Pulmonary Function Tests Reveal Unrecognized Lung Dysfunction and Have Independent Prognostic Significance in Patients with Systemic AL Amyloidosis

Lung involvement in patients with systemic AL amyloidosis is not very common and consensus criteria require direct biopsy verification with symptoms or typical radiographic changes of diffuse interstitial lung disease. Dyspnea and other symptoms are commonly attributed to cardiac dysfunction and thus, lung dysfunction may go unrecognized while, in some series evidence suggest that lung involvement is probably more frequent than reported. No prospective comprehensive evaluation of lung function has been performed in patients with AL amyloidosis; the aim of our study was to prospectively assess lung function by performing comprehensive pulmonary function tests (PFTs) in consecutive patients with systemic AL amyloidosis.

This was a non-interventional prospective study that included consecutive patients with systemic AL amyloidosis treated in the Department of Clinical Therapeutics (Athens, Greece). Patients with localized lung amyloidosis were excluded. PFTs were performed in a Master screen Body (Jaeger, Germany), according to manufacturer's instructions and standard European Respiratory Society / American Thoracic Society guidelines. We performed spirometry, lung volumes measurement, single-breath determination of carbon monoxide uptake in the lung corrected for hemoglobin (carbon monoxide diffusion capacity, DLCO) and maximal expiratory (Pe) and inspiratory (Pi) pressures measurement, in a sitting position. The patient's age, height and weight were recorded for use in the calculation of reference values. We adjusted DLCO for Hb prior to the interpretation of the maneuver in the predicted values. Smoking habits were recorded (smoker or no, pack/years, years of smoking cessation).

We report on the first 84 patients with systemic AL amyloidosis that were included in the study. Median age was 63 years (range 44-84), 60% were males, median baseline dFLC was 162 mg/L, median BM infiltration was 15% (range 0-30%). Kidney involvement was present in 73%, median eGFR was 63 ml/min/1.73 m2. Heart was involved in 72% and 12%, 62%, 17% & 8% of patients were Mayo stage 1,2, 3A and 3B respectively. Liver was involved in 25%, peripheral/autonomic nerve in 21% and soft tissue in 12%. Based on imaging and/or lung biopsy, lung involvement was present in 2 (2%) patients; 48% of the patients were current or ex-smokers. Primary treatment was bortezomib-based in 89% of the patients.

According to PFTs, breathing pattern was normal in 49%, restrictive in 37%, obstructive in 11% and mixed in 3%. The presence of a restrictive pattern was marginally associated with heart involvement (p=0.056) but not with Mayo stage and was more common in patients with liver (p=0.022) and soft tissue involvement (0.031) and there was no association with renal or nerve involvement or FLC levels. In univariate analysis, restrictive pattern was associated with worse survival (24 months vs not reached for obstructive and normal, p=0.015); 1-year mortality was 42% for restrictive vs 13% for obstructive and 5% for normal breathing patterns. When adjusted for Mayo stage, restrictive pattern (HR 2.63, p=0.033) and Mayo stage 3B (HR: 12, p=0.033) were independently associated with survival.

Among individual PFTs indices, corrected DLCO (p=0.02), TLC% (p=0.012) and Pe% (p=0.019) were associated with survival. A DLCO <60% was associated with poor survival (7 months vs not reached, p=0.002) and remained significant even after adjustment for Mayo stage (HR: 2.5, p=0.027). Pe%, (maximum expiratory pressure, a simple to do and helpful indicator of muscle weakness and lung compliance), was associated with shorter survival when was <70% of the predicted (not reached vs 27 months, p=0.002), even after adjustment for Mayo stage (HR: 6.4, p=0.003). TLC%, a measure of total lung capacity, when <75% of predicted was associated with a median survival of 8.5 months vs not reached (p=0.012), even after adjustment for Mayo stage (HR: 3.1, p=0.027). Among these indices, however, a Pe%<70% was the most important in multivariate analysis (HR: 7, p=0.003) along with stage 3B (HR:17.7, p=0.017)

In this comprehensive evaluation of lung function by PFTs we found that restrictive breathing pattern is common among patients with systemic AL, and indices of lung function are associated with prognosis independently of cardiac dysfunction. Our results point to the presence of unrecognized pulmonary involvement, despite the absence of typical imaging findings.