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A Case of Plasmodium falciparum Malaria Treated with Artesunate in a 55-Year-Old Woman on Return to Florida from a Visit to Ghana

Jose a. rodriguez.

1 Department of Internal Medicine, Memorial Healthcare System, Pembroke Pines, FL, U.S.A.

Alejandra A. Roa

Ana-alicia leonso-bravo, pratik khatiwada, paula eckardt.

2 Division of Infectious Disease, Memorial Regional Hospital, Memorial Healthcare System, Hollywood, FL, U.S.A.

Juan Lemos-Ramirez

Patient: Female, 55-year-old

Final Diagnosis: Severe malaria

Symptoms: Altered mental status • dyspnea • fever

Medication: —

Clinical Procedure: —

Specialty: Critical Care Medicine • Infectious Diseases

Management of emergency care

Background:

Malaria is the infection caused by inoculation with the mostly obligate intraerythrocytic protozoa of the genus Plasmodium. Severe malaria manifests as multiple organ dysfunction with high parasitemia counts characterized by coma, stupor, and severe metabolic acidosis. Physicians in the United States do not frequently encounter patients with malaria, and the drugs are only available through the Centers for Disease Control and Prevention, which makes the management of this disease somewhat complicated. In 2019, the marketing of quinine for malaria was discontinued. In May 2020, the US Food and Drug Administration approved the use of intravenous artesunate for the treatment of adults and children with severe malaria. This case report describes a case of Plasmodium falciparum malaria in a 55-year-old woman who returned home to Florida from a visit to Ghana.

Case Report:

A previously healthy 55-year-old woman with no significant past medical history presented to the Emergency Department (ED) of a hospital in south Florida due to cyclic fever for 7 days. The patient’s family reported mental status changes since symptom onset. The patient had returned from a 10-day trip to Ghana 18 days prior to admission. On arrival to the ED, the patient appeared lethargic and within hours was in respiratory distress. She was intubated and mechanically ventilated in the ED for acute hypoxemic respiratory failure. A malaria smear was positive with 25% parasitemia, and a diagnosis of severe malaria was made, consistent with P. falciparum infection complicated by multi-organ failure. Infectious disease consultation was obtained and an infusion of intravenous (IV) quinidine and IV doxycycline was emergently started due to the anticipated delay in obtaining artesunate. During the second day of admission, the patient had QTc prolongation, so quinidine was switched to IV artesunate. The parasitemia and acidosis started improving by the third day of therapy.

Conclusions:

Given that artesunate is more effective, easier to dose, and more tolerable than quinidine, it is now the treatment of choice for severe malaria in the United States.

Malaria is the infection caused by the mostly obligate intraerythrocytic protozoa of the genus Plasmodium , which is spread to people by the inoculation from infected female Anopheles mosquitoes. Plasmodium falciparum is the major cause of severe malaria, which manifests as multiple organ dysfunction with high parasitemia counts that is characterized by coma, stupor, and severe metabolic acidosis [ 1 ].

Malaria occurs primarily in tropical and some subtropical regions of Africa, Central and South America, Asia, and Oceania, with an estimated 228 million cases worldwide in 2018 (93% of them occurring in Africa) [ 2 ]. About 2000 cases of malaria are diagnosed in the United States each year. Almost all these cases are imported by returning travelers or immigrants from endemic regions, with a limited number possibly occurring through local mosquito-borne transmission [ 2 ]. The US Centers for Disease Control and Prevention (CDC) has reported that among the 2000 cases of malaria diagnosed in the United States each year, about 300 cases are severe. The majority of these severe cases involve travelers returning from sub-Saharan Africa and South Asia [ 3 ].

In 2019, the marketing of quinine for malaria was discontinued in the United States. In May 2020, the US Food and Drug Administration (FDA) approved the use of intravenous artesunate for the treatment of severe malaria, with the recommendation that it should be followed by a full course of oral antimalarial treatments [ 4 ].

Physicians in the United States do not encounter patients with malaria frequently, and the drugs are only available through the CDC, which makes the management of this disease somewhat complicated. Among patients with unexplained fever or clinical deterioration who have traveled to an endemic area, malaria must be included in the differential diagnosis to avoid delays in appropriate treatment of malaria that would increase morbidity and mortality [ 5 , 6 ]. Therefore, it is imperative to have a better understanding of this disease and also to inform readers about the management and ways of improving it.

Case Report

A previously healthy 55-year-old woman with no significant past medical history presented to the Emergency Department (ED) of a hospital in south Florida owing to a fever for 7 days. Fever was quantified with readings of 40°C coming every 48 h, associated with various nonspecific symptoms such as malaise, fatigue, decreased appetite, productive cough for 2–3 days, and abdominal pain with associated watery diarrhea for 2–3 days. The patient’s family reported mental status changes (nonresponsive to her name, visual hallucinations) since symptom onset. The patient denied headache, loss of consciousness, neck rigidity, seizure, focal neurological symptoms, chest pain, hemoptysis, and difficulty breathing at the time of presentation. She denied any similar episodes in the past. She reported allergy (rash) to penicillin. No pertinent family history was noted. She lived with her son, who was asymptomatic, and worked as a biomedical engineer. The patient had returned from a 10-day trip to Ghana 18 days prior to admission, and she had also traveled to California 1 week before admission. She denied receiving malaria prophylaxis or vaccination against yellow fever and hepatitis A virus. She developed symptoms while in California and went to a hospital there, but she was discharged following unremarkable examination and normal laboratory results.

A few hours after arrival to the ED, the patient became lethargic and was found to be in respiratory distress. Vital signs were an oral temperature of 38.6°C, heart rate 121 beats/min, blood pressure 100/51 mmHg, respiratory rate 45 breaths/min, and SpO 2 93% on room air. She had dry mucous membranes, decreased bilateral breath sounds, and tenderness to palpation of the left lower quadrant abdomen. No obvious jaundice, enlarged lymph nodes, or splenomegaly was observed. On neurological examination, she was lethargic and confused with Glasgow coma scale (GCS) score of 14 (E4V4M6); her pupils were equal, round, and reactive to light; she had no cranial nerve or sensory deficit; and her neck was supple, with Brudzinski’s and Kernig’s signs both being negative.

Initial laboratory studies revealed leukocytosis with white cell count of 19 800/µL with 44% neutrophils, 22% lymphocytes, and 1% eosinophil; platelets 51 000/µL; hemoglobin 11.8 g/dL; hematocrit 35.3%; red blood cell distribution width 16.9%; lactate dehydrogenase 2714 U/L; haptoglobin <8 mg/dL; prothrombin time/international normalized ratio 14.9/1.4; troponin 0.161 ng/mL; blood glucose 26 mg/dL; blood urea nitrogen 157 mg/dL; creatinine 7.52 mg/dL; estimated glomerular filtration rate 6 mL/min; bicarbonate 5 mmol/L; anion gap 36; lactic acid 16.2 mmol/L; sodium 131 mmol/L; potassium 5.5 mmol/L; chloride 91 mmol/L; alanine transaminase 542 U/L; aspartate transaminase 1328 U/L; total bilirubin 14.5 mg/dL; and albumin 2.2 mg/dL. A malaria smear was positive with 25% parasitemia initially, and ring forms/trophozoites and a few elongated structures suggestive of developing gametocytes were reported ( Figure 1 ). An arterial blood gas obtained in the ED on 3 L of oxygen via nasal cannula showed pH of 7.03 and pCO 2 of 20 and HCO 3 of 0.

Numerous malaria organisms are present, affecting approximately 25% of red blood cells. Ring forms/ trophozoites have 1 or 2 chromatin dots. Multiply-infected red cells are not uncommon (2–4 trophozoites). A few elongated structures suggestive of developing gametocytes are seen.

The patient’s mental status gradually deteriorated while she was being evaluated at the ED. Her GCS score after 3 h of presentation was 10/15 (E2V3M3), and she had to be intubated and mechanically ventilated in the ED for acute hypoxemic respiratory failure and transferred to the Intensive Care Unit (ICU). Severe malaria was diagnosed, consistent with Plasmodium falciparum malaria complicated by multi-organ failure including respiratory, renal, and hepatic failure; septic shock; and disseminated intravascular coagulation. The acute toxic-metabolic encephalopathy was most likely due to cerebral malaria. The acute hypoxemic respiratory failure evolved into acute respiratory distress syndrome driven by the shock and severe acidemia, so vasopressors and steroids were started. Infectious disease consultation was obtained and an infusion of intravenous (IV) quinidine at a rate of 115.2 mg/h and IV doxycycline 100 mg every 12 h was emergently started due to the anticipated delay in obtaining artesunate. This was done with close monitoring of QTc, blood glucose, and parasitemia, while the CDC was contacted to request the emergent release of the artesunate. Empiric broad-spectrum antibiotic coverage was started with IV meropenem 1 g every 12 h and intermittently dosed IV vancomycin. Exchange transfusion was considered as a salvage therapy in case of nonresponse to medical therapy.

During the second day of admission, the patient had QTc prolongation, so quinidine was switched to IV artesunate every 24 h. The parasitemia and acidosis started improving and the positive end-expiratory pressure and FiO 2 requirements decreased. Computed tomography of the brain was unremarkable, and a lumbar puncture showed 3 white blood cells per high-power field, 12% neutrophils, 48% lymphocytes, 38% monocytes, and no organisms on gram stain. Vancomycin and meropenem were discontinued due to no evidence of bacterial meningitis. By the third day of therapy, the parasitemia decreased to 0.3% and was negative on day 6 ( Table 1 ). The multi-organ failure and septic shock were treated with supportive care including renal replacement therapy and platelet transfusions, and the patient was clinically improving. A 5-day course of IV artesunate and doxycycline was completed with an additional 7-day course of oral doxycycline at discharge to a rehabilitation facility with a favorable outcome and recuperation.

Daily parasitemia percentage.

This case illustrates the need to recognize severe malaria, especially cerebral malaria, and the need for more readily available parenteral artesunate in the United States. Severe malaria is defined as P. falciparum parasitemia >10% and signs of major organ dysfunction including impaired consciousness, prostration, 2 or more convulsive episodes in 24 h, acidosis (bicarbonate <15 mmol/L), hypoglycemia (glucose <40 mg/dL), severe anemia (hemoglobin <6 g/dL), recurrent or prolonged bleeding, renal impairment (creatinine >3 mg/dL), pulmonary edema, and shock. Less commonly, severe malaria can be caused by other Plasmodium species. Severe malaria tends to occur in young children in endemic areas and adults traveling to endemic countries owing to their lack of immunity; these populations are also at the highest risk for cerebral malaria for the same reasons [ 7 , 8 ]. The incubation period for P. falciparum is 12–14 days (range of 7–30 days). Severe malaria can cause many complications, with cerebral malaria being one of the most important to recognize due to its poor prognosis. It presents as impaired consciousness, delirium, and/or seizure [ 9 ].

Treatment of severe malaria requires prompt antimalarial therapy with supportive care and management of complications because mortality is highest in the first 24 h of presentation [ 8 , 10 , 11 ]. Prompt treatment is especially critical if cerebral malaria is suspected because it has a 15–20% mortality rate when treated and above 30% in cases with multiple vital organ dysfunction [ 9 , 12 ]. For severe malaria, the WHO recommends parenteral artesunate (if the artesunate of reliable quality is available); otherwise, treatment with quinidine is recommended. Quinidine was used in the United States because artesu-nate was neither approved by the FDA nor was it was commercially available before May 2020 [ 13 ].

Treatment is generally parenteral initially. It is then completed with oral antimalarial if the patient is tolerating oral intake and parasitemia is ≤1% when using artesunate. Completion of oral antimalarial therapy is 3–7 days afterward depending on the regimen, which can include doxycycline, clindamycin, quinidine, atovaquone-proguanil, and mefloquine (refer to Table 2 for dosing and duration of therapy) [ 12 , 14 ]. Mefloquine should be avoided if the patient has cerebral malaria due to the increased risk of neuropsychiatric effects, and it is not recommended if malaria was acquired in Southeast Asia due to drug resistance [ 8 , 12 , 14 ].

Antimalarial therapy.

FDA approval for the use of intravenous artesunate was based on evidence from multiple randomized controlled trials abroad, including Europe, as well as trials in adults and children from endemic areas in Asia and Africa [ 8 , 10 – 13 ]. The benefits tend to be most pronounced in patients with hyperparasitemia in endemic/nonendemic areas (reduced ICU and hospitalization length of stays). The patients also tend to have faster parasite clearance from the blood by about 1–2 days when treated with artesunate. The difference in outcomes is less pronounced with parasitemia less than 5% [ 10 – 14 ]; nonetheless, adult travelers to endemic areas have a higher likelihood of developing hyperparasitemia, so artesunate would likely still provide a benefit over quinidine. The mechanism of action for artesunate is incompletely understood, but it is hypothesized to involve the formation of free radicals that interfere with parasitic function and it has a broader spectrum of action against ring-stage parasites. By preventing maturation and sequestration of infected erythrocytes, artesunate improves removal by the spleen and allows for less microvascular obstruction and subsequent organ damage. This may explain why the benefits of artesunate are the most profound in patients with hyperparasitemia [ 10 , 11 , 15 , 16 ].

The WHO recommends artesunate for the treatment of severe malaria because it has been shown to reduce the adult mortality rate by about 39% relative to quinidine (24% greater reduction in the child mortality rate) [ 6 ], has fewer adverse effects and drug-drug interactions, and is easier to dose [ 9 – 11 ]. Quinidine is known to cause QTc prolongation, ototoxic effects, and hyperinsulinemic hypoglycemia. Artesunate is relatively quick acting and tolerated, but patients on this treatment must be monitored for delayed hemolytic anemia at 7, 14, and 30 days after completion of therapy [ 8 , 12 , 14 ].

The patient presented in this case had severe malaria, specifically cerebral malaria, 18 days after returning to the United States from a 10-day trip to Ghana. Other causes for the patient’s symptoms were excluded, including viral infection, meningitis, bacteremia, and so forth. When the patient was started on quinidine, there was minimal effect on the parasitemia (25% to 23.43% in 24 h). Once treatment was switched to artesunate due to QTc prolongation, the parasitemia dropped from 23.43% to 6.8% in 24 h, and the smear was negative within 5 days. This patient had complications from severe malaria but likely benefited from the faster clearance of malaria from the blood with artesunate, which the quinidine did not provide.

Ideally, this patient could have prevented contracting malaria with mosquito bite prevention and by receiving prophylaxis from a travel clinic, which can provide detailed, individualized, and effective travel counseling. Prophylaxis with atovaquoneproguanil, doxycycline, mefloquine, primaquine, tafenoquine, or rarely chloroquine (due to high rates of resistance) is started prior to travel, and it is continued during the trip and for a period of time after returning home. The regimen depends on the region of travel, length of stay, and local malaria resistance patterns [ 6 , 17 ].

Conclusions

This report presents a case of severe P. falciparum malaria treated with artesunate in a 55-year-old woman who returned to Florida from a visit to Ghana. The case highlights the importance of early diagnosis of malaria, particularly in patients who have returned from travel to countries where malaria is endemic. It also underscores the use of current diagnostic guidelines and regulatory approved treatment, which now includes IV artesunate.

Conflict of interest

References:

Malaria Questions & Answers

• Author: William N Bennett, V, MD; Chief Editor: Michael Stuart Bronze, MD  more...
• Sections Malaria
• Practice Essentials
• Epidemiology
• Pathophysiology
• Patient Education
• Physical Examination
• Approach Considerations
• Blood Smears
• Alternatives to Blood Smear Testing
• Histologic Findings
• Laboratory Studies
• Pharmacologic Therapy
• Inpatient Care
• Deterrence and Prevention
• Consultations
• Medication Summary
• Antimalarials
• Questions & Answers
• Media Gallery

What is malaria?

What are the signs and symptoms of malaria?

Which physical findings suggest malaria?

What should be the focus of patient history in suspected malaria?

Which blood studies should be performed in the workup of malaria?

What is the role of imaging studies in the workup of malaria?

What is the role of lab testing in the workup of malaria?

How are Plasmodium species histologically distinguished?

What is the basis for treatment selection in patients with malaria?

What are the general recommendations for pharmacologic treatment of malaria?

Which medications are used for the treatment of malaria in pregnancy?

Where is malaria most prevalent and how is malaria infection transmitted?

Which Plasmodium species cause malaria?

How are Plasmodium species that cause malaria differentiated?

How common is malaria infection caused by multiple Plasmodium species?

Who is at increased risk for malaria infection?

