Non-falciparum malaria: P. vivax, P. ovale, and P. malariae

INTRODUCTION — Non-falciparum malaria refers to malaria infection due to Plasmodium species other than P. falciparum; these include P. vivax, P. ovale, P. malariae, and P. knowlesi (table 1).

Worldwide, the greatest mortality due to malaria is associated with P. falciparum infection. However, the non-falciparum malarias can also cause significant morbidity and mortality, including clinical deterioration after initiation of treatment [1,2]. P. vivax malaria is a relapsing illness with recurrent episodes of malaria leading to a cumulative risk of severe anemia and associated comorbidities [3,4]. Infection with P. ovale also causes a relapsing illness but infrequently causes severe illness, whereas P. malariae results in chronic low level parasitemia and associated anemia which can be severe [5-8].

The epidemiology, clinical manifestations, diagnosis, and treatment of non-falciparum malaria due to P. vivax, P. ovale, and P. malariae in nonpregnant adults and children will be reviewed here. Issues related to non-falciparum malaria in pregnant women are discussed separately, as are issues related to malaria caused by P. falciparum and P. knowlesi. (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children" and "Treatment of severe malaria" and "Malaria in pregnancy: Prevention and treatment", section on 'Non-falciparum malaria' and "Non-falciparum malaria: Plasmodium knowlesi".)

EPIDEMIOLOGY — The epidemiology of non-falciparum malaria varies depending on the species, as described in the following sections. Issues related to chloroquine susceptibility are most significant in the setting of P. vivax infection, as discussed below.

Non-falciparum malaria species

Plasmodium vivax

●Global distribution

•Worldwide – P. vivax is the second most common cause of human malaria after P. falciparum; in 2021 there were an estimated 4.9 million cases [9]. There is endemic transmission throughout most of the tropics including Africa, Asia, the South Pacific, and Central and South America; approximately one-third of the world population is at risk of infection [9,10]. An estimated 82 percent of the global vivax burden arises from four high-burden countries: India, Pakistan, Ethiopia, and Sudan [10].

P. vivax causes only 2 percent of malaria attacks worldwide; this relatively small proportion may be attributed to the huge burden of P. falciparum in sub-Saharan Africa, where the prevalence of P. vivax is low [11,12]. Outside of sub-Saharan Africa, intense malaria control activities in countries where both P. falciparum and P. vivax are endemic have led to a declining burden of P. falciparum but a concomitant rise in the proportion of malaria due to P. vivax, which is now the predominant cause of malaria in 31 of 49 countries where P. vivax is endemic [13].

In most areas where P. vivax is prevalent, malaria transmission rates are low (the island of New Guinea is an exception). Many individuals achieve a level of immunity that permits asymptomatic submicroscopic infections; however, people of all ages are at risk of symptomatic infection. Among travelers diagnosed with P. vivax in North American or European clinics, those visiting friends and relatives in India and Pakistan are at greatest risk [14]. Local outbreaks of P. vivax infection have occurred as a result of transmission of infection from migrant workers to local Anopheline mosquitoes in Greece and the United States [15,16].

•United States – Locally acquired mosquito-transmitted (autochthonous) cases of P. vivax were reported in the United States (Florida and Texas) in 2023 [17]. The occurrence of these cases underscores the potential for imported malaria cases in regions with competent vectors to produce local mosquito transmission of malaria parasites.

●Relapse – Both P. vivax and P. ovale form dormant liver stages (hypnozoites) that can activate weeks, months, or years after the initial infection, causing relapse [18]. The frequency and timing of these relapses varies considerably with the geographic region and the sporozoite inoculum [19]. Relapses are an important source of ongoing transmission, undermining control and elimination efforts [13,20]. They account for 66 to 95 percent of all recurrent vivax malaria episodes [21]. (See 'Relapse' below and 'Preventing relapse' below and 'Recurrent infection' below.)

●Role of Duffy factor – The absence of Duffy factor on the surface of red blood cells among most Africans was previously believed to protect most West and Central African populations from malaria due to P. vivax. However, additional evidence suggests that P. vivax transmission is possible even among Duffy antigen-negative populations in East and West Africa, the Amazon River basin, and Madagascar [12,22-26]. The true prevalence of P. vivax infection and the frequency and character of associated morbidity among Duffy-negative individuals in Africa remain largely unexplored. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Duffy blood group system'.)

●Mortality – The reported risk of mortality associated with P. vivax infection varies considerably [2]. The greatest risk occurs in vulnerable populations in endemic settings with recurrent episodes of malaria, resulting in a cumulative risk of severe anemia and associated comorbidities [27]. Among patients presenting with severe disease, mortality ranges from 5 to 25 percent, confounded by bacterial coinfection in the context of severe anaemia [4,28-33]. Young infants and pregnant women are at particular risk [34,35]. Nonimmune travelers are also at risk for life-threatening illness [36,37], although mortality in nonendemic resource-rich settings is generally lower compared with endemic settings [6].

Plasmodium ovale — P. ovale malaria is endemic to tropical western Africa. It is also endemic in Southeast Asia and Oceania, but is rarely seen in conventional prevalence surveys in these areas [38]. Sensitive molecular diagnostic methods applied in the Asia-Pacific typically demonstrate P. ovale prevalence of about 0.2 percent in most endemic areas. In one survey in Indonesia including more than 15,000 blood smears, 34 individuals with P. ovale infection were identified; the frequency of P. ovale relative to P. falciparum and P. vivax was <1:1000 [39].

There are two distinct subspecies of P. ovale: P. ovale curtisi and P. ovale wallikeri [40].

Similar to P. vivax, P. ovale forms dormant liver stages (hypnozoites) that can activate weeks, months, or years after the initial infection, leading to relapses [18]. (See 'Relapse' below and 'Preventing relapse' below.)

Severe complications may arise with P. ovale infection, including jaundice, anemia, and respiratory syndromes; however, these are infrequent compared with severe P. falciparum malaria. Mortality associated with P. ovale infection is estimated to be 0.15 percent [7].

