We identified 111 families who met our case definition of FIP; within these families, 417 self-reported as unaffected and 291 self-reported as affected (). For the familial cases, we used a sequential sampling strategy in which all first-degree relatives (adults) of cases are asked to participate in the study. Of potential family members who were approached, 237 (25%) declined to participate. Because of institutional review board restrictions, we have neither clinical nor questionnaire data concerning these nonparticipants. The types of data collected with self-report status are shown in . Either a questionnaire, DlCO, or radiographic study (chest X-ray or HRCT scan) was obtained in 97.4% of the subjects, and 92.5% of the subjects had at least two of these three evaluations (questionnaire, DlCO, or radiographic study).
Clinical data collected according to self-report categories
After extensive clinical evaluation, we determined that 360 were unaffected, 309 were found to have definite or probable FIP, and 44 were found to have possible FIP (). Nine individuals had an indeterminate diagnosis. Fifty-two of the 111 families had at least one case of surgical lung biopsy-proven, definite interstitial pneumonia. In aggregate, the diagnosis of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, DlCO, and chest X-ray in 16 cases (5.2%); clinical history, DlCO, and HRCT scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy 18 cases (5.8%; ). Of those classified as probable or definite FIP, the diagnosis based on HRCT scan or histopathologic pattern was most consistent with IPF/UIP in 248 cases (80.2%), NSIP in 20 cases (6.4%), COP in 2 cases (0.6%), and centrilobular nodules in 1 case (0.3%), and 38 cases (12.3%) had an unclassifiable form of interstitial pneumonia (). Of those classified as definite FIP based on histopathologic pattern (n = 78), the diagnosis was IPF/UIP in 67 cases (85.6%), NSIP in 8 cases (10.25%), COP in 2 cases (2.5%), and unclassified in 1 case (1.3%), which is a similar distribution compared with probable FIP assessed by clinical history, DlCO, and HRCT scan.
Clinical evaluation used to identify affection status
Idiopathic interstitial pneumonia subtypes among probable and definite cases of familial interstitial pneumonia
Of 417 subjects initially self-reported as unaffected, 1.4% (n = 6) met the consensus diagnosis of indeterminate, 6.7% (n = 28) met the consensus definition of possible FIP, and 7.9% (n = 33) met the consensus definition of probable or definite FIP. Of the 291 subjects who initially self-reported as affected, 0.7% (n = 2) met the consensus diagnosis of indeterminate, 1% (n = 3) met the consensus definition of unaffected, and 4.8% (n = 14) met the consensus definition of possible FIP. For probable or definite FIP, the sensitivity, specificity, and accuracy of self-reported affected status were 89.2, 95.7, and 92.8%, respectively. The positive predictive value and negative predictive value of self-reported affected status were 94.1 and 92%, respectively. For individuals self-reported as unaffected with a consensus diagnosis of probable or definite FIP (n = 33), there were 20 patients with features of probable IPF/UIP, 2 with features of probable NSIP, 4 with definite IPF/UIP, and 7 with unclassifiable FIP.
Within the 111 families, we found that older age (68.3 vs. 53.1 yr; p < 0.0001) and male sex (55.7 vs. 37.2%; p < 0.0001) were associated with the presence of FIP (). Whereas older age may simply reflect the demographics of IIP, the age range of disease onset is quite broad (30.3–95.4 yr) and the frequency distribution of age at diagnosis demonstrates a group of younger affected subjects (), although the evidence of bimodality in age at diagnosis is nonsignificant. Moreover, age at diagnosis was highly correlated (intraclass correlation, 0.78; p < 0.01) among affected siblings, suggesting a genetic basis for the age of onset of this disease. Male sex was associated with the presence of FIP (55.7 vs. 37.2%; p < 0.0001), although age at diagnosis did not differ significantly between males and females (p > 0.20).
Demographic and clinical characteristics by affection status in familial interstitial pneumonia
Figure 1. Age of affected subjects at diagnosis. Age at diagnosis is defined as a subject's age at which the first abnormal diagnostic test is reported, prioritized in the following order: (1) CXR, (2) HRCT, and (3) lung biopsy, reported for those with either probable (more ...)
