PCP is a common opportunistic infection both in HIV and non-HIV immunocompromised patients. Previous studies have suggested that long-term high-dose glucocorticoid, low lymphocyte counts, males, CMV infection, and older than 65 years of age are risk factors for PCP[16–17]. However, there are few studies on the prognostic factors of PCP in non-HIV immunocompromised patients with inconsistent conclusions. In our study, the PCP mortality was as high as 41.2%, 82.3% (29/34) of the patients admit to the ICU, 50% patients (17/34) required mechanical ventilation, and the mortality in the ICU was 48.3% (14/29).
In our study, kidney recipients accounted for 55.8%, connective tissue diseases accounted for 14.8%, hematological diseases accounted for 11.7%, and other 14.7%. The mortality of kidney PCP recipients was 31.5%, and the mortality of non-kidney transplant PCP patients was 53.3%. Univariable analysis found that age, BMI, ALB, SOFA score on the first day of ICU admission, delayed initiation of the treatment, and invasive mechanical ventilation may be risk factors for death in PJP patients. This is consistent with the results of a meta-analysis of prognostic factors for death of non-HIV PCP patients conducted by Yao Liu et al, the risk factors associated with increased mortality include old age, women, respiratory failure, high LDH, Hypoproteinemia, bacterial infection, Aspergillus co-infection, etc. (P < 0.05)[18]. Older age, low BMI, and hypoalbuminemia all reflect the nutritional status of patients, and patients with poor nutritional status often had high risk of death. Malnutrition may cause the immunosuppress in HIV-related immunodeficiency and is an independent factor associated with poor survival[19], which is consistent with the study conducted in children HIV patients [20]. Mouna Hanachi et al. reported a case of anorexia nervosa patient suffered PCP in a malnourished status, and its secondary immune deficiency is related to malnutrition,besides that༌the degree of immunodeficiency is directly related to the degree of malnutrition[21]. Therefore, for malnourished PCP patients, nutritional support should be strengthened to reduce the persistent state of immunosuppression. Jumpei Akahane et al. retrospectively analyzed 102 cases of non-HIV PJP with a 30-day mortality about 20.5%. Compared with survivors, the serum ALB level significantly lower and the age was older in non-survivors. Multi-logistic regression analysis showed that high nitrogen/ALB ratio is significantly correlated with the 30-day mortality risk at the beginning of treatment[22].
Multi-logistic regression analysis found no independent risk factors associated with death in our research. However, there was a significant difference in the survival time between patients older than 60 years and younger than 60 years. (See Table 5 for the survival curve), which is similar with a study conducted by Benjamin Jean Gaborit and other scholars on the outcome and prognostic factors of non-HIV PJP patients, they found that advanced age may be independent risk factor of progressing to severe PCP, the SOFA score and co-infected with virus are closely related to the 90-day high mortality of the patient, and if the BALF present lymphocyte elevation of alveolar inflammation ((lymphocytes > 10%, neutrophils > 5%, and activation Macrophages), that might be the protective factors[23].
However, in our study, there were no difference on whether there was shock at admission, co-infected with CMV, bacteria or fungi, the average daily dose of TMP/SMX in the first 7 days of treatment, and LDH level on the 7th day. However, the LDH of the death group on day 7 was significantly higher than that of the recovered group. Zaman et al. reported that LDH > 450 U/L can predict Pneumocystis jirovecii infection, normal LDH cannot rule out the Pneumocystis jirovecii infection, and the progressive increase of LDH level during treatment can predict poor prognosis, but without specificity[24]. A 17 years retrospective study conducted by Julius J Schmidt et al. found that LDH was a predictor of hospital mortality by multi-logistic regression analysis (adjusted OR 1.17 (95% CI 1.09–1.27), p < 0.0001), the cut-off point of LDH was 495U/L, and the specificity and sensitivity of predicting hospital mortality was 70%[25].
Previous studies have suggested that the combined infection of CMV and Pneumocystis jirovecii increased the risk of ARDS and the length of stay in the ICU, but there was no statistical difference in mortality between the two groups, but ARDS was an independent risk factor of death in PCP patients[26]. This is consistent with our research. In this study, 15 patients in the recovered group were simultaneously infected with CMV, and 8 patients in the death group were infected with CMV,there was no statistical difference between the two groups. However, CMV infection may be a risk factor for PCP in kidney transplant patients, because CMV infection may change the recipient’s immune response and cause immunocompromise[17]. In our research, we calculated the average daily dose of TMP/SMX and found that there was no statistical difference between the recovered group and the death group. However, 55.8% of patients did not reach the recommended dose, there was a statistical difference in the time from symptom onset to the initiation time of TMP/SMX treatment. The earlier the treatment started, the less likely that to progress to severe cases. An observational study conducted by Ryoung-Eun Ko et al. concluded that when the non-HIV PCP patients present hypoxemic respiratory failure, there is no correlation between the time of PCP treatment and the outcome, but age (adjusted OR 1.07, 95% confidence interval 1.01–1.14) and initial treatment failure (adjusted OR 13.03, 95% confidence interval 2.34–72.65) were independently associated with increased mortality[11]. The study by Julius J Schmidt et al. found that 40% of patients received TMP/SMX at a lower dose than recommended, and these patients had a higher risk of death (HR 1.80 (95% CI 1.10–3.44), P = 0.02)[25].