Plasmodium malariae — P. malariae infection occurs throughout Africa, Asia, Oceania, and the Americas [41]. In general, P. malariae occurs sporadically in areas of stable malaria transmission, although at a relatively low prevalence [42,43]. P. malariae is unique in its ability to cause attacks even decades after exposure; the mechanism of persistence is unknown [44]. P. knowlesi may be misdiagnosed as P. malariae microscopically. (See "Non-falciparum malaria: Plasmodium knowlesi", section on 'Diagnosis'.)

Severe complications may arise with P. malariae infection, including jaundice, anemia, and respiratory syndromes; however, these are infrequent compared with severe P. falciparum malaria. Mortality associated with P. malariae infection is estimated to be 0.2 to 2.4 percent [8,45].

Chloroquine resistance — In most malaria-endemic countries, chloroquine is the first-line blood schizonticidal agent for all non-falciparum malarias. However, chloroquine resistance (defined as persistent parasitemia after three days of chloroquine therapy or recurrent parasitemia within 28 days following chloroquine therapy) has been documented in the setting of P. vivax infection.

Chloroquine-resistant P. vivax (CRPV) was first reported from the island of New Guinea (including Papua New Guinea and Papua, Indonesia) in the early 1990s [46-48]. This area remains the epicenter of chloroquine resistance; clinical trials have demonstrated that more than 60 percent of patients treated with chloroquine in this region have early recurrent infection, with a high proportion requiring hospitalization [49,50]. High levels of treatment failure have also been reported from Sabah, Malaysia and south Sumatra, Indonesia [51,52]. There is also evidence of CRPV to a lesser degree in most P. vivax-endemic countries [53]. Additional information regarding regions with reduced chloroquine efficacy may be found on the website of the Worldwide Antimalarial Resistance Network [54].

There has been one report of chloroquine failure in patients with infection due to P. malariae, although this may reflect inadequate drug absorption rather than drug resistance [55]. Prolonged clearance time for P. malariae parasitemia (≥3 days) has been described in some cases and likely reflects the life cycle duration (72 hours) [56].

CLINICAL MANIFESTATIONS — Some clinical manifestations are common to all species of non-falciparum malaria (see 'Overview' below), and some clinical manifestations are associated with a particular species. (See 'By species' below.)

Relapse can occur in association with P. vivax or P. ovale infection (see 'Relapse' below), and hyper-reactive malarial splenomegaly (HMS) is a complication of chronic malaria (see 'Hyper-reactive splenomegaly' below).

Overview — The incubation periods among the non-falciparum malarias typically range from 8 to 30 days. Nonimmune patients usually develop an acute febrile illness, and most will have daily episodes of spiking fever over several hours. Semi-immune individuals may present with low-grade fever, may be asymptomatic, or may present with illness in the absence of fever. In semi-immune individuals, the interval between febrile episodes may reflect the duration of the reproductive cycle of the infecting species (P. falciparum, P. vivax, and P. ovale: 48 hours [tertian]; P. malariae: 72 hours [quartan]) (figure 1). In P. knowlesi, the reproductive cycle duration is 24 hours. (See "Non-falciparum malaria: Plasmodium knowlesi".)

Clinical manifestations of uncomplicated malaria are nonspecific and typically include fever, chills, diaphoresis, headache, fatigue, malaise, myalgia, arthralgia, tachycardia, tachypnea, cough, anorexia, nausea, vomiting, abdominal pain, or diarrhea. Physical findings may include jaundice, splenomegaly, and/or hepatomegaly. Febrile seizures may occur in the setting of uncomplicated malaria.

Clinical manifestations of severe malaria may occur with any malaria species, in the presence or absence of coinfection with P. falciparum (table 2) [6]. These manifestations include hemodynamic instability, pulmonary edema, hemolysis, severe anemia, coagulopathy, hypoglycemia, metabolic acidosis, renal failure, hepatic dysfunction, altered mental status, focal neurological deficits, and seizures [57].

By species — In addition to the above manifestations, some clinical syndromes are associated with a particular malaria species.

P. vivax and P. ovale — The life cycles of P. vivax and P. ovale include a dormant hepatic stage called the hypnozoite. Although these dormant parasites are asymptomatic, they can activate in the weeks, months, or years after the initial infection, causing recurrent illness known as a relapse (rather than a recrudescence or reinfection) [18]. (See 'Relapse' below.)

Uncomplicated infection due to P. vivax in nonimmune patients typically causes nausea, vomiting, high fevers, rigors, and myalgia. The acute symptoms usually subside quickly with treatment but may linger for several days. Without prompt treatment, progression to severe manifestations can occur, including anemia, disseminated intravascular coagulation, thrombocytopenia, and acute lung injury [2,3,58-60]. Hemodynamic instability, hepatic failure, renal failure, and coma have also been described [28,61]. Splenic rupture or infarct is an unusual but serious complication of P. vivax infection [62-64]. High rates of sepsis in patients presenting with severe P. vivax malaria have been reported [4,65].

P. vivax occurs in tropical and temperate latitudes, and these strains exhibit distinct relapse behaviors. The more prevalent tropical form causes malaria that relapses within three weeks of onset of the primary attack, and then at approximately six- to eight-week intervals thereafter (unless slowly eliminated antimalarial drugs are given, in which case the first relapse is delayed to five to seven weeks after treatment). The majority of relapses in tropical strains occur within six months, but heavily infected patients or patients with prolonged exposure may continue relapsing up to two years and rarely up to four years or more. The temperate form may have an incubation period of up to nine months before relapse after its primary infection and a similarly long interval between subsequent relapses [19].

Reports of severe P. ovale malaria are uncommon; this likely reflects the relative rarity of P. ovale infection [6]. Splenic rupture, thrombocytopenia, and disseminated intravascular coagulation have been associated with P. ovale infection [7,66-69].

