ICD Cold Shivers after a Hot Trip LeeChuy, Katherine Lee, Sidney Abert Lerma, Daniel Joseph Legaspi, Roberto Jose Li, Henry Winston Li, Kingbherly Lichauco,

ICD“Cold Shivers after a Hot Trip”

LeeChuy, KatherineLee, Sidney Abert

Lerma, Daniel JosephLegaspi, Roberto Jose

Li, Henry WinstonLi, Kingbherly

Lichauco, RafaelLim, Imee Loren

Lim, Jason MorvenLim, John Harold

Lim, MaryLim, Phoebe RuthLim, Syndel Raina

Lipana, Kirk AndrewLiu, Johanna

Llamas, Camilla Alay

General Data and History of Presented Illness

33 y/o, news correspondent

ADMISSION

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

Pertinent FindingsPositive• 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

Negative

• BP 120/60 mmHg• no skin lesions• no pedal edema• pupils equally reactive to

light• no thyromegaly• Heart, lungs, and GI: normal

Areas with Malaria

Estimated relative risk

of malaria for US travelers

Drug Resistance

Malaria Species

Recommended

Chemoprophylaxis

Present in rural areas

below 600m (1,969ft), on

islands of Luzon,

Palawan, and Mindanao.

None in urban areas.

Low Chloroquine P. falciparum

70-80%

P. vivax

20-30%

Atovaquone/

proguanil,

doxycycline, or

mefloquine

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

• 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

• 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

What are the probable reasons for this patient to have another episode of

malaria?

RELAPSEREINFECTION

RECRUDESCENCE

• 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

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

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

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.

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

Processes Essential for the Pathogenesis of Malaria

Erythrocyte Changes in Malaria

1. 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

Cytoadherence

HOST RESPONSE

Complications of Malaria

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

Complications add pictures

• Cerebral malaria• Hypoglycemia• Lactic acidosis• Noncardiogenic pulmonary edema• Renal impairment• Hematologic abnormalities• Liver dysfunction

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

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

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

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

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)

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

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

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

Treatment of Malaria

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

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

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

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

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

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:

1. Tetracycline (4 mg/kg qid for 7 days)2. Doxycycline (3 mg/kg qd for 7 days)3. Clindamycin (10 mg/kg bid for 7 days)

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

Prevention of Malaria

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

Table 203-8 Drugs Used in the Prophylaxis of Malaria

Drug Usage Adult Dose Comments

Atovaquone/proguanil (Malarone)

Prophylaxis in areas with chloroquine- or mefloquine-resistant Plasmodium falciparum

1 adult tablet PO

Good for last-minute travelers; 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. Side effects are uncommon. Contraindicated in persons with severe renal impairment (creatinine clearance rate <30 mL/min).

Chloroquine phosphate (Aralen and generic)

Prophylaxis only in areas with chloroquine-sensitive P. falciparumc

300 mg of base (500 mg of salt) PO once weekly

Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Can be given in all trimesters of pregnancy.

Harrison’s Internal Medicine, 17th ed.

Global Health – Division of Parasitic Diseases. Centers for Disease Control and Prevention, updated Feb. 8, 2010.

Doxycycline (many brand names and generic)

Prophylaxis in areas with chloroquine- or mefloquine-resistant P. falciparumc

100 mg PO qd

•Good for last-minute travelers; begin 1–2 days before travel to malarious areas. Least expensive among anti-malarial agents. Take daily at the same time each day while in the malarious areas and for 4 weeks after leaving such areas.

Hydroxychloroquine sulfate (Plaquenil)

An alternative to chloroquine for primary prophylaxis only in areas with chloroquine-sensitive P. falciparumc

310 mg of base (400 mg of salt) PO once weekly

Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas.

Harrison’s Internal Medicine, 17th ed.

Global Health – Division of Parasitic Diseases. Centers for Disease Control and Prevention, updated Feb. 8, 2010.

Mefloquine (Lariam and generic)

Prophylaxis in areas with chloroquine-resistant P. falciparum

228 mg of base (250 mg of salt) PO once weekly

Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas.

Primaquine An option for prophylaxis in special circumstances; used for presumptive antirelapse therapy (terminal prophylaxis) to decrease risk of relapses of P. vivax and P. ovale.

30 mg of base (52.6 mg of salt) PO qd for 14 days after departure from the malarious area

Good for last-minute travelers; begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 7 days after leaving such areas. This therapy is indicated for persons who have had prolonged exposure to P. vivax and/or P. ovale.