Malaria

What’s New in the Management of Malaria?

Katherine Plewes, MSc, MD, DPhil, FRCPCa,b, Stije J. Leopold, MD, PhD
a
,
Hugh W.F. Kingston, BMBCh, MRCP, PhDc,d,
Arjen M. Dondorp, MD, PhDc,e,*

KEYWORDS
Malaria Plasmodium Management Antimalarials Resistance

KEY POINTS
Intravenous artesunate for severe malaria and oral artemisinin-based combination thera-
pies for uncomplicated malaria are first-line treatment for all Plasmodium species causing
disease in humans.
Species-specific diagnosis is important to guide appropriate primaquine administration
for gametocytocidal treatment of falciparum malaria to reduce transmission in endemic
areas, and for radical treatment of vivax and ovale malaria to prevent relapse.
Severe malaria management requires early renal replacement therapy for acute kidney
failure and cautious fluid resuscitation to prevent lethal pulmonary edema.
Post-artesunate delayed-onset hemolysis of once-infected red blood cells is an expected
consequence of the removal of pyknotic ring form parasites through splenic pitting after
artesunate treatment.
Artemisinin and partner drug resistant falciparum malaria is spreading in the Greater Me-
kong Subregion, and increasingly causes treatment failure of artemisinin-based combina-
tion therapies.

Disclosure Statement: The authors declare that they have no relationship with a commercial
company that has a direct financial interest in subject matter or materials discussed in article
or with a company making a competing product.
a
Malaria Department, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol
University, 3/F 60th, Anniversary Chalermprakiat Building, 420/6 Rajvithi Road, Bangkok 10400,
Thailand; b Department of Medicine, University of British Columbia, Vancouver General Hos-
pital, 452D Heather Pavilion East, 2733 Heather Street, Vancouver, British Columbia V5Z 3J5,
Canada; c Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus,
Headington, Oxford OX3 7BN, UK; d Malaria Department, Mahidol Oxford Research Unit,
Faculty of Tropical Medicine, Mahidol University, 3/F 60th, Anniversary Chalermprakiat Build-
ing, 420/6 Rajvithi Road, Bangkok 10400, Thailand; e Mahidol-Oxford Tropical Medicine
Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 3/F 60th, Anniversary
Chalermprakiat Building, 420/6 Rajvithi Road, Bangkok 10400, Thailand
* Corresponding author. Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of
Tropical Medicine, Mahidol University, 3/F 60th, Anniversary Chalermprakiat Building, 420/6
Rajvithi Road, Bangkok 10400, Thailand.
E-mail address: [email protected]

Infect Dis Clin N Am 33 (2019) 39–60

https://doi.org/10.1016/j.idc.2018.10.002 id.theclinics.com
0891-5520/19/ª 2018 Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
40 Plewes et al

INTRODUCTION

Malaria affected an estimated 216 million people causing 445,000 deaths in 2016.1
This reduced burden of disease and death is a result of more than a century of world-
wide effort and research aimed at improving prevention, diagnosis, and management
of malaria.
Since the first description of a protozoan parasite causing malaria,2 it is now recog-
nized that 6 Plasmodium species cause infection in humans living in tropical and sub-
tropical regions. Plasmodium falciparum and Plasmodium vivax cause the most
infections worldwide with differing geographic distributions. The contribution of Plas-
modium malariae, and sympatric species Plasmodium ovale curtisi and Plasmodium
ovale wallikeri to the global burden of disease is low. The zoonotic Plasmodium knowl-
esi, jumping species from Macaque monkeys, is predominantly found in Southeast
Asia. Molecular diagnostics have recently identified human cases of zoonotic Plasmo-
dium simium and Plasmodium cynomolgi; however, the prevalence and clinical impact
of these species are unclear.3,4
Plasmodium infections result in a spectrum of clinical effects, including asymptom-
atic parasitemia, uncomplicated malaria, severe malaria, and death. Severe and fatal
malaria are predominantly caused by P falciparum principally due to endothelial
cytoadherence causing sequestration of mature-staged infected red blood cells in
vital organs. This results in microcirculatory obstruction and end-organ dysfunction.
Although P vivax and P knowlesi infection can cause severe malaria,5,6
cytoadherence-mediated sequestration has not been clearly observed. Understand-
ing factors related to the infecting parasite species and host immunity is critical to opti-
mizing treatment and preventing death. This review highlights recent developments in
our understanding of malaria pathophysiology and the translation to new aspects of
management.

DIAGNOSIS

Appropriate species-specific management of malaria requires early confirmation of

the diagnosis. All febrile travelers, particularly visiting friend and relative travelers,
returning from malaria-endemic areas should be considered to have malaria until
proven otherwise. Febrile patients living in or recently immigrating from endemic re-
gions should have malaria ruled out. The clinical features of severe and uncomplicated
malaria are nonspecific; therefore, a parasitologic diagnosis is required by microscopy
or a rapid diagnostic test (RDT). Regardless of species, a diagnosis of severe or un-
complicated malaria can be made based on specific diagnostic criteria (Box 1).
Microscopic analysis of stained thick and thin blood smears is the diagnostic refer-
ence standard. Thick-smear diagnosis allows sensitive parasitemia quantification (as
low as 30 parasites per microliter), and thin-smear diagnosis permits speciation and
prognostic assessment via parasite staging and proportion of pigment-containing
neutrophils. In severe falciparum malaria, the presence of late-stage parasites and/
or more than 5% of neutrophils containing pigment predict poor outcomes.7,8 In un-
stable transmission regions, nonimmune patients with signs of severity and low para-
sitemia may reflect a high sequestered parasite biomass and should not falsely
reassure the treating physician.8 A high parasitemia in the absence of signs of severity
is associated with increased mortality. Large differences between the number of pe-
ripheral blood infected cells and number of sequestered infected cells may exist, such
that rapid increases in parasitemia can occur in synchronous infections.9 In regions of
high transmission, diagnosis is challenging because partially immune parasitemic in-
dividuals are asymptomatic. RDTs detecting P falciparum histidine-rich protein 2
Malaria 41

Box 1
Diagnostic criteria for severe malaria

I. Falciparum malaria
Clinical criteria
Prostration
Convulsions (>2 within 24 hours)
Coma (Glasgow Coma Scale <11 in adults or Blantyre Coma Scale <3 in children)
Respiratory distress (acidotic breathing)
Shock (capillary time 3s, with or without systolic blood pressure <80 mm Hg [adults],
less than 70 mm Hg [children])
Pulmonary edema (confirmed radiologically)
Abnormal bleeding
Jaundice
Anuria
Hemoglobinuria (blackwater)
Repeated vomiting
Laboratory criteria
Anemia (hemoglobin <70 g/L in adults, <50 g/L in children)
Acidosis (base deficit >8 mEq/L or bicarbonate <15 mmol/L, or venous lactate >5 mM)
Hypoglycemia (blood glucose <2.2 mmol/L or <40 mg/dL)
Renal impairment (creatinine >265 mmol/L [3 mg/dL] or blood urea >20 mmol/L)
Jaundice (bilirubin >50 mM [3 mg/dL] and parasite count >100,000/mL)
Hyperparasitemia >10%
II. Knowlesi malaria
Clinical criteria
Criteria as per falciparum malaria
Inability to tolerate oral therapy
Laboratory criteria
Criteria as per falciparum malaria with modified parasitemia cutoffs as follows
Jaundice and parasitemia >20,000/mL
Parasitemia >100,000/mL
III. Vivax malaria
Criteria as per falciparum malaria excluding parasite density thresholds

Data from World Health Organization. Severe malaria. Trop Med Int Health 2014;19 Suppl
1:7–131.