P. malariae — Malaria due to P. malariae typically causes a relatively mild illness with relatively low parasitemia. However, low-level asymptomatic infection can persist for months or years and the associated anemia can be severe and result in significant mortality [3,45]. In addition, P. malariae may be associated with recurrence even decades after exposure; the mechanism of persistence is unknown [44].

Chronic P. malariae infection in children has been associated with nephrotic syndrome due to a mixed immunoglobulin (Ig)M and IgG basement membrane immune complex nephropathy [70-73]; one study noted the risk of this complication of 1 in 200 children <5 years of age [45]. Most patients die within two years of this diagnosis, although cure has been described with early recognition and prompt treatment with antimalarial and glucocorticoid therapy [74-77].

P. knowlesi may be misdiagnosed as P. malariae microscopically. (See "Non-falciparum malaria: Plasmodium knowlesi", section on 'Diagnosis'.)

Relapse — The life cycles of P. vivax and P. ovale include hypnozoites, which are dormant stages in the liver that can activate and cause relapse weeks, months, or years after the initial infection (figure 1) [18]. The presence of hypnozoites in the liver is not associated with clinical symptoms, and available diagnostic tools cannot detect these latent parasites. Relapse occurs with onset of similar symptoms as in a primary attack. Relapse may also occur in the absence of a primary attack; this typically occurs in individuals who have taken malaria prophylaxis during travel in endemic areas [78,79]. At the northernmost reaches of P. vivax endemicity, some strains do not cause a primary attack, but first appear as relapses eight months or more after infection [19].

The character of relapses varies with geography of transmission [80].

●For malaria strains acquired in most tropical areas, the risk of relapse exceeds 80 percent; first relapses typically occur 21 to 30 days after the initial symptomatic illness. Four or more relapses may occur at approximately two-month intervals [81]. As many as 10 to 20 relapses within two years have been described (in heavily exposed American soldiers repatriated from the Southwestern Pacific theater of World War II).

●For malaria strains acquired in temperate areas, the risk of relapse is often <30 percent; relapses usually occur 6 to 12 months after infection, typically with fewer than three relapses occurring in the subsequent months [19]. In tropical India, P. vivax seems to behave more like temperate strains [82], likely due to the monsoonal seasonality of malaria transmission.

The timing of hypnozoite activation appears to depend on the seasonal abundance of Anopheline mosquitoes. The long latency of temperate strains coincides with the reappearance of Anopheline mosquitoes after a long winter and spring or with onset of monsoons after a prolonged dry period that is inhospitable to Anopheline mosquitoes. Extrinsic triggers for activation have been hypothesized [83,84]. In malaria-endemic areas, patients undergoing splenectomy have a high risk of P. vivax parasitemia, which is hypothesized to arise from a large reservoir of viable parasites accumulated in the spleen and displaced into the peripheral circulation [85,86].

Few studies have reported clinical details of relapses due to P. ovale. Most reports describe relapse within 17 to 255 days, although one report describes relapse four years following infection [87-89]. The risk of relapse with P. ovale is lower than with P. vivax malaria. In a retrospective report of returning travelers in Sweden, relapse rates following antimalarial treatment (in the absence of antirelapse treatment with primaquine) were 33 versus 10 percent, respectively [90]. In a study from Gabon, the risk of recurrence within 12 months was higher among patients with P. ovale curtisi than among those with P. ovale wallikeri (61 versus 19 percent); however, it was not possible to confirm whether these cases represented reinfection or true relapse [91].

Relapse may be prevented by administration of presumptive anti-relapse therapy that targets hypnozoites. The temperate form of hypnozoites tend to be more sensitive to primaquine than the tropical form. (See 'Preventing relapse' below.)

Hyper-reactive splenomegaly — HMS, previously known as tropical splenomegaly syndrome, is a complication of chronic malaria. The prevalence is high in eastern Indonesia and the Papuan highlands where P. vivax and P. malariae are the predominant species, although it can occur in association with any malaria species [92-95].

HMS is due to an overproduction of IgM secondary to repeated infection, with subsequent formation of immune complexes that cause prolonged stimulation of splenic reticuloendothelial cells. Among patients in Indonesia with HMS and elevated P. vivax antibody titers, antibody overproduction has been linked to a decrease in T-suppressor lymphocytes that normally downregulate B-lymphocyte function and antibody production [96].

Clinical manifestations of HMS include left upper quadrant pain, fatigue, ascites, lower extremity edema, and dyspnea; these symptoms become more severe as the disease progresses [97]. Parasitemia is uncommon; the diagnosis is generally made among long-term residents of malarious areas who have massive splenomegaly, high serum antimalarial antibody levels, and polyclonal IgM hypergammaglobulinemia. Diagnosis is based on a constellation of clinical, epidemiological, hematological, and immunological findings [98].

Management of HMS is discussed below. (See 'Hyper-reactive splenomegaly' below.)

DIAGNOSIS — Malaria should be suspected in the setting of any febrile illness after exposure in a region where malaria is endemic [99,100]. The diagnosis is established by blood smear microscopy or rapid diagnostic test (RDT). Polymerase chain reaction (PCR) diagnostics can also be used, although they remain primarily tools of research in most locations.

Microscopic examination of Giemsa-stained blood smears is the traditional method for diagnosis of malaria. This technique allows determination of species identity, quantification of parasitemia, and the life cycle stages present (figure 2 and table 1). The limit of detection of microscopy is about 25 parasites/microL in expert hands. Previously malaria-naïve individuals can develop acute symptoms at low-level parasitemia below the limit of detection of microscopy [101]. Hence, even if microscopic examination is negative, it should be repeated at least twice over the course of two days if malaria is suspected. Competent microscopy requires ongoing training, certification, specific supplies, and a properly maintained light microscope capable of 1000x oil immersion magnification.