What is the pathogenesis of malaria?

What complications are associated with Plasmodium falciparum (P falciparum) malarial infection?

How is malaria infection transmitted?

What are possible outcomes of Plasmodium falciparum (P falciparum) malaria infection?

Which factors influence malaria immunity?

How long do Plasmodium species incubate in humans?

What is the life cycle of Plasmodia?

What are the possible sequelae from replication of Plasmodia inside red blood cells (RBCs)?

What is the role of hemozoin in the etiology of malaria?

What is the role of Plasmodia metabolism in the pathophysiology of malaria?

What is the pathogenesis of Plasmodium falciparum (P falciparum) malaria?

What is the pathophysiology of malaria caused by Plasmodium vivax (P vivax)?

What is the pathophysiology of malaria caused by Plasmodium ovale (P ovale)?

What is the disease course of malaria caused by Plasmodium malariae (P malariae)?

What is the disease course of malaria caused by Plasmodium knowlesi (P knowlesi)?

What is the incidence of malaria in the US?

What is the mortality rate for malaria?

What is the global incidence of malaria?

Which malaria comorbidity is associated with a worse prognosis?

How does the incidence of malaria vary between men and women?

Which age group is at an increased mortality risk from malaria?

What is the prognosis of malaria?

What are the possible complications of malaria caused by Plasmodium falciparum (P falciparum)?

What is the mortality rate of malaria?

What are the host protective factors against malaria?

What information about malaria should be given to individuals traveling to endemic regions?

Presentation

What should be the focus of the patient history for suspected malaria?

What is the incubation period for malaria infection and what symptoms occur?

How is the onset of malaria symptoms characterized?

What are less common symptoms of malaria?

What is the presentation of Plasmodium vivax (P vivax) malaria infection?

What is the presentation of Plasmodium malariae (P malariae) malaria infection?

What findings suggest Plasmodium knowlesi (P knowlesi) malaria?

What are the symptoms of malarial infection?

What is the presentation of severe malaria?

What are the symptoms of malaria in children?

What is cerebral malaria?

What causes anemia in patients with malaria?

What is the treatment of renal failure in patients with severe malaria?

What are the respiratory symptoms of malaria?

Which conditions should be included in the differential diagnoses of malaria?

In travelers returning from endemic areas, which findings suggest malaria?

What should be considered in patients who do not respond to antimalarial therapy?

What lab tests are performed in the workup of malaria?

What test must be performed before treating a malaria patient with primaquine?

What is the role of blood glucose testing in the diagnosis and management of malaria?

What are the BCSH recommendations for the lab diagnosis of malaria?

What is the role of microhematocrit centrifugation in the workup of malaria?

What is the indication for fluorescent and ultraviolet testing in the workup of malaria?

What is the role of PCR assay testing in the workup of malaria?

What is the role of lumbar puncture in the workup of malaria?

What is the role of blood smears in the workup of malaria?

How are blood smears examined for malaria?

What is the difference between thick and thin blood smears in the workup of malaria?

When should alternative diagnostic methods to blood smears be used in the workup of malaria?

How effective are rapid diagnostic tests (RDT) in the workup of malaria?

What is the role of PCR assay testing and nucleic acid sequence-based amplification (NASBA) in the diagnosis of malaria?

What is the role of the quantitative buffy coat (QBC) technique in the diagnosis of malaria?

How should a diagnosis of malaria be reported?

What are the histologic findings for the Plasmodium species associated with malaria?

What monitoring is needed of patients treated for malaria?

What may increase the risk of morbidity and mortality in patients with malaria?

What are approach considerations for mixed infections of malaria?

Which Plasmodium species have known resistance to antimalarial agents?

When is inpatient treatment indicated in the treatment of malaria?

What are the increased risks for pregnant women who contract malaria?

How is malaria treated during pregnancy?

What is the disease course of malaria in children?

How is malaria treated in children?

How should diet and activity be modified in patients with malaria?

What are the treatment options for severe complicated malaria?

What is the efficacy of artesunate for the treatment of malaria?

How common is drug resistance in Plasmodium falciparum (P falciparum) malaria?

What is the role of artemisinin in the treatment of malaria?

Is there a vaccine for malaria?

What are the general recommendations for the treatment of malaria?

What is the role of mefloquine hydrochloride for the treatment of malaria?

What is the role of tafenoquine (Krintafel) in preventing malaria relapse?

Which medications are used to treat malaria during pregnancy?

When is inpatient care indicated for the treatment of malaria?

How often should blood smears be obtained during the treatment of malaria?

How is malaria prevented?

How much DEET should be used to repel mosquitoes and prevent malaria?

What is the role of chemoprophylaxis in the prevention of malaria?

What progress is being made on the development of a malaria vaccine?

When are specialist consultations needed for the diagnosis and treatment of malaria?

What consultations are needed for the treatment of pregnant patients with malaria?

Medications

Which major drug classes are used to treat malaria?

What is the prevalence of counterfeit antimalarial drugs?

What is the role of antipyretics in the treatment of malaria?

What are the possible adverse effects of antimalarial drugs for the treatment of malaria?

What are the possible complications of high-dose quinine for the treatment of malaria?

Which medications in the drug class Antimalarials are used in the treatment of Malaria?

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de Sousa LP, Rosa-Gonçalves P, Ribeiro-Gomes FL, Daniel-Ribeiro CT. Interplay Between the Immune and Nervous Cognitive Systems in Homeostasis and in Malaria. Int J Biol Sci . 2023. 19 (11):3383-3394. [QxMD MEDLINE Link] .

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• Malarial merozoites in the peripheral blood. Note that several of the merozoites have penetrated the erythrocyte membrane and entered the cell.
• This micrograph illustrates the trophozoite form, or immature-ring form, of the malarial parasite within peripheral erythrocytes. Red blood cells infected with trophozoites do not produce sequestrins and, therefore, are able to pass through the spleen.
• An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other red blood cells. Notice the darkened central portion of the cell; this is hemozoin, or malaria pigment, which is a paracrystalline precipitate formed when heme polymerase reacts with the potentially toxic heme stored within the erythrocyte. When treated with chloroquine, the enzyme heme polymerase is inhibited, leading to the heme-induced demise of non–chloroquine-resistant merozoites.
• A mature schizont within an erythrocyte. These red blood cells (RBCs) are sequestered in the spleen when malaria proteins, called sequestrins, on the RBC surface bind to endothelial cells within that organ. Sequestrins are only on the surfaces of erythrocytes that contain the schizont form of the parasite.
• Malaria life cycle. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Proportion of 2021 Global Malaria Burden. Gray area accounts for the remaining estimated 4.4% of worldwide malaria burden. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• Confirmed P falciparum or P vivax Cases Per Country 2021. The map accounts for the total of the cases per country where either species were confirmed as the primary infection. The map does not include confirmed “mixed infections.” Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• North American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• South American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• African Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• Asian and Oceanic Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• South Pacific Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• Global P falciparum to P vivax Case Ratios 2021. Gray indicates that there were either no data available or there were zero endemic cases. Red indicates higher proportion of P vivax cases, whereas blue indicates higher proportion of P falciparum cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
• Thin blood smear showing the ring forms of P falciparum that look like headphones with double chromatin dots. Note how P falciparum is seen infecting erythrocytes of all ages – a trait that can be utilized by the microscopist by noting the similar size of infected erythrocytes to other surrounding uninfected erythrocytes. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Thick blood smear depicting the banana shaped gametocyte of P falciparum. Multiple ring-form trophozoite precursors are also visible in the background. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Thin blood smear of the ring forms of P vivax. Note that P vivax typically has a single chromatin dot vs the two chromatin dots in P falciparum. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• The diagnostic form of P vivax is the amoeboid trophozoite form where the cytoplasm has finger-like projections (pseudopods) without a typical round/oval structure. These pseudopods are unique to P vivax. Numerous small pink-red dots are also seen in both P vivax and P ovale; these are known as caveola-vesicle complexes (CVCs or Schüffner’s dots) and are composed of numerous flask-like indentations on infected reticulocytes membrane skeleton associated with tube-like vesicles. CVCs are thought to play a role in nutrient uptake or release of metabolites from parasite-infected erythrocytes. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Thin smear of P ovale in ring stage. Note that typically there is a single chromatin dot, larger cells are infected indicative of reticulocytes, and multiple ring forms may be present intracellularly. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Thin smear of P ovale trophozoite. Note that this species is difficult to differentiate from P vivax as it contains CVCs (Schüffner’s dots) and infects reticulocytes; a notable unique characteristic of P ovale is the presence of fimbriae on the reticulocyte membrane, which are even more likely to be seen in gametocyte infected red blood cells. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Thin blood smear of “band form” trophozoite of P malariae. Note that the infected erythrocyte is smaller than surrounding cells, indicating that P malariae infects older erythrocytes. As the trophozoite matures, the cytoplasm elongates and dark pigment granules of hemozoin are visualized toward the periphery. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Thin blood smear of P knowlesi trophozoites. An immature ring form is seen on the right next to the mature band form trophozoite on the left. Note the small size of the infected red blood cells and how the band form is similar in appearance to P malariae. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
• Table 1. Histologic Variations Among Plasmodium Species

Contributor Information and Disclosures

William N Bennett, V, MD Staff Physician, Infectious Disease Service, Chair, Antimicrobial Stewardship, Department of Medicine, Wright-Patterson Medical Center; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences School of Medicine William N Bennett, V, MD is a member of the following medical societies: American College of Physicians , American Medical Association , Infectious Diseases Society of America Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape.

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Medical Association , Association of Professors of Medicine , Infectious Diseases Society of America , Oklahoma State Medical Association , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, Public Health, Dayton and Montgomery County (Ohio) Tuberculosis Clinic Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha , Infectious Diseases Society of America , Infectious Diseases Society of Ohio Disclosure: Received research grant from: Regeneron.

Joseph R Masci, MD, FACP, FCCP Professor of Medicine, Professor of Preventive Medicine, Icahn School of Medicine at Mount Sinai; Director of Medicine, Elmhurst Hospital Center Joseph R Masci, MD, FACP, FCCP is a member of the following medical societies: American Academy of HIV Medicine , American Association for the Advancement of Science , American College of Chest Physicians , American College of Physicians , American Medical Association , American Society for Microbiology , American Society of Tropical Medicine and Hygiene , Association of Professors of Medicine , Association of Program Directors in Internal Medicine , Association of Specialty Professors , Federation of American Scientists , HIV Medicine Association , Infectious Diseases Society of America , International AIDS Society , International Association of Providers of AIDS Care , International Society for Infectious Diseases , New York Academy of Medicine , New York Academy of Sciences , Physicians for Human Rights , Physicians for Social Responsibility , Royal Society of Medicine Disclosure: Nothing to disclose.

Emilio V Perez-Jorge, MD, FACP Staff Physician, Division of Infectious Diseases, Lexington Medical Center Emilio V Perez-Jorge, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine , Infectious Diseases Society of America , Society for Healthcare Epidemiology of America , South Carolina Infectious Diseases Society Disclosure: Nothing to disclose.

Ryan Q Simon, MD Infectious Disease Specialist, Wright State Physicians, Wright State University School of Medicine Disclosure: Nothing to disclose.

The views expressed are those of the author and do not necessarily reflect the official policy or position of the Department of the Air Force, the Defense Health Agency, the Department of Defense, or the U.S. Government.

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A Case of Plasmodium Falciparum Malaria Presentation

Editor(s): Naveed, Khan.

From the Lincoln Medical and Mental Health Center, New York, New York, USA.

Correspondence: Osman Nawazish Salaria, Lincoln Medical Center, New York, New York USA (email: [email protected] ).

Abbreviations: BPb = lood pressure, bpm = beats per minute, BUNb = lood urea nitrogen, CDC = Center for Disease Control, cm = centimeters, Creatc = reatinine, DOHMH = Department of Health and Mental Hygiene, ED = Emergency Department, Hb = hemoglobin, Hct = hematocrit, ICU = intensive care unit, IV = intravenous, IVP = intravenous push, Plt = platelet, WBC = white blood cell, WHO = World Health Organization, y/o = year old.

Methods: Ethical approval was not necessary for this study as the study was focused on the patient hospital course and did in no way alter or affect her treatment. Informed Consent was taken from the patient regarding the publishing of this case report and the patient accepted.

The authors have no conflicts of interest to disclose.

This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Received April 20, 2015

Received in revised form July 11, 2015

Accepted July 27, 2015

New York City is a multicultural city where people of different ethnicities and backgrounds from all over the world live together. Of the different ethnicities, it is home to a large population of Western African immigrants. This case report is that of an elderly female of Western African descent presenting to Lincoln Hospitals Emergency Department with fevers and fatigue.

The patients travel history to Togo, along with her symptoms, resulted in a differential diagnosis which included Ebola as well as Malaria. New York City's Department of Health and Mental Hygiene was contacted for further clarification of presence of Ebola in Togo. The present case report is meant to educate about the presentation, hospital course, and differential diagnoses of a patient traveling from Western Africa with fever and chills.

INTRODUCTION

Malaria is a frequent parasitic infection prevalent in Africa. Around 300 million are infected annually in Africa by malaria and 1 to 2 million will die from the disease. 1 Of the 4 human parasitic species that have been identified, Plasmodium falciparum has been known to cause significant morbidity and mortality, particularly in children and pregnant women. 1 Strategies to counteract malaria incidence, such as community health workers outreach and insecticide treated nets have been instituted in recent years; however, their effect has not been of much significance. 2

Ebola virus disease has caused much concern with its global rise in incidence and prevalence recently. The current epidemic which has centered mainly in Western African nations of Guinea, Sierra Leone, and Liberia has now spread outside of borders of Africa to involve the United States. 3 Much of the presenting symptoms and signs of the disease mimic other diseases such as typhoid fever and malaria. 3,4

There is much overlap between presentations of both P. falciparum malaria and Ebola virus disease. Without confirmatory blood tests searching for malaria parasites or viral RNA and viral antibodies a diagnosis is very difficult to achieve.

CASE REPORT

A 67 y/o (year old) female from Western Africa initially presented to the Emergency Department (ED) complaining of fatigue and subjective fevers for the past 2 days. Patient complained that her fevers were associated with headaches, but not chills, rigors, or chest pain. Index of suspicion for malaria was high as patient had recently traveled from an endemic region. Patients travel history to Western Africa and the presenting symptoms also made us consider a possibility of Ebola virus disease.

Past medical history included diabetes, hypertension, and a history of recent travel to her home country of Togo for 5 months. Patient had returned 5 days ago from her travel and started to develop symptoms of fevers and fatigue. Patient denied any immunizations received before traveling. Past surgical history included a left breast mastectomy done back in France 1987. Medication history included Amlodipine, Aspirin, Calcium Carbonate, Synthroid, Pioglitazone, Humalog, Glucovance, Crestor, Januvia, and Lisinopril. After initial presentation to the ED for 2 days of fevers and fatigue, she was accepted by Medicine and transferred to the general medical floors. The patient had a blood pressure of 123/55, pulse of 86 beats per minute (bpm), Temperature of 98.5 °F, and respiratory rate of 16 at the time of admission. Physical examination did not disclose any specific abnormalities.

Labs including complete blood count, chemistry, liver function tests, malaria peripheral smears, and reitculocyte level were withdrawn from the patient. Patient had white blood cell (WBC) count of 12.6, Hb (hemoglobin) 10.7, Hct (hematocrit) 30.6, Plt (platelet) 80, BUN (blood urea nitrogen) 12, Creat (creatinine) 0.3, and blood glucose of 291 consistent with diabetes. Blood smears were positive for P. falciparum malaria at 9.6% and reticulocyte count was reported at 3.2%. New York City's Department of Health and Mental Hygiene (DOHMH), was contacted and Ebola was not considered to be in Togo, most likely diagnosis was malaria from chloroquine resistant region. Patient was started on quinine 648 mg and doxycycline 100 mg, intravenous (IV) fluids, Lantus 21 U, Lispro 7 U, and was monitored in telemetry unit of medicine (Figures 1–3).

Attention was drawn to the patient at 4:45 AM on her 3rd hospital course day after becoming suddenly dyspneic. Patient denied any chest pain but upon pulmonary examination bilateral coarse crackles were heard up to mid lung level. Patient received 60 mg intravenous push (IVP) Lasix and sublingual nitroglycerin. She continued to be dyspneic and was given additional 40 mg IV Lasix and 4 mg Morphine IV were given. Bi-continuous positive airway pressure was started but patient did not tolerate well and decision was made to intubate the patient for acute hypoxemic respiratory failure. Patient was transferred to the medical intensive care unit (ICU) for further care.

