Severe Plasmodium Falciparum Malaria: Utility of Exchange Transfusion

1. Severe Plasmodium Falciparum Malaria: Utility of Exchange Transfusion JC Hofmann, MD; SJ Smith, RN; RM Rohe, RN; DD Kiprov, MD Division of Immunotherapy California Pacific Medical Center Bay Area Mobile Apheresis Program (BAMAP) San Francisco, California

2. Background • Infections due to malaria ? estimated 1.0-2.5 million deaths/yr. • Most malaria deaths due to plasmodium falciparum. • Non-immune travelers and children < 5 y.o. susceptible to severe infection. • Case fatality rate of imported falciparum malaria = 0.6-3.8%. • Progression from asymptomatic infection to death: 36-48 hrs. • Among U.S. civilians who die of malaria ? dx missed in 40%. • severe falciparum malaria ? altered consciousness, jaundice, severe normocytic anemia, oliguria, hypoglycemia, multiorgan failure, and parasitemia > 5%. Infections due to malaria cause an estimated 1.0 to 2.5 million deaths each year, mainly in tropical developing countries. Most malaria associated deaths are due to Plasmodium falciparum; children under the age of 5 years and non-immune travelers are especially vulnerable to severe infection. The case fatality rate of imported falciparum malaria varies from 0.6 to 3.8%. Progression from asymptomatic infection to death can occur in as little as 36 to 48 hours. Among US citizens who die of malaria, the diagnosis is initially missed in approximately 40% of cases. Patients are considered to have severe malaria (which is almost always caused by plasmodium falciparum), if they exhibit altered consciousness, jaundice, severe anemia, oliguria, hypoglycemia, multiorgan failure, and a parasitemia > 5%. Other complications of severe falciparum malaria include: seizures, acute renal failure, ARDS, and electrolyte & acid/base disorders. Infections due to malaria cause an estimated 1.0 to 2.5 million deaths each year, mainly in tropical developing countries. Most malaria associated deaths are due to Plasmodium falciparum; children under the age of 5 years and non-immune travelers are especially vulnerable to severe infection. The case fatality rate of imported falciparum malaria varies from 0.6 to 3.8%. Progression from asymptomatic infection to death can occur in as little as 36 to 48 hours. Among US citizens who die of malaria, the diagnosis is initially missed in approximately 40% of cases. Patients are considered to have severe malaria (which is almost always caused by plasmodium falciparum), if they exhibit altered consciousness, jaundice, severe anemia, oliguria, hypoglycemia, multiorgan failure, and a parasitemia > 5%. Other complications of severe falciparum malaria include: seizures, acute renal failure, ARDS, and electrolyte & acid/base disorders.

3. Treatment Severe Falciparum Malaria: • ICU management for close monitoring. • Blood smears Q 12 hrs. until parasitemia levels < 1%. • Antimalarial drugs: • quinoline derivatives: quinine, quinidine, chloroquine, mefloquine. • antimicrobials: clindamycin, doxycycline, tetracycline. • antifolates: sulfonamides, dapsone, pyrimethamine. • artemisinin derivatives: artemisinin, artemether. The treatment for severe falciparum malaria includes: Managing patients in an ICU setting where close monitoring of respiratory, cardiac, renal, and neurologic status can be done optimally. Thick and thin blood smears should be done at least every 12 hours to monitor the efficacy of therapy until the parasitemia is < 1%. Most patients with severe falciparum malaria will need to be treated with intravenous antimalarial drugs until they can tolerate oral medications. Quinolone derivatives such as quinidine and quinine, and antimicrobials such as doxycycline and clindamycin are usually the primary drug therapy for falciparum malaria because they target parasites in the intra-erythrocytic phase. ----------------------------------------------------------------------------------------------------------------------------------------------- The antifolates kill intrahepatic forms of the parasite. The artemisinin derivatives bind iron in the malarial pigment to produce free radicals that damage parasite proteins.The treatment for severe falciparum malaria includes: Managing patients in an ICU setting where close monitoring of respiratory, cardiac, renal, and neurologic status can be done optimally. Thick and thin blood smears should be done at least every 12 hours to monitor the efficacy of therapy until the parasitemia is < 1%. Most patients with severe falciparum malaria will need to be treated with intravenous antimalarial drugs until they can tolerate oral medications. Quinolone derivatives such as quinidine and quinine, and antimicrobials such as doxycycline and clindamycin are usually the primary drug therapy for falciparum malaria because they target parasites in the intra-erythrocytic phase. ----------------------------------------------------------------------------------------------------------------------------------------------- The antifolates kill intrahepatic forms of the parasite. The artemisinin derivatives bind iron in the malarial pigment to produce free radicals that damage parasite proteins.