(PfHRP2) have a detection threshold of approximately 200 parasites per microliter but
new ultrasensitive PfHRP2 RDTs can detect parasitemias as low as 2 to 4 parasites
per microliter.10 However, PfHRP2-based RDTs are not quantitative, remain positive
for up to 1 month, exhibit prozone effect at high parasitemias, and may be falsely
negative in individuals with PfHRP2 gene deletions, which is reported mainly from
South America as well as increasingly from Africa.11–14
In Southeast Asia, speciation may be challenging, as young ring stages of
P knowlesi, P falciparum, and P vivax look similar, whereas mature trophozoites of
P knowlesi and P malariae also may be confused. In Africa, P vivax is sporadically
being diagnosed in Duffy-negative populations, suggesting alternative mechanisms
of red blood cell invasion.15 In absence of a peripheral blood smear, an RDT with a
panspecific or species-specific lactate dehydrogenase (pLDH) or aldolase is
required for diagnosing nonfalciparum infections. In high resourced regions, diag-
nosis by polymerase chain reaction should be pursued for accurate species-
specific diagnosis and treatment of exported malaria, particularly from Africa and
Southeast Asia.
42 Plewes et al

CASE MANAGEMENT

Uncomplicated falciparum malaria can progress rapidly to severe disease and death,
particularly in nonimmune individuals. Physicians must be alert to the fact that
decreasing transmission in Africa will result in older age groups being at risk for severe
malaria as premunition (protection from disease despite presence of peripheral blood
parasites) is lost (Fig. 1). Thus, it is important that a malaria diagnosis is made soon
after onset of malaria symptoms and antimalarial treatment started without delay. If
severe malaria is suspected, particularly in high-risk groups, but parasitologic diag-
nosis is delayed antimalarial treatment should be started immediately. Treatment re-
quires combination therapy with at least 2 effective antimalarials with different
mechanisms of action to prevent drug resistance. Antimalarial dosing must be
weight-based to ensure necessary drug concentrations; population specific age-
based derived schedules can be more practical to implement. Goals of care are to pre-
vent progression of disease and death by ensuring rapid clinical cure and parasite
clearance. In malaria-endemic regions, treatment also aims to reduce transmission
of a treated infection. In low transmission areas additional gametocytocidal therapy
is added to further reduce transmission potential. In malaria caused by P vivax or
P ovale, additional hypnozoitocidal therapy is indicated to prevent relapse infection.

SEVERE MALARIA

Severe malaria is mainly caused by P falciparum, but also observed in P vivax and
P knowlesi infections. It is rarely seen with the other Plasmodium species. Severe ma-
laria caused by any Plasmodium species is a medical emergency requiring prompt
administration of an effective antimalarial and supportive management, ideally in an
intensive care unit. In resource-limited settings, transfer to higher-level facilities should
be considered if mechanical ventilation, renal replacement therapy (RRT) or hemody-
namic monitoring are required. Mortality from severe malaria is still 10% to 20%
despite optimal treatment and reaches 100% if left untreated.16,17 Mortality in preg-
nant women is approximately 50%. Coma, kidney dysfunction and acidosis indepen-
dently predict mortality in both non-pregnant adults and children with severe
falciparum malaria.18–20 Severe malaria is more likely in pregnant women in the second
and third trimesters compared to other adults and is more often complicated by pul-
monary edema and hypoglycemia. Severe knowlesi malaria is associated with hyper-
parasitemia due to its 24-h erythrocytic cycle, shock, acute kidney injury (AKI) and
respiratory failure.21,22 Severe vivax malaria is most commonly associated with respi-
ratory failure, AKI and severe anemia.23
Antimalarials
Immediate antimalarial treatment
Intravenous artesunate is first-line treatment for severe malaria worldwide caused by
any Plasmodium species. All adults and children with severe malaria, including infants,
lactating women, and pregnant women in all trimesters should receive intravenous
artesunate for at least 24 hours until oral medication is tolerated (Box 2).17 Two land-
mark randomized controlled trials (RCTs) showed that intravenous artesunate is supe-
rior to intravenous quinine, reducing mortality by 35% (95% CI 18.5–47.6) in Southeast
Asian adults and by 22% (95% CI 8.1–36.9) in African children.24,25 Artesunate is well-
tolerated and rapidly metabolized to its active metabolite dihydroartemisinin, reaching
peak concentrations within 10 minutes and is rapidly eliminated (half-life 45 minutes).26
It has broad stage specificity, killing young circulating ring-staged parasites up to
late-staged sequestered parasites (Fig. 2).9,27 This activity against circulating ring-
Malaria 43

Fig. 1. Relationship between age and malaria severity in moderate transmission intensity re-
gions. (A) Repeated exposures lead to acquired protection against severe malaria then against
illness from malaria then in adulthood protective against microscopy-detected parasitemia.18
With decreasing transmission intensity protection against illness and parasitemia (blue and
green curves) will be lost and older age groups will be at risk of severe disease (red curve shifting
to right). (B) Manifestations of severe falciparum by age in unstable transmission regions. (From
White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet
2014; 383:723-35. Reprinted with permission from Elsevier (The Lancet, 2014; 383:723–35)

stage parasites is considered its critical advantage over quinine, as artesunate kills
parasites before they can mature and sequester in the microvasculature.28 Quinine
has more adverse drug effects, including hypoglycemia, hyperinsulinemia, cardiotox-
icity, and hypotension, particularly if given as a rapid injection rather than infusion.23
Artemether showed a smaller survival benefit than does artesunate, likely due to its
44 Plewes et al

Box 2
Antimalarial treatment of severe malaria

Adults, pregnant women, and children

First-line initial therapy
Artesunate intravenously 2.4 mg/kg per dose at hour 0, 12, and 24, then every 24 hoursa
If <20 kg: artesunate intravenous 3.0 mg/kg per dose
Alternative initial therapy
Quinine dihydrochloride intravenous infusion 20 mg/kg loading dose (over 4 hours) then
maintenance dose 10 mg/kg (over 2 hours) every 8 hoursb
Artemether intramuscularc injection 3.2 mg/kg loading dose, then 1.6 mg/kg every
24 hours
After 24 hours and able to eat and drinkd
Artemisinin-based combination therapy orally for 3 days (not mefloquinee)
Travel history to countries with artemisinin resistance
Intravenous artesunate PLUS intravenous quinine (expert opinion, no evidence)

If intravenous artesunate is not available, use artemether in preference to quinine in adults and
children.
a
Artesunate dose does not need to be adjusted if renal impairment or liver dysfunction
present.
b
Quinine requires dose adjustment according to renal dysfunction after 48 hours of full
dosage. Dose adjustments are not required if receiving dialysis but quinine should be given
post-RRT dosing if on dialysis.
c
Intramuscular injections administered to anterior thigh.
d
See uncomplicated malaria treatment (see Box 3) for oral artemisinin-based combination
therapy options and alternatives.
e
Mefloquine increases risk of postmalaria neurologic syndrome and is contraindicated in pa-
tients with epilepsy or neuropsychiatric disorders.
Data from World Health Organization guidelines for the treatment of malaria. 3rd edition.
2015. Available at: http://www.who.int/malaria/publications/atoz/9789241549127/en/. Accessed
April 24, 2017.

erratic intramuscular absorption.29 Pre-referral rectal formulated artesunate given to

severely ill children younger than 6 unable to take oral medications may reduce mor-
tality.30 Parasite clearance with artesunate typically occurs within 72 hours and should
be documented by assessing thick and thin smears every 6 to 12 hours.

Fig. 2. Stage of parasite development and pathogenicity with rough estimates of stage
specificity and “time windows” of antimalarial drug effects. (Adapted from White NJ,
Krishna S. Treatment of malaria: some considerations and limitations of the current methods
of assessment. Trans R Soc Trop Med Hyg 1989;83:767–77; with permission.)
Malaria 45

Follow-on antimalarial treatment

After a minimum of 24 hours of intravenous antimalarial treatment and when oral medi-
cation can be tolerated, treatment must be completed with an effective, full course of
an oral artemisinin-cased combination therapy (ACT) (Box 3). If an ACT is not avail-
able, then a non-ACT regimen can be used. Mefloquine should not be given as

