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(Chest. 2005;127:2034-2041.)
© 2005 American College of Chest Physicians

Familial Idiopathic Pulmonary Fibrosis*

Clinical Features and Outcome

Hong-Lyeol Lee, MD; Jay H. Ryu, MD, FCCP; Michael H. Wittmer, MD; Thomas E. Hartman, MD; James F. Lymp, PhD; Henry D. Tazelaar, MD, FCCP and Andrew H. Limper, MD

* From the Divisions of Pulmonary, Critical Care, and Internal Medicine (Drs. Lee, Ryu, and Limper) and Anatomic Pathology (Dr. Tazelaar), the Department of Diagnostic Radiology (Drs. Wittmer and Hartman), and the Section of Biostatistics (Dr. Lymp), Mayo Clinic College of Medicine, Rochester, MN.

Correspondence to: Andrew H. Limper, MD, 8–24 Stabile Building, Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905; e-mail: limper.andrew{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Familial idiopathic pulmonary fibrosis (FIPF) has been defined as idiopathic pulmonary fibrosis (IPF) occurring in two or more members of a family. The clinical course of FIPF has not been fully defined. Accordingly, the current study was undertaken to establish clinical, radiologic, and histologic features, and survival in a consecutive series of patients with FIPF.

Design: Retrospective analysis of clinical, radiologic, and pathologic data from a consecutive series of patients with FIPF who were seen at Mayo Medical Center. Survival in patients with FIPF was contrasted to that of previously characterized patients with nonfamilial IPF who were evaluated at our institution.

Setting: Tertiary referral medical center.

Patients: We screened 47 patients and family members with FIPF from 15 families who were identified between the years 1992 and 2002. We further analyzed the subgroup of FIPF patients that was composed of 27 patients from 15 families in whom the complete clinical course was monitored at our institution.

Measurements: All patients exhibited clinical features that were compatible with IPF and either compatible high-resolution CT (HRCT) scan findings or histologic evidence of usual interstitial pneumonia. Clinical data, including symptoms, physical findings, HRCT scan findings, lung function test results, biopsy results, and survival were abstracted from the clinical records.

Results: Compared to patients with nonfamilial IPF, patients with FIPF did not demonstrate any notable differences in clinical, radiologic, or pathologic features. We observed that the total number of affected members in a family with FIPF was a significant risk factor for earlier mortality (p = 0.0157; hazard ratio, 1.434). Overall, however, patients with FIPF had a statistically similar outcome to those patients with nonfamilial IPF.

Conclusions: Although uncommon, FIPF represents a distinct syndrome, which has clinical features and patient survival rates that are similar to those of nonfamilial IPF.

Key Words: familial • idiopathic pulmonary fibrosis • prognosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that is characterized by the deposition of extracellular matrix in the interstitium with variable parenchymal inflammation. Clinical features include marked dyspnea, bibasilar end-inspiratory crackles (termed velcro rales), diffuse interstitial lung infiltrates seen on radiologic examination, restrictive pulmonary physiology, and impaired gas exchange in the absence of any other specific underlying disorder. The pathologic correlate of IPF is usual interstitial pneumonia (UIP). Patients usually experience initial symptoms in their sixth or seventh decade. The disorder is ultimately fatal in most patients, and the treatment options remain unsatisfactory. The median survival time for patients with IPF is between 3 and 6 years.1

Although knowledge of the cellular and cytokine interactions associated with inflammation and fibrosis has increased over the last decade, the pathogenesis of IPF still remains incompletely understood. However, it is postulated that the initial event is likely repetitive and undefined injury to alveolar epithelial cells. The resulting inflammatory responses, coupled with repetitive attempts at tissue repair, result in the scarring and structural changes that are responsible for the symptoms and pathologic abnormalities of these disorders.2 There are several defined agents known to cause pulmonary fibrosis (eg, asbestos and bleomycin), which injure the pulmonary parenchyma with stereotypic tissue responses that are extremely similar to those observed in IPF. Interestingly, however, only a subset of individuals exposed to these fibrogenic agents actually develops clinical manifestations of lung fibrosis. Thus, host susceptibility and genetic factors have been implicated as important variables that determine the phenotypic expression of pulmonary scarring.34

