LETTER TO THE EDITOR

Citrobacter freundii-induced cold agglutinin hemolysis

Avishek Kumar & Hamid Shaaban & Karthik Koduru &

Stephen Abo & Ibrahim Sidhom & Gunwant Guron

Received: 2 September 2010 /Accepted: 25 September 2010 /Published online: 12 October 2010# Springer-Verlag 2010

Dear Editor,A 64-year-old Hispanic woman with a past medical historyof hypertension, diabetes mellitus type 2, and dyslipidemiawas admitted with symptoms of fever, left-sided flank pain,and blood in her urine of 2 days duration. Seven daysbefore admission, the patient had been treated as outpatientfor urinary tract infection with trimethoprim/sulfametoxazole(Bactrim). Physical exam revealed left costovertebral angletenderness and some scleral icterus. The patient was awake,alert and oriented, and showed no changes in mental status.Her temperature was febrile, 38.5°C. Initial laboratory resultsrevealed a hemoglobin (Hgb) of 8.2 g/dL, hematocrit of23.6 g/dL, platelet count of 524,000×103/μL, creatinine of1.1 mg/dL, a total bilirubin of 1.6 mg/dL, haptoglobin of5.8 mg/dL, and a lactic dehydrogenase of 699 U/L. Bloodcultures returned positive for Citrobacter freundii within24 h of collection. A direct Coombs’ test (DAT) was positivefor C3d but negative for IgG, and high-titer cold agglutininswere detected. Tests for influenza A and B, Epstein–Barrvirus, and Mycoplasma were negative. The patient wastreated for Citrobacter infection and transfused with warmblood. She was kept in a heated room with body warmingblankets. Two days after admission, the patient’s Hgbdropped to 5.4 g/dL, with increasing lactic dehydrogenase

levels and indirect bilirubin suggesting an ongoing activehemolysis. The patient was started on intravenousmethylprednisolone 80 mg IV daily for 10 days, andthe hemolysis resolved. Her Hgb improved gradually to7.8 g/dL, and repeat blood cultures as well as a repeatDAT were negative. Subsequently, she was dischargedhome on a tapering dose of oral corticosteroids. Fourweeks after discharge, corticosteroids were completelystopped without any relapse of cold agglutinins.

Several viral and bacterial pathogens have been reportedin the literature as causative factors for secondary coldagglutinin disease. Cytomegalovirus, parvovirus B19, andvaricella-zoster virus are commonly associated viral etiologies.Mycoplasma pneumoniae, Chlamydia, Legionella, andLeptospira have been reported as bacterial predisposingagents to cold agglutinin disease as well [1, 2].

To our knowledge, ours is the first case of Citrobacter-associated cold agglutinin hemolysis to be reported in theliterature. Citrobacter bacteria are gram-negative rodsbelonging to the Enterobacteriaceae family and are oftenfound in water supplies as well as food sources, in additionto other parts of the environment [3]. In some humans,Citrobacter is part of the normal bacterial flora of the colon,but this occurs in only a small percentage of the population.

In our patient, the concomitant sepsis with C. freundii isthe likely precipitating factor for the cold agglutinin-induced hemolytic anemia. The spontaneous resolution ofcold agglutinins as well as hemolysis after the treatment ofCitrobacter sepsis supports Citrobacter as the most likelytrigger [4]. C. freundii has been reported in the past as oneof the causes of Shiga toxin-mediated hemolytic uremicsyndrome [5]; however, cold agglutinin disease has neverbeen associated with it. Like in cases associated withMycoplasma pneumoniae, it is possible that some polyclonalIgM cold agglutinins arise in association with Citrobacter

A. Kumar (*)Department of Medicine, Saint Michael’s Medical Center,111 Central Avenue,Newark, NJ 07101, USAe-mail: Ice9996@aol.com

H. Shaaban :K. Koduru : S. Abo : I. Sidhom :G. GuronDepartment of Hematology/Oncology, Saint Michael’s MedicalCenter,111 Central Avenue,Newark, NJ 07101, USA

Ann Hematol (2011) 90:855–856DOI 10.1007/s00277-010-1096-9

infections. The mechanisms underlying Citrobacter-inducedcold agglutinin hemolysis require further exploration.

References

1. Bowsher B, Callahan CW, Person DA, Ruess L (1999) Unilateralleptospiral pneumonia and cold agglutinin disease. Chest 116(3):830–832

2. Khan FY, Ayassin M (2009) Mycoplasma pneumoniae associatedwith severe autoimmune hemolytic anemia: case report andliterature review. Brazillian J Infect Dis 13(1):77–79

3. Levinson W (2006) Minor bacterial pathogens. In: Review ofmedical microbiology and immunology, 9th edn. McGraw Hill,New York

4. Gertz M (2008) Management of cold haemolytic syndrome. Br JHaematol 138(4):422–429

5. Schmidt H, Montag M, Bockemühl J, Heesemann J, Karch H (1993)Shiga-like toxin II-related cytotoxins in Citrobacter freundii strainsfrom humans and beef samples. Infect Immun 61(2):534–543

856 Ann Hematol (2011) 90:855–856