-
PLoS Neglected Tropical Diseases Jun 2023This systematic review and network meta-analysis (NMA) aimed to compare the efficacy of all available treatments for severe melioidosis in decreasing hospital mortality... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This systematic review and network meta-analysis (NMA) aimed to compare the efficacy of all available treatments for severe melioidosis in decreasing hospital mortality and to identify eradication therapies with low disease recurrence rates and minimal risk of adverse drug events (AEs).
METHODOLOGY
Relevant randomized controlled trials (RCT) were searched from Medline and Scopus databases from their inception until July 31, 2022. RCTs that compared the efficacy between treatment regimens for severe melioidosis or eradication therapy of melioidosis, measured outcomes of in-hospital mortality, disease recurrence, drug discontinuation, or AEs, were included for review. A two-stage NMA with the surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of treatment regimens.
PRINCIPAL FINDINGS
Fourteen RCTs were included in the review. Ceftazidime plus granulocyte colony-stimulating factor (G-CSF), ceftazidime plus trimethoprim-sulfamethoxazole (TMP-SMX), and cefoperazone-sulbactam plus TMP-SMX had a lower mortality rate than other treatments and were ranked as the top three most appropriate treatments for severe melioidosis with the SUCRA of 79.7%, 66.6%, and 55.7%, respectively. However, these results were not statistically significant. For eradication therapy, treatment with doxycycline monotherapy for 20 weeks was associated with a significantly higher risk of disease recurrence than regimens containing TMP-SMX (i.e.,TMP-SMX for 20 weeks, TMP-SMX plus doxycycline plus chloramphenicol for more than 12 weeks, and TMP-SMX plus doxycycline for more than 12 weeks). According to the SUCRA, TMP-SMX for 20 weeks was ranked as the most efficacious eradication treatment (87.7%) with the lowest chance of drug discontinuation (86.4%), while TMP-SMX for 12 weeks had the lowest risk of AEs (95.6%).
CONCLUSION
Our results found a non-significant benefit of ceftazidime plus G-CSF and ceftazidime plus TMP-SMX over other treatments for severe melioidosis. TMP-SMX for 20 weeks was associated with a lower recurrence rate and minimal risk of adverse drug events compared to other eradication treatments. However, the validity of our NMA may be compromised by the limited number of included studies and discrepancies in certain study parameters. Thus, additional well-designed RCTs are needed to improve the therapy of melioidosis.
Topics: Humans; Trimethoprim, Sulfamethoxazole Drug Combination; Melioidosis; Doxycycline; Ceftazidime; Network Meta-Analysis; Granulocyte Colony-Stimulating Factor; Drug-Related Side Effects and Adverse Reactions
PubMed: 37307278
DOI: 10.1371/journal.pntd.0011382 -
Journal of the International AIDS... Jun 2023Co-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections... (Review)
Review
INTRODUCTION
Co-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale-up of maternal antiretroviral therapy, most children remain HIV-exposed uninfected (HEU) and the benefits of universal co-trimoxazole are uncertain. We assessed the effect of co-trimoxazole on mortality and morbidity of children who are HEU.
METHODS
We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa-Wide Information, SciELO and WHO Global Index Medicus for peer-reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co-trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity.
RESULTS
We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co-trimoxazole prophylaxis started at 2-6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub-studies found that antimicrobial resistance was higher in infants receiving co-trimoxazole. Two trials in Uganda investigating prolonged co-trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence.
DISCUSSION
Studies show no clinical benefit of co-trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co-trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non-malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings.
CONCLUSIONS
In low-mortality settings with few HIV transmissions and well-performing early infant diagnosis and treatment programmes, universal co-trimoxazole may not be required.
Topics: Infant; Female; Child; Humans; Trimethoprim, Sulfamethoxazole Drug Combination; HIV Infections; Malaria; Uganda; Anti-Infective Agents; World Health Organization; Randomized Controlled Trials as Topic
PubMed: 37292018
DOI: 10.1002/jia2.26079 -
Infectious Diseases (London, England) Jul 2023Whipple's disease is an uncommon chronic systemic disease caused by . The most characteristic findings of late Whipple's disease include diarrhoea, abdominal pain,... (Review)
Review
Whipple's disease is an uncommon chronic systemic disease caused by . The most characteristic findings of late Whipple's disease include diarrhoea, abdominal pain, weight loss, and arthralgias, however, other clinical findings can occur, including lymphadenopathy, fever, neurologic manifestations, myocarditis and endocarditis. The aim of the present study was to systematically review all cases of Whipple's disease-associated infective endocarditis (IE) in the literature. A systematic review of PubMed, Scopus, and Cochrane Library (all published studies up to 28 May 2022) for studies providing data on epidemiology, clinical characteristics as well as data on treatment and outcomes of Whipple's disease-associated IE was performed. A total of 72 studies, containing data for 127 patients, were included. A prosthetic valve was present in 8% of patients. The aortic valve was the most commonly involved intracardiac site followed by the mitral valve. Heart failure, embolic phenomena, and fever were the most common clinical presentations, however, fever occurred in less than 30% of patients. Sepsis was rarely noted. The diagnosis was most commonly performed through pathology through positive PCR or histology in cardiac valves in 88.2% of patients. Trimethoprim with sulfamethoxazole were the most commonly used antimicrobials followed by cephalosporins and tetracyclines. Surgery was performed in 84.3% of patients. Mortality was 9.4%. A multivariate logistic regression analysis model identified presentation with sepsis or development of a paravalvular abscess to be independently associated with increased mortality, while treatment with the combination of trimethoprim with sulfamethoxazole was independently associated with reduced mortality.