Chest X-ray in the medical ICU revealed bilateral alveolar infiltrates; patient was started on Cefepime 2 g IV. Presumption was made that patient had Acute Respiratory Distress Syndrome secondary to sepsis from an unknown source of infection, but possibly from Falciparum Malaria. Abdominal ultrasound showed tiny echogenic foci within the gallbladder, prominent liver measuring 18.7 cm, and a dilated common bile duct measuring 8.2 mm. Choledocholithiasis was questioned although not directly visualized. Decision was made to monitor liver enzymes and if worsening of abdominal status cholecystostomy tube could be placed.

Patient remained in the medical ICU where she was daily monitored. Vital signs monitoring showed daily fever spikes of 101 to 103 °F 2 to 3 times per day. Liver enzymes were down trending after week 1, repeat right upper quadrant ultrasound was negative most probably from passage of a gallstone. On day 9 of hospital course patient was extubated and transferred to medical floors for continuation of care.

Patients of Western African descent presenting with symptoms of fevers and fatigue must be approached with precaution in present day circumstances. The Ebola virus disease outbreak has currently heightened healthcare professional's fears of contracting the virus by exposure to their patients. Furthermore, the impact of the Ebola virus disease in West Africa has left the local population vulnerable to other deadly diseases such as malaria. Control efforts for disease transmission and treatment of malaria have come to a halt. Anti-malaria medication, preventive insecticide bed nets are lying in warehouses far from the people which could benefit from them. International agencies such as the World Health Organization (WHO), US Agency for International Development supported and funded programs malaria control initiatives have virtually been shut down. 5 The similarities of the symptoms and signs of presentation of both diseases intimidates people from seeking treatment for fear of being infected with Ebola.

In face of all these difficulties, Ebola control efforts including government education programs partnered with WHO, travel measures has reduced the incidence significantly. Early identification of symptoms, isolation of contacts, and early monitoring and treatment has played a major role in limiting spread of infection of Ebola. This case report illustrates an example of how a patient with recent travel history to West Africa presenting with typical fevers, myalgias, and fatigue could be considered to have either or both diseases.

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• Communicable Diseases Module: Ethiopian Federal Ministry of Health
• Communicable Diseases Module: Acknowledgements
• Communicable Diseases Module: Introduction
• Communicable Diseases Module: 1. Basic Concepts in the Transmission of Communicable Diseases
• Communicable Diseases Module: 2. Prevention and Control of Communicable Diseases and Community Diagnosis
• Communicable Diseases Module: 3. Bacterial Vaccine-Preventable Diseases
• Communicable Diseases Module: 4. Viral Vaccine-Preventable Diseases
• Communicable Diseases Module: 5. Malaria Epidemiology and Transmission
• Communicable Diseases Module: 6. Factors that Affect Malaria Transmission
• Communicable Diseases Module: 7. Diagnosis of Malaria
• Introduction
• Learning Outcomes for Study Session 8
• 8.1.1  Treatment of uncomplicated malaria based on RDT confirmation
• 8.1.2  Treatment of uncomplicated malaria based on clinical diagnosis
• 8.1.3  Supportive treatment of uncomplicated malaria cases
• 8.2  Pre-referral treatment of severe malaria at the Health Post level
• 8.3  Management of malaria in special groups
• 8.4  Adherence to malaria treatment
• 8.5.1  Key messages and instructions

Summary of Study Session 8

Self-Assessment Questions (SAQs) for Study Session 8

• Communicable Diseases Module: 9. Malaria Prevention: Environmental Management and Larviciding for Vector Control
• Communicable Diseases Module: 10. Malaria Prevention: Indoor Residual Spraying of Houses
• Communicable Diseases Module: 11. Malaria Prevention: Insecticide Treated Nets
• Communicable Diseases Module: 12. Monitoring and Control of Malaria Epidemics
• Communicable Diseases Module: 13. Introduction, Transmission and Tuberculosis Case Finding
• Communicable Diseases Module: 14. Diagnosis and Treatment of Tuberculosis
• Communicable Diseases Module: 15. Follow-up of Patients on Anti-Tuberculosis Treatment and Defaulter Tracing
• Communicable Diseases Module: 16. Tuberculosis Treatment in Special Conditions: TB in Children, HIV/TB and Drug Resistant TB
• Communicable Diseases Module: 17. Tuberculosis Infection Control
• Communicable Diseases Module: 18. Leprosy Diagnosis
• Communicable Diseases Module: 19. Leprosy Treatment
• Communicable Diseases Module: 20. Introduction to HIV/AIDS
• Communicable Diseases Module: 21. Opportunistic Infections and WHO HIV Clinical Staging
• Communicable Diseases Module: 22. Introduction to Antiretroviral Therapy
• Communicable Diseases Module: 23. Adherence to HIV Care and Treatment
• Communicable Diseases Module: 24. Provider-Initiated HIV Testing and Counselling
• Communicable Diseases Module: 25. Prevention of HIV Infection, and Community Mobilisation
• Communicable Diseases Module: 26. Universal Precautions, Infection Prevention and Post-Exposure Prophylaxis for Health Workers
• Communicable Diseases Module: 27. Prevention of Mother-to-Child Transmission of HIV
• Communicable Diseases Module: 28. HIV in Children
• Communicable Diseases Module: 29. Positive Living and Prevention of HIV Transmission for PLHIV
• Communicable Diseases Module: 30. Providing Palliative Care for People Living with HIV
• Communicable Diseases Module: 31. Prevention and Control of Sexually Transmitted Infections
• Communicable Diseases Module: 32. General Features of Faeco-Orally Transmitted Diseases
• Communicable Diseases Module: 33. Bacterial and Viral Faeco-Oral Diseases
• Communicable Diseases Module: 34. Intestinal Protozoa, Ascariasis and Hookworm
• Communicable Diseases Module: 35. Acute Respiratory Tract Infections
• Communicable Diseases Module: 36. Louse-Borne Diseases: Relapsing Fever and Typhus
• Communicable Diseases Module: 37. Other Vector-Borne Diseases of Public Health Importance
• Communicable Diseases Module: 38. Common Zoonotic Diseases in Ethiopia: Rabies and Taeniasis
• Communicable Diseases Module: 39. Diseases of Poor Hygiene and Environmental Health: Trachoma, Scabies and Podoconiosis
• Communicable Diseases Module: 40. General Principles of Public Health Surveillance
• Communicable Diseases Module: 41. Integrated Disease Surveillance and Response
• Communicable Diseases Module: 42. Epidemic Investigation and Management
• Download PDF versions
• Communicable Diseases Part 1 PDF (3.8MB)
• Communicable Diseases Part 2 PDF (2.1MB)
• Communicable Diseases Part 3 PDF (3.3MB)
• Communicable Diseases Part 4 PDF (2MB)

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• 84 hours study
• 1 Level 1: Introductory
• Course description

Communicable Diseases

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Now that you have completed this study session, you can assess how well you have achieved its Learning Outcomes by answering these questions. Write your answers in your Study Diary and discuss them with your Tutor at the next Study Support Meeting. You can check your answers with the Notes on the Self-Assessment Questions at the end of this Module.

SAQ 8.1 (tests Learning Outcomes 8.1 and 8.3)

Which of the following statements about supportive treatment is false ? In each case, state why it is incorrect.

A  Supportive treatment is given to kill the malaria parasites in the blood circulation of the patient.

B  Malaria patients with high grade fever should be given supportive treatment.

C  Patients with moderate dehydration have to be immediately referred to a health centre without giving any supportive treatment.

D  No supportive treatment is required for women with malaria, with normal temperature, who can breastfeed very well and with no anaemia.

E  If the malaria patient has moderate anaemia, then treat with ferrous sulphate (iron tablets).

A is false . Supportive treatment is what is given to treat other conditions at the same time as the malaria treatment. It is not the supportive treatment that kills the parasites; rather it is the anti-malaria drugs that you give to the patient that kills the parasites in the blood circulation.

B is true. Malaria patients with high grade fever should be given supportive treatment such as paracetamol tablets, or cooling the body of the patient with clean pieces of cloth dipped in slightly warm water, or by fanning.

C is false . Malaria patients with moderate dehydration should be given oral rehydration salts (ORS) as supportive treatment. The patient should also be advised to drink increased amounts of clean water or other fluids.

D is true. If the temperature is normal, there is no sign of dehydration and no anaemia, you do not need to give supportive treatment to a malaria patient even if she is breastfeeding. Just treat the malaria.

E is true. Malaria patients with mild or moderate anaemia should be treated with ferrous sulphate (iron tablets) 200 mg once daily for two months, and advised to return for recheck in two months.

SAQ 8.2 (tests Learning Outcomes 8.2 and 8.3)

What anti-malaria drug would you give a patient with a clinical diagnosis of uncomplicated malaria, if you cannot do an RDT? How many times a day does the patient take this drug?

If you diagnose malaria clinically (if there is no RDT) you give the patient Coartem, unless the patient is a pregnant woman in the first trimester, or an infant under 5 kg or under four months (they get quinine tablets instead).

Coartem is given two times a day (in the morning and in the evening) for three days. The first dose is given in front of you immediately after the diagnosis of malaria. The rest of the drug is given to the patient/caregivers to take at home.

SAQ 8.3 (tests Learning Outcome 8.4)

Molamo is a 15 year-old boy who came to your Health Post. You diagnosed him with malaria and gave him Coartem. He took the medicine correctly as you ordered. Three days after his first visit he came back to your Health Post with no improvement of the fever. Describe the actions that you have to take.

Give pre-referral treatment to Malomo (one 50 mg rectal suppository of Artesunate — see Table 8.4) and immediately refer him to the nearest health centre.

SAQ 8.4 (tests Learning Outcomes 8.2 and 8.4)

Describe what you would do if you found that a patient who came to your Health Post is a suspected severe malaria case?

Severe malaria should be referred to the health centre very fast. Before referring the patient it is important to give a pre-referral treatment with rectal Artesunate (or intramuscular injection of Artemether, if available). This will help to prevent the patient’s condition from getting worse.

SAQ 8.5 (tests Learning Outcome 8.5)

What could happen if a malaria patient does not take the full course of treatment or does not adhere to the treatment?

If the patient does not adhere to the treatment he or she will not get cured completely and the disease will come back. It also leads to the development of resistance to the drug by the malaria parasites.

Read Case Study 8.1 about Beka and answer the questions that follow it.

Case Study 8.1  Is Beka sick with malaria?

Beka is a five-year-old boy. His mother brought him to you to seek treatment. Beka and his family are living in your catchment area, which is malarious. The mother says he was well until this morning when he woke up and said he was feeling tired and refused his breakfast. When the mother touched him, he felt hot and she gave him ½ a tablet of paracetamol.

When you examined Beka, you found a well-nourished 15-kg child, not pale, alert and with temperature of 38.5°C measured with the thermometer under his armpit. You could not do a RDT because you used the last kit two days ago. In the rest of the examination, Beka is normal.

SAQ 8.6 (tests Learning Outcomes 8.2, 8.3, 8.4 and 8.5)

• a. What is your diagnosis?
• b. What treatment will you give Beka? And what dose?
• c. What will you tell his mother?
• a. Uncomplicated malaria is the diagnosis you should give to Beka.
• b. Coartem is the correct treatment for a child of five years. The full dose is 12 tablets. Beka takes two tablets in the morning and two tablets in the evening for three days. You give two tablets to swallow immediately and give the remaining 10 tablets to Beka’s mother to take home.
• Tell her the reason for giving the drug.
• Demonstrate to her on how to give the correct dose.
• Tell her to watch while Beka is taking each dose of the drug.
• Explain that the drugs must be finished even if Beka feels well.
• Advise her on when to return if Beka does not improve.

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• How It Spreads
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• Malaria Surveillance & Case Investigation Best Practices
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Malaria Surveillance & Case Investigation Best Practices

At a glance.

The information in this section provides best practices for health departments to consider as part of their usual activities to investigate malaria cases. It includes case definitions, classifying disease acquisition, laboratory confirmation information, case investigation and patient interview recommendations, and more. There is also a list of various resources to assist in these efforts.

Malaria is a serious disease caused by a parasite that infects the Anopheles mosquito. You get malaria when bitten by an infective mosquito.

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• Globally in 2022, there were an estimated 249 million malaria cases and 608 000 malaria deaths in 85 countries.
• The WHO African Region carries a disproportionately high share of the global malaria burden.
• In 2022, the Region was home to 94% of malaria cases (233 million) and 95% (580 000) of malaria deaths.
• Children under 5 accounted for about 80% of all malaria deaths in the Region.

Malaria is a life-threatening disease spread to humans by some types of mosquitoes. It is mostly found in tropical countries. It is preventable and curable.

The infection is caused by a parasite and does not spread from person to person.

Symptoms can be mild or life-threatening. Mild symptoms are fever, chills and headache. Severe symptoms include fatigue, confusion, seizures, and difficulty breathing.

Infants, children under 5 years, pregnant women, travellers and people with HIV or AIDS are at higher risk of severe infection. 

Malaria can be prevented by avoiding mosquito bites and with medicines. Treatments can stop mild cases from getting worse.

Malaria mostly spreads to people through the bites of some infected female  Anopheles  mosquitoes. Blood transfusion and contaminated needles may also transmit malaria. The first symptoms may be mild, similar to many febrile illnesses, and difficulty to recognize as malaria. Left untreated, P. falciparum  malaria can progress to severe illness and death within 24 hours.

There are 5 Plasmodium parasite species that cause malaria in humans and 2 of these species –  P. falciparum  and  P. vivax  – pose the greatest threat. P. falciparum is the deadliest malaria parasite and the most prevalent on the African continent. P. vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa. The other malaria species which can infect humans are P. malariae, P. ovale and P. knowlesi .

The most common early symptoms of malaria are fever, headache and chills.

Symptoms usually start within 10–15 days of getting bitten by an infected mosquito.

Symptoms may be mild for some people, especially for those who have had a malaria infection before. Because some malaria symptoms are not specific, getting tested early is important. 

Some types of malaria can cause severe illness and death. Infants, children under 5 years, pregnant women, travellers and people with HIV or AIDS are at higher risk. Severe symptoms include:

• extreme tiredness and fatigue 
• impaired consciousness
• multiple convulsions
• difficulty breathing
• dark or bloody urine
• jaundice (yellowing of the eyes and skin) 
• abnormal bleeding.

People with severe symptoms should get emergency care right away. Getting treatment early for mild malaria can stop the infection from becoming severe. 

Malaria infection during pregnancy can also cause premature delivery or delivery of a baby with low birth weight.

Disease burden

According to the latest  World malaria report , there were 249 million cases of malaria in 2022 compared to 244 million cases in 2021. The estimated number of malaria deaths stood at 608 000 in 2022 compared to 610 000 in 2021.

The WHO African Region continues to carry a disproportionately high share of the global malaria burden. In 2022 the Region was home to about 94% of all malaria cases and 95% of deaths. Children under 5 years of age accounted for about 78% of all malaria deaths in the Region.

Malaria can be prevented by avoiding mosquito bites and by taking medicines. Talk to a doctor about taking medicines such as chemoprophylaxis before travelling to areas where malaria is common.

Lower the risk of getting malaria by avoiding mosquito bites:  

• Use mosquito nets when sleeping in places where malaria is present
• Use mosquito repellents (containing DEET, IR3535 or Icaridin) after dusk
• Use coils and vaporizers.
• Wear protective clothing.
• Use window screens.

Vector control

Vector control is a vital component of malaria control and elimination strategies as it is highly effective in preventing infection and reducing disease transmission. The 2 core interventions are insecticide-treated nets (ITNs) and indoor residual spraying (IRS).

Progress in global malaria control is threatened by emerging resistance to insecticides among  Anopheles  mosquitoes. As described in the latest World malaria report , other threats to ITNs include insufficient access, loss of nets due to the stresses of day-to-day life outpacing replacement, and changing behaviour of mosquitoes, which appear to be biting early before people go to bed and resting outdoors, thereby evading exposure to insecticides.

Chemoprophylaxis

Travellers to malaria endemic areas should consult their doctor several weeks before departure. The medical professional will determine which chemoprophylaxis drugs are appropriate for the country of destination. In some cases, chemoprophylaxis drugs must be started 2–3 weeks before departure. All prophylactic drugs should be taken on schedule for the duration of the stay in the malaria risk area and should be continued for 4 weeks after the last possible exposure to infection since parasites may still emerge from the liver during this period.

