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What’s the connection between Covid-19 and cytokine release syndrome?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Severe Covid-19 is associated with a high inflammatory state similar to that seen in cytokine release syndrome (CRS) in adults with secondary hemophagocytic lymphohistiocytosis (sHLH) which is often due to viral infections.1,2

sHLH is characterized by unremitting fever, pulmonary involvement (including ARDS), pancytopenias, and high serum levels of ferritin, C-reactive protein (CRP) and many inflammatory cytokines, such as Interleukin (IL)-6. These features are also often seen in severe Covid-19 disease. In fact, elevated serum IL-6 has been shown to be associated with respiratory failure, ARDS, adverse clinical outcomes, and death in Covid-19.1,2  

Why CRS in Covid-19? It all begins with SARS-CoV2 activation of monocytes, macrophages and dendritic cells leading to IL-6 release. IL-6 in turn activates B and T lymphocytes as well as the innate immune system. In addition, IL-6 has a profound effect on endothelial cells resulting in vascular permeability, neutrophil recruitment and further increase in IL-6 production, setting the stage for a “perfect  cytokine storm.”  IL-6 also induces the liver to synthesize CRP and ferritin.

The importance of IL-6 in severe Covid-19 is further highlighted by the excitement surrounding drugs that block its action, potentially improving morbidity and mortality in this disease. Tocilizumab, a monoclonal antibody against IL-6 receptor used in the treatment of certain rheumatological diseases and CRS in CAR T cell therapy, looks promising.3

Bonus Pearl: Did you know that IL-6 was formally called B-cell stimulatory factor-2 because it induced B cells to produce immunoglobulins?

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References

 

  1. Moore JB, June CH. Cytokine release syndrome in severe Covid-19. Science 2020;368:473-4. doi:10.1126/science.abb8925
  2. Mehta P, McAuley DF, Brown M, et al. Covid-19:consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
  3. Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19. J Transl Med 2020;18:164. https://translational-medicine.biomedcentral.com/track/pdf/10.1186/s12967-020-02339-3
  4. Kishimoto T. IL-6: From its discovery to clinical applications. Int Immunol 2010;22:347-52. https://pubmed.ncbi.nlm.nih.gov/20410258/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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!

What’s the connection between Covid-19 and cytokine release syndrome?

Should I routinely screen my patients with heart failure for iron deficiency?

FA Manian MD, MPH, , , , , , , Leave a comment

Even in the absence of anemia, screening for iron deficiency (ID) has been recommended in patients with heart failure (HF) with reduced ejection fraction (HFrEF) by some European and Australia-New Zealand cardiology societies. 1

In contrast, the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines do not mention routine screening for ID in such patients but instead state (under “Anemia”) that in patients with NYHA class II and III HF and ID (ferritin < 100 ng/mL or 100 to 300 ng/mL plus transferrin saturation <20%), IV iron replacement “might be reasonable” to improve functional status and quality of life (IIb-weak recommendation).2

As these guidelines are primarily based on data derived from patients with HFrEF, whether patients with HF with preserved (eg, >45%) ejection fraction (HFpEF) should undergo routine screening for ID is even less clear due to conflicting data based on limited small studies 3,4

What is known is that up to 50% or more of patients with HF with or without anemia may have ID. 5 Although most studies involving ID and HF have involved patients with HFrEF, similarly high prevalence of ID in HFpEF has been reported. 6,7

A 2016 meta-analysis involving patients with HFrEF and ID found that IV iron therapy alleviates HF symptoms and improves outcomes, exercise capacity and quality of life irrespective of concomitant anemia; all-cause and cardiovascular mortality rates were not significantly impacted, however.8  

Fortunately, larger trials in the setting of acute and chronic systolic HF are underway (Affirm-AHF, 9 IRONMAN 10).  Stay tuned!

