Malaria is typically transmitted to humans by the bite of a female Anopheles mosquito, the carrier of Plasmodium parasites.
Malaria is caused by protozoa parasites of the genus plasmodium.
Female Anopheles mosquitoes acquire the parasites from an infected person during a blood meal and, on subsequent human bite, transmit infection to a new host who the injection of sporozoites.
The parasite infects hepatocytes and replicates until it becomes an exoerythrocytic merozoite which enters the blood and invades erythrocytes.
The intraerythrocytic trophozoite subsequently ruptures the eryhrocyte, releasing merozoites into the blood, repeating the erthrocytic infection cycle.
Five species that infect humans: Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and knowlesi.
Plasmodium falciparum is associated with the highest death rates.
A parasitemia level of at least 5% for a P falciparum defines severe disease.
Rarely malaria can occur by vertical transmission from pregnancy or at birth, through blood transfusion, from needle sharing, or after an organ transplant from a malaria infected donor.
P. Vivax and P. Ovale have a hypnozoite stage in the liver which remains dormant for weeks to yesrs before becoming activated and entering the bloodstream initiating a blood stage infection.
Approximately 200-400, 000,000 people infected worldwide annually, with nearly 600,000 deaths, mostly in African children.
Malaria what is the cause of death worldwide in 2020 with 627,000 deaths.
In 2022, approximately 249 million cases of malaria worldwide resulted in an estimated 608000 deaths, with 80 percent being 5 years old or less.
Malaria related mortality has been increasing by more than 10% over the past few years.
In many regions it is seasonal or an epidemic disease that responds to changes in rainfall, humidity and temperature.
Temperature increases have been associated with the spread of malaria to higher elevations in involved countries.
Approximately 241 million people cases of malaria occurred in 85 countries with endemic malaria.
Cases acquired by international travelers numbers approximately 25,000 annually.
In 2017 2161 reported imported cases among people in the US.
Endemic malaria has been eliminated from the US more than 50 years ago.
In 2008 imported malaria most commonly attributed to P falciparum, 69%, P vivax, 25%, and acquired in Africa 71%, or Asia 22%: A 12% increase in mortality since 2019.
72 % of patients with imported malaria had not taken chemotherapeutic prophylactic medications.
Endemic in more than 100 countries and territories worldwide.
90% of cases in African continent, with the remainder of cases concentrated in Asia, Pacific and Latin America.
90% of deaths occur in sub-Saharan Africa.
Death among children five years of age or younger account for approximately 80% of all deaths from malaria in sub-Saharan Africa.
1.5-2.5 million children die each year in sub-Saharan Africa.
Imperils more than 3 billion people each year, with almost 250,000,000 people infected.
Travelers with a fever have increased likelihood of malaria diagnosis, as do those with hyperbilirubinemia and thrombocytopenia.
Death due to cerebral malaria and anemia and these two complications are the cause of almost every malaria-related death, with children between one and five years old being especially vulnerable.
Cerebral malaria is responsible for half of all malaria related deaths, even though the parasite does not cross the blood-brain barrier.
Cerebral malaria is an encephalopathy due to malaria with a mortality rate of approximately 15 to 20%.
Cerebral malaria often is associated with cerebral edema, seizures, and other vital organ involvement.
No specific therapy for cerebral malaria has demonstrated beneficial effects.
Anopheline mosquitoes transmit infected forms of the parasite from infected individuals to uninfected people.
Following inoculation into an uninfected human parasites pass from the dermis to the liver.
The parasite multiplies in the hepatic stage and when the hepatocyte ruptures released parasites can infect red blood cells and lead to the blood stage of the infection.
Clinical symptoms begin following the mosquito bite by 7-14 days.
The primary clinical features of malaria are a result of the blood stage with parasitic multiplication within the erythrocyte eventually leading to erythrocyte rupture and release of parasites.
Hemolysis results in generation of cytokines which are associated with fever and chills.
Fever is the most common symptom.
Other common symptoms include headache cough, nausea, vomiting, abdominal pain, diarrhea, and muscle, joint pain and altered mental ion.
In malaria, the parasites enter the liver, grow there and then attack the red blood cells which causes rupture of these cells and release of a toxic substance hemozoin which causes chills recurring every 3 to 4 days.
Anemia occurs as a result of hemolysis, dyseryhropoiesis and increased splenic clearance of impaired and uninfected red cells.
Hemolysis and hyperbilirubinemia along with hepatic dysfunction.
Splenomegaly and hepatomegaly result from damaged eryhthrocytes and cellular debris and gorging the sinusoids of the spleen and liver.
Patients manifest with febrile lists, with fluctuating fever rigors with malaise, headache, myalgias, arthralgias, pallor, jaundice, hepatsplenomegaly, thrombocytopenia and anemia
Most children who die in sub-Saharan Africa are younger than 5 years of age and are infected with Plasmodium falciparum.
