential diagnosis can be established, and empiric antibiotic therapy tailored to treat the most likely pathogens and minimize toxicity and cost. This may also avoid unnecessary broad-spectrum antimicrobial coverage. (See 'Selection of initial therapy' above.)

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