Post-artesunate Delayed Hemolysis in Patients With Severe Malaria in the United States-April 2019 Through July 2021.

BACKGROUND: Studies have demonstrated the safety and efficacy of intravenous artesunate (IVAS) for treatment of severe malaria in endemic and nonendemic countries. However, post-artesunate delayed hemolysis (PADH) is an increasingly recognized phenomenon after its administration. This study describes the prevalence and outcomes of PADH events among severe malaria cases treated with IVAS in the United States. METHODS: Patients diagnosed with severe malaria and treated with IVAS from April 2019 to July 2021 were included. Demographic, clinical, laboratory, therapeutic, and outcome measures were described using proportions, medians, and interquartile range. Patients reported to experience PADH were compared with those not reported to have PADH, and tests of significance were performed. RESULTS: Of 332 patients included in our analysis, 9 (2.7%) experienced PADH. The majority of infections in both groups were in non-Hispanic Black individuals. Parasite density (11.0% vs 8.0%), admission hemoglobin (11.0 g/dL vs 11.8 g/dL) were similar in the 2 groups. Total bilirubin levels at admission (4.7 mg/dL vs 2.2 mg/dL) and within 8 hours after completion of IVAS (2.6 mg/dL vs 1.2 mg/dL) were notably higher in PADH patients. Cumulative IVAS dose of >9.5 mg/kg and >3 doses of IVAS were risk factors for PADH. The majority (7 of 9) of PADH cases were diagnosed within 2 weeks after initiation of IVAS. Five patients (56%) required blood transfusions, and all recovered without sequelae. CONCLUSIONS: PADH is an uncommon and self-limiting adverse event in many cases; weekly monitoring of hemoglobin and hemolytic markers may identify cases requiring intervention in a timely manner.

Return to Travel in the Coronavirus Disease 2019 Pandemic Recovery Period and Implications for Imported Malaria: Reinforcing Prevention, Early Diagnosis, and Appropriate Treatment of Malaria.

Return to international travel in the COVID-19 pandemic recovery period is expected to increase the number of patients with imported malaria in the United States (US). Malaria prevention in travelers and preparedness for timely diagnosis and appropriate treatment are key to minimize imported malaria morbidity and mortality. Intravenous artesunate (IVAS) is now available from commercial distributors in the US for the treatment of severe malaria. Hospitals and pharmacists should have a plan for malaria treatment, including stocking artemether-lumefantrine for uncomplicated malaria, and stocking or planning for rapid procurement of IVAS for the treatment of severe malaria.

Receipt of First and Second Doses of JYNNEOS Vaccine for Prevention of Monkeypox - United States, May 22-October 10, 2022.

Vaccination with JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic) to prevent monkeypox commenced shortly after confirmation of the first monkeypox case in the current outbreak in the United States on May 17, 2022 (1). To date, more than 27,000 cases have been reported across all 50 states, the District of Columbia (DC), and Puerto Rico.* JYNNEOS vaccine is licensed by the Food and Drug Administration (FDA) as a 0.5-mL 2-dose series administered subcutaneously 28 days apart to prevent smallpox and monkeypox infections (2) and has been found to provide protection against monkeypox infection during the current outbreak (3). The U.S. Department of Health and Human Services (HHS) allocated 1.1 million vials of JYNNEOS vaccine from the Strategic National Stockpile, with doses allocated to jurisdictions based on case counts and estimated size of population at risk (4). However, initial vaccine supplies were severely constrained relative to vaccine demand during the expanding outbreak. Some jurisdictions with highest incidence responded by prioritizing first dose administration during May-July (5,6). The FDA emergency use authorization (EUA) of 0.1 mL dosing for intradermal administration of JYNNEOS for persons aged ≥18 years on August 9, 2022, substantially expanded available vaccine supply† (7). The U.S. vaccination strategy focuses primarily on persons with known or presumed exposures to monkeypox (8) or those at high risk for occupational exposure (9). Data on monkeypox vaccine doses administered and reported to CDC by U.S. jurisdictions were analyzed to assess vaccine administration and completion of the 2-dose series. A total of 931,155 doses of JYNNEOS vaccine were administered and reported to the CDC by 55 U.S. jurisdictions during May 22-October 10, 2022. Among persons who received ≥1 dose, 51.4% were non-Hispanic White (White), 22.5% were Hispanic or Latino (Hispanic), and 12.6% were non-Hispanic Black or African American (Black). The percentages of vaccine recipients who were Black (5.6%) and Hispanic (15.5%) during May 22-June 25 increased to 13.3% and 22.7%, respectively, during July 31-October 10. Among 496,888 persons who received a first dose and were eligible for a second dose during the study period, 57.6% received their second dose. Second dose receipt was highest among older adults, White persons, and those residing in the South U.S. Census Bureau Region. Tracking and addressing disparities in vaccination can reduce inequities, and equitable access to and acceptance of vaccine should be an essential factor in planning vaccination programs, events, and strategies. Receipt of both first and second doses is necessary for optimal protection against Monkeypox virus infection.

