Safety of high-dose ivermectin: a systematic review and meta-analysis.

BACKGROUND: Ivermectin is a key anthelmintic for the control of neglected tropical diseases. The main indications for population-level control with ivermectin through mass drug administration are onchocerciasis and lymphatic filariasis; however, there is interest in using higher, fixed-dose regimens for the control of scabies, soil-transmitted helminths and malaria. Safety data for these higher-dose regimens are needed. METHODS: A systematic literature review and meta-analysis on the safety and doses of ivermectin was conducted. Eligible studies reported patient-level data and, for the meta-analysis, clinical trials reporting data on doses ≥200 and ≥400 µg/kg were included. Incidence ratios were used to compare adverse events by severity and organ system affected. RESULTS: The systematic search identified six studies for inclusion, revealing no differences in the number of individuals experiencing adverse events. A descriptive analysis of these clinical trials for a variety of indications showed no difference in the severity of the adverse events between standard (up to 400 µg/kg) and higher doses of ivermectin. Organ system involvement only showed an increase in ocular events in the higher-dose group in one trial for the treatment of onchocerciasis, all of them transient and mild to moderate in intensity. CONCLUSIONS: Although within this review the safety of high-dose ivermectin appears to be comparable to standard doses, there are not enough data to support a recommendation for its use in higher-than-approved doses. Ocular adverse events, despite being transient, are of concern in onchocerciasis patients. These data can inform programme managers and guide operational research activities as new approaches for the use of ivermectin are evaluated.

Positive direct antiglobulin test in post-artesunate delayed haemolysis: more than a coincidence?

BACKGROUND: Delayed haemolysis is a frequent adverse event after treatment with artesunate (AS). Removing once-infected "pitted" erythrocytes by the spleen is the most accepted mechanism of haemolysis in these cases. However, an increasing number of cases with positive direct antiglobulin test (DAT) haemolysis after AS have been reported. METHODS: All malaria cases seen at Hospital Clinic of Barcelona between 2015 and 2017 were retrospectively reviewed. Clinical, parasitological and laboratory data from patients treated with intravenous artesunate-specifically looking for delayed haemolysis and DAT-was collected. RESULTS: Among the 36 severe malaria patients treated with artesunate at the hospital, 10 (27.8%) developed post-artesunate delayed haemolysis. Out of these, DAT was performed in six, being positive in four of them (at least 40%). DAT was positive only for complement-without IgG-suggesting drug-dependent immune-haemolytic anaemia of the immune-complex type. Three of the four patients were treated with corticosteroids and two also received blood transfusion, with a complete recovery. CONCLUSIONS: Drug-induced auto-immune phenomena in post-artesunate delayed haemolysis may be underreported and must be considered. The role of corticosteroids should be reassessed.

Dengue severity by serotype in 19 years of pediatric clinical studies in Nicaragua.

Background: Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease. Methods: This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the influence of serotype and immune status on dengue severity. Study participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients, with dengue cases confirmed by molecular, serological, and/or virological methods. Results: We enrolled a total of 14071 participants, of whom 2954 (21%) were positive for DENV infection. Of 2425 cases with serotype result by RT-PCR, 541 corresponded to DENV1, 996 to DENV2, 718 to DENV3 and 170 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 had a higher proportion of severe disease compared to other serotypes, whereas DENV3 had the greatest percentage of severity under the WHO-2009 classification. DENV2 was associated with pleural effusion and low platelet count, while DENV3 correlated with both hypotensive and compensated shock. Conclusions: These findings emphasize the critical need for a dengue vaccine with balanced efficacy against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and immune status, posing challenges for comprehensive protection, particularly in dengue-naïve individuals.

Correction: Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients.

[This corrects the article DOI: 10.1371/journal.pone.0242184.].

Persistent replication of SARS-CoV-2 in a severely immunocompromised patient treated with several courses of remdesivir.

Microbiological response of SARS-CoV-2 to remdesivir in immunocompromised patients has not been evaluated. We present the case of a severely immunocompromised patient with persistent replication of SARS-CoV-2, who required different courses of remdesivir. Short courses of remdesivir might be insufficient in immunocompromised patients due to prolonged viral clearance.

Zika virus infection in pregnant travellers and impact on childhood neurodevelopment in the first two years of life: A prospective observational study.

