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Review

Prophylaxis for Pneumocystis


jiroveci pneumonia: is it
a necessity in pulmonary
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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.

without HIV and/or AIDS who are potentially predisposed to PJP, including patients with
Department of Pulmonary, Critical Care,
and Sleep Medicine, Carilion Clinic, P.O.
sarcoidosis, cryptogenic organizing pneumonia, interstitial lung disease, asthma and chronic
Box 13367, Roanoke, VA 24033, USA obstructive pulmonary disease, who may require high dose of prolonged corticosteroids for
*Author for correspondence: disease maintenance or to prevent relapses. In this review, the authors examine the available
Tel.: +1 540 853 0186 literature regarding prophylaxis in these groups, elaborate on the pathogenesis of PJP, when
Fax: +1 540 983 1133
Maryjane_Liebling@yahoo.com 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- pulmonary disease but without HIV and/or
sidered in those with known immunosuppres- AIDS, who may still be at risk for developing
sive disorders, such as HIV or AIDS, these PJP secondary to corticosteroid treatment. To
organisms may also be present in normal better understand the issues, we also review the
hosts undergoing immunosuppressive ther- pathophysiology of PJP in both HIV-positive
apy [1,2]. Prophylaxis has had a major impact and HIV-negative patients and the current
in reducing the incidence of Pneumocystis jiro- accepted indications for prophylaxis. In this
vecii pneumonia (PJP), but such practice is not regard, we will focus this part of the discus-
routine in patients without HIV/AIDS who sion on the use of trimethoprim/sulfamethoxa-
may have a compromised immune state [3,4]. zole, the agent of choice.
Furthermore, there are no published guidelines
regarding the need for PJP prophylaxis in Review of the literature
HIV-negative patients necessitating therapy with Historical perspective
corticosteroids. An extensive review of the litera- P. jirovecii is a fungus that was first described
ture is presented, focusing on patients with by Carlos Chagas in 1909 who noted cystic

informahealthcare.com 10.1586/17476348.2015.1002471  2015 Informa UK Ltd ISSN 1747-6348 171


Review Liebling, Rubio & Ie

organisms in the lungs of guinea pigs infected with Trypanosoma a normal range 522 g/dl) that these patients were at increased
cruzi, but incorrectly identified them as part of a sexual stage of risk of PJP compared to contracting other opportunistic infections
the trypanosome life cycle. Two years later, Antonio Carini also such as aspergillosis and cryptococcosis [3,18].
misclassified these cystic organisms that he found in rat lungs. Physiologically, corticosteroid use has been demonstrated to
However, it was correctly categorized by Drs. Delonae and significantly affect host immunological defenses, thus increasing
Delanoe in 1912 and was later named Pneumocystis carinii in the susceptibility to PJP. In a study of rats, it was noted that
honor of Antonio Carini [5]. The organism was later found in with courses of cortisone acetate injection subcutaneously
limited numbers in premature and debilitated or malnourished biweekly for up to 8 weeks, the host had redistribution of
infants and young children [1,2]. Then, it was again reported in peripheral lymphocytes that adversely affected destruction of
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the 1970s in children with acute lymphoblastic leukemia (ALL) PJP, and also the amount of lymphocytes produced by the mar-
and has since also been identified in many other conditions row was decreased leading to both a qualitative and quantitative
associated with immunosuppression, including Hodgkins dis- reduction in lymphocyte action against the pathogen [3,1922]. In
ease, rhabdomyosarcoma and severe combined immunodefi- humans, the distribution and number of circulating T-helper
ciency syndrome. The incidence of PJP in these previously lymphocytes has been shown to markedly decrease with cortico-
mentioned disorders was noted to be greater than 20% prior to steroids, even after administration of 5 mg of Prednisone. Also,
the initiation of routine prophylaxis [1,3,4,6]. Patients with alloge- to a lesser extent, a reduction in counts of cytotoxic T-cells and
neic stem cell transplant (hematopoietic stem cell transplanta- B-cells was noted [23], with the depressed macrophage function
tion) as well as patients with solid organ transplants on related to corticosteroid use [24] thought to be related to the
immunosuppression had an incidence of PJP ranging from 5 to suppression of cytokines [25].
15%, with solid organ transplant percentages varying depending It has also been cited in the literature that malnutrition may
on the transplanted organ. For example, heart-lung transplant play a role in the predisposition of a patient in contracting
recipients and heart transplant recipients experienced rates as PJP, especially in the context of corticosteroid therapy. In the
high as 25 and 41%, respectively [13,714]. However, it was not Sprague-Dawley rat model of PJP, it was demonstrated that
until the AIDS epidemic that this organism was under intense animals on a low-protein diet as opposed to well-nourished
For personal use only.

