Bronchiolitis and in infancy – , function and quality of life at a 30-year follow-up

KATRI BACKMAN1,2, EIJA PIIPPO-SAVOLAINEN1, HERTTA OLLIKAINEN2, HEIKKI KOSKELA3 AND MATTI KORPPI4 SUMMARY

Bronchiolitis and pneumonia in ronchiolitis is an acute, viral, symptoms resolve by the age of 6 infancy have been associated lower infec- years (7). However, some children, with respiratory morbidity, tion (LRTI) presenting in early with wheezing before the age of 3 lung function impairment and B childhood (1). It is usually defined years, continue to and lower health-related quality of as the first wheezing episode in the develop asthma later in childhood. life (HRQoL) in later life. The aim of the present study was to childhood (2). It is a disease with high So, in some children early wheezing study 30-year sequelae of morbidity, since about 30–40 % of may be the first sign of respiratory bronchiolitis and pneumonia in children develop bronchiolitis before morbidity such as asthma (7). infancy. In 1981–1982, 83 the 2 years of age (1). There is There is evidence that LRTIs like children were hospitalized for evidence that respiratory syncytial bronchiolitis and pneumonia in bronchiolitis and 44 for (RSV) is the predominant virus infancy are associated with increased pneumonia at Kuopio associated with bronchiolitis and risk of lung function disorders, such University Hospital at less than pneumonia in young children (3, 4). as asthma and chronic obstructive 2 years of age. In 2010, 48 However in older age groups the role pulmonary disease (COPD), even in (58%) bronchiolitis and 22 of other , especially rhinovrus- adulthood (8–10). In two post-bron- (50%) pneumonia patients and es, becomes more pronounced (5). chiolitis follow-up studies impaired 138 controls attended the clinical study. Asthma was The link between early childhood lung function was demonstrated at defined as doctor-diagnosed or respiratory infections and later the age of 17–20 years in former self-reported asthma as an respiratory morbidity has been an bronchiolitis patients (9, 10). However indicator of the certainty of the issue of interest during recent there are no prospective post-bron- diagnosis. Participants decades, and an association between chiolitis studies including longer completed St. George´s lower respiratory tract infections follow-up than this. Respiratory Questionnaire as a (LRTI) in early childhood and later There are only a few studies HRQoL tool and underwent respiratory morbidity even in adult- describing health-related quality of pre-bronchodilatation (pre-BD) hood has been well established (6). life (HRQoL) after early childhood and post-BD spirometry. In 60 % of wheezing infants tendency LRTIs. In line with impaired lung Doctor-diagnosed asthma was to wheeze is a self-improving condi- function, also impaired HRQoL significantly more common in bronchiolitis patients (31%) tion (7). These transient wheezers has been described after LRTI´s compared to controls (9%). form a group of children, who have in infancy, but so far these studies Self-reported asthma was also wheezing symptoms at early age have not continued beyond child- significantly more common in during viral infections, but the hood (11, 12). bronchiolitis group (35%) compared to controls (15%). Asthma figures were similar in 1 Department of , Kuopio University Hospital, Kuopio, Finland the former pneumonia patients 2 Department of Pediatrics, University of Eastern Finland, Kuopio, Finland and in controls. In addition, 3 Center of Medicine and Clinical Research, Division of Pulmonology, Kuopio University Hospital, hospitalization for bronchiolitis Kuopio, Finland 4 Pediatric Research Centre, Tampere University and Tampere University Hospital, or pneumonia in infancy was Tampere, Finland associated with an impaired HRQoL and irreversible corresponding author: Katri Backman, MD obstructive lung function Department of Pediatrics, University of Eastern Finland impairment in adulthood. P.O. Box 1627, FI-70211 Kuopio [email protected]

40 ALLERGI I PRAKXSIS 1/2015 Bronchiolitis and pneumonia in infancy – asthma, lung function and quality of life at a 30-year follow-up

Bronchiolitis is an acute, viral, lower respiratory tract infection presenting in early childhood. It is a disease with high morbidity, since about 30–40 % of children develop bronchiolitis before the 2 years of age. PHOTO: COLOURBOX.COM

