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Mdecine et maladies infectieuses 44 (2014) 185198

General review

Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients

Linfection pulmonaire Pneumocystis jirovecii chez les patients VIH ngatifs : mise au point
A. Roux a , F. Gonzalez b , M. Roux c , M. Mehrad d , J. Menotti e,f , J.-R. Zahar g,h , V.-X. Tadros b ,
E. Azoulay i,f , P.-Y. Brillet c,j , F. Vincent k, ,
for the Groupe de recherche respiratoire en ranimation en onco-hmatologie (Grrr-OH)
b

a Service de pneumologie, hpital Foch, 92151 Suresnes, France

Service de ranimation mdico-chirurgicale, hpital Avicenne, Assistance publiqueHpitaux de Paris (APHP), 93009 Bobigny, France
c Service de radiologie, hpital Avicenne, Assistance publiqueHpitaux de Paris (APHP), 93009 Bobigny, France
d Service des urgences, Gustave Roussy, Cancer Campus Grand Paris, 94805 Villejuif, France
e Service de parasitologie-mycologie, hpital Saint-Louis, Assistance publiqueHpitaux de Paris (APHP), 75010 Paris, France
f Universit Paris-Diderot, Sorbonne Paris-Cit, 75010 Paris, France
g UPLIN, CHU dAngers, 49100 Angers, France
h Universit dAngers, 49100 Angers, France
i Service de ranimation mdicale, hpital Saint-Louis, Assistance publiqueHpitaux de Paris (APHP), 75010 Paris, France
j Universit Paris-13, 93009 Bobigny, France
k Service de ranimation polyvalente, CHI Le Raincy-Montfermeil, 10, rue du Gnral-Leclerc, 93370 Montfermeil, France

Received 14 July 2013; received in revised form 4 December 2013; accepted 15 January 2014
Available online 11 March 2014

Abstract
Pneumocystis jirovecii is the only fungus of its kind to be pathogenic in humans. It is primarily responsible for pneumonia (PJP). The key to
understanding immune defences has focused on T-cells, mainly because of the HIV infection epidemic. Patients presenting with PJP all have a
CD4 count below 200/mm3 . The introduction of systematic primary prophylaxis and the use of new anti-retroviral drugs have significantly reduced
the incidence of this disease in the HIV-infected population, mainly in developed countries. The increasingly frequent use of corticosteroids,
chemotherapy, and other immunosuppressive drugs has led to an outbreak of PJP in patients not infected by HIV. These patients presenting with
PJP have more rapid and severe symptoms, sometimes atypical, leading to delay the initiation of a specific anti-infective therapy, sometimes a
cause of death. However, the contribution of new diagnostic tools and a better understanding of patients at risk should improve their survival.
2014 Elsevier Masson SAS. All rights reserved.
Keywords: Pneumocystis jirovecii; Immunodepression; Pneumonia

Rsum
Pneumocystis jirovecii est le seul champignon de son espce tre pathogne chez ltre humain. Il est essentiellement responsable de pneumopathie (PJP). Lessentiel de la comprhension des dfenses immunitaires sest concentr sur les lymphocytes T, essentiellement du fait de
lpidmie dinfection par le VIH. Les patients dveloppant une PJP ont tous un taux de CD4 infrieur 200/mm3 . Linstauration de prophylaxie
primaire systmatique et le recours aux nouveaux anti-rtroviraux ont considrablement diminu lincidence de cette pathologie dans la population
infecte par le VIH, essentiellement dans les pays dvelopps. Lutilisation de plus en plus frquente de corticodes, chimiothrapies et autres
immunosuppresseurs a conduit une closion de PJP chez les patients non infects par le VIH. Chez ceux-ci, la PJP se manifeste par une symptomatologie plus rapide et grave, parfois atypique, conduisant au retard la mise en route dun traitement anti-infectieux spcifique pouvant tre
responsable de dcs. Il semble cependant que lapport de nouveaux outils diagnostiques et quune meilleure connaissance des patients risque
puissent amliorer la survie.
2014 Elsevier Masson SAS. Tous droits rservs.
Mots cls : Pneumocystis jirovecii ; Immunodpression ; Pneumopathie

Corresponding author.
E-mail address: frncsvncnt@aol.com (F. Vincent).

0399-077X/$ see front matter 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.medmal.2014.01.007

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A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

1. Introduction
Pneumocystis pneumonia is caused by Pneumocystis jirovecii
(P. jirovecii) in humans. The fungus was identified in the early
1900s, but cases of PJP were first reported among premature
and malnourished children especially in Central Europe at the
end of the Second World War and in the early 1950s. The incidence increased later with the emergence of HIV in the 1980s.
However, many other non-HIV-patients are at risk of PJP, and
some observations suggest an increase of the incidence in these
patients (Fig. 1). The authors of a retrospective study performed
in Sweden between 1991 and 2001, reported that in the last
period of the study, 75% of PJP cases occurred in non-HIVpatients; only 13% of these patients had received prophylaxis.
Several factors may have caused the increased incidence of PJP
in these patients. Immunosuppressive drugs were used more
commonly, in higher doses, or in combinations that may have
increased the susceptibility of patients to P. jirovecii infection
(Table 1). Improved diagnostic procedures may also have contributed to a better detection of PJP. Moreover, the physicians
experience with similar cases in AIDS-patients may improve the
diagnostic suspicion of PJP in non-HIV-patients [1]. Some new
risks have regularly been reported, all related to the use of new
immunomodulatory or antineoplastic agents (Table 1) [2]. However, the diagnosis of PJP remains challenging, despite recent
progress in diagnostic methods [3]. Moreover, the pathogenesis
of P. jirovecii infection from latent to fulminant fatal pneumonitis in immunocompromised hosts remains to be explained. Thus,
the aim of this review was to better determine the new risks,
requiring preventive measures, the contribution of new diagnostic tools, and to address so-called pending questions.

2. Patients at risk
New groups of patients have been identified at risk, after
the epidemic of PJP in AIDS-patients (Fig. 1). Several authors
of retrospective studies have described the epidemiology of
PJP in non-HIV-patients (Table 2). Many hypotheses could
explain the increased risk of PJP in these populations, such
as the use of intensive immunosuppressive treatments, new
anticancer and immunomodulating agents, and progress in

Table 1
Main drugs associated with pneumonia (PJP).
Principaux mdicaments associs avec la survenue de pneumocystose pulmonaire.
Corticosteroids
Alkylating agents
Cyclophosphamide
Temozolomide
Antibiotics
Bleomycin
Anticalcineurins
Cyclosporine
Tacrolimus
Antimetabolites
Cytarabine
Fluorouracil
Methotrexate
Purine analogs
Azathioprine
Cladribine
Fludarabine
TNF inhibitors
Adalimumab
Etanercept
Infliximab
Monoclonal antibodies
Abatacept
Alemtuzumab
Rituximab
Miscellaneous
Sirolimus
Tocilizumab
Adapted from Carmona and Limper [3].
TNF: tumor necrosis factor alpha.

the diagnosis of infection. The most significant risk factors

for PJP in non-HIV-patients are the use of corticosteroids
and defects in cell-mediated immunity. Corticosteroids have
been administered in 90% and as the sole immunosuppressant in 1728% of non-HIV-patients [4]. Lymphocytopenia
(idiopathic or drug-induced), immunomodulatory agents, monoclonal or polyclonal antibody therapies, calcineurin inhibitors
and other immunosuppressive medications, solid cancers or
hematological malignancies (Table 3), solid organ transplantation (Table 4), anti-transplant rejection treatment, treatment

Table 2
Pathologies associated with pneumonia (PJP) in five series of non-HIV-patients.
Pathologies associes la survenue de pneumocystose pulmonaire chez des patients srongatifs pour le VIH.