scrutiny with respect to risk factors, epidemiology, diagnosis, controls developed infectious pneumonitis in 68 weeks of
treatment and prevention. In regards to its evolution in identifi- immunosuppression, with corticosteroids being the most fre-
cation and nomenclature, the organism was first classified as a quent causative agent when compared to Chlorambucil, Cyclo-
protozoan until the 1980s when it was determined to be a fun- phosphamide and Methotrexate [24,26,27]. It is believed that
gus based on its composition [15]. Then, Frenkel proposed a malnourishment may further be a contributing factor to the
new name for the pathogen that caused P. carinii pneumonia in acquisition of PJP due to a lack of antibody-mediated immu-
humans, in honor of Otto Jiroveci, the Czech parasitologist nity in this state [27]. The authors will discuss exogenous corti-
who is credited with describing the microbe in man [16], and costeroids as lone immunosuppressant agents and their effect
referred it as P. jirovecii. on predisposition to PJP in this paper; other immunosuppres-
sant agents and related PJP acquisition will not be addressed
Pathophysiologic associations of PJP or reviewed.
When considering immunosuppression, there appears to be a
possible pathophysiologic association between P jirovecii and Predisposition to P. jirovecii & corticosteroid
the use of exogenous corticosteroids. In a study from Memorial dosing & duration
Sloan Kettering Cancer Center, 1.3% of patients who were There is a poor understanding of what is the minimum dose
administered corticosteroid therapy for primary central nervous and duration of corticosteroids that may constitute a significant
system tumors acquired PJP [3,17]. This highlights the concept risk of a patient acquiring PJP, as this has not been definitively
that the use of exogenous corticosteroids may predispose a determined in the literature and actually varies greatly among
patient to PJP in a dose-dependent fashion, with the median sources. Some believe that patients who receive an equivalent
maximum corticosteroid dose being 80 mg of Prednisone of at least 20 mg of Prednisone a day for over a month should
(range, 15480 mg) and the median length of time of cortico- receive PJP prophylaxis [1]. Others have noted that a median
steroid administration being 3 months (range, 148 months) in daily dose of 30 mg of Prednisone or the equivalent for
113 patients in this study. An additional 3 patients who 12 weeks is a significant risk factor, which seems to be better
acquired PJP had endogenous corticosteroid production due to supported in the literature [28,29]. This is also the dose and
an adrenocorticotropic hormone or cortisol-producing tumor. duration which we, the authors, consider to represent high
It should be noted, however, that in patients with adrenocorti- dose and chronic for the purposes of discussion in this paper.
cotropic hormone or cortisol-producing tumor, the endogenous However, according to one case series at Mayo Medical Cen-
corticosteroid level was not specifically equated to a particular ter, 25% of patients who received as little as 16 mg of Predni-
dose of exogenous steroid [17]. Furthermore, it was found in sone daily over a course of only 8 weeks developed PJP [29].
another study of 23 patients with endogenous Cushings syn- Some disorders that have been cited as having a higher predi-
drome with an elevated plasma cortisol level (>121 g/dl, with lection at these relatively low corticosteroid doses include

