key: cord-0684080-3r8weo2e authors: Mo, X.‐D.; Zhang, X.‐H.; Xu, L.‐P.; Wang, Y.; Yan, C.‐H.; Chen, H.; Chen, Y.‐H.; Han, W.; Wang, F.‐R.; Wang, J.‐Z.; Liu, K.‐Y.; Huang, X.‐J. title: Late‐onset severe pneumonia after allogeneic hematopoietic stem cell transplantation: prognostic factors and treatments date: 2016-08-02 journal: Transpl Infect Dis DOI: 10.1111/tid.12553 sha: 77fbd68252a7d914d2ab7cb7c79871296f7027cb doc_id: 684080 cord_uid: 3r8weo2e BACKGROUND: In this study, we aimed to evaluate the prognostic factors associated with and treatments for late‐onset severe pneumonia (LOSP) in patients who underwent allogeneic hematopoietic stem cell transplantation (allo‐HSCT). METHODS: Fifty consecutive patients who underwent non‐T‐cell‐depleted allo‐HSCT at the Peking University Institute of Hematology and met the criterion of LOSP after allo‐HSCT were enrolled. RESULTS: The median time from allo‐HSCT to the occurrence of LOSP was 231 (90–1487) days. Twenty‐eight patients harbored 1 or more pathogens (infectious LOSP, I‐LOSP), whereas 22 did not harbor any pathogens (non‐infectious LOSP, NI‐LOSP). The 100‐day survival rate of LOSP patients was 31.1%. Patients smoking before allo‐HSCT (0% vs. 35.4%, P = 0.002) and male gender (20.0% vs. 61.9%, P = 0.026) had lower 100‐day survival rate. Patients with a lower bronchoalveolar lavage fluid (BALF) neutrophil percentage had higher 100‐day survival rate relative to those with higher BALF neutrophil percentage (45.5% vs. 16.7%, P = 0.012). The 100‐day survival rate of patients with I‐LOSP was lower than that of patients with NI‐LOSP (19.1% vs. 46.9%, P = 0.043). Patients given late (≥1 week after LOSP diagnosis) and low‐dose methylprednisolone (MP) therapy (≤2 mg/kg/day) had the best 100‐day survival rate. In the multivariate analysis, nonsmoking before allo‐HSCT and late and low‐dose MP therapy were significantly associated with a better survival after LOSP. CONCLUSION: LOSP is a severe complication after allo‐HSCT. The correct timing and corticosteroid dosage in the context of broad‐spectrum antimicrobial therapy might further improve the outcomes of patients with LOSP. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies, by which many patients are cured or achieve long-term remission. Although transplant techniques have progressed significantly, treatment-related mortality continues to seriously influence the survival of patients who have undergone allo-HSCT, and severe pulmonary complications are considered among the worst complications associated with this procedure. Infectious and non-infectious pulmonary complications are found in 68% and 29% of HSCT recipients, respectively (1) . Severe pulmonary complications, therefore, account for a significant percentage of deaths after transplantation. Pulmonary complications (infectious or non-infectious) commonly occur within 3 months after transplantation (2) . As increasing numbers of patients achieve long-term survival, further attention should be given to late-onset pulmonary complications (≥3 months after transplantation). Chen et al. (3) observed that during a median follow-up of 2 years, 25% of patients developed at least 1 episode of pneumonia after transplantation, and the cumulative incidence of a first pneumonia episode at 4 years ranged from 18% to 39%. We observed that some patients suffered from acute severe pneumonia >3 months after allo-HSCT and that these patients had some common features, such as rapid progression, an absence of pathogens, and high mortality. Liu et al. (4) reported a study of 20 patients who experienced lateonset severe pneumonia (LOSP) after allo-HSCT. The incidence of LOSP was 1.3%; among the affected patients, only 8 tested positive for pathogens, and 11 died despite receiving comprehensive therapy. It has been suggested that LOSP might be a severe complication affecting the clinical outcomes of allo-HSCT recipients. However, relatively few studies have addressed the prognostic factors associated with and treatments for LOSP after allo-HSCT. In this retrospective study, we therefore aimed to evaluate these prognostic factors and treatments in patients with LOSP after undergoing human leukocyte antigen (HLA)-related donor HSCT. Consecutive patients who underwent non-T-celldepleted allo-HSCT at the Peking University Institute of Hematology from June 1, 2012 to June 30, 2015 