![Main parasites responsible for pneumonia [107]](https://www.researchgate.net/profile/Philippe-Bauer/publication/339136004/figure/tbl2/AS:867233475616773@1583775981877/Main-parasites-responsible-for-pneumonia-107_Q320.jpg)
Content uploaded by Philippe Bauer
Author content
All content in this area was uploaded by Philippe Bauer on Sep 15, 2020
Content may be subject to copyright.
Intensive Care Med (2020) 46:298–314
https://doi.org/10.1007/s00134-019-05906-5
REVIEW
Diagnosis ofsevere respiratory infections
inimmunocompromised patients
Elie Azoulay1,2* , Lene Russell3, Andry Van de Louw4, Victoria Metaxa5, Philippe Bauer6, Pedro Povoa7,
José Garnacho Montero8, Ignacio Martin Loeches9, Sangeeta Mehta10, Kathryn Puxty11, Peter Schellongowski12,
Jordi Rello13,14, Djamel Mokart15, Virginie Lemiale1 and Adrien Mirouse1,2 on behalf of the Nine-i Investigators
© 2020 Springer-Verlag GmbH Germany, part of Springer Nature
Abstract
An increasing number of critically ill patients are immunocompromised. Acute hypoxemic respiratory failure (ARF),
chiefly due to pulmonary infection, is the leading reason for ICU admission. Identifying the cause of ARF increases the
chances of survival, but may be extremely challenging, as the underlying disease, treatments, and infection combine
to create complex clinical pictures. In addition, there may be more than one infectious agent, and the pulmonary
manifestations may be related to both infectious and non-infectious insults. Clinically or microbiologically docu-
mented bacterial pneumonia accounts for one-third of cases of ARF in immunocompromised patients. Early antibiotic
therapy is recommended but decreases the chances of identifying the causative organism(s) to about 50%. Viruses
are the second most common cause of severe respiratory infections. Positive tests for a virus in respiratory samples do
not necessarily indicate a role for the virus in the current acute illness. Invasive fungal infections (Aspergillus, Mucor-
ales, and Pneumocystis jirovecii) account for about 15% of severe respiratory infections, whereas parasites rarely cause
severe acute infections in immunocompromised patients. This review focuses on the diagnosis of severe respiratory
infections in immunocompromised patients. Special attention is given to newly validated diagnostic tests designed to
be used on non-invasive samples or bronchoalveolar lavage fluid and capable of increasing the likelihood of an early
etiological diagnosis.
Keywords: Pneumocystis pneumonia, Influenza, Aspergillosis, Mucormycosis, Toxoplasmosis, Cytomegalovirus
Introduction
e proportion of critically ill patients with deficient
immune systems has risen in recent years to about a third
of all ICU admissions. Immunocompromised patients
include patients receiving long-term (> 3 months) or
high-dose (> 0.5 mg/kg/day) steroids or other immu-
nosuppressant drugs, solid-organ transplant recipients,
patients with solid tumor requiring chemotherapy in
the last 5years or with hematological malignancy what-
ever the time since diagnosis and received treatments,
and patients with primary immune deficiency. Patients
with AIDS are discussed in another manuscript from
this issue. Factors contributing to this trend include the
increased aggressiveness and duration of cancer treat-
ments [1], greater use of organ and hematopoietic cell
transplantation, and introduction for the treatment of
autoimmune and autoinflammatory diseases of steroid-
sparing agents that induce specific immune defects.
us, a large number of patients are now expected to live
for many years with immune deficiencies that put them
at risk for severe infections.
Severe respiratory infection is the leading reason for
intensive care unit (ICU) admission in immunocom-
promised patients, who are at risk for hypoxemic acute
respiratory failure (ARF) and sepsis [2]. Life-supporting
interventions must be implemented at the same time
as extensive investigations are conducted to identify
the cause of the pulmonary involvement [2]. Failure to
*Correspondence: elie.azoulay@aphp.fr
2 Université de Paris, Paris, France
Full author information is available at the end of the article
299
identify the etiology of ARF is associated with a higher
risk of dying [3]. Moreover, identifying a pathogen is cru-
cial for antimicrobial stewardship in immunocompro-
mised patients. However, the etiological diagnosis can
be extremely challenging, as the effects of the infection
combine with those of the underlying disease and treat-
ments to create extraordinarily complex clinical pictures.
In addition, some patients have more than one concur-
rent infection, and others have non-infectious causes
of ARF that mimic infection. Furthermore, fiberoptic
bronchoscopy and bronchoalveolar lavage (FOB/BAL)
are commonly used for diagnosis, but may cause further
respiratory deterioration in patients with hypoxemia [4].
e development of non-invasive diagnostic tests with
high sensitivity and specificity (e.g., on blood, plasma,
sputum, urine, or nasal swabs) has obviated the need
for FOB/BAL in some patients [5, 6]. e utility of these
non-invasive tests is being evaluated, and will hopefully
provide clinicians with additional tools in the diagnosis
of these complex patients.
In this review, we summarize contemporary literature
and clinical practice guidelines regarding diagnostic
testing for severe respiratory infections in immunocom-
promised critically ill patients. Additionally, we briefly
discuss ongoing research, treatments, and outcomes.
Literature search strategy
We searched PubMed and the Cochrane database for
relevant articles published between 1998 and 2019 using
“humans” and “English language” as filters. e main
search terms were “respiratory infection” OR “pneumo-
nia” OR “opportunistic infection” OR “bacterial infec-
tion” OR “fungal infection” OR “viral infection” OR
“parasitic infection”. e additional search terms were
“immunocompromised” OR “cancer” OR “transplants”
OR “steroids” OR “immunosuppressive drugs” to iden-
tify publications about the epidemiology, outcomes, and
diagnosis of acute respiratory failure; and “ICU” OR
“intensive care” OR “critical care” OR “critical illness”
to retrieve publications about the ICU management of
immunocompromised patients with ARF. Additional
articles were identified by Internet searches using the
same terms.
General considerations
ARF in an immunocompromised patient may be due
to infection by more than one viral, bacterial, fungal,
or parasitic agent [7]. In addition, non-infectious fac-
tors may contribute to cause ARF and should be sought
routinely. ese factors, which are not discussed in this
review, include radiation, drug-related pulmonary toxic-
ity, diffuse alveolar hemorrhage, pulmonary edema, and
lung lesions due to the underlying disease (e.g., leukemic
infiltrates, engraftment syndrome, GVHD, lymphangitic
carcinomatosis, and pulmonary vasculitis).
Existing guidelines for managing lung disease in criti-
cally ill immunocompromised patients emphasize the
importance of obtaining valid diagnostic samples [8].
However, antimicrobial therapy is often started immedi-
ately, before samples are collected. As a result, causative
pathogens are identified in only about half the patients
with bacterial pneumonia. A detailed analysis of the clini-
cal, laboratory, and imaging-study findings can provide
valuable diagnostic orientation in these cases. Neverthe-
less, the frequency of bacterial pneumonia is probably
underestimated as many cases are atypical and, therefore,
escape recognition. On the other hand, non-infectious
pulmonary abnormalities may be mistakenly diagnosed
as clinically documented infections.
e basic rules shown in Table1 provide helpful guid-
ance for determining the cause of pulmonary infiltrates
and selecting the appropriate diagnostic strategy. In
immunocompromised patients with ARF, the first step
in the etiological evaluation is a clinical assessment. We
advocate the use of the mnemonic DIRECT (Table2)
based on days since respiratory symptom onset, type
of immunodeficiency (Fig. 1), radiographic pattern,
experience of the assessing clinician, clinical findings,
and high-resolution computed tomography (HRCT)
findings (Fig.2) [2, 9, 10]. Most of these variables are
easily evaluated at the bedside, and their analysis usu-
ally restricts the number of possible etiologies to two or
three. Additional invasive and non-invasive investiga-
tions should be obtained as needed [5]. e diagnostic
strategy should be tailored to the pretest probability of
the disease being sought, which governs the diagnos-
tic yield. Importantly, the indications of FOB/BAL are
changing to avoid exposing patients to potential adverse
events (Table1). When FOB/BAL is considered as man-
datory, it should be performed under optimal moni-
toring and high-flow oxygen therapy should be used to
correct hypoxemia [11]. e risk for intubation should
be assessed carefully as it is associated with higher
mortality. e introduction of non-invasive tests, nota-
bly those based on next-generation sequencing (NGS),
transcriptomics, and proteomics, may reduce the need
for FOB/BAL [12–16]. Updated research is needed,
Take‑home message
Appropriate diagnosis of respiratory infections is crucial to improve
survival of critically ill immunocompromised with acute hypoxemic
respiratory failure. Diagnostic strategy relies on a series of clinical
and radiographic elements available at the bedside on the use of
non-invasive sampling, thanks to innovative tests, and sometimes
on bronchoscopy and bronchoalveolar lavage.
300
however, to determine their exact diagnostic yield in
critically ill immunocompromised patients with hypox-
emic ARF. Diagnostic performance of BAL should be
reported in specific case vignettes (ARF with bilateral
ground-glass opacities in an organ transplant recipient
as opposed to ill-defined alveolar consolidation in neu-
tropenic patients with febrile ARF), or in specific ARF
etiologies (bacterial infections as opposed to invasive
fungal infections), or when patients are suspected to
have ARF from either an infectious or a non-infectious
origin (i.e., drug-related pulmonary toxicity, pulmonary
infiltration from the underlying disease, etc.).
Bacterial pneumonia
Bacterial pneumonia accounts for about 30% of ICU
admissions in cancer patients [7]. Depending on the type
of immunosuppression, the incidence rate varies from 5%
after chemotherapy for lung cancer to 30% after remis-
sion–induction chemotherapy for acute leukemia [17,
18]. e incidence rate is 30% after lung transplantation,
10% after heart or liver transplantation, and 5% after
renal transplantation [19, 20]. Splenectomy also increases
the relative risk for developing pneumonia, more particu-
larly for encapsulated bacteria. Pneumococcal, Menin-
gococcal, and Haemophilus influenzae vaccinations are
indicated for patients after splenectomy.
