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Literature review current through: Feb 2019. | This topic last updated: Aug 20, 2018.
INTRODUCTION
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), 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. These patients are defined by their susceptibility to infection with
organisms of low native virulence for immunologically normal hosts. Survival has improved with
the availability of newer antimicrobial agents but is threatened by the emergence of antimicrobial
resistance.
Pulmonary infection remains the most common form of tissue-invasive infection in these hosts [1-
6]. In particular, the incidence of pulmonary fungal infection is increasing in immunocompromised
individuals despite advances in antifungal prophylaxis and therapy [7,8].
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 "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".)
GENERAL PRINCIPLES
Early diagnosis and specific therapy of opportunistic infections is the cornerstone 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
(formerly Clostridium) difficile colitis. Invasive diagnostic techniques are often required.
A number of general principles are useful for the evaluation of immunocompromised patients
presenting with fever and pulmonary infiltrates.
● Most immunocompromised patients with any sign of possible invasive infection should be
hospitalized for evaluation.
● Multiple simultaneous pulmonary processes are common. 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.
● The presence or absence of pulmonary infiltrates should be defined by chest imaging. A chest
radiograph is not sufficient to exclude pulmonary involvement if there are any respiratory
symptoms or historical features that suggest a possible pulmonary process. Thus, minor
abnormalities on a chest radiograph in the immunocompromised host merit further evaluation,
generally including computed tomography scanning. Comparison with old imaging studies is
essential.
● In some patients, radiographic evidence of pneumonitis may appear only with immune
reconstitution, notably engraftment after neutropenia. In such patients, there are few data to
guide decisions regarding empiric antimicrobial therapies [9].
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, multidrug-
resistant bacteria, azole-resistant molds, and ganciclovir-resistant cytomegalovirus [10-12]. 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 [13].
Rates of infection vary depending upon the host. 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) [14]. The rate of infection was similar in another 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 [15]. 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 [16-18].
When identified, common sources of infection in the febrile neutropenic patient are colonizing
organisms from the upper and lower respiratory tract, the gastrointestinal tract (including the
perineal and perirectal areas), the urinary tract, and the skin (including intravenous lines and
wounds). Pulmonary infections are among the leading causes of morbidity and mortality in febrile
neutropenic patients [19]. Many infections are detected only at autopsy, particularly disseminated
fungal or combined fungal and bacterial infections.
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 and treat graft-versus-host disease (GVHD). These
patients are therefore at particularly high risk of infection, often with organisms resistant to
prophylactic agents.
Biologic agents — 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. (See "Tumor necrosis factor-alpha
inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Bacterial,
viral, and fungal infections".)
The agents used to suppress T lymphocyte function include the calcineurin (eg, cyclosporine,
tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) used in
organ and hematopoietic cell transplantation. These predispose to herpesvirus infections
(cytomegalovirus, 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) [22,23]. Fludarabine produces
a prolonged deficit in T cell functions. Malignancies related to viral activation (eg, Epstein Barr
virus–associated post-transplant lymphoproliferative disorder, skin cancers) are common
complications of these agents [20].
Autoimmune and inflammatory conditions — Patients with autoimmune diseases, antibody
deficiencies (eg, glomerulonephritis with proteinuria or Goodpasture's syndrome), 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. Bacterial
infections may be related to deficiencies in opsonization and phagocytosis. Dual infections
(respiratory virus followed by bacterial or fungal infections) are common. The severity and nature
of these infections 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 agents, costimulatory blockade, and other biologic
agents. Specific risk for infection varies with the agent used.
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.)
HIV infection — Pulmonary infections associated with HIV infection are discussed in detail
separately. (See "Approach to the HIV-infected patient with pulmonary symptoms" and "Bacterial
pulmonary infections in HIV-infected patients" and "Clinical presentation and diagnosis of
Pneumocystis pulmonary infection in HIV-infected patients" and "Toxoplasma pneumonia and
other parasitic pulmonary infections in HIV-infected patients" and "Treatment of pulmonary
tuberculosis in HIV-infected adults: Initiation of therapy".)
Transplantation — The risk of infection in solid organ and hematopoietic cell transplant recipients
is reviewed in detail separately, driven largely by T cell suppression [22,23]. (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".)
The spectrum of pulmonary fungal infection has broadened to include 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. (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, hematopoietic cell transplant
(HCT) recipients [32-38], and solid organ transplant recipients. Pneumocystis pneumonia (PCP) is
most common in patients receiving glucocorticoids as a part of a chemotherapeutic or
maintenance regimen [39].
