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5 year old with fever and vomiting David H. Rubin, MD Department of Pediatrics St. Barnabas Hospital Professor of Clinical Pediatrics Albert Einstein College of Medicine PATIENT PROFILE 5 year old male with recent visit to Guinea for 2 months without any prophylaxis for malaria; home x 1 week Poor intake PE: • Barely responsive • Dehydrated • Impressive splenomegaly and tenderness PATIENT PROFILE Abdominal ultrasound? • Deferred Lab: blood smear showed plasmodium species 35%, platelets 25,000 Treatment • IV quinine Discharged home after 7 days MALARIA Derived from Italian….”mal’aria” meaning “bad air” – association with marshy areas 1890’s: Charles Laveran, French Army Surgeon: parasites in blood of patient dying from malaria Dr. Ronald Ross (British Army in India): mosquitoes transmitted malaria Dr. Giovanni Grassi: human malaria only transmitted by Anopheles mosquitoes MALARIA 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 KING TUT DIED OF MALARIA (>3,000 YEARS AGO) MALARIA (WHO) 2004: 350-400 million cases worldwide Endemic in over 90 countries Over 2 billion people (40% of world’s population) at risk of contracting disease 1.1-1.3 million deaths/year 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 Disease is transmitted through bite of Anopheles mosquito Malaria parasites are single celled organisms of genus Plasmodium • Only 4 species can infect humans • P. Falciparum, P. vivax, P. ovale, P. malariae MALARIA 95% of human infections caused by p. vivax (80%) and p. falciparum (15%) • 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 2004 – p. knowlesi causes sporatic human cases in SE Asia GLOBAL IMPACT OF MALARIA (Milner 2008) 1.1-1.3 million deaths/year are 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 footwear Future goals: vaccine, improved treatment of severe disease INCREASED INCIDENCE OF MALARIA RELATED TO DESTRUCTION OF FORESTS WHAT ABOUT THE USA? MALARIA MAP EASTERN USA 1870 Local Mosquito-Borne Transmission United States, 1957-2005 MALARIAL INFECTION Pathophysiology: 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: 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) “ The role of an animal reservoir in malaria transmission is negligible MANAGEMENT OVERVIEW Suspect in any febrile child from any endemic area CBC, platelets may show anemia and thrombocytopenia Constant updates from CDC web site: “Guidelines for Treatment” PEDIATRIC SEVERE MALARIAL ANEMIA What risk factors contribute to severe anemia (Hg<5 g/dl) seen in children with malaria? Potential risk factors • • • • • • Malaria Bacteremia HIV Hookworm Vitamin A, B12 deficiency G6PD deficiency Anemia results in deformability and uptake of uninfected erythrocytes by monocytes and macrophages 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 LIFE CYCLE LIFE CYCLE 1: EXO-ERYTHROCYTIC STAGE (Human Liver Stage) Sporozoite entry into blood stream (mosquito takes a blood meal) • Infective sporozoites from salivary gland of Anopheles mosquito injected into human host (contains anticoagulant saliva) • Once in bloodstream, P. falciparum sporozoites reach the liver, remain for 916 days and undergo asexual replication LIFE CYCLE 1: EXO-ERYTHROCYTIC STAGE (Human Liver Stage) Each sporozoite gives rise to thousands of merozoites, which invade RBC’s when released from the liver (8-25 days) Ensures protection of parasite from host immune system LIFE CYCLE 2: ERYTHROCYTIC STAGE (Human Blood Stage) Trophozoite development • “Ring” form • Multiple rounds of nuclear division • Formation of schizonts 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 stimulate TNF and other cytokines producing clinical presentation LIFE CYCLE 3: SPORE FORMATION AND RELEASE (Mosquito Stage) Mosquito takes a blood meal; spore formation begins Small number of merozoites in RBC’s differentiate to form gametocytes Release and transmission of infection to new hosts through female Anopheles MALARIA AND RED BLOOD CELLS MALARIA AND RED BLOOD CELL DEFENSE 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 DEFENSE 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 • At risk for overwhelming disease 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 Vaccine 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 • Targets are parasites that infect erythrocytes released from liver Worldwide resistance of p. falciparum to chloroquine 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 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 APPROACH TO ILL CHILD AFTER INTERNATIONAL TRAVEL (Tolle 2010) Travel history • Countries visited, length of stay, onset of symptoms • Consider diff diagnosis based on incubation time and setting risk • Febrile child 3 days after return from 1 week visit to Brazil – more likely dengue fever than malaria APPROACH TO ILL CHILD AFTER INTERNATIONAL TRAVEL (Tolle 2010) Travel physical examination • Countries visited, length