Preventive chemotherapies

Preventive chemotherapy  is the use of medicines, either alone or in combination, to prevent malaria infections and their consequences. It requires giving a full treatment course of an antimalarial medicine to vulnerable populations at designated time points during the period of greatest malarial risk, regardless of whether the recipients are infected with malaria.

Preventive chemotherapy includes perennial malaria chemoprevention (PMC), seasonal malaria chemoprevention (SMC), intermittent preventive treatment of malaria in pregnancy (IPTp) and school-aged children (IPTsc), post-discharge malaria chemoprevention (PDMC) and mass drug administration (MDA). These safe and cost-effective strategies are intended to complement ongoing malaria control activities, including vector control measures, prompt diagnosis of suspected malaria, and treatment of confirmed cases with antimalarial medicines.

Since October 2021, WHO has recommended broad use of the RTS,S/AS01 malaria vaccine among children living in regions with moderate to high  P. falciparum  malaria transmission. The vaccine has been shown to significantly reduce malaria, and deadly severe malaria, among young children. In October 2023, WHO recommended a second safe and effective malaria vaccine, R21/Matrix-M. The availability of two malaria vaccines is expected to make broad-scale deployment across Africa possible. 

Questions and answers on the RTS,S vaccine .

Early diagnosis and treatment of malaria reduces disease, prevents deaths and contributes to reducing transmission. WHO recommends that all suspected cases of malaria be confirmed using parasite-based diagnostic testing (through either microscopy or a rapid diagnostic test).

Malaria is a serious infection and always requires treatment with medicine.

Multiple medicines are used to prevent and treat malaria. Doctors will choose one or more based on: 

• the type of malaria 
• whether a malaria parasite is resistant to a medicine
• the weight or age of the person infected with malaria 
• whether the person is pregnant.

These are the most common medicines for malaria:

• Artemisinin-based combination therapy medicines are the most effective treatment for P. falciparum malaria.
• Chloroquine is recommended for treatment of infection with the  P. vivax  parasite only in places where it is still sensitive to this medicine.
• Primaquine should be added to the main treatment to prevent relapses of infection with the  P. vivax  and  P. ovale  parasites. 

Most medicines used are in pill form. Some people may need to go to a health centre or hospital for injectable medicines.

Antimalarial drug resistance

Over the last decade, partial artemisinin resistance has emerged as a threat to global malaria control efforts in the Greater Mekong subregion. WHO is very concerned about reports of partial artemisinin resistance in Africa, confirmed in Eritrea, Rwanda, Uganda and, most recently, Tanzania. Regular monitoring of antimalarial drug efficacy is needed to inform treatment policies in malaria-endemic countries, and to ensure early detection of, and response to, drug resistance.

For more on WHO’s work on antimalarial drug resistance in the Greater Mekong subregion, visit the Mekong Malaria Elimination Programme webpage. WHO has also developed a strategy to address drug resistance in Africa .

Elimination

Malaria elimination is defined as the interruption of local transmission of a specified malaria parasite species in a defined geographical area as a result of deliberate activities. Continued measures to prevent re-establishment of transmission are required.

In 2022, 34 countries reported fewer than 1000 indigenous cases of the disease, up from just 13 countries in 2000. Countries that have achieved at least 3 consecutive years of zero indigenous cases of malaria are eligible to apply for the  WHO certification of malaria elimination . Since 2015, 12 countries have been certified by the WHO Director-General as malaria-free, including Maldives (2015), Sri Lanka (2016), Kyrgyzstan (2016), Paraguay (2018), Uzbekistan (2018), Argentina (2019), Algeria (2019), China (2021), El Salvador (2021), Azerbaijan (2023), Tajikistan (2023) and Belize (2023).

Countries and territories certified malaria-free by WHO .

Malaria surveillance is the continuous and systematic collection, analysis and interpretation of malaria-related data, and the use of that data in the planning, implementation and evaluation of public health practice. Improved surveillance of malaria cases and deaths helps ministries of health determine which areas or population groups are most affected and enables countries to monitor changing disease patterns. Strong malaria surveillance systems also help countries design effective health interventions and evaluate the impact of their malaria control programmes.

WHO response

The WHO  Global technical strategy for malaria 2016–2030 , updated in 2021, provides a technical framework for all malaria-endemic countries. It is intended to guide and support regional and country programmes as they work towards malaria control and elimination.

The strategy sets ambitious but achievable global targets, including:

• reducing malaria case incidence by at least 90% by 2030
• reducing malaria mortality rates by at least 90% by 2030
• eliminating malaria in at least 35 countries by 2030
• preventing a resurgence of malaria in all countries that are malaria-free.

Guided by this strategy, the Global Malaria Programme  coordinates the WHO’s global efforts to control and eliminate malaria by:

• playing a leadership role in malaria, effectively supporting member states and rallying partners to reach Universal Health Coverage and achieve goals and targets of the Global Technical Strategy for Malaria;
• shaping the research agenda and promoting the generation of evidence to support global guidance for new tools and strategies to achieve impact;
• developing ethical and evidence based global guidance on malaria with effective dissemination to support adoption and implementation by national malaria programmes and other relevant stakeholders; and
• monitoring and responding to global malaria trends and threats.
• World malaria report 2023
• Global technical strategy for malaria 2016–2030, 2021 update
• A framework for malaria elimination
• WHO guidelines for malaria
• World Malaria Day 2024
• Malaria health topic page
• World Malaria Day (25 April)
• WHO Global Malaria Programme (GMP)
• Malaria Policy Advisory Group

Pulmonology (previously Revista Portuguesa de Pneumologia) is the official journal of the Portuguese Society of Pulmonology (Sociedade Portuguesa de Pneumologia/SPP). The journal publishes 6 issues per year, mainly about respiratory system diseases in adults and clinical research. This work can range from peer-reviewed original articles to review articles, editorials, and opinion articles. The journal is printed in English, and is freely available in its web page as well as in Medline and other databases.

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The Impact Factor measures the average number of citations received in a particular year by papers published in the journal during the two preceding years. © Clarivate Analytics, Journal Citation Reports 2022

CiteScore measures average citations received per document published.

SRJ is a prestige metric based on the idea that not all citations are the same. SJR uses a similar algorithm as the Google page rank; it provides a quantitative and qualitative measure of the journal's impact.

SNIP measures contextual citation impact by wighting citations based on the total number of citations in a subject field.

• Palavras-chave
• Introduction
• Case report
• Discussion and conclusions

We report a clinical case of severe malaria, where the rate of initial parasitaemia by Plasmodium falciparum was 43 %.

Multiple organ dysfunction, including ARDS, forced admission in a close surveillance unit, with survival of the same.

A brief review of the subject is made, focusing on severity and general conduct, alerting and awareness for this entity, whose expression, among us, could take on increasing importance.

Apresenta-se o caso clínico de um doente regressado de Angola com malária grave, em que o índice de parasitémia inicial pelo P. falciparum era de 43 %.

Disfunção múltipla de orgãos, incluindo ARDS, implicaram o ingresso do doente numa unidade de alta vigilância, com sobrevivência do mesmo.

Faz-se uma breve revisão do assunto, com enfoque nos indicadores de gravidade e na conduta geral, alertando e sensibilizando para esta entidade, cuja expressão, entre nós, poderá vir a assumir importância crescente.

Malaria is caused by the protozoa Plasmodium , 1 with an intra and extra erythrocyte life cycle, and man is infected by the bite of the anopheles mosquito. There are four species responsible for human malaria: Plasmodium falciparum, P. vivax, P. ovale and P. malariae.

Most cases of imported malaria are caused by P. falciparum. It is characterized by fever, chills, intense sweating and headaches, that arise between the 9 th and 14 th days after bite. Incubation can last for months.

With postponed diagnosis erythrocyte parasitemia may reach critical values, massive hemolysis and multiorgan dysfunction resulting in death.

The pulmonary involvement with edema is a major complication. 2 More common in adults, is more severe in pregnant and non-immunized individuals. 3 The alveolar-capillary barrier suffers increased permeability and alveolar flooding, conditioning acute lung injury/acute respiratory distress syndrome (ARDS). 4

Man, 44 year old, black, born in Angola and resident in Portugal for 24 years, where he works in building construction.

Medical and surgical history irrelevant. Denies alcohol or smoking habits, illicit drug use or sexual risk contacts. He had returned from Angola two weeks ago from his first trip there, without taking any precaution.

He recurs to the emergency room with fever (40 ºC) and general malaise of a week duration, and watery stools since the last three days.

He presented with a reasonable general condition, dry mucous membranes and icteric sclerae. A hypotensive and tachycardic profile was noted, while being apyretic with good peripheral saturations on ambient air.

No obvious focus of infection was detected and the rest of the objective examination was irrelevant.

Initial laboratory parameters was as follow: hemoglobin 11.9 g/dL, WBC 7,200/μL, platelets 27,000/μL; normal ionogram and renal function, mild liver cytolysis without hyperbilirubinemia, LDH 693 U/L, C-reactive protein (CRP) 228.9 mg/dL. Positive thick smear for Plasmodium with 43 % of parasitemia ( Fig. 1 ).

Picture of the patient's peripheral blood smear showing a very high level of parasitemia with images of trophozoites and merozoites, as well as significant schizocytes. There were no gametocytes and therefore cannot be seen here.

Therapy was started with quinine sulfate and doxycycline.

Infection with hepatotropic virus, HIV I/II, intestinal parasites, urinary tract infection, bacterial gastroenteritis or bacteraemia was excluded. The chest radiograph shows no abnormality.

On the 3 rd hospital day (D3), the patient became more obtunded, pale, dehydrated, and more icteric with profuse sweating, fever, tachypnea and hemodynamic instability. On pulmonary auscultation there was new bilateral inspiratory crackles.

Hemoglobin fall to 6.8 g/dL accompanied by hyperbilirubinemia, LDH = 801 U/L, haptoglobin mg/dL, thrombocytopenia (37,000/μL), creatinine 1.7 mg/dL and mild hyponatremia. The CRP remained high and procalcitonin reached 42.6 mg/dL. Plasmodium on direct examination was negative. The characterization of the agent trough the BinaxNOW® test showed a single antigen band for P. falciparum.

The patient was admitted to a High-Dependency Unit (HDU), with multiple dysfunctions, including cardiovascular, hematological, renal, hepatic and respiratory systems (PaO 2 /FiO 2 = 129) with criteria for ARDS ( Fig. 2 ). After attempts was made to exclude secondary septic complications, to the general support measures, which included liberal fluids infusion and transfusion of packed red blood cells, an empiric antimicrobial coverage with linezolid plus piperacillin/tazobactam was instituted.

Chest anteroposterior teleradiography of the 5 th day, on the left, and of the 10 th day of hospitalization, on the right.

By D7 the clinical situation allowed us to continue treatment in the general ward. On D8, a clear improvement on radiological findings and gas exchange was noted. The microbiological screening remained negative, and so, we proceed therapy with only quinine sulfate.

By D11 hemoglobin was 9.2 g/dL, with no leukocytosis or thrombocytopenia, and renal function, bilirubin and CRP normalized or continued to improve. Plasmodium on ticks mear remained negative. Abdominal ultrasound excluded pathologic findings.

The patient lived the hospital with a good general condition, with permanent apyrexia and without need for oxygen supply. On a subsequent ambulatory revision, a completely normal clinical status was verified.

Malaria presentation is very unspecific so alternative and more frequent diagnoses should be excluded, such as severe pneumonia, meningitis, hemorrhagic fevers, salmonellosis, viral hepatitis and dengue. Fever is common and should be treated with paracetamol, to minimize bleeding diathesis. It responds poorly to antipyretics and physical measures can be necessary.

Imported malaria, in the beginning rarely follows the classical pattern of tertian or quartan fever, which appears only after a few cycles when synchronization occurs. Additional symptoms include chills, headache, malaise, nausea, vomiting, diarrhea, abdominal pain and myalgia. Splenomegaly is an inconstant finding. In practice, malaria should be suspected in any febrile individual returning from tropics, especially if coexisting anemia, thrombocytopenia or cytolysis.

10 % of all cases have a malignant evolution. These are mostly induced by P. falciparum and may follow a explosive course with 50 % of deaths occurring in the first 24 hours. 5

Diagnosis is made by direct demonstration of parasites in blood. Parasitaemia should be determined initially, at D3, D7 and D28, to assess severity, therapy monitoring and late failures detection. 6

Agent detection can imply repeating tests at 12 h intervals, but is generally accepted treating patients empirically if suspicion remains high.

Malaria is a paradigmatic example where the early therapy and intensive monitoring brings benefits.

ARDS is defined by acute onset of bilateral pulmonary infiltrates in the absence of heart failure and a PaO 2 /FiO 2 ≤ 200 mmHg.

The absence jugular engorgement, hepatojugular reflux, peripheral edema and the typical “butterfly” infiltrates and cephalic pulmonary blood redistribution on chest x-ray, don't support cardiogenic edema. These parameters helped us to guide the fluids supplementation, without jeopardize gas exchange. However, alveolar-capillary damage really favors pulmonary edema formation.

Non-cardiogenic pulmonary edema rarely occurs with other species then P. falciparum.

Quinine sulfate is the drug of choice for severe malária, but caution should be taken in those patients with a family history of sudden death or long QT by its intrinsic arrhythmogenicity. Glocunato form is even more pro-arrhythmic.

Severe and recurrent hypoglycemia can result from hyperinsulinism induced by quinine/quinidine, malarious toxins or massive parasitism.

Renal failure, usually oliguric, rarely requires dialysis support and reverses in days.

Thrombocytopenia is common, but rarely contributes to hemorrhagic diathesis. Anemia is induced by parasitic hemolysis.

The fever increases during the first two days but should disappear after 48 hours of treatment.

The efficacy of treatment must be verified by microscopic examination of the blade. The degree of parasitaemia decreases 90 % in 48 hours and must be zero at D3.

The actual case illustrates the counsequencies of preventive measures failure, such as chemoprophylaxis.

If a parasitaemia score of 5 % reflects severity, the 43 % presented by out promised a complicated evolution, as was the case with the installation of successive failures that culminated in ARDS.

The inability to microscopically characterize the type of Plasmodium, do limited therapy institution. Results of the BinaxNOW® test, showing a single band for P. falciparum antigen, comes later. Genomic identification by polymerase chain reaction (PCR) is another available mean to identify the Plasmodium.

Compared with PCR, BinaxNOW® test showed a sensitivity of 94 % for detection of P falciparum and 84 % for other species, with overall specificity of 99 %.(7,8)

Multiorgan dysfunction, led us to admit secondary sepsis superposed on malaria, influencing the strategy.

Despite severity of the condition and the limited clinical experience, admission to a HDU capable of monitoring and early warning to complications, associated with elected conduct, proved critical to reverse the various dysfunctions, allowing the avoidance of mechanical ventilation.

Although relatively rare in Portugal, the clinical picture of malaria tends to change with progressive flow of people between countries with multiple affinities, as is the case of Portugal with African ex-colonies.

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Are you a health professional able to prescribe or dispense drugs?

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• Published: 10 September 2024

CUREMA project: a further step towards malaria elimination among hard-to-reach and mobile populations

• Alice Sanna 1 ,
• Yann Lambert 1 ,
• Irene Jimeno Maroto 1 ,
• Muriel Suzanne Galindo 1 ,
• Lorraine Plessis 1 ,
• Teddy Bardon 1 ,
• Carlotta Carboni 1 ,
• Jane Bordalo 2 ,
• Helene Hiwat 3 ,
• Hedley Cairo 3 ,
• Lise Musset 4 ,
• Yassamine Lazrek 4 ,
• Stéphane Pelleau 5 ,
• Michael White 5 ,
• Martha Suárez Mutis 6 ,
• Stephen Vreden 7 &
• Maylis Douine 1  

Malaria Journal volume  23 , Article number:  271 ( 2024 ) Cite this article

Metrics details

In most countries engaged on the last mile towards malaria elimination, residual transmission mainly persists among vulnerable populations represented by isolated and mobile (often cross-border) communities. These populations are sometimes involved in informal or even illegal activities. In regions with Plasmodium vivax transmission, the specific biology of this parasite poses additional difficulties related to the need for a radical treatment against hypnozoites to prevent relapses. Among hard-to-reach communities, case management, a pillar of elimination strategy, is deficient: acute malaria attacks often occur in remote areas, where there is limited access to care, and drugs acquired outside formal healthcare are often inadequately used for treatment, which typically does not include radical treatment against P. vivax . For these reasons, P. vivax circulation among these communities represents one of the main challenges for malaria elimination in many non-African countries. The objective of this article is to describe the protocol of the CUREMA study, which aims to meet the challenge of targeting malaria in hard-to-reach populations with a focus on P. vivax .

