Review

Prophylaxis for Pneumocystis

jiroveci pneumonia: is it
a necessity in pulmonary
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15

patients on high-dose,
chronic corticosteroid
therapy without AIDS?
Expert Rev. Respir. Med. 9(2), 171181 (2015)

Maryjane Liebling*, The benefit of prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is well documented in
Edmundo Rubio and immunocompromised patients, particularly those with HIV and/or AIDS; therefore, guidelines
Susanti Ie dictate this as standard of care. However, there is a paucity of literature regarding those
For personal use only.

Department of Pulmonary, Critical Care,
and Sleep Medicine, Carilion Clinic, P.O.
Box 13367, Roanoke, VA 24033, USA
*Author for correspondence:
Tel.: +1 540 853 0186
Fax: +1 540 983 1133
Maryjane_Liebling@yahoo.com
without HIV and/or AIDS who are potentially predisposed to PJP, including patients with
sarcoidosis, cryptogenic organizing pneumonia, interstitial lung disease, asthma and chronic
obstructive pulmonary disease, who may require high dose of prolonged corticosteroids for
disease maintenance or to prevent relapses. In this review, the authors examine the available
literature regarding prophylaxis in these groups, elaborate on the pathogenesis of PJP, when
to suspect PJP in these patients, as well as explore current recommendations that guide
clinical practice regarding implementation of PJP prophylaxis, namely with trimethoprim/
sulfamethoxazole being the preferred agent. In summary, the role of PJP prophylaxis in
non-HIV patients on chronic steroids remains controversial. The authors present a review of
the literature to provide better guidance to the clinician regarding the need to initiate PJP
prophylaxis in this patient population.

KEYWORDS: asthma . chronic obstructive pulmonary disease . corticosteroids . cryptogenic organizing pneumonia
. immunosuppression . interstitial lung disease . Pneumocystis jirovecii pneumonia . prophylaxis . sarcoidosis
. trimethoprim/sulfamethoxazole

While opportunistic infections are usually con-
sidered in those with known immunosuppres-
sive disorders, such as HIV or AIDS, these
organisms may also be present in normal
hosts undergoing immunosuppressive ther-
apy [1,2]. Prophylaxis has had a major impact
in reducing the incidence of Pneumocystis jiro-
vecii pneumonia (PJP), but such practice is not
routine in patients without HIV/AIDS who
may have a compromised immune state [3,4].
Furthermore, there are no published guidelines
regarding the need for PJP prophylaxis in
HIV-negative patients necessitating therapy with
corticosteroids. An extensive review of the litera-
ture is presented, focusing on patients with
pulmonary disease but without HIV and/or
AIDS, who may still be at risk for developing
PJP secondary to corticosteroid treatment. To
better understand the issues, we also review the
pathophysiology of PJP in both HIV-positive
and HIV-negative patients and the current
accepted indications for prophylaxis. In this
regard, we will focus this part of the discus-
sion on the use of trimethoprim/sulfamethoxa-
zole, the agent of choice.
Review of the literature
Historical perspective
P. jirovecii is a fungus that was first described
by Carlos Chagas in 1909 who noted cystic

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2015 Informa UK Ltd ISSN 1747-6348 171

