Malaria

Microbiology:

• Malaria is caused by Plasmodium parasites.
• It is transmitted by night-time or pre-dawn biting female Anopheles sp.
mosquitoes.
• Saudi Arabia (2014) reported species:
P. falciparum (38.8%)
P. vivax (60.8%)
P. ovale (0.2%)
P. malariae (0.2%)

P. knowlesi:

• It is a monkey malaria parasite (Zoonosis), noted to cause human malaria in Southeast Asia.
• It resembles P. malariae morphologically.
• It may cause rapidly progressive, severe disease.

Background to refresh your knowledge:

Pathophysiology differs by species:

• P. falciparum invades RBCs of all ages, causes most severe and lethal illness as RBCs rosette and
sequester in microvasculature, and damage heart, brain, kidney, lung, placenta.
• P. vivax and P. ovale can persist in hepatocytes as hypnozoites for months to years.
• P. vivax preferentially invades reticulocytes and requires Duffy antigen for RBC entry.
• P. malariae infects older RBCs and causes low level parasitemia and chronic, low-grade infection.
Characteristic of human malaria:

Type P. falciparum P. knowlesi P. vivax P. ovale P. malariae
Incubation 8-25 days Probably 8-25 days 2 weeks 2 weeks 3-4 weeks
Yes Yes
Hypnozoites No No No
The reason for relapses !
Any Any Young Young Old
RBC age Bannana shaped
Band form Schüffner’s dots Band form
gametocytes
< 2% < 2% < 1%
Parasitemia High High
> 2% Can’t be any one of these Plasmodia
Morbidity High High High Moderate Low
Mortality High Moderate Low Low Low

Possible evolutionary defenses against malaria:

Duffy antigen negative:

• P. vivax uses Duffy antigen to enter RBCs (West Africans are resistant to P. vivax infections because
they lack the Duffy glycoprotein receptor).

Sickle cell trait:

• Increases survival during P. falciparum infection, perhaps by selective sickling of infected RBCs.

Glucose-6-phosphate dehydrogenase deficiency:

• Malaria parasites grow poorly in G6PD deficient RBCs, perhaps because this results in an overall
increase in reactive oxygen species in RBCs.
When to suspect Malaria:
Acquired during travel:
Clinical Presentation: • Fever +LR 5.1
• Splenomegaly +LR 6.5
• Hypebilirubinemia +LR 7.3
• The #1 cause of fever (FUO) in a returned traveler in most of the studies. • Thrombocytopenia + LR 5.6
Living in endemic area:
• Infected individuals can rapidly progress from clinically appearing well to • Splenomegaly +LR 3.3
being critically ill. • Hepatomegaly +LR 2.4

Parameter Uncomplicated (mild) malaria Complicated (severe) malaria
• Fevers, chills, headache, fatigue, • Cerebral malaria (change in mental status,
Symptoms

abdominal pain presenting symptom in confusion, coma persisting for > 30 min after a
20% seizure).
• periodicity of fevers not common when • Respiratory distress.
patients seen acutely. • Severe anemia (HgB < 5 g/dL or hct <15%)
• Thrombocytopenia in 50%. • Renal failure.
• Mild anemia in 30%. • Hypoglycemia.
Laboratory

• Typically no leukocytosis. • Circulatory collapse and lactic acidosis

• It may see evidence of hemolysis with (bicarbonate < 15mmol/L or lactate >5mmol/L).
mild increase T bilirubin and LDH. • Bleeding disorder (spontaneous bleeding
(hemoglobinuria, jaundice) or evidence of DIC).
• Rarely presents with splenic rupture.

Complications: Funduscopic exam:

Malarial retinopathy is pathognomonic for
• Primarily occur with Plasmodium falciparum. cerebral malaria in patients who satisfy
• Usually when parasitemia (>2% by WHO 2010, >5% by the standard clinical case definition.
CDC criteria).
Definitions:

Malaria case:

A patient who presents with symptoms of malaria and a positive parasitological test (microscopy or RDT)
but with no features of severe malaria is defined as having uncomplicated malaria or simple malaria.

Clinical malaria (probable malaria):

Patients who present with signs and symptoms of malaria without parasitological confirmation and receive
antimalarial treatment, it can be uncomplicated or severe.

Parasitological malaria (confirmed malaria):

Patients with signs and symptoms with parasitological confirmation done by blood film microscopy, RDT, or
molecular diagnostic test (in the context of malaria elimination) are considered as confirmed malaria.
It can be asymptomatic, uncomplicated or severe.