Box 3
Antimalarial oral treatment of uncomplicated malaria

Uncomplicated Plasmodium falciparum, and Plasmodium knowlesi malaria

Artemisinin-based combination therapy (ACT): 3-day regimens
Artemether-lumefantrine (1.4–4.4/10–16 mg/kg) by mouth (PO) twice daily x 3 days (with
fat-containing food)**
Dihydroartemisinin-piperaquine (4/18 mg/kg) PO daily for 3 days
If <25 kg: Dihydroartemisinin 4 (2.5–10) mg/kg and Piperaquine 24 (20–32) mg/kg PO
daily for 3 days
Artesunate (4 mg/kg) plus mefloquine (8 mg/kg) PO daily for 3 daysa
Artesunate (4 mg/kg) plus amodiaquine (10 mg/kg) PO daily for 3 daysa
Artesunate (4 mg/kg) PO daily for 3 days plus single-dose sulfadoxine-pyrimethamine
(25/1.25 mg/kg)b
ACT: 7-day regimens
Artesunate (2 mg/kg) PO daily plus tetracycline (4 mg/kg) PO every 6 hours for 7 daysc
Artesunate (2 mg/kg) PO daily plus doxycycline 100 mg PO twice daily for 7 daysc
Artesunate (2 mg/kg) PO daily plus clindamycin (20mg/kg) PO divided 2 times daily for
7 daysd
Non-ACT regimens
Atovaquone-proguanil (15/6 mg/kg) PO daily for 3 days
Quinine (10 mg/kg) plus EITHER tetracycline OR doxycycline OR clindamycin for 7 daysc,d
Uncomplicated P falciparum, and travel to countries with artemisinin resistancef
Atovaquone-proguanil (15/6 mg/kg) PO daily for 3 days
Quinine (10 mg/kg) plus EITHER tetracycline OR doxycycline OR clindamycin for 7 daysc,d
Uncomplicated chloroquine-sensitive Plasmodium vivax, Plasmodium ovale, or Plasmodium
malariaee
Chloroquine (10 mg base/kg) per day at hour 0 and hour 24 then 5 mg base/kg at hour 48
Uncomplicated chloroquine-resistant P. vivaxe
Oral ACT (except sulfadoxine-pyrimethamine) for 3 days
Quinine (10 mg/kg) plus EITHER tetracycline OR doxycycline OR clindamycin for 7 daysc,d
a
World Health Organization prequalified fixed-dose tablets preferable to loose tablets.
b
Chloroquine-resistant P vivax can be treated with any oral ACT except artesunate plus
sulfadoxine-pyrimethamine.
c
Doxycycline preferred, as it does not accumulate in renal failure and it can be dosed daily.
Contraindicated in children younger than 8 years and pregnant/lactating women (Class D).
d
Recommended in first-trimester pregnant women.
e
P vivax and P ovale should be followed by a course of primaquine for radical cure to prevent
relapse. Contraindicated if glucose-6-phosphate-dehydrogenase deficient, pregnant or age
younger than 6 months. Primaquine 0.5 mg base/kg daily for 14 days (G6PD normal; East
Asia and Oceania); Primaquine 0.25 mg base/kg daily for 14 days (G6PD normal; elsewhere)
or 0.75 mg base/kg weekly for 8 weeks (G6PD deficient).
f
Admit patient, monitor clinical and parasitologic response until recovery or parasite
clearance, follow-up at 4 weeks to ensure cure.
** Number of tablets per dose according to pre- defined weight bands (5–14 kg: 1 tablet;
15–24 kg: 2 tablets; 25–34 kg: 3 tablets; and > 34 kg: 4 tablets) given twice a day for 3 days.
Data from World Health Organization Guidelines for the treatment of malaria. 3rd edition.
2015. Available at: http://www.who.int/malaria/publications/atoz/9789241549127/en/. Accessed
April 24, 2017.
46 Plewes et al

follow-on treatment if impaired consciousness was present at diagnosis due to the

increased risk of neuropsychiatric complications. In returning travelers, follow-on anti-
malarial medication should be different from any prophylactic drug used during travel.
In severe vivax malaria, a full course of radical treatment with primaquine should also
be given after recovery.

Cerebral Malaria and Convulsions

Cerebral malaria is a clinical malaria syndrome of impaired consciousness character-
ized by unrousable coma, as defined in Box 1, in the absence of hypoglycemia, convul-
sions, sedative drugs, and nonmalarial meningoencephalitis. Generalized convulsions
are observed in approximately 80% of children and 15% of adults and may progress
to status epilepticus and coma.24,25 Blood cultures should be drawn and glucose should
be checked 4-hourly, especially if there is a decline in the coma score. Hypoglycemia is
more frequent in children, pregnant women, and patients receiving quinine. In comatose
children with suspected cerebral malaria, lumbar puncture does not increase mortality
even when swelling on MRI brain or papilledema is present.31 Funduscopic examination
for malaria retinopathy is specific, but not highly sensitive, for the diagnosis of cerebral
malaria and is prognostic in patients with severe malaria.32,33 Patients should be posi-
tioned in the lateral recovery position, alternating sides every 2 hours.23 A large random-
ized controlled trial is currently being conducted to assess whether recovery positioning
in acutely comatose adults decreases aspiration pneumonia and improves outcomes
(ClinicalTrials.gov NCT02427633). An oropharyngeal airway may be sufficient and/or
bridge until endotracheal intubation is possible if the patient cannot maintain a patent
airway. Nasogastric tube with suction may protect from aspiration but it should be
clearly communicated to avoid early enteral feeding because feeding within 60 hours
is associated with an increased risk of aspiration pneumonia.34
Supportive therapies include glucose and acetaminophen to maintain euglycemia
and fever control. Mannitol administration to reduce intracranial pressure in patients
is not recommended.17 An RCT of a single dose of mannitol in children with cerebral
malaria found no impact on clinical outcomes compared with placebo.35 In adults with
cerebral malaria and brain swelling on computed tomography imaging, mannitol pro-
longed coma recovery time compared with controls not receiving mannitol.36 RCTs of
dexamethasone to reduce vasogenic edema in adults37 and children38 found no
benefit on coma recovery or survival and is therefore not recommended. Corticoste-
roids increase the risk for gastrointestinal bleeding, seizures, and prolonged coma res-
olution times compared with placebo. Seizure prophylaxis with phenobarbital or
fosphenytoin has not shown to be beneficial in preventing seizures, where the former
was associated with increased mortality likely due to respiratory depression.39–41
Therefore, routine seizure prophylaxis is currently not recommended in patients with
seizures or cerebral malaria. Witnessed seizures should be treated with up to 2 doses
of a benzodiazepine 10 minutes apart with careful respiratory monitoring. Recurrent
seizures likely indicate status epilepticus and should be treated with phenytoin or
phenobarbital loading, then maintenance dosing in a highly monitored setting.

Shock, Dehydration, and Acidosis

Fluid management is a critical but challenging intervention in the management of se-
vere malaria. Patients present at differing times during their infections with variable de-
grees of hypovolemia, acidosis, and AKI. Most adult patients have a stable blood
pressure in the low-normal range. Thus, fluid therapy should be individualized, as adult
patients are at risk of developing pulmonary capillary leakage and subsequent acute
respiratory distress syndrome (ARDS), particularly if excess fluids are administered
Malaria 47

too rapidly. However, ARDS can develop after admission unpredictably and irrespec-
tive of fluid administration. In a study of Bangladeshi adults, 70% of patients were
hypovolemic at the time ARDS developed.42 Clinical assessment and invasive hemo-
dynamic monitoring at admission do not necessarily reflect effective circulating blood
volume nor predict fluid responsiveness or ARDS.42–44 Further, correction of fluid def-
icits has not been shown to improve acidosis or AKI and increases the incidence of
ARDS. This is likely due to the sequestration with subsequent microvascular obstruc-
tion and tissue hypoperfusion driving the acidosis and acute tubular injury that is not
corrected by fluid loading. Aggressive fluid resuscitation in pediatric patients with
compensated hemodynamic shock is also harmful. A landmark multinational study
in African children with severe febrile illness and compensated shock showed a rela-
tive risk for death of 1.45 (95% CI 1.13–1.86; P 5 .003), with fluid bolus therapy (20 or
40 mL/kg of 0.9% saline or 5% albumin).45 The case fatality rate of the 1793 children
with a positive malaria slide was 9.2% with fluid bolus therapy compared with 5.8% in
the control group (relative risk for death of 1.59; 95% CI 1.10–2.31). The increased
mortality was suggested to be due to cardiovascular collapse rather than fluid over-
load in a retrospective analysis.46
Hemodynamic shock is not common on admission in severe malaria (approximately
16% of adults and 12% of children) and should prompt investigation for an alternative
cause of the septic syndrome.24,25 Concomitant bacteremia is observed in 6% to 13%
of children and adults with malaria, and is frequently associated with increased mortal-
ity.47–49 The incidence of bacteremia is likely underestimated due to minimal microbio-
logical diagnostics and frequent preadmission antibiotic use in resource-limited
settings. Gram-negative organisms are most commonly isolated, particularly nontyphoi-
dal Salmonella, followed by Streptococcus pneumoniae and Staphylococcus
aureus.47–49 Gram-negative bacteremia complicating malaria is thought to be due to in-
testinal translocation from sequestration-mediated increased gut permeability, along
with macrophage and neutrophil dysfunction.47,50,51 Shock and leukocytosis are
frequently associated with concomitant bacteremia in malaria; however, there is no reli-
able clinical or laboratory predictor. The metabolic acidosis in severe malaria is predom-
inantly due to lactic acid from sequestration-induced tissue hypoxia. However,
hydroxyphenyllactic and other gut-derived microbial acids are also elevated and predic-
tive of mortality (ClinicalTrials.gov NCT02451904).52 Thus, loss of gut integrity likely con-
tributes to acidosis and gram-negative bacteremia in severe malaria; whether these gut-
derived acids are predictive biomarkers of bacteremia is yet to be determined.
Given the frequently fatal outcome of ARDS even in settings with mechanical venti-
lation, the World Health Organization (WHO) recommends individualized restrictive
fluid management, keeping the patient slightly dry (Table 1). Isotonic crystalloids
(not colloids) are recommended because there is some evidence for harm using col-
loids in resuscitation.23,53 However, fluid type has yet to be trialed in adult malaria.
Dextrose-containing fluids should be used in unconscious patients to maintain
glucose concentrations greater than 4 mmol/L. Transfusion is recommended for chil-
dren with a hemoglobin less than 5 g/dL in areas of moderate to high transmission, and
less than 7 g/dL in adults and children in low transmission regions.23 An RCT is
currently being conducted to evaluate best transfusion strategies to prevent death
in severely anemic African children, as evidence for the recommended threshold is
lacking (ISRCTN84086586). As anemia can develop rapidly, hematocrit should be
monitored every 6 to 12 hours. Preparation for transfusion should occur at higher
thresholds in patients with hyperparasitemia and/or blackwater fever because of the
expected drop in hemoglobin. Recently, a more conservative weight-based fluid strat-
egy assessed in adult patients hospitalized with malaria, found that administering
48 Plewes et al

