key: cord-1049674-ohq8l8mn authors: Choi, Yu Hyeon; Jeong, Hyung Joo; An, Hong Yul; Kim, You Sun; Lee, Eui Jun; Lee, Bongjin; Kang, Hyoung Jin; Shin, Hee Young; Park, June Dong title: Early predictors of mortality in children with pulmonary complications after haematopoietic stem cell transplantation date: 2017-10-12 journal: Pediatr Transplant DOI: 10.1111/petr.13062 sha: 4f4e9b22eef9a69f2c98833ac60e080ecb0dad31 doc_id: 1049674 cord_uid: ohq8l8mn PC are a main cause of death following HSCT in children. We aimed to evaluate early predictors of mortality in paediatric recipients with PCs. A retrospective observational study of 35 patients with 49 episodes of PI on chest radiography (of 124 patients) who had undergone HSCT at a tertiary university hospital between January 2011 and December 2012 was performed. During follow‐up (median 26.1 months), 15 episodes led to death (30.6%). An aetiologic diagnosis was made by non‐invasive tests in 24 episodes (49.0%) and by adding bronchoalveolar lavage and/or lung biopsy in 7 episodes with diagnostic yield (77.8%, P = .001). Thus, a specific diagnosis was obtained in 63.3% of the episodes. Aetiology identification and treatment modification after diagnosis did not decrease mortality (P = .057, P = .481). However, the number of organ dysfunctions at the beginning of PI was higher in the mortality group, compared to the survivor group (1.7 ± 1.2 vs 0.32 ± 0.59; P = .001). Hepatic dysfunction (OR, 11.145; 95% CI, 1.23 to 101.29; P = .032) and neutropaenia (OR, 10.558; 95% CI, 1.07 to 104.65; P = .044) were independently associated with risk of mortality. Therefore, hepatic dysfunction and neutropaenia are independent early predictors of mortality in HSCT recipients with PCs. that contribute to the deterioration of patients with PCs should be investigated. However, most previous studies have reported on factors related to PC development, focusing on preventive strategies. Thus, few studies currently exist regarding the early predictors of respiratory failure and death associated with PCs after HSCT. 4 Therefore, the aim of this study was to evaluate the ability of diagnostic work-ups, final diagnoses, treatment modification, and medical conditions at the time of PC initiation to predict mortality in HSCT recipient children. Between January 2011 and December 2012, 128 paediatric patients underwent 144 HSCTs at our hospital. We initially excluded 3 recipients with a loss of graft and 1 recipient who was transferred to another hospital due to the progression of an underlying disease immediately following stem cell infusion. Sixteen patients underwent a second HSCT as a planned transplantation during the study period. In such cases, we considered only the second HSCT. Among the 124 evaluated paediatric patients, PCs were investigated until relapse, death, or December 31, 2015, whichever came first. A total of 49 PI episodes in 35 patients were retrospectively identified during the median follow-up period of 26.1 months (IQR, 2.9-38.4) and were finally included in the present study. This study is in accordance with the Helsinki Declaration of 1975. Institutional review board approval was obtained for this study (2016/08/16). Data were collected regarding general characteristics, including transplant-related factors, clinical findings, and outcomes for each PC episode. The general characteristics assessed included age, sex, underlying disease, previous lung problems, the number and type of HSCTs, stem cell source, engraftment day, and human leucocyte antigen compatibility of the allograft. The underlying diseases were categorized as leukaemia/lymphoma, solid tumour, and non-malignant disease, including primary immunodeficiency, aplastic anaemia, and osteopetrosis. Previous lung problems were identified when the patients had an active lung disease at the time of the HSCT infusion. Neutrophil engraftment day was defined as 3 consecutive days with an absolute neutrophil count greater than or equal to 1.0 × 10 9 cells/L. A PC was defined as the new development of PIs on chest radiography simultaneously with respiratory symptoms requiring admission for evaluation or treatment. Respiratory symptoms included cough, sputum, dyspnoea, chest pain, blood tinged sputum, and cyanosis. For each PC episode, the time to diagnosis from transplantation, diagnostic procedures applied, time to BAL or LB since PI appearance, and relevant medical conditions were investigated. In addition, changes in the empirical treatment attributable to the results from diagnostic tests were recorded. The evaluation of medical conditions at the time of PI initiation considered the following: the presence of engraftment syndrome, acute GVHD, chronic GVHD, VOD, or CMV infection; medication being administrated; and organ dysfunction, identified using the specific Pediatric Critical Care Medicine criteria published in 2003. 