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Fibrotic Idiopathic Interstitial Pneumonia

The Prognostic Value of Longitudinal Functional Trends

Interstitial Lung Disease Unit, Department of Radiology and Department of Pathology, Royal Brompton Hospital, London, United Kingdom; and Department of Pathology, Mayo Clinic, Scottsdale, Arizona

Correspondence and requests for reprints should be addressed to Athol U. Wells, Interstitial Lung Disease Unit, Emmanuel Kaye Building, Manresa Road, Chelsea, London SW6 LR6, UK. E-mail: a.wells{at}rbh.nthames.nhs.uk

	ABSTRACT

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Survival is linked to the histopathologic distinction between usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), the most commonly encountered fibrotic idiopathic interstitial pneumonia. We retrospectively compared the prognostic significance of histopathologic diagnoses, baseline pulmonary function indices, and serial trends in pulmonary function indices (diffusing capacity, FVC, FEV₁, the recently defined composite physiologic index) at 6 and 12 months in 104 patients (UIP, n = 63; fibrotic NSIP, n = 41). Survival was lower in UIP than in fibrotic NSIP (p = 0.001) but not in patients with severe functional impairment; mortality during the first 2 years was linked solely to the severity of functional impairment at presentation. The composite physiologic index was the strongest determinant of outcome (p < 0.001). At 6 months, serial diffusing capacity levels (p = 0.003) and histopathologic diagnosis (p = 0.002) were prognostically equivalent. At 12 months, serial pulmonary function trends were the only major prognostic determinant (p < 0.0005 for all variables), with no independent significance associated with the distinction between UIP and fibrotic NSIP. We conclude that at 12 months, serial pulmonary function trends have considerable prognostic value in UIP and NSIP. Their histologic distinction provides no additional prognostic information when pulmonary function trends are clear cut or when functional impairment is severe.

Key Words: pulmonary function tests • usual interstitial pneumonia • nonspecific interstitial pneumonia • prognosis

The recently published American Thoracic Society/European Respiratory Society classification for idiopathic interstitial pneumonias (IIPs) (1, 2) now provides clinicians with an invaluable framework with which to estimate prognosis and the likely impact of treatment. The application of this system, based on either thoracoscopic biopsy or agreed noninvasive diagnostic criteria, is particularly useful when the diagnosis discloses an expected good outcome (e.g., inflammatory disorders such as respiratory bronchiolitis with associated interstitial lung disease and cellular nonspecific interstitial pneumonia [NSIP]). Prognostication is less certain in the two categories of IIP in which fibrosis predominates, hereafter termed fibrotic IIP (usual interstitial pneumonia [UIP] and fibrotic NSIP). The more indolent examples of fibrotic NSIP—associated with connective tissue disease (3, 4) or with clinical and radiologic features of organizing pneumonia (5, 6) or hypersensitivity pneumonitis (7)—are usually readily identifiable at initial evaluation and are not included here among the fibrotic IIPs. However, an important subgroup of fibrotic NSIP patients present with clinical features indistinguishable from those showing UIP and having idiopathic pulmonary fibrosis. Although analyses of the fibrotic NSIP group consistently show a better survival than in UIP (8–11), there is considerable individual overlap in outcome, with many fibrotic NSIP patients having a UIP-like outcome (9–11). Thus, it has been argued that when a histopathologic diagnosis of NSIP has been made, the work of the clinician has only just begun (12).

In practice, clinicians generally refine prognostic impressions (and sometimes revisit histologic diagnoses) in individual cases according to longitudinal behavior. Pulmonary function evaluation at presentation is disappointingly imprecise, prognostically (13, 14); however, the prognostic value of pulmonary function trends over time may prove more useful. We have therefore retrospectively compared the prognostic value of the histopathologic diagnosis, baseline functional impairment, and observed pulmonary function trends at 6 and 12 months in the combined group of patients presenting with features of idiopathic pulmonary fibrosis and a biopsy diagnosis of UIP or NSIP. Some of this work has been presented previously in the form of American Thoracic Society abstracts (15, 16).