Period of inclusion
Hematological malignancies
Solid malignancies and
corticosteroids
Solid organ transplant
recipients
Chronic inflammatory
diseases
Miscellaneous
a

Sepkowitz et al. [5]

n = 142 (%)

Yale et al. [4]

n = 116 (%)

Zahar et al. [6]

n = 39 (%)

Roblot et al.
n = 130 (%)

Bolle et al. [7]

n = 56 (%)

19781989
67 (47.2)
37 (26)

19851991
35 (30.2)
15 (12.9)

19891999
28 (71.8)
7 (17.9)

19951999
75 (57.7)
18 (13.8)

20012006
44 (78.6)
9 (16.1)

29 (25)

9 (6.9)

26 (22.4)

27 (20.8)

38 (26.8)a

11 (9.5)

4 (10.3)

1 (0.8)

3 (5.4)

Twenty-five (17.6%) allogeneic bone marrow transplant recipients, 7 (4.9%) solid malignancies without corticosteroids.

A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

187

Fig. 1. Non-HIV patients at risk for pneumonia (PJP).

Patients srongatifs pour le VIH risque de pneumocystose pulmonaire.

for some inflammatory conditions (particularly rheumatologic

diseases) (Tables 57), primary immunodeficiencies (especially
severe combined immunodeficiency and X-linked hyper-IgM
syndrome), and severe malnutrition are additional risk factors.

lymphoid leukemia, and bone marrow or stem cell transplant

recipients. Multiple factors may contribute to higher risks in
these patients, including corticosteroid therapy, purine analogues, and other cytostatic agents (i.e. fludarabine, cytarabine,

2.1. Hematological malignancies

Table 5
Incidence of pneumonia (PJP) among patients with autoimmune and inflammatory diseases.
Incidence de la pneumocystose pulmonaire au cours de diffrentes pathologies
auto-immunes ou inammatoires.

The most frequent underlying hematological malignancies

related to a higher risk of PJP are lymphoproliferative diseases,
Table 3
Pneumonia (PJP) according to the type of malignancy.
Incidence de pneumocystose pulmonaire chez les patients doncologie en fonction du type de cancer.
Cases
Lymphomas
Acute lymphoblastic leukemia
Other types of leukemia
Solid malignancies and corticosteroids
Brain malignancies and corticosteroids
Allogeneic bone marrow transplantation

34
5
16
30
21
22

Number of
patients
9907
2929
5023
26085
3098
1348

Incidence
(%)
0.34
0.17
0.32
0.11
0.68
1.63

Disease

Incidence (%)

References

Granulomatosis with polyangiitis

Periarteritis nodosa
Polymyositis and dermatomyositis
Systemic lupus erythematosus
Rheumatoid arthritis

812
6.5
2.7
2
0.10.3

[1]
[1,4]
[9]
[10]
[1]

Table 6
Risk factors of pneumonia (PJP) among patients with systemic lupus erythematosus.
Facteurs de risque de pneumocystose pulmonaire chez des patients souffrant de
lupus rythmateux dissmin.

Adapted from Sepkowitz et al. [5].

Table 4
Incidence of pneumonia (PJP) among solid organ recipients in the absence of
P. jirovecii prophylaxis.
Incidence de la pneumocystose pulmonaire chez des transplants dorgane en
labsence de prophylaxie.
Organ transplanted

Incidence (%)

Kidney
Liver
Heart
Heart-lung/lung

0.614
311
241
6.543

Adapted from Martin et al. [27].

Higher activity
index (MEXSLEDAI)
Renal involvement
Cumulative dose
of prednisone
(mean SD)
Total lymphocyte
count
(mean SD)

PJP+
(n = 15)

PJP
(n = 60)

13.6 5.83

6.73 3.22

< 0.01

86%
49 29 mg/day

11.1%
20 4.8 mg/day

< 0.01
< 0.001

520 226/mm3

1420 382/mm3

< 0.01

Adapted from Lertnawapan et al. [11].

MEX-SLEDAI: Mexican Systemic Lupus Erythematosus; SD: standard deviation.

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A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

Table 7
Drugs associated with pneumonia (PJP) in rheumatoid arthritis patients.
Traitements associs ave la survenue de pneumocystose pulmonaire chez les
patients traits pour polyarthrite rhumatode.
Drug

Action

PJP incidence (%)

Infliximab (Remicade )
Etanercept (Embrel )
Adalimumab (Humira )
Tocilizumab (RoActemra )
Abatacept (Orencia )

Anti-TNF
Anti-TNF
Anti-TNF
Anti IL6
Anti CD 28

0.3
0.1
0.3
0.2
0.1

associated with a higher risk of infection, but prophylaxis based

on CD4+ T-cell count (< 200 or 300/mm3 ) failed (Table 8).
2.4. Autoimmune and inammatory diseases
Patients with autoimmune or inflammatory diseases may
present with PJP, usually in the setting of long-term
corticosteroid therapy, combined or not with another immunosuppressive therapy. It is unclear if PJP is more frequent in some
autoimmune or inflammatory disease (Table 5).

