Keywords
pulmonary interstitial glycogenosis - respiratory failure - interstitial lung disease
- ECMO - pulmonary hypertension
Respiratory insufficiency in term infants is usually caused by meconium aspiration,
sepsis, or pneumonia. Interstitial lung disease, a heterogeneous group of diffuse
lung diseases, is a rare cause of respiratory insufficiency in newborns. A new classification
of this group of lung diseases was established by the Children's Interstitial Lung
Disease Network.[1]
[2]
[3]
[4]
[5]
[6]
In this case report, we present a full-term infant with pulmonary interstitial glycogenosis
(PIG) together with bronchopulmonary dysplasia (BPD) like features.
Case Report
An 11-day-old Moroccan boy was transferred from another neonatal intensive care unit
(NICU) due to refractory pulmonary hypertension requiring extracorporeal membrane
oxygenation (ECMO). It was the mother's fourth pregnancy, which was uneventful. The
parents were first cousins, there is no family history of respiratory problems. The
boy was born at a gestational age of 39 weeks and 3 days. Birth weight was 3,730 g
and Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. Initially, he was
discharged home without problems. After 1 day, parents sought medical attention due
to tachypnea and feeding problems, after which he was admitted to the NICU for hypoxia.
Cardiac ultrasound showed normal cardiac anatomy and a patent ductus arteriosus (PDA)
with signs of persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric
oxide and inotropic support were started. Antibiotics were started empirically, though
there were no signs of viral or bacterial infection. With these interventions, his
condition improved, but after 2 days, he became hypoxic again due to severe pulmonary
hypertension with right-to-left shunting through the PDA. Surfactant was administered
without any beneficial effect. Despite intensive treatment, the PPHN could not be
reversed, and the boy was referred to our center for extracorporeal membrane oxygenation
(ECMO). Cardiac ultrasound showed a severe persistent pulmonary hypertension with
suprasystemic pressures, enlarged right ventricle, and a continuous right-to-left
shunting through the PDA. Veno-venous ECMO was started on day 10.
Chest radiographs ([Fig. 1]) showed diffuse pulmonary opacities consistent with atelectasis or edema. Because
it was impossible to wean the patient from ECMO support and due to lack of a definitive
diagnosis, an open lung biopsy was performed on day 8 of ECMO treatment.
Fig. 1 Chest radiographs. (a) Portable frontal chest radiograph 1 day after birth showed
a normal configuration of the heart. There are some prominent interstitial markings
bilateral. (b) Portable frontal chest radiograph 10 days after birth. Endotracheal
tube is in a high position. ECMO canula is in a good position. Interstitial markings
bilateral consistent with atelectasis or edema. ECMO, extracorporeal membrane oxygenation.
Histological examination of the biopsy showed partially atelectatic and partially
emphysematous lung parenchyma, including interstitial emphysema. Radial alveolar count
(RAC, i.e., the number of alveoli in a subpleural acinus between the central bronchiole
and the visceral pleura) could be measured at only one place in the biopsy and was
four to five, which is within the normal parameters ([Fig. 2a]). Except for a few remnants of hyaline membranes, the alveoli were empty. Pneumocytes
were enlarged and showed large round nuclei with prominent nucleoli. The alveolar
septa were widened due to three factors: first, there were several accumulations of
histiocytic cells with abundant, clear cytoplasm. Second, the amount of collagen fibers
was increased as demonstrated by Elastica-Masson stain ([Fig. 2b]). Finally, there was an increase of interstitial smooth muscle bundles as shown
by an immunohistochemical SM1-staining ([Fig. 2c]). Small arterioles showed a constricted media, but no significant intimal proliferation
or fibrosis. An immunohistochemical CD34 staining highlighted numerous capillaries
at considerable distance from the alveolar surface, yet evenly distributed in the
septa. There was no misalignment of venous vessels. A periodic acid Schiff (PAS) stain
revealed some granular material digestable by diastase, consistent with glycogen,
in the clear cytoplasm of the interstitial histiocytes ([Fig. 2e, f]) In summary, the presence of PAS-positive histiocytes led to the diagnosis of PIG,
whereas the interstitial increase of collagen and smooth muscle bundles were interpreted
as reparative phase of BPD.[7] Based on this biopsy, there was no convincing evidence of an anatomical maturational
arrest, infection, alveolar proteinosis, or alveolar capillary dysplasia. The distribution
of the PAS positive histiocytes was somewhat irregular, the largest concentrations
being located at the intersections of alveolar septa.
Fig. 2 Histological aspects of open lung biopsy. (a) (×50, H&E stain) scanning view: double
arrow indicates radial alveolar count; (b) (×100, Elastica-van Masson stain): increase
of interstitial collagen fibers (arrows); (c) immunohistochemistry: arrows indicate
increase of interstitial smooth muscle cells (×100, SM1 stain); (d) immunohistochemistry:
some capillaries (simple arrow) are in touch with alveolar basal membrane, but many
(double arrow) are not (×100, CD34 stain); (e and f) (PAS and PAS-D, ×200) interstitial
cells with PAS-positive cytoplasmatic granules (arrows in [Fig. 2e]) which disappear after diastase treatment.
The boy was treated with glucocorticoids due to the reported potential beneficial
effect in cases of PIG.[2]
[8]
[9]
[10]
[11]
[12] After a few days of prednisolone, we were able to take the patient off ECMO. A few
hours later, the patient again developed acute severe pulmonary hypertension with
acute right ventricular failure. There was no evidence of a pulmonary embolism at
this time. Maximal ventilator support with inhaled nitric oxide failed, and the patient
expired. Autopsy was not permitted by the patient's family.
