key: cord-0010139-o1xic89x authors: Lin, Beryl; Kennedy, Brendan; McBride, Jamie; Dalla‐Pozza, Luciano; Trahair, Toby; McCowage, Geoffrey; Coward, Emma; Plush, Leanne; Robinson, Paul D.; Hardaker, Kate; Widger, John; Ng, Anthea; Jaffe, Adam; Selvadurai, Hiran title: Long‐term morbidity of respiratory viral infections during chemotherapy in children with leukaemia date: 2019-08-08 journal: Pediatr Pulmonol DOI: 10.1002/ppul.24456 sha: 0050cb5ead95958706cd183ab1115e70c6a626ba doc_id: 10139 cord_uid: o1xic89x BACKGROUND: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated. AIM: To evaluate the long‐term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL). METHODS: Childhood ALL survivors, aged 7 to 18 years, greater than 6 months posttreatment were recruited. Exclusion criteria included HSCT or proven bacterial/fungal respiratory infection during treatment. Subjects were classified into “viral” or “control” groups according to retrospective medical records that documented the presence of laboratory‐proven RVIs during chemotherapy. Symptom questionnaires (Liverpool, ISAAC) and lung function testing (spirometry, plethysmography, diffusing capacity, forced oscillation technique to ATS/ERS standards) were then performed cross‐sectionally at the time of recruitment. RESULTS: Fifty‐four patients (31 viral, 23 control) were recruited: median (range) age 11.2 (7.2‐18.1) years, and at 4.9 (0.5‐13) years posttherapy. Abnormalities were detected in 17 (31%) individuals (8 viral, 9 control), with the most common being DLCO impairment (3 viral, 4 control) and reduced respiratory reactance at 5 Hz (5 viral, 6 control). Children with RVIs during chemotherapy reported more current respiratory symptoms, particularly wheeze (odds ratio [OR], 3.0; 95% confidence interval [CI]: 0.9‐10.0; P = .09) and cough (OR, 2.7; 95% CI: 0.8‐9.5; P = .11). No differences in lung function tests were observed between the two groups. CONCLUSIONS: Our study found children with RVIs during chemotherapy developed more long‐term respiratory symptoms than controls; however, differences did not reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of ALL survivors treated without HSCT. Larger, prospective studies are warranted to evaluate the etiology and clinical significance of these findings. reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of ALL survivors treated without HSCT. Larger, prospective studies are warranted to evaluate the etiology and clinical significance of these findings. follow-up studies have found respiratory-related deaths to be second only to subsequent malignancy, and pulmonary abnormalities have been detected in up to 81% of survivors before the age of 50 years. Of all childhood cancers, acute lymphoblastic leukemia (ALL) is the most common and carries an excellent prognosis with a 10-year survival exceeding 90%. 3 In an era of rising cure rates, late pulmonary effects will become increasingly important for a growing population of survivors. 4 Historically, research has focused on identifying pulmonary-toxic therapies, such as radiation and hematopoietic stem cell transplant (HSCT), to inform risk-based pulmonary follow-up. [4] [5] [6] However, respiratory infections are also a significant cause of pulmonary morbidity during treatment. 7 In particular, recent studies using polymerase chain reaction (PCR) diagnostics have found respiratory viral infections (RVI) cause up to 57% of febrile episodes, and that children undergoing chemotherapy are at risk of more severe RVIs with a prolonged clinical course and higher viral loads. [7] [8] [9] [10] [11] In general population-based studies, respiratory syncytial virus (RSV) and rhinovirus (HRV) bronchiolitis during infancy have been associated with subsequent wheeze and obstructive defects. 12, 13 RVIs have also been shown to precipitate late airflow decline 14 and alloimmune lung syndromes 15 in transplant recipients. However, the long-term pulmonary sequelae of these RVIs in children undergoing chemotherapy alone have not been investigated. Currently, the Children's Oncology Group (COG) 16 have not prescribed recommendations for long-term pulmonary function screening for this cohort. This study aimed to evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in childhood ALL survivors, as defined by (a) static lung function tests and (b) respiratory symptoms beyond 6 months posttherapy. We hypothesized that children with RVIs during chemotherapy would demonstrate increased respiratory symptoms and poorer lung function, compared to those without RVI during treatment. This cross-sectional cohort study of childhood ALL survivors was conducted at two tertiary pediatric hospitals. Lung function assessments were performed to compare respiratory outcomes in children with and without proven RVIs during chemotherapy. Ethical approval was granted by The Sydney Children's Hospitals Network Human Research Ethics Committee (LNR/15/SCHN/309). Written, informed consent was obtained from all caregivers and participants where applicable. Childhood survivors of primary ALL, aged 7 to 18 years, at least 6 months posttherapy were eligible for this study. Exclusion criteria included: pulmonary-toxic therapy as prescribed by COG long-term follow-up (LTFU) guidelines, 16 including craniospinal irradiation; HSCT; proven bacterial or fungal respiratory infections (microbiologically detected from sputum) during chemotherapy; and developmental or psychosocial preclusions as determined by their oncologist. Hospital-based oncology databases were reviewed for all patients diagnosed with primary ALL from 1 April 1999 to 1 April 2015 at our two sites. Eligible patients were recruited in an order determined by an online random sequence generator, and classified into the "viral" or "control" group by the presence or absence of retrospectively All participants underwent an assessment of (a) static lung function testing: forced oscillation technique (FOT), pre and postbronchodilator spirometry, body plethysmography, and diffusion capacity for carbon monoxide (DLCO) in the order shown, and (b) respiratory symptoms by questionnaire. Participants were clinically well at the time of assessment. FOT was conducted with a multifrequency composite waveform (5-37 Hz) using the tremoFlo C-100 device (Thorasys, Canada) in accordance with published recommendations. 