172 Expert Rev. Respir. Med. 9(2), (2015)


Prophylaxis for Pneumocystis jiroveci pneumonia Review

malignant conditions such as ALL, chronic lymphocytic leuke- day) either alone or in combination with Cyclophosphamide.
mia, and non-Hodgkins lymphoma; organ transplantation; Interestingly, PJP did not occur in any patient on Cyclophos-
and inflammatory disorders such as giant cell arteritis, granulo- phamide alone for immunosuppression. Thus, it was theorized
matosis with polyangiitis (GPA, formerly Wegeners granulo- that the more dominant and detrimental risk factor for PJP
matosis) and glomerulonephritis, among others [29]. acquisition was the profound lymphocyte and monocyte
Unfortunately, studies have not sufficiently investigated the functional abnormalities particularly induced by corticoste-
role of routine prophylaxis in many respiratory disorders that roid therapy [30]. Related to this, Saito et al. evaluated
may often require what can be considered high-dose, prolonged 29 patients with various connective tissue disorders and it
corticosteroid therapy, such as sarcoidosis, cryptogenic organiz- was noted that there was a higher incidence of PJP in those
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ing pneumonia, interstitial lung disease (ILD), asthma and receiving greater than 30 mg/day of Prednisone with or with-
chronic obstructive pulmonary disease (COPD). There is some out additional immunosuppressants [32].
study regarding polyangiitis with granulomatosis, which, though Acquisition of PJP during steroid tapering while the patient
limited, has been more integrally associated with a heightened was only on corticosteroid therapy has been described in the
predisposition to PJP than the other previously mentioned literature, such as in patients with primary brain tumors [33]. In
respiratory disorders [30]. one of the patients, PJP developed as the dosage of corticoste-
Hence, the benefit of PJP prophylaxis poses a clinical chal- roid was tapered to 20 mg/day [26]. The exact mechanism as to
lenge in the setting of scarcity of established data. This can be why this occurs is unclear, although it could be postulated that
especially problematic in that prophylactic therapy using tri- as corticosteroids are tapered, PJP may be more likely to be
methoprim/sulfamethoxazole (the preferred agent) carries a risk expressed as a result of the resurgence of the immune system.
for significant side effects. These can include skin rashes, which Also, there has been a report of PJP in an HIV-negative
at times have been life-threatening (StevensJohnson syndrome patient with rapidly progressive glomerulonephritis requiring
being rarely reported), as well as fever, hepatitis, renal failure, pulse Methylprednisolone at a dose of 30 mg/kg administered
hyperkalemia and myelosuppression [1,3,28]. Therefore, the risk/ intravenously over 6 days, with subsequent oral taper to Pred-
benefit ratio of prophylaxis must be carefully considered when nisone 80 mg every other day which was then rapidly reduced
For personal use only.

prescribing this agent to prevent P. jirovecii. by 20 mg every 2 weeks. The patient was eventually placed on
It has been noted that PJP has rarely occurred in asthmatics a maintenance dose of Prednisone 15 mg daily, at which point
who were receiving at least 20 mg of Prednisone daily for disease he was diagnosed with PJP after he developed acute onset of
maintenance. It is thought that this is because asthma is not an shaking chills, rigors, fever and dyspnea with profound hypox-
immunologic disorder [1,28,31]. One of these instances is that of a emia and bilateral diffuse interstitial densities on chest imaging.
case report of a life-long asthmatic on Methylprednisolone at a The development of PJP in this patient with no other recog-
dose of 32 mg every other day who experienced not one, but nized risk factors for the disease was thought to be primarily
two separate episodes of PJP 8 years apart. Following her first due to the significant suppressive effect of corticosteroids on
episode, she was not noted to be on secondary prophylaxis for cellular immunity [34]. Attention should be rendered to case
PJP of any type. She was successfully treated with trimethoprim/ reports of PJP that has occurred in the context of pulse corti-
sulfamethoxazole and stress dose steroids (Methylprednisolone costeroids and plasmapheresis in patients with rapidly progressive
125 mg every 6 h). Following completion of her 21-day glomerulonephritis, with plasma exchange further predisposing
course, she was placed on trimethoprim/sulfamethoxazole pro- to immunodeficiency through the process of removal of up to
phylaxis and did not show recurrence during 16 months of 30% of immunoglobulins and complement components; thus,
follow-up [25]. this combination further adversely affects both cell-mediated and
In a report of two cases of HIV-negative patients with GPA humoral immunity [35].
(formerly Wegeners granulomatosis) who acquired PJP, both
patients were noted to be malnourished (defined as serum albu- Differences in disease manifestations in HIV-negative &
min <31 g/l and body mass index <20 kg/m2) and both HIV-positive patients
received steroids of dosage >40 mg/day for more than 6 weeks. The clinical manifestations of PJP in HIV and/or AIDS-
However, it should be noted that both patients were also infected individuals may differ considerably when compared to
receiving Cyclophosphamide 100 mg/day as additional immu- those patients without HIV and/or AIDS. Animal models have
nosuppressive therapy, which can suppress CD4+ T-lympho- demonstrated that low numbers of P. jirovecii organisms can
cytes [30]. The notion of predisposition to PJP due to activate alveolar macrophages, increase the levels of pro-
corticosteroids as a component of the immunosuppressive regi- inflammatory interleukins, as well as induce changes in surfac-
men (either with or without additional immunosuppressant tant components [3638]. Two major factors that contribute to
agents such as Cyclophosphamide) in patients with GPA was the virulence of PJP include the number of pathogenic organ-
also explored by Ognibene et al. In this retrospective chart isms and the amount of inflammation present in the lung. In a
review, there were 11 cases of PJP out of 180 patients with study by Limper et al. of 75 patients with and without HIV/
GPA who received daily corticosteroid therapy (range of doses AIDS investigating how PJP can affect these varying popula-
being 60 mg/day to 60 mg alternating with 5 mg every other tions, patients with PJP and HIV/AIDS had more P. jirovecii