Adapted from Mori et al. [12].

vincristine, cyclophosphamide, methotrexate, and monoclonal

antibody therapy such as anti-CD52). These therapies induce
severe and prolonged T-cell immunosuppression predisposing to
PJP. Corticosteroids play a major role in the occurrence of PJP.
High doses of corticosteroids (i.e. > 20 mg prednisone daily for
4 weeks) and steroid dose tapering have been identified as major
risk factors. However, the intensity of chemotherapy is probably
a very important issue and should be taken into account when
the diagnosis is suspected.
2.2. Solid tumors
Primary or metastatic brain tumors, lung, and breast cancers are associated with higher risk of PJP; whereas PJP rarely
occurs in patients with malignancies of the digestive organs [5].
Corticosteroid use and radiotherapy are considered as risk factors [5]. The incidence of PJP in patients with solid tumors has
increased, probably because of better overall survival and use
of more aggressive chemotherapy; but only a few authors have
assessed this issue. However, the most important risks seems to
affect some subgroups of patients, such as those with high-grade
glioma receiving temozolomide (75 mg/m2 ) during 6 to 7 weeks,
or a high-dose temozolomide regimen, especially associated
with a chronic use of corticosteroids.
2.3. Solid organ transplantation
Five to 15 percent of patients who undergo solid organ transplantation present with PJP without any prophylaxis, depending
on organ type, transplant center, and immunosuppressive regimens (Table 4). Most cases of PJP occur in the first 6
months after transplantation but some infections are reported
later. Moreover, individual risk increases during the period of
anti-rejection treatment. The risk factors for PJP are corticosteroid treatment associated with immunosuppressive drugs
(cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil),
and anti-lymphocyte therapies. Mycophenylate mofetil may
have some intrinsic anti-P. Jirovecii activity, while tacrolimus
(FK506) boosts its growth in vitro. Active cytomegalovirus
(CMV) infection may boost the growth of Pneumocystis. It is
unclear whether the CMV directly stimulates the proliferation
of Pneumocystis, acts systemically as an immunosuppressive
agent, or is a fellow-traveler. Prediction of PJP risk in solid
organ transplant recipients is not assessed. Lymphocytopenia is

2.4.1. Rheumatoid arthritis (RA)

The early use of methotrexate as a first-line treatment and
the emergence of innovative biologic agents targeted at specific
molecules and pathways in the immune system, especially antiTNF-, have altered the course of RA and improved patient and
social outcome [12]. But this has come with an increased rate of
PJP in this population (Table 7). Outbreaks have been observed
among outpatients as in renal transplant recipients [12].
2.4.2. Granulomatosis with polyangiitis
The authors of a systematic review focusing on infection
in patients with connective tissue diseases, published in 2007,
reported that granulomatosis with polyangiitis was the disease
most frequently associated with PJP (Table 5).
2.4.3. Systemic lupus erythematosus (SLE)
Gupta et al. reported that the frequency of PJP in SLE patients
treated with cyclophosphamide remained low (0.1588%) and
concluded that routine prophylaxis against P. jirovecii was not
necessary, given the high incidence of severe drug reactions and
lupus flares with trimethoprim-sulfamethoxazole (TMP/SMX)
[13]. However, they and others identified risk factors suggesting
initiation of prophylaxis (Table 6) [11].
2.4.4. Other connective tissue and autoimmune diseases
PJP has been described in all other connective tissue and
autoimmune diseases, although only a few case reports have
been published on patients with dermatoses such as pemphigus,
pemphigoid, or Behcets syndrome (Table 5). Some reports suggest that patients with dermatomyositis are at higher risk for PJP
[9].
2.4.5. Inammatory bowel diseases (IBD)
Patients with Crohns disease and ulcerative colitis are treated
with an increasing number of immunomodulatory and immunosuppressive medications, including corticosteroids, thiopurines,
cyclosporine, and antibody-based biologic agents. The authors
of a large retrospective epidemiological study including 50,932
patients with Crohns disease, 56,403 patients with ulcerative
colitis, and 1269 patients with unspecified IBD, reported that
the raw incidence of PJP was 10.6/100,000 [14]. Patients with
Crohns disease were identified as being at the highest risk.
The authors stressed the pivotal role of corticosteroids. However, there are no clear guidelines concerning the management
of PJP in this population. A recent survey was performed among
gastroenterology providers for PJP prophylaxis in patients with

A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

189

inflammatory bowel disease. Eight percent of the respondents

reported that patients had developed PJP on immunosuppressive therapy, 11% reported initiating PJP prophylaxis, mostly for
patients on triple immunosuppressive therapy.
3. Clinical and radiological diagnosis
Non-HIV-patients exhibit more atypical presentations, a
more fulminant course and higher mortality, and are more difficult to diagnose because of the lower inoculum. These clinical
differences of PJP are thought to be caused by differences in the
host immune response [15].
3.1. Clinical presentation
Pneumonia is the primary manifestation of P.jirovecii infection in non-HIV-patients. Extra-respiratory symptoms as well as
shock remain very rare and should lead to consider co- infection or another diagnosis [3,16]. The time from the onset of
symptom to diagnosis/treatment is a main risk factor for PJP
mortality. So the first, and not the least important reaction, is
to consider the diagnosis in case of association of: underlying
condition at risk of PJP; absence of any specific prophylaxis,
and common, but non-specific presentation, with fever (54 to
86%), dyspnea (24 to 81%), and dry cough (8% to 76%). This
common presentation must lead to diagnostic investigations and
to initiation of a prompt probabilistic specific treatment. Seven
percent of patients are asymptomatic, so if 1 or more of these
non-specific symptoms are absent, it does not allow ruling out
PJP [3]. For non-typical PJP presentations, clinician should first
consider the wide spectrum of differential diagnosis in those
immunosuppressed/multi treated patient. AIDS-patients present
with sub-acute onset (a few weeks) and longer symptom duration
(2528 days) than non-HIV-patients (a few days, 56 days), and
less than 3 days in 20% of the cases [7]. But these PJP symptoms
are missing in non-HIV-patients because of immunosuppressive
treatment. Lungs examination ranges from normal auscultation
(20%, even in hypoxemic presentation) to bilateral diffuse crackles [7]. A pneumothorax may present as acute respiratory failure
(2%4%).
3.2. Biological ndings
No biological finding can suggest PJP. Neither the absolute
lymphocyte count nor the subpopulation study are contributive for the diagnosis of PJP (Table 8). Higher levels of lactate

Fig. 2. HRCT scan of a 63-year-old male patient treated with long-term corticosteroid therapy for a pemphigus, showing bilateral symmetrical ground-glass
opacities (GGO) predominant in the upper lung.
Scanner thoracique dun homme de 63 ans traits par corticodes pour un
pemphigus, montrant des opacits en verre dpoli bilatrales, symtriques,
prdominant dans les territoires suprieurs.

dehydrogenase (LDH), as lung injury marker, correlate with the

disease severity but this is not contributive for the etiological
diagnosis.
3.3. Radiological features
Radiographic imaging in non-HIV-patients is almost similar to that of AIDS-patients. The chest radiographic images are
non-specific and may even seem normal. They typically show
bilateral, symmetric, reticular or granular opacities. In mild
presentations, these opacities are typically perihilar. In severe
presentations, the opacities are diffuse, stemming from the hila
in a butterfly pattern. Typically, reticular and poorly defined
ground-glass opacities (GGO) progress to alveolar consolidation
in 3 to 4 days. High-resolution computed tomography (HRCT)
may be indicated for non-HIV-patients patients with normal or
almost normal chest radiograph [17]. The sensitivity is 100%
and the specificity is 89%. Indeed, a normal HRCT may allow
excluding PJP [18] (Figs. 2 and 3). Extensive GGO are the
main findings [17]. Several patterns of GGO distribution have
been described: central distribution with symmetric distributed
GGO and relative peripheral sparing (33 to 54% of patients),
mosaic pattern (57%), diffuse and nearly homogeneous

Table 8
Lymphocytes count at the diagnosis of pneumonia (PJP) in 3 series of non-HIV-patients.
Lymphocytes totaux et sous populations au diagnostic de pneumocystose pulmonaire dans 3 sries de patients srongatifs pour le VIH.

