Abstract

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

Author and Article Information

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.

E-mail Muhammad.irfan@aku.edu

Introduction

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 [1]. Familial variant is clinically indistinguishable from sporadic cases. Its average survival is 2-3 years after diagnosis [2, 3].

Case presentation

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.

Investigations

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.

Discussion

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[4]; in an index case with at least two other relatives[5]; 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[1]. 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 [14]. 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 [7]. 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 [6]. 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 [15]. 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 [21].

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.

Author contributions

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

Acknowledgements

Dr Rasida Ahmed (Histopathologist).

References

1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK et al.(2011) An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med. 183; 788–824
2. Lee HL, Ryu JH, Wittmer MH, Hartman TE, Lymp JF, Tazelaar HD et al. (2005) Familial idiopathic pulmonary fibrosis: clinical features and outcome. Chest 127(6): 2034–41 doi:10.1378/chest.127.6.2034
3. Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR et al. (1998) Prognostic significance of histopathological subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 157:199–203 doi:10.1164/ajrccm.157.1.9704130
4. Marshall RP, Puddicombe A, Cookson WOC, Geoffrey J L. (2000) Adult familial cryptogenic fibrosing alveolitis in the United Kingdom. Thorax 55: 143–146 doi:10.1136/thorax.55.2.143
5. Bitterman PB, Rennard SI, Keogh BA, Wewers MD, Adelberg S, Crystal RG. (1986) Familial idiopathic pulmonary fibrosis: evidence of lung inflammation inunaffected family members. N Engl J Med 314:1343–1347 doi:10.1056/NEJM198605223142103
6. Marshall RP, McAnulty RJ, Laurent GJ. (1997) The pathogenesis of pulmonary fibrosis: is there a fibrosis gene? Int J BiochemCell Bio. 29: 107–120 doi:10.1016/S1357-2725(96)00141-0
7. Sandoz E ( 1907) Uber zwei falle von fotaler bronchektasie. BeitrPathol Anat 41: 496–517
8. Raghu G, Mageto YN Genetic predisposition of interstitial lung disease. Schwarz MI and King TE Jr, eds. interstitial lung disease. Hamilton, ON, Canada: B.C. Decker, 1998 119–132
9. Hodgson U, Laitinen T, Tukiainen P.(2002) Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax. 57(4):338–342. doi:10.1136/thorax.57.4.338
10. Loyd JE. (2003) Pulmonary fibrosis in families. Am J Respir Cell Mol Biol. 29 (3 Suppl):S47–50.
11. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ,et al. (2010) Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med. 182(11):1419–1425. doi:10.1164/rccm.200906-0953OC
12. Bridget A F,George F, Rick B, Eric S, Barbara N, Nash D,et al.(2012) A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features. Respir Res. 13:64 doi:10.1186/1465-9921-13-64
13. Lawson WE, Loyd JE.(2006) The genetic approach in pulmonary fibrosis. Proc Am Thorac Soc. 3: 345–9.
14. García-Sancho C, Buendía-Roldán I, Fernández-Plata MR, Navarro C, Pérez-Padilla R, Vargas MH, Vargas MH et al.(2011) Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis. Respir Med. 105 (12): 1902-7. 10.1016/j.rmed.2011.08.022
15. Lawson WE, Loyd JE, Degryse AL. (2011) Genetics in pulmonary fibrosis – Familial cases provide clues to the pathogenesis of Idiopathic Pulmonary Fibrosis. Am J Med Sci. 341 (6): 439–443 doi:10.1097/MAJ.0b013e31821a9d7a
16. Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA.. (2001) A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 344: 573–579 doi:10.1056/NEJM200102223440805
17. Calado, RT and Young, NS. ( 2009) Telomere diseases. N Engl J Med. 361: 2353–2365 doi:10.1056/NEJMra0903373
18. Seibold, MA, Wise, AL, Speer, MC ,Steele MP, Brown KK, Loyd JE et al. (2011) A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 364: 1503–1512 doi:10.1056/NEJMoa1013660
19. P Spagnolo ,Johan Grunewald, Roland M du Bois.(2014) Genetic determinants of pulmonary fibrosis: evolving concepts. Lancet resp med. 2: 416-428. doi:10.1016/S2213-2600(14)70047-5
20. Kropski JA, Lawson WE, Young LR, Blackwell TS.(2013) Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis Model Mech. 6(1):9-17 doi:10.1242/dmm.010736
21. Raghu G, Rochwerg B, Zhang Y, Garcia CAC, Azuma A, Behr J (2015) An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. AJRCCM 192:e3-e19 doi:10.1164/rccm.201506-1063ST