Approach To The Immunocompromised Patient With Fever and Pulmonary Infiltrates

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Approach to the immunocompromised patient with

fever and pulmonary infiltrates
AUTHOR: Jay A Fishman, MD
SECTION EDITOR: Emily A Blumberg, MD
DEPUTY EDITOR: Sheila Bond, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Aug 29, 2021.
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. 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" and "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" and "Pulmonary complications after allogeneic hematopoietic cell
transplantation: Causes".)
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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 pulmonary processes occur often. These include infectious (eg,
viral, bacterial, fungal, parasitic) and noninfectious (eg, pulmonary edema, malignancy)
etiologies. Routine chest radiography and sputum sampling may fail to detect these
concomitant diseases.
● Serologic testing is generally not useful in the acute management of

immunocompromised patients. These patients often fail to generate an adequate or
timely antibody response to infection. Microbiologic testing should include antigen
detection and/or nucleic acid detection-based assays as well as cultures.
● The presence or absence of pulmonary infiltrates should be defined by chest imaging. A

routine chest radiograph may be insufficient to exclude pulmonary involvement if there
are respiratory symptoms or historical features that suggest a possible pulmonary
process. Minor abnormalities on a chest radiograph in the immunocompromised host
merit further evaluation, generally including computed tomography scanning.
Comparison with prior imaging studies is essential.
● 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 intensities of chemotherapeutic
and/or immunosuppressive regimens and with patterns of antimicrobial use. Routine
prophylaxis has increased the risk for unusual pathogens that are resistant to prophylactic
agents including fluoroquinolone-resistant streptococci, other multidrug-resistant bacteria,
azole-resistant molds, and ganciclovir-resistant cytomegalovirus (CMV) [6,9,10]. As a result,
empiric therapies for infection require use of agents not used for prophylaxis in the recent
past and review of prior microbiology data from individual patients.
Neutropenia — Neutropenia is the most common risk factor for pulmonary infection in
immunocompromised patients. Whether due to underlying malignancy, chemotherapy, or
the side effects of other drugs, the depth and duration of neutropenia are correlated with
the risk for infection [11].
Rates of infection vary depending upon the host and increase with the duration of
neutropenia. Nosocomial infections in neutropenic cancer patients occur at a rate of 46.3
episodes per 1000 neutropenic days (48.3 episodes per 100 neutropenic patients) [12]. The
rate of infection was similar in a study that included patients with acute leukemia, non-
Hodgkin's lymphoma, or after conditioning for hematopoietic cell transplantation (37.7
episodes per 1000 neutropenic days), although over 64 percent of patients had febrile
episodes while neutropenic [13]. The risk for infection increases in the neutropenic host in
patients unable to achieve disease remission (eg, for acute leukemia) [14]. Rates of infection
in solid tumor patients and solid organ transplant recipients are somewhat less.
The originating site of infection frequently cannot be identified in febrile cancer patients [15-
17]. When identified, common sources of infection in the febrile neutropenic patient are
colonizing organisms from the upper and lower respiratory tract especially with mucositis
and aspiration, the gastrointestinal tract (including the perineal and perirectal areas), the
urinary tract, and the skin (including intravenous lines and wounds) [6,18,19]. Pulmonary
infections are among the leading causes of morbidity and mortality in febrile neutropenic
patients [20]. Many infections are detected only at autopsy, particularly disseminated fungal
or combined fungal and bacterial infections [21-23].
Mismatched allogeneic hematopoietic cell transplant recipients (eg, umbilical cord blood or
matched unrelated donor transplants) being treated for hematologic malignancies require
intensive induction chemotherapy, which may result in prolonged neutropenia. Such patients
also require immunosuppression to prevent or treat graft-versus-host disease (GVHD). These
patients are at particularly high risk of infection, often with organisms resistant to
prophylactic agents. Breakthrough invasive fungal infection may occur despite prophylaxis
[24,25]. Noninfectious pulmonary syndromes are notable in pre-engraftment or marrow
recovery phases including idiopathic pneumonia syndrome, pulmonary hemorrhage
(sometimes with Stenotrophomonas maltophilia in hematopoietic cell transplantation [26]),
and engraftment syndrome, which is increased in those receiving hematopoietic growth
factors [27,28].
Glucocorticoids — Glucocorticoids play an important role in the pathogenesis of pneumonia

due to depression of phagocytic function of alveolar macrophages and neutrophils,
decreased mobilization of inflammatory cells into areas of infection, and alterations in
antigen presentation and lymphocyte mobilization. These effects increase the risk of
bacterial and fungal infections (including those due to Pneumocystis jirovecii, Nocardia spp,
and Aspergillus spp) and the risk for pulmonary involvement in the setting of certain herpes
virus infections (eg, CMV, varicella zoster virus) [29]. A meta-analysis of 42 observational
studies described a dose-dependent increase in serious infection risk of 1.5- to 4-fold for
glucocorticoid doses of <5 mg to >20 mg/day [30]. (See "Glucocorticoid effects on the
immune system".)
T cell suppression and lymphocyte depletion — Use of T lymphocyte-depleting agents has

increased the risk of certain infections based on the prolonged duration of lymphocytopenia
and, depending on the preparation used, depletion of other cell types (eg, NK cells, B-
lymphocytes). The most common infections in patients receiving these agents are those due
to reactivation of latent herpesviruses as well as mold infections [4,7,31]. B lymphocyte
depletion is used in the treatment of certain hematologic malignancies and various antibody
depletion strategies (eg, plasmapheresis, proteasome inhibition, eculizumab) for antibody-

mediated rejection of transplanted organs and may predispose to infection due to
encapsulated bacteria [32].
The agents used to suppress T lymphocyte function include the calcineurin inhibitors (eg,
cyclosporine, tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (eg,
sirolimus, everolimus) used in organ and hematopoietic cell transplantation. These
predispose to herpesvirus infections (CMV, herpes simplex, and varicella-zoster) and
community-acquired respiratory viruses, fungal infections (including Cryptococcus,
Pneumocystis, and Aspergillus spp), and parasites (eg, Strongyloides, Toxoplasma, and
Trypanosoma cruzi) [7,33-37]. CMV infection predisposes to fungal infections including
Pneumocystis and Aspergillus [38]. Fludarabine produces a prolonged deficit in T cell
functions. mTOR inhibitors are associated with a form of pneumonitis, often in association
with community acquired viral infections [39]. This syndrome presents with dyspnea and
cough with interstitial pneumonitis and fibrosis and, occasionally, alveolar hemorrhage.
Malignancies related to viral activation (eg, Epstein Barr virus-associated posttransplant
lymphoproliferative disorder, skin cancers, anogenital cancer) are common complications of
these agents [31].
Transplantation — The risk of infection in solid organ and hematopoietic cell transplant
recipients is reviewed in detail separately, driven largely by T cell suppression [4,7,33,40].
(See "Infection in the solid organ transplant recipient" and "Evaluation for infection before
solid organ transplantation" and "Prophylaxis of infections in solid organ transplantation"
and "Overview of infections following hematopoietic cell transplantation" and "Evaluation for
infection before hematopoietic cell transplantation" and "Prevention of infections in
hematopoietic cell transplant recipients".)
Autoimmune and inflammatory conditions — Patients with autoimmune diseases,