	METHODS

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Between January 1, 1978, and December 31, 1998, 104 patients met clinical and open-lung or thoracoscopic biopsy criteria for fibrotic IIP and make up the study population. These comprise all biopsied patients included in our files as cryptogenic fibrosing alveolitis, a term considered equivalent to idiopathic pulmonary fibrosis. A further six patients with cellular NSIP were excluded. Part of the cohort has been reported previously in studies of outcome against histopathologic diagnosis in IIP (10, 11). In patients presenting before 1987 (n = 42), clinical criteria comprised the following: (1) bilateral predominantly basal crackles, (2) evidence of predominantly basal bilateral lung fibrosis on chest radiography with no consolidation, (3) a restrictive functional defect (total lung capacity of less than 80% of predicted, in association with a restrictive FEV₁/FVC ratio) or isolated reduction in diffusing capacity (DL_CO), and (4) no known primary cause for pulmonary fibrosis (17). After 1987 (n = 64), computed tomography criteria were used (predominantly basal/subpleural distribution; a mixture of reticular and ground-glass abnormalities, with traction bronchiectasis when ground-glass attenuation was prominent; the absence of consolidation or nodules) (18) in addition to clinical criteria.

Slides were reviewed by two pulmonary histopathologists (A.G.N. and T.V.C.) who were without knowledge of clinical data, and they were classified according to consensus criteria (2, 19). When classification differed between pathologists ( coefficient of agreement = 0.46), a joint opinion on the overall histopathologic pattern was reached. When biopsies were taken from two sites (n = 58, 56%), both were interpreted; a pattern of UIP in one biopsy was taken to indicate an overall diagnosis of UIP.

Clinical data (smoking status, drug treatment, clinical findings, absence of previous environmental exposures, and connective tissue disease) were extracted from case records. Patients were categorized as nonsmokers, current smokers, or ex-smokers (a minimum of one cigarette a day for a minimum of 1 year, stopping at least 6 months before presentation). In all but two cases, both with mild disease, patients were treated during follow-up. The treatment regimen consisted of (1) high-dose prednisolone initially (40–60 mg daily), reducing to a maintenance average daily dose of 10 mg, or (2) prednisolone 10 mg daily in combination with azathioprine or cyclophosphamide. Changes were made during follow-up (introduction of or changes in immunosuppressive agents) as clinically warranted; for this reason and because efficacy differs little between these regimens (20, 21), treatment effects were not evaluated.

Analyzed lung function measurements consisted of FVC, FEV₁ (both measured using an Ohio water-seal spirometer; Ohio instruments, Atlanta, GA), and carbon monoxide DL_CO using a single breath technique or a rebreathing technique with adjustment to single breath values (P.K Morgan respirometer; P.K Morgan, Chatham, Kent, UK). Results were expressed as percentages of predicted values (22). The recently defined composite physiologic index (CPI) (23), derived from FEV₁, FVC, and DL_CO levels (CPI = 91.0 – [0.65 x percent predicted DL_CO] - [0.53 x percent predicted FVC] + [0.34 - percent predicted FEV₁]), which corrects for the confounding effects of concurrent emphysema, was also evaluated. Measurement of earlobe capillary gases was performed on air at rest. Serial trends in pulmonary function tests (DL_CO, FVC, FEV₁, all quantified as percentage change from baseline, and unadjusted changes in CPI scores) were defined in survivors at 6 months (4–8 months, n = 85) and at 1 year (9–15 months, n = 72). Trends in earlobe capillary gases (not repeated in a significant minority) were not evaluated.

