ORIGINAL ARTICLE

The Clinical Respiratory Journal

Spinal deformities and lung function in adults with osteogenesis imperfecta Lena L. Wekre1, Aina Kjensli2, Kjersti Aasand3, Jan A. Falch4 and Erik F. Eriksen3 1 TRS National Resouce Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, Bjørnemyr, Nesoddtangen, Norway 2 Glittreklinikken, Hakadal, Norway 3 Oslo University Hospital, Oslo, Norway 4 Norwegian Institute of Public Health, Oslo, Norway

Abstract Introduction: There are no larger studies of adults with osteogenesis imperfecta (OI), focusing on the impact of spinal cord deformities on lung function assessment. Objectives: To assess prevalence and severity of spinal deformities and lung function in an adult population with OI and to explore whether compromise of lung function correlated with deformities of the spine. Methods: Ninety-two adults with OI had radiographs of the spine, 75 underwent spirometry. Deformities were assessed radiographically using a semi-quantitative (SQ) approach grading each vertebra from mild to severe (0–3 SQ grades). The spinal deformity index (SDI) was calculated by summing the SQ grades of all vertebrae from TH4 to L4. Scoliosis was measured using the Cobb method. Pulmonary function tests were performed; both current measured and arm-span height were used for calculating the predicted lung volumes and flow rates. Results: Vertebral deformities were found in 67%, the majority of deformities were found in the mid thoracic region. Scoliosis was found in 46%, nine patients exhibited torsion scoliosis. Median values of SDI were 2.0 in type I, 4.0 in type IV and 2.5 in the total population. Only correction with arm-span height had a significant impact on the assessment of lung function. Significant negative correlations were obtained when spirometry variables were correlated to spine deformities. Conclusions: OI patients show spinal deformities influencing body height and lung function. Lung function tests should be corrected for reductions in body height by using arm-span height. OI patients should be evaluated with spirometry when vertebral deformities are suspected.

Key words adults – lung function – osteogenesis imperfecta – spinal deformities Correspondence Lena Lande Wekre MD, PhD, TRS National Resouce Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, Bjørnemyr, 1450 Nesoddtangen, Norway. Tel: +47 66969000 Fax: +47 66962576 Email: [email protected] Received: 07 November 2012 Revision requested: 11 September 2013 Accepted: 02 December 2013 DOI:10.1111/crj.12092

Please cite this paper as: Wekre LL, Kjensli A, Aasand K, Falch JA and Eriksen EF. Spinal deformities and lung function in adults with osteogenesis imperfecta. Clin Respir J 2014; 8: 437–443.

Authorship and contributorship Lena L. Wekre – Planning of project. Collection and analyzing of data. Writing the manuscript. Aina Kjensli – Analyzing of data. Contribution to manuscript. Kjersti Aasand – Collection and analyzing of data. Review of the manuscript. Jan A. Falch – Planning of project. Contribution to manuscript. (Senior author) Erik F. Eriksen – Data processing. Analyzing of data. Contribution to manuscript. (Senior author)

Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.

Ethics Written informed consent was obtained from each participant, and the study was approved by the regional committee for medical research ethics in Norway.

Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by increased bone fragility and other connective tissue manifestations because of quantitative and/or qualitative defects in the synthesis of collagen type 1 (1, 2). Severity varies widely, from perinatal lethality to very mild forms without frac-

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2013 John Wiley & Sons Ltd

tures. Typical extraskeletal manifestations like blue sclera, hearing impairment, dentinogenesis imperfecta, hyperlaxity of ligaments, Wormian bones and different internal organ complications vary in onset and severity, and are characterized by heterogeneity in its phenotypic expression.

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Table 1. Patient characteristics OI type

All patients

I

III

IV

Unclassified

N Sex (male-female) Age mean ± SD Height (cm) mean ± SD Weight (kg) mean ± SD (min–max) Respiratory disease* Smoking habits -Never smoked (%) -Former smoker (%) -Current smoker (%) -Missing inform (%)

97 41-56

75 28-47

9 3-6

11 9-2

2 1-1

44 ± 12

45 ± 13

35 ± 7

47 ± 7

49

156 ± 20

163 ± 10

106 ± 13

157 ± 17

157

68 ± 14 (30–97) 10

69 ± 12 (44–97) 7

45 ± 14 (30–67) 2

70 ± 13 (54–97) 1

0

52 14 29 2

39 (52) 11 (15) 23 (40)

8 (89) 1 (11)

3 (27) 3 (27) 5 (46)

(54) (14) (30) (2)

2

*Based on self-reporting by the patients at the first interview.