antibody deficiencies (eg, glomerulonephritis with proteinuria, Goodpasture syndrome, or
receipt of chimeric antigen receptor-modified T [CAR-T] therapy), and some hematologic
malignancies are susceptible to bacterial infections (ie, bacteremia) and to a lesser extent to
opportunistic infections similar to those of cancer and transplant patients. Infections (eg,
Pneumocystis, Nocardia spp) may result from deficiencies in opsonization and phagocytosis,
notably during corticosteroid or cyclophosphamide therapies. The severity and nature of
infection depend on the type, duration, and intensity of immunosuppressive therapy. The
spectrum of opportunistic infections seen in this patient population is widening as the
number and variety of immunosuppressive agents used to treat autoimmune diseases has
increased, ranging from calcineurin inhibitors, anti-TNF alpha and anti-interleukin 6 (IL-6)
agents, costimulatory blockade, Janus kinase (JAK)-signal transducer and activator of
transcription (STAT) pathway inhibitors, and other biologic agents.
In patients with primary connective tissue/collagen vascular diseases (eg, granulomatosis

with polyangiitis), infection may be difficult to distinguish from the effects of the primary
disease or toxicities of therapy. Pulmonary manifestations of these diseases are discussed
below. (See 'Other mimics of infection' below.)
Checkpoint inhibitors and CAR-T cells — Immune checkpoint inhibitors (ICIs) and targeted
chimeric antigen receptor-modified T (CAR-T) cells can cause systemic immune-related
adverse events (irAEs), which mimic or amplify infectious syndromes, including pneumonitis
[41]. Differentiating irAEs from infection is often challenging [35-38,42-44].
Cell surface "immune checkpoint receptors" normally prevent nonspecific or excessive

activation of T cells including cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and
programmed cell death receptor 1 (PD-1) or PD-1 ligands (PD-1L). Antibodies targeting these
molecules upregulate endogenous immune responses. Following adoptive cell transfer of
genetically engineered immune effector cells such as T lymphocytes carrying receptors for
tumor antigens (CAR-T cells), CAR-T cells proliferate, kill tumor cells, and provide long-term
surveillance. However, these therapies can be associated with profound inflammatory
responses that can be difficult to distinguish from infection. Toxicities vary by agent and may
manifest weeks to months after initial treatment [42-44].
Infections following CAR-T cell therapy are most often related to cytopenia from prior cancer
therapies or following glucocorticoid, IL-6 inhibitor, and/or TNF-alpha inhibitor treatment for
cytokine release syndrome (CRS) [45,46]. CAR-T cell therapy can be associated with B cell
aplasia and hypogammaglobulinemia. As with other immunosuppressive treatments,
infections that occur early after therapy are often nosocomial, whereas those that occur later
can be opportunistic related to prolonged immune defects. In one case series evaluating 53
patients treated with CD19 CAR-T cell therapy for relapsed acute B cell leukemia, treatment
was complicated by infection in 22 patients (42 percent) in the first 30 days following therapy
[46]. A total of 26 infections were reported, 17 bacterial, 4 fungal, and 5 viral, occurring at a
median of 18, 23, and 48 days post-CAR-T cell infusion, respectively. Three of 53 patients (6
percent) died from infection. Grade ≥3 CRS was independently associated with risk of
infection (adjusted hazard ratio 2.67; 95% CI 1.0-7.3); whether the increased infectious risk
was related to immunosuppressive therapies used to treat high-grade CRS is unclear.
Biologic agents and targeted therapies — Inhibitors of tumor necrosis factor (TNF)-alpha
and blockade of other mediators of inflammation (cytokines and chemokines) predispose to
infection with intracellular pathogens (mycobacteria, Legionella species) as well as systemic
viral and fungal infections, including those caused by molds (Aspergillus spp), yeasts
(Cryptococcus spp), dimorphic fungi (Histoplasma capsulatum, Coccidioides spp), and P. jirovecii
[47]. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors"
and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)
Certain cancer therapies such as ibrutinib have unique cellular targets (Bruton’s tyrosine
kinase in B-cell malignancies) and are associated with an excess incidence of invasive fungal
infections [48]. Inhibitors of cytokine-mediated cell processes including the JAK/STAT pathway
are achieving broad use in oncology and in autoimmune and inflammatory diseases. Use of
these agents in organ transplantation resulted in increased rates of infection and post-
transplant lymphoproliferative disorder compared with calcineurin inhibitor-based
immunosuppression [49].
HIV infection — Pulmonary infections associated with HIV infection are discussed in detail
separately. (See "Evaluation of pulmonary symptoms in persons with HIV" and "Bacterial
pulmonary infections in patients with HIV" and "Epidemiology, clinical presentation, and
diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Toxoplasma
pneumonia and other parasitic pulmonary infections in patients with HIV" and "Treatment of
drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation
of therapy".)
Concomitant viral infection — The observation that pulmonary or systemic viral infection is
associated with subsequent pneumonia has been described best for cytomegalovirus (CMV),
influenza, and severe acute respiratory syndrome coronavirus 2. Factors that predispose to
superinfection vary with the specific virus and include systemic and local immune responses
(eg, in the lung transplant recipient), decreased mucociliary function, impaired recruitment
of and phagocytosis by macrophages and neutrophils, neutropenia, or injury to type 2
pneumocytes [50]. Thus, pulmonary fungal infections (eg, Pneumocystis pneumonia,
Aspergillosis) are not uncommon in the weeks following viral infection. Increased rates of
nosocomial bacterial and mold infections have also been observed in patients on assisted
ventilation with coronavirus disease 2019 pneumonia, generally in the setting of
glucocorticoid and other immune modulatory therapies [51].
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 [2,3,40,52-59]. 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) [60]. 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 [60-62]:
● 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) [35,63,64]. 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 [65-69]. Pneumocystis pneumonia (PCP) is most common in
patients receiving glucocorticoids as a part of a chemotherapeutic or maintenance regimen
[38].
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) [70,71]. 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 [72-74]. 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 [75]. 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 [76]. (See "Pulmonary toxicity
associated with antineoplastic therapy: Molecularly targeted agents", 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 [77]. 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) [27]. 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'.)
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Other mimics of infection — A variety of other noninfectious processes can mimic

