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Malaria - Knowledge @ AMBOSS

2/22/22, 1 :01 AM

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Malaria

Last updated: October 7, 2021

Summary

Malaria is a potentially life-threatening tropical disease caused by Plasmodium parasites, which are transmitted through the bite of an infected female Anopheles mosquito. The clinical presentation and prognosis of the disease depend on the Plasmodium species. Malaria has an incubation period of 7–30 days and may present with relatively unspecific symptoms like fever, nausea, and vomiting. Therefore, it is often misdiagnosed. Clinically suspected cases are confirmed by direct parasite detection in a blood smear . Patients are treated with antimalarial drugs (e.g., chloroquine , quinine), some of which may also be used as prophylaxis during trips to endemic regions. However, the most important preventive measure is adequate protection against the Anopheles mosquito (e.g., mosquito nets, repellents, protective clothing, etc.). Malaria is a notifiable disease and should be suspected in all patients with fever and a history of travel to an endemic region.

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Epidemiology

Distribution [1] Most cases of malaria occur in tropical Africa (West and Central Africa). Transmission also occurs in other tropical and subtropical regions such as Asia (e.g., India, Thailand, Indonesia), and Latin America (e.g., Brazil, Colombia)

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Pathogen: : Plasmodia [1] Eukaryotic parasites (belonging to the Sporozoa group) For different species, see table below Vector : the female Anopheles mosquito Host: humans Partial resistance against malaria [2] Carriers of sickle-cell mutation Individuals with either certain Duffy antigens or no Duffy antigens are resistant to P. vivax and P. knowlesi

[3]

Other hemoglobinopathies (e.g., thalassemia , HbC ) Infection with malaria subsequently leads to the development of specific Plasmodium Collapse all sections

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Disease and fever patterns of different plasmodium species Different species of

Disease

Fever spikes

plasmodium [4][5] Tertian malaria (usually less severe)

Every 48 hours

Plasmodium malariae

Quartan malaria (usually less severe)

Every 72 hours

Plasmodium falciparum

Falciparum malaria (most severe form; also known as malignant tertian malaria)

Irregular

Plasmodium knowlesi

Quotidian malaria

Irregular

Plasmodium vivax Plasmodium ovale

Pathophysiology

Life cycle of Plasmodium (simplified) [6]

Asexual development in humans 1. Transmission of Plasmodium sporozoites via Anopheles mosquito bite → sporozoites travel through the bloodstream to the liver of the host 2. Liver: sporozoites enter hepatocytes → sporozoites multiply asexually → schizonts formed containing thousands of merozoites → release of merozoites into the https://www.amboss.com/us/knowledge/Malaria/

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bloodstream 3. Circulatory system (two possible outcomes) Merozoites enter erythrocytes → maturation to trophozoites → red cell schizonts are formed containing thousands of merozoites → release of merozoites into the bloodstream (which causes fever and other manifestations of malaria) → penetration of erythrocytes recurs Merozoites enter erythrocytes → differentiation into gametocytes (male or female) Sexual development in female Anopheles mosquito A mosquito bites an infected human and ingests gametocytes → gametocytes mature within the mosquito intestines → sporozoites are formed and these migrate to the salivary glands → transmission of sporozoites to humans via mosquito bite See “Developmental stages of Plasmodium in RBCs ” in “Diagnostics” below.

Clinical features

Incubation period 7–30 days [7]

The incubation period of malaria is a minimum of seven days; if fever occurs before the seventh day following exposure in an endemic region, it is most likely not due to malaria.

Course Infection → asymptomatic parasitemia → uncomplicated illness → severe malaria → death Asymptomatic parasitemia: Especially in endemic regions, cases of asymptomatic plasmodia carriers are reported. [8] https://www.amboss.com/us/knowledge/Malaria/

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Tertian and quartan malaria are associated with less severe symptoms; , the involvement of fewer organs (rarely CNS or gastrointestinal symptoms), and a markedly lower risk of severe malaria. Following the successful treatment of tertian malaria, dormant P. ovale or P. vivax forms (hypnozoites) may persist within the liver and cause reinfection (relapse) after months or even years.

