High mortality in patients with influenza A ph1n admitted to a pediatric intensive care unit: A predictive model of mortality

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1 High mortality in patients with influenza A ph1n admitted to a pediatric intensive care unit: A predictive model of mortality Silvio Fabio Torres, MD; Thomas Iolster, MD; Eduardo Julio Schnitzler, MD; Julio Alberto Farias, MD; Adriana Claudia Bordogna, MD; Daniel Rufach, MD; María José Montes, MD; Alejandro Javier Siaba, MD; María Gabriela Rodríguez, MD; Roberto Jabornisky, MD; Carmen Colman, MD; Analia Fernández, MD; Gustavo Caprotta, MD; Silvia Diaz, MD; Roxana Poterala, MD; Marcela De Meyer, MD; Matías Enrique Penazzi, MD; Gustavo González, MD; Silvia Saenz, MD; Oscar Recupero, MD; Luis Zapico, MD; Blanca Alarcon, MD; Esen Ariel, MD; Pablo Minces, MD; Eduardo Mari, MD; Antonio Carnie, MD; Mónica Garea, MD; Roxana Jaen, MD Objective: To describe the clinical characteristics and outcome of patients admitted to pediatric intensive care with influenza A (ph1n1) 2009 in Argentina. Design: Retrospective observational study. Setting: Thirteen pediatric intensive care units in Argentina. Subjects:. Interventions: None. Measurements and Main Results: We included 142 critically ill patients. The median age was 19 months (range, months) with 39% of the patients <24 months of age. Ninety-nine patients (70%) had an underlying disease. Influenza A (ph1n1) 2009 infection was confirmed in 90 patients and the remaining 52 had a positive direct immunofluorescence assay for influenza A. The median length of stay in the pediatric intensive care unit was 12 days (range, 2 52 days). One hundred eighteen patients (83%) received invasive mechanical ventilation and 19 patients were treated with noninvasive ventilation; however, seven of the patients receiving noninvasive ventilation later needed mechanical ventilation. Sixty-eight patients died (47%) with the most frequent cause refractory hypoxemia. Multivariate logistic regression analysis showed that age <24 months (odds ratio, 2.87; ), asthma (odds ratio, 1.34; ), and respiratory coinfection with respiratory syncytial virus (odds ratio, 2.92; ) were associated with higher mortality. As expected, mechanical ventilation and treatment with inotropes were also associated with increased mortality. Conclusions: The mortality of children admitted to the pediatric intensive care unit with 2009 ph1n1 influenza was high (47%) in our population. Age <24 months, asthma, respiratory coinfection, need of mechanical ventilation, and treatment with inotropes were predictors of poorer outcome. (Pediatr Crit Care Med 2012; 13: ) KEY WORDS: high mortality; influenza A ph1n1; pediatric intensive care unit; predictive model of mortality In April 2009, Mexico reported the first cases of influenza A (ph1n1) 2009 and during the next month reported patients with severe disease and death (1). Since then, thousands of cases have been confirmed around the world. By December 2009, 9340 deaths had been reported (2) with one-third of these from South America. Approximately 20% of deaths in South America occurred in Argentina. From Hospital Universitario Austral (SBT, TI, EJS, AJS); Hospital de Niños Ricardo Gutierrez (A Farias, A Fernández); Hospital Interzonal De Agudos Sor Maria Ludovica (CB); Hospital Interzonal General Agudos Eva Peron (DR, MDM); Hospital de Niños de la Santísima Trinidad de Córdoba (MJM, SS); Hospital de Trauma y emergencia Dr Federico Abete (MGR, GC, EA), Hospital de Clínicas José de San Martín; Hospital Pediátrico Juan Pablo II (RJ, BA); Hospital Pediáatrico Dr Avelino L. Castelán (CC, LZ); Hospital Italiano de Buenos Aires (SD, PM); Sanatorio Anchorena (RP, AC); Hospital de Niños de The influenza pandemic posed a problem of great magnitude determined by a combination of urgency, uncertainty, and the impact of the disease on specific health systems. The southern hemisphere entered the influenza season 2 months after the first reports. The spread of ph1n1 influenza to this region posed a high risk of mortality as a result of limited resources, fragmented health systems, and a nonorganized response. San Justo (MEP, EM); Hospital Churruca (GG, MG); Hospital Interzonal De Agudos Sor Maria Ludovica (OR); and Hospital de Clínicas José de San Martin (RJ). The authors have not disclosed any potential conflicts of interest. For information regarding this article, Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: /PCC.0b013e b