Abstract
Introduction:
Mycoplasma pneumoniae infection commonly causes mild respiratory illness, but cold agglutinin syndrome (CAS) is an uncommon extrapulmonary complication. CAS typically results in mild, predominantly extravascular hemolysis; however, severe intravascular hemolysis and acute kidney injury (AKI) are rare.
Case presentation:
A 59-year-old woman presented with profound weakness, jaundice, dark urine, and anuria following a mild upper respiratory illness. Laboratory evaluation revealed severe intravascular hemolysis, markedly elevated LDH activity, undetectable hemoglobin (Hb) level, hemoglobinuria, and AKI. Direct antiglobulin testing was positive for C3d only, and the cold agglutinin titer was markedly elevated (1:2048). Mycoplasma pneumoniae IgM serology was positive. She required warmed blood transfusions, antibiotics, thermal protection, and continuous renal replacement therapy. Over 10 days, hemolysis-related laboratory parameters and serum creatinine level improved significantly.
Conclusion:
This case illustrates a rare and severe form of Mycoplasma pneumoniae-associated CAS presenting with massive intravascular hemolysis and AKI. Early recognition and supportive interventions—particularly warmed transfusions and renal support—were critical to recovery. Clinicians should consider cold agglutinin-mediated hemolysis in patients with dark urine and AKI following respiratory infection.
Keywords
Introduction
Mycoplasma pneumoniae is a well-known cause of community-acquired pneumonia. While most Mycoplasma pneumoniae infections are mild respiratory illnesses, extrapulmonary complications occur in a minority (20%-25%) of cases. Among these, Cold Agglutinin Syndrome (CAS) is a recognized but uncommon sequela. In CAS, polyclonal IgM autoantibodies target the erythrocyte I antigen. These cold agglutinins fix complement and cause red-cell agglutination at low temperatures, typically producing only mild, subclinical hemolysis. In practice, about half of Mycoplasma pneumoniae infections elicit detectable cold antibodies, but the resulting anemia is usually modest. 1
IgM cold agglutinins bind to red cells in cooler peripheral circulation and activate complement. The bound C3b/C3d then opsonizes erythrocytes for clearance by the reticuloendothelial system (chiefly liver and spleen macrophages), so that hemolysis is predominantly extravascular. Consequently, most Mycoplasma pneumoniae-associated CAS cases feature only moderate hemolysis.1,2 A case series reported that the great majority of patients recover with conservative care. Only in very severe cases, when complement activation is robust, does hemolysis become intravascular, resulting in hemoglobinuria and potential acute tubular injury. 2
IgM cold agglutinins develop in approximately 15% to 20% of Mycoplasma pneumoniae infections. 3 Although autoimmune hemolysis associated with Mycoplasma pneumoniae is generally mild or subclinical, severe intravascular hemolysis occurs in fewer than 5% of cases, and progression to acute kidney injury (AKI) is reported in less than 1% of adult patients.4,5 Only isolated case reports describe life-threatening cold agglutinin hemolysis or AKI in this setting. Consequently, the combination of Mycoplasma pneumoniae-triggered CAS with intravascular hemolysis and AKI is exceedingly rare. The present case, marked by severe hemoglobinuria and oliguric AKI, represents an unusual and clinically significant manifestation of Mycoplasma-associated CAS.2-5
Case Presentation
A 59-year-old female presented to the emergency department with complaints of progressive weakness, dizziness, and dark brown urine for 1 week. She also noted the recent development of yellowing of her eyes and skin. Over the past 24 hours prior to admission, the patient’s urine output decreased to approximately 50 mL/day, consistent with anuria. Laboratory evaluation confirmed AKI, with a serum creatinine level of 4.2 mg/dL and BUN 85 mg/dL. Due to worsening metabolic acidosis and hyperkalemia, continuous renal replacement therapy (CRRT) was initiated on hospital day 2. Her urine output gradually improved during CRRT, reaching approximately 400 mL/day by day 5, consistent with oliguric recovery, and CRRT was discontinued on day 8 as renal function continued to recover. The patient reported a mild, self-resolving cough and a sore throat 2 weeks prior. Her past medical history was significant for well-controlled hypertension. She was a non-smoker and denied any alcohol or illicit drug use.
On physical examination, she was alert but pale and visibly icteric. Vital signs were: temperature 37.1°C, blood pressure 150/90 mmHg, heart rate 110 bpm, respiratory rate 18 bpm, and oxygen saturation 98% on room air. Cardiopulmonary examination was unremarkable. Abdominal examination revealed a non-tender, palpable spleen 3 cm below the costal margin. There was no lymphadenopathy. Acrocyanosis or livedo reticularis was not observed.
The initial laboratory findings were consistent with intravascular hemolysis: severe anemia (Hb 5.8 g/dL), markedly elevated LDH activity, undetectable haptoglobin level, and elevated indirect bilirubin level. The presence of hemoglobinuria confirmed active intravascular hemolysis. The renal panel revealed AKI. A direct antiglobulin test (DAT) was positive for C3d only, and the cold agglutinin titer was significantly elevated at 1:2048, supporting the diagnosis of cold agglutinin disease. Infectious workup demonstrated a positive Mycoplasma pneumoniae IgM, indicating a likely triggering factor (Table 1).
