Spectrum of Lung and Cardiovascular Diseases in Association with Pulmonary Interstitial Glycogenosis

“Pulmonary Interstitial Glycogenosis (PIG) associated with a spectrum of neonatal pulmonary disorders”, reported by Cutz et al represents one of the largest series published to date. The report included twenty-eight cases of lung or cardiac disorders with coincident diffuse, patchy, or focal PIG reviewed in Division of Pathology, The Hospital for Sick Children. The authors focused on reporting a spectrum of disorders associated with PIG and described four clinicopathological subgroups including imaging, ultrastructural findings, and clinical outcome. The present paper highlights the main findings reported by Cutz et al, and a review of literature is also presented.

PIG is a rare interstitial lung disease of infancy that is placed in the category of "specific conditions of undefined etiology" in the childhood interstitial lung disease (ChILD) classification (1).PIG has been reported mainly in either pre-term or full-term babies younger than six months of age (2,3).Infants with PIG usually present with persistent tachypnea and hypoxemia shortly after birth or in the first few weeks of life (3,4,5).The reported PIG cases have been described in otherwise normal lungs (isolated/diffuse or patchy pattern)  (3,5) or often in conjunction with other cardiovascular or pulmonary abnormalities (2,3,6,7).To the best of my knowledge, approximately 78 cases of patients with PIG (not including the cases published by Cutz et al) have been reported in the literature with variable information regarding the clinical presentation, comorbidities, imaging, histopathology, and outcome were published.The described findings are summarized in Table 1.1A & 1B) due to glycogen accumulation demonstrable by periodic acid-Schiff positivity (diastase sensitive) on light microscopy.However, the presence of glycogen is best identified on electron microscopy (EM).The ultrastructural examination showed poorly differentiated interstitial mesenchymal cells with vesicular nuclei and cytoplasm containing sparse organelles and abundant monoparticulate glycogen (fig.1C & 1D).Some PIG cells showed features of differentiation toward the fibroblast lineage differentiation (2).Additionally, 28 cases of PIG in association with a spectrum of lung or cardiac disorders have been reported recently by Cutz et al.In this paper, we described four clinicopathologic subgroups including comorbidities, imaging and outcome (summarized in Table 2).As previously reported (3,6,8), we found that PIG is most commonly The second subgroup represented patients with PIG associated with congenital heart diseases (CHD) (including hypoplastic left-heart syndrome, hypertrophic cardiomyopathy in patient with Noonan syndrome).Chest imaging studies showed variable non-specific changes (including ground glass opacity, septal thickening).The mean age at lung biopsy was 2.4 weeks (5 days-6weeks).The PIG changes on light microscopy were focal to patchy.Most infants died of complications despite corrective surgery.
The third category consisted of a specific group of patients with combined PIG and hyperplasia of pulmonary neuroendocrine cells (PNEC), referred to as neuroendocrine hyperplasia of infancy-like (NEHI-like).Infants of this group were either pre-term or full-term, mostly presented with tachypnea and wheezing between 3 and 10 weeks of age.Chest imaging studies revealed variable changes including "crazy paving" appearance, bilateral ground-glass opacities or basal hyperinflation.Lung biopsies demonstrated patchy to diffuse PIG, and prominent hyperplasia of PNEC (identified with immunohistochemistry studies).The patients of this group were mostly asymptomatic over time with normal lung function or persistent mild obstructive defects.The clear significance and etiology of this combined pathology is unknown.PNEC system has multifaceted roles including lung development, neonatal adaptation as airway oxygen sensors, and postnatal airway homeostasis as guardians of a stem cell niche (9).Hyperplasia of PNEC has been identified in several perinatal pediatric lung disorders including bronchopulmonary dysplasia, neuroendocrine hyperplasia of infancy, central hypoventilation syndrome, Sudden Infant Death Syndrome, and cystic fibrosis (9).
The fourth and final group consisted of cases of congenital lung malformation with coincident PIG.This included 5 patients with CPAM type 1 (large cyst type) and 4 patients with congenital lobar emphysema/hyperinflation (CLE).All patients presented with respiratory distress, soon after birth for CPAM, and between 4 weeks and 8 months of age for CLE cases.Chest imaging studies demonstrated changes related to the underlying diseases; localized cystic lesion in patients with CPAM, and lobar emphysema/hyperinflation in patients with CLE.The mean age at time of biopsy was 8.8 weeks for CPAM (range 3 days -4 weeks), and 11.6 weeks for CLE (range 4 weeks-8 months).Pathologic examination confirmed the diagnosis of CPAM type 1 or CLE.In addition, it showed patchy PIG changes in both the lesion and adjacent <<normal>> areas of pulmonary tissue.All patients underwent lobectomy of the affected lung.Except for one case, who had CLE and congenital heart disease, patient with CPAM and CLE all recovered post-surgery and were asymptomatic on followup.
In summary, the spectrum of disorders in association with PIG reported by us ( 2) is diverse and is quite like that reported by Langston et al (3), Liptzin et al. ( 6), Dishop M. ( 8), and Weinman (10).We found that PIG is most commonly seen in association with lung alveolar growth abnormality (alveolar simplification) and / or cardiovascular diseases.We have also described additional cases of PIG associated with persistent pulmonary hypertension with or without CHD, cardiovascular disease, Noonan syndrome (23), and congenital lobular emphysema (28).In addition, we have reported a new association of PIG with other lung disorders including NEHI-like, and CPAM type 1 (large cyst type).Similarly, to previous published studies by Liptzin et al. (6), Weinman et al (10), Deutsch et al. (11), Castillo et al. (12), and Lee E. (13), we noticed that the imaging of PIG is variable, non-specific (including diffuse ground-glass opacities, hyperinflation, and cystic spaces), and is likely affected by the presence of coexisting lung disorders.Based on available literature, PIG is considered to have a favorable prognosis, although clinical outcome is dependent on the severity of any associated lung disorders or other comorbidities.In our series, we found that the mortality rate was high when PIG coincided with lifethreatening comorbidities (including severe lung growth abnormality, complex cardiovascular disease).This note was also emphasized by multiple previously published reports (6,11,12,14,15,16).In the review by Deutsch et al (16), no mortality occurred among the six cases of diffuse/ isolated PIG, although respiratory symptoms persist in most patients.Given no radiographic patterns, genetic findings, or biomarkers were characteristic of PIG, the lung biopsy remains the gold standard for diagnosis.
Finally, the precise nature and clinical significance of PIG is unknown.While the pathology demonstrated poorly differentiated interstitial mesenchymal cells, there is a debate whether PIG is a primary developmental lung disorder or a reactive process to abnormal lung development and injury.Our finding of a close association of PIG with different lung developmental disorders and comorbid cardiac developmental diseases favors a defect in interstitial fibroblast differentiation.Further studies are required to define the precise pathogenesis and significance of PIG and its impact on concurrent disease processes.
* large patent PDA, secundum atrial septal defect with left to right shunting, associated left atrial, right atrial and right ventricular enlargement, and pulmonary insufficiency with right ventricular hypertrophy.Moderate to severe pulmonary arterial hypertension.**diffuse pulmonary hyperinflation, pruning of the peripheral pulmonary vasculature, and patchy areas of atelectasis.± recurrent respiratory infections, reduced exercise tolerance ±± tachypnea at rest