Table 1
General guidelines for fluid management in severe malaria

Clinical Status Adults Children

1. No severe dehydration, Initial: 0.9% saline intravenous (IV) Initial: 0.9% salineb
no anuria, no shock 2–4 mL/kg per h for 6 hc IV 3–5 mL/kg per h
Maintenance: 5% dextrose/0.9% for 3–4 hc
saline IV 2–3 mL/kg per h Maintenance: 5%
Monitoring: every 2 h for first 6 h dextrose IV 2–3 mL/kg
per h
Monitoring: every 2 h
for first 6 h
2. Severe dehydration, Initial: 0.9% saline IV 10 mL/kg per h —
urine output for 2 hc
<0.5 mL/kg per houra If no urine output (>0.5 mL/kg per h)
response:
Repeat: 5% dextrose/0.9% saline
IV 5 mL/kg per h for 4 h
Monitoring: every 2 h
3. Hemodynamic shock Initial: 0.9% saline IV 20 mL/kg bolus —
If no blood pressure response:
Repeat: 0.9% saline IV 20 mL/kg
bolus
Monitoring: every 30 min
If no response start vasopressor
a
Accurate urine output monitored with a urinary catheter is valuable to monitor fluid responsive-
ness to initial fluid administration; however, is an unreliable marker of kidney perfusion during
acute kidney injury and may result in overresuscitation or underresuscitation if used to guide fluid
therapy.
b
Alternate resuscitation fluid in children: 0.45% saline/5% dextrose.23
c
During initial fluid administration, assess for pulmonary crepitations and work of breathing
every 2 h and reassess individualized fluid needs.
Data from World Health Organization. Severe malaria. Trop Med Int Health 2014;19 Suppl
1:7–131.

2.5 mg/kg per hour in the first 6 hours did not result in any adverse disease complica-
tions.54 This is reassuring for the treatment of moderately severe patients without
anuria, ARDS, or shock, but this strategy needs to be evaluated in a larger cohort
with more severe disease. Empiric antibiotics should be initiated in pediatric severe
malaria and in all patients with shock in severe malaria.23 Antibiotic choice should
be guided by local hospital susceptibility patterns, source of suspected sepsis, and
ideally should be non-nephrotoxic. Inadequate hemodynamic response after initial
fluid resuscitation is an indication for vasopressors to be started (see Table 1). Norepi-
nephrine is recommended over dopamine and epinephrine, but evidence regarding
optimal vasopressor therapy is limited. Epinephrine has been shown to worsen lactic
acidosis in severe malaria.55 Bicarbonate is not recommended unless blood pH is less
than 7.10, based on sepsis guideline consensus and the potential harms with overuse.
Acute Kidney Injury
AKI, defined by WHO criteria, complicates up to 40% of P falciparum,24 55% of
P knowlesi,22 and 6% of P vivax56 adult severe malaria and 10% of P falciparum25
pediatric falciparum malaria. As the WHO AKI definition is not applicably defined for
children, a high index of suspicion is needed because nearly 50% of children with fal-
ciparum malaria have AKI57 as defined by current nephrology guidelines (creatinine
rise 1.5 times baseline or 26.5 mmol/L increase within 48 hours).58 Malaria is a risk
Malaria 49

for AKI, therefore all patients should have creatinine and urine output measured from
admission. Sequestration contributes to the acute tubular necrosis in falciparum ma-
laria.59,60 Cell-free hemoglobin-mediated damage is a common pathophysiological
pathway contributing to AKI in falciparum,61 knowlesi malaria,62 and potentially vivax
malaria, although the latter has yet to be studied.
Fluid management and avoidance of nephrotoxic drugs are foundations of AKI
management. Patients with severe malaria with volume depletion and less severe
AKI (moderately elevated creatinine) at admission, show normalization of creatinine
with careful volume expansion.54 However, patients with severe AKI (creatinine >175–
300 mmol/L) and/or anuria are not necessarily hypovolemic and are unlikely to respond
to fluid administration.42,43 There is no predictive model or biomarker to determine
which patients will respond to fluid or not. Therefore, in patients with moderate AKI
(creatinine >177 mmol/L), creatinine should be measured daily after initial cautious fluid
administration. A low threshold for early RRT in malaria-associated AKI should be
maintained. Early hemodialysis in acute renal failure reduces mortality from 75% to
26%.63 Patients with anuria, rapidly rising creatinine (>220 mmol/L/d), or severe meta-
bolic acidosis (pH <7.1) should have prompt RRT because rapid renal recovery is
unlikely.63,64 All RRT modalities are lifesaving; however, hemodialysis has been shown
to be superior to peritoneal dialysis in reducing mortality.65–67
Furosemide has not been studied in malaria, and in nonmalaria, AKI is ineffective in
preventing or treating AKI and potentially may be harmful.68 Bicarbonate urine alkali-
zation in blackwater fever has not been trialed and in general is not recommended.58
Multiple studies in nonmalaria populations show that there is no benefit of low-dose
dopamine in preventing or treating AKI and may cause harm.69 In severe malaria,
low-dose dopamine was shown to increase renal blood flow but did not improve ox-
ygen consumption or reduce peak creatinine or RRT requirement.55 Based on the
mechanism of acetaminophen inhibiting hemoprotein-mediated AKI,70 a recent RCT
in adults with severe malaria found that acetaminophen improved kidney function
and reduced AKI development, particularly in patients with high cell-free hemoglobin
levels.71 Larger studies of acetaminophen are being conducted to further assess this
renoprotective effect in adults and children with falciparum and knowlesi malaria
(ClinicalTrials.gov NCT03056391).

Other Adjunctive Therapies

Various other adjunctive treatments targeting the underlying pathophysiology of ma-
laria have been evaluated without showing benefit, including heparin, desferrioxamine,
anti–tumor necrosis factor antibody, levamisole, hyperimmune serum, N-acetylcys-
teine, and exchange transfusion.17,72

UNCOMPLICATED MALARIA
Plasmodium falciparum
Blood-stage cure
ACT is recommended first-line therapy for uncomplicated falciparum malaria in all
populations except in first-trimester pregnancy; this latter exception might be lifted
in the near future (see Box 3). ACT is also efficacious against nonfalciparum malaria
and therefore recommended to treat mixed infections and unspeciated infections.
ACT consists of an artemisinin component (artesunate, artemether, or dihydroartemi-
sinin) that rapidly reduces parasitemia, and a second partner antimalarial drug that is
slowly eliminated to kill the residual parasites. Oral ACT treatments are reliably effec-
tive with few adverse effects73 and are available as fixed-dose combinations
50 Plewes et al