Number of patients
Median CD4 cells (range)
Median CD4/CD8 ratio
CD4 < 300/mm3
CD4 < 400/mm3

Roblot et al. (2004)

Mansharamani et al. (2000)

Overgaard et al. (2007)

25
280 (101000)
NA
80%
80%

22
61 (0546)
0.6
91%
95%

17
280 (42900)
1.5
52%
40%

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A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

Fig. 3. HRCT scan of a 62-year-old male patient with arthropathic psoriasis

treated with anti-TNF therapy, revealing diffuse patchy GGO in the upper
lung with relative peripheral sparing. In this case, PJP was associated with
Pseudomonas aeruginosa pneumonia.
Scanner thoracique dun homme de 62 ans trait pour un rhumatisme psoriasique par anti-TNF mettant en vidence des opacit en verre dpoli respectant
la corticalit et prdominant dans les territoires suprieurs. Pneumocystose
pulmonaire associe une pneumonie Pseudomonas aeruginosa.

areas of GGO are not seen in other types of pneumonia except in

association with areas of consolidation and nodules [20]. Areas
of consolidation are less frequently observed in patients with PJP
(9%) than in patients with other types of pneumonia (75 to 85%),
excluding viral pneumonia [7]. PJP is also sometimes difficult to
differentiate, on imaging, from other pulmonary comorbidities
such as pulmonary edema, specific hematologic causes, drug
toxicity, or transfusion related acute lung injury. Differences
between CT findings of pulmonary edema and PJP include:
enlargement of pulmonary vessels, pleural effusion and rapid
improvement after treatment. The radiographic improvement
usually lags behind clinical improvement, and early radiological follow-up must be kept for patients with clear evidence of
clinical worsening or a suspected complication such as pneumothorax. GGO resolved completely after initiation of treatment
in 97% of patients after a median period of 13 days (mean 26,
range 158) [19]. Occasionally, patients recovering from PJP
may present with mild or severe residual interstitial fibrosis
(Fig. 5).

4. Microbiological diagnosis
distribution (24%). An apical predominance is also described
in 86% patients. In more advanced disease stages, some bilateral areas of consolidation may appear (17-21%). Septal lines
with or without intralobular lines superimposed on GGO (pattern commonly referred to as crazy paving) are observed in
6 to 18% patients [19]. The presence of cavitations, intrathoracic adenopathy, and pleural effusion is uncommon and could
suggest another diagnosis [19]. Pulmonary cysts or pneumatoceles of varying shape, size, and wall thickness occur in 3 to
6% of non-HIV-patients with PJP. They are associated with an
increased frequency of spontaneous pneumothorax [19]. Compared to AIDS-patients, a more rapid spread and larger extent
without peripheral sparing of GGO is sometimes described,
with more common lung consolidations, reflecting pulmonary
damage from the host immune response. A second difference is the lower incidence of pulmonary cysts (3 vs. 56%
in non-HIV vs. AIDS-patients). Parenchymal bands, centrilobular nodules, and thickened interlobular septal lines are also
observed more often in non-HIV-patients. HRCT images may
also differ according to the underlying condition and the level of
immunodepression. Leukemic patients who undergo intensive
chemotherapy or BMT sometimes present with centrilobular
opacities or Y-shaped branching structures in association with
typical GGO pattern, corresponding to bronchiolitis and bronchioles that are impacted with inflammatory material. Nodular
forms (solitary nodule or mass, or multiple nodules) have
been described in non-HIV-patients, reflecting the presence of
granulomatous inflammation. The usual diagnostic techniques
can all be negative for P. jirovecii in these nodular patterns
(Fig. 4).
The authors of several retrospective studies suggest that PJP
can be discriminated from other infections in immunocompromised patients. The initial diagnosis of PJP based on bilateral
GGO on HRCT is accurate in most pulmonary infections among
non-HIV-patients (87,5%) [20]. Extensive symmetric bilateral

4.1. Samples
The diagnosis of PJP is preferentially performed on bronchoalveolar lavage (BAL) fluid or induced sputum; the latter is
proposed in some hospitals as the initial diagnostic procedure so as to decrease the need for bronchoscopy. A higher
detection sensitivity allows using less invasive procedure such
as swabbing or aspiration. The development of highly sensitive detection techniques such as real-time PCR or antigen
detection assays offers the opportunity to assess the diagnostic contribution of these techniques with less invasive
samples from the upper respiratory tract or blood samples.

4.2. Usual techniques

The usual diagnostic techniques rely on the microscopic
observation of P. jirovecii cysts (which actually should be
named asci and correspond to the sexual forms of the
fungus) and/or trophic forms. Both forms can be visualized after May-Grnwald Giemsa staining or its RAL 555
variant (RAL Diagnostics , Martillac, France), but several
other staining techniques have been proposed, such as the
Grocott or toluidine blue staining. The use of an immunofluorescence assay with anti-Pneumocystis antibodies (Biorad ,
Marnes-la-Coquette, France) can improve the sensitivity of
microscopic detection of cysts. The sensitivity of microscopic diagnosis performed by experienced microscopists is
sufficient to diagnose P. jirovecii in BAL fluids from AIDS
patients. However, the microscopic diagnosis has a weak
sensitivity for the diagnosis of PJP in non-HIV immunocompromised patients, requiring the use of molecular diagnostic
techniques.

A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

191

Fig. 4. 53-year-old male patient with chemotherapy for an angioimmunoblastic T-cell lymphoma: a: acute PJP the day of the onset of symptoms: discrete GGO is
seen bilaterally in the upper lobes, with pre-existent lesions of pulmonary emphysema; b: 2 days later in the course of the disease, still without any specific treatment,
GGO have increased. After initiating therapy, GGO progressively resolved; c: three months later, no GGO can be observed; a few small irregular linear opacities
with discrete structural distortion persisted.
Patient de 53 ans trait par chimiothrapie pour un lymphome T angio-immunoblastique : a : scanner thoracique ralis le jour du dbut des symptmes de
pneumocystose pulmonaire : discret verre dpoli bilatral des sommets ; lsions demphysme ; b : 2 jours plus tard, en labsence de traitement, les opacits en verre
dpoli se sont majores et sont devenues plus denses. Aprs le dbut du traitement, celles-ci ont rgress ; c : trois mois plus tard les opacits en verre dpoli avaient
totalement disparu. Il ne persistait plus que quelques opacits rticules avec distorsions bronchiques.