Group comparisons were made using unpaired t tests, Wilcoxon's rank sum tests, or chi-squared statistics as appropriate. Survival was evaluated using proportional hazards regression (24) (STATA software; Computing Resource Center, Santa Monica, CA). The prognostic values of clinical indices, histopathologic diagnosis, functional indices at baseline, and serial functional trends were examined at presentation and after 6 and 12 months of follow-up.

	RESULTS

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Population Demographic Data and Determinants of Outcome
Of 104 patients who had a prior clinicopathologic diagnosis of cryptogenic fibrosing alveolitis (roughly equivalent to idiopathic pulmonary fibrosis), 61 (59%) were reclassified as UIP and 43 (41%) as NSIP. As shown in Table 1 , demographic details, smoking histories, clinical features (including the duration of dyspnea and prevalence of clubbing), total gas transfer, lung volumes, and PO₂ levels did not differ between UIP and NSIP.

View larger version (22K): [in this window] [in a new window]   Figure 1. Survival compared between patients with usual interstitial pneumonia (UIP, n = 61) and nonspecific interstitial pneumonia (NSIP, n = 43). Early mortality was associated solely with the severity of lung function impairment at presentation, but mortality after 2 years of follow-up was primarily linked to the histopathologic diagnosis.

View larger version (21K): [in this window] [in a new window]   Figure 2. Three-year survival in relationship to the level of gas transfer at presentation. Survival was better in patients with diffusing capacity (DLCO) of more than 35% predicted (n = 76) than in those with DLCO of less than 35% predicted (n = 28, shown as separate UIP and NSIP subgroups) (p = 0.03). In the latter group, survival did not differ between UIP and NSIP (p = 0.28).

Pulmonary function trends in all variables were examined jointly in a further proportional hazards model, with the histopathologic diagnosis also included as a covariate. Trends in DL_CO levels (p = 0.003) and the histopathologic diagnosis (p = 0.002) were independent determinants of mortality, with no independent prognostic information obtained from trends in other functional indices. When the analysis was repeated with the exclusion of DL_CO data, trends in the CPI (p = 0.02) and the histopathologic diagnosis (p = 0.002) were the sole independent determinants of mortality (p < 0.0005).

Determinants of Mortality after 1 Year of Follow-up
At 12 months, 72 of the 82 known survivors remained under review and underwent repeat pulmonary function tests (UIP, n = 41; NSIP, n = 31). Survival (from the date of repeat pulmonary function testing) was examined in relationship to age, sex, histopathologic diagnosis, the CPI, and pulmonary function trends over the preceding 12 months (with trends in each functional variable examined in a separate model). Pulmonary function trends predicted mortality much more strongly than other covariates (change in DL_CO, CPI, FVC, FEV₁, all p < 0.0005). Age, sex, and the histopathologic diagnosis had no independent prognostic value in any analysis. As shown in Figure 3 , DL_CO trends remained strongly predictive of survival when dichotomized as a significant (more than 15% of baseline) decline (n = 28), or stability/improvement (n = 44) (p < 0.0005).

View larger version (24K): [in this window] [in a new window]   Figure 3. Survival in 72 patients remaining under follow-up at 12 months in relationship to serial 12-month changes in total gas transfer (DLCO). Mortality was substantially higher in those with a significant (more than 15%) deterioration in gas transfer (p < 0.0005) but did not differ between UIP and NSIP, after DLCO trends had been taken into account.

	DISCUSSION

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In fibrotic IIP, the histopathologic distinction between UIP and fibrotic NSIP provides useful prognostic information (8–11). However, the considerable overlap in longitudinal behavior between these two entities poses considerable difficulties in prognostic evaluation. We compare, for the first time, the prognostic values of short-term serial pulmonary function trends and the histopathologic diagnosis. After 6 months of follow-up, changes in functional indices (especially changes in gas transfer levels) were as powerful a determinant of outcome as the original histopathologic diagnosis. After 12 months of follow-up, the distinction between UIP and fibrotic NSIP provided no additional prognostic information, once serial pulmonary function trends had been taken into account. Thus, our findings confirm the anecdotal impression of many clinicians that in the difficult clinical problem of fibrotic IIP, longitudinal behavior is a more accurate determinant of outcome than evaluation at a single point in time. Changes in gas transfer levels provided the most accurate indication of survival, with no additional information gained by evaluating changes in other pulmonary function indices. However, changes in other indices at 1 year, including the recently described CPI (23), were also substantially more predictive of outcome than the histopathologic diagnosis.