All types of immunosuppression are risk factors for
classic bacterial pneumonia, and 1 out of 5 patients hos-
pitalized for community-acquired pneumonia (CAP) is
immunocompromised [21]. Long-term steroid therapy
(> 10mg/day of prednisone-equivalent for ≥ 3 months) is
the main cause of immunosuppression. Neutropenia is also
associated with a higher risk of bacterial pneumonia, nota-
bly when profound and prolonged (neutrophils < 100/µL
Table 1 General considerations forthe diagnosis ofhypoxemic acute respiratory failure (ARF) inimmunocompromised
patients
1. Diagnostic tests should be selected based on a clinical assessment of the most likely cause(s) of ARF. This assessment relies on the clinical and
radiological presentation and on the nature of the underlying condition
2. A clinical suspicion for a given diagnosis must be confirmed by the most appropriate diagnostic strategy. A differential diagnosis should always be
considered and assessed as appropriate
3. All immunocompromised patients with suspected respiratory infection should undergo a minimal diagnostic workup that must include a chest
X ray, standard blood tests (blood cell counts, electrolytes, renal function test, liver enzymes, LDH level, and hemostasis parameters), blood cul-
tures, sputum examination for bacteria, echocardiography, urine bacterial antigens, and viral PCRs on nasal swabs or nasopharyngeal aspirates
4. When diagnostic yields are similar non-invasive diagnostic tests should be preferred over fiberoptic bronchoscopy with bronchoalveolar lavage
(FOB/BAL)
5. A positive test is not necessarily diagnostic (false-positives, colonization)
6. A negative test is sometimes diagnostic
7. When the initial evaluation suggests that a disease is unlikely, a test with a high negative predictive value should be preferred
8. When the initial evaluation suggests that a disease is likely, a test with high sensitivity should be preferred
9. When selecting the diagnostic strategy, the risk/benefit ratio must be assessed. FOB/BAL should be reserved for situations in which this approach
has a high diagnostic yield (organ transplantation, associated HIV infection, systemic inflammatory joint disease, high probability of Pneumocystis
pneumonia, diffuse ground-glass opacities) and discouraged in other situation (patients with malignancies, neutropenia, alveolar consolidations,
or bronchial/bronchiolar disease)
10. Patients with respiratory distress and/or severe hypoxemia are at risk for respiratory deterioration following FOB/BAL. Non-invasive tests should
be preferred. If FOB/BAL is indicated by the bedside physicians, high-flow nasal oxygen should be considered. Whether patients should be intu-
bated for the procedure questions about the risk/ratio benefit and remains unsure for the authors
Table 2 The DIRECT approach toacute respiratory failure inimmunocompromised patients
D. Delay: time since respiratory symptoms onset, since antibiotic prophylaxis or treatment, since transplantation, since the diagnosis of malignancy or
inflammatory disease
I. Immune deficiency: nature of immune defects and ongoing antibiotic prophylaxis will help avoid missing opportunistic infections
R. Radiographic appearance: A chest radiograph will not only report the extent and the patterns of pulmonary infiltrates (consolidation, air broncho-
gram, nodules, interstitial pattern), but also presence and importance of pleural effusion, mediastinal mass, cardiomegaly, pericarditis, etc
E. Experience: the clinical experience of the ICU team and specialists consultants with this type of patients (treatment-related toxicity, viral reactivation,
atypical form of diseases, cardiac involvement, etc.)
C. Clinical picture: the presence of shock is likely to be associated with bacterial infection, but may be seen in hemophagocytic lymphohistiocytosis,
toxoplasmosis, adenoviral infections, or HHV6 reactivations. Similarly, absence of fever or presence of tumoral syndrome (liver, spleen, and lymph
nodes) will be considered as a possible orientation
CT scan provides a better description of the radiographic patterns and guides the diagnostic strategy towards non-invasive or invasive diagnostic tests
301
for > 7days). About 10% of critically ill cancer patients with
severe pneumonia have neutropenia [22]. Lymphopenia is
also associated with an increased risk of pneumonia [23].
Humoral immunosuppression and hypogammaglobuline-
mia are risk factors for bacterial pneumonia, especially
with Streptococcus pneumoniae and Haemophilus influen-
zae [24]. In addition to immunosuppression, patients may
have other factors associated with both bacterial pneumo-
nia and Pseudomonas pneumonia, such as structural lung
disease [chronic obstructive pulmonary disease (COPD)
or bronchiectasis], diabetes mellitus, smoking, and alcohol
abuse [21].
Specific risk factors have been reported for pneu-
monia due to Nocardia, Neisseria, Rhodococcus, and Q
fever (Coxiella burnetii). Nocardiosis is associated with
hematological and solid malignancies, high-dose steroid
therapy, and TNFα antagonist therapy [25]. Risk factors
for N. meningitidis infection are nasopharyngeal carriage
and complement deficiencies [26]. Rhodococcus pneumo-
nia has been reported in recipients of hematopoietic stem
cells or solid organs [27]. Legionella has been described
in cancer patients, as well as those taking systemic corti-
costeroids or biologic therapies [28, 29].
Bacterial pneumonia should be considered in patients
presenting with nonspecific symptoms (e.g., cough,
dyspnea, fever, sputum production, and pleuritic chest
pain) and pulmonary infiltrates. However, the symp-
toms are often blunted in patients with immune defi-
ciencies [30]. Bacterial pneumonia may be complicated
by septic shock and/or acute respiratory distress syn-
drome. Chest radiographs and HRCT findings are not
specific and include lobar consolidation, alveolar or
Fig. 1 Pulmonary infections according to immunosuppression. AML acute myeloid leukemia, CMV cytomegalovirus, GM galactomannan, HSCT
hematopoietic stem-cell transplantation, HSV herpes simplex virus, MDS myelodysplastic syndrome, PCR polymerase in chain reaction, SOT solid
organ transplantation, VZV Varicella–Zoster virus
302
interstitial infiltrates, cavitation, and/or pleural effusion
[31]. Extra-pulmonary manifestations suggest infection
with Legionella or Nocardia. Nocardia can disseminate
to the bloodstream, skin, bones, joints, retina, heart,
and/or central nervous system.
Streptococcus pneumoniae, Klebsiella pneumoniae,
and Haemophilus spp. are the most frequently iden-
tified causative pathogens [21]. Pseudomonas spp.,
enteric Gram-negative bacilli, Stenotrophomonas spp.,
and methicillin-resistant Staphylococcus aureus should
be considered [32]. Multidrug-resistant (MDR) patho-
gens are significantly more common in immunocom-
promised patients; in one study, they were responsible
for 72% of ventilator-associated lower respiratory tract
infections [33]. Data are scarce on Mycoplasma,
Legionella, and Chlamydia species in this population.
Routine non-invasive tests for bacterial pneumo-
nia include sputum sampling, blood cultures, and urine
antigen detection. e sputum Gram stain is rarely
informative, and the yield of sputum bacterial cultures
is low, although it improves with optimal sampling and
absence of prior antibiotic therapy. Endotracheal aspi-
rates are more likely to recover the causative organism
than expectorated sputum, and organisms recovered
immediately after intubation is unlikely to reflect mere
colonization; in patients with malignancies and ARF, a
Fig. 2 Etiologies of pulmonary infections according to CT-scan patterns. CMV cytomegalovirus, GM galactomannan, HSV herpes simplex virus, MDS
myelodysplastic syndrome, IF immunofluorescence, PCR polymerase in chain reaction, VZV Varicella–Zoster virus
303
randomized-controlled trial reported that a strategy with
non-invasive testing only (including sputum sampling)
was not inferior to FOB/BAL [5]. In patients admitted for
CAP, urine antigen detection was 61% sensitive and 39%
specific for S. pneumoniae, and corresponding values for
L. pneumophila were 63% and 35% [34]. Blood cultures
also have low yields of 5–14% in patients admitted for
CAP [5, 35], although higher yields have been reported
when the pulmonary involvement was severe. Bacterial
identification by polymerase chain reaction (PCR) on res-
piratory samples has been reported to provide up to 81%
sensitivity and may be superior over standard culturing
in patients with CAP, especially those previously given
antibiotics [36]. e diagnostic yield of pleural fluid cul-
tures is about 35%, but can reach 60% when blood culture
bottles are used [37].
e diagnosis of nocardiosis requires specific culture
media and PCR. N. meningitidis infection is diagnosed
based on blood and cerebrospinal fluid culture. Rhodoc-
occus grows readily on ordinary media. Serological test-
ing is the cornerstone of the diagnosis of Q fever.
Real-time PCR (RT-PCR) produces quantitative infor-
mation that can help to distinguish between colonization
and infection [38]. PCR can be used to detect resistance
genes, thereby guiding the initial antibiotic treatment.
New tools such as NGS are being developed to identify
bacteria, fungi, and viruses in respiratory samples and
may improve the diagnosis of concomitant infections
[39]. Real-time metagenomics also holds promise for rap-
idly identifying the pathogens that cause bacterial pneu-
monia [40].
Initial empiric treatment of pneumonia should follow
clinical practice guidelines and local resistance patterns.
Severe pneumonia in immunocompromised patients
is still often fatal; in a study of cancer patients—75% of
whom had septic shock—the hospital mortality rate was
64.9% [22].
Mycobacterial pneumonia
e risk of active tuberculosis is increased in patients
with immune impairments such as HIV, diabetes, cancer,
or solid-organ transplantation (SOT), and those receiving
systemic steroids or TNFα antagonist therapy [41].
e symptoms of mycobacterial infections are more
insidious compared to those of CAP, and include persis-
tent cough, lymphadenopathy, fever, night sweats, and
weight loss. Immunocompromised patients may have
only one or a few mild symptoms, such as persistent fever
[42], even though dissemination of the organism outside
the lungs is common [43]. HRCT findings include miliary
nodules, cavitation, centrilobular tree-in-bud nodules,
consolidation, mediastinal lymphadenopathy, and pleural
effusion [44]. Cavitation and centrilobular tree-in-bud
nodules are often located in the upper lobes.
e diagnosis of pulmonary tuberculosis is based on
the demonstration of acid-fast bacilli on three induced
sputum samples (smears and cultures) or a single FOB
specimen. Culture requires Lowenstein–Jensen medium,
and PCR testing should be done on the first sample [41].
False-negatives cultures are common. PCR testing on
sputa has been reported to be 89% sensitive and 99% spe-
cific overall, with corresponding values of 67% and 99%
in patients with negative sputum smear findings [41].
PCR may have a lower yield in HIV-negative than in
HIV-positive immunocompromised patients. Adenosine
deaminase and IFN-γ are markers for tuberculosis that
can be measured in pleural fluid [41]. e interferon-γ
release assay (IGRA) and tuberculin skin test (TST)
serve to detect latent tuberculosis [41]. A combination
of tuberculosis drugs must be given. ere is some sug-
gestion that steroid therapy might decrease mortality in
critically ill patients with tuberculosis and ARF, although
further data are needed [45]. Mortality rates in patients
with tuberculosis and ARF have ranged from 50 to 70%
[46].
Nontuberculous mycobacteria (NTM) species are
mycobacteria other than M. tuberculosis and M. leprae.
NTM are generally free-living organisms that are ubiqui-
tous in the environment. To date, 200 NTM species have
been identified. Human disease due to NTM is classified
into four clinical syndromes: chronic pulmonary disease,
lymphadenitis, cutaneous disease, and disseminated dis-
ease [47]. Risk factors for disseminated disease are simi-
lar to those for tuberculosis and include HIV infection,
steroids, TNFα antagonists, diabetes, cancer, and SOT.
Patients present with a cough, fatigue, malaise, weakness,
dyspnea, chest discomfort, and, occasionally, hemop-
tysis. e extra-pulmonary manifestations seen in dis-
seminated disease consist of arthritis, tenosynovitis, skin
lesions, and gastrointestinal manifestations [48]. Fever
and weight loss are less common than in patients with
tuberculosis. Because NTMs exist in the environment,
their presence in nonsterile respiratory specimens does
not necessarily indicate a role in causing lung disease
[47]. e American oracic Society (ATS)/Infectious
Disease Society of America (IDSA) diagnostic criteria
for NTM lung disease are as follows: pulmonary symp-
toms; compatible radiographic findings; and two posi-
tive sputum cultures or one positive BAL sample or other
evidence of NTM such as a positive lung-biopsy culture
with compatible histological features [47]. In dissemi-
nated disease, blood culture on special media should be
performed. Mycobacterial cultures must be kept for at
least 6 weeks. Bone marrow or fluid or tissue samples
from suspected sites of involvement should be sent for
304
culture and histological examination with special stains.
e treatment relies on a combination of antibiotics. e
treatment duration depends on the type of NTM and the
manifestations [47].
