Erin Capina, YinD 127

History and Epidemiology

Malaria is a vector-borne disease caused by parasites and spread via female Anopheles mosquitoes. It is an ancient disease; malaria or a disease like it has been noted for more than 4,000 years. In fact, symptoms of malaria were described in 2700 BC in ancient Chinese medicinal writings such as the Nei Ching, The Canon of Medicine.1 On November 6, 1880, French army surgeon, Charles Louis Alphonse Laveran, became the first person to discover a malaria parasite in the blood a patient suffering from malaria, this discovery won him the Noble Prize in 1907.1 In 1886, Camillo Golgi, an Italian neurophysiologist, established that there are at least two different forms of malaria, one with fever every other day and one with fever every third day. Golgi also observed that the two different malaria produced differing numbers of merozoites, new parasites, upon maturity and that fever coincided with the release of merozoites into the blood stream. For his work in neurophysiology, Golgi received the Noble Prize in 1906.1 Italian investigators, Giovanni Batista Grassi and Raimondo Filetti, were the first to introduce the names Plasmodium vivax and P. malariae for the malaria parasites in 1890. American William H. Welch named the third malaria parasite P. falciparum in 1897. John William Watson Stephens named the fourth malaria parasite P. ovale in 1922 and in 1931 Robert Knowles and Biraj Mohan Das Gupta named the fifth malaria parasite, P. knowlesi.1 On August 20, 1897, British officer Ronald Ross became the first person to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes. Ross’ later work with bird malaria showed that mosquitoes could transmit malaria parasites from bird to bird. Ross’ discovery earned him the Noble Prize in 1902.1 A team of Italian investigators led by Giovanni Batista Grassi showed the complete sporogonic cycle of Plasmodium falciparum, P.vivax, and P. malariae in 1898.

Anopheles Distribution (Source: Center for Disease Control and Prevention)

Anopheles mosquitoes are found on every continent except Antarctica.2 The exact anopheline malaria vector present in an area depends on region and environment and because Anopheline malaria vectors are found in both malaria-endemic regions, as well as regions where malaria has already been eliminated, constant vigilance is required to ensure that there is no re-introduction of malaria. The vast spread of Anopheles mosquitoes means that predicting the impact of ecological changes, such as from deforestation or agricultural development, on species density can be difficult, but a 2007 study shows that it is also possible to predict potential changes to species density by taking into account available information on the planned agricultural development, as well as information about the local ecology of present anopheline species.3 Of the five malaria parasites, P. falciparum and P. vivax pose the greatest threat. P. falciparum is responsible for most malaria-related deaths globally, in addition to being the most prevalent parasite on the African continent, and P. vivax is the most dominant parasite in most countries outside of sub-Saharan Africa. The World Health Organization (WHO) estimated that in 2015 about 3.2 billion people—almost half the world’s population—were at risk for malaria and 95 countries had ongoing malaria transmission.4 Sub-Sahara Africa is disproportionally affected by malaria, in 2015 Sub-Sahara Africa accounted for 88% of global malaria cases and 90% of global malaria deaths.4  There are 15 countries—mainly in Sub-Sahara Africa—that account for 80% of malaria cases and 78% of malaria deaths.4 In high malaria transmission areas children under five are highly susceptible to illness and death, this age group accounts for about 70% of all malaria deaths.5 While child mortality makes up the bulk of malaria mortality, adult mortality is also high. Malaria deaths in the 15-49, 50-69, and 70+ age groups were 20%, 9%, and 6% respectively in 2010. There is some good news, between 2000 and 2015 global malaria incidence, the number of new cases, among at-risk populations fell by 37%.4 In this same period, malaria mortality in at-risk populations fell by 60% for all age groups and 65% for children under five.4

Population at Risk for Malaria in 2013 (Source: WHO Global Malaria Mapper)

Social and Economic Burden

Aside from mortality, malaria also carries an economic and social cost. Poverty is concentrated in the tropical and subtropical zones, the same areas where malaria transmission happens. A comparison of income between countries with malaria transmission, and those without, shows a fivefold difference between the GDPs in 1995 of malaria endemic countries and those without malaria, $1,526 USD compared to $8,268 USD, showing that not only are malaria-endemic countries poorer, but they also have lower rates of economic growth. This can be seen between 1965 and 1990 when P. falciparum malaria endemic countries had an average per-capita GDP growth of 0.4% per year versus non-malaria-endemic countries that had an average per-capita GDP growth of 2.3% per year.6 Malaria does not necessarily cause poverty or vice versa, but there is an unmistakable correlation between the two.