RDTs are straightforward to use and interpret and do not require specialized laboratory skills or equipment. However, RDTs have a limit of detection >100 to 200 parasites/microL and do not allow determination of parasitemia or life cycle stages present. Ideally, RDTs should complement standard microscopic examinations of Giemsa-stained blood films if possible. Identification of the species depends on the type of RDT and may be limited to P. falciparum only, P. falciparum versus non-falciparum species (not specified), or P. falciparum versus P. vivax, depending on the RDT used. A systematic review evaluating RDTs for P. vivax demonstrated sensitivity and specificity of 77 to 99 percent and >95 percent, respectively [102].

There are no RDTs for definitive diagnosis of P. malariae, P. ovale, or P. knowlesi. Fewer studies have investigated the performance of RDTs for these species; those that have suggest sensitivities of 14 to 80 percent, 20 to 100 percent, and <50 percent, respectively [103].

PCR diagnosis typically detects as low as 1 parasite/microL. PCR diagnosis with a negative RDT may be useful where competent malaria microscopy is not available.

P. knowlesi appears morphologically similar to P. malariae by microscopy; molecular diagnostic procedures are required for confirmation of P. knowlesi infection [104]. (See "Non-falciparum malaria: Plasmodium knowlesi", section on 'Diagnosis'.)

Mixed infections represent a diagnostic challenge, as microscopists may miss detection of an additional species. Some RDTs can detect multiple species (such as pf-HRP2/pan-pLDH and pf-HRP2/aldolase). In some cases, molecular diagnostics may be needed to definitively exclude falciparum malaria, however, access to such tools may not be available in all locations. (See 'Mixed infection' below.)

Additional evaluation should include:

●Complete blood count (evaluating for severe anemia, thrombocytopenia) [105]

●Coagulopathy screen

●Liver function testing, including fractionated bilirubin (evaluating for hepatitis, hemolysis)

●Basic metabolic panel (evaluating for renal failure, metabolic acidosis, hypoglycemia)

●Blood and urine cultures [4,65]

Instances of P. vivax infection of bone marrow in the absence of detectable parasitemia have been reported [106-108]. In one case series including 108 patients in India with fever and anemia, thrombocytopenia, or pancytopenia, P. vivax infection of bone marrow was observed in 43 percent of cases [109].

Issues related to diagnosis of malaria are discussed further separately. (See "Laboratory tools for diagnosis of malaria".)

TREATMENT

Uncomplicated infection — Uncomplicated malaria consists of symptomatic infection, in the absence of symptoms and signs consistent with severe malaria (table 2).

If the infecting species is not known with certainty, treatment for uncomplicated P. falciparum should be administered. All patients with mixed infections that include P. falciparum should receive definitive treatment for P. falciparum. (See 'Mixed infection' below and "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children" and "Malaria in pregnancy: Prevention and treatment".)

Antimalarial selection — Treatment of non-falciparum malaria consists of treating the erythrocytic asexual stages that cause symptomatic illness (figure 1 and algorithm 1). In addition, treatment of infections caused by P. vivax and P. ovale requires eradication of liver hypnozoites to prevent clinical attacks caused by relapse. (See 'Preventing relapse' below.)

Chloroquine-sensitive infection — Treatment of acute non-falciparum malaria consists of chloroquine or an artemisinin combination therapy (ACT) [57,110]. Dosing is summarized in the table (table 3).

We use the regimen endorsed by the WHO (and most malaria-endemic countries) consisting of a total dose of 25 mg base/kg orally administered over 3 days in 3 doses (10 mg base/kg on day 1, 10 mg base/kg on day 2; and 5 mg base/kg orally on day 3) [110]. Our approach differs from the CDC guidance which consists of a total dose of 25 mg base/kg orally administered over 3 days in 4 doses (10 mg base/kg initial dose, followed by 5 mg base/kg at 6, 24, and 48 hours) [111].

Chloroquine is highly effective against erythrocytic stages of chloroquine-sensitive P. vivax, P. malariae, and P. ovale [112]. In a meta-analysis including 5240 patients with P. vivax malaria, the three-dose chloroquine regimen was well tolerated; when administered as monotherapy, it resulted in 90 percent of patients being recurrence free at 28 days (which rose to 98.6 percent being recurrence free when chloroquine was co-administered with primaquine) [113]. In addition, a higher total dose of chloroquine (30 mg/kg) was associated with a 40 percent lower risk of early recurrence in children <5 years old. Further studies are in progress to confirm whether a higher dose should be used in young children.

Minor side effects of chloroquine (including bitter taste, gastrointestinal disturbances, dizziness, blurred vision, and headache) may be alleviated by taking the drug with food. (See "Antimalarial drugs: An overview".)

ACTs are also effective against non-falciparum malaria species and advocated by WHO in areas of chloroquine resistance. Those containing the partner drugs piperaquine, mefloquine, or lumefantrine are favored; artesunate-amodiaquine and pyronaridine-artesunate are also likely to be effective and useful in some regions; however, there have been few clinical trials for use of these ACTs for treatment of non-falciparum malaria [1,54].

In a systematic review including 14 trials and more than 2500 participants, ACTs were at least equivalent to chloroquine at treating the blood stage of P. vivax infection [114]. Dihydroartemisinin-piperaquine is the most studied ACT for treatment of non-falciparum malaria; it may provide a longer period of post-treatment suppressive prophylaxis (against untreated relapse) than artemether-lumefantrine or artesunate-amodiaquine [115]. Resistance has compromised the efficacy of artesunate-sulfadoxine-pyrimethamine, and this agent is not an appropriate regimen for treatment of non-falciparum malaria [57]. Dosing for ACTs is summarized in the table (table 4).

Other agents with activity against non-falciparum malaria include hydroxychloroquine (for chloroquine-sensitive malaria), atovaquone-proguanil, mefloquine, or a combination of quinine plus tetracycline or doxycycline (table 3) [116-121].

The sexual stages (gametocytes) of non-falciparum malaria species are susceptible to all schizonticidal antimalarial compounds (including chloroquine and ACTs); hence, no additional therapy against gametocytes is required to reduce the risk of onward transmission. (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children", section on 'Reducing transmissibility'.)