The Centres for Disease Control and Prevention provided details about the first patients admitted to intensive care in a California hospital in May 2009 (3). From then onward, many countries have reported their experiences regarding severe influenza infection characterized by rapidly progressive lower tract disease that results in respiratory failure (4). In Argentina, the first suspected case was admitted on April 28; the first confirmed case was on May 26 in a patient entering the country from abroad; and the first confirmed case with local transmission was reported on June 3 (5). Viral respiratory season usually is between May and August with a preponderance of respiratory syncytial virus (RSV) infection. During the 2009 season, influenza ph1n1 virus worsened the respiratory epidemic with a large number of cases reported around the country. Pediatr Crit Care Med 2012 Vol. 13, No. 4 1

2 This study describes the clinical and epidemiologic characteristics, prognosis, and risks factors of severe 2009 ph1n1 infection in children admitted to a pediatric intensive care unit (PICU) in Argentina with or without ventilatory support. Our principal objective was to measure the association between mortality and risk factors among patients with ph1n1 presenting with respiratory symptoms so as to build a predictive model. MATERIALS AND METHODS Design. A retrospective, cohort study was conducted of patients with influenza A (ph1n1) 2009 admitted to 13 PICUs in Argentina between May 15 and July 31, Patient Selection and Data Collection. An invitation was sent to members of the two societies that gather pediatric intensivists in Argentina (Sociedad Argentina de Pediatria and Sociedad Argentina de Terapia Intensiva). A Web portal was prepared with an area for data collection and detailed information about how to complete the form. The inclusion criteria were all patients admitted in PICU with confirmed or suspected influenza A (ph1n1) Infection was confirmed when the real-time polymerase chain reaction (RT PCR) for 2009 ph1n1 influenza was positive; suspected cases included patients with clinical diagnosis consistent with 2009 ph1n1 infection and positive direct immunofluorescence (DFA) for influenza (6). Exclusion criteria were patients without pneumonia or without oxygen requirements, patients transferred to another institution, or an incomplete data sheet. Patients included in other observational studies were allowed and the authors knew that another database collecting children with ph1n1 respiratory distress oriented mainly to mechanical ventilation characteristics was in course. Patients admitted between May 15 and July 31, 2009, were included in the study. Reasons for PICU admission included rapidly progressive pneumonia, severe respiratory failure, need for intubation, and/or respiratory disease with hemodynamic instability. The following variables were evaluated: age, gender, death, nosocomial infection, length of stay, days of mechanical ventilation (MV), MV mode (pressure control, volume control), noninvasive ventilation (NIV), highfrequency oscillatory ventilation, extracorporeal membrane oxygenation, renal replacement techniques (dialysis, hemodialysis, hemofiltration), Pediatric Index of Mortality 2 (PIM2) score (7), use of inotropes, antibiotic treatment, use of corticosteroids, underlying conditions, respiratory coinfections, infectious complications, RT PCR testing for influenza A (ph1n1) 2009 virus, DFA testing for influenza A infection, treatment with oseltamivir, and chest x-ray findings. Figure 1. Participating units and mortality.* *Patients from units 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, and 12 participated in other epidemiologic studies. Figure 2. Treatment with positive pressure. MV, mechanical ventilation; NIV, noninvasive ventilation. Table 1. Patient characteristics Total (N 142) Dead (N 68) Alive (N 74) Age, months a 19; months old 55 (39%) months old 22 (15%) months old 65 (46%) Sex, no. (%) Male 86 (60%) Female 56 (40%) Hospital-acquired influenza 47 (33%) 39 8 Family contacts 98 (68%) Underlying condition b 99 (70%) Asthma 37 (26%) 31 6 Bronchopulmonary dysplasia 19 (13%) 10 9 Congenital heart disease 35 (25%) 27 8 Immunosuppression 26 (18%) Premature 35 (25%) 27 8 Neurologic impairment 28 (20%) Mechanical ventilation 116 (81%) Inotrope treatment 83 (58%) Renal replacement therapy 6 (4%) 5 1 Respiratory coinfections 54 (38%) Respiratory syncytial virus 29 (20%) Streptococcus pneumoniae 18 (13%) 12 6 Influenza 4 (3%) 3 1 Adenovirus 2 (1.5%) 2 0 Parainfluenza 1 (0.7%) 0 1 Ventilator-associated pneumonia 24 (16%) 20 4 a Median, interquartile range; b 55% in this group shared one or more underlying conditions. 2 Pediatr Crit Care Med 2012 Vol. 13, No. 4