4.3. New diagnostic tools

4.3.1. Polymerase Chain Reaction
Polymerase Chain Reaction (PCR) can improve the sensitivity of detection, particularly in non-HIV-patients. Given its high
negative predictive value, close to 100%, some authors have suggested that a negative PCR allows discontinuing cotrimoxazole
therapy [21]. Several targets have been used for PCR, including the major surface glycoprotein gene and the mitochondrial
large subunit ribosomal RNA gene. The development of molecular techniques for the diagnosis of PJP has allowed proving
the presence of P. jirovecii DNA in BAL fluids or induced sputum from patients with no sign of pneumonia, leading to the
concept of P. jirovecii carriage or colonization. Conventional
PCR cannot differentiate PJP from P. jirovecii colonization,
so real-time quantitative PCR assays have been proposed to
discriminate between these two entities, using threshold values
of fungal load.
4.3.2. Limits of PCR
The differentiation between infection and colonization
according to a threshold remains the main difficulty for quantitative PCR interpretation for two obvious reason:
as most reports concern non commercial PCR kits, the extrapolation of a threshold from one technique to another is
difficult;

qPCR diagnostic performance is supposed to be higher

than the current gold standard (standard coloration and
immunofluorescence), so defining a PJP case with either
gold standard negative subsequently confirmed PJP occurring early in the follow-up or expert analysis [22]
(Table 9).

Since the diagnostic performance depends on the disease prevalence, it would be necessary to quantify pre-test
probability of PJP according to underlying diseases, clinical,
and radiological presentation (Table 10).

Table 9
Diagnostic performance of Polymerase Chain Reaction (PCR) according to the
respiratory sample in HIV negative patients.
Valeur diagnostique de la PCR chez les patients srongatifs pour le VIH en
fonction du type de prlvement respiratoire.

Sensibility
Specificity
Positive predictive value
Negative predictive value
Adapted from Takahashi [23].

Induced
sputum (%)

Broncho-alveolar
lavage fluid (%)

100
90
87
100

84
93
53.1
98.3

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A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

Table 10
Clinical and radiological prediction of pneumonia (PJP) in non-HIV-patients.
Probabilit clinique et radiologique de pneumocystose pulmonaire chez les patients srongatifs pour le VIH.

Context

Onset of symptoms
Clinical presentation

Lung auscultation
Chest X-ray and HRCT
findings

Typical

Possible

Unlikely

Absence of prophylaxis and known

risk factors as lymphoid
hemopathies, use of
immunosuppressive therapies
(Table 1), solid tumors with
corticosteroids, especially brain
Abrupt in a few days

Prophylaxis with lomidine and known

risk factors
Neutropenia associated with
corticosteroids especially in solid organ
cancers

Compliance with prophylaxis

Myeloid hemopathies
Neutropenia without corticosteroids

One week

More than one week

Hacking cough
Absence of expectoration
Mild fever
Acute respiratory failure
Profound hypoxemia
(PaO2 < 60 mmHg while breathing
ambient room air)
Absence of extra-respiratory
symptom
Normal
Diffuse crackles

Loose cough
Purulent expectorations
Associated septic shock

Loose cough
Purulent expectorations
Hemoptysis
Absence of fever
Progressive respiratory failure
Absence of hypoxemia
Presence of extra-respiratory symptom

Normal
Bilateral interstitial opacities
Extensive ground-glass opacities
(GGO)
central, bilateral and symmetric
distribution, with relative peripheral
sparing
mosaic pattern
diffuse and nearly homogeneous
distribution
apical predominance

Unilateral interstitial opacities

Nodular opacity
Crazy paving (septal lines intralobular
lines superimposed on GGO)
Pulmonary cysts
initially developed in areas of
consolidation
multiseptate unusual-appearing
thick-walled cysts
increased risk of pneumothorax
Parenchymal bands
Centrilobular nodules
Nodular pattern: solitary nodule or mass,
or multiple nodules

Focal abnormality
Pleural fremitus

Biology

Cavitation
Pleural effusion
Mediastinal or hilar adenomegaly
Normal HRCT

Normal LDH level

HRCT: high-resolution computerized tomography; LDH: lactic dehydrogenase.

4.3.3. Serum -D-glucan

Serum -D-glucan (BDG) detection has also been proposed
as a diagnostic tool for PJP since this component of fungal cell
wall has been observed in high levels in the serum of patients
with PJP [24]. Serum BDG detection test has a good negative
predictive value. However, as many factors can induce BDG elevation (Table 9), a specific diagnosis of PJP cannot be achieved
with this pan-fungal marker. The diagnostic performance for
PJP seems to be better than for invasive fungal infections (IFI)
(i.e. candidemia and aspergillosis). A meta-analysis of BDG
detection performance for PJP diagnostic studies was conducted
by Karageorgopoulos et al. [25]. Fourteen studies including
357 patients with PJP and 1723 controls were included. Most
of the authors used the Fungitel test with a threshold set
between 80 and 100 g/mL. The average (95% confidence
interval) sensitivity and specificity of BDG were 94.8%
(90.897.1) and 86.3% (81.789.9) respectively, and the positive and negative likelihood ratios were 6.9 (5.19.3) and 0.06
(0.030.11), respectively. The very high sensitivity of BDG suggests that a negative result in patients without a high pretest

probability of PJP should lead to considering an alternative diagnosis. Karageorgopoulos et al. concluded that it was necessary to
pretest for PJP to improve the diagnostic performance. Sax et al.
reported a high PJP prevalence (65%) in their study, but the negative predictive value was only 80% [26]. So we do agree with
them about the imperative need for pretest prevalence evaluation
[26]. This study had many limitations:
among the 14 mixed studies, some were retrospective and
other were prospective, and their purpose was diagnostic performance for either IFI (including PJP) or only PJP;
different techniques with different thresholds were tested;
since the method for control case differed, the frequency of
PJP in the various populations were very different;
the case definition of PJP (excluding or including only positive
P. jirovecii PCR) differed among the various studies.
Those limitations stress that the study methods for the evaluation of serum BDG for the diagnosis of PJP are clearly
insufficient and that there is an urgent need for accurate