17 The ISAAC questionnaire evaluates the presence of atopic diseases including asthma, eczema, hay fever and their associated symptoms. The LRSQ consists of 32 questions across 8 domains, assessing respiratory symptoms and their impact on the child and family over the last 3 months (Table 1) . Each item was scored on a five-point Likert scale from "not at all" (0) to "everyday" (4) and then totaled for a domain score and overall score. As previously recommended, the snoring question in the "night-time" domain was excluded. 25 The prevalence of day, night, and exercise symptoms including wheeze, cough, and dyspnoea were also extracted. Responses "not at all" or "few days" were classified as "infrequent"; and responses "some days", "most days", or "everyday" were classified as "frequent." These symptoms were specifically analyzed, as they were considered to be clinically significant and have been noted in the COG-LTFU guidelines. 16 The primary outcome measure for this study was the total respiratory system resistance at 5 Hz, as determined by FOT. This was chosen for its sensitivity to peripheral airway function. 26 Based on a previous asthma study, 27 Primary comparisons between the viral and control groups were made using the student t test for continuous variables, and Fisher's exact test for categorical variables. To adjust for potential confounders, multiple regression models were built for each lung function and symptom outcome using the forwards sequential Note: The Liverpool Respiratory Symptom Questionnaire consists of eight domains which assess respiratory symptoms and their impact on the child/family over the last three months. The frequency of each item is indicated on a five-point Likert scale and assigned a corresponding score, from "not at all" (0) to "everyday" (4). Item scores are totalled for a domain score and overall score. were retained if their P value was < .10 without inflating standard error greater than 10%. Due to correlation between "years posttherapy" and "age at testing" (P < .001), and "age at testing" being already adjusted for by lung function endpoints expressed as z-scores, only "years posttherapy" was tested for a parsimonious model. Statistics were performed using SPSS version 23.0 (IBM) with significance assigned when P < .05. Between 1999 and 2015, 355 children treated for ALL across our two institutions were eligible for this study. Of the 116 patients contacted, 54 (47%) were enrolled (Figure 1 ). Demographic and clinical characteristics were not different between those patients who consented and those who declined to participate (Table S1 ). Baseline characteristics of our study population (N = 54) are displayed in Table 2 . The viral (n = 31) and control (n = 23) group had no significant differences in demographic or clinical characteristics. Children were of a median (range) age of 11.2 (7. Patients in the viral group (n = 31) had a median of 3 (range 1-7) proven RVIs during chemotherapy. Ten ( Acceptable and repeatable FOT, spirometry, body plethysmography and DLCO data were obtained in 48 (88%), 51 (94%), 48 (88%), and F I G U R E 1 CONSORT flow diagram of recruitment. † Patients may have been excluded due to several criteria. ‡ Note: After sufficient patients were recruited for the viral group, patients continued to be randomly selected until adequate controls were recruited. In this period, 13 additional "viral" patients were randomly selected, but not invited to participate 50 (93%) subjects, respectively ( The prevalence of wheeze, cough, and dyspnea in each group are shown in Table 4 The viral group totaled a slightly higher overall LRSQ score (17. To our knowledge, this is the first study to investigate the long-term pulmonary morbidity of respiratory viruses during chemotherapy in childhood cancer survivors. Compared to controls, children with RVIs during chemotherapy had more ongoing respiratory symptoms particularly wheeze and cough, although these results did not reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities were detected in nearly a third of ALL survivors when evaluated up to 13 years posttherapy. Of note, these patients were treated without pulmonary-toxic therapies recognized by the COG-LTFU guidelines and thus, do not receive routine lung function screening. Our results suggest that children with proven RVIs during chemotherapy may be at risk of developing more long-term respiratory symptoms. A threefold increase in odds of wheeze and nocturnal cough was observed, and the viral group reported a higher prevalence in nearly all other symptoms and LRSQ scores. These results however were not statistically significant. As our study was not powered for symptom outcomes, particularly for wheeze (OR, 2.7, P = .09) and cough (OR, 2.7, P = .11), the moderate effect sizes were considered a type II error and suggest larger studies are warranted in future. These findings are similarly documented following infant RSV and HRV bronchiolitis, where RVIs have been associated with subsequent asthma and atopy. 12, 13 While the pathogenesis of early-life respiratory viruses remains unknown, some studies have implicated excess type 2 immunity and aberrant lung remodeling. 