3 Because this was a retrospective observational study with nonidentified data, approval by the institutional review board of the participating centers was not requested. Statistical Analysis. Data analysis was done with STATA 8.0 software. Discrete variables were expressed as percentage and continuous variables as means SD, median with range, and interquartile range (25th 75th). Differences between groups were assessed using the chi-squared test and Fisher s exact test for categorical variables and Wilcoxon test for continuous variables. Univariate analysis was used to compare mortality and different risk factors. A subgroup analysis was made by transforming data into ordinal and discrete variables. With the statistical significant results from the univariate analysis, a multivariate model was built using the step-bystep technique consisting of adding one by one the variables of interest with the idea of controlling confounders and interactions. Risks were expressed as odds ratio (OR). A p value.05 was considered statistically significant with a 95% confidence interval that did not include 1. After the final model, performance was tested with the Hosmer-Lemeshow and receiver operating characteristic curve tests. The model was also tested with or without outliers Table 2. Signs and symptoms at admission Total (N 142) Fever 136 (96%) Dyspnea 102 (72%) Cough 129 (91%) Wheezing 90 (63%) Acute respiratory failure 80 (56%) and potential influencing cases. After passing all these tests, we considered our predictive model to be robust. The predictive model was also tested with the population of 90 patients that had a positive RT PCR for influenza ph1n1 (confirmed cases) to validate the model. RESULTS A total of 17 PICU directors answered and 15 of these accepted the proposal; however, only 13 units completed the data (Fig. 1). Five units were from pediatric hospitals and eight from pediatric departments of general hospitals. Three of the units were from cities km distance from Buenos Aires. The mean number of PICU beds was 13. Data of 153 patients were collected. Of these, 11 patients were excluded because admission periods were not filled out adequately. Finally, 142 patients admitted from May 15, 2009, to July 31, 2009, were included in the database (Fig. 2). The patients characteristics are presented in Table 1. The median age was 19 months (range, months) with 39% of the patients 24 months of age. Eighty-six patients (60%) were male. Ninety-nine (70%) had an underlying disease. Not all units in Argentina calculate PIM2 routinely, so it was used in 109 patients of our sample. Based on these 109 patients, the mean PIM2 was 10.5 (SD, 2.75) and the standardized mortality ratio was 1.5. Influenza A (ph1n1) 2009 infection was confirmed with RT PCR in 90 patients. The remaining 52 patients were Figure 3. Predictive model of mortality receiver operating characteristic (ROC) curve (total population of the study, n 142). CI, confidence interval. not tested with RT PCR or the results had not been reported but had a positive DFA for influenza and were considered suspected cases. Of the 90 patients with positive RT PCR, 81 were also tested with DFA and 66 of these patients had a positive test (81%). Thirty-six patients (25%) had viral respiratory coinfection detected with DFA from nasal aspirate, 29 (20%) with RSV and seven with adenovirus. All of the patients were treated with oseltamivir during their PICU stay. The most frequent signs and symptoms at admission included fever, cyanosis, dyspnea, cough, wheezing, and acute respiratory failure (Table 2). Chest x-ray findings were abnormal in all patients with single consolidation in 13 (9%) patients and multiple consolidations or diffuse compromise in the remaining cases. The median length of stay in PICU was 12 days (range, 2 52 days). MV was used in 118 (83%) patients. The mode of conventional MV was pressure control in 73 of the cases (62%) and volume control in 45 (38%). Eight of these patients also received high-frequency oscillatory ventilation and one was treated with extracorporeal membrane oxygenation. The median time of MV was 6 days (range, 4 15 days). Nineteen patients were treated with NIV; seven of these patients presented