20 Criteria for organ dysfunction of the cardiovascular, neurological, haematological, renal, gastrointestinal, and hepatic systems were evaluated, and the data indicating the most severe condition within 48 hours of PI appearance were used. Respiratory dysfunction was excluded from the criteria as arterial blood gas was not frequently measured in children with mild respiratory distress. Acute and chronic GVHDs were assessed as described elsewhere. 21, 22 CMV infection was defined as the need for pre-emptive or curative induction therapy with ganciclovir. Pre-emptive treatment was started with a halfdose therapy of ganciclovir when the CMV antigenemia assay results showed 1 to 10 antigen-expressing cells/200 000 polymorphonuclear leucocytes, and induction therapy was started when the results showed more than 10 antigens expressing cells/200 000 polymorphonuclear leucocytes. For drugs already being administered, we noted the following: antibiotics or antifungal agents intravenously injected; inotropic or vasopressors; and immunosuppressants including tacrolimus, cyclosporine, mycophenolate mofetil, and steroids as prophylaxis or treatment of transplantation-related complications. According to the analysis of accompanying medical conditions, an early predictor of mortality was defined as a statistically significant comorbidity occurring with PCs within 48 hours of PI initiation. The outcome of each episode was considered in terms of the number of admissions to the PICU, unexpected events such as CPR or unplanned transfer to the PICU, and survival to hospital discharge. Cause of death was clarified as related to the PI or not, and non-survivors included only those patients who died as a result of PCs. For that reason, two patients who died were classified into the survivor group, because they died due to the recurrence of underlying disease. PIs were evaluated using non-invasive and/or invasive work-ups. The non-invasive tests included blood cultures, sputum examination, serology tests, chest CT scans, echocardiography, and pulmonary function tests. Sputum was collected by expectoration, using nasopharyngeal aspiration, a swab, or transtracheal aspiration if the patient was already intubated. Sputum was Gram stained; cultured for bacteria, virus, and fungi; and subjected to a PCR for viruses and Mycoplasma pneumoniae. Additionally, an acid-fast bacillus stain and sputum culture were performed when a high suspicion of Mycobacterium tuberculosis infection existed. For serology tests, the CMV antigen test or viral load, aspergillus antigen test, and mycoplasma antibody were assessed. As invasive tests, BAL and LB were arranged based on a joint discussion between an oncologist, pulmonologist, intensivist, and radiologist. BAL was performed by a paediatric pulmonologist using an age-adjusted flexible bronchoscope. Sterile normal saline was instilled in 2 aliquots of 10 to 20 mL, which was suctioned and sent for pathology and microbiology evaluation. VATS LBs were performed by paediatric thoracic surgeons and ultrasound-guided LBs were performed by a paediatric radiologist. All biopsy and BAL samples were screened for infectious pathogens with Gram, acid-fast, Gomori methenamine silver stains, and viral immunostains. Samples were also processed for bacteria, viruses, and fungi cultures. The PCR for Mycobacterium, CMV, and respiratory virus including respiratory syncytial virus, metapneumovirus, parainfluenza, influenza, rhinovirus, and adenovirus was additionally performed using BAL fluid. An immunofluorescence assay and PCR for the detection of Pneumocystis jiroveci were also utilized. Diagnoses were based on clinical, radiologic, microbiologic, and pathologic findings and were thoroughly reviewed by two of the authors (YHC and JDP). 23 For non-infectious PCs, the following diagnoses were confirmed: IPS, non-cardiogenic pulmonary oedema and/or pleural effusion, PERDS, lung GVHD, transfusion-related acute lung injury, and ILD. IPS was defined as diffuse alveolar damage in the absence of identifiable infectious aetiologies on histologic examination. 27 ILD was defined in a similar manner to IPS, but was characterized by a different injury site and clinical features as according to recent study. 28 PERDS was considered in the presence of fever and evidence of pulmonary injury in the form of hypoxia (SpO 2 < 90%) and/or infiltrates on chest radiographs in the absence of clinical cardiac dysfunction. 29 To be diagnosed with PERDS, the symptoms and/or the radiographic findings had to have occurred within 5 days of neutrophil engraftment. 29 Lung GVHD was diagnosed primarily by the presence of obstructive pulmonary dysfunction based on pulmonary function tests, and accompanied by chest CT findings of areas showing patchy infiltration, bronchial dilatation, and hypo-attenuation or increased density. 30 Transfusion-related acute lung injury was identified whenever a patient developed a hypoxemic respiratory insufficiency during, or shortly after, transfusion of any blood product, according to outlined diagnostic criteria. 