were enrolled if they met the criteria used to define LOSP after allo-HSCT and underwent chest computerized tomography (CT) and bronchoalveolar lavage (BAL). Patients who experienced severe pneumonia within 3 months after HSCT and those who did not receive CT or BAL were excluded. A total of 50 patients were enrolled; 16 and 34 had undergone HLA-identical sibling donor HSCT and HLA-haploidentical related donor (haplo-RD) HSCT, respectively ( Table 1 ). The final follow-up visits for the endpoint analysis were conducted in September 1, 2015. Informed consent was obtained from all patients, and the study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Peking University People's Hospital. Five included patients were previously reported by Liu et al. (4) . Preconditioning comprised cytarabine, busulfan (3.2 mg/kg/day, days À8 to À6), cyclophosphamide (1.8 g/m 2 /day, days À5 to À4), and simustine (250 mg/m 2 , day À3). Cytarabine was administered at 4 g/m 2 /day (days À10 to À9) in the haplo-RD group and 2 g/m 2 /day (day À9) in the identical sibling donor group, and rabbit anti-thymocyte globulin (2.5 mg/kg/ day, days À5 to À2; Thymoglobulin, Sanofi, France) was administered in the haplo-RD group (5, 6) . Granulocyte colony-stimulating factor-mobilized, fresh, and unmanipulated harvested bone marrow and peripheral blood were infused into the recipients on the same day as collection. Granulocyte colony-stimulating factor (5 lg/kg/day subcutaneously) was administered to all haplo-RD HSCT recipients from day 6 after transplantation until their white blood cell counts exceeded 2 9 10 9 cells/L for 3 consecutive days. In addition, patients received cyclosporine, mycophenolate mofetil, and short-term methotrexate for graft-versus-host disease (GVHD) prophylaxis (7, 8) . Comorbidities in HSCT recipients were assessed according to the hematopoietic cell transplantation-specific comorbidity index (9) . The donor selection, HLA typing, and stem cell harvesting procedures have been described elsewhere (10) . All patients were hospitalized in rooms with high efficiency particle-air filters for 4-5 weeks, from day À10 to the time at which neutrophil recovery was achieved. All received antibiotic prophylaxis with oral trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii infection from days À10 to +180. Patients also received fluconazole for Candida albicans from days À10 to +75, acyclovir for herpex simplex virus (HSV) and varicella zoster virus (VZV) from day +1 to the time of cyclosporine discontinuation, and ciprofloxacin for intestinal decontamination. Ganciclovir (5 mg/kg) was administered intravenously (IV) twice daily from days À9 to À2 for prophylaxis against cytomegalovirus (CMV) infection. The infection surveillance and treatment protocols used at our institute were previously described elsewhere (11) (12) (13) . The following major criteria were used to define LOSP: (i) invasive mechanical ventilation and (ii) septic shock requiring vasopressors. The following minor criteria were used: (i) a respiratory rate ≥30 breaths/min; (ii) arterial oxygen pressure/fraction of inspired oxygen ratio ≤250; (iii) multilobar infiltrate; (iv) confusion/ disorientation; (v) uremia (blood urea nitrogen level ≥20 mg/dL); (vi) leukopenia resulting solely from infection (white blood cell count <4.0 9 10 9 cells/L); (vii) thrombocytopenia (platelet count <100 9 10 9 cells/L); (viii) hypothermia (core temperature, <36°C); and (ix) hypotension requiring aggressive fluid resuscitation (14) . No evidence of cardiogenic pulmonary edema was observed according to clinical findings, central venous pressure measurements, or cardiac echocardiography. Patients who experienced pneumonia >3 months after allo-HSCT and exhibited 1 major criterion or 3 minor criteria were diagnosed as having LOSP. All patients underwent CT and BAL. Blood and BAL fluid (BALF) samples were routinely subjected to the following tests: (i) Gram stain, fungal stain, Grocott-Gomori methenamine-silver stain, and acid-fast bacilli stain; (ii) cytology examination; (iii) bacterial and fungal culture; and (iv) real-time polymerase chain reaction (PCR) and reverse transcription-PCR assays for the detection of atypical bacteria (e.g., Legionella species, Mycoplasma pneumoniae, and Chlamydia pneumoniae), herpesviruses (HSV types 1 (15) . For positive CMV and EBV