As previously mentioned, much of the malaria mortality is concentrated in children less than five years old and it can be argued that even before science discovered this devastating fact natural selection understood the serious threat that malaria posed to child and infant mortality. As part of the malaria lifecycle, malaria parasites infect red blood cells, but sickle cell anemia affords a person some protection from malaria by making it hard for malaria parasites to survive inside red blood cells affected by sickle cell anemia. In other words, the consequences and likelihood of dying from malaria were severe enough that introducing a potentially fatal genetic mutation that could offer some protection against malaria into the genome was considered desirable. While the high child mortality has a direct demographic and social cost there are also indirect costs. Historically, high infant and child mortality have been closely linked to high fertility rates, the reason being that parents will have more children than usual either to replace lost children or in anticipation of future loss.6 High fertility rates lead to rapid population growth as well as reduced investments in education per child. Women can lose valuable working years due to high fertility since multiple children mean more time spent raising them opposed to working. In malaria-endemic areas, adults usually develop partial immunity to the symptoms of malaria, but children, particularly young children, have high morbidity—incidence of disease or ill health—and mortality, resulting in absenteeism from school.6 The negative consequences of school absenteeism extend beyond days of learning missed per year, they can include increased failure rates, repeated school years, and drop-out rates.6 Over time these factors can have a substantial impact on economic growth and productivity.

Both malaria and poverty are geographically specific. (Source: The Economic Burden of Malaria)

Clinical Disease

Malaria infections can be classified as uncomplicated or complicated (severe) malaria. The incubation period after the bite from an infected Anopheles mosquito will last anywhere from 7 to 30 days, depending on the specific malaria parasite. Antimalarial drugs taken as prophylaxis can delay the emergence of malaria symptoms by weeks or months, long after a traveler has left a malaria-endemic region.  

The “classic” but rarely observed malaria attack lasts between 6 and 10 hours and consists of a cold stage (feeling cold, shivering), a hot stage (fever, headaches, vomiting, and possible seizures in children), and a sweating stage (sweating, return to normal temperature, general tiredness). In uncomplicated malaria, symptoms include fever, chills, sweats, headaches, nausea and vomiting, body ache, and general malaise. Findings from a physical exam can include elevated temperatures, weakness, mild jaundice, sweating, enlarged spleen, enlarged liver, and increased respiratory rate.8

In complicated malaria, the infections are compounded by serious organ failures or abnormalities in the patients’ blood or metabolism. Complicated malaria manifestations can include the following: severe anemia due to hemolysis (destruction of red blood cells), hemoglobinuria—hemoglobin in urine—due to hemolysis, abnormalities in blood coagulation, metabolic acidosis—excessive acidity in blood and tissues, acute respiratory distress syndrome (ARDS), acute kidney failure, hypoglycemia or low blood sugar, hyperparasitemia—when more than five percent of red blood cells are infected with malaria parasites, and cerebral malaria.8

In the case of infections from P. vivax and P. ovale parasites, malaria relapses are possible months or even years after initially contracting the disease because both P. vivax and P. ovale have dormant liver stages that can be reactivated. There is treatment available to reduce the possibility of relapse and should be followed immediately after the first malaria attack.8

Lifecycle of Malaria

The lifecycle of malaria involves two hosts, female Anopheles mosquitoes, and humans. There are two stages that Plasmodium parasites go through, asexual and sexual. The asexual phase happens in humans, the sexual phase happens in mosquitoes. In humans, the parasites begin their lifecycle in liver cells where they grow and reproduce and then they move onto red blood cells. In the red blood cells, the parasites continue to grow, eventually destroying the red blood cells. The released daughter parasites, merozoites, continue the cycle by invading other red blood cells. The blood stage parasites, gametocytes, are the ones that cause malaria symptoms; when these gametocytes are taken up by a female Anopheles the sexual growth cycle begins. After 10-18 days the parasites, now called sporozoites, can be found in the mosquito’s salivary glands. When the mosquito takes a blood meal from another human the sporozoites along with the mosquito saliva are injected into this new human, a new human infection begins once the parasites enter liver cells. Unlike humans, mosquito hosts do not suffer from malaria.9

Life cycle of malaria parasite (Source: Center for Disease Control and Prevention)

Vector Control

Vector control is an essential part of malaria prevention. The two core components of malaria vector control that the WHO recommends are long-lasting insecticidal nets (LLIN) and indoor residual spraying (IRS).10 LLINs, unlike conventional insecticide-treated nets, do not require regular retreatment; instead, they will just need to be replaced after their useful lifespan has expired. The WHO recommends LLINs that use pyrethroid insecticides only. These nets are designed for a minimum lifespan of 20 standard washes or three years of use under field conditions.11 These nets not only add a physical barrier between humans and malaria-carrying mosquitoes but they also benefit from the added insecticide effect. IRS is an effective strategy for vector control; it involves spraying a potent amount of insecticide with long residual activity about once or twice a year. This insecticide is sprayed on indoor walls and ceilings where malaria vectors are likely to rest after biting.11 Dichlorodiphenyltrichloroethane, DDT, has a long residual effect, lasting more than six months, and it is because of this that it continues to be used in IRS in limited situations. While the use of DDT in agriculture was banned under the Stockholm Convention on Persistent Organic Pollutants, its use for malaria vector control is allowed provided that countries meet the recommendations and guidelines of the WHO and the Stockholm Convention, and until locally appropriate alternatives are available to allow for a transition from DDT.11