Summary of Laboratory Findings at Admission and During Hospitalization in a Patient with Mycoplasma Pneumoniae-Associated Cold Agglutinin Syndrome Complicated by Intravascular Hemolysis and Acute Kidney Injury.
Abbreviations: BUN, blood urea nitrogen; DAT, direct antiglobulin test; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase.
Laboratory values are presented at admission (Day 1), during hospitalization (Day 3), and at discharge (Day 10). The asterisk (*) denotes post-transfusion values measured after transfusion of 2 units of warmed, leukocyte-reduced packed red blood cells, while a dash (–) indicates that the test was not performed or that results were unavailable at the specified time point.
Post-transfusion of 2 units of warmed packed red blood cells.
A peripheral blood smear performed on a warmed sample showed marked red blood cell agglutination, spherocytes, and polychromasia, consistent with autoimmune hemolysis. No schistocytes were seen, ruling out a thrombotic microangiopathy. Flow cytometry on peripheral blood did not show evidence of a lymphoproliferative disorder. A chest X-ray was unremarkable. Renal ultrasound showed normal-sized, echogenic kidneys, consistent with medical renal disease.
The patient was admitted to the intensive care unit for close monitoring and comprehensive management. Strict thermal protection was implemented, with the patient placed in a warm room and all intravenous fluids and blood products administered via a blood warmer to prevent exacerbation of hemolysis. Transfusion support was provided with 2 units of warmed, leukoreduced packed red blood cells (RBCS), which were transfused slowly under careful monitoring, resulting in a satisfactory rise in Hb without overt hemolytic reaction. Due to worsening metabolic acidosis and hyperkalemia in the setting of critical illness, CRRT was initiated on hospital day 2 rather than intermittent hemodialysis to allow continuous and controlled correction of metabolic abnormalities. Given the high cold agglutinin titer and severity of hemolysis, a single dose of Rituximab (375 mg/m2) was administered on day 4 as adjunctive B-cell-directed therapy to reduce production of pathogenic IgM cold agglutinins while supportive measures were continued. The patient also completed a course of oral azithromycin for treatment of Mycoplasma pneumoniae infection. Her urine output began to improve by day 5, and CRRT was discontinued on day 8 as renal function showed signs of recovery. By day 10, Hb level had stabilized, LDH activity normalized, and serum creatinine decreased to 1.5 mg/dL. She was discharged in stable condition with close follow-up arranged with Hematology and Nephrology. The patient demonstrated hematologic improvement, with stabilization and rise in Hb levels and normalization of hemolysis markers over 2 to 4 weeks. Renal function recovered over 4 to 8 weeks. The clinical course and laboratory improvement during hospitalization, including the recovery of renal function and hemolysis parameters, are demonstrated in Figure 1.
Clinical course and laboratory trends during hospitalization in a patient with Mycoplasma pneumoniae–associated CAS. Figure 1. A multi-panel line graph illustrating key laboratory values over the 10-day hospital stay. Panel A: Hemoglobin (g/dL, left Y-axis, blue line) and lactate dehydrogenase (LDH, U/L, right Y-axis, recd line). Hemoglobin drops on admission, rises post-transfusion (Tx), and gradually stabilizes. LDH shows a steep decline, normalizing by Day 10. Panel B: Serum creatinine (mg/dL, Y-axis, purple line). Creatinine peaks at admission, remains elevated during continuous renal replacement therapy (CRRT; shaded area from Day 2 to Day 8), and then steadily declines as renal function recovers. Annotations: Key events are marked, including “Admission,” “Transfusion (Tx),” “Initiation of CRRT,” “Rituximab dose,” and “Discontinuation of CRRT.” The CRRT shading has been made visually distinct to clearly differentiate CRRT days from non-CRRT periods.