4. Adjunctive Treatment RBC exchange transfusion (ET) recommended in falciparum infection: Parasitemia > 10%. In coma, renal failure, or ARDS, regardless of parasitemia level. ET removes parasitized RBCs, parasitic toxins, & cytokines. • ET should be combined with drug therapy ? parasitemia < 5%. • Phillips et al (1990): ET not proven to enhance survival. • Riddle et al (2002): meta-analysis: no greater survival rate with using ET compared to antimalarials alone. • No RCT has yet been performed. The general recommendation in the literature is that RBC exchange transfusion is currently recommended in Falciparum infection: When the parasitemia level > 10%. In patients with coma, renal failure, or ARDS, regardless of the parasitemia level. Exchange transfusion removes parasitized red blood cells, parasitic toxins, & cytokines, and replaces them with fresh plasma and unparasitized red cells. Exchange transfusion should be combined with drug therapy and continued until the level of parasitemia < 5% Despite dramatic clinical improvements associated with exchange transfusions in patients with severe malaria and many case reports attesting to this fact, studies have not borne this out: In 1990, Phillips et al showed that exchange transfusion did not enhance survival. In 2002, Riddle et al in a meta-analysis showed no greater survival rate among patients who received exchange transfusions compared to antimalarials alone. The problem, in general, with these analyses is that patients in these studies who received the exchange transfusions had higher degrees of parasitemia and more severe disease, and were not comparable to those receiving medications alone. To date, no randomized controlled trial has been done. The general recommendation in the literature is that RBC exchange transfusion is currently recommended in Falciparum infection: When the parasitemia level > 10%. In patients with coma, renal failure, or ARDS, regardless of the parasitemia level. Exchange transfusion removes parasitized red blood cells, parasitic toxins, & cytokines, and replaces them with fresh plasma and unparasitized red cells. Exchange transfusion should be combined with drug therapy and continued until the level of parasitemia < 5% Despite dramatic clinical improvements associated with exchange transfusions in patients with severe malaria and many case reports attesting to this fact, studies have not borne this out: In 1990, Phillips et al showed that exchange transfusion did not enhance survival. In 2002, Riddle et al in a meta-analysis showed no greater survival rate among patients who received exchange transfusions compared to antimalarials alone. The problem, in general, with these analyses is that patients in these studies who received the exchange transfusions had higher degrees of parasitemia and more severe disease, and were not comparable to those receiving medications alone. To date, no randomized controlled trial has been done.

5. Patients 3 patients diagnosed with severe falciparum malaria in 11 months (referred for RBC exchange transfusion): 44-68 y.o. and non- or partially-immunized travelers. 67% patients were female. visited rural sub-Saharan Africa in prior 30 days. experienced a 4-5 day h/o flu-like symptoms. • 33% patients had prior h/o falciparum malaria. We report on 3 patients with severe falciparum malaria in the past 11 months who were referred for red blood cell exchange transfusion. All patients were middle-aged to elderly (44-68 years old), and non- (or partially) immunized travelers. 1 patient was a 45 y.o. ICU nurse with h/o moderately severe RA (on MTX and infliximab) who had returned from Mali, Africa and had taken no malaria prophylaxis. Our second patient was a 44 y.o. African male (living in the U.S.) who had rushed back to Cameron, Africa to visit his father who had just had a stroke; he also took no prophylaxis. And our last patient was a 68 y.o. female scientist who had spent 4 days in the rain forest in part of Kenya and was partially immunized. 67% (2 of 3) patients were female. All of our patients had visited rural areas of sub-Saharan Africa within the past 30 days and experienced a 4-5 day h/o of flu-like symptoms, including fever, chills, headaches, myalgias, fatigue, nausea, and abdominal pain, prior to admission. 33% (1 of 3) patients had a history of prior falciparum malaria infection.We report on 3 patients with severe falciparum malaria in the past 11 months who were referred for red blood cell exchange transfusion. All patients were middle-aged to elderly (44-68 years old), and non- (or partially) immunized travelers. 1 patient was a 45 y.o. ICU nurse with h/o moderately severe RA (on MTX and infliximab) who had returned from Mali, Africa and had taken no malaria prophylaxis. Our second patient was a 44 y.o. African male (living in the U.S.) who had rushed back to Cameron, Africa to visit his father who had just had a stroke; he also took no prophylaxis. And our last patient was a 68 y.o. female scientist who had spent 4 days in the rain forest in part of Kenya and was partially immunized. 67% (2 of 3) patients were female. All of our patients had visited rural areas of sub-Saharan Africa within the past 30 days and experienced a 4-5 day h/o of flu-like symptoms, including fever, chills, headaches, myalgias, fatigue, nausea, and abdominal pain, prior to admission. 33% (1 of 3) patients had a history of prior falciparum malaria infection.

