How does iron overload increase the risk of infection?

Iron overload, either primary (eg, hereditary hemochromatosis) or secondary (eg, hemolysis/frequent transfusion states), may increase the risk of infections through at least 2 mechanisms: 1. Enhancement of the virulence of the pathogen; and 2. Interference with the body’s normal defense system.1-7

Excess iron has been reported to enhance the growth of numerous organisms, ranging from bacteria (eg, Yersinia, Shigella, Vibrio, Listeria, Legionella, Ehrlichia, many other Gram-negative bacteria, staphylococci, streptococci), mycobacteria, fungi (eg, Aspergillus, Rhizopus/Mucor, Cryptococcus, Pneumocystis), protozoa (eg, Entamaeba, Plasmodium, Toxoplasma) and viruses (HIV, hepatitis B/C, cytomegalovirus, parvovirus). 1-7

In addition to enhancing the growth of many pathogens, excess iron may also inhibit macrophage and lymphocyte function and neutrophil chemotaxis .1,2 Iron loading of macrophages results in the inhibition of interferon-gamma mediated pathways and loss of their ability to kill intracellular pathogens such as Legionella, Listeria and Ehrlichia. 2

Not surprisingly, there are numerous reports in the literature of infections in hemochromatosis, including Listeria monocytogenes meningitis, E. Coli septic shock, Yersinia enterocolitica sepsis/liver abscess, Vibrio vulnificus shock (attributed to ingestion of raw oysters) and mucormycosis causing periorbital cellulitis. 2

Bonus pearl: Did you know that the ascitic fluid of patients with cirrhosis has low transferrin levels compared to those with malignancy, potentially enhancing bacterial growth and increasing their susceptibility to spontaneous bacterial peritonitis? 8

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 References

  1. Weinberg ED, Weinberg GA. The role of iron in infection. Curr Opin Infect Dis 1995;8:164-69. https://journals.lww.com/co-infectiousdiseases/abstract/1995/06000/the_role_of_iron_in_infection.4.aspx
  2. Khan FA, Fisher MA, Khakoo RA. Association of hemochromatosis with infectious diseases: expanding spectrum. Intern J Infect Dis 2007;11:482-87. https://www.sciencedirect.com/science/article/pii/S1201971207000811
  3. Thwaites PA, Woods ML. Sepsis and siderosis, Yersinia enterocolitica and hereditary haemochromatosis. BMJ Case Rep 2017. Doi:10.11336/bvr-206-218185. https://casereports.bmj.com/content/2017/bcr-2016-218185
  4. Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis 1999;5:346-52. https://wwwnc.cdc.gov/eid/article/5/3/99-0305-t3
  5. Matthaiou EI, Sass G, Stevens DA, et al. Iron: an essential nutrient for Aspergillus fumigatus and a fulcrum for pathogenesis. Curr Opin Infect Dis 2018;31:506-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579532/
  6. Alexander J, Limaye AP, Ko CW, et al. Association of hepatic iron overload with invasive fungal infection in liver transplant recipients. Liver Transpl 12:1799-1804. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/lt.20827
  7. Schmidt SM. The role of iron in viral infections. Front Biosci (Landmark Ed) 2020;25:893-911. https://pubmed.ncbi.nlm.nih.gov/31585922/
  8. Romero A, Perez-Aurellao JL, Gonzalez-Villaron L et al. Effect of transferrin concentration on bacterial growth in human ascetic fluid from cirrhotic and neoplastic patients. J Clin Invest 1993;23:699-705. https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2362.1993.tb01289.x

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!

How does iron overload increase the risk of infection?

My patient with acute onset headache, photophobia, and neck stiffness does not have CSF pleocytosis. Could she still have meningitis?

Although the clinical diagnosis of meningitis is often supported by the presence of abnormal number of WBCs in the CSF (AKA pleocytosis), meningitis may be present despite its absence.

Among viral causes of meningitis in adults, enteroviruses are associated with lower CSF WBC count compared to herpes simplex and varicella zoster, with some patients (~10%) having 0-2 WBC’s/mm31,2.  Of interest, among children, parechovirus (formerly echovirus 22 and 23) meningitis is characterized by normal CSF findings3.

Though uncommon, bacterial meningitis without CSF pleocytosis has been reported among non-neutropenic adults,  including Neisseria meningitidis, Streptococcus pneumoniae, Hemophilus influenzae, Listeria monocytogenes, E. coli, and Proteus mirabilis4A European study also reported normal CSF WBC in nearly 10% of patients with Lyme neuroborreliosis (including meningitis) caused primarily by Borrelia garinii5.

Cryptococcal meninigitis may also be associated with normal CSF profile in 25% of patients with HIV infection6.

 

References

  1. Ihekwaba UK, Kudesia G, McKendrick MW. Clinical features of viral meningitis in adult:significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections. Clin Infect Dis 2008;47:783-9. https://www.ncbi.nlm.nih.gov/pubmed/18680414
  2. Dawood N, Desjobert E, Lumley J et al. Confirmed viral meningitis with normal CSF findings. BMJ Case Rep 2014. Doi:10.1136/bcr-2014-203733. http://casereports.bmj.com/content/2014/bcr-2014-203733.abstract
  3. Wolthers KC, Benschop KSM, Schinkel J, et al. Human parechovirus as an important viral cause of sepsis like illness and meningitis in young children. Clin Infect Dis 2008;47:358-63. https://www.ncbi.nlm.nih.gov/pubmed/18558876
  4. Hase R, Hosokawa N, Yaegashi M, et al. Bacterial meningitis in the absence of cerebrospinal fluid pleocytosis: A case report and review of the literature. Can J Infect Dis Med Microbiol 2014;25:249:51. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211346/pdf/idmm-25-249.pdf
  5. Ogrinc K, Lotric-Furlan S, Maraspin  V, et al. Suspected early Lyme neuroborreliosis in patients with erythema migrans. Clin Infect Dis 2013; 57:501-9. https://www.ncbi.nlm.nih.gov/pubmed?term=23667259
  6. Darras-Joly C, Chevret S, Wolff M, et al. Cryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus. Clin Infect Dis 1996;23:369-76. https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/cid/23/2/10.1093/clinids/23.2.369/2/23-2-369.pdf?Expires=1501035620&Signature=FhHMHUHAMmT3rz4ld8QAMet-weu-BWgm5YR6nA4jjSGVGIeaVlMNPgeOkW2fniiel54HQhIs1Kkp3PpzT1glxhJeZvQiGXQCSOoF-jS1SK7S~kBb-oHs4qsIJzN0OJxNAXfoJi4bl7OeKaLTyIE3P8~slwH0BBi7RncSYVgVR4NkOnFpYgn27~wY7pDSUNWvzGFKoSeYGeM0TsAqna-QmXzodITB5bgr1mO6Q6OGUxCsqRwhr6xNb~4G93oqRcsO19gyUluCE0xYt0KbKWuQxJeh8AbtJkNrS08~XInMR50bQZOUb80j0~dtg9jRTGzXQaDllVByoX2Alr48hlhogw__&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q
My patient with acute onset headache, photophobia, and neck stiffness does not have CSF pleocytosis. Could she still have meningitis?