Safety and Effectiveness of Intravenous Artesunate for Treatment of Severe Malaria in the United States-April 2019 Through December 2020.

BACKGROUND: Severe malaria can be deadly and requires treatment with intravenous artesunate (IVAS). The Centers for Disease Control and Prevention provided IVAS starting 1 April 2019 for all patients with severe malaria in the United States. This study describes the safety and effectiveness of IVAS in these patients. METHODS: Patients meeting criteria for severe malaria April 2019-December 2020 who received IVAS were included. Demographic, clinical, laboratory, adverse event, and outcome information were collected. Clinical presentation, time to reach 1% and 0% parasitemia, adverse events, and death were described using proportions, medians, interquartile range (IQR), and tests of significance for differences in proportions. RESULTS: Of 280 patients included, the majority were male (61.4%), Black (75.0%), with a median age of 35 years (IQR: 15.8-53.9). Most had Plasmodium falciparum (83.6%) with median parasitemia of 8.0% (IQR: 4.6-13.2). Of 170 patients with information, 159 (93.5%) reached ≤1% parasitemia by the third IVAS dose with a median time of 17.6 hours (IQR: 10.8-28.8), and 0% parasitemia in a median of 37.2 hours (IQR 27.2-55.2). Patients with parasite densities >10% and those requiring adjunct therapy had significantly higher parasite clearance times. Adverse events associated with IVAS were reported in 4.8% (n = 13 of 271). Eight patients had post-artesunate delayed hemolysis that resolved. There were 5 (1.8%) deaths, all attributable to severe malaria. CONCLUSIONS: IVAS is a safe and effective drug for the treatment of severe malaria in the United States; timely administration can be lifesaving.

Attrition, physical integrity and insecticidal activity of long-lasting insecticidal nets in sub-Saharan Africa and modelling of their impact on vectorial capacity.

BACKGROUND: Long-lasting insecticidal nets (LLINs) are the primary malaria prevention and control intervention in many parts of sub-Saharan Africa. While LLINs are expected to last at least 3 years under normal use conditions, they can lose effectiveness because they fall out of use, are discarded, repurposed, physically damaged, or lose insecticidal activity. The contributions of these different interrelated factors to durability of nets and their protection against malaria have been unclear. METHODS: Starting in 2009, LLIN durability studies were conducted in seven countries in Africa over 5 years. WHO-recommended measures of attrition, LLIN use, insecticidal activity, and physical integrity were recorded for eight different net brands. These data were combined with analyses of experimental hut data on feeding inhibition and killing effects of LLINs on both susceptible and pyrethroid resistant malaria vectors to estimate the protection against malaria transmission-in terms of vectorial capacity (VC)-provided by each net cohort over time. Impact on VC was then compared in hypothetical scenarios where one durability outcome measure was set at the best possible level while keeping the others at the observed levels. RESULTS: There was more variability in decay of protection over time by country than by net brand for three measures of durability (ratios of variance components 4.6, 4.4, and 1.8 times for LLIN survival, use, and integrity, respectively). In some countries, LLIN attrition was slow, but use declined rapidly. Non-use of LLINs generally had more effect on LLIN impact on VC than did attrition, hole formation, or insecticide loss. CONCLUSIONS: There is much more variation in LLIN durability among countries than among net brands. Low levels of use may have a larger impact on effectiveness than does variation in attrition or LLIN degradation. The estimated entomological effects of chemical decay are relatively small, with physical decay probably more important as a driver of attrition and non-use than as a direct cause of loss of effect. Efforts to maximize LLIN impact in operational settings should focus on increasing LLIN usage, including through improvements in LLIN physical integrity. Further research is needed to understand household decisions related to LLIN use, including the influence of net durability and the presence of other nets in the household.