 Review Liebling, Rubio & Ie
organisms in the lungs of guinea pigs infected with Trypanosoma
cruzi, but incorrectly identified them as part of a sexual stage of
the trypanosome life cycle. Two years later, Antonio Carini also
misclassified these cystic organisms that he found in rat lungs.
However, it was correctly categorized by Drs. Delonae and
Delanoe in 1912 and was later named Pneumocystis carinii in
honor of Antonio Carini [5]. The organism was later found in
limited numbers in premature and debilitated or malnourished
infants and young children [1,2]. Then, it was again reported in
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the 1970s in children with acute lymphoblastic leukemia (ALL)
and has since also been identified in many other conditions
associated with immunosuppression, including Hodgkins dis-
ease, rhabdomyosarcoma and severe combined immunodefi-
ciency syndrome. The incidence of PJP in these previously
mentioned disorders was noted to be greater than 20% prior to
the initiation of routine prophylaxis [1,3,4,6]. Patients with alloge-
neic stem cell transplant (hematopoietic stem cell transplanta-
tion) as well as patients with solid organ transplants on
immunosuppression had an incidence of PJP ranging from 5 to
15%, with solid organ transplant percentages varying depending
on the transplanted organ. For example, heart-lung transplant
recipients and heart transplant recipients experienced rates as
high as 25 and 41%, respectively [13,714]. However, it was not
until the AIDS epidemic that this organism was under intense
For personal use only.
scrutiny with respect to risk factors, epidemiology, diagnosis,
treatment and prevention. In regards to its evolution in identifi-
cation and nomenclature, the organism was first classified as a
protozoan until the 1980s when it was determined to be a fun-
gus based on its composition [15]. Then, Frenkel proposed a
new name for the pathogen that caused P. carinii pneumonia in
humans, in honor of Otto Jiroveci, the Czech parasitologist
who is credited with describing the microbe in man [16], and
referred it as P. jirovecii.
Pathophysiologic associations of PJP
When considering immunosuppression, there appears to be a
possible pathophysiologic association between P jirovecii and
the use of exogenous corticosteroids. In a study from Memorial
Sloan Kettering Cancer Center, 1.3% of patients who were
administered corticosteroid therapy for primary central nervous
system tumors acquired PJP [3,17]. This highlights the concept
that the use of exogenous corticosteroids may predispose a
patient to PJP in a dose-dependent fashion, with the median
maximum corticosteroid dose being 80 mg of Prednisone
(range, 15480 mg) and the median length of time of cortico-
steroid administration being 3 months (range, 148 months) in
113 patients in this study. An additional 3 patients who
acquired PJP had endogenous corticosteroid production due to
an adrenocorticotropic hormone or cortisol-producing tumor.
It should be noted, however, that in patients with adrenocorti-
cotropic hormone or cortisol-producing tumor, the endogenous
corticosteroid level was not specifically equated to a particular
dose of exogenous steroid [17]. Furthermore, it was found in
another study of 23 patients with endogenous Cushings syn-
drome with an elevated plasma cortisol level (>121 g/dl, with
172
a normal range 522 g/dl) that these patients were at increased
risk of PJP compared to contracting other opportunistic infections
such as aspergillosis and cryptococcosis [3,18].
Physiologically, corticosteroid use has been demonstrated to
significantly affect host immunological defenses, thus increasing
the susceptibility to PJP. In a study of rats, it was noted that
with courses of cortisone acetate injection subcutaneously
biweekly for up to 8 weeks, the host had redistribution of
peripheral lymphocytes that adversely affected destruction of
PJP, and also the amount of lymphocytes produced by the mar-
row was decreased leading to both a qualitative and quantitative
reduction in lymphocyte action against the pathogen [3,1922]. In
humans, the distribution and number of circulating T-helper
lymphocytes has been shown to markedly decrease with cortico-
steroids, even after administration of 5 mg of Prednisone. Also,
to a lesser extent, a reduction in counts of cytotoxic T-cells and
B-cells was noted [23], with the depressed macrophage function
related to corticosteroid use [24] thought to be related to the
suppression of cytokines [25].
It has also been cited in the literature that malnutrition may
play a role in the predisposition of a patient in contracting
PJP, especially in the context of corticosteroid therapy. In the
Sprague-Dawley rat model of PJP, it was demonstrated that
animals on a low-protein diet as opposed to well-nourished
controls developed infectious pneumonitis in 68 weeks of
immunosuppression, with corticosteroids being the most fre-
quent causative agent when compared to Chlorambucil, Cyclo-
phosphamide and Methotrexate [24,26,27]. It is believed that
malnourishment may further be a contributing factor to the
acquisition of PJP due to a lack of antibody-mediated immu-
nity in this state [27]. The authors will discuss exogenous corti-
costeroids as lone immunosuppressant agents and their effect
on predisposition to PJP in this paper; other immunosuppres-
sant agents and related PJP acquisition will not be addressed
or reviewed.
Predisposition to P. jirovecii & corticosteroid
dosing & duration
There is a poor understanding of what is the minimum dose
and duration of corticosteroids that may constitute a significant
risk of a patient acquiring PJP, as this has not been definitively
determined in the literature and actually varies greatly among
sources. Some believe that patients who receive an equivalent
of at least 20 mg of Prednisone a day for over a month should
receive PJP prophylaxis [1]. Others have noted that a median
daily dose of 30 mg of Prednisone or the equivalent for
12 weeks is a significant risk factor, which seems to be better
supported in the literature [28,29]. This is also the dose and
duration which we, the authors, consider to represent high
dose and chronic for the purposes of discussion in this paper.
However, according to one case series at Mayo Medical Cen-
ter, 25% of patients who received as little as 16 mg of Predni-
sone daily over a course of only 8 weeks developed PJP [29].
Some disorders that have been cited as having a higher predi-
lection at these relatively low corticosteroid doses include
Expert Rev. Respir. Med. 9(2), (2015)
 Prophylaxis for Pneumocystis jiroveci pneumonia
malignant conditions such as ALL, chronic lymphocytic leuke-
mia, and non-Hodgkins lymphoma; organ transplantation;
and inflammatory disorders such as giant cell arteritis, granulo-
matosis with polyangiitis (GPA, formerly Wegeners granulo-
matosis) and glomerulonephritis, among others [29].
Unfortunately, studies have not sufficiently investigated the
role of routine prophylaxis in many respiratory disorders that
may often require what can be considered high-dose, prolonged
corticosteroid therapy, such as sarcoidosis, cryptogenic organiz-
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ing pneumonia, interstitial lung disease (ILD), asthma and
chronic obstructive pulmonary disease (COPD). There is some
study regarding polyangiitis with granulomatosis, which, though
limited, has been more integrally associated with a heightened
predisposition to PJP than the other previously mentioned
respiratory disorders [30].
Hence, the benefit of PJP prophylaxis poses a clinical chal-
lenge in the setting of scarcity of established data. This can be
especially problematic in that prophylactic therapy using tri-
methoprim/sulfamethoxazole (the preferred agent) carries a risk
for significant side effects. These can include skin rashes, which
at times have been life-threatening (StevensJohnson syndrome
being rarely reported), as well as fever, hepatitis, renal failure,
hyperkalemia and myelosuppression [1,3,28]. Therefore, the risk/
benefit ratio of prophylaxis must be carefully considered when
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prescribing this agent to prevent P. jirovecii.
It has been noted that PJP has rarely occurred in asthmatics