Within the 111 families, we found that a history of ever cigarette smoking (67.3 vs. 34.1%; p < 0.0001) was associated with the presence of FIP (). The association was similar for either probable (odds ratio, 4.0; p < 0.00001) or definite (odds ratio, 3.7; p < 0.00001) FIP (). After controlling for age and sex, ever cigarette smoking remained strongly associated with the presence of FIP (odds ratioadj, 3.6; 95% confidence interval, 1.3–9.8; ). When the analysis was limited to include unaffected siblings only when they were older than the youngest age at diagnosis of an affected sibling, the results were nonsignificant; however, the small sample size (n = 39) indicates that power to detect a significant difference is small. Furthermore, the correlation of smoking in affected siblings was not significant (intraclass correlation, 0.25; p = 0.10), indicating that smoking status is not correlated among affected siblings, and that even among cigarette smokers, genetic susceptibility plays an important etiologic role in the development of this disease. We did not identify a relationship between the number of pack-years of cigarette smoking and the age at diagnosis.
Relationship between cigarette smoking and familial interstitial pneumonia
Among patients with either probable (n = 231) or definite (n = 78) FIP, subjects with definite FIP were significantly (p = 0.006) younger at diagnosis than subjects with probable FIP (). In addition, subjects with definite FIP died at a younger age (p = 0.02), had higher mortality (p < 0.0001), and had a shorter time to death from age at diagnosis (p = 0.02) when compared with subjects with probable FIP (). Interestingly, 21.9% of patients with probable FIP and 28.2% of patients with definite FIP reported no dyspnea, further suggesting that screening pulmonary function measurements and radiographic studies are important in determining affected status within these families.
Comparison of probable and definite familial interstitial pneumonia
Although 61 families (54.9%) had uniform radiographic and/or histopathologic features of IPF/UIP among the affected individuals, 50 families (45.1%) demonstrated radiographic and/or histopathologic features consistent with more than one type of IIP among affected individuals (see Figure E1 in the online supplement). Of the heterogeneous families with only two types of disease, 58.3% included both unclassified ILD and IPF/UIP and 35.4% included both NSIP and IPF/UIP. Other combinations of disease found in single pedigrees included surgical lung biopsy-proven UIP and COP (pedigrees VAF44 and DUK196) and UIP with an RB-ILD–like pattern on HRCT scan, having centrilobular nodules and ground glass highly atypical of UIP/IPF (VAF47). Although most families demonstrated only two forms of the disease, two families had more complex mixtures. DUK164 included one affected individual with an HRCT scan consistent with IPF, another with probable NSIP on HRCT scan characterized by ground glass and reticulation without honeycombing, and a third with an HRCT scan having RB-ILD–like features characterized by centrilobular nodules and ground glass. None of the family members in DUK164 had a history of tobacco smoking or reported environment exposures. The effect of smoking was similar in both the clinically uniform families and the families with clinical heterogeneity (p > 0.50).
The 111 pedigrees have an average size of 10.8 ± 6.9 individuals. The pedigrees include 1,574 parent–offspring pairs, 1,047 sibling pairs, and 785 cousin pairs (Figure E1). As a measure of familial aggregation, we investigated independence in disease status among all sibling pairs in the 111 families (n = 1047) and observed a statistically significant association for risk of disease among siblings (χ2, 1 df = 75.6; p < 0.0001). However, 340 sibling pairs had one or both members with incomplete phenotype data. Even when these were added to the calculations (assuming all were discordant pairs), the results remained highly significant (χ2, 1 df = 11.8; p < 0.001).
Visual inspection of the pedigrees (Figure E1) revealed 20 pedigrees with confirmed vertical transmission involving probable and/or definite cases, including three families with male-to-male transmission, consistent with autosomal dominant inheritance. These pedigrees are consistent with autosomal dominant inheritance; however, autosomal recessive inheritance, more complex modes of inheritance, or heterogeneity in underlying genetic basis between families cannot be fully excluded.