The prevalence of spinal deformity in OI varies between 39% and 100% depending on OI type, and the deformities, especially scoliosis, seem to progress continuously during life, and may ultimately adversely affect lung capacity (3, 4). Widmann et al. found that thoracic scoliosis of more than 60° has severe adverse effects on pulmonary function in those with OI (5). Most information material and guidelines on OI address respiratory issues because respiratory insufficiency have been identified as leading causes of death in this patient group (1, 6–9). However, the literature assessing lung function in these patients is scarce, and the prevalence of respiratory abnormalities has received little attention, especially in adults. As lung function measurements are presented as percent of predicted values which depend on age, sex and height, height reduction may influence the evaluation of such tests (10). People with OI are often short in stature caused by deformities of the spine and compression fractures. Predicted values for lung function might therefore be underestimated, and hence, lung function overestimated. Different approaches to height measurements have been used to calculate predicted values for lung function, with some investigators using current measured height (CMH) and others using arm-span. These different measurements will result in different estimates for lung function and may affect the medical intervention offered to these patients. It is therefore important that current recommendations for lung function testing include protocols for how to measure and when to use respectively CMH and armspan for patients with for example spinal deformities (10, 11).

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To our knowledge, there are no larger studies of adults with OI focusing on the impact of spinal deformities on lung function assessment. The aim of the present study was therefore threefold: (i) to study deformities of the spine and lung function in an adult population with OI; (ii) to study the influence of correction of height reduction on spirometry indices; and (iii) to explore whether pulmonary compromise in the adult OI population correlated with deformities of the spine.

Materials and methods This study was part of a larger Norwegian study on adult patients with OI (12). All patients with OI aged 25 and older registered at TRS – National Resource Centre for Rare Disorders were invited to participate (n = 154). Ninety-seven accepted to take part in the main study and were clinically typed according to Sillence classification criteria (Table 1) (13). Ninetytwo of the participants had radiographs of the spine (two were pregnant, one was not able to perform this investigation and two did not want to participate in this part of the study) and 75 underwent pulmonary function tests. Regarding ambulation, wheelchairs were used by seven persons (9%) with OI type I (four persons had an electrical wheelchair), all nine persons with type III (all of them had electrical wheelchairs) and three persons (27%) with type IV (1 used electrical wheelchair). Written informed consent was obtained from each participant, and the study was approved by the regional committee for medical research ethics.

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2013 John Wiley & Sons Ltd

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Data collection Height without shoes was measured in centimeters with a wall-mounted stadiometer, Kawe 44444® (Firm; Svalland AS, Oslo, Norway), while the person was standing with the back against the wall. Patients who were unable to stand were measured with a measuring tape in horizontal position. Arm span defined as the distance between the tips of the middle fingers of maximally extended horizontal arms was measured in standing position while the person was standing with the front against the wall. Those who had significant flexion deformities in the elbow joints had their arm span measured with a soft measuring tape. Arm-span height (ASH, body height estimated from arm span) was calculated by algorithms from Parker et al. (14). Patients’ weight wearing only underwear was measured on a digital weight for professional use (Firm; Soehnle Professional, Backnang, Germany) in standing position. Those who were unable to stand were sitting on the same weight. Radiographs of the entire spine were taken in anteroposterior and lateral positions using routine positioning and exposure. Radiographs of the cervical column were taken with the patient standing (in those who were able to stand independently). Thoracic, lumbar and sacral spine radiographs were taken in supine position. Each part of the spine was evaluated separately, except in those who expressed large deformities like torsion scoliosis. All radiographs were evaluated by the same radiologist. Vertebral deformities were assessed using a semi-quantitative (SQ) approach where the severity of deformities for each vertebrae were graded to normal = 0, mild = 1, moderate = 2 or severe = 3 in accordance to Genant et al. (15). In addition, a spinal fracture index (SFI) was calculated for each patient by summing the individual vertebral deformity scores and dividing by the number of vertebrae evaluated (15). To assess the reproducibility of SFI, radiographs from a random sample of 33% of the participants were re-evaluated at a later time point by the same radiologist, blinded to the previous assessment and following the same procedures as for the initial assessments. The coefficient of variation for SFI in our population was 5%. To characterize the total burden of the vertebral deformities, both the number and the severity of the vertebral deformities were incorporated to a single measure, the spinal deformity index (SDI). SDI is calculated by summing the SQ grades of all vertebrae from TH4 to L4 (16). In theory, the SDI value can vary between 0 (no deformities) and 39 (all assessed vertebra are grade 3). The magnitude of scoliosis was measured by using the Cobb method (17).

