Online Supplementary 1
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Clinical and virus surveillance after the first wheezing episode: special
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reference to rhinovirus A and C species
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Riitta Turunen
1, 3, Tytti Vuorinen
2, 3, Yury Bochkov
4, James Gern
4, Tuomas Jartti
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1
Department of Pediatrics, Turku University Hospital, Turku, Finland;
2Department of Clinical 8
Virology, Division of Microbiology and Genetics, Turku University Hospital, Turku, Finland;
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3
Department of Virology, University of Turku, Finland;
4the Departments of Pediatrics and 10
Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 11
12 USA
Results 13
14 F 15 i 16 g 17 u 18 r
19 e 20 21 S 22 1
23 . 24 25 S tudy flow chart.
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Table S1. Virus etiology of the follow-ups and recurrent wheezing episodes.
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Virus 2 weeks N = 102 2 months N = 101 12 months N = 92
symptomatic n = 59
asymptomatic n = 43
symptomatic n = 52
asymptomatic n = 49
symptomatic n = 34
asymptomatic n = 58
Recurrent wheezing episode n = 65
RV 32 (54%) 17 (40%) 15 (29%) 8 (16%) 14 (41%) 22 (38%) 40 (62%)
RV-A 3 (5.1%) 4 (9.3%) 8 (15%) 2 (4.1%) 3 (8.8%) 2 (3.4%) 6 (9.2%)
RV-B 1 (1.7%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (5.2%) 1 (1.5%)
RV-C 14 (24%) 2 (4.7%) 8 (15%) 2 (4.1%) 9 (27%) 6 (10%) 26 (40%)
Non-typeable RV 15 (25%) 11 (26%) 2 (3.8%) 4 (8.2%) 5 (15%) 9 (16%) 7 (11%)
RSV 5 (8.5%) 4 (9.3%) 8 (15%) 1 (2.0%) 1 (2.9%) 3 (5.2%) 9 (14%)
RSV A 3 (5.1%) 1 (2.3%) 7 (14%) 1 (2.0%) 1 (2.9%) 1 (1.7%) 3 (4.6%)
RSV B 1 (1.7%) 0 (0%) 1 (1.9%) 0 (0%) 0 (0%) 2 (3.4%) 3 (4.6%)
HBoV 12 (20%) 8 (19%) 5 (9.6%) 7 (14%) 2 (5.9%) 3 (5.2%) 8 (12%)
PIV 1 (1.7%) 0 (0%) 5 (9.6%) 1 (2.0%) 0 (0%) 0 (0%) 6 (9.2%)
PIV 1 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
PIV 2 0 (0%) 0 (0%) 2 (3.8%) 1 (2.0%) 0 (0%) 0 (0%) 4 (6.2%)
PIV 3 1 (1.7%) 0 (0%) 3 (5.8%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
MPV 2 (3.4%) 1 (2.3%) 2 (3.8%) 0 (0%) 1 (2.9%) 1 (1.7%) 3 (4.6%)
EV 2 (3.4%) 2 (4.7%) 4 (7.7%) 2 (4.1%) 2 (5.9%) 2 (3.4%) 8 (12%)
CV 3 (5.1%) 2 (4.7%) 3 (5.8%) 3 (6.1%) 4 (12%) 2 (3.4%) 1 (1.5%)
OC43/HKU1 1 (1.7%) 1 (2.3%) 2 (3.8%) 2 (4.1%) 1 (2.9%) 0 (0%) 1 (1.5%)
229E/NL43 2 (3.4%) 1 (2.3%) 1 (1.9%) 1 (2.0%) 3 (8.8%) 2 (3.4%) 0 (0%)
AdV 2 (3.4%) 0 (0%) 1 (1.9%) 0 (0%) 1 (2.9%) 0 (0%) 4 (6.2%)
Flu 2 (3.4%) 0 (0%) 2 (3.8%) 0 (0%) 2 (5.9%) 1 (1.7%) 1 (1.5%)
Flu A 2 (3.4%) 0 (0%) 2 (3.8%) 0 (0%) 2 (5.9%) 1 (1.7%) 1 (1.5%)
Flu B 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
1 virus 28 (48%) 18 (42%) 18 (35%) 16 (32%) 19 (56%) 25 (43%) 43 (66%)
2 viruses 15 (25%) 8 (19%) 12 (23%) 1 (2.0%) 1 (2.9%) 3 (5.2%) 14 (22%)
3 viruses 1 (1.7%) 0 (0%) 1 (1.9%) 0 (0%) 2 (5.9%) 1 (1.7%) 4 (6.2%)
≥ 1 viruses/sample 44 (75%) 26 (61%) 31 (60%) 19 (39%) 21 (62%) 29 (50%) 61 (94%)
≥ 2 viruses/sample 16 (27%) 8 (19%) 13 (25%) 3 (6.1%) 3 (8.8%) 4 (6.9%) 18 (28%)
≥ 3 viruses/sample 1 (1.7%) 0 (0%) 1 (1.9%) 0 (0%) 2 (5.9%) 1 (1.7%) 4 (6.2%)
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Values are presented as numbers of cases (%). Symptomatic group included children with 30
respiratory symptoms (rhinitis or cough) within one week. Asymptomatic group included children 31
without respiratory symptoms within one week. In recurrent wheezing group, 10/75 children had no 32
virus infection. The viral etiology of study entry has been previously reported (Turunen PAI 2014).
