Medical Guidelines

Key Points for the Family Physician:

• Malaria occurs in tropical and subtropical world regions, where warm temperatures allow the Anopheles Gambiae mosquito to thrive.
• Suspect malaria in any febrile patient who has had exposure to an endemic region. Screen for persistent headache, myalgias and other flu like symptoms.
• According to the BC CDC (BC Centre for Disease Control) there were 27 cases of Malaria in BC during 2009 (rate of 0.6 per 100, 000). From 2010 to present, preliminary reports show increasing rates from Fraser South in keeping with increasing travel to endemic areas.
• The CDC reports a 0.1% fatality rate for falciparum malaria if treated early. If treated in later stages, rates rise to 15 - 20 %.
• There is currently no malaria vaccine approved for human use. Promising clinical trials are ongoing.
• The CDC recommends the following for all travellers to endemic countries: anti-malarial prophylaxis, insecticide spray, bed nets for sleep, insect repellant for clothing and skin, full coverage clothing from dusk to dawn. These measures reduce transmission by 90%.
• Inappropriate use of antimalarial drugs has contributed to widespread drug resistance, specifically to chloroquine type drugs. A new group of artemisinin-based anti-malarial combination therapies has revolutionized treatment.
• Travellers returning home from endemic areas are deferred from donating blood for 1 year, depending on place of travel and length of stay.
• Contact the BC CDC at 655 West 12th Avenue Vancouver with any point of care questions. Main line: 604-707-2400.

The basics

Image: CDC - Global Health Division of Parasitic Disease

Malaria is a mosquito borne illness caused by eukaryotic protist parasites of the genus Plasmodium. Dr. Charles Louis Alphonse Laveran discovered Plasmodium in 1880. His discovery was made after drawing blood from a cyclically febrile patient, using the microscope for investigation. For this, Laveran was awarded the Nobel Prize in 1907.

Malarial disease results from multiplication of malarial parasites within red blood cells. Female mosquitoes of the Anopheles genus are the primary hosts of this parasite. Mosquitoes act as transmission vectors while humans act as secondary hosts. In the anopheles genus, only females feed on blood. Males feed on plant nectar and are therefore benign in the disease cycle.

Topographic description of malarial transmission world wide. For a detailed look at Malaria across the globe use the Malaria Map Application found on at the US Center for Disease Control.

Five Species of Plasmodium Infect Humans

This thin film blood smear micrograph depicts an immature Plasmodium malariae schizont. Photo by CDC/ Dr. Mae Melvin, 1965

1. Plasmodium falciparum
   • Most common human malarial infection.
   • Severe malaria almost exclusively caused by falciparum.
   • Clinical symptoms 6-14 days after infection
   • Responsible for 80% of infection worldwide.
   • Responsible for 90% of malaria death worldwide.
2. Plasmodium Malariae (rarely fatal)
3. Plasmodium Ovale (rarely fatal)
4. Plasmodium Vivax (rarely fatal)
5. Plasmodium Knowlesi (mostly zoonotic, but can cause mild malaria in humans rarely)

Pathogenesis Made Simple

There are two phases of malaria pathogenesis: ¹⁾ the exoerythrocytic phase, that which takes place outside of the red blood cell, and ²⁾ the erythrocytic phase.

--> The female Anopheles mosquito becomes infected with malarial parasite.
--> Malaria sporozoites develop within the salivary glands of the mosquito.
--> The mosquito pierces human skin from dusk to dawn searching for a blood meal.

THIS MARKS THE BEGINNING OF THE EXOERYTHROCYTIC PHASE

--> Sporozoites from mosquito saliva enter the human (secondary host).
--> Sporozoites gain vascular entry and migrate to human liver.
--> Sporozoites infect hepatocytes immediately.
--> Asexual multiplication occurs within hepatocytes for a period of 8 – 30 asymptomatic days.
--> Sporozoites differentiate within hepatocytes to yeild thousands of merozoites.
--> Rupture of hepatocyte host cells with merozoite escape into blood.
--> Further erythrocyte infection

THIS MARKS THE BEGINNING OF THE ERYTHROCYTIC PHASE

--> Asexual multiplication within erythrocyte
--> Periodic rupture of RBCs to invade fresh hosts
--> Continuous amplification of exoerythrocytic and erythrocytic host cycles.