Insecticide resistance is a worry when it comes to LLIN and IRS. In fact, resistance has been detected in all major vector species and all classes of insecticides. Since 2010 mosquito resistance to insecticides used in public health has been identified in 60 countries.10 However, this does not give us the full scale of the problem because many countries do not carry out adequate testing so we do not have a full understanding of how common mosquito resistance is. To better understand this problem and its potential impacts on malaria control, adequate testing and more robust surveillance on insecticide resistance are needed.

Antimalarial Drugs

The drugs used to treat malaria are referred to as antimalarial drugs; these same drugs can also be used as prophylaxis for travelers traveling to malaria endemic regions. Antimalarial medications include doxycycline, chloroquine, primaquine, atovaquone/proguanil (Malarone), and mefloquine (Lariam).12 The WHO recommends artemisinin-based combination therapies (ACT) to treat uncomplicated P. falciparum infections, artemisinin also known by its Chinese name, quinghao.13 Currently, ACTs are the most effective antimalarial medications available. To treat uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi infections the WHO recommends treatment with either ACT or chloroquine if still susceptible to chloroquine—if it is a chloroquine-resistant area then treatment should be ACT. To prevent P. vivax or P. ovale relapses, the WHO recommends treatment with primaquine.14

ACTs are effective because they use at least two different modes of action in combination. This provides adequate cure rates and helps delay resistance. Resistance to antimalarials is an ever-present concern; to date three malaria parasites (P. falciparum, P. vivax, and P. malariae) show resistance to antimalarials.14 Resistance happens when either delayed or incomplete clearance of malaria parasites from the blood of a patient being treated with antimalarials occurs. The resistance problem is compounded by cross-resistance when resistance to one antimalarial confers resistance to other antimalarials in that same chemical family or have a similar mode of action. The consequences for resistance can be devastating, for example when chloroquine resistance spread across the African continent in the 1980s there was a dramatic rise in malaria-related deaths.15 While ACTs can delay resistance they are not immune to resistance. Since at least 2009, indications of resistance to ACTs have been found along the Thai-Cambodian border, historically a site of emerging antimalarial resistance.16 If ACT resistance spreads beyond this region the resulting fallout could be as devastating as the consequences for widespread chloroquine resistance.

Mefloquine Controversy

The antimalarial mefloquine has been around since the 1970s but has come under scrutiny in recent years due to its potent psychiatric side effects. After mefloquine’s initial licensure in 1989 mefloquine became the drug of choice as prophylaxis for travelers traveling to chloroquine-resistant malaria regions due to its presumed safety and convenient dosing schedule.  Early prelicensure studies showed that nausea and vertigo were commonly reported side effects, but in the absence of sensitive and unbiased prospective reporting mefloquine was considered to be largely free of the psychiatric side effects that plagued related antimalarial compounds chloroquine and quinacrine.17 Mefloquine’s presumed safety was so well established that when severe psychiatric side effects (amnesia, confusion, psychosis) first began being reported in the literature following mefloquine’s early European licensure these symptoms were dismissed as coincidental or caused by other factors, such as bias.17 In 2001 the first formal blinded and controlled prospective studies were conducted in a representative civilian population (earlier studies were mostly conducted on male prisoners, military personnel, and subjects in developing countries) and showed that psychiatric symptoms such as nightmares, anxiety, and psychosis during prophylaxis use are each at least 100 times more common than previously reported.17 Recent reports linking mefloquine to acts of violence as well as reports of suicide and suicide ideation have further raised safety concerns surrounding mefloquine.17 In 2013, the U.S. Food and Drug Administration (FDA) changed the labeling to mefloquine due to safety concerns. Mefloquine now carries the FDA’s box warning—the most serious kind of warning—regarding the psychiatric and neurological side effects associated with mefloquine.18 The neurological symptoms associated with mefloquine include dizziness, loss of balance, or ringing in the ears; these side effects can occur at any time during drug use and may take months or years to resolve, they may also be permanent. 18 The psychiatric symptoms associated with mefloquine include feeling anxious, hallucinations, feeling depressed, feeling mistrustful, or psychosis.17,18 Previously mefloquine was mandatory among deployed US military personnel but has since been changed to be the drug of last resort, according to U.S. military policy, in light of growing safety concerns.17

