ICD “Cold Shivers after a Hot Trip”

1. ICD“Cold Shivers after a Hot Trip” LeeChuy, Katherine Lee, Sidney Abert Lerma, Daniel Joseph Legaspi, Roberto Jose Li, Henry Winston Li, Kingbherly Lichauco, Rafael Lim, Imee Loren Lim, Jason Morven Lim, John Harold Lim, Mary Lim, Phoebe Ruth Lim, Syndel Raina Lipana, Kirk Andrew Liu, Johanna Llamas, Camilla Alay

2. General Data and History of Presented Illness 33 y/o, news correspondent ADMISSION

3. Physical Examination • Temp 40°C; PR 110/min; RR 22/min; BP 120/60 mmHg • General: Ill-looking but well-nourished, no skin lesions, no pedal edema • Eyes: Pale palpebral conjunctivae, slightly icteric sclera, pupils equally reactive to light • Neck: no thyromegaly • Heart and lungs: normal, JVP normal • GI: Traube’s space obliterated

4. Pertinent Findings Positive Negative BP 120/60 mmHg no skin lesions no pedal edema pupils equally reactive to light no thyromegaly Heart, lungs, and GI: normal • Travel history to Palawan • Chloroquine prophylaxis • Fever and chills accompanied by headaches • Treated with sulfadoxine-pyrimethamine (Fansidar) • Febrile, tachycardic, tachypnic • Pale palpebral conjunctivae • slightly icteric sclera • Splenomegaly

6. http://www.cdc.gov/malaria/travelers/country_table/p.html Doxycycline 100 mg daily for 2 – 3 days before going to an endemic area, continue while in the endemic area and continue for 4 more weeks after leaving the endemic area. http://www.doh.gov.ph/faq/show/450.html

7. high fever • malarial toxins direct systemic release of proinflammatory cytokines (TNF-a) • stimulate T cells to directly secrete or induce production of cytokines • icteric sclerae • Increased hemolysis due to malaria • elevated pulse rate • compensatory mechanism for the hemolytic anemia Science. 1994 Jun 24;264(5167):1878-83

8. enlargement of the spleen • engorgement and edema • reticulo-endothelial hyperplasia • increased hemolytic and phagocytic function of the organ due to dysmorphic red blood cells • absence of skin lesions • thrombocytopenia during the paroxysms of fever • no pedal edema • Synthetic function of the liver

9. What are the probable reasons for this patient to have another episode of malaria? RELAPSE REINFECTION RECRUDESCENCE

10. Most re-infected with malaria: • live in endemic areas • travel repeatedly to these areas • develop immunity to malaria by acquiring mechanisms which can kill the parasites or stop the replication of these parasites • Regulation of response so as not to produce an overblown reaction to malaria • first infection “primes” the immune system, while re-infection leads to an exaggerated, and very harmful response by the body

11. RELAPSE • renewed manifestation arising from survival of exoerythrocytic forms (hypnozoites) either at relatively short intervals or after long period (8-24 weeks) • confined to P. vivax and P. ovale infections • primaquine resistance or incomplete response or inadequate primaquine treatment • Chloroquine-resistant Plasmodium • Counterfeit/substandard chemoprophylactic drug

12. REINFECTION • fresh infection occurring in a patient who has suffered from Malaria and can occur at any time after 2 weeks of the 1st attack • persistent source of infection such as an asymptomatic carrier or persistent malaria in the neighborhood or household because of high endemicity and persistent breeding centers for mosquitoes • Luty et al in a study of Plasmodium falciparum infection in African children • production of interferon - gamma by peripheral blood mononuclear cells in response to either Liver-stage or merozoite antigen peptides • delayed first re-infection or lower rates of re-infection • re-infections among select few members of a family may be due to lack of gamma interferon response to the first attack of malaria

13. RECRUDESCENCE • renewed manifestation of infection due to survival of erythrocytic forms • a repeated attack of malaria (short term relapse or delayed), due to the survival of malaria parasites in red blood cells. • Characteristic of P. malariae infections.

