Malaria II

Section Contents

Diagnosis
Malaria Pharmacology
Treatment & Management
Prevention
Assessment: Did I Get It? (DIG IT)
Treatment
Prevention
References

In this second part we will discuss the considerations surrounding diagnosis, treatment and management of malaria. This is probably the hardest part, but we tried our best to explain the most important concepts.

Diagnosis

There are three diagnostic modalities to detect malaria you should be familiar with:

Microscopy (thick and thin blood smears)

Microscopy is the gold standard for diagnosis of malaria and are based on the visualization of parasitic forms in Giemsa-stained blood smears. May require serial blood smears every 12-24h if clinical suspicion is high

*Thick blood smear → test of choice to confirm/rule out malaria.

* Thin blood smear → test of choice to identify species or calculate parasitemia.

NOTE: Identifying malaria species in a blood smear is hard. Plasmodium spp. share some similarities but each species has distinguishing features. We will not explain the nuances of identification, but we encourage you to visit this blog (Plasmodium species) and review how to recognize Plasmodium spp. in a blood smear.

Threshold to detection: ~50-500 parasites/mcL, but may vary depending on the expertise of the microscopist.
Advantages: gold standard testing, allows species identification & calculation of parasitemia, requires small amount of blood
Disadvantages: requires a trained microscopist and is dependent on competency of technician and equipment.

Rapid diagnostic test (RDT)

RDTs are lateral flow assays that have antibodies that detect the presence of malaria antigens in the blood. They are validated to detect 1-3 Plasmodium antigens and each commercial brand has different combinations of antigen detection (e.g., HRP2/pLDH, HRP2/Aldolase, etc). Overall performance in P. knowlesi is still unclear and widely variable

Antigens used:
1. Histidine rich protein-2 (HRP-2) → found in P. falciparum, and can persist after parasite death.
2. Parasite Lactate Dehydrogenase (pLDH) → found in P. falciparum, P. vivax, P. ovale & P. malariae,
  and it is not detectable after parasite death.
3. Aldolase → found in P. falciparum, P. vivax, P. ovale & P. malariae, and it is not detectable
  after parasite death.
HRP-2 pLDH Aldolase

Plasmodium spp. P. falciparum All four spp of Plasmodium All four spp of Plasmodium

Persistence after parasite death Yes (up to 2 weeks after treatment) No No

Table 2. Rapid diagnostic tests
Threshold to detection: >100 parasites/mcL
Advantages: simple to perform, does not require trained microscopists, inexpensive, rapid turnout time (<20
minutes), requires small amount of blood
Disadvantages:
1. false negatives reported due to P. falciparum HRP2 deletions,
2. false positives if performed soon after treatment, and cross-reactivity with other auto-antibodies,
3. results are only qualitative.

Molecular Testing

	RDTs	Microscopy	Molecular methods
Limit of detection	>100 parasites/mcL	>50 parasites/mcL	>1 parasite/mcL
Key advantages	Rapid turnaround time, easy to perform, inexpensive	Allows species indentification and calculation of parasitemia	High sensitivity, allows species identification
Key disadvantages	Cross-reactivity with multiple autoantibodies (e.g., rheumatoid factor) and other diseases (Hepatitis C virus, Salmonella, Dengue virus, T. cruzi, among others); HRP-2 deletions and persistence after treatment	Requires trained microscopists	Lengthy turnaround time, costly, not widely available

Table 3. Comparison of all available diagnostic methods

Malaria Pharmacology

Before we dive into treatment, it’s important to be familiar with the most commonly used drugs for both the treatment and prevention of malaria. Most of these medications fall into three main drug categories.

Artemisinin derivatives: artemisinin is derived from the plant Artemisia annua and is the parent drug for its three main clinically-used derivatives - artesunate, artemether, and dihydroartemisinin. These drugs are highly active against all species of Plasmodium, and act rapidly on all blood stages in the life cycle. However, they have very short half-lives and are therefore combined with second a second drug class (often slowly eliminated) with a distinct mechanism of action to clear the reminder of the parasite burden and avoid the development of resistance - known as artemisin combination therapies (ACT), examples are:
1. Examples: artemether-lumefantrine, artesunate-mefloquine, dihydroartemisinin-piperaquine, artesunate-amodiaquine, and artesunate-sulfadoxine-pyrimethamine
  1. Artesunate is the only one available as IV formulation
Quinoline derivatives → these heterogeneous groups of drugs are chemically related to quinine - which is now considered to be too toxic for routine use, although may still have some role in severe malaria. Remember they all end in “-quine”. With this group, drug toxicities are important and are summarized below.
1. Examples: quinine, chloroquine, mefloquine, primaquine, amodiaquine
2. Important indications:
  1. Chloroquine → drug of choice for P. vivax, P. ovale, P. malariae (except in resistant areas), and can be used in chloroquine-sensitive P. falciparum areas
  2. Primaquine/Tafenoquine → drug of choice (and only option!) for radical cure of hypnozoites in P. vivax and P. ovale
  3. Mefloquine → more commonly used for prophylaxis, but it is sometimes paired with artemisinin derivatives to produce ACTs (e.g. artesunate-mefloquine) to overcome chloroquine resistance