Although usually a sporadic condition, IPF can also occasionally occur in familial form. First described in 1907 by Sandoz,5 approximately 61 families have been reported with familial IPF (FIPF), mostly in small series.456 FIPF has previously been defined in the literature with various criteria including the following: patients with clinical features compatible with IPF in combination with either compatible high-resolution CT (HRCT) scan findings or histologic evidence of UIP found on lung biopsy specimens in two or more family members6; in an index case with at least two other affected relatives7; or as IPF in at least two first-degree relatives.38 Although the mode of genetic transmission of FIPF is not entirely clear, it seems likely that it is an autosomal-dominant disorder with variable penetrance. The clinical features of FIPF have not been fully defined, although some studies34 have suggested an earlier age of onset in the familial group. This may represent a true younger onset of disease in FIPF patients, a more rapid progression to clinically overt illness in FIPF patients, or perhaps heightened awareness with earlier diagnosis of individuals from affected families.

The clinical features and outcome of FIPF are not well understood. The current study was undertaken to establish clinical, radiologic, and histologic parameters, and survival time in a consecutive series of patients with FIPF. Herein, we report our experience with all patients with documented FIPF who were seen at the Mayo Medical Center (Rochester, MN) over the 10-year period from 1992 to 2002. In particular, clinical, radiologic, and histologic features, and patient outcomes were analyzed in this consecutive series. Furthermore, we contrasted the survival of these patients with FIPF to a well-characterized cohort of patients with nonfamilial IPF from our institution, who were previously reported on.9


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection and Definitions
This study was reviewed and approved by the Mayo Institutional Review Board. Using the Mayo Medical Center medical record registry and the Interstitial Lung Disease Clinic registry, the records of all patients who had received a diagnosis of FIPF or were suspected of having FIPF were reviewed at Mayo Clinic Rochester for the 10-year period from 1992 to 2002. A diagnosis of IPF was accepted if compatible clinical features were present in combination with either HRCT scan findings or histologic evidence of UIP.679 Clinical criteria for a diagnosis of IPF included the presence of typical bibasilar end-inspiratory crackles, finding of a restrictive defect on pulmonary function tests (PFTs), and the absence of an obvious cause for pulmonary fibrosis, including environmental or occupational exposures, or collagen vascular diseases known to be associated with lung fibrosis. Radiologic HRCT scan findings consistent with IPF included the presence of diffuse bilateral interstitial lung infiltrates with predominant reticular and honeycomb patterns that were distributed preferentially to peripheral and subpleural lung regions and to the lung bases. Cultures for bacteria, mycobacteria, and fungi were negative.

For the purposes of the current study, FIPF was defined as the presence of the above findings of IPF in two or more members of a biological family.368 Family members in whom IPF was diagnosed outside of our center were only accepted if the same established diagnostic criteria that were detailed above could be independently verified by review of the medical records, radiographs, or tissue samples. Cases with insufficient information to verify a diagnosis of IPF were excluded. Using these criteria, 15 families consisting of a total of 47 individuals (27 patients evaluated at our institution and 20 additional family members evaluated outside of our institution) were initially identified for this study of FIPF. Further analysis then was performed specifically in the cohort of affected individuals who were directly evaluated and managed at Mayo Medical Center. This group of 27 patients from 15 families had complete detailed follow-up information over their clinical course available from clinical records of the Mayo Medical Center.

Collection of Clinical Data
All available baseline and follow-up data were recorded, including age, gender, symptoms, and smoking status. Care was taken to identify relevant occupational information, history of environmental exposures, associated connective tissue disorders, medication use, symptoms, and signs, as well as pulmonary function data, radiologic information, and biopsy materials. Pulmonary function variables were expressed as percent predicted, and included FVC, total lung capacity (TLC), and residual volume (RV) using plethysmographic methods, and diffusing capacity of the lung for carbon monoxide (DLCO) using the single-breath technique. The date of the initial diagnosis was defined as the date when IPF was first confirmed according to the above criteria, irrespective of whether that occurred before or after the initial evaluation at our center. The date of symptom onset was defined by month and year, as recorded in the medical records.