further deterioration and needed MV, whereas the other 12 recovered from NIV. Twelve children needed only oxygen therapy without mechanical support (Fig. 3). Eighty-three patients (58%) received vasoactive treatment. Of this group, only 10% (eight patients) had pure ph1n1 infection without coinfection. Hemodynamic effects of influenza infection could not be analyzed because only eight patients who needed vasoactive therapy had pure ph1n1 infection and all of these patients received sedation that could have justified hemodynamic instability. Bacterial infection was a frequent complication. Ventilator-associated pneumonia (8) was detected in 24 patients (16%) with bronchoalveolar lavage isolation of Pseudomonas aeruginosa in five patients and Acinetobacter species in four patients; however, bronchoalveolar lavage was not performed in all cases. Blood cultures were positive in 27 patients (19%); eight of these were associated with central venous catheters. The most frequent pathogen isolated from blood cultures was Streptococcus pneumoniae (17 cases) and of these, eight patients had a positive bronchoalveolar lavage for the same micro-organism. The Pediatr Crit Care Med 2012 Vol. 13, No. 4 3

4 remaining positive blood cultures detected coagulase-negative staphylococcus in five patients, Acinetobacter in two patients, Klebsiella pneumoniae in two patients, and Pseudomonas aeruginosa in one patient. Twenty patients met criteria of septic shock (Appendix 1); 12 of these patients died, all of them with bacterial coinfection confirmed with bronchoalveolar lavage or blood cultures. Of the remaining eight patients, four had associated viral infection and four had only ph1n1 infection without detection of any other organism. Sixty-eight patients died (47%). The main reason of mortality was refractory hypoxemia followed by septic shock and multiorgan dysfunction (Table 3). After a first statistical analysis (univariate analysis), we found a relationship between Table 3. Causes of death Total Deaths (N 68) Refractory hypoxemia 43 (63%) Septic shock 12 (18%) Multiorgan failure 14 (21%) Table 4. Univariate analysis mortality and age 24 months, male gender, transfer from another hospital, confection with RSV, previous asthma, bronchopulmonary dysplasia, use of inotropes, MV, and presence of congenital heart disease (Table 4). Although we did not find an association between perinatal history and death, after a subgroup analysis, this relationship was significant for patients 12 months (OR, 3.9; ). The predictive model using multivariate analysis showed that treatment with inotropes (OR, 5.36; ), need for MV (OR, 5.04; ), age 24 months (OR, 2.87; ), asthma (OR, 1.34; ), and respiratory coinfection with RSV (OR, 2.92; ) were associated with mortality (Table 5). Evaluation of the model with the Hosmer-Lemeshow test (p.4283) and receiver operating characteristic curve (Fig. 3) shows that the model is reliable. When the predictive model was tested with the population of 90 patients that had positive polymerase chain reaction for ph1n1 (confirmed cases), we found that the same predictive variables were associated with mortality (Table 6; Fig. 4). Odds Ratio; 95% Confidence Interval Age 24 months 3.24; Male 1.752; Influenza vaccination 0.525; Transferred from another hospital 1.931; Nosocomial influenza 0.56; Coinfection with respiratory syncytial virus 2.017; Asthma 2.12; Mechanical ventilation 5.24; Inotropes 7.801; Use of steroids 1.932; Congenital heart disease 4.456; Bronchopulmonary dysplasia 2.198; Premature 0.89; Breastfeeding history 0.572; Immunosuppression 0.651; Previous neurologic impairment ; Table 5. Predictive model of mortality (total population of the study, n 142) a Risks Factors Odds Ratio; 95% Confidence Interval Age 24 months 2.870; Mechanical ventilation 5.039; Inotrope treatment ; Coinfection with respiratory ; syncytial virus Asthma 1.341; a Multivariable analysis (logistic regression). p p DISCUSSION In this study, we included patients with influenza ph1n1 infection and respiratory symptoms with a wide variation in severity but managed in a PICU. Because there were no reports of patients with severe ph1n1 infection without respiratory disease in the participating units while our study was being designed, we decided to focus on respiratory illness. Our expectations were to evaluate patients with severe respiratory failure and others with less severe respiratory disease, including those admitted for monitoring who only