Pulmonary Function In Children

J Bras Pneumol. 2010;36(4):453-459

Pulmonary function in children and adolescents with postinfectious bronchiolitis obliterans*, **

Função pulmonar de crianças e adolescentes com bronquiolite obliterante pós-infecciosa

Rita Mattiello, Javier Mallol, Gilberto Bueno Fischer,

Helena Teresinha Mocelin, Belkys Rueda, Edgar Enrique Sarria

Abstract

Objective: To describe the pulmonary function in children and adolescents with postinfectious bronchiolitis obliterans (PIBO), as well as to evaluate potential risk factors for severe impairment of pulmonary function. Methods: The pulmonary function of 77 participants, aged 8-18 years, was assessed by spirometry and plethysmography. The following parameters were analyzed: FVC; FEV1; FEF25-75%; FEV1/FVC; RV; TLC; RV/TLC; intrathoracic gas volume; and specific airway resistance (sRaw). We used Poisson regression to investigate the following potential risk factors for severe impairment of pulmonary function: gender; age at first wheeze; age at diagnosis; family history of asthma; tobacco smoke exposure; length of hospital stay; and duration of mechanical ventilation. Results: The mean age was 13.5 years. There were pronounced decreases in FEV1 and FEF25-75%, as well as increases in RV and sRaw. These alterations are characteristic of obstructive airway disease. For the parameters that were the most affected, the mean values (percentage of predicted) were as follows: FEV1 = 45.9%; FEF25-75% = 21.5%; RV = 281.1%; RV/TLC = 236.2%; and sRaw = 665.3%. None of the potential risk factors studied showed a significant association with severely impaired pulmonary function. Conclusions: The patients with PIBO had a common pattern of severe pulmonary function impairment, characterized by marked airway obstruction and pronounced increases in RV and sRaw. The combination of spirometric and plethysmographic measurements can be more useful for assessing functional damage, as well as in the follow-up of these patients, than are either of these techniques used in isolation. Known risk factors for respiratory diseases do not seem to be associated with severely impaired pulmonary function in PIBO.

Keywords: Respiratory function tests; Airway obstruction; Bronchiolitis obliterans.

Resumo

Objetivo: Descrever a função pulmonar de crianças e adolescentes com bronquiolite obliterante pós-infecciosa (BOPI) e avaliar potenciais fatores de risco para pior função pulmonar. Métodos: A função pulmonar de 77 participantes, com idades de 8-18 anos, foi avaliada por meio de espirometria e pletismografia. Os seguintes parâmetros foram analisados: CVF, VEF1, FEF25-75%, VEF1/CVF, VR, CPT, VR/CPT, volume de gás intratorácico e specific airway resistance (sRaw, resistência específica das vias aéreas). Foi utilizada a regressão de Poisson para investigar os seguintes potenciais fatores de risco para pior função pulmonar: sexo, idade do primeiro sibilo, idade ao diagnóstico, história familiar de asma, exposição ao tabaco, tempo de hospitalização e tempo de ventilação mecânica. Resultados: A idade média foi de 13,5 anos. Houve uma diminuição importante de VEF1 e FEF25-75%, assim como um aumento de VR e sRaw, característicos de doença obstrutiva das vias aéreas. Os parâmetros mais afetados e as médias percentuais dos valores previstos foram VEF1 = 45,9%; FEF25-75% = 21,5%; VR = 281,1%; VR/ CPT = 236,2%; e sRaw = 665,3%. Nenhum dos potenciais fatores de risco avaliados apresentou uma associação significativa com pior função pulmonar. Conclusões: As crianças com BOPI apresentaram um padrão comum de comprometimento grave da função pulmonar, caracterizado por uma obstrução importante das vias aéreas e um expressivo aumento de VR e sRaw. A combinação de medidas espirométricas e pletismográficas pode ser mais útil na avaliação do dano funcional, assim como no acompanhamento desses pacientes. Fatores de riscos conhecidos para doenças respiratórias não parecem estar associados a pior função pulmonar em BOPI.

Descritores: Testes de função respiratória; Obstrução das vias respiratórias; Bronquiolite obliterante.