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2013 John Wiley & Sons Ltd

Adults with osteogenesis imperfecta

Pulmonary function tests were carried out by trained operators at Aker University Hospital (Pulmonary Department) in accordance with ATS/ERS guidelines (18). Reference values were based on European Community for Steel and Coal (19). Lung volume measurements were determined by helium dilution. Both CMH and ASH were used for calculating the predicted lung volumes and flow rates. Total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), residual volume (RV) and FEV1/FVC were determined for each patient. In accordance with ATS/ERS guidelines obstructive lung function was defined as FEV1/FVC < 0.70, and restrictive lung disease was defined as FEV1/FVC ≥ 0.80 and TLC < 80% or FVC < 80% (20). TLC was missing in many of the patients, and we therefore decided to use FVC. However, we found that the measurements for FVC were relative to those for TLC in patients where these indices were available.

Statistics Descriptive statistics are frequencies, mean and standard deviation (SD) and median and quartiles. Descriptives were also stratified in groups according to the type of OI obtained from Sillence classification. Paired sample t-test was used to compare lung indices using respectively CMH vs ASH. The Pearson correlation coefficient was estimated between pairs of continuous variables. A P value of less than or equal to 0.05 was considered statistically significant. All analyses were performed using SPSS 17.0 for Windows (IBM SPSS Statistics, NY, USA).

Results Basic information about the study group is presented in Table 1. Ten persons reported that they had some sort of respiratory disease diagnosed by a medical doctor. Four of them (two type III and two type I) were not able to perform spirometry in our study, mostly because of skeletal deformities. According to the criteria presented above, four (type I) of them have normal lung function, one (type I) have an obstructive lung pattern and one (type 4) have a restrictive lung pattern when using height estimated from arm-span (see below). According to SDI estimates, at least one vertebral deformity was found in 56 (67%) of the participants. The majority of deformities were found at the mid thoracic region (Th7) (Fig. 1a and 1b). Nine patients exhibited torsion scoliosis of such magnitude that single vertebrae were impossible to evaluate. Table 2 439

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(a)

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Number of patients with deformities in vertebrae TH4-12 and L1-4 45

Women Men

40 35

Number

30 25 20 15 10 5 0 TH4

TH5

TH6

TH7

TH8

TH9 TH10 TH11 TH12

L1

L2

L3

L4

L1

L2

L3

L4

Vertebrae

Percent of deformed vertebrae

(b)

Deformities in vertebrae TH4-12 and L1-4 60 % 50 % 40 % 30 % 20 % 10 % 0% TH4

TH5

TH6

TH7

TH8

TH9 TH10 TH11 TH12 Vertebrae

Figure 1. (a) Localization of vertebral deformities. (b) Percent of deformities in each measured vertebrae.

Table 2. Description of spinal deformities N

All

N

Scoliosis None (%) 50 (54) Yes (%) 42 (46) Cobb’s 35 angle (°)* mean ± SD 24 ± 13 (min–max) (5–60)

84 2.5 84 0.23

N OI type III

N OI type IV

0 8 (100)

3 (30) 7 (70)

46 (64) 26 (36) 26

Median Q1,Q3 SDI SFI

OI type I

2

1 1 1 20

6

25 ± 15 (5–60)

20

22 ± 10 (10–35)

Median Q1,Q3

Median Q1,Q3

Median Q1,Q3

0,8 71 2 0.0,0.69 71 0.15

0,6 2 6.5 0.0,0.55 2 0.93

9 4 9 0.31

N Unclassified

Median Q1,Q3

0,11 2 11.5 0.04,1.04 2 0.94

*Cobb’s angle for those who expressed scoliosis. If two curves were present, the larger thoracic curve was used. Seven patients with scoliosis exhibited torsion of such magnitude that Cobb’s angle was impossible to measure. SDI, spinal deformity index (possible range: 0–39); SFI, spinal fracture index (possible range: 0–3). Median and quartiles are used for SDI and SFI because of highly skewed data.

