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Pulmonary Interstitial Glycogenosis

Background

Pulmonary Interstitial Glycogenosis (PIG) is a children’s interstitial lung disease (chILD) and was first described in 2002. This disorder is relatively rare and only few cases have been reported in the medical literature. However, given its relatively recent description and the fact that it is only diagnosed through lung biopsy, PIG may be under-recognized and under-reported. PIG has only been reported in infants, usually diagnosed within the first few months of life.

What causes PIG?

The cells of the body use glucose, a sugar, for energy. Most cells of the body use glucose from the blood, but it can be stored in a larger molecule called glycogen. Glycogen is found in large amounts in skeletal muscle and the liver and is used to supply energy to the body when needed. It is not typically found in large amounts in other cells of the body.

Pulmonary Interstitial Glycogenosis (PIG) is caused by an abnormal accumulation of glycogen in specific cells of the lung. These cells are located in the interstitium, the space between the air sacs in the lungs. The excess glycogen leads to a thickening of this space, making it difficult for oxygen to get from the air sacs into the bloodstream.

The cause of PIG remains unclear. The accumulation of glycogen has also been seen in other lung conditions to different degrees, especially those associated with poor lung growth. Based on these observations and the lack of inflammation in the lungs, it is thought that PIG is a result of abnormal development of the lungs in the fetus and young infant. However, a report of PIG in a pair of identical twins also point to the likely genetic predisposition for this disorder. Further studies are needed to accurately define this lung disorder.

Symptoms

Infants with PIG present with rapid and laborious breathing and the need for oxygen supplementation in the first few weeks of life. These symptoms are similar to those of many other respiratory disorders of infancy, such as respiratory distress syndrome and surfactant protein deficiencies. However, a common pattern in the presentation of these infants is an initial stable period, followed by an unexplained deterioration in their respiratory status several days or weeks after birth.

Diagnosis

As in other forms of chILD, several tests can help with the diagnosis.

  • Lab work to rule out other causes of these symptoms, such as cystic fibrosis or immunodeficiency, is often performed.
  • A high-resolution computed tomography (CT) scan of the lungs may show findings consistent with an interstitial lung disease. However, the imaging appearance of PIG is highly variable and non-specific for PIG. With the few case reports of PIG, it is currently difficult to make the diagnosis solely based on radiographic imaging.
  • A bronchoscopy with bronchoalveolar lavage (BAL) may be performed which can look for infection, inflammation, and signs of aspiration into the lungs. Currently, a definitive diagnosis of PIG can only be made through lung biopsy. The biopsy tissue typically shows little inflammation. The hallmark of PIG is the accumulation of glycogen in the lung interstitial cells.

Treatment

As for any child, optimizing nutrition for adequate growth and the prevention of respiratory infections are important in the overall health. In addition, oxygen supplementation may be required.

Most of the reported infants with PIG have received and responded favorably to therapy with intravenous or oral corticosteroids. However, given the potential side effects of corticosteroids and that the evidence of this treatment is based on few patients, careful consideration before initiating treatment is warranted for each patient.

Prognosis

The cases of PIG described in medical literature have been associated with a favorable prognosis. Clinical improvement is noted in most cases and only one death has been reported in a premature infant with PIG. Again, these statistics are based on few patients. Caution must be exerted before drawing conclusions about the prognosis of PIG, especially if PIG is present along with lung growth abnormalities, in which case the prognosis may be poorer.

Future Directions

There is still much to learn about Pulmonary Interstitial Glycogenosis (PIG). Along with the chILD Foundation and the Children’s Interstitial Lung Disease Research Network (CHILDRN), there is an ongoing multi-center collaboration on a Rare Pediatric Lung Disease Patient Registry. This database will enable doctors and researchers to collect more information and better understand rare pediatric lung disorders such as PIG.

Similar chILD Disorders

Surfactant Deficiency

Background

The surface of the tiny air sacs of the lungs (alveoli), where oxygen goes into the bloodstream and carbon dioxide comes out, is coated in a thin watery layer that contains water and pulmonary surfactant. Water is important because it helps oxygen and carbon dioxide move from the air to the blood, but it has special properties that can be a problem. Water is polar which means that the atoms within the molecule carry partial charges. These charges can attract or repel each other like the poles of a magnet which causes water to have surface tension. When air enters the alveoli, they fill up and expand. Without normal pulmonary surfactant present, the attractive forces of the water will cause the alveoli to collapse.

