Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression

Abstract

Background & Aims

Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics.

Methods

We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn’s disease (n=427) or ulcerative colitis (n=510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP and associated with use corticosteroids, immune-suppressive medications, and biologics by patients with IBD.

Results

Our analysis included 937 patients and 6066 patient-yrs (p-y) of follow up (median, 14.8 yrs per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 p-y of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 p-y of exposure), and biologics (193 patients; 20.5%; 670 p-y of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 p-y of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 p-y of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01–1.0) to corticosteroids, 0.1 (95% CI, 0.02–0.5) cases per 100 p-y of exposure to immunosuppressants, 0.3 (95% CI, 0.04–1.1) cases per 100 p-y of exposure to biologics, 0.6 (95% CI, 0.01–3.2) cases per 100 p-y of exposure to double therapy, and 0 (95% CI, 0.0–19.5) cases per 100 p-y of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 p-y of exposure.

Conclusion

In a population-based cohort of patients with IBD patients treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such patients receiving triple therapy.

Introduction

Pneumocystis jirovecii (formerly known as Pneumocystis carinii) is a ubiquitous fungus that causes pneumonia in immunosuppressed patients.¹ The incidence of Pneumocystis jirovecii pneumonia (PJP) is increasing in immunocompromised non-HIV-infected patients.^{2, 3} Risk factors include systemic corticosteroid (CS) use,⁴ particularly at or above a daily dose of 16 mg of prednisone for at least 8 weeks,⁵ other immunosuppressant (IS) use, lymphocyte count <600/mm³, more specifically a CD4 cell count <300/mm^{3,6, 7}, and co-morbidities such as cancer, solid organ or bone marrow transplantation, collagen vascular disease, preexisting lung disease and inflammatory bowel disease (IBD).^8–12 IBD is associated with conditions that may predispose to opportunistic infections, such as malnutrition, surgery and the use of immunosuppressive medications. As a result of the increasing use of immunosuppressive and biologic drugs, the occurrence of opportunistic infections has become a key safety issue for patients with IBD.^{13, 14}

There is a growing body of evidence suggesting an increased risk of PJP in IBD patients. Although the incidence has not been clearly defined, multiple cases of PJP in patients with IBD have been reported, associated with the use of IS alone and in combination, including cyclosporine,^{15, 16} azathioprine,^{17, 18} high dose CS¹⁹ (a systemically delivered corticosteroid in a dose equivalent to prednisone >20 mg daily), 6-mercaptopurine,²⁰ and infliximab.^21–25 In an analysis of the Federal Drug Administration (FDA) database for the Adverse Event Reporting System, 84 cases of PJP were reported between 1998 and 2003 in patients receiving infliximab with or without concomitant IS.²⁶ Of these, 14 were receiving infliximab for Crohn’s disease (CD) and 2 for ulcerative colitis (UC).²⁶ A recent study estimated the crude incidence of PJP in patients with IBD at 10.6 per 100,000 person-years,²⁷ increasing to 32 per 100,000 person-years in patients on IS, substantially higher than the crude incidence of PJP in patients without IBD at 3 per 100,000 person-years.²⁷ Of note, this study included enteral budesonide as IS although it has been shown not to increase pulmonary infection risk, possibly resulting in underestimation of risk.²⁸