CUREMA is a multi-centre, international public health intervention research project. The study population is represented by persons involved in artisanal and small-scale gold mining who are active and mobile in the Guiana Shield, deep inside the Amazon Forest. The CUREMA project includes a complex intervention composed of a package of actions: (1) health education activities; (2) targeted administration of treatment against P. vivax after screening against G6PD deficiency to asymptomatic persons considered at risk of silently carrying the parasite; (3) distribution of a self-testing and self-treatment kit (malakit) associated with user training for self-management of malaria symptoms occurring while in extreme isolation. These actions are offered by community health workers at settlements and neighbourhoods (often cross-border) that represent transit and logistic bases of gold miners. The study relies on hybrid design, aiming to evaluate both the effectiveness of the intervention on malaria transmission with a pre/post quasi-experimental design, and its implementation with a mixed methods approach.

Conclusions

The purpose of this study is to experiment an intervention that addresses both Plasmodium falciparum and P. vivax malaria elimination in a mobile and isolated population and to produce results that can be transferred to many contexts facing the same challenges around the world.

In 2022, the worldwide number of malaria cases was estimated at 249 million, causing approximately 608000 deaths [ 1 ]. While global scaling-up of malaria control interventions led to apparent decrease between 2000 and 2015, the main indicators of morbidity and mortality remained broadly stable between 2015 and 2020, and even increased after the Covid-19 pandemic. This suggests that the limits of current strategies have been reached and that new methods need to be developed, both in terms of technology and of operational approaches, to achieve the target 90% reduction of malaria morbidity and mortality by 2030, as set by WHO Global malaria technical Strategy [ 2 ].

Plasmodium vivax is the second malaria parasite species by order of incidence on a global scale, with an estimated 6.9 million cases per year in the World [ 1 ]. It is currently responsible for two thirds of malaria cases in the Americas, with up to 80% relapses [ 3 ]. The only means of prevention of relapses is a radical pharmacological treatment by a cure of 8-aminoquinoline drugs (primaquine for 7 or 14 days or, recently, a single-dose of tafenoquine) [ 4 , 5 , 6 ]. Testing for G6PD deficiency (a red blood cell hereditary condition) is recommended before administering this radical treatment, in order to avoid serious adverse reactions such as haemolysis [ 5 ]. No direct diagnostic test is available to detect P. vivax hypnozoites carriage, meaning that it is impossible to identify a latent infection when blood-stage parasites are no longer detectable [ 7 ]. For all these reasons, territories endemic for P. vivax usually struggle with access to radical treatment for all affected individuals [ 8 ].

In territories progressing toward malaria elimination, a typical transition in epidemiology is often observed: spatial heterogeneity becomes more marked, the proportion of cases caused by P. vivax more important, and adult males become the most affected sub-population [ 9 , 10 , 11 ]. Spatial strata characterized by more intense transmission combine favourable environmental characteristics (including recent anthropization of natural environments), geographic isolation, human mobility (particularly in cross border contexts), and often occupational and socio-economic and/or political vulnerability [ 9 , 10 , 12 , 13 , 14 ]. Indeed, among mobile and isolated populations, case management, is often deficient: attacks often occur in remote areas with no access to care and treatment is often inadequate with smuggled drugs, usually not including P. vivax anti-hypnozoite treatment [ 15 , 16 ]. These individuals might be asymptomatic carriers of Plasmodium, due to acquired partial immunity [ 17 , 18 , 19 ] and thus contribute to sustaining transmission in remote rural or forested areas, but also in urban and peri-urban settings through continuous spillover [ 20 , 21 , 22 , 23 , 24 ]. In this light, populations living in remote areas represent hotspots of P. vivax transmission, and Plasmodium clearance among mobile and isolated groups is the ultimate challenge for malaria elimination in many low and medium transmission settings [ 9 ]. Plasmodium vivax patients should be rationally treated with radical therapy; irrational drug use, such as with smuggled drugs is discouraged.

In the Amazon region, persons involved in artisanal and small-scale gold mining (ASGM) are a typical hard-to-reach population [ 25 ]. They live and work for weeks or months deep in the rainforest, where the density of malaria vectors ( Anopheles spp.) is high [ 20 , 25 , 26 ] . As they are often involved in informal or illegal mining, national health systems may be unable to implement specific interventions to reach them, due to unfavourable regulations or an unsupportive political environment. These miners regularly move to other areas in search of more productive sites, or for logistical or personal reasons. Gold mining areas are often characterized by high malaria endemicity, and miners can fuel malaria reintroduction in low burden areas [ 25 , 27 , 28 , 29 , 30 ]. Their mobility is often cross-border or transnational in the Amazon region, making it a complex challenge to individual as well as public health management [ 25 , 28 , 31 ].

French Guiana (FG) is the only territory in the European Union where indigenous transmission of malaria is currently ongoing. It is located within the Guiana Shield and shares land borders with Brazil (Amapá State) and Suriname [ 32 , 33 ]. FG, Amapá State and Suriname share a common decreasing malaria incidence, a predominance of P. vivax and transmission mainly concentrated in gold mining areas and in some cases in remote indigenous communities [ 32 , 34 , 35 ]. In this region, persons involved in ASGM ( garimpeiros) are mainly of Brazilian origin, and are highly mobile across the Guiana Shield [ 25 , 28 , 31 , 36 , 37 ]. The World Health Organization (WHO) included Suriname and FG among the territories that could defeat malaria by 2025 (E-2025 initiative) [ 1 ].

A first public health intervention research project, Malakit, was implemented from 2018 to 2020 at the borders between FG and Brazil and Suriname to address access to malaria diagnostic testing and good quality treatment for persons working in remote and illegal mines in FG [ 20 , 36 , 38 , 39 ]. The project’s intervention consisted in making available a kit, including malaria rapid diagnostic tests (RDTs) and an artemisinin-based combination therapy (ACT), as well as a training on how to correctly self-test and self-treat delivered at the garimpeiros ’ cross-border staging areas by community health workers (CHWs). This study, evaluating an innovative intervention, has constituted an urgent and pragmatic response to the risk of emergence of resistant P. falciparum linked to inappropriate use of smuggled ACT doses among the target population [ 15 , 40 , 41 ]. The project’s strategy showed to be successful: the proportion of garimpeiros reporting proper treatment with an ACT after a positive RDT significantly increased (OR = 1.8 95% CI [1.1–3.0]) [ 39 ]. Mathematical modelling estimates that the Malakit project helped prevent 43% of the cases imported from FG to Brazil and Suriname [ 39 , 42 ]. However, the Malakit intervention does not offer a solution to prevent P. vivax relapses: while the overall malaria prevalence and incidence decreased, the proportion of P. vivax infection among the target population increased after the intervention (from 42 to 85% among persons recruited at the FG-Suriname border, and from 85.7% to 100% at the FG-Brazil border) [ 39 ].

Recently, several tools have joined the arsenal against P. vivax malaria . Tafenoquine has been approved for P. vivax radical cure by health authorities from an increasing number of endemic countries [ 43 ]. This drug has stricter contraindications because of its long half-life and a higher haemolytic risk in case of G6PD deficiency [ 44 , 45 ], but its use at a single-dose presents an important advantage compared to primaquine, which is subject to sub-optimal adherence even with a short 7 day regimen [ 46 , 47 ]. A recent point-of-care device for quantitative evaluation of G6PD activity [ 48 , 49 , 50 ] has performed very well in identifying severe and intermediate G6PD deficiency compared to the gold standard. It has been successfully tested in the field in Asian countries [ 51 , 52 , 53 ] and in Brazil [ 54 , 55 , 56 ], and allows for field implementation of tafenoquine treatment. The roll out of this innovative technology in the routine of health care services is currently being planned and implemented in the territories of the Guiana Shield.

Considering the evolution of the malaria epidemiology with a predominance of P. vivax among garimpeiros , the importance to tailor specific strategies to reach this population, and the availability of new tools for P. vivax radical cure, a new interventional project called CUREMA ( Radical CURE for MAlaria among highly mobile and hard-to-reach populations in the Guiana Shield ) has been designed. The aim of this project is to evaluate an intervention targeting malaria elimination ( P. falciparum and P. vivax ) among the persons working in ASGM in the Region.

This article presents the protocol of the CUREMA project.

The CUREMA project is a mixed-methods interventional, multicentric, international study.

It aims at evaluating a new public health intervention targeting malaria among hard-to-reach and mobile populations [ 57 ]. The main objectives of the project are:

To evaluate the impact of the intervention on malaria transmission among persons involved in ASGM in the Guiana Shield.

To evaluate the implementation of the intervention and to identify obstacles and levers to inform on transferability and scaling-up.

Intervention’s target population

The target population of the intervention is represented by people actively involved in ASGM in the Region. Active participation in gold mining is defined as having worked in a gold mine in the last 12 months, or planning to enter a gold mine in the next month. As described in previous publications [ 20 , 36 , 38 ] the population is predominantly male (around three quarters), adult, and is involved in a variety of activities: the various aspects of metal extraction and site management, support services, such as cooking, sales (through small grocery stores or as mobile vendors), transport of people or goods (by river or land, with portage or ATVs), mechanics, wood removal for site structures, and sex work.

Criteria for participation in the study are summarized in Table  1 .

Study settings

The study is carried out in Suriname and Brazil (Amapá State). The study’s facilities and inclusion sites are mainly located at cross-border points (towns or small informal settlements located on the riverbanks) along the two river borders of FG, considered crossing points and logistics hubs for the target population, where can be found shops, bars and accommodation facilities mainly receiving garimpeiros . These are “neutral” places where the public is easy to meet and not in a clandestine situation. They are illustrated in Fig.  1 .

Map illustrating the study locations (red dots) and the respective project’s field teams

CUREMA intervention and its implementation strategy

Intervention.

The CUREMA intervention is a package of actions including three components: two different services offered to participants, with a common core component of health education.

The health education activities focus on malaria: its causes, means of prevention, the main differences between P. falciparum and P. vivax , and the importance of a complete anti-malarial treatment. It is provided to participants as part of the inclusion process in the study, and to the community during out-reach activities.

Each participant, after collection of written and informed consent, is able to choose whether to participate in one or both services: the “radical cure” and the “malakit”. During the inclusion process (Fig.  2 ), the participants answer a short questionnaire designed (1) to collect socio-demographic and occupational data, and (2) to assess eligibility criteria to the service(s) selected by the participants.

Inclusion process for the CUREMA intervention

The “radical cure” represented by the treatment of asymptomatic individuals considered at risk of carrying P. vivax hypnozoites. The objective of this service is to prevent relapses and thus to reduce further transmission of this parasite.

Individuals considered at risk of carrying P. vivax are identified through questions from the inclusion questionnaire, regarding their recent exposure to malaria. Contra-indications to radical cure are also documented within the questionnaire (breastfeeding, history of allergy or other side effect to 8-aminoquinoline or chloroquine, severe mental health disorders history) and point-of-care tests: quantitative assessment of G6PD activity level performed with capillary blood through STANDARD G6PD tests from SD Biosensor performed by CHWs, and urine pregnancy test for women of childbearing age.

Eligible participants receive a three-day course of chloroquine associated to an 8-aminoquinoline drug (a 7 day course of primaquine 0.5 mg/kg/day adjusted by weight categories, or a unique dose of 300 mg of tafenoquine). The treatment is started immediately, and the first dose uptake is directly observed. During the inclusion process participants receive oral and written instructions on how to take the tablets, potential side effects and what to do in case of an adverse event (AE), including the potential need to seek urgent care (Fig.  3 ).

Kits for participants to the CUREMA intervention: A self-test and self treatment kit, called malakit, consisting in a test pocket (green) and a treatment kit (pink), both illustrated in order to guide kit use by illiterate participants; B radical cure kit, consisting of a treatment pocket (with numbered Ziploc with daily treatment doses) and illustrated flyers informing on posology, contra-indication and potential side effects

Adherence and safety data are collected by a 14 day follow-up. Follow-up visits (planned at 2, 5 and 14 days after the start of the treatment) are ensured by several tools tailored to the context and to the usual short-term mobility of the target population: an in-person or phone follow-up by CHWs, or self-reporting via a smartphone application. In both cases the follow-up consists in a short questionnaire exploring the main symptoms of significant AEs (haemolysis, allergy, cardiac rhythm modifications). In order to detect any further serious adverse events, participants are also asked about their perceived general state of health, and whether they have had to seek medical attention since starting treatment. In case of positive answer to either one of these questions, the participant is invited to stop the treatment and to seek care at the nearest health facility; an interview is also performed by one of the physician investigators of the study and, if deemed necessary, further clinical and biological explorations are proposed to assess (1) the severity of the AE and (2) the causal link with the medications delivered in the context of the study. Serious adverse events (e.g. severe haemolysis) are collected and reported immediately to the relevant authorities, the sponsor's pharmacovigilance team and the Data and Safety Monitoring Board of the study.

The 8-aminoquinoline initially implemented at inclusion sites is primaquine; tafenoquine will be gradually introduced in the inclusion process as soon as the field procedures of inclusion and follow-up are robust and the drug available (donation by GSK).

The malakit represented by the delivery, after appropriate training, of a self-testing and self-treatment kit. The objective of this service is to provide access to quality diagnosis and treatment for episodes of symptoms compatible with malaria that occur in situations of extreme remoteness from health services. The kit is composed of two illustrated plastic pouches. The diagnostic pouch contains three malaria rapid diagnostic tests Bioline malaria rapid tests by Abbott, chosen because they are prequalified by the WHO, have individual packaging and are capable of detecting the malaria species circulating in the region; the models used depend on the purchasing possibilities of the countries concerned according to the local regulations. The treatment pouch contains a blister of paracetamol, a full course of artemether-lumefantrine (20 mg/120 mg) and a single low dose of primaquine (15 mg) to target P. falciparum gametocytes and prevent onwards transmission (Fig.  3 ) [ 39 ]. Participants receive training about malaria symptoms, how to correctly perform rapid tests and how to follow the treatment. Knowledge assessment is carried out after the training, and participants have to perform and interpret a self-test correctly in order to be eligible to receive the kit.

Implementation strategy

The aim of this study is to evaluate both the intervention and its implementation under the conditions relevant to the target population and context. It is, therefore, essential to describe in systematic manner the main features of the chosen implementation strategy [ 58 ].

The intervention is offered by community health workers speaking the same language and belonging (or being near) to the community itself. The study’s CHWs have a similar profile to that of health workers recruited by a number of malaria control programmes, particularly in remote areas. Field activities are implemented through civil society partner organizations, who hire the CHWs and are responsible for sites’ logistics: in Suriname by the SWOS foundation, which has the purpose of developing the scientific research in health in the country; in Brazil through the NGO DPAC Fronteira, whose main activity is social mediation in health and community development at the French-Brazilian border [ 59 ].

Dose and temporality:

In the context described above, the strategy takes advantage of the regular mobility of the potential participants between the inclusion sites and gold mines, approaching the target population where and when they are easily accessible, thus overcoming the obstacles presented by the isolation of the community at their gold mines, which are often inaccessible to health teams due to security and regulatory constraints. Therefore, they will be reached on an ongoing basis rather than through one-off operations. The expected inclusion rate is between 25 and 50 participants per site per month, allowing a gradual increase of the coverage of the study’s target population. The intervention is planned to be offered for 20 months.

Additional features of the implementation strategy should be mentioned:

Training and supervision at the core of the implementation strategy:

CHWs have received comprehensive initial training allowing them to correctly carry out inclusions and follow-up [ 59 ], and benefit from continuous refresher training. The coordination team and the field supervisors ensure the fidelity of inclusions and follow-up through supervision visits and standardized evaluation, activity assessment, stocks follow-up, management of operational issues. As a part of this process, quality assurance procedures for STANDARD™ G6PD analyzer are implemented according to the PATH G6PD Operational Research Community of Practice (GORCoP) [ 60 ], and supervised inclusion processes are regularly realized including a checklist evaluating the fidelity in the G6PD testing.

Tailored tools elaborated through a participatory approach:

The content of the participants’ training as well as the information, education and communication (IEC) tools elaborated in the context of the project are the fruit of pre-intervention qualitative research about malaria knowledge and health perceptions, available at the project’s website [ 61 ]. They have been designed with the participation of the target population, to be acceptable, relevant and understandable.