Chloroquine-resistant infection — Chloroquine-resistant P. vivax has been reported at varying frequencies and degrees of severity in almost all endemic regions. (See 'Chloroquine resistance' above.)

Chloroquine resistance is defined as persistent P. vivax parasitemia after three days of chloroquine therapy or recurrent parasitemia within 28 days following chloroquine therapy with adequate drug concentrations (defined as >100 ng/mL whole blood concentrations of chloroquine plus its metabolite desethylchloroquine) [47].

Chloroquine resistance is difficult to diagnose, since recurrent parasitemia may be due to recrudescent infection (treatment failure and appearance of the same parasite strain), relapse, or reinfection [122]. (See 'Recurrent infection' below.)

In areas of low-grade chloroquine resistance (eg, less than 10 percent P. vivax recurrence by day 28 post-treatment), patients may be treated with chloroquine plus a course of primaquine or tafenoquine for prevention of relapse [53,123] (see 'Preventing relapse' below). Primaquine also has effective blood schizonticidal effects against P. vivax [124]. However, some countries favor a universal policy of treating all patients with uncomplicated malaria due to any Plasmodia species with an ACT [125].

In areas of highly chloroquine-resistant non-falciparum malaria, the preferred treatment regimen consists of ACT plus a course of primaquine for prevention of relapse (table 4) [51,110,126-130].

Other agents with activity against chloroquine-resistant non-falciparum malaria include atovaquone-proguanil, mefloquine, or a combination of quinine plus tetracycline or doxycycline (table 3) [124,131,132].

Mixed infection — Patients with mixed infections that include P. falciparum should receive definitive treatment for P. falciparum. In areas where both P. vivax and P. falciparum are endemic and species diagnosis is not reliable, a regimen with activity against both falciparum and non-falciparum malaria (such as an ACT) should be administered. (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

Primaquine should also be administered to patients with P. vivax or P. ovale infection to prevent relapse (in the absence of glucose-6-phosphate dehydrogenase [G6PD] deficiency) [57]. (See 'Preventing relapse' below.)

Preventing relapse

Clinical approach — Presumptive anti-relapse therapy is required to eradicate the dormant hypnozoite liver stages of P. vivax and P. ovale and prevent relapses (figure 1) [57,133,134]. (See 'Relapse' above.)

The available drugs are primaquine and tafenoquine; both are 8-aminoquinoline compounds which can induce acute hemolysis in individuals with G6PD deficiency [135,136]. For this reason, patients should undergo G6PD screening prior to administration of anti-relapse therapy. (See 'G6PD screening' below.)

Antirelapse treatment is administered in combination with appropriate antimalarial therapy for P. vivax or P. ovale asexual stage infection (such as chloroquine or an ACT) (see 'Antimalarial selection' above). Our approach to primaquine dosing is as follows (table 5) (see 'Primaquine' below):

●G6PD enzyme activity ≥30 percent − For nonpregnant individuals >6 months of age with G6PD enzyme activity ≥30 percent (using a quantitative assay) or ‘normal’ G6PD status (using a qualitative assay), we dose primaquine as follows: 0.5 mg/kg daily over 14 days (total dose 7 mg/kg), coadministered with appropriate antimalarial therapy for asexual stage infection. This regimen prevents relapses of P. vivax acquired from all endemic areas [133,137-139], and has a greater efficacy than the lower dose regimen (total dose 3.5 mg/kg) which is recommended in most endemic countries where G6PD enzyme screening is not available [140].

For nonpregnant individuals ≥16 years of age with G6PD enzyme activity >70 percent (using a quantitative assay) [141], an alternative approach consists of tafenoquine (300 mg single dose). In addition, a dispersible formulation is licensed for children >2 years of age in Australia but not in the United States [142].

Tafenoquine should be reserved for patients with concerns over adherence to a 14-day primaquine regimen, since tafenoquine has lower efficacy than primaquine in areas of high-relapse periodicity [143]. In addition, tafenoquine should only be used in combination with chloroquine (eg, not ACT) [143].

●G6PD enzyme activity <30 percent

•For nonpregnant G6PD-deficient individuals >6 months of age with G6PD activity <30 percent, we administer a modified primaquine regimen as follows: 0.75 mg base/kg once weekly for eight weeks (total dose 6 mg/kg), with close monitoring for hemolysis [57,110]; however, safety and efficacy data for this regimen are limited [57,144-146]. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

•For patients who are ineligible for primaquine or tafenoquine therapy (including pregnant patients, patients <6 months of age, or patients with prior severe reaction to these drugs), counseling regarding the possibility of relapsing infection should be provided, including guidance to seek repeat treatment if symptoms recur [147].

No radical cure regimens have been validated for use in these individuals; chloroquine prophylaxis (300 mg base weekly for six months) may be administered, although late relapses may still occur [116]. In the setting of chloroquine-resistant P. vivax, mefloquine prophylaxis (228 mg base weekly) may be used.

●Unknown G6PD status − For patients with unknown G6PD status, we dose primaquine as follows: 0.25 mg/kg daily over 14 days (total dose 3.5 mg/kg), with close monitoring to minimize the risk of drug-induced hemolysis [148]. This lower dose regimen is sufficient for preventing P. ovale relapse and may be sufficient for preventing P. vivax relapse for infection acquired in areas of lower relapse periodicity [57,133,149]. However, in areas with high-relapse periodicity, it may have poor efficacy [140,150].

Hypnozoitocidal drugs can cause gastrointestinal upset when taken without food. If the patient is able to tolerate a light snack or meal, then hypnozoitocidal therapy may be coadministered with blood schizontocidal therapy. If not, hypnozoitocidal therapy should be initiated once normal oral intake can be resumed.

Patients treated with primaquine or tafenoquine should be monitored for clinically significant hemolysis; hemoglobinuria, jaundice, or dyspnea should prompt treatment discontinuation.

Hypnozoitocidal drugs can also cause methemoglobinemia; this is rarely of clinical concern and is usually self-limiting. (See "Methemoglobinemia".)