Statistical Analysis
Clinical and physiologic data from the group of 27 patients with longitudinal follow-up information were analyzed. Initial descriptive statistical analyses were performed on this group of patients with FIPF. Unless indicated otherwise, the data are reported as the mean ± SD for continuous variables and as percentages for discrete variables. Survivors and nonsurvivors were compared for the presence or absence of clinical parameters and the degree of physiologic impairment using Fisher exact tests and rank sum tests, respectively. The survival period was defined as the time interval from date of the first diagnosis to the date of death, or until the date of the last follow-up. The date of death was obtained from death certificates or next of kin. Cumulative survival probabilities were estimated using the Kaplan-Meier method.10 Potential factors associated with survival were evaluated including the following: age of symptom onset and diagnosis; smoking history (pack-years); baseline PFT function (eg, FVC, TLC, RV, DLCO, and arterial oxygen saturation [SaO2] at rest and with exercise); the total number of patients in a family with FIPF; gender; smoking status; and treatment vs no treatment. Cox proportional hazards regression modeling was used to identify variables that were significantly associated with survival.11 In addition, patients with FIPF were contrasted to patients with nonfamilial IPF using a well-described database of individuals with IPF, who had been confirmed to have UIP by open-lung biopsy findings, who had been previously reported on by our institution.9 The log-rank test was used to compare the survival time between the FIPF patients and patients with nonfamilial IPF from that earlier series.12 A p value of < 0.05 was defined to represent a statistically significant difference.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Demographic Features and Symptoms
The mean age at onset of symptoms and at first diagnosis of these 27 patients with FIPF were 58.3 years (median age, 58.0 years) and 59.4 years (median age, 61.0 years), respectively (Table 1 ). Six patients received diagnoses before the age of 50 years, and seven patients received diagnoses between the ages of 50 and 59 years. The ratio of men to women in this series was 2:1. More than half of these patients were current or former smokers, with a mean exposure of 26.0 pack-years. Affected siblings were the most common familial relationship identified in this cohort (Table 2 ). In 71% of the families studied, either two or three patients with FIPF were detected. Furthermore, 87% of cases were limited to families exhibiting either one or two generations of affected individuals. Two families consisting of three generations were observed. In one family with a total seven affected individuals, FIPF occurred in four brothers, one sister, and one nephew of the male patient in the index case. Figure 1 describes the pedigree of this multiply affected family. One family included two patients who were identical twins. The diagnosis of IPF was established using clinical and radiologic criteria in 53% of patients, by clinical and pathologic criteria in 34% of patients, and by using clinical, radiologic, and pathologic criteria in 13% of patients.


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  		Table 1. Demographic and Clinical Findings (n = 27)*

 

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  		Table 2. Relationship of Index Patients Within Family (n = 15)*

 


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  		Figure 1. Pedigree of three generations from a family evaluated for FIPF with seven affected members. The arrow indicates the index case. Dark shading reflects the affected family members.

 
The most common initial symptom in these 27 patients with FIPF was dyspnea on exertion (85%) [Table 1]. Four patients complained of sputum production in the morning, which was usually scant and white. One patient who was asymptomatic with no abnormal finding noted on physical examination, had IPF diagnosed at the time of undergoing a pneumonectomy for lung cancer resection and eventually also at autopsy. The most common physical finding was bibasilar end-inspiratory crackles on auscultation in 93% of patients. Digital clubbing was observed in 30% of patients (Table 1).

Physiologic and Radiographic Features
Most patients had mild-to-moderate airway restriction. At the time of diagnosis, DLCO was reduced in 96% of patients and lung volumes (both TLC and RV) were reduced in 83% of patients. The SaO2 with exercise was decreased in 71% of patients (Table 3 ). An isolated reduction in DLCO with normal lung volumes was observed in a pair of identical twins who presented with exertional breathlessness. Ten patients exhibited normal resting SaO2, but 60% of these patients demonstrated exercise-induced oxygen desaturation.


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  		Table 3. PFTs at Diagnosis (n = 27)*