BACKGROUND: The emergence of Zika virus (ZIKV) represents a threat with consequences on maternal and children's health. We aimed to assess the clinical and epidemiological characteristics of pregnant women returning from ZIKV affected areas, and the effects of maternal ZIKV infection on birth outcomes and children's health. METHODS: This was a hospital-based prospective observational study conducted at the Hospital Clínic of Barcelona and Hospital Sant Joan de Déu, Barcelona, Spain, from January 2016 to February 2020. RESULTS: One hundred and ninety-five pregnant women who had travelled to ZIKV affected areas during pregnancy were recruited. Four women (2.1%) had a confirmed ZIKV infection, 40 women (20.5%) a probable infection, and 151 (77.4%) were negative for ZIKV. Among the ZIKV confirmed cases, a pregnant woman suffered a miscarriage, highly plausible to be associated with ZIKV infection. Brain cysts and microcalcifications were detected in 7% of fetuses or infants from women with confirmed or probable ZIKV infection. Neurodevelopmental delay in the language function was found in 33.3% out of the 21 children evaluated. CONCLUSIONS: These findings contribute to the understanding of ZIKV prevalence estimates, and the impact of maternal ZIKV infection on pregnancy outcomes and children's health. Results highlight the importance of long-term surveillance in pregnant travellers and their children.

Pre-exposure prophylaxis with hydroxychloroquine for high-risk healthcare workers during the COVID-19 pandemic: A structured summary of a study protocol for a multicentre, double-blind randomized controlled trial.

OBJECTIVES: The aim of this study is to assess the efficacy of the use of pre-exposure prophylaxis (PrEP) with hydroxychloroquine against placebo in healthcare workers with high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in reducing their risk of coronavirus disease 2019 (COVID-19) disease during an epidemic period. As secondary objectives, we would like to: i) assess the efficacy of the use of PrEP with hydroxychloroquine against placebo in healthcare workers with high risk of SARS-CoV-2 infection in reducing their risk of exposure to SARS-CoV-2 (defined by seroconversion) during an epidemic period, ii) evaluate the safety of PrEP with hydroxychloroquine in adults, iii) describe the incidence of SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 infection, iv) identify clinical, analytical and microbiological predictors of COVID-19 among healthcare workers at high risk of SARS-CoV-2 infection, v) set up a repository of serum samples obtained from healthcare workers at high risk of SARS-CoV-2 infection for future research on blood markers to predict SARS-CoV-2 infection. TRIAL DESIGN: Multicentre double-blind parallel design (ratio 1:1) randomized controlled clinical trial. PARTICIPANTS: Approximately 440 healthcare workers of four Spanish hospitals (Hospital Clínic of Barcelona, Hospital de la Santa Creu i Sant Pau of Barcelona, Hospital Plató of Barcelona, Hospital General de Granollers, Barcelona) will be recruited. Participants are considered to be at high-risk of SARS-CoV-2 infection due to their frequent contact with suspected and confirmed cases of COVID-19. For eligibility, healthcare workers with 18 years old or older working at least 3 days a week in a hospital with both negative SARS-CoV-2 polymerase chain reaction (PCR) assays and serological COVID-19 rapid diagnostic tests (RDT) are invited to participate. Participants with any of the following conditions are excluded: pregnancy, breastfeeding, ongoing antiviral, antiretroviral or corticosteroids treatment, chloroquine or hydroxychloroquine uptake the last month or any contraindication to hydroxychloroquine treatment. INTERVENTION AND COMPARATOR: Eligible participants will be allocated to one of the two study groups: Intervention group (PrEP): participants will receive the standard of care and will take 400mg of hydroxychloroquine (2 tablets of 200 mg per Dolquine® tablet) daily the first four consecutive days, followed by 400 mg weekly for a period of 6 months. CONTROL GROUP: participants will receive placebo tablets with identical physical appearance to hydroxychloroquine 200 mg (Dolquine®) tablets following the same treatment schedule of the intervention group. Both groups will be encouraged to use the personal protection equipment (PPE) for COVID-19 prevention according to current hospital guidelines. MAIN OUTCOMES: The primary endpoint will be the number of confirmed cases of a COVID-19 (defined by a positive PCR for SARS-CoV-2 or symptoms compatible with COVID-19 with seroconversion) in the PrEP group compared to the placebo group at any time during the 6 months of the follow-up in healthcare workers with negative SARS-CoV-2 PCR and serology at day 0. As secondary endpoints, we will obtain: i) the SARS-CoV-2 seroconversion in the PrEP group compared to placebo during the 6 months of follow-up in healthcare workers with negative serology at day 0; ii) the occurrence of any adverse event related with hydroxychloroquine treatment; iii) the incidence of SARS-CoV-2 infection and COVID-19 among healthcare workers in the non-PrEP group, among the total of healthcare workers included in the non-PrEP group during the study period; iv) the risk ratio for the different clinical, analytical and microbiological conditions to develop COVID-19; v) a repository of serum samples obtained from healthcare workers confirmed COVID-19 cases for future research on blood markers to predict SARS-CoV-2 infection. RANDOMISATION: Participants meeting all eligibility requirements will be allocated to one of the two study arms (PrEP with hydroxychloroquine or non-PrEP control group) in a 1:1 ratio using simple randomisation with computer generated random numbers. BLINDING (MASKING): Participants, doctors and nurses caring for participants, and investigators assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Each intervention group will have 220 participants, giving a total of 440 participants. TRIAL STATUS: The current protocol version is 1.5, 2nd of June 2020. Two hundred and seventy-fiveparticipants were recruited and completed first month follow-up until date. The estimated sample size could not be reached yet due to the declining national epidemic curve. Thus, 275 is the total number of participants included until date. The study has been suspended (26th of June) until new epidemic curve occurs. TRIAL REGISTRATION: This trial was registered on April 2nd 2020 at clinicaltrials.gov with the number NCT04331834. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Infectiousness of patients with smear-negative pulmonary tuberculosis, assessed by Real-time Polymerase Chain Reaction, XpertⓇMTB/RIF.

