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.