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Cold Shivers After A Hot Trip Subsection A-2 USTFMS General Data • 33 y/o • News correspondent History of Present Illness • He had a 3 month assignment in Palawan • Took chloroquine weekly for malaria prophylaxis •Fever, chills, and headache 2 weeks •Treated with sulfadoxine-pyrimethamine (Fansidar) •2 other companions also experienced similar symptoms Physical Examination • • • • • • • • • • • • • Ill-looking but well-nourished male Temperature – 40˚C PR 110 bpm RR 22 breaths per minute BP 120/60 Pale palpebral conjunctiva Icteric sclera Pupils equally reactive to light JVP is normal (-) thyromegaly Heart and Lungs are normal Traube’s space is obliterated No skin lesions nor pedal edema Objective Findings Positive • High Fever • Tachycardia • Tachypnea • Icteric Sclera • Splenomegaly Negative • Absence of skin lesions If this is malaria, what are the probable reasons for this patient to have another episode of malaria? Host Response • Initially, the host responds to plasmodial infection by activating nonspecific defense mechanisms – Stop the infection’s expansion • Subsequent specific immune response controls the infection Harrison’s Principle of Internal Medicine, 17th ed. Host Response • Exposure to sufficient strains confers protection from high-level parasitemia and disease, but not from infection • Immunity is mainly specific for both the species and the strain of infecting malarial parasite • Both humoral and cellular immunity are necessary for protection Harrison’s Principle of Internal Medicine, 17th ed. Host Response • Immune individuals have a polyclonal increase in serum levels of IgM, IgG, and IgA • Antibodies to a variety of parasitic antigens act in concert to limit in vivo replication of the parasite • This complex immunity to disease declines when a person lives outside an endemic area for several months or longer Harrison’s Principle of Internal Medicine, 17th ed. Factors that retard development of cellular immunity to malaria • Absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct T cell recognition • Malaria antigen-specific immune unresponsiveness • Enormous strain diversity of malarial parasite – Ability of the parasites to express variant immunodominant antigens on the erythrocyte surface Harrison’s Principle of Internal Medicine, 17th ed. Relapsing Malaria • Parasites can remain dormant (inactive or hibernating) in the liver cells • Some of these dormant parasites can remain even after a patient recovers from malaria • Patient can get sick again http://www.medicinenet.com/malaria/page2.htm#5whatis Malaria Pathogenesis • Two phases of development: exoerythrocyticand erythrocytic phase. – Exoerythrocyticphase involves infection of the liver. – Erythrocyticphase involves infection of the erythrocytes, or red blood cells. • When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. • Within 30 minutes the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. • In the liver, these organisms differentiate to yield thousands of merozoites. • Following rupture of their host cells they escape into the blood and infect red blood cells. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Malaria Pathogenesis • In the RBC’s, parasites multiply again asexually, periodically breaking out of their hosts to invade fresh red blood cells. – Several amplification cycles occur. Waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells. • Some P. vivax and P. ovalesporozoites do not immediately develop into exoerythrocytic-phase merozoites. – Produce hypnozoites that remain dormant for periods ranging from several months to years. – Reactivation will then occur producing more merozoites. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Malaria Pathogenesis • Circulating infected blood cells are destroyed in the spleen. • P. falciparumdisplays adhesive proteins (i.e. PfEMP1) on the surface of the infected blood cells to overcome this aspect. – Blood cells stick to the walls of small blood vesselswhich sequester the parasite from passage through the general circulation and the spleen. – “Stickiness" is the main factor giving rise to hemorrhagic complications of malaria. – High endothelial venulescan be blocked by the attachment of masses of these infected red blood cells. – Blockage of these vessels causes symptoms such as in placental and cerebral malaria. – Have extreme diversity so not good targets for the immune system. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Malaria Pathogenesis • Some merozoites turn into male and female gametocytes. • When a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. • Fertilization and sexual recombination of the parasite occurs in the mosquito's gut • New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Malaria Pathogenesis • There are at least 60 variations of the red blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1)within a single parasite and effectively limitless versions within parasite populations. • The parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Complications of Severe Falciparum Malaria Cerebral Malaria • Manifests as diffuse symmetric encephalopathy • Focal neurologic signs are unusual • Passive resistance to head flexion may be detected and signs of meningeal irritation are lacking • The eyes may be divergent and a pout reflex is common. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Cerebral Malaria • The corneal reflexes are preserved, except in deep coma. • Muscle tone may be either increased or decreased. • The tendon reflexes are variable, and the plantar reflexes may be flexor or extensor • The abdominal and cremasteric reflexes are absent. • Flexor or extensor posturing may be seen. • Retinal hemorrhages Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Cerebral Malaria • Convulsions, usually generalized and often repeated • Coma is a characteristic and ominous feature • Neurologic sequelae: – hemiplegia, cerebral palsy, cortical, blindness, deafness, and impaired cognition and learning – Language deficit Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Hypoglycemia • Due to failure of hepatic gluconeogenesis and an increase in the consumption of glucose. • Quinine and quinidine- stimulants of pancreatic insulin secretion • In severe disease, the clinical diagnosis of hypoglycemia is difficult: – the usual physical signs(sweating, gooseflesh, tachycardia) are absent – neurologic impairment caused by hypoglycemia cannot be distinguished from that caused by malaria. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA ACIDOSIS Acidosis • Results from accumulation of organic acids. – Hyperlactatemia commonly coexists with hypoglycemia. – Renal impairment compounds the acidosis in adults (rare in children) – Ketoacidosis in children may also contribute. • Lactic acidosis is caused by: – Anaerobic glycolysis in tissues due to sequestered parasites interfering with microcirculatory flow – Lactate production by the parasites – Failure of hepatic and renal lactate clearance. • Manifestations: – Acidotic breathing – Circulatory failure refractory to volume expansion or inotropic drugs. – Respiratory arrest. • The prognosis of severe acidosis is poor. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA NON-CARDIOGENIC PULMONARY EDEMA Non-Cardiogenic Pulmonary Edema • The pathogenesis of this variant of the adult respiratory distress syndrome is unclear. – Can be aggravated by overly vigorous administration of IV fluid. • Noncardiogenic pulmonary edema can also develop in otherwise uncomplicated vivax malaria, where recovery is usual. • The mortality rate is >80%. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA RENAL IMPAIRMENT Renal Impairment • Common in adults with severe falciparum malaria, but rare in children. • The pathogenesis may be related to erythrocyte sequestration interfering with renal microcirculatory flow and metabolism. • Manifests as acute tubular necrosis, although renal cortical necrosis never develops. • Acute renal failure may occur simultaneously. • In survivors, urine flow resumes in a median of 4 days, and serum creatinine levels return to normal in a mean of 17 days. • Early dialysis or hemofiltration considerably enhances the likelihood of a patient’s survival, particularly in acute hypercatabolic renal failure. Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Hematologic Abnormalities • Anemia results – accelerated RBC removal by the spleen – obligatory RBC destruction at parasite schizogony – ineffective erythropoiesis • Infected and uninfected RBCs show reduced deformability • Increased splenic clearance of RBCs • Repeated malarial infections: – development of severe anemia resulting from both shortened RBC survival and marked dyserythropoiesis Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Hematologic Abnormalities • Slight coagulation abnormalities are common, • Mild thrombocytopenia is usual. • <5% of malaria patients have significant bleeding with evidence of DIC. • Hematemesis may occur – stress ulceration – acute gastric erosions Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Liver Dysfunction • Severe jaundice – associated with P. falciparum infections – more common in adults – results from hemolysis, hepatocyte injury, and cholestasis • When accompanied by other vital-organ dysfunction (often renal impairment), liver dysfunction carries a poor prognosis. – Hepatic dysfunction contributes to: – Hypoglycemia – lactic acidosis Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Other Complications… • Septicemia may complicate severe malaria, particularly in children • In endemic areas, Salmonella bacteremia has been associated specifically with P. falciparum infections • Chest infections and catheter-induced urinary tract infections are common among patients who are unconscious for >3 days Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA Treatment of Complicated Malaria • Any patient with complicated or severe falciparum malaria must be considered as a medical emergency and managed at the highest possible level of