An information system that supports the inclusion and follow-up activity:

The inclusion and follow-up process are supported by “smart” electronic questionnaires filled-in on tablets by the CHWs. The information system of the former Malakit project was adapted to meet the needs of CUREMA [ 62 ]. The questionnaires, based on the Open Data Kit (ODK) Collect Android application, can be used offline, and according to the information entered by CHWs, advise them on the next steps of the inclusion process, on the eligibility of participants to either services of the project, or on specific actions that need to be taken. Thanks to the weekly upload of inclusion and follow-up data to the study servers an ongoing monitoring and evaluation of data quality is performed by the coordination team.

Moreover, a tailored smartphone application has been developed for the project. In this app, which can be used offline, participants are able to find educational videos. For participants receiving radical cure, popup notifications appear on the screen and prompt follow-up questionnaires. Data can be collected offline and sent to the study servers whenever an internet connection becomes available. Satellite based wireless connections are increasingly available even in remote gold mining sites, and regularly accessed for personal purposes by the gold miners [ 63 ].

Design and outcomes

The CUREMA study relies on a hybrid design, assessing both population-scale effectiveness of the intervention and its implementation [ 57 ], to facilitate its translation into programme action. More precisely, this will be a type I hybrid study, testing effects of an intervention on relevant outcomes while observing and gathering information on implementation (Table  2 ).

The effectiveness of the intervention on malaria transmission is evaluated by a pre/post quasi-experimental design. Therefore, the main outcome of the study is the variation of the proportion of people carrying Plasmodium spp. parasites by ultrasensitive PCR measured before and after the intervention. To support the interpretation of this outcome, the evolution of malaria epidemiology in the region over the study period will be assessed by: (1) data from the surveillance systems of the three countries involved in the project; (2) the analysis of the evolution of serologically positivity rate for P. vivax ; (3) collection of dry blood spot (DBS) samples for each participant in the intervention (usPCr and Pv serology). This will allow a modelling of malaria epidemiological fluctuations occurring in the region during the intervention.

The main outcome chosen to evaluate the implementation of the intervention is its penetration [ 64 ] within the target population, i.e. the proportion of the target population included in the intervention at the end of the study period. The effectiveness of the intervention is in fact closely dependent on its actual execution and on the coverage of the target population. To put this outcome into context and to provide food for thought about possible scale-up or transferability, acceptability, safety, appropriateness, feasibility, fidelity and sustainability will be assessed by quantitative data and qualitative surveys [ 64 ].

The underlying assumptions about how these objectives should be achieved are set out in the logic model proposed in Fig.  4 .

Intervention's theory

Data sources

Data for evaluation are provided through different study components which articulation is illustrated in Fig.  5 .

CUREMA project design and timeline

The intervention:

Inclusion and follow-up questionnaires provide information on the number of participants, their socio-demographic and occupational profile, the actual delivery of the services (dependent on participants’ choice and eligibility), the adherence to the treatments and their safety. DBS are collected for all the participants undergoing fingerpick for G6PD test or self-test training. Data generated from participants follow-up and from AE investigations will allow to produce evidence on the safety of the intervention. For the intervention, no sample size has been defined from a statistical perspective: its target is to include as many persons as feasible. Between 2500 and 5000 participants are expected during the study’s period, in the same order of magnitude as the Malakit project [ 39 ]. A non-inclusion registry collects anonymous information about individuals that did not wish to participate in the study or did not meet the inclusion criteria, contributing to the acceptability evaluation. Important additional data for the evaluation of the implementation are the information produced by the supervision activities (check-lists, audits) and the evaluation of the training of facilitators performed during the initial session [ 59 ].

The pre-and post-intervention epidemiological surveys:

Two cross-sectional surveys take place at inclusion sites before and at the end of the intervention implementation, during the same period of the year (during the last quarters of 2022 and 2024) in order to limit potential biases associated with seasonality. The participants are selected among individuals having left an illegal gold mine located in FG within the past seven days [ 20 , 39 ]. These surveys include a detailed questionnaire about recent malaria history and mobility, a clinical examination and a venous blood sample. The proportion of malaria parasite carriage will be assessed by a Plasmodium us-qPCR (ultra-sensitive quantitative polymerase chain reaction) [ 65 ], with species-specific probes for P. vivax , P. falciparum and Plasmodium malariae asexual and sexual forms. Plasmodium vivax serology by Luminex assay will be performed following methodology described by Longley et al. [ 66 ], in order to assess recent (and thus potentially latent) infections, as well as medium-term transmission trends [ 66 , 67 , 68 , 69 ]. The biological collection will be stored at biobank Centre de Ressources Biologiques Amazonie in Cayenne.

The sample size requirements have been calculated based on the univariate analysis of the main effectiveness outcome: with a hypothetic pre-intervention all-species prevalence of 2%, and a target 75% reduction after two years of intervention (leading to a post-intervention prevalence of 0.5%), 860 participants should be included in each survey in order to perform this comparison with a two-sided 0.05 alpha risk and a 0.8 beta risk.

Qualitative research :

Qualitative surveys are performed before, during and after the intervention by a social science researcher. The aim of these surveys is to support community engagement and to analyse the specific constraints and levers of the intervention under study and the pre-elimination context, to understand which elements could influence the success or the failure of the intervention and implementation strategy under evaluation. The qualitative research addresses three groups involved in the study: (i) the target population of the intervention, (ii) the field workers who participate in the inclusion and supervision activities, (iii) scientific and institutional (technical officers and decision-makers) stakeholders of the study.

Interviews and discussion groups are proposed at different times to all stakeholders of the study. Participant and non-participant observation are conducted to collect descriptive data on context, behaviours, interactions and dynamics, experiences, and will allow researchers to better describe and interpret the data.

National and regional epidemiological surveillance data:

Data from the malaria programmes surveillance systems of French Guiana, Brazil and Suriname regarding cases notified, according to their origin and (while available) occupational category will allow to evaluate the general context of the regional malaria epidemiology.

The Centre d’Investigation Clinique Antilles-Guyane is an INSERM (Institut National de la Santé et de la Recherche Médicale) research unit based at Cayenne Hospital and is the sponsor of the CUREMA study. Key scientific partners include the SWOS and the Fundação Oswaldo Cruz (FIOCRUZ): these institutions host the principal investigators responsible for inclusions in Suriname and Brazil, respectively. Major scientific collaborations with the Pasteur Network support the project, providing expertise in the molecular biology and immunology of malaria. In Brazil, collaboration with the NGO DPAC-Fronteira brings to the project significant experience in social mediation, health education and mobilization, and empowerment of vulnerable communities.

The project is supported by the health authorities competent for the three territories and their respective malaria elimination programmes. These institutions are also part of the steering and scientific committee of the project. Besides the financial or in-kind support from health authorities, the CUREMA project is also funded by the European Funds of Regional Development from PCIA (Programme de Coopération Interreg Amazonie, SYNERGIE 7128 and 8754).

The project received ethical clearance from the Ministry of Health of Suriname (CMWO 005/22), the Fiocruz ethics committee (CEP 5.210.165) and the National ethical committee for health research of Brazil (CONEP 5.507.241). It also complies with the European Regulation on Data Protection. A Data and Safety Monitoring Board (DSMB) has been established to provide external monitoring of the study, specifically advising the investigators and the sponsor about potential safety concerns. Field implementation of the study started in the last quarter of 2022 and is planned to take 27 months (Fig.  5 ). Results will be available at the end of 2025.

The CUREMA project aims at evaluating a complex intervention [ 70 , 71 ]: several components make up the CUREMA intervention per se, including pharmacological intervention and health education activities; the context of the intervention is complex, being cross-border, characterized by challenging operational and logistical aspects due to the Amazonian environment and the fragility of infrastructures, by the interaction of numerous actors belonging to a multicultural and multisector context; the implementation of the intervention and its effectiveness can be significantly influenced by the epidemiological, migratory, political, economic and climatic context of the region. In this context, the authors' objectives cannot be limited to a simple evaluation of effectiveness, but it is fundamental to address the question of for whom, when, why and how this intervention can be effective and relevant [ 70 ].

In terms of intervention’s environment, the CUREMA project is the natural continuation of the Malakit project, which was carried out between 2018 and 2020 by the same nexus of scientific, operational and institutional partners, and whose experience CUREMA capitalizes on. Both projects were born from a virtuous dynamic in which these players, belonging to different professional backgrounds and the three countries in the Region, sought to collectively build creative solutions to common challenges. The reduction in the level of malaria transmission in the three territories is an important contextual element. On the one hand, the participation of Suriname and French Guiana in the E-2025 initiative, as well as the Brazilian government’s commitment to eliminating malaria transmission in the Amazon by 2035, are levers of increased political support to implement ambitious interventions to achieve these goals. On the other hand, paradoxically, the decreasing number of malaria cases may lead to a gradual demotivation of the community and of field professionals involved, whose reduced level of commitment may jeopardize the ability of these interventions to produce the expected effects. The evaluation of the CUREMA project will need to take these contextual factors into account, in order to understand the factors at play in the implementation of the project and its acceptance.

The CUREMA project and the previous MALAKIT project have been conceived with two core principles in mind. The first is medical neutrality and impartiality, i.e. the fact that access to health should be universal, a key principle of medical ethics and humanitarian law [ 72 , 73 ]. The study population has de facto restricted access to healthcare due to its clandestine status, and the aim of the project’s approach is to restore this access, at least in the fight against malaria. Secondly, the “harm reduction” perspective, which involves a non-judgemental approach to promoting health and reducing the harmful effects of a not easily avoidable exposure [ 74 ]. In this case, the exposure is represented by the activity of gold mining, which has very complex social and economic determinants, and on which the health sector is unable to intervene. Precautions must be taken when working in this context. As mentioned above, project’s actions are carried out in neutral contexts, where participants are not in conditions of illegality at the time of inclusion. It is also important to note that these places are widely known in literature and by the authorities [ 36 ], and not revealed by the project. Additionally, data collection carefully avoids gathering information on possible criminal activities (including human trafficking, violence, drug trafficking). Finally, it is important to emphasize that the majority of the study population, although in irregular migratory conditions and involved in unauthorized mineral exploitation, are simple “workers” who are not involved in criminal activities [ 36 ]. They also suffer from very vulnerable socio-economic and health conditions [ 38 , 75 ].

The project team has gradually built up a relationship of trust with the ASGM communities [ 76 ]. Participation in the study by this “hidden” population is facilitated by the fact that the intervention is carried out in “neutral” locations, through work with members of the community, and by the history of collaboration and trust established by the research team and field partners over more than a decade. This has helped to nurture a community-engagement approach with a dual objective: to produce services and results considered relevant by the target community, and to strengthen its involvement and awareness around malaria elimination efforts. The CUREMA project intervention and evaluation components have been designed by researchers and malaria experts, but the opinion of the target population was sought throughout the development process, and most project tools (questionnaires, application, educational material) were developed with their direct participation. In this regard, the participation of the community is situated, on the continuum described by Sanderson and colleagues, between consultation and cooperation [ 77 ]. Nevertheless, the fact that the project proposal is not generated per se by a community approach, could have the effect that the community does not feel it is relevant and does not embrace it, despite efforts to improve their participation.

Interventional health studies can be qualified according to their characteristics on a continuum between the attributes explanatory and pragmatic [ 78 ]. In explanatory trials the object of evaluation is the drug (or technology) per se, which is compared to placebo or standard of care under ‘‘optimal’’ and balanced conditions, in order to identify its specific role in the evolution of a health state. In pragmatic trials, the intervention is evaluated under conditions as close to real life as possible, in order to generate information about its effective applicability [ 78 ]. The drugs used in the study have already been the subject of explanatory studies, or even are already included in national recommendations for the treatment of acute malaria episodes. The CUREMA project proposes an approach that changes the indications or modalities of such treatments, as well as the mode of recruitment of patients receiving the drugs. However, it did not seem relevant to carry out an explanatory study for this approach, and on the contrary, a pragmatic design seems more interesting: due to the nature of the intervention, its applicability in real conditions is indispensable, and a result obtained in controlled ‘‘optimal’’ conditions would not have any added value in terms of decision support for the health authorities. For example, a study recruiting patients in a health facility by medical or paramedical professionals (rarely available in the target locations), with an ‘‘ideal’’ in person clinical and biological follow-up (which does not take into account the high mobility of the target population), would not only make this intervention difficult to transpose to the reality of places with residual transmission in endemic countries, but would also end up missing the very target of the intervention. Field health workers with a similar profile are in charge of treating malaria and other communicable diseases on a daily basis in many countries of the world (including Brazil and Suriname) [ 79 , 80 , 81 , 82 , 83 ]. In Suriname, a partnership with the National Malaria Programme allow to hire as collaborators of the project the same CHWs involved in the programme’s activities. However, setting up an intervention in a research project is by its very nature different from scaling it up in a healthcare system, in terms of organization, administrative, political and logistical constraints, and funding capacity [ 84 ]. These limitations will need to be taken into account when assessing the transferability of the intervention.

The effectiveness evaluation the authors are interested in measuring is the impact of the intervention on malaria transmission at a population level. Field conditions (limited number of inclusion sites, high mobility of the target population across the region between different gold mining areas) would not allow the implementation of a cluster randomized trial, as well as of other types of controlled designs. Effectiveness evaluation with a non-randomized design without a control group will require caution when interpreting the main outcome results. Potential confounding factors must be considered in the interpretation of the results, as changes in malaria prevalence could be linked to external factors such as changes in mobility patterns, environmental variations, or evolutions in malaria control programme activities. Contextual data on the epidemiological, health, environmental, economic and political context will provide additional insight.

Evaluation of implementation (using quantitative and qualitative data) will also allow to interpret the results of the impact assessment more adequately: to what extent was the intervention implemented satisfactorily, and what are the factors favouring or hindering its implementation in general and on specific aspects. The triangulation of these elements will help to understand whether, how and why the intervention worked in the study’s context. This will also provide a basis for imagining whether and how it might work in similar contexts.

Another very important point that will be analysed with CUREMA is the risk–benefit balance (real and perceived) of this targeted drug administration against P. vivax silent carriage. On the one hand, mass drug administration (MDA) aiming at eliminating P. vivax has already been carried out in the past [ 85 , 86 ]. However, these actions were fraught with a dubious risk–benefit balance because of the high proportion of people unnecessarily treated, especially in contexts of medium–low endemicity. An alternative to MDA would be to carry out targeted treatment of people who are seropositive for P. vivax (serological test-and-treat, seroTaT), serology being used as a proxy for recent infection with P. vivax and of the carriage of hypnozoites. This has been used in the past for malaria elimination in southern Brazil, and has been advocated as a mass strategy more recently in several modelling papers [ 66 , 87 ]. However, the unavailability of rapid serological tests that can be used in the field implies that this strategy is not currently applicable to such an isolated and highly mobile population. The proposal for a targeted drug administration strategy based on epidemiological criteria (recent individual history compatible with asymptomatic carriage) is an innovative compromise aimed at improving the risk–benefit balance using simple methods available everywhere and with low cost. The epidemiological criteria used in the study will be compared with serology retrospectively to assess their performance.

The risk of error in the delivery of radical cure intervention by community health workers will be assessed, particularly the risk of delivering 8-aminoquinoline to persons with contra-indications such as G6PD deficiency. To prevent this risk, a comprehensive initial training program [ 59 ] has been set up, as well as periodic supervision and refresher trainings to guarantee the quality of the test performance. The choice of whether to deliver the radical treatment is accompanied by the electronic inclusion form, which provides recommendations in relation to the level of G6PD and other contraindications explored. Although project’s field workers are not professionals with specific training in laboratory techniques, other experiences in Brazil shows that field performance of this test by community health workers without formal qualifications is possible and safe [ 54 , 55 ]. An unpublished study was also carried out in Suriname on the feasibility of testing by community health workers in the malaria programme (the same ones recruited for CUREMA), with satisfactory results (personal communication with Dr. S. Vreden). The frequency and severity of adverse events recorded during the participants’ follow-up will assess the risk incurred by participants. The balance as perceived by participants will be evaluated during qualitative surveys carried out after the intervention. All these elements will thus contribute to the analysis of the risk–benefit balance of this service offered under field conditions, in low to moderate malaria transmission settings to asymptomatic persons.