who were receiving at least 20 mg of Prednisone daily for disease
maintenance. It is thought that this is because asthma is not an
immunologic disorder [1,28,31]. One of these instances is that of a
case report of a life-long asthmatic on Methylprednisolone at a
dose of 32 mg every other day who experienced not one, but
two separate episodes of PJP 8 years apart. Following her first
episode, she was not noted to be on secondary prophylaxis for
PJP of any type. She was successfully treated with trimethoprim/
sulfamethoxazole and stress dose steroids (Methylprednisolone
125 mg every 6 h). Following completion of her 21-day
course, she was placed on trimethoprim/sulfamethoxazole pro-
phylaxis and did not show recurrence during 16 months of
follow-up [25].
In a report of two cases of HIV-negative patients with GPA
(formerly Wegeners granulomatosis) who acquired PJP, both
patients were noted to be malnourished (defined as serum albu-
min <31 g/l and body mass index <20 kg/m2) and both
received steroids of dosage >40 mg/day for more than 6 weeks.
However, it should be noted that both patients were also
receiving Cyclophosphamide 100 mg/day as additional immu-
nosuppressive therapy, which can suppress CD4+ T-lympho-
cytes [30]. The notion of predisposition to PJP due to
corticosteroids as a component of the immunosuppressive regi-
men (either with or without additional immunosuppressant
agents such as Cyclophosphamide) in patients with GPA was
also explored by Ognibene et al. In this retrospective chart
review, there were 11 cases of PJP out of 180 patients with
GPA who received daily corticosteroid therapy (range of doses
being 60 mg/day to 60 mg alternating with 5 mg every other
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Review
day) either alone or in combination with Cyclophosphamide.
Interestingly, PJP did not occur in any patient on Cyclophos-
phamide alone for immunosuppression. Thus, it was theorized
that the more dominant and detrimental risk factor for PJP
acquisition was the profound lymphocyte and monocyte
functional abnormalities particularly induced by corticoste-
roid therapy [30]. Related to this, Saito et al. evaluated
29 patients with various connective tissue disorders and it
was noted that there was a higher incidence of PJP in those
receiving greater than 30 mg/day of Prednisone with or with-
out additional immunosuppressants [32].
Acquisition of PJP during steroid tapering while the patient
was only on corticosteroid therapy has been described in the
literature, such as in patients with primary brain tumors [33]. In
one of the patients, PJP developed as the dosage of corticoste-
roid was tapered to 20 mg/day [26]. The exact mechanism as to
why this occurs is unclear, although it could be postulated that
as corticosteroids are tapered, PJP may be more likely to be
expressed as a result of the resurgence of the immune system.
Also, there has been a report of PJP in an HIV-negative
patient with rapidly progressive glomerulonephritis requiring
pulse Methylprednisolone at a dose of 30 mg/kg administered
intravenously over 6 days, with subsequent oral taper to Pred-
nisone 80 mg every other day which was then rapidly reduced
by 20 mg every 2 weeks. The patient was eventually placed on
a maintenance dose of Prednisone 15 mg daily, at which point
he was diagnosed with PJP after he developed acute onset of
shaking chills, rigors, fever and dyspnea with profound hypox-
emia and bilateral diffuse interstitial densities on chest imaging.
The development of PJP in this patient with no other recog-
nized risk factors for the disease was thought to be primarily
due to the significant suppressive effect of corticosteroids on
cellular immunity [34]. Attention should be rendered to case
reports of PJP that has occurred in the context of pulse corti-
costeroids and plasmapheresis in patients with rapidly progressive
glomerulonephritis, with plasma exchange further predisposing
to immunodeficiency through the process of removal of up to
30% of immunoglobulins and complement components; thus,
this combination further adversely affects both cell-mediated and
humoral immunity [35].
Differences in disease manifestations in HIV-negative &
HIV-positive patients
The clinical manifestations of PJP in HIV and/or AIDS-
infected individuals may differ considerably when compared to
those patients without HIV and/or AIDS. Animal models have
demonstrated that low numbers of P. jirovecii organisms can
activate alveolar macrophages, increase the levels of pro-
inflammatory interleukins, as well as induce changes in surfac-
tant components [3638]. Two major factors that contribute to
the virulence of PJP include the number of pathogenic organ-
isms and the amount of inflammation present in the lung. In a
study by Limper et al. of 75 patients with and without HIV/
AIDS investigating how PJP can affect these varying popula-
tions, patients with PJP and HIV/AIDS had more P. jirovecii
173
 Review Liebling, Rubio & Ie
organisms and fewer neutrophils in the lung on bronchoalveo-
lar lavage (BAL) than those with PJP without HIV/AIDS. It
has been speculated that the higher amount of lavage neutro-
phils is indicative of a more pronounced inflammatory response
rather than the actual number of organisms and is associated
with greater impairment of gas exchange and lower patient sur-
vival [39]. This is also consistent with the clinical evidence for
improved oxygenation with the use of steroid therapy during
early active PJP [40,41]. Also, this lower amount of neutrophils
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in the BAL of HIV/AIDS patients correlated with higher arte-
rial oxygen tension and, thus, a less-extensive inflammatory cas-
cade contributing to hypoxemic respiratory deterioration [40,41].
Therefore, the clinical course of PJP in patients with and
without HIV/AIDS can be quite different. Patients with HIV/
AIDS have a disease course that is notably subtle with subacute
and progressive non-productive cough, dyspnea, malaise and
low-grade fever that develops over several weeks. In fact, in
patients with HIV/AIDS presenting with purulent sputum
along with rigors or night sweats, PJP should be considered as
an alternate diagnosis to routine bacterial pneumonia or tuber-
culosis. There have even been reports of PJP presenting initially
with asthma-like symptoms, including daily cough, daytime
and nocturnal wheezing and nasal congestion, along with
fatigue and low-grade fever in a patient with HIV infection,
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being later diagnosed with PJP on transbronchial biopsy [42].
In contrast, patients without HIV/AIDS and PJP have a
more severe course, with acute respiratory failure in up to 43%.
Mortality in these patients can reach up to 40%, which is twice
as high as in patients with HIV/AIDS with PJP [29,43,44]. Also,
in another retrospective study it was demonstrated that there
was a higher risk of failure of non-invasive mechanical ventila-
tion, more days spent on the ventilator with greater require-
ments of positive-end expiratory pressure and fraction of
inspired oxygen, as well as overall increased severity of illness
and mortality in HIV-negative patients versus HIV-positive
patients [45]. Thus, it has been discerned that patients without
HIV/AIDS and PJP may have a paradoxical increase in mor-
bidity and mortality due to their enhanced inflammatory
response as a result of their more intact immune system [2,4648].
However, it has been also retrospectively demonstrated that a
low clinical suspicion and under-recognition of the need for
early empiric therapy in HIV-negative immunosuppressed
patients with PJP, despite presentation and imaging consistent
with the disease, may result in a treatment delay and further
contribute to higher mortality in this population [49].
The impact of infection versus colonization
The concept of infection versus colonization in various disease
states may reflect unrealized interhuman transmission of the
organism. In a prospective study of 91 patients, 82 of whom
were HIV negative and 9 were HIV positive, 13 of the HIV-
negative patients and 1 of the HIV-positive patients were con-
sidered to be colonized with PJP as the organisms DNA was
detected in BAL in the absence of clinical signs or symptoms.