30, 31 The complexity of this however, is further highlighted by studies which suggest that inherent susceptibility to any type of respiratory episode, including bacterial infections, is more important than viral triggers. 32 In our study, only one child had a positive bronchodilator response and atopy was low in both the viral and control groups. This suggests a different phenotype of disease in our cohort, who were older but more severely immunosuppressed. We hypothesize cancer survivors may have suffered direct tissue damage or neuroimmune modifications of respiratory mucosa following the RVI; however, further study is required to examine the role of other pathogens such as bacteria. As with infant bronchiolitis, there also remains the question of cause and effect: whether RVIs during chemotherapy predispose respiratory morbidity, or if children with pre-existing defects are more susceptible to RVIs. Static lung function testing found no differences between the viral and control groups. In isolation, this is an important negative finding that supports conservative management of RVIs during cancer therapy and suggests viral infections do not confer long-term airflow defects. It is possible that immunosuppression and a failure to mount inflammatory responses were protective against scarring and lung damage. 33, 34 This is however, incongruent with a 12-year retrospective study reporting late airflow decline associated with RVIs in HSCT recipients, independent of alloimmune lung disease. 14 Here, prolonged viral-shedding and subsequent airway inflammation were proposed to be the mechanisms of injury. These findings suggest that the pathogenesis of RVIs in immunosuppressed cohorts is unique and remains poorly understood. In our patients with RVIs, there may be several explanations for the preservation of lung function despite an increase in respiratory symptoms. Firstly, the reliability of self-reported symptoms may be questioned; however a difference in the same patient-reported To date, this is one of the largest cross-sectional lung function studies in leukemia survivors, and the only report to examine the late morbidity of respiratory viruses. All lung function data were crosssectionally collected and included objective pulmonary function measures and patient-related outcomes. Our patients were a homogenous cohort of primary ALL survivors, treated on contemporary chemotherapy protocols. Exclusion of children exposed to known pulmonary-toxic therapies and proven bacterial/fungal respiratory infections enabled respiratory viruses to be examined with minimal confounders. However, this retrospective study also had a number of limitations. With our relatively small sample size, results did not reach statistical significance and thus these data should only be considered hypothesisgenerating. While sufficient patients were recruited to test R5, power calculations were based on an asthma study, and this study was not powered to evaluate specific risk factors or viruses and their subspecies. To preserve a parsimonious model, only covariates with a univariate P > 0.1 could be retained in the multivariate regression analysis. Thus some clinically important factors, such as "age at diagnosis" were not retained as they were weak predictors in our small sample size, and require larger studies to power statistical models that can meaningfully test the impact of covariates. As this was a retrospective study, we relied on past medical records of microbiological testing on sputum samples collected from patients at the time of therapy. These data were used to classify the "viral" and "control" groups, and exclude children with proven respiratory bacterial and fungal infections, although sputum samples would not have been routinely tested on all patients. Incomplete medical records also precluded characterization of RVIs by severity, and as upper or lower tract infections. Furthermore, the microbiological methods used to isolate respiratory viruses were variable, where cell culture and immunofluorescence had limitations in the diagnosis of specific viruses such as HRV and HMPV as compared to newer molecular techniques. Thus, our viral cohort may only represent children with severe infections warranting investigation, or only those with viruses detectable by the microbiological method available at time of testing. As these children did not receive pulmonary assessments prior or during therapy, we also lack longitudinal data to evaluate trends in pulmonary function or the chronology of respiratory symptoms with respect to therapy. Our study found children with respiratory viral infections during chemotherapy developed more long-term respiratory symptoms than controls, however these differences were not statistically significant. No differences in static lung function outcomes were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of our ALL survivors treated with non-myeloablative chemotherapy, when evaluated up to 13 years posttreatment. These findings warrant future prospective studies into the etiology, clinical significance, and therapeutic options for these respiratory complications. Long-term respiratory follow-up should be considered in ALL survivors to facilitate early detection and management of late pulmonary effects. We are sincerely grateful to the patients and families who participated in this study. We also wish to thank the oncologists of the Sydney Children's Hospitals Network for their valuable support, and Professor Jenny Peat for her statistical advice. 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Pulmonary complications in survivors of childhood hematological malignancies: single-center experience Long-term morbidity of respiratory viral infections during chemotherapy in children with leukaemia The authors declare that there are no conflict of interests. http://orcid.org/0000-0002-2299-9770