A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

193

Table 11
Main indications for prophylaxis against pneumonia (PJP) in non-VIH/AIDS patients.
Principales indications de prophylaxie de la pneumocystose chez les patients srongatifs pour le VIH.
Solid tumors
Prednisone, or equivalent, of at least 20 mg/day fore more than 4 weeks
Temozolomide and radiation therapy until CD4 > 200 mm3
Hematological malignancies
Alemtuzumab: during treatment and for at least 2 months after cessation until CD4 > 200 mm3
Fludarabine and T-cell depleting agents (e.g., cladribine) until CD4 > 200 mm3
All ALL patients while receiving anti leukemic therapy
Allogeneic stem cells recipients for at least 6 months
Autologous stem peripheral stem cells recipients for 3-6 months
Allogeneic bone marrow recipients receiving immunosuppressive therapy or with chronic GVHD for > 6 months or the duration of immunosuppression
Solid organ transplant recipients
All for 612 months
Renal transplant recipients for a minimum of 4 months after transplantation; consider longer duration for other organs recipients
Keep in mind to reinstitute, for a length of at least 6 weeks, in case of transplant rejection treatment
Vasculitis and inammatory diseases
Granulomatosis with polyangiitis (i.e. Wegener) treated with cyclophosphamide, especially if receiving corticosteroids
Primary systemic vasculitis treated with corticosteroids and steroid-sparing agent (e.g., methotrexate)
ANCA-associated vasculitis treated with cyclophosphamide and corticosteroids
Rheumatoid arthritis treated with TNF- inhibitors, especially if on corticosteroids or other immunosuppression
Connective tissue diseases treated with prednisolone > 20 mg per day, or equivalent, for more than 2 weeks
Inammatory bowel diseases
Patients receiving TNF- inhibitors, especially if on corticosteroids or other immunosuppression
Primary immunodeciencies
Severe combined immunodeficiency
Idiopathic T CD4+ -lymphocytopenia
X-linked hyper-IgM syndrome
Adapted from Carmona and Limper [3], Martin and Fishman [27] and, Tasaka and Tokuda [28].
ANCA: anti-neutrophil cytoplasmic antibodies; ALL: acute lymphocytic leukemia; GVHD: graft versus host disease; TNF-: tumor necrosis factor .

evaluation. No correlation was found between clinical feature,

prognosis, P. jirovecii load in the lungs detected by Real-Time
PCR, and serum BDG levels. It should be stressed that all these
new diagnostic tools should be included in the pre-test probability of PJP (Table 10).

5. Prophylaxis and treatment

Most of the data was drawn from experience with AIDSpatients.
5.1. Primary prophylaxis
There is no consensus on the strategy of disease prevention
against P. jirovecii in non-HIV-patients, contrary to AIDSpatients, (Table 11).

Fig. 5. HRCT scan of a 54-year-old male patient, under chemotherapy for a stage
4 pulmonary adenocarcinoma, showing bilateral diffuse infiltrates, including
GGO and patchy consolidations with inhomogeneous distribution and spared
peripheral lung parenchyma.
Scanner thoracique dun homme de 54 ans trait par chimiothrapie pour adnocarcinome bronchique stade 4. Inltrats pulmonaires diffus associant opacits
en verre dpoli et consolidations inhomognes pargnant la corticalit.

5.1.1. For which patients?

The incidence of PJP could be increasing in non-HIVpatients, but little data is available to determine the indications
for primary prophylaxis, except in patients having undergone
allogeneic bone marrow transplantation, organ transplantation
(especially kidney), or in children with acute lymphoblastic
leukemia. It should be kept in mind that in such patients, there
is no reliable marker for susceptibility (low peripheral blood
CD4+ cell count, Table 8). Thus, the benefit of prophylaxis
should be balanced with the risk of severe adverse events and
relies on the cumulative incidence of PJP. A systematic review
and meta-analysis of available randomized controlled trials was
published in 2007 [29]. The authors suggested that prophylaxis
should be initiated when the risk of PJP is higher than 3.5%. On
the other hand, the results of a cost-benefit analysis, performed
on patients presenting with granulomatosis with polyangiitis,

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A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

showed increased life expectancy and reduced lifetime medical

costs for patients receiving TMP-SMX prophylaxis [8]. The recommendations for solid organ transplant recipients were updated
in 2013 [27]. These guidelines are often updated since new
patients at risk are regularly reported.
5.1.2. Duration
This question remains unsolved, especially for patients
with autoimmune or inflammatory diseases. Some recent data
suggests that treatment duration can vary according to the transplanted organ; from 1month in kidney recipients to 1 year or
more in lung recipients [30]. Although studied for long years,
there are still discrepancies in the recommendations for kidney
transplant recipients, although the have been studied for a long
time [31]. The European Renal Association recommends a prophylaxis period of 4 months after transplantation, the American
Society of Transplantation 6 to 12 months, and the Kidney Disease Improving Global Outcomes guidelines 3 to 6 months [31].
Lifelong prophylaxis with TMP-SMX is not recommended for
renal transplant recipients; however, in many cases, PJP occurred
after the recommended post-transplantation prophylaxis periods
[32].
5.1.3. Which agent?
TMP-SMX should be considered as the first line for PJP prophylaxis in non-HIV-patients [33]. All other prophylactic agents
should be considered as second-line agents due to breadth of coverage, drug intolerance, cost, and effectiveness issues that cannot
compare with TMP-SMX. Its effectiveness and good tolerance
in the prevention of PJP for patients presenting with hematological malignancies was demonstrated 30 years ago. It also
has the potential advantage being active against other infectious
complications (such as common bacterial infections, listeriosis,
nocardiosis, and toxoplasmosis). The authors of a meta-analysis
of 12 randomized trials, including 1245 patients (50% children) having undergone autologous bone marrow or solid organ
transplantation, or who presented with hematological malignancies, reported no difference between once-daily and three times
weekly administration schedules and suggested effectiveness of
TMP-SMX as prophylaxis for PJP [29]. However, in daily clinical practice, TMP-SMX administration, especially for patients
with rheumatic diseases, can sometimes lead to adverse effects
(drug allergy, renal dysfunction, thrombocytopenia, and electrolyte disorders). However, it should be noted that in a review
of methotrexate drug interactions, none was reported with TMPSMX used as a prophylactic agent against PJP. Dapsone is
an alternative for preventive treatment. It is contraindicated in
patients with documented glucose-6-phosphate dehydrogenase
(G6PD) deficiencies. Like TMP-SMX, it inhibits the enzyme
dihydropteroate synthase (DHPS). Some authors argue that the
mutation of DHFS may be a leading cause of prophylaxis failure
when using these drugs. However no sufficient data has been
documented in large clinical trials to support this hypothesis
[34]. Dapsone, alone or associated with pyrimethamine, seems
less effective than association TMP-SMX, but this is still questionable. It must be kept in mind that TMP-SMX intolerance
is often predictive of dapsone intolerance. So dapsone is not

