Idiopathic pulmonary fibrosis (IPF) is fatal interstitial lung disease. It has a rare familial subset, which share similar characteristics as sporadic cases. At present, lung transplantation is the only hope for improved survival.
We report a case of familial IPF in two siblings who had rapidly progressive respiratory failure proved fatal in one brother and making other a pulmonary cripple.
Keywords:Idiopathic pulmonary fibrosis, usual interstitial pneumonitis, familial
1） Aga Khan university hospital, Aga khan university hospital stadium road Karachi, Pakistan
RecievedOct 13 2015 AcceptedJan 14 2016 PublishedJan 27 2016
CitationSharif N, Irfan M (2015) Familial idiopathic pulmonary fibrosis in two Pakistani siblings-case report and topic review. Science Postprint 1(2): e00054. doi:10.14340/spp.2016.01C0001.
Copyright©2016 The Authors. Science Postprint published by GH Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 2.1 Japan (CC BY-NC-ND 2.1 JP) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
FundingNo significant financial support.
Competing interestNo competing interest.
Corresponding authorMuhammad Irfan
AddressAga khan university hospital stadium road Karachi, Pakistan.
Familial idiopathic pulmonary fibrosis is an interstitial lung disease of unknown cause with pathological findings of usual interstitial pneumonia (UIP) in two or more family members of same biological family . Familial variant is clinically indistinguishable from sporadic cases. Its average survival is 2-3 years after diagnosis [2, 3].
A 30 years old gentleman referred to us for evaluation of progressive shortness of breath associated with dry cough for 1 year. There was no associated chestpain, hemoptysis, weight loss, arthralgias, myalgias or body rash.
He had been working since 2 years in a biscuit factory until 8 months before presentation. He is in the packaging department of factory with no exposure to fumes or chemicals He had no addictions, no exposure to pets and no history of travel abroad. There was nothing remarkable regarding drug history. He lives in an urban city of Pakistan with nothing remarkable about surroundings except of traffic pollution. His family history was significant as his only brother died of similar illness about 1 year back (figure1).
At presentation his vitals were Pulse :86 beats/min, blood pressure :130/75 mmHg respiratory rate :18/min and oxygen saturations :93% at room air. There were no palpable lymph nodes, jaundice, edema, JVP,body rash, hypo or hyper pigmentation of skin. The chest examination revealed bilateral end inspiratory Velcro like crackles in middle and lower part of chest. On abdominal examination there was no organomegaly. Neurological exam revealed intact sensory, motor and cerebellar functions. Cardiovascular and musculoskeletal exam was unremarkable.
The laboratory workup at admission showed: hemoglobin:16.9g/dl, leukocyte count :12.3 x10 9/L [4.0-10], platelets:258 x10 9/L(150-400). His renal functions, urine D/R ,liver function tests were within normal limits. Chest-X-ray showed reduced lung volumes with interstitial shadowing and shaggy diaphragm and heart borders. HRCT chest showed septal thickening, traction bronchiectasis and evidence of honey combing in lower lobes bilaterally (figure 3). When compared with CT scan chest 4 months back (done in home town), there was rapid progression of the process (figure 2). He walked a distance of 250m in 3minutes and desaturated upto 75% . 6MWT was held because of significant desaturation and breathlessness.
Patient underwent lung biopsy through VATS, which showed findings consistent with UIP :distorted lung architecture with areas of honey combing. Few air spaces, showed polypoid projection of fibrous tissues into the lumina along with collection of foamy histocytes. Interstitium showed fibrosis and chronic inflammation. (Figure 4)
Rheumatoid factor and ANA was homogenously positive. However anti CCP antibody, AMA,ASMA,dsDNA,Scl-70 antibody, anti Ro, anti La,Jo-1 antibodies were absent.
Management and outcome:
Patient was started on pirfenidone. He has been referred for lung transplantation. Although in our case the only other sibling of the patient died but otherwise would like to screen the family members of the patient.