* Study carried out under the auspices of the Graduate Program in Pediatrics, Universidade Federal do Rio Grande do Sul – UFRGS,

Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Correspondence to: Rita Mattiello. Hospital da Criança Santo Antonio, Avenida Independência, 155, 5º andar, CEP 90035-074,

Porto Alegre, RS, Brasil.

Tel 55 51 3214-8646. E-mail: [email protected]

Financial support: Rita Matiello is the recipient of a grant from the Brazilian Conselho Nacional de Desenvolvimento Científico e

Tecnológico (CNPq, National Council for Scientific and Technological Development).

Submitted: 11 December 2009. Accepted, after review: 15 March 2010.

** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

Original Article

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Mattiello R, Mallol J, Fischer GB, Mocelin HT, Rueda B, Sarria EE

J Bras Pneumol. 2010;36(4):453-459

Methods

This was a cross-sectional study involving

children and adolescents (8-18 years of age)

with PIBO, in Brazil and Chile. The participants

were periodically monitored at one of two

tertiary care pediatric pulmonology outpatient

clinics: that of the Hospital da Criança Santo

Antonio, located in the city of Porto Alegre,

Brazil; or that of the Centro de Referencia de

Salud del Hospital El Pino, located in the city

of Santiago, Chile. The staff at both clinics

have extensive clinical experience in diagnosing

and monitoring pediatric patients with PIBO,

having done so for more than 15 years. For the

purposes of this study, we analyzed the results of

pulmonary function tests carried out in 2007. Of

the 83 patients initially eligible for inclusion in

the study, 5 presented with pulmonary function

test results that did not meet the acceptability/

reproducibility criteria of the American Thoracic

Society/European Respiratory Society (ATS/

ERS) and another declined to participate in the

study. Those 6 patients were therefore excluded.

Consequently, the final sample consisted of

77 patients: 41 in Brazil and 36 in Chile.

The criteria for a diagnosis of PIBO were

based on previous reports(1,8,13,14) and included

all of the following:

• acute, severe bronchiolitis/viral pneumonia

during the first 3 years of life in children

who had previously been healthy

• evidence of persistent airway obstruction

after the acute event (identified either

by physical examination or by pulmonary

function testing) that was unresponsive to at

least two weeks of treatment with systemic

corticosteroids and bronchodilators

• chest X-ray findings indicative of chronic

lung disease (e.g., hyperinflation,

atelectasis, airway wall thickening, and

bronchiectasis)

• mosaic pattern and air trapping on chest CT

• exclusion of other conditions that progress

to permanent respiratory symptoms,

including chronic lung diseases such

as tuberculosis, cystic fibrosis, and

bronchopulmonary dysplasia, as well as

immunodeficiency and alpha-1-antitrypsin

deficiency

Spirometric

parameters—FVC,

FEV1,

FEF25-75%, and FEV1/FVC—and plethysmographic

parameters—intrathoracic gas volume (ITGV),

Introduction

Bronchiolitis obliterans (BO) is an uncommon

form of chronic lung disease that follows a

severe insult to the lower respiratory tract. From

the pathological perspective, it is characterized

by partial or complete luminal obstruction of

the small airways by scar tissue, secondary to

inflammation and fibrosis.(1,2)

Because organ

transplantation has improved survival in patients

with lung disease patients, the incidence of

BO as a manifestation of graft rejection has

increased.(3) In children and adolescents, however,

the most common form of BO, especially in

developing countries, is postinfectious BO

(PIBO).(4)

There have been reports of PIBO on most

continents, interesting data coming from South

American countries and corresponding to the

adenovirus epidemics that occurred during the

1990s.(4-6) In PIBO, as in other chronic lung

diseases, determining pulmonary function is

crucial for the diagnosis, as well as for classifying

the severity of the condition and monitoring

its progression. Unfortunately, there is only

sparse information in the literature regarding

the pulmonary function of patients with PIBO.

