malaria is a serious and sometimes fatal disease caused by a parasite , which is commonly seen in developing countries . parenteral artesunate is the first line treatment for severe malaria worldwide , however it is not yet licensed in the united states . we report a case of a returning traveler with fever and delayed hemolytic anemia from artesunate given while in nigeria . a 68 year old african american woman presented with a three day history of fever to 102  f , periods of intermittent confusion , fatigue , anorexia , and myalgia . the patient was treated with artesunate for malaria in nigeria 3 weeks prior to admission . the temperature was 101.6  f , with a pulse of 106  beats / min , blood pressure of 125/80 and oxygen saturation of 99% on room air . laboratory examination revealed a leukocyte count of 21,000/l with 70% neutrophils , 23% lymphocytes , 4% monocytes and 3% eosinophils , a hemoglobin of 8.4  g / dl which dropped to 7.0 on the fifth day of hospitalization , and a platelet count of 306,000 . the serum in the chemistry tube was grossly hemolyzed , with a potassium of 15  meq / l and normal renal function . however , the peripheral smear was remarkable for rouleaux formation and erythrocytes with atypical diamond - shaped central blanched pitting [ fig . 1 ] . further laboratory testing on hospital day 2 revealed an indirect bilirubin of 3.2  mg / dl , total bilirubin 4.4  mg / dl , ldh 965  iu / dl and haptoglobin 326  mg / dl ( normal 43212 ) . the anemia and hemolytic picture worsened over the next few days , before improving [ table 1 ] . on hospital day 3 , the patient was treated with hydroxychloroquine , despite having several peripheral smears negative for parasites . it was later discontinued because the patient developed a diffuse puritic rash thought to be a hypersensitivity reaction . on hospital the patient was discharged to home on hospital day 11 with oral anticoagulation for the pulmonary embolus . severe malaria remains a serious clinical condition with considerable mortality . according to the world health organization , there were an estimated 198 million cases of malaria worldwide ( range 124283 million ) in 2013 , and an estimated 584,000 deaths ( range 367,000755,000 ) an estimated 207 million clinical cases of malaria each year and more than 600,000 malaria related deaths , the burden of disease remains unacceptably high . artesunate is a derivative of the  quing hao  , or sweet wormwood plant , which has been used worldwide for more than 20 years for the treatment of malaria . it is used as first line therapy for severe malaria in sub saharan africa and southeast asia , but is not yet licensed in the united states . although other agents are fda - approved for the treatment of uncomplicated malaria , intravenous quinidine gluconate is currently the only non - oral drug that is fda approved and available to treat severe malaria in the united states . in 2007 , intravenous artesunate was only approved as an investigational new drug ( ind ) protocol by the fda in the united states . there have been 19 reported cases of delayed hemolytic anemia after treatment of severe malaria with artesunate during 20102012 . worldwide , there have been 37 reported cases of hemolysis associated with the use of artemisinin derivatives in the treatment of severe malaria . to our knowledge , there have been only two similar cases of delayed hemolysis due to artesunate therapy described in the united states . two distinct patterns of hemolysis after artesunate therapy have been described : a delayed onset or a persistent pattern of hemolysis . persistent hemolysis is defined as continuing hemolysis starting around day 7 of artemisinin treatment and persisting beyond day 14 . delayed hemolysis typically occurs 23 weeks after completion of artesunate therapy , as in our patient . a delayed hemolytic pattern is defined by a decrease in hemoglobin associated with a low haptoglobin or increase in ldh occurring at least 7 days following artesunate treatment . these latter findings were demonstrated in our patient , and after reviewing the clinical presentation and peripheral smear , it was determined that fever and delayed hemolysis were more likely to have been secondary to recent artesunate therapy in nigeria . one proposed mechanism is a splenic process called pitting , a process where artesunate exposed parasites are expelled from infected erythrocytes in the spleen . the erythrocytes then reseal ( instead of lysing ) and reenter circulation as pitted erythrocytes where they have a shortened lifespan . the delayed clearance of these pitted erythrocytes by the spleen may explain the features of post artesunate delayed hemolysis . a recent french study analyzed the hematologic parameters of 123 travelers treated with arteusnate for severe malaria . among 60 nontransfused patients observed for more than 8 days , 13 ( 22% ) the onset of hemolysis in the second or third week after treatment means that it is most likely to occur after a patient has been discharged from the hospital . . physicians should be aware of this delayed side effect in order to prevent unnecessary further treatment of presumed malaria . cdc has amended the artesunate ind protocol and now recommends that persons treated for severe malaria with artesunate be followed for 4 weeks after treatment and evaluated for hemolytic anemia . still , in many parts of the world where malaria is endemic , artemisinin - based drugs are considered miracle drugs for resistant malaria . a multidisciplinary team approach is important for early diagnosis and appropriate management of this clinical presentation . in returning travelers from countries in which malaria is endemic , physicians in the u.s.a . parenteral artesunate is only released by the cdc when parenteral quinidine is contraindicated , not tolerated or not available . hemolysis probably results from delayed clearance of once infected erythrocytes which continue to circulate after artesunate has killed the parasites .
malaria is a serious and sometimes fatal disease caused by an intraerythrocytic parasite , and is commonly seen in developing countries . 
 approximately 1500 cases of malaria are diagnosed in the united states each year , mostly in travelers and immigrants returning from endemic areas [ 1 ] . 
 there are many different regimens used to treat malaria , some of which are not approved in the usa . 
 the side effects of these medications may not be familiar to physicians in the usa . 
 we report a case of a returning traveler from nigeria presenting with fever and hemolytic anemia caused by a delayed response to artesunate given 3 weeks earlier while in nigeria . to our knowledge , there are few cases reported in the united states of hemolytic anemia secondary to artesunate therapy [ 2 ] .