clinical care appropriate. • All patients with any form of complicated or severe disease should be treated parenterally. Quinine • Quinine is given by slow intravenous infusion but in an emergency may be given intramuscularly in split doses as has been done in children. • Quinine and Quinidine, are potent stimulants of insulin secretion, glucose should be carefully monitored especially in pregnant women. • Once the parasitemia is less than 1% and the patient is able to take drugs by mouth, treatment may be completed with oral quinine. • Complete the treatment with a course of oral Doxycycline, or in pregnant women and children, Clindamycin to prevent recrudescent infection which is common after monotherapy. Artemisinin and its derivatives • Artemisinin derivatives are increasingly being used in the treatment of malaria of all degrees of severity. • Result in more rapid parasite clearance (being active on the immature parasite forms. • Safer and simpler to administer. Recommendations for Prevention of Malaria http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx MOSQUITO AVOIDANCE MEASURES • remain in well-screened areas • Use of mosquito nets (preferably insecticide-treated nets) • Using a pyrethroid-containing flying-insect spray in living and sleeping areas during evening and nighttime hours • Wearing clothes that cover most of the body • Use of effective mosquito repellent http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter2/malaria.aspx DEET (N,N-diethylmetatoluamide) • The most effective repellent against a wide range of vectors • DEET formulations – 50% are recommended for both adults and children older than 2 months of age – should be applied to the exposed parts of the skin • Permethrin-containing product may be applied to bed nets and clothing for additional protection. http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/malaria.aspx Chemoprophylaxis • Primary chemoprophylaxis regimens – taking medicine before travel, during travel, and for a period of time after leaving the malaria endemic area. – Beginning the drug before travel allows the antimalarial agent to be in the blood before the traveler is exposed to malaria parasites. • Presumptive antirelapse therapy (terminal prophylaxis) – medication taken towards the end of the exposure period – generally indicated only for prolonged exposure in malaria-endemic areas – most malarious areas of the world (except the Caribbean) have at least one species of relapsing malaria – Prevent relapses or delayed-onset clinical presentations of malaria caused by hypnozoites (dormant liver stages) • P. vivax or P. ovale. http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx • Choosing the appropriate chemoprophylactic agent – Country of travel – Significant reports of antimalarial drug resistance in that location – medical conditions, medications being taken, cost of the medicines, potential side effects http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Medications Used for Chemoprophylaxis • Atovaquone/Proguanil (Malarone) • Chloroquine (Aralen) and Hydroxychloroquine (Plaquenil) • Doxycycline (Many Brand Names and Generic) • Mefloquine • Primaquine http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Drugs used for Prophylaxis Drug Atovaquone/proguanil (Malarone) Usage Prophylaxis in all areas Adult Dose Adult tablets contain 250 mg atovaquone and 100 mg proguanil hydrochloride. 1 adult tablet orally, daily Prophylaxis only in Chloroquine phosphate areas with (Aralen and generic) chloroquinesensitive malaria 300 mg base (500 mg salt) orally, once/week Doxycycline (many brand names and generic) 100 mg orally, daily Prophylaxis in all areas Pediatric Dose Pediatric tablets contain 62.5 mg atovaquone and 25 mg proguanil hydrochloride. 5–8 kg: 1/2 pediatric tablet daily; >8–10 kg: 3/4 pediatric tablet daily; >10–20 kg: 1 pediatric tablet daily; >20–30 kg: 2 pediatric tablets daily; >30–40 kg: 3 pediatric tablets daily; >40 kg: 1 adult tablet daily Comments Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in persons with severe renal impairment (creatinine clearance <30 mL/min). Atovaquone/proguanil should be taken with food or a milky drink. Not recommended for prophylaxis for children <5 kg, pregnant women, and women breastfeeding infants weighing <5 kg. Partial tablet dosages may need to be prepared by a pharmacist and dispensed in individual capsules, as described in the text. Begin 1–2 weeks before travel to 5 mg/kg base (8.3 mg/ kg malarious areas. Take weekly on the same salt) orally, once/week, day of the week while in the malarious up to maximum adult area and for 4 weeks after leaving such dose of 300 mg base areas. May exacerbate psoriasis. Begin 1–2 days before travel to malarious areas. Take daily at the same time each ≥8 years of age: 2 mg/ kg day while in the malarious area and for 4 up to adult dose of 100 weeks after leaving such areas. mg/day Contraindicated in children <8 years of age and pregnant women. http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Drugs used