The CUREMA study will provide an evaluation of a new intervention for hard-to-reach populations, who represent the main challenge for countries approaching the elimination of malaria. These results will, therefore, be disseminated and used to inspire solutions in similar realities, for example in Latin America and Asia [ 13 , 16 , 24 , 28 , 37 ], in the context of transfer to health systems or of further scientific evaluation (including consolidation of the effectiveness results, or medico-economic assessment). Furthermore, the same intervention could also be considered for the management of epidemic phenomena when logistical, political and/or administrative constraints make it impossible to set up on-site interventions (including clandestine populations, war contexts). These results would, therefore, prove extremely valuable to face the challenges of malaria elimination in a growing number of countries [ 88 ].

Data availability

Not applicable.

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Acknowledgements

We would like to thank all the members of the study population who contributed to the development of this project.

The CUREMA study has been funded by the European Funds for Regional Development (Programme de Coopération Interreg Amazonie, SYNERGIE 7128 and 8754) and the Regional Health Agency of French Guiana.

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Sanna, A., Lambert, Y., Jimeno Maroto, I. et al. CUREMA project: a further step towards malaria elimination among hard-to-reach and mobile populations. Malar J 23 , 271 (2024). https://doi.org/10.1186/s12936-024-05040-8

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Study Protocol

Investigating the association between household exposure to Anopheles stephensi and malaria in Sudan and Ethiopia: A case-control study protocol

Contributed equally to this work with: Temesgen Ashine, Yehenew Asmamaw Ebstie, Rayyan Ibrahim, Adrienne Epstein

Roles Conceptualization, Investigation, Methodology, Writing – review & editing

Affiliations Malaria and NTD Research Division, Armauer Hansen Research Institute, Addis Ababa, Ethiopia, Department of Biology, College of Natural and Computational Sciences, Arba Minch University, Arba Minch, Ethiopia

Affiliation Malaria and NTD Research Division, Armauer Hansen Research Institute, Addis Ababa, Ethiopia

Affiliation Department of Community Medicine, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

Roles Conceptualization, Investigation, Methodology, Visualization, Writing – original draft

Affiliation Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

Affiliation Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom

Roles Data curation, Investigation, Software, Writing – review & editing

Roles Data curation, Software, Writing – review & editing

Roles Investigation, Methodology, Writing – review & editing

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Affiliation Sennar Malaria Research and Training Centre (SMART Centre), Federal Ministry of Health, Khartoum, Sudan

Roles Investigation, Methodology, Project administration, Writing – review & editing

Affiliation Tropical and Infectious Disease Research Centre, Jimma University, Jimma, Ethiopia

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Affiliation Unit of Socio-Ecological Health Research, Department of Public Health, Institute of Tropical Medicine, Antwerpen, Belgium

Affiliation School of Public Health, College of Medicine and Health Sciences, Hawassa University, Hawassa, Ethiopia

Roles Funding acquisition, Investigation, Methodology, Writing – review & editing

Affiliation Primary Health Care General Directorate, Federal Ministry of Health, Khartoum, Sudan

Roles Methodology, Writing – review & editing

Affiliation Disease Prevention and Control Directorate, Ethiopian Federal Ministry of Health, Addis Ababa, Ethiopia

Affiliation Department of Biology, College of Natural and Computational Sciences, Arba Minch University, Arba Minch, Ethiopia

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Affiliation Directorate General of Global Health, Federal Ministry of Health, Khartoum, Sudan

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• Temesgen Ashine, 
• Yehenew Asmamaw Ebstie, 
• Rayyan Ibrahim, 
• Adrienne Epstein, 
• John Bradley, 
• Mujahid Nouredayem, 
• Mikiyas G. Michael, 
• Amani Sidiahmed, 
• Nigatu Negash, 

• Published: September 3, 2024
• https://doi.org/10.1371/journal.pone.0309058
• Reader Comments

Endemic African malaria vectors are poorly adapted to typical urban ecologies. However, Anopheles stephensi , an urban malaria vector formerly confined to South Asia and the Persian Gulf, was recently detected in Africa and may change the epidemiology of malaria across the continent. Little is known about the public health implications of An . stephensi in Africa. This study is designed to assess the relative importance of household exposure to An . stephensi and endemic malaria vectors for malaria risk in urban Sudan and Ethiopia.

Case-control studies will be conducted in 3 urban settings (2 in Sudan, 1 in Ethiopia) to assess the association between presence of An . stephensi in and around households and malaria. Cases, defined as individuals positive for Plasmodium falciparum and/or P . vivax by microscopy/rapid diagnostic test (RDT), and controls, defined as age-matched individuals negative for P . falciparum and/or P . vivax by microscopy/RDT, will be recruited from public health facilities. Both household surveys and entomological surveillance for adult and immature mosquitoes will be conducted at participant homes within 48 hours of enrolment. Adult and immature mosquitoes will be identified by polymerase chain reaction (PCR). Conditional logistic regression will be used to estimate the association between presence of An . stephensi and malaria status, adjusted for co-occurrence of other malaria vectors and participant gender.

Conclusions

Findings from this study will provide evidence of the relative importance of An . stephensi for malaria burden in urban African settings, shedding light on the need for future intervention planning and policy development.

Citation: Ashine T, Ebstie YA, Ibrahim R, Epstein A, Bradley J, Nouredayem M, et al. (2024) Investigating the association between household exposure to Anopheles stephensi and malaria in Sudan and Ethiopia: A case-control study protocol. PLoS ONE 19(9): e0309058. https://doi.org/10.1371/journal.pone.0309058

Editor: Vivekanandhan Perumal, Chiang Mai University Faculty of Agriculture, THAILAND

Received: March 6, 2024; Accepted: August 6, 2024; Published: September 3, 2024

Copyright: © 2024 Ashine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

Funding: This work was supported by the National Institute for Health Research (NIHR) (using the UK’s Official Development Assistance (ODA) Funding) and Wellcome [220870/Z/20/Z] under the NIHR-Wellcome Partnership for Global Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed are those of the authors and not necessarily those of Wellcome, the NIHR or the Department of Health and Social Care.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: CDC LT, CDC light trap; CI, confidence interval; ETH, Ethiopia; IRS, indoor residual spraying; ITN, insecticide-treated net; M, meter; PCR, polymerase chain reaction; SOP, standard operating procedure; SUD, Sudan; RDT, rapid diagnostic test

Introduction

Africa currently has the highest rate of urbanization of any continent. The United Nations estimates that the world’s urban population will increase by 2.5 billion by 2050, with 90 percent of the growth in Asia and Africa [ 1 ]. Historically, the malaria burden in Africa has been concentrated in rural areas because African malaria vectors are not well adapted to urban ecologies [ 2 – 4 ]. However, Anopheles stephensi , a species of mosquito formerly confined to South Asia and the Persian Gulf but recently identified in Africa [ 5 , 6 ], may change the epidemiology of malaria across the African continent. An . stephensi thrives in urban environments and is a highly competent vector for both Plasmodium falciparum and P . vivax [ 7 , 8 ]; it therefore constitutes a potential new threat to African malaria control and hopes of elimination [ 5 – 7 ].

The WHO Malaria Threats Map highlights the current state of knowledge on An . stephensi detections across Africa with detections so far in Djibouti, Ethiopia, Sudan, Puntland, Nigeria, Somaliland, Ghana, Eritrea and Kenya [ 9 ]. Larval habitats of An . stephensi are typically man-made containers such as household/community water storage containers, construction water storage and overhead tanks, wells and drums, but it has also been identified in stream margins, sewage overflows, and flooded areas [ 10 – 12 ]. An . stephensi is an opportunistic vector, with biting behaviour driven by availability of hosts. Preliminary entomological surveillance in Ethiopia has revealed a propensity for resting in animal shelters [ 13 , 14 ]. Surveillance indicates both indoor and outdoor biting, indoor and outdoor resting, and a preference for biting at dusk and during the night [ 15 ]. Further investigation is needed to determine if these behaviours are observed in African populations of An . stephensi . It is possible that additional vector control strategies will be necessary to control An . stephensi , in addition to current vector control tools that target vectors indoors (insecticide-treated nets [ITNs] and indoor residual spraying [IRS]).

There is a critical need to understand the public health impact of the threat posed by An . stephensi . An efficient urban malaria transmission cycle could turn cities and towns from areas with minimal malaria transmission to large-scale sources of infection, confounding global elimination efforts. An . stephensi was first detected in Djibouti in 2012 [ 5 ], where it was associated with a significant rise in malaria cases [ 7 ], from 1,684 malaria cases in 2013 to 72,332 confirmed cases reported in 2020 [ 16 ]. A recent dry season malaria outbreak in Dire Dawa, Eastern Ethiopia appears to be associated with An . stephensi [ 17 ]. Mathematical modelling also suggests that over 100 million people in cities across Africa are at risk of An . stephensi mediated malaria transmission [ 15 ]. Modelling by Hamlet et al suggests that annual P . falciparum malaria cases in Ethiopia could increase by 50% (95% CI 14–90) if no additional interventions are implemented [ 18 ]. Despite this growing evidence suggesting the potential involvement of An . stephensi in malaria transmission, there is great uncertainty about the malaria epidemiology in towns and cities in Sudan and Ethiopia; in particular, it is not known if, or to what extent, An . stephensi contributes to malaria transmission compared to native malaria vectors.

This manuscript describes a study protocol for a case-control study aimed at assessing the relative importance of An . stephensi and endemic malaria vectors for malaria burden in urban Sudan and Ethiopia. Case-control studies have been underused for malaria [ 19 – 23 ] but are well suited for our purpose since malaria cases are at present low in urban settings [ 24 – 26 ]. Results from this study will guide public health strategies for malaria control and elimination.

Materials and methods

Study design.

We will conduct a community-based, age-matched case-control study in three study sites: two in Sudan and one in Ethiopia. Within these sites, cases and controls will be selected from health facilities over a 12-month period. Upon identification of cases and controls, entomological surveillance will be conducted at study participant households to assess the association between household entomological exposure and malaria case status.

Study areas

Study sites have been selected using the following criteria: (1) presence of An . stephensi ; (2) heterogeneity of An . stephensi density across a site; (3) ongoing malaria transmission; and (4) accessibility by study teams with minimal security threats. Entomological criteria (criteria #1 and #2) were assessed through ongoing entomological surveillance by study teams conducted at 61 sites in Sudan and 28 sites in Ethiopia. Epidemiological criteria (criterion #3) were assessed through using Health Management Information Systems (HMIS) data.

In Sudan, the study will be conducted at two sites: Tuti Island in Khartoum State (15.621457, 32.504861) and Almaelig in Gezira State (15.017992, 33.094729) ( Fig 1 ). An . arabiensis is considered the major malaria vector in both sites [ 27 ]. Tuti Island is an eight square kilometre island situated where the White Nile and Blue Nile meet in Sudan’s capital city, Khartoum, with a population of approximately 37,702. The island has a settlement, vegetable farms and orchards and is connected to the city via a single suspension bridge. An . stephensi was first detected in Tuti Island in 2018 [ 27 ] and a 2022 entomological survey found that 28% of randomly selected households had An . stephensi adults or larvae within 50 metres (Kafy et al , unpublished). Malaria transmission is seasonal, with a peak from October to December [ 28 ]. There is a single public health facility on Tuti Island from which cases will be recruited. The second site in Sudan, Almaelig, is a small town with a population of approximately 15,370. Almaelig is in the Gezira irrigation scheme which produces cotton, wheat, and groundnut. Presence of An . stephensi in Almaelig was first identified by our team in 2022 with 24% of randomly selected households positive for An . stephensi adults or larvae within 50 m of the home (Kafy et al , unpublished). Like Tuti, malaria transmission is seasonal with malaria transmitted by An . arabiensis (Kafy et al , unpublished). A total of four health facilities in Almaelig town and neighbouring settlements will be included for case and control selection: Almaelig Hospital, Aldibaiba, Alrayhana and Marakraka.

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https://doi.org/10.1371/journal.pone.0309058.g001

In Ethiopia, the study will be conducted in Metehara town, Oromia Region (8.903536, 39.917514) ( Fig 1 ). Metehara town has a population of approximately 47,661. The main commercial activities are service-based and retail, and farming, including subsistence farming and a large government-owned sugar cane plantation, which supplies the government owned Metehara Sugar Factory located south of the town. Malaria transmission is seasonal with peaks from September to December. In Ethiopia, An . arabiensis is the main malaria vector while An . pharoensis , An . funestus and An . nili are secondary vectors [ 29 ]. Our team and others previously reported presence of An . stephensi in Metehara in 2022 with 18% of randomly selected households positive for either An . stephensi adults or larvae within 50m [ 30 ]. There are several public, faith-based, and private health facilities in the town. The study will recruit cases and controls at two public health centres, one serving Kebele 1 (Dire Gobu) and the other serving Kebele 2 (Haro Adi).

Sample size

Entomological surveillance conducted in 2022 in and around 50 randomly selected households at each site informed the sample size calculations. Sampling for larval mosquitoes was conducted within 50m of each selected household. Similarly, adult collections were performed indoors and outdoors (within 50m of the household in Sudan, and within the compound in Ethiopia) using Prokopack aspirators and Centers for Disease Control miniature light traps (CDC LT). The proportion of households positive for An . stephensi larvae and/or adults was considered in the exposure probability for controls. A ratio of 1 case to 2 controls was adopted to increase statistical power given the identification of cases was thought to be the limiting factor in both settings.

In Sudan, across Tuti Island and Almaelig, 26% of households were exposed to An . stephensi adults or larvae (Kafy et al, unpublished). Assuming this (26%) exposure probability among controls, a 1:2 ratio of cases to controls, an odds ratio of 1.5, 20% correlation of exposure between cases and controls, 80% power, and a significance level of 5%, a total of 407 cases and 814 matched controls will be required. In Ethiopia, 18% of households in Metehara were exposed to An . stephensi adults or larvae (Ashine et al, unpublished). Assuming this (18%) exposure probability among controls, a 1:2 ratio of cases to controls, an odds ratio of 1.5, 20% correlation of exposure between cases and controls, 80% power, and a significance level of 5%, a total of 514 cases and 1028 matched controls will be required. Sample size calculations were run using the power mcc command in Stata (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.).

Case and control definitions

The criteria for defining cases and controls are presented in Table 1 . In both countries, the cases and controls or their caregivers must provide voluntary written informed consent to participate in the study, reside within the catchment of the health facility (within 30 minutes journey time) and be willing to be visited at home for additional data collection. In Ethiopia, an additional criterion will be that the participant must have been living in the study area for at least 4 weeks. This will restrict recruitment of non-locally derived cases given that there are seasonal workers who migrate to Metehara to work in the sugarcane plantation. The age range of cases and controls will differ between Sudan and Ethiopia. In Sudan, malaria cases are still predominantly in children; cases will therefore be aged greater than 6 months and less than 12 years. Controls will be matched to cases on two age groups: 6 months to less than 5 years; and 5 years and above to less than 12 years. In Ethiopia, HMIS data indicates that all ages are at risk for malaria; as such, cases and controls will be above 6 months of age with controls matched to cases on three age groups: above 6 months to less than 5 years; 5 years or above to less than 18 years; and 18 years and above. In Sudan, cases must be positive for P . falciparum and/or P . vivax detected using a rapid diagnostic test (RDT) (Bioline™ Malaria Ag P.f/P.v test), while controls must test negative by RDT. In Ethiopia, concerns over pfhrp2/3 gene deletions [ 31 ] and lack of an appropriate and approved RDT means that cases must be positive for P . falciparum and/or P . vivax detected using microscopy, while controls must test negative by microscopy. Cases must have fever (axillary temperature ≥37.5°C) at the time of presentation or a history of fever within the previous 48 hours, while controls must be negative for fever (axillary temperature <37.5°C) or history of fever within the previous 48 hours. Cases and controls should have no signs or symptoms suggesting progression to severe malaria and should not have history of malaria treatment in the preceding two weeks. Controls must attend the same health centre as their matched case within 72 hours of case identification.

Country specific criteria are indicated with acronyms, SUD for Sudan and ETH for Ethiopia.

https://doi.org/10.1371/journal.pone.0309058.t001

Study procedures

Identification and enrolment of study participants and blood sample collection..

At each health facility, staff of the health facility trained by the project teams will be responsible for screening and enrolment in collaboration with the rest of the health facility staff. Potential study participants attending the health centre as outpatients, or their caregivers will be approached and invited to participate in the study. The individual or their caregiver will be provided with information about the study, have an opportunity to ask questions, and will be asked to consider providing written informed consent to participate in the study. Children aged 8 years and above in Sudan and aged 11–17 years in Ethiopia will be asked to provide verbal assent to participate in the study. If the child does not assent, then they will not be included.