infection in immunocompromised patients:
● Pulmonary edema or bleeding. (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 [26]. (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
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 [78-80]. 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 [81,82]. 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 [83].
● 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 [41].
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 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) [58].
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)
● Recent hematopoietic cell transplant recipients, especially those with 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 [84,85]
● 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)
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
Since the differential diagnosis of pulmonary infiltrates in the immunocompromised host is

broad, historical (eg, epidemiologic) and radiologic clues may be useful in narrowing the
possibilities ( table 2). Molecular diagnostics and whole genome sequencing tools are
valuable adjuncts to culture-based approaches. Nevertheless, sampling tissue 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), 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
● Sputum for Gram stain, fungal smears, and cultures
● 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, whole genome sequencing) [86]
Hypoxemia — The presence or absence of hypoxemia can assist in the differential diagnosis
of pulmonary infiltrates in immunocompromised patients. Hypoxemia with an elevation in
lactic dehydrogenase or beta-1,3-glucan and minimal radiographic findings are common in
Pneumocystis pneumonia (PCP), whereas the absence of hypoxemia with pulmonary

consolidation is more common in nocardiosis, tuberculosis, and fungal infections 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 [87,88]. 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) [89]. 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 fungi, 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 [90]. The most

common features include patchy infiltrates, nodules, cavitation, and pleural-based
wedge-shaped lesions with associated pleurisy [69]. 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 [25]:
● 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 [91]. Thus, CT can provide precise
guidance for needle biopsy or for thoracoscopic or open lung excision [91-97]. 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 [60,62,98,99].
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 [92-96,98-105]. 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 [98,105,106]. 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 [107].
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 [108]. 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 [108].
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 [109]. 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. BAL samples should be coupled
to microbiologic studies (cultures, polymerase chain reaction, Aspergillus galactomannan
antigen) to improve sensitivity [110-112]. 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 [105,113]. 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 [75]. 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 [108]. In many cases,
bronchoscopy with BAL is required to obtain adequate specimens ( table 3) [104].
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 and viral cultures) may be used
for the diagnosis of community-acquired viral infections due to influenza,
parainfluenza, adenovirus, metapneumovirus, 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 [111,114], 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 can be applied to tissue and respiratory
specimens to identify unculturable pathogens [86,115].
● 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. 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 [116] (see "Clinical manifestations, diagnosis, and

treatment of cytomegalovirus infection in lung transplant recipients")
● 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.
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Masur H, Shelhamer J, Parrillo JE. The management of pneumonias in

immunocompromised patients. JAMA 1985; 253:1769.
2. Ramsey PG, Rubin RH, Tolkoff-Rubin NE, et al. The renal transplant patient with fever
and pulmonary infiltrates: etiology, clinical manifestations, and management. Medicine
(Baltimore) 1980; 59:206.
3. Winston DJ, Emmanouilides C, Busuttil RW. Infections in liver transplant recipients. Clin
Infect Dis 1995; 21:1077.
4. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357:2601.
5. Greene R. The radiology of pulmonary infection. In: Fishman's Pulmonary Diseases and
Disorders, 4th, Fishman AP, Elias JA, Fishman JA, et al (Eds), McGraw-Hill, New York 2008.
p.2017.
6. Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and
hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2004; 170:22.
7. Fishman JA. Infection in Organ Transplantation. Am J Transplant 2017; 17:856.
8. Fishman JA, Dey BR, Hasserjian RP. Case records of the Massachusetts General Hospital.
Weekly clinicopathological exercises. Case 10-2004. A 58-year-old man with acute
myeloid leukemia and Fever after chemotherapy. N Engl J Med 2004; 350:1339.
9. Costa SF, Alexander BD. Non-Aspergillus fungal pneumonia in transplant recipients. Clin
Chest Med 2005; 26:675.
10. Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in
hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34:909.
11. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between
circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med
1966; 64:328.
12. Carlisle PS, Gucalp R, Wiernik PH. Nosocomial infections in neutropenic cancer patients.
Infect Control Hosp Epidemiol 1993; 14:320.
13. Castagnola E, Fontana V, Caviglia I, et al. A prospective study on the epidemiology of
febrile episodes during chemotherapy-induced neutropenia in children with cancer or
after hemopoietic stem cell transplantation. Clin Infect Dis 2007; 45:1296.
14. Hammond SP, Marty FM, Bryar JM, et al. Invasive fungal disease in patients treated for
newly diagnosed acute leukemia. Am J Hematol 2010; 85:695.
15. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of
antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious
diseases society of america. Clin Infect Dis 2011; 52:e56.
16. Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related
infections. J Natl Compr Canc Netw 2012; 10:1412.
17. Pagano L, Caira M, Rossi G, et al. A prospective survey of febrile events in hematological
malignancies. Ann Hematol 2012; 91:767.
18. Dettenkofer M, Wenzler-Röttele S, Babikir R, et al. Surveillance of nosocomial sepsis and
pneumonia in patients with a bone marrow or peripheral blood stem cell transplant: a
multicenter project. Clin Infect Dis 2005; 40:926.
19. Aguilar-Guisado M, Jiménez-Jambrina M, Espigado I, et al. Pneumonia in allogeneic stem
cell transplantation recipients: a multicenter prospective study. Clin Transplant 2011;
25:E629.
20. Evans SE, Ost DE. Pneumonia in the neutropenic cancer patient. Curr Opin Pulm Med
2015; 21:260.
21. Aliberti S, Di Pasquale M, Zanaboni AM, et al. Stratifying risk factors for multidrug-
resistant pathogens in hospitalized patients coming from the community with
pneumonia. Clin Infect Dis 2012; 54:470.
22. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ
transplant recipients: results of the Transplant-Associated Infection Surveillance
Network (TRANSNET). Clin Infect Dis 2010; 50:1101.
23. Al-Hasan MN, Razonable RR, Eckel-Passow JE, Baddour LM. Incidence rate and outcome
of Gram-negative bloodstream infection in solid organ transplant recipients. Am J
Transplant 2009; 9:835.
24. Girmenia C, Busca A, Candoni A, et al. Breakthrough invasive fungal diseases in acute
myeloid leukemia patients receiving mould active triazole primary prophylaxis after
intensive chemotherapy: An Italian consensus agreement on definitions and
management. Med Mycol 2019; 57:S127.
25. Lionakis MS, Lewis RE, Kontoyiannis DP. Breakthrough Invasive Mold Infections in the
Hematology Patient: Current Concepts and Future Directions. Clin Infect Dis 2018;
67:1621.
26. Tada K, Kurosawa S, Hiramoto N, et al. Stenotrophomonas maltophilia infection in

