First identified by Carlos Chagas (yes, that Chagas) back in 1909, pneumocystis was identified as a cause of plasma cell pneumonia in debilitated infants following WWII (1). Since then, it has been identified as a unicellular fungus that is of low virulence and unique amongst the other fungi in that it lacks ergosterol in its plasma membrane. As a result, it is insensitive to antifungal agents that target ergosterol biosynthesis (i.e. azoles and polyenes). Its role in HIV/AIDS during the early stages of the epidemic has led to the standardization of prophylaxis in those who are profoundly immunosuppressed. Patients with solid organ transplantation and those with leukemia have also been identified as being at high risk for PJP and also tend to be placed on prophylaxis. Given that a lot of the same drugs that are used for chemotherapy are used in rheumatological disorders, it begs the question as to whether or not PJP prophylaxis should be routinely used.
The pathophysiology behind PJP is actually kind of interesting. Defect in the T-cell arm of immunity seems to be a key factor in the development of PJP (2), as one can infer given we risk stratify HIV patients based on their CD4 count. CD4 cells function as memory cells that orchestrate the host’s inflammatory response by recruiting and activating other arms of the immune system (3,). As one review notes, mice with SICD infected with pneumocystis do not have a significant impairment in oxygenation as they are unable to mount such an inflammatory response to the pathogen. This inflammatory reaction leads to the decrease in oxygenation in the lungs (3) and may also play a role in the presentation of disease. In short, patients with HIV/AIDS have a subacute and progressive course of disease, likely due to the lack of inflammatory response due to low T-cell activity. This is in contrast to the non-HIV/AIDS population, whose course is much more abrupt (i.e., crash and burn, 4). The clinical presentation and how these differ between the HIV and non-HIV population is the topic of the next post.
Risk of Autoimmune Disease
Whether the disease PJP is a result of colonization or new infection is unknown (and I am not even going to attempt to answer that question) but it seems those with rheumatological conditions are at a higher risk of colonization with PJP. In a study of 102 patients with autoimmune disorder (12) and 117 controls, the rate of PJP colonization was higher in the group with autoimmune disorder, 28.5% vs 2.6% (OR 15.1, 95% CI 4.43-51.38), suggesting that any degree of immunosuppression puts someone at risk of at least colonization. When evaluating the autoimmune disorder group, those who were colonized were older, but had no statistical difference in terms of prednisone equivalent dose (5.6mg/d vs 5mg/d) or duration of therapy, 301 weeks vs 246 weeks, p=0.879). Furthermore, There was no statistical difference in the rate of carriage when looking at either prednisone alone or a combination of immunosuppressants:
Who Gets Prophylaxis
As a result, one can conclude that immunosuppression with something that targets the adaptive immune system (typically rituximab, cyclophosphamide) would lead to higher risk of PJP and hence, would warrant prophylaxis. In other words, lower lymphocyte count = need to give prophylaxis, specially with higher rates of colonization in this population. This was seen in a retrospective study of patients with autoimmune disease who were infected with PJP (5). After matching and adjustment, patients with PJP tended to have a lower lymphocyte count on admission (0.4 vs 1.3, p=0.04) and at nadir (0.2 vs 0.8, p=0.05). Another review noted that drugs such as infliximab and etanercept were associated with higher risk of PJP, especially in RA patients during the first 6 months (6). Given what we know about PJP in HIV/AIDS and in those with hematological malignancies, the above shouldn’t be surprising. What about steroids, though? These tend to blast all branches of the immune system, so one would expect that within rheumatology, a certain threshold of steroid dosage would mean an automatic TMP-SMX prescription for prophylaxis.
