Malaria-Transmission-Diagnosis and Treatment

Abstract

Malaria is a potentially fatal infectious disease, considered a serious public health problem in the world, caused by a parasite of the Plasmodium genus. It is transmitted by the bite of the infected female Anopheles mosquito, also after blood transfusions, organ transplantation, sharing contaminated syringes in parenteral drug users, in hospitals, and during pregnancy by vertical transmission. The possibility of diagnosis should be considered in any patient with fever during the stay or return from an endemic area, applying microscopy examination through thick drop and smear, rapid diagnostic tests (RDTs), and molecular diagnostic tests (PCR). Specific treatment is based on the parasite species identified, drug resistance, severity of symptoms, or presence of mixed infection. Treatment is based on oral or intravenous artemisinin and severe forms may require supportive measures and surveillance in intensive care units. This chapter aims to provide knowledge about the dynamics of malarial infection, with emphasis on transmission, diagnostic methods, Plasmodium species, and current treatment regimen.

1. Introduction

Malaria is an infectious disease caused by a Plasmodium parasite, which is transmitted by the bite of an infected mosquito, of which the main vector is the female of the genus Anopheles [1].

The high number of malaria cases in 2021 (241 million) and deaths (627,000) reveal the fragility of medical services. Especially in the African region where 96% of all deaths were due to malaria, and 80% in children under 5 years of age, more efforts are needed to reverse the trends of recent years. Globally, the number of people at risk of acquiring the disease is high and in areas of high transmission, the most affected with the development of severe disease and death are children and pregnant women. In 2019, it ranked 6th among the leading causes of death in low-resource countries [1, 2, 3].

Symptoms of the disease may include the classic form of manifestation “fever, sweating and chills” that appear 10–15 days after the mosquito bite; in addition, headache and vomiting, among others, may be associated. To make the diagnosis, microscopic studies of the patient’s blood, such as thick and thin blood smear, are required. Rapid diagnostic tests (RDTs) are also available to identify malaria in dispersed rural areas, with difficult geographical access and without infrastructure for microscopic diagnosis [1, 4].

There are five species of Plasmodium responsible for producing the disease in humans, the most frequent being P. vivax, P. falciparum, and P. malariae and P. ovale are rarer. Some primate malarial parasites such as P. knowlesi, P. cynomolgi, and P. simium can also infect humans and P. knowlesi is mentioned as a species that is naturally transmitted to macaques in Southeast Asia and infects humans causing “zoonotic” malaria; cases have been described in Malaysia with hyperparasitemia and severe complications that can lead to death [4, 5].

Of all these, P. falciparum infection is the most severe and causes several clinical conditions of organ damage, called complicated malaria; it can be fatal, if not treated in time [4, 6].

Chloroquine was the drug of choice for malaria and is still administered in most countries to treat P. vivax infection; however, it is rarely used in cases of P. falciparum because there is currently disseminated resistance to it; therefore, Artemisinin-based combination therapies (ACTs) are now recommended as the main treatment for this parasitic species [1].

In this chapter, the special relevance of this disease in the world will be discussed, with the general objective being to present updated knowledge on general aspects of malaria, its transmission mode, diagnostic methods, and recommended treatment.

2. Transmission

Malaria occurs mainly in tropical regions of sub-Saharan Africa, Asia, Oceania, and Latin America and is transmitted, as previously described, by the bite of the infected female Anopheles mosquito. Other forms of transmission are: through blood transfusions, organ transplantation, use of contaminated syringes in intravenous drug users, in hospitals where syringes are reused, and from mother to fetus (called gestational malaria) [4, 5].

2.1 High and low transmission areas

Devastating epidemics can occur when the parasite is introduced into an area where the population has had little contact with it and lacks immunity, or when people living in malaria-free areas move to regions where the disease is endemic and can be triggered by climatic conditions, aggravated by natural phenomena such as floods or massive population movements caused by conflicts [1].

