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.