Topics: Humans; Whipple Disease; Endocarditis, Bacterial; Anti-Bacterial Agents; Trimethoprim; Sulfamethoxazole; Sepsis
PubMed: 37198913
DOI: 10.1080/23744235.2023.2214610 -
Journal of Global Antimicrobial... Sep 2023Stenotrophomonas maltophilia (S. maltophilia), an opportunistic pathogen, causes infection in patients undergoing immunosuppressive therapy, mechanical ventilation, or... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Stenotrophomonas maltophilia (S. maltophilia), an opportunistic pathogen, causes infection in patients undergoing immunosuppressive therapy, mechanical ventilation, or catheters and in long-term hospitalized patients. Due to its extensive resistance to various antibiotics and chemotherapeutic agents, S. maltophilia is challenging to treat. Using case reports, case series, and prevalence studies, the current study provides a systematic review and meta-analysis of antibiotic resistance profiles across clinical isolates of S. maltophilia.
METHODS
A systematic literature search was performed for original research articles published in Medline, Web of Science, and Embase databases from 2000 to 2022. Statistical analysis was performed using STATA 14 software to report antibiotic resistance of S. maltophilia clinical isolates worldwide.
RESULTS
223 studies (39 case reports/case series and 184 prevalence studies) were collected for analysis. A meta-analysis of prevalence studies demonstrated that the most antibiotic resistance worldwide was to levofloxacin, trimethoprim-sulfamethoxazole (TMP/SMX), and minocycline (14.4%, 9.2%, and 1.4%, respectively). Resistance to TMP/SMX (36.84%), levofloxacin (19.29%), and minocycline (1.75%) were the most prevalent antibiotic resistance types found in evaluated case reports/case series studies. The highest resistance rate to TMP/SMX was reported in Asia (19.29%), Europe (10.52%), and America (7.01%), respectively.
CONCLUSION
Considering the high resistance to TMP/SMX, more attention should be paid to patients' drug regimens to prevent the emergence of multidrug-resistant S. maltophilia isolates.
Topics: Humans; Trimethoprim, Sulfamethoxazole Drug Combination; Levofloxacin; Minocycline; Stenotrophomonas maltophilia; Prevalence; Drug Resistance, Bacterial
PubMed: 36906172
DOI: 10.1016/j.jgar.2023.02.018 -
Frontiers in Endocrinology 2023Hypoglycemia is a sporadic and serious adverse reaction of trimethoprim-sulfamethoxazole (TMP-SMX) due to its sulfonylurea-like effect. This study explored the clinical...
OBJECTIVE
Hypoglycemia is a sporadic and serious adverse reaction of trimethoprim-sulfamethoxazole (TMP-SMX) due to its sulfonylurea-like effect. This study explored the clinical characteristics, risk factors, treatment, and prognosis of TMP-SMX-induced hypoglycemia.
METHODS
Case reports and series of TMP-SMX-induced hypoglycemia were systematically searched using Chinese and English databases. Primary patient and clinical information were extracted for analysis.
RESULTS
A total of 34 patients were reported from 31 studies (16 males and 18 females). The patients had a median age of 64 years (range 0.4-91), and 75.8% had renal dysfunction. The median duration of a hypoglycemic episode was six days (range 1-20), and the median minimum glucose was 28.8 mg/dL (range 12-60). Thirty-two patients (97.0%) showed neuroglycopenic symptoms, with consciousness disturbance (30.3%) and seizure (24.2%), sweating (18.2%), confusion (15.2%), asthenia (12.1%) being the most common symptoms. Fifteen patients (44.1%) had elevated serum insulin levels, with a median of 31.8 μU/mL (range 3-115.3). C-peptide increased in 13 patients (38.2%), with a median of 7.7 ng/mL (range 2.2-20). Complete recovery from symptoms occurred in 88.2% of patients without sequelae. The duration of hypoglycemia symptoms was 8 hours to 47 days after the intervention. Interventions included discontinuation of TMP-SMX, intravenous glucose, glucagon, and octreotide.
CONCLUSION
Hypoglycemia is a rare and serious adverse effect of TMP-SMX. Physicians should be aware of this potential adverse effect, especially in patients with renal insufficiency, increased drug doses, and malnutrition.
Topics: Male; Female; Humans; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Trimethoprim, Sulfamethoxazole Drug Combination; Risk Factors; Hypoglycemia; Renal Insufficiency; Glucose
PubMed: 36843590
DOI: 10.3389/fendo.2023.1059522 -
Pediatric Pulmonology May 2023Cepacia syndrome (CS) is an acute, necrotizing pneumonia with a high mortality rate, occurring in patients with cystic fibrosis (CF) infected with Burkholderia cepacia... (Review)
Review
BACKGROUND
Cepacia syndrome (CS) is an acute, necrotizing pneumonia with a high mortality rate, occurring in patients with cystic fibrosis (CF) infected with Burkholderia cepacia complex (BCC). Due to its low incidence, data on this condition are limited.
METHODS
We conducted a systematic review of the reported cases of CS by searching MEDLINE, Embase and the Cochrane Library to improve knowledge of this rare but potentially lethal condition.