targets, the pathogen load was determined by quantitative PCR. All patients with LOSP received oxygen therapy, empirical broad-spectrum antimicrobial therapies (covering Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, Aspergillus [itraconazole: 200 mg IV, 12 hourly for 48 h then 200 mg IV daily; voriconazole: 6 mg/kg IV, 12-hourly for 24 h then 4 mg/kg IV, 12-hourly; caspofungin: 70-mg loading dose, then 50 mg IV, daily; micafungin: 100-150 mg IV, daily; liposomal amphotericin B: 1-3 mg/kg IV, daily; and amphotericin B deoxycholate: 0.5-1.0 mg/kg IV, daily], and P. jiroveciii), and corticosteroids. Some patients received donor lymphocyte infusions (DLIs). Patients with increased hypoxemia despite receiving high levels of supplemental nasal oxygen were transferred to the intensive care unit (ICU), where some required noninvasive ventilation or endotracheal intubation. High-risk patients were defined as follows: (i) acute leukemia patients in the first or second complete remission with a cytogenetic marker of "poor-risk," including t(4,11) and t(9,22); (ii) patients in complete remission after third complete remission; (iii) patients in partial remission, nonremission, or in a state of relapse before HSCT; and (iv) patients with chronic myelogenous leukemia beyond the first chronic phase. All other patients were stratified into standard-risk categories (7) . Neutrophil engraftment was defined as the first day when the absolute neutrophil count was ≥0.5 9 10 9 /L for 3 consecutive days, and platelet engraftment was defined as the first day when the platelet count was ≥20 9 10 9 /L for 7 consecutive days without transfusion. GVHD was diagnosed in accordance with the accepted international criteria (16, 17) . Overall survival (OS) was defined as the time from pneumonia to death from any cause or the date of last contact. Infectious LOSP (I-LOSP) was defined as the identification of any pathogen in blood and/or BALF samples; non-infectious LOSP (NI-LOSP) was defined as the absence of pathogens in blood and/or BALF samples. Data were censored at the time of death or the last available follow-up. Continuous variables were compared using the Mann-Whitney U-test; categorical variables were compared using the chi-squared test and Fisher's exact test. The Kaplan-Meier method was used to estimate the probability of OS. A landmark analysis was performed to assess the survival of patients with LOSP. The post-transplant day of LOSP diagnosis was defined as the landmark day. OS was calculated from the landmark day to death from any cause or the date of last contact. Potential prognostic factors for 100-day OS after LOSP were evaluated through univariate and multivariate analyses, using Cox proportional hazards regression with a backwardstepwise model selection approach. Independent variables with P-values >0.1 were sequentially excluded from the model, and the level of significance was set at P < 0.05. All reported P-values were based on 2-sided tests. Data analyses were conducted with SPSS software (SPSS Inc., Chicago, Illinois, USA). breaths/min. One patient exhibited confusion, and 2 patients experienced septic shock. Thirty-six patients were transferred to the ICU; 21 required noninvasive ventilation, and 31 required endotracheal intubation. Thirty-four of the 35 patients who died after treatment, died of LOSP, and the median duration from LOSP diagnosis to death was 29 (6-82) days. The remaining patient was cured after treatment but died of relapse 275 days after LOSP. The OS rate at 100 days after LOSP was 31.1% (Fig. 1A) . Patients smoking before allo-HSCT (0% vs. 35.4%, P = 0.002) and male gender (20.0% vs. 61.9%, P = 0.026, Fig. 1B ) had lower 100-day survival rate. However, pre-HSCT lung function test did not influence the 100-day OS rate of LOSP patients (FEV1%: ≥median vs. 2 mg/kg/day). In addition, the 100-day OS rate after LOSP for patients given late MP therapy (≥1 week after LOSP diagnosis) was better than that of patients given early MP therapy (<1 week after LOSP diagnosis). Patients who received late, low-dose MP therapy had the best outcomes ( Fig. 3A-C) . Eight patients received DLI, and the median time from LOSP diagnosis to DLI was 12 (4-32) days. The median CD3 + cell dose was 0.5 (0.3-0.6) 9 10 8 cells/ kg. DLI did not improve survival among patients with LOSP ( Figure S2B ). Female