Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
11 year old male with fever and malaise Chairman’s Rounds September 24, 2010 David H. Rubin, MD Department of Pediatrics St. Barnabas Hospital Professor of Clinical Pediatrics Albert Einstein College of Medicine PATIENT PROFILE 11 year old male with spiking temperatures to 103F for 3 days, vomiting, diarrhea, abdominal pain Recent 1.5 month visit to Togo (West Africa) Labs blood smear plasmodium species 10.8% Treatment: quinidine MALARIA Derived from Italian….”mal’aria” meaning “bad air” – association with marshy areas End of 19th century, Charles Laveran, French Army Surgeon: parasites in blood of patient dying from malaria Dr. Ronald Ross; British Army in India: mosquitoes transmitted malaria Professor Giovanni Grassi: human malaria only transmitted by Anopheles mosquitoes MALARIA An ancient human disease Mentioned as early as 2700 BC in European and Chinese writings European colonists imported malaria to America (p vivax and p. malariae); p. falciparum coincided with African slave trade Prevention difficult, no drug universally effective MALARIA 2004: 350-400 million cases worldwide Over 2 billion people (40% of world’s population) at risk of contracting disease Malaria deaths (1999-2004, WHO data) estimated at 1.1-1.3 million Cost (in Africa): $12 billion; 25% of all deaths of children < 5 years of age USA and Europe: health measures, economic development have achieved near elimination of disease MALARIA Transmitted through bite of Anopheles mosquito (400 species-60 malaria vectors) Malaria parasites are single celled organisms of genus Plasmodium • Only 4 species can infect humans • P. Falciparum, P. vivax, P. ovale, P. malariae GLOBAL BURDEN OF MALARIA (Milner 2008) 1.1-1.3 million deaths worldwide; primarily young children with severe malaria presenting as coma, severe anemia, or respiratory distress Current response: drugs, impregnated bed nets, indoor spraying, DEET, long sleeves, pants, and footware Future goals: vaccine, improved treatment of severe disease MALARIA P. falciparum – severe potentially fatal malaria; primary cause of malaria deaths of young children in Africa • Infected erythrocytes can obstruct small vessels causing cerebral malaria P. vivax – most commonly causes anemia P. ovale – least common; primarily in West Africa COMPLICATIONS FROM P. falciparum Massive hemolysis (Blackwater fever) Renal failure Pulmonary edema Cerebral dysfunction • • • • • level of consciousness Behavioral changes Hallucinations Seizures LP is usually NORMAL Local Mosquito-Borne Transmission United States, 1957-2005 SYMPTOMS OF MALARIAL INFECTION Accumulation and sequestration of parasitic infected RBC’s in brain, heart, kidney, lung, is common Symptoms: as early as 6-8 days after bite or several months later Typical attack: chills and tachycardia, high temperature followed by a profuse diaphoresis Also may have: cough, respiratory distress, joint pain, headache, watery diarrhea, vomiting, seizures Severe malaria: jaundice, kidney failure, severe anemia DIAGNOSIS OF MALARIA Clinical observations, case history, and diagnostic testing Collect blood when temperature rising (best yield) Examine thick/thin smears; 1 parasite/200ųL blood can be detected – CAUTION: these may be negative early in illness; interpretation variable Rapid diagnostic dip tests – expensive and only falciparum can be diagnosed TRANSMISSION (CDC) In rare cases malaria parasites can be transmitted from one person to another without requiring passage through a mosquito (from mother to child in "congenital malaria", or through transfusion, organ transplantation or shared needles) Some species of monkeys and apes can be experimentally infected with some of the four "human" malaria parasite species, and in nature some apes are infected with parasites similar to those infecting humans. But for all practical purposes the role of an animal reservoir is negligible. MANAGEMENT Suspect in any febrile child from endemic area CBC, platelets may show anemia and thrombocytopenia See CDC “Guidelines for Treatment” (www.cdc.gov/malaria/pdf/treatmentta ble.prf) LIFE CYCLE LIFE CYCLE Sporozoite entry into blood stream (mosquito takes a blood meal) • Infective sporozoites from salivary gland of Anopheles mosquito injected into human host (with anticoagulant saliva) • Once in bloodstream, P. falciparum sporozoites reach the liver, remain for 916 days and undergo asexual replication (exo-erythrocytic schizogony) LIFE CYCLE Each sporozoite gives rise to thousands of merozoites, which invade RBC’s when released from the liver This process takes 8-25 days Ensures protection of parasite from host immune system ERYTHROCYTIC SCHIZOGONY Trophozoite development • “Ring” form • Multiple rounds of nuclear division • Formation of schizonts, which contains 20 merozoites; released after RBC lysis to further invade infected RBC’s • • Coincides with increase in temperature Usually occurs at same time of the day • Infected RBC’s (after lysis) stimulates TNF and other cytokines producing clinical presentation GAMETOCYTE FORMATION Small number of merozoites in RBC’s differentiate to form micro- and macro-gametocytes (male/female) and have no other activity These gametocytes transmit the infection to new hosts through female Anopheles MALARIA AND RED BLOOD CELLS MALARIA AND THE RED BLOOD CELL Malaria defenses inherent in RBC’s – constant creation and destruction RBC defenses have arisen by natural selection Mechanisms not well understood Cell Component Alteration Global Distribution Membrane Duffy antigen wall Africa Hemoglobin Melanesian elliptocytosis Hb S Africa, Middle East, India Africa Hb C Africa Hb E SE Asia Thalassemia Africa, Medit., India, SE Asia Africa, India Thalassemia RBC Enzymes G6PD Africa, Medit., India, SE Asia MALARIA AND THE RED BLOOD CELL Sickle Cell Trait • Sickle cell trait offspring may have 1 gene for normal Hg and 1 for sickle Hg transmitted to next generation • Impairs malaria growth and development • Sickle cell trait is the genetic condition selected for in regions of endemic malaria SPECIAL POPULATIONS Malaria especially dangerous to • Pregnant women • • • Parasitic infiltration of placenta Associated with premature delivery, low birthweight, increased mortality in newborn After repeated exposure to malaria, pregnant women develop immunity • Young children MALARIA AND PREGNANCY Susceptibility to malaria greatest in 1st and 2nd pregnancy Ability of infected erythrocytes to accumulate in the maternal vascular area of the placenta; other stages are sequestered in the placenta Clinical trials now occurring CONGENITAL MALARIA 5 cases reported since 2000 (75 since 1950) Diagnosis when parasites are seen on peripheral smear during 1st week of life In the USA, presentation usually with fever, splenomegaly, hepatomegaly, irritability, icterus, fever TREATMENT ANTIMALARIAL MEDICATIONS Chloroquine, mefloquine, doxycycline do not prevent initial malarial infections in humans; they act on parasites that infect erythrocytes once released from maturational phase in the liver Currently high worldwide resistance of p. falciparum to chloroquine MALARIA TREATMENT ALGORITHM Griffith, K.may S. apply. et al. Copyright restrictions JAMA 2007;297:2264-2277. ?SAFETY OF ANTIMALARIAL DRUGS Chloroquine • Headaches, nausea, vomiting, blurred vision, pruritis, itching • Long term use: neuropathy (rare) • Safe in pregnancy; but low safety margin • Cardiotoxicity in overdoses a major problem • Contraindicated if H/O seizures, renal disease, hepatic disease ?SAFETY OF ANTIMALARIAL DRUGS Quinine • Oral prep may cause “cinchonism” – nausea, vomiting, vertigo, tinnitus, headache, blurred vision; these are reversible symptoms • Increased insulin secretion; causes severe hypoglycemia in pregnancy in 50% of patients • May damage auditory nerve MALARIA VACCINES Clinical trials now underway using target antigens at each parasite stage Vaccine and field trials extremely expensive Sterile immunity NOT observed in a large proportion of subjects • Are children in endemic areas ready for multiple doses? ETIOLOGY OF TRAVEL RELATED FEVER (Wilson, 2007) Geosentinel Surveillance Network – worldwide multicenter database From 3/97-3/06, N=24,920 travelers • 28% had fever • 26% hospitalized • Malaria: 21% • 33% of all deaths (N=12) • Others: Dengue fever, enteric fever, rickettsioses SUMMARY Malaria is caused by mosquito transmitted parasite P. falciparum and is responsible for deaths in tropical/subtropical regions Genome of p. falciparum clone 3D7 already sequenced – will be able to reveal drug targets Race is on to develop vaccines/drugs to interrupt life cycle of parasite Think of diagnosis with FUO and travel history – watch for neurologic signs and symptoms REFERENCES Tuteja R. Malaria – an overview. FEBS Journal. 2007;274:4670-4679. Wilson ME, Freedman DO. Etiology of travel related fever. Curr Opin Infect Dis 2007;20:449-453. Hagmann et al. Congenital malaria. Ped Emerg Care 2007:23(5):326-329. WWW.CDC.GOV REFERENCES Freedman D. Malaria prevention in short term travelers. N Engl J Med 2008;359:60312. Sharma S and Pathak S. Malaria vaccine: a current perspective. J Vector Borne Dis 2008;45:1-20. Milner DA et al. Severe malaria in children and pregnancy: an update and perspective. Trends in parasitology 2008;24:12:590-595.