Despite its excess mortality and the efficacy of chemoprophylaxis,²⁹ there is no consensus on the need for primary PJP prophylaxis in IBD patients on immunosuppression.³⁰ Some experts have advocated for routine use of PJP prophylaxis in patients with IBD treated with a tumor necrosis factor (TNF)-alpha inhibitor with or without combination IS, although the cases of PJP in patients treated with these medications represent a small fraction of all IBD patients so treated.^{26, 30–32} In 2014, the European Crohn’s and Colitis Organisation (ECCO) published their second evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in IBD recommending primary PJP prophylaxis in patients on 3 immunosuppressants, if one agent is a calcineurin inhibitor or anti-TNF agent, and consideration of primary PJP prophylaxis in patients on double immunosuppressive therapy, if one is a calcineurin inhibitor.³³ No consensus was reached regarding primary PJP prophylaxis with single or dual agent combination therapy without a calcineurin inhibitor, leaving the decision for prophylaxis to a discussion between providers and patients with IBD who are taking these medications.³³ In a recent survey of gastroenterology providers in the United States, only 9% of respondents reported using PJP prophylaxis in patients treated with triple therapy.³⁴ Providers who prescribed PJP prophylaxis were more likely to have previous personal experience with PJP and practice in an academic medical center.³⁴ Moreover, a recent study, using a Markov microsimulation model to simulate the natural history of CD in 1 million virtual patients, concluded that at the current PJP incidence, no PJP prophylaxis was the preferred strategy from a population perspective.³⁵

The existing literature on the risk of PJP in patients with IBD is subject to referral bias, and the true risk of PJP in a population-based cohort with IBD is unknown. Furthermore, the additive risk of combination therapy with CS and other IS and or biologic therapy has not been well studied. Therefore, we aimed to estimate the risk of PJP infection in a well-defined population-based cohort of patients receiving CS, IS, and/or biologic therapy for IBD in an attempt to better define the subgroups who may benefit most from PJP prophylaxis.

Methods

Study population

Using the data resources of the Rochester Epidemiology Project (REP) (discussed below), adult and pediatric residents of Olmsted County, Minnesota diagnosed with CD or UC between 1970 and 2011 (inclusive) were identified. These cases have been previously validated.^{36, 37} Exclusion criteria included HIV infection, any solid organ or bone marrow transplant, current malignancy or chemotherapy during the study period, hereditary immunocompromising conditions, or history of splenectomy.

Defining immunosuppressive therapy

The records of patients were reviewed to identify all episodes of immunosuppressive therapy including CS, IS and biologics - and concomitant PJP prophylaxis, through February 2016. For the purpose of this study, budesonide was not considered immunosuppressive therapy. A meta-analysis of 5 randomized controlled trials found no difference between oral budesonide and placebo with regard to respiratory infections,²⁸ justifying this decision. In this study, immunosuppressive therapy was divided into 3 groups – CS (prednisone, methylprednisolone), IS (azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, tacrolimus) and biologic therapy (infliximab, adalimumab, certolizumab pegol, natalizumab, golimumab, vedolizumab).

Identification of PJP cases

A manual chart review was performed on all IBD patients for cases of PJP, cross-referenced with the REP patient database (using PJP diagnostic codes) and two microbiology databases (Mayo Clinic and Olmsted Medical Center). The diagnosis of PJP was made by the identification of Pneumocystis from sputum, bronchoalveolar fluid, tracheal secretions or lung tissue by special stains or a non-nested polymerase chain reaction (PCR), specifically designed to diagnose pneumonia rather than colonization.³⁸

This study was approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards.

Study setting

Olmsted County, in southeastern Minnesota, had a population of 144,248 during the 2010 census,³⁹ estimated to have increased to 151,436 in 2015.⁴⁰ Eighty-three percent of the population is non-Hispanic white, and a substantial portion is of North European ancestry. The majority of people reside in Rochester, which is the urban center of an otherwise rural county. While residents of Olmsted County are socioeconomically similar to the general US population, there are some differences, including ethnic diversity (86% of the county population is Caucasian compared to 72% of the US population) and education (39% have completed a bachelor’s degree or higher compared to 28% of the US population).⁴¹ Moreover, 25% of Olmsted County residents are employed in health care versus 8% nationwide.⁴² The REP is a unique medical records linkage system which exploits the fact that virtually all of the health care for the residents of Olmsted County is provided by two organizations: Mayo Clinic and Olmsted Medical Center.⁴³ Information generated from all medical contacts for all Olmsted County residents seen since 1908 is available through a central diagnostic index. In any three-year period, over 90% of county residents are examined at either one of the two health care systems, with REP population estimates being consistently higher than those reported by the U.S. Census.⁴⁴ Thus, it is possible to identify all diagnosed cases of a given disease for which patients sought medical attention.