Viral pneumonia
Common community-acquired respiratory viruses
(CARVs) can cause severe and potentially fatal ARF in
immunocompromised patients (Table3). CARVs include
influenza virus, parainfluenza virus (PIV), respiratory
syncytial virus (RSV), rhinovirus/enterovirus, and human
metapneumovirus (hMPV).
Influenza is caused by influenza A and B viruses and
characterized by annual seasonal epidemics and spo-
radic pandemic outbreaks. e WHO has estimated that
annual influenza outbreaks affect 48.8 million people, of
whom 22.7 million see a healthcare provider and nearly a
million are admitted to hospital [49]. Among critically ill
patients with influenza, 12.5% are immunocompromised,
and their mortality is 2.5 times as high as in non-immu-
nocompromised patients [50].
Among patients admitted for influenza, 10% are
immunocompromised [51]. RSV infections are typically
seasonal and pose similar serious risks to immunocom-
promised patients as does the influenza virus. RSV infec-
tion has been found in up to 12% of patients undergoing
HCT, of whom one-third progressed to lower respira-
tory tract infection, which was fatal in about 30% of cases
[52]. PIV causes respiratory diseases similar to those
seen with RSV. RSV and PIV were found in 11% and
2.5% of nasopharyngeal swabs from critically ill hematol-
ogy patients, respectively [53]. In a prospective study of
HSCT recipients, PIV-3 accounted for 71% of viral res-
piratory infections [54]. e virus is often acquired in
the community and brought into the transplant ward by
staff, where it may mimic other opportunistic infections,
thereby raising diagnostic challenges [55]. e hMPV
is closely related to RSV and often causes severe infec-
tions requiring mechanical ventilation in patients who
are elderly and/or have comorbidities [56]. Rhinoviruses/
enteroviruses are Picornaviridae that circulate through-
out the year and are increasingly recognized as a cause
of lower respiratory tract infection in immunocompro-
mised patients [53]. In critically ill hematology patients,
rhinoviruses/enteroviruses were the most prevalent
viruses detected at ICU admission (56%) [53].
Risk factors for viral pneumonia overlap those for bac-
terial pneumonia, and co-infection is common in patients
with severe pneumonia [53]. Steroid therapy, hematologi-
cal malignancies, lymphopenia, older age, and HCT are
strongly associated with viral infections [21]. ere is a
seasonal distribution with peaks in the winter and spring
[53]. e symptoms and imaging-study findings are not
specific for viral infections, and overlap occurs with the
changes seen in bacterial infections, although a diffuse
airspace pattern is more common in bacterial pneumonia
[57]. e main findings are the tree-in-bud and ground-
glass patterns [58]. e diagnosis relies on identification
of the virus in various samples. CARVs can be identi-
fied by cultures, serology, or rapid diagnostic tests based
on enzyme immunoassay (EIA), immunofluorescence,
Table 3 Community‑acquired respiratory virus (CARV)
#Nomenclature according to the 2018 International Committee on Taxonomy of Viruses statement
Type Family Genus Virus
RNA viruses Orthomyxoviridae Influenza A All Influenza A subtypes
Influenza B Influenza B
Paramyxoviridae Rubulavirus Human parainfluenza virus type 2 (PIV-2)
Human parainfluenza virus type 4a (PIV-4a)
Human parainfluenza virus type 4b (PIV-4b)
Respirovirus Human parainfluenza virus type 1 (PIV-1)
Human parainfluenza virus type 3 (PIV-3)
Pneumoviridae Metapneumovirus Human metapneumovirus (hMPV)
Orthopneumovirus Human orthopneumovirus/Respiratory syncytial virus A (RSV-A)
Human orthopneumovirus/Respiratory syncytial virus B (RSV-B)
Coronaviridae Betacoronavirus Middle East respiratory syndrome-related coronavirus (MERS-CoV)
Severe acute respiratory syndrome-related coronavirus (SARS-CoV)
Human coronavirus NL63
Human coronavirus 229E
Human coronavirus HKU1
Human coronavirus OC43
Picornaviridae Enterovirus Enterovirus A-L
Rhinovirus A, B, C
305
or PCR. Molecular amplification techniques have
largely superseded cell cultures as the primary means
of detecting and identifying viruses in clinical samples.
PCR is now the reference standard diagnostic test [59].
e IDSA recommends that all immunocompromised
patients presenting with acute onset of respiratory symp-
toms be tested for influenza. PCR-based diagnostic pan-
els can detect multiple respiratory viruses simultaneously
within 2–3h [60]. ese new sensitive methods increase
the ability to identify a broader range of viruses, such as
rhinovirus, whose clinical significance should be carefully
assessed. Uncertainty still surrounds the type of sample
most appropriate for detecting each type of virus (nasal/
throat swab, BAL, mini-BAL, cytopathology, or even lung
biopsy when performed) [61]. An important considera-
tion when choosing the sampling technique is the clinical
condition of the patient. In patients receiving mechanical
ventilation, endotracheal aspirates or BAL fluid should
be collected, even when influenza tests on upper respira-
tory tract specimens are negative [59]. In a study of pul-
monology ward patients that used BAL as the reference
standard, nasopharyngeal PCR testing had positive and
negative predictive values of 88% and 89%, respectively
[62]. When a virus is identified in the respiratory tract,
differentiating colonization from infection may be chal-
lenging [53]. However, presence of the influenza virus
usually indicates infection. In RSV infection, blood test-
ing may be helpful, as RSV-RNA was detected in plasma
samples of one-third of HSCT patients with pulmonary
RSV infection and was associated with a poor outcome
[48].
Both the World Health Organization (WHO) and the
Centers for Disease Control and Prevention (CDC) rec-
ommend oseltamivir as the first-line agent for influenza.
Systemic steroids should not be used unless strongly indi-
cated for another condition [63]. In patients with severe
illness, prolonged treatment may be in order, although
the optimal duration is uncertain. Testing for antiviral
resistance at this stage should be considered, as immu-
nocompromised patients are at higher risk of develop-
ing resistance and prolonged viral shedding [64]. RSV
treatment with intravenous immunoglobulins and riba-
virin has been suggested, but there is no published evi-
dence that this treatment can benefit to the patient [65].
In recent epidemiologic studies, the prevalence of CARV
in critically ill hematological patients was similar to that
in the general population with CAP; however, the pres-
ence of CARV doubled the mortality rate [53]. Allogeneic
HSCT recipients are at particularly high risk of death
from CARV infection [54]. Among immunocompro-
mised patients with the most severe forms of influenza,
one-third requires ICU admission and mechanical venti-
lation and one-fifth have a fatal outcome [66].
In immunocompromised patients, the viruses most
commonly responsible for systemic viral infections are
DNA viruses. e herpes viruses responsible for pneu-
monia include herpes simplex viruses 1 and 2 (HSV-1,
HSV-2), varicella–zoster virus (VZV), and cytomegalo-
virus (CMV). Herpes viruses are known to establish life-
long infections and can often reactivate during episodes
of immunosuppression [67]. Adenoviridae include
human adenoviruses (HAdV) A to G, each of which
produces a different clinical pattern. In immunocom-
promised patients, HAdV can cause life-threatening mul-
tiorgan damage [68]. Risk factors change over time with
the changes in immunosuppression [69]. Viral infections
are most common in patients with T-cell deficiencies
and are of particular concern in those taking high-dose
steroids (≥ 20 mg/day for ≥ 4weeks) or having received
T-cell-depleted allogeneic HSCT or treatment with alem-
tuzumab or fludarabine [70]. Viral infections may be
community-acquired or opportunistic, arise due to reac-
tivation of latent infection, come from a transplant donor,
or come from the transplant recipient (e.g., CMV reacti-
vation when a seronegative patient receives a solid trans-
plant from a seropositive donor or when a seropositive
recipient receives an HSCT from a seronegative donor)
[71]. Endogenous reactivation appears to be the predom-
inant cause of viral disease in severely immunocompro-
mised patients.
In patients with immunosuppression, the presenta-
tion of systemic viral infections varies widely depending
on the causative organism and degree of immunosup-
pression (Table4). When the lungs are involved, the res-
piratory symptoms are nonspecific (tachypnea and/or
dyspnea, hypoxia). e lung infiltrates typically appear
as a crazy-paving pattern, ground-glass opacities, micro-
nodules, and/or consolidations. A definite diagnosis of
CMV pneumonia requires clinical symptoms of pneu-
monia and identification of CMV in lung tissue by virus
isolation, rapid culture, histopathology, immunohisto-
chemistry, or DNA hybridization techniques [72]. Prob-
able CMV pneumonia is defined as clinical symptoms
and/or signs of pneumonia combined with CMV detec-
tion by viral isolation, rapid BAL fluid culture, or CMV
DNA quantitation in BAL fluid. No reliable cut-off for the
CMV DNA load has been established, however. Further-
more, CMV shedding may occur in the lower respiratory
tract, and the CMV DNA load may, therefore, be low in
patients with asymptomatic infection [72]. On the other
hand, a negative CMV DNA test in BAL fluid has nearly
100% negative predictive value and, therefore, excludes
CMV pneumonia, assuming satisfactory sampling. VZV
pneumonia is usually readily diagnosed based on the typ-
ical skin rash, although it may fail to develop in patients
306
with severe immunosuppression [73]. Replicating VZV is
almost always found in BAL fluid [73].
HSV pneumonia is more challenging to diagnose, as
reactivation in blood, saliva, or the throat is frequent
in critically ill patients [74]. us, HSV detection in the
lower airways may merely indicate airway contamination
without parenchymal involvement. e diagnosis rests
on HSV detection in BAL fluid and on the demonstra-
tion of specific nuclear inclusions in BAL cells [74]. Mac-
roscopic bronchial lesions may be seen during fiberoptic
bronchoscopy, albeit only rarely [74].
Further research is needed to improve the early detec-
tion of systemic viral infections at the subclinical phase.
e ways in which immune deficiencies affect host
defenses against viral infections need clarification. In the
field of treatment, the optimal indications and duration
of antiviral prophylaxis should be better defined, and
the potential influence of new immunotherapeutic and
molecular-targeted approaches on the emergence of sys-
temic viral infections should be assessed [8]. e use of
quantitative real-time PCR on biopsies and BAL fluid is
the focus of active research that may allow the differen-
tiation of CMV pneumonia and colonization [75]. Antivi-
ral drugs and immunomodulation are the main treatment
tools.
Invasive fungal infections
e three most important causes of fungal pulmonary
infection are Pneumocystis jirovecii, Aspergillus spp.,
and Cryptococcus spp [76]. Pneumocystis jirovecii is an
airborne pathogen transmitted from asymptomatic car-
riers to immunocompromised hosts [77]. e main
risk factors are treatments that impair T-cell immunity,
including steroids; acute lymphocytic leukemia; HSCT
and SOT; and a number of primary immunodeficien-
cies [78]. Aspergillus spp. are molds that cause infection
in the lungs and sinuses. e risk factors consist chiefly
of severe and prolonged neutropenia, acute myeloid leu-
kemia, HSCT, high-dose steroid therapy, and drugs or
conditions that chronically impair the T-cell responses.
