INTERSTITIAL LUNG DISEASE (ILD) OVERVIEW continued
The pathophysiology of ILD is unknown, but proposed to start with an initial injury to the alveolar epithelium, perhaps with a viral agent. This damage is followed by an exudation of serum proteins onto the alveolar surface, and an attraction of neutrophils, lymphocytes and finally macrophages. These inflammatory cells release oxidants, proteases, and mesenchymal growth factors. Stimulated fibroblasts produce type I collagen, which thickens the interstitum and replaces the normal architecture. Type II alveolar cells differentiate, replicate and blanket the area affected, replacing the sloughed type I cells. This leads to type II cell hyperplasia. Immune complexes have also been purported to play a role, as these have been found in BAL fluid and serum of patients with ILD.
In terms of a history to support a potential case of ILD, a review of the feeding history, inquiries into possible environmental exposures, a family history of lung disease, and the presence of signs such as hemoptysis or a rash should be elicited.
PRESENTATION OF ILD
The presentation of ILD is variable, including wheeze, cough, dyspnea, tachypnea, retractions, exercise limitation, and frequent infections. The typical finding upon ausculation is that of "Velcro crackles". If severe enough, the presentation can include cyanosis, clubbing, signs of pulmonary hypertension and cor pulmonale, and growth failure. Onset of ILD occurs most frequently in infancy (46%), with decreasing frequency occurring in older age groups.
IN A NEWBORN
The presentation of a newborn with ILD should prompt consideration of three main etiologies:
deficiency of surfactant protein (often B, also C)
alveolar capillary dysplasia, or
Surfactant deficiencies and ILD are an active area of research at present.
Four surfactant proteins have been characterized - A, B, C and D.
Deficiencies of both protein B and C have been described, and the mutation in the gene coding for SP-C has now been found, though the mode of transmission remains unknown. Deficiency of surfactant protein B usually presents similarly to RDS, though protein B deficiency is more often associated with term or near-term deliveries, as opposed to that associated strictly with prematurity as with RDS. Lung biopsy is not necessary if surfactant protein B deficiency is suspected, as the gene can be identified in serum, and the proteins can be analyzed if retrieved by BAL. The only treatment for surfactant protein B deficiency is lung transplant.
Alveolar capillary dysplasia is characterized by abnormal pulmonary vasculature, abnormal lung parenchyma and in one-third of cases, pulmonary lymphangiectasis. This diagnosis should be entertained in the term or near-term infant who presents with respiratory failure and persistent pulmonary hypertension of the newborn, who may occasionally have a family history of the same. Therapy in this instance is futile.
Hypoplastic lungs from deficient alveolarization are a final possibility for the newborn suspected to have ILD, particularly if antenatal conditions favoured abnormal intrauterine growth.
OUTSIDE OF NEWBORN
Outside of the newborn period, infants presenting with ILD are usually of two groups: those who were previously well, and those who were preterms with symptoms that then recur.
Some rarer processes to consider in the former group include infantile cellular interstitial pneumonitis, persistent tachypnea of infancy, chronic idiopathic bronchitis of infancy, follicular bronchitis and chronic interstitial pneumonitis of infancy (ICIP).
The latter is of interest because of recent research showing an association with surfactant protein C abnormalities, and because the course is often more severe than other forms of ILD. Both GERD and lysinuric protein intolerance have been linked to this entity. ICIP is also seen with BPD, but can occur on its own. If not associated with an underlying disease, these children do well. This diagnosis is not considered beyond the age of 6 months.
The second group of infants presenting outside the newborn period consist of former pre-term infants with postnatal growth failure. They can develop airspace enlargement, small airways and excessive airway smooth muscle as a result of repair of the processes initiated by RDS.
The above approach to an infant with ILD is by no means comprehensive, as this case demonstrates. This child's biopsy was most consistent with a diagnosis of desquamative interstitial pneumonitis, or DIP, one of the rare classic forms of ILD. DIP is so named because of an accumulation of cells in the alveolar space thought to be desquamated alveolar epithelium. The pathology is characterized by hyperplasia of type II pneumocytes, a large number of macrophages in the airspaces, a mononuclear infiltrate of histiocytes, lymphocytes, plasma cells and eosinophils, and by mild thickening of the alveolar septae by an increase in connective tissue. The lesions are described as monotonous and uniform throughout the affected lung. The prognosis for DIP is better in adults than in children, with some quotes for pediatric cases ranging as high as 39% mortality (Stillwell et al.). There is also a familial form of DIP which is almost uniformly fatal.