RESULTS
We included 15 eligible articles, describing 18 cases (9 females) of CS. Median age at onset was 22 years (range: 10-60 years); median time to CS after first infection by BCC was 5 years (range: 1-26 years). Burkholderia cenocepacia was the most frequently reported causative agent. All patients received intravenous antibiotic treatment (most frequently including cotrimoxazole), while inhaled antibiotics were used in five patients (27.8%). Immunosuppressant agents were the most commonly prescribed supportive treatment (n = 7, 38.9%). Half of the patients died (9/18, 50%).
CONCLUSIONS
This study describes epidemiological, clinical characteristics, and prognosis of CS cases reported over the last 24 years. CS is a rare yet severe complication of BCC infection in patients with CF, which occurs several years after BCC colonization and has a negative outcome in 50% of the patients. Data are too scanty to identify the most effective therapeutic approach.
Topics: Female; Humans; Child; Adolescent; Young Adult; Adult; Middle Aged; Cystic Fibrosis; Anti-Bacterial Agents; Burkholderia cepacia complex; Prognosis; Trimethoprim, Sulfamethoxazole Drug Combination; Burkholderia Infections
PubMed: 36815622
DOI: 10.1002/ppul.26359 -
JAMA Dermatology Apr 2023Antibiotics are an important risk for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), which are the most severe types of drug hypersensitivity... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Antibiotics are an important risk for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), which are the most severe types of drug hypersensitivity reaction with a mortality rate up to 50%. To our knowledge, no global systematic review has described antibiotic-associated SJS/TEN.
OBJECTIVE
To evaluate the prevalence of antibiotics associated with SJS/TEN worldwide.
DATA SOURCES
The MEDLINE and Embase databases were searched for experimental and observational studies that described SJS/TEN risks since database inception to February 22, 2022.
STUDY SELECTION
Included studies adequately described SJS/TEN origins and specified the antibiotics associated with SJS/TEN.
DATA EXTRACTION AND SYNTHESIS
Two reviewers (E.Y.L. and C.K.) independently selected the studies, extracted the data, and assessed the risk of bias. A meta-analysis using a random-effects model was performed in the studies that described patient-level associations. Subgroup analyses were performed to explore the heterogeneity. The risk of bias was assessed using the Joanna Briggs Institute checklist, and the certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.
MAIN OUTCOMES AND MEASURES
Prevalence of antibiotic-associated SJS/TEN was presented as pooled proportions with 95% CIs.
RESULTS
Among the 64 studies included in the systematic review, there were 38 studies that described patient-level associations; the meta-analysis included these 38 studies with 2917 patients to determine the prevalence of single antibiotics associated with SJS/TEN. The pooled proportion of antibiotics associated with SJS/TEN was 28% (95% CI, 24%-33%), with moderate certainty of evidence. Among antibiotic-associated SJS/TEN, the sulfonamide class was associated with 32% (95% CI, 22%-44%) of cases, followed by penicillins (22%; 95% CI, 17%-28%), cephalosporins (11%; 95% CI, 6%-17%), fluoroquinolones (4%; 95% CI, 1%-7%), and macrolides (2%; 95% CI, 1%-5%). There was a statistically significant heterogeneity in the meta-analysis, which could be partially explained in the subgroup analysis by continents. The overall risk of bias was low using the Joanna Briggs Institute checklist for case series.
CONCLUSION AND RELEVANCE
In this systematic review and meta-analysis of all case series, antibiotics were associated with more than one-quarter of SJS/TEN cases described worldwide, and sulfonamide antibiotics remained the most important association. These findings highlight the importance of antibiotic stewardship, clinician education and awareness, and weighing the risk-benefit assessment of antibiotic choice and duration.
Topics: Humans; Stevens-Johnson Syndrome; Anti-Bacterial Agents; Prevalence; Sulfanilamide; Retrospective Studies
PubMed: 36790777
DOI: 10.1001/jamadermatol.2022.6378 -
Journal of Cosmetic Dermatology May 2023Silver sulfadiazine is commonly used to treat local burn wounds. Aquacel-Ag is a hydrogen fiber dressing containing ionic silver that reduces burn wound infection and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Silver sulfadiazine is commonly used to treat local burn wounds. Aquacel-Ag is a hydrogen fiber dressing containing ionic silver that reduces burn wound infection and promotes antimicrobial activity. It is necessary to compare the efficacy of the two in the healing of burns.
AIMS
The aim of this study was to systematically evaluate the effect of Aquacel-Ag on burn wound healing.
METHODS
A computerized search of CNKI, VIP, Wanfang, SinoMed, PubMed, Cochrane Library, EMbase, Science Direct, Web of Science, Wiley Online Library, and Open Access Library databases was performed from January 1, 2000 to December 31, 2021 for randomized controlled clinical trials. The trials on Aquacel-Ag dressing and silver sulfadiazine in the treatment of burns were selected. Meta-analysis was performed using Review Manager 5.0 software.
RESULTS
Eleven articles were finally included, with 794 burn patients. Meta-analysis results showed that compared with patients treated with silver sulfadiazine, burn patients treated with Aquacel-Ag dressing had shorter wound healing time [MD = -2.49, 95% CI (-5.64-0.65), p = 0.12], significantly lower tumor necrosis factor-α (TNF-α) level [MD = -0.52, 95% CI (-0.82-0.22), p = 0.0008], higher wound healing rate [MD = 8.41, 95% CI (3.39-13.43), p = 0.001], fewer dressing changes [MD = -3.27, 95% CI (-4.90-1.63), p < 0.0001].