There is suggestion by the authors that these patients may be
174
potentially underappreciated reservoirs of PJP and, thus, may
somehow contribute to increasing the incidence of the disease
in a hospital environment. Of note, colonized HIV-negative
patients included five patients with either corticosteroid-treated
or untreated sarcoidosis or asthma [50]. Also, there have been
cases related to probable contact in treatment and/or waiting
rooms. These were detected in renal transplant patients visiting
outpatient facilities which, in some sporadic cases, may have
been shared by HIV-positive patients who recently or currently
have had PJP [5153]. Also, there have been reports of coloniza-
tion in immunocompetent healthcare workers due to occupa-
tional contact with patients with PJP [54]. These infer and raise
concern for possible occult sources for disease outbreaks via
airborne droplets.
Colonization with PJP has also been demonstrated by PCR
testing in up to 33.8% of patients with ILD who required
bronchoscopy and BAL for suspicion of the disease and were
not on corticosteroids at the time of their procedure. The
authors also postulated that the organisms ability to incite an
avid inflammatory response could be integrally involved in the
pathogenesis of ILD and its progression to fibrosis [36,55]. Also,
there have been prospective studies using various serum markers
for PJP, such as b-D-glucan, along with peripheral lymphocyte
counts for detecting PJP colonization in patients with ILD,
with a higher rate of colonization noted with systemic steroid
use (defined as Prednisone >5 mg/day). In this population, PJP
colonization was noted to be as high as 23.3% in the corticoste-
roid therapy group [56]. Knowing if a patient is colonized with
PJP and considering this pathogen as a potential cause of an
exacerbation may be important as the mortality rate of ILD
exacerbations is known to be extremely high (78% after hospital
admission) [57].
Recently, information has been emerging in regards to the
role of PJP in COPD, being not only an acute infectious path-
ogen but also a colonizer [58,59]. Organisms including Strepto-
coccus pneumoniae and Haemophilus influenzae are frequent
colonizers of the lower respiratory tract of COPD patients, in
addition to Pseudomonas aeruginosa.
Although these microbes are known to be formidable when
associated with acute COPD exacerbations, their colonization
may also be a marker of severity of disease in the stable COPD
patient. This could relate to the degree of obstruction, with
other factors such as current smoking status contributing to
impaired mucociliary clearance and, hence, S. pneumonia and
H. influenza infections [6063]. Also, various other organisms
such as Aspergillus fumigatus, Candida sp. and Mycobacterium
xenopi have been documented as being lung colonizers in
COPD. A. fumigatus has been associated with the use of Pred-
nisone at a dose of >60 mg daily in the context of COPD,
conferring a high risk of morbidity and mortality [64]. Further-
more, there have case reports of Candida bronchitis causing
morbidity and mortality in patients with obstructive lung dis-
ease with or without chronic corticosteroid therapy, in addition
to the established association of Candida albicans colonization
and the development of P. aeruginosa ventilator-associated
Expert Rev. Respir. Med. 9(2), (2015)
 Prophylaxis for Pneumocystis jiroveci pneumonia
pneumonia in a critical care setting [65,66]. Conversely, M. xen-
opi has been frequently isolated from HIV patients and is usu-
ally non-pathogenic [67].
Carriage of P. jirovecii has also been noted to correlate with
disease severity due to various inflammatory mechanisms
involving elevated CD8+ cells and avid neutrophilic infiltration
of the lung by a mechanism independent of smoking [6873]. It
has been demonstrated that patients with COPD and PJP col-
onization had higher circulating levels of TNF-a, IL-6 and
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IL-8 than COPD patients without carriage of PJP [74,75]. These
pro-inflammatory markers, especially TNF-a, are widely
accepted as important factors in the progression of COPD in
respect to the development of cachexia and malnutrition,
which, as previously noted, may also play a role in PJP acqui-
sition. A study by Morris et al. utilized PCR to identify DNA
via BAL on bronchoscopy indicative of asymptomatic carriage
in a collection of COPD subjects. Their findings revealed that
36.7% of patients with severe COPD, classified as Stage IV
according to Global Health Initiative on Obstructive Lung
Disease criteria, were colonized with PJP compared to only
5.3% of those with less severe COPD (stages IIII) [68]. In this
study, colonization was also independent of the use of cortico-
steroids. However, data from other studies suggest not only an
increased risk of infection but also an augmented risk of colo-
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nization with the use of corticosteroids [76]. In a study by
Maskell et al., up to 44% of patients on Prednisone at a dose
of >20 mg/day of varying durations, both noted to be short
and long as per the authors, were found to have detectable
P. jirovecii organisms on bronchoscopic BAL, as opposed to
only 13% in patients who were not on corticosteroids [76].
Interestingly, in this study, COPD was not determined to be a
risk factor for PJP colonization [76]. Therefore, in light of
inconsistent data, it is certainly difficult to discern if PJP is
the cause of worsening COPD or if worsening COPD is a
predisposing factor leading to colonization by this organism as
a result of the increased exposure to corticosteroid therapy
associated with more severe disease. This may be a further
confounder in determining indications for PJP routine prophy-
laxis in these patients and requires more clarification.
The role of monitoring CD4+ count
In patients with HIV and/or AIDS, PJP prophylaxis is indi-
cated when CD4+ counts become less than 250 cells/l. The risk
of PJP in HIV and/or AIDS can be up to 75% compared to
the previously mentioned 40% in organ transplant recipients
and those receiving chemotherapy for malignancies [1,7782].
P. jirovecii has been demonstrated in a retrospective chart review
of 10 allogeneic stem cell transplant (hematopoietic stem cell
transplantation) patients, with infection being a late complica-
tion (greater than 6 months following transplantation) in those
who had their prophylactic regimen (all except one being tri-
methoprim/sulfamethoxazole) discontinued due to various rea-
sons, including toxicity and intolerance of the medication. In
the eight subjects for whom CD4+ counts were available, the
counts were <200 cells/l [83]. An interesting connection with
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Review
decreased CD4+ counts, especially in renal transplant patients,
has been described. CD4+ T-lymphocytopenia is a common
immunodeficiency in these patients. However, the specifics of
this predilection in this population compared to other trans-
plant patients, such as those receiving allogeneic hematopoietic
stem cell transplantation, remain undefined [84]. In an addi-
tional retrospective study by Overgaard and Helweg-Larsen,
a higher risk of acquiring PJP was associated with corticoste-
roid use and lymphopenia (CD4+ count <300 cells/l) in
HIV-negative patients with hematological malignancy (non-
Hodgkins and Hodgkins lymphomas, ALL, among others),
inflammatory diseases including vasculitis (otherwise undefined
in the study), lung and liver solid organ transplantation, and
other conditions associated with immunodeficiency such as
severe combined immunodeficiency syndrome. Nevertheless,
only a small amount of CD4+ counts was available for the
subjects, and thus, recommendations for using CD4+ as a tool
for identification for PJP risk and need for prophylaxis was
not confirmed according to the authors. Interestingly, in this
study, overall mortality attributable to P. jirovecii was strongly
correlated with delayed diagnosis and treatment [85].
In a study of HIV-negative patients with an array of condi-
tions treated with corticosteroids and/or an additional immuno-
suppressive agent, including one patient with sarcoidosis on
corticosteroids and Methotrexate, PJP infection was associated
