Familial Interstitial Pneumonia (FIP).

Pulmonary fibrosis describes the process of progressive scarring and ultimately structural changes to the basement membranes of the alveolar interstitium, leading to impaired gas exchange and respiratory insufficiency. This process occurs in the interstitial lung diseases (ILDs), of which there are greater than 150 disease types. ILDs are also known as diffuse parenchymal lung diseases (DPLDs) which include not only the alveolar interstitium, but adjacent structures such as capillaries, terminal and respiratory bronchioles, and lymphatics of the bronchovascular bundle and interlobular septae [1] The ILDs are a clinically heterogeneous group with both known and unknown causes of fibrosis. The known causes of pulmonary fibrosis include occupational and environmental exposures (both inorganic and organic), drug toxicities, and collagen vascular diseases [2]. Pulmonary fibrosis can also occur in the absence of these causes as an isolated finding limited to the lungs. This latter category is known as the idiopathic interstitial pneumonias (IIPs) which were defined by the American Thoracic Society in 2002 into distinct classifications [3]. The IIPs are composed of several subtypes, identified by their clinico-radiological- pathological classification. The IIPs consist of idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), and lymphoid interstitial pneumonia (LIP). Of these, IPF is the most common and the most severe [4]. IPF is associated with fibrosing interstitial pneumonia of unknown cause, a usual interstitial pneumonia pattern (UIP) on surgical lung biopsy and/or high-resolution CT scan (HRCT), an older age of onset, (usually >50 years), and exclusion of other known causes of ILD. IPF affects men greater than women and has been associated with cigarette smoking. IPF has a median survival of 3–5 years [2] and currently there is no approved treatment other than lung transplantation [4]. While IPF is thought to be a disease of unknown origin, risk factors such as cigarette smoking, certain environmental exposures (e.g. metal dusts, wood dusts, farming, bird-raising, hair-dressing), microbial agents (viruses-EBV, CMV, HHV-7,8), gastroesophageal reflux and genetic factors are risk factors for this disease [4]. Several lines of evidence exist that pulmonary fibrosis has a genetic basis. First, it is known that pulmonary fibrosis is a consistent finding in other rare pleiotropic hereditary conditions. Pulmonary fibrosis is a reported finding in such heritable disorders such as Hermansky-Pudlak syndrome (HPS) [5], neurofibromatosis (NF) [6], Gaucher’s disease [7], familial hypocalciuric hypercalcemia [8], tuberous sclerosis (TS) [9] and dyskeratosis congenita (DC) [10]. Second, it has been shown that there is variability in the developmental outcome of pulmonary fibrosis amongst workers exposed to similar exposures, whether it was fibrogenic dusts or organic antigens [11, 12]. Third, mouse models have shown a difference in the development of pulmonary fibrosis when exposed to bleomycin or asbestos depending upon whether they were wild-type mice or inbred strains [13, 14]. The most compelling epidemiological evidence for a genetic basis is the observation of familial clustering of pulmonary fibrosis. This clustering has been reported in monozygotic twins raised apart [15–17], in consecutive generations of families [18], and in family members separated at an early age [19]. The majority of pedigrees exhibit an autosomal dominant with reduced penetrance transmission pattern [18, 20] although one report proposed an autosomal recessive pattern [20]. The recognition of familial clustering has since led to a designation of a familial form of pulmonary fibrosis, familial interstitial pneumonia (FIP).