The World Health Organization (WHO) recommends the use of different categories depending on the magnitude of transmission according to the situation of each region, the annual parasite incidence, and prevalence of P. falciparum and P. falciparum/P. vivax infection [2]:

• High transmission when there is an annual parasite incidence of 450 or more cases per 1000 population and the prevalence of P. falciparum malaria is ≥35%.

• Moderate transmission if there is an annual parasite incidence of 250–450 cases per 1000 population and the prevalence of P. falciparum/ P. vivax malaria is 10–35%.

• Low transmission if there is an annual incidence of 100–250 cases per 1000 population and the prevalence of P. falciparum/ P. vivax malaria is 1–10%.

• Very low transmission areas have an annual parasite incidence of less than 100 cases per 1000 population and the prevalence of P. falciparum/ P. vivax malaria is greater than zero but less than 1% [7].

Differences in propagation from one area to another may be due to geographic characteristics, parasite species and vector distribution, socio-demographic characteristics, access to antimalarial treatment, and extensive vector control [8].

A serious problem is the presence of asymptomatic people with malaria and its impact on the transmission and prevalence of the disease, which usually goes unnoticed. They are reservoirs and constitute a focus of infection for people without immunity, which should keep control programs alert in order to initiate and maintain a surveillance system for the early diagnosis of these people, active case detection is important to diagnose these patients. In 2010, in Amazonas state, Venezuela, 81% of PCR tests for Plasmodium spp. were diagnosed in asymptomatic persons [9].

3. Diagnosis

Clinical suspicion of malaria is established in any patient with fever during the stay or upon return from an endemic area. Diagnostic tests for this entity are: thick and thin blood smears (gold standard), rapid diagnostic tests (RDTs), and PCR molecular diagnostic tests [4].

Symptoms and signs are nonspecific; suspicion is raised primarily on clinical grounds, based on fever. In endemic areas, any patient with temperature ≥ 37.5°C should be considered for confirmation with a parasitological test; results should preferably be available in less than 2 hours.

Parasitological diagnosis: The two methods routinely used to identify microorganisms are: optical microscopy and immunochromatography, the latter detects specific antigens of the parasite or its enzymes that are genus or species specific.

In almost all cases of symptomatic malaria, thick and thin blood smears performed by a competent microscopist will reveal the presence of malarial parasites [2, 4].

3.1 Diagnosis of malaria

In patients with suspected malaria and in other risk groups such as those living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), the absence of a parasitological diagnosis should not delay the initiation of antimalarial treatment, which should be started immediately.

3.2 Optical microscopy

Microscopic results have not only high sensitivity and specificity for the diagnosis of malaria but also allow quantification of the magnitude of the infection and the parasite species involved. However, the use of this diagnostic resource is costly because it requires the experience and vigilance of the personnel.

Although molecular biology tests are more sensitive, the thick blood smear is still considered the “field standard” against which the sensitivity and specificity of other methods must be compared [10].

Therefore, microscopic examination provides good specificity for the diagnosis of malaria as a febrile illness present. Other important advantages of light microscopy are:

• Low direct costs.

• High sensitivity.

• Differentiation of Plasmodium species.

• Determination of the parasite density.

• Detection of gametocytes.

• Follow-up of response to therapy.

• Other infectious agents can be visualized [11].

Numerous tests have been done to improve it, but none have proven superior to the classical Giemsa and immersion oil staining method [2, 12].

3.3 Rapid diagnostic test (RDTs)

There are several tests, which are increasingly useful to complement microscopic findings [13, 14, 15].

Rapid diagnostic tests detect by immunochromatography specific Plasmodium antigens in the blood of people with malaria. Some tests identify a single species (P. falciparum); others identify one or more of the other parasites that affect humans [16, 17, 18].

They are commercially available, in strips, cassettes and cards, and easy to use. They are relatively simple to execute and interpret and do not require electricity or special equipment [16, 19].

Since 2012, the World Health Organization (WHO) has recommended that these tests should be selected according to criteria based on contribution results from the WHO Malaria RDT Product Testing program [2, 20].