It is the cyclic ruptures and dissemination that cause cyclical fevers, chills and rigors.

Incubation Period

Following a bite from a female Anopheles mosquito infected with malaria, inoculated sporozoites seek the liver within 1 to 2 hours. Most humans are asymptomatic for 8-30 days.

Early Onset Symptoms

The classic symptoms include sudden onset chills, rigors, diaphoresis, followed by recurrent fever every 24 – 48 hours. Fevers usually last 4-6 hours, but can present as low grade but constant for days.

Treatment

Early diagnosis of malaria and prompt effective treatment, reduces morbidity and mortality. See below for a listing of anti-malarial agents.

Clinical Manifestations

Initial symptoms are nonspecific. Most patients will have/develop uncomplicated disease. Consider malaria in patients who have travelled or lived in endemic areas who presents with:

• Tachycardia
• Tachypnea
• Malaise
• Rigors
• Fatigue
• Anorexia
• Abdo pain
• Myalgias
• Headache
• Splenomegaly
• Anemia (usually mild)
• Jaundice
• Parasitemia (<5000 parasites/microl of blood)
• Thrombocytopenia
• Transaminase elevation
• BUN/Creatinine elevation

Splenic enlargement is a common finding in endemic areas. This may represent repetitive infection. Repeat infections may lead to splenic infarctions causing splenic fibrosis.

Complicated Malaria

These patients may have hyperparasitemia > 100,000 parasites/microl of blood) or >5 to 10 percent of parasitized RBCs. The World Health Organization uses the latter as diagnostic criteria for diagnosis of 'severe malaria'. Parasitized RBCs adhere to small blood vessels causing microinfarctions sparing no organ system.

Clinical Presentations of Severe Malaria

• Seizure
• Decreased level of consciousness
• Metabolic acidosis
• Hepatic failure
• Renal failure
• Severe anemia
• Hypoglycemia
• Coagulopathy/DIC
• ARDS (acute respiratory distress syndrome)

Physical Findings of Severe Malaria

• Pallor
• Jaundice
• Widespread petechiae
• Hepatosplenomegaly
• Splenic rupture (rare)

Diagnosis

In BC, order at any lab:

1. Two thick and two thin blood smears for malaria, preferably one while febrile. 3 smears in 48 hours are required to rule out malaria.
2. One tube of EDTA, which is sent to BCCDC Parasitology Lab (604-707-2629) for antigen dipstick testing.

PCR testing is not used.

Standard Tools for Diagnosis:

Giemsa stained blood smears are interpreted by light microscopy. With this technique however, diagnostic errors do occur in the setting of parasitemia of low-density. Microscopy allows for 1) calculation of parasitemia and 2) detection of Plasmodium species. Parasitic load is important for monitoring response to therapy. When rapid diagnostic testing is available, microscopy should be used as an adjunct. Microscopy is also useful for the diagnosis of other infectious agents which may be present in the setting of a malaria work up. These include Borrelia Recurrentis, Filariasis, Trypanosomiasis.

Rapid Diagnostic Tests:

RDTs were introduced in the 1990s. These utilize immunochromatographic lateral flow technology.

Accurate diagnosis of malaria is important for appropriate therapy. Empiric treatment of malaria with chloroquine is no longer appropriate. The emergence of chloroquine-resistant P. falciparum is epidemic. Today, Artemisinin combination therapies are the mainstay of treatment. These however are expensive. Thus, accurate diagnosis is essential.

Antimalarial medications

(Information retrieved from the US CDC)

Antimalarial drugs are used for both the prophylaxis and treatment of malarial disease.

Treatment – Quinolone Derivatives:

• Quinoline derivatives were the original mainstay of malaria treatment. Included in this class are chloroquine, amodiaquine, quinine, quinidine, mefloquine, primaquine. Chloroquine was the first drug widely distributed for the treatment and prophylaxis of malaria. Wide spread resistance in most endemic regions however, has led to its decline in treatment of P. Falciparum. Chloroquine remains effective for the treatment of P. Ovale.

Treatment – 4 – Methanolquinolines – Quinine & Quinidine:

• Quinine is a derivative of the South American Cinchona tree bark. This is the most common drug used in the World's endemic areas. In many regions it is the only drug available despite resistance patterns.
• Quinidine is a stereoisomer of quinine. It is very effective against severe malaria and is available in parenteral form.
• Adverse effects include tinnitus, nausea, headaches, dizziness, visual changes. Quinidine has a narrow therapeutic window. Overdose can lead to cardiotoxicity, arrhythmia, hypotension, blind and deafness.
• For areas where quinine has decreased susceptibility combine with an anti-biotic such as tetracycline, doxycycline or clindamycin.