gender, nonsmoking before allo-HSCT, a lower BALF neutrophil percentage (using the median as the cutoff point), NI-LOSP, and late and low-dose MP therapy were associated with a better OS after LOSP in the univariate analysis. In the multivariate analysis, nonsmoking before allo-HSCT and late and low-dose MP therapy were significantly associated with a better OS after LOSP (Table 5 ). Although transplant techniques have progressed significantly, LOSP after allo-HSCT continues to seriously influence patient survival. In this study, the 100-day OS rate after LOSP was only 31.1%, despite the use of several therapies. We observed that patients who smoked before allo-HSCT had poorer outcomes and that the BALF neutrophil percentage might predict the outcomes of patients with LOSP. In addition, the correct MP dose and timing might further improve the outcomes of these patients. In this study, blood and/or BALF samples from 28 of the 50 patients were positive for pathogens, indicating that infection may be an important cause of LOSP. Chen et al. (3) also observed that infection was an important cause of late-onset pneumonia after allo-HSCT. In addition, pathogens were not detected in 22 patients and most of them might thus meet the diagnostic criteria for IPS (18) , suggesting that alloimmune reactions play an important role in the development of LOSP (19) . However, Seo et al. (20) reported that more than half of the patients previously diagnosed with IPS were found to harbor pathogens according to currently available diagnostic methods, which suggests that infection remains the most important cause of LOSP. In addition, most infectious agents can trigger autoimmunity via different mechanisms (21) , and many studies have observed that infections, particularly the viral infections, can trigger a graft-versus-host (GVH) reaction (22) (23) (24) . Therefore, we suggest that the immune reactions in patients with NI-LOSP might also have occult infectious etiologies. Although some pathogens detected in BALF likely represent the shedding of pulmonary pathogens rather than invasive disease (25), we observed higher CMV and EBV loads in BALF than in plasma. Patients with LOSP might be too ill to undergo further invasive examinations (e.g., biopsy for histological confirmation). In addition, Seo et al. (20) observed that IPS patients with detectable pathogens had a significantly worse 100-day OS rate, compared to patients without pathogens, which was in accordance with our results. Therefore, the correct method of identifying pathogens from blood and/or BALF might be critical to improving the outcomes of patients with LOSP. We observed that the median duration from LOSP diagnosis to death was 29 days. We also observed that the median value of oxygenation index was <200, and as high as 62% (31/50) of the LOSP patients need mechanical ventilation. It is suggested that LOSP progresses rapidly and acute respiratory distress syndrome occurred in most of the patients. Therefore, our strategy of empirical broad-spectrum antimicrobial therapy administration was reasonable. In addition, we observed that the initial corticosteroid therapy dosage and timing were associated with the outcomes of patients with LOSP; notably, early and high-dose MP therapy did not improve the outcomes. The hypothesized benefit gained from corticosteroid administration for severe pneumonia might be due to reduced proinflammatory cytokine production, downregulated leukocyte adhesion protein expression, and the prevention of excessive alveolar collagen deposition (26) . However, infection may be an important cause of LOSP, and highdose MP did not help to eliminate the pathogens; additionally secondary infections might associate with high-dose MP therapy. Many studies found that lowdose corticosteroid therapy may improve the outcomes of patients with severe pneumonia (27, 28) . In a systematic review by Lamontagne et al. (29) , treatment with a corticosteroid dosage equivalent to ≤2 mg/kg/ day of MP was associated with lower hospital mortality in patients with severe pneumonia, and Tang et al. (30) found that an MP dosage of 0.5-2.5 mg/kg/day or the equivalent was associated with improved mortality and morbidity outcomes without increased adverse reactions in patients with severe pneumonia. We observed better survival rates among patients with LOSP treated with