CONCLUSION
Aquacel-Ag dressing can shorten wound healing time and effectively reduce inflammatory reactions in burn patients compared with silver sulfadiazine, but their safety still needs further exploration and analysis.
Topics: Humans; Anti-Infective Agents, Local; Bandages; Burns; Carboxymethylcellulose Sodium; Silver; Silver Sulfadiazine; Wound Healing
PubMed: 36683314
DOI: 10.1111/jocd.15639 -
Journal of Cardiac Surgery Dec 2022Acute kidney injury (AKI) is a common complication of cardiac surgical patients, the occurrence of which is multifactorial. Furosemide is the most common loop diuretic... (Meta-Analysis)
Meta-Analysis
Furosemide does not reduce the incidence of postoperative acute kidney injury in adult patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis.
OBJECTIVE
Acute kidney injury (AKI) is a common complication of cardiac surgical patients, the occurrence of which is multifactorial. Furosemide is the most common loop diuretic and widely used in cardiac surgery to reduce fluid overload, increase tubular flow and urine output. It remains unknown whether furosemide affects the incidence or prognosis of cardiac surgery-induced acute kidney injury (CS-AKI). Therefore, the current study was performed to address this question.
METHODS
PubMed, Embase, Scopus, Cochrane Library, and Web of Science databases were searched for relevant studies. Primary outcomes of interest included postoperative CS-AKI incidence, need for renal replacement therapy (RRT) rate. Secondary outcomes of interest included postoperative serum creatinine (Scr) and blood urea nitrogen (BUN) levels, postoperative mechanical ventilation duration (MVD), length of stay (LOS) in intensive care unit (ICU) and in hospital, and mortality. The odds ratio (OR) and/or the weighted mean difference (WMD) with 95% confidence interval (CI) were used to pool the data.
RESULTS
Database search yielded six studies including 566 adult patients, and 283 patients were allocated into Group Furosemide and 283 into Group Control (Placebo). Heterogeneity between studies was deemed acceptable, and the publication bias was low. Meta-analysis suggested that furosemide administration in adult cardiac surgical patients had no effect on CS-AKI incidence (n = 4 trials; OR = 0.92; 95% CI: 0.37-2.30; p = .86; I = 57%) and need for RRT rate (n = 2 trials; OR = 4.13; 95% CI: 0.44-38.51; p = .21; I = 0%). Diversely, furosemide administration in adult cardiac surgical patients significantly decreased postoperative BUN level (n = 3 trials; WMD = 0.71; 95% CI: 0.10-1.33; p = .02; I = 0%), postoperative MVD (n = 2 trials; WMD = -3.13; 95% CI: -3.78 to -2.49; p < .00001; I = 0%) and postoperative LOS in ICU (n = 3 trials; WMD = -0.47; 95% CI: -0.76 to -0.18; p = .001; I = 0%). However, it had no significant impact on postoperative Scr level, postoperative LOS in hospital, and postoperative mortality.
CONCLUSION
This meta-analysis suggested that furosemide administration in adult cardiac surgical patients had no significant effect on CS-AKI incidence, need for RRT rate, postoperative Scr level, LOS in hospital and mortality, but could reduce postoperative BUN level, MVD, and LOS in ICU. As only a limited number of studies were included, these results should be interpreted carefully and cautiously. Future high-quality randomized controlled trials are needed to define the role of furosemide in CS-AKI prevention and management.
Topics: Humans; Adult; Furosemide; Incidence; Acute Kidney Injury; Cardiac Surgical Procedures; Renal Replacement Therapy
PubMed: 36345680
DOI: 10.1111/jocs.17120 -
The Cochrane Database of Systematic... Feb 2022Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria since it was first introduced in Malawi in 1993 (Filler 2006). Due to increasing resistance to SP, in 2000 the WHO recommended that one of several artemisinin-based combination therapies (ACTs) be used instead of SP for the treatment of uncomplicated malaria caused by Plasmodium falciparum (Global Partnership to Roll Back Malaria 2001). However, despite these recommendations, SP continues to be advised for intermittent preventive treatment in pregnancy (IPTp) and intermittent preventive treatment in infants (IPTi), whether the person has malaria or not (WHO 2013). Description of the intervention Folate (vitamin B9) includes both naturally occurring folates and folic acid, the fully oxidized monoglutamic form of the vitamin, used in dietary supplements and fortified food. Folate deficiency (e.g. red blood cell (RBC) folate concentrations of less than 305 nanomoles per litre (nmol/L); serum or plasma concentrations of less than 7 nmol/L) is common in many parts of the world and often presents as megaloblastic anaemia, resulting from inadequate intake, increased requirements, reduced absorption, or abnormal metabolism of folate (Bailey 2015; WHO 2015a). Pregnant women have greater folate requirements; inadequate folate intake (evidenced by RBC folate concentrations of less than 400 nanograms per millilitre (ng/mL), or 906 nmol/L) prior to and during the first month of pregnancy increases the risk of neural tube defects, preterm delivery, low birthweight, and fetal growth restriction (Bourassa 2019). The WHO recommends that all women who are trying to conceive consume 400 micrograms (µg) of folic acid daily from the time they begin trying to conceive through to 12 weeks of gestation (WHO 2017). In 2015, the WHO added the dosage of 0.4 mg of folic acid to the essential drug list (WHO 2015c). Alongside daily oral iron (30 mg to 60 mg elemental iron), folic acid supplementation is recommended for pregnant women to prevent neural tube defects, maternal anaemia, puerperal sepsis, low birthweight, and preterm birth in settings where anaemia in pregnant women is a severe public health problem (i.e. where at least 40% of pregnant women have a blood haemoglobin (Hb) concentration of less than 110 g/L). How the intervention might work Potential interactions between folate status and malaria infection The malaria parasite requires folate for survival and growth; this has led to the hypothesis that folate status may influence malaria risk and severity. In rhesus monkeys, folate deficiency has been found to be protective against Plasmodium cynomolgi malaria infection, compared to folate-replete animals (Metz 2007). Alternatively, malaria may induce or exacerbate folate deficiency due to increased folate utilization from haemolysis and fever. Further, folate status measured via RBC folate is not an appropriate biomarker of folate status in malaria-infected individuals since RBC folate