A further novel aspect of this study was the separation of outcome into early and late mortality, not attempted formally in previous comparisons between UIP and NSIP. The fact that mortality in the first 2 years was primarily linked to the severity of pulmonary function impairment and not to the histopathologic diagnosis has important clinical implications for the initial management of fibrotic IIP. The role of thoracoscopic biopsy needs to be considered critically in the context of functionally severe disease, in which fibrosis appears to be established. In a minority of patients (approximately 25% in the present cohort) with DL_CO levels less than 35% of predicted normally, biopsy evaluation provided no prognostically useful information. This cutoff was selected for two reasons. This level of functional impairment should stimulate consideration of transplantation (25) (in view of the need to avoid a delay in pretransplant investigations in inexorably progressive disease and the predicament of referring for transplantation too late). However, importantly, the risks of thoracoscopic biopsy may rise significantly as gas transfer levels approach 30% of predicted normal (26). The lack of a histopathologic diagnosis in this situation is stressful for clinicians. However, these data indicate that a UIP-like course is usual in this context, even when a diagnosis of fibrotic NSIP has been secured.

This observation is likely to explain a striking dichotomy in the determinants of early and late mortality in our cohort. During the first two years of follow-up, the level of functional impairment was the sole major determinant of survival in the combined cohort, and this can be ascribed to the strong link between early death and severe functional impairment, in UIP and fibrotic NSIP alike. In contrast, in individuals with less severe functional impairment, the longitudinal behavior of fibrotic NSIP appears to be truly heterogeneous, whereas UIP continues to progress in almost all cases: Thus, the histopathologic diagnosis was the cardinal determinant of late mortality. A decline in serial lung function indices at 1 year was much more prevalent in UIP than in NSIP, although a minority of NSIP cases with the longitudinal functional behavior of UIP at 1 year appear to have a UIP-like outcome.

From the overall survival profile in this study and the contrasts in longitudinal behavior within the NSIP cohort, it can thus be concluded that there are two important groups of patients associated with a histopathologic diagnosis of fibrotic NSIP. A large subset, identifiable by their functional severity at presentation or a decline in functional indices at 6 to 12 months despite treatment can be regarded, for practical therapeutic purposes, as equivalent to UIP. In contrast, a long-term survival of 40% in the fibrotic NSIP cohort is indicative of a separate important subset with a much better outcome.

Flaherty and colleagues have argued that the histopathologic distinction between UIP and (at least some cases of) fibrotic NSIP is flawed because of heterogeneity between and even within biopsied lobes in histopathologic classification (27). They showed that in patients with multiple biopsies, not all lobes showed the same histology: Those with UIP in one biopsy and NSIP in another were termed discordant UIP (approximately 25% of patients). The remaining 75% were either concordant UIP (approximately 50%) or concordant NSIP (approximately 25%). The authors suggested that some cases of NSIP may "evolve" to UIP, a hypothesis that has not been proven but might provide some support for the recent concept of "active" and "inactive" UIP (12). The observations of Flaherty and colleagues might also support our concept that there may be subgroups among patients with fibrotic NSIP, some of whom fare better than others. It appears clear that a separate entity of "true" fibrotic NSIP among the IIPs exists, with no evolution to UIP, judging from outcome findings in a subset of patients in this study. Thus, our findings highlight the importance of distinguishing between an NSIP/UIP overlap picture and true NSIP, a distinction probably best made using serial lung function trends.