General symptoms [1][7] Flu-like symptoms, headache Diaphoresis High fever Tertian malaria: periodic fever spikes every 48 hrs Quartan malaria: periodic fever spikes every 72 hrs Falciparum malaria (malignant tertian malaria ): irregular fever spikes without a noticeable rhythm

Organ-specific symptoms [1][7] Blood Thrombocytopenia: increased bleeding risk Hemolytic anemia: weakness, paleness, dizziness Gastrointestinal Nausea, vomiting Diarrhea, abdominal pain Liver: : hepatosplenomegaly , discrete jaundice

Severe malaria [7] Description: potentially fatal manifestation or complication of malaria Etiology: most commonly a result of falciparum malaria Pathophysiology: infected erythrocytes occlude capillaries, which can lead to severe organ dysfunction https://www.amboss.com/us/knowledge/Malaria/

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Manifestations Kidneys: flank pain, oliguria, hemoglobinuria , acute kidney injury Cerebral: hallucinations , confusion, impaired consciousness, seizures, or even coma Cardiopulmonary: heart failure, pulmonary edema, ARDS, shock Hematologic: severe anemia , coagulation disorders Metabolic: hypoglycemia , metabolic acidosis Hyperparasitemia: > 5% of RBC are infected with plasmodia

Malaria can present in many different ways and is therefore often misdiagnosed. In patients with fever who have recently traveled to endemic regions, malaria must always be considered.

Diagnostics

General measures History: recent or distant travel to regions where malaria is endemic CBC Hemolytic anemia: ↓ Hb, ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes Thrombocytopenia Possibly leukocytopenia

Blood smear Description: confirms suspected cases by visualizing parasites within RBCs Best initial test: thick blood smear High sensitivity Detects the presence of parasites https://www.amboss.com/us/knowledge/Malaria/

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Confirmatory testing: thin blood smear Lower sensitivity than thick blood smear, but higher specificity Parasites are visible within red blood cells since the morphology of erythrocytes is preserved Allows determination of Plasmodium species Schuffner granules (fine, brick-red dots) within the cytoplasm of P. vivax and P. ovale Evaluation of negative test results [9] If parasite densities are very low, malaria may be initially undetectable. If an initial test result is negative, blood smears should be repeated three times every 12–24 hours If all three sets are negative, malaria can be ruled out. Developmental stages of Plasmodium in RBCs [6] All Plasmodium spp.

Plasmodium falciparum

Thick, dark purple ring-shaped inclusions (similar to signet ring cell carcinoma)

Fine rings

Ameboid rings

Finer rings in comparison to immature trophozoites

Immature

Irregular round, ameboid

schizont

Almost filling the entire erythrocytes

Hardly detectable in the blood

Mature

Conglomerate of 6–24 merozoites (round with central darkening)

Immature trophozoite Mature trophozoite

schizont

Develop from an immature schizont

Gametocytes

Macrogamete Mature female (sexual) form Visible as a round structure filling almost the entire erythrocyte Microgamete Mature male (sexual) form

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Visible as a round structure within the erythrocyte Smaller and has a brighter nucleus than macrogametes

If symptoms persist despite negative microscopy and rapid testing, blood smears should be repeated 3 times every 12-24 hours.

Other tests [9][10][11] Rapid diagnostic tests (RDTs) Determination of specific malaria antigens, e.g., HRP2, pLDH, and aldolase Benefits: quick determination of malaria infection in areas lacking high-quality malaria microscopy All RDT results should be confirmed via microscopy (if available). Serological tests Not appropriate for acute diagnosis of malaria because antibodies are undetectable for 1–2 weeks after primary infection Positive serological results indicate prior exposure to Plasmodium

Treatment

General considerations [12][13][14] https://www.amboss.com/us/knowledge/Malaria/

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When choosing antimalarial drugs, age, side effects, cost, geographic region, and dosing schedule should all be taken into consideration. The increasing resistance to chloroquine due to the development of efflux membrane pumps (especially in P. falciparum) should also be considered.