Carrier state:

A carrier is the person or animal that shows no symptoms of a disease but harbors the infectious agent of
that disease and is capable of transmitting it to others.
In malaria it occurs in two forms:
1. Person who is carrying the sexual form (gametocyte) with no signs and symptoms of malaria
usually due to incomplete treatment.
2. Patients who had some degree of natural resistance to one parasite species or another

Diagnostics:

Light microscopy (Using Giemsa stain) Gold standard:

• Thick smears used to detect parasites.
• Thin smears (oil immersion, 100x) used to determine species and degree of parasitemia.

Repeat blood smear every 12 hours (for total of 3 sets) to detect parasitemia that may lag behind clinical
presentation.
Three target enzymes or proteins are available
Rapid diagnostic tests (RDTs): for Rapid Diagnostic Testing RDT:

1. P. falciparum Histidine Rich Protein 2 (Pf
• Employ lateral flow immunochromatography with capture HRP2) which identify recent P. falciparum
and detection antibodies (Qualitative). infection with very high sensitivity. If the
• Diagnostic targets are malaria antigens conserved across all parasite density of >100 (parasite/µl) and
species or antigens specific to P. falciparum or P. vivax high specificity (93%)
2. Parasite specific Lactate Dehydrogenase
• Used in Blood banks for screening purposes.
(P. LDH) which identify P. falciparum and
other species is less sensitive and more
Disadvantages: specific than Pf HRP2 which has the

advantage of differentiating Plasmodium
• Cannot confirm degree/load of parasitemia.
falciparum P. LDH from other Plasmodium
• Sensitivity decreases with parasitemia < 100/uL. species (93.2% sensitive if the parasite
• The HRP2 can remain detectable in the blood for up to four density >100 (parasite/µl))
weeks after the complete parasitological cure and may thus give 3. Plasmodium anti-Aldolase pan test which
false positive results. react to all Plasmodia species.

PCR:

• it is not routinely done.

• It is used to confirm microscopy or in setting of low parasitemia.
Treatment:
Treatment of P. falciparum

Uncomplicated (no organ dysfunction, low parasitemia, able to take orally)

Saudi MOH Protocol/CDC (only for P. falciparum)/ WHO 2015 (for other Plasmodium species)
(ACT)
First Line:

Days Day 1 Day 2 Day 3
Sulfadoxine-Pyrimethamine (SP) Artesunate (AS) Artesunate (AS) Artesunate (AS)
Drug 500+25 mg Tab 50 mg Tab 50 mg Tab 50 mg Tab
Adult dose 3 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg

Second Line:

Days Day 1 Day 2 Day 3
Time Artemether 20 mg + Lumefantrine 120 mg (The only FDA Approved)
Drug AM PM AM PM AM PM
Adult dose 4 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg

A single dose of primaquine (0.25 mg base/kg bw, maximum dose 15 mg) should be added on the
first day of treatment to ACT for uncomplicated falciparum malaria as a gametocytocidal medicine (Not by
MOH).

WHO Protocol:
If chloroquine sensitive area:

• Chloroquine phosphate 600 mg base (=1,000 mg salt) PO once, then 300 mg base (=500 mg salt) PO at 6, 24 and
48 hours.
• Hydroxychloroquine 620 mg base (=800 mg salt) PO once, then 310 mg base (=400 mg salt) PO at 6, 24 and 48
hours.

If chloroquine resistant area:

First Line:

• Atovaquone-proguanil (Malarone 250/100):
4 tabs PO once-daily for 3 days, taken with milk or fatty meal (third line agent in Saudi Arabia).
• Artemether-lumefantrine (Coartem 20/120):
4 tabs PO initial dose then 4 tabs PO second dose 8 hours later, then 4 tabs PO twice-daily x 2 days.

Second line (third line in Saudi Arabia):

• Quinine sulfate 542 mg base (=650 mg salt) PO tid x 7 days (for infections acquired in SE Asia) or 3 days (for
infections acquired elsewhere) PLUS any of the following:
1. Doxycycline 100 mg PO twice-daily for 7 days
2. Tetracycline 250mg PO q6h x for 7 days or
3. Clindamycin 20 mg base/kg/day PO divided q8h (average dose 450 PO q8h) for 7 days.
• Mefloquine 684 mg base (=750 mg salt) PO initial dose, then 456 mg base (=500 mg salt) PO 6-12h later.

Important to know:

• Quinine use is associated with cinchonism (reversible tinnitus and reversible high-tone hearing loss).
• Use mefloquine as last choice due to neuropsychiatric reactions seen at treatment doses.
• Avoid in infections acquired in SE Asia due to drug resistance.
Complicated Severe (hyperparasitemia, CNS symptoms, severe anemia, renal failure, ARDS, DIC)
(Severe = IV therapy)

Artemisinin-containing combination therapy (ACT):

Artesunate 2.4 mg/kg/dose IV at 0, 12, 24, 48 and 72 hrs (7 days in MOH). Avoid Artemether and
Follow artesunate by one of the following: Mefloquine in Cerebral
• Atovaquone-proguanil(Malarone), Malaria
• Doxycycline (clindamycin in pregnant women), or
• Mefloquine (The preferred in MOH 2016 policy).

NOTE: there is increasing artemisinin resistance in SE Asia but it has not yet emerged in Africa

IV quinidine (or quinine):

• Admit to telemetry unit.

• Monitor for QTc prolongation, QRS widening, ventricular arrhythmia, hypotension and
hypoglycemia.
• If significant QRS widening, slow or hold infusion.
• Hypotension common with quinidine/quinine (may be due to drug or the infection itself). Treat
hypotension with judicious use of fluids.
• Use artemisin-based therapy if parasitemia > 10% of baseline at 48 hours after initiation of
quinidine.

Additional management:

• Consider exchange transfusion for parasitemia >10%, coma, ARDS or kidney failure.
• Early hemofiltration and mechanical ventilation may improve survival.
• Treat severe malaria aggressively with IV antimalarials in pregnancy.

P. vivax, P. ovale, P. malariae, and P. knowlesi:

Chloroquine-sensitive:

• Chloroquine phosphate 600 mg base (1,000 mg salt) PO once, then 300 mg base (500 mg salt) at 6,
24 and 48 hours.
• Treatment of liver forms (P. vivax/ovale only):
• primaquine 30 mg base PO once-daily x 14d.

Chloroquine-resistant P. vivax:

• Quinine sulfate + doxycycline
• Tetracycline + primaquine
• Atovaquone/proguanil + primaquine OR
• mefloquine + primaquine.

Rare case reports of chloroquine resistant P. vivax documented in Myanmar, India, and Central and South
America.

For uncomplicated P. malariae and P. knowlesi:

• chloroquine remains drug of choice.


Things to know about antimalarial drugs:

Primaquine:

• Contraindicated in pregnancy/breastfeeding.
• Primaquine treatment is not mandatory. Some prefer to wait for the low risk of relapse rather than
face potential side-effects of the drug.
• Need to check G6PD status before administering primaquine as primaquine can cause severe
hemolysis in patients with G6PD deficiency
• Primaquine requires cytochrome P-450 2D6 to be effective. Therefore, clinical failure to cure P.
vivax can be due to low host levels of CYP450-2D6. N Engl J Med 2013; 369:1381-1382
• Interact with ethanol (alcoholic).

Mefloquine:

• Changed from pregnancy category C to caregory B in 2011 by FDA. Considered safe during all
trimesters of pregnancy.
• FDA black box warning in 2013 that mefloquine can cause neurologic symptoms, hallucinations, and
feelings of anxiety, mistrust, and depression mefloquine. Thus, many U.S. practitioners now reserve
mefloquine for pregnant travelers to areas with chloroquine resistance.
• In HIV:
PI decreases mefloquine levels (clinical significance is unclear).
Avoid in HIV patient taking PIs.

Artesunate:

• Contraindicated in first trimester in MOH 2015 policy but not any more in 2016!!.
• Can be given in second and third trimester.
• No dose adjustment in renal or hepatic failure.

Fancidar:

• Pyramithamine-sulfadoxine.
• Used to be a prophylaxis for chloroquine resistant malaria but discontinued.

Treatment Failure:

• It is defined as; failure to resolve or recurrence of fever and/or parasitaemia within 2 weeks of the
start of treatment, it is divided into:
1. Early treatment failure (1-3 days of treatment).
2. Late treatment failure (after 4 days up to 4 weeks).

Causes of treatment failure:

a) Poor adherence to treatment.
b) Low or incomplete dose.
c) Abnormal individual pharmacokinetics.
d) Drug resistance.

Treatment failure management:

1) Failure within 14 days; Shift to the second line immediately.
2) Failure after 14 days; this may be due to recrudescence or re-infection so it can be retreated with
the first-line drug. In recrudescence, the first-line drug should be effective in most of the cases.

Malaria in pregnancy:

• More severe with greater frequency of hypoglycemia and pulmonary compromise due to relative
immunosuppression and parasite sequestration.
• Malaria in pregnancy is associated with abortion, stillbirth, low birth weight, increased anaemia
and, in low transmission areas, an increased risk of severe malaria.
• Falciparum malaria in setting of pregnancy may be considered criteria for IV therapy.

Treatment:

Complicated Severe (hyperparasitemia, CNS symptoms, severe anemia, renal failure, ARDS, DIC)

Saudi MOH Protocol:

• IV Artesunate is the treatment of choice of SEVERE falciparum malaria in pregnant ladies including the
first trimester of pregnancy.
• Quinine + Clindamycin to be given for 7 days (if ACT is not available).

Uncomplicated (no organ dysfunction, low parasitemia, able to take orally)

Saudi MOH Protocol:

First trimester:

• Oral Quinine + Clindamycin to be given for 7 days

In Second and third trimesters:

• ACT is recommended for uncomplicated falciparum malaria in 2nd and 3rd trimester of pregnancy (Saudi
Arabia).
• Quinine + Clindamycin to be given for 7 days.

Note !

• ACT should be used if it is the only effective treatment available.

WHO Protocol:

For chloroquine-sensitive species:

• Use chloroquine or hydroxychloroquine.

For chloroquine-resistant species:

• Quinine sulfate +clindamycin.

Drugs contraindicated in pregnancy:

1) Tetracycline
2) Doxycycline
3) Primaquine.

Atovaquone-proguanil and artemether-lumefantrine are not generally recommended during pregnancy,
especially during first trimester, due to lack of sufficient safety data.

Use of dihydroartemisinin-piperaquine for uncomplicated malaria in second and third trimesters has been
associated with reduced risk of vertical transmission.
Malaria Chemoprophylaxis:

Drug Pre-Exposure During Post-Exposure

Middle East
1 tablet weekly for 2 1 tablet weekly for 2
Chloroquine 1 tablet weekly
weeks weeks
Everywhere else
Atovaquone/proguanil 1 tablet daily for 2 days 1 tablet daily 1 tablet daily for 7 days
1 tablet daily for 4
Doxycycline none 1 tablet daily
weeks
1 tablet weekly for 2 1 tablet weekly for 4
1 tablet weekly
Mefloquine weeks weeks
Mefloquine is NOT RECOMMENDED due to potential side effects

Things to know about Malaria prophylaxis:

• Atovaquone/proguanil (Malarone):
Take with food (preferably after the main meal) or milky drink.
Always on the same day each week, until 4 weeks after return.
• Doxycycline:
Optimally taken in evening or same time each day.
Photosensitivity risk >3%, avoid sun, use sunscreen.

For pregnant women who travel to areas with chloroquine-resistant P falciparum:

• Mefloquine should be recommended for prophylaxis.

Central America north of Panama Canal (only):

• Chloroquine

Mosquitoes bite at any time of day but Anopheles bite mainly at night with most activity at dawn and dusk.
Use insecticide-treated bed netting, sprays (DEET) and screens.

Terminal prophylaxis:

• Primaquine 30 mg base PO daily x 14 days at end of malaria exposure period.
• Screen for G6PD deficiency prior to treatment.













Important Definitions:

Recrudescence:

• It is described when parasitaemia falls below detectable levels after treatment and then later
increases to a patent parasitaemia.
• This results from incomplete clearance of parasitaemia due to inadequate or ineffective treatment
(drug resistance or improper choice of medication).

Recurrence:

• The recurrence of asexual parasitaemia following treatment can be caused by a recrudescence, a
relapse (in P. vivax and P. ovale infections only) or a new infection.

Relapse:

• The recurrence of asexual parasitaemia in P. vivax and P. ovale malaria deriving from persisting liver
stages.
• Relapse occurs when the blood stage infection has been eliminated but Hypnozoites persist in the
liver and mature to form hepatic schizonts.
• After variable intervals of weeks to 7 months, the hepatic schizonts burst and liberate merozoites
into the bloodstream.













References:

• IDBR Lecturs.
• Sandford Antibiotic guide
• Johns Hopkins ABX guide.
• UpToDate.
• National Malaria Drug Policy by MOH 2015/2016.
• Dr. M. Alhazmi Lecture.








Good Luck
Jweida