In our cohort study, we demonstrated a markedly increased relative risk of PCP in patients with IBD as compared to the general population, with an adjusted effect estimate of HR 2.96, 95% CI 1.75–4.29. However, the absolute risk remained quite low. The risk was higher in the IBD cohort on immunosuppressive medications during screening (32/100,000) than the IBD population on no immunosuppression during this time period (5.5/100,000). Because these calculations incorporated medication use during the screening period, chronic medications were more likely to be captured and corticosteroid use was likely underrepresented. If PCP prophylaxis were 100% effective, and all individuals on any form of immunosuppression were placed on prophylaxis, this would equate to a number needed to treat (NNT) of 3750 to prevent 1 case of PCP in the IBD population. As there was the possibility of underestimation of immunosuppressant exposure status, we recalculated the NNT assuming 25, 50 and 75% underestimation of immunosuppressant exposure among the PCP cases. The NNT remained quite high at 2952, 2432 and 2070 respectively, due to the rarity of the outcome. Therefore, it is evident that other risk factors must also be taken into consideration when targeting a population for prophylaxis. Also, these calculations are for any immunosuppression, and the risk profile may differ in those on multiple immunosuppressive agents. This is particularly important given the increased use of combination immunosuppressive agents to treat certain patients with CD.
Our case series described medication and hospitalization risk factors in the 38 IBD patients who developed PCP. In this group, the majority were on corticosteroids. Other immunosuppressive medications were also common, as was hospitalization in the 60 days preceding the diagnosis. Interestingly, rates of comorbidities were also high in this group of individuals with IBD and PCP. The medication risk factors have been previously described in case series in the IBD population,2–7
and also in the transplant population.
The overall risk of PCP post solid organ transplant (SOT) has been estimated to be between 5 to 15% in the absence of PCP prophylaxis, with attack rates lowest after renal transplant and highest in lung and heart transplant patients.19
The risk factors for PCP have been more extensively studied in this population than the IBD population, likely because of the higher incidence seen with the use of very potent immunosuppressive medications. Risk factors in this population include high-dose corticosteroid therapy, malnutrition and post SOT medications including antilymphocyte agents, calcineurin inhibitors, and biologic agents like alemtuzumab.20, 21
These medications can cause severe neutropenia and lymphopenia, which are believed to increase PCP risk. In addition, previous CMV infection, which has been shown to have immunomodulatory effects; and underlying pulmonary disease, also increase the risk of PCP in SOT patients.22, 23
As a result, post SOT, routine TMP-SMX prophylaxis is recommended in most centers and is continued for at least the first 3 to 12 months, and in some situations for life.24, 25
Similar recommendations do not currently exist in the IBD population. Data on risk of PCP in the IBD population currently consist of descriptive series. Often, the individuals who develop PCP are on multiple immunosuppressive agents.26
There are several strengths to this study of PCP in IBD. We were able to analyze a large sample size. We also had considerable geographic diversity, with patients from all regions of the US. By drawing from a large number of health plans of varying size, type, and location, we believe these results to be broadly generalizable to the commercially insured US population. We attempted to exclude individuals with known HIV, as this population is known to have an increased risk of PCP. We obtained complete data on all billed outpatient prescriptions in order to completely capture medication exposures; rather than relying on patient recall. We were also able to account for health care utilization, as we had access to all health care contacts within the database. Finally, we were able to account for comorbidities through a validated comorbidity index for administrative data.17, 18
There are also several limitations to this study of administrative claims data. There is the possibility of misclassification of exposure and outcome related to the lack of clinical detail. We did use an IBD exposure definition previously used by our group11, 12
that requires multiple health contacts and/or IBD related prescriptions. A similar, but even less specific, administrative case definition has been validated by Herrinton et al.27
The Herrinton definition was found to have a sensitivity exceeding 90% and a PPV exceeding 80% for overall IBD. We used an outcome definition of PCP that required either inpatient claims with an ICD-9 code specific for PCP or outpatient claims with this code in conjunction with appropriate antibiotic dispensing. However, this definition has not been validated. Due to the rarity of the outcome, there were relatively few overall cases of PCP. Another limitation to this study is that the elderly and uninsured were not represented in our population; however, this should not affect the internal validity of the relative risks (IRRs, HRs, ORs) for the under 65 population. Further studies are needed to assess the risk of PCP among the elderly and uninsured. As the risk of PCP increased with age, excluding patients 65 and over may lead to an underestimation of the risk of PCP in this group of patients. While we had access to all billed outpatient prescriptions, we did not have access to those medications given during hospitalizations. As many immunosuppressive medications, such as corticosteroids, are given during hospitalizations for IBD exacerbations, we could not specifically determine medication risk factors in those with a hospitalization preceding their diagnosis of PCP. There were too few cases to evaluate immunosuppression other than as an any/none variable. The type and dose of immunosuppression may play a role in PCP risk, but we were unable to assess this. Additionally, the case series may also have underestimated exposure to medications prescribed more than 60 days prior to PCP diagnosis, for example 90 day prescriptions or prednisone left over from prior prescriptions. Finally, we were unable to account for certain exposures that may be related to the outcome, particularly smoking status. We were able to obtain data on chronic obstructive pulmonary disease (COPD), which has been used as a proxy for smoking status in other studies using administrative data, and controlled for this exposure in our analyses. In our study, COPD was more common among CD patients than UC patients, consistent with prior reports in the literature of increased smoking prevalence among those with CD. However, COPD was also more common in both UC and CD patients as compared to the non-IBD cohort. COPD diagnosis may therefore be a manifestation of both former and current smoking, as UC is often diagnosed after smoking cessation.
In summary, we demonstrated an increased relative risk of PCP in patients with IBD. However, the absolute risk remained quite low, even when considering only those on immunosuppressive medications for IBD, and the NNT to prevent one case of PCP is considerable. Moreover, there can be significant side effects with PCP prophylaxis, including Stevens Johnson’s syndrome, methemoglobinemia, aplastic anemia and an increased risk of pseudomembranous colitis. We therefore would not endorse global PCP prophylaxis in IBD, but rather, consider prophylaxis on an individual basis. We found a particularly increased risk with corticosteroids, prior hospitalization, and comorbid conditions consistent with existing reports in the literature. Any targeted PCP prophylaxis recommendations should consider these potential risk factors.