(artemether-lumefantrine, dihydroartemisinin-piperaquine, artesunate-amodiaquine,

artesunate-sulfadoxine/pyrimethamine, artesunate-mefloquine, and recently added
artesunate-pyronaridine). The recommended dosing of dihydroartemisinin-
piperaquine was recently revised for children less than 25 kg after it was shown that
children were suboptimally dosed resulting in reduced efficacy.74,75 A recent meta-
analysis and systematic review provides evidence of the low risk of cardiotoxicity of
dihydroartemisinin-piperaquine.76 Partner drugs with slow elimination (eg, mefloquine,
piperaquine) provide 4 to 6 weeks’ prophylaxis, whereas rapidly eliminated partner
drugs (eg, lumefantrine) expose a risk to reinfection within a month. The choice of
oral ACT depends on risk of drug resistance of the partner drug and potential for
treatment failure, which is increased in regions of Southeast Asia (Fig. 3). Fake and
substandard antimalarials are widespread; therefore, quality-assured drugs are
required to maintain effectiveness and prevent selecting for drug resistance.77
Non-ACT regimens are still recommended in certain circumstances. Atovaquone-
proguanil is highly effective for returned travelers without hyperparasitemia and who
have not taken the drug as prophylaxis.17 In endemic countries, it is not recommen-
ded for widespread use as high-grade atovaquone resistance emerges from a sin-
gle point mutation. However, it can be given with artesunate plus primaquine in
cases of standard ACT treatment failure. Quinine in combination with clindamycin
or doxycycline is poorly tolerated but is recommended as second-line treatment
in certain countries with ACT failure, as quinine remains efficacious. Quinine
plus clindamycin 7-day treatment is the recommendation for uncomplicated falcip-
arum malaria in first-trimester pregnancy.17 However, this recommendation will
likely be revised in the near future, as safety data of ACT in the first trimester are
reassuring.78
Patients with uncomplicated malaria can be treated as outpatients if the patient
remains clinically stable after confirming that oral therapy is tolerated and parasitemia
has declined. If vomiting occurs within 1 hour of the oral antimalarial dosing, then the
dose should be repeated. Mefloquine is associated with increased rates of vomiting
and all quinolines (quinine, mefloquine, and chloroquine) are associated with

Fig. 3. Global distribution of P falciparum drug resistance. Countries shown by level of antima-
larial resistance of local P falciparum. Countries approaching malaria elimination also shown (as
defined in Malaria World Report 2016). (From Ashley EA, Phyo AP, Woodrow C. Malaria. Lancet
2018;391:1608–21. Reprinted with permission from Elsevier (The Lancet, 2018;391:1608–21).
Malaria 51

orthostatic hypotension, which may result in patients not completing therapy. Higher-
risk populations, including pregnant women, infants, nonimmune travelers, individuals
infected with the human immunodeficiency virus, patients on tuberculosis therapy,
and uncomplicated hyperparasitemic (2% nonimmune; 4% immune) patients
should be considered for admission due to increased risks of treatment failure and/
or severe disease. Ideally, parasite clearance should be documented in all patients.

Gametocytocidal treatment
In low-transmission areas, primaquine should be given as a single dose (0.25 mg
base/kg) with all ACT regimens for the treatment of falciparum malaria, except in preg-
nancy and infants.17 This treatment serves to prevent onward transmission by killing
mature stage gametocytes thereby sterilizing the infection.79 This low dose is consid-
ered safe even in glucose-6-phosphate dehydrogenase (G6PD) deficiency, and there-
fore G6PD testing is not required before administration.

Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium

knowlesi
Blood-stage cure
Unspeciated malaria and P malariae-like infections acquired in Southeast Asia should
be treated as for uncomplicated falciparum malaria. Uncomplicated P vivax, P ovale,
and P malariae acquired in chloroquine-sensitive regions are treated with chloroquine
(see Box 3). While chloroquine remains efficacious against P knowlesi, ACT is recom-
mended in the Malaysian malaria treatment guidelines due to the risk of misdiagnosed
falciparum malaria, presence of chloroquine-resistant vivax, and trials confirming effi-
cacy with faster parasite clearance times with ACT compared with chloroquine.80–82
In chloroquine-resistant regions (Fig. 4), adults and children with uncomplicated P
vivax, P ovale, P malariae, and P knowlesi should be treated with an ACT containing
piperaquine, mefloquine, or lumefantrine (except first-trimester pregnancy).17,83 Mixed
infections are common in coendemic areas. Microscopy and RDT diagnostics may un-
derestimate mixed infections. ACTs are the treatment of choice for mixed infections.

Liver-stage cure
Radical cure with primaquine is required to kill liver hypnozoites of vivax or ovale
malaria to prevent relapse in all settings. Individuals with G6PD-deficiency may
experience potentially dangerous dose-dependent primaquine-induced hemolysis.
The severity of hemolysis also depends on the G6PD genetic variant. Testing for
G6PD deficiency is required before treatment. In most trials, primaquine has been
given daily for 14 days if there is no G6PD deficiency, and for 8 weeks as weekly
supervised doses if G6PD deficient.84 Adherence and hemolysis remain issues for
delivery of effective radical cure. A recent trial of a 7-day course of higher-dose pri-
maquine (1 mg base/kg) resulted in significant hemolysis in G6PD heterozygous fe-
male individuals compared with a standard 14-day course of primaquine (0.5 mg
base/kg).85 Tafenoquine is a longer-acting 8-aminoquinoline given as a single
dose for radical cure that is currently under review.86 However, this new treatment
will not obviate the need for primaquine in G6PD-deficient individuals due to the risk
of hemolysis.87

FOLLOW-ON MANAGEMENT
Post-artesunate Delayed-Onset Hemolysis
Delayed-onset hemolysis after intravenous artesunate can occur in nonimmune trav-
elers returning from malaria-endemic regions, particularly if hyperparasitemia is
52 Plewes et al

Fig. 4. Global distribution of P vivax chloroquine resistance. Chloroquine resistance was

categorized according to the strength of evidence99: Category 1: greater than 10% recur-
rence by day, irrespective of confirmation of adequate blood chloroquine concentration;
Category 2: confirmed recurrences by day 28 within reported whole-blood chloroquine con-
centration of greater than 100 nm; and Category 3: greater than 5% recurrences by day 28,
irrespective of chloroquine concentration. Chloroquine sensitivity was confirmed if patients
had enrolled after a symptomatic clinical illness, fewer than 5% recurrences had occurred by
day 28, no primaquine was given before day 28, and studies had a sample size of at least 10
patients. Case reports were observations in individual patients of treatment failure during
chloroquine prophylaxis, prolonged parasite clearance or P vivax recurrence following treat-
ment. (From Price RN, von Seidlein L, Valecha N, et al. Global extent of chloroquine-resistant
Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis 2014;14:982–91;
and Creative Commons Attribution License (CC BY). Available at: https://doi.org/10.1016/
S1473-3099(14)70855-2. Accessed September 13, 2014; with permission.)

present.88 The mechanism of this hemolysis relates to the mechanism of clearance of

young ring-stage parasites after artesunate treatment. When artesunate rapidly kills
ring-stage parasites, which confers its lifesaving advantage over quinine, the dead
parasites become pyknotic. These are then removed from the red cells in the spleen
by a process called pitting, leaving the once-infected red cells to be recirculated.89
The once-infected red cells retaining PfHRP2 have a shortened life span, resulting
in the observed delayed hemolysis and persistently positive PfHRP2 RDT. The
PfHRP2 concentration after parasite clearance predicts delayed hemolysis.90 This
phenomenon is less pronounced in African children living in high-transmission re-
gions,91 and post-artesunate late anemia in this setting is uncommon and not more
frequent than after quinine treatment. Nonimmune patients, including travelers, should
be followed up to 2 weeks after parenteral artesunate treatment to monitor hemoglo-
bin levels, along with creatinine if hemolysis is evident.

Treatment Failures
Treatment failure is defined as the “failure to clear parasitemia or resolve clinical symp-
toms despite use of an antimalarial drug at correct doses,” which does not equate to
resistance.17 Treatment failures can be a result of different factors, including
nonadherence, inadequate drug concentrations, poor drug quality, altered pharmaco-
kinetics, host immunity, high initial parasitemia or drug resistance. Artemether-
lumefantrine (AL) treatment failures have been reported in nonimmune, returning
Malaria 53

traveling men weighing a median of 77 kg, suggesting that AL dosing may need to
optimized in heavier individuals.92 Until trials assess optimal dosing, overweight adults
should be followed up to assess treatment outcomes.

Primaquine Radical Cure Failures

Failure of primaquine to prevent P vivax relapses has been proposed as primaquine
tolerance or resistance.93 Similar to failures in treating asexual blood parasitemia,
suboptimal dosing and drug concentrations can be an alternative explanation for
primaquine failures.94 Lower primaquine efficacy and increased risk of relapse has
been linked to poor or intermediate metabolism of primaquine in individuals with
polymorphisms in the cytochrome P450 CYP isoform CYP2D6.95 Tafenoquine efficacy
for preventing P vivax relapses was not decreased in individuals with decreased
CYP2D6 activity96; however, prospective studies are still needed to confirm this
finding.

