Pediatric Radiology

, Volume 35, Issue 3, pp 311–316

Primary alveolar capillary dysplasia (acinar dysplasia) and surfactant protein B deficiency: a clinical, radiological and pathological study

Authors

    • Department of Radiology MBC#28King Faisal Specialist Hospital and Research Centre
  • Husam M. Salama
    • Department of PaediatricsKing Faisal Specialist Hospital and Research Centre
  • Fouad Al-Dayel
    • Department of PathologyKing Faisal Specialist Hospital and Research Centre
  • Nuha Khoumais
    • Department of Radiology MBC#28King Faisal Specialist Hospital and Research Centre
  • Abdul H. Kattan
    • Department of PaediatricsKing Faisal Specialist Hospital and Research Centre
Original Article

DOI: 10.1007/s00247-004-1349-7

Cite this article as:
Hugosson, C.O., Salama, H.M., Al-Dayel, F. et al. Pediatr Radiol (2005) 35: 311. doi:10.1007/s00247-004-1349-7

Abstract

Background: Full-term infants with severe and prolonged respiratory distress represent a diagnostic challenge. Plain radiographic findings may be nonspecific or similar to classic surfactant deficiency disease for infants with surfactant protein B deficiency and acinar dysplasia. Objectives: To describe the similar clinical-radiolgical patterns of two rare neonatal conditions. Materials and methods: Six newborn babies with severe respiratory distress at birth demonstrated clinical and radiographically prolonged and progressive diffuse pulmonary opacification. Results: All infants demonstrated hyperinflation of the lungs. The diffuse hazy opacification, which varied from mild (n=3) to moderate (n=3), progressed to severe diffuse opacification preceding death, which occurred at 12–36 days of life. Open lung biopsy confirmed the diagnosis of primary alveolar acinar dysplasia (AD) in four infants and surfactant protein B deficiency (SPBD) in two infants. Conclusions: In full-term babies with unexplained progressive respiratory distress from birth and progress of radiological changes, both AD and SPBD should be considered.

Keywords

LungsAcinar dysplasiaSurfactant protein B deficiencyRespiratory distressNeonates

Introduction

The embryological development of the lung depends on an interaction between the branching lung bud, mesenchyme and epithelium. Three phases are described: pseudoglandular, canalicular and saccular [1, 2]. Any disturbance of this process may result in a maldeveloped lung, ranging from lung agenesis and pulmonary hypoplasia to a wide spectrum of microscopic abnormalities with dysplastic immature lung. Deficient alveolar and capillary development will lead to respiratory failure [1, 2].

In surfactant protein B deficiency (SPBD) the pathology is absence of one of the surfactant-specific proteins, protein B, within the alveolar lining cells, whereas in acinar dysplasia (AD), the malformation occurs at the canalicular phase with poor development of the acinar structures. Both conditions result in a clinical picture of severe respiratory failure in full-term babies [2, 3].

Both SPBD and AD are rare entities and most often published as case reports with only few series in the literature [2, 48]. They demonstrate diffuse radiographic pulmonary changes. The similarity of the clinical course and the radiological appearance, which correlates with the microscopic appearance, has not been previously stressed. Alveolar lavage and peripheral blood DNA may give the diagnosis in SPBD, but lung biopsy is needed for definitive diagnosis for AD [2]. Based on the clinical course and the radiological findings, a diagnosis of either SPBD or AD may be suggested.