Overview of antimalarial drugs Overview Agents

Indications

Mechanism of

Adverse effect

action Chloroquine

Hydroxychloroquine

Treatment and prophylaxis of malaria due to Plasmodium malariae, Plasmodium ovale

Porphyria cutanea tarda Rheumatoid arthritis SLE, DLE

, or Plasmodium vivax

Doxycycline/ tetracycline

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Drug accumulation in the parasite's food vacuole → inhibition of heme polymerization → lysis of membranes

Gastrointes discomfort

Interference with antigen processing → antirheumatic effects

Chloroquine -resistant tertian malaria

Chloroquineresistant uncomplicated falciparum

Bind to bacterial ribosomal 30S subunit →

Quartan malaria

malaria

inhibition of protein synthesis

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Thought to inhibit protein

Mefloquine

synthesis of Plasmodium falciparum by targeting the 80S ribosome [15]

Quinine

Falciparum malaria

Similar to chloroquine [16][17]

Artemetherlumefantrine Atovaquoneproguanil

Chloroquineresistant

Inhibition of mitochondrial

uncomplicated falciparum malaria

electron transport chain → ↓ ATP and nucleic acid

Severe falciparum malaria

Quinidine

Severe falciparum malaria

synthesis [18] Moderate blockade of Na+ channels Weak blockade of the K+ channel

Artesunate

Prodrug: The

Hemolytic c

active substance, DHA, generates free radicals that inhibit the synthesis of proteins and nucleic acid. https://www.amboss.com/us/knowledge/Malaria/

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[19]

Tertian malaria

Primaquine

Thought to involve the inhibition of the parasitic electron transport chain [20]

Treatment regimens Tertian and quartan malaria Overview of treatment for tertian and quartan malaria Plasmodium species

Treatment

Tertian malaria P. vivax,

Chloroquine-

Chloroquine OR hydroxychloroquine

P. ovale

sensitive

PLUS primaquine or tafenoquine: to eradicatehypnozoites of P. vivax and P. ovale and prevent relapse

Chloroquine-

Artemether-lumefantrine

resistant

OR atovaquone-proguanil OR quinine PLUS doxycycline OR tetracycline OR mefloquine (if no other options are available) PLUS primaquine OR tafenoquine to eradicatehypnozoites of P. vivax and P. ovale and prevent relapse

Quartan malaria P. malariae, P. knowlesi

Chloroquine or hydroxychloroquine OR artemether-lumefantrine OR atovaquone-proguanil

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OR quinine PLUS doxycycline OR quinine PLUS tetracycline OR quinine PLUS clindamycin OR mefloquine

Falciparum malaria Overview of treatment for falciparum malaria Severity of

Region

Treatment

disease Uncomplicated

Chloroquine-sensitive

Chloroquine ORhydroxychloroquine

Chloroquine-resistant

Artemether-lumefantrine

falciparum malaria

OR atovaquone-proguanil OR mefloquine OR quinine PLUS doxycycline OR quinine PLUS tetracycline OR quinine PLUS clindamycin

Severe

All regions

falciparum malaria

IM or IV artesunate Reassess 4 hours after the third dose and if the parasite density is ≤ 1% on blood smear and the patient tolerates oral medication, switch to: Oral artemether-lumefantrine (drug of choice) OR atovaquone-proguanil OR quinidine (in the US; quinine elsewhere) PLUS doxycycline or clindamycin Mefloquine (if no other options are available) Intensive care and supportive therapy (lowering fever, avoiding hypoglycemia) are essential.

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Plasmodium falciparum and, more recently, Plasmodium vivax are becoming increasingly resistant to chloroquine.

