To the Editor: Calis et al. (Feb. 28 issue)1 report a significantassociation of bacteremia with severe anemia in Malawi. Bacteremiain case patients and control patients was mainly due to nontyphoidsalmonella. The study showed that nontyphoid salmonella bacteremiawas present in 10.0% of case patients with severe anemia andin 1.5% of controls. This association has been consistentlynoted in other studies of childhood bacteremia in tropical Africa.2
As discussed in the report, the association does not necessarilymean that nontyphoid salmonella bacteremia is a common causeof severe anemia. There are data suggesting that nontyphoidsalmonella bacteremia is more likely to be a consequence ofsevere anemia, especially when anemia is due to hemolysis ratherthan to other causes, such as blood loss.2,3,4 The questionof whether nontyphoid salmonella bacteremia is a cause or aconsequence of severe anemia has implications for clinical managementand potential preventive strategies.
Stephen M. Graham, F.R.A.C.P. University of Melbourne Melbourne, VIC 3052, Australia steve.graham{at}rch.org.au
References
Calis JCJ, Phiri KS, Faragher EB, et al. Severe anemia in Malawian children. N Engl J Med 2008;358:888-899. [Free Full Text]
Graham SM, Molyneux EM, Walsh AL, Cheesbrough JS, Molyneux ME, Hart CA. Nontyphoidal Salmonella infections of children in tropical Africa. Pediatr Infect Dis J 2000;19:1189-1196. [ISI][Medline]
Bronzan RN, Taylor TE, Mwenechanya J, et al. Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection, and outcome. J Infect Dis 2007;195:895-904. [CrossRef][ISI][Medline]
Kaye D, Hook EW. The influence of hemolysis or blood loss on susceptibility to infection. J Immunol 1963;91:65-75. [Free Full Text]
To the Editor: The conclusion by Calis et al. that iron deficiencywas not a prominent cause of severe anemia in Malawian childrenwould have been more convincing if the results of bone marrowiron staining in the case patients had been reported. Analysisof the amount of stainable iron in bone marrow aspirates isconsidered to be the most valuable tool for assessing whethersufficient iron is available for erythropoiesis. Furthermore,the accuracy of the ratio of soluble transferrin receptor (TfR)to log ferritin for diagnosing iron deficiency may have beenhampered by the high prevalence of viral, bacterial, and parasiticinfections in the case patients. TfR levels are predominantlydetermined by erythropoietic activity,1 and suppressed erythropoiesisis a common observation in infections,2 such as malaria andhuman immunodeficiency virus infection. Moreover, inflammationincreases ferritin levels independently of body iron stores.3
Quirijn de Mast, M.D. Dorine Swinkels, M.D., Ph.D. Andre van der Ven, M.D., Ph.D. Radboud University Nijmegen Medical Center 6500 HB Nijmegen, the Netherlands q.demast{at}aig.umcn.nl
References
Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta 2003;329:9-22. [CrossRef][ISI][Medline]
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-1023. [Free Full Text]
Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002;99:3505-3516. [Free Full Text]
To the Editor: On the basis of plasma folate measurements, Caliset al. assert that folate deficiency was absent among Malawianchildren with severe anemia. However, the authors did not conclusivelyrule out folate deficiency by measurement of plasma homocysteine(and methylmalonic acid).1,2
Low plasma folate values support the diagnosis of folate deficiencyin uncomplicated anemia, but because erythrocyte folate valuesare 30 times as high as plasma folate values, even a small degreeof (intravascular) hemolysis can raise plasma folate valuesand mask cellular folate deficiency. The burden rests on theseinvestigators to unambiguously establish the absence of folatedeficiency in sick and undernourished children.3
Asok C. Antony, M.D. Indiana University School of Medicine Indianapolis, IN 46202
References
Antony AC. Megaloblastic anemias. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al., eds. Hematology: basic principles and practice. 4th ed. Philadelphia: Churchill Livingstone, 2005:519-56.
Antony AC. Vegetarianism and vitamin B-12 (cobalamin) deficiency. Am J Clin Nutr 2003;78:3-6. [Free Full Text]
Antony AC. Prevalence of cobalamin (vitamin B-12) and folate deficiency in India -- audi alteram partem. Am J Clin Nutr 2001;74:157-159. [Free Full Text]
The authors reply: In response to Graham: bacteremia —and especially nontyphoid salmonella — is a common findingin severely anemic children in Malawi. Excessive hemolysis maybenefit the growth of nontyphoid salmonella,1 and thus, nontyphoidsalmonella may not necessarily cause severe anemia. We foundthat gross hemolysis was not a major feature in our population(unpublished data). Alternatively, nontyphoid salmonella maycause or worsen the anemia and can jeopardize bone marrow function.We concluded that, since 15% of the severely anemic childrenhad bacteremia, routine treatment with antibiotics may be justified.
In response to de Mast and colleagues: we assessed the diagnosticaccuracy of peripheral-blood markers for iron status using iron-stainedbone marrow slides as the standard and found that the ratioof soluble TfR to log ferritin best predicted bone marrow ironstatus.2 Using this ratio, we assessed the iron status in thecase–control study and found a reversed odds ratio. Wevalidated this finding using four other, well-known markersof iron deficiency (see Table 3 of our article). All analysesshowed the same reversed odds ratio, which makes it unlikelythat our findings can be explained by an effect of inflammationon erythropoiesis.
In response to Antony: it is theoretically possible that hemolysisand vitamin B12 deficiency have masked folate deficiency. Weperformed an additional analysis to study the possible confoundingeffect of hemolysis. Laboratory values compatible with hemolysiswere found in only a minority of severely anemic children. Wefound folate deficiency in the absence of abnormal hemolysis.We did not evaluate the source of dietary folate intake in thesechildren in detail, but green vegetables and fruits accountfor a large proportion of the dietary intake of children inMalawi and are well-known sources of folate. Considering thediet in Malawi and the findings of previous studies from Africaon folate deficiency and supplementation, our findings are notsurprising.3,4
Chlosta S, Fishman DS, Harrington L, et al. The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica. Infect Immun 2006;74:3065-3067. [Free Full Text]
Phiri KS. Assessment of iron deficiency in Malawian children living in an area of high malaria and bacterial infection morbidity. Liverpool, England: Liverpool School of Tropical Medicine, 2006.
Abdalla SH. Iron and folate status in Gambian children with malaria. Ann Trop Paediatr 1990;10:265-272. [Medline]
van Hensbroek MB, Morris-Jones S, Meisner S, et al. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Trans R Soc Trop Med Hyg 1995;89:672-676. [CrossRef][ISI][Medline]
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