Daniela Dinu, MD – Neonatal-Perinatal Fellow, Baylor College of Medicine

Martha Douglas-Escobar, MD – Assistant Professor Neonatology, Baylor College of Medicine

Pulmonary Interstitial Glycogenosis

- a literature review -

Background

Pediatric Interstitial Lung disease encompasses a group of unusual pulmonary disorders characterized by impaired gas exchange and diffuse infiltrates on imaging studies. Its nomenclature, classification, treatment and true incidence is controversial because most of the literature comes from case reports or small case series.

National survey of cases in children (0-16 years) estimates the prevalence as 3.6 per million in United Kingdom-Ireland and the incidence as 1.32 cases per million children per year in Germany.

Interstitial Pulmonary Glycogenosis (PIG) is a type of interstitial lung disease of unknown etiology. It appears to be limited to young children and has a good prognosis.

Baby OC was a 850 grams, 30 2/7 weeks old preemie born to a G2P1 mother. OC was intubated at birth, received 2 doses of surfactant and received a combination of conventional and high frequency ventilation since birth to 42 days of age. He was on nasal CPAP for 10 days and weaned to nasal cannula at 62 days.

He required at times to go back to nasal CPAP or mechanical ventilation. OC received diuretics and inhaled steroids for his chronic lung disease.

By 4 months he required Sidenafil due to severe pulmonary hypertension and by 5 months he had tracheostomy. His respiratory status gradually worsened and by 7 months a second anti-pulmonary hypertension medication was added (Bosentan).

Case presentation

Negative genetic testing for surfactant protein B, C, and ABCA3 deficiency

Chest CT scan

• at 3 months minimal scattered areas of air trapping and atelectasis, but no growth lung abnormalities

• at 7 months worsening with moderately pronounced bilateral pulmonary parenchymal opacities

Negative multiple blood, tracheal and BAL aspirate cultures

Negative immunologic work-up for immunodeficiency.

At 7 months an open lung biopsy showed:

• mild BPD

• increased interstitial glycan rich matrix without fibrosis

• focally marked increase in interstitial PAS positive cells consistent with pulmonary interstitial glycogenosis

Diagnosis: pulmonary interstitial glycogenosis.

Work-up for pulmonary disease

0 1 5 6 732 4

On conventional or HFOV

Surfactant( 2 doses) Sidenafil Bosentan

On conventional ventilatory support

Tracheostomy

Months of age

Diuretics

CT chest

at 3 months at 7 months

LUNG Biopsy

Electron microscopy

H&E PAS positive cells

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Canakis et al. (2002) described the clinical, radiological and pathological findings of 7 infants with atypical lung disease and proposed for the first time the term of Pulmonary interstitial glycogenosis (PIG).

• 3 infants were term and 4 preterm, and all developed symptoms in the first month of life. Infection and congenital heart disease were excluded in all cases.

• On the lung biopsy specimens the most striking feature noted was uniform interstitial thickening due to immature interstitial cells containing abundant cytoplasmic glycogen.

• The proposed underlying mechanism was dysmaturity of the interstitial cells (as opposed to other types of interstitial lung disease where the mechanism is infectious or inflammatory).

• The favorable response to steroids was proposed to be an acceleration in maturation, rather than inflammatory modulation.

• Authors emphasized the more favorable prognosis associated with PIG compared with other types of interstitial lung disease.

Review of literature

Smets et al (2004) described an additional case, confirming the findings of Canakis’s article, and proposed the term of pulmonary interstitial glycogen accumulation disorder, to avoid any link with a metabolic disease.

• The case described a term infant with significant respiratory distress a few hours after birth, that required mechanical ventilation. No cardiac, surfactant deficiency or infectious cause was found.

• CT scan distorted lung architecture with linear opacities mixed with areas of overinflation and ground-glass opacities.

• Open lung biopsy diffuse thickening of the alveolar septae and abundant glycogen in the cytoplasm of the interstitial cells.

• The infant’s good response to pulse doses of methyl-prednisolone was explained by the acceleration of the glycogenolysis (as there was no inflammatory reaction on lung biopsy).

• This case confirmed the initial observation of the more favorable prognosis in this particular type of interstitial lung disease.

Review of literature

Onland et al. (2005) described a case of monozygotic twins born at 31 weeks after a pregnancy complicated by twin-to-twin transfusion syndrome.

• Both twins developed respiratory distress syndrome, were intubated and received surfactant. They continued to require supplemental oxygen at 6 weeks of life presumed to be chronic lung disease (CLD).

• Both twins underwent CT scan and open lung biopsy due to worsening of respiratory status at 6-8 weeks.

• Lung biopsy for both diffuse interstitial thickening, and the interstitial cells contained abundant glycogen.

• Both had improvement on steroid therapy.

• The authors hypothesize that pulmonary glycogenosis could be a hystopathological sub-form of CLD.