Pulmonary surfactant is a complex substance in the lungs which reduces the surface tension of water and therefore, prevents the collapse of the alveoli. Surfactant also plays a role in defending the lungs from bacteria and viruses. The lungs start making surfactant around 24 weeks gestation (4 months before term, which is 37-40 weeks) and adequate amounts are present starting at 35 weeks gestation. Premature infants often receive artificial surfactant to help their breathing.

There are many components in pulmonary surfactant which require the cell to make the surfactant, package it for delivery to the surface of the lung, and then move the molecules to the surface of the alveoli. There are several diagnoses that can affect the proteins themselves or one of the processes within the cell that makes or delivers the surfactant. Surfactant proteins A, B, C, and D are specialized proteins that make up about 5% of the pulmonary surfactant. Surfactant protein B (SP-B) and C (SP-C) are mainly involved in preventing alveolar collapse while surfactant protein A (SP-A) and D (SP-D) play a role in the lung’s immune defense. ABCA3 is a protein that transports surfactant within the alveolar Type II cell, the cell type in the lung that produces pulmonary surfactant. The thyroid transcription factor (TTF1) is a protein that activates surfactant associated genes, among others. Problems with any of these can cause lung damage.

Surfactant protein deficiencies account for about 10% of all childhood interstitial lung diseases (chILD). The presentation, treatment, and prognosis is variable depending on the surfactant associated protein that is deficient. Newborns with unexplained respiratory distress or failure and older children with unclear chronic respiratory insufficiency, especially in the context of a family history of lung disease, should be evaluated for surfactant protein deficiency.

Surfactant Protein B (SP-B) Deficiency

SP-B deficiency is caused by inherited mutations in the surfactant protein-B gene (SFTPB) on chromosome 2, which leads to a partial or complete absence of surfactant protein B. It is an autosomal recessive condition. Infants present shortly after birth with respiratory distress and failure, despite assisted ventilation and surfactant replacement therapy. The diagnosis is made by genetic testing for the mutation in the child and both parents. SP-B deficiency carries a poor prognosis and children with this disorder do not survive beyond the first few months of life. The only effective treatment is lung transplantation.

ABCA3 Deficiency

ABCA3 deficiency is caused by inherited mutations in the ABCA3 gene (ABCA3) on chromosome 16. Individuals with ABCA3 deficiency may present at birth, similar to SP-B deficiency, or in older children in whom course of the disease may be milder and more chronic with cough and failure to thrive. It is an autosomal recessive condition, meaning that a child must inherit two copies of an abnormal gene (one from each parent) in order to show symptoms. The prognosis is variable, depending on the severity of the disease. Some children require lung transplantation while others do not.

Surfactant Protein C Associated Disease

Disease due to mutations in the surfactant protein-C gene (SFTPC) on chromosome 8 results from an alteration in the structure of surfactant protein C and accumulation of this dysfunctional protein in lung cells. It is a dominant condition, meaning that a child only needs one copy of an abnormal gene to show symptoms. The mutation arises spontaneously in the child in about 55% of the cases or is inherited from one parent in the remainder of cases. This condition has a highly variable presentation, from acute respiratory distress to a more slow-onset and chronic lung disease. It can affect infants, children, and adults. The diagnosis is made by genetic testing for a mutation in SFTPC in the child and both parents. Although several affected individuals can have the same mutation, the prognosis may be very different and thus very difficult to predict. Some patients require lung transplantation while others will improve with time.

Thyroid Transcription Factor Related Disease

Mutations in the thyroid transcription factor 1 gene (NKX2.1) on chromosome 14 may cause respiratory disease, an under-active thyroid gland, and/or neurologic problems. Individuals with respiratory problems due to these mutations may present at birth with respiratory distress or later in childhood with more chronic disease. It is an autosomal dominant condition; most of the mutations arise spontaneously and are not inherited.

Diagnosis

As in other forms of chILD, several tests can help with the diagnosis.