Discussion
Pulmonary interstitial glycogenosis (PIG) is a rare and poorly understood lung disorder.[5]
[8]
[12]
[13] Diagnosis can only be made by means of a lung biopsy. Its characteristic histological
finding is interstitial thickening due to increased mesenchymal cellularity without
evidence of inflammatory cells. The inter-alveolar septa are expanded by oval- to
spindle-shaped cells with pale cytoplasm, indistinct cell membranes, and oval, bland
nuclei. Staining with PAS shows patchy PAS-positive diastase sensitive material within
the cytoplasm of these interstitial cells, indicating the presence of glycogen. The
true function of these interstitial cells is unclear, but is probably similar to fibroblastic
cells.[1]
[3]
[5]
[8]
[9] The interstitial cells found in our patient's lung biopsy matched this description,
although the amount of cytoplasmatic PAS digestable granules was not very large. We
could not perform electron microscopy, because our standard fixation protocol for
perinatal lung biopsies does not contain glutaraldehyde. There are two patterns of
PIG observed: a diffuse interstitial PIG without growth abnormalities or patchy PIG
involvement in preterm patients with alveolar growth abnormalities.[4]
[14]
[15] In our small biopsy, it was difficult to determine the overall distribution pattern
of the diagnostic cells; we can state that it was not entirely diffuse. PIG has been
described as both an isolated finding and an additional finding in abnormal lung development
and pulmonary vascular growth, hemodynamically significant cardiac disease, Hunter
syndrome and Noonan syndrome.[4]
[11]
[12]
[13]
[15]
[16]
[17]
[18]
[19] At histological investigation of our biopsy, the predominant features were interstitial
changes of the lung parenchyma resembling BPD, which we don't expect in a full term
infant. However, the boy was all the time artificially ventilated with high pressures
potentially contributing to lung damage which made differentiation between a developmental
disorder and secondary changes due to ventilation difficult. Therefore, as parameter
of maturity, we used the RAC, which was within normal limits. We are aware of the
fact that there were only two bronchioli visible in the slides; however, we assumed
that we would have seen more bronchioles if there had been significant delay in the
development of alveoli. The walls of the smallest arterioles were thickened due to
an increase of smooth muscle cells. We considered these changes consistent with pulmonary
hypertension as a consequence of the interstitial changes. There were no signs of
alveolar capillary dysplasia and no misalignment of pulmonary veins. Unfortunately,
since autopsy was not permitted, there was no further possibility to obtain more lung
tissue to exclude a sampling error. In summary, our patient is a full-term infant
with histological features of PIG and bronchopulmonary dysplasia without an anatomical
maturation arrest or a misalignment of pulmonary veins. But because of the technical
limitations mentioned above, and since no genetic tests for surfactant genes were
performed we cannot rule out a functional immature lung nor can we decide with certainty
if PIG alone caused PPHN or if PPHN was due to the BPD like changes and PIG has to
be considered as an epiphenomenon. However, histological signs of surfactant deficiency
were not seen and PPHN was already present shortly after birth, at a time point where
eventual BPD was not yet present.
All patients presenting with PIG demonstrated tachypnea and hypoxemia, most of them
immediately after birth or in the first 2 days of life. It has not been seen past
8 months of age. The majority required assisted ventilation.[1]
[4]
[6]
[8]
[9] In the relatively small number of reported cases, there is a male gender preference.[8]
[10]
[20]
Radiological findings of PIG are nonspecific. They vary considerably, depending on
whether there is any associated underlying growth abnormality. Infants with PIG not
associated with an underlying growth abnormality show progressive bilateral hyperinflation
and eventual evolution to diffuse interstitial markings on their chest X-rays. High-resolution
computed tomography (CT) scan of the chest demonstrates segmental, or subsegmental
ground-glass opacities, interlobular septal thickening, and reticular changes in a
primarily subpleural distribution with few centrilobular nodules. Infants with PIG
associated with underlying growth abnormalities, show multiple small scattered cystic
changes of variable size combined with underlying diffuse ground-glass opacity, interlobular
septal thickening and reticular changes on CT.[6]
[8]
[9]
[14]
The etiology and underlying pathogenic mechanism of PIG are unknown. There have been
no reported associations with glycogenoses or other metabolic diseases. The current
hypothesis is that this lung abnormality originates in utero and is a developmental
abnormality.[4]
[8]
[9]
[10]
[11]
[12]
[13]
[16] Maybe is patchy PIG associated with anatomical abnormal lung development and pulmonary
vascular growth is an early development disorder and diffuse isolated PIG a late development
disorder.
Currently, there are no guidelines for the treatment of PIG. Administration of glucocorticoids
has been recommended and has demonstrated a favorable outcome in affected patients.[2]
[8]
[9]
[10]
[11]
[12]
The prognosis remains uncertain. The clinical outcomes are quite varied. Deaths have
been reported when PIG exists with an abnormal lung development and pulmonary vascular
growth, and congenital heart disease. No mortality has been reported in isolated PIG.[4]
[11]
[13]
[19]
In this article, we reported on a full-term infant with features of PIG and BPD, who
expired. There was no convincing evidence of an anatomical maturational arrest or
a congenital heart disease. It is also possible that our patient had an undiagnosed
genetic or pulmonary abnormality. So maybe PIG is an epiphenomenon at lung development
disorders in different stages and is the prognosis depending on the stage of the development
disorder.[16]
[18]
[20]
In conclusion, our knowledge of incidence, etiology, and pathogenesis of PIG is lacking.
The diagnosis can be made only after lung biopsy demonstrates the characteristic histological
findings. The prognosis of PIG continues to evolve. Further investigation beyond simple
case reports is needed to thoroughly characterize this disorder.