Invasive aspergillosis (IA) is most common in patients
exposed to heavy fungal loads, for instance on construc-
tion sites [79]. e cumulative incidence of IA 12months
after SOT was 0.7% in one study and was highest in lung
transplant recipients [80]. In HSCT recipients, the inci-
dence at 12 months was 1.6% [81]. Cryptococcus spp.
are yeasts that can affect the lungs and central nerv-
ous system in patients with impaired T cell-mediated
responses. C. neoformans and C. gattii account for most
cases of cryptococcosis. Reactivation of dormant organ-
isms is probably the main mechanism of lung involve-
ment. Risk factors for pulmonary cryptococcosis include
malignancies, HSCT, SOT, cirrhosis, chronic kidney
disease, chronic lung disease, diabetes, and treatment
with steroids or TNFα antagonists [82]. In SOT recipi-
ents, cryptococcosis accounted for about 8% of invasive
fungal infections, with an overall incidence of 0.2–5%
[83]. Mucorales causes aggressive invasive infections in
patients with hematological malignancies and in HSCT
recipients. Fusarium mostly affects patients with hema-
tological malignancies and HSCT recipients and involves
the lungs and sinuses. Other pulmonary fungal infections
are shown in Table5.
Patients with pulmonary fungal infections present
with nonspecific symptoms such as a fever, cough, dysp-
nea, pleuritic pain, and/or hemoptysis. Extra-pulmonary
Table 4 Systemic viruses responsible forpneumonia inimmunocompromised patients
HSV herpes simplex virus, VZV varicella–zoster virus, CMV cytomegalovirus, PCR polymerase chain reaction, BAL bronchoalveolar lavage, CSF cerebrospinal uid, EIA
enzyme immunoassay
Virus type Source Extra-respiratory manifestations Diagnosis
HSV (HSV-1, HSV-2) Donor transmission to transplant recipient
Reactivation in T-cell defects Skin and genital eruption
Encephalitis, esophagitis,
Keratitis
PCR (blood, BAL, tissue)
Tissue culture
Serology
Histopathology
VZV Donor transmission to transplant recipient
Reactivation in T-cell defects Varicella, herpes zoster
Encephalitis, cerebellitis, hepatitis, myelitis
Herpes zoster ophthalmicus
PCR
Direct fluorescent antibody testing
Viral culture
Histopathology
CMV Donor transmission to transplant recipient
Reactivation in T-cell defects Esophagitis, gastritis, colitis
Retinitis, encephalitis, myelitis, polyradicu-
lopathy
Neutropenia
PCR (blood, BAL)
Histopathology
Serology
Adenovirus Reactivation Hemorrhagic cystitis, nephritis
Colitis, hepatitis, encephalitis Viral culture (nasal, blood, urine, CSF,
tissues)
EIA, Immunofluorescence, PCR, serology
Histopathology
307
symptoms may help to suspect invasive fungal disease. In
IA, HRCT shows macronodules with a halo sign, pleural-
based wedge-shaped consolidations, or masses. Mucor-
mycosis and IA share clinical and radiological findings,
but mucormycosis should be suspected in the presence
of sinus involvement, prior voriconazole therapy, or a
reversed halo sign on HRCT. In P. jirovecii pneumonia,
HRCT shows bilateral ground-glass opacities predomi-
nating at the apices and sparing the periphery. e most
common findings in pulmonary cryptococcosis are soli-
tary or sparse, well-defined, non-calcified nodules that
are often pleural-based [84].
Invasive fungal infections (IFI) are classified as proven
(signs of infection and fungus identified by histopathol-
ogy, cytopathology, or culture), probable (based on host
factors, clinical criteria, microscopy, culture, galactoman-
nan antigen [GM], or possible (based on host factors and
clinical criteria) [88]. e diagnosis of P. jirovecii pneu-
monia (PJP) relies on identification of the pathogen by
immunofluorescence and quantitative PCR (on BAL
fluid ideally and induced sputum otherwise); serum BDG
testing can be helpful for difficult cases where there is a
discrepancy between the clinical picture and PCR find-
ings, or to make the difference between colonization and
infection when PCR findings are in the gray zone [85]. In
a study of HIV-negative immunocompromised patients,
quantitative PCR on BAL fluid was 87% sensitive and 92%
specific and helped to differentiate infection and colo-
nization [86]. According to a meta-analysis, the serum
BDG assay is 95% sensitive and 86% specific [87]. In IA
(Figure S1), BAL microscopy and culture show branching
septate hyphae. Aspergillus spp. grows in 2–5days, but
the culture yield is low. When IA is suspected in patients
at high risk due to a hematological malignancy, HSCT, or
SOT, serum Aspergillus PCR and GM testing are recom-
mended (Fig.1). PCR and GM testing may perform better
on BAL fluid than on serum, although FOB/BAL should
be done only if indicated by a careful risk/benefit assess-
ment [88]. Serum BDG testing is recommended in high-
risk patients, but is not specific for IA. A 2015 systematic
review found that sensitivity and specificity for diagnos-
ing IA were 81.6% and 91.6% for serum GM and 76.9%
and 89.4% for serum BDG, compared to 77–88% sensitiv-
ity and 75–95% specificity for PCR [89]. Mucormycosis is
diagnosed by sample microscopy, culture, and/or histo-
pathology. Immunohistochemistry is 100% sensitive and
100% specific [90]. Mucorales fungi contain neither BDG
nor GM, and negative results from these tests in a patient
whose HRCT findings are consistent with IFI, there-
fore, suggest mucormycosis [91]. However, concomitant
Aspergillus infection is possible. e diagnosis of Cryp-
tococcus pneumonia, whether isolated or with central
nervous system involvement, relies on visualization of the
pathogen by microscopy or on culturing of cerebrospinal
fluid, blood, and/or sputum, in which Cryptococcus grows
within 2–3days. e cryptococcal antigen assay is less
sensitive in HIV-negative than in HIV-positive patients:
values of 56–83% have been reported in HIV-negative
immunocompromised patients with Cryptococcus pneu-
monia [82, 92].
PJP is treated with trimethoprim-sulfamethoxazole
[85]. e addition of steroid therapy in severe forms is
currently not recommended in HIV-negative patients,
but is being assessed in a randomized-controlled trial
(NCT02944045). IA is treated with voriconazole [93].
e first-line treatment for mucormycosis is liposomal
amphotericin B, although isavuconazole constitutes a
valid alternative [94]. Severe cryptococcus pneumonia
requires amphotericin B and flucytosine followed by
fluconazole [95]. Fusarium infections are managed with
voriconazole or amphotericin B [96].
New diagnostic methods are being developed to allow
earlier diagnosis with greater sensitivity in patients
with fungal infections. Assays for Mucorales-specific
antigen or T cells and Mucorales PCR have shown good
sensitivity and specificity with earlier positivity com-
pared to cultures [97]. In patients with IFIs, mass spec-
trometry to detect panfungal serum disaccharide was
51% and 64% sensitive for diagnosing invasive candidia-
sis and IA, respectively, with higher specificities of 87%
and 95%, respectively; for mucormycosis, the test made
a similar contribution to the diagnosis as did quantita-
tive PCR [98].
Although survival has improved over time, IA
remains an often fatal complication after HSCT. In
a retrospective study of patients with hematological
malignancies who developed ARF due to IA, 1-year
mortality was 72% [99]. Mortality in transplant recipi-
ents was 49.4%, with a higher rate after HSCT (57.5%)
than after SOT (34.4%) [100]. PJP is more often fatal
in HIV-negative than in HIV-positive patients, and in
HIV-negative patients, mortality varies widely, from
18% to 50%, depending on the underlying disease [101].
Finally, mortality rates of up to 66% have been reported
in patients with pulmonary mucormycosis [102].
Parasitic infections
Many parasites cause respiratory infections in immu-
nocompromised patients (Table6) [103]. e two most
common, Toxoplasma gondii and Strongyloides sterc-
oralis, are associated with considerable mortality if left
untreated.
Factors that promote T. gondii reactivation include
impaired T-cell immunity, HIV infection, hematologi-
cal malignancies, HSCT, and SOT [104]. After allogeneic
HSCT, 16% of patients had a positive routine blood PCR,
308
Table 5 Invasive fungal infections: clinical characteristics anddiagnostic tools. Source of images: Public Health Images
Library, CDC (https ://phil.cdc.gov)
Morphology using
H&E, GMS, or
PAS staining
Risk factorsDisease
characteristics
Main diagnostic tools First-line
treatment
Aspergillus
spp.
Nonpigmented
(hyaline) septate
hyphae with acute-
angle branching
Prolonged
neutropenia
Allogeneic HSCT
SOT
Steroids
AIDS
Chronic
granulomatous
disease
Nonspecific clinical
signs,
Chest pain
(neutropenia),
Wheezing (invasive
airway disease),
Halo sign (HRCT),
Sinus involvement
Sputum and/or BAL:
microscopy and culture,
Serum GM: Se~75%, Sp~85%
BAL culture: Se~50%,
Sp~95%
BAL GM: Se~85%, Sp~90%
BAL PCR: Se~90%, Sp~90%
PCR blood: Se~80%, Sp~80%
Serum BDG: Se~70%,
Sp~90%
Voriconazole
Mucorales
spp.
Nonpigmented
(hyaline) pauci-
septate ribbon-like
hyphae with right-
angle branching
Hematological
malignancies
(AML+++)
HSCT
Disseminated
disease (sinus, brain,
skin, gut),
Clinical and
radiological findings
similar to
aspergillosis with
reversed halo sign
Clinical specimens:
microscopy (optical
brighteners), culture, and
histopathology
Negative GM (BAL, blood)
Blood PCR: Se~81-92%%,
Sp~98%
BAL PCR: Se~90%, Sp~99%
Tissue PCR: Se~80%,
Sp~100%
Negative BDG
Liposomal
amphotericin B
Surgery
P. jiroveci
Spherical, cup-
shaped or crescent-
Steroids,
Prolonged
lymphopenia
(chemotherapy,
immunotherapy,
ALL)
Faster onset and
greater severity
compared to AIDS-
related P. jirovecii
pneumonia,
BAL, induced sputum:
- Immunofluorescence:
Se>90%
- Classic staining: Se>90%
- PCR: Se~99%, Sp~92%
TMP/SMX
shaped cysts (4-8
µm)
Lack of
prophylaxis,
Fludarabin
Ibrutinib
Bilateral ground-
glass opacities by
HRCT
Serum BDG: Se~95%,
Sp~85%
Cryptococcus
spp.