  • Lab work to rule out other causes of these symptoms, such as cystic fibrosis or immunodeficiency, is often performed.
  • A high-resolution computed tomography (CT) scan of the lungs may show changes found with chILD.
  • A bronchoscopy with bronchoalveolar lavage (BAL) may be performed which can look for infection, inflammation and signs of aspiration into the lungs.
    • In older children, pulmonary function testing is usually performed in the outpatient setting and may show decreased lung function.
  • In addition, a lung biopsy may provide useful information to rule out other lung diseases with similar clinical presentations.
  • The diagnosis of a surfactant protein deficiency is made through genetic testing of the child and both parents.

Treatment

The prognosis of the lung disease is variable, depending on the severity of the disease. Some children require lung transplantation while others do not. As for any child, optimizing nutrition for adequate growth and the prevention of respiratory infections are important in the overall health. In addition, oxygen supplementation and assisted breathing through a ventilator may be required.

Currently, there is no specific treatment for any of the surfactant protein deficiencies. For affected newborns, surfactant replacement therapy may improve respiratory status transiently but is ineffective in treating the underlying deficiency.

Lung transplantation may be considered. However, given the critically-ill and unstable state of these infants, the pre-transplant period is associated with a high risk of dying (up to 30%). The 5-year survival rate following lung transplantation has been reported to be about 50%.

In older children with milder forms of surfactant protein deficiency, corticosteroids and hydroxychloroquine may be considered. Further studies are needed to evaluate the benefits of these medications.

Pulmonary Capillaritis

Background

Pulmonary capillaritis is an inflammatory condition that causes the destruction of the tiny blood vessels that surround the air sacs, called capillaries. This inflammation is associated with an increased number of neutrophils (a type of immune cell) in the capillary walls and surrounding tissue followed by death of the cells in the capillary walls (necrosis).

Symptoms

The symptoms can be acute, but are often slow in developing. Commonly, these children are anemic, experience exercise limitations, and have shortness of breath (dyspnea). Other symptoms include low oxygen levels in the blood (hypoxemia), cough, and abnormal chest x-rays. Some children will cough up blood or bloody mucus, but this is not always seen because some children swallow the secretions.

Diagnosis

Chest x-rays will show a ‘butterfly or batwing’ appearance of symmetric airspace opacities (lighter areas in the lung image) in most cases of alveolar hemorrhage, but some will have the opacities on one side or in an irregular pattern. A high-resolution CT scan is a more sensitive test that shows patchy ground-glass opacities and consolidation due to the blood filling up the air sacs. If the condition is chronic, septal thickening and nodular opacities can be seen. It can indicate capillaritis if small fluffy opacities are seen in the middle of the lobes around blood vessels. A biopsy is often used to confirm this diagnosis.

Capillaritis is often associated with other vascular disorders including, but not limited to, Wegener’s granulomatosis, microscopic polyangiitis, and Goodpasture’s disease.

Treatment

Pulmonary capillaritis must be treated aggressively. If left untreated, the inflammation causes damage and fibrosis of the lung tissue and is associated with high morbidity and mortality. The goal of the treatment is to cause remission of the symptoms. Current therapy includes high dose corticosteroids, cyclophasamide, and/or IV immunoglobulin. Once remission has been obtained, it is maintained with low-dose prednisone and either azathioprine or methotrexate, which suppress the immune system.

Prognosis

Historically, this diagnosis had a poor prognosis with mean survival of under 3 years. However, as treatments and our understanding improve, the survival rate has improved to over 80%.

Neuroendocrine Hyperplasia of Infancy

Background

NEHI is a relatively rare disorder of the lungs that was first classified and described in 2005. As a result, it is difficult to estimate the number of children with this disorder in the US. However, this is one of the most common forms of chILD and is still underdiagnosed.

Symptoms

Children with NEHI often have rapid and difficult breathing, low levels of oxygen in the blood (hypoxemia), and crackles are heard on examination with a stethoscope. Wheezing, although not characteristic, may also occur. Children may be initially diagnosed with asthma or prolonged respiratory infections as the symptoms may overlap with these. However, children with NEHI generally do not respond to asthma treatments and corticosteroids.

What causes NEHI?

