Types of chILD
This diagnosis is characterized by the sudden onset of pulmonary haemorrhage in a previously healthy infant less than 1 year of age, in whom medical problems that might cause pulmonary hemorrhage, including physical abuse, have been ruled out. Severe cases will be in respiratory distress.
Blood is often found in the nose and airways, though not always, with no evidence of gastrointestinal bleeding. Bronchoscopy shows the source of bleeding in the lung below the larynx and can originate from the upper or lower airways. Typical, severe cases present with respiratory distress, which may require mechanical ventilation, and chest X-ray or CT scan may show infiltrates. However, some infants present with sudden onset of pulmonary bleeding without distress, and their radiological studies may be unremarkable. Variation in severity might be related to the duration, severity, or nature of the etiologic agent(s) involved.
The treatment for acute idiopathic pulmonary hemorrhage of infancy varies with the severity of the hemorrhage. Causes of the hemorrhage, like an underlying genetic abnormalities, immunodeficiency or blood clotting problems should be investigated. Some cases have been found in clusters which suggests possible environmental factors such as fungi, toxins, smoke or chemical pollutants. It is also important that the social circumstances are investigated in each case and that a careful search is undertaken for signs of physical abuse. It is important to note that it may be impossible to identify a causative agent.
The outcome of this diagnosis is dependent on the severity of the bleeding. If the bleeding is severe, the patient may require mechanical ventilation and the prognosis is worse. However, mild bleeding is not as severe.
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 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.
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.
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 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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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 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.
Most cases of idiopathic pulmonary hemosiderosis can be managed with corticosteroids.
Pulmonary aspiration is the entry of substances such as food, drink, or stomach contents into the larynx (voice box) and lower respiratory tract (from the trachea [windpipe] to the lungs). A person might inhale the substance or it might enter the lungs from the digestive tract during reflux or exhalation. This can occur in the neonate with meconium aspiration at delivery or can be associated with chronic aspiration in older infants and children.
Some infants have meconium aspiration from delivery. These patients are typically diagnosed clinically and do not require a biopsy. It can cause breathing difficulties due to swelling (inflammation) in the baby’s lungs after birth. The infant may need help with breathing or heartbeat immediately after birth, and therefore may have a low Apgar score. The health care team will listen to the infant’s chest with a stethoscope and may hear abnormal breath sounds, especially coarse, crackly sounds. A blood gas analysis will show low blood pH (acidic), decreased oxygen, and increased carbon dioxide. A chest x-ray may show patchy or streaky areas in the infant’s lungs. The infant may be placed in the special care nursery or newborn intensive care unit for close observation. Other treatments may include antibiotics for infection, oxygen therapy and breathing assistance, and radiant warmers. Most patients with meconium aspiration recover with no long-term health effects.
In some children, small amounts of food or liquids enter the lungs and causes inflammation and potentially infection. Over time, this can affect lung function and if left untreated, can lead to scarring and other complications.
A swallow study can be performed by a radiologist and a speech-language pathologist to test for aspiration. During this study, the patient will swallow substances of varying thickness that contain barium. This allows the liquid to be seen on a screen as the person swallows. The doctors will look for problems with the muscles that coordinate swallowing, as well as, food actually penetrating the vocal cords. Depending on the type of problem seen, the doctors will work with the patient and their family to avoid further aspiration. In infants, milk or formula aspiration can be seen with lipid-laden macrophages (the cells that clean up the lungs become full of fats from the breakdown of the milk product), and granular eosinophilic debris (these cells are involved in inflammation and release their granules at sites of inflammation) in bronchoalveolar lavage (BAL) fluid or on biopsy. In older children, food particles can sometimes be seen.
Since aspiration can cause inflammation and infection. Antibiotics and breathing treatments are commonly used. The primary concern is to stop the recurrence of aspiration to avoid acute infection, and other chronic, permanent changes in the lung tissue, such as fibrosis.
When we breathe, air enters our lungs and fills tiny air sacs called alveoli. Each air sac is surrounded by an extensive capillary bed, which is a network of tiny, thin blood vessels. In order for us to bring in oxygen and release carbon dioxide, the alveoli and capillaries must be properly aligned. If there are not enough capillaries or the capillaries are too far away from the surface of the alveoli, gas exchange cannot occur effectively, which means there is not enough oxygen for the body and the heart must work much harder.