14. Pathogenesis of Malaria

16. Processes Essential for the Pathogenesis of Malaria Merozoites in the bloodstream invade RBC.When these reach a density of 50/uL in the blood, symptomatic stage begins. Merozoites from the blood, attach to erythrocytes to become trophozoites Trophozoites consuming all hemoglobin inside the RBC (schizont) Schizogony inside the RBC then rupture of daughter merozoites

17. Erythrocyte Changes in Malaria • Consumes and degrades proteins especially hemoglobin 2. Toxic heme is detoxified (polymerization) to biologically innert hemozoin 3. Cytoadherence Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008

18. Cytoadherence

19. HOST RESPONSE

20. Complications of Malaria

21. Complications of severe falciparum malaria • Morbidity and mortality of P. falciparum species is greatest among the malaria species because of its increased parasetemia and its ability to cytoadhere • Mortality rises once vital organ dysfunction occurs or proportion of erythrocytes infected increases to >3% • P. falciparum is also known for developing drug resistance to chloroquine, quinine and tetracycline

22. Complications add pictures • Cerebral malaria • Hypoglycemia • Lactic acidosis • Noncardiogenic pulmonary edema • Renal impairment • Hematologic abnormalities • Liver dysfunction

23. Cerebral malaria • Coma: characteristic & ominous feature of falciparum malaria; mortality rate of ~0.1%, but if there is vital-organ dysfunction, mortality rises steeply • Manifests as diffuse symmetric encephalopathy • Eyes may be divergent • Muscle tone increase or decrease • ~15% have retinal hemorrhages • Convulsions: generalized; occur up to 50% of children with cerebral malaria

24. Cerebral malaria • ~15% of children with cerebral malaria have been reported to suffer neurologic deficit when they regain consciousness: • Hemiplegia • Cerebral palsy • Cortical blindness • Deafness • Impaired cognition and learning

25. Hypoglycemia • Common complication of severe malaria • Associated with poor prognosis • Particularly problematic in children and pregnant women • Results from a failure of hepatic gluconeogenesis & an ↑ in the consumption of glucose both by host & the malaria parasites • Quinine & quinidine are powerful stimulants of pancreatic insulin secretion

26. Lactic acidosis • Commonly coexists with hypoglycemia • Caused by combination of: • Anaerobic glycolysis in tissues where sequestered parasites interfere with microcirculatory flow • Hypovolemia • Lactate production by the parasites • Failure of hepatic and renal lactate clearance • Coexisting renal impairment compounds acidosis • Acidotic breathing: sign of poor prognosis • Plasma concentrations of bicarbonate or lactate: best biochemical prognosticators in severe malaria

27. Noncardiogenic pulmonary edema • Mortality rate: >80% • Aggravated by overly vigorous administration of IV fluid • Can also develop in otherwise- uncomplicated vivax malaria (recovery is usual)

28. Renal impairment • Rare among children • May be related to RBC sequestration interfering with renal microcirculatory flow & metabolism • Manifests as acute tubular necrosis • Early dialysis or hemofiltration enhances the likelihood of a patient’s survival, particularly in acute hypercatabolic renal failure

29. Hematologic Abnormalities • Anemia • results from accelerated RBC destruction & removal by the spleen in conjunction with ineffective erythropoiesis • both infected & uninfected RBCs show reduced deformability • ↑ splenic clearance of RBCs • Slight coagulation abnormalities & mild thrombocytopenia

30. Liver Dysfunction • Severe jaundice – more common among adults than children • Results from hemolysis, hepatocyte injury, and cholestasis • Hepatic dysfunction contributes to hypoglycemia, lactic acidosis, and impaired drug metabolism