Discussion
Mycoplasma-associated CAS is mediated by polyclonal IgM antibodies that target the I antigen on RBCs.2,6 During Mycoplasma pneumoniae infection, the organism induces a structural modification of the I antigen on RBC membranes; this molecular mimicry leads to production of cold-agglutinin IgM autoantibodies against the antigen. 2 These IgM molecules bind RBCs in cooler peripheral circulation, fix complement, and cause agglutination. The bound complement (primarily C3b/C3d) marks erythrocytes for clearance by reticuloendothelial cells, especially Kupffer cells in the liver. 6 Thus, the hemolysis is largely extravascular. Complement activation proceeds to intravascular hemolysis and hemoglobinuria only in very severe cases. Massive intravascular hemolysis can theoretically precipitate acute tubular injury from Hb casts and iron deposition, which may explain any renal dysfunction seen in these patients. 7
Most Mycoplasma pneumoniae infections produce only low-titer cold agglutinins and mild anemia. 6 By contrast, clinically overt CAS (with Hb < 10 g/dL) is rare. A multicenter study of adults with Mycoplasma pneumoniae found that only 60 cases of CAS were identified among thousands of pneumonia patients. These patients presented a median 10 days after respiratory symptoms onset with severe anemia (median Hb ~6.9 g/dL) and often required ICU care. Despite this severity, 90% eventually recovered Hb > 10 g/dL, suggesting a generally good prognosis with supportive care. Notably, venous thromboembolism occurred in 17% of that cohort, underscoring that cold agglutinins (like other AIHAs) can induce a hypercoagulable state. 8 Our case joins the few reported instances of life-threatening Mycoplasma pneumoniae-CAS. In the literature, only sporadic case reports describe severe hemolysis or AKI in this context. 6
Primary CAD should be distinguished from this secondary syndrome. Primary CAD is a chronic, clonal IgM AIHA (often in the elderly) that is not driven by acute infection. By contrast, our patient’s presentation (an otherwise healthy adult with pneumonia) and the temporal relationship to Mycoplasma pneumoniae seroconversion support a secondary CAS. Other hemolytic conditions (eg, warm AIHA, paroxysmal cold hemoglobinuria, G6PD deficiency, hemolytic-uremic syndrome) were excluded based on the laboratory profile and clinical context. For example, warm AIHA typically shows IgG-mediated hemolysis and spherocytes, and HUS would show schistocytes and thrombocytopenia. In our patient, the isolated C3d positivity and high cold agglutinin titer were classic for CAS.2,8
The pathophysiology of CAS explains the rarity of renal failure in this syndrome. Hemolysis is usually extravascular, so hemoglobinuria is limited. However, when massive hemolysis does occur, free Hb can cause acute tubular necrosis. A prior case report of Mycoplasma pneumoniae-associated hemolysis documented glomerulonephritis and extensive tubular injury with Hb casts on biopsy. The incidence of AKI in CAS is not well-defined in medical literature, underscoring the unusual nature of this complication. 7
Management of CAS is mainly supportive. Treatment focuses on the underlying infection and avoidance of cold. In cases secondary to Mycoplasma pneumoniae, appropriate antibiotics ( such as macrolides or tetracyclines) are administered. Transfusion of warm, leukocyte-reduced RBCs may be needed for profound anemia; blood products should be warmed to prevent further agglutination. Glucocorticoids and immunosuppressive agents generally have limited efficacy in CAS, since the hemolysis is complemented-mediated.2,6
Glucocorticoids and conventional immunosuppressive agents generally have limited and inconsistent efficacy in CAS because hemolysis is predominantly IgM- and complement-mediated. Consequently, B-cell depletion with rituximab is considered a therapeutic option in severe or refractory cases, as it reduces pathogenic autoantibody production, although its clinical effect is not immediate and must be combined with prompt supportive care.
A cohort study reported that corticosteroid therapy did not significantly alter clinical outcomes. Therapies targeting complement, such as eculizumab or sutimlimab, have been used in refractory disease but are not routinely recommended for infection-associated CAS. In our patient, antibiotic therapy and supportive management were sufficient, and Hb levels improved as the infection resolved, consistent with previous reports of Mycoplasma pneumoniae–associated CAS resolving with infection control.2,8,9
Conclusion
This case highlights a rare and severe form of Mycoplasma pneumoniae-associated CAS presenting with profound intravascular hemolysis and AKI. Although cold agglutinins are common in Mycoplasma pneumoniae infection, clinically significant hemolysis and renal failure are distinctly uncommon. Early recognition and supportive management—particularly thermal protection, warmed transfusions, and renal support—were essential for recovery. This case underscores the importance of considering cold agglutinin-mediated hemolysis in patients presenting with dark urine, jaundice, or AKI after a respiratory infection.
Supplemental Material
sj-docx-1-icr-10.1177_11795476261426064 – Supplemental material for Severe Intravascular Hemolysis and Acute Kidney Injury Triggered by Mycoplasma-Associated Cold Agglutinin Disease: A Case Report
Supplemental material, sj-docx-1-icr-10.1177_11795476261426064 for Severe Intravascular Hemolysis and Acute Kidney Injury Triggered by Mycoplasma-Associated Cold Agglutinin Disease: A Case Report by Ziad W. Elmezayen and Mohammad Adi in Clinical Medicine Insights: Case Reports
Footnotes
Acknowledgements
None.
Ethical Considerations
Ethical approval was not required for this case report, as it involves a single patient and does not meet the criteria for research requiring institutional review board (IRB) oversight. The use of authorized medications was consistent with clinical practice guidelines, and the management of this individual patient did not require IRB approval. This case report adheres to the CARE (CAse REport) Guidelines for accurate and transparent reporting of clinical cases (
).
Consent for Publication
Written informed consent was obtained from the patient prior to publication of this case report and any accompanying images. This consent includes permission for the use of unauthorized, off-label medications as part of the treatment plan. The completed consent form is available to the Editor upon request and will be treated confidentially.
Author Contributions
Ziad W. Elmezayen: Conceptualization, Supervision, Study Design, Visualization, Writing – Review & Editing. Mohammad Adi: Data Collection, Literature Review, Writing – Original Draft Preparation.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
All data pertinent to this case report have been included in this article. Further inquiries can be directed to the corresponding author.
Supplemental Material
Supplemental material for this article is available online.