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Wheezing

in Infants

with

Cystic

Fibrosis:

Clinical

Course,

Pulmonary

Function,

and

Survival

Analysis

Eitan Kerern, MD*; Joseph Reisman, MD; Mary Corey, MSc;

Lea Bentur, MDt; Gerard Canny, MD; and Henry Levison, MD

ABSTRACT. Wheezing is a common finding in infants

with cystic fibrosis (CF). This study was undertaken to

determine the prevalence of wheezing in infants with

CF and to compare the clinical outcome of those who

wheezed in infancy with that of those who did not. The

study cohort included 229 CF patients born between 1965

and 1979 with CF diagnosed before 2 years of age.

Fifty-seven (25%) had physician-documented wheezing during

the first 2 years of life. Wheezing had resolved by the

age of 2 years in 50% of the patients and by the age of 4

years in 75%. Although wheezing seemed to be linked

to a family history of allergy and asthma, the frequency

of the iXF5O8 mutation was similar to that of the

non-wheezers. There was no significant difference in survival

at the age of 13 years between the two groups. At the age

of 7 years, patients who had wheezed had significantly

lower forced expiratory flow rate at mid-expiratory phase

(85 ± 34% predicted) compared with those with no

wheezing history (101 ± 34% predicted). At the age of 13

years, forced expiratory volume in 1 second values was

lower in the wheezing group (69 ± 24% predicted vs 78

± 21% predicted), as was forced expiratory flow rate at

mid-expiratory phase (56 ± 33% predicted vs 69 ± 30%

predicted). In conclusion, although wheezing in infants

with CF seems to have diminished with age, pulmonary

function abnormalities were more evident at 7 and 13

years of age in the group that wheezed than in the group

that did not. Pediatrics 1992;90:703-706; cystic fibrosis,

wheezing, infants.

ABBREVIATIONS. CF. cystic fibrosis; FEV5, forced expiratory

vol-ume in I second; FEF25.75 forced expiratory flow rate at

mid-expiratory phase.

Infants with cystic fibrosis (CF) may exhibit

respi-ratory manifestations such as coughing and wheezing

as part of their illness.’ Wheezing, a term commonly

used by parents and physicians, has had numerous

definitions.2’3 Wheezing may be the initial symptom

in infants with CF. The reported incidence of

wheez-ing in infants with CF varies considerably, and

res-piratory illness in infants with CF has been associated

with a poor clinical outcome.46 Little information is

available pertaining to the clinical outcome of

chil-dren with CF who wheezed in infancy. Several

pos-From the Pulmonary Division, Hospital for Sick Children, Toronto, Ontario,

Canada; *Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem,

Israel; and Department of Pediatrics B, Rambam Medical Center, Haifa,

Israel.

Received for publication Oct 24, 1991; accepted Apr 8, 1992.

Reprint requests to (JR.) Hospital for Sick Children, 555 University Aye,

Toronto, Ontario, Canada M5G 1X8.

PEDIATRICS (ISSN 0031 4005). Copyright (#{176}1992 by the American

Acad-emy of Pediatrics.

sibilities exist for the subsequent course of their

pul-monary involvement. The children might (1)

dem-onstrate improvement in their lung disease with age,

just as many wheezing children without CF do as

they grow older; (2) continue to wheeze and have

asthma-like manifestations but maintain a stable

course, similar to other relatively well CF patients; or

(3) demonstrate more rapid deterioration than the

average CF patient population. To clarify this

ques-tion, we analyzed the clinical characteristics of

chil-dren with CF who wheezed in infancy and compared

them with the characteristics of those who did not.