Unfortunately, this is not the case. There are no clear guidelines as far as this question goes, with one survey of practicing rheumatologists noting that 30% have never written for PJP prophylaxis (7). These numbers seemed to be skewed a bit, as those who are newly minted rheumatologists and those who come from academic centers tended to write for PJP prophylaxis more often, as those who had patients with chronic steroid therapy (OR 2.04). Whether steroids in and of themselves put you at risk of PJP is unknown (anyone have a patient on chronic steroids for, lets say, COPD or asthma come in with PJP?) it seems certain conditions lead to higher risk. For instance, the rate of PJP in several autoimmune conditions was calculated in a large retrospective study of 240 patients who were diagnosed with both connective tissue disease and PJP (8). The frequencies of cases/10,000 hospitalizations/year were highest for GPA (89), followed by polyarteritis nodosa (65), inflammatory myopathy (27), and SLE (12). Multivariate analysis found that PAN (OR 10.20, 95% CI 5.69-18.29), GPA (7.81, 95% CI 4.71-13.03), and inflammatory myopathy (4.44, 95% CI 2.67-7.38) had the highest likelihood for PJP. SLE had an OR of 2.52 (95% CI 1.66-3.82). Mortality rates were highest for SLE (63%), GPA (58%) and PAN (48%). All those numbers were relative to rheumatoid arthritis. This could be due to the fact that most cases of RA tend to be treated with HCQ and things such as GPA or PAN require pulsed dose steroids, amongst other things. This seems to be the case, as a retrospective analysis found the rate of PJP in 858 hospitalized patients with SLE was only 0.6% (9). When looking at other studies, the incidence ranged from 0 to 2.56%. Within this cohort, however, the 5 patients who ended up having PJP were on 0.5mg/kg/d equivalent to prednisone and another immunosuppressant. The practice of prophylaxis seems to match the above rates. A cohort study of 316 patients (10) on immunosuppressive drugs (including azathioprine, cyclophosphamide, MMF, rituximab, or at least >20mg of prednisone) found that 124 (39%) received some sort of PJP prophylaxis, with those with vasculitis and dermatomyositis (75% and 60%, respectively) being more likely to get it compared to dermatomyositis (35%), and SLE (36%). Further, those who got primarily cyclophosphamide in combination with other drugs were more likely to receive prophylaxis. Multivariate analysis found that diagnosis (relative to SLE) and anchor drug were the only factors associated with receipt of PJP prophylaxis:
A retrospective cohort compared 12 patients with GPA and PJP and 32 patients with only GPA (11). There were no differences in the amount of steroids or the number of cytotoxic drugs in each group. Multivariate analysis found that lymphocyte count of 800 at the start of treatment and lymphocyte count of 600 at 3 months were associated with increased incidence of PJP:
Similar findings were reported in a chart review of 180 patients with GPA, of which 11 were diagnosed with PJP (12). While all patients received a wide range of steroids, however only those who received a combination of steroids and cyclophosphamide were subsequently found to have PJP.
This suggests that if you’re only on steroids, one may not necessarily need to prophylax against PJP, but this may not be the case. A retrospective study of 128 patients with PJP found that 44% of patients only received steroids prior to a diagnosis of pneumocystis (14) while another study of 142 patients found that corticosteroids were a risk factor in 116/134 patients (15). Of note, 70% of those patients with steroids were diagnosed while on a steroid taper while an additional 25% were getting a stable steroid dose. It should be noted that most of these patients were heme or SOT patients, and none had a rheumatological condition, but it highlights the fact that steroids, by themselves, can be a risk factor. Doses as low as 16mg were found in 25% of cases in a cohort of 116 patients (16), though only 13% of the overall cohort were rheumatological disease patients.
How much steroid is too much steroid?
A retrospective study of patients who received corticosteroids for at least 4 weeks for a rheumatological condition compared those who received PJP prophylaxis with TMP-SMX and those who did not (17). Over 28,000 episodes of therapy with non-high dose steroids and over 1600 episodes of therapy with high dose steroids (>30mg/day) were identified, with a significant increase in the incidence of PJP with rising steroid use:
Another cohort of 1092 patients who received at least >30mg/d of prednisolone equivalent were evaluated (18). Patients who received at least >60mg of prednisolone had the highest incidence of PJP when compared to a dose of at least 30mg (OR 3.35, 95% CI 1.19-10).
Mortality seems to be related to the overall steroid dose, with a retrospective study of 95 patients finding that the median prednisolone dose was higher in non-survivors (20mg vs 12.5mg), though the use of cyclophosphamide was associated with higher mortality as well (19). Multivariate analysis found that lymphocyte count and older age were associated with higher mortality, but not prednisolone dose:
But the effect of prednisolone may be a dose-dependent effect, with doses <5mg having a mortality rate of 13% compared to any dose above 10%:
Does PJP prophylaxis help? One study (17) found TMP-SMX did not reduce the one-year incidence of PJP, even when limited to the high risk subgroup (i.e those with pulsed steroids and baseline lymphopenia, which were independent factors associated with increased incidence in PJP by multivariate analysis):
This is at odds with another study (18) where after propensity score matching, univariate and multivariate analysis (using age and MPA as covariates) found that prophylaxis decreased the one year incidence of PCP:
Here, the biggest reduction was seen in the group with a steroid dose >60mg/day of prednisone (aHR 0.05, 95% CI 0.0004 to 0.4) but not in the lower dose group (HR 0.36, 95% CI 0.04 to 2.21). Notably, only GPA was associated with increased risk for PJP while high steroid use was not:
What to make of all of this?
In general, it seems that having an autoimmune disorder and being on a relative high dose of prednisone (think of 30mg) should warrant consideration for prophylaxis. Those who receive less steroids can most likely avoid prophylaxis, as long as they do not have another immunosuppressive on board. Vague, I know. One editorial (20) recommended that PCP prophylaxis should be limited to those with GPA, patients treated with cyclophosphamide or high dose MTX, and those who receive at least 20mg of steroids for at least 30 days OR >16mg of steroids for 60 days with at least one of the following:
- Age >50
- Lymphopenia <600
Another editorial (21) proposes the following table as a recommendation for when to start and stop prophylaxis
Note that certain diagnosis (GPA and microscopic polyangiitis) get you prophylaxis despite the low dose of steroids, while others (SLE and dermatomyositis), prophylaxis for low dose steroids is contingent upon things such as baseline lymphopenia, low CD4, cyclophosphamide use, or initial steroid use >60mg.
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