Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and connective tissue disease-related usual interstitial pneumonia

uip ipf lung disease



Although usual interstitial pneumonia (UIP) appears to portend better survival when associated with connective tissue disease (CTD-UIP), little is known about the presenting clinical, radiologic, and pathologic features that differentiate pathologically confirmed UIP with CTD from idiopathic pulmonary fibrosis (IPF). In patients with atypical radiologic and clinical features, what specific findings predict underlying IPF vs. CTD-UIP diagnosis and their respective long term survival?


A large retrospective cohort analysis was done of consecutive patients seen from 1995 through 2010 with biopsy confirmed UIP completed or reviewed at our institution. CTD-UIP was defined by independent rheumatology consultation with exclusion of all other secondary causes of lung fibrosis. Primary clinical data was collected and compared for IPF and CTD-UIP along with logistic regression performed for predictors of disease likelihood and Cox proportional hazards analysis for predictors of survival.


Six hundred and twenty five patients were included in the study of which 89 had diagnosed CTD-UIP representing 7 disease entities. Survival was better among those with CTD-UIP except in UIP associated with rheumatoid arthritis, which had similar presenting features and survival to IPF. Predictors of underlying CTD included female gender, younger age, positive autoimmune serology, and inconsistent presenting radiologic findings. Only age and forced vital capacity corrected for a priori covariates were predictive of survival in CTD-UIP.


UIP pathology occurs frequently among patients with atypically presenting clinical and radiologic features, and may represent IPF or CTD-UIP with improved prognosis if underlying CTD is diagnosed. Presenting radiologic and pathologic features alone are not predictive of underlying secondary cause or survival between the two groups.


Idiopathic pulmonary fibrosis Usual interstitial pneumonia Connective-tissue disease interstitial lung disease


Usual interstitial pneumonia (UIP) is characterized by temporally heterogenous parenchymal fibrosis with architectural distortion, interstitial thickening, fibroblast foci, and honeycombing [ 1 ]. Although a defining pathologic finding in idiopathic pulmonary fibrosis (IPF), it has been found in other chronic fibrotic lung disease such as the connective tissue-disease associated interstitial lung disease (CTD-ILD) [ 2 ],[ 3 ], chronic hypersensitivity pneumonitis (HP) [ 4 ], sarcoidosis [ 5 ], and advanced asbestosis [ 6 ].

Current classification of the idiopathic interstitial pneumonias (IIP) allows not only pathological distinction of fibrotic disease, but implied characteristic clinical and prognostic significance [ 7 ]. For example, it is well known that UIP has worse prognosis than non-specific interstitial pneumonia (NSIP), the two most commonly presenting pathologies [ 8 ],[ 9 ]. Both again may be idiopathic or associated with known etiologies, which has clinical significance in terms of survival and response to therapy [ 10 ]. Prior studies have suggested secondary UIP such as that seen in certain connective-tissue diseases (CTD-UIP) may have better prognosis and survival than IPF [ 2 ],[ 10 ]. Other studies have been conflicting regarding better

survival in difficult to diagnose CTD or all CTD-ILD [ 11 ],[ 12 ]. Specific features of disease severity such as presenting CT findings [ 13 ] (reticulation vs. presence of honeycombing), pulmonary function testing [ 14 ],[ 15 ], and physiology scores [ 16 ],[ 17 ] have been used to predict disease progression and mortality.

Surgical lung biopsy is often avoided in those with typical radiologic features consistent with IPF or clinical association with connective-tissue disease. Even so, many biopsies are obtained because of atypically presenting radiologic or clinical features that do not allow for directed management or discussion of a care plan. As survival in CTD-UIP has been accepted as better than IPF, we sought to review the clinical, radiologic, and pathologic features of all biopsy proven UIP patients with either IPF or CTD seen at our institution, assessing for all-cause mortality. We hypothesized that variations in presenting clinical, pathologic, and radiologic findings may differentiate IPF from CTD-UIP in terms of predicting diagnosis and survival.

Materials and methods

Institutional IRB approval was obtained (IRB# 11–003506). A computer-assisted search of the pathological database was performed and consecutive patients with biopsy proven UIP seen at Mayo Clinic Rochester from 1995–2010 were included in the initial review. Biopsies were obtained either at Mayo Clinic Rochester or outside institutions, with pathological UIP defined using standard criteria [ 18 ] by experienced pulmonary pathologists at the time of clinical assessment.

Pathology from outside biopsies was re-reviewed at our institution at the time of referral. Atypical pathological findings in addition to underlying UIP if noted by the reading pathologist were collated and included presence but not predominance of any of the following: 1) poorly formed granuloma, 2) organizing pneumonia, 3) lymphoid aggregates or hyperplasia, 4) chronic inflammation, and 5) diffuse alveolar damage (DAD). Patients were excluded if pathologic findings only suggested possible UIP or had UIP-like features but were not consistent with UIP criteria.

IPF was diagnosed according to recent consensus guideline as biopsy-confirmed UIP without clinical evidence of a known secondary etiology [ 18 ]. In our cohort, all patients presenting with signs or symptoms suggestive of rheumatologic disease underwent directed autoimmune serologic testing, and if positive were considered undifferentiated connective tissue disease (UCTD) if no further definable rheumatologic disease was found. For patients with positive screening serology but no rheumatologic symptoms, IPF was still considered the underlying diagnosis. If initial CT was atypical for IPF but progressed over time to become probable or consistent UIP along with worsened respiratory symptoms, IPF was also considered the final diagnosis. Underlying CTD was defined by standard criteria through formal Rheumatology consultation at the time of referral or if diagnosed previously. These included rheumatoid arthritis (RA), scleroderma (Scl), dermatomyositis/polymyositis (DM/PM), mixed-connective tissue disease (MCTD), lupus erythematosus (SLE), primary Sj

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