G6PD screening — G6PD testing should be performed prior to administration of anti-relapse therapy with primaquine or tafenoquine. While a modified primaquine dosing regimen may be administered in the absence of G6PD test results, G6PD testing is compulsory prior to use of tafenoquine. (See 'Clinical approach' above.)

G6PD enzyme activity can be assessed by quantitative or qualitative tests. Qualitative G6PD screening produces a binary reading that can reliably detect individuals with enzyme activity less than 30 percent of normal. The most commonly used qualitative assay test is the fluorescent spot test. There are also commercially available G6PD test kits for use with a capillary or venous blood sample that render an easily read color change within 10 minutes [151]. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

G6PD deficiency is an X-linked enzymopathy in which almost all hemizygous males and homozygous females have residual enzyme activity below 30 percent and so can be reliably detected using a qualitative assay. However, female heterozygotes with mosaicism for the trait can have intermediate enzyme activity (30 to 70 percent) and thus screen as G6PD-normal by the qualitative test [152,153]. Heterozygous females with intermediate G6PD activity may have significant hemolysis when treated with primaquine or tafenoquine [154].

Antirelapse agents

Primaquine — Primaquine dosing is discussed above. (See 'Clinical approach' above.)

●General principles − Primaquine is the antirelapse agent for which there is greatest clinical experience; it has been used for decades [155]. It is contraindicated in G6PD-deficient individuals, pregnant women (since the G6PD status of the fetus cannot be determined), and infants <6 months of age. In addition, primaquine is not recommended in lactating women who are breastfeeding infants <6 months old. One report found very low concentrations of primaquine in breast milk after 28 days postpartum, suggesting administration of primaquine to lactating women may be safe for the infant [156]; further studies are needed. (See "Malaria in pregnancy: Prevention and treatment", section on 'Non-falciparum malaria'.)

The main determinant of primaquine efficacy is the total dose administered (table 5) [155]. The duration is usually spread over 14 days to reduce the risks of acute drug-induced hemolysis and gastrointestinal discomfort [110]. Gastrointestinal symptoms can be reduced by administering the drug with food [155,157]. Adherence may be diminished after resolution of symptoms; therefore, patients should be educated on the importance of completing a full course of treatment [158-160].

●Rationale for use of high-dose primaquine − Given marked heterogeneity in the risk and timing of relapse in different regions and patient populations [155], we favor high-dose primaquine (total dose 7 mg/kg rather than 3.5 mg/kg) administered over 14 days; this approach provides more reliable antirelapse efficacy and is preferred in patients who are not G6PD deficient [140]. Our approach differs from the 2022 World Health Organization (WHO) guidance [1].

The WHO guidance varies by region and accommodates the frequent lack of G6PD testing in remote malaria endemic areas. In most regions, the WHO recommends lower dose primaquine (3.5 mg/kg, administered as 0.25 mg/kg/day over 14 days or 0.5 mg/kg/day over 7 days), whereas in East Asia and Oceania, the WHO recommends higher dose primaquine (7 mg/kg, usually administered as 0.5 mg/kg/day over 14 days) [1].

A 2020 systematic review noted no difference in recurrence rates or adverse events with 3.5 mg/kg versus 7 mg/kg over 14 days, although only two randomized controlled trials were included in the comparison of these regimens [139]. In a subsequent randomized trial including 254 Brazilian patients ≥5 years of age with nonsevere P. vivax malaria, patients received initial treatment with chloroquine and then were randomly assigned to treatment with low-dose primaquine (3.5 mg/kg; 0.5 mg/kg for 7 days) or high-dose primaquine 7 mg/kg (0.5 mg/kg for 14 days) [150]. Those who received high-dose primaquine were more likely to reach the 24-week follow-up with no recurrence (86 versus 58 percent).

Similarly, in a meta-analysis including 36 trials and 8589 patients with P. vivax malaria, the risk of recurrent infection was lower after treatment with high-dose primaquine compared with the low-dose primaquine (adjusted hazard ratio [AHR] 0.45, 95% CI 0.34-0.60); this was apparent both in areas of East Asia and Oceania (AHR 0.55) and other endemic regions (AHR 0.42) [140].

●Use of shorter-course primaquine regimens − Shorter-course regimens with a higher daily dose may improve adherence to a complete course of treatment. In G6PD normal patients (≥30 percent G6PD activity), the efficacy of a 7-day high dose primaquine regimen (1 mg/kg per day) has been shown to be non-inferior to a 14-day regimen (0.5 mg/kg per day) [137,138,161]:

•In a randomized trial including 2336 G6PD-normal patients enrolled in Afghanistan, Ethiopia, Indonesia, and Vietnam, rates of recurrent vivax malaria for the 7-day regimen and the 14-day regimen were 0.18 and 0.16 episodes per person-year, respectively [138]. Adverse events were observed more frequently in the group treated for 7 days (1.0 versus 0.1 percent), but most were generally mild, self-limited, and of short duration. There were nine related serious adverse events in the 7-day regimen (five due to gastrointestinal intolerance, three due to hemolysis, and one due to methemoglobinemia) compared with only one in the 14-day regimen.

•Similarly, in a randomized trial including 680 G6PD-normal patients on the Thailand-Myanmar border, recurrence rates for the 7-day regimen and the 14-day regimen were comparable (12 percent with no difference between groups) [137]. Both regimens were generally well tolerated; however, two heterozygous women (undetected by qualitative screening) had clinically significant hemolysis.

Tafenoquine — Tafenoquine was approved by the US Food and Drug Administration in 2018 for preventing relapse of P. vivax infection in nonpregnant individuals ≥16 years of age. Approval in Australia was expanded in 2022 for children ≥2 years of age. The antirelapse efficacy of tafenoquine likely extends to P. ovale, in view of the biologic similarities between P. vivax and P. ovale and the supposed good efficacy of primaquine for prevention of P. ovale relapse [162].