MATERIALS AND METHODS

The study population included all the CF patients followed at

the CF clinic of the Hospital for Sick Children, Toronto, Canada,

born between 1965 and 1979, with CF diagnosed before 2 years of

age. In all the patients, the diagnosis was confirmed by typical

clinical characteristics, and/or family history of CF, and by an

abnormal sweat chloride test.t Patient records were reviewed for

the occurrence of wheezing in the admission records and the reports

of the assessments at 3-monthly clinic visits. Consistent with the

present generally accepted definitions, we define wheezing as a

prolonged musical adventitial lung sound of varying intensity that

can be heard with and sometimes without a stethoscope.2’3 While

more often expiratory in nature, wheezes can be both expiratory

and inspiratory.2’3 The wheezing was in all cases documented by a

pulmonary physician involved in caring for our CF patients. An

assessment of family history in first-degree relatives of eczema,

allergic rhinitis, and asthma was made. Determinations of allergic

rhinitis and eczema were based on retrospective analysis of charted physician description. It is the routine of the CF clinic at our hospital

that patients are seen every 3 months for routine clinic visits,

during which height and weight are recorded and a history and

physical examination performed. All patients 6 to 7 years of age

and older have routine pulmonary function tests performed every

6 months. Forced vital capacity, forced expiratory volume in 1

second (FEV1), and forced expiratory flow rate at mid-expiratory

phase (FEF2575, ), were measured and expressed as a percentage

of predicted values for sex and height, according to previously

described standardized equations.7 Height and weight percentiles,

and weight as a percentage of ideal for height, were computed for

each patient according to the tables of Tanner et aI.M Chest

radio-graphs were performed every 6 months and scored according to

the Brasfield scoring system.v These data have been collected

prospectively and entered in our computerized database. Sputum

was obtained (if possible) or oropharyngeal secretions were

suc-tioned for culture every 3 months. Culture material was processed

using standard hospital laboratory techniques.’#{176} Pancreatic function

was determined according to previously described methods.nt The

presence of the F5O8 CF mutation was determined using

previ-ously described genetic methodology.’t

Patients were classified into two groups: those who wheezed

during the first 2 years of life and those who did not. Life-table

analysis was used to compare survival in the two groups and to

compare the age at which pulmonary colonization by Pseudomonas

aerugitiosa first occurred. Student’s t test was used to compare

group means (±standard deviation in all tables) for continuous

variables such as age at time of diagnosis, pulmonary function

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(2)

Sn

x

I-z

0

I 108

96

84

72

60

48

36

24

12

0 NO WHEEZE

#{149}WHEEZE

]

100

80

60

40

20

.

I

_

I

FIRST WHEEZE CESSATION OF WHZZ

Fig 1. Box plots for the time of first wheeze in infants with cystic

fibrosis (left) and time when wheezing ceased to be a problem

(right). The box represents the middle 50% of the data. The horizontal line inside the box is the median value. The upper and

lower ends of the box show the upper and lower quartiles. The

vertical lines show the 95% range. Filled circles represent points

outside this range.

-a

>

U)

0

AGE (YEARS)

Fig 2. Survival curves for cystic fibrosis patients who wheezed

prior to 2 years of age and for those who did not.

5 10 15 20 25

704 WHEEZING IN INFANTS WITH CYSTIC FIBROSIS

measurements, radiograph score, and anthropometric data.

Pro-portions were compared using x2analysis.’2

RESULTS

Cystic fibrosis was diagnosed before the age of 2

years in 336 (73%) of the 458 patients born in the

years 1965 to 1979. Fifty-nine were referred to our

clinic after 2 years of age, and 5 left the clinic before

age 2 years. Two patients died in the neonatal period

before wheezing could be assessed, and 41 were

excluded from the study because of incomplete

infor-mation on wheezing in infancy or insufficient data.

Our study population therefore included 229 patients.

Fifty-seven patients (25%) had

physician-docu-mented wheezing during the first 2 years of life. The

median age when wheezing was first documented

was 5 months (Fig 1). Of the 57 patients who

wheezed, 51 (89%) were hospitalized for wheezing;

50%

of these patients required one hospitalization

and 25% required more than two hospitalizations.

Resolution of wheeze was determined by a CF clinic

pulmonary physician and was based on both history

and physical examination. Wheezing had resolved by

the age of 2 years in 50% of patients and by the age

of 4 years in 75% of the patients (Fig 1).