Invasive CMV disease is often difficult to distinguish from viral shedding in the
immunocompromised host. 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 1). 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) [40,41]. 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-).
(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".)
Site of entry — A number of infections, especially those due to mycobacteria, 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 2).
Noninfectious — Noninfectious etiologies for pulmonary infiltrates are common in
immunocompromised patients, including pulmonary embolus, tumor, radiation pneumonitis,
atelectasis with pulmonary edema, drug allergy or toxicity, and pulmonary hemorrhage [42]. Often,
the resolution of fever in response to a trial of antibiotics is the only evidence suggesting that
infection was present.
In a 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 [43]. 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); lung function may not stabilize for
up to two years. (See "Radiation-induced lung injury".)
● Sirolimus (rapamycin) used for immune suppression may be associated with a form of
interstitial pneumonitis in transplant recipients [44]. (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,
BCNU, 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).
Other mimics of infection — A variety of other noninfectious processes can mimic infection in
immunocompromised patients:
● Alveolar proteinosis may be associated with hematologic malignancies or can coexist with
infection due to Nocardia, PCP, or less often with cryptococcosis, aspergillosis, tuberculosis,
or histoplasmosis. The presentation of patients with pulmonary infarction can also resemble
infection; chest radiographs tend to have segmental pleural-based infiltrates. (See "Causes,
clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults".)
● Therapy for rheumatic disease (eg, penicillamine, gold salts, anti-inflammatory agents) may
cause acute or chronic reticulonodular pulmonary infiltrates associated with fever, dyspnea,
and cough. Anti-tumor necrosis factor (TNF)-alpha therapy has been associated with the
reactivation of latent intracellular infections including tuberculosis and histoplasmosis. (See
"Overview of lung disease associated with rheumatoid arthritis" and "Tumor necrosis factor-
alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors:
Bacterial, viral, and fungal infections".)
● Acute respiratory distress syndrome is usually the result of severe pneumonia or ongoing
infectious or inflammatory extrapulmonary processes. (See "Acute respiratory distress
syndrome: Clinical features, diagnosis, and complications in adults".)
● Ischemia-reperfusion injury after lung transplantation. (See "Primary lung graft dysfunction".)
INITIAL EVALUATION
Recognition that infection is present 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) [30]. 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 CSF if relevant) should be
obtained before starting antimicrobial therapy.
● Recent hematopoietic cell transplant (HCT) recipients, especially those with severe graft-
versus-host disease, or delayed engraftment, such as after umbilical cord blood
transplantation
● 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
These patients are generally considered to be at higher risk of infection and are best managed as
inpatients until clinically stable. Patients with frank rigors or hypotension should also be admitted.
A very low threshold should also exist for admission and treatment of splenectomized patients with
fever. Patients with a history of recent or recurrent infection after organ transplantation (eg,
Pseudomonas spp or Stenotrophomonas 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. Immunocompromised patients with
fever without a clear etiology are considered at high risk without admission and careful follow-up
must be assured.
Diagnostic approach — The initial evaluation for immunocompromised patients with fever with or
without pulmonary findings should include:
● Blood cultures (minimum of two sets, with at least one peripheral set and one set from any
indwelling catheter)
● Imaging of the lungs (chest radiography or, whenever possible, chest computed tomographic
scanning) and imaging of any symptomatic site (eg, abdomen)
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). Nevertheless, sampling tissue is frequently required in order 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:
● 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)
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 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 late in the course of disease.
Chest radiography — 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) [48]. The following radiographic parameters are useful in
developing clinical-radiographic-pathologic correlations [6]:
Other findings may include pleural fluid, atelectasis, cavitation (image 5), 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:
● 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), P. jirovecii, or, in the lung
transplant recipient, rejection (image 6).
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.
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. Precise 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 [50]. (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:
● Rapidly expanding pulmonary lesions with cavitation and/or hemorrhage are associated with
the Mucorales, especially in diabetics.
● Opacified secondary pulmonary lobules in the lung periphery are suggestive of bland
pulmonary infarcts or septic or hemorrhagic Aspergillus infarcts (if cavitary).
● Opacities in a peribronchial (or interstitial) distribution are suggestive of fluid overload, viral
infection such as CMV (image 7), or P. jirovecii infection (image 8), and, in the lung transplant
recipient, allograft rejection.