31 Pulmonary oedema and/or pleural effusion was defined as the presence of characteristic infiltrates or fluid within pleural spaces, negative cultures, and beneficial response to diuresis without cardiac dysfunction and excluding the above-mentioned lung problems. 32 Statistical analyses were performed using SPSS software (version 22; SPSS Inc., IBM, Armonk, NY, USA). Qualitative variables are described as numbers (%). Continuous variables are reported as means (±SD) or medians (IQR). The general characteristics were compared between survivors and non-survivors via a chi-square test or Fisher's exact test for categorical data, and via a t-test for continuous data. Logistic regression was performed to identify variables that were significantly associated with poor outcomes for each PI episode as assessed by an estimated odds ratio (OR) and 95% confidence interval (CI). Variables that showed a significant univariate result (P < .05) were included in a multivariate logistic regression. A multivariate model was constructed with forward stepwise methods using threshold P-values of .10 for removal or .05 for addition to the model. Survival was estimated using the Kaplan-Meier method, and differences were assessed using the log-rank test. The general characteristics of the 35 recipients (25 males and 10 females) with one or more PI episode following HSCT are summarized in Table 1 Using non-invasive tests, specific aetiologies were discovered in almost half of the PI episodes (24 episodes, 49%; Figure 1 ). Among these, two episodes included additional invasive tests, which did not show further useful information. However, 7 of the 25 episodes without pathogen discovered through non-invasive tests were given an aetiologic diagnosis by adding BAL and/or LB, resulting in a diagnostic yield (77.8%, P = .001). Finally, after vigorous diagnostic investigations, infectious causes were diagnosed in 17 episodes (34.7%), and non-infectious causes were diagnosed in 14 episodes (28.6%). However, about one-third of PCs were not identified (18 episodes, 36.7%; Table 2 ). In infectious PCs, viral pneumonia was the most commonly identified aetiology (13 episodes), and one of three patients with parainfluenza viral infection experienced TA-TMA at the same time. Among the non-infectious PCs, pulmonary oedema and/or pleural effusion without heart dysfunction, and lung GVHD were found in 4 episodes each. In this study, no patients were diagnosed with cryptogenic organizing pneumonia, bronchiolitis obliterans syndrome, or diffuse alveolar haemorrhage after diagnostic work-ups. Among transplantation-related complications present at the beginning of the PI, VOD had a higher incidence in the non-survivor group compared to that in the survivor group (2.9% vs 33.3%; P = .015; Table 3 ). In addition, among the medications being administered, (Table 4 ). Neutropaenia was significantly associated with poor outcome among infectious causes, but not among non-infectious causes (P = .005 vs P = .207). Figure 2 shows the overall survival rates of patients without either haematological and hepatic dys- F I G U R E 1 Aetiology identification and the diagnostic yield of non-invasive and invasive tests performed in children with PI after hematopoietic stem cell transplantation are depicted. After non-invasive tests, aetiologic diagnosis was confirmed in almost half of the episodes (49%). Among episodes with negative results on non-invasive tests, invasive tests were additionally performed in 9 episodes, which showed a higher diagnostic yield (77.8%) compared to that for the non-invasive tests (P = .001). Finally, 63% of PI were aetiologically identified especially for non-infectious PCs. The overall diagnostic yield of invasive tests in our study was similar (63.6%) and increased up to 77.8% in the group with negative results on the non-invasive tests. However, the majority of episodes (49%) were diagnosed using the non-invasive tests, and BAL and LB were performed in only 18% and 10% of the total episodes, respectively. Nevertheless, the mortality rate was lower (30.6%) in the present study compared to previous reports of paediatric recipients. 1, 38 As management of PCs is critically dependent on the possible or presumptive diagnosis, clinicians expect that the identification of specific aetiologies would allow for therapy to be removed, changed, or added, which would lead to survival. Consistent with previous studies, 2,4,10 we found that the modification of treatment based on examination results (performed in 29 episodes; 60.0%) did not influence the outcome. In contrast, Yoo et al 8 reported an affirmative effect of therapeutic modification following procedures for diffuse PI causing respiratory failure in cancer patients. However, their study may not generalize to HSCT patients as it was limited to a specialized ICU for critically ill cancer patients. Furthermore, most physicians decide treatment based on not only aetiologic