Guidance for Using Tafenoquine for Prevention and Antirelapse Therapy for Malaria - United States, 2019.

An estimated 219 million cases of malaria occurred worldwide in 2017, causing approximately 435,000 deaths (1). Malaria is caused by intraerythrocytic protozoa of the genus Plasmodium transmitted to humans through the bite of an infective Anopheles mosquito. Five Plasmodium species that regularly cause illness in humans are P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi (2). The parasite first develops in the liver before infecting red blood cells. Travelers to areas with endemic malaria can prevent malaria by taking chemoprophylaxis. However, most antimalarials do not kill the liver stages of the parasite, including hypnozoites that cause relapses of disease caused by P. vivax or P. ovale. Therefore, patients with these relapsing species must be treated with two medications: one for the acute infection, and another to treat the hypnozoites (antirelapse therapy). Until recently, primaquine was the only drug available worldwide to kill hypnozoites. Tafenoquine, a long-acting 8-aminoquinoline drug related to primaquine, was approved by the Food and Drug Administration (FDA) on July 20, 2018, for antirelapse therapy (Krintafel) and August 8, 2018, for chemoprophylaxis (Arakoda) (3,4). This report reviews evidence for the efficacy and safety of tafenoquine and provides CDC guidance for clinicians who prescribe chemoprophylaxis for travelers to areas with endemic malaria and treat malaria.

Malaria Diagnostic Practices in U.S. Laboratories in 2017.

In the United States, the gold standard for malaria diagnosis is microscopic blood smear examination. Because malaria is not endemic in the United States, diagnostic capabilities may be limited, causing delays in diagnosis and increased morbidity and mortality. A survey of the malaria diagnostic practices of U.S. laboratories was conducted from June to July 2017; members of the American Society for Microbiology's listserv received a questionnaire inquiring about malaria diagnostic test availability, techniques, and reporting. Results were assessed using the Clinical and Laboratory Standards Institute (CLSI) guidelines for malaria diagnostics. After excluding incomplete and duplicate responses, responses representing 175 laboratories were included. Most labs (99%) received at least one specimen annually for malaria diagnosis, and 31% reported receiving only 1 to 10 specimens. The majority (74%) diagnosed five or fewer cases of malaria per year. Most (90%) performed blood smears on-site. Two-thirds (70%) provided initial blood smear results within 4 h. Although diagnostic testing for malaria was available 24/7 at 74% (141) of responding laboratories, only 12% (17) met criteria for analysis and reporting of malaria testing, significantly more than reported in a similar survey in 2010 (3%; P < 0.05). The majority of laboratories surveyed had the capability for timely diagnosis of malaria; few comply with CLSI guidelines. Inexperience may factor into this noncompliance; many laboratories see few to no cases of malaria per year. Although reported adherence to CLSI guidelines was higher than in 2010, there is a need to further improve laboratory compliance with recommendations.

Investigation of a case of suspected transfusion-transmitted malaria.

BACKGROUND: Transfusion-transmitted malaria (TTM) is a rare occurrence with serious consequences for the recipient. A case study is presented as an example of best practices for conducting a TTM investigation. CASE REPORT: A 15-year-old male with a history of sickle cell disease developed fever after a blood transfusion. He was diagnosed with Plasmodium falciparum malaria and was successfully treated. The American Red Cross, New York State Department of Health, and the Centers for Disease Control and Prevention investigated the eight donors who provided components to the transfusion. The investigation to identify a malaria-positive donor included trace back of donors, serologic methods to identify donor(s) with a history of malaria exposure, polymerase chain reaction (PCR) testing, microsatellite analysis to identify the parasite in a donor and match its genotype to the parasite in the recipient, and reinterview of all donors to clarify malaria risk factors. RESULTS: One donor had evidence of infection with P. falciparum by PCR, elevated antibody titers, and previously undisclosed malaria risk factors. Reinterview revealed that the donor immigrated to the United States from Togo just short of 3 years before the blood donation. The donor was treated for asymptomatic low parasitemia infection. CONCLUSION: This investigation used standard procedures for investigating TTM but also demonstrated the importance of applying sensitive laboratory techniques to identify the infected donor, especially a donor with asymptomatic infection with low parasitemia. Repeat interview of all donors identified as having contributed to the transfused component provides complementary epidemiologic information to confirm the infected donor.

Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States.

Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.

A survey on outcomes of accidental atovaquone-proguanil exposure in pregnancy.

BACKGROUND: Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies. RESULTS: A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone-proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects. CONCLUSIONS: Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed.

Inadequate Diagnosis and Treatment of Malaria Among Travelers Returning from Africa During the Ebola Epidemic--United States, 2014-2015.

Among 1,683 persons in the United States who developed malaria following international travel during 2012, more than half acquired disease in one of 16 countries in West Africa. Since March 2014, West Africa has experienced the world's largest epidemic of Ebola virus disease (Ebola), primarily affecting Guinea, Sierra Leone, and Liberia; in 2014, approximately 20,000 Ebola cases were reported. Both Ebola and malaria are often characterized by fever and malaise and can be clinically indistinguishable, especially early in the course of disease. Immediate laboratory testing is critical for diagnosis of both Ebola and malaria, so that appropriate lifesaving treatment can be initiated. CDC recommends prompt malaria testing of patients with fever and history of travel to an area that is endemic for malaria, using blood smear microscopy, with results available within a few hours. Empiric treatment of malaria is not recommended by CDC. Reverse transcription-polymerase chain reaction (RT-PCR) testing is recommended to diagnose Ebola. During the Ebola outbreak in West Africa, CDC received reports of delayed laboratory testing for malaria in travelers returning to the United States because of infection control concerns related to Ebola. CDC reviewed documented calls to its malaria consultation service and selected three patient cases to present as examples of deficiencies in the evaluation and treatment of malaria among travelers returning from Africa during the Ebola epidemic.

A longitudinal study of the durability of long-lasting insecticidal nets in Zambia.

BACKGROUND: A key goal of malaria control is to achieve universal access to, and use of, long-lasting insecticidal nets (LLINs) among people at risk for malaria. Quantifying the number of LLINs needed to achieve and maintain universal coverage requires knowing when nets need replacement. Longitudinal studies have observed physical deterioration in LLINs well before the assumed net lifespan of 3 years. The objective of this study was to describe attrition, physical integrity and insecticide persistence of LLINs over time to assist with better quantification of nets needing replacement. METHODS: 999 LLINs distributed in 2011 in two highly endemic provinces in Zambia were randomly selected, and were enrolled at 12 months old. LLINs were followed every 6 months up to 30 months of age. Holes were counted and measured (finger, fist, and head method) and a proportional hole index (pHI) was calculated. Households were surveyed about net care and repair and if applicable, reasons for attrition. Functional survival was defined as nets with a pHI <643 and present for follow-up. At 12 and 24 months of age, 74 LLINs were randomly selected for examination of insecticidal activity and content using bioassay and chemical analysis methods previously described by the World Health Organization (WHO). RESULTS: A total of 999 LLINs were enrolled; 505 deltamethrin-treated polyester nets and 494 permethrin-treated polyethylene nets. With 74 used to examine insecticide activity, 925 were available for full follow-up. At 30 months, 325 (33 %) LLINs remained. Net attrition was primarily due to disposal (29 %). Presence of repairs and use over a reed mat were significantly associated with larger pHIs. By 30 months, only 56 % of remaining nets met criteria for functional survival. A shorter functional survival was associated with having been washed. At 24 months, nets had reduced insecticidal activity (57 % met WHO minimal criteria) and content (5 % met WHO target insecticide content). CONCLUSIONS: The median functional survival time for LLINs observed the study was 2.5-3 years and insecticide activity and content were markedly decreased by 2 years. A better measure of net survival incorporating insecticidal field effectiveness, net physical integrity, and attrition is needed.