We have followed a group of patients after bronchiolitis and pneumonia in hospitalized for bronchiolitis or pneu- infancy. We also studied whether Methods monia in early childhood in 1981–82, permanently reduced lung function, In 1981–1982 127 children, hospital- and found an increased risk of both irreversible obstruction in particular, ized for LRTI in Kuopio University asthma and lung function disorders up is present in young adults after severe Hospital, Department of Pediatrics to the age of 18–20 years (10). In the LRTI in infancy. If so, LRTI in early at less than 2 years of age, were present study, at the age of 28–31 childhood could predispose infants enrolled in the study (13). Among the years, our aim was to evaluate asthma even to chronic obstructive pulmonary 127 recruited children with LRTI, 83 prevalence and HRQoL in adulthood disease (COPD) in adulthood. were diagnosed with bronchiolitis and A

ALLERGI I PRAKXSIS 1/2015 41 44 with pneumonia. The cohort has breathlessness), and the impact use of was required. been followed-up since, until the age scores (social or psychological Cases with doctor-diagnosed asthma of 18–20 years (10, 14, 15). disturbances resulting from airway were included (16). In 2010, 48 (58 %) former bronchiol- disease). The scores are expressed PEF was measured using a Mini itis and 22 (50 %) former pneumonia as a percentage of complete impair- Wright PEF meter (Clement-Clarke patients and 138 population controls ment; thus, the score 100 means International LTD, Harlow, Essex UK) attended the clinical study, which the worst possible and the score 0 three times every morning and every consisted of an examination by a the best possible respiratory health evening for two weeks (18). Daily doctor , spirometry including both status (17). variability over 20 % between the PEF pre-BD and post-BD measurements, Bronchial asthma was defined morning and evening values or PEF and monitoring two-week home in two different ways, reflecting improvement of 15 % or more after peak expiratory flow (PEF) (16). the certainty of the diagnosis. inhalation for two The study subjects completed a For doctor-diagnosed asthma, or more days were considered as questionnaire including questions an on-going regular maintenance abnormal (16,19). for example about asthma symptoms medication for asthma and a previ- Skin prick test (SPTs) (ALK Solu- and the presence of previous doctor- ously settled asthma diagnosis were prick®, Copenhagen, Denmark) diagnosed asthma and smoking required. In addition, study subjects included the most common inhaled status (16). Participants also com- who reported asthma symptoms allergens. Clinical atopy was defined pleted the St. George’s Respiratory and/or repeated use of bronchodila- by the presence of allergic , Questionnaire (SGRQ), designed tors, and in addition had a patho- allergic conjunctivitis or atopic to measure HRQoL in adults with logical result in the home PEF eczema, combined with one or more asthma or COPD (17). SGRQ consists monitoring, were regarded to positive SPT results. of three parts: symptom scores (the have doctor-diagnosed asthma. Lung function was measured with frequency and severity of respiratory For self-reported asthma, previously a Medikro SpiroStar USB spirometer symptoms), the activity scores (the diagnosed asthma combined with (Medikro, Kuopio, Finland) using Spiro activities that are limited due to asthma symptoms or with repeated 2000, Software version 2.2., according to international standards before TABLE 1. The scores calculated from the St. George’s Respiratory (pre-BD) and after (post-BD) broncho- Questionnaire at the age of 28–31 years in the three study groups. dilatation (18, 20). The measured

BRONCHIOLITIS N=48 PNEUMONIA N=22 CONTROL N=138 indices were forced vital capacity

SGRQ MEDIAN MEDIAN MEDIAN (FVC) and forced expiratory volume P – VALUE2 P – VALUE2 COMPONENTS IQ1 25–75 IQ1 25–75 IQ1 25–75 in one second (FEV1) and FEV1/FVC 9.1 18.4 0.005 5.0 Symptom score 0.044 and the results were presented as 0.0–26.3 5.1–29.9 0.0–16.3 percentages of the means of age- 5.7 0.0 0.146 0.0 Activity Score 0.002 0.0–12.1 0.0–13.4 0.0 – 6.0 and sex-specific, height-related reference values (FVC %, FEV1 %, 2.4 0.0 0.475 0.0 Impact Score < 0.001 0.0–9.5 0.0–8.4 0.0 – 2.4 FEV1/FVC %) (21). 5.4 4.9 0.012 1.5 Total Score < 0.001 0.0–14.7 1.3–14.8 0.0 – 6.0 Statistics The data was analyzed by using SPSS FIGURE 1. Asthma by two definitions at the age of 28–31 years in the study subjects 19.0 software (SPSS Inc., Chicago, IL, hospitalized40 for bronchiolitis or pneumonia at less than 24 months of age, compared with USA). Chi-square test and logistic 1 population controls. p =0.003 regression were used in the analyses p1=0.002 35% of the categorized asthma data. The 40 30 31% p1=0.003 Mann-Whitney U-test was used in the

oup s p2=0.760 analysis of the continuous SGRQ p1=0.002 35% scores. Analysis of variance (ANOVA) 0