Review of literature

Lanfranchi et al. (2009) published an additional case of pulmonary interstitial glycogenosis in a non-intubated 31 weeks premature infant.

• Infant received oxygen by nasal cannula for 17 days and then developed significant respiratory distress requiring mechanical ventilation.

• Chest X-ray at 18 days showed diffuse interstitial lung disease and hyperinflation and a CT scan confirmed the radiologic findings.

• Open lung biopsy at 30 days of life demonstrated diffuse expansion of the interstistium by cells containing glycogen.

• The symptoms and radiographic findings significantly improved after corticosteroid treatment.

Review of literature

A multidisciplinary work group (2007) reviewed the lung biopsies performed between 1999 and 2004 in children less than 2 years, at 11 centers in North America.

• The aim was to reach a consensus terminology and diagnostic criteria for disorders presenting with diffuse lung disease in infants.

• From the study cohort (187 patients), pulmonary interstitial glycogenosis was the only histological finding in 3% cases (6 patients 5 term newborns and one late preterm).

• All of them presented with symptoms in the first week of life, and the mean age at biopsy was 1.3 +/- 0.4 months. There were no deaths reported in this group.

Review of literature

Castillo et al. (2010) published a case of pulmonary interstitial glycogenosis in the setting of lung growth abnormality.

• The case described a term boy with tachypnea and persistent oxygen requirement since birth. Chest X-ray (at 10 days of life) showed hyper-inflated lungs and diffuse bilateral opacities.

• Lung biopsy:

severe alveolar growth abnormality with alveolar enlargement and

simplification with focal microcystic change, similar to BPD.

mild patchy interstitial widening by non-inflammatory structural cells

was also present.

PAS staining demonstrated interstitial PAS-positive diastase labile

material, confirmed to be glycogen by electron microscopy.

• By 5 months of age the infant was weaned off oxygen.

Review of literature

Since 2002 there have been 18 case reports of Pulmonary Interstitial Glycogenosis (PIG) in newborns.

• 10 newborns were term and 8 preterm, and almost all described cases were boys.

• The hallmark was respiratory distress during the first week of life with radiological evidence of hyperinflation.

• In all cases, work-up for surfactant deficiency, infectious disease and cardiac disease was negative.

• Lung biopsy was performed at 45 days on average, although it was earlier in premature infants (mean age 35 days) when compared with term infants (mean age 57 days).

• 50% patients improved with steroid therapy and 1 infant improved on steroids and hydroxychloroquine. There was no treatment discussion on 40% of the cases. In our case, the patient received steroids but did not improve.

• PIG appears to have a good prognosis with only one reported death due to significant prematurity and BPD.

Conclusions

Pulmonary interstitial glycogenosis:

• It is a recently described form of interstitial lung disease, of unknown etiology and with an unknown incidence.

• It is unknown why all the cases described have been male: newborns and infants.

• Diagnosis is achieved by lung biopsy with:

cells containing glycogen and

no inflammatory changes (important to differentiate it from other interstitial lung diseases).

• Due to the unknown etiology, there are no therapy guidelines; 50% patients improved on steroids, but it is still unclear if steroids accelerate the cell maturation or they increase the cell glycogenolysis.

• It appears to have a favorable prognosis when compared with other subtypes of interstitial lung diseases, with only one reported death.

Due to the rarity of this condition, multi-center collaboration should be encouraged, because no single center can see a sufficient number of patients to study this disease adequately.

Conclusions

• Canakis A.M., et al. – Pulmonary interstitial glycogenosis. A new variant of neonatal interstitial lung disease, Am. J. Resp. Crit. Care Med., 2002; 165: 1557–1565.

• Castillo M., et al. – Pulmonary interstitial glycogenosis in the setting of lung growth abnormality: radiographic and pathologic correlation, Pediatric Radiology, 2010; DOI 10.1007.

• Deutsch G., et al. – Diffuse Lung Disease in Young Children, Am. J. Respir. Crit. Care Med., 2007; Vol. 176 pp. 1120–1128.

• Dinwiddie R., et al. – Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland, Pediatric Pulmonology, 2002; 34(1):23–9.

• Fan L., et al. – Pediatric Interstitial Lung Disease Revisited, Pediatric Pulmonology, 2004; 38:369–378.

• Griese M., et al. – Incidence and classification of pediatric diffuse parenchymal lung disease in Germany, Orphanet Journal of Rare Diseases, 2009; 4:26.

• Lanfranchi M., et al. – Pulmonary interstitial glycogenosis, Pediatric Radiology, 2010; 40:361–365.

• Onland W., et al. – Pulmonary interstitial Glycogenosis in Identical Twins, Pediatric Pulmonology, 2005; 40:362–366.

• Smets K., et al. – Neonatal pulmonary interstitial glycogen accumulation disorder, Eur. J. Pediatr., 2004; 163: 408–409.

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