 
HRCT scanning was performed in 66% of patients. In all cases, the reported findings were consistent with IPF, and included predominantly reticular and honeycomb patterns that were distributed preferentially in the peripheral and basilar regions of the lung. Of the 27 patients whose conditions had been managed longitudinally at our institution, 17 had HRCT scans performed at Mayo Medical Center that were available for repeat blinded review by an experienced pulmonary radiologist (T.E.H.). Bilateral irregular linear opacities were seen in all cases. A subpleural predominance of linear opacities was observed in 94% of patients, and subpleural traction bronchiectasis was observed in 82%. Honeycombing (29% of patients) and adenopathy (29% of patients) also were observed. Two family members (12% were) demonstrated ground-glass densities involving < 10% of the total lung volume. Emphysematous changes (18%) and bronchial wall thickening with irregularities (6%) were occasionally observed, possibly representing smoking-induced changes. In the four cases in which patients had undergone follow-up HRCT scans, three patients showed progression of honeycombing and traction bronchiectasis. The condition of the other patient remained unchanged at the time of data analysis. Interestingly, the patient mentioned previously, who had UIP diagnosed at the time of resection for lung carcinoma, underwent chest radiography and standard CT scanning prior to surgery, with the findings of neither study indicating the presence of pulmonary fibrosis.

Additional Laboratory Features
In this series, 7 of 16 patients (44%) tested had antinuclear antibodies (ANAs) in their serum, and 5 of 15 patients (33%) had detectable levels of rheumatoid factor (RF), although their titers were not high. The ANA patterns observed were either homogenous or speckled. BAL was performed in six patients. All patients exhibited abnormal findings for BAL fluid testing, with one patient showing increased levels of neutrophils alone (40% of the nucleated cells in BAL fluid). The BAL fluid from one patient had increased numbers of eosinophils (7% of the nucleated cells in BAL fluid). The remaining four patients had elevations of both neutrophils and eosinophils in the BAL fluid. The mean values of the BAL fluid differential cell counts in these six patients were 22% neutrophils and 10% eosinophils.

Histology Review
Eight patients had histologic materials available at our medical center for review by a senior lung pathologist (H.D.T.). The materials included five surgical lung biopsy samples and five autopsy specimens. Two patients had both lung biopsy material as well as autopsy material. Seven of these specimens showed UIP, and one specimen was thought to have probable UIP. That biopsy sample consisted almost solely of honeycombing in the lung. Interestingly, three of these patients exhibited features of diffuse alveolar damage superimposed on a background pattern of UIP. One notable patient had undergone a pneumonectomy for lung cancer treatment and was found to have previously unrecognized UIP with minimal symptoms prior to surgery. He died 31 months later with an autopsy demonstrating UIP and superimposed diffuse alveolar damage without any evidence of residual or recurrent lung cancer.

Clinical Outcome
Among the 27 patients who were managed longitudinally at Mayo Clinic Rochester, the mean follow-up period was 28.5 months. Over this period, 21 patients died and 6 patients survived. Of those patients surviving at the time of analysis, two patients showed progressive deterioration and four were relatively stable. Although we currently believe that effective pharmacologic therapy does not yet exist for IPF, during the period of the study (from 1992 to 2002) many patients were offered treatment in an attempt to slow disease progression. In light of this, 15 patients (56%) had received systemic corticosteroid therapy, and 14 patients (52%) had received colchicine therapy at some point during their course of treatment. In five patients (19%), no pharmacologic therapy was prescribed. No sustained benefit was reported in any of the treated patients.

Initial analyses failed to identify any factor that was significantly associated with survival. The mean age at the onset of symptoms and at diagnosis in the survivors was not significantly different compared to the nonsurvivors (rank sum test). The extent of tobacco smoking and the degree of impairment shown at the time of initial diagnosis by PFT findings also showed no significant differences between the survivors and nonsurvivors (rank sum tests). Other clinical parameters, including gender, smoking status (current or former smoker vs never-smoker), and the presence of positive ANA and RF test results, also showed no significant differences with survival outcome using the Fisher exact test. Analyses comparing PFT parameters and others factors, such as age, smoking history, laboratory features, and treatment, also did not reveal significant associations. Only the SaO2 following exercise was observed to exhibit significant correlation with smoking, and the RV correlated with age. Both correlations met the significance criteria of p < 0.05, but neither of these associations demonstrated high correlation coefficients (r < 0.5 for each comparison).

In an attempt to further identify the variables associated with survival, clinical parameters were analyzed using Cox proportional hazards regression. Modeling each variable separately, only the total number of affected patients in a family proved to be associated with worse prognosis (p = 0.0157), with a hazard ratio of 1.434 for every increase of one affected family member (95% confidence interval, 1.070 to 1.921) [Fig 2 ]. Since the number of affected members in a given family with FIPF correlated with earlier mortality, one might postulate that lung function might also vary in relation to the number of affected individuals within a family (Table 2). However, analysis of FVC and DLCO did not reveal any significant differences that were related to the number of affected persons in these families (FVC, p = 0.5591 [analysis of variance]; DLCO, p = 0.4672 [analysis of variance]).