Narrow-based
encapsulated
budding yeasts (4-10
µm)
Steroids
Monoclonal
antibodies
(TNFaantagonists)
CNS involvement,
Bloodstream
infection
BAL, CSF: India ink staining,
Culture
- Antigen: Se~70-80%
Blood cultures: Se~40%
Amphotericin
B + flucytosine
(2 weeks)
Histoplasma
spp. [92]
Small narrow-based
budding yeasts (2-4
µm)
Hematological
malignancies
SOT
HSCT
Immuno-
suppressants
Endemic (America,
Asia, Africa),
Disseminated
histoplasmosis with
multiorgan
involvement
Serum/urine antigen: Se~80%,
Sp~98%
Culture of tissue/body fluids
Histopathology
Liposomal
amphotericin B
Blastomyces
spp. [92]
Broad-based
budding yeasts (10-
15 µm)
HSCT
SOT
Immuno-
suppressants
Endemic (North
America),
Mimics bacterial
pneumonia,
Disseminated
blastomycosis (skin,
bone, urinary tract,
CNS)
Urine antigen (cross-reacts
with Histoplasma): Se~75%
Sputum or BAL:
- microscopy (KOH,
calcofluor, Papanicolaou):
Se~35%
- culture: Se~75%
Serum antibodies: Se~85%
Histopathology (extra-
pulmonary sites)
Liposomal
amphotericin B
Coccidioides
spp. [92]
Impaired cellular
immunity
Endemic (America),
Rheumatologic and
skin manifestations,
Serology: Se~80%
Culture of respiratory
specimen
Liposomal
amphotericin B
Spherules with
endospores
Disseminated
coccidioidomycosis
Antigen (urine, serum:
Se~70%, Sp~98%
PCR
Histopathology (extra-
pulmonary lesions)
Fusarium
spp. [100]
Hyphae similar to
Aspergillus; hyaline,
unicellular or
multicellular clusters
Prolonged
neutropenia
HSCT
Hematological
malignancies
Invasive fusariosis
(skin, lungs, sinuses)
may mimic invasive
aspergillosis,
Fungemia,
Lung nodules
(HRCT)
Culture (blood, lung, sinuses,
skin)
Microscopy and histopathology
of clinical specimens
GM
BDG
Pan-fungal PCR
Voriconazole
Amphotericin
B
309
and 6% had invasive disease [105]. e risk is highest in
seropositive allogeneic HSCT recipients who receive a
seronegative graft [106]. e sparse data available for
SOT recipients suggest lower rates. e risk of a seron-
egative recipient acquiring T. gondii from a seropositive
donor depends on the organ type, being highest after
heart transplantation [106]. Data on patients with solid
tumors are scarce, but toxoplasmosis has only rarely
been reported in patients receiving cancer chemotherapy
[107].
In immunocompromised patients, fever may be the
presenting symptom of toxoplasmosis, which may pro-
gress to multiple organ failure. e symptoms of dis-
seminated toxoplasmosis are nonspecific; the lungs and
central nervous system are often involved, and hepatitis,
myocarditis, and chorioretinitis may develop [108]. Other
features include lymphopenia, thrombocytopenia, rhab-
domyolysis, and lactate dehydrogenase elevation [104].
In the rare cases with isolated pulmonary involvement,
the presentation may mimic interstitial pneumonia, PJP,
or CMV pneumonia. CT may show lobar consolidations,
ground-glass opacities, and thickening of the interlobular
septa [108]. Serological testing is unreliable in immuno-
compromised patients, but may be useful in previously
seronegative patients. e diagnosis rests on PCR on
blood and BAL fluid samples and on microscopic exam-
ination of stained BAL fluid smears [109]. In a study of
transplant recipients, blood PCR was 90% sensitive [106].
e treatment consists of at least 6 weeks of pyrimeth-
amine, sulfadiazine, and leucovorin induction, followed
by reduced-dose maintenance therapy [109]. e prog-
nosis of disseminated toxoplasmosis involving the lungs
is grim, with a 78% mortality rate in ICU patients [104,
106].
Streptococcus stercoralis is a nematode that infects
humans through skin contact with larvae contain-
ing soil. e prevalence varies across geographic areas,
with Africa, South America, and Asia being regions of
high endemicity. About 30–100 million people may be
infected worldwide [110]. In industrialized countries,
strongyloidiasis is seen in immigrants, tourists, and mili-
tary personnel returning from endemic areas [111]. In
a US cohort of kidney transplant candidates, 9.9% were
seropositive for S. stercoralis [112]. Risk factors include
walking barefoot, engaging in work that involves skin
contact with soil, and poor sanitary conditions [111].
Streptococcus stercoralis hyperinfection syndrome
(SSIS) occurs when chronically infected patients become
immunosuppressed (notably those receiving steroids), or
if immunosuppressed patients develop acute strongyloi-
diasis. is results in uncontrolled over-proliferation of
larvae with dissemination to end-organs, including the
lungs, liver, and brain [113]. HTLV-1 infection is also a
major risk factor for SSIS [114]. Patients present with
nonspecific respiratory symptoms such as a cough, fever,
hemoptysis, asthma, and ARF. e gastrointestinal symp-
toms include ileus and hemorrhage. Chest imaging may
reveal nodular, reticular, or alveolar opacities, which may
reflect a combination of edema, hemorrhage, and pneu-
monitis. Gram-negative sepsis is a common complica-
tion of SSIS, as larval invasion of the gut wall promotes
bacterial translocation [115]. During SSIS, filariform lar-
vae may be found in bodily fluids such as sputum, BAL,
and pleural, and/or peritoneal fluid. Blood eosinophilia is
present in most immunocompetent patients, but may be
absent in immunocompromised patients [113], in whom
serological testing is also unreliable. Given the nonspe-
cific presentation of SSIS, the differential diagnosis is
broad and includes all causes of pulmonary hemorrhage,
ARF, and sepsis.
Ivermectin is the first-line treatment. e treatment
is continued until 2 weeks after the last positive stool
sample, to cover a complete autoinfection cycle. SSIS is
always fatal if left untreated and has a reported 60% mor-
tality rate in ICU patients [115].
Conclusion
As survival of cancer patients improves and break-
through therapies are being developed, rising num-
bers of critically ill patients are immunocompromised.
Severe bacterial pneumonias, followed by viral, fungal,
and more rarely parasitic infections are the leading
cause for acute hypoxemic respiratory failure. When
ICU admission is needed, mortality rates are high.
Knowledge of the underlying immune deficiency and
thorough clinico-radiological evaluation can guide the
diagnostic strategy by targeting the most likely infec-
tious agents and deciding on invasive versus non-inva-
sive approach. Increasingly sophisticated non-invasive
diagnostic tools avoid clinical deterioration sometimes
encountered with invasive approaches and are now
available or under evaluation (e.g., real-time PCR, next-
generation sequencing, and transcriptomics), which
H&E hematoxylin and eosin, GMS Grocott methenamine silver, PAS periodic acid Schi, HSCT hematopoietic stem-cell transplant, SOT solid-organ transplant, AIDS
acquired immunodeciency syndrome, HRCT high-resolution computed tomography of the chest, BAL bronchoalveolar lavage, GM galactomannan, BDG beta-d
glucan, Se sensitivity, Sp specicity, PCR polymerase chain reaction, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, HIV human immunodeciency
virus, TMP/SMX trimethoprim/sulfamethoxazole, TNF tumor necrosis factor, CNS central nervous system, CSF cerebrospinal uid
Table 5 (continued)
310
Table 6 Main parasites responsible forpneumonia [107]
Disease Parasite Transmission Endemic areas Pulmonary mani-
festations Extra-pulmonary
manifestations Diagnosis
Löffler syndrome - Ascaris: A. lumbri-
coides, A. suum
- Hookworms:
Ancylostoma duo-
denale, Necator
americanus
- Ascaris: oro-fecal
or uncooked pig
or chicken meat
- Hookworms: skin
contact with
infected soil
- Ascaris: world-
wide
- Hookworms:
Sub-Saharan
Africa, Asia, Latin
America, Carib-
bean
- Cough
- Burning subster-
nal discomfort
- Dyspnea
- Wheezing
- Blood-tinged
sputum contain-
ing eosinophil-
derived Charcot-
Leyden crystals
- Blood eosinophilia
- Fever - Detection of Ascaris
or hookworm lar-
vae in respiratory
secretions
Pulmonary ame-
biasis Entamoeba histo-
lytica
Oro-fecal Worldwide - Hemoptysis
- Expectoration of
anchovy sauce-
like pus
- Respiratory
distress
- Gastrointestinal
symptoms
- Liver abscess
- Brain abscess
- Microscopy of
sputum or pleural
fluid
- PCR
- Serology
- Antigen detection
Pulmonary leish-
maniasis Leishmania dono-
vani and Leishma-
nia infantum
Sandflies - L. donovani: South
Asia, East Africa
- L. infantum: Medi-
terranean basin,
western Asia,
South America
- Pleural effusion
- Mediastinal lym-
phadenopathy
- Pneumonitis
- Fever
- Splenomegaly
- Jaundice
- Hemophagocytic
lymphohistiocy-
tosis
- Bone marrow
aspiration
- Microscopy
- Culture
- PCR
- Serology
Pulmonary larva
migrans Toxocara canis
Toxocara cati - Dogs (Toxocara
canis)
- Cats (Toxocara
cati)
- Worldwide - Asthma - Hepato-spleno-
megaly
- Lymph node
enlargement
- Eye pain, strabis-
mus
- Abdominal pain
- Neurological
manifestations
- IgE antibody detec-
tion
- Antigen detection
Tropical pulmonary
eosinophilia Lymphatic fila-
riasis: Wuchereria
bancrofti, Brugia
malayi, Brugia
timori
- Mosquitoes - Tropical countries - Paroxysmal and
nocturnal cough
- Asthma-like
attacks
- Eosinophilia
- Weight loss
- Lymphadenopa-
thy
- Hepatomegaly,
and/or spleno-
megaly
- Serology
- Antigen detection
Pulmonary para-
gonimiasis - Paragonimus sp - Eating raw cray-
fish or crabs - Far East
- West Africa
- America
- Cough
- Rusty brown or
blood-stained
sputum
- Chest pain
- Pleural effusion
- Pneumonitis
- Fever - Sputum micros-
copy
- Stool sample
examination
- Serology
Pulmonary schisto-
somiasis - Shistosoma sp - Swimming in
infected water - Sub-Saharan
Africa - Dry cough - Myalgia, arthralgia
- Diarrhea
- Headache
- Eosinophilia
- Stool sample
examination
- Serology
- Antigen detection
in stool, blood, or
urine
Pulmonary trich-
inellosis - Trichinella spiralis - Eating under-
cooked meat - Worldwide - Dry cough - Abdominal pain
- Diarrhea
- Muscle pain and
weakness
- Myocarditis
- Eosinophilia
- Serology
- Muscle biopsy
Pulmonary babe-
siosis - Babesia divergens
and Babesia
microti
- Tick bite - United States
- Asia
- Sporadic cases in
Europe
- Interstitial pneu-
monia - Fever
- Headache
- Drenching sweats
- Blood smear exami-
nation
- Serology
- PCR
311
could allow earlier diagnosis and thus improve survival
in immunocompromised patients with severe pulmo-
nary infections.
Electronic supplementary material
The online version of this article (https ://doi.org/10.1007/s0013 4-019-05906 -5)
contains supplementary material, which is available to authorized users.
Author details
1 Médecine Intensive et Réanimation, APHP, Saint-Louis Hospital and Paris
University, Paris, France. 2 Université de Paris, Paris, France. 3 Department
of Intensive Care, Rigshospitalet and Copenhagen Academy for Medical
Simulation and Education, University of Copenhagen, Copenhagen, Denmark.
