| Abstract|| |
Pulmonary alveolar proteinosis (PAP) – an unusual diffuse lung disease characterized by alveolar accumulation of phospholipoprotein material, with a peak incidence in third to fourth decade and male predominance is also described in children. Recorded prevalence is 0.1/100,000 individuals. Major clinicopathogenetic subtypes include autoimmune (idiopathic) associated with granulocyte–macrophage colony-stimulating factor autoantibodies, secondary form, and the congenital form (associated with surfactant gene mutations). Common presenting features include dyspnea, cough, low-grade fever, inspiratory crackles, and digital clubbing. Pulmonary function shows a restrictive ventilatory defect. X-rays show bilateral patchy to extensive consolidations, and bronchial lavage yields a milky fluid. Characteristic microscopic findings on lung biopsy include filling of terminal bronchioles and alveolar spaces by deep pink granular PAS-positive material. Whole lung lavage is the safest and most effective form of treatment. We present brief profiles of two young children identified as having PAP, along with follow-up data on one of them.
Keywords: Alveolar proteinosis, respiratory failure, therapeutic lavage
|How to cite this article:|
Iyengar JN, R. Reddy BK. Pulmonary alveolar proteinosis in children: An unusual presentation with significant clinical impact. Indian J Pathol Microbiol 2018;61:418-20
|How to cite this URL:|
Iyengar JN, R. Reddy BK. Pulmonary alveolar proteinosis in children: An unusual presentation with significant clinical impact. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Feb 21];61:418-20. Available from: http://www.ijpmonline.org/text.asp?2018/61/3/418/236597
| Introduction|| |
Pulmonary alveolar proteinosis (PAP) first described by Rosen et al. in 1958 (as quoted by Shah et al.) is an unusual diffuse lung disease with reported incidence of 0.1/100,000. Peak incidence is in the third and fourth decades with a male dominance. Its occurrence in children is rare  and can in this age group be categorized into two classes: congenital – with a positive family history suggesting autosomal recessive transmission, which is fulminant and fatal and later-onset PAP that appears after a postnatal symptom-free period of few weeks to several years. Presenting symptoms and signs are nonspecific including progressive dyspnea, cough, fever, cyanosis, and digital clubbing. Disease progression is variable and ranges from mild to rapid resulting in uncontrollable respiratory failure. Classic radiological appearance of PAP is bilaterally symmetric consolidation with perihilar distribution giving a “bat-wing” appearance on plain X-ray of the chest. Diagnosis of postnatal onset of pediatric PAP is based on examination of bronchoalveolar lavage (BAL) fluid, which is characteristically milky, and/or lung biopsy.
Ramirez in 1965 proposed mechanical removal of the proteinaceous material by whole lung lavage (WLL), and this is still the most effective treatment for the later-onset PAP in the pediatric age group.
| Case Report|| |
Male child born full term through unassisted vaginal delivery, presented at the age of 8 months with mild fever, tachypnea, chest retractions, and bilateral crepitations which persisted after treatment with antibiotics, requiring oxygen. Chest X-ray repeated on multiple occasions showed hyperinflated lung fields with bilateral nonhomogeneous opacities. Computed tomography (CT) scan done then showed segmental hyperinflation with interstitial thickening prompting a diagnosis of childhood interstitial lung disease. Biopsy was deferred due to respiratory failure and oxygen dependence (PaO2 40–50 mm Hg), and the child was advised home oxygen therapy along with oral prednisolone and hydroxychloroquine. Follow-up over the next 2 months showed slightly reduced oxygen dependence and significant hypoxemia and requiring mechanical ventilation. Steroid dosage was tapered in view of cushingoid features. The child deteriorated over the next 1 month requiring ventilator support. Chest X-ray showed bilateral “white-out” lung fields. BAL yielded milky white fluid in large amounts which was suspicious with a diagnosis of PAP. The BAL fluid that was negative for organisms on culture studies. Biopsy of the lower lobe of the left lung was done.