with markedly depressed CD4+ counts (<300 cells/l) similar to
HIV-positive patients, which indicated PJP prophylaxis [86]. In
an additional study by Nevez et al. that included asthma and
sarcoidosis patients, it was noted that only those with sarcoido-
sis had PJP detected on BAL, with these showing low CD4+
counts (<400 cells/l) as well as a reduced CD4+/CD8+ ratio of <1.
However, the CD4+ counts and CD4+/CD8+ ratio were obtained
retrospectively and not all CD4+ counts and CD4+/CD8+ ratios
were available for all colonized patients in the study [87].
Furthermore, the association of sarcoidosis and idiopathic
CD4+ cell T-lymphocytopenia with PJP has been described in
a case study of an asymptomatic young homosexual male
presenting with anal condylomata with incidental findings of
diffuse nodular shadowing and hilar lymphadenopathy on
imaging. He underwent bronchoscopy with BAL notable for
PJP on blue toluidine O stain as well as non-caseating granulo-
mas on transbronchial biopsy consistent with sarcoid. He under-
went an exhaustive work-up which was persistently negative,
including repeated negative HIV testing; however, CD4+ count
was consistently <300 cells/l without a discernible cause and was
thus deemed idiopathic. It is unknown whether the pulmonary
sarcoidosis occurred before or after CD4+ cell depletion, postu-
lated to be due to CD4+ cell compartmentalization at sites of
disease that result in peripheral lymphocytopenia [88].
These small studies and case reports seem to suggest the
possible utility in measuring CD4+ counts in HIV-negative
patients to stratify their risk to develop either asymptomatic or
active P. jirovecii infection [89]. However, this may differ
according to the type of respiratory disorder. Data have indi-
cated that the immunopathology of COPD with tobacco use
175
 Review Liebling, Rubio & Ie
may also entail a low CD4+/CD8+ ratio by virtue of the
inflammatory pathophysiology of the disease [90]. There have
been further conflicting data in that patients with chronic lung
disease, such as COPD, may have higher peripheral lymphocyte
and mean CD4+ lymphocyte counts in the context of coloniza-
tion theorized to be due to an exacerbation of the underlying
chronic bronchitis [58]. It seems that implementing CD4+ count
and CD4+/CD8+ ratio measurement in PJP standards of care
for non-HIV infected patients requires larger patient popula-
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tion studies and more extensive investigation in regards to their
role in the natural course of the patients respective disease,
as well as their value in determining the actual occurrence of
PJP infection and/or colonization and, hence, the need for
prophylaxis.
Trimethoprim/sulfamethoxazole as the agent of choice
for prophylaxis
In regards to the efficacy of trimethoprim/sulfamethoxazole, a
study by Hughes et al. demonstrated a significant difference in
the incidence of PJP in children with ALL with the agents use.
The drugs administered were 150 mg/m2/day of trimethoprim
and 750 mg/m2/day of sulfamethoxazole in 80 children in the
experimental group, and placebo was given to another 80 chil-
dren. The result was that PJP occurred in 17 of the 80 (21%)
For personal use only.
patients receiving placebo, compared to none of the patients
from the experimental group [4,6]. Subsequent studies have noted
that administration of this agent for three consecutive days per
week is as effective as daily administration in preventing PJP
with no higher incidence of associated adverse effects [4]. This is
similar to the current CDC/Infectious Diseases Society of Amer-
ica guidelines for prophylactic trimethoprim/sulfamethoxazole
regimens for adult patients with HIV/AIDS [77]. The authors
will not discuss the other agents used for PJP prophylaxis in
this paper.
In a systematic review and meta-analysis of 12 randomized
controlled trials examining PJP routine prophylaxis in immu-
nocompromised non-HIV and/or AIDS-infected subjects, the
authors investigated the risk/benefit ratio in regards to the use
of trimethoprim/sulfamethoxazole in various populations,
including those patients on chronic, high-dose corticosteroids,
with a dose and duration of 30 mg of Prednisone or the equiv-
alent for 12 weeks being a significant risk factor for acquisition
of PJP [28,29]. The number needed to treat (NNT) was 110 in
this population. This was compared to more specific immuno-
compromised populations including allogeneic bone marrow
transplant, ALL, solid organ transplants and severe combined
immunodeficiency syndrome, all of which had an NNT of 11.
Other conditions, such as GPA and rhabdomyosarcoma, for
example, had an NNT of 32. When the NNT is balanced with
the number needed to harm (or the number needed to cause
severe adverse effects requiring treatment discontinuation), it
was demonstrated that trimethoprim/sulfamethoxazole should
be considered when the anticipated risk for PJP is at least
3.5% through the period of immunodeficiency, as in the disor-
ders given above [28]. This may imply that the underlying
176
immunological mechanisms and processes of the immunocom-
promised state may have an overall profound impact on a
patients need for prophylaxis, as this may confer higher suscep-
tibility to PJP apart from use of 30 mg of Prednisone or the
equivalent for 12 weeks, as compared to other conditions.
However, despite this, the role of routine prophylaxis even in
these subgroups remains debated and may be warranted only in
a few selected patients based on careful consideration of the
risk/benefit ratio, as mentioned above.
Diagnostic considerations
In the proper setting of a clinical picture of fever, dyspnea,
cough, hypoxemia and radiographic findings consistent with
bilateral pulmonary infiltrates, PJP should be suspected, with
confirmation requiring microscopic findings of the organism
with cytochemical procedures (such as Gomori methenamine
silver stain or Giemsa stain) or immunocytochemical staining.
Unfortunately, in certain cases, PJP may also present with atyp-
ical findings and particularly under any condition of immuno-
suppression, such as with chronic steroid therapy, PJP should
also be considered, especially when more common etiologies do
not prove causal. In many cases, confirmation will require
fiberoptic bronchoscopy with BAL, which has a sensitivity of
>90% [91,92] and is the usual procedure of choice for the diag-
nosis of PJP in HIV-positive patients. A much less-costly and
less-invasive method to diagnose PJP pneumonia is sputum
induction with a diagnostic accuracy ranging from 25 to
90% [91,92]. Unfortunately, in the HIV-negative patient, diag-
nosing PJP pneumonia may become more difficult due to the
lower pathogen burden and airway colonization with PJP,
which further lowers the specificity. Unlike the HIV-positive
patients, bronchoscopy and BAL shows a much lower sensitiv-
ity, ranging from 38 to 53%, in an HIV-negative patient [93,94].
One can increase the sensitivity to diagnosing PJP in the HIV-
negative patient by performing PCR, thus hopefully preventing
the need for further invasive procedures such as pulmonary
biopsies. It is recommended that patients with a high clinical
suspicion for PJP and a positive PCR result be treated for
PJP, although the PCR does not differentiate PJP colonization
from active infection. At some point, quantitative PCR may
help to differentiate PJP colonization from active infection.
PCR has a high negative predictive value [93,94]; therefore, a neg-
ative PCR can allow one to exclude PJP with a high degree of
certainty. Further, it can take up to 310 days to get the results
of the PCR back. Finally, 1,3 b-D-glucan is a potential tool for
screening for PJP infection, with a reportedly high sensitivity
and good specificity of 94.8 and 86.3%, respectively [95,96].
Five-year view & expert commentary
In general, the available evidence of how much steroid is too
much and how long is too long to predispose an otherwise
immunocompetent patient to the risk of developing PJP and,
in turn, assess who will require routine prophylaxis remains a
real and present clinical challenge now and will remain so even
in the next 5 years. Also, as discussed, PJP may carry a
Expert Rev. Respir. Med. 9(2), (2015)
 Prophylaxis for Pneumocystis jiroveci pneumonia Review