The efficacy of tafenoquine (single dose) for relapse prevention is supported by data from randomized trials [135,163-165]. In the Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE), a randomized trial including more than 500 patients that evaluated the efficacy of chloroquine plus tafenoquine (300 mg single dose) or chloroquine plus placebo in patients with phenotypically normal G6PD activity, chloroquine plus tafenoquine proved more efficacious than chloroquine plus placebo for prevention of P. vivax malaria relapse (62 versus 28 percent) during the six months following therapy [163,164].

A meta-analysis of the data from DETECTIVE [164] and another trial, Global Assessment of Tafenoquine Hemolytic Risk (GATHER) [165], compared the efficacy of tafenoquine (300 mg single dose) and primaquine (15 mg once daily for 14 days) for preventing recurrence of P. vivax malaria. The risk of relapse at six months was nonsignificantly higher after tafenoquine compared with primaquine (33 versus 27 percent), with an odds ratio of 1.81 (95% CI 0.82-3.96) [165].

The GATHER trial also evaluated hemolysis associated with tafenoquine and primaquine [165]. Among patients with normal (>70 percent) G6PD enzyme activity phenotype, there was no significant difference in the decline in hemoglobin level between the groups (2.4 versus 1.2 percent).

Administration of tafenoquine in the licensing studies was restricted to patients with >70 percent G6PD enzyme activity [164,165]. For this reason, the manufacturers advise against administering tafenoquine unless a quantitative G6PD measurement is performed with the ability to identify patients with >70 percent G6PD enzyme activity. A quantitative point-of-care assay has been developed to support tafenoquine implementation [166].

Tafenoquine use for radical cure should only be used in patients receiving chloroquine against acute P. vivax infection; it cannot be used with other antimalarials due to concerns about reduced antirelapse efficacy [167]. Thus, if ACT is used to treat P. vivax, then primaquine should be used for radical cure [168].

Monitoring and follow-up — With appropriate treatment, fever and parasitemia usually resolve within two to four days; this may vary depending on strain differences, host factors, and type of antimalarial therapy. Serial blood smears should be performed after initiation of treatment until parasitemia is no longer detectable. In general, following chloroquine treatment, the parasite density should be lower than 25 percent of the pretreatment density by day 3 and undetectable by day 4. The speed of the parasite clearance (assessed by microscopy) has been proposed as a marker of parasite susceptibility; parasite clearance in 95 percent of patients by day 2 or all patients by day 3 is 100 percent predictive of chloroquine sensitivity [53]. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

Patients with normal G6PD activity may have a significant decline in hemoglobin, attributable to parasite-induced hemolysis. Patients with decreased G6PD activity may also have a significant decline in hemoglobin, attributable to parasite and/or drug-induced hemolysis [141,169]. Repeat testing should be performed on days 7 and 28 following initiation of therapy to confirm cure and hematologic recovery, even in the absence of symptoms. Recurrent fever over the ensuing six months may signal recurrent infection and should prompt repeat evaluation with blood smear.

Severe infection — Patients with severe malaria should be treated for presumed P. falciparum infection, regardless of species diagnosis (table 2). (See "Treatment of severe malaria".)

Severe non-falciparum malaria refers to malaria infection caused by a non-falciparum species associated with manifestations such as hemodynamic instability, pulmonary edema, hemolysis, severe anemia, coagulopathy, hypoglycemia, metabolic acidosis, renal failure, hepatic dysfunction, altered mental status, focal neurological deficits, or seizures [57].

Recurrent infection

Causes — Recurrent infection can result from recrudescence, relapse, or reinfection; these may be difficult to distinguish:

●Recrudescence (failed schizonticidal therapy) refers to the re-emergence of blood stage forms following reduction of parasitemia and resolution of clinical symptoms yet incomplete clearance of infection; it generally occurs within six to nine weeks after an initial infection [170].

●Relapse refers to reactivation of liver hypnozoites weeks to months after the initial treatment; if hypnozoitocidal treatment was administered, it represents failed hypnozoitocidal therapy. Relapses account for 66 to 95 percent of all recurrent vivax malaria episodes [21]. (See 'Impaired primaquine metabolism' below.)

●Reinfection refers to new infection transmitted via mosquito exposure.

Patients with recurrent infection should be treated promptly with an alternate agent. Options include ACT, atovaquone-proguanil, mefloquine, or quinine plus tetracycline (or doxycycline). Antimalarial selection should be individualized based on local resistance patterns where the infection was acquired.

Impaired primaquine metabolism — Primaquine is a prodrug metabolized by cytochrome P450 isozyme 2D6 (CYP2D6) to derivatives that kill parasites attempting hepatic development [171]. Patients who have experienced relapses following directly observed high-dose primaquine therapy have been found to have genotypes of CYP2D6 associated with impaired primaquine metabolism [172].

For this reason, patients who relapse following primaquine therapy with adequate dosing and good adherence should be evaluated for CYP2D6 genotype, with categorization of the predicted activity phenotypes (null, intermediate, normal, or ultra-metabolizer) [173]. Null metabolizers are unlikely to benefit from even high doses of primaquine, whereas others may benefit from an escalated dosing regimen.

In a case-control study nested within a clinical trial of primaquine (high-dose directly observed therapy) against P. vivax relapse in 177 individuals, 21 of 26 therapeutic failures (cases) were evaluated for CYP2D6 genotype and dextromethorphan metabolism phenotype (along with 36 randomly selected controls who did not relapse) [174]; 20 of those 21 cases had impaired CYP2D6 genotypes and phenotypes compared with relatively few controls (odds ratio 18, 95% CI 2.2-148).

Impaired CYP2D6 metabolism has not been associated with increased risk of relapses following treatment with tafenoquine [175].

Hyper-reactive splenomegaly — Clinical manifestations of hyper-reactive splenomegaly are described above. (See 'Hyper-reactive splenomegaly' above.)