recommended as an alternative drug in case of TMP-SMX intolerance. Atovaquone has been studied in small prospective trials
concerning stem cell and solid organ transplant recipients. It
appears to be effective and well tolerated, even in bone marrow
transplantation receivers. It was initially thought to be a promising alternative for PJP, despite the unknown optimal dosage
and its extremely variable absorption (enhanced by fatty food).
Breakthrough infections were documented in patients taking
1000 mg or less daily [35]. Finally, inhaled pentamidine should
be considered as a third-line agent. It is less effective than TMPSMX, dapsone, or atovaquone. The use of inhaled pentamidine
has been associated with breakthrough infections, especially in
the upper lung. Inhaled pentamidine may negatively affect the
sensitivity of diagnostic assays using respiratory secretions in
patients with PJP.
5.2. Secondary prophylaxis
The data in this field is even smaller than for primary prophylaxis. Some authors recently suggested that patients presenting
with PJP during rituximab therapy should benefit from such
treatment until immune reconstitution was ensured. However,
no definitive recommendations were issued.
5.3. Curative treatment
5.3.1. Anti-infectious agents
Historically, the mainstay of treatment for PJP was TMPSMX given orally or intravenously for 3 weeks (Table 12).
TMP-SMX acts by interfering on folate metabolism: TMP and
SMX respectively inhibit dihydrofolate reductase (DHFR) and
dihydropteroate synthase (DHPS), which are 2 integral enzymes
for folate synthesis. It is still the recommended first-line therapy
for patients with mild, moderate, and severe disease. Adverse
effects occur less commonly (around 15%) in non-HIV-patients
[36]. Combination with other antimicrobial molecules is not
recommended to treat PJP due to the lack of synergy and the
risk of adverse effects. The recommended daily dose is TMP
1520 mg/kg plus SMX 75100 mg/kg. But this dose recommendation was not based on a randomized controlled trial
results, so the optimal dose of TMP-SMX remains unclear. Some
authors recommend that SMX drug levels should be monitored
for patients receiving IV therapy, although published data is
controversial and there are no current guidelines as to when
or how often the levels should be monitored [3]. Patients with
a seriously compromised pulmonary status (PaO2 < 60 mmHg
while breathing ambient room air) or pending respiratory failure (PaCO2 normal or elevated in a patient with low PaO2
or high respiratory rate) should probably receive IV therapy.
In other cases, oral administration seems effective, in accordance with findings in AIDS-patients. It is very important to
note that the recommended duration of treatment is 21 days
in AIDS-patients and 14 days in non-HIV-patients. The recommendation for longer treatment in HIV-infected patients is
based on the higher fungal load and slower clinical response,
which may result in a higher risk of relapse after only 14
days of treatment. Extended treatment should be considered for

A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

195

Table 12
Therapeutic options for treating pneumonia (PJP).
Anti-infectieux utiliss dans le traitement de la pneumocystose pulmonaire.
Agents

Dosing

Comments

Trimethoprim-sulfamethoxazole
(TMP-SMX)
Pentamidine isethionate

1520 mg/kg/day in divided doses every 68 hours

Drug of choice considered to be the most effective

4 mg/kg/day IV over 12 hours

Many adverse effects including pancreatitis (consider avoiding in

case of pancreas transplantation), hypo- or hyperglycemia, bone
marrow suppression, renal failure, electrolyte disorders
Rarely used as aerosol (600 mg/kg/day) with risk of failure.

Atovaquone

750 mg/12 hours per os

Reserved for mild or moderate PJP (PaO2 on ambient room

air > 70 mmHg)
Optimal dose uncertain (up to 1500 mg/12 hours)
Variable oral absorption (best with fatty foods)

Dapsone

50 mg/day per os

Not to be used in case of G6PD deficiency

Proposed in case of sulfamide allergy despite the fact that dapsone
may elicit sulfamide allergy

Caspofungin

70 mg IV loading dose on day one followed by

50 mg/day

Case reports as salvage therapy

Adapted from Martin and Fishman [38].

non-HIV-patients, in case of severe immunosuppression, high

fungal load, or delayed clinical improvement. No randomized
trial has validated risk factors for TMP-SMX treatment failure.
Patients usually worsen within the first 3 to 5 days of treatment without corticosteroid treatment. Therefore changes in the
treatment should not be made before 5 to 8 days of treatment;
and concurrent infectious or non-infectious processes should be
ruled out. Patients who fail to improve after 5 to 7 days of oral
therapy should be switched to an IV regimen and those who
experience treatment failure on IV therapy should receive an
alternative IV regimen. Other drugs may be administrated in
case of intolerance to TMP-SMX, despite the fact that data on
their use comes from studies performed on AIDS-patients. Pentamidine can be administrated intravenously. The most common
adverse drug reaction to pentamidine is renal toxicity, which usually occurs after 2 weeks of treatment and can be prevented by
adequate hydration. Other adverse effects, including hypotension (especially in case of rapid infusion), heart arrhythmia,
hypo or hyperglycemia, hypercalcemia, hyperkalemia, pancreatitis, and metallic taste may also occur. Atovaquone, dapsone,
and clindamycin-primaquine are the other options for the treatment of PJP in AIDS-patients. A combination of primaquine and
clindamycin seems to be the most effective regimen. However,
due to the lack of data, these drugs cannot be recommended
for routine use in non-HIV-patients with PJP. Caspofungin acts
on the P. jirovecii cell wall by inhibiting BDG synthesis: It has
thus been reported to be effective, especially in salvage therapy.
However the recently reviewed data mainly comes from case
reports and remains highly controversial [37].
5.3.2. Adjuvant corticosteroids
The usefulness of adjunctive corticosteroid therapy is well
established for AIDS-patients with moderate-to-severe PJP,
defined as PaO2 < 70 mmHg while breathing ambient room air.
But it remains questionable for non-HIV-patients with moderateto-severe PJP. Very few authors have addressed this question,

and all their studies were retrospective, including very heterogeneous populations of non-HIV-patients, most of them treated
with corticosteroids at the onset of PJP, with very heterogeneous
dosage of corticosteroids, the whole leading to contradictory
conclusions. The authors of a recent study, although performed
in a single center and retrospectively, included 139 cases of
PJP in non-HIV-patients; they suggested that an adjunctive high
dose corticosteroids (> 1 mg/kg/day) increased the death rate
[39]. This was unrelated to a higher rate of nosocomial infections. Thus, we believe that there is currently not enough data to
recommend adding such a treatment for these patients.
6. Prognosis of PJP in non-HIV-patients
The prognosis of PJP is worse in these patients than in patients
with AIDS. The reported death rate ranges from 30 to 40% (vs.
10% to 20% in AIDS-infected patients). It may reach 80.9% and
86.8%, respectively, for patients requiring invasive mechanical
ventilation and for those with an acute respiratory distress syndrome (ARDS). Initiating an anti-infectious treatment within
7 days after onset of symptoms is important because intubation and mechanical ventilation may be avoided in many cases.
Poor control of the underlying disease, performans status over 2,
high temperature, and high oxygen flow at presentation, shock,
development of ARDS, and clinical worsening at day 5 are
related to a poor prognosis [40]. Hypoalbuminemia is another
independent predictor of mortality. Pulmonary co-infection with
herpes simplex virus (HSV) or CMV may contribute to a fatal
outcome. A high neutrophil count in BAL samples is also associated with more severe hypoxemia and higher mortality [6,15].
It seems crucial to identify patients at risk of PJP considering
new immunosuppressive or immunomodulatory drugs, because
several authors have reported that the morbidity and mortality are significantly worse in this population than in those with
AIDS [4]. It is important to keep in mind that conventional
prognostic guidelines for community-acquired pneumonia could

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A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

underestimate the severity of non-HIV PJP, leading to a therapeutic delay resulting in higher mortality. The most important
ways to decrease mortality among non-HIV patients presenting
with PJP are to make an early diagnosis and initiate the PJPspecific antimicrobial therapy as soon as possible. Thus, keeping
in mind a high level of suspicion especially in patients receiving
corticosteroids is crucial.