30 23% 31% adjusted for asthma and current daily

oup s p2=0.760 smoking was used in the analysis of % of study gr

0 2 23% 15% continuous lung function data and 02 p =0.532 11% the results are given as means and 9% 95 % confidence intervals (95 %CI) % of study gr 2 15% 02 p =0.532 and p-values. 01 11% Doctor-diagnosed9% asthma Self-reported asthma Results 01 Doctor-diagnosed asthma Self-reported asthma There were 30 (63 %) males in the Bronchiolitis N = 48 Pneumonia N = 22 Control N = 138 bronchiolitis, 8 (36 %) males in the pneumonia and 75 (54 %) males in the 1 paired comparison between bronchiolitis and control group, 2 paired comparison between pneumonia and control group as adjusted for age, sex, clinical atopy, and current daily smoking (for definitions, see the text). control group. The mean age (SD) was Bronchiolitis N = 48 Pneumonia N = 22 Control N = 138

42 ALLERGI I PRAKXSIS 1/2015 29.5 years (0.72) in the bronchiolitis, 29.4 years (0.58) in the pneumonia, and 29.6 years (0.75) in the control group, respectively. Fourteen (29 %) former bronchiolitis patients (p = 0.007 vs. controls), 10 (46 %) former pneumonia patients (p = 0.000 vs. controls), and 17 (12 %) control subjects were current daily smokers. Clinical atopy was common in all groups, since 23 (48 %) of bronchiolitis patients (p=0.724 vs. controls), 10 (46 %) of pneumonia patients (p=0.674 vs controls) and 66/136 (49 %) of controls were diagnosed to have atopy. Doctor-diagnosed asthma was significantly more common in bronchiolitis patients (31 %) compared to controls (9 %). Self-reported asthma was also significantly more common in bronchiolitis group (35 %) compared to controls (15 %) (FIGURE 1). Asthma figures by both definitions were similar in the former pneumonia patients and in controls. Both former bronchiolitis patients Follow up studies of patients hospitalized for bronchiolitis in early childhood found an and former pneumonia patients had increased risk of asthma until the age of 30. There was no difference between former significantly higher total scores in the pneumonia patients and population controls in asthma prevalence. PHOTO: COLOURBOX.COM SGRQ than the controls indicating lower HRQoL (TABLE 1). The former Second, SGRQ scores were signifi- has been associated with increased bronchiolitis group differed from cantly higher in former bronchiolitis risk of asthma in childhood (14, 27) the control group in all parts of the and pneumonia patients compared to and early adulthood (23–25). The 31 % questionnaire, whereas the former controls, indicating impaired HRQoL asthma prevalence after bronchiolitis pneumonia group differed in terms after early childhood LRTI (16). Third, in the current study is in line with of symptom scores (TABLE 1). study subjects hospitalized for recently published follow-up of Pre-BD and post-BD FVC %, FEV1 % bronchiolitis or pneumonia in infancy Swedish bronchiolitis cohort, in which and FEV1/FVC % were lower in the presented with irreversible, obstruc- Goksör et al. presented 37 % asthma former bronchiolitis patients than in tive, lung function impairment in prevalence in former bronchiolitis controls (FIGURE 2, PAGE 44). Instead, the spirometry at the age of 28–31 years patients at the age of 25–28 years, former pneumonia patients differed (20). compared to 7 % asthma prevalence from controls only for pre-BD and The link between respiratory in controls (24). post-BD FEV1 % (FIGURE 2). infections like bronchiolitis or In the 1990´s Martinez et al. pneumonia in early childhood and documented, that in about 60 % of subsequent respiratory morbidity like children, wheezing tendency at early Discussion asthma and COPD in adulthood is well age is transient and these children The three main results of this documented in population-based become symptom free by the age of 6 prospective long-term follow-up of studies (8, 22). Despite the numerous years (7). However, in a proportion of early childhood bronchiolitis and post-bronchiolitis studies going on in children, early wheezing is a sign of pneumonia have been recently the world, there are only four pro- asthma predicting later respiratory published (16, 20). First, after spective post-bronchiolitis studies, morbidity, as described also in the hospitalization for bronchiolitis in started in the 1980’s and 1990´s, two present study. Tucson study demon- infancy, an increased asthma risk in Sweden and two in Finland, that strated, that in over 70 % of cases could be demonstrated at least until have continued beyond puberty with current asthma at the age of 28- to 31- years of age. Asthma was (23–26). Thus far, the results have 22 years, wheezing episodes had present in one-third of the former been published up to the early happened before the age of 6 years bronchiolitis patients. However there adulthood (23, 26) and two cohorts (28). So far, the results of the birth was no difference between former have been followed up to the age of cohort studies and post-bronchiolitis pneumonia patients and population 25–29 years (24, 25). In post-bronchi- studies, regarding later asthma risk controls in asthma prevalence (16). olitis studies bronchiolitis in infancy have agreed in documenting that A

ALLERGI I PRAKXSIS 1/2015 43 asthma in adulthood has its roots in until early adulthood after bronchiol- newborn (33). In addition to Tucson early childhood. itis in infancy (9, 10, 23). The type of results Bisgaard et al. demonstrated Asthma and wheezing have been the lung function impairment is in line that 14 % of children with asthma by associated with reduced HRQoL both with the 17–20 years follow-up of the the age of 7 already had a significant in childhood (29) and adulthood (30). Swedish post-bronchiolitis cohort, airflow deficit as neonates. However In the child population, pneumonia which demonstrated reduced FEV1/ this deficit progressed significantly has been described to affect HRQoL FVC and MEF50 before and after during early childhood and it was in short term (31). However there are bronchodilatation after history of concluded that approximately 40 % of not many studies about HRQoL after bronchiolitis in infancy, indicating the airflow deficit associated with early bronchiolitis or pneumonia. irreversible in asthma at the age of seven is present In a recent Norwegian study infants former bronchiolitis patients (9). at birth, whereas 60 % develops with with a history of bronchiolitis had However post-bronchiolitis studies clinical disease (34). As a conclusion, lower quality of life than controls in have been unable to answer the it seems that even if part of the lung the overall health and general health question whether impairment of lung function is determined before birth or domains of the Infant Toddler Quality function is a consequence or a cause very soon after that, the lung develop- of Life Questionnaire (ITQOL) 9 of respiratory infections in early ment can be influenced by various months after the index episode of childhood. events, such as respiratory infections wheezing (11). Similar findings were Tucson Childrens’ Respiratory in later life. also presented in another study 3 Study was the first birth cohort that As maximal lung function is years after hospitalization for RSV tried to answer this question of the reached in early adulthood, subjects bronchiolitis (12). However there are origin of impaired lung function. In who start adult life with a lower FEV1/ no previous studies on HRQoL after the Tucson study, lung function was FVC-ratio may attain the threshold early childhood bronchiolitis or measured in young infants before any of COPD earlier during normal lung pneumonia that would have included respiratory infections and it became ageing than those starting with a a longer follow-up. SGRQ scores have evident, that those children who higher FEV1/FVC-ratio (6). We found been described to correlate with lung wheezed during respiratory illness in preliminary evidence that subjects function (32). So, impaired HRQoL their first year of life had lower levels with bronchiolitis in infancy more found in the present study is in line of lung function than the future non- often have obstructive airways at with the obstructive airway function, wheezers. (7). Maternal smoking the age of 28–31 years than controls presented in current study after early during pregnancy hampers lung with no history of LRTI hospitalization bronchiolitis or pneumonia. development in utero and there is in infancy. There is a concern that Previous prospective post-bronchi- evidence that it is the most important these alterations in airways may olitis studies have demonstrated that preventable insults associated with progress to COPD during normal lung function may remain reduced lung function impairment of the lung ageing. The strengths of the present study FIGURE 2. Pre- and post-bronchodilator lung function at the age of 28-31 are the long follow-up time, a careful years after bronchiolitis or pneumonia in infancy compared to controls. collection of clinical data in early 110 110

100 100

90 90 edicted value (mean, 95%CI) edicted value (mean, 95%CI) % of pr

% of pr 80 80 Pre-BD1 Post-BD1 Pre-BD1 Post-BD1 Pre-BD1 Post-BD1 Pre-BD1 Post-BD1 Pre-BD1 Post-BD1 Pre-BD1 Post-BD1