Currently, pulmonary tuberculosis (TB) isolation recommendations are based on serial sputum smear microscopy. To assess infectiousness of smear-negative/GeneXpert-positive (Sm-/GXpert+) pulmonary TB, we evaluated 511 contacts of pulmonary TB patients attended at a teaching hospital in Spain (2010-2018). There were no statistically significant differences in rates of Mycobacterium tuberculosis infection (46.2% contacts of smear-positive and 34.6% contacts of Sm-/GXpert+ pulmonary TB patients, p = 0.112). Sm-/GXpert+ pulmonary TB poses a substantial risk of transmission of M. tuberculosis infection. Our results add evidence to support including Real-time Polymerase Chain Reaction (XpertⓇMTB/RIF) in the work-up diagnosis of suspected pulmonary TB cases to make decisions on air-borne isolation.

Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients.

Ivermectin has recently shown efficacy against SARS-CoV-2 in-vitro. We retrospectively reviewed severe COVID-19 patients receiving standard doses of ivermectin and we compared clinical and microbiological outcomes with a similar group of patients not receiving ivermectin. No differences were found between groups. We recommend the evaluation of high-doses of ivermectin in randomized trials against SARS-CoV-2.

Post-malarial anemia in Mozambican children treated with quinine or artesunate: A retrospective observational study.

OBJECTIVES: This retrospective analysis performed in Manhiça, Southern Mozambique, aimed to describe the frequency of post-malarial anemia (measured as a decrease of hematocrit ≥10%) and the need for blood transfusions in children with severe malaria treated with intravenous quinine or parenteral artesunate. METHODS: All children <15 years admitted with a parasitologically-confirmed diagnosis of malaria from 1st January 2003 to 31st December 2017, alive at hospital discharge, and with at least one measurement of hematocrit within 28 days after hospital discharge, detected by passive case detection, were included. RESULTS: The overall prevalence of post-malarial anemia observed in the study was 23.13%, with an estimated incidence rate of 288.84 episodes/1,000 children-month at risk in the follow-up period (28 days after discharge). There were no differences between treatment groups, although the study showed a higher association between blood transfusions and artesunate treatment. CONCLUSIONS: In this setting, children with severe malaria frequently present a meaningful decrease of hematocrit (>=10%) in the first weeks after their episode, sometimes requiring blood transfusions. Because of the high underlying prevalence of anemia in malaria-endemic settings, all children with severe malaria need to be actively followed up, irrespective of the treatment received.

Diagnostic Value of Platelet and Leukocyte Counts in the Differential Diagnosis of Fever in the Returning Traveler.

Malaria, arbovirus infection and travelers' diarrhea are among the most common etiologies of fever after a stay in the tropics. Because the initial symptoms of these diseases often overlap, the differential diagnostic remains a challenge. The aim of this study was to establish the effectiveness of platelet and leukocyte counts in the differential diagnosis of fever in the returning traveler. Between 2013 and 2016, patients with a clinical suspicion of malaria, who had thick blood smears performed were retrospectively included. The microbiological etiology of each episode was established based on molecular detection in the case of arbovirus infection, the detection of pathogens in stool samples for diarrhea and other gastrointestinal symptoