Cold Shivers After A Hot Trip Subsection A-2 USTFMS.

Cold Shivers After A Hot Trip

Subsection A-2USTFMS

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?

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

http://www.medicinenet.com/malaria/page2.htm

Relapsing Malaria

• P. vivax and P. ovale infections– a proportion of the intrahepatic forms do not

divide immediately but remain dormant for a period ranging from 3 weeks to a year before reproduction begins

• HYPNOZOITES = dormant form

Harrison’s Principle of Internal Medicine, 17th ed.

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.


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.


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.



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.


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.


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


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


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.


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.


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%.


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.


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


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


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


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


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


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.


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.


• 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


Medications Used for Chemoprophylaxis

• Atovaquone/Proguanil (Malarone)• Chloroquine (Aralen) and

Hydroxychloroquine (Plaquenil)• Doxycycline (Many Brand Names and

Generic)• Mefloquine• Primaquine


Drugs used for ProphylaxisDrug Usage Adult Dose Pediatric Dose Comments

Atovaquone/proguanil (Malarone)

Prophylaxis in all areas

Adult tablets contain 250 mg atovaquone and 100 mg proguanil hydrochloride. 1 adult tablet orally, daily

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

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.

Chloroquine phosphate (Aralen and generic)

Prophylaxis only in areas with chloroquine-sensitive malaria

300 mg base (500 mg salt) orally, once/week

5 mg/kg base (8.3 mg/ kg salt) orally, once/week, up to maximum adult dose of 300 mg base

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

Doxycycline (many brand names and generic)

Prophylaxis in all areas 100 mg orally, daily

≥8 years of age: 2 mg/ kg up to adult dose of 100 mg/day

Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in children <8 years of age and pregnant women.


Drugs used for Prophylaxis

Hydroxychloroquine sulfate (Plaquenil)

An alternative to chloroquine for

prophylaxis only in areas with chloroquine-sensitive malaria

310 mg base (400 mg salt) orally,

once/week

5 mg/kg base (6.5 mg/ kg salt) orally, once/week, up to

maximum adult dose of 310 mg base

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

MefloquineProphylaxis in areas with

mefloquine-sensitive malaria

228 mg base (250 mg salt) orally,

once/week

≤9 kg: 4.6 mg/kg base (5 mg/kg salt) orally, once/week;

>9–19 kg: 1/4 tablet once/week;



≥45 kg: 1 tablet once/ week

Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in persons allergic to mefloquine or related compounds (e.g., quinine, quinidine) and in persons with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Use with caution in persons with psychiatric disturbances or a previous history of depression. Not recommended for persons with cardiac conduction abnormalities.


Drugs used for Prophylaxis

PrimaquineProphylaxis for short-duration travel to areas with principally P.vivax

30 mg base (52.6 mg salt) orally, daily

0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, daily

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 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

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


Travel to Areas with Mainly P. vivax Malaria

• mosquito avoidance measures• primaquine - primary prophylaxis for travelers

who are not G6PD-deficient


Travel to Areas with Chloroquine-Sensitive Malaria

• mosquito avoidance measures• chemoprophylaxis alternatives:

– chloroquine, atovaquone/proguanil, doxycycline, mefloquine,

– primaquine for travelers who are not G6PD-deficient

• Longer-term travelers - weekly chloroquine• shorter-term travelers - atovaquone/proguanil

or primaquine.


Travel to Areas with Chloroquine-Resistant Malaria

• to mosquito avoidance measures• chemoprophylaxis limited to

atovaquone/proguanil, doxycycline, and mefloquine.


Travel to Areas with Mefloquine-Resistant Malaria

• mosquito avoidance measures• chemoprophylaxis options are reduced to

either atovaquone/proguanil or doxycycline


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).


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.


Cold Shivers After A Hot Trip Subsection A-2 USTFMS.

Documents

ustfms slide

malaria patient

malaria pathogenesis

episode of malaria

pedal edema slide

relapsing malaria parasites

infection immunity

malaria prophylaxis