Of the wheezing infants, 48% had a family history

of allergic disorders (eczema, allergic rhinitis) vs 18%

of those who did not wheeze (P < .001), and 19%

had a family history of asthma vs 10% of those who

did not wheeze (P > .10). The median age of diagnosis

(4.3

vs 4.0 months) and the proportions of boys (54%

vs 55%) were similar in the wheezing and

nonwheez-ing groups. Ninety-five percent of the patients who

wheezed and 98% of the nonwheezing patients had

pancreatic insufficiency and 18% and 21

%,

respec-tively, had meconium ileus. The relatively high

mci-dence of pancreatic insufficiency and meconium ileus

120

reflects the restriction in the study subjects to those

whose CF was diagnosed before 2 years of age.

Ninety-one of the study patients had been assessed

for presence of F5O8 in serum DNA, and both

groups had similar proportions of homozygotes and

heterozygotes for this most common CF mutation

(62% and 33% vs 66% and 27%, respectively).

Twenty patients (35%) from the wheezing group

died, compared with 42 patients (24%) from the

nonwheezing group. Figure 2 shows the survival

curves for both groups. These were not significantly

different (Wilcoxon P = .4). Survival to age 13 was

85% in the wheezing group compared with 87% in

the nonwheezing group. Several thousand subjects

would be necessary to detect a true difference as

small as 5% . After age 1 3 the numbers at risk in Fig

2 are progressively reduced, further reducing

statisti-cal power to detect a small difference. Further

follow-up will show whether an apparent tendency for

poorer survival during and after adolescence exists in

the wheezing group.

Brasfield chest radiograph score of the wheezing

infants was similar to that of those who did not

wheeze at ages 2 and 5 years (20. 1 ± 2.5 vs 20.5 ±

3.6 and 20.2 ± 3.1 vs 20.6 ± 3.2, respectively). When

pulmonary function was first studied, patients with

wheezing had significantly lower FEF25%75% values

(Table 1). The wheezing patients were similar to the

nonwheezmg patients in percentiles for weight and

height and in the percent of ideal weight for height.

Comparison of patients who reached age 13 years

during the follow-up period (Table 2) demonstrated

a continuing difference in pulmonary function values;

those with wheezing in infancy had significantly

lower FEy, and FEF25%75% values. The linear rate of

decline in FEy1 up to the age of 13 was also computed

for each patient. The mean decline per year in percent

predicted FEy1 was 3.5 ± 3.0 in wheezing patients

and 2.1 ± 2.8 in the nonwheezing patients (P < .02).

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(3)

TABLE 1. First Pulmonary Function and Anthropometric

Measurements in Cystic Fibrosis (CF) Patients Who Wheezed in

Infancy, Compared With CF Patients in Whom CF Was Diagnosed

Before the Age of 2 Years and Who Did Not Wheeze (Mean ± SD)*

Wheezing No Wheezing P

n 52 142

Age, y 7.1 ± 1.6 7.2 ± 1.3 .5

FVC, % predicted 83 ± 21 83 ± 19 .9

FEV,, % predicted 82 ± 22 86 ± 21 .2

7c.,, % predicted 85 ± 34 101 ± 37 .006

Weight, percentile 37 ± 25 40 ± 27 .9

Height, percentile 33 ± 22 38 ± 28 .3

% Weight for height 102 ± 9 101 ± 10 .3

CFVC, forced vital capacity; FEV,, forced expiratory volume in 1

second; FEF2. , forced expiratory flow rate at mid-expiratory

phase.

TABLE 2. Pulmonary Function and Anthropometric

Measure-ments Around Age I 3 Years in Patients Who Had Wheezing or No

Wheezing Before 2 Years of Age (Mean ± SD)*

Wheezing No Wheezing P

n 37 114

Age, y 13.5 ± 0.2 13.5 ± 0.4 .3

FVC, % predicted 76 ± 22 82 ± 19 .1

FEV,, % predicted 69 ± 24 78 ± 21 .02

.c,,., %predicted 56 ± 33 69 ± 30 .03

Weight, percentile 26 ± 25 28 ± 24 .8

Height, percentile 25 ± 25 32 ± 28 .2

%Weight for height 100 ± 15 100 ± 13 .9

CAbbreviations are explained in the footnote to Table 1.