Treatment of hyper-reactive splenomegaly consists of antimalarial therapy for the duration of ongoing malaria exposure. Chloroquine (300 mg base [= 500 mg salt]) once weekly is effective in reducing spleen size and symptoms over several months in 70 to 80 percent of cases [93,97]. In areas with known chloroquine resistance, alternative agents should be used at full dose for initial treatment followed by prophylactic doses at intermittent intervals. Splenectomy carries an appreciable risk of mortality and so should only be considered as a treatment for severely debilitating massive splenomegaly unresponsive to medical management [93,176].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)

SUMMARY AND RECOMMENDATIONS

●Non-falciparum malaria − Non-falciparum malaria refers to malaria infection due to Plasmodium species other than P. falciparum; these include P. vivax, P. ovale, P. malariae, and P. knowlesi (table 1). P. vivax is the most common non-falciparum malaria species; approximately one-third of the world's population is at risk for infection caused by this species. Infections caused by P. knowlesi and P. vivax are associated with significant risk of morbidity and mortality; severe disease due to P. malariae and P. ovale is less common. (See 'Epidemiology' above.)

●Clinical manifestations – The incubation periods of the non-falciparum malarias are 8 to 30 days. Clinical manifestations of uncomplicated malaria include fever, chills, headache, fatigue, malaise, myalgia, and other symptoms. Clinical manifestations of severe malaria include hemodynamic instability, severe anemia, metabolic acidosis, renal failure, altered mental status, and other symptoms. (See 'Clinical manifestations' above.)

●Relapse − The life cycles of P. vivax and P. ovale include hypnozoites, which are dormant stages in the liver that can reactivate weeks, months, or years after the initial infection, causing relapse. (See 'Relapse' above.)

●Diagnosis − Malaria should be suspected in the setting of febrile illness after exposure to a region where malaria is endemic. The diagnosis is established by blood smear microscopy or rapid diagnostic test. (See 'Diagnosis' above.)

●Treatment

•Antimalarial selection

General principles − Treatment of uncomplicated non-falciparum malaria consists of treating the erythrocytic forms (figure 1 and algorithm 1). If the infecting species is not known with certainty, treatment for uncomplicated P. falciparum should be administered. Patients with mixed infections that include P. falciparum should receive definitive treatment for P. falciparum. Patients with severe malaria should be treated for presumed severe P. falciparum infection, regardless of species diagnosis (table 2). (See 'Antimalarial selection' above.)

-Chloroquine-sensitive infection − We suggest treating chloroquine-sensitive non-falciparum malaria with chloroquine or artemisinin combination therapy (ACT) (Grade 2B). Dosing is summarized in the tables (table 4 and table 3). (See 'Chloroquine-sensitive infection' above.)

-Chloroquine-resistant infection − A high prevalence of chloroquine resistance has been associated with P. vivax infection in southeastern Asia and Oceania; it is defined as persistent P. vivax parasitemia after three days of chloroquine therapy or recurrent parasitemia within 28 days following chloroquine therapy. We suggest treating chloroquine-resistant non-falciparum malaria with an ACT (Grade 2B) (table 4). (See 'Chloroquine resistance' above and 'Chloroquine-resistant infection' above.)

•Antirelapse therapy − We recommend presumptive antirelapse therapy to eradicate the hypnozoite liver stages of P. vivax and P. ovale (Grade 1A). Such treatment can be started after symptoms have begun to subside and normal glucose-6-phosphate dehydrogenase (G6PD) status has been confirmed. Antirelapse therapy dosing is summarized in the table (table 5).

-G6PD enzyme activity ≥30 percent − For patients with G6PD enzyme activity ≥30 percent (using a quantitative assay) or ‘normal’ G6PD status (using a qualitative assay), we dose primaquine as follows: 0.5 mg/kg daily over 14 days (total dose 7 mg/kg), coadministered with appropriate antimalarial therapy for asexual stage infection.

An alternative approach for nonpregnant individuals ≥16 years of age with G6PD enzyme activity >70 percent (using a quantitative assay) who received chloroquine consists of tafenoquine (300 mg single dose). In countries where the dispersible formulation is licensed, tafenoquine can also be used in children >2 years of age (weight-based dosing). Tafenoquine should be reserved for patients with concerns over adherence to a 14-day primaquine regimen, since tafenoquine has lower efficacy than primaquine in areas of high-relapse periodicity.

-G6PD enzyme activity <30 percent − For nonpregnant G6PD-deficient individuals >6 months of age with G6PD activity <30 percent, we administer a modified primaquine regimen as follows: 0.75 mg base/kg once weekly for eight weeks (total dose 6 mg/kg). Primaquine administration should be combined with careful supervision for hemolysis, particularly in the first week.

For patients who are not eligible for antirelapse therapy (including pregnant patients, patients <6 months of age, or patients with prior severe reaction to these drugs), counseling regarding the possibility of relapsing infection should be provided, including guidance to seek repeat treatment if symptoms recur.

-Unknown G6PD status − For patients with unknown G6PD status in whom G6PD testing is not available, we dose primaquine as follows: 0.25 mg/kg daily over 14 days (total dose 3.5 mg/kg), to minimize the risk of drug-induced hemolysis. This lower dose regimen is sufficient for preventing P. ovale relapse and may be sufficient for preventing P. vivax relapse for infection acquired in areas of lower relapse periodicity. However, in areas with high-relapse periodicity, it may have poor efficacy.

●Monitoring and follow-up − With appropriate treatment, fever and parasitemia usually resolve within two to four days. Daily smears should be performed until parasitemia is no longer detectable. Repeat testing on days 7 and 28 following initiation of therapy is warranted to confirm hematologic recovery and cure, even in the absence of symptoms. (See 'Monitoring and follow-up' above.)

●Recurrent infection − Recurrent infection after therapy may result from recrudescence (failed schizontocidal therapy), relapse (failed hypnozoitocidal therapy), or reinfection; these may be difficult to distinguish. Failed hypnozoitocidal therapy following primaquine may be due to impaired CYP2D6 metabolism of primaquine. (See 'Recurrent infection' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Jason Maguire, MD, and J Kevin Baird, PhD, who contributed to earlier versions of this topic review.