Long-lasting insecticidal nets in Zambia: a cross-sectional analysis of net integrity and insecticide content.

BACKGROUND: Long-lasting insecticidal nets (LLINs) are a mainstay of malaria prevention in Africa. More LLINs are available now than in any time previously due to increases in funding for malaria control. LLINs are expected to last three to five years before they need to be replaced. Reports of nets lasting less than three years are frequent in Zambia, which, if true, will increase the number of LLINs needed to maintain universal coverage. METHODS: This study collected nets distributed during mass distribution campaigns. One net was collected from each participating home in 12 districts in 2010 and all nets were examined for holes. One household member was surveyed about net use and care. RESULTS: The study collected 713 polyester nets with a median age of 31 months (range 27-44 months, interquartile (IQR) range: 29-36 months), median number of holes was 17 (IQR: 5-33), and median total hole size was 88.3 sq cm (IQR: 14.5-360.4). The median total number of holes did differ by age of the net, from 27-44 months, but not in a linear fashion. The difference in the number of holes in the newest and oldest nets was not statistically significant. The mean deltamethrin level for all nets was 23 mg/sq m (≥8 mg/sq m is considered effective). There was a larger total hole area in the lower half of the nets (repeat measures ANOVA, F=228.43, df=2, p<0.0001) compared to the upper half and roof of the net. Only 8.7% of nets had evidence of repairs. CONCLUSIONS: At 27-30 months, LLINs already had a large total hole surface area that was equivalent to the oldest nets observed. Nets were often tucked under reed mats which may explain the finding that the largest hole area was found in the lower half of the net. Studies need to be conducted prospectively to determine when physical deterioration occurs and why nets are discarded. Re-enforcing the lower half of the sides of LLINs may help decrease holes.

Evaluation of sulphadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy: a retrospective birth outcomes study in Mansa, Zambia.

BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) decreases placental parasitaemia, thus improving birth outcomes. Zambian policy recommends monthly SP-IPTp doses given presumptively during pregnancy at each antenatal examination, spaced one month apart after 16 weeks of gestation. The effectiveness of SP-IPTp was evaluated in Zambia where a recent study showed moderate prevalence of Plasmodium falciparum parasites with genetic mutations that confer SP resistance. METHODS: HIV-negative women were enrolled at the time of delivery at two facilities in Mansa, Zambia, an area of high malaria transmission. Women were interviewed and SP exposure was determined by antenatal card documentation or self-reports. Using Poisson regression modelling, the effectiveness of SP-IPTp was evaluated for outcomes of parasitaemia (microscopic examination of maternal peripheral, cord, and placental blood films), maternal anaemia (Hb < 11 g/dl), placental infection (histopathology), and infant outcomes (low birth weight (LBW), preterm delivery, and small for gestational age) in women who took 0-4 doses of SP-IPTp. RESULTS: Participants included 435 women, with a median age of 23 years (range 16-44). Thirty-four women took zero doses of SP-IPTp, while 115, 142 and 144 women took one, two, or ≥ three doses, respectively. Multivariate Poisson regression models considering age, mosquito net usage, indoor residual spraying, urban home, gravidity, facility, wet season delivery, and marital status showed that among paucigravid women ≥ two doses of SP-ITPp compared to one or less doses was associated with a protective effect on LBW (prevalence ratio (PR) 0.33, 95% confidence interval (CI) 0.12-0.91) and any infection (PR 0.76, CI 0.58-0.99). Multivariate models considering SP-IPTp as a continuous variable showed a protective dose-response association with LBW (paucigravid women: PR 0.54, CI 0.33-0.90, multigravid women: PR 0.63, CI 0.41-0.97). CONCLUSIONS: In Mansa, Zambia, an area of moderate SP resistance, ≥ two doses of SP-IPTp were associated with a protective effect from malaria in pregnancy, especially among paucigravid women. Each dose of SP-IPTp contributed to a 46 and 37% decrease in the frequency of LBW among paucigravid and multigravid women, respectively. SP-IPTp remains a viable strategy in this context.

Enhanced surveillance and data feedback loop associated with improved malaria data in Lusaka, Zambia.

BACKGROUND: Accurate and timely malaria data are crucial to monitor the progress towards and attainment of elimination. Lusaka, the capital city of Zambia, has reported very low malaria prevalence in Malaria Indicator Surveys. Issues of low malaria testing rates, high numbers of unconfirmed malaria cases and over consumption of anti-malarials were common at clinics within Lusaka, however. The Government of Zambia (GRZ) and its partners sought to address these issues through an enhanced surveillance and feedback programme at clinic level. METHODS: The enhanced malaria surveillance programme began in 2011 to verify trends in reported malaria, as well as to implement a data feedback loop to improve data uptake, use, and quality. A process of monthly data collection and provision of feedback was implemented within all GRZ health clinics in Lusaka District. During clinic visits, clinic registers were accessed to record the number of reported malaria cases, malaria test positivity rate, malaria testing rate, and proportion of total suspected malaria that was confirmed with a diagnostic test. RESULTS AND DISCUSSION: Following the enhanced surveillance programme, the odds of receiving a diagnostic test for a suspected malaria case increased (OR = 1.54, 95 % CI = 0.96-2.49) followed by an upward monthly trend (OR = 1.05, 95 % CI = 1.01-1.09). The odds of a reported malaria case being diagnostically confirmed also increased monthly (1.09, 95 % CI 1.04-1.15). After an initial 140 % increase (95 % CI = 91-183 %), costs fell by 11 % each month (95 % CI = 5.7-10.9 %). Although the mean testing rate increased from 18.9 to 64.4 % over the time period, the proportion of reported malaria unconfirmed by diagnostic remained high at 76 %. CONCLUSIONS: Enhanced surveillance and implementation of a data feedback loop have substantially increased malaria testing rates and decreased the number of unconfirmed malaria cases and courses of ACT consumed in Lusaka District within just two years. Continued support of enhanced surveillance in Lusaka as well as national scale-up of the system is recommended to reinforce good case management and to ensure timely, reliable data are available to guide targeting of limited malaria prevention and control resources in Zambia.

Knowledge, attitudes, and practices regarding antimalarial chemoprophylaxis in U.S. Peace Corps Volunteers--Africa, 2013.

Long-term travelers to areas where malaria is endemic are at risk for this potentially fatal disease; however, malaria can be prevented through the use of insecticide-treated bednets, mosquito repellents, and chemoprophylaxis. Three options for chemoprophylaxis are available in the Africa region: mefloquine, doxycycline, and atovaquone-proguanil. These options differ by dosing regimen, cost, and side effect profile. Long-term adverse effects of these drugs have been reported rarely.

Efficacy of sulphadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy, Mansa, Zambia.

BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) decreases adverse effects of malaria during pregnancy. Zambia implemented its IPTp-SP programme in 2003. Emergence of SP-resistant Plasmodium falciparum threatens this strategy. The quintuple mutant haplotype (substitutions in N51I, C59R, S108N in dhfr and A437G and K540E in dhps genes), is associated with SP treatment failure in non-pregnant patients with malaria. This study examined efficacy of IPTp-SP and presence of the quintuple mutant among pregnant women in Mansa, Zambia. METHODS: In Mansa, an area with high malaria transmission, HIV-negative pregnant women presenting to two antenatal clinics for the 1st dose of IPTp-SP with asymptomatic parasitaemia were enrolled and microscopy for parasitaemia was done weekly for five weeks. Outcomes were parasitological failure and adequate parasitological response (no parasitaemia during follow-up). Polymerase chain reaction assays were employed to distinguish recrudescence from reinfection, and identify molecular markers of SP resistance. Survival analysis included those who had reinfection and incomplete follow-up (missed at least one follow-up). RESULTS: Of the 109 women included in the study, 58 (53%) completed all follow-up, 34 (31%) had incomplete follow-up, and 17 (16%) were lost to follow-up after day 0. Of those who had complete follow-up, 15 (26%, 95% confidence interval [CI] [16-38]) had parasitological failure. For the 92 women included in the survival analysis, median age was 20 years (interquartile range [IQR] 18-22), median gestational age was 22 weeks (IQR range 20-24), and 57% were primigravid. There was no difference in time to failure in primigravid versus multigravid women. Of the 84 women with complete haplotype data for the aforementioned loci of the dhfr and dhps genes, 53 (63%, 95% CI [50-70]) had quintuple mutants (two with an additional mutation in A581G of dhps). Among women with complete follow-up and quintuple mutants, 22% had parasitological failure versus 0% without (p = 0.44). CONCLUSIONS: While underpowered, this study found 26% failure rates of SP given the moderate prevalence of the quintuple mutant haplotype. Despite the presence of resistance, SP retained some efficacy in clearing parasites in pregnant women, and may remain a viable option for IPTp in Zambia.

