Pathophysiology of respiratory failure in patients with osteogenesis imperfecta: a systematic review

Figures & data

Figure 1. Flow diagram of the systematic review following the PRISMA guidelines.

Table 1. Summary of mouse model characteristics.

Authors	Mouse Model	OI Phenotype	Analyzed tissue	Lung and other significant abnormalities	Authors supported pathophysiology
Baglole et al. (2018)	Col1a1Jrt/+ mice (number = 6) and wild-type littermates (number = 6). Col1a1Jrt/+: dominant mutation leading to collagen type I α1–chain alteration.	Model of severe dominant OI.	Lungs tissue and diaphragmatic histology.	Significant increase (+27%) in the mean linear intercept length (Lm) value in lungs of all OI mice compared to their Wild Type controls. Substantial decrease in the diaphragmatic thickness in the OI group (reduction of ∼28%). Reduced muscle mass and intrinsic contractile weakness of the diaphragm.	Intrapulmonary: emphysematous changes Extra-pulmonary: diaphragm weakness
Baldridge et al. (2010)	Crtap^−/− mice and wild type littermates. Lack of a functional prolyl 3-hydroxylation complex in the endoplasmic reticulum, which is essential for type I collagen post-translational modification and folding (number not reported).	Model of recessively inherited OI forms.	Lungs, kidneys, testes, and skin from the upper back histology.	Diffuse increase in alveolar airway space often accompanied by a thinning of the alveolar walls. This became more evident in the adult lung, indicated by an increased mean linear intercept. Crtap expressions in the lung parenchyma in all pneumocytes.	Intrapulmonary: emphysematous changes
Dimori et al. (2020)	Crtap^−/− mice (number 18) and wild-type littermates (number 18). Lack of a functional prolyl 3-hydroxylation complex in the endoplasmic reticulum, which is essential for type I collagen post-translational modification and folding.	Model of recessive inherited OI forms.	Lung tissue histology.	Clear and dramatic enlargement of the acinar airspace and frequent loss of alveolar septa between all Crtap^−/− mice and wild-type littermates (at three months of age). Statistically significant difference of the linear intercept measurement.	Intrapulmonary: emphysematous changes, abnormal collagen synthesis
Thiele et al. (2012)	Aga2 mice severe (number = 6). Aga2 mice mild (number = 6), wild type (number = 6). Aga2: dominant frameshift mutation in the Col1a1 C-propeptide domain.	Model of OI II and III.	Lung tissue histology.	Aga2 severely affected lungs were haemorrhagic with alveolar bleeding, infiltrated with polymorphonuclear neutrophils and alveolar macrophages. Blood gas analysis revealed a reduction of 44% in arterial pO2 accompanied by a 61% decrease in oxygen saturation.	Intrapulmonary: abnormal collagen synthesis

pO₂: partial pressure of oxygen.

Table 2. Patients characteristics of studies supporting extrapulmonary causes of abnormal lung function in OI patients.