required oxygen supply. However, most of the patients included had severe respiratory failure and required ventilatory support. Based on this population, we built a predictive model of mortality. As expected, cases that needed MV and treatment with inotropes had high mortality. On the other hand, NIV was useful in a subgroup of children with less severe disease. All of the children who received NIV survived, and most of them did not receive MV. A history of disease and associated conditions increased the risk of mortality. After univariate and multivariate analysis, age, history of asthma, need of MV, use of inotropes, and respiratory coinfection increased the risk of mortality. Although MV and use of inotropes always imply high risk, we can conclude that after controlling the confounder variables, the impact of asthma, age 24 months, and respiratory coinfection with RSV predict higher risk of mortality in our population of children with respiratory disease as a result of influenza ph1n1 infection. Of these, coinfection with RSV is of special interest as a result of its high incidence during the viral respiratory infection season. In relation to asthma, its high incidence in the pediatric population ( 10%) (9) and its possible association with greater mortality in patients with ph1n1 influenza raises the question whether these patients should be included in the population with urgent indications for vaccination. Increased risk of death was also found in previously healthy children 24 months making this population another target for early vaccination and other preventive policies. On the other hand, increased mortality was not found in immunosuppressed patients; however, this should be validated in further studies. 4 Pediatr Crit Care Med 2012 Vol. 13, No. 4

5 Table 6. Predictive model of mortality (only patients with positive real-time polymerase chain reaction for influenza ph1n1, n 90) a Risks Factors Figure 4. Predictive model of mortality receiver operating characteristic (ROC) curve. (Only patients with a positive polymerase chain reaction for influenza H1N1, n 90.) CI, confidence interval. In this report, we include confirmed and suspected cases depending on whether the diagnosis was made by means of RT PCR or DFA for influenza A. DFA is much more accessible and distributed in our country and the results are much faster. It was used as a screening test to have an early diagnostic suspicion so as to start early antiviral treatment and take adequate isolation measures. Compared with the gold standard test (RT PCR), DFA had a sensitivity of 81% (66 of 81) in the group that had both tests done. Reported sensitivity for direct and indirect immunofluorescence assays is variable ranging from 47% to 93%. Under conditions with a majority of circulating influenza ph1n1 viruses, a positive test result can be assumed to be 2009 ph1n1 (6). We also tested our predictive model with the 90 patients with a confirmed diagnosis by means of polymerase chain reaction so as to validate the model and Odds Ratio; 95% Confidence Interval Age 24 months 3.027; Mechanical ventilation 4.873; Inotrope treatment 5.796; Coinfection with respiratory syncytial virus 2.023; Asthma 1.678; a Multivariable analysis (logistic regression). Pediatr Crit Care Med 2012 Vol. 13, No. 4 found the same predictive variables of mortality. We could not establish clearly the incidence of hospital transmission of ph1n1 infection; however, it was the case in some patients admitted as a result of other medical or surgical conditions. Since the beginning of the 2009 ph1n1 pandemic, middle age groups seemed to be at particular risk of developing severe disease with higher mortality. On the other hand, people 70 yrs of age seemed to have some protection (10). As the pandemic continued spreading, pregnant women (11) and children proved to be other groups at risk of developing severe disease. With 616 deaths, Argentina was the second country in South America (after Brazil) and the fourth country in the world with more deaths attributed to influenza ph1n Furthermore, we cannot rule out the possibility of deaths related to ph1n1 infection in areas of the p country without access to intensive care or ph1n1 infection-related deaths without a virologic diagnosis. Need for intensive care in hospitalized children with 2009 ph1n1 infection in Argentina was reported to be 19% with a hospital mortality rate of 5% (12). This study also mentions that 17% of hospitalized children needed MV