31. Treatment of Malaria

32. First of all… • The diagnosis of malaria has to be confirmed • Microscopy (blood smear) • Rapid Detection Test (PfHRP, LD antigen) • The infecting species has to be identified Upon confirmation • Treatment should be based on the ff factors; • Plasmodium species • Uncomplicated or Complicated (Severe) • Drug susceptibility Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008 Guidelines for the treatment of malaria – 2nd edition

33. Uncomplicated malaria Known chloroquine-sensitive strains of Plasmodium vivax, P. malariae, P. ovale, P. falciparum • Chloroquine (10 mg of base/kg stat followed by 5 mg/kg at 12, 24, and 36 h or by 10 mg/kg at 24 h and 5 mg/kg at 48 h) • Amodiaquine (10–12 mg of base/kg qd for 3 days) Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008 Guidelines for the treatment of malaria – 2nd edition

34. Uncomplicated malaria Radical treatment for P. vivax or P. ovale infection  • Primaquine (0.25 mg of base/kg qd; 0.375–0.5 mg of base/kg qd in Southeast Asia and Oceania) should be given for 14 days to prevent relapse. In mild G6PD deficiency, 0.75 mg of base/kg should be given once weekly for 6 weeks. Primaquine should not be given in severe G6PD deficiency. Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008 Guidelines for the treatment of malaria – 2nd edition

35. Uncomplicated malaria 1st line Treatment for Sensitive P. falciparum malaria • Artesunate (4 mg/kg qd for 3 days) plus sulfadoxine (25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single dose   • Artesunate (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days) Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008 Guidelines for the treatment of malaria – 2nd edition

36. Uncomplicated malaria 1st line Treatment for Multidrug-resistant P. falciparum malaria  • Either artemether-lumefantrine (1.5/9 mg/kg bid for 3 days with food) • artesunate (4 mg/kg qd for 3 days) plus Mefloquine (25 mg of base/kg—either 8 mg/kg qd for 3 days or 15 mg/kg on day 2 and then 10 mg/kg on day 3) Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008 Guidelines for the treatment of malaria – 2nd edition

37. Uncomplicated malaria 2nd line Treatment for P. falciparum malaria • Either artesunate (2 mg/kg qd for 7 days) or quinine (10 mg of salt/kg tid for 7 days)plus 1 of the following 3: • Tetracycline (4 mg/kg qid for 7 days) • Doxycycline (3 mg/kg qd for 7 days) • Clindamycin (10 mg/kg bid for 7 days)

38. Severe Falcifarum malaria If patient is unable to tolerate oral therapy • Artesunate (2.4mg/kg stat IV followed by 2.4mg/kg at 12 and 24 h then daily if necessary) • Artemether (3.2mg/kg stat IM followed by 1.6mg/kg qd) • Quinidine (20mg of salt/kg infused over 4 h, followed by 10mg of salt/kg infused over 2-8 h q8h) • Quinine (10mg of base/kg infused over 1-2 h, followed by 1.2mg of base/kg/h with electrocardiac monitoring) Once oral therapy is tolerable a full course of ACT is recommended Fauci et.al. Harrison’s principles of Internal Medicine 17th edition, 2008 Guidelines for the treatment of malaria – 2nd edition

39. Prevention of Malaria

40. Personal Protection Against Malaria • avoidance of exposure to mosquitoes at their peak feeding times (usually dusk and dawn) and throughout the night • use of insect repellents containing DEET (10–35%) or picaridin (7%; if DEET is unacceptable),suitable clothing, and insecticide-impregnated bed nets or other materials • Widespread use of bed nets treated with residual pyrethroids reduces the incidence of malaria in areas where vectors bite indoors at night

41. Harrison’s Internal Medicine, 17th ed. Global Health – Division of Parasitic Diseases. Centers for Disease Control and Prevention, updated Feb. 8, 2010.

42. Harrison’s Internal Medicine, 17th ed. Global Health – Division of Parasitic Diseases. Centers for Disease Control and Prevention, updated Feb. 8, 2010.