FVC%2 FEV1%3 FEV1/FVC%4 FVC%2 FEV1%3 FEV1/FVC%4

Bronchiolitis N=47 Pneumonia N=22 Control N=138 Bronchiolitis N=47 Pneumonia N=22 Control N=138 Pre- and post-bronchodilator measurements are presented as means and 95 % confidence intervals (95 %CI). P-values are adjusted with asthma and current daily smoking, * p < 0.05, ** p < 0.005, *** p < 0.001. 1Pre-BD, pre-bronchodilator; post-BD, post-bronchodilator, 2FVC %, forced vital capacity ( % of predicted value, 3FEV1 %, forced expiratory volume in one second ( % of predicted value, 4FEV1/FVC %, FEV1/FVC ratio presented as % of predicted value.

44 ALLERGI I PRAKXSIS 1/2015 Hospitalization for bronchiolitis or pneumonia in early childhood was associated with impaired health-related quality of life and irreversible obstructive lung function in later life. There is a concern that these alterations in airways may progress to COPD during normal lung ageing. PHOTO: COLOURBOX.COM childhood, and a well-conducted early-life LRTI, and further, to low van den Hoogen B, Osterhaus AD, et al. clinical study at the age of 28–31 lung function at the age of 28–31 Respiratory picornaviruses and respiratory syncytial virus as causative agents of acute years. In all cases, spirometry was years. However our study provides expiratory wheezing in children. Emerg performed by a trained respiratory important information about the Infect Dis 2004; 10: 1095–101. 4. Pavia AT. What is the role of respiratory nurse of the research group, using long-term outcome of patients who viruses in community-acquired pneumonia?: the same spirometer and following experience bronchiolitis or pneu- What is the best therapy for and the current international standards monia in early childhood. other viral causes of community-acquired pneumonia? Infect Dis Clin North Am 2013; (18). The main shortcoming of the In conclusion, the study was able 27: 157–75. study was the small number of to confirm the high prevalence of 5. Korppi M, Kotaniemi-Syrjanen A, Waris M, Vainionpaa R, Reijonen TM. -as- subjects. We were able to clinically asthma at 28–31 years of age in sociated wheezing in infancy: Comparison examine 70 (57 %) of the 122 study subjects who were hospitalized for with respiratory syncytial virus bronchiolitis. subjects with a current address bronchiolitis at less than 2 years Pediatr Infect Dis J 2004; 23: 995–9. 6. Martinez FD. The origins of asthma and available. The participation rate in of age. In addition, hospitalization chronic obstructive pulmonary disease in the control group was even lower. for bronchiolitis or pneumonia in early life. Proc Am Thorac Soc 2009; 6: 272–7. The asthma prevalence of the controls infancy is associated with an impaired 7. Martinez FD, Wright AL, Taussig LM, was 15 %, which is higher than the 5 % respiratory health-related quality Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. asthma prevalence in non-selected of life in adulthood. Irreversible, the group health medical associates. Finnish young adults of the same age obstructive, lung function impairment N Engl J Med 1995; 332: 133–8. (35), which may diminish the differ- is present 30 years after bronchiolitis 8. de Marco R, Accordini S, Marcon A, Cerveri I, Anto JM, Gislason T, et al. Risk factors for ences in asthma prevalence between and pneumonia in infancy. chronic obstructive pulmonary disease in study groups, especially between a european cohort of young adults. Am J REFERENCES Respir Crit Care Med 2011; 183: 891–7. pneumonia and control group. Lung 1. Zorc JJ, Hall CB. Bronchiolitis: Recent 9. Goksor E, Gustafsson PM, Alm B, Amark M, function was not measured before evidence on diagnosis and management. Wennergren G. Reduced airway function any early childhood infections, and Pediatrics 2010; 125: 342–9. in early adulthood among subjects with 2. Jartti T, Lehtinen P, Vuorinen T, Ruuskanen wheezing disorder before two years of age. therefore our present study was O. Bronchiolitis: Age and previous wheezing Pediatr Pulmonol 2008; 43: 396–403. unable to answer the question of episodes are linked to viral etiology and atopic 10. Piippo-Savolainen E, Remes S, Kannisto S, characteristics. Pediatr Infect Dis J 2009; Korhonen K, Korppi M. Asthma and lung whether or not the low lung function 28: 311–7. function 20 years after wheezing in infancy: in infancy has predisposed infants to 3. Jartti T, Lehtinen P, Vuorinen T, Osterback R, Results from a prospective follow-up study. A

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