key: cord-0926694-i5u0hm1z
authors: Granbom, Elin; Fernlund, Eva; Sunnegårdh, Jan; Lundell, Bo; Naumburg, Estelle
title: Respiratory Tract Infection and Risk of Hospitalization in Children with Congenital Heart Defects During Season and Off-Season: A Swedish National Study
date: 2016-04-19
journal: Pediatr Cardiol
DOI: 10.1007/s00246-016-1397-4
sha: ebe0d973920ee994de1508f14b987f5bd8b04680
doc_id: 926694
cord_uid: i5u0hm1z

Respiratory tract infections (RTI) are common among young children, and congenital heart defect (CHD) is a risk factor for severe illness and hospitalization. This study aims to assess the relative risk of hospitalization due to RTI in winter and summer seasons for different types of CHD. All children born in Sweden and under the age of two, in 2006–2011, were included. Heart defects were grouped according to type. Hospitalization rates for respiratory syncytial virus (RSV) infection and RTI in general were retrieved from the national inpatient registry. The relative risk of hospitalization was calculated by comparing each subgroup to other types of CHD and otherwise healthy children. The relative risk of hospitalization was increased for all CHD subgroups, and there was a greater increase in risk in summer for the most severe CHD. This included RSV infection, as well as RTI in general. The risk of hospitalization due to RTI is greater for CHD children. Prophylactic treatment with palivizumab, given to prevent severe RSV illness, is only recommended during winter. We argue that information to healthcare staff and parents should include how the risk of severe infectious respiratory tract illnesses, RSV and others, is present all year round for children with CHD.

Respiratory tract infection (RTI) is common in young children, and RSV infection is among the leading causes of hospitalization [1] [2] [3] [4] . About 95 % of infants under the age of two have been infected with RSV [2] . RSV is the most common pathogen, but rhinoviruses, influenza and parainfluenza viruses, human metapneumovirus, coronaviruses and bocaviruses can also be detected in young children who are admitted to hospital with respiratory tract symptoms [4, 5] . Other viral infections can present with similar symptoms to RSV [6] .

Congenital heart disease (CHD) is a known risk factor for severe illness and hospitalization due to RSV infection [7] [8] [9] . Delay in postoperative recovery after cardiac surgery has been reported in RSV-infected children, as well as for other airway infections [10] . Palivizumab is a prophylactic treatment that reduces the severity of RSV infection and hospitalization rates [8, 11, 12] . Palivizumab is administrated monthly during the winter in Sweden, as an intramuscular injection to children with hemodynamically significant congenital heart defects.

RSV activity is dependent on a complex interaction of latitude, temperature, humidity and sunlight ultraviolet radiation [13] . Human susceptibility to viral infections might be altered by weather conditions, and indoor infections are likely to increase with extreme cold and heavy rainfall [14] . RSV infection is a seasonal disease in temperate climates such as Sweden, with activity peak when the temperature is lower as it is in the winter, but the virus is present all year round [15] . In areas with persistently warm temperatures and high humidity (close to the equator), however, RSV activity is more continuous throughout the year. More continuous RSV activity is also seen in areas with colder temperatures throughout the year [13] .

The aim of this study was to calculate the relative risk of hospitalization due to RSV infection and respiratory tract infection (RTI) in general in CHD children and in different subgroups of CHD. The risk estimations were calculated for summer and winter respectively.

The five-year study period was defined as November 1, 2006-October 31, 2011. Rates of hospitalization caused by RSV infection (International Classification of Diseases codes J20.5 and J21.0) and RTI in general (International Classification of Diseases codes J21.9, J20.9, J18.9, J12.9 and J22.9) were retrieved for children under the age of two from the Swedish Inpatient Registry [16] , held by the Swedish National Board of Health and Welfare (Socialstyrelsen). The Inpatient Registry includes information on dates of admissions to and discharges from hospitals in Sweden, as well as primary and secondary diagnoses (International Classification of Diseases 10 codes) [17] . Information on hospitalization was retrieved for the sixmonth periods 1 May-31 October (defined as the summer period) and 1 November-30 April (defined as the winter period). Using the unique 12-digit national registration number assigned to all Swedish residents, additional information about the type of congenital heart defect was retrieved for hospitalized as well as non-hospitalized patients. The registration number makes it possible to identify individuals and collect certain information from different registers in Sweden [18] . The types of congenital heart disorder were divided into eight subgroups ( Table 1) .

The total number of residents under the age of two was estimated using the number of live births recorded in the National Statistics Sweden database [19] , so that all children born in Sweden and \2 years old during 2006-2011 were included in the study. The relative risk of hospitalization, due to RSV and unspecified RTI, was calculated for CHD children compared to children without CHD, for summer and for winter. The relative risk of hospitalization was also calculated separately for each heart defect subgroup and compared to the other subgroups and to otherwise healthy children. The relative risk was calculated using MedCalc Ò (www.medcalc.org) and Chi-square test. A result with p \ 0.05 was considered statistically significant.