4 Division of Pulmonary and Critical Care, Penn State University College
of Medicine, Hershey, PA, USA. 5 Department of Critical Care, King’s College
Hospital NHS Foundation Trust, London, UK. 6 Division of Pulmonary and Criti-
cal Care Medicine, Mayo Clinic, Rochester, MN, USA. 7 Polyvalent Intensive
Care Unit, Hospital de São Francisco Xavier, NOVA Medical School, New
University of Lisbon, Lisbon, Portugal. 8 Intensive Care Clinical Unit, Hospital
Universitario Virgen Macarena, Seville, Spain. 9 Department of Intensive Care
Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St.
James’s Hospital, St James Street, Dublin 8, Ireland. 10 Department of Medicine
and Interdepartmental Division of Critical Care Medicine, Sinai Health System,
University of Toronto, Toronto, ON, Canada. 11 Department of Intensive Care,
Glasgow Royal Infirmary, Glasgow, UK. 12 Department of Medicine I, Intensive
Care Unit 13i2, Comprehensive Cancer Center, Center of Excellence in Medical
Intensive Care (CEMIC), Medical University of Vienna, Vienna, Austria. 13 Centro
de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES),
Instituto Salud Carlos III, Madrid, Spain. 14 CRIPS Department, Vall d’Hebron
Institut of Research (VHIR), Barcelona, Spain. 15 Critical Care Department,
Institut Paoli Calmettes, Marseille, France.
Funding
None.
Compliance with ethical standards
Conflict of interest
EA has received fees for lectures from Gilead, Pfizer, Baxter, and Alexion. His
research group has been supported by Ablynx, Fisher & Payckle, Jazz Pharma,
and MSD. IML reports personal fees from MSD and Gilead. PV has received
consultation fees from Orion, Pfizer, and Technofage. PS received honoraria
from Astellas, Basilea, Fisher & Paykel, Getinge, Gilead, Hill-Rom, Jazz Pharma-
ceuticals, Kite, Merck, Orion, Pfizer Rokitan, and Shire. He also declares research
support from Amgen, Astellas, Astro-Pharma, and Baxter. JR served a consult-
ant or in the speakers bureau for Merck, Anchoagen, Pfizer, ROCHE and in the
speakers bureau for Pfizer and MSD. JGM has received fees for lectures from
Gilead. All other authors have no conflict of interest to disclose.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 20 November 2019 Accepted: 19 December 2019
Published online: 7 February 2020
References
1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J
Clin 68:7–30. https ://doi.org/10.3322/caac.21442
2. Azoulay E, Mokart D, Kouatchet A et al (2019) Acute respiratory failure
in immunocompromised adults. Lancet Respir Med 7:173–186. https ://
doi.org/10.1016/S2213 -2600(18)30345 -X
3. Contejean A, Lemiale V, Resche-Rigon M et al (2016) Increased mortality
in hematological malignancy patients with acute respiratory failure
from undetermined etiology: a Groupe de Recherche en Réanimation
Respiratoire en Onco-Hématologique (Grrr-OH) study. Ann Intensive
Care 6:102. https ://doi.org/10.1186/s1361 3-016-0202-0
4. Bauer PR, Chevret S, Yadav H et al (2019) Diagnosis and outcome of
acute respiratory failure in immunocompromised patients after bron-
choscopy. Eur Respir J. https ://doi.org/10.1183/13993 003.02442 -2018
5. Azoulay E, Mokart D, Lambert J et al (2010) Diagnostic strategy for
hematology and oncology patients with acute respiratory failure: rand-
omized controlled trial. Am J Respir Crit Care Med 182:1038–1046. https
://doi.org/10.1164/rccm.20100 1-0018O C
6. Evangelatos N, Satyamoorthy K, Levidou G et al (2018) Multi-Omics
Research Trends in Sepsis: a Bibliometric, Comparative Analysis
Between the United States, the European Union 28 Member States, and
China. OMICS 22:190–197. https ://doi.org/10.1089/omi.2017.0192
7. Azoulay E, Pickkers P, Soares M et al (2017) Acute hypoxemic respiratory
failure in immunocompromised patients: the Efraim multinational
prospective cohort study. Intensive Care Med 43:1808–1819. https ://
doi.org/10.1007/s0013 4-017-4947-1
8. Maschmeyer G, Carratalà J, Buchheidt D et al (2015) Diagnosis and
antimicrobial therapy of lung infiltrates in febrile neutropenic patients
(allogeneic SCT excluded): updated guidelines of the Infectious
Diseases Working Party (AGIHO) of the German Society of Hematol-
ogy and Medical Oncology (DGHO). Ann Oncol 26:21–33. https ://doi.
org/10.1093/annon c/mdu19 2
9. Azoulay E, Schlemmer B (2006) Diagnostic strategy in cancer patients
with acute respiratory failure. Intensive Care Med 32:808–822. https ://
doi.org/10.1007/s0013 4-006-0129-2
10. Azoulay E, Roux A, Vincent F et al (2018) A Multivariable prediction
model for Pneumocystis jirovecii pneumonia in hematology patients
with acute respiratory failure. Am J Respir Crit Care Med 198:1519–1526.
https ://doi.org/10.1164/rccm.20171 2-2452O C
11. Lemiale V, Mokart D, Resche-Rigon M et al (2015) Effect of noninvasive
ventilation vs oxygen therapy on mortality among immunocompro-
mised patients with acute respiratory failure: a randomized clinical trial.
JAMA 314:1711–1719. https ://doi.org/10.1001/jama.2015.12402
12. Charpentier E, Garnaud C, Wintenberger C et al (2017) Added value of
next-generation sequencing for multilocus sequence typing analysis
of a Pneumocystis jirovecii pneumonia outbreak1. Emerging Infect Dis
23:1237–1245. https ://doi.org/10.3201/eid23 08.16129 5
13. Chibucos MC, Soliman S, Gebremariam T et al (2016) An integrated
genomic and transcriptomic survey of mucormycosis-causing fungi.
Nat Commun 7:1–11. https ://doi.org/10.1038/ncomm s1221 8
14. Guiton PS, Sagawa JM, Fritz HM, Boothroyd JC (2017) An in vitro model
of intestinal infection reveals a developmentally regulated transcrip-
tome of Toxoplasma sporozoites and a NF-κB-like signature in infected
host cells. PLoS One 12:e0173018. https ://doi.org/10.1371/journ
al.pone.01730 18
15. Salas A, Pardo-Seco J, Barral-Arca R et al (2018) Whole exome sequenc-
ing identifies new host genomic susceptibility factors in empyema
caused by Streptococcus pneumoniae in children: a pilot study. Genes
(Basel). https ://doi.org/10.3390/genes 90502 40
16. Toma I, Siegel MO, Keiser J et al (2014) Single-molecule long-read
16S sequencing to characterize the lung microbiome from mechani-
cally ventilated patients with suspected pneumonia. J Clin Microbiol
52:3913–3921. https ://doi.org/10.1128/JCM.01678 -14
17. Lee J-O, Kim D-Y, Lim JH et al (2008) Risk factors for bacterial pneumo-
nia after cytotoxic chemotherapy in advanced lung cancer patients.
Lung Cancer 62:381–384. https ://doi.org/10.1016/j.lungc an.2008.03.015
18. Garcia JB, Lei X, Wierda W et al (2013) Pneumonia during remission
induction chemotherapy in patients with acute leukemia. Ann Am
Thorac Soc 10:432–440. https ://doi.org/10.1513/Annal sATS.20130
4-097OC
19. Aguilar-Guisado M, Givaldá J, Ussetti P et al (2007) Pneumonia after
lung transplantation in the RESITRA Cohort: a multicenter pro-
spective study. Am J Transpl 7:1989–1996. https ://doi.org/10.111
1/j.1600-6143.2007.01882 .x
20. Chang G-C, Wu C-L, Pan S-H et al (2004) The diagnosis of pneumonia in
renal transplant recipients using invasive and noninvasive procedures.
Chest 125:541–547. https ://doi.org/10.1378/chest .125.2.541
21. Di Pasquale MF, Sotgiu G, Gramegna A et al (2019) Prevalence and
etiology of community-acquired Pneumonia in immunocompromised
312
patients. Clin Infect Dis 68:1482–1493. https ://doi.org/10.1093/cid/ciy72
3
22. Rabello LSCF, Silva JRL, Azevedo LCP et al (2015) Clinical outcomes
and microbiological characteristics of severe pneumonia in cancer
patients: a prospective cohort study. PLoS One 10:e0120544. https ://
doi.org/10.1371/journ al.pone.01205 44
23. Warny M, Helby J, Nordestgaard BG et al (2018) Lymphopenia and risk
of infection and infection-related death in 98,344 individuals from a
prospective Danish population-based study. PLoS Med 15:e1002685.
https ://doi.org/10.1371/journ al.pmed.10026 85
24. Gathmann B, Mahlaoui N, Ceredih GL et al (2014) Clinical picture
and treatment of 2212 patients with common variable immunodefi-
ciency. J Allergy Clin Immunol 134:116–126. https ://doi.org/10.1016/j.
jaci.2013.12.1077
25. Abreu C, Rocha-Pereira N, Sarmento A, Magro F (2015) Nocardia infec-
tions among immunomodulated inflammatory bowel disease patients:
a review. World J Gastroenterol 21:6491–6498. https ://doi.org/10.3748/
wjg.v21.i21.6491
26. Fijen CA, Kuijper EJ, te Bulte MT et al (1999) Assessment of complement
deficiency in patients with meningococcal disease in The Netherlands.
Clin Infect Dis 28:98–105. https ://doi.org/10.1086/51507 5
27. Vergidis P, Ariza-Heredia EJ, Nellore A et al (2017) Rhodococcus infec-
tion in solid organ and hematopoietic stem cell transplant recipients.
Emerg Infect Dis J CDC. https ://doi.org/10.3201/eid23 03.16063 3
28. Bodro M, Carratalà J, Paterson DL (2014) Legionellosis and biologic
therapies. Respir Med 108:1223–1228. https ://doi.org/10.1016/j.
rmed.2014.04.017
29. Jacobson K, Miceli M, Tarrand J, Kontoyiannis D (2008) Legionella
Pneumonia in Cancer Patients. Medicine 87:152–159. https ://doi.
org/10.1097/MD.0b013 e3181 779b5 3
30. Sickles EA, Greene WH, Wiernik PH (1975) Clinical presentation of infec-
tion in granulocytopenic patients. Arch Intern Med 135:715–719
31. Jain S, Self WH, Wunderink RG, et al (2015) Community-Acquired
Pneumonia Requiring Hospitalization among U.S. Adults. In: http://
dx.doi.org.proxy .inser mbibl io.inist .fr/10.1056/NEJMo a1500 245. https
://www-nejm-org.proxy .inser mbibl io.inist .fr/doi/10.1056/NEJMo a1500
245?url_ver=Z39.88-2003&rfr_id=ori%3Arid %3Acro ssref .org&rfr_
dat=cr_pub%3Dwww .ncbi.nlm.nih.gov. Accessed 13 Oct 2019
32. Bonatti H, Pruett TL, Brandacher G et al (2009) Pneumonia in solid
organ recipients: spectrum of pathogens in 217 episodes. Transpl Proc
41:371–374. https ://doi.org/10.1016/j.trans proce ed.2008.10.045
33. Moreau A-S, Martin-Loeches I, Povoa P et al (2018) Impact of immu-
nosuppression on incidence, aetiology and outcome of ventilator-
associated lower respiratory tract infections. Eur Respir J. https ://doi.