values in these individuals are indicative of both the person's stores and the parasite's folate synthesis. A study in Nigeria found that children with malaria infection had significantly higher RBC folate concentrations compared to children without malaria infection, but plasma folate levels were similar (Bradley-Moore 1985). Why it is important to do this review The malaria parasite needs folate for survival and growth in humans. For individuals, adequate folate levels are critical for health and well-being, and for the prevention of anaemia and neural tube defects. Many countries rely on folic acid supplementation to ensure adequate folate status in at-risk populations. Different formulations for folic acid supplements are available in many international settings, with dosages ranging from 400 µg to 5 mg. Evaluating folic acid dosage levels used in supplementation efforts may increase public health understanding of its potential impacts on malaria risk and severity and on treatment failures. Examining folic acid interactions with antifolate antimalarial medications and with malaria disease progression may help countries in malaria-endemic areas determine what are the most appropriate lower dose folic acid formulations for at-risk populations. The WHO has highlighted the limited evidence available and has indicated the need for further research on biomarkers of folate status, particularly interactions between RBC folate concentrations and tuberculosis, human immunodeficiency virus (HIV), and antifolate antimalarial drugs (WHO 2015b). An earlier Cochrane Review assessed the effects and safety of iron supplementation, with or without folic acid, in children living in hyperendemic or holoendemic malaria areas; it demonstrated that iron supplementation did not increase the risk of malaria, as indicated by fever and the presence of parasites in the blood (Neuberger 2016). Further, this review stated that folic acid may interfere with the efficacy of SP; however, the efficacy and safety of folic acid supplementation on these outcomes has not been established. This review will provide evidence on the effectiveness of daily folic acid supplementation in healthy and malaria-infected individuals living in malaria-endemic areas. Additionally, it will contribute to achieving both the WHO Global Technical Strategy for Malaria 2016-2030 (WHO 2015d), and United Nations Sustainable Development Goal 3 (to ensure healthy lives and to promote well-being for all of all ages) (United Nations 2021), and evaluating whether the potential effects of folic acid supplementation, at different doses (e.g. 0.4 mg, 1 mg, 5 mg daily), interferes with the effect of drugs used for prevention or treatment of malaria.
OBJECTIVES
To examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?
METHODS
Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (including but not limited to sulfadoxine/pyrimethamine (SP), pyrimethamine-dapsone, pyrimethamine, chloroquine and proguanil, cotrimoxazole) for the prevention or treatment of malaria (studies will be included if more than 70% of the participants live in malaria-endemic regions) Studies assessing participants with or without anaemia and with or without malaria parasitaemia at baseline will be included Exclusion criteria Individuals not taking antifolate antimalarial medications for prevention or treatment of malaria Individuals living in non-malaria endemic areas Types of interventions Inclusion criteria Folic acid supplementation Form: in tablet, capsule, dispersible tablet at any dose, during administration, or periodically Timing: during, before, or after (within a period of four to six weeks) administration of antifolate antimalarials Iron-folic acid supplementation Folic acid supplementation in combination with co-interventions that are identical between the intervention and control groups. Co-interventions include: anthelminthic treatment; multivitamin or multiple micronutrient supplementation; 5-methyltetrahydrofolate supplementation. Exclusion criteria Folate through folate-fortified water Folic acid administered through large-scale fortification of rice, wheat, or maize Comparators Placebo No treatment No folic acid/different doses of folic acid Iron Types of outcome measures Primary outcomes Uncomplicated malaria (defined as a history of fever with parasitological confirmation; acceptable parasitological confirmation will include rapid diagnostic tests (RDTs), malaria smears, or nucleic acid detection (i.e. polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), etc.)) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Severe malaria (defined as any case with cerebral malaria or acute P. falciparum malaria, with signs of severity or evidence of vital organ dysfunction, or both) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Parasite clearance (any Plasmodium species), defined as the time it takes for a patient who tests positive at enrolment and is treated to become smear-negative or PCR negative. This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Treatment failure (defined as the inability to clear malaria parasitaemia or prevent recrudescence after administration of antimalarial medicine, regardless of whether clinical symptoms are resolved) (WHO 2019). This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Secondary outcomes Duration of parasitaemia Parasite density Haemoglobin (Hb) concentrations (g/L) Anaemia: severe anaemia (defined as Hb less than 70 g/L in pregnant women and children aged six to 59 months; and Hb less than 80 g/L in other populations); moderate anaemia (defined as Hb less than 100 g/L in pregnant women and children aged six to 59 months; and less than 110 g/L in others) Death from any cause Among pregnant women: stillbirth (at less than 28 weeks gestation); low birthweight (less than 2500 g); active placental malaria (defined as Plasmodium detected in placental blood by smear or PCR, or by Plasmodium detected on impression smear or placental histology). Search methods for identification of studies A search will be conducted to identify completed and ongoing studies, without date or language restrictions. Electronic searches A search strategy will be designed to include the appropriate subject headings and text word terms related to each intervention of interest and study design of interest (see Appendix 1). Searches will be broken down by these two criteria (intervention of interest and study design of interest) to allow for ease of prioritization, if necessary. The study design filters recommended by the Scottish Intercollegiate