Current tests are based on the detection of histidine-rich protein 2 (PfHRP2), which is specific for P. falciparum, pan-specific or species-specific Plasmodium lactate dehydrogenase (LDH), or pan-specific aldolase [2, 21, 22, 23].

They have potential advantages including:

• Provides rapid results and extension of diagnostic services to lower levels of health care and communities.

• Few requirements for staff training and skills.

• Strengthening of patient confidence in diagnosis and health service in general.

Disadvantages:

• In countries of the Amazon region, HRP2 deletion in P. falciparum exists in variable frequency, making HRP2-based tests not useful in that area [24].

• PfHRP2-based tests cannot distinguish new infections after recent infection, due to the persistence of PfHRP2 in blood for 1–5 weeks after effective therapy [25].

• Poor sensitivity to detect P. malariae and P. ovale.

• The heterogeneous quality of commercial products available [2].

3.4 Immunodiagnostic and nucleic acid amplification test methods

Immunodiagnostic tests directly detect the presence of the parasite by capturing parasite antigens during infection, which can be useful for epidemiological studies but lack sensitivity [26].

Techniques to detect nucleic acids such as polymerase chain reaction (PCR) and loop-mediated isothermal amplification are highly sensitive and useful for detecting mixed infection, particularly when there is a low degree of parasitemia, not detectable by light microscopy or with RDTs. They are recommended for drug resistance and epidemiological studies, but their use is not recommended in malaria-endemic areas for routine diagnosis.

So far, nucleic acid amplification tests do not play a role in the clinical management of malaria or in surveillance systems [2, 27].

It is worth noting that malaria surveillance programs should use conventional methods for diagnosis: thick blood smears and RDTs, and leave molecular tests (PCR) for special situations. At the community level, clinical symptoms suggestive of the disease can be used to initiate treatment when RDTs are not available. While in primary care centers, thick blood smears or RDTs or both should be used to decide on treatment. In secondary or tertiary care, light microscopy is important to confirm the diagnosis, measure parasitemia and control follow-up, and only if there are an excessive number of patients, the use of RDTs is preferred. Some patients negative to microscopy and RDTs may have a low degree of parasitemia and will only be diagnosed by performing PCR, which is a more sensitive method [9, 28]

4. Treatment

Treatment depends on the Plasmodium species, severity of the disease, drug resistance, age of the patient, and pregnancy [2, 4].

4.1 Treatment of uncomplicated P. falciparum malaria

Uncomplicated malaria is defined as a patient who presents symptoms and signs of this entity (fever, myalgia, among others) and a positive parasitological examination (microscopy or RDTs) without features of severity and the objectives of treatment are to cure the infection as quickly as possible and prevent the progression to severe disease [2].

4.2 Artemisinin-based combination therapy (ACTs)

For this clinical form, artemisinin combinations (ACTs) are available, with duration of 3 days and covering two asexual cycles. In relation to the doses, they must be optimal to guarantee rapid clinical and parasitological cure, decrease transmission, and avoid drug resistance [2, 4, 6].

The WHO recommends the following treatment regimens: [2].

4.2.1 Artemether + Lumefantrine

Dosage of 5–24 mg/kg/bw of artemether and 29–144 mg/kg/bw of lumefantrine; administer twice daily, for 3 days (total of 6 doses), the first 2 doses should be given 8 hours apart.

The formulations currently available are tablets of 20 mg of artemether and 120 mg of lumefantrine and another presentation of 40 mg of artemether and 240 mg of lumefantrine, in fixed doses and in combination formulation.

4.2.2 Artesunate + Amodiaquine

Dosage of 4 mg/kg/bw artesunate and 10 mg/kg/bw amodiaquine, once daily for 3 days. A total therapeutic dose of 6–30 mg/kg/bw artesunate and 22.5–45 mg/kg/bw amodiaquine daily dose is recommended.

Available formulations: fixed-dose combination in tablets of 25 + 67.5 mg, 50 + 135 mg, or 100 + 270 mg of artesunate and amodiaquine respectively.

Adverse effects described: severe neutropenia, particularly in patients co-infected with HIV receiving antiretroviral therapy (zidovudine) and/or clotrimoxazole. Concomitant use of efavirenz increases exposure to amodiaquine and the risk of hepatotoxicity. These combinations should be avoided unless it is the only ACTs available.

4.2.3 Artesunate + Mefloquine

Doses of 4 mg/kg/bw per day of artesunate and 8.3 mg/kg/bw per day of mefloquine, once daily for 3 days.

A pediatric tablet formulation of 25 mg artesunate and 5.5 mg mefloquine hydrochloride (equivalent to 50 mg mefloquine base) and adult tablets with 100 mg artesunate and 220 mg mefloquine hydrochloride (equivalent to 200 mg mefloquine base) are available.

Mefloquine is associated with nausea, vomiting, dyskinesia, dysphoria and sleep disturbances, and has been well tolerated. Combination with rifampicin reduces its efficacy.

4.2.4 Artesunate + Sulfadoxine-pyrimethamine

Currently available in 50 mg artesunate tablets and fixed-dose combination tablets with 500 mg sulfadoxine +25 mg pyrimethamine; the dose is 4 mg/kg/bw per day of artesunate for 3 days and a single administration of 25/1.25 mg/kg/bw of sulfadoxine-pyrimethamine, single dose on day 1 of treatment.

4.2.5 Dihydroartemisinin + piperaquine

With the use of this drug the cure rate is excellent (>95%), although in children under 5 years of age, the risk of therapeutic failure is increased by three times. The recommended doses are 4 mg/kg/bw per day of Dihydroartemisinin and 18 mg/kg/bw per day of piperaquine, daily for 3 days for adults and children weighing ≥25 kg. Children weighing less than 25 kg should receive a minimum of 2.5 mg/kg/bw per day of Dihydroartemisinin, and 20 mg/kg/bw per day of piperaquine daily for 3 days. It is available as a fixed-dose combination in tablets of 40 mg Dihydroartemisinin and 320 mg piperaquine and pediatric tablets with 20 mg Dihydroartemisinin and 160 mg piperaquine.

There are factors that alter the efficacy of the drug and the response to therapy: the ingestion of high-fat meals modifies the absorption of piperaquine and increases the risk of arrhythmias, delayed ventricular repolarization with prolongation of the corrected QT interval in the electrocardiogram, and malnourished children are at high risk of not obtaining an adequate response [2, 29, 30].

4.3 Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae, and P. knowlesi

The goal of treatment of P. vivax malaria is twofold: to cure the acute infection in the blood and to clear the hypnozoites from the liver to prevent relapse.

In areas where P. vivax is sensitive to chloroquine, treatment of malaria with oral chloroquine at a dose of 25 mg/kg/bw is effective and well tolerated. It is started with a dose of 10 mg/kg/bw on the first day, continued on the second day with 10 mg/kg/bw and it is ended on the third day with 5 mg/kg/bw.

ACTs are highly effective in the treatment of this parasitic species in areas where chloroquine-resistant P. vivax exists; ACTs containing piperaquine, mefloquine, lumefantrine are recommended.

In the therapy of uncomplicated P. ovale, P. malariae, and P. knowlesi malaria, the resistance of these species to these drugs has not been well characterized, and they are considered sensitive to chloroquine and should be treated with standard chloroquine or ACT regimens [2].

Tafenoquine: It is a new drug belonging to the family of 8-aminoquinoleins. It was discovered in 1978, in response to the search for a drug that acts on acute and latent forms of P. vivax infection and although the mechanism of action is not exactly known, it is hypothesized that it induces spontaneous oxidation by redox cycles, causing the death of the parasite. It has few adverse effects, and they occur in approximately 13%, predominantly gastrointestinal symptoms, vortex keratopathy without sequelae, prolongation of the QT interval, and hemolytic anemia in people with G6PD deficiency. In three studies subjected to meta-analysis, the efficacy of treatment with tafenoquine compared to primaquine was evaluated and showed no inferiority, being an alternative that improves treatment compliance and is administered in a single dose [31].