org/10.1183/13993 003.01656 -2017
34. Bellew S, Grijalva CG, Williams DJ et al (2019) Pneumococcal and
Legionella urinary antigen tests in community-acquired pneumo-
nia: prospective evaluation of indications for testing. Clin Infect Dis
68:2026–2033. https ://doi.org/10.1093/cid/ciy82 6
35. Metlay JP, Waterer GW, Long AC et al (2019) Diagnosis and treatment of
adults with community-acquired pneumonia. an official clinical prac-
tice guideline of the American Thoracic Society and Infectious Diseases
Society of America. Am J Respir Crit Care Med 200:e45–e67. https ://doi.
org/10.1164/rccm.20190 8-1581S T
36. Johansson N, Kalin M, Tiveljung-Lindell A et al (2010) Etiology of
community-acquired pneumonia: increased microbiological yield
with new diagnostic methods. Clin Infect Dis 50:202–209. https ://doi.
org/10.1086/64867 8
37. Menzies SM, Rahman NM, Wrightson JM et al (2011) Blood culture bot-
tle culture of pleural fluid in pleural infection. Thorax 66:658–662. https
://doi.org/10.1136/thx.2010.15784 2
38. Strålin K, Ehn F, Giske CG et al (2016) The IRIDICA PCR/electrospray
ionization-mass spectrometry assay on bronchoalveolar lavage for
bacterial etiology in mechanically ventilated patients with suspected
pneumonia. PLoS One 11:e0159694. https ://doi.org/10.1371/journ
al.pone.01596 94
39. Xie Y, Du J, Jin W et al (2019) Next generation sequencing for diagnosis
of severe pneumonia: China, 2010–2018. J Infect 78:158–169. https ://
doi.org/10.1016/j.jinf.2018.09.004
40. Pendleton KM, Erb-Downward JR, Bao Y et al (2017) Rapid pathogen
identification in bacterial pneumonia using real-time metagenomics.
Am J Respir Crit Care Med 196:1610–1612. https ://doi.org/10.1164/
rccm.20170 3-0537L E
41. Lewinsohn DM, Leonard MK, LoBue PA et al (2017) Official American
Thoracic Society/Infectious Diseases Society of America/Centers for
Disease Control and Prevention Clinical Practice Guidelines: diagnosis
of Tuberculosis in Adults and Children. Clin Infect Dis 64:e1–e33. https
://doi.org/10.1093/cid/ciw69 4
42. Marques IDB, Azevedo LS, Pierrotti LC et al (2013) Clinical features
and outcomes of tuberculosis in kidney transplant recipients in Brazil:
a report of the last decade. Clin Transpl 27:E169–176. https ://doi.
org/10.1111/ctr.12077
43. Gras J, De Castro N, Montlahuc C et al (2018) Clinical characteristics, risk
factors, and outcome of tuberculosis in kidney transplant recipients: a
multicentric case-control study in a low-endemic area. Transpl Infect
Dis 20:e12943. https ://doi.org/10.1111/tid.12943
44. Pereira M, Gazzoni FF, Marchiori E et al (2016) High-resolution CT
findings of pulmonary Mycobacterium tuberculosis infection in renal
transplant recipients. Br J Radiol 89:20150686. https ://doi.org/10.1259/
bjr.20150 686
45. Yang JY, Han M, Koh Y et al (2016) Effects of corticosteroids on critically
ill pulmonary tuberculosis patients with acute respiratory failure: a
propensity analysis of mortality. Clin Infect Dis 63:1449–1455. https ://
doi.org/10.1093/cid/ciw61 6
46. Ryu YJ, Koh W-J, Kang EH et al (2007) Prognostic factors in pul-
monary tuberculosis requiring mechanical ventilation for acute
respiratory failure. Respirology 12:406–411. https ://doi.org/10.111
1/j.1440-1843.2006.01007 .x
47. Griffith DE, Aksamit T, Brown-Elliott BA et al (2007) An official ATS/IDSA
statement: diagnosis, treatment, and prevention of nontuberculous
mycobacterial diseases. Am J Respir Crit Care Med 175:367–416. https ://
doi.org/10.1164/rccm.20060 4-571ST
48. Longworth SA, Daly JS (2019) Management of infections due to non-
tuberculous mycobacteria in solid organ transplant recipients—Guide-
lines from the American Society of Transplantation Infectious Diseases
Community of Practice. Clin Transpl 33:e13588. https ://doi.org/10.1111/
ctr.13588
49. Estimated Influenza Illnesses, Medical visits, Hospitalizations, and
Deaths in the United States—2017–2018 influenza season| CDC. https
://www.cdc.gov/flu/about /burde n/2017-2018.htm. Accessed 1 Oct
2019
50. Garnacho-Montero J, León-Moya C, Gutiérrez-Pizarraya A et al (2018)
Clinical characteristics, evolution, and treatment-related risk factors for
mortality among immunosuppressed patients with influenza A (H1N1)
virus admitted to the intensive care unit. J Crit Care 48:172–177. https ://
doi.org/10.1016/j.jcrc.2018.08.017
51. Collins JP, Campbell AP, Openo K et al (2019) Outcomes of immuno-
compromised adults hospitalized with laboratory-confirmed influenza
in the United States, 2011–2015. Clin Infect Dis. https ://doi.org/10.1093/
cid/ciz63 8
52. Khanna N, Widmer AF, Decker M et al (2008) Respiratory syncytial virus
infection in patients with hematological diseases: single-center study
and review of the literature. Clin Infect Dis 46:402–412. https ://doi.
org/10.1086/52526 3
53. Legoff J, Zucman N, Lemiale V et al (2019) Clinical significance of
upper airway virus detection in critically ill hematology patients. Am J
Respir Crit Care Med 199:518–528. https ://doi.org/10.1164/rccm.20180
4-0681O C
54. Kakiuchi S, Tsuji M, Nishimura H et al (2018) Human parainfluenza virus
Type 3 infections in patients with hematopoietic stem cell transplants:
the mode of nosocomial infections and prognosis. Jpn J Infect Dis
71:109–115. https ://doi.org/10.7883/yoken .JJID.2017.424
55. Hall CB (2001) Respiratory syncytial virus and parainfluenza virus. N Engl
J Med 344:1917–1928. https ://doi.org/10.1056/NEJM2 00106 21344 2507
56. Vidaur L, Totorika I, Montes M et al (2019) Human metapneumovirus
as cause of severe community-acquired pneumonia in adults: insights
from a ten-year molecular and epidemiological analysis. Ann Intensive
Care 9:86. https ://doi.org/10.1186/s1361 3-019-0559-y
57. Miller WT, Mickus TJ, Barbosa E et al (2011) CT of viral lower respira-
tory tract infections in adults: comparison among viral organisms
and between viral and bacterial infections. AJR Am J Roentgenol
197:1088–1095. https ://doi.org/10.2214/AJR.11.6501
313
58. Koo HJ, Lim S, Choe J et al (2018) Radiographic and CT features of
viral pneumonia. Radiographics 38:719–739. https ://doi.org/10.1148/
rg.20181 70048
59. Uyeki TM, Bernstein HH, Bradley JS et al (2019) Clinical Practice Guide-
lines by the Infectious Diseases Society of America: 2018 Update on
Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak
Management of Seasonal Influenzaa. Clin Infect Dis 68:895–902. https
://doi.org/10.1093/cid/ciy87 4
60. Walter JM, Wunderink RG (2018) Testing for respiratory viruses in adults
with severe lower respiratory infection. Chest 154:1213–1222. https ://
doi.org/10.1016/j.chest .2018.06.003
61. Tasbakan MS, Gurgun A, Basoglu OK et al (2011) Comparison of bron-
choalveolar lavage and mini-bronchoalveolar lavage in the diagnosis of
pneumonia in immunocompromised patients. Respiration 81:229–235.
https ://doi.org/10.1159/00032 3176
62. Lachant DJ, Croft DP, Minton HM et al (2017) Nasopharyngeal viral PCR
in immunosuppressed patients and its association with virus detection
in bronchoalveolar lavage by PCR. Respirology 22:1205–1211. https ://
doi.org/10.1111/resp.13049
63. Pastores SM, Annane D, Rochwerg B, Corticosteroid Guideline Task
Force of SCCM and ESICM, (2018) Guidelines for the Diagnosis and
Management of Critical Illness-Related Corticosteroid Insufficiency
(CIRCI) in Critically Ill Patients (Part II): Society of Critical Care Medicine
(SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.
Crit Care Med 46:146–148. https ://doi.org/10.1097/CCM.00000 00000
00284 0
64. Fiore AE, Fry A, Shay D et al (2011) Antiviral agents for the treatment
and chemoprophylaxis of influenza—recommendations of the Advi-
sory Committee on Immunization Practices (ACIP). MMWR Recomm
Rep 60:1–24
65. Shah JN, Chemaly RF (2011) Management of RSV infections in adult
recipients of hematopoietic stem cell transplantation. Blood 117:2755–
2763. https ://doi.org/10.1182/blood -2010-08-26340 0
66. Taylor G, Abdesselam K, Pelude L et al (2016) Epidemiological features
of influenza in Canadian adult intensive care unit patients. Epidemiol
Infect 144:741–750. https ://doi.org/10.1017/S0950 26881 50021 13
67. Lee HS, Park JY, Shin SH et al (2012) Herpesviridae viral infections after
chemotherapy without antiviral prophylaxis in patients with malignant
lymphoma: incidence and risk factors. Am J Clin Oncol 35:146–150.
https ://doi.org/10.1097/COC.0b013 e3182 09aa4 1
68. Hemmersbach-Miller M, Bailey ES, K appus M et al (2018) Disseminated
adenovirus infection after combined liver-kidney transplantation. Front
Cell Infect Microbiol 8:408. https ://doi.org/10.3389/fcimb .2018.00408
69. Fishman JA (2007) Infection in solid-organ transplant recipients. N Engl
J Med 357:2601–2614. https ://doi.org/10.1056/NEJMr a0649 28
70. Sandherr M, Hentrich M, von Lilienfeld-Toal M et al (2015) Antiviral
prophylaxis in patients with solid tumours and haematological
malignancies–update of the Guidelines of the Infectious Diseases
Working Party (AGIHO) of the German Society for Hematology and
Medical Oncology (DGHO). Ann Hematol 94:1441–1450. https ://doi.
org/10.1007/s0027 7-015-2447-3
71. Koval CE (2018) Prevention and treatment of cytomegalovirus infec-
tions in solid organ transplant recipients. Infect Dis Clin North Am
32:581–597. https ://doi.org/10.1016/j.idc.2018.04.008
72. Ljungman P, Boeckh M, Hirsch HH et al (2017) Definitions of cytomeg-
alovirus infection and disease in transplant patients for use in clinical
trials. Clin Infect Dis 64:87–91. https ://doi.org/10.1093/cid/ciw66 8
73. Mirouse A, Vignon P, Piron P et al (2017) Severe varicella-zoster virus
pneumonia: a multicenter cohort study. Crit Care 21:137. https ://doi.
org/10.1186/s1305 4-017-1731-0
74. Luyt C-E, Combes A, Deback C et al (2007) Herpes simplex virus lung
infection in patients undergoing prolonged mechanical ventilation.