The clinical treatment plan of all patients in our study were mainly divided into the single TMP/SMX group, the early combination with echinocandin, delayed combination with echinocandin and single echinocandin group. We found that the P value was equal to 0.07 between the four groups, there was no statistical difference, maybe it was because of the small sample size. However, it can be seen from Table 6 that the early combination group accounted for the highest proportion in the recovered group. The patients who died were mainly distributed in the single TMP/SMX group or delayed combination group. TMP/SMX is the first-line treatment choice of PCP. It is recommended that TMP (trimethoprim) 15-20mg/kg/day, 3–4 times per day, and last about 14–21 days. Or 5mg/kg TMP, 25mg/kg SMX 3–4 times per day, for 21 days[13] .However, the effectiveness of TMP/SMX in the treatment of PCP is limited by its serious adverse drug side effects. The drug side effects and intolerance can cause the initial treatment failure or insufficient dose which may cause bad outcome. In our study, we also calculated the total dose of TMP/SMX in the first 7 days of patients, and found that the total dose in the first 7 days in the improvement group (35.1 ± 16.01g) was higher than that of the death group (29.08 ± 15.01g), but there was no statistical difference between the two groups. As we know, Pneumocystis jirovecii is divided into three forms: trophozoites, cysts, and sporozoites. Caspofungin can inhibit the formation of Pneumocystis jirovecii cysts, but there are few studies on the safety and effectiveness of combined with TMP/SMX. In a retrospective study of HIV-infected patients with moderate to severe PJP, it was found that compared with TMP/SMX monotherapy, combination of caspofungin and TMP/SMX was an effective and promising first-line treatment without more adverse events. Patients receiving caspofungin treatment have a better treatment response and lower all-cause hospital mortality. It is recommended that we should start combination with caspofungin as soon as possible[27]. A retrospective cohort study conducted by Zhang Gensheng et al. found that caspofungin combined with TMP/SMX was an effective treatment for severe non-HIV PCP patients, especially mechanical ventilated patients, although the samples size was just 14[28],which is consistent with our research. Fan Jin et al. found that high initial BDG concentration may be an indicator for predicting the efficacy of caspofungin in non-HIV PCP patients, and even suggest that in non-HIV PCP patients with moderate to severe respiratory failure and whose BDG ≥ 800 pg/ml, caspofungin and TMP/SMX combination should be chosen as initial treatment[29], which was the same with our research that early combination tend to get better prognosis. Besides, other studies have shown that low-dose TMP/SMX combined with caspofungin for kidney transplant recipients can effectively treat PCP and reduce the adverse reactions of TMP/SMX[30].
The guidelines recommend that glucocorticoids can be used to treat moderate to severe HIV-positive PCP patients. However, the use of glucocorticoids in non-HIV PCP patients is still controversial. In this study, glucocorticoids are not used as routine treatments for non-HIV patients, except for liver and kidney transplantation, in whom we suspended all the anti-rejection drugs, and prescribed 40–80 mg methylprednisolone per day as an alternative treatment. Recently, William Mundo et al. found that glucocorticoids can significantly reduce the mortality of non-HIV PCP patients[31], although it still remains controversial. Glucocorticoid treatment may increase the risk of Candida and other fungal infections.
The PCP guidelines for SOT recommend routine TMP-SMX prevention for 6–12 months after transplantation. Routine prevention should also be carried out for patients who suffered connective tissue diseases and take 20 mg prednisone for more than 8 weeks. The recommended preventive dose is 0.48-0.96g qd or 0.96g tiw. Due to the adverse effects of TMP-SMX, no patients in our research were routinely prevented before PCP occurred, which is similar to other previous studies[13–14].
According to our research, for patients with poor nutritional status, elderly SOT or oral prednisone 20mg glucocorticoid patients, more education should be strengthened, we should perform targeted prevention, because these patients may have higher mortality and worse prognosis.
This study still has some limitations. First, because PCP is a rare disease, the sample size of the study is small, which may affect the results of multi-logic regression analysis, resulting in false negatives and unable to establish a prognostic model. But recently we included more and more PCP patients than before because the application of mNGS and can screen more PCP patients earlier than before, we are conducting prospective research and looking forward to sharing more research results in the future. Second, as a retrospective study, patients came from different ICU, and there may be differences in diagnosis and treatment which may cause selection bias. Third, because the enrolled patients are immunocompromised patients with different primary diseases, such as stem cell transplantation, kidney transplantation and autoimmune disease itself, whose different immunosuppression status may lead to selection bias.