Authors	Patient phenotype	Age median (range) year	Type of assessment	Lung and chest abnormalities	Authors supported pathophysiology
LoMauro et al. (2012)	7 patients with OI III	26.1 (9.8–42.4)	Spirometry Opto-electronic plethysmography (rib cage geometry, breathing pattern, regional chest wall volume changes) Radiographic measurements	Altered breathing pattern in severe OI was present since childhood and it worsened with age. OI type III with by pectus carinatum and inspiratory paradoxical inward motion of the pulmonary rib cage, were associated with a high level of asynchrony between the three chest wall compartments.	Extra-pulmonary: pectus carinatum, brittle ribs, spinal deformity
	15 patients with OI IV	15.9 (4.5–27.3)
	26 healthy controls	22.4 (4.1–40.7)
LoMauro et al. (2018)	8 patients with OI III	5 (4.0–8.2)	Opto-electronic plethysmography Radiographic measurements	Patients with OI type III and IV showed decreased FVC and FEV1 compared to the predicted values. In the supine position, OI type III patients exhibited greater decrease in FVC due to pectus carinatum, paradoxical inspiratory inward motion of the pulmonary rib cage, significant thoraco-abdominal asynchrony and rib cage deformities.	Extra-pulmonary: pectus carinatum, brittle ribs, spinal deformity
	7 patients with OI I and IV	7 (6.5–8.0)
	9 healthy controls	6.5 (5.0–8.0)
Gimeno et al. (2019)	9 patients with OI III	41.0 (30.5–50.75)	Spirometry CT scans Geometric morphometrics in 3 D	Lower FEV1 and FVC values were observed in OI patients (males and females) with more horizontally aligned ribs, greater antero-posterior depth due to extreme transverse curve at rib angles and a strong spine invagination, greater asymmetry, and a shorter vertically, thoracic lumbar spine, which is relatively straight at levels 1–8 and shows marked kyphosis in the thoraco-lumbar junction. Regression analyses on the full sample showed a significant relation between rib shape and FEV1, FVC and FVC % predicted whereas thoracic spine shape was not related to any parameter.	Extra-pulmonary: horizontally aligned ribs
	3 patients with OI IV	41.0 (30.5–50.75)
	12 healthy controls	64.5 (61–68.5)
Wekre et al. (2013)	74 patients with OI I	45 (32–58)	Spirometry Radiographic measurements	Pulmonary compromise, as reflected in spirometry indices corrected with arm span height, revealed significant correlations to spinal deformities. Vertebral deformities were found in 67% of patients, most deformities were found in the mid-thoracic region. Scoliosis was found in 46%, nine patients exhibited torsion scoliosis.	Extra-pulmonary: spinal deformities
	9 patients with OI III	35 (28–42)
	11 patients with OI IV	47 (40–54)
Widmann et al. (1998)	15 OI patients (OI type undefined)	33.3 (24.8–41.8)	Spirometry Radiographic measurements Validated health self-assessment questionnaire	Thoracic scoliosis was strongly correlated with decreased predicted vital capacity. Significant diminution in the vital capacity below 50% occurred at an angle of 60°. Kyphosis and chest wall deformity were not predictive of decreased pulmonary function.	Extra-pulmonary: spinal deformities
Pan et al. (2006)	1 patient with OI IV	14	Spirometry Radiographic measurements Pedicle screw fixation technique (intervention)	Intervention (Table 3)	Extra-pulmonary: kyphoscoliosis
Kaplan et al. (2013)	4 patients with OI III with Thoracic Insufficiency Syndrome (TIS)	6, 7, 9, 11	Spirometry Radiographic measurements Expandable spinothoracic fixation device (intervention)	Intervention (Table 3)	Extra-pulmonary: pectus carinatum, brittle ribs, spinal deformity
Falvo et al. (1973)	11 patients (4 severe OI, 7 mild OI)	13.5 (4–34)	Standard Spirometry Radiographic measurements Blood gas measurements?	Reduction of VC and increase in RV and RV/TLC ratio were found only in patients with kyphoscoliosis. Other parameters of pulmonary function were within normal limits. No patient had severe hypoxaemia or hypercapnea.	Extra-pulmonary: pectus carinatum, brittle ribs, spinal deformity

FEV1: volume in 1 s; FVC: forced vital capacity; VC: vital capacity; RV: residual volume; TLC: total lung capacity.

Table 3. Lung and chest abnormalities after surgery.

Authors	Patient phenotype	Intervention	Lung and chest abnormalities after intervention
Pan et al. (2006)	1 patient with OI IV	Correction of severe kyphoscoliosis using the 3-rod all pedicle screw fixation technique.	The predicted forced vital capacity predicted forced expiratory volume in 1 s and vital capacity of the lung of the patient had improved 2-fold. The Cobb angles of scoliosis and thoracic kyphosis were corrected from 110 to 68° and from 107 to 39°.
Kaplan et al. (2013)	4 patients with OI III with Thoracic Insufficiency Syndrome (TIS)	Patients were treated with a novel expandable spinothoracic fixation device.	The mean Cobb angle improved to 32% in the coronal plane. Pulmonary function improved in all patients, with mean increases of 45% in forced vital capacity, 93% in forced expiratory flow, and 43% in pO2, PaCO2 decreased an average of 30% and returned to normal values.

pO₂: partial pressure of oxygen; PaCO₂: partial pressure of carbon dioxide.

Table 4. Patients characteristics of the studies supporting intrapulmonary causes of abnormal lung function in OI patients.