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  		Figure 2. Cox proportional hazard ratios and 95% confidence intervals for parameters tested against survival time. Clinical parameters were analyzed to identify the potential association with survival time using the Cox proportional hazards regression model. Only the total number of patients in a family was a significant prognostic factor (p = 0.0157). Dots represent the value of the hazard ratios, and the lines represent the range of the 95% confidence interval for each parameter.

 
Comparison of FIPF Survival With IPF
To further contrast the outcome of patients with FIPF with patients with nonfamilial IPF, we compared the survival outcomes of patients in this series with a well-characterized database of patients with IPF from our institution who had previously been reported on.9 Kaplan-Meier survival curves were generated and contrasted (Fig 3 ). The median survival time of nonfamilial IPF patients with biopsy confirmation of UIP was 2.78 years from the time of diagnosis. In contrast, in this current study, the median survival time of these patients with FIPF was 2.41 years. Although the survival of the FIPF patients was very slightly shorter than those patients with biopsy-proven idiopathic UIP, this was not statistically significant. Thus, the overall the clinical features and outcomes of FIPF patients are quite similar to those of patients with nonfamilial UIP.



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  		Figure 3. Comparison of the survival curves between patients with FIPF and UIP, which were diagnosed by open-lung biopsy at the Mayo Medical Center. There was no significant difference between FIPF patients and those patients with IPF confirmed by biopsy to have the pattern of UIP. The median survival time for FIPF patients was 2.41 years, while that for UIP patients was 2.78 years.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The current study establishes that the clinical presentation, radiologic and pathologic features, and survival of FIPF patients are essentially similar to those of nonfamilial IPF patients. In the series, there were no particular clinical features that distinguished FIPF patients from nonfamilial IPF patients. We did observe a slightly reduced incidence of digital clubbing in our patients with FIPF (30%) compared to that previously reported1 in patients with nonfamilial forms of IPF, which ranged from 50 to 65%. However, based on the limited data available from this series, it is difficult to determine whether this is a clinically significant difference. We do not believe that the mechanisms responsible for digital clubbing are any different in patients with FIPF compared to patients with nonfamilial IPF. The radiologic findings in our patients with FIPF were also similar to those of patients with nonfamilial IPF, although there appeared to be a somewhat lower incidence of honeycombing and adenopathy than previously described for IPF.131415 Honeycombing (29%) and adenopathy (29%) were also observed. This occurred in a lower frequency than that previously reported for patients with nonfamilial IPF or UIP.131415 Physiologic and pathologic findings were also strikingly similar to those for nonfamilial IPF or UIP patients reported by our group and others.

Furthermore, the outcomes for FIPF patients were also equivalent to the survival of nonfamilial UIP cases. To assess this, we compared data from patients in the current FIPF series to data from a well-characterized database of patients with IPF, which we had previously reported.9 This IPF database contained a large cohort of patients with biopsy-proven UIP (63 patients) for comparison to the current cohort of patients with FIPF. Notably, there was no significant difference in survival time between our patients with FIPF and those IPF patients with biopsy-proven UIP. Thus, FIPF patients exhibit similar outcomes to patients with UIP. The sole finding associated with worse prognosis in FIPF patients was the total number of affected patients within a given family. Such findings support the variable penetrance of the FIPF in families and further suggest that multiple patterns of inheritance may be active in the phenotypic expression of FIPF.

FIPF has also been suggested to occur at a younger age than IPF in nonfamilial cases.346 In the current study, the mean age of diagnosis was 59.4 years, which was only slightly and not significantly different from that reported for nonfamilial IPF patients from our institution (63 years).9 All of our patients were symptomatic at the time of diagnosis. A previous study7 reported evidence of lower respiratory tract inflammation in BAL fluid from half of clinically unaffected family members in three cohorts of familial lung fibrosis. However, it remains unclear whether this represents a universal finding among FIPF families, or whether asymptomatic lung inflammation predicts future lung fibrosis.7 Another study demonstrated mutations in the surfactant protein C gene in one large kindred study of patients with UIP and cellular nonspecific pneumonia.16 The extent to which this abnormality is present in other families with FIPF has not yet been fully established.