Worldwide an extensive work has been done to understand the pathophysiology, genetic basis of the disease, mode of inheritance, clinical features and outcome of Idiopathic pulmonary fibrosis (IPF) and its familial variant. Unfortunately no such data is available in Pakistan. To our knowledge this is the first ever case report of familial idiopathic pulmonary fibrosis (FIPF) from Pakistan.
IPF is an interstitial lung disorder of unknown etiology. It is usually a sporadic condition but rarely reported to run in families (FIPF). In literature a number of definitions have been used for FIPF including :patients having clinical features of IPF in combination with either compatible high-resolution CT (HRCT) scan or histological evidence of usual interstitial pneumonia (UIP) on lung biopsy specimens in two or more family members; in an index case with at least two other relatives; or as IPF in at least two first-degree relatives.[4,6-8].ATS/ERS guidelines for diagnosis and management of IPF define FIPF as those affecting two or more members of the same primary biological family. It was first described by Sandoz in 1907 and since then about 76 families have been reported with familial IPF [1, 5, 9]. The true incidence of FIPF remains uncertain. In various studies it is estimated to represent 0.5 % to 36% of all patients with IPF [4, 9-12]. The mode of inheritance in majority of studies is suggested to be autosomal dominant with variable penetrance however possibility of autosomal recessive inheritance cannot be excluded [2,4, 13]. In one of the recent studies FIPF is reported to be the strongest risk factor for IPF followed by gastro esophageal reflux disease (GERD), smoking and occupational exposures . Apparently our patient does not have any of these risk factors.
Several studies have compared the clinical, radiological and histological features of sporadic and familial IPF [2, 4, 9].Both of them share similar characteristics with slightly younger age of onset in familial cases.
In our patient, the radiological and histological findings were indistinguishable from a typical sporadic case.The mean age for FIPF in various studies is 40-55 years versus 60-70 years in sporadic cases[2, 4, 9]. In this case both brothers were even younger than most reported series i.e. below the age of 30 years. The average survival of FIPF is similar to sporadic cases i.e. 2-3 years after diagnosis[2, 3]. However our patient had rapid clinical and radiological deterioration in a year. Even his brother died within one year of diagnosis.
It has been proposed that worse prognosis in FIPF is associated with total number of family members affected . In this case, to our knowledge only 2 brothers were affected with rest of the family members are at leastasymptomatic to the date,although no screening has been done.
The identified genes for FIPF accounts for only 15-20% of cases [14, 15]. This suggests that there may be unidentified genes as well. So currently there is no recommendation for genetic testing as evaluation of IPF . So far several genes have been identified to be associated with FIPF: mutations in SFTPC surfactant protein C, mutations in TERT encoding telomerase reverse transcriptase, promoter polymorphism of gene encoding a mucin (MUC5B) though the later associated with both sporadic IPF and its familial variant [16-18]. These genetic tests are currently not available in our country. However it is interesting that patients may exhibit reduce penetrance i.e. not all patients with these genes develop IPF . It is proposed that genetically susceptible patients when exposed to irritant stimulus like aspiration, inhaled particulates, tobacco smoke and respiratory viruses would develop lung fibrosis, but this concept requires further studies and clarification [19, 20].
At present, except for lung transplantation there are no effective treatment options available to improve the survival. Although Pirfenidone and Nintedanib are among the promising agents as they slow the progression of disease yet they are not curative .
So in conclusion, FIPF is a rare subset of IPF with almost similar clinical, radiological, histopathological features and outcome. Once the knowledge about all culprit genes responsible for FIPF become available, the screening of susceptible family members, prenatal genetic testing, genetic counseling and avoidance of other known risk factors like smoking and GERD may help us to intervene earlier at amenable phase of disease. Currently lung transplantation is the only hope for survival.
Conceived and designed the work: Sharif N, Irfan M
Acquired the data: Sharif N
Analyzed and/or interpreted the data: Sharif N, Irfan M
Drafted the work: Sharif N
Revised and approved the work: Sharif N, Irfan M
Dr Rasida Ahmed (Histopathologist).