Survival analysis of the age of P aeruginosa acquisition

showed that there was no difference between the

wheezing and the nonwheezing CF patients, median

age of P aeruginosa acquisition being 3.7 and 3.2 years,

respectively. To rule out a potential bias due to

dif-ferential diagnosis and treatment of wheezing over

the study period, analysis of follow-up data was

repeated for two subgroups of patients: those born

1965 through 1972, and those born 1973 through

1979. The results were virtually the same in both

groups.

DISCUSSION

The results of this study show that wheezing

ap-pears to be more common among infants with CF

(25%) than among the normal infant population (5%

to 10%).’ Previous studies have demonstrated an

increased incidence of atopic disorders in first-degree

relatives of patients with CF.’4”5 The higher incidence

of a history of atopy in the families of the wheezing

patients found in our study is similar to that of

families of wheezing infants in the general

popula-tion.’3 This suggests that the wheezing tendency in

CF may, at least partially, be inherited. The similar

prevalence of the zF508 mutation in both groups

suggests that wheezing is not directly associated with

a particular CFTR mutation, but with other

multifac-torial genetic and/or environmental factors.

Further-more, the similar proportion of pancreatic

insuffi-ciency in both groups suggests that wheezing is not

necessarily a characteristic of the severe phenotype.’1

The mechanism of wheezing in CF is not clear.

Generally, in infants, the most common precipitant

of wheezing is viral infection of the respiratory

tract.’6”7 The incidence of viral respiratory tract

infec-tions in CF patients is comparable with that of

unaf-fected children.’8”9 Furthermore, viruses2022 and in

particular influenza20 have been associated with

pul-monary exacerbations in CF. However, the role of

viruses in the pathogenesis of wheezing in infants

with CF has not been determined yet. Wheezing also

may be caused by airway narrowing due to secretions,

mucosal inflammation, increased bronchial smooth

muscle tone, or dynamic compression of airways. A

recent study suggested the possibility of an

independ-ent or vagally mediated bronchoconstriction in CF.23

Cross-sectional studies using inhaled histamine24’25 or

methacholine,26 as provoking agents, found an

in-creased incidence of airway hyperreactivity in

be-tween 24% and 68% of the CF patients tested.

Fur-thermore, bronchodilation after bronchodilator

inha-lation has been demonstrated previously.27’28 The

response is not seen in all patients, and it varies

according to season, pulmonary function status, and

presence of airway hyperreactivity.29

The clinical course of wheezing in infants with CF

is similar to that of wheezers who do not have CF. It

starts in early infancy, and as the child grows, the

severity and the number of episodes of wheezing

decrease. Later, wheezing seems to become less of a

problem in the management of CF patients. Infants

with CF who wheezed did not experience earlier

colonization by P aeruginosa than did other infants

with CF. This finding is consistent with our previous

observations that respiratory disease in CF does not

predispose to P aeruginosa colonization.30’3’

In this study, wheezing in infancy was not

associ-ated with reduced survival rate, at least up to 13 years

of age. However, there was a significant difference in

FEF25%75% values, even at the time of the first

pul-monary function test around the age of 7 years, and

differences were evident in both FEF25%75% and FEy,

by age 13 years. Of the pulmonary function

param-eters, it has been shown that FEF25%75% is the most

sensitive test to detect early lung disease.’ Holtzer et

a125 in a longitudinal study found that generally, the

patients with severe disease were more likely to

dem-onstrate airway hyperreactivity and atopy. Mitchell

et al26 also found that positive response to

methacho-line was associated with poor pulmonary function.

Furthermore, they showed a strong association

be-tween a history of wheezing and a positive

metha-choline challenge test. They could not determine

whether the diminished pulmonary function was a

cause or an outcome of the hyperresponsiveness.