hematopoietic SCT recipients: high mortality due to pulmonary hemorrhage. Bone
Marrow Transplant 2013; 48:74.
27. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation.
Bone Marrow Transplant 2001; 27:893.
28. Lee CK, Gingrich RD, Hohl RJ, Ajram KA. Engraftment syndrome in autologous bone
marrow and peripheral stem cell transplantation. Bone Marrow Transplant 1995; 16:175.
29. Roux A, Canet E, Valade S, et al. Pneumocystis jirovecii pneumonia in patients with or
without AIDS, France. Emerg Infect Dis 2014; 20:1490.
30. Dixon WG, Suissa S, Hudson M. The association between systemic glucocorticoid
therapy and the risk of infection in patients with rheumatoid arthritis: systematic review
and meta-analyses. Arthritis Res Ther 2011; 13:R139.
31. Issa NC, Fishman JA. Infectious complications of antilymphocyte therapies in solid organ
transplantation. Clin Infect Dis 2009; 48:772.
32. Koo S, Marty FM, Baden LR. Infectious complications associated with
immunomodulating biologic agents. Infect Dis Clin North Am 2010; 24:285.
33. Díaz-Ravetllat V, Greer M, Haverich A, et al. Significance of new lung infiltrates in
outpatients after lung and heart-lung transplantation. Transpl Infect Dis 2014; 16:359.
34. Anesi JA, Baddley JW. Approach to the Solid Organ Transplant Patient with Suspected
Fungal Infection. Infect Dis Clin North Am 2016; 30:277.
35. Gavaldà J, Meije Y, Fortún J, et al. Invasive fungal infections in solid organ transplant
recipients. Clin Microbiol Infect 2014; 20 Suppl 7:27.
36. Herrera S, Husain S. Early diagnosis of fungal infections in lung transplant recipients,
colonization versus invasive disease? Curr Opin Organ Transplant 2018; 23:381.
37. Lemonovich TL. Mold Infections in Solid Organ Transplant Recipients. Infect Dis Clin
North Am 2018; 32:687.
38. Fishman JA, Gans H, AST Infectious Diseases Community of Practice. Pneumocystis
jiroveci in solid organ transplantation: Guidelines from the American Society of
Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019;
33:e13587.
39. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity.
Transplantation 2004; 77:1215.
40. Giannella M, Muñoz P, Alarcón JM, et al. Pneumonia in solid organ transplant recipients:
a prospective multicenter study. Transpl Infect Dis 2014; 16:232.
41. Fishman JA, Hogan JI, Maus MV. Inflammatory and Infectious Syndromes Associated
With Cancer Immunotherapies. Clin Infect Dis 2019; 69:909.
42. Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse Events Associated with Immune
Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports. PLoS
One 2016; 11:e0160221.
43. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with
Immune Checkpoint Blockade. N Engl J Med 2018; 378:158.
44. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune
checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54:139.
45. Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen
receptor-modified T-cell immunotherapy. Blood 2018; 131:121.
46. Park JH, Romero FA, Taur Y, et al. Cytokine Release Syndrome Grade as a Predictive
Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic
Leukemia Treated With Chimeric Antigen Receptor T Cells. Clin Infect Dis 2018; 67:533.
47. Novosad SA, Winthrop KL. Beyond tumor necrosis factor inhibition: the expanding
pipeline of biologic therapies for inflammatory diseases and their associated infectious
sequelae. Clin Infect Dis 2014; 58:1587.
48. Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal
infections in patients treated with ibrutinib. Blood 2018; 131:1955.
49. Busque S, Vincenti FG, Tedesco Silva H, et al. Efficacy and Safety of a Tofacitinib-based
Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term
Extension Trial. Transplant Direct 2018; 4:e380.
50. Sen P, Wilkie AR, Ji F, et al. Linking indirect effects of cytomegalovirus in transplantation
to modulation of monocyte innate immune function. Sci Adv 2020; 6:eaax9856.
51. Marr KA, Platt A, Tornheim JA, et al. Aspergillosis Complicating Severe Coronavirus
Disease. Emerg Infect Dis 2021; 27.
52. Rosenow EC 3rd, Wilson WR, Cockerill FR 3rd. Pulmonary disease in the
immunocompromised host. 1. Mayo Clin Proc 1985; 60:473.
53. Rosenow EC 3rd. Diffuse pulmonary infiltrates in the immunocompromised host. Clin
Chest Med 1990; 11:55.
54. Bodey GP, Rodriguez V, Chang HY, Narboni . Fever and infection in leukemic patients: a
study of 494 consecutive patients. Cancer 1978; 41:1610.
55. HERSH EM, BODEY GP, NIES BA, FREIREICH EJ. CAUSES OF DEATH IN ACUTE LEUKEMIA: A
TEN-YEAR STUDY OF 414 PATIENTS FROM 1954-1963. JAMA 1965; 193:105.
56. Chanock S. Evolving risk factors for infectious complications of cancer therapy. Hematol
Oncol Clin North Am 1993; 7:771.
57. Coker DD, Morris DM, Coleman JJ, et al. Infection among 210 patients with surgically
staged Hodgkin's disease. Am J Med 1983; 75:97.
58. Sickles EA, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic
patients. Arch Intern Med 1975; 135:715.
59. Di Pasquale MF, Sotgiu G, Gramegna A, et al. Prevalence and Etiology of Community-
acquired Pneumonia in Immunocompromised Patients. Clin Infect Dis 2019; 68:1482.
60. Rañó A, Agustí C, Jimenez P, et al. Pulmonary infiltrates in non-HIV immunocompromised
patients: a diagnostic approach using non-invasive and bronchoscopic procedures.
Thorax 2001; 56:379.
61. Shorr AF, Susla GM, O'Grady NP. Pulmonary infiltrates in the non-HIV-infected
immunocompromised patient: etiologies, diagnostic strategies, and outcomes. Chest
2004; 125:260.
62. Danés C, González-Martín J, Pumarola T, et al. Pulmonary infiltrates in
immunosuppressed patients: analysis of a diagnostic protocol. J Clin Microbiol 2002;
40:2134.
63. Person AK, Kontoyiannis DP, Alexander BD. Fungal infections in transplant and oncology
patients. Infect Dis Clin North Am 2010; 24:439.
64. Shoham S. Emerging fungal infections in solid organ transplant recipients. Infect Dis Clin
North Am 2013; 27:305.
65. Junghanss C, Marr KA, Carter RA, et al. Incidence and outcome of bacterial and fungal
infections following nonmyeloablative compared with myeloablative allogeneic
hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow
Transplant 2002; 8:512.
66. Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic stem cell
transplant recipients: changes in epidemiology and risk factors. Blood 2002; 100:4358.
67. Ison MG, Hayden FG, Kaiser L, et al. Rhinovirus infections in hematopoietic stem cell
transplant recipients with pneumonia. Clin Infect Dis 2003; 36:1139.
68. Alangaden GJ, Wahiduzzaman M, Chandrasekar PH, Bone Marrow Transplant Group.
Aspergillosis: The most common community-acquired pneumonia with gram-negative
Bacilli as copathogens in stem cell transplant recipients with graft-versus-host disease.
Clin Infect Dis 2002; 35:659.
69. Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in
immunocompromised patients with cancer and hematopoietic stem cell transplants: an
international consensus. Clin Infect Dis 2002; 34:7.
70. Konoplev S, Champlin RE, Giralt S, et al. Cytomegalovirus pneumonia in adult
autologous blood and marrow transplant recipients. Bone Marrow Transplant 2001;
27:877.
71. Nguyen Q, Champlin R, Giralt S, et al. Late cytomegalovirus pneumonia in adult
allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999; 28:618.
72. Escuissato DL, Warszawiak D, Marchiori E. Differential diagnosis of diffuse alveolar
haemorrhage in immunocompromised patients. Curr Opin Infect Dis 2015; 28:337.