4.4 Mixed malaria

Common in endemic areas, ACTs are effective against all malaria species and are the shock treatment for mixed infections [2].

4.5 Use of primaquine in the treatment of malaria

To reduce the transmissibility of P. falciparum infection in areas of low transmission intensity, it should be administered in a single dose of 0.25 mg/kg/bw and accompanied by ACTs (except in pregnant women, children under 6 months of age, and women breastfeeding children under 6 months of age).

To prevent relapses in P. vivax malaria, P. ovale in children and adults (except pregnant women, children under 6 months, women breastfeeding children under 6 months, and persons with G6PD deficiency) should be treated with primaquine at doses of 0.25–0.50 mg/kg/bw, once daily for 14 days [2, 4].

4.6 Treatment of severe malaria

Treatment includes a general approach and the use of antimalarial drugs; general measures include: parenteral hydration, transfusion of globular or platelet concentrates; according to the patient’s condition. In situations of advanced clinical deterioration, nutritional support, renal replacement therapy (hemodialysis), and mechanical ventilation may be required.

Severe malaria is a medical emergency, and it is essential to perform supportive measures and give full and effective parenteral or rectal doses of antimalarial drugs in the initial treatment. Two groups of drugs are available for intravenous administration: artemisinin derivatives (artesunate or artemether) and cinchona alkaloids (quinine and quinidine) [2, 4, 6, 32, 33].

The clinical and rapid assessment with emphasis on the patient’s general condition includes: assessing the state of consciousness using the Glasgow scale, quantifying vital signs (blood pressure, frequency, and depth of respiration), as well as the degree of skin pallor.

General treatment for severe malaria and its complications:

1. Immediately hospitalize.

2. Close and continuous monitoring of vital signs and hemodynamic parameters.

3. Maintain general metabolic functions.

4. Immediate indication of specific antimalarial chemotherapy.

5. Medical work in a multidisciplinary team: internists, pediatricians, infectious disease specialists, obstetrician-gynecologists, intensivists, nephrologists, hematologists, epidemiologists.

6. Admission to the intensive care unit (ICU) or intermediate care unit for close monitoring.

7. To ensure airway patency, place cannula.

8. If hypoxia (oxygen saturation < 90%) administer oxygen.

9. In respiratory failure, manual or oxygen-assisted ventilation can be initiated.

10. Place bladder catheter for control of liquids eliminated, record the water balance including inflow and outflow.

11. Process priority and immediate tests such as thick and thin blood smear and rapid diagnostic tests (RDTs), complete hematology, glycemia, serum electrolytes, total and fractionated bilirubin, transaminases, urea, and creatinine.

12. Perform peripheral blood smears every 12 hours to determine parasitemia during the first 2–3 days.

13. Administer paracetamol or acetaminophen. Do not give NSAIDs or steroids.

Hydration: If there is no evidence of fluid overload, patients with oral intolerance (adults and pediatric) should receive 5% dextrose solutions, and those who tolerate the oral route, administer isotonic saline solution at a rate of 1–2 mL/kg/hour. Take care not to overhydrate the patient [2, 6].

Treatment of anemia: In adults, if the hematocrit <20 or Hb < 7 g/dL, transfuse whole blood or packed red cells over 6 hours [2, 6].

The advantages of artemisinin over quinine are evident, demonstrating a decrease in mortality with the administration of artesunate; it is simple and safe, it is applied in bolus intravenously or intramuscularly, without the adverse effects of quinine, nor the difficulties of intravenous dilution several times a day [2, 6, 32, 33, 34].

Antimalarial drugs: In any case of severe malaria, antimalarial chemotherapy should be initiated early [2, 4, 6, 35, 36, 37, 38, 39, 40].