Tepper and coworkers32’33 have used infant

pulmo-nary function testing techniques to characterize

in-fants and young children with CF. They found

in-creased bronchomotor tone to be present, and a

sig-nificant increase in maximal expiratory flows after

/32-agonist inhalation. Interestingly, there was no

cone-lation between bronchodilator response and

wheez-ing history. The results of our study point to an

association of lower lung function at the ages of 7

and 13 years in those with a history of wheezing in

infancy, which may be consistent with recent work

by Martinez and coworkers34 that demonstrated that

in normal infants younger than 6 months of age,

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(4)

706 WHEEZING IN INFANTS WITH CYSTIC FIBROSIS

diminished initial airway function may be a

predis-posing factor for recurrent wheezing illnesses during

the first 3 years of life. Our study suggests that

wheezing in infants is a significant predictor of

pul-monary function abnormalities in young CF patients.

It is yet to be determined whether aggressive

treat-ment with bronchodilators, sodium cromoglycate,

and/or corticosteroids may prevent or slow down

these changes in CF patients with a history of

wheez-ing in infancy.

In conclusion, wheezing occurs in about 25% of

infants with CF. Although wheezing did seem to be

linked to a family history of allergy and asthma, the

predisposition to wheeze was not directly associated

with a particular CFTR mutation. Wheezing can

usu-ally be managed in an ambulatory setting, and the

number of required hospitalizations for treatment of

wheezing per se is small. As the child grows its

incidence and prevalence decreases. There was no

significant decrease in survival to age 13 years, but

during the study period pulmonary function tests

showed greater decline in infants with CF who

wheezed than in those who did not wheeze, and this

finding suggests more severe lung disease, which may

predict poorer survival at older ages.

ACKNOWLEDGMENT

We thank Jennifer Chay for secretarial assistance.

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1990:692-729

2. Mikami R, Murao M, Cugell DW, et al. International Symposium on

Lung Sounds: synopsis of proceedings. Chest. 1987;92:342-345

3. Pastercamp H, Montgomery M, Wiebicke W. Nomenclature used by

health care professionals to describe breath sounds in asthma. Chest.

1987;92:346-352

4. Hudson I, Phelan PD. Are sex, age at diagnosis, or mode of presentation prognostic factors for cystic fibrosis? Pediatr Puinnonol. 1987;3:288-297 5. Lloyd-still JD, Khaw KT, Shwachman H. Severe respiratory disease in

infants with cystic fibrosis. Pediatrics. 1974;53:678-682

6. Katz JN, Horwitz RI, Dolan TF, Shapiro ED. Clinical features as

predic-tory of functional status in children with cystic fibrosis. IPediatr. 1986;

I 08:352-358

7. Corey M, Levison H, Crozier D. Five to seven year course of pulmonary function in cystic fibrosis. Am Rev Respir Dis. 1976;1 14:1085-1092

8. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to

ma-turity for height, weight. height velocity and weight velocity: British

children 1965. Arc!, Dis Child. 1966;41:613-635

9. Brasfield D, Hick C, Soong T, Tiller RE. The chest roentgenogram in

cystic fibrosis: a new scoring system. Pediatrics. 1979;63:24-29

10. Nolan C, Mclvor P. Levison H, et al. Antibiotic prophylaxis in cystic fibrosis: inhaled cephaloridine as an adjunct to oral cloxacillin. IPediatr.

1982;101:626-630

I I. Kerem E, Corey M, Kerem B, et al. The relation between genotype and

phenotype in cystic fibrosis: analysis of the most common mutation .F508. N Engi JMed. 1990;323:1517-1522

12. SAS Institute Inc. SAS User’s Guide: Statistics. 5th ed. Cary, NC: SAS Institute; 1985

13. Mok J, Levison H. The wheezing infant. In: Tinkelman DC, Falliers CJ,

Naspitz CK, eds. Cliitical Asthma: Pathophysiology arid Treatment. New

York, NY: Marcel Dekker Inc; 1987:159-181

14. Counahan R, Mearns MB. Prevalence of atopy and exercise-induced bronchial lability in relatives of patients with cystic fibrosis. Arc!, Dis Child. 1975;50:477-481

15. Warner JO, Taylor BW, Norman AP, et al. Association of cystic fibrosis with allergy. Arch Dis Child. 1976;51:507-511

I 6. McIntosh K, Ellis EF, Hoffman LS, Lybass TG, Eller JJ, Fulginiti VA. The

association of viral and bacterial respiratory infections with exacerbation

of wheezing in young asthmatic children. IPediatr. 1973;82:578-590 17. Horn MEC, Reed SE, Taylor P. Role of viruses and bacteria in acute

wheezy bronchitis in childhood: a study of sputum. Arc!, Div Child.