6. Patients 3 patients diagnosed with severe falciparum malaria: presented with moderately severe hypotension, anemia, & thrombocytopenia. 67% patients experienced mental status abnormalities, renal insufficiency, hematuria, and cholestasis (1 patient had mild DIC). 1 patient fulfilled criteria for cerebral malaria. All of our patients presented with moderately severe hypotension (1 patient required vasopressor therapy), as well as anemia, and thrombocytopenia. 67% (2 of 3) patients experienced CNS abnormalities (including headaches, aphasia, somnolence, seizures, and obtundation), in addition to renal insufficiency, hematuria, and cholestasis. 1 patient had mild DIC. And finally, 1 patient fulfilled the WHO criteria for cerebral malaria (which is defined as reversible encephalopathy with seizures and LOC, or unarousable coma not localizing to noxious stimuli). [this was the ICU nurse with an underlying autoimmune disease (on systemic immunosuppressants) who took no prophylaxis] All of our patients presented with moderately severe hypotension (1 patient required vasopressor therapy), as well as anemia, and thrombocytopenia. 67% (2 of 3) patients experienced CNS abnormalities (including headaches, aphasia, somnolence, seizures, and obtundation), in addition to renal insufficiency, hematuria, and cholestasis. 1 patient had mild DIC. And finally, 1 patient fulfilled the WHO criteria for cerebral malaria (which is defined as reversible encephalopathy with seizures and LOC, or unarousable coma not localizing to noxious stimuli). [this was the ICU nurse with an underlying autoimmune disease (on systemic immunosuppressants) who took no prophylaxis]

7. Treatment IV quinidine (+/- IV doxycycline) for 8-24 hrs. prior to receiving single RBC exchange transfusion (8-10 units of RBCs). Premedication: acetaminophen, diphenylhydramine, & hydrocortisone. Mean volume of RBCs exchanged = 2777 ml (2500-3060 ml). Average FCR (fraction cells remaining) = 33% (27-42%). All patients were treated with intraveneous quinidine (+/- intraveneous doxycycline) for 8-24 hours prior to receiving a single RBC exchange transfusion using 8-10 units of packed RBCs. Pre-medication included acetaminophen, diphenylhydramine, and hydrocortisone. The mean volume of RBCs exchanged was 2777 ml (with a range of 2500-3060 ml). The average fraction of cells remaining (this is the fraction of original red cells remaining after the RBC exchange) was 33% (with a range of 27-42%). All patients were treated with intraveneous quinidine (+/- intraveneous doxycycline) for 8-24 hours prior to receiving a single RBC exchange transfusion using 8-10 units of packed RBCs. Pre-medication included acetaminophen, diphenylhydramine, and hydrocortisone. The mean volume of RBCs exchanged was 2777 ml (with a range of 2500-3060 ml). The average fraction of cells remaining (this is the fraction of original red cells remaining after the RBC exchange) was 33% (with a range of 27-42%).