73. Bergeron A. Late-Onset Noninfectious Pulmonary Complications After Allogeneic
Hematopoietic Stem Cell Transplantation. Clin Chest Med 2017; 38:249.
74. Vande Vusse LK, Madtes DK. Early Onset Noninfectious Pulmonary Syndromes after
Hematopoietic Cell Transplantation. Clin Chest Med 2017; 38:233.
75. White DA, Wong PW, Downey R. The utility of open lung biopsy in patients with
hematologic malignancies. Am J Respir Crit Care Med 2000; 161:723.
76. Hamour IM, Mittal TK, Bell AD, Banner NR. Reversible sirolimus-associated pneumonitis
after heart transplantation. J Heart Lung Transplant 2006; 25:241.
77. Fukuda T, Hackman RC, Guthrie KA, et al. Risks and outcomes of idiopathic pneumonia
syndrome after nonmyeloablative and conventional conditioning regimens for
allogeneic hematopoietic stem cell transplantation. Blood 2003; 102:2777.
78. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-
Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2017; 35:709.
79. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of Programmed Cell Death 1
Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review
and Meta-analysis. JAMA Oncol 2016; 2:1607.
80. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 Inhibitor-Related Pneumonitis in
Advanced Cancer Patients: Radiographic Patterns and Clinical Course. Clin Cancer Res
2016; 22:6051.
81. Del Castillo M, Romero FA, Argüello E, et al. The Spectrum of Serious Infections Among
Patients Receiving Immune Checkpoint Blockade for the Treatment of Melanoma. Clin
Infect Dis 2016; 63:1490.
82. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from
immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-
up. Ann Oncol 2017; 28:iv119.
83. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse
Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society
of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36:1714.
84. Ison MG, Fishman JA. Cytomegalovirus pneumonia in transplant recipients. Clin Chest
Med 2005; 26:691.
85. Hadjiliadis D, Steele MP, Chaparro C, et al. Survival of lung transplant patients with cystic
fibrosis harboring panresistant bacteria other than Burkholderia cepacia, compared
with patients harboring sensitive bacteria. J Heart Lung Transplant 2007; 26:834.
86. Rossen JWA, Friedrich AW, Moran-Gilad J, ESCMID Study Group for Genomic and
Molecular Diagnostics (ESGMD). Practical issues in implementing whole-genome-
sequencing in routine diagnostic microbiology. Clin Microbiol Infect 2018; 24:355.

87. Reynolds JH, Banerjee AK. Imaging pneumonia in immunocompetent and
immunocompromised individuals. Curr Opin Pulm Med 2012; 18:194.
88. Kunihiro Y, Tanaka N, Kawano R, et al. Differential diagnosis of pulmonary infections in
immunocompromised patients using high-resolution computed tomography. Eur Radiol
2019; 29:6089.
89. Donowitz GR, Harman C, Pope T, Stewart FM. The role of the chest roentgenogram in
febrile neutropenic patients. Arch Intern Med 1991; 151:701.
90. Patterson TF, Thompson GR 3rd, Denning DW, et al. Executive Summary: Practice
Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the
Infectious Diseases Society of America. Clin Infect Dis 2016; 63:433.
91. Greene R. Transthoracic needle aspiration biopsy. In: International Radiology, Athanazou
lis C, Pfister R, Greene R, et al (Eds), WB Saunders, Philadelphia 1981. p.587.
92. Jaffe JP, Maki DG. Lung biopsy in immunocompromised patients: one institution's
experience and an approach to management of pulmonary disease in the compromised
host. Cancer 1981; 48:1144.
93. Janzen DL, Adler BD, Padley SP, Müller NL. Diagnostic success of bronchoscopic biopsy in
immunocompromised patients with acute pulmonary disease: predictive value of
disease distribution as shown on CT. AJR Am J Roentgenol 1993; 160:21.
94. McKenna RJ Jr, Mountain CF, McMurtrey MJ. Open lung biopsy in immunocompromised
patients. Chest 1984; 86:671.
95. Toledo-Pereyra LH, DeMeester TR, Kinealey A, et al. The benefits of open lung biopsy in
patients with previous non-diagnostic transbronchial lung biopsy. A guide to
appropriate therapy. Chest 1980; 77:647.
96. Westcott JL. Percutaneous transthoracic needle biopsy. Radiology 1988; 169:593.
97. Scott WW Jr, Kuhlman JE. Focal pulmonary lesions in patients with AIDS: percutaneous
transthoracic needle biopsy. Radiology 1991; 180:419.
98. Shannon VR, Andersson BS, Lei X, et al. Utility of early versus late fiberoptic
bronchoscopy in the evaluation of new pulmonary infiltrates following hematopoietic
stem cell transplantation. Bone Marrow Transplant 2010; 45:647.
99. Chellapandian D, Lehrnbecher T, Phillips B, et al. Bronchoalveolar lavage and lung
biopsy in patients with cancer and hematopoietic stem-cell transplantation recipients: a
systematic review and meta-analysis. J Clin Oncol 2015; 33:501.
100. Moore EH, Shepard JA, McLoud TC, et al. Positional precautions in needle aspiration lung
biopsy. Radiology 1990; 175:733.
101. Naidich DP, Sussman R, Kutcher WL, et al. Solitary pulmonary nodules. CT-bronchoscopic
correlation. Chest 1988; 93:595.
102. Perlmutt LM, Johnston WW, Dunnick NR. Percutaneous transthoracic needle aspiration:
a review. AJR Am J Roentgenol 1989; 152:451.
103. Plunkett MB, Peterson MS, Landreneau RJ, et al. Peripheral pulmonary nodules:
preoperative percutaneous needle localization with CT guidance. Radiology 1992;
185:274.
104. Brownback KR, Thomas LA, Simpson SQ. Role of bronchoalveolar lavage in the diagnosis
of pulmonary infiltrates in immunocompromised patients. Curr Opin Infect Dis 2014;
27:322.
105. Maschmeyer G, Donnelly JP. How to manage lung infiltrates in adults suffering from
haematological malignancies outside allogeneic haematopoietic stem cell
transplantation. Br J Haematol 2016; 173:179.
106. Marr KA, Laverdiere M, Gugel A, Leisenring W. Antifungal therapy decreases sensitivity
of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis 2005; 40:1762.
107. Hummel M, Rudert S, Hof H, et al. Diagnostic yield of bronchoscopy with
bronchoalveolar lavage in febrile patients with hematologic malignancies and
pulmonary infiltrates. Ann Hematol 2008; 87:291.
108. Fishman JA, Roth RS, Zanzot E, et al. Use of induced sputum specimens for microbiologic
diagnosis of infections due to organisms other than Pneumocystis carinii. J Clin
Microbiol 1994; 32:131.
109. Joos L, Chhajed PN, Wallner J, et al. Pulmonary infections diagnosed by BAL: a 12-year
experience in 1066 immunocompromised patients. Respir Med 2007; 101:93.
110. Maertens J, Maertens V, Theunissen K, et al. Bronchoalveolar lavage fluid
galactomannan for the diagnosis of invasive pulmonary aspergillosis in patients with
hematologic diseases. Clin Infect Dis 2009; 49:1688.
111. Clancy CJ, Jaber RA, Leather HL, et al. Bronchoalveolar lavage galactomannan in
diagnosis of invasive pulmonary aspergillosis among solid-organ transplant recipients. J
Clin Microbiol 2007; 45:1759.
112. Reinwald M, Spiess B, Heinz WJ, et al. Diagnosing pulmonary aspergillosis in patients
with hematological malignancies: a multicenter prospective evaluation of an Aspergillus
PCR assay and a galactomannan ELISA in bronchoalveolar lavage samples. Eur J
Haematol 2012; 89:120.
113. Kontoyiannis DP. Rational approach to pulmonary infiltrates in leukemia and
transplantation. Best Pract Res Clin Haematol 2013; 26:301.
114. Fortún J, Martín-Dávila P, Gomez Garcia de la Pedrosa E, et al. Galactomannan in
bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in non-hematological
patients. J Infect 2016; 72:738.