CT scans will frequently detect multiple patterns simultaneously, in contrast with conventional
radiographs, which can raise the possibility of dual or sequential infection 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, often secondary 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 [51]. Thus, CT can provide precise guidance for
needle biopsy or for thoracoscopic or open lung excision [51-57]. 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 sputum in
order to make a specific diagnosis. 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 later [58,59].
Skin and CSF sampling — As discussed above, a number of infections, especially those due
to mycobacteria, 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 the microbiologic results from
sputum or lung biopsy specimens are available. (See 'Site of entry' above.)
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
[67]. 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
[67].
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.
Conversely, transbronchial biopsy may be considered with BAL in HIV-uninfected
immunocompromised hosts without specific contraindications to avoid the need for multiple
sequential procedures. In particular, BAL alone is less often useful for the diagnosis of invasive
fungal infection than for PCP or bacterial processes. Further, biopsy allows distinction between
colonization and invasion of fungal (or viral) infection 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. BAL fluid may be tested for Aspergillus
galactomannan antigen, potentially aiding in the diagnosis of pulmonary aspergillosis [68,69].
In patients in whom transbronchial biopsy is not feasible, VATS or open lung biopsy will often
provide the best means for establishing a diagnosis [65,70]. 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 [43]. 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 [67]. In many cases, bronchoscopy with BAL is
required to obtain adequate specimens (table 3) [64].
● Nasal washings or swabs (direct fluorescent antibody [DFA] and viral cultures) may be used
for the diagnosis of community-acquired viral infections due to influenza, parainfluenza,
adenovirus, metapneumovirus, and respiratory syncytial virus.
● Various antigen detection and nucleic acid-based assays can be performed using serum
samples as well as CSF and BAL fluid. Examples include CMV viral loads (nucleic acid
testing [NAT]) or antigenemia, serum cryptococcal antigen (with any signs of meningitis),
syphilis serology, human herpesvirus 6 NAT, Aspergillus galactomannan antigen [71],
Histoplasma antigen, and 1,3-beta-D-glucan.
In the case of CMV or Aspergillus infection, the finding of the agent or antigens in the lungs may
be the basis of therapy in immunocompromised patients with consistent clinical syndromes and
radiologic findings ("probable disease"). Such evidence is useful as a basis for empiric therapy but
are confounded by colonization. Some of these assays are more useful for screening of
asymptomatic patients than for diagnosis; the sensitivity and specificity of each assay should be
ascertained. As an example, the presence of CMV viremia indicates CMV reactivation but may not
provide information about the presence of invasive disease. Conversely, 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 recipients" and "Approach to the diagnosis of
cytomegalovirus infection".)
The decision of which studies to send depends upon the individual patient's clinical findings and
on availability at specific hospital 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 9). As an example, CMV infection may
complicate the treatment of graft rejection or veno-occlusive disease or contribute to the
pathogenesis of PCP or Aspergillus pneumonia [73].
Algorithms exist for empiric antibiotic therapy in immunocompromised hosts [74,75]. 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.
● 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")
● Infections in lung transplant recipients (see "Fungal infections following lung transplantation"
and "Bacterial infections following lung transplantation")
● 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), and autoimmune disorders, as well as the
development of novel cancer therapies including immunotherapies and checkpoint inhibitors.
(See 'Introduction' 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.)
● 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 should be
hospitalized for evaluation. (See 'General principles' above and 'Hospital admission' above.)
• Recent hematopoietic cell transplant (HCT), matched unrelated HCT (MUD), umbilical
cord HCT, and allogeneic HCT recipients with significant graft-versus-host disease
(GVHD)
• 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
● 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. (See 'Selection of initial therapy' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Kieren A Marr, MD, who contributed to
an earlier version of this topic review.
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Immune
Common causes Organisms
deficit
Neutrophil disorders
Neutropenia Chemotherapy Gram-negative bacilli (enteric and nonenteric)
Leukemia Staphylococcus aureus
AIDS Coagulase-negative Staphylococcus
Felty's syndrome Streptococci
Viral infections Fungi (Aspergillus spp, Candida spp)
Congenital Campylobacter
Cirrhosis Capnocytophaga
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.
Adenopathy Lymphoma
Kaposi's sarcoma
Castleman's Disease
Lung cancer
Tuberculosis
Pneumothorax P. jirovecii
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.
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.
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.
Type of infection
Direct smear/stain Culture Other
or condition
Legionella spp Modified Gimenez stain Legionella culture Direct fluorescent antibody
using BCYE
medium §
Mycoplasma pneumoniae N/A N/A PCR
Viruses
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.
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