In both Sudan and Ethiopia, recruitment will be integrated with standard care as much as possible with RDTs and microscopy performed by health facility laboratory staff. A finger-prick blood sample will be taken to perform an RDT (Bioline™ Malaria Ag P.f/P.v test) in Sudan or microscopy in Ethiopia where thick and thin blood films will be prepared and stained with Giemsa. In addition, dried blood spots will be collected using filter paper to be analysed for the presence of 18s rRNA gene using PCR [ 32 , 33 ]. Dried blood spots will also be stored for future molecular analyses to determine the proportion of P . vivax cases that are relapses and for whole genome sequencing of all species of Plasmodium [ 34 , 35 ].

Household survey.

Cases and controls will be visited at home by study personnel within 48 hours of enrolment.

Study fieldworkers will conduct a household survey to collect information on several variables ( Table 2 ), including demographics, house structure, use of malaria preventive methods, and environment. Socio-economic status will be assessed using an asset index from an established questionnaire [ 36 ]. The condition of ITNs will be assessed and a proportionate hole index calculated according to established methods [ 37 ]. Households will also be mapped using a GPS receiver.

https://doi.org/10.1371/journal.pone.0309058.t002

Entomological survey.

During the household visit, fieldworkers will conduct entomological surveillance for both adults and immature mosquitoes both inside and outside the participant household (within 50 m). Adult mosquito surveillance will be performed both indoor and outdoor using CDC LTs and Prokopack aspirators (both John W. Hock Company, Florida, USA). CDC LTs will be placed indoors at the foot end of an occupied bed net 1.5m off the floor and collections will be conducted for a 12-hour period overnight. Prokopack aspiration will be conducted inside and outside of the house between 5.00–6.00 AM before the CDC LT is retrieved. Collections will be performed for 20 minutes, with an additional 10 minutes for any out-buildings sheltering animals. Prokopack aspiration will also be performed in potential outdoor resting sites such as house exteriors, grain or rice stores, wood stacks, water pipes, drains, wells, trees, and bushes. In addition, Biogents Pro CDC-style traps (Biogents AG, Regensburg, Germany) will be deployed outdoor. BG Pro traps with lure will be placed outside the main dwelling structure close to presumed mosquito resting places, suspended 1.5m off the floor, and out of direct sunlight, wind, or heavy rain. BG Pro traps will be deployed with BG Lures releasing artificial human skin odour (Biogents AG, Regensburg, Germany) and light and run for 12 hours overnight. Immature collections will be done by systematically sampling aquatic habitats within 50 m of the study participant house using a standard dipper [ 38 ]. Both adult and larval collections will be done on one occasion only.

Additional entomological surveillance.

We will attempt to determine whether collections of larvae and adult anophelines in and around the homes of cases and controls shortly after recruitment can be used to infer the presence of larvae/adult and mosquito density at the time of malaria transmission, approximately 10 days previously. Here we will adopt a similar approach to a previous case-control study conducted in The Gambia [ 19 ]. Entomological surveillance of larvae and adult anophelines will be performed within 48 hours of recruitment and repeated 10 days later for 20% of all cases and controls. The presence/absence of larvae/adult and the density of An . stephensi and other anopheline species will be compared between the two catches in the same location for quality assurance.

Due to low catch numbers of adult An . stephensi in Ethiopia, additional entomological surveillance will be conducted every two months. An initial census conducted in December 2023 suggests the presence of permissive and An . stephensi positive aquatic habitats across Metehara. The two Kebeles (Dire Gobu and Haro Adi) will be divided into 8 quadrants (4 quadrants per Kebele) and sampling efforts allocated to each proportional to household and potential aquatic habitat density. Every 2 months, permissive aquatic habitats identified in the census will be surveyed for An . stephensi , along with a subset of habitats selected purposively during each sampling round. Human and animal structures within 20 metres of each aquatic habitat will be surveyed for adult An . stephensi using Prokopack aspiration, CDC LT and BG Pro traps.

Mosquito species identification.

For adult collections, mosquitoes will be sorted to anophelines and culicines. Anophelines will be identified morphologically [ 39 ]. Morphological identification of adults and larvae will be confirmed using polymerase chain reaction (PCR) [ 40 ]. To reduce the number of PCRs run, larvae will be pooled into groups of 20 samples according to their catch location.

Blood meal source and infection rate determination.

Blood meal analysis of adults will be conducted; abdomens of freshly blood-fed An . stephensi and other malaria vectors will be subjected to amplification [ 41 ]. Furthermore, adult An . stephensi and a random sample of other malaria vectors will be screened for P . falciparum and P . vivax DNA. qPCR amplification will target the SSU RNA gene with species-specific primers [ 32 ].

Data management

Study data will be collected and managed using REDCap [ 42 , 43 ] electronic data capture tools hosted at the Liverpool School of Tropical Medicine (for Sudan) and Armauer Hansen Research Institute (for Ethiopia).

Statistical analysis plan

The primary analysis for this study will include three separate exposure variables: 1) presence/absence of adult An . stephensi in and around the household; 2) presence/absence of immature An . stephensi in and around the household; and 3) combined presence/absence of adults and/or immature An . stephensi in and around the household. Should sufficient An . stephensi be caught, additional analyses will assess the impact of adult vector density on malaria status. Association between exposure variables and case status will be assessed using conditional logistic regression. Covariates will include co-occurrence of other anopheline vectors and participant gender. Effect estimates will be expressed as odds ratios with 95% confidence intervals.

A similar approach to the above will be used to assess the associations between other key risk factors for malaria and malaria case status. These include (but are not limited to) presence/absence and density of adult and/or immature endemic malaria vectors, ITN use, ITN quality, travel history, and proximity of the sleeping space to animals. The distance between case and control households and An . stephensi positive habitats or structures identified in the overlaid entomological surveillance will be assessed, taking into account the most recent surveillance round only.

Sensitivity analysis.

While the primary analysis will include all cases and controls recruited into the study, a sensitivity analysis will be conducted to adjust for potential misclassification of cases and controls. Cases with negative PCR for Plasmodium species will be excluded, as will controls with positive PCR results.

Community sensitisation

Meetings have been held to introduce the study to relevant stakeholders in each country, including the Federal Ministry of Health, Regional Health Bureau, and City Administration Health Office in Ethiopia and Federal and State Ministry of Health, Locality Health Affairs, and the facility director in Sudan. During these meetings we presented the objectives of the research, research activities and potential implications for policy. Furthermore, regional health bureaus from the selected sites have been informed of the research and the methods involved. Prior to the start of the study, we will hold meetings with community leaders in the study sites (e.g. urban dwellers association in Ethiopia, Development & Public Services committees, and Health Facility Development Committee in Sudan) to inform them about the project and give them an opportunity to ask questions.

This study received ethical approval from the Liverpool School of Tropical Medicine Research Ethics Committee (Ref # 22–005, Ethiopia: 27 Jan 2023, Sudan: 18 Aug 2022), the London School of Hygiene and Tropical Medicine Research Ethics Committee (Ref # 28287, 24 Nov 2022), the Republic of Sudan National Health Research Ethics Review Committee (Ref # 8-1-21, 7 Feb 2021), the Armauer Hansen Research Institute Ethics Review Committee (Ref # PO-35-22, 20 Aug 2022), and the National Ethics Review Committee in Ethiopia (Ref # 1724642123, 23 Jan 2023).

We will adhere to guidelines set forth by the Declaration of Helsinki. All staff and investigators will receive training on human subjects protection, safeguarding and study-specific standard operating procedures (SOPs). Data collection activities (both epidemiological and entomological) will require written informed consent from the study participant or their caregiver. Consent forms are translated into local languages and explain in-depth the purpose of the study, procedures, risks and benefits, and the voluntary nature of participation.

Dissemination

Findings will be disseminated in the study health facilities and communities through meetings to which local community members and local stakeholders will be invited. During these meetings, plain language summaries of the key findings of the study will be presented. Findings will be presented through meetings and briefs to stakeholders including the Federal Ministry of Health and National Malaria Control Programme. Internationally, findings from this work will be presented through peer-reviewed publications and presentations at scientific conferences and international policy fora.

This case-control study will provide evidence of the relative impact of An . stephensi on malaria in Ethiopian and Sudanese urban settings as compared to endemic Anopheles species. Recruiting cases and controls from health facilities and conducting entomological surveillance in and around houses will determine whether household-level exposure to An . stephensi is associated with greater risk of malaria. This study employs a unique design, pairing epidemiological principles with entomological surveillance.

To date, little is known about the impact of An . stephensi on malaria burden in urban Africa, but some preliminary evidence points to a potential positive association. A 2019 paper from Djibouti describes a simultaneous rise in An . stephensi occurrence and malaria cases from 2013–2017, including an increase in P . vivax cases [ 7 ]. While not able to draw causal conclusions, this paper provides descriptive evidence for the potential that the rise in An . stephensi contributed to malaria transmission. To support this finding, the authors detected a 3.1% sporozoite rate among captured adult An . stephensi females. Furthermore, a case-control study conducted during a dry season malaria outbreak in 2022 in Dire Dawa, Eastern Ethiopia found that presence of An . stephensi adults and/or larvae was associated with 3.30-times the odds of malaria cases compared to controls (95% CI 1.65–6.47) [ 17 ]. Importantly, abundance of An . stephensi in this setting was markedly high: all Anopheles larvae collected from artificial containers were identified as An . stephensi , and 97% of adult Anopheles mosquitoes were An . stephensi . The case-control study proposed here will further contribute to this body of evidence, expanding both geographically and temporally, and allowing for the assessment of potential seasonal changes in the associations between An . stephensi and malaria risk through the 12-month study period. This study will also include important urban settings, including those that rely heavily on irrigation schemes and plantations.

This study design is not without challenges and limitations. Firstly, the design assumes that entomological exposures around households are relatively stable. To test this assumption, entomological surveillance will be repeated after 10 days for a subset of all cases and controls. If the correlation between entomological collections is low, findings from this study may be attenuated. Secondly, this study will assess household-level exposure to vectors, yet malaria transmission could take place outside of the household, in the workplace or during travel. To better understand this, household surveys will collect information on employment, school attendance, and travel history. Finally, from an operational perspective, harmonizing the study in two countries with distinct settings and malaria profiles poses challenges. Substantial work has been done to tailor the studies to each setting, while maintaining the core design across the two countries. Civil unrest in Sudan beginning in April 2023 presents further challenges to the implementation of the study; for this reason, protocol details, including study locations, are subject to change. Civil unrest in Ethiopia close to Metehara may also hinder study progress.

This study will address the critical need to understand the public health impact of the threat posed by An . stephensi . With this understanding, future work can evaluate how existing control interventions can be used against the vector and develop additional strategies to protect urban populations from malaria.

Acknowledgments

We would like to thank the Sudanese Federal Ministry of Health, Sudanese National Malaria Control Programme, Entomological Surveillance teams in the 9 states of Sudan included in the Research, Ethiopian Federal Ministry of Health, Ethiopian National Malaria Elimination Programme, State and District health offices, health facility staff and local communities in the study sites for their kind cooperation with this study.

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Patient presentation

Differential diagnosis, examination, investigations, final outcome.

• Evaluation - Questions & answers

A 17 year old adolescent presents to a refugee camp infirmary obtunded. He has been febrile for the last 4 days and has been complaining of back pain and stomach aches accompanied with diarrhoea.

Acknowledgement This case study was kindly provided by Barclay Stewart, Medical University of South Carolina, Fogarty International Clinical Research Scholar, Nairobi, Keny a

The patient is a refugee from the northern part of Sudan who was relocated to a northern Ugandan refugee camp. On arrival 2 months ago he received a comprehensive medical exam. He was noted to be undernourished but not suffering from any acute or chronic illnesses. He was placed on a nutrition supplementation program during his first month at the camp and given all appropriate vaccinations.

He was fine until 4 days ago when he told one of the staff that he was having back and stomach pains. He was taken to the camp clinic, examined, given medication and released. He later admitted he had not taken the medication. A gentleman staying in the bed next to him alerted the clinic staff because he was concerned about the patient’s shivering and mumbling. The clinic staff came to see him and immediately had him taken to the infirmary.

• Encephalitis
• Endocarditis
• Gastroenteritis with secondary severe dehydration
• Toxic Shock Syndrome
• Typhoid Fever
• Brucellosis
• Relapsing Fever
• Katayama Fever

On Admission The young man is thin, drenched in sweat, and obtunded Vitals

• Respiratory Rate-34
• Temperature-40.1
• Blood Pressure- not recorded
• Pulse-Oxygen-91%

Head and Neck

• Jaundice seen in sclera.
• Eyes sunken and unresponsive.
• No papillidema.
• Non-inflamed nasal passage without discharge.
• Oral mucosa pale, without lesions.
• No cervical lymphadenopathy , midline trachea

Respiratory System

• Chest is symmetrical in appearance, no scars.
• Breathing deep and rapid.
• No vocal or tactile fremitus.
• Clear on auscultation bilaterally.

Cardiovascular System

• Non displaced, bounding apex beat.
• Tachycardic with a regular rhythm.
• Normal S1 and S2.
• Radial, femoral and dorsalis pedis pulses present and bounding.
• Capillary refill within 2 seconds.
• Normal upon inspection.
• No masses palpable.
• No hepatosplenomegally.
• Bowel sounds diminished but present.

Neurological

• Young man obtunded, not following commands although appears to attempt to by moving slightly on the initial command.
• Localises to pain.
• Eyes open in response to pain

The pathophysiology of Plasmodium sp ., is considered to arise from one of two possible mechanisms. One advocates the mechanical hypothesis of insufficient tissue oxygenation resulting in sequestration of the parasitized red blood cells in the microvasculature. The second advocates the cytokine hypothesis in which the exuberant release of pro-inflammatory cytokines is the basis of the disease and accompanying mortality. This case study discussion focuses on the cytokine hypothesis.

Generally it is thought that the pro-inflammatory cytokines are central to the pathophysiology of systemic disease caused by infectious and non-infectious agents. These cytokines bring about symptoms which include anorexia, malaise, myalgia, arthralgia and fever, which patients experience during systemic disease such as malaria.  Furthermore, the release of these cytokines in large amounts are responsible for severe illnesses. Of special note is TNF-α . When this cytokine is produced in appropriate concentrations it is vital to the immune response and subsequent clearance of malaria. However, pathology ensues when TNF is produced in large amounts. Many systemic diseases, both infectious and non-infectious, have been linked to this superabundant pro-inflammatory cytokine release. Effects of this release, seen in malaria, sepsis and tissue injury syndromes, include metabolic acidosis , hyperlactatemia  and encephalopathy.

During the blood stage, infection with Plasmodium falciparum  is associated with high levels of pro-inlammatory cytokines such as IL-1 , IL-6 , TNF-α, IL-12 and   INF-γ  and low levels of anti-inflammatory cytokines IL-10 and TGF-B causing symptoms associated with malaria such as fever and anaemia. Although it is also true that lysis of infected red cells, splenic removal of infected red cells and red-cell occlusion in blood vessels contributes to anaemia, cytokines, particularly  IL-1 and TNF-α, play an additive role by causing mitochondrial dysfunction, bone marrow suppression and upregulation of endothelial adhesion molecules.

Furthermore, inflammatory cytokines upregulate endothelial cell adhesion molecules in order to entice circulating blood elements to undergo diapedesis and intercellular migration. In many disease states, including  malaria, these blood elements which include activated leukocytes and platelets promote coagulation. In malaria, circulating monocytes, placental macrophages and thrombin enhance adhesion by increasing CD36, a receptor known to bind parasitized erythrocytes on platelet surfaces. These adherent cells set up local foci of inflammation which produces more inflammatory cytokines. In combination with the effects of systemic inflammation, these local inflammatory reactions cause a cycle of endothelial integrity loss, vascular permeability, cellular destruction and inflammatory cytokine release. These responses can result in complications such as decreased consciousness and coma.

The patient was given a full course of quinine and recovered well.

After the course of malaria treatment he was begun on weekly malaria prophylaxis with mefloquin because the region of Sudan from which he came was not a malaria endemic region, unlike the area surrounding the refugee camp in northern Uganda.

Evaluation – Questions & answers

What is the diagnosis?

Which two mechanisms have been proposed to cause disease in falciparum malaria cases?

What contributes to the anaemia seen in malaria?

What is the relationship between parasitized red cell adhesion, inflammatory cytokines, and coma?

In sepsis and malaria , what are some of the consequences of greatly increased TNF-α levels?

What symptoms do pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 bring about?

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