115. Zinter MS, Dvorak CC, Mayday MY, et al. Pulmonary Metagenomic Sequencing Suggests
Missed Infections in Immunocompromised Children. Clin Infect Dis 2019; 68:1847.
116. Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines
on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation
2018; 102:900.
Topic 1401 Version 31.0
GRAPHICS
Organisms associated with infection in individuals with various immune

deficits
Immune deficit Common causes Organisms
Neutrophil disorders
Neutropenia Chemotherapy Gram-negative bacilli (enteric and

nonenteric)
Leukemia
Staphylococcus aureus
AIDS
Coagulase-negative Staphylococcus
Felty syndrome
Streptococci
Viral infections
Fungi (Aspergillus spp, Candida spp)
Neutrophil Diabetes mellitus S. aureus

chemotaxis
Cirrhosis, alcoholism Candida spp
Uremia Streptococci
Hodgkin's disease Mucorales
Trauma, burns
Lazy leukocyte syndrome
Neutrophil Chronic granulomatous disease S. aureus

killing
Myeloperoxidase deficiency Escherichia coli
Fungi (Aspergillus spp, Candida spp)
T lymphocyte HIV/AIDS Viruses (latent herpesviruses,

deficiency papillomaviruses, respiratory viruses)
Lymphoma
Intracellular bacteria (Legionella spp,
Chemotherapy
mycobacteria)
Transplantation
Nocardia spp
Glucocorticoids
Fungi (Pneumocystis jirovecii, Cryptococcus
Viral infection spp, Histoplasma capsulatum)
T cell-depleting antibodies Parasites (Strongyloides spp, Toxoplasma
spp)
B lymphocyte Multiple myeloma Encapsulated bacteria (Pneumococcus,

deficiency Haemophilus influenzae, Neisseria
Acute leukemia
meningitides)
Burns
Salmonella spp
Congenital
Campylobacter
Drugs (anti-B-cell therapies,
Giardia
azathioprine, mycophenylate)
Enteropathies
Plasmapheresis
Glucocorticoids
Spleen Splenectomy Encapsulated bacteria (Pneumococcus, H.

influenzae, N. meningitidis)
Sickle cell disease
Capnocytophaga
Cirrhosis
Complement Congenital/acquired deficiencies S. aureus
Encapsulated bacteria (Pneumococcus, H.

influenzae, N. meningitidis)
Graphic 57336 Version 5.0
Breakthrough pulmonary infection with Mucorales while receiving

voriconazole for Aspergillus flavus invasive pulmonary infection
65-year-old male underwent heart transplantation for ischemic cardiomyopathy. Posttransplant

course was complicated by allograft rejection treated with high-dose glucocorticoids. Patient
developed CMV colitis (CMV donor seropositive/recipient seronegative) and invasive pulmonary
aspergillosis diagnosed by bronchoalveolar lavage. Chest CT at the time of diagnosis (A) showed
consolidative opacities in the right upper lobe (arrow) with additional diffuse nodular opacities. He
was treated with valganciclovir and voriconazole. However, follow-up chest CT scan at 3 months (B)
revealed resolution of Aspergillus nodules with (C) a new right upper lobe infiltrate (arrow) concerning
for breakthrough fungal infection. Bronchoscopy demonstrated a necrotic mass obstructing the
anterior segment of the right upper lobe. Microscopy from the lobectomy specimen (D) demonstrated
broad, ribbon-like aseptate fungal hyphae (arrow) concerning for mucormycosis, subsequently
confirmed by culture. He was treated with surgical right upper lobectomy and liposomal amphotericin
and posaconazole.
CMV: cytomegalovirus; CT: computed tomography.
Courtesy of Jay A Fishman, MD.
Cytomegalovirus pneumonitis
(A, B) High-resolution computed tomography images (1.0 mm collimation) at the levels of the azygos
arch (A) and bronchus intermedius (B) show bilateral ground-glass opacities and poorly defined small
nodules (arrows). A small right pleural effusion is also present.
(C) Photomicrograph of a biopsy specimen shows a moderate degree of interstitial fibrosis and
chronic inflammation (thick arrow) as well as plugs of fibroblastic tissue in the lumens of several
airspaces (thin arrows).
(D) Highly magnified photomicrograph shows several large cells containing intranuclear inclusions
consistent with cytomegalovirus (thin arrows). (Compare size with hyperplastic type 2 pneumocytes
[thick arrow].) The patient was a 28-year-old man with acute myelogenous leukemia.
Reproduced with permission from: Muller NL, Fraser RS, Lee KS, Johkoh T. Pulmonary Infection. In: Diseases of the Lung -
Radiologic and Pathologic Correlations, Lippincott Williams & Wilkins, Philadelphia, 2003. Copyright © 2003 Lippincott
Williams & Wilkins. www.lww.com.
Lung abscesses
Chest computed tomography in a patient with hematogenous lung infection due to Staphylococcus
aureus. There are multiple peripheral abscesses in both lung fields. The infection arose from a
contaminated Hickman catheter.
Courtesy of Jay Fishman, MD.
Common radiographic appearances of pulmonary disorders in HIV patients
Etiology by rate of disease Etiology by rate of disease

