Paroxysmal cold hemoglobinuria: a difficult diagnosis in adult patients

BACKGROUND Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia caused by a biphasic (Donath-Landsteiner [DL]) immunoglobulin G autoantibody. Estimates of disease frequency after syphilis are lacking and the diagnostic yield of testing for PCH is uncertain. The objectives of this study were: 1) to describe DL testing practices in Canada, 2) to determine how often a biphasic RBC antibody is detected in adults and children, and 3) to evaluate inter-rater reliability of interpretations of positive DL test results in adults. STUDY DESIGN AND METHODS We performed a national survey of reference laboratories, chart review of all test-positive cases, and independent panel adjudication. RESULTS Of 18 reference laboratories invited, 14 participated in the survey. In a representative year, 52 DL tests were requested across 14 centers, a region that serves more than 60% of Canada's population. In 124 cumulative testing-years, three positive tests were reported in adults and 14 positive tests were reported in children. There was poor agreement on interpretation of the three positive test results in adults among a panel of four experts (Fleiss κ = −0.1852; standard error, 0.1309; 95% confidence interval, −0.4418 to 0.0715). At a large academic center, 34 samples from 27 patients were sent for DL testing from 2006 to 2013 with 97% (33/34) reported as negative, inconclusive, or unacceptable samples. CONCLUSION Positive DL test results are rare and occur more commonly in children than adults. There was poor agreement among experts on the interpretation of a positive DL test in adults. These observations highlight the difficulties in establishing the diagnosis of PCH in adults and calls for scrutiny of current laboratory practice.