informahealthcare.com 173
Review Liebling, Rubio & Ie

organisms and fewer neutrophils in the lung on bronchoalveo- potentially underappreciated reservoirs of PJP and, thus, may
lar lavage (BAL) than those with PJP without HIV/AIDS. It somehow contribute to increasing the incidence of the disease
has been speculated that the higher amount of lavage neutro- in a hospital environment. Of note, colonized HIV-negative
phils is indicative of a more pronounced inflammatory response patients included five patients with either corticosteroid-treated
rather than the actual number of organisms and is associated or untreated sarcoidosis or asthma [50]. Also, there have been
with greater impairment of gas exchange and lower patient sur- cases related to probable contact in treatment and/or waiting
vival [39]. This is also consistent with the clinical evidence for rooms. These were detected in renal transplant patients visiting
improved oxygenation with the use of steroid therapy during outpatient facilities which, in some sporadic cases, may have
early active PJP [40,41]. Also, this lower amount of neutrophils been shared by HIV-positive patients who recently or currently
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in the BAL of HIV/AIDS patients correlated with higher arte- have had PJP [5153]. Also, there have been reports of coloniza-
rial oxygen tension and, thus, a less-extensive inflammatory cas- tion in immunocompetent healthcare workers due to occupa-
cade contributing to hypoxemic respiratory deterioration [40,41]. tional contact with patients with PJP [54]. These infer and raise
Therefore, the clinical course of PJP in patients with and concern for possible occult sources for disease outbreaks via
without HIV/AIDS can be quite different. Patients with HIV/ airborne droplets.
AIDS have a disease course that is notably subtle with subacute Colonization with PJP has also been demonstrated by PCR
and progressive non-productive cough, dyspnea, malaise and testing in up to 33.8% of patients with ILD who required
low-grade fever that develops over several weeks. In fact, in bronchoscopy and BAL for suspicion of the disease and were
patients with HIV/AIDS presenting with purulent sputum not on corticosteroids at the time of their procedure. The
along with rigors or night sweats, PJP should be considered as authors also postulated that the organisms ability to incite an
an alternate diagnosis to routine bacterial pneumonia or tuber- avid inflammatory response could be integrally involved in the
culosis. There have even been reports of PJP presenting initially pathogenesis of ILD and its progression to fibrosis [36,55]. Also,
with asthma-like symptoms, including daily cough, daytime there have been prospective studies using various serum markers
and nocturnal wheezing and nasal congestion, along with for PJP, such as b-D-glucan, along with peripheral lymphocyte
fatigue and low-grade fever in a patient with HIV infection, counts for detecting PJP colonization in patients with ILD,
For personal use only.