Two studies (both conducted by the same

research group) evaluated pulmonary function

in infants with PIBO.(5,7)

Those two studies

produced consistent results, since both included

a representative number of patients. That is

not the case for studies involving children and

adolescents with PIBO; the few articles providing

lung function data usually have small sample

sizes and different methodology or focus, which

precludes an appropriate characterization of

LF.(8-11) This effectively prevents us from drawing

reliable conclusions regarding the characteristics

of pulmonary function in this age bracket.

Profiling the pulmonary function of children

and adolescents with PIBO could give us a better

insight of the long-term respiratory effects of

the disease. This could be of interest not only

to those studying and treating patients with

PIBO, but also to those in the field of lung

transplantation, since the histopathological

similarities between transplant and PIBO(12) could

translate to similarities in pulmonary function.

The objective of this study was to describe the

pulmonary function of children and adolescents

with PIBO and to evaluate the potential risk

factors for severe impairment of pulmonary

function.

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J Bras Pneumol. 2010;36(4):453-459

455

by a forced expiratory maneuver in which the

patient exhaled down to RV. The effort with

the greatest VC and the best shutter maneuver,

which included the loop closest to the pressure-

volume axis, was considered the best effort.

Spirometric measurements were taken after the

patient had rested for 5 min. Appropriate values

were selected from the best three acceptable and

reproducible FVC maneuvers, and the selected

maneuver was the one with the greatest sum of

FVC and FEV1.

We employed the reference values and

equations devised by Perez-Padilla et al. and

Zapletal et al. for spirometry and plethysmography,

respectively.(18,19) All pulmonary function data

are expressed as a percentage of the predicted

reference value. The severity of impairment

for spirometric parameters was based on FEV1

according to the ATS/ERS recommendations,(20)

and the normality ranges accepted for volumes

were those recommended by the Sociedad

Española de Neumología y Cirugía Torácica

(Spanish Society of Pulmonology and Thoracic

Surgery).(21)

We defined severely impaired

pulmonary function as that classified as severe

or very severe impairment, according to the ATS

criteria.(20)

Continuous variables are expressed as mean

and 95% CI, whereas categorical variables are

expressed as absolute and relative frequency.

The adjusted prevalence ratios of potential risk

factors for severe impairment of pulmonary

function were calculated by Poisson regression

with robust error variance in bivariate and

multivariate analyses. This was followed by an

interactive procedure, initially considering all

covariates with a p value < 0.10 in a multiple

regression model. The covariates with the

RV, TLC, RV/TLC, and specific airway resistance

(sRaw)—were measured in accordance with

international recommendations for acceptability

and reproducibility.(15,16) The pulmonary function

parameters were measured only if patients

had been free of respiratory exacerbations

and clinically stable for at least two weeks.

Short-acting and long-acting β2 agonists were

withheld for, respectively, 12 h and 48 h prior

to the tests, although inhaled corticosteroids

were maintained as prescribed. Before any tests

were conducted, the patients were familiarized

with the basic maneuvers for spirometric and

plethysmographic measurements.

At each facility, the measurements were

conducted by an accredited laboratory technician.

All measurements were taken in the morning

(plethysmography followed by spirometry).

Both centers used the same type of spirometer

(MasterScreen Body, with software, v4.3; Jaeger,

Würtzburg, Germany), which was calibrated daily

using a 3-L syringe, and measurements were

electronically corrected to body temperature and

pressure, saturated conditions.(15-17)

During the plethysmography, the patients

were instructed to breathe calmly through a

mouthpiece until reaching a stable end-expiratory

level. The shutter then closed automatically for

2-3 s while the patients performed a series of

shallow panting maneuvers (against 0.5-1.0 Hz

of resistance), with both hands supporting their

cheeks. The results of three to five technically

satisfactory maneuvers were registered for

subsequent analysis. The shutter was opened,

and the patients slowly exhaled as completely as

possible (to allow the expiratory reserve volume

to be determined). Subsequently, the patients

slowly inhaled up to TLC, and this was followed

Table 1 – Demographic data of the participants, by country.