Bonus Pearl: Did you know that iron deficiency directly affects human cardiomyocyte function by impairing mitochondrial respiration  and reducing its contractility and relaxation?11

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References

  1. Silverberg DS, Wexler D, Schwartz D. Is correction of iron deficiency a new addition to the treatment of the heart failure? Int J Mol Sci 2015;16:14056-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490538/
  2. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2017;136:e137-e161. https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000509
  3. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. International J of Cardiol 2013;168:12:4652-57. https://www.ncbi.nlm.nih.gov/pubmed/23968714
  4. Enjuanes C, Klip IT, Bruguera J, et al. Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. Int J Cardiol 2014;174:268-275. https://www.ncbi.nlm.nih.gov/pubmed/24768464
  5. Drodz M, Jankowska EA, Banasiak W, et al. Iron therapy in patients with heart failure and iron deficiency: review of iron preparations for practitioners. Am J Cardiovasc Drugs 2017;17:183-201. https://www.ncbi.nlm.nih.gov/pubmed/28039585
  6. Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2018, July 26. Doi: 10. 1007/s00392-018-1344-x. https://www.ncbi.nlm.nih.gov/pubmed/30051186
  7. Nunez J, Dominguez E, Ramon JM, et al. Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction. International J Cardiol 2016;207:365-67. https://www.internationaljournalofcardiology.com/article/S0167-5273(16)30185-1/abstract
  8. Jankowska EA, Tkaczynszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Failure 2016;18:786-95. https://www.ncbi.nlm.nih.gov/pubmed/26821594
  9. https://clinicaltrials.gov/ct2/show/NCT02937454
  10. https://clinicaltrials.gov/ct2/show/NCT02642562
  11. Hoes MF, Beverborg NG, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyoctyes through decreased mitochondrial function. Eur J Heart Failure 2018;20:910-19. https://www.ncbi.nlm.nih.gov/pubmed/29484788  

 

Should I routinely screen my patients with heart failure for iron deficiency?

What is the mechanism of anemia of chronic disease in my patient with rheumatoid arthritis?

FA Manian MD, MPH, , , , , , Leave a comment

Anemia of chronic disease (ACD)—or more aptly “anemia of inflammation”— is the second most common cause of anemia after iron deficiency and is associated with numerous acute or chronic conditions (eg, infection, cancer, autoimmune diseases, chronic organ rejection, and chronic kidney disease)1.

The hallmark of ACD is disturbances in iron homeostasis which result in increased uptake and retention of iron within cells of the reticuloendothelial system, with its attendant diversion of iron from the circulation and reduced availability for erythropoiesis1. More specifically, pathogens, cancer cells, or even the body’s own immune system stimulate CD3+ T cells and macrophages to produce a variety of cytokines, (eg, interferon-ɤ, TNF-α, IL-1, IL-6, and IL-10) which in turn increase iron storage within macrophages through induction of expression of ferritin, transferrin and divalent metal transporter 1.

In addition to increased macrophage storage of iron, ACD is also associated with IL-6-induced synthesis of hepcidin, a peptide secreted by the liver that decreases iron absorption from the duodenum and its release from macrophages2. TNF-α and interferon-ɤ also contribute to ACD by inhibiting the production of erythropoietin by the kidney.  Finally, the life span of RBCs is adversely impacted in AKD due to their reduced deformability and increased adherence to the endothelium in inflammatory states3.

Of interest, it is often postulated that by limiting access to iron through inflammation, the body hinders the growth of pathogens by depriving them of this important mineral2.

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References

  1. Weiss, G and Goodnough, L. Anemia of chronic disease. N Engl J Med 2005; 352; 1011-23. http://www.med.unc.edu/medclerk/medselect/files/anemia2.pdf
  2. D’Angelo, G. Role of hepcidin in the pathophysiology and diagnosis of anemia. Blood Res 2013; 48(1): 10-15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624997/pdf/br-48-10.pdf                                                                                                                                  
  3. Straat M, van Bruggen R, de Korte D, et al. Red blood cell clearance in inflammation. Transfus Med Hemother 2012;39:353-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678279/pdf/tmh-0039-0353.pdf

 

Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

                     

What is the mechanism of anemia of chronic disease in my patient with rheumatoid arthritis?