for Prophylaxis An alternative to 5 mg/kg base (6.5 mg/ kg salt) Begin 1–2 weeks before travel to malarious areas. chloroquine for 310 mg base (400 Hydroxychloroquine orally, once/week, up to Take weekly on the same day of the week while in prophylaxis only in areas mg salt) orally, sulfate (Plaquenil) maximum adult dose of 310 mg the malarious area and for 4 weeks after leaving with chloroquineonce/week base such areas. sensitive malaria Mefloquine Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in ≤9 kg: 4.6 mg/kg base (5 mg/kg the malarious area and for 4 weeks after leaving salt) orally, once/week; such areas. Contraindicated in persons allergic to >9–19 kg: 1/4 tablet mefloquine or related compounds (e.g., quinine, Prophylaxis in areas with 228 mg base (250 once/week; quinidine) and in persons with active depression, a mefloquine-sensitive mg salt) orally, >19–30 kg: 1/2 tablet recent history of depression, generalized anxiety malaria once/week once/week; disorder, psychosis, schizophrenia, other major >31–45 kg: 3/4 tablet psychiatric disorders, or seizures. Use with caution once/week; in persons with psychiatric disturbances or a ≥45 kg: 1 tablet once/ week previous history of depression. Not recommended for persons with cardiac conduction abnormalities. http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Drugs used for Prophylaxis Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Primaquine Prophylaxis for shortduration travel to areas with principally P.vivax 0.5 mg/kg base (0.8 30 mg base (52.6 mg salt) orally, mg/kg salt) up to adult daily dose orally, daily Contraindicated in persons with G6PD1 deficiency. Also contraindicated during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level. Primaquine Used for presumptive antirelapse therapy (terminal prophylaxis) to decrease the risk for relapses of P. vivax and P. ovale 30 mg base (52.6 mg salt) orally, once/day for 14 days after departure from the malarious area. 0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, once/day for 14 days after departure from the malarious area http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Indicated for persons who have had prolonged exposure to P. vivax and P. ovale or both. Contraindicated in persons with G6PD1 deficiency. Also contraindicated during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level. Travel to Areas with Limited Malaria Transmission • mosquito avoidance measures only, and no chemoprophylaxis should be prescribed http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Travel to Areas with Mainly P. vivax Malaria • mosquito avoidance measures • primaquine - primary prophylaxis for travelers who are not G6PD-deficient http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Travel to Areas with ChloroquineSensitive Malaria • mosquito avoidance measures • chemoprophylaxis alternatives: – chloroquine, atovaquone/proguanil, doxycycline, mefloquine, – primaquine for travelers who are not G6PDdeficient • Longer-term travelers - weekly chloroquine • shorter-term travelers - atovaquone/proguanil or primaquine. http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Travel to Areas with ChloroquineResistant Malaria • to mosquito avoidance measures • chemoprophylaxis limited to atovaquone/proguanil, doxycycline, and mefloquine. http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Travel to Areas with MefloquineResistant Malaria • mosquito avoidance measures • chemoprophylaxis options are reduced to either atovaquone/proguanil or doxycycline http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Chemoprophylaxis for Infants, Children, and Adolescents • All children traveling to malaria-risk areas should take an antimalarial drug. • Pediatric dosages should be calculated according to body weight but should never exceed adult dosage. • Chloroquine and mefloquine • Primaquine can be used for children who are not G6PD-deficient traveling to areas with principally P. vivax. • Doxycycline may be used for children who are at least 8 years of age. • Atovaquone/proguanil may be used for prophylaxis for infants and children weighing at least 5 kg (11 lbs). http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx Chemoprophylaxis during Pregnancy and Breastfeeding • Malaria can increase the risk for adverse pregnancy outcomes, including prematurity, abortion, and stillbirth. • Women who are pregnant or likely to become pregnant should be advised to avoid travel to areas with malaria transmission if possible. • If travel to a malarious area cannot be deferred, use of an effective chemoprophylaxis regimen is essential. • Chloroquine – to areas where chloroquine-resistant P. falciparum has not been reported – has not been found to have any harmful effects on the fetus – pregnancy is not a contraindication for malaria prophylaxis • If Chloroquine resistance is present: – mefloquine is currently the only medication recommended for malaria chemoprophylaxis during pregnancy. http://wwwnc.cdc.gov/travel/yellowbook/ 2010/chapter-2/malaria.aspx