and reports a mortality rate of 28% in children admitted to intensive care. Initially, the pandemic affected metropolitan and suburban areas of the city of Buenos Aires that counts with a significant number of PICU beds distributed mainly in pediatric hospitals and big pediatric departments of university health centers. Two wks later, it spread to other cities where the number of PICU beds was more limited. The amount of children with respiratory failure caused by influenza pneumonia requiring intensive care and MV generated an acute misbalance between demand and available PICU beds. The health system that usually works at complete capacity had a threat of collapse under these circumstances. Interventions of the health authorities that included the appointment of selected hospitals exclusively for patients with influenza and the opening of new intensive care areas in public hospitals probably avoided a higher death toll. All of the participating units guarantee conventional MV or NIV, basic monitoring, and qualified pediatric intensivists. The admission criteria can be different in PICUs from pediatric hospitals as compared with general hospitals. Differences in the severity of illness at admission are also possible, especially in the context of scarcity of intensive care beds. Outcome evaluations done in these units using PIM2 (13) or collaborative studies of MV (14) show some results from our country. Collaborative data from PICUs in Argentina show a PIM2 standardized mortality score of 1.47 (15). With limitations, these data give an approximation of the standards of care related to mortality. Because not all units use PIM2 and it was not filled in 23% of the cases, we considered that it should not be used in the analysis of the final predictive model. Patients who developed severe respiratory failure and needed PICU had high mortality mainly as a consequence of refractory hypoxemia. Other factors associated with fatality risk were septic shock and multiorgan dysfunction consistent with the usual causes of death in the 5

6 PICU. These causes of mortality have also been described in other countries, including Mexico, Canada, and the United States (16, 17). Some reports have suggested that severe pulmonary damage develops as a result of primary viral pneumonia and secondary host immune responses (18); however, other conditions such as ventilator-associated pneumonia or ventilator-associated lung injury could also contribute to the progression of pulmonary disease. The principal weakness of this study is its retrospective design with data collection from the clinical charts. Another weakness is regarding the loading of the data; although indications and definitions were available on the Web, we did not have an active verification process of the data that was included. Also, the participating units are only a sample of the total PICUs in the country; however, some of the most representative units are present. Prospective studies are needed to evaluate the specific impact of ventilatory strategies, rescue therapies with surfactant, or to define the role of extracorporeal membrane oxygenation. CONCLUSIONS In our population of children admitted to the PICU with 2009 ph1n1 infection, the main reason for admission was severe respiratory failure with need for MV. There was a high rate of mortality (47%) being the most frequent cause refractory hypoxemia. Age 24 months, MV, use of inotropes, respiratory coinfections, and a history of asthma were predictors of mortality. REFERENCES 1. Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, et al; INER Working Group on Influenza: Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med 2009; 361: European Center for Disease Prevention and Control. 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JAMA 2009; 302: Kumar A, Zarychanski R, Pinto R, et al; Canadian Critical Care Trials Group H1N1 Collaborative: Critically ill patients with 2009 influenza A (H1N1) infection in Canada. JAMA 2009; 302: Rello J, Rodríguez A, Ibañez P, et al; H1N1 SEMICYUC Working Group: Intensive care adult patients with severe respiratory failure caused by influenza A (H1N1)v in Spain. Crit Care 2009; 13:R148 APPENDIX 1 Definition of Septic Shock. Suspected infection with presence of cardiovascular organ dysfunction despite administration of isotonic intravenous fluid bolus of 40 ml/kg/hr or the need of vasoactive drugs to maintain blood pressure in the normal range. 6 Pediatr Crit Care Med 2012 Vol. 13, No. 4