Guidelines Network (SIGN), and those designed by Cochrane for identifying clinical trials for MEDLINE and Embase, will be used (SIGN 2020). There will be no date or language restrictions. Non-English articles identified for inclusion will be translated into English. If translations are not possible, advice will be requested from the Cochrane Infectious Diseases Group and the record will be stored in the "Awaiting assessment" section of the review until a translation is available. The following electronic databases will be searched for primary studies. Cochrane Central Register of Controlled Trials. Cumulative Index to Nursing and Allied Health Literature (CINAHL). Embase. MEDLINE. Scopus. Web of Science (both the Social Science Citation Index and the Science Citation Index). We will conduct manual searches of ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the United Nations Children's Fund (UNICEF) Evaluation and Research Database (ERD), in order to identify relevant ongoing or planned trials, abstracts, and full-text reports of evaluations, studies, and surveys related to programmes on folic acid supplementation in malaria-endemic areas. Additionally, manual searches of grey literature to identify RCTs that have not yet been published but are potentially eligible for inclusion will be conducted in the following sources. Global Index Medicus (GIM). African Index Medicus (AIM). Index Medicus for the Eastern Mediterranean Region (IMEMR). Latin American & Caribbean Health Sciences Literature (LILACS). Pan American Health Organization (PAHO). Western Pacific Region Index Medicus (WPRO). Index Medicus for the South-East Asian Region (IMSEAR). The Spanish Bibliographic Index in Health Sciences (IBECS) (ibecs.isciii.es/). Indian Journal of Medical Research (IJMR) (journals.lww.com/ijmr/pages/default.aspx). Native Health Database (nativehealthdatabase.net/). Scielo (www.scielo.br/). Searching other resources Handsearches of the five journals with the highest number of included studies in the last 12 months will be conducted to capture any relevant articles that may not have been indexed in the databases at the time of the search. We will contact the authors of included studies and will check reference lists of included papers for the identification of additional records. For assistance in identifying ongoing or unpublished studies, we will contact the Division of Nutrition, Physical Activity, and Obesity (DNPAO) and the Division of Parasitic Diseases and Malaria (DPDM) of the CDC, the United Nations World Food Programme (WFP), Nutrition International (NI), Global Alliance for Improved Nutrition (GAIN), and Hellen Keller International (HKI). Data collection and analysis Selection of studies Two review authors will independently screen the titles and abstracts of articles retrieved by each search to assess eligibility, as determined by the inclusion and exclusion criteria. Studies deemed eligible for inclusion by both review authors in the abstract screening phase will advance to the full-text screening phase, and full-text copies of all eligible papers will be retrieved. If full articles cannot be obtained, we will attempt to contact the authors to obtain further details of the studies. If such information is not obtained, we will classify the study as "awaiting assessment" until further information is published or made available to us. The same two review authors will independently assess the eligibility of full-text articles for inclusion in the systematic review. If any discrepancies occur between the studies selected by the two review authors, a third review author will provide arbitration. Each trial will be scrutinized to identify multiple publications from the same data set, and the justification for excluded trials will be documented. A PRISMA flow diagram of the study selection process will be presented to provide information on the number of records identified in the literature searches, the number of studies included and excluded, and the reasons for exclusion (Moher 2009). The list of excluded studies, along with their reasons for exclusion at the full-text screening phase, will also be created. Data extraction and management Two review authors will independently extract data for the final list of included studies using a standardized data specification form. Discrepancies observed between the data extracted by the two authors will be resolved by involving a third review author and reaching a consensus. Information will be extracted on study design components, baseline participant characteristics, intervention characteristics, and outcomes. For individually randomized trials, we will record the number of participants experiencing the event and the number analyzed in each treatment group or the effect estimate reported (e.g. risk ratio (RR)) for dichotomous outcome measures. For count data, we will record the number of events and the number of person-months of follow-up in each group. If the number of person-months is not reported, the product of the duration of follow-up and the number of children evaluated will be used to estimate this figure. We will calculate the rate ratio and standard error (SE) for each study. Zero events will be replaced by 0.5. We will extract both adjusted and unadjusted covariate incidence rate ratios if they are reported in the original studies. For continuous data, we will extract means (arithmetic or geometric) and a measure of variance (standard deviation (SD), SE, or confidence interval (CI)), percentage or mean change from baseline, and the numbers analyzed in each group. SDs will be computed from SEs or 95% CIs, assuming a normal distribution of the values. Haemoglobin values in g/dL will be calculated by multiplying haematocrit or packed cell volume values by 0.34, and studies reporting haemoglobin values in g/dL will be converted to g/L. In cluster-randomized trials, we will record the unit of randomization (e.g. household, compound, sector, or village), the number of clusters in the trial, and the average cluster size. The statistical methods used to analyze the trials will be documented, along with details describing whether these methods adjusted for clustering or other covariates. We plan to extract estimates of the intra-cluster correlation coefficient (ICC) for each outcome. Where results are adjusted for clustering, we will extract the treatment effect estimate and the SD or CI. If the results are not adjusted for clustering, we will extract the data reported. Assessment of risk of bias in included studies Two review authors (KSC, LFY) will