8. Results Significant ? level of parasitemia: Initial mean parasitemia = 38% (10-90%). Mean parasitemia (prior to RBC exchange transfusion) = 8% (5-15%). Mean parasitemia (6-12 hrs. after treatment) = 1.1% (0.3-2.0%). Dramatic improvement in clinical status: Significant resolution of fever, chills, hypotension, mental status abnormalities, nausea, and abdominal pain. 67% patients able to tolerate oral quinine and doxycycline after single RBC exchange transfusion. All patients experienced a significant decrease in the level of parasitemia and a dramatic improvement in their clinical status. The initial mean parasitemia level was 38% (with a range of 10-90%); the non-immunized immunosuppressed ICU nurse had the initial parasitemia level of 90% and subsequently developed cerebral malaria. The mean parasitemia level prior to RBC exchange transfusion was 8% (with a range of 5-15%). The mean parasitemia level 6-24 hours after a single treatment was 1.1% (range of 0.3-2.0%) indicating an 8-fold decrease in circulating parasite burden. Concurrent with the improvement in lab indices, each of the patients experienced significant resolution of fever, chills, hypotension, CNS abnormalities, nausea, and abdominal pain. 67% (2 of 3) patients were able to tolerate oral quinine and doxycycline after a single treatment. [Given the clinical improvement in all three cases, a second RBC exchange was not felt to be necessary (and was not advised).] All patients experienced a significant decrease in the level of parasitemia and a dramatic improvement in their clinical status. The initial mean parasitemia level was 38% (with a range of 10-90%); the non-immunized immunosuppressed ICU nurse had the initial parasitemia level of 90% and subsequently developed cerebral malaria. The mean parasitemia level prior to RBC exchange transfusion was 8% (with a range of 5-15%). The mean parasitemia level 6-24 hours after a single treatment was 1.1% (range of 0.3-2.0%) indicating an 8-fold decrease in circulating parasite burden. Concurrent with the improvement in lab indices, each of the patients experienced significant resolution of fever, chills, hypotension, CNS abnormalities, nausea, and abdominal pain. 67% (2 of 3) patients were able to tolerate oral quinine and doxycycline after a single treatment. [Given the clinical improvement in all three cases, a second RBC exchange was not felt to be necessary (and was not advised).]

9. Table I: Demographics & Outcomes of Patients with Severe Falciparum Malaria This very busy table shows the demographics, clinical progression, treatment, and outcome of our three patients. I just want to point out a few things. If you look to the far left …This very busy table shows the demographics, clinical progression, treatment, and outcome of our three patients. I just want to point out a few things. If you look to the far left …

10. Summary In patients with severe plasmodium falciparum malaria, RBC exchange transfusion: • is useful in removing parasitized RBCs, toxins, and cytokines. • should be instituted if parasitemia > 10%, and continued until parasitemia < 5.0 %. • may be life saving. • Adequate immunization is extremely important when traveling to endemic areas. In summary, in patients with severe falciparum malaria, RBC exchange transfusion: Is useful in removing parasitized RBCs, toxins, and cytokines. Should be instituted if parasitemia is > 10%, or instituted regardless of the parasitemia level in patients with coma, ARF, or ARDS, and continued until the parasitemia is < 5%. In conjunction with aggressive anti-malarial medication and supportive care, exchange transfusion may be lifesaving. As always, adequate immunization is extremely important when traveling to endemic areas. As a final comment, I want to thank my co-authors, two of whom are nurse managers who went out in the middle of the night to perform these red cell exchanges. I know I speak for them when I say that it is incredibly satisfying to perform a single apheresis procedure and see a patient improve so dramatically. Thank you very much. In summary, in patients with severe falciparum malaria, RBC exchange transfusion: Is useful in removing parasitized RBCs, toxins, and cytokines. Should be instituted if parasitemia is > 10%, or instituted regardless of the parasitemia level in patients with coma, ARF, or ARDS, and continued until the parasitemia is < 5%. In conjunction with aggressive anti-malarial medication and supportive care, exchange transfusion may be lifesaving. As always, adequate immunization is extremely important when traveling to endemic areas. As a final comment, I want to thank my co-authors, two of whom are nurse managers who went out in the middle of the night to perform these red cell exchanges. I know I speak for them when I say that it is incredibly satisfying to perform a single apheresis procedure and see a patient improve so dramatically. Thank you very much.

11. Parasite Density 1) Calculate the # of parasites per 200 WBC on a thick smear. 2) Divide the total WBC count by 200. 3) Multiply the # parasites in 1) by the result in 2) = # parasites/uL. 4) % parasitemia = # parasites/uL divided by the WBC. Ex: thick smear: 10 parasites/200 WBC and WBC=8000/uL, 8000/200 = 40. 10 parasites X 40 = 400 parasites/uL. Percent parasitemia = 400/8000 = 5%.