Am J Respir Crit Care Med 175:935–942. https ://doi.org/10.1164/
rccm.20060 9-1322O C
75. Lee HY, Rhee CK, Choi JY et al (2017) Diagnosis of cytomegalovirus
pneumonia by quantitative polymerase chain reaction using bronchial
washing fluid from patients with hematologic malignancies. Onco-
target 8:39736–39745. https ://doi.org/10.18632 /oncot arget .14504
76. Fishman JA, Rubin RH (1998) Infection in organ-transplant recipients. N
Engl J Med 338:1741–1751. https ://doi.org/10.1056/NEJM1 99806 11338
2407
77. Ponce CA, Gallo M, Bustamante R, Vargas SL (2010) Pneumocystis
colonization is highly prevalent in the autopsied lungs of the general
population. Clin Infect Dis 50:347–353. https ://doi.org/10.1086/64986 8
78. Stern A, Green H, Paul M et al (2014) Prophylaxis for Pneumocystis
pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane
Database Syst Rev. https ://doi.org/10.1002/14651 858.CD005 590.pub3
79. Kanamori H, Rutala WA, Sickbert-Bennett EE, Weber DJ (2015) Review of
fungal outbreaks and infection prevention in healthcare settings during
construction and renovation. Clin Infect Dis 61:433–444. https ://doi.
org/10.1093/cid/civ29 7
80. Pappas PG, Alexander BD, Andes DR et al (2010) Invasive fungal infec-
tions among organ transplant recipients: results of the Transplant-
Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis
50:1101–1111. https ://doi.org/10.1086/65126 2
81. Kontoyiannis DP, Marr KA, Park BJ et al (2010) Prospective surveillance
for invasive fungal infections in hematopoietic stem cell transplant
recipients, 2001–2006: overview of the Transplant-Associated Infection
Surveillance Network (TRANSNE T) Database. Clin Infect Dis 50:1091–
1100. https ://doi.org/10.1086/65126 3
82. Pappas PG, Perfect JR, Cloud GA et al (2001) Cryptococcosis in human
immunodeficiency virus-negative patients in the era of effective azole
therapy. Clin Infect Dis 33:690–699. https ://doi.org/10.1086/32259 7
83. Sun H-Y, Wagener MM, Singh N (2009) Cryptococcosis in solid-organ,
hematopoietic stem cell, and tissue transplant recipients: evidence-
based evolving trends. Clin Infect Dis 48:1566–1576. https ://doi.
org/10.1086/59893 6
84. Lindell RM, Hartman TE, Nadrous HF, Ryu JH (2005) Pulmonary cryp-
tococcosis: CT findings in immunocompetent patients. Radiology
236:326–331. https ://doi.org/10.1148/radio l.23610 40460
85. Alanio A, Hauser PM, Lagrou K et al (2016) ECIL guidelines for the
diagnosis of Pneumocystis jirovecii pneumonia in patients with haema-
tological malignancies and stem cell transplant recipients. J Antimicrob
Chemother 71:2386–2396. https ://doi.org/10.1093/jac/dkw15 6
86. Azoulay É, Bergeron A, Chevret S et al (2009) Polymerase chain reaction
for diagnosing pneumocystis pneumonia in non-HIV immunocompro-
mised patients with pulmonary infiltrates. Chest 135:655–661. https ://
doi.org/10.1378/chest .08-1309
87. Karageorgopoulos DE, Qu J-M, Korbila IP et al (2013) Accuracy of
β-d-glucan for the diagnosis of Pneumocystis jirovecii pneumonia: a
meta-analysis. Clin Microbiol Infect 19:39–49. https ://doi.org/10.111
1/j.1469-0691.2011.03760 .x
88. Hage CA, Carmona EM, Epelbaum O et al (2019) Microbiological
laboratory testing in the diagnosis of fungal infections in pulmonary
and critical care practice. an official American Thoracic Society Clinical
Practice Guideline. Am J Respir Crit Care Med 200:535–550. https ://doi.
org/10.1164/rccm.20190 6-1185S T
89. White PL, Wingard JR, Bretagne S et al (2015) Aspergillus polymerase
chain reaction: systematic review of evidence for clinical use in com-
parison with antigen testing. Clin Infect Dis 61:1293–1303. https ://doi.
org/10.1093/cid/civ50 7
90. Choi S, Song JS, Kim JY et al (2019) Diagnostic per formance of immu-
nohistochemistry for the aspergillosis and mucormycosis. Mycoses.
https ://doi.org/10.1111/myc.12994
91. Cornely OA, Arikan-Akdagli S, Dannaoui E et al (2014) ESCMID and
ECMM joint clinical guidelines for the diagnosis and management of
mucormycosis 2013. Clin Microbiol Infect 20(Suppl 3):5–26. https ://doi.
org/10.1111/1469-0691.12371
92. Singh N, Alexander BD, Lortholary O et al (2008) Pulmonary cr yp-
tococcosis in solid organ transplant recipients: clinical relevance of
serum cryptococcal antigen. Clin Infect Dis 46:e12–18. https ://doi.
org/10.1086/52473 8
93. Ullmann AJ, Aguado JM, Arikan-Akdagli S et al (2018) Diagnosis and
management of Aspergillus diseases: executive summary of the 2017
ESCMID-ECMM-ERS guideline. Clin Microbiol Infect 24(Suppl 1):e1–e38.
https ://doi.org/10.1016/j.cmi.2018.01.002
94. Tissot F, Agrawal S, Pagano L et al (2017) ECIL-6 guidelines for the
treatment of invasive candidiasis, aspergillosis and mucormycosis in
leukemia and hematopoietic stem cell transplant patients. Haemato-
logica 102:433–444. https ://doi.org/10.3324/haema tol.2016.15290 0
95. Perfect JR, Dismukes WE, Dromer F et al (2010) Clinical practice guide-
lines for the management of cryptococcal disease: 2010 update by the
314
infectious diseases society of america. Clin Infect Dis 50:291–322. https
://doi.org/10.1086/64985 8
96. Tortorano AM, Richardson M, Roilides E et al (2014) ESCMID and ECMM
joint guidelines on diagnosis and management of hyalohyphomyco-
sis: Fusarium spp., Scedosporium spp. and others. Clin Microbiol Infect
20(Suppl 3):27–46. https ://doi.org/10.1111/1469-0691.12465
97. Millon L, Herbrecht R, Grenouillet F et al (2016) Early diagnosis and
monitoring of mucormycosis by detection of circulating DNA in serum:
retrospective analysis of 44 cases collected through the French Surveil-
lance Network of Invasive Fungal Infections (RESSIF). Clin Microbiol
Infect 22:810.e1–810.e8. https ://doi.org/10.1016/j.cmi.2015.12.006
98. Cornu M, Sendid B, Mery A et al (2019) Evaluation of mass spectrome-
try-based detection of panfungal serum disaccharide for diagnosis of
invasive fungal infections: results from a collaborative study involving
six European Clinical Centers. J Clin Microbiol. https ://doi.org/10.1128/
JCM.01867 -18
99. Pardo E, Lemiale V, Mokart D et al (2019) Invasive pulmonary aspergil-
losis in critically ill patients with hematological malignancies. Intensive
Care Med. https ://doi.org/10.1007/s0013 4-019-05789 -6
100. Baddley JW, Andes DR, Marr KA et al (2010) Factors associated with
mortality in transplant patients with invasive aspergillosis. Clin Infect
Dis 50:1559–1567. https ://doi.org/10.1086/65276 8
101. Sepkowitz KA (2002) Opportunistic infections in patients with and
patients without acquired immunodeficiency syndrome. Clin Infect Dis
34:1098–1107. https ://doi.org/10.1086/33954 8
102. Roden MM, Zaoutis TE, Buchanan WL et al (2005) Epidemiology and
outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis
41:634–653. https ://doi.org/10.1086/43257 9
103. Cheepsattayakorn A, Cheepsattayakorn R (2014) Parasitic pneumo-
nia and lung involvement. Biomed Res Int 2014:874021. https ://doi.
org/10.1155/2014/87402 1
104. Schmidt M, Sonneville R, Schnell D et al (2013) Clinical features and
outcomes in patients with disseminated toxoplasmosis admitted to
intensive care: a multicenter study. Clin Infect Dis 57:1535–1541. https
://doi.org/10.1093/cid/cit55 7
105. Martino R, Bretagne S, Einsele H et al (2005) Early detection of Toxo-
plasma infection by molecular monitoring of Toxoplasma gondii in
peripheral blood samples after allogeneic stem cell transplantation.
Clin Infect Dis 40:67–78. https ://doi.org/10.1086/42644 7
106. Robert-Gangneux F, Meroni V, Dupont D et al (2018) Toxoplasmosis in
transplant recipients, Europe, 2010–2014. Emerg Infect Dis 24:1497–
1504. https ://doi.org/10.3201/eid24 08.18004 5
107. Israelski DM, Remington JS (1993) Toxoplasmosis in patients with
cancer. Clin Infect Dis 17:S423–S435. https ://doi.org/10.1093/clini ds/17.
Suppl ement _2.S423
108. Sumi M, Norose K, Hikosaka K et al (2016) Clinical characteristics and
computed tomography findings of pulmonary toxoplasmosis after
hematopoietic stem cell transplantation. Int J Hematol 104:729–740.
https ://doi.org/10.1007/s1218 5-016-2077-0
109. La Hoz RM, Morris MI, Infectious Diseases Community of Practice of the
American Society of Transplantation (2019) Tissue and blood protozoa
including toxoplasmosis, Chagas disease, leishmaniasis, Babesia,
Acanthamoeba, Balamuthia, and Naegleria in solid organ transplant
recipients- Guidelines from the American Society of Transplantation
Infectious Diseases Community of Practice. Clin Transpl. https ://doi.
org/10.1111/ctr.13546 ->
110. Prevention C-C for DC and (2019) CDC—Strongyloides—Epidemiology
& Risk Factors. https ://www.cdc.gov/paras ites/stron gyloi des/epi.html.
Accessed 10 Sept 2019
111. Schär F, Trostdorf U, Giardina F et al (2013) Strongyloides stercoralis:
global distribution and risk factors. PLoS Negl Trop Dis 7:e2288. https ://
doi.org/10.1371/journ al.pntd.00022 88
112. Al-Obaidi M, Hasbun R, Vigil KJ et al (2019) Seroprevalence of Strongyloi-
des stercoralis and evaluation of universal screening in kidney transplant
candidates: a single-center experience in Houston (2012–2017). Open
Forum Infect Dis. https ://doi.org/10.1093/ofid/ofz17 2
113. Greaves D, Coggle S, Pollard C et al (2013) Strongyloides stercoralis infec-
tion. BMJ 347:f4610–f4610. https ://doi.org/10.1136/bmj.f4610
114. Carvalho EM, Da Fonseca Porto A (2004) Epidemiological and clinical
interaction between HTLV-1 and Strongyloides stercoralis. Parasite
Immunol 26:487–497. https ://doi.org/10.1111/j.0141-9838.2004.00726 .x
115. Geri G, Rabbat A, Mayaux J et al (2015) Strongyloides stercoralis
hyperinfection syndrome: a case series and a review of the literature.
Infection 43:691–698. https ://doi.org/10.1007/s1501 0-015-0799-1