Chest radiograph or CT progression progression
abnormality
Acute <24 hours* Chronic
Consolidation Any organism (especially Fungi

bacteria)
Nocardia spp, Actinomyces spp
Mycobacteria
Bronchoalveolar cancer
Bronchiolitis obliterans
organizing pneumonia
Diffuse interstitial infiltrate Pneumocystis jirovecii Mycobacteria
Bacteria (especially Haemophilus Drug toxicity

influenzae)
Lymphocytic interstitial
Virus (Influenza, CMV, SARS-CoV- pneumonia
2)
Metastatic disease
Pulmonary edema
Pulmonary alveolar proteinosis
Acute respiratory distress
syndrome
Nodular infiltrate Bacteria Nocardia spp, Actinomyces spp
Fungi
Kaposi's sarcoma
Other tumors (especially lung

cancer)
Castleman's Disease
Adenopathy Lymphoma
Kaposi's sarcoma
Castleman's Disease
Lung cancer
Tuberculosis
Pleural effusion Bacteria (parapneumonic) Lymphoma (especially non-

Hodgkin's lymphoma and
Tuberculosis
primary effusion lymphoma)
Empyema
Kaposi's sarcoma
Pneumothorax P. jirovecii
CT: computed tomography; CMV: cytomegalovirus; SARS-CoV-2: severe acute respiratory syndrome
coronavirus 2.
* Some infections that are typically chronic may appear acutely with immune recovery/reconstitution.
Nocardia infection
A 43-year-old man who, after bone marrow transplantation for acute leukemia, developed fever and
dyspnea with a clear chest radiograph while neutropenic. Following bone marrow engraftment
(absolute neutrophil count >500/mm 3 ), an infiltrate appeared on chest radiograph (panel A), which
was more apparent by chest computed tomography (panel B). Cultures revealed Nocardia asteroides.
Respiratory syncytial virus infection
Chest radiograph shows interstitial infiltrates in a peribronchovascular distribution in a neutropenic

patient with malignant melanoma. The etiology was proven to be respiratory syncytial virus.
Normal chest radiograph
Posteroanterior view of a normal chest radiograph.
Courtesy of Carol M Black, MD.
Lung abscess
Aspergillus fumigatus lung abscess in a liver transplant recipient. The patient had recently purchased a
farm, leading to extensive exposure to soil-borne pathogens; the patient subsequently developed
cryptococcosis.
Interstitial pneumonitis
Chest radiograph in a patient with interstitial pneumonitis six months after liver transplantation.
Diffuse, bilateral infiltrates and marked hypoxemia are consistent with Pneumocystis jirovecii
pneumonia.
Normal chest radiograph
Posteroanterior view of a normal chest radiograph.
Courtesy of Carol M Black, MD.
Cytomegalovirus pneumonitis in an immunosuppressed patient
(A and B) Acute cytomegalovirus pneumonitis in an immunosuppressed patient. Patchy ground-glass

opacities are visible bilaterally.
Reproduced with permission from: Webb WR, Muller NL, Naidich DP. Infections. In: High-resolution CT of the Lung, 4th ed,
Lippincott Williams & Wilkins, Philadelphia 2009. Copyright © 2009 Lippincott Williams & Wilkins. www.lww.com.
Interstitial pneumonitis
Chest computed tomography scan in a patient six months after liver transplantation reveals both
interstitial and consolidative infiltrates. This pattern suggests a dual infection with cytomegalovirus
and Pneumocystis jirovecii, both of which were documented by transbronchial biopsy.
Studies on bronchoalveolar lavage fluid for the assessment of pneumonia in

immunocompromised hosts*
Type of infection or Direct

Culture Other
condition smear/stain
Bacteria Gram stain Aerobic and

anaerobic culture
Fungi – molds Calcofluor white/KOH Fungal culture ¶ Aspergillus

preparation, silver galactomannan antigen
stain PCR
Fungi – endemic Calcofuor white/KOH Fungal culture Histoplasma antigen

preparation
Mycobacteria AFB stain Mycobacterial

culture
Pneumocystis jirovecii Fluorescein- N/A PCR

(formerly P. carinii) conjugated
monoclonal antibody Δ
, cytology
Nocardia spp Modified AFB stain Culture ◊
Legionella spp Modified Gimenez Legionella culture Direct fluorescent

stain using BCYE antibody
medium §
Mycoplasma pneumoniae N/A N/A PCR
Viruses
Cytomegalovirus N/A Shell vial culture, PCR, cytology ¥

viral culture ¥
Influenza virus N/A Viral culture PCR, direct or indirect

fluorescent antibody,
rapid antigen test ‡
Parainfluenza virus N/A Viral culture PCR, direct or indirect

fluorescent antibody
Respiratory syncytial virus N/A Viral culture PCR, rapid antigen test ‡
Adenovirus N/A Viral culture PCR
Human N/A N/A PCR, direct fluorescent

metapneumovirus antibody
Herpes simplex virus N/A Viral culture † PCR, direct fluorescent