Variable

Brazil

Chile

Both countries

(n = 41)

(n = 36)

(n = 77)

Age,a years

11.5 (10.7-12.3)

15.1 (14.0-16.3)

13.3 (12.4-14.0)

Height,a cm

144.6 (139.7-149.5)

157.3 (152.6-162.0)

150.5 (146.9-154.1)

BMI,a kg/m2

17.9 (16.9-18.9)

21.4 (20.0-22.9)

19.5 (18.6-20.5)

Age at diagnosis,a months

12.2 (9.6-14.6)

10.78 (8.2-13.3)

11.4 (9.7-13.2)

0-6b

7 (17.1)

9 (25.0)

16 (20.8)

7-12b

22 (53.6)

17 (47.2)

39 (50.6)

13-24b

10 (24.4)

9 (25.0)

19 (24.7)

>24b

2 (4.9)

1 (2.8)

3 (3.9)

Male genderb

31 (75.6)

19 (52.8)

50 (64.9)

aValues expressed as mean (95% CI). bValues expressed as n (%).

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J Bras Pneumol. 2010;36(4):453-459

RV, RV/TLC, and sRaw) were markedly high, with

the exception of TLC, which was within normal

limits.

In the regression model, none of the potential

risk factors demonstrated a significant association

with severely impaired pulmonary function. There

was a moderate correlation between RV/TLC and

FEV1 (r = −0.657, p < 0.001) and between RV/

TLC and FEF25-75% (r = −0.669, p < 0.001).

Discussion

The present study describes pulmonary

function in one of the largest samples of

pediatric patients with PIBO evaluated to date.

Our results show that, at both of the facilities

involved, the children and adolescents with PIBO

presented with moderate to very severe airway

obstruction.(20) This impairment, which probably

reflects major chronic damage of the medium

and small airways, is characterized by decreased

expiratory airflow, together with increased RV

and sRaw.

In order to elucidate the great impact that

PIBO has on the major morphological and

functional components of the respiratory system,

a combination of methods must be employed.

One such method is pulmonary function testing,

which allows us to assess, in a relatively practical

and noninvasive manner that is most suitable

for diagnostic and follow-up routines, how the

viscoelastic and flow-resistive properties of the

system are impaired.(22)

Because PIBO is a rare disease with a relatively

small number of patients in any given country,

the use and results of pulmonary function testing

highest p values were removed from the model,

which was then recalculated. The final model

comprised only covariates with a p value < 0.10.

We included the following variables as potential

risk factors: ggender; age at first wheeze;

age at diagnosis; family history of asthma;

tobacco smoke exposure; length of hospital

stay; and duration of mechanical ventilation.

The correlation between RV/TLC and FEV1, as

well as that between RV/TLC and FEF25-75%, was

assessed using Pearson’s correlation coefficient

(r). The level of statistical significance was set

at p < 0.005.

The study was approved by both local

research ethics committees. The parents or

legal guardians of the participants gave written

informed consent, and the participating patients

verbally agreed to be included in the study.

Results

The demographic data are shown in Table 1.

In both groups, there was a predominance of

males (Brazil: 75.6%; Chile: 52.8%). The overall

means (and the group means for Brazil and Chile,

respectively) were as follows: age, 13.3 years

(11.5 and 15.1 years); height, 150.5 cm (144.6

and 157.3 cm); and BMI, 19.5 kg/m2 (17.9 and

21.4 kg/m2). The onset of the disease occurred

between 1 and 24 months of age in most of the

patients (97% of the group in Brazil and 97% of

the group in Chile).

Table 2 shows the pulmonary function

parameters. In both groups, the mean values

of all spirometric variables, especially FEV1 and

FEF25-75%, were low. Correspondingly, the mean

values of most plethysmographic variables (ITGV,

Table 2 – Pulmonary function parameters of the participants, by country.

