Cold Autoimmune Hemolytic Anemia Secondary to Mycoplasma Pneumoniae Infection in Adults: Results from a Large French Observational Study (MYCOLD study)
Authors: Chevalier Kevin , Holub Matthieu , Palich Romain , Blanckaert Karine , Terriou Louis , Arnould Bérangère , Deshayes Samuel , Merindol Julie , Rolland Simon , Valentin Simon , Amarsy Rishma , Audia Sylvain , Baltes Virginie , Barret Amaury , Chopin Dorothée , Clément Mélissa , Coeffier Marine , Comont Thibault , De Monteynard Soline , Declerck Charles , Haioun Corinne , Durand Pauline , Ebbo Mikael , Godot Amélie , Hamrouni Sarra , Kaueffer Charlotte , Kahn Jean-Emmanuel , Lassel Ludovic , Leautez Sophie , Lecapitaine Anne-Lise , Lemoal Gwenael , Luque Paz David , Martinot Martin , Mrozek Natacha , Pagis Valentine , Perpoint Thomas , Viallard Jean-Francois , Viguier Clément , Mahevas Matthieu , Godeau Bertrand , Crickx Etienne , Michel Marc 
Published: December 2024

Introduction
Mycoplasma pneumoniae (MP) is mostly responsible for infections of the lower respiratory tract but can also be associated with extrapulmonary manifestations, including cold antibody autoimmune hemolytic anemia (cAIHA). While the detection of cold agglutinins (CA) is relatively common in MP infection, symptomatic and/or severe forms of cAIHA are rare in this context. This association is poorly described in the literature as no large series of patients have been reported so far. The outbreak of MP infections that occurred in Northern Europe and France during last fall and winter gave rise to an unusual number of MP-associated cAIHAs. The aim of this study were to better describe the characteristics, the management and outcome of patients diagnosed with MP-associated cAIHA. and to assess the usefulness of glucocorticoids (GC) in this setting.
Patients and Methods
We conducted an ambispective (retrospective and prospective), observational, multicenter, national study. Patients were recruited by i) call for observations throughout the network of the French national society of internal medicine (SNFMI) and the French reference center for autoimmune cytopenias (CERECAI) and ii) identification of cases included in the MYCADO study (a large national multicenter observational study of MP infections). To be included, patients had to be 18 years of age or older, have a confirmed MP infection requiring hospitalization associated with cAIHA, with a nadir hemoglobin (Hb) level &lt; 10 g/dL and a positive direct antiglobulin test with a C3d pattern.
Results
In total, 50 patients (50% of females, with a median age [IQR] of 47 [38.5-63.5] years) at diagnosis were included. Of these, 24 (48%) had risk factors for respiratory infection (active smoking in 16 (32%) patients, asthma in 6 (12%) others), 21 (42%) had cardiovascular risk factors (hypertension, diabetes, dyslipidemia, or obesity), 4 (8%) had a history of malignant hemopathy, and 4 (8%) patients were immunocompromised. Forty-eight (96%) patients had respiratory signs related to MP infection, 20 (40%) had gastrointestinal manifestations (31.3%), 14/40 (35%) had “dark” urine and 1 (2%) had acrocyanosis. Eight (16%) patients had venous thromboembolism (including pulmonary embolism in 7 (14%)) and 22 (44%) had to be admitted in intensive care unit.
The median Hb level at cAIHA diagnosis was 7 [5.9-9.8] g/dL, with a median reticulocytes count of 90 [60-144] x 109/L, and median LDH, haptoglobin, and undirect bilirubin levels of respectively 676 [470-1358] IU/L, 0 [0-0.38] g/L and 16 [7.7-51] μmol/L. Thirty-nine (78%) patients required red blood cell (RBC) transfusions, with a mean of 3 packed RBC/patient. Nineteen (38%) patients received one or more treatments “specifically” for AIHA, including GC in 14 (25%) cases and erythropoietin in 4 (8%). All patients received antibiotics, mostly macrolides (92% of the patients) for treating MP infection
MP infection resolved completely without sequelae in 43/50 (86%) cases. After a mean follow-up of 54 [27-80] days after cAIHA onset, 39/47 (83%) patients were in complete remission (defined by a stable Hb level beyond 10 g/dL off therapy), 6 (12.7%) in partial remission (defined by an increase of at least 2 g/dL of the Hb level from baseline but below 10 g/dL) and 2 (4%) patients died (one from septic shock secondary and one from pulmonary embolism).
When we compared patients who did not receive any “specific” treatment for AIHA other than antibiotic ± transfusion (n=31, 62%) with those treated with GC alone (n=14, 28%), we found that patients with GC had more severe cAIHA with a lower Hb nadir (6.4 [5.9-7.4] vs. 5 [5.7-5.9] g/dl, p=0.001), a greater number of packed RBC transfused (2 [0-2] vs. 1.25 [3.5-4.75], p=0.03), and a lower rate of complete remission of cAIHA (4/14 (28.6%) vs. (26/28 (92.9%), p=0.02). However, GC did not appear to improve neither the outcome nor the time to Hb normalization in patients with MP -associated cAIHA.
Conclusion
These data show that cAIHA associated with MP infection is not exceptional; and that although being often initially severe, with a high rate of venous thrombotic events, it has a good prognosis and recovers (either spontaneously or after transfusion) within few weeks in parallel with the bacterial infection. Based on our study, there is no evidence suggesting that GC, which were used for the management of the most severe cases, are helpful in this setting for reducing the duration of cAIHA.