antibody †
Varicella-zoster virus N/A Viral culture PCR, direct fluorescent

antibody
Middle East N/A N/A PCR

respiratory syndrome
coronavirus
Malignancy** Cytology (Wright- N/A

Giemsa stain,
Papanicolaou stain)
KOH: potassium hydroxide; AFB: acid-fast bacillus; N/A: not applicable; BCYE: buffered charcoal yeast
extract; PCR: polymerase chain reaction.
* The decision of which studies to send depends upon the individual patient's clinical findings and on
availability at specific hospital laboratories. When the diagnosis is not established by studies of
bronchoalveolar lavage fluid or noninvasive testing, histopathology of lung tissue is often helpful. For
detailed discussions regarding the diagnosis of specific causes of pneumonia, refer to the individual
UpToDate topic reviews. If mucormycosis is suspected, do not grind culture samples.
¶ The detection of Candida species from respiratory specimens should generally be interpreted as
reflecting colonization of the oropharynx since Candida pneumonia is extremely rare.
Δ Other stains for P. jirovecii include calcofluor white, cresyl echt violet, Gomori methenamine silver,
and toluidine blue.
◊ Most routine aerobic bacterial, fungal, and mycobacterial culture media can support Nocardia, but
selective media, such as BCYE, modified Thayer-Martin agar, or Lowenstein-Jensen (LJ) media, may be
beneficial in decreasing the overgrowth of other organisms in specimens derived from nonsterile
sites.
§ If Legionella pneumonia is suspected, a Legionella urinary antigen should also be obtained.
¥ If cytomegalovirus infection is suspected, a peripheral blood sample should also be sent for PCR
(from whole blood or plasma) or antigenemia assay (from peripheral blood polymorphonuclear
leukocytes).
‡ Rapid antigen testing lacks sensitivity. Thus, PCR is considered the gold standard for the detection of
respiratory viruses in bronchoalveolar lavage fluid. For patients with a negative rapid antigen test in
whom a respiratory virus is suspected, PCR should also be sent.
† The detection of herpes simplex virus may represent contamination of the specimen from
reactivation within the oropharynx rather than pneumonia.
** Cytology is often performed on BAL fluid in immunocompromised hosts to evaluate for

malignancy.
Combined pulmonary infection
Chest radiograph shows extensive bilateral pulmonary infiltrates in a patient on high-dose

glucocorticoids for granulomatosis with polyangiitis (Wegener’s) who developed acute fever and
dyspnea. Lung biopsy demonstrated dual infection with cytomegalovirus and Legionella pneumophila.

Approach To The Immunocompromised Patient With Fever and Pulmonary Infiltrates

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21/2/24, 20:12 Approach to the immunocompromised patient with fever and pulmonary infiltrates - UpToDate

Official reprint from UpToDate®

Approach to the immunocompromised patient with

Literature review current through: Jan 2024.

Pulmonary infection is the most common tissue-invasive infection in immunocompromised

● Most immunocompromised patients with any signs of possible invasive infection

● Awareness of the epidemiology of infection in the community (eg, respiratory viruses,

● Serologic testing is generally not useful in the acute management of

● The presence or absence of pulmonary infiltrates should be defined by chest imaging. A

● In some patients, radiographic evidence of pneumonitis may appear or intensify with

● After obtaining microbiologic samples, empiric antimicrobial therapy is initiated and is

EPIDEMIOLOGY AND RISK OF PNEUMONIA

Glucocorticoids — Glucocorticoids play an important role in the pathogenesis of pneumonia

T cell suppression and lymphocyte depletion — Use of T lymphocyte-depleting agents has

depletion strategies (eg, plasmapheresis, proteasome inhibition, eculizumab) for antibody-

Autoimmune and inflammatory conditions — Patients with autoimmune diseases,

In patients with primary connective tissue/collagen vascular diseases (eg, granulomatosis

Cell surface "immune checkpoint receptors" normally prevent nonspecific or excessive

ETIOLOGY OF PULMONARY INFILTRATES

Infectious and noninfectious causes of pulmonary infiltrates may coexist in

Infection — The etiology of infectious pneumonitis in immunocompromised patients, when

documented in 24 percent, fungi in 17 percent, and viruses in 10 percent. In 7 percent, the

The spectrum of pulmonary fungal infection includes infection with non-fumigatus

Mixed infections with combinations of respiratory viruses, cytomegalovirus (CMV), Aspergillus

treatment of cytomegalovirus infection in lung transplant recipients" and "Prevention of

Noninfectious — Noninfectious etiologies for pulmonary infiltrates are common in

Drug-induced injury — Acute, drug-induced lung disease may reflect hypersensitivity to

● Methotrexate, bleomycin, and procarbazine can cause a syndrome of nonproductive

radiographs generally demonstrate diffuse reticular infiltrates. (See "Methotrexate-

● Cyclophosphamide may cause a syndrome of pulmonary disease with interstitial

Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS) is an

Engraftment syndrome — The engraftment syndrome is generally suspected when a

Other mimics of infection — A variety of other noninfectious processes can mimic

● Pulmonary edema or bleeding. (See "Pathophysiology of cardiogenic pulmonary

● Alveolar proteinosis may be associated with hematologic malignancies or can coexist

● In patients with primary connective tissue/collagen vascular diseases, infection may be

(See "Acute respiratory distress syndrome: Clinical features, diagnosis, and

● Transfusion-associated leukoagglutinin reactions (transfusion-related lung injury

● Allograft rejection, chronic lung allograft dysfunction (CLAD), or primary graft

● Posttransplant lymphoproliferative disorders may present with pulmonary nodules or

● Bronchiolitis obliterans (BOS) following allogeneic HCT is associated with GVHD,

● Checkpoint inhibitor therapy may cause pneumonitis in up to 6 percent of patients

altered mental status and neurologic dysfunction, or hemophagocytic

Recognition of infection in immunocompromised hosts is often delayed because the usual

Certain subgroups of immunocompromised patients are highly susceptible to infection.

● Aggressive tumors (eg, new or relapsed leukemia or lymphoma or uncontrolled

● Recent infections, especially due to cytomegalovirus (CMV) or respiratory viruses, or

● High-dose glucocorticoid therapy or recent intensification of immunosuppression (eg,

Since the differential diagnosis of pulmonary infiltrates in the immunocompromised host is

● Travel and occupation – Exposures to tuberculosis, endemic fungi (eg, H. capsulatum,

● Prolonged duration of neutropenia (higher risk for gram-negative infections, Aspergillus

● Recent intensification of immunosuppression for graft rejection (cytomegalovirus

● Potential or witnessed aspiration (risk for anaerobic infection)

● Presence of potential pulmonary pathogens in prior cultures, particularly molds

● Cardiac abnormalities (endocarditis), indwelling catheters, or intravascular clot

● Obstructing metastatic tumors, particularly intrathoracic malignancies (which can lead

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

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

● Rapid assessment of vital signs, including oxygen saturation

● Complete blood count with differential

● Electrolytes, blood urea nitrogen, and creatinine

● Urine sediment examination and culture

● Sputum for Gram stain, fungal smears, and cultures