Table 1. Key differences in clinical manifestations, diagnostic strategies and outcome in HIV-positive and
HIV-negative patients with Pneumocystis jirovecii pneumonia.
HIV-positive patients with PJP HIV-negative patients with PJP
Clinical manifestations Insidious, subacute disease often with Acute severe disease, often with
hypoxemia responsive to non-invasive pronounced hypoxemic respiratory failure,
ventilation with higher requirements in PEEP and
FiO2 and unresponsive to non-invasive
ventilation [74]
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15

Amount of organisms/neutrophils on More P. jirovecii organisms and fewer Higher amount of lavage neutrophils
bronchoalveolar lavage neutrophils in the lung on bronchoalveolar indicative of a more pronounced
lavage inflammatory response associated with
greater impairment of gas exchange and
lower patient survival [35]
Use of CD4+ count in determining the Indicated with CD4+ <250 cells/l No guidelines to support use of CD4+
need for prophylaxis count in determining the need for
prophylaxis
Suspicion of diagnosis based on clinical Likely high if HIV status is known Likely low if HIV negative status despite
manifestations other possible risk factors for
immunosuppression, which may lead to
delayed diagnosis and treatment and, thus,
higher mortality [78]
FiO2: Fraction of inspired oxygen; PEEP: Positive-end expiratory pressure; PJP: Pneumocystis jirovecii pneumonia.
For personal use only.