Plasmodium falciparum is the most lethal malarial parasite of humans.
Plasmodium falciparum is found worldwide.
Patients with Plasmodium falciparum may have life-threatening syndromes such as cerebral malaria with altered consciousness, seizures and coma.
P falciparum patients may present with severe anemia, acidosis, respiratory distress, hypoglycemia, acute renal insufficiency and shock.
Severe malaria is seen in individuals at high risk include young children, pregnant persons, older travelers, and people who are immunosuppressed.
Non P falciparum malaria usually associated with less severe illness, often with only relapsing fevers, anemia, and/or splenomegaly.
Recurrent fevers may result from maintenance and reemergence of dormant liver parasites with P ovale and P vivax or from chronic low-grade infection with P malariae.
P malariae is associated with low levels of peripheral parasitemia, because it invades only aged red blood cells, which are uncommon in blood.
P malariae can cause illness months to years after a patient has left the endemic region.
P. knowlesi is a zoonotic parasite of macaque monkeys endemic in southeast Asia, and can cause high parasite loads, severe malaria, and death.
Plasmodium vivax is endemic in tropical areas outside of sub-Saharan Africa and accounts for a large proportion of infections in Latin America, and Southeast Asia.
P. vivax preferentially, invades reticulocytes and therefore the maximal peripheral blood parasite load is rarely greater than 2% of the low number of circulating reticulocytes.
Unlike P. falciparum, vascular sequestration, does not occur with P vivax.
Plasmodium ovale and plasmodium malariae widespread distribution.
P. ovale preferentially, invades young red cells, and associated with low levels of peripheral blood parasitemia.
Patients with P, ovale have a hypnozoite stage and could present weeks to years after returning to the US or can relapse after treatment of a blood stage infection.
Treatment of P ovale requires medications that are active against liver hypnozoites to prevent illness.
Plasmodium knowlesi presently only documented in Southeast Asia.
Virulence of Plasmodium falciparum related the ability of infected RBC�s to sequester in and obstruct the microvasculature of various organs.
Plasmodium falciparum infection in pregnancy associated with maternal and perinatal morbidity.
During pregnancy use of insecticide treated bednets, intermittent treatment with sulphadoxine-pyrimethamine in the second and third trimesters with prompt treatment of malaria and anemia are encouraged in Africa.
Chloroquine and sulphadoxine-pyrimethamine safest treatments for the prevention of malaria in pregnancy in Africa.
Infected erythrocytes have abnormal circulatory properties with altered biochemical and adhesive properties.
In children who survive repeated bouts of malaria a protective immunity develops.
In areas of the highest rates most deaths occur in children younger than 2 years of age and most severe cases occur among children younger than 6 years.
Infants and children often die from severe anemia and cerebral involvement.
Maternal malaria can lead to low birth weight infants and neonatal deaths.
Transmission by blood transfusion less than 1 case per million units collected and is similar to hepatitis C or HIV.
Untreated severe malaria is nearly always fatal, with timely and effective treatment, the death rate to the malaria in the US is less than 2%.
Insecticides reduce the number of vectors and also reduce the lifespan of infected mosquitoes.
P. vivax may be associated with persistent exoerythrocytic bodies in the liver and can result in relapses occurring many years later.
Organ damage rarely associated with P. vivax infection because asexual stages circulate in the peripheral blood without sequestration and microvascular insult.
Associated with a rise in HIV load and drop in CD4 cells counts in patients with HIV infection.
More common and severe in patients with HIV infections.
Children with high levels of EPO in their cerebrospinal fluid have less risk of dying from brain malaria.
EPO is an active molecule in the brain where it can protect the brain cells from damage in malaria (J Kurtzhals).
Most effective tools for control, include indoor residual insecticide spraying with pyrethroids, dichlorodiphenyltrichloroethane (DDT), or other insecticides, use of insecticide treated bed nets and rapid diagnostic tests and effective management with artemisinin drug treatments: this could decrease malaria mortality by 30 to 80%.
Malaria is typically treated with antimalarial medications, which aim to eradicate the malaria parasite from the body.
The specific treatment regimen can vary based on factors such as the type of malaria parasite, the severity of the infection, and the patient’s age and overall health.
1. Chloroquine: This drug is effective against Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.
However, many regions have reported chloroquine-resistant strains of malaria.
2. Artemisinin-based Combination Therapies (ACTs): These combinations of artemisinin derivatives with other antimalarial drugs are highly effective against Plasmodium falciparum, the most dangerous malaria parasite.
Artemisinin is often combined with drugs like mefloquine, lumefantrine, or amodiaquine.
3. Primaquine: This medication is often used to eliminate the liver-stage parasite of Plasmodium vivax or Plasmodium ovale.
It is usually used in combination with chloroquine or an ACT.