being later diagnosed with PJP on transbronchial biopsy [42]. with a higher rate of colonization noted with systemic steroid
In contrast, patients without HIV/AIDS and PJP have a use (defined as Prednisone >5 mg/day). In this population, PJP
more severe course, with acute respiratory failure in up to 43%. colonization was noted to be as high as 23.3% in the corticoste-
Mortality in these patients can reach up to 40%, which is twice roid therapy group [56]. Knowing if a patient is colonized with
as high as in patients with HIV/AIDS with PJP [29,43,44]. Also, PJP and considering this pathogen as a potential cause of an
in another retrospective study it was demonstrated that there exacerbation may be important as the mortality rate of ILD
was a higher risk of failure of non-invasive mechanical ventila- exacerbations is known to be extremely high (78% after hospital
tion, more days spent on the ventilator with greater require- admission) [57].
ments of positive-end expiratory pressure and fraction of Recently, information has been emerging in regards to the
inspired oxygen, as well as overall increased severity of illness role of PJP in COPD, being not only an acute infectious path-
and mortality in HIV-negative patients versus HIV-positive ogen but also a colonizer [58,59]. Organisms including Strepto-
patients [45]. Thus, it has been discerned that patients without coccus pneumoniae and Haemophilus influenzae are frequent
HIV/AIDS and PJP may have a paradoxical increase in mor- colonizers of the lower respiratory tract of COPD patients, in
bidity and mortality due to their enhanced inflammatory addition to Pseudomonas aeruginosa.
response as a result of their more intact immune system [2,4648]. Although these microbes are known to be formidable when
However, it has been also retrospectively demonstrated that a associated with acute COPD exacerbations, their colonization
low clinical suspicion and under-recognition of the need for may also be a marker of severity of disease in the stable COPD
early empiric therapy in HIV-negative immunosuppressed patient. This could relate to the degree of obstruction, with
patients with PJP, despite presentation and imaging consistent other factors such as current smoking status contributing to
with the disease, may result in a treatment delay and further impaired mucociliary clearance and, hence, S. pneumonia and
contribute to higher mortality in this population [49]. H. influenza infections [6063]. Also, various other organisms
such as Aspergillus fumigatus, Candida sp. and Mycobacterium
The impact of infection versus colonization xenopi have been documented as being lung colonizers in
The concept of infection versus colonization in various disease COPD. A. fumigatus has been associated with the use of Pred-
states may reflect unrealized interhuman transmission of the nisone at a dose of >60 mg daily in the context of COPD,
organism. In a prospective study of 91 patients, 82 of whom conferring a high risk of morbidity and mortality [64]. Further-
were HIV negative and 9 were HIV positive, 13 of the HIV- more, there have case reports of Candida bronchitis causing
negative patients and 1 of the HIV-positive patients were con- morbidity and mortality in patients with obstructive lung dis-
sidered to be colonized with PJP as the organisms DNA was ease with or without chronic corticosteroid therapy, in addition
detected in BAL in the absence of clinical signs or symptoms. to the established association of Candida albicans colonization
There is suggestion by the authors that these patients may be and the development of P. aeruginosa ventilator-associated

174 Expert Rev. Respir. Med. 9(2), (2015)


Prophylaxis for Pneumocystis jiroveci pneumonia Review

pneumonia in a critical care setting [65,66]. Conversely, M. xen- decreased CD4+ counts, especially in renal transplant patients,
opi has been frequently isolated from HIV patients and is usu- has been described. CD4+ T-lymphocytopenia is a common
ally non-pathogenic [67]. immunodeficiency in these patients. However, the specifics of
Carriage of P. jirovecii has also been noted to correlate with this predilection in this population compared to other trans-
disease severity due to various inflammatory mechanisms plant patients, such as those receiving allogeneic hematopoietic
involving elevated CD8+ cells and avid neutrophilic infiltration stem cell transplantation, remain undefined [84]. In an addi-
of the lung by a mechanism independent of smoking [6873]. It tional retrospective study by Overgaard and Helweg-Larsen,
has been demonstrated that patients with COPD and PJP col- a higher risk of acquiring PJP was associated with corticoste-
onization had higher circulating levels of TNF-a, IL-6 and roid use and lymphopenia (CD4+ count <300 cells/l) in
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IL-8 than COPD patients without carriage of PJP [74,75]. These HIV-negative patients with hematological malignancy (non-
pro-inflammatory markers, especially TNF-a, are widely Hodgkins and Hodgkins lymphomas, ALL, among others),
accepted as important factors in the progression of COPD in inflammatory diseases including vasculitis (otherwise undefined
respect to the development of cachexia and malnutrition, in the study), lung and liver solid organ transplantation, and
which, as previously noted, may also play a role in PJP acqui- other conditions associated with immunodeficiency such as
sition. A study by Morris et al. utilized PCR to identify DNA severe combined immunodeficiency syndrome. Nevertheless,
via BAL on bronchoscopy indicative of asymptomatic carriage only a small amount of CD4+ counts was available for the
in a collection of COPD subjects. Their findings revealed that subjects, and thus, recommendations for using CD4+ as a tool
36.7% of patients with severe COPD, classified as Stage IV for identification for PJP risk and need for prophylaxis was
according to Global Health Initiative on Obstructive Lung not confirmed according to the authors. Interestingly, in this
Disease criteria, were colonized with PJP compared to only study, overall mortality attributable to P. jirovecii was strongly
5.3% of those with less severe COPD (stages IIII) [68]. In this correlated with delayed diagnosis and treatment [85].
study, colonization was also independent of the use of cortico- In a study of HIV-negative patients with an array of condi-
steroids. However, data from other studies suggest not only an tions treated with corticosteroids and/or an additional immuno-
increased risk of infection but also an augmented risk of colo- suppressive agent, including one patient with sarcoidosis on
For personal use only.