Statistical Analysis

The risk of PJP and associated 95% confidence intervals (CIs) were estimated using a Poisson regression model. For CS, IS or biologics, this risk was assumed to exist from the start of the single agent until the stop date for the same single agent, irrespective of additional concomitant immunosuppressant therapy. For double therapy (CS + either IS or biologic), and triple therapy (CS + IS + biologic) the risk was assumed to exist from the start to the end of the specific combination, exclusively. Demographic and clinical data were summarized using frequency (percent) for discrete variables, and mean ± standard deviation (SD) or median (range) for continuous variables. All statistical analyses were done using SAS^® version 9.2 (SAS institute Inc. Cary NC).

Results

There were a total of 937 patients with IBD (510 with UC and 427 with CD). The total number of patient-years of follow-up from IBD diagnosis to last follow-up was 16,066.2 years (median of 14.8 years per patient). Demographic characteristics of the total cohort and of the cohort exposed to immunosuppressive therapy are outlined in Table 1. In 364 patients (39%), CS, IS, and a biologic were not used, and no cases of PJP diagnosed in this group.

Table 1.

Demographics of Olmsted County Inflammatory Bowel Disease cohort (1970 – 2011) and subset exposed to immunosuppression

	Entire Cohort (N = 937)			Cohort on Immunosuppressive Therapy (N = 573)
	CD (N = 427)	UC (N = 510)	Combined	CD (N = 307)	UC (N = 266)	Combined
Female, n (%)	221 (52.8%)	220 (43.1%)	441 (47.1%)	160 (52.1%)	115 (43.2%)	275 (48.0%)
Age (years), median (IQR)	29.5 (21.2, 46.6)	35 (24.8, 48)	32.8 (23.7, 47.4)	27.9 (20.5, 42.1)	34.2 (24.2, 48.3)	30.8 (22.3, 46.0)
White race	412 (96.5%)	487 (95.5%)	899 (95.9%)	296 (96.4%)	259 (97.4%)	555 (96.9%)
Follow up (years), median (IQR)	14.3 (7.9, 24.1)	15.3 (7.8, 25.8)	14.8 (7.9, 25)	14.6 (8.2, 24.7)	14.4 (8.3, 23.2)	14.5 (8.3, 23.9)

CD, Crohn’s disease; UC, Ulcerative colitis; IQR, Interquartile range

Corticosteroids were used in 520 patients (55.5%), with 555.4 patient-years of exposure. A total of 406 patients (43.3%) used CS for greater that 8 weeks. IS were used in 304 patients (32.4%), with 1555.7 patient-years of exposure, and biologic agents were used in 193 patients (20.5%), with 670 patient-years of exposure. Double therapy with systemic CS together with either IS or biologic agents were used in 236 patients (25.2%), with 173 patient-years of exposure. Triple therapy with CS, IS and biologic therapy was used in 70 patients (7.5%), with 18.9 patient-years of exposure.

There were 4 cases of PJP in this cohort. One case occurred in 1997 in a patient with UC who had undergone colectomy in the 1970s, and was on no specific UC therapy. He developed PJP in the setting of chemoradiation therapy for a brain tumor – and was thus omitted from the formal analysis of PJP risk. The demographic and clinical features of the 3 remaining cases of PJP are shown in Table 2. None of the 3 cases had been receiving prophylaxis at the time of PJP onset. The mean total lymphocyte count of these 3 cases was 970 ± 520 mm³, compared to 1430 ± 780 mm³ in a random sample of 30 patients without PJP over the age of 60 years.

Table 2.