Materials and methods

Six infants, three girls and three boys, developed respiratory distress at birth. Five were full term and one 36 weeks gestational age. All neonates had serial chest radiographs as well as ECHO for assessment of persistent pulmonary hypertension during the course of the disease. One infant had helical CT scanning at 7 days of age. The infants were treated in the intensive care unit, but failed to respond to treatment. Lung biopsy was performed in each case and established the diagnosis. All infants died between 12 and 36 days of life. The clinical features are summarized in Table 1.
Table 1

Clinical features in six infants with maldeveloped lungs. All had onset respiratory distress at birth. Surfactant was administered to all infants

Case

Diagnosis

Consanguinity

Sex

GA

Weight

Lung biopsy

Life span

1

SPBD

NK

M

Term

NK

31 days

36 days

2

SPBD

Yes

M

Term

3,100

22 days

33 days

3

AD

Yes

F

Term

3,050

3 days

12 days

4

AD

NK

M

36 weeks

2,560

19 days

26 days

5

AD

Yes

F

Term

2,650

20 days

25 days

6

AD

Yes

F

Term

3,050

15 days

27 days

NK not known, M male, F female

Results

Radiological findings

The infants had either mild (Fig. 1) or moderate (Fig. 2) opacification of the lungs. The opacification varied somewhat between the infants, from diffuse consolidation with obscured vessels consistent with an alveolar-type pattern, a granular appearance similar to surfactant deficiency disease of the premature, to a more alveolar-interstitial-type pattern. The radiological findings demonstrated three types of progress—slow progress (Fig. 3), static appearance after a previous period of rapid progress (Fig. 4), or rapid progress close to the death of the infant (Fig. 5). Moderate hyperinflation of the lungs was present in all patients. In one child, bilateral pneumothoraces was the presenting finding. The period of rapid progress of the lung changes in two infants occurred for one of the infants at the end of the first week and was then static (Fig. 4). For the other infant the time of rapid progress was in the second week (Fig. 5), and the child died at age 12 days. The other five infants lived for 25–36 days. Interstitial air was seen in two patients on day 17 (Fig. 2) and 21 respectively. Both children were intubated. The radiological findings are summarized in Table 2.
Fig. 1

Patient 2: SPBD. a Frontal chest radiograph at age 21 days shows hyperinflation and mild diffuse opacification of both lungs. b Open lung biopsy at age 22 days demonstrates the alveolar spaces filled with proteinaceous material (arrow). This morphology is highly suggestive of SPBD.

Fig. 2

Patient 5: AD. Frontal chest radiograph at age 17 days shows hyperinflation and moderate diffuse pulmonary opacification with an interstitial-alveolar pattern. There is a suggestion of interstitial air.

Fig. 3

Patient 4: AD. a Frontal chest radiograph at age 7 days shows mild hyperinflation and mild-to-moderate, severe diffuse opacification of both lungs with somewhat granular appearance and predominant alveolar pattern. b Frontal chest radiograph at age 15 days again shows hyperinflation, but the diffuse opacification of both lungs has worsened, showing mainly a granular pattern. c Open lung biopsy at age 19 days demonstrates, at low-power magnification, somewhat primitive looking alveoli separated by primitive stroma. d High-power magnification demonstrates alveoli lined by cuboidal epithelium (black arrow). Some of the alveoli are filled with foamy macrophages (white arrow).

Fig. 4

Patient 1: SPBD. a Axial helical CT scan of the chest at age 7 days shows diffuse severe consolidation of both lungs with obscured vessels, prominent bronchial tree and an alveolar-type pattern. b Frontal chest radiograph at age 20 days shows hyperinflation and diffuse opacification of both lungs. Lung disease has not progressed since the CT scan at age 7 days.

Fig. 5

Patient 3: AD. a Frontal chest radiograph at age 6 days, post lung biopsy, shows mild pulmonary haziness. b Frontal chest radiograph at age 12 days shows marked progression of disease with severe diffuse pulmonary opacification.

Table 2

Radiological findings in six infants with maldeveloped lungs. All children had hyperinflation of the lungs and demonstrated progress of radiological changes

Case

Diagnosis

Initial changes

Slow progress

Period of rapid progress

1

SPBD

Moderate

No

Yes

2

SPBD

Mild

Yes

No

3

AD

Mild

Yes

Yes

4

AD

Mild

Yes

No

5

AD

Moderate

Yes

No

6

AD

Moderate

Yes

No

Pathological findings

For both SPBD and AD, the histopathological findings were very similar both within and between the two groups. For SPBD, the alveolar spaces were filled with proteinaceous material (Fig. 1), whereas for AD the alveolar spaces were filled with foamy alveolar macrophages (Fig. 3).