significantly more severe course leading to increased mortality
in the host that does not have HIV and/or AIDS, not only by
virtue of the pathogenesis of the disease in the HIV-negative
host but also due to a lack of early recognition for the condi-
tion and, hence, a delay in therapy. For these reasons, one
could argue that prophylaxis in the HIV-negative population
susceptible to PJP due to alternate risk factors for immunosup-
pression is even more important; unfortunately, the available
small prospective and retrospective studies and case reports
merely propose rather than prove this. It seems logical that
when taking into consideration the safety profile as well as the
noted good response of sulfamethoxazole/trimethoprim in effec-
tively preventing active PJP, identifying these patients in jeop-
ardy is a reasonable approach in order to optimize this care.
Unfortunately, there is an astounding deficiency of adequate
and reproducible data to appropriately address this issue.
Needless to say, more intensive investigation is warranted as
PJP remains a major cause of morbidity and mortality in HIV-
negative and HIV-positive patients alike. As it stands, based on
the current available literature, there seems to be an indication
for PJP prophylaxis in adult non-HIV infected populations
such as those with primary immune deficiency diseases, severe
protein malnutrition, those who have undergone allogeneic
bone marrow transplantation or organ transplants, using 160/
800 mg of trimethoprim/sulfamethoxazole by mouth three-
times a week or daily [28]. However, we cannot make a strong
recommendation for PJP routine prophylaxis in other non-
HIV infected populations, particularly in regards to primary
chronic respiratory disorders such as asthma and COPD, as
well as other pulmonary conditions including sarcoidosis, cryp-
togenic organizing pneumonia and ILD that may necessitate
chronic high-dose corticosteroid therapy (being defined by the
use of a median daily dose of Prednisone 30 mg or the equiva-
lent for 12 weeks or longer [28,29]). In these cases, associated
co-morbidities such as malnutrition should be taken into con-
sideration when assessing the need for prophylactic therapy. In
regards to patients with ILD and COPD, one could entertain
the possibility of infection versus colonization by P. jirovecii
and whether the latter may actually be more of an active player
rather than an innocent bystander. Whether treatment for this
is warranted is an unanswered question that needs further
research, which may become a focus of study in the next 5 years
as diseases such as ILD and, especially, COPD have become a
more prominent public concern and pervasive healthcare issue.
Finally, to further distinguish those who are more likely predis-
posed to developing PJP, one could also consider obtaining a
CD4+ level to better stratify their risk, but this has not been
convincingly established in HIV-negative patients with
various respiratory disorders such as sarcoidosis, asthma and
COPD (TABLE 1). Hopefully, as more studies are performed and
consistent data collected, there will be a better understanding as
to why certain populations are at higher risk for contracting
PJP, and with further testing, we will be able to identify those
non-HIV infected patients who need prophylaxis.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