Demographics and clinical features of the patients diagnosed with Pneumocystis jiroveci pneumonia in the Olmsted Country Inflammatory Bowel Disease cohort (1970 – 2011), with follow-up through February 2016

	Case 1	Case 2	Case 3
Age, years	63	74	78
Sex	Male	Male	Male
IBD subtype	CD	UC	UC
Duration of IBD at time of PJP diagnosis, years	9.2	6.2	5.2
Relevant co-morbidities	COPD	None	Bronchiectasis
Immunosuppression	4.2 years of infliximab and methotrexate	1 month of infliximab and prednisone	3.7 years of azathioprine
PJP prophylaxis	No	No	No
Treatment	TMP/SMX	TMP/SMX, prednisone	TMP/SMX
Responded to Treatment	Yes	Yes	Yes

IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; COPD, chronic obstructive pulmonary disease; TMP/SMX, trimethoprim/sulfamethoxazole

The risk of PJP was ≤ 0.6 case per 100 patient-years of exposure in all study groups (Table 3). Additional subgroup analysis was performed in patients treated with CS + calcineurin inhibitors (61 days of exposure) and CS + methotrexate/thiopurines (145.4 years of exposure), revealing no cases of PJP (95% CI 0.0–21.7 and 0.0–2.5 per 100 patient-years of exposure, respectively.

Table 3.

Risk of Pneumocystis jiroveci pneumonia in the Olmsted Country Inflammatory Bowel Disease cohort (1970 – 2011) in patients exposed to immunosuppression, with follow-up through February 2016

	Patient-years of exposure	PJP cases per 100 Patient-years of exposure (95% CI)	Patient-years of exposure pre one PJP cases
Corticosteroids	555.4	0.2 (0.01–1.0)	555
Immunosuppressants	1555.7	0.1 (0.02–0.5)	778
Biologic	670	0.3 (0.04–1.1)	335
CS + either IS or biologic	173	0.6 (0.01–3.2)	173
CS + IS + biologic	18.9	0.0 (0.0–19.5)	N/A

PJP, Pneumocystis jiroveci pneumonia; CS, systemic corticosteroids; IS, immunosuppressants; CI, confidence interval; N/A, not applicable

Only 37 patients were prescribed primary PJP prophylaxis concomitantly with CS, or IS or biologic therapy, for a total of 24.9 years during follow-up (3.5 years on CS, 9 years on biologics, 10 years on double therapy, and 2.4 years on triple therapy). Trimethoprim-sulfamethoxazole (TMP-SMX) was used for 23.3 years, dapsone for 1.3 years and atovaquone for 0.3 years.

Discussion

In this population-based IBD inception cohort, most of whom were treated with CS, IS, and/or biologics, there were only 3 cases of PJP despite very infrequent use of PJP prophylaxis. The risk of PJP was ≤0.3 cases per 100 patient-year of exposure in patients receiving either CS, IS or biologics. The risk increased to 0.6 per 100 patient-years of exposure on double therapy. There were no cases while on triple therapy, although caution is advised in interpreting this result considering there were fewer than 19 patient-years of exposure studied. Our 3 cases of PJP were all over 60 years old, 2 had a pulmonary comorbidity, and their mean total lymphocyte was lower than a random comparable sample group who did not develop PJP.

These results are consistent with a recent retrospective cohort study of over 100,000 IBD patients in the USA, which showed an increased risk of PJP in IBD patients as compared to the general population, with an overall hazard risk of 2.96, and 4.01 for CD patients.²⁷ However, the absolute risk was low, with 38 individuals (0.03%) with IBD developing PJP; of these, 20 (53%) were on CS alone or in combination with other immunosuppression.²⁷ The investigators calculated that the number needed to treat (NNT) with prophylaxis equated to 3750 to prevent 1 case of PJP in the IBD cohort on immunosuppression.²⁷