A review of the available lung tissue samples from these patients with FIPF has consistently demonstrated the presence of UIP. Interestingly, three of the patients also exhibited superimposed features of diffuse alveolar damage and accelerated lung fibrosis. This likely reflects the timing of those biopsies, as these three patients had more rapid clinical deterioration just prior to undergoing surgical sampling. Although some studies1718 have revealed that the number of fibroblastic foci correlates with outcome in UIP patients, the limited amounts of remaining biopsy material precluded us from undertaking such an analysis. Additional investigations19202122 have further implicated transforming growth factor-ß1 as a cytokine that is central to mediation of the pathogenesis of nonfamilial IPF. However, immunochemical analysis of transforming growth factor-ß1 expression and distribution in these biopsy materials also revealed no significant differences when contrasted to nonfamilial lung biopsy materials (data not shown). Thus, the overall histologic features of FIPF were again highly equivalent to nonfamilial manifestations of this disorder.

The true incidence of FIPF remains uncertain. Prior estimates have suggested that patients with FIPF represent 0.5 to 2.2% of all patients with IPF.6 The genetic inheritance pattern of FIPF has been proposed to be autosomal-dominant with variable penetrance, and at least some of our data strongly support that contention (Fig 1). Even though FIPF is relatively uncommon, such cases indicate that genetic factors can regulate the responses to lung injury and repair leading to the development of fibrosis. In addition, a number of classic genetic syndromes, including neurofibromatosis and Hermanksy-Pudlak syndrome, demonstrate interstitial lung disease with deposition of extracellular matrix as part of their clinical spectrums, although the patterns of lung fibrosis in those disorders are clinically distinct from those in IPF.

It also remains unclear to what extent genetic factors play a role in nonfamilial forms of IPF. Previous studies evaluating histocompatibility loci, {alpha}1-antitrypsin phenotypes, and Ig allotypes in patients with IPF have yielded inconclusive or conflicting findings.23242526 If the spectrum of nonfamilial IPF includes currently undefined genetic factors, it is highly likely that these are multigenic in nature, rendering them extremely difficult to define using currently available methods.

Genetic testing for FIPF has not yet been established. Nonetheless, the prudent clinical screening of unaffected family members, the avoidance of injurious inhalational agents (eg, tobacco smoke), and periodic monitoring would appear to be justified, and will further define the incidence of FIPF. At present, IPF is generally fatal, and treatments are not yet effective, although a number of novel therapeutic agents are currently under investigation.92728 If such agents ultimately prove to be effective, screening and early diagnosis may conceivably permit earlier intervention at a more amenable phase of the disease.

In summary, this study has characterized the clinical features of a series of patients with FIPF. FIPF was indistinguishable from nonfamilial IPF with respect to most clinical, physiologic, radiologic, and pathologic findings. Our study suggests that the total number of affected patients in a family may portend a worse prognosis for the individuals in these families. Patients with FIPF exhibited similar survival times when specifically compared to patients with nonfamilial IPF patients who had biopsy confirmation of the presence of UIP. The careful screening and monitoring of family members of individuals with IPF will be necessary to determine the overall incidence and outcome of FIPF. Furthermore, genetic analysis of large pedigrees of autosomal transmitted FIPF may provide important new insights into the molecular pathogenesis of pulmonary fibrosis.


   Acknowledgements
 
The authors thank Drs. David. E. Midthun and Daren G. Tobert for providing additional case materials of patients with FIPF. We also appreciate the efforts of Megan Maurer for her assistance with the statistical analysis of the data. Finally, the authors acknowledge the continuing academic support of the Interstitial Lung Disease Workgroup of the Mayo Clinic (Rochester, MN).


   Footnotes
 
Abbreviations: ANA = antinuclear antibody; DLCO = diffusing capacity of the lung for carbon monoxide; FIPF = familial idiopathic pulmonary fibrosis; HRCT = high-resolution CT; IPF = idiopathic pulmonary fibrosis; PFT = pulmonary function test; RF = rheumatoid factor; RV = residual volume; SaO2 = arterial oxygen saturation; TLC = total lung capacity; UIP = usual interstitial pneumonia

This work was supported by the Robert N. Brewer Family Foundation.

Received for publication July 26, 2004. Accepted for publication December 7, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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