nization with the use of corticosteroids [76]. In a study by corticosteroids and Methotrexate, PJP infection was associated
Maskell et al., up to 44% of patients on Prednisone at a dose with markedly depressed CD4+ counts (<300 cells/l) similar to
of >20 mg/day of varying durations, both noted to be short HIV-positive patients, which indicated PJP prophylaxis [86]. In
and long as per the authors, were found to have detectable an additional study by Nevez et al. that included asthma and
P. jirovecii organisms on bronchoscopic BAL, as opposed to sarcoidosis patients, it was noted that only those with sarcoido-
only 13% in patients who were not on corticosteroids [76]. sis had PJP detected on BAL, with these showing low CD4+
Interestingly, in this study, COPD was not determined to be a counts (<400 cells/l) as well as a reduced CD4+/CD8+ ratio of <1.
risk factor for PJP colonization [76]. Therefore, in light of However, the CD4+ counts and CD4+/CD8+ ratio were obtained
inconsistent data, it is certainly difficult to discern if PJP is retrospectively and not all CD4+ counts and CD4+/CD8+ ratios
the cause of worsening COPD or if worsening COPD is a were available for all colonized patients in the study [87].
predisposing factor leading to colonization by this organism as Furthermore, the association of sarcoidosis and idiopathic
a result of the increased exposure to corticosteroid therapy CD4+ cell T-lymphocytopenia with PJP has been described in
associated with more severe disease. This may be a further a case study of an asymptomatic young homosexual male
confounder in determining indications for PJP routine prophy- presenting with anal condylomata with incidental findings of
laxis in these patients and requires more clarification. diffuse nodular shadowing and hilar lymphadenopathy on
imaging. He underwent bronchoscopy with BAL notable for
The role of monitoring CD4+ count PJP on blue toluidine O stain as well as non-caseating granulo-
In patients with HIV and/or AIDS, PJP prophylaxis is indi- mas on transbronchial biopsy consistent with sarcoid. He under-
cated when CD4+ counts become less than 250 cells/l. The risk went an exhaustive work-up which was persistently negative,
of PJP in HIV and/or AIDS can be up to 75% compared to including repeated negative HIV testing; however, CD4+ count
the previously mentioned 40% in organ transplant recipients was consistently <300 cells/l without a discernible cause and was
and those receiving chemotherapy for malignancies [1,7782]. thus deemed idiopathic. It is unknown whether the pulmonary
P. jirovecii has been demonstrated in a retrospective chart review sarcoidosis occurred before or after CD4+ cell depletion, postu-
of 10 allogeneic stem cell transplant (hematopoietic stem cell lated to be due to CD4+ cell compartmentalization at sites of
transplantation) patients, with infection being a late complica- disease that result in peripheral lymphocytopenia [88].
tion (greater than 6 months following transplantation) in those These small studies and case reports seem to suggest the
who had their prophylactic regimen (all except one being tri- possible utility in measuring CD4+ counts in HIV-negative
methoprim/sulfamethoxazole) discontinued due to various rea- patients to stratify their risk to develop either asymptomatic or
sons, including toxicity and intolerance of the medication. In active P. jirovecii infection [89]. However, this may differ
the eight subjects for whom CD4+ counts were available, the according to the type of respiratory disorder. Data have indi-
counts were <200 cells/l [83]. An interesting connection with cated that the immunopathology of COPD with tobacco use