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RV, rhinovirus; RSV, respiratory syncytial virus; HBoV, human bocavirus; PIV, parainfluenza 34
virus; MPV, metapneumovirus; EV, enterovirus; CV, corona virus; Adv, adenovirus; Flu, influenza 35
virus.
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Appendix 1. Parental questionnaire.*
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The key questions 40
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To be filled by study physician at parental interview 42
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Name: __________________________________________________
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Social security number: __________________________________________________
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Names of the parents / guardians: ______________________________________
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______________________________________
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Address: _______________________________________________________
48 Phone: _______________________________________________________
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Email: _______________________________________________________
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Does the child fulfill inclusion criteria of the study: age 3-23 months, >h37+0, first episode of 52
breathing difficulty and written informed consent from the parents?
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Yes 54 55
Does the child fulfill inclusion criteria of the intervention trial: rhinovirus PCR positive and still 56
signs of lower respiratory infection (breathing difficulty, noisy breathing or cough)?
57 58 59
Yes No 60 61
Randomized to receive the study drug:
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Yes No
63 If yes, when (day, time) _________________________________________________________
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Any exclusion criteria: chronic other than atopy related illness, previous systemic or inhaled 66 corticosteroid treatment, participation to another study (excluding long-term follow-up studies in 67
childhood), varicella contact if previously intact, need for intensive care unit treatment, or poor 68
understanding of Finnish No
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Parents / guardians have received routine hospital wheezy questionnaires (2 forms) and symptom 71
diaries (3 forms):
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Yes 73 74
Height _________ cm and weight _______ kg 75
Still breastfeeding Yes No
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Duration of breastfeeding ___ months
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Duration of exclusive breastfeeding ___ months
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Does the child have doctor-diagnosed atopic eczema: Yes No 79 80
Mother Father
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Doctor-diagnosed asthma: Yes No Yes No 82
Allergic rhinitis: Yes No Yes No 83
Smoking: Yes No Yes No 84
Furry pets: Yes No
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Number of children in the family: ___ children
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Daycare: Home Small group Kindergarden
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Wheezy questionnaire
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To be filled by a parent/guardian 90
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1. Does your child have a family doctor?
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No Yes , Dr ____________________ practicing in _______________________________
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2. Type of daycare?
94 1) Home 2) Family day care 3) Day care center 4) Other , what? _______________
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3. Type of home?
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1) Apartment building 2) House 3) Row house 4) Farm 5) Other , what?
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______________
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4. Number of children in the family? ____
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5. Parental smoking? No Yes , if yes, smoking:
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1) inside No Yes 101
2) in the car No Yes 102
6. Pets at home?
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dog No Yes
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cat No Yes
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other animals No Yes , what? ____________________________
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7. Other allergen sources at home?
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feather pillows/blankets No Yes 108
fitted carpet No Yes 109
8. At day care 110
pets/animals? No Yes , what? ____________________________
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smoking? No Yes
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9. At other places, weekly exposure to 113
animals ? No Yes
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smoking? No Yes
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10. Are there allergic symptoms in the family?
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eczema No Yes , underline: mother / father / 117
sibling 118
rhinitis No Yes , underline: mother / father / 119
sibling 120
asthma No Yes , underline: mother / father / 121
sibling 122
11. Does the child have allergic symptoms? Please, mark the suspected source on the reverse side.
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eczema No Yes
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rhinitis No Yes
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asthma No Yes
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12. Does your child have an “allergy diet”?
127 No Yes . Please, specify the diet to the study nurse.
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13. Has your child ever undergone skin prick tests?
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No Yes , when ___/___(month/year), where 130
________________________
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14. Information about allergies (please circle the suspected sources):
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1) Dietary: chocolate, cocoa, citrus, egg, fish, tomato, strawberry, pea, apple, 133
carrot, nuts, pear, peach, cow´s milk, breast milk substitute, rye, barley, oats, 134
wheat, other 135
______________________________________________________
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2) Animals: dog, cat, horse, cow, guinea pig, feather, other 137
_________________
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3) Pollen: birch, alder, conifer, hay, mugworth, other ______________________
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4) Other causes: room dust, fungal spore, other ___________________________
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15. Information about the child´s respiratory infections:
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During the last 12 months:
142 1) “common cold” ___ times
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2) antibiotic prescription ___ times 144
3) pneumonias ___ times
145 4) bronchitis ___ times
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5) otitis ___ times
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6) parasenthesis ___ times
148 7) other, what? ______________________________________________________
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16. Adenoidectomy 150
No Yes , when ___/___ (month/year), where __________________________________
151 17. Maxillary sinus puncture 152
No Yes , when ___/___ (month/year), where __________________________________
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18. Information about breathing difficulty symptoms:
154 Were there “common cold” symptoms during the current difficulty in breathing?
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No Yes I can’t say 156
If you suspect other causes, please name them: _____________________________________
157 19. The duration of respiratory symptoms before study entry?
