In this case study, we provide background and discussion on cold agglutinin disease. Throughout the case, we recommend medical algorithms from our knowledge base which can be used to aid in clinical decision making.

Betty is a 28-year-old Caucasian female who presented to the Emergency Room with shortness of breath, cough, chills, and fever of 4 day duration. Her sputum was yellow and thick in consistency.  It was winter and she had noticed skin lesions after she had spent some time outside. The same lesions occurred when she was repacking the freezer a few days ago.

Her past history was only remarkable for depression treated with paroxetine (Paxil).

Physical exam was suggestive of pneumonia with decreased aeration and crackles auscultated over several areas of the back. A chest X-ray showed right upper lobe airspace disease with patchy opacities in the right middle and left lower lobes. She was admitted to the hospital and started on IV antibiotics.

Her CBC showed a white blood cell (WBC) count of 24,000 and a red blood cell (RBC) count of 0.88 M per microliter. The hemoglobin level was normal, which did not match with the RBC count. When the blood smear was examined there were large clumps of red blood cells. Warming the blood caused these to get smaller but not to go away completely. The warmed blood had a normal RBC count. The diagnosis of cold agglutinin disease was made.

The next day the blood culture collected in the ED was positive for Streptococcus pneumoniae. IV antibiotics were completed during the hospitalization and the patient was discharged home with instructions to avoid cold weather exposure.  The patient decided to move to Miami.


    • Benign vs Pathologic Cold Agglutinins, Cryoglobulins
      Cold agglutination refers to immunoglobulin-mediated clumping of red blood cells on exposure to cold (“cryo”). Some cases may represent an in vitro phenomenon that can cause problems in the laboratory but not clinically for the patient. Other cases can occur in vivo and some of these can be clinically significant. Cold agglutinins can occur with conditions that range from benign cold agglutinin disease to high-grade malignant lymphoma. Benign causes of cold agglutinins are most commonly seen in the post-infectious setting, especially to mycoplasma, Epstein-Barr virus, and Legionella pneumonia. Malignant causes, on the other hand, are usually related to a lymphoproliferative disorder such as IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenstrom macroglobulinmena.  Patients with cold agglutinin disease should be evaluated for infections, malignancies, autoimmune disease.

      • Types of CryoglobulinsTypes of Cryoglobulins


  • Causes
    Cold agglutinin disease is a rare cause of autoimmune hemolytic anemia mediated by IgM antibodies. The IgM molecules bind to the red blood cell membranes at the periphery of the body as the temperature cools and activates the complement cascade and causes extravascular hemolysis in the liver.Clinical findings at time of presentation include anemia, acrocyanosis, fatigue, weakness, and dyspnea on exertion. Additional clinical manifestation can include livedo reticularis, Raynaud’s disease, and cutaneous necrosis.

    • Clinical Findings in a Patient with CryoglobulinemiaClinical Findings in a Patient with Cryoglobulinemia
    • Reasons for Failure to Detect a CryoglobulinReasons for Failure to Detect a Cryoglobulin
    • Response to therapy
      Rituximab is most commonly used as therapy to cold agglutinin disease. Studies have shown response around 50% within 4 weeks, but most patients (>60%) are likely to remit. For those refractory to therapy to rituximab, dual therapy with fludarabine and rituximab has been shown to have a response rate of 76%.  Case reports have also reported success with eculizumab and bortezomib.

      • Criteria for Response to Therapy for a Patient with CryoglobulinemiaCriteria for Response to Therapy for a Patient with Cryoglobulinemia


  • Hazards of Exposure to Cold
    Managing cold agglutinin disease also requires important nonpharmacologic intervention such as avoiding exposure to the cold and wearing warm clothing. In many patients the thermal amplitude between the core and the periphery is enough to cause antibody binding and anemia. In these patients, transfusions may be necessary to manage the disease.