informahealthcare.com 175
Review Liebling, Rubio & Ie

may also entail a low CD4+/CD8+ ratio by virtue of the immunological mechanisms and processes of the immunocom-
inflammatory pathophysiology of the disease [90]. There have promised state may have an overall profound impact on a
been further conflicting data in that patients with chronic lung patients need for prophylaxis, as this may confer higher suscep-
disease, such as COPD, may have higher peripheral lymphocyte tibility to PJP apart from use of 30 mg of Prednisone or the
and mean CD4+ lymphocyte counts in the context of coloniza- equivalent for 12 weeks, as compared to other conditions.
tion theorized to be due to an exacerbation of the underlying However, despite this, the role of routine prophylaxis even in
chronic bronchitis [58]. It seems that implementing CD4+ count these subgroups remains debated and may be warranted only in
and CD4+/CD8+ ratio measurement in PJP standards of care a few selected patients based on careful consideration of the
for non-HIV infected patients requires larger patient popula- risk/benefit ratio, as mentioned above.
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tion studies and more extensive investigation in regards to their


role in the natural course of the patients respective disease, Diagnostic considerations
as well as their value in determining the actual occurrence of In the proper setting of a clinical picture of fever, dyspnea,
PJP infection and/or colonization and, hence, the need for cough, hypoxemia and radiographic findings consistent with
prophylaxis. bilateral pulmonary infiltrates, PJP should be suspected, with
confirmation requiring microscopic findings of the organism
Trimethoprim/sulfamethoxazole as the agent of choice with cytochemical procedures (such as Gomori methenamine
for prophylaxis silver stain or Giemsa stain) or immunocytochemical staining.
In regards to the efficacy of trimethoprim/sulfamethoxazole, a Unfortunately, in certain cases, PJP may also present with atyp-
study by Hughes et al. demonstrated a significant difference in ical findings and particularly under any condition of immuno-
the incidence of PJP in children with ALL with the agents use. suppression, such as with chronic steroid therapy, PJP should
The drugs administered were 150 mg/m2/day of trimethoprim also be considered, especially when more common etiologies do
and 750 mg/m2/day of sulfamethoxazole in 80 children in the not prove causal. In many cases, confirmation will require
experimental group, and placebo was given to another 80 chil- fiberoptic bronchoscopy with BAL, which has a sensitivity of
dren. The result was that PJP occurred in 17 of the 80 (21%) >90% [91,92] and is the usual procedure of choice for the diag-
For personal use only.

patients receiving placebo, compared to none of the patients nosis of PJP in HIV-positive patients. A much less-costly and
from the experimental group [4,6]. Subsequent studies have noted less-invasive method to diagnose PJP pneumonia is sputum
that administration of this agent for three consecutive days per induction with a diagnostic accuracy ranging from 25 to
week is as effective as daily administration in preventing PJP 90% [91,92]. Unfortunately, in the HIV-negative patient, diag-
with no higher incidence of associated adverse effects [4]. This is nosing PJP pneumonia may become more difficult due to the
similar to the current CDC/Infectious Diseases Society of Amer- lower pathogen burden and airway colonization with PJP,
ica guidelines for prophylactic trimethoprim/sulfamethoxazole which further lowers the specificity. Unlike the HIV-positive
regimens for adult patients with HIV/AIDS [77]. The authors patients, bronchoscopy and BAL shows a much lower sensitiv-
will not discuss the other agents used for PJP prophylaxis in ity, ranging from 38 to 53%, in an HIV-negative patient [93,94].
this paper. One can increase the sensitivity to diagnosing PJP in the HIV-
In a systematic review and meta-analysis of 12 randomized negative patient by performing PCR, thus hopefully preventing
controlled trials examining PJP routine prophylaxis in immu- the need for further invasive procedures such as pulmonary
nocompromised non-HIV and/or AIDS-infected subjects, the biopsies. It is recommended that patients with a high clinical
authors investigated the risk/benefit ratio in regards to the use suspicion for PJP and a positive PCR result be treated for
of trimethoprim/sulfamethoxazole in various populations, PJP, although the PCR does not differentiate PJP colonization
including those patients on chronic, high-dose corticosteroids, from active infection. At some point, quantitative PCR may
with a dose and duration of 30 mg of Prednisone or the equiv- help to differentiate PJP colonization from active infection.
alent for 12 weeks being a significant risk factor for acquisition PCR has a high negative predictive value [93,94]; therefore, a neg-
of PJP [28,29]. The number needed to treat (NNT) was 110 in ative PCR can allow one to exclude PJP with a high degree of
this population. This was compared to more specific immuno- certainty. Further, it can take up to 310 days to get the results
compromised populations including allogeneic bone marrow of the PCR back. Finally, 1,3 b-D-glucan is a potential tool for
transplant, ALL, solid organ transplants and severe combined screening for PJP infection, with a reportedly high sensitivity
immunodeficiency syndrome, all of which had an NNT of 11. and good specificity of 94.8 and 86.3%, respectively [95,96].
Other conditions, such as GPA and rhabdomyosarcoma, for
example, had an NNT of 32. When the NNT is balanced with Five-year view & expert commentary
the number needed to harm (or the number needed to cause In general, the available evidence of how much steroid is too
severe adverse effects requiring treatment discontinuation), it much and how long is too long to predispose an otherwise
was demonstrated that trimethoprim/sulfamethoxazole should immunocompetent patient to the risk of developing PJP and,
be considered when the anticipated risk for PJP is at least in turn, assess who will require routine prophylaxis remains a
3.5% through the period of immunodeficiency, as in the disor- real and present clinical challenge now and will remain so even
ders given above [28]. This may imply that the underlying in the next 5 years. Also, as discussed, PJP may carry a