7. Pending questions
7.1. P. jirovecii colonization
P. jirovecii colonization occurs in patients without any signs
or symptoms of acute pneumonia. The recent use of new
detection tools suggests that colonization prevalence could be
higher than previously thought. Ponce et al., in an autopsy
study, found that 65% of individuals in a general population
were colonized [41]. The colonization rate ranged from 13
to 23% when examining only oral lavage or nasal swabs. A
high colonization prevalence was also reported among various
populations of immunosuppressed patients and/or patients presenting with chronic lung disease [23]. Using corticosteroids
appears to be a major risk factor for colonization. The contribution of serum BDG to distinguish infection from colonization
among patient with positive PCR detection needs to be further
studied.
7.2. P. jirovecii transmission
Whether PJP occurs after reactivation of latent infection/colonization (earlier preferred theory) or is due to de novo
acquisition is still debated. Convincing evidence has recently
challenged the reactivation theory. Indeed, the results of several genotyping epidemiological studies seem to support de
novo person-to-person or environmental P. jirovecii transmission and subsequent infection. This hypothesis is also supported
by reports of patients having experienced 2 episodes of PJP with

genetically different isolated strains associated to each episode.

Moreover, studying PJP outbreaks shows that clusters of specific genotypes are geographically associated with the place of
residence rather than the birth place, supporting the infectionreinfection theory. Another argument for the latter theory is the
short P. jirovecii cyst clearance period observed after PJP, never
exceeding one year. The authors of other studies have reported
PJP occurring after a short period of colonization by P. jirovecii
with the same genotype, emphasizing the fact that PJP might
not be due to reactivation of childhood colonization, but that
colonized individuals are at risk for PJP. The results of several
molecular studies of PJP outbreaks seem to support the possibility of a nosocomial acquisition of the infection. Even though the
main route of P. jirovecii transmission is airborne, the mode of
transmission itself, i.e. direct person-to-person spread or from
an environmental source, remains unclear. P. jirovecii colonized
individuals, including healthcare workers, may serve as a transient reservoir for disease transmission, raising the question of
the appropriateness of respiratory isolation of patients suspected
to have PJP, even though current guidelines do not recommend it.
As recently underlined by Hauser et al., whether outbreak genotypes are always predominant and whether these harbor specific
virulence factors remain open questions [42].
7.3. New insights into PJP infection control
PJP infection control relies upon identification of patients
at risk and chemoprophylaxis, but not just that. The risk of
developing PJP was not prevented by the use of chemoprophylaxis as demonstrated among kidney transplant receivers
during PJP outbreaks. Considering new evidence on person-toperson airborne and environmental transmission, and de novo
infection, supported by several reports of nosocomial outbreaks
among immunocompromised patients, and taking into account
that immunocompetent asymptomatic carriers may act as fungal
reservoirs and infection sources of limited duration, new infection control measures could be recommended such as geographic
and respiratory isolation of infected patients from susceptible

Table 13
Sensibility and specificity of various techniques on various samples in non-HIV-patients.
Sensibilit et spcicit des diffrentes techniques utilises pour le diagnostic de pneumocystose pulmonaire chez les patients srongatifs pour le VIH en fonction
du type de prlvement respiratoire.
Technique

Sample

Sensibility (%)

Specificity (%)

Reference

Conventional staining

BAL
IS

86
9297

97
92

[44]

Silver or DQ

BAL
IS

81
92

97
100

Immunofluorescence

BAL
IS

6090
97

100

Conventional PCR

BAL

100

87

[45]

Quantitative PCR

BAL
IS
NPA

87.2100
100
100

84.999.1
100
100

[21,46]

BDG

Plasma

94.8

86.3

[25]

BAL: broncho-alveolar lavage; BDG: beta-d-glucan; IS: induced sputum; NPA: nasopharyngeal aspirate; PCR: polymerase chain reaction.

A. Roux et al. / Mdecine et maladies infectieuses 44 (2014) 185198

patients, in single room. Some authors suggest that patients

highly suspected of having PJP without previous chemoprophylaxis should be preventively isolated until PJP has been ruled out.
Moreover, even if there is no positive evidence of any benefit,
it might be effective to provide surgical masks for compromised outpatient visits. The definitive eradication of P. jirovecii
from colonized patients seems both ineffective and illusory,
since fungal acquisition and clearance appear to be dynamic,
cyclic, and depend on the variations of the patients immunologic status. Indeed, since the global population is a main but
transient source of infection, reducing PJP carriage in immunocompromised patient would only reduce the potential for spread
between immunocompromised hospitalized patients. We believe
that a multimodal approach considering monitoring of colonization, fungal load, type of used or to-be-used immunosuppressive
therapy, length and severity of current or expected immunosuppression, and pre-emptive therapy should allow lowering PJP
incidence among immunocompromised patients.
7.4. Non-invasive diagnosis strategy
The high sensitivity of PCR allows detecting P. jirovecii
DNA in non-invasive samples (oral lavage, nasopharyngeal
swab or lavage). To et al. recently reported a positive predictive value of 78.9% and a negative predictive value of 100%
using nasopharyngeal aspirate in non-HIV-patients [43]. However, more studies with adapted methods are needed to confirm
the performance of a strategy associating pre-test PJP probability
and use of these samples (Tables 10 and 13).
8. Conclusions
PJP is a severe opportunistic respiratory infection that can
complicate the evolution of many diseases related to immunosuppression. Long-term corticosteroid therapy appears to be
the main but not the only risk factor. of the availability of
immunomodulatory treatments, intensive chemotherapy, prolonged cancer survival, make it mandatory for the clinician to
integrate easily this disease in the spectrum of a possible etiological diagnosis when confronted by a non-HIV-patient presenting
with clinical respiratory signs. The prognosis of this disease
is closely related to the precocity of diagnosis and treatment.
The availability of PCR, of non-invasive and easy sampling
procedures (oropharyngeal lavage), or of serum BDG dosage
have greatly contributed to the diagnosis of PJP and optimal
patient care. Yet, many clinical issues still have to be dealt with
concerning PJP in non-HIV patients:
how should PCR be uses for PJP diagnosis?
how should serum BDG testing be used as a diagnostic aid?
how and when should adjunctive corticosteroid therapy be
used?
Finally, the attention of searchers was mainly focused on
T-cell quantitative or qualitative defects, but the results of
recent animal studies suggest that B-cell deficiency may also

197

be integrated in the process of prophylaxis, diagnosis, and

treatment.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
Acknowledgements
This review is dedicated to the memory of Patricia Roux who
passed away recently. She was an eminent physician, working
in the laboratory of parasitology and mycology of the SaintAntoine teaching hospital (Paris, France).
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.medmal.
2014.01.007.
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