Vaccines

Currently, there is no vaccine available to prevent malaria. The most advanced malaria vaccine candidate is RTS, S/AS01 (RTS, S).19 Clinical testing for RTS, S is at least 5 to 10 years ahead of other candidate vaccines and the first malaria vaccine to gain a positive scientific opinion from the European Medicines Agency, a medicine regulatory agency with stringent standards.20 RTS, S acts against P. falciparum, the deadliest malaria parasite globally and the most prevalent parasite in Africa, but it offers no protection against P. vivax, the most common parasite outside of Africa. A Phase 3 clinical trial in seven sub-Saharan African countries enrolling over 15,000 children showed promise.  RTS, S had a vaccine efficacy against clinical malaria in infants and a 39% vaccine efficacy against clinical malaria in children between 5 and 17 months old.20 On November 17, 2016, the WHO announced that RTS, S will be rolled out in pilot programs in three sub-Saharan African countries. The purpose of the pilot program is to access how well the protective effects of the vaccine can be replicated in real life settings.20 The pilot program is expected to begin vaccinations in 2018.

Malaria has long stalked humanity and has killed many in its wake. Now, however, the goal of having a vaccine that could potentially prevent malaria is finally more than a pipe dream. Hopefully, the centuries of research will mean better prevention methods (both vector control and potential vaccines) as well as new antimalarials, for when resistance overcomes current antimalarials, will be within our reach.

Citations

1 The History of Malaria, An Ancient Disease. Centers for Disease Control and Prevention website. https://www.cdc.gov/malaria/about/history/index.html. Updated March 11, 2016.  Accessed November 19, 2016. 2 Anopheles Mosquitoes. Centers for Disease Control and Prevention website. https://www.cdc.gov/malaria/about/biology/mosquitoes/index.html. Updated October 21, 2015. Accessed November 19, 2016. 3 Yasuoka J, Levins R. Impact of deforestation and agricultural development on anopheline ecology and malaria epidemiology. American Journal of Tropical Medicine and Hygiene. 2007; 76(3): 450-460. 4 Malaria. World Health Organization website. http://www.who.int/mediacentre/factsheets/fs094/en/. Updated December 2016. Accessed December 1, 2016. 5  Murray CJL, Rosenfeld LC, Lim SS, et al. Global malaria mortality between 1980 and 2010: a systemic analysis. The Lancet. 2012; 379: 413-431. 6 Sachs J, Malaney P. The economic and social burden of malaria. Nature. 2002; 415: 680-685. 7 Cyrklaff M, Sanchez CP, Kilian N, et al. Hemoglobins S and C interfere with actin remolding in Plasmodium falciparum-infected erythrocytes. Science. 2011; 334(6060): 1283-1286. 8 Disease. Centers for Disease Control and Prevention website. https://www.cdc.gov/malaria/about/disease.html. Updated October 7, 2015. Accessed December 2, 2016. 9 Biology. Centers for Disease Control and Prevention website. https://www.cdc.gov/malaria/about/biology/index.html. Updated March 1, 2016. Accessed December 2, 2016. 10 Entomology and Vector Control. World Health Organization website. http://www.who.int/malaria/areas/vector_control/en/. Accessed December 2, 2016. 11 Core Vector Control Methods. World Health Organization website. http://www.who.int/malaria/areas/vector_control/core_methods/en/. Updated December 11, 2015. Accessed December 5, 2016. 12 Choosing a Drug to Prevent Malaria. Centers for Disease Control and Prevention website. https://www.cdc.gov/malaria/travelers/drugs.html. Reviewed November 9, 2012. Accessed December 5, 2016. 13 Overview of Malaria Treatment. World Health Organization website. http://www.who.int/malaria/areas/treatment/overview/en/. Updated March 18, 2016. Accessed December 7, 2016. 14 World Health Organization. Guidelines for treatment of malaria: third edition. 2015. 15 Antimalarial drug efficacy. World Health Organization website. http://www.who.int/malaria/areas/treatment/drug_efficacy/en/. Updated March 25, 2014. Accessed December 8, 2016. 16 Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine. 2009; 361(5):455-467. 17 Ritchier EC, Block J, Nevin RL. Psychiatric side effects of mefloquine: Applications to forensic psychiatry. The Journal of the American Academy of psychiatry and the law. 2013; 41: 224-235. 18 Mefloquine Hydrochloride: Drug Safety Communication – Label Changes Due to Risk of Serious Psychiatric and Nerve Side Effects. U.S. Food and Drug Administration website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm362887.htm. Posted July 29, 2013. Accessed December 9, 2016. 19 Malaria Vaccines. World Health Organization website. http://www.who.int/immunization/research/development/malaria/en/. Accessed December 9, 2016. 20 Questions and Answers on RTS, S/AS01 Malaria Vaccine. World Health Organization website.http://www.who.int/immunization/research/development/malaria_vaccine_qa/en/. Updated November 22, 2016. Accessed December 9, 2016.