low-dose MP (≤2 mg/kg/day). In addition, as mentioned above, immune reactions, which might also have occult infectious etiologies, could play an important role in the development of LOSP. Although Meduri et al. (28) observed that MP used in early severe acute respiratory distress syndrome was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay, we observed that patients receiving MP therapy within 1 week after LOSP diagnosis had poor outcomes. We speculate that early MP therapy might lead to a loss of infection control and may thus worsen the situation. In cases of LOSP after allo-HSCT, wherein pathogens were cleared using effective anti-infection treatments but infection-related immune reactions remained, corticosteroid therapy could improve patient outcomes. Thus, this is an important finding and underscores that corticosteroid therapy should not be used in all patients with LOSP after allo-HSCT. We observed that viral infection might be an important cause of LOSP; however, we did not identify effective treatments for most viral infections. As donor leukocytes usually contain cytotoxic T cells presensitized to various viruses, DLI might be a potential treatment for viral infection after allo-HSCT. Liu et al. (4) observed that among 6 patients with LOSP who received DLI, 3 survived until the end of follow-up. However, in our study, DLI did not improve the outcomes of patients with LOSP. We speculated that DLI could trigger GVH effects, which might exacerbate immune-related lung injuries, and could also lead to myelosuppression and secondary infection. Several factors were also associated with OS in patients with LOSP. For example, we observed that female patients with LOSP had a better OS. Similarly, Schwartz et al. (31) showed that the male gender was associated with diminished survival in idiopathic pulmonary fibrosis. This might be a result of the higher frequency of smokers among male patients (i.e., all smokers in this study were male), as smoking before HSCT was an independent risk factor for worse survival in our multivariate analysis. In addition, patients with a higher BALF neutrophil percentage had a worse OS. Several studies observed that a higher BALF neutrophil percentage was associated with a poor outcome in both infectious and non-infectious lung injury patients (32) (33) (34) . It has therefore been suggested that overzealous neutrophil activation might result in severe alveolar damage resulting from the release of cytotoxic and immune cell-activating agents (35) . This study had several limitations. First, this was a retrospective study with a relatively small number of patients with LOSP, which might have influenced the accuracy of our findings. Second, we might have underestimated the occurrence of I-LOSP in this study because the number of pathogens that could be tested was relatively small. Third, we could not detect the loads of viruses except for CMV and EBV, and therefore, we could not further identify the association between the virus load and the outcomes of LOSP. Finally, the large number of different treatments administered to treat patients in both the I-LOSP and NI-LOSP groups introduced heterogeneity to our justification of the generic conclusion regarding the advantage given by late and low-dose MP therapy with respect to the clinical outcomes of patients with LOSP. Future prospective and multicenter studies will provide more information about the prognostic factors and treatments of LOSP after allo-HSCT. In summary, we observed that LOSP is a severe complication after allo-HSCT. Patients who smoked before allo-HSCT had a worse survival rate. The correct dosage and timing of MP in the context of broadspectrum antimicrobial therapy could further improve the outcomes of patients with LOSP. Additional Supporting Information may be found online in the supporting information tab for this article: Figure S1 . Clinical outcomes of late-onset severe pneumonia according to bronchoalveolar lavage fluid (BALF) neutrophil (A) and lymphocyte (B) percentage. Figure S2 . Clinical outcomes of late-onset severe pneumonia according to patients (A) with and without ribavirin (B) with and without donor lymphocyte infusion (DLI). 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Conflicts: None of the authors have any potential financial conflict of interest related to this report.