Parametera

Brazilb

Chileb

Both countriesb

(n = 41)

(n = 36)

(n = 77)

FVC

61.7 (56.9-66.4)

72.5 (68.2-76.8)

66.8 (63.4-70.2)

FEV1

42.5 (37.6-47.0)

49.7 (44.7-54.8)

45.9 (42.4-49.4)

FEF25-75%

19.9 (16.0-23.8)

23.4 (19.1-27.7)

21.5 (18.6-24.4)

FEV1/FVC

67.6 (63.1-72.1)

66.8 (62.5-71.1)

67.2 (64.1-70.3)

TLC

116.8 (113.1-120.5)

112.5 (10.8-117.1)

116.8 (113.2-120.5)

ITGV

162.7 (154.0-171.4)

144.5 (134.6-154.3)

162.7 (154.0-171.4)

RV

281.1 (258.6-303.7)

231.0 (203.2-258.7)

281.1 (258.6-303.7)

RV/TLC

236.2 (222.5-250.40)

200.9 (184.7-217.1)

236.2 (222.5-250.0)

sRaw

746.6 (597.5-895.7)

572.8 (431.9-713.6)

665.3 (562.5-768.2)

ITGV: intrathoracic gas volume; and sRaw: specific airway resistance. aValues expressed as percentage of the predicted

value. bValues expressed as mean (95% CI).

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457

when airflow obstruction becomes more severe

as a result of decreased lung elastic recoil or

changes in dynamic mechanisms, ITGV, RV, TLC,

and RV/TLC tend to increase.

We found only two studies evaluating lung

volumes in pediatric patients with PIBO.(9,10)

We pooled the data of their collective sample

(n = 25) and, disregarding any methodological

differences, found that all of the patients

showed a marked increase in RV. In our study

sample (n = 77), we also identified patients

with reduced FVC. However, in those patients,

the TLC was also considerably above 80% of

the predicted value, with a noticeable increase

in RV and RV/TLC. These lung volume data,

obtained by plethysmography, leave no doubt as

to the obstructive nature of PIBO. In addition,

we found that, overall, RV/TLC presented

good correlations with two of the spirometric

parameters, FEV1 and FEF25-75%, indicating that

the degree of hyperinflation paralleled the

severity of airway obstruction. This situation

can lead to progressive clinical consequences,

such as a permanent need for oxygen therapy or

impaired quality of life.

Although FEV1/FVC and FEV1

are the

spirometric parameters most often employed

in order to determine airway obstruction,

FEF25-75% has also been considered a relevant early

indicator of this abnormality, since it appears to

show a proportionately greater reduction than

does FEV1 or FEV1/FVC.(9,10,20) Our results show

that all of the patients had abnormal values

for FEF25-75%

and FEV1, the FEF25-75%

value

being half of that obtained for FEV1. This is in

agreement with the current recommendations

for diagnosing bronchiolitis obliterans syndrome

(BOS) in transplant patients. Since FEF25-75% has

been found to deteriorate sooner after BOS onset

than does FEV1,(3) the criteria for early detection

of BOS now include a decline in FEF25-75%, as

well as a decrease in FEV1.(26) Because FEF25-75%

presents considerable variability, as evidenced

in a recent study,(27) its routine use in clinical

practice has been controversial. However, its

considerable and consistent reduction in our

patients with PIBO suggests that FEF25-75% should

be considered together with the established duo

of FEV1 and FEV1/FVC to define the extent of

functional damage, as well as in the routine

follow-up of such patients. The fact that it is

obtained simultaneously with other spirometric

in PIBO patients have been addressed in only a

few studies, six of which have been notable:

• Studying a sample of 13 infants in

Argentina, Teper et al. suggested that the

functional impairment caused by PIBO is

established at its early stages.(7)

• Kim et al. described the pulmonary

function of 14 children within a study

group of 31 children with PIBO in the USA

and South Korea. The authors found that

all 14 presented with severe, fixed airway

obstruction.(9)

• Castro-Rodriguez et al., using the impulse

oscillometry technique, found evidence

of peripheral airway dysfunction in 18

preschool children in Chile.(23)

• Cazzato et al. conducted a longitudinal

study of the pulmonary function of 14

children in Italy and found an annual

decline of 1% in the predicted values of

FEV1, FEV1/FVC and FEF25-75%.(10)

• In Brazil, Mattiello et al. assessed the

functional capacity of 20 children during

cardiopulmonary exercise testing and

compared the results with those of

conventional pulmonary function testing.