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1) rhinitis _____ days 159
2) cough _____ days 160 3) rhinitis _____ days 161
20. Have other family members had “common cold” symptoms?
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No Yes
163 21. Is this your child’s first episode of breathing difficulties?
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No Yes 165
22. Does your child have any regular medication?
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No Yes , what? __________________________________________________________
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*The key questions are directly translated from Finnish study form. The wheezy 170
questionnaire contains selected questions from 2 page standard wheezy questionnaire and 7 171
page standard allergy questionnaire used at Turku University Hospital.
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Appendix 2. Clinical score chart at the emergency room or hospital ward.
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Name _____________________________ Social security number ___________________
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(After study entry, to be filled in the mornings 2 hours after bronchodilator).
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An example
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Date, time 7.9.2007
8.00
Heart rate/min 112
Breathing frequency/min 55
Oxygen saturation 98
Body temperature 37.6
Inspiratory:expiratory time: 0 (2:1), 1 (1:1), 2 (1:2), 3 (1:3)
1:2 Degree of dyspnea: 0 (normal), 1
(mild), 2 (moderate), 3 (severe)
2 Auscultatory findings on wheezing: 0 (none), 1 (expiratory), 2 (inspiratory and expiratory), 3 (audible without stethoscope)
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Type of breathing: 0 (normal), 1 (use of stomach muscles), 2 (use of intercostal muscles), 3 (nasal flaring)
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Pneumonic crackles: 0 (no), 1 ( mild), 2 (moderate), 3 (severe)
0 Otitis media: 0 (no), 1 (yes) 0 Antibiotic: 0 (no), 1 (yes),
what and when initiated
0 Other symptoms +/++/+++ and their
connection to study medication: 1 (no), 2 (maybe), 3 (yes)
Cough ++/1
Rhinitis +/1
Eye symptoms -
Eczema -
Any other symptoms/signs (report everything)
Restlesness ++/1 Other notes, e.g. the cause of symptoms flu Study drug given (tally) lll Mediacation (drug name, dosage) before physical examination (tally)
ER:
albuterol 1.2 mg x2, ward:
albuterol 1.5 mg x2
…and before blood draw + albuterol 1.5 mg x2 Oxygen (hour) or
i.v. or nasogastric hydration (volume/time)
Oxygen 5 h i.v. fluid 700 ml Exact times: Study entry at ER/ward (1),
study drug initiation (2), ready for discharge considering breathing difficulties (3), actual discharge (4).
(1) 15.30
Name _______________________________ Social security number ___________________
Daily symptom and medications until 2-week visit.
Date (fill in one column per day) An example 1.1.07 Hospitalization for expiratory breathing
difficulty, yes or no
Yes
Cough, 0 (no) - 3 (severe) 2
Expiratory breathing difficulty, 0 (no) - 3 (severe)
1 Noisy breathing, 0 (no) - 3 (loud) 0
Rhinitis, 0 (no) - 3 (severe) 0
Night wakening for breathing difficulties, 0 (no), 1 (once), 2 (often), 3 (continuously)
1 Temperature, exact or on scale 0 (no) - 3 (high)
Fever 37.9, or 1 Any other symptom (report any deviation
from normal)
Fell in stairs, tearful Other notes (e.g. cause of symptom) scute otitis media,
playing with a cat
Study drug taken (tally) 111
Bronchodilator (name, dose, number of doses; tally)
Ventoline 0.1 mg, puffs 1111
Other medication Naprosyn mixt. 5
mg/ml 3 ml/dose, 111 Amorion mixt 80 mg/ml 3.7 ml x2 Doctor’s appointment: where, why, name of
the doctor, and treatment
Healthcenter Mäntymäki 1, fever, cough, tearful, Naprosyn and Amorion for acute otitis media If any questions, do not hesitate to contact study physician by phone.
Name _______________________________ Social security number __________________
Daily symptoms and medications for 2 months. Check a box if yes.
Month _________ (fill in one column per day) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Rhinitis Cough
Expiratory breathing difficulty Noisy breathing
Nocturnal symptoms Bronchodilator Oral corticosteroid Inhaled corticosteroid Antibiotic
Doctor’s visit for expiratory breathing difficulty Hospitalization for expiratory breathing difficulty
Month _________ (fill in one column per day) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Rhinitis Cough
Expiratory breathing difficulty Noisy breathing
Nocturnal symptoms Bronchodilator Oral corticosteroid Inhaled corticosteroid Antibiotic
Doctor’s visit for expiratory breathing difficulty Hospitalization for expiratory breathing difficulty
Month _________ (fill in one column per day) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Rhinitis Cough
Expiratory breathing difficulty Noisy breathing
Nocturnal symptoms Bronchodilator Oral corticosteroid Inhaled corticosteroid Antibiotic
Doctor’s visit for expiratory breathing difficulty Hospitalization for expiratory breathing difficulty
If any questions, do not hesitate to contact study physician by phone.