Discussion

Pulmonary surfactant is a lipid-rich material that prevents lung collapse by lowering surface tension at the air-liquid interface in the alveoli of the lung. It is composed primarily of phospholipids with lesser amounts of cholesterol and surfactant-associated protein. Two groups of surfactant-associated proteins have been described based on their mobility in organic solvent—proteins A and D, which are hydrophilic proteins and proteins B and C, which are hydrophobic proteins. The role of the surfactant protein-B (SP-B) tubular myelin component is to enhance absorption while respreading of SP-B is necessary for lung function. Humans with genetic SP-B dysfunction die soon after birth. Lack of SP-B is linked to improper processing of SP-C, so its effect cannot be entirely isolated [9]. SP-B can increase the fluid properties of a monolayer by preventing lipid packing. This leads to smaller domains in a liquid-condensed state, and makes widespread collapse more difficult [10]. SP-B may also promote buckling and other reversible collapse structures.

Deficiency of SP-B results in a clinical picture of severe progressive respiratory failure soon after birth in full-term babies. It necessitates aggressive mechanical ventilation, even with high-frequency oscillatory ventilation and eventually nitric oxide as a selective pulmonary vasodilator. This treatment is not associated with any significant improvement; instead, the infant will continue to require intensive ventilation therapy for several days before a possible diagnosis of either SPBD or AD is raised. The somewhat similar clinical and radiological appearances and the development of lung opacities might be due to some shared maldevelopment. Wallot et al. [11] identified five infants with congenital alveolar proteinosis in a consanguineous kindred of Kurdish descent. Each had respiratory failure and persistent severe pulmonary hypertension detected shortly after birth; all died despite intensive care. They reported the histological findings in lung tissue of two infants as showing a combination of alveolar proteinosis and malalignment of lung vessels in one patient and alveolar proteinosis in the other. They suggested that malalignment of lung vessels and congenital alveolar proteinosis may have a common pathogenetic basis.

Similar findings were also described by Boggs et al. [12] Pulmonary hypertension was considered to be due to malalignment of lung vessels, also termed congenital alveolar capillary dysplasia or acinar dysplasia. Pulmonary AD was first described in 1981 as a cause of persistent pulmonary hypertension in the newborn [6, 7]. It is characterized histologically by poor development of capillaries and small veins. As a result, new venous channels develop in the bronchovascular bundle. These channels then connect with larger, normally situated, pulmonary veins. This syndrome occurs in term babies of both sexes. Affected infants may have normal Apgar scores at birth, but soon develop cyanosis and difficulty in breathing. In contrast to other types of persistent pulmonary hypertension of the newborn, which are often reversible, this condition is probably irreversible. Death usually occurs at 3–4 weeks of age despite maximum life support, including ECMO or nitric oxide. The histological changes are parenchymal and vascular. The airways appear normal, but the alveoli are poorly developed. Alveolar ducts are enlarged, and distal air spaces are described as diminished in number. Air-space walls are thickened by oedematous connective tissue and lined by flat-to-cuboid type II cells.

The triad of hyperinflation, diffuse opacification of both lungs and progression of radiological changes usually excludes major morphological lung abnormalities, as these conditions usually demonstrate absence of a lung, a small lung or hypoinflation. The appearance of diffuse hazy lungs supports a generalized lung pathology. Surfactant deficiency disease of the premature newborn can demonstrate similar lung changes. Hyperinflation, interstitial prominence and diffuse increased pulmonary density were demonstrated in two cases of AD by Newman and Yunis [2] in 1990. Hypoplasia of the lungs has been reported with AD [13, 14]. In the present series, both SPBD and AD demonstrated hyperinflation of normal sized lungs. Pneumothorax, which was found in one patient of the present series of AD, has been reported in a few cases, most likely secondary to barotrauma [2, 7, 15].