The children presented with reduced

oxygen consumption, which correlated

positively with FVC, FEV1, and RV/TLC.(11)

• Mattiello et al. also studied a group of

21 children in Brazil and showed that the

CT findings in early life seem to predict

severely impaired pulmonary function a

decade later.(24)

Our results corroborate and expand upon a

conclusion drawn on the basis of those studies:

the functional hallmark of the disease is marked

airway obstruction with air trapping. Another

group of authors described PIBO patients

with a restrictive or mixed pattern of obstruction.

(25) However, those authors based their analysis

solely on a reduced FVC that was associated with

a normal or low FEV1/FVC ratio.(25) Therefore,

their finding can be explained in the context of

a considerable airway obstruction that leads to

pronounced air trapping, the degree of which is

best determined through the assessment of lung

volumes.(20) The ATS and ERS both recommend

the determination of lung volumes in patients

with obstructive lung diseases, such as PIBO,

because it allows a better understanding of the

underlying respiratory impairment.(16,20) In fact,

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J Bras Pneumol. 2010;36(4):453-459

www.thoracic.org/global-health/mecor-

courses/mecor-program-description.pdf), for

their support and suggestions regarding this

manuscript.

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parameters and through the same technique

strengthens its feasibility.

One limitation of our study is that our two

groups of patients with PIBO were each from a

different country. However, since both of those

countries are in the southern portion of South

America, there are geographic, ethnic, and

nutritional similarities between the two groups. In

addition, they all developed the disease at similar

(young) ages, corresponding to simultaneous

regional bursts of severe adenovirus respiratory

infections during the early and mid 1990s.(28)

Furthermore, the measurements corresponded

to pulmonary function testing obtained during

the same year, both pulmonary function testing

laboratories are board certified, both follow the

ATS/ERS recommendations, and both used the

same apparatus and software. The group results

are presented together with those of the sample

as a whole, and it is clear that the two patient

groups were similar in terms of pulmonary

function.

Our sample size was adequate to run the

statistical model used, and our analyses revealed

that none of the factors studied constituted a risk

for severe impairment of pulmonary function.

We believe that the value of our study lies

in the large number of participants and the

broad age range of the sample, as well as in

the use and analysis of an extensive number

of pulmonary function variables. These aspects

allowed us to obtain data that are consistent and

reliable. Our data can inform decisions regarding

the evaluation and treatment of patients with

PIBO, as well as those regarding future studies in

children or adolescents with post-transplant BO.

In conclusion, pediatric patients with PIBO

have a common pattern of severe pulmonary

function impairment, characterized by

marked airway obstruction and a pronounced

increase in RV and sRaw. Our results suggest

that the combined use of spirometric and

plethysmographic measurements is more useful

than is that of each method alone in assessing

functional damage at a given time and in the

follow-up of children or adolescents suffering

from this rare disease.

Acknowledgments

The authors wish to thank Dr. Sonia Buist

and Dr. Gordon Rubenfeld, both of whom are

professors for the ATS-MECOR Course (http://

Page 7

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Sobre os autores

Rita Mattiello

Doctoral Fellow in Pediatrics. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School

of Medicine, Porto Alegre, Brazil.

Javier Mallol

Physician. Department of Pediatric Respiratory Medicine, Centro de Referencia de Salud del Hospital El Pino – Hospital-CRS El Pino,

El Pino Referral Hospital – University of Santiago, Santiago, Chile.

Gilberto Bueno Fischer

Professor of Pediatrics. Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA, Federal University of Health Sciences

of Porto Alegre, Porto Alegre, Brazil.

Helena Teresinha Mocelin

Physician. Pediatric Pulmonology Sector, Hospital da Criança Santo Antônio, Porto Alegre, Brazil.

Belkys Rueda

Physician. Department of Pediatric Respiratory Medicine, Centro de Referencia de Salud del Hospital El Pino – Hospital-CRS El Pino,

El Pino Referral Hospital – University of Santiago, Santiago, Chile.

Edgar Enrique Sarria

Research Fellow in Pediatric Pulmonology. Indiana University, Indianapolis (IN) USA.