Is there a connection between eosinophils and sickle cell anemia?

Patients with sickle cell anemia (SCA) frequently (~55%) demonstrate absolute eosinophil count (AEC) (>450 cells/uL) during non-crisis steady state without significant change during sickle cell crisis [1-4]. Although the exact mechanism for this finding is not clear, it may be related to elevated plasma levels of circulating factors such as eotaxin, IL-5, and GM-CSF in SCA [2,3].

Cumulative data from 3 independent cross-sectional studies involving 131 SCA patients reported a mean AEC of ~498 cells/u (range 490-504 cells/uL) when not in crisis [2,3,6]. Surprisingly, two additional studies evaluating 200 patients did not observe a significant difference in AEC between steady- and crisis-states [1,4].

The significance of elevated AEC in patients with SCA is unclear. Of interest, several studies of eosinophils isolated from patients with SCA have demonstrated increased eosinophil adhesion to blood vessels, degranulation, and reactive oxygen species production compared to healthy controls [5,6]. In another study, hydroxyurea was shown to reduce eosinophil adhesion and degranulation [2].

While it is unknown whether eosinophils directly contribute to the development of vaso-occlusive crisis, these studies suggest eosinophils may be an important therapeutic target in SCA. 

Bonus pearl: Did you know that low eosinophil count may help predict infection in SCA patients? A retrospective study of SCA patients with and without infection showed that relative eosinopenia (0.025 compared to 0.2 x 109 cells/L) was highly sensitive (100%) and specific (93.3%) for infection [7].

Contributed by Michael Nance MD, PhD, Department of Medicine, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Ekeke GI. Sickle cell disease: some haematological changes in steady state and crisis. Biomed Biochem Acta 1987; 46:S197-S201. https://pubmed.ncbi.nlm.nih.gov/3593298/
  2. Pallis FR, Nicola Conran, Kleber Yotsumoto Fertrin, Sara T. Olalla-Saad, Fernando Ferreira Costa, Carla Fernanda Franco-Penteado; Altered Functional Properties of Eosinophils In Sickle Cell Anemia and Effects of Hydroxyurea Therapy. Blood 2010; 116 (21): 2656. https://doi.org/10.1182/blood.V116.21.2656.2656
  3. Conran N, Saad ST, Costa FF, Ikuta T. Leukocyte numbers correlate with plasma levels of granulocyte-macrophage colony-stimulating factor in sickle cell disease. Ann Hematol. 2007; 86(4):255-261. https://pubmed.ncbi.nlm.nih.gov/17205286/
  4. Klouda T, Raybagkar D, Bernstein B, Apollonsky N, “Changes in Blood Profile from Steady State in Patients with Sickle Cell Anemia Admitted for Vaso-occlusive Crisis and Acute Chest Syndrome”, Advances in Hematology, vol. 2020, Article ID 3656717, 5 pages, 2020. https://doi.org/10.1155/2020/3656717
  5. Canalli AA, Conran N, Fattori A, Saad ST, Costa FF. Increased adhesive properties of eosinophils in sickle cell disease. Exp Hematol. 2004; 32(8):728-734. https://pubmed.ncbi.nlm.nih.gov/15308324/
  6. Pallis FR, Conran N, Fertrin KY, Olalla Saad ST, Costa FF, Franco-Penteado CF. Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients. Br J Haematol. 2014; 164(2):286-295. https://pubmed.ncbi.nlm.nih.gov/24383847/
  7. Ahmed, SG and Uraka, A. Eosinopenia as a marker of infection in patients with sickle cell anemia: A preliminary report. Int. J. Biomed. Health Sci. 2010. 6(1):57-61. http://www.ojs.klobexjournals.com/index.php/ijbhs/article/viewFile/671/741

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is there a connection between eosinophils and sickle cell anemia?

My patient has developed isolated eosinophilia without symptoms while receiving an antibiotic. Should I consider discontinuing the antibiotic or can I just continue it as long as she has no symptoms?

Short answer: We don’t really know what’s the best way to manage patients with  isolated (asymptomatic) eosinophilia (IE) that develops during antibiotic therapy. We do know that the majority of patients with IE may never develop hypersensitivity reaction such as rash, renal or liver injuries, but predicting who will or will not get HSRs is a challenge.1-3 Couple of studies may help us in our decision making, however.

In a 2015 study1 involving patients receiving outpatient parenteral antibiotics, eosinophilia was present in 25% of patients during their course of treatment, of whom 30% subsequently developed HSR and 5% developed more than 1 sign of HSR. Patients with IE and subsequent HSR developed eosinophilia earlier in their course of treatment (median 11 vs 17 days) and had a higher peak absolute eosinophil count (~ 850 vs ~700/ ml).  The authors suggested that close monitoring for rash and renal injury in patient with IE during antibiotic therapy be considered, and that medication changes may be necessary when IE is associated with earlier onset of eosinophilia or higher absolute eosinophil count.

In a 2017 prospective study2 of patients with eosinophilic drug reactions (~20% related to antibiotics), the majority (56%) were asymptomatic. Earlier onset of eosinophilia and higher eosinophil count were associated with symptomatic eosinophilia, similar to the aforementioned study. The frequency of patients with IE who went on to have symptomatic eosinophilia when the suspect drug was continued vs those in whom it was not continued remains unclear from these studies.

Ultimately, the decision to continue or discontinue a suspect antibiotic when your patient has new-onset IE should be made on a case-by-case basis, taking into account the severity of the patient’s infection, availability of equally effective and tolerated alternative drugs and the ability to closely monitor for symptomatic disease. The timing of onset of eosinophilia and its peak absolute count may also play a role.

Bonus pearl: Did you know that only 18% of inpatients with cutaneous drug eruptions may have peripheral eosinophilia?4

The author acknowledges the invaluable input of Kimberly Blumenthal, MD in composing this pearl.

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References

  1. Blumenthal KG, Youngster I, Rabideau DJ, et al. Peripheral blood eosinophilia and hypersensitivity reactions among patients receiving outpatient parenteral antibiotics. J Allergy Clin Immunol 2015;136:1288.1294. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640981/
  2. Ramirez E, Mdrano-Casique N, Tong HY, et al. Eosinophilic drug reactions detected by a prospective pharmacovigilance programme in a tertiary hospital. Br J Pharmacol 2017;83:400-15. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.13096
  3. Rauscher C, Freeman A. Drug-induced eosinophilia. Allergy Asthma Proc 2018;39:252-56. https://www.ncbi.nlm.nih.gov/pubmed/29669671
  4. Romagosa R, Kapoor S, Sanders J, et al. inpatient adverse cutaneous drug erutpions and eosinophilia. Arch Dermatol 2001; 137:511-12. https://www.ncbi.nlm.nih.gov/pubmed/11295947   

 

 

My patient has developed isolated eosinophilia without symptoms while receiving an antibiotic. Should I consider discontinuing the antibiotic or can I just continue it as long as she has no symptoms?