1979;54:587-592

18. Wang EEL, Prober CC, Manson B, Corey M, Levison H. Association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis. N ErtglJMed. 1984;311:1653-1658

19. Ramsey BW, Gore EJ, Smith AL, Cooney MK, Redding GJ, Foy H. The

effect of respiratory viral infections on patients with cystic fibrosis.

AJDC. 1989;143:662.-668

20. Stroobant J. Viral infection in cystic fibrosis. I R Soc Med. 1986; 79(suppl 12):19-22

21. Hordvik NL, Konig P. Hamory B, et al. Effect of acute viral respiratory

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22. Pribble CG, Black PG, Bosso JA, Turner RB. Clinical manifestations of

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Pediatr. 1990;1 17:200-204

23. Van Asperen PP, Manglick P. AlIen M. Mechanisms of bronchial hy-perreactivity in cystic fibrosis. Pediatr Pulmonol. 1988;5:139-144

24. Mellis CM, Levison H. Bronchial reactivity in cystic fibrosis. Pediatrics.

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25. Holtzer FJ, Olinsky A, Phelan PD. Variability of airways hyperreactivity

and allergy in cystic fibrosis. Arch Dis Child. 1981;56:455-459

26. Mitchell I, Corey M, Woenne R, Krastins IRB, Levison H. Bronchial hyperreactivity in cystic fibrosis and asthma. J Pediatr. 1978;93: 744-748

27. Macfarlane P1, Heaf D. Changes in airflow obstruction and oxygen saturation in response to exercise and bronchodilators in cystic fibrosis.

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28. Hordvik NL, Konig P. Morris D, Kreutz C, Barbero GJ. A longitudinal

study of bronchodilator responsiveness in cystic fibrosis. Ant Rev Respir Dis. 1985;13:889-893

29. Eggleston PA, Rosenstein BJ, Stackhouse CM, Mellits ED, Baumgardner RA. A controlled trial of long-term bronchodilator therapy in cystic fibrosis. Chest. 1991;99:1088-1093

30. Kerem E, Corey M, Stein R, Gold R, Levison H. Risk factors for Pseu-dornonas aeruginosa in cystic fibrosis patients. Pediatr infect Dis 1.1990; 9:494-498

31. Kerem E, Corey M, Gold R, Levison H. Pulmonary function and clinical

course in cystic fibrosis patients following pulmonary colonization with

Pseudornonas aeruginosa. IPediatr. 1990;1 16:714-719

32. Tepper RS, Hiatt P. Eigen H, et al. Infants with cystic fibrosis: pulmonary

function at diagnosis. Pediatr Pulntonol. 1988;5:15-18

33. Hiatt P. Eigen H, Yu P. Tepper RS. Bronchodilator responsiveness in

infants and young children with cystic fibrosis. Ann, Ret Respir Dis. 1988;

137:119-122

34. Martinez FD, Morgan WJ, Wright AL, et al. Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first

three years of life. Am Rev Respir. 1991;143:312-316

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1992;90;703

Pediatrics

Joseph Reisman, Mary Corey, Gerard Canny, Henry Levison, Eitan Kerem and Lea Bentur

Survival Analysis

Wheezing in Infants with Cystic Fibrosis: Clinical Course, Pulmonary Function, and

Services

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1992;90;703

Pediatrics

Joseph Reisman, Mary Corey, Gerard Canny, Henry Levison, Eitan Kerem and Lea Bentur

Survival Analysis

Wheezing in Infants with Cystic Fibrosis: Clinical Course, Pulmonary Function, and

http://pediatrics.aappublications.org/content/90/5/703

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