	Relevant side effects	Use in pregnancy
Quinine	Cinchonism, QTc prolongation	Yes
Chloroquine	GI upset, retinopathy (uncommon)	Yes
Mefloquine	GI upset, neuropsychiatric side effects, seizures	Yes
Primaquine	GI upset, hemolytic anemia in G6PD deficiency	No
Tafenoquine	GI upset, hemolytic anemia in G6PD deficiency	No

Table 4. Summary of most common sides effects from quinoline derivatives

Antifolates → these medications interfere in various ways with the metabolism of folic acid and DNA synthesis. They include: sulfonamides (e.g. sulfadoxine), pyrimethamine, dapsone, proguanil. Are often part of drug combinations: sulfadoxine-pyrimethamine, atovaquone-proguanil.
Miscellaneous → atovaquone, doxycycline, clindamycin

Treatment & Management

Managing malaria can get very complicated, because it requires careful consideration of several factors, including: the patient's clinical status, the level of parasitemia, the confirmed or suspected Plasmodium species, prior use of antimalarial prophylaxis, local patterns of drug resistance, and the availability of treatment options at your institution. Both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) provide comprehensive and easily accessible guidelines for malaria treatment and management. We highly encourage you to keep these resources readily available for quick reference in the event of a suspected or confirmed malaria case.

Just as an educational resource, we will simplify and summarize these recommendations, understanding that this is not comprehensive, nor does it encompass all the nuances of clinical management of malaria. As a quick summary, these are some basic concepts you need to know when treating a patient with confirmed or suspected malaria:

Recognize malaria
Determine if case falls under category of uncomplicated or severe malaria (refer to Clinical Presentation)
Identify the species - remember that for P. vivax and P. ovale after completing the treatment course, either primaquine or tafenoquine will need to be added to treat hypnozoites!

If no resistance is suspected or present, these are the drugs of choice:

	Uncomplicated Malaria	Severe Malaria
P. falciparum	ACTs	IV Artesunate
P. knowlesi	ACTs	IV Artesunate
P. malariae	Chloroquine	IV Artesunate
P. vivax, P. ovale	Chloroquine + Primaquine/Tafenoquine	IV Artesunate

Table 5. Comparing treatment strategies per Plasmodium spp

Some of the selection or duration of the regimens described above may change if an individual acquired malaria in one of the areas of drug resistance. Keep these table close to you for reference:

P. falciparum chloroquine-sensitive areas	Caribbean and Central America west of the Panama Canal
P. falciparum ACTs-resistant areas	Greater Mekong subregion (GMS) and Africa -- specifically in Eritrea, Rwanda and Uganda
P. falciparum mefloquine-resistant areas	Southeast Asia on the borders of Thailand with Burma (Myanmar) and Cambodia, in the western provinces of Cambodia, in the eastern states of Burma on the border between Burma and China, along the borders of Burma and Laos, and in Southern Vietnam
P. vivax chloroquine-resistant areas	Papua New Guinea and Indonesia

Table 6. Most common areas of resistance to common antimalarials

Managing special scenarios

Clinical resistance to malaria

This is different from what we discussed above. In the table above we described areas where the parasite might be resistant to the drugs. Instead, now we're talking to when the host is intrinsically resistant to the parasite.

How does this work? Well, Plasmodium spp. has applied selective pressure in the human genome over time. Certain genetic traits, such as mutations in the Duffy antigen, enzymatic deficiencies (i.e., G6PD) or hemoglobinopathies (i.e., sickle cell disease, thalassemias, Hemoglobin C/E) can confer partial immunity against malaria infection. This partial protection occurs because of many factors, including: increased splenic clearance of aberrant erythrocytes, and interfering with the parasite’s ability to invade.

Let's use mutations in the Duffy antigen (DA) as an example -- DA mediates invasion of erythrocytes in Plasmodium vivax. Individuals with mutations in this receptor may have partial immunity to P. vivax infection. Mostly seen in West Africa.