    • Hazards of Hypothermia During Surgery in a Patient with a Significant Cold AgglutininHazards of Hypothermia During Surgery in a Patient with a Significant Cold Agglutinin
    • Community Acquired Pneumonia
      For this patient the cold agglutinin was associated with a community-acquired pneumonia (CAP), which was severe enough to require hospitalization. CAP is one of the most common infectious diseases in the world. The most common pathogens of CAP are Streptococcus pneumoniae, Haemophilus influenza, and Moraxella catarrhalis. Among young adults, atypical pathogens, such as Mycoplasma pneumoniae are a common etiology. Elderly patients and those with immunocompromised conditions or chronic conditions are at increased risk for morbidity and mortality with community-acquired pneumonia.

      • Scoring System for Grading the Severity of Community Acquired PneumoniaScoring System for Grading the Severity of Community Acquired Pneumonia
      • Prognostic Score for a Patient with Severe Community-Acquired PneumoniaPrognostic Score for a Patient with Severe Community-Acquired Pneumonia
      • Criteria of the Infectious Diseases Society of America and American Thoracic Society for Hospital Discharge Following Severe Community-Acquired PneumoniaCriteria of the Infectious Diseases Society of America and American Thoracic Society for Hospital Discharge Following Severe Community-Acquired Pneumonia


  • Interference by Cold Agglutinins with the Detection of Viral Hepatitis C
    The presence of cold agglutinins can interfere with laboratory testing. This includes a false negative test for Hepatitis C virus (HCV). This can cause the diagnosis to be missed or delayed, which can have serious consequences for the patient. It also can cause confusion when a previously diagnosed patient now appears to be negative.

    • False Negative PCR for Hepatitis C Virus Due to a CryoglobulinFalse Negative PCR for Hepatitis C Virus Due to a Cryoglobulin

Take Home Points

  • Proper identification of rare conditions can improve morbidity and clinical outcome of patients.
  • Whether treating common conditions, such as community acquired pneumonia, managing rare diseases, or rare presentations of common conditions, medical algorithms can assist in clinical decision making for members of the healthcare team.
  • When contemplating rare diseases during a differential diagnosis, the evidence-based studies cited on our website and via iOS and Android app, can serve as educational reminders to physicians.
  • The medical algorithms highlighted in this case study are available at The Medical Algorithms Company and also on the apervita health analytics platform.

About the Authors

Adam Vohra is a Health Innovation Fellow at Apervita. He is currently a dual-degree MD/MBA student in his final year at The University of Chicago Pritzker School of Medicine and Booth School of Business. He plans to pursue a residency in internal medicine next year. Adam is interested in issues related to health care quality and delivery and has published research on predictors of intensive care unit admission for pneumonia. He is currently working on research to create analytics to predict heart failure readmissions. Adam is also involved heavily in health care policy and currently serves on the Board of Trustees of the Illinois State Medical Society as the sole medical student member. In the past, Adam has also represented medical students in the American Medical Association House of Delegates. Prior to coming to The University of Chicago, Adam completed his undergraduate studies at Northwestern University where he studied biology and political science.

Dr. Chad Rudnick, MD, FAAP is a board-certified pediatrician in Boca Raton, FL. He is the Medical Director of The Medical Algorithms Company. A proponent of incorporating medical technology into his practice, Dr. Rudnick uses telemedicine and medical algorithms from The Medical Algorithms Company in his daily practice to better serve his patients and their families. An accomplished medical writer, he maintains a popular pediatric blog, All Things Pediatric, and has written for numerous online and print publications including

John Svirbely, MD is a founder and Chief Medical Officer of The Medical Algorithms Company and the primary author of its medical algorithms. John is a co-founder of the Medical Algorithms Project and has developed its medical content for nearly 20 years. He has a BA degree from the Johns Hopkins University and his MD from the University of Maryland. He is a board-certified pathologist with a fellowship in medical microbiology and biomedical computing at Ohio State University. Currently he is in private practice in Cincinnati, Ohio. He has authored multiple books and articles on medical algorithms.