First line in severe malaria: The therapeutic scheme is of international use.

Artesunate: WHO (2012) has indicated that the isolated use of this parenteral drug is the initial treatment of choice for this clinical form, the benefit is due to the fact that rapid therapeutic plasma concentrations are obtained, it is well tolerated, unlike quinine it eliminates parasitemia faster and has few adverse effects, it can be administered intravenously or intramuscularly [40].

Dosage according to patient’s weight:

1. Patient with less than 20 kg: 3 mg/kg/bw/dose.

2. Patient ≥20 kg: 2.4 mg/kg/bw/dose.

The first three doses of Artesunate are administered following an hourly interval; the first, upon admission (hour 0); the second 12 hours after the previous one and the third, 24 hours after the initial dose; with the option of prescribing additional doses, if the patient requires it. In this situation, continue with the medication until oral tolerance is recovered and a maximum of 7 days. Once the oral route is recovered, full therapy with Artemether 20 mg + Lumefantrine 120 mg for 3 days plus Primaquine at 0.50 mg/kg bw in a single dose is prescribed in case of P. falciparum infection, or in case of P. vivax or mixed infections at 0.25 mg/kg bw daily for 14 days.

Artemether attack dose: 3.2 mg/kg/bw and maintenance dose: 1.6 mg/kg/bw. First dose at admission (hour 0), then a maintenance dose every 24 hours until oral tolerance is achieved, for a maximum of 5 days. When tolerance is restored, oral treatment with Artemether 20 mg + Lumefantrine 120 mg for 3 days plus Primaquine at 0.50 mg/kg bw in a single dose in case of P. falciparum infection, or 0.25 mg/kg bw, daily for 14 days in case of P. vivax or mixed infections.

Quinine dihydrochloride dose of 10 mgs/kg/bw + Clindamycin 10 mgs/kg/bw, both intravenously. First dose at admission (hour 0), continue with Quinine every 8 hours plus Clindamycin every 12 hours until oral tolerance is recovered, for a maximum of 7 days. Depending on oral availability, complete 7 days with Quinine in tablets at 10 mg/kg bw every 8 hours, plus Clindamycin at 10 mg/kg bw every 12 hours for 7 days or Doxycycline at 4 mg/kg bw per day for 7 days, plus Primaquine at 0.50 mg/kg bw in single dose in case of P. falciparum infection, or 0.25 mg/kg bw per day for 14 days in case of P. vivax or mixed infection [2, 4, 34, 36, 37, 38, 39, 40, 41].

Some authors propose giving high, supervised doses of Primaquine at 7 mgs/kg/bw day for 14 days to reduce relapses of P. vivax and P. falciparum malaria [42, 43].

5. Conclusions

In this chapter, the review of national and international literature related to malaria shows its importance worldwide as a potentially fatal disease, is transmissible in tropical countries, more frequent in Africa, Asia, Oceania, and Latin America; the alternative diagnostic methods are exposed with their strengths and weaknesses, especially the parasitological ones with the thick blood smear as the gold standard, accompanied by thin blood smear; also, the usefulness of RDTs in remote sites, where microscopy is not available for an immediate diagnosis. In relation to antimalarial treatment, the current guidelines and recommendations are presented with the use of Artemisinin combinations (ACTs) and their different presentations for the therapy of uncomplicated P. falciparum malaria, or in mixed malaria, and the conduct in case of severe malaria with the use of ACTs in their different forms of administration: oral, rectal, intramuscular, and intravenous. Finally, the indication of primaquine and tafenoquine to avoid relapses and contagion of this entity; without diagnostic delay and early initiation of medication to prevent fatal outcomes due to severe complications, we should be waiting for updates on the different diagnostic, therapeutic, and preventive options, as long as the fight toward the eradication of this disease is a reality in the world.

Acknowledgments

The author acknowledges to Dr. María Eugenia Guzmán Siritt, for her contributions to the review of the chapter.

Conflict of interest

“The author declares no conflict of interest”.