diagnoses, but also responsiveness to empirical treatment and clinical experiences. Thus, it is difficult to find a direct effect of aetiologic diagnosis and treatment modification on outcomes without consideration of the medical condition. However, the previously mentioned studies on PCs did not analyse comorbidities, which occur in the majority of recipients following transplantation, and may affect treatment choice and outcome. Our study extensively investigated the predictors of outcome through the inclusion of comorbidities, as well as aetiologic diagnosis and treatment modifications. Although our study did not find a relationship between treatment modification and outcome, targeted therapy according to the evaluation result is still recommended (such as early de-escalation antibiotics) and may lead to other positive effects including lower levels of multidrug resistant bacteria and medication toxicity. Organ dysfunction is a frequent complication in HSCT recipients. [39] [40] [41] Whether organ dysfunction is a result of high-dose conditioning chemotherapy or transplant-related insult, inflammatory cytokines, such as interleukin-6 and tumour necrosis factor-alpha, have been suggested as important mediators. 39, 40, 42, 43 The common pathway leading to organ damage may be a toxic effect of inflammatory cytokines on the vascular endothelium, which leads to a proinflammatory and pro-coagulant state. TA-TMA, which has a high mortality rate, is also known to occur as a result of vascular endothelial damage. 44 In our study, one case with viral pneumonia, coexisting with TA-TMA, died because of MODS. Among several organs, pulmonary, hepatic, and central nervous system dysfunction have shown similar findings in laboratory tests such as low anticoagulant protein C and antithrombin III, and clinical outcomes such as subsequent other organ dysfunction and death. [39] [40] [41] In the multivariate analysis, organ dysfunction at the beginning of the PI was found to be the most significant prognostic factor in patients with PCs following HSCT. Recipients with PI who also suffered from hepatic dysfunction more frequently had a poor outcome. Half of patients with hepatic dysfunction had co-occurring VOD. Although the number of patients was too small to evaluate outcomes according to the cause of hepatic dysfunction, it could be presumed that VOD, as the common cause of liver dysfunction, might be related to mortality in patients with PCs. In addition, whatever the cause, hepatic dysfunction in an early stage of respiratory distress, rather than in an advanced stage, may aggravate respiratory failure and other organ dysfunction, leading to a poor outcome. Gordon et al 45 T A B L E 3 Univariate analysis of mortality factors studied. 48 Therefore, further studies on organ dysfunction treatments are needed to improve outcomes. The present study has several limitations. First, the study was conducted at a single centre, which may limit the generalizability of our findings to other centres in which close discussions among an experienced oncologist, pulmonologist, and intensivist are not possible. Second, due to the study's retrospective nature, a selection bias may have influenced the results. Third, our patient group was too small to draw powerful conclusions. However, the present study adds to the literature by focusing on the importance of comorbidities and organ dysfunction, which are often neglected in studies focusing on diagnoses. In addition, the adjusted multivariable analysis served to minimize the potential for selection bias. Finally, the lack of the results for pulmonary function tests before and after HSCT is a limitation of our study. However, about 40% of recipients were children younger than 5 years old, so the lung function tests could not be performed routinely and therefore could not be used as a relative factor of PCs. In conclusion, hepatic dysfunction and neutropaenia at the time of PI initiation were ascertained to be independent early predictors of mortality. Although additional invasive diagnostic tests led to higher diagnostic yield, aetiologic diagnoses and associated treatment modification did not significantly affect mortality. However, this observation needs to be further evaluated in a multicentre, prospective study. Variables that showed a significant result in the univariate analysis (P < .05), noted in Table 3 , were included in the multivariate logistic regression: veno-occlusive disease, medications administered (antibiotics, antifungal agent, cytomegalovirus treatment), hepatic dysfunction, neutropaenia, and thrombocytopaenia as the representatives of haematologic dysfunction, and the presence of dysfunction in two or more organs. Finally, three of these variables were found to be statically significant using the forward stepwise methods. a Absolute neutrophil count less than 1000/μL. b Platelet level less than 100 × 10 3 /μL. 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