RESISTANCE
Plasmodium falciparum
P falciparum resistance to chloroquine and sulfadoxine-pyrimethamine is globally
widespread. Artemisinin-resistant falciparum malaria is now prevalent in parts of
Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand, and Viet
Nam (see Fig. 3).97 Artemisinin resistance affects ring-stage parasites and is charac-
terized by delayed parasite clearance following treatment with an artesunate
monotherapy or an ACT. At the population level, artemisinin resistance is confirmed
when 5% of infections carry resistance-related mutations in the Kelch13 gene
in combination with a parasite clearance half-life 5 hours or persistent para-
sitemia 3 days after treatment assessed by light microscopy.98 With retained full
sensitivity to the ACT partner drug, ACT efficacy is largely maintained in the presence
of artemisinin resistance; however, reduced efficacy of artemisinins facilitates the se-
lection of partner drug resistance, as was observed with piperaquine and mefloquine.
Once resistance to both ACT partner drugs appears, treatment failure is high, and
spread of resistance accelerates quickly. Kelch13 mutations have been observed at
low frequency outside Southeast Asia, including sub-Saharan Africa. However, selec-
tion for these mutations has not occurred and there is currently no confirmed artemi-
sinin resistance in Africa.
New antimalarials are not expected within the next 5 years, and the treatment and
control of falciparum malaria in the Greater Mekong Subregion (GMS) will become
increasingly challenging.97 Rotating between different ACTs, sequential treatment
with 2 different ACTs or extending the current 3-day regimens have been proposed.
A promising approach is deployment of triple artemisinin combinations, combining
an artemisinin with 2 matching partner drugs (dihydroartemisinin–piperaquine–meflo-
quine and artemether–lumefantrine–amodiaquine), which are currently being trialed
(ClinicalTrials.gov NCT02453308).

Plasmodium vivax
High-grade resistance to chloroquine in P vivax is widespread in Indonesia and Papua
New Guinea and resistance has now been reported in more than 10 countries in
endemic areas (see Fig. 4).99 However, the geographic extent is unclear due to coad-
ministration of primaquine, or subtherapeutic drug concentrations (inadequate dose
or duration), that could mask low-level chloroquine resistance, or accentuate treat-
ment failures, respectively.
54 Plewes et al

SUMMARY

Management of malaria has changed significantly in the past 15 years, both on an in-
dividual and population level. ACTs have, together with the widespread distribution of
insecticide-treated bednets, contributed to the impressive reduction in malaria trans-
mission globally. ACTs for falciparum malaria have replaced older therapies given the
undisputed survival benefit, safety, and tolerance. Further, there has been a shift to-
ward unified ACT treatment for all human malaria infections, given the challenges in
speciation and potential rise in chloroquine-vivax malaria infection. Deployment of
parenteral artesunate has importantly improved case fatality. Restricted fluid manage-
ment has become again the standard in severe malaria. Less progress has been made
toward developing adjunctive therapies for severe malaria; however, acetaminophen
is a first adjunctive treatment showing benefit by reducing AKI. Sevuparin, which
inhibits sequestration, has potential to improve the compromised microcirculation in
severe malaria. With malaria transmission decreasing in many parts of sub-Saharan
Africa, waning immunity will shift symptomatic and severe disease to older children
and adults in Africa.
At the same time, the emergence and spread of artemisinin and partner drug resis-
tance in falciparum malaria threatens to undo the progress made in reducing malaria
morbidity and mortality. Accelerated elimination of falciparum malaria in the GMS is
required to contain further spread of multidrug-resistant parasite strains. This requires
a well-coordinated effort to deploy malaria services to the most remote, vulnerable,
and often mobile populations. In addition to conventional vector control measures
and community-based facilities for early diagnosis and treatment, targeted mass
drug administration of ACT and single-dose primaquine have shown potential for rapid
elimination of falciparum malaria in eastern Myanmar.100 In Africa, intermittent
preventive therapy in pregnancy and infants, and seasonal childhood chemo-
prevention in the sub-Sahel region are being scaled up; however, increasing
sulfadoxine-pyrimethamine resistance threatens its impact.1 Enhanced deployment
of long-lasting insecticide (pyrethroid)-treated bednets and indoor residual spraying
with insecticide significantly reduced morbidity and mortality in high-transmission re-
gions; however insecticide resistance may also threaten this success. Increased use
of primaquine to reduce transmission of falciparum malaria may assist toward elimina-
tion, whereas increased use of primaquine to prevent relapse of vivax malaria is
required for elimination of this species. Limited access to G6PD deficiency testing
for safe primaquine administration is a critical issue. The emergence of zoonotic ma-
laria infecting humans from monkey reservoirs increases the complexity of global elim-
ination strategies. To prevent increases in malaria morbidity and mortality, WHO calls
for improved access to effective interventions along with an escalation in funding for
malaria control programs and research.

REFERENCES

1. World Health Organization. World malaria report 2017. Geneva (Switzerland):

World Health Organization; 2017.
2. Laveran CL. Classics in infectious diseases: a newly discovered parasite in the
blood of patients suffering from malaria. Parasitic etiology of attacks of malaria:
Charles Louis Alphonse Laveran (1845-1922). Rev Infect Dis 1982;4:908–11.
3. Brasil P, Zalis MG, de Pina-Costa A, et al. Outbreak of human malaria caused by
Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epide-
miological investigation. Lancet Glob Health 2017;5:e1038–46.
Malaria 55

4. Ta TH, Hisam S, Lanza M, et al. First case of a naturally acquired human infec-
tion with Plasmodium cynomolgi. Malar J 2014;13:68–74.
5. Anstey NM, Douglas NM, Poespoprodjo JR, et al. Plasmodium vivax: clinical
spectrum, risk factors and pathogenesis. Adv Parasitol 2012;80:151–201.
6. Barber BE, William T, Grigg MJ, et al. A prospective comparative study of knowl-
esi, falciparum, and vivax malaria in Sabah, Malaysia: high proportion with
severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortal-
ity with early referral and artesunate therapy. Clin Infect Dis 2013;56:383–97.
7. Nguyen PH, Day N, Pram TD, et al. Intraleucocytic malaria pigment and prog-
nosis in severe malaria. Trans R Soc Trop Med Hyg 1995;89:200–4.
8. Silamut K, White NJ. Relation of the stage of parasite development in the periph-
eral blood to prognosis in severe falciparum malaria. Trans R Soc Trop Med Hyg
1993;87:436–43.
9. White NJ, Krishna S. Treatment of malaria: some considerations and limitations
of the current methods of assessment. Trans R Soc Trop Med Hyg 1989;83:
767–77.
10. Das S, Peck RB, Barney R, et al. Performance of an ultra-sensitive Plasmodium
falciparum HRP2-based rapid diagnostic test with recombinant HRP2, culture
parasites, and archived whole blood samples. Malar J 2018;17:118–24.
11. Berhane A, Anderson K, Mihreteab S, et al. Major threat to malaria control pro-
grams by Plasmodium falciparum lacking histidine-rich protein 2, Eritrea. Emerg
Infect Dis 2018;24:462–70.
12. Beshir KB, Sepulveda N, Bharmal J, et al. Plasmodium falciparum parasites with
histidine-rich protein 2 (pfhrp2) and pfhrp3 gene deletions in two endemic re-
gions of Kenya. Sci Rep 2017;7:14718–27.
13. Global Malaria Programme. False-negative RDT results and implications of new
reports of P. falciparum histidine-rich protein 2/3 gene deletions. World Health
Organization; 2017. Available at: https://www.who.int/malaria/publications/atoz/
information-note-hrp2-based-rdt/en/. Accessed December 7, 2017.
14. Gillet P, Scheirlinck A, Stokx J, et al. Prozone in malaria rapid diagnostics tests:
how many cases are missed? Malar J 2011;10:166–76.
15. Gunalan K, Niangaly A, Thera MA, et al. Plasmodium vivax infections of duffy-
negative erythrocytes: historically undetected or a recent adaptation? Trends
Parasitol 2018;34:420–9.
16. Bruneel F, Tubach F, Corne P, et al. Severe imported falciparum malaria: a cohort
study in 400 critically ill adults. PLoS One 2010;5:e13236–43.
17. World Health Organization. World Health Organization Guidelines for the treat-
ment of malaria. Third edition. 2015. Available at: http://www.who.int/malaria/
publications/atoz/9789241549127/en/. Accessed May 7, 2016.
18. Dondorp AM, Lee SJ, Faiz MA, et al. The relationship between age and the man-
ifestations of and mortality associated with severe malaria. Clin Infect Dis 2008;
47:151–7.
19. Sypniewska P, Duda JF, Locatelli I, et al. Clinical and laboratory predictors of
death in African children with features of severe malaria: a systematic review
and meta-analysis. BMC Med 2017;15:147–63.
20. von Seidlein L, Olaosebikan R, Hendriksen IC, et al. Predicting the clinical
outcome of severe falciparum malaria in African children: findings from a large
randomized trial. Clin Infect Dis 2012;54:1080–90.
21. Daneshvar C, Davis TM, Cox-Singh J, et al. Clinical and laboratory features of
human Plasmodium knowlesi infection. Clin Infect Dis 2009;49:852–60.
56 Plewes et al