The cause of NEHI is poorly understood at this point in time. When a biopsy is performed and examined with bombesin staining, NEHI patients will have an increased number of pulmonary neuroendocrine cells (PNECs) in their lung tissue. The high numbers of these cells leads to the NEHI diagnosis, but the role of these cells in NEHI remains unclear. NEHI has been found to run in some families so it suggests there is some genetic basis for this disorder. However, a gene abnormality has not been identified to date. Environmental causes may also influence the development of NEHI, but much more research must be done to answer these questions.

Diagnosis

When any form of chILD is suspected, there are several tests that are commonly done to help with the diagnosis. Lab work to rule out other causes of these symptoms, such as cystic fibrosis or immunodeficiency, is often performed. A bronchoscopy with bronchoalveolar lavage (BAL) is often performed which can look for infection, inflammation, and signs of aspiration into the lungs.

A high-resolution computed tomography (CT) scan of the lungs is often useful in the diagnosis of NEHI, showing a characteristic pattern called ground glass opacities. The lungs also show areas that are inflated to different extents, with some areas being overinflated and some underinflated, creating a mosaic pattern on CT.

An Infant Pulmonary Function Test (infant PFT) has become more important in diagnosing NEHI. This test is not always used, because it takes specialized equipment that is not always available to the clinician. These usually show trapping of air in the lungs in NEHI patients and characteristic results.

If all of these tests are characteristic of NEHI, the child may receive a diagnosis of NEHI Syndrome without a biopsy. However, if any of the results or symptoms are not typical, the only way to conclusively confirm the NEHI diagnosis is through a lung biopsy. The biopsy tissue typically has little or no inflammation and when stained with a particular bombesin stain, demonstrates an abnormally increased number of pulmonary endocrine cells (PNECs) within the small airways. PNECs are cells that are usually present in the lining of the airways, alone or in clusters called neuroepithelial bodies (NEBs), and are thought to be involved in lung development. In NEHI, the number of PNECs and NEBs in the airways is always significantly increased.

Treatment

The treatment for NEHI is mainly supportive. NEHI children often have labored breathing, which uses more calories than normal and can be accompanied by gastroesophageal reflux (GERD). As a result, poor weight gain (failure to thrive) is often seen with NEHI. Optimizing the child’s nutritional status to promote adequate growth is important for overall health.

Oxygen supplementation may also be required. The amount of oxygen needed varies in NEHI patients. Some need oxygen 24 hours a day, while others will only wear it at night and during illness, while some do not require it at all. Most NEHI patients decrease their need for oxygen over time and most eventually grow out of the need for supplementation.

Common colds and flu can be more severe in NEHI patients, so limiting exposure to respiratory infections is also important. Seasonal flu shots and prevention of Respiratory Syncytial Virus (RSV) is recommended.

Oral corticosteroids, which are used to decrease inflammation in other lung disorders, have not been shown to be helpful with the symptoms in most NEHI patients. This is consistent with the limited inflammation seen on lung biopsy.

Prognosis

There is currently limited information on the long-term prognosis, as NEHI has only been recently recognized. To date, we do not know of any children that have died from NEHI and most improve with time.

DOCUMENTS

Abnormal Infant Pulmonary Function in Young Children (pdf)
Brody NEHI (pdf)
Detering Pye and Fan NEHI (pdf)
Dr. Young – A Mutation of TTF1NKX21 (pdf)
Familial NEHI Popler et al 2010 (pdf)
NEHI – June 25, 2011 (Power Point)
NEHI Pamphlet (pdf)
Neuroendocrine Cell Distribution (pdf)

Idiopathic Pulmonary Hemosiderosis

Symptoms

Idiopathic pulmonary hemosiderosis is a subset of the pulmonary hemorrhage syndromes that involves anemia, infiltrates seen on chest x-ray, and some children will cough up blood or bloody mucus, but this is not always seen because some children swallow the secretions. Bronchoalveolar lavage (BAL) contains hemosiderin-laden macrophages or gastric aspirates. The onset can be acute and life-threatening which requires intubation and mechanical ventilation. Lung biopsy is rarely used in these patients.

It is important to differentiate between pulmonary hemosiderosis and pulmonary capillaritis, because the treatment and course of the disease is quite different. Pulmonary capillaritis is exacerbated by an over-active immune response so antibody titers should be performed to measure the immune response.

Treatment

Most cases of idiopathic pulmonary hemosiderosis can be managed with corticosteroids.