key: cord-0837463-ea0dh03q authors: Soudani, Nadia; Caniza, Miguela A.; Assaf‐Casals, Aia; Shaker, Rouba; Lteif, Mireille; Su, Yin; Tang, Li; Akel, Imad; Muwakkit, Samar; Chmaisse, Ahmad; Homsi, Maysam; Dbaibo, Ghassan; Zaraket, Hassan title: Prevalence and characteristics of acute respiratory virus infections in pediatric cancer patients date: 2019-02-27 journal: J Med Virol DOI: 10.1002/jmv.25432 sha: 594cd36557e675e5c0c3388b55e89c716f7538b5 doc_id: 837463 cord_uid: ea0dh03q BACKGROUND: Patients with pediatric cancer have a higher risk of morbidity and mortality because of respiratory viral infections than other patient populations. OBJECTIVES: To investigate the causative viruses of respiratory infections and their burden among patients with pediatric cancer in Lebanon. STUDY DESIGN: Nasopharyngeal swabs along with clinical and demographic data were collected from patients with pediatric cancer presenting febrile episodes with upper respiratory tract symptoms. Total nucleic acid was extracted from specimens followed by the real‐time PCR analysis targeting 14 respiratory viruses to estimate the frequency of infections. RESULTS: We obtained 89 nasopharyngeal swabs from patients with pediatric cancer (mean age, 5.8 ± 4.2 years). Real‐time PCR confirmed viral infection in 77 swabs (86.5%). Among these, 151 respiratory viruses were detected. Several viruses cocirculated within the same period; respiratory syncytial virus (RSV) being the most common (45.45%), followed by parainfluenza virus (PIV; 26%), influenza type B (26%), human metapneumovirus (24.6%), and human coronavirus (HCoV; 24.6%). Coinfections were detected in 55% of the subjects, and most of them involved RSV with one or more other viruses. A strong correlation was found between PIV, Flu (influenza of any type), RSV, and HCoV with the incidence of coinfections. RSV was associated with lower respiratory tract infections, nasal congestion, bronchitis, and bacteremia. HCoV was associated with bronchiolitis; rhinovirus was associated with hospital admission. CONCLUSION: Patients with pediatric cancer have a high burden of respiratory viral infections and a high incidence of coinfections. Molecular diagnostics can improve management of febrile episodes and reduce antibiotic use. Immunocompromised patients, such as those with cancer and hematopoietic stem cell transplantation, have a higher risk for respiratory infections, 1 and single or mixed respiratory viruses are frequently detected in those with acute respiratory symptoms. [2] [3] [4] [5] [6] Defects in innate and adaptive immunity 3 coupled with damage in the mucosal membrane and frequent exposure to a healthcare environment contribute to increased morbidity 7, 8 and mortality of respiratory infections in these patients. 2, 3, 7, [9] [10] [11] In healthy children, respiratory viruses are usually confined to the upper respiratory tract; in immunocompromised patients, progression to the lower respiratory tract is a more frequent and feared complication. 2, 12, 13 Despite advances in cancer therapy and outcomes during the last decade, respiratory viral infections and complications are frequent barriers to the success of antineoplastic treatment. 11, 12, 14 Respiratory infections are major causes of febrile episodes in patients with pediatric cancer. 3 These patients often are initiated on broad-spectrum antibiotics to cover serious bacterial diseases, leading to unnecessary increased exposure to antibiotics and the potential emergence of antibiotic resistance. 3, 15, 16 Accurate respiratory viral diagnosis and early access to treatment can improve outcomes, allow the prompt initiation of infection control measures, and limit antibiotic use. 10 Molecular diagnostic assays for respiratory virus detection and identification are becoming increasingly popular because they outperform traditional viral detection methods, such as antigen detection and cell culture-based assays in terms of speed, efficiency, specificity, and sensitivity. 10, 12 Altogether, these facts highlight the need for surveillance studies that utilize molecular diagnostic tools to elucidate the role of viral pathogens during respiratory infections, their risk factors, and outcomes. 12, [17] [18] [19] Epidemiological studies of respiratory viral infections in patients with pediatric cancer in low-resource settings are scarce. 