22. William T, Menon J, Rajahram G, et al. Severe Plasmodium knowlesi malaria in a

tertiary care hospital, Sabah, Malaysia. Emerg Infect Dis 2011;17:1248–55.
23. World Health Organization. Severe malaria. Trop Med Int Health 2014;19(Suppl 1):
7–131.
24. Dondorp A, Nosten F, Stepniewska K, et al. SEAQUAMAT Trial Group. Artesu-
nate versus quinine for treatment of severe falciparum malaria: a randomised
trial. Lancet 2005;366:717–25.
25. Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the
treatment of severe falciparum malaria in African children (AQUAMAT): an open-
label, randomised trial. Lancet 2010;376:1647–57.
26. Simpson JA, Agbenyega T, Barnes KI, et al. Population pharmacokinetics of
artesunate and dihydroartemisinin following intra-rectal dosing of artesunate
in malaria patients. PLoS Med 2006;3:e444–54.
27. ter Kuile F, White NJ, Holloway P, et al. Plasmodium falciparum: in vitro studies of
the pharmacodynamic properties of drugs used for the treatment of severe ma-
laria. Exp Parasitol 1993;76:85–95.
28. Udomsangpetch R, Pipitaporn B, Krishna S, et al. Antimalarial drugs reduce
cytoadherence and rosetting Plasmodium falciparum. J Infect Dis 1996;173:
691–8.
29. Esu E, Effa EE, Opie ON, et al. Artemether for severe malaria. Cochrane Data-
base Syst Rev 2014;(9):CD010678.
30. Gomes MF, Faiz MA, Gyapong JO, et al. Pre-referral rectal artesunate to prevent
death and disability in severe malaria: a placebo-controlled trial. Lancet 2009;
373:557–66.
31. Moxon CA, Zhao L, Li C, et al. Safety of lumbar puncture in comatose children
with clinical features of cerebral malaria. Neurology 2016;87:2355–62.
32. Beare NA, Taylor TE, Harding SP, et al. Malarial retinopathy: a newly established
diagnostic sign in severe malaria. Am J Trop Med Hyg 2006;75:790–7.
33. Maude RJ, Beare NA, Abu Sayeed A, et al. The spectrum of retinopathy in
adults with Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 2009;
103:665–71.
34. Maude RJ, Hoque G, Hasan MU, et al. Timing of enteral feeding in cerebral ma-
laria in resource-poor settings: a randomized trial. PLoS One 2011;6:e27273–9.
35. Namutangula B, Ndeezi G, Byarugaba JS, et al. Mannitol as adjunct therapy for
childhood cerebral malaria in Uganda: a randomized clinical trial. Malar J 2007;
6:138–43.
36. Mohanty S, Mishra SK, Patnaik R, et al. Brain swelling and mannitol therapy in
adult cerebral malaria: a randomized trial. Clin Infect Dis 2011;53:349–55.
37. Warrell DA, Looareesuwan S, Warrell MJ, et al. Dexamethasone proves delete-
rious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J
Med 1982;306:313–9.
38. Hoffman SL, Rustama D, Punjabi NH, et al. High-dose dexamethasone in
quinine-treated patients with cerebral malaria: a double-blind, placebo-
controlled trial. J Infect Dis 1988;158:325–31.
39. Abubakar A, Van De Vijver FJ, Mithwani S, et al. Assessing developmental out-
comes in children from Kilifi, Kenya, following prophylaxis for seizures in cere-
bral malaria. J Health Psychol 2007;12:417–30.
40. Crawley J, Waruiru C, Mithwani S, et al. Effect of phenobarbital on seizure fre-
quency and mortality in childhood cerebral malaria: a randomised, controlled
intervention study. Lancet 2000;355:701–6.
Malaria 57

41. Gwer SA, Idro RI, Fegan G, et al. Fosphenytoin for seizure prevention in child-
hood coma in Africa: a randomized clinical trial. J Crit Care 2013;28:1086–92.
42. Hanson JP, Lam SW, Mohanty S, et al. Fluid resuscitation of adults with severe
falciparum malaria: effects on acid-base status, renal function, and extravas-
cular lung water. Crit Care Med 2013;41:972–81.
43. Nguyen HP, Hanson J, Bethell D, et al. A retrospective analysis of the haemody-
namic and metabolic effects of fluid resuscitation in Vietnamese adults with se-
vere falciparum malaria. PLoS One 2011;6:e25523–31.
44. Hanson J, Lam SW, Alam S, et al. The reliability of the physical examination to
guide fluid therapy in adults with severe falciparum malaria: an observational
study. Malar J 2013;12:348–56.
45. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African chil-
dren with severe infection. N Engl J Med 2011;364:2483–95.
46. Maitland K, George EC, Evans JA, et al. Exploring mechanisms of excess mor-
tality with early fluid resuscitation: insights from the FEAST trial. BMC Med 2013;
11:68–82.
47. Church J, Maitland K. Invasive bacterial co-infection in African children with
Plasmodium falciparum malaria: a systematic review. BMC Med 2014;12:31–47.
48. Nyein PP, Aung NM, Kyi TT, et al. High frequency of clinically significant bacter-
emia in adults hospitalized with falciparum malaria. Open Forum Infect Dis
2016;3:1–5.
49. Scott JA, Berkley JA, Mwangi I, et al. Relation between falciparum malaria and
bacteraemia in Kenyan children: a population-based, case-control study and a
longitudinal study. Lancet 2011;378:1316–23.
50. Cunnington AJ, Njie M, Correa S, et al. Prolonged neutrophil dysfunction after
Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-
1 induction. J Immunol 2012;189:5336–46.
51. Dasari P, Reiss K, Lingelbach K, et al. Digestive vacuoles of Plasmodium falcip-
arum are selectively phagocytosed by and impair killing function of polymorpho-
nuclear leukocytes. Blood 2011;118:4946–56.
52. Herdman MT, Sriboonvorakul N, Leopold SJ, et al. The role of previously unmea-
sured organic acids in the pathogenesis of severe malaria. Crit Care 2015;19:
317–27.
53. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill
patients. Cochrane Database Syst Rev 2007;(4):CD000567.
54. Aung NM, Kaung M, Kyi TT, et al. The safety of a conservative fluid replacement
strategy in adults hospitalised with malaria. PLoS One 2015;10:e0143062–76.
55. Day NPJ, Phu NH, Bethell DP, et al. The effects of dopamine and adrenaline in-
fusions on acid-base balance and systemic haemodynamics in severe infection.
Lancet 1996;348:219–23.
56. Rahimi BA, Thakkinstian A, White NJ, et al. Severe vivax malaria: a systematic
review and meta-analysis of clinical studies since 1900. Malar J 2014;13:
481–90.
57. Conroy AL, Hawkes M, Elphinstone RE, et al. Acute kidney injury is common in
pediatric severe malaria and is associated with increased mortality. Open Forum
Infect Dis 2016;3:1–9.
58. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury
Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney
Int Suppl 2012;2:1–138.
58 Plewes et al