Male child aged 4 born full term through unassisted vaginal delivery with normal development presented with hurried breathing and oxygen dependence of 6 months' duration and a history of similar episodes in the past for which he was medicated with oral and inhaled steroids at various peripheral centers. Examination revealed cushingoid features and respiratory rate of 70–80/min. Bilateral crackles and occasional wheeze could be heard. There was oxygen dependence and nonresponsiveness to nebulization. Other systems were normal. Blood gas analysis revealed persistent hypoxemia (PO2 50). Chest X-ray showed bilateral nonhomogeneous infiltrates in lung fields. High-resolution CT scan showed ground-glass opacities with diffuse alveolar infiltrates in both lung fields. BAL yielded a milky white fluid from both lungs [Figure 1]. Lung biopsy was done.
There was no positive family history with either of the children.
Alveoli-contained finely granular eosinophilic acellular material was admixed with eosinophilic globules and cyst macrophages [Figure 2]. The globules stained positive with PAS and PTAH stains and showed faint reddish tint with Masson Trichrome. Alveolar walls were mildly thickened, but inflammation was minimal. Bronchioles were not identified.
|Figure 2: Alveoli of lung filled with granular acellular material along with eosinophilic globules and macrophages (H and E, ×10)|
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The histology appeared like that seen in case 1. In addition, bronchioles were seen filled with the acellular material and alveoli contained numerous cholesterol clefts [Figure 3].
|Figure 3: Thickened alveolar septae with spaces containing cholesterol crystals appearing as clefts (H and E, ×20)|
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A diagnosis of alveolar lipoproteinosis was made in both cases based on light microscopy findings.
The first child underwent multiple lavages with decreasing oxygen requirement and currently is off oxygen. Anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) antibody levels were negative; clinical exome sequencing was negative for typical PAP genes such as SPA1 (SFTPA1), SPA2 (SFTPA2), SPB, SPC, SPD, ABCA3, NKX2, and CSF2RB. Homozygous mutations of MASP2 gene were detected. The second child underwent lavage of the right lung with significant improvement in oxygenation but was however lost to follow-up.
| Discussion|| |
The incidence of alveolar proteinosis is low and adult males are more often affected. Incidence in pediatric population is very rare, though not unknown. Clinical presentation is rather nonspecific and often insidious resulting in diagnosis being either delayed or missed. The disease is polymorphic in its presentation and has multiple underlying factors including genetic (familial), autoimmune, acquired, and idiopathic., Etiopathogenesis ranges from GM-CSF autoantibodies, mutations of surfactant protein-coding genes, association with malignancy, chemical inhalants, and infections. Mutations in MASP2 gene as reported in our patient has not been previously reported in a child with PAP and needs further evaluation and understanding. It is found to be associated with adult pulmonary fibrosis in other studies. Imaging studies of the chest in uncomplicated cases reveal bilateral lung space disease with perihilar accentuation (bat-wing appearance). Routine hematological and biochemical investigations may be nonspecific or may point toward an underlying cause. The characteristic bedside finding rests with obtaining an opaque, milky BAL fluid. The fluid is rich in foamy alveolar macrophages and acellular proteinaceous debris. Electron microscopy reveals that the debris is made up of numerous osmophilic-fused membranous structures with periodicity of 4.7 nm bearing resemblance to lamellar bodes and tubular myelin. Histopathological examination of lung biopsy confirms the presence of granular eosinophilic material that is PAS positive and appears red with trichrome stain. Foamy macrophages and cholesterol clefts are also present.
WLL is found to be a convenient and useful mode of managing patients with late-onset form of PAP in the pediatric age group.
| Conclusion|| |
Childhood PAP should be considered in a clinical setting, and missed/delayed diagnosis should be avoided. Examination of BAL sample gives an important lead, and lung biopsy findings are characteristic. WLL could be the most suited treatment for late-onset PAP in the pediatric population.
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Conflicts of interest
There are no conflicts of interest.
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Jayaram N Iyengar
Anand Diagnostic Laboratory, Bowring Tower, 54 Bowring Hospital Road, Shivajinagar, Bengaluru - 560 001, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]