The relative risk of hospitalization due to RSV infection among children under the age of two was increased for all children with CHD (Table 2) , and for all CHD subgroups (Tables 3, 4 ). The risk of hospitalization for all CHD children was greater in the summer than in the winter, and the risk was higher for RTI in general than for RSV infection. Other complex CHD (ventricular double outflow, Ebstein's anomaly, congenital anomaly/disorder of aortic or mitral valve, cor triatriatum, malformation of coronary vessels, malformation of great veins) in winter, compared to 7154 (0.7 %) of non-CHD children.

During summer time, 276 (3 %) children with CHD and 3158 (0.3 %) of non-CHD children were hospitalized due to RTI in general (Table 2) . During winter, the relative risk of hospitalization was increased for the most severe cases, such as univentricular heart defects. However, cases with less severe types of CHD, such as systemic to pulmonary shunt defects, had an even higher risk of RSV hospitalization in the winter (Table 3) .

During summer, the relative risk of RSV hospitalization for the most severely ill cases, such as univentricular heart defects, increased severalfold compared to the risk of RSV hospitalization during the winter. There are few numbers of infected cases in all groups, but the results are statistically significant ( Table 4 ). The same pattern was seen for RTI in general; there was a greater risk of hospitalization in the summer than in the winter for the most severely ill CHD children (Tables 5, 6 ).

This study shows that children with CHD have an increased risk of hospitalization due to RSV infection as well as RTI in general, in summer as well as winter. The risk increased further in summer, especially for the most severe heart conditions. Respiratory tract infections are common in early childhood, with RSV being the most common pathogen. Influenza viruses, rhinoviruses, human metapneumovirus, human coronaviruses and human bocaviruses can also be detected in young children who are admitted to hospital with respiratory tract symptoms [4, 5] . In this study, we chose to study hospitalization rates for RSV infection and RTI in general, in order to cover all types of viruses that affect young CHD children. The pattern of risk of hospitalization was similar for all types of RTI, with an elevated risk during summer for the most severe cases. In our study, 4.3 % of children with CHD who were infected by RSV during the winter were hospitalized, while only 0.7 % of RSV-infected children without CHD were hospitalized. In summer, 0.4 % of RSV-infected children with CHD were hospitalized, compared to 0.05 % of RSVinfected children without CHD. These figures were similar for RTI in general. Among children with CHD who were infected with general RTI, hospitalization rates were 5.0 % in the winter and 3.0 % in the summer; children without CHD who were infected by RTI in general had hospitalization rates of 0.7 % in the winter and 0.3 % in the summer. The individual risk of any child being hospitalized for RSV was approximately 17.2/1000 (1.7 %) during the first year of life, according to a recent Swedish study [20] . Our study presents lower risk estimations for non-CHD children, but greatly increased risk for children with CHD.

Prophylactic treatment with palivizumab reduces hospitalization rates and the severity of RSV infection in children with congenital heart defects [9, 11, 21] . This prophylactic treatment is only recommended during the winter, according to the Swedish national guidelines for the study period, and includes children less than six months of age with congenital heart defects, such as Down syndrome with non-operated shunt defects, and shunt defects with heart failure. Children 1 year of age with univentricular heart defects in status post-bidirectional Glenn-operation, children with additional lung disease and pulmonary hypertension and those waiting for transplantation were also included. Prophylaxis with palivizumab is individually prescribed to each child with CHD who fulfills the indications for prophylactic treatment according to the guidelines. The overall risk of RSV hospitalization for CHD children during winter was lower than the risk hospitalization due to RTI in general. Thus, one can argue that the prophylactic treatment for RSV was effective. Additionally, according to our results, the strategy of RSV prophylactic treatment seems to lower the risk of hospitalization among the most severe cases during the winter. Perhaps, these children are less likely to be missed in the prophylactic treatment program by the pediatric cardiologist. In a previous study, we found that almost half the CHD patients had delays to the start of prophylactic treatment, but this accounted mainly for children with systemic-pulmonary shunt defects [22] . Since children with less severe forms of CHD have a higher risk of RSV hospitalization in the winter than the more severe cases of CHD, the present study indicates that even the less severe forms of CHD carry a substantial risk of hospitalization. Prophylactic respiratory syncytial virus treatment with palivizumab is both expensive and painful, and is recommended when RSV incidence is at its highest level [23, 24] . In our study, there were a low number of RSV-infected CHD children during the summer. Rather than suggesting extensive prophylactic treatment, we would like to stress the overall vulnerability for these children, including the risks of RSV infection as well as severe RTI in general, throughout the whole year. Information to parents and healthcare staff must include the risk of severe viral RTI during winter season but also in summer. We also argue that seasonal and regional variations in the onset of the RSV epidemic should indicate when to start treatment, rather than a specific date.