TMP-SMX is the treatment of choice for PJP prophylaxis in non-HIV infected patients as it is effective and well tolerated,^{45, 46} with a meta-analysis of 12 randomized trials involving patients post-transplant and with hematological cancers revealing a 91% relative risk reduction in PJP in patients on prophylaxis, leading to the conclusion that prophylaxis is warranted when the risk of PJP is higher than 3.5% in adults²⁹ Mortality related to PJP was also significantly reduced by prophylaxis (RR, 0.17; 95% CI 0.03–0.94). Given this studied population, it is difficult to make direct inferences about the threshold of when to treat IBD patients on immunosuppression, but it does confirm that TMP-SMX is effective and well tolerated, should PJP primary prophylaxis be decided upon.

Sulfasalazine may have activity against PJP by reducing Pneumocystis-induced inflammation and enhancing macrophage-mediated Pneumocystis clearance during PJP.⁴⁷ Sulfasalazine was used in over 40% of our cohort, none of whom developed PJP. However, patients with IBD treated with sulfasalazine are typically not receiving CS, IS or biologics and generally do not have severe IBD. Therefore, they are often not considered high risk for PJP. Nevertheless, the possible protective effects of sulfasalazine against PJP merits further study.

Strengths of this study include the large number of patients with prolonged follow-up, as well as detailed information regarding the use of CS, IS and biologics, including periods of combination therapy. In addition, the study of a population-based cohort avoids issues with referral bias, with results potentially generalizable to a Western population of IBD patients with similar characteristics to our cohort. Limitations include the retrospective study design. It would have been helpful if specific CS dosage exposures were examined; however, because IBD patients are typically managed with a home tapering schedule, it was not possible for us to know reliably what dose they were on for a specified duration. The 1 case of PJP that occurred on CS therapy occurred after 4 weeks of exposure to prednisone on a tapering schedule, and the patient was on 10 mg daily at time of diagnosis. While it is plausible that PJP may have occurred in patients who were then treated at another facility, thus leading to failure to capture these events, such an occurrence is unlikely given the nature of health care in our region and the fact that over 90% of county residents are examined at either one of the two healthcare systems in any 3-year period.⁴³ It is also possible that a PJP diagnosis may have been missed, especially earlier in the study period. Our microbiology laboratory began using a sensitive PCR test on March 1, 2005.³⁸ Before this time, we used Pneumocystis stains, which are somewhat less sensitive than PCR.^{38, 48}

In summary, this is the first population-based cohort study investigating the risk of PJP in IBD patients on immunosuppression, with only 3 clinically relevant cases of PJP identified, despite little use of TMP-SMX prophylaxis. Our results suggest that routinely initiating chemoprophylaxis against PJP in IBD patients on immunosuppression may not be warranted, given the low PJP risk. Caution is advised, however, in drawing conclusions about the risk of PJP (and consequently the advisability of prophylaxis) in patients on triple therapy given the low patient-years of follow-up on triple therapy. Moreover, the risk of CS in combination with calcineurin inhibitors may be increased relative to methotrexate/thiopurines. There was no difference in this risk in our cohort; however, calcineurin inhibitors are rarely used in our local practice, so the patient-years of exposure are not high enough to enable definitive conclusions to be made in this regard. Given the potentially high morbidity and mortality associated with PJP, we would recommend gastroenterology providers to continue assessing the need for primary PJP prophylaxis on a case-by-case basis, particularly in older patients with pulmonary co-morbidities, patients on multiple immunosuppressive agents, and patients with lymphopenia, balancing the risks and benefits for each individual patient. Monitoring CD4 T-cell counts in patients with a total lymphocyte count <600/mm³ may also help to identify those at high risk of PJP.⁷ Providers should monitor patients on immunosuppressive medications closely, educate them about early or subtle signs of infection, and have a high index of suspicion for PJP in patients with respiratory symptoms or febrile illness.⁴⁹ Additional studies are warranted to better define subgroups of IBD patients who are at increased risk of PJP, and who therefore would be most appropriate to receive primary prophylaxis.