3, 11, [17] [18] [19] [20] [21] The main purpose of this study was to screen for viral etiologic agents and associated risk factors and complications during respiratory infections in patients with pediatric cancer in Lebanon to address the joint need for surveillance studies using molecular diagnostic tools and additional studies of respiratory infections in developing countries. Extraction controls were screened to exclude cross-contamination during extraction. Flu A-positive samples were further subtyped via real-time PCR using the CDC-established protocol. RSV-positive samples were subtyped by conventional PCR followed by 1.5% gel electrophoresis using RSV-A and RSV-B primers specific for the G gene hypervariable region. 22, 23 The univariate regression analysis was performed to determine the association between viral mono-and coinfections with variables and outcomes, including demographics, hospital/ICU admission, lower respiratory tract infection (LRTI), and other clinical symptoms, such as bronchitis, fever, mechanical ventilation, nasal congestion, respiratory distress, vomiting, neutropenia (absolute neutrophil count [ANC] < 1500 cells/µL), and lymphopenia (absolute lymphocyte count < 2000 cells/µL). The χ2 test and odds ratio were computed to test the association between the categorical variables. All variables that were statistically associated with severe outcomes in the univariate models were included in multivariate logistic regression using the backward selection method; a significance level of 0.10 or less was required for a covariate to stay in the model. Then, odds ratio estimates with P values for tested variables were monitored after adjusting for age and sex. Similarly, the correlation analysis between variables was also included, and correlation coefficients were calculated to measure the strength of the relationship between different variables. For these tests, P value < 0.05 was considered significant. Statistical analysis was performed using SAS 9.4 software. During the 14-month study period, 89 febrile episodes were recorded in 67 individual patients. The median age of patients was 4.5 years (IQR 3-8 years), and 54% of the patients were male ( The univariate analysis was used to assess the association between demographic variables, clinical findings, and respiratory viruses with ARTI ( Table 2 ). Children younger than 2 years were at a significantly higher risk of developing respiratory distress than were those aged 2 to 6 years (P < 0.01, OR, 0.077 [CL 0.015-0.400]) or those older than 6 years (P = 0.0053, OR, 0.086 [CL 0.015-0.482]). Neutropenia (ANC < 1500 cells/µL) was identified as a risk factor for hospital admission (P = 0.0192, OR, 3.625 [CL 1.234-10.65]). No statistically significant association was observed with respect to sex, cancer type and treatment, lymphopenia, or antiviral drug administration and the tested variables. The type of cancer, receiving an anticancer drug, neutropenia, and lymphopenia was not associated with an increased risk of coinfection. In addition, the presence of viral coinfection did not seem to correlate with any of the recorded clinical symptoms (Table 2) (Table 2) . Variables were further analyzed via multivariate logistic regression analysis with the selection method of backward elimination, whereby a P value of 0.1 was required for a covariate to stay in the model. Children aged 2 to 6 years and those older than 6 years had lower odds (94.8%, and 95.2%, respectively) of having respiratory distress than those younger than 2 years (P < 0.01). The correlation analysis showed that RSV (r = 0.5, P < 0.0001), Figure 3C ). During the study period, 17 of the 67 patients (25.4%) had repeated febrile episodes, which often led to the detection of the same virus (es) associated with the first episode ( need for vaccines and effective drugs against the commonly circulating viral pathogens, which will limit unnecessary administration of antivirals and antibacterials, and best management of isolation precautions of infected patients. A substantial subset (55%) of our study population had coinfections with multiple viruses. We did not find any association between Interval between specimen collection (days) 1 2 3 4 5 febrile neutropenia in children with mixed malignancies. 19 A similar rate of respiratory viral infections in children with leukemia or mixed malignancies was reported in the USA, Germany, Finland, and Chile. 2, 18, 28, 29 In contrast, in Spain, respiratory viral infections were detected in only 12% of patients with cancer, and all viral infections were monoinfections. 11 In the mentioned studies, RSV, RhV, and Flu A were the most commonly detected viruses. 2, 3, 11, 18, 19, 29 [41] [42] [43] In infants at high-risk (preterm or having chronic illness), RSV neutralizing monoclonal antibodies, including the FDAapproved palivizumab, are effective for prophylaxis but remain very expensive in developing countries. 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