Testing for RSV is possible in all hospitals in Sweden all year round, but there are regional and seasonal variations in RSV testing. As the treatment is similar for all types of RTI, it is of little importance to the clinician whether the child has RSV or not, so not all affected children are tested. Only the tested cases are reported to the Swedish Public Health Agency [25] , and the agency only collected data on the numbers of RSV infections during the winter season and published weekly on their Web site. Waiting for this reporting to start may delay prophylactic treatment and RSV protection for children with CHD. We argue for local testing and reporting to pediatric cardiologists, as well as to the Swedish Public Health Agency. Testing for RSV can be less common during summer, so there is a risk of underreporting. This must account for CHD children as well as non-CHD children. RSV infections can occur sporadically throughout the year, especially in areas with colder weather throughout the year, or areas with small seasonal changes in the climate [13] . However, prophylaxis with palivizumab in the summer, when RSV prevalence is generally low in Sweden, cannot be recommended. In countries with subtropical climates, the RSV season can last up to ten months, so the period for giving prophylaxis may follow the local epidemiology [26] . The Swedish National Inpatient Registry does not provide information on whether or not a child has received prophylactic treatment, which limits this study. However, the nationwide setting of this study with a large number of cases covering a long period of time is a strength and rules out the difference in testing and decreases the impact of the annual variation of RSV in the study. We chose to study RSV in particular and RTI in general, to eliminate the risk of under-reporting of RSV cases, as they are most likely included in the group of children with general RTI.

This register-based study is limited by its dependence on correctly registered diagnostic codes. The exact number of patients with missing data on primary diagnoses and other diagnostic errors (such as incorrect diagnoses) has not been validated for congenital heart disorders, but this has been done overall for several other diagnoses. The positive predictive values are reported to be approximately 85-95 % in the Inpatient Register [16] . The risk of misclassification among RSV, RTI and CHD can be regarded as limited in our study.

Migration of families in and out of Sweden may have occurred during the study period and may limit the study. However, the risk of hospitalization is calculated from exact numbers retrieved from inpatient register. The hospitalized children were then subgrouped into different congenital cardiac malformations and compared to all other children (other CHD malformations as well as otherwise healthy children). For a large national population, we do not estimate migration to influence the risk estimations.

Relative risk of hospitalization as an estimation of morbidity in RSV among children with CHD is used in several studies [7, 12, 27] . Even though the number of CHD children with a specific heart condition is small in our study, the risk estimation for hospitalization is significant. However, hospitalization rates do not necessarily reflect the current condition of the child. Thresholds for admission may vary between different hospitals with different geographic settings and may also vary on an individual basis between different clinicians who have different experience. Further studies are needed to determine the morbidity and indications for hospitalization in all respiratory tract infections among CHD children in Sweden.

In conclusion, the relative risk of hospitalization was increased for all CHD children in all subgroups, both for RSV infection and RTI in general. However, the risk was found to be even higher for the children with the most severe forms of CHD during the summer, which indicates that risk of severe infectious illness may be present all year round for CHD children.

A comparison of characteristics and outcomes in severe human metapneumovirus and respiratory syncytial virus infections in children treated in an intensive care unit

Viral bronchiolitis for the clinician

New Vaccine Surveillance N (2004) Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children

Viral aetiology and clinical outcomes in hospitalised infants presenting with respiratory distress

Role of respiratory pathogens in infants hospitalized for a first episode of wheezing and their impact on recurrences

Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up

Risk factors for respiratory syncytial virus hospitalisation in children with heart disease

Respiratory syncytial virus immunoprophylaxis in high-risk infants with heart disease

Respiratory syncytial virus infection in children with congenital heart disease: a review

The impact of human rhinovirus infection in pediatric patients undergoing heart surgery

Cardiac Synagis Study G (2003) Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease

Immunoprophylaxis of respiratory syncytial virus: global experience

The relationship of meteorological conditions to the epidemic activity of respiratory syncytial virus

Seasonal trends of viral respiratory tract infections in the tropics

Climatic factors and lower respiratory tract infection due to respiratory syncytial virus in hospitalised infants in northern Spain

External review and validation of the Swedish national inpatient register

The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research

SCB. Statistical database Sweden. Population, live births

Incidence, risk factors and hospital burden in children under five years of age hospitalised with respiratory syncytial virus infections

Evaluating national guidelines for the prophylactic treatment of respiratory syncytial virus in children with congenital heart disease

Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection

Swedish national recommendations for prophylactic treatment with palivizumab. Nationell rekommendation för profylax med Palivizumab mot RSV-infektion hos barn med hjärtsjukdom

Prolonged seasonality of respiratory syncytial virus infection among preterm infants in a subtropical climate

Respiratory syncytial virus-associated hospitalizations among infants and young children in the United States

Acknowledgment We acknowledge the Swedish registers and all Swedish doctors for contributing to the registers.Funding This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Conflicts of interest None.Ethical Standards All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required. The study was approved by the Regional Ethical Review Boards in Umeå, Sweden (D-nr 2014/100-31).