informahealthcare.com 177
 Review Liebling, Rubio & Ie

Key issues
. Prophylaxis has had a major impact in reducing the incidence of Pneumocystis jirovecii pneumonia (PJP) in patients with HIV and/or
AIDS, but such practice is not routine in patients without these disorders who may have a compromised immune state, as there are no
published guidelines regarding the need for PJP prophylaxis (i.e., trimethoprim/sulfamethoxazole as the agent of choice) in HIV-negative
patients.
. When considering immunosuppression, there appears to be a possible pathophysiologic association between P. jirovecii and the use of
exogenous corticosteroids, especially at a median daily dose of 30 mg Prednisone or the equivalent for 12 weeks according to the litera-
ture; nonetheless, there remains a poor understanding of what is the minimum dose and duration of corticosteroids that may constitute
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15

a significant risk of a patient acquiring PJP.

. Various disorders have been cited as having a higher predisposition at these relatively low corticosteroid doses; however, studies have
not sufficiently investigated the role of routine prophylaxis in many respiratory disorders that may often require similar high-dose, pro-
longed corticosteroid therapy, such as sarcoidosis, cryptogenic organizing pneumonia, interstitial lung disease, asthma and chronic
obstructive pulmonary disease (COPD).
. The benefit of PJP prophylaxis poses a clinical challenge in the setting of a scarcity of data in that the use of trimethoprim/
sulfamethoxazole (the preferred agent) carries a risk for significant side effects including skin rashes (with the most severe Stevens
Johnson syndrome being rarely reported), fever, hepatitis, renal failure, hyperkalemia and myelosuppression.
. The clinical manifestations of PJP in HIV and/or AIDS-infected individuals may differ considerably when compared to those patients
without HIV and/or AIDS, and it has been recognized that patients without HIV/AIDS and PJP may have a paradoxical increase in mor-
bidity and mortality due to their enhanced inflammatory response as a result of their relatively more intact immune system as opposed
to the more subtle, smoldering disease presentation seen in patients with HIV/AIDS. Also, delayed diagnosis and treatment may play an
integral role in increased mortality due to PJP in HIV-negative patients.
. Data have been emerging in regards to the role of PJP in Stage IV COPD, being not only an acute infectious pathogen but also a
For personal use only.

colonizer, which may make it difficult to discern if PJP is the cause of worsening COPD or if worsening COPD is a predisposing factor
leading to the colonization; thus, this may further confound indications for PJP routine prophylaxis in these patients.
. In patients with HIV and/or AIDS, PJP prophylaxis is indicated when CD4+ counts become less than 250 cells/l; however, the utility in
measuring CD4+ counts in HIV-negative patients to stratify their risk to develop either asymptomatic or active P. jirovecii infection has
not been clearly defined or definitively supported.
. It is imperative that more studies be performed to obtain a better understanding as to why certain HIV-negative populations are at
higher risk for PJP, in order to identify those patients who need prophylaxis, hopefully leading to the establishment of clinical guidelines
as the standard of care.

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