Alveolar Capillary Dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare disorder where the capillaries around the air sacs fail to develop normally. There are fewer capillaries, and the ones that are present are not positioned correctly within the walls of the alveoli. This makes gas exchange very difficult and ineffective.
Normally, the blood is brought to the capillaries by arteries, and the veins carry blood away from the alveoli to the heart in bundles with lymph vessels. In ACD/MPV patients, these veins are found abnormally bundled with the arteries and the smooth muscle tissue in the arteries is often thickened, which restricts normal blood flow. When this occurs, it increases the blood pressure in the pulmonary arteries and makes the heart work harder. This causes pulmonary hypertension and is one of the main symptoms of this disease.
Frequently asked questions
What are the symptoms of ACD?
Are there any treatments for ACD?
Other support groups:
ACD Prognosis and Treatment
This is considered a fatal diagnosis, however, some patients have survived with “patchy ACD” long enough to receive lung transplants. Much more research needs to be done to find the underlying causes of ACD and to find treatments for this condition.
Symptoms of ACD
Babies born with this disorder typically develop respiratory distress within a few minutes to a few hours after birth. They experience shortness of breath, their lips, skin, and fingernails often appear bluish (cyanosis), and they have persistent pulmonary hypertension that does not respond to treatment.
Other abnormalities of the cardiovascular, digestive and urogenital systems are found in a large percentage of these patients and there are cases in families that have lost more than one child to this disorder, which suggests a genetic cause. Two genetic causes have been identified (FoxF1 and 16q24.1 microdeletions), but they do not explain all of the cases of ACD.
The interstitium in the lung is the tissue that lies between the surface of the alveoli and the capillaries that surround the alveoli. In normal lungs, this tissue is very thin to allow oxygen and carbon dioxide to cross between the surface of the alveoli (air sacs) and the capillaries that carry blood. During gas exchange, oxygen is absorbed into the blood and carried throughout the body within red blood cells and carbon dioxide leaves the blood and crosses into the alveoli so it can be released when the person exhales.
If the interstitial tissue becomes thickened due to infection, inflammation or scarring, it makes it harder for oxygen and carbon dioxide to cross the interstitium, which can make the patient quite sick. Interstitial pneumonia is inflammation of the interstitial tissue (not the alveoli themselves).
In the beginning, these patients can have a dry, unproductive cough, shortness of breath, and/or a low-grade fever. Unfortunately, this form of interstitial lung disease is rapidly progressing and is often fatal.
The common diagnostic tests are chest x-ray, chest CT scan, and lung biopsy. High-resolution CT scans show patchy or geographic ground glass opacity initially, followed by architectural distortion (honeycomb appearance with small cystic spaces surrounded by fibrosis), and traction bronchiectasis (dilated airways surrounded by fibrosis). If biopsied, the histology shows diffuse alveolar damage.
Corticosteroids and other treatments are often ineffective and many patients require mechanical ventilation and intensive care support. Even with medical intervention, this is a serious form of chILD and can be fatal.
Rare disorders that are currently being supported by the chILD Foundation:
Acute interstitial pneumonia
Alveolar capillary dysplasia with misalignment of pulmonary veins
Alveolar hemorrhage syndromes:
- Pulmonary capillaritis
- Acute idiopathic pulmonary hemorrhage of infancy
- Idiopathic pulmonary hemosiderosis
Autoimmune-related lung disease
Cryptogenic organizing pneumonia
Desquamative interstitial pneumonia
DNA repair disorders
Drug-induced lung disease
Immune-mediated lung disease
Lung disease in the immunocompromised host: (Idiopathic pneumonia syndrome)
Lymphocytic interstitial pneumonia
Lysosomal storage disorders
Neuroendocrine Hyperplasia of Infancy (NEHI)
Nonspecific interstitial pneumonia
Pulmonary Alveolar Proteinosis (GMCSF antibody mediated)
Pulmonary Interstitial Glycogenosis (PIG)
Pulmonary alveolar microlithiasis
Pulmonary vascular disorders
Radiation-induced lung disease
- GMCSF receptor