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Table 3. Lung function using respectively current measured height and arm span height

CMH (cm) ASH (cm) FVCCMH (% pred) FVCASH (% pred) FEV1CMH (% pred) FEV1ASH (% pred) TLCCMH (% pred) TLCASH (% pred) RVCMH (% pred) RVASH (% pred) FEV1/FVC (%)

N

OI type I Mean ± SD (min–max)

N

OI type III Mean ± SD (min–max)

N

OI type IV Mean ± SD (min–max)

63 63 60 60 60 60 53 53 53 53 60

163 ± 10 (138–190) 168 ± 10 (144–189) 103 ± 21 (59–187) 97 ± 20 (32–159) 101 ± 18 (64–170) 95 ± 18 (34–145) 100 ± 17 (78–180) 94 ± 15 (73–153) 99 ± 19 (70–148) 95 ± 19 (61–151) 83 ± 0.6 (69−93)

5 5 3 3 3 3 1 1 1 1 3

113 ± 11 (95–125) 143 ± 14 (119–155) 129 ± 46 (77–165) 67 ± 77 (46–80) 137 ± 50 (80–176) 69 ± 19 (47–82) 122 67 90 57 88 ± 0.1 (86−89)

10 10 10 10 10 10 7 7 7 7 10

157 ± 17 (119–181) 173 ± 9 (160–187) 107 ± 14 (81–126) 85 ± 22 (42–115) 106 ± 13 (85–124) 83 ± 18 (44–110) 106 ± 7 (95–114) 88 ± 12 (73–103) 103 ± 25 (82–155) 93 ± 26 (67–146) 82 ± 0.7 (69−92)

CMH, current measured height; ASH, arm span height (body height estimated from arm span) was calculated by the algorithm from Parker. % pred, percent of predicted; N, number of participants. One person was unclassified according to OI type and is not included in this table (Obs. 74 patients in Fig. 2 and Table 4).

describes the spinal deformities encountered. Scoliosis was found in 42 (46 %) of the patients, 26 (36%) with type I, all type III and seven (70%) type IV. The Cobb angle was measured in 35 patients (seven participants exhibited deformities of such magnitude that Cobbs angle was impossible to measure) and the average angle was 24° (range 5°–60°). Two of these had torsion scoliosis. Median (Q1,Q3) for the SDI was 2.5 (0,8), ranging from 2 (0,6) in type I patients to 4 (0,11) in type IV patients (Table 2). Median (Q1,Q3) for the SFI was 0.23 (0,0.69), ranging from 0.15 (0,0.55) in type I patients to 0.31 (0.04,1.04) in type IV. These differences did not reach statistical significance, but reflect the severity of disease in type IV. All type III had deformities of the spine, six had torsion scoliosis.

former smoker, and both had elevated values for TLC and RV (above 100%). Figure 2 shows flowcharts of the patients reflecting a restrictive lung pattern using respectively FVCCMH (2a), and FVCASH (2b). The number of patients reflecting restrictive lung disease increased from 4 to 11 when using values corrected with ASH. When spirometry variables were correlated to spine deformities as reflected in SFI or SDI (Table 4), significant negative correlations were obtained for the values of TLC, FVC and FEV1 when using indices corrected with ASH. Using predicted values based on CMH did not result in any significant correlations. Table 4. Correlation of spine deformities with pulmonary function tests SFI

Influence of correction of height reductions on spirometry indices Because of technical reasons, the results from one of the patients was excluded, making n = 74. Table 3 shows pulmonary function tests indices for type I, III and IV OI using respectively CMH and ASH for calculating predicted values. Correction with ASH had a significant impact on the values of FVC, FEV1 and TLC in OI types I (P < 0.001 for the differences in all indices) and IV (P = 0.005, P = 0.012 and P = 0.005). Although the sample size of OI type III were small, mean values for FVC was reduced from 129% to 67% and FEV1 from 137% to 69% when using CMH respectively ASH in this OI group. Two persons exhibited obstructive lung function with FEV1/FVC < 70% (both 69%), one with OI type I and one with type IV. One was a smoker and one a

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2013 John Wiley & Sons Ltd

RVCMH RVASH RVuncor TLCCMH TLCASH TLCuncor FVCCMH FVCASH FVCuncor FEV1CMH FEV1ASH FEV1uncor

SDI

N

r

P

r

P

62 62 62 62 62 62 74 74 74 74 74 74

−0.26 −0.30 −0.17 −0.21 −0.41 −0.34 −0.22 −0.44 −0.41 −0.16 −0.43 −0.19

Spinal deformities and lung function in adults with osteogenesis imperfecta.

There are no larger studies of adults with osteogenesis imperfecta (OI), focusing on the impact of spinal cord deformities on lung function assessment...
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