Treatment – Mefloquin:

• Available orally.
• Can be used for treatment or prophylaxis.
• Adverse effects include vomiting dizziness, an disruptions in cardiac conduction.

Treatment – Anti-microbials:

• Antimicrobials such as tetracycline, doxycycline, and clindamycin are sometimes used.
• These have relatively slow anti-malarial activity. They are typically partnered with fast-acting anti-malarials such as quinine.
• Resistance is limited.

Treatment – Artemisinin Derivatives:

• Artemisinin based therapies are derived from the leaves of the Chinese sweet wormwood plant 'artemisia annua'. These have been utilized in China for over 2000 years as malaria treatment. In the 1970's – 1980's these drugs began receiving international scientific attention. Artemisinins are now the cornerstone of anti-malarial therapy, revolutionizing treatment. They are generally used as combination therapies. They are not to be used as single agents, in efforts to prevent resistance. Prolonged therapy should also be avoided.
• Artemisinin drugs appear to bind iron, break down peroxide bridges, create fee radicals. These processes lead to the destruction of important proteins that parasites create. Artemisinins are Rapid acting. These drugs have the fastest ability to clear parasites.
• In places with Artemisinin accessibility IV artesunate is used for treatment of severe malaria. This drug is superior to quinine at reducing mortality. Artemisinins generally well tolerated.
• Artemisinin combination therapies couple highly effective short acting artemisinins with other long acting agents. These are usually dosed for three days. Fixed dose tablets are available.
• According to the WHO, Western Cambodia has no begun to demonstrate artemisinin resistance. In response, the WHO has banned all manufacturing of artemisinin monotherapy to stave resistance.

Five Artimisinin Based Combination Therapies Recommended by WHO to Treat Uncomplicated Malaria

1. artemether-lumefantrine (most widely used in Africa)
2. artesunate-amodiaquine
3. artesunate – mefloquine
4. artesunate-sulfadoxine-pyrimethamine
5. dihydro-artemisinin-piperaquine

Malaria Vaccine

• July 2009, Phase III trial of malaria vaccine candidate launched in Kisumu Kenya
• The vaccine candidate is GlaxoSmithKline Biologicals' RTS,S.
• This is the first of the malaria vaccines of this generation to move forward to Phase III testing.
• The RTS, S vaccine allegedly shpws a promising safety profile.
• Shown to be more than 50% effective in reducing clinical malaria episodes between the ages of 5 – 17 months.
• Phase III testing will evaluate vaccine effectiveness in two groups of children across Africa, (6-12weeks and 5-17 months).

Immunity

Scientists have discovered immunity in many persons living in endemic areas of Africa. The degree of immunity directly correlates to degrees of parasitemia. Those living in Sub-Saharan Africa tend to develop complete immunity by the time of adulthood. Endemic areas of low transmission are shown to develop semi-immunity.

Counterfeit Antimalarials – An Emerging Problem

The counterfeiting of anti-malarials is a significant and growing problem worldwide.

Surveys of anti-malarial medications purchased in southeast Asia indicate that 30 – 50 percent of medications were counterfeit. Counterfeit medications often contain subtherapeutic amounts of active drug. Some counterfeit medications have been shown to contain no active compound.

Links and references

Interested in Malaria worldwide?

Check out the WHO's Malaria Report 2010. This report discusses the World Health Assembly (WHA) malaria targets, and the international progress being made. The report is created using information received from 106 malaria endemic countries around the globe.

To learn more about World Malaria Day search here.

References

Dondorp AM, Newton PN, Mayxay M, et al. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int Health 2004; 9:1241.

Newton P, Proux S, Green M, et al. Fake artesunate in southeast Asia. Lancet 2001; 357:1948.

Newton PN, Fernández FM, Plançon A, et al. A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med 2008; 5:e32.

WHO – Malaria

WHO – World Malaria Report 2010

Malaria – BC Centre for Disease Control

BC Annual Summary of Reportable Disease – BC CDC

Where Malaria Occurs: US CDC