4. Atovaquone-proguanil: This combination drug is effective against both chloroquine-resistant Plasmodium falciparum and chloroquine-sensitive malaria parasites.
Artemisinin based combination is critical for the effective treatment and control of Plasmodium falciparum malaria.
The emergence of clinically resistant artemisinin P falciparum has been identified recently.
Pyronaridine-artesunate, fixed dose 3:1 is highly effective in falciparum malaria with a cure rate on day 28 of more than 98%.
The efficacy in P vivax malaria equal to chloroquine, but with faster clearance times for parasites.
Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoitea are cleared from the liver.
P. vivax can arise weeks to years after an individual lives in endemic area and relapse can also occur weeks to years after treatment of the primary illness with anti-malarial drugs.
Malaria treatment do not eradicate hypnozoites which can reactivate and cause malaria.
8 aminoquinolines are required to eradicate hypnozoites.
Tafenoquine therapy results in a significantly lower risk of Plasmodium vivax recurrencethan placebo.
Indoor residual insecticide spraying can reduce the risk of infection by 75%.
Insecticide treated bed nets can decrease child mortality by nearly 20%.
Diagnosis can be established using blood smears, rapid antigen tests or molecular assays.
Diagnosis involves laboratory tests for confirmation.
The BinaxNOW malaria test is the only approved, rapid diagnostic test available.
This test uses monoclonal antibodies to detect the presence of P falciparum specific histidine, rich protein II and a pan malarial antigen common to all species except P knowlesi from a bblood sample.
The BinaxNOW test can confirm where the P falciparum is present in the blood with a 99.7% sensitivity and then 94.2% specificity for parasite levels greater than 5000 parasites per microliter.
Examination of a drop of blood on thick and thin Giemsa stained blood films is required as is an experienced microscopist.
Thick smears, allow the analysis of a greater number of parasites and are more sensitive than detecting parasites.
Three blood smears every 12 to 24 hours are required to establish a diagnosis.
All species have a similar appearance in the early ring stage.
Patients with malaria are often misdiagnosed with a viral illness.
Microscopy of blood smears reveals infection of reticulocytes with Schuffner dots scattered throughout the cytoplasm.
Early ring stage or later stage ameboid trapezoid forms can be seen.
Once malaria is diagnosed the identification of the malaria species is necessary to select the appropriate anti-malarial treatment.
The region of travel, length of time between return to the US and symptom onset, microscopy appearance, and a malaria rapid diagnostic test can help identify the species.
The diagnosis should be considered in febrile patients returning from a malaria endemic country.
The delay in diagnosis or inappropriate treatment is associated with increased mortality, therefore prompt diagnosis assessment of disease severity, and appropriate treatment are required.
96% of patients infected with P falciparum became ill within one month after returning to the US, whereas 47.5% of patients presenting with P ovale malaria became ill within one month after return.
P falciparum can cause deaths rapidly in an individual without immunity.
Virulence of P falciparum is related to its ability to infect erythrocytes of all ages and sequestration of large numbers of late stage infected erythrocytes in the microvascular which may contribute to high pathogen burden.
Patients can be infected with more than one species.
Diagnosed patients are categorized as having either uncomplicated or severe infection.
Uncomplicated malaria is usually treated with oral antimalarials, the choice of which is guided by the plasmodium species and it’s susceptibility to antimalarial drugs in the region of the acquired infection.
With severe malaria in US which represents a estimated 10 to 15% of imported cases, parenteral therapy, intensive monitoring, frequent reassessment, because recent case fatality rates among were touring travelers range from 1 to 5%.
Criteria for severe malaria:
Impaired consciousness
Acidosis
Hypoglycemia
Severe anemia
Acute kidney injury
Jaundice
Pulmonary edema
Significant bleeding
Shock
Hyperparisitemia
Treatment for uncomplicated P falciparum acquired in areas with chloroquine resistance is atovaquone-proguanil, artemether-lumefantrine, or oral quinine plus doxycycline.
Recent reliably effective artemisinin based combination therapies and bed nets have been the two main contributors to recent decline in morbidity and mortality from malaria.
Patients with severe malaria should be hospitalized in receiving intravenous artesunate therapy.
Atovaquone-proguanil oral fixed-dose combination inhibits parasite mitochondrial electron transport.
Proguanil inhibits dihydrofolate reductase step in purine synthesis and decreases the atovaquone level needed to kill Plasmodium species.
Atovaquone-proguanil side effects include nausea, vomiting, abdominal pain and hepatitis.
In areas of high risk, personal protective measures, are used with malarial infection, including mosquito repellent, protective clothing, bed, nets, screened accommodations, infected control devices.
Chemoprophylaxis prevents infection and should be prescribed for individuals traveling to endemic areas.
Malaria vaccine phase 3 study of RTS,S/AS01 had an efficacy of approximately 50% (RTS,S Clinical Trials Partnership).