Malaria in pregnancy

Pregnant individuals have higher rates of complications (e.g., severe malaria), blood parasitemia can be higher, and blood smears can be less sensitive (due to parasitic sequestration in the placenta);

Basic pathophysiology → (refer back to Malaria I) infected erythrocytes express Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) which binds to chondroitin sulfate A (CSA) in the placenta. This allows erythrocytes to sequester in the small capillaries, induce hypoxia, inflammation, and reduce the delivery of nutrients to the fetus. In the first/second pregnancies, individuals may lack antibodies that protect from this sequestration, and thus malaria can be more severe in the first pregnancies.
Treatment considerations → treatment of malaria in pregnancy is very complicated! This by no means is comprehensive, but please remember a few pointers in malaria treatment in pregnant individuals:
- First trimester - uncomplicated malaria → traditionally the regimen of choice was Quinine-Clindamycin for 7 days, but some guidelines are now favoring ACTs during the first trimester.
- Second/Third trimester - uncomplicated malaria → regimen of choice are ACTs.
- Severe malaria (regardless of trimester) → regimen of choice is IV artesunate.
  - Infection with P. vivax/P. ovale → primaquine/tafenoquine is contraindicated in pregnancy. In this case, treatment is chloroquine weekly for one year or as long as primaquine can be used (needs G6PD level in infant before giving)
Chemoprophylaxis during pregnancy → malaria in pregnancy is so bad that all pregnant women living in areas with high transmission should be offered intermittent preventive treatment in pregnancy (IPTp) - which essentially means giving them antimalarials (typically sulfadoxine-pyrimethamine) at each prenatal visit starting in the second trimester (total: 3-6 doses).

Prevention

Vector avoidance → avoid outdoor spaces from dawn to dusk (highest activity of the mosquito), apply mosquito repellent, use metallic fabric in doors and windows, spray insecticides in the rooms overnight, avoid malaria endemic zones (particularly if pregnant!), use clothes that covers exposed areas, use of mosquito nets + insecticide-treated nets;
Vector control → use of larvicides, destruction of breeding sites, DDT (used in the past, but use was waned due to cost and environmental consequences), indoor residual spraying;

Chemoprevention: are strategies employed to prevent malaria disease; however, they DO NOT prevent malaria infection or its initial liver stages. In English, this means that individuals can still get malaria, but the parasite is killed by the chemotherapeutic agent before it causes any symptoms. Because it does not prevent the formation of hypnozoites, certain individuals can still relapse following the use of chemoprevention.

Chemoprophylaxis → used typically in travelers - often non-immune individuals- going from a non-endemic to an endemic area. These drugs prevent malaria disease, but not malaria infection, and thus they need to be taken some time before (need time to work) and have to be stopped some time after travel (to kill any circulating parasites). Drug options should be individualized to the patient’s travel schedule, preference, tolerability, resistance profile in area of travel, and cost. Options are summarized in the table and diagram below:

	Site of action	Schedule	High-yield side effects	Contraindications
Atovaquone- proguanil	Acts on liver and blood stages	1-2 days before; daily during travel; 7 days after return	GI upset; headaches. Can be costly	Pregnancy
Considerations → ideal for short trips
Mefloquine	Acts on blood stages	14 days before; weekly during travel; 28 days after return	GI upset, anxiety, vivid dreams, visual side effects	Psychiatric disorders, epilepsy, arrhythmias
Considerations → consider in pregnancy; avoid in Southeast Asia
Doxycycline	Acts on blood stages	1-2 days before; daily during travel; 28 days after return	Pill-esophagitis, Photosensitivity, Yeast infections	Pregnancy, Children <8
Considerations → prevents acne, also acts as prophylaxis for leptospirosis and rickettsioses
Chloroquine	Acts on blood stages	7 days before; weekly during travel; 28 days after return	GI upset	Psoriasis
Considerations → consider in pregnancy; avoid in most areas of the world
Tafenoquine	Acts on liver and blood stages	3 days before; weekly during travel; 7 days after return	Hemolytic anemia in G6PD deficiency	Pregnancy, Lactation, G6PD deficiency
Considerations → when used for radical cure can only be used with chloroquine

Table 7. Most common drugs used in malaria prevention

Seasonal malaria chemoprevention → this strategy is employed in areas with seasonal transmission of malaria (e.g., rainy season in West Africa) and consists in giving children under the age of 5 courses of anti-malarial treatment regardless of the presence of symptoms. Regimens should be dissimilar to first-line drugs used in that area to minimize resistance.
Mass drug administration → this strategy consists in giving antimalarials to most individuals at risk in an endemic area to decrease prevalence and interrupt transmission.
Intermittent preventive treatment in pregnant women → explained above in “malaria in pregnancy"

Vaccination: there are two vaccines recommended by the WHO (RTS,S and R21). Both act by inducing antibodies that prevent sporozoites from infecting hepatocytes. Clinical efficacy is over 30%, but benefit is synergistic with other strategies (i.e., chemoprevention). Currently only recommended in children living in endemic areas - especially those in areas of moderate to high transmission.

Assessment: Did I Get It? (DIG IT)

DIG ITs are online modules designed to reinforce key learning points for you! Please choose the best answer, then check all of the answer choices for more learning pearls

Begin Assessment

References

View All References

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This lesson was last updated August 21 2025