59. Nguansangiam S, Day NP, Hien TT, et al. A quantitative ultrastructural study of
renal pathology in fatal Plasmodium falciparum malaria. Trop Med Int Health
2007;12:1037–50.
60. Plewes K, Royakkers AA, Hanson J, et al. Correlation of biomarkers for parasite
burden and immune activation with acute kidney injury in severe falciparum ma-
laria. Malar J 2014;13:91–100.
61. Plewes K, Kingston HWF, Ghose A, et al. Cell-free hemoglobin mediated oxida-
tive stress is associated with acute kidney injury and renal replacement therapy
in severe falciparum malaria: an observational study. BMC Infect Dis 2017;17:
313–24.
62. Barber BE, Grigg MJ, Piera KA, et al. Intravascular hemolysis in severe Plasmo-
dium knowlesi malaria: association with endothelial activation, microvascular
dysfunction, and acute kidney injury. Emerg Microbes Infect 2018;7:106–12.
63. Tran TMT, Phu NH, Vinh H, et al. Acute renal failure in patients with severe fal-
ciparum malaria. Clin Infect Dis 1992;15:874–80.
64. Hanson J, Hasan MM, Royakkers AA, et al. Laboratory prediction of the require-
ment for renal replacement in acute falciparum malaria. Malar J 2011;10:
217–25.
65. Mishra OP, Gupta AK, Pooniya V, et al. Peritoneal dialysis in children with acute
kidney injury: a developing country experience. Perit Dial Int 2012;32:431–6.
66. Phu NH, Hien TT, Mai NT, et al. Hemofiltration and peritoneal dialysis in infection-
associated acute renal failure in Vietnam. N Engl J Med 2002;347:895–902.
67. Asinobi AO, Ademola AD, Alao MA. Haemodialysis for paediatric acute kidney
injury in a low resource setting: experience from a tertiary hospital in South West
Nigeria. Clin Kidney J 2016;9:63–8.
68. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal
failure. Br Med J 2006;333:420–5.
69. Kellum JA, Decker JM. Use of dopamine in acute renal failure: a meta-analysis.
Crit Care Med 2001;29:1526–31.
70. Boutaud O, Moore KP, Reeder BJ, et al. Acetaminophen inhibits hemoprotein-
catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal fail-
ure. Proc Natl Acad Sci U S A 2010;107:2699–704.
71. Plewes K, Kingston HWF, Ghose A, et al. Acetaminophen as a renoprotective
adjunctive treatment in patients with severe and moderately severe falciparum
malaria: a randomized, controlled, open-label trial. Clin Infect Dis 2018;67(7):
991–9.
72. Varo R, Crowley VM, Sitoe A, et al. Adjunctive therapy for severe malaria: a re-
view and critical appraisal. Malar J 2018;17:47–64.
73. Adjuik M, Babiker A, Garner P, et al. Artesunate combinations for treatment of
malaria: meta-analysis. Lancet 2004;363:9–17.
74. Tarning J, Rijken MJ, McGready R, et al. Population pharmacokinetics of dihy-
droartemisinin and piperaquine in pregnant and nonpregnant women with un-
complicated malaria. Antimicrob Agents Chemother 2012;56:1997–2007.
75. WorldWide Antimalarial Resistance Network Dihydroartemisinin-Piperaquine
Study Group. The effect of dosing regimens on the antimalarial efficacy of
dihydroartemisinin-piperaquine: a pooled analysis of individual patient data.
PLoS Med 2013;10:e1001564–80.
76. Chan XHS, Win YN, Mawer LJ, et al. Risk of sudden unexplained death after use
of dihydroartemisinin–piperaquine for malaria: a systematic review and
Bayesian meta-analysis. Lancet Infect Dis 2018;18(8):913–23.
Malaria 59

77. Nayyar GM, Breman JG, Newton PN, et al. Poor-quality antimalarial drugs in
southeast Asia and sub-Saharan Africa. Lancet Infect Dis 2012;12:488–96.
78. Dellicour S, Sevene E, McGready R, et al. First-trimester artemisinin derivatives
and quinine treatments and the risk of adverse pregnancy outcomes in Africa
and Asia: a meta-analysis of observational studies. PLoS Med 2017;14:
e1002290.
79. World Health Organization Global Malaria Programme. Single dose primaquine
as a gametocytocide in Plasmodium falciparum malaria. Available at: http://
www.who.int/malaria/publications/atoz/who_pq_policy_recommendation/en/. Ac-
cessed December 20, 2012.
80. Barber BE, Grigg MJ, William T, et al. The treatment of Plasmodium knowlesi ma-
laria. Trends Parasitol 2017;33:242–53.
81. Grigg MJ, William T, Barber BE, et al. Artemether-lumefantrine versus chloro-
quine for the treatment of uncomplicated Plasmodium knowlesi malaria: an
open-label randomized controlled trial CAN KNOW. Clin Infect Dis 2018;66:
229–36.
82. Grigg MJ, William T, Menon J, et al. Artesunate-mefloquine versus chloroquine
for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT
KNOW): an open-label, randomised controlled trial. Lancet Infect Dis 2016;16:
180–8.
83. Gogtay N, Kannan S, Thatte UM, et al. Artemisinin-based combination therapy
for treating uncomplicated Plasmodium vivax malaria. Cochrane Database Syst
Rev 2013;(10):CD008492.
84. Galappaththy GN, Tharyan P, Kirubakaran R. Primaquine for preventing relapse
in people with Plasmodium vivax malaria treated with chloroquine. Cochrane
Database Syst Rev 2013;(10):CD004389.
85. Chu CS, Bancone G, Moore KA, et al. Haemolysis in G6PD heterozygous fe-
males treated with primaquine for Plasmodium vivax malaria: a nested cohort
in a trial of radical curative regimens. PLoS Med 2017;14:e1002224–39.
86. Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, et al. Tafenoquine plus
chloroquine for the treatment and relapse prevention of Plasmodium vivax ma-
laria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-
selection study. Lancet 2014;383:1049–58.
87. Watson J, Taylor WRJ, Bancone G, et al. Implications of current therapeutic re-
strictions for primaquine and tafenoquine in the radical cure of vivax malaria.
PLoS Negl Trop Dis 2018;12:e0006440–53.
88. Zoller T, Junghanss T, Kapaun A, et al. Intravenous artesunate for severe malaria
in travelers, Europe. Emerg Infect Dis 2011;17:771–7.
89. Jaureguiberry S, Ndour PA, Roussel C, et al. Postartesunate delayed hemolysis
is a predictable event related to the lifesaving effect of artemisinins. Blood 2014;
124:167–75.
90. Ndour PA, Larreche S, Mouri O, et al. Measuring the Plasmodium falciparum
HRP2 protein in blood from artesunate-treated malaria patients predicts post-
artesunate delayed hemolysis. Sci Transl Med 2017;9:1–11.
91. Fanello C, Onyamboko M, Lee SJ, et al. Post-treatment haemolysis in African
children with hyperparasitaemic falciparum malaria; a randomized comparison
of artesunate and quinine. BMC Infect Dis 2017;17:575–82.
92. Sonden K, Wyss K, Jovel I, et al. High rate of treatment failures in nonimmune
travelers treated with artemether-lumefantrine for uncomplicated plasmodium
falciparum malaria in Sweden: retrospective comparative analysis of effective-
ness and case series. Clin Infect Dis 2017;64:199–206.
60 Plewes et al

93. Spudick JM, Garcia LS, Graham DM, et al. Diagnostic and therapeutic pitfalls
associated with primaquine-tolerant Plasmodium vivax. J Clin Microbiol 2005;
43:978–81.
94. Pedro RS, Guaraldo L, Campos DP, et al. Plasmodium vivax malaria relapses at
a travel medicine centre in Rio de Janeiro, a non-endemic area in Brazil. Malar J
2012;11:245–51.
95. Marcsisin SR, Reichard G, Pybus BS. Primaquine pharmacology in the context
of CYP 2D6 pharmacogenomics: current state of the art. Pharmacol Ther 2016;
161:1–10.
96. St Jean PL, Xue Z, Carter N, et al. Tafenoquine treatment of Plasmodium vivax
malaria: suggestive evidence that CYP2D6 reduced metabolism is not associ-
ated with relapse in the Phase 2b DETECTIVE trial. Malar J 2016;15:97–105.
97. Dondorp AM, Smithuis FM, Woodrow C, et al. How to contain artemisinin- and
multidrug-resistant falciparum malaria. Trends Parasitol 2017;33:353–63.
98. World Health Organization Global Malaria Programme. Artemisinin and
artemisinin-based combination therapy resistance - Status Report. 2017.
Available at: http://www.who.int/malaria/publications/atoz/artemisinin-resistance-
april2017/en/. Accessed February 1, 2018.
99. Price RN, von Seidlein L, Valecha N, et al. Global extent of chloroquine-resistant
Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis
2014;14:982–91.
100. Landier J, Parker DM, Thu AM, et al. Effect of generalised access to early diag-
nosis and treatment and targeted mass drug administration on Plasmodium
falciparum malaria in Eastern Myanmar: an observational study of a regional
elimination programme. Lancet 2018;391:1916–26.