independently assess the risk of bias for each included trial using the Cochrane 'Risk of bias 2' tool (RoB 2) for randomized studies (Sterne 2019). Judgements about the risk of bias of included studies will be made according to the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Disagreements will be resolved by discussion, or by involving a third review author. The interest of our review will be to assess the effect of assignment to the interventions at baseline. We will evaluate each primary outcome using the RoB2 tool. The five domains of the Cochrane RoB2 tool include the following. Bias arising from the randomization process. Bias due to deviations from intended interventions. Bias due to missing outcome data. Bias in measurement of the outcome. Bias in selection of the reported result. Each domain of the RoB2 tool comprises the following. A series of 'signalling' questions. A judgement about the risk of bias for the domain, facilitated by an algorithm that maps responses to the signalling questions to a proposed judgement. Free-text boxes to justify responses to the signalling questions and 'Risk of bias' judgements. An option to predict (and explain) the likely direction of bias. Responses to signalling questions elicit information relevant to an assessment of the risk of bias. These response options are as follows. Yes (may indicate either low or high risk of bias, depending on the most natural way to ask the question). Probably yes. Probably no. No. No information (may indicate no evidence of that problem or an absence of information leading to concerns about there being a problem). Based on the answer to the signalling question, a 'Risk of bias' judgement is assigned to each domain. These judgements include one of the following. High risk of bias Low risk of bias Some concerns To generate the risk of bias judgement for each domain in the randomized studies, we will use the Excel template, available at www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2. This file will be stored on a scientific data website, available to readers. Risk of bias in cluster randomized controlled trials For the cluster randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 1b (bias arising from the timing of identification or recruitment of participants) and its related signalling questions. To generate the risk of bias judgement for each domain in the cluster RCTs, we will use the Excel template available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-cluster-randomized-trials. This file will be stored on a scientific data website, available to readers. Risk of bias in cross-over randomized controlled trials For cross-over randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 2 (bias due to deviations from intended interventions), and Domain 3 (bias due to missing outcome data), and their respective signalling questions. To generate the risk of bias judgement for each domain in the cross-over RCTs, we will use the Excel template, available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-crossover-trials, for each risk of bias judgement of cross-over randomized studies. This file will be stored on a scientific data website, available to readers. Overall risk of bias The overall 'Risk of bias' judgement for each specific trial being assessed will be based on each domain-level judgement. The overall judgements include the following. Low risk of bias (the trial is judged to be at low risk of bias for all domains). Some concerns (the trial is judged to raise some concerns in at least one domain but is not judged to be at high risk of bias for any domain). High risk of bias (the trial is judged to be at high risk of bias in at least one domain, or is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result). The 'risk of bias' assessments will inform our GRADE evaluations of the certainty of evidence for our primary outcomes presented in the 'Summary of findings' tables and will also be used to inform the sensitivity analyses; (see Sensitivity analysis). If there is insufficient information in study reports to enable an assessment of the risk of bias, studies will be classified as "awaiting assessment" until further information is published or made available to us. Measures of treatment effect Dichotomous data For dichotomous data, we will present proportions and, for two-group comparisons, results as average RR or odds ratio (OR) with 95% CIs. Ordered categorical data Continuous data We will report results for continuous outcomes as the mean difference (MD) with 95% CIs, if outcomes are measured in the same way between trials. Where some studies have reported endpoint data and others have reported change-from-baseline data (with errors), we will combine these in the meta-analysis, if the outcomes were reported using the same scale. We will use the standardized mean difference (SMD), with 95% CIs, to combine trials that measured the same outcome but used different methods. If we do not find three or more studies for a pooled analysis, we will summarize the results in a narrative form. Unit of analysis issues Cluster-randomized trials We plan to combine results from both cluster-randomized and individually randomized studies, providing there is little heterogeneity between the studies. If the authors of cluster-randomized trials conducted their analyses at a different level from that of allocation, and they have not appropriately accounted for the cluster design in their analyses, we will calculate the trials' effective sample sizes to account for the effect of clustering in data. When one or more cluster-RCT reports RRs adjusted for clustering, we will compute cluster-adjusted SEs for the other trials. When none of the cluster-RCTs provide cluster-adjusted RRs, we will adjust the sample size for clustering. We will divide, by the estimated design effects (DE), the number of events and number evaluated for dichotomous outcomes and the number evaluated for continuous outcomes, where DE = 1 + ((average cluster size 1) * ICC). The derivation of the estimated ICCs and DEs will be reported. We will utilize the intra-cluster correlation coefficient (ICC), derived from the trial (if available), or from another source (e.g., using the ICCs derived from other, similar trials) and then calculate the design effect with the formula provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If this approach is used, we will report it and undertake sensitivity analysis to investigate the effect of variations in ICC. Studies with more than two treatment groups If we identify studies with more than two