176 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]
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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 chronic high-dose corticosteroid therapy (being defined by the
in the host that does not have HIV and/or AIDS, not only by use of a median daily dose of Prednisone 30 mg or the equiva-
virtue of the pathogenesis of the disease in the HIV-negative lent for 12 weeks or longer [28,29]). In these cases, associated
host but also due to a lack of early recognition for the condi- co-morbidities such as malnutrition should be taken into con-
tion and, hence, a delay in therapy. For these reasons, one sideration when assessing the need for prophylactic therapy. In
could argue that prophylaxis in the HIV-negative population regards to patients with ILD and COPD, one could entertain
susceptible to PJP due to alternate risk factors for immunosup- the possibility of infection versus colonization by P. jirovecii
pression is even more important; unfortunately, the available and whether the latter may actually be more of an active player
small prospective and retrospective studies and case reports rather than an innocent bystander. Whether treatment for this
merely propose rather than prove this. It seems logical that is warranted is an unanswered question that needs further
when taking into consideration the safety profile as well as the research, which may become a focus of study in the next 5 years
noted good response of sulfamethoxazole/trimethoprim in effec- as diseases such as ILD and, especially, COPD have become a
tively preventing active PJP, identifying these patients in jeop- more prominent public concern and pervasive healthcare issue.
ardy is a reasonable approach in order to optimize this care. Finally, to further distinguish those who are more likely predis-
Unfortunately, there is an astounding deficiency of adequate posed to developing PJP, one could also consider obtaining a
and reproducible data to appropriately address this issue. CD4+ level to better stratify their risk, but this has not been
Needless to say, more intensive investigation is warranted as convincingly established in HIV-negative patients with
PJP remains a major cause of morbidity and mortality in HIV- various respiratory disorders such as sarcoidosis, asthma and
negative and HIV-positive patients alike. As it stands, based on COPD (TABLE 1). Hopefully, as more studies are performed and
the current available literature, there seems to be an indication consistent data collected, there will be a better understanding as
for PJP prophylaxis in adult non-HIV infected populations to why certain populations are at higher risk for contracting
such as those with primary immune deficiency diseases, severe PJP, and with further testing, we will be able to identify those
protein malnutrition, those who have undergone allogeneic non-HIV infected patients who need prophylaxis.
bone marrow transplantation or organ transplants, using 160/
800 mg of trimethoprim/sulfamethoxazole by mouth three- Financial & competing interests disclosure
times a week or daily [28]. However, we cannot make a strong The authors have no relevant affiliations or financial involvement with
recommendation for PJP routine prophylaxis in other non- any organization or entity with a financial interest in or financial conflict
HIV infected populations, particularly in regards to primary with the subject matter or materials discussed in the manuscript. This
chronic respiratory disorders such as asthma and COPD, as includes employment, consultancies, honoraria, stock ownership or options,
well as other pulmonary conditions including sarcoidosis, cryp- expert testimony, grants or patents received or pending, or royalties.
togenic organizing pneumonia and ILD that may necessitate 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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