Initially clear lungs in AD have been reported twice [2, 15]. Granularity, similar to surfactant deficiency disease in premature neonates was reported in the majority of previous cases of SPBD, but only in one case with AD in the present series [24, 16, 17]. The progress to diffuse haziness has been reported for both conditions [2, 16]. In the present series the radiological findings and the clinical course for both SPBD and AD were similar. Diffuse lung changes in the newborn are usually referred to as either capillary leak, which would create interstitial fluid, a reticular-granular-type pattern as seen in surfactant deficiency disease in the premature newborn which represents generalised homogeneous collapse of alveoli, or diffuse opacification [15]. No increased interstitial fluid was noticed at lung biopsy, and the radiological appearance has to be explained by alveoli gradually filling with proteinaceous material in SPBD and foamy macrophages in AD. However, foamy macrophages within the proteinaceous material in a case of SPBD was reported by Norgee et al. [3] The gradual, but somewhat slow worsening of the radiographic findings correlates well with the gradual worsening of the clinical picture and later death. Despite the grave prognosis the radiological changes were fairly mild for a long period of time (Fig. 1). As lung biopsy was, in the majority of the cases, undertaken late in the course of the disease (3–31 days, mean 18 days), early lung biopsy is needed for further correlation between the radiological and histological appearances. There was no explanation why one infant survived only 12 days whereas the others survived 25–36 days.

The radiological appearance is nonspecific and several differential diagnoses in a full-term infant with severe respiratory distress have to be excluded. These include congenital cardiovascular diseases, pulmonary conditions such as meconium aspiration or pulmonary haemorrhage, and infections. High-resolution CT (HRCT) has, in a few cases with SPBD, demonstrated a diffuse ground-glass opacity with interlobular septal thickening, labelled ‘crazy paving’ pattern, suggestive of ‘alveolar proteinosis’ [815]. CT findings for AD are not known and lung biopsy is needed for a definitive diagnosis. Antenatal diagnosis of SPBD with analysis of amniotic fluid late in pregnancy has been suggested [17].

Several studies support both conditions having possible autosomal recessive inheritance [3, 4, 1315]. High consanguinity in SPBD was found by Tredano et al. [18]. The presence of a brother and a sister with AD in the present series probably excludes an X-linked dominant inheritance that has been previously suggested [13]. With a history of a sibling death with unexplained respiratory distress, the possibility of SPBD or AD increases [16]. The possible autosomal recessive inheritance and high consanguinity in SPBD justifies genetic counselling [13, 14, 18].

The fact that surfactant replacement, corticosteroid therapy or ECMO failed as treatments, suggests that endogenous SP-B synthesis is necessary for mature surfactant metabolism and function [19]. Pulmonary lavage as a treatment for congenital alveolar proteinosis in somewhat older infants has proven successful and has been undertaken as a diagnostic procedure in the neonatal period [8, 20]. Late onset of SPBD with survival may reflect phenotypic heterogeneity, as suggested by deMello et al. [5]. Survival up to 1 year of age in a full-term newborn with SPBD and onset of symptoms immediately after birth was reported by Coleman et al. [21]. Chetcuti and Ball [22] suggested that the only treatment for SPBD at present is lung transplantation, but suitable donor organs are scarce, the procedure has considerable morbidity and long-term outcome is still unknown. They stated that “compassionate withdrawal of intensive care may be more appropriate”. They also suggested the possibility of gene therapy in the future. The same approach appears valid for AD.

In conclusion, the clinical course and pathological findings of SPBD and AD are fairly typical, whereas the radiological appearances vary between different studies, although with similarities in the present series. The role of radiology is to suggest the possible diagnosis in a full-term infant with severe respiratory distress in order to achieve early diagnosis: pulmonary lavage or HRCT for SPBD and lung biopsy for AD.

Copyright information

© Springer-Verlag 2004