Authors	Patient phenotype	Age	Type material	Lung and chest abnormalities	Authors supported pathophysiology
Bronheim et al. (2019)	3 patients with OI I	27.6 (12.9–42.3)	Spirometry Radiographic measurements	Restrictive lung function in 83% of the patients, pulmonary comorbidity like asthma or chronic obstructive pulmonary disease was in 40% of individuals. Scoliosis was present in 25 individuals (83.3%), 4 of whom (13.3%) had undergone corrective surgery. No correlation was detected between the largest curve and FEV1/FVC1 ratio. No significant correlation between scoliosis and pulmonary function parameters.	Intra-pulmonary: intrinsic consequence of altered collagen type I
	10 patients with OI III
	14 patients with OI IV
	1 patient with OI VIII
	2 patients with OI IX
Khan et al. (2020)	9 patients with OI I	39 (19–67)	Spirometry Radiographic measurements ECG, echocardiogram Quality-of-life assessments	Seventy percent (21 of 30) of the population had scoliosis. Seventy-seven percent of participants (23 of 30) had restrictive lung function. Forty-three percent (13 of 30) of the study participants had lower total lung capacity than the reported reference value FEV1/FVC did not correlate with scoliosis curve magnitude. Twenty-five of 29 individuals had bronchial wall thickening, 16 had ground-glass opacities, 12 had atelectasis, 11 had scarring, and five had mosaic air trapping.	Intra-pulmonary: intrinsic consequence of altered collagen type I
	8 patients with OI III
	12 patients with OI IV
Morikawa et al. (2016)	1 patient with OI (unspecified)	19	Radiographic measurements CT scan Lung histology	Diffuse reticular shadows on chest X-ray images Diffuse reticulonodular shadows in both lungs Old and recent haemorrhagic areas and emphysematous change around bone formation were observed by stereomicroscopy	Intra-pulmonary: pulmonary ossifications with fibrosis
SHAPIRO et al. (1989)	1 patient with OI II	1 day	Lung histology Fibroblast culture	Histopathologic examination of the lungs showed a marked decrease in the quantity of parenchyma in relation to hilar structures. Alveolar number per acinus was reduced. No bronchopneumonia or hyaline membrane formation was observed.	Intra-pulmonary: defective pro-alpha 1(I) synthesis
Thibeault et al. (1995)	1 patient with OI II	1 day	Lung histology	The volume density of the combined alveolar and alveolar duct spaces and parenchymal septal tissue in the OI II lung was increased compared with the control lungs. The absolute number of conducting airway generations and the proportion and number of terminal bronchioles were similar in both infants. The proportion of respiratory bronchioles and the number per unit area were lower in the OI II, suggesting that each acinus had fewer saccular clusters.	Intra-pulmonary: intrinsic consequence of altered collagen type I
	1 patient healthy control
Himakhun et al. (2012)	1 patient with OI II	6 day	Lung histology	Decrease in size of both lungs. Histology showing immature lungs with congestion and hyaline membrane, compatible with clinically diffuse alveolar damage and respiratory failure.	Intra-pulmonary: intrinsic consequence of altered collagen type I
Thiele et al. (2012)	23 patients with OI III	9.6 (3–18)	Spirometry Radiographic measurements ECG, echocardiograms	Thirty six of 46 children and young adults in the study group (78.3%) developed scoliosis >10*, with mean curvature ≈25*. OI patients with scoliosis have progressive decline of forced vital capacity (FVC), tidal lung capacity (TLC) and vital capacity (VC) with worsening scoliosis. Pulmonary function parameters decline significantly with age for all OI patients, including lung volumes and flow rates. The decline in FVC, TLC and VC with age was significantly greater for type III than the milder type IV OI patients. Although scoliosis contributes to pulmonary function test decline in OI, significant decline occurs in the absence of scoliosis. Lung function declined significantly in 20 participants who had minimal scoliosis (≤10* curvature).	Intra-pulmonary: intrinsic consequence of altered collagen type I
	23 patients with OI IV

FEV1: volume in 1 s; FVC: forced vital capacity; VC: vital capacity; RV: residual volume; TLC: total lung capacity.*Degree.

Data availability statement

There is no raw data associated with this systematic review. The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.