Exchange transfusion for severe malaria: evidence base and literature review.

BACKGROUND: Exchange transfusion (ET) has biologic plausibility as an adjunct to antimalarial drugs in treating severe malaria and has been used for decades despite limited evidence of its efficacy in improving survival. We examined the efficacy of ET as an adjunct treatment for severe malaria using US surveillance data and reviewed the literature to update recommendations. METHODS: Patients with severe malaria reported to the US national malaria surveillance system during 1985-2010 were matched, and survival outcomes were compared between patients receiving and not receiving ET. The literature review used search terms "severe malaria" and "exchange transfusion." Case reports and series, observational and case-control studies, and meta-analysis were included. RESULTS: One hundred one patients receiving ET were matched to 314 patients not receiving ET. There was no statistically significant association between ET and survival outcome (odds ratio, 0.84; 95% confidence interval, .44-1.60). We found 87 articles, mostly case reports or series, showing successful use of ET, likely reporting bias. There were 12 comparative studies, most of which were retrospective cohort studies, underpowered with no significant differences in survival. A previously published meta-analysis of 8 comparative studies found no significant survival differences. Adverse events were rarely reported but included acute respiratory distress syndrome, ventricular fibrillation, and hypotension. CONCLUSIONS: Despite rapid parasite clearance times resulting from ET, there is no evidence for efficacy of ET as adjunctive therapy in severe malaria. Adjunct ET cannot be recommended. When rapidly acting antimalarials, specifically artemisinins, become more widely available, the biologic plausibility argument for ET will become less relevant.

Malaria Surveillance - United States, 2018.

PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. Most malaria infections in the United States and its territories occur among persons who have traveled to regions with ongoing malaria transmission. However, among persons who have not traveled out of the country, malaria is occasionally acquired through exposure to infected blood or tissues, congenital transmission, nosocomial exposure, or local mosquitoborne transmission. Malaria surveillance in the United States and its territories provides information on its occurrence (e.g., temporal, geographic, and demographic), guides prevention and treatment recommendations for travelers and patients, and facilitates rapid transmission control measures if locally acquired cases are identified. PERIOD COVERED: This report summarizes confirmed malaria cases in persons with onset of illness in 2018 and trends in previous years. DESCRIPTION OF SYSTEM: Malaria cases diagnosed by blood smear microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments through electronic laboratory reports or by health care providers or laboratory staff members directly reporting to CDC or health departments. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), the National Notifiable Diseases Surveillance System (NNDSS), or direct CDC clinical consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood specimens submitted by health care providers or local or state health departments. This report summarizes data from the integration of all cases from NMSS and NNDSS, CDC clinical consultations, and CDC reference laboratory reports. RESULTS: CDC received reports of 1,823 confirmed malaria cases with onset of symptoms in 2018, including one cryptic case and one case acquired through a bone marrow transplant. The number of cases reported in 2018 is 15.6% fewer than in 2017. The number of cases diagnosed in the United States and its territories has been increasing since the mid-1970s; the number of cases reported in 2017 was the highest since 1972. Of the cases in 2018, a total of 1,519 (85.0%) were imported cases that originated from Africa; 1,061 (69.9%) of the cases from Africa were from West Africa, a similar proportion to what was observed in 2017. Among all cases, P. falciparum accounted for most infections (1,273 [69.8%]), followed by P. vivax (173 [9.5%]), P. ovale (95 [5.2%]), and P. malariae (48 [2.6%]). For the first time since 2008, an imported case of P. knowlesi was identified in the United States and its territories. Infections by two or more species accounted for 17 cases (<1.0%). The infecting species was not reported or was undetermined in 216 cases (11.9%). Most patients (92.6%) had symptom onset <90 days after returning to the United States or its territories from a country with malaria transmission. Of the U.S. civilian patients who reported reason for travel, 77.0% were visiting friends and relatives. Chemoprophylaxis with antimalarial medications are recommended for U.S. residents to prevent malaria while traveling in countries where it is endemic. Fewer U.S. residents with imported malaria reported taking any malaria chemoprophylaxis in 2018 (24.5%) than in 2017 (28.4%), and adherence was poor among those who took chemoprophylaxis. Among the 864 U.S. residents with malaria for whom information on chemoprophylaxis use and travel region were known, 95.0% did not adhere to or did not take a CDC-recommended chemoprophylaxis regimen. Among 683 women with malaria, 19 reported being pregnant. Of these, 11 pregnant women were U.S. residents, and one of whom reported taking chemoprophylaxis to prevent malaria but her adherence to chemoprophylaxis was not reported. Thirty-eight (2.1%) malaria cases occurred among U.S. military personnel in 2018, more than in 2017 (26 [1.2%]). Among all reported malaria cases in 2018, a total of 251 (13.8%) were classified as severe malaria illness, and seven persons died from malaria. In 2018, CDC analyzed 106 P. falciparum-positive and four P. falciparum mixed species specimens for antimalarial resistance markers (although certain loci were untestable in some specimens); identification of genetic polymorphisms associated with resistance to pyrimethamine were found in 99 (98.0%), to sulfadoxine in 49 (49.6%), to chloroquine in 50 (45.5%), and to mefloquine in two (2.0%); no specimens tested contained a marker for atovaquone or artemisinin resistance. INTERPRETATION: The importation of malaria reflects the overall trends in global travel to and from areas where malaria is endemic, and 15.6% fewer cases were imported in 2018 compared with 2017. Of imported cases, 59.3% were among persons who had traveled from West Africa. Among U.S. civilians, visiting friends and relatives was the most common reason for travel (77.1%). PUBLIC HEALTH ACTIONS: The best way for U.S. residents to prevent malaria is to take chemoprophylaxis medication before, during, and after travel to a country where malaria is endemic. Adherence to recommended malaria prevention strategies among U.S. travelers would reduce the number of imported cases. Reported reasons for nonadherence include prematurely stopping after leaving the area where malaria was endemic, forgetting to take the medication, and experiencing a side effect. Health care providers can make travelers aware of the risks posed by malaria and incorporate education to motivate them to be adherent to chemoprophylaxis. Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age, pregnancy status, medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Antimalarial use for chemoprophylaxis and treatment should be determined by the CDC guidelines, which are frequently updated. In April 2019, intravenous (IV) artesunate became the first-line medication for treatment of severe malaria in the United States and its territories. Artesunate was approved by the Food and Drug Administration (FDA) in 2020 and is commercially available (Artesunate for Injection) from major U.S. drug distributors (https://amivas.com). Stocking IV artesunate locally allows for immediate treatment of severe malaria once diagnosed and provides patients with the best chance of a complete recovery and no sequelae. With commercial IV artesunate now available, CDC will discontinue distribution of non-FDA-approved IV artesunate under an investigational new drug protocol on September 30, 2022. Detailed recommendations for preventing malaria are online at https://www.cdc.gov/malaria/travelers/drugs.html. Malaria diagnosis and treatment recommendations are also available online at https://www.cdc.gov/malaria/diagnosis_treatment. Health care providers who have sought urgent infectious disease consultation and require additional assistance on diagnosis and treatment of malaria can call the Malaria Hotline 9:00 a.m.-5:00 p.m. Eastern Time, Monday-Friday, at 770-488-7788 or 855-856-4713 or after hours for urgent inquiries at 770-488-7100. Persons submitting malaria case reports (care providers, laboratories, and state and local public health officials) should provide complete information because incomplete reporting compromises case investigations and public health efforts to prevent future infections and examine trends in malaria cases. Molecular surveillance of antimalarial drug resistance markers enables CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and globally. A greater proportion of specimens from domestic malaria cases are needed to improve the completeness of antimalarial drug resistance analysis; therefore, CDC requests that blood specimens be submitted for any case of malaria diagnosed in the United States and its territories.