Side effects of antimalarial medication[21][22][23] Drug

Most important side effects

Chloroquine

Gastrointestinal discomfort

Hydroxychloroquine

Irreversible retinopathy Pruritus: most commonly seen in dark-skinned individuals

[24]

CNS: agitation, anxiety, confusion

Primaquine

Hemolytic crisisin individuals with G6PD deficiency(must be ruled out before initiating treatment)

Mefloquine

Gastrointestinal discomfort Rash CNS: dizziness, confusion, nightmares, hallucinations, seizures

Atovaquone-

Gastrointestinal discomfort

proguanil Quinine

Cinchonism: a group of adverse effects including nausea, dizziness , headache , tinnitus, and visual changes. Gastrointestinal discomfort Fever, flushing CNS: headache, mental status altered

Doxycycline

Photosensitivity

Tetracycline

Nephrotoxicity and hepatotoxicity Damage to mucous membranes (should be taken with a lot of water)

Artemether-

Gastrointestinal discomfort

lumefantrine

Prolonged QT interval

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Quinidine

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Gastrointestinal discomfort Rash Palpitations, angina pectoris CNS: dizziness, fatigue, headache

Artesunate

Hemolytic crisis in individuals with G6PD deficiency (must be ruled out before initiating treatment)

Prevention

Mosquito bite prevention[25] Avoid exposure Exercise particular caution during peak biting periods

[26]

Mosquito nets Protective clothing (covering most of the skin, light colors) Mosquito repellent, such as DEET (N,N-diethyl-meta-toluamide) Mosquito control Reduce breeding sites (e.g., eliminate pools of water, optimize plant watering) Insecticide spraying

Malaria prophylaxis[14][27][28] Should be initiated before traveling to regions with a high risk of malaria, e.g., tropical Africa, Asia, and Latin America Drug of choice is based on the region travelled Areas with P. falciparum If chloroquine-resistant P. falciparum (most malaria endemic regions): atovaquone-proguanil , doxycycline , mefloquine If chloroquine-sensitive P. falciparum: chloroquine https://www.amboss.com/us/knowledge/Malaria/

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Areas without P. falciparum; (some areas of Central/South America, Mexico, China, South Korea): primaquine Agents that are safe during pregnancy : chloroquine , mefloquine

Prophylactic medication cannot prevent infection but instead suppresses the course of the disease and its symptoms by killing the parasite within the host before it can cause severe disease. There is no prophylactic medication that provides protection against all species of the Plasmodium genus.

Standby emergency treatment [14] Indication Traveling to endemic regions with a medium to high risk of malaria Depending on the risk, either prophylactic or standby emergency treatment may be recommended (when in doubt: prophylactic medication). Drugs Atovaquone-proguanil Artemether-lumefantrine Chloroquine with limitations: there are now many chloroquine-resistant Plasmodium strains with membrane pumps that lower intracellular chloroquine concentrations

Obligation to report Report all laboratory-confirmed cases of malaria to the local or state health department.

References

1. Malaria. http://www.who.int/mediacentre/factsheets/fs094/en/ December 1, 2016. Accessed: March 20, 2017.

. Updated:

2. Williams TN, Mwangi TW, Wambua S et al. Sickle cell trait and the risk of https://www.amboss.com/us/knowledge/Malaria/

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Plasmodium falciparum malaria and other childhood diseases. J Infect Dis. 2005; 192 (1): p.178-186. doi: 10.1086/430744 . | Open in Read by QxMD 3. Gledson Barbosa de Carvalho and Glauber Barbosa de Carvalho. Duffy Blood Group System and the malaria adaptation process in humans. Revista Brasileira de Hematologia e Hemoterapia. 2011 . 4. Mvumbi DM, Bobanga TL, Melin P et al. High Prevalence of Plasmodium falciparum Infection in Asymptomatic Individuals from the Democratic Republic of the Congo. Malar Res Treat. 2016; 2016 (2016): p.5405802. doi: 10.1155/2016/5405802 . | Open in Read by QxMD 5. Antinori S, Galimberti L, Milazzo L, Corbellino M. Biology of human malaria plasmodia including Plasmodium Knowlesi. Mediterr J Hematol Infect Dis. 2012; 4 (1): p.2...