The finding that serial trends in gas transfer were the most accurate determinants of outcome should be interpreted with caution. Serial trends in FVC were little inferior in this regard and may be more reliable than gas transfer trends in lung function laboratories without high exposure to interstitial lung disease, in view of the well recognized variability in gas transfer measurements (28). Serial trends in the recently defined CPI (23) did not add usefully to DL_CO trends, although providing similarly strong prognostic information. This finding is not surprising; the value of the CPI lies in correcting for the confounding effects of emphysema, which is likely to be less prevalent in a younger population undergoing lung biopsy. Moreover, the value of an index at a single point in time does not always equate with its role in longitudinal monitoring. It is likely that the functional effects of emphysema change relatively little in 12 months; thus, changes in DL_CO and FVC may be little affected by concurrent emphysema, despite major confounding by emphysema of measured values at presentation.

It should be stressed that our findings do not justify a policy of nonbiopsy at presentation in fibrotic IIP. First, our analysis presupposes that other histopathologic entities have been excluded, including inflammatory IIPs and hypersensitivity pneumonitis, and this conclusion cannot always be made confidently using noninvasive modalities. More importantly, the prognostic value of longitudinal functional behavior has been established in a treated cohort.

It appears possible, although unproven, that treatment is crucial in some patients with fibrotic NSIP, even if current regimens may be of limited value in UIP. In this cohort, the duration of dyspnea and levels of functional impairment were virtually identical at presentation in UIP and fibrotic NSIP, implying little difference in the rate of disease progression before presentation. Thus, it is possible that the good outcome in some NSIP patients in our cohort resulted from therapeutic intervention. If treatment is to be rationalized at presentation, immediate biopsy evaluation remains useful; however, our findings do suggest that biopsy is most useful when performed immediately, rather than when instigated following the observation of longitudinal behavior. It is also likely that biopsy evaluation will itself be refined, with additional prognostic information gleaned from the profusion of fibroblastic foci (29, 30) and clinical information (31) in proven UIP. Furthermore, lung function trends are especially useful when they show unequivocal change (decline or clear-cut stability). However, a large subset of patients exhibits marginal deterioration, which may represent either true decline or the "noise" of measurement. Thus, despite its cardinal prognostic role in the whole cohort in this study, longitudinal behavior over 1 year is not an infallible guide to outcome in every case.

In common with all histopathologic studies, the problem of selection bias needs to be considered. In the first half of the study period, a prospective policy was in place to biopsy all patients with suspected idiopathic pulmonary fibrosis. The group of patients with the most severe disease were necessarily excluded, but our findings indicate that in patients with more severe disease undergoing biopsy, the prognostic distinction between UIP and fibrotic NSIP adds little. Furthermore, in common with all biopsied cohorts from referral centers, the mean patient age was considerably lower than in populations drawn from secondary centers or the community. More important, in the last decade, computed tomography has been an increasingly important influence on the selection of cases to biopsy. In common with others (32, 33), we have tended to place most reliance on a computed tomography picture of predominantly peripheral subpleural honeycombing, as strongly indicative of underlying UIP, often obviating biopsy. Thus, there is undoubtedly some bias in the latter half of our cohort toward a biopsy diagnosis of fibrotic NSIP. However, in all of these regards, our patients may be typical of those in whom biopsy is generally performed, in the computed tomography era.

In conclusion, we have documented the considerable prognostic value in fibrotic IIP of serial pulmonary function trends at 6 and 12 months in a treated cohort. Longitudinal behavior is an invaluable prognostic supplement to lung biopsy at presentation. In treated patients, observed pulmonary function trends at 12 months may obviate biopsy in some cases. Our findings also disclose the marginal prognostic value of biopsy evaluation in functionally severe fibrotic IIP, underlining the potential importance of early biopsy evaluation in these difficult diseases.

Received in original form October 30, 2002; accepted in final form May 25, 2003

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