intervention groups (multi-arm studies), where possible we will combine groups to create a single pair-wise comparison or use the methods set out in the Cochrane Handbook to avoid double counting study participants (Higgins 2021). For the subgroup analyses, when the control group was shared by two or more study arms, we will divide the control group (events and total population) over the number of relevant subgroups to avoid double counting the participants. Trials with several study arms can be included more than once for different comparisons. Cross-over trials From cross-over trials, we will consider the first period of measurement only and will analyze the results together with parallel-group studies. Multiple outcome events In several outcomes, a participant might experience more than one outcome event during the trial period. For all outcomes, we will extract the number of participants with at least one event. Dealing with missing data We will contact the trial authors if the available data are unclear, missing, or reported in a format that is different from the format needed. We aim to perform a 'per protocol' or 'as observed' analysis; otherwise, we will perform a complete case analysis. This means that for treatment failure, we will base the analyses on the participants who received treatment and the number of participants for which there was an inability to clear malarial parasitaemia or prevent recrudescence after administration of an antimalarial medicine reported in the studies. Assessment of heterogeneity Heterogeneity in the results of the trials will be assessed by visually examining the forest plot to detect non-overlapping CIs, using the Chi2 test of heterogeneity (where a P value of less than 0.1 indicates statistical significance) and the I2 statistic of inconsistency (with a value of greater than 50% denoting moderate levels of heterogeneity). When statistical heterogeneity is present, we will investigate the reasons for it, using subgroup analysis. Assessment of reporting biases We will construct a funnel plot to assess the effect of small studies for the main outcome (when including more than 10 trials). Data synthesis The primary analysis will include all eligible studies that provide data regardless of the overall risk of bias as assessed by the RoB2 tool. Analyses will be conducted using Review Manager 5.4 (Review Manager 2020). Cluster-RCTs will be included in the main analysis after adjustment for clustering (see the previous section on cluster-RCTs). The meta-analysis will be performed using the Mantel-Haenszel random-effects model or the generic inverse variance method (when adjustment for clustering is performed by adjusting SEs), as appropriate. Subgroup analysis and investigation of heterogeneity The overall risk of bias will not be used as the basis in conducting our subgroup analyses. However, where data are available, we plan to conduct the following subgroup analyses, independent of heterogeneity. Dose of folic acid supplementation: higher doses (4 mg or more, daily) versus lower doses (less than 4 mg, daily). Moderate-severe anaemia at baseline (mean haemoglobin of participants in a trial at baseline below 100 g/L for pregnant women and children aged six to 59 months, and below 110 g/L for other populations) versus normal at baseline (mean haemoglobin above 100 g/L for pregnant women and children aged six to 59 months, and above 110 g/L for other populations). Antimalarial drug resistance to parasite: known resistance versus no resistance versus unknown/mixed/unreported parasite resistance. Folate status at baseline: Deficient (e.g. RBC folate concentration of less than 305 nmol/L, or serum folate concentration of less than 7nmol/L) and Insufficient (e.g. RBC folate concentration from 305 to less than 906 nmol/L, or serum folate concentration from 7 to less than 25 nmol/L) versus Sufficient (e.g. RBC folate concentration above 906 nmol/L, or serum folate concentration above 25 nmol/L). Presence of anaemia at baseline: yes versus no. Mandatory fortification status: yes, versus no (voluntary or none). We will only use the primary outcomes in any subgroup analyses, and we will limit subgroup analyses to those outcomes for which three or more trials contributed data. Comparisons between subgroups will be performed using Review Manager 5.4 (Review Manager 2020). Sensitivity analysis We will perform a sensitivity analysis, using the risk of bias as a variable to explore the robustness of the findings in our primary outcomes. We will verify the behaviour of our estimators by adding and removing studies with a high risk of bias overall from the analysis. That is, studies with a low risk of bias versus studies with a high risk of bias. Summary of findings and assessment of the certainty of the evidence For the assessment across studies, we will use the GRADE approach, as outlined in (Schünemann 2021). We will use the five GRADE considerations (study limitations based on RoB2 judgements, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence as it relates to the studies which contribute data to the meta-analyses for the primary outcomes. The GRADEpro Guideline Development Tool (GRADEpro) will be used to import data from Review Manager 5.4 (Review Manager 2020) to create 'Summary of Findings' tables. The primary outcomes for the main comparison will be listed with estimates of relative effects, along with the number of participants and studies contributing data for those outcomes. These tables will provide outcome-specific information concerning the overall certainty of evidence from studies included in the comparison, the magnitude of the effect of the interventions examined, and the sum of available data on the outcomes we considered. We will include only primary outcomes in the summary of findings tables. For each individual outcome, two review authors (KSC, LFY) will independently assess the certainty of the evidence using the GRADE approach (Balshem 2011). For assessments of the overall certainty of evidence for each outcome that includes pooled data from included trials, we will downgrade the evidence from 'high certainty' by one level for serious (or by two for very serious) study limitations (risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias).
Topics: Child; Infant; Pregnancy; Infant, Newborn; Female; Humans; Child, Preschool; Antimalarials; Sulfadoxine; Pyrimethamine; Folic Acid Antagonists; Birth Weight; Parasitemia; Vitamins; Folic Acid; Anemia; Neural Tube Defects; Dietary Supplements; Iron; Recurrence
PubMed: 36321557
DOI: 10.1002/14651858.CD014217