of stay, onset of symptoms • Focus on physical signs associated with tropical illness • Splenomegaly (malaria, typhoid) or rash (dengue) APPROACH TO ILL CHILD AFTER INTERNATIONAL TRAVEL (Tolle 2010) Differential Diagnosis • Associated with travel • Tropical or nonendemic area? • Not associated with travel • Longer symptoms are present the less likely associated with travel (although p. vivax can present months after visit to tropics APPROACH TO ILL CHILD AFTER INTERNATIONAL TRAVEL (Tolle 2010) Diagnostic evaluation • Driven by differential diagnosis • • Thrombocytopenia and hyperbilirubinemia seen with malaria Leukopenia with typhoid, dengue Treatment • Resolution should be achieved INCUBATION PERIODS FOR TROPICS ILNESSES (Tolle 2010) ≤14 days • Dengue, malaria, yellow-fever, chikungunya, typhoid fever, rickettsial infections, leptospirosis 15-30 days • Malaria, typhoid fever, leptospirosis, hepatitis A and E (2-6 weeks), viral leshmaniasis, acute schistosomiasis, tuberculosis INCUBATION PERIODS FOR TROPICS ILNESSES (Tolle 2010) >30 days • • • • • Malaria Hepatitis A and E Acute schistosomiasis Visceral leshmaniasis Tuberculosis COMMON PRESENTATIONS -FEVER Malaria Dengue Typhoid Rickettsial diseases Leptospirosis Workup: CBC, LFTs, UA and culture, blood culture, peripheral blood smear, serologic assays for dengue, rickettsiae, schistosomes, leptospirosis DENGUE FEVER Most common diagnosis for travelers returning to USA from tropics except Africa Usually a short, self limited illness • Exception 250,000 cases/year of hemorrhagic shock Most commonly transmitted in urban areas during the daytime (malaria rural areas at night) Dengue Fever mosquito (Aedes Aegypti) DENGUE FEVER Clinical presentation: rash, leukopenia, thrombocytopenia Treatment is supportive; ICU for severe dengue CHIKUNGUNYA VIRUS Transmitted by Aedes spp mosquito Location overlaps with geographic location of dengue Unique clinical presentation: febrile arthralgia syndrome Severe disease is rare Treatment symptomatic TYPHOID/PARATYPHOID FEVER Caused by fecal oral transmission of salmonella typhi, salmonella paratyphi Fever, abdominal pain, myalgias, nausea, vomiting, diarrhea “Stepladder” fever pattern Relative bradycardia, splenomegaly TYPHOID/PARATYPHOID FEVER Lab: Normal or reduced WBC, increased LFTs Diagnosis by culture – bone marrow cultures most sensitive (80-95%), blood most sensitive 1st week of illness (70%), stool most sensitive as disease progresses Complications: highest in young children, ill >14 days • Most dangerous: GI bleeding, perforation TYPHOID/PARATYPHOID FEVER Treatment dependant on where disease was contracted • Latin America, Caribbean amoxicillin, TMP-SMZ, quinilones • SE Asia multidrug resistance; use azithromycin or cefixime RICKETTSIAL INFECTIONS African Tick Bite Fever (rickettsia africae) Prevalent in southern African game parks Primary eschar at tick bite, followed by flu like illness and generalized rash Diagnosis by serology Treatment: docycycline LEPTOSPIROSIS Recreational exposure to water or soil contaminated with infected animal urine especially seen after heavy rainfall Clinical: systemic illness with negative malaria testing and conjunctival inflammation May progress to jaundice, renal failure and hemorrhage Treatment: ampicillin or tetracycline; severe disease: IV ceftriaxone or penicillin G GASTROINTESTINAL SYMPTOMS Traveler’s diarrhea • > 2 years usually bacteria (salmonella, shigella) • < 2 years usually viral (norovirus, rotavirus) • Persistent (>2 weeks) protozoal (giardia, cryptosporidium) ?History of antibiotic exposure test for c. difficile Stool culture, giardia antigen, hemocult, stain for fecal leukocytes GASTROINTESTINAL SYMPTOMS/Persistent Diarrhea Tropical sprue (usually seen after travel to SE Asia) • Inflammatory cells in small intestine. • Low levels of vitamins A, B12, E, D, and K, as well as albumin, calcium, folate • Excess fat in feces • Thickened small bowel folds seen on barium swallow • Limited to within about 30 degrees north and south of equator Viral hepatitis febrile jaundice • Hepatitis A and E • Both have fecal oral routes of transmission DERMATOLOGIC SYMPTOMS Cutaneous larval migrans • Seen after exposure of bare skin to sand • Subcutaneous movement of larval stage of the dog hookworm • Treatment: albendazole, ivermectin Myiasis • Fly larva infests the skin, creating a painful boil • Treatment: petroleum jelly and remove larva MYIASIS 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 When treating ill child after travel consider most likely diagnoses based on history and PE 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 and www.cdc.gov/malaria/pdf/treatmenttable.prf REFERENCES Freedman D. Malaria prevention in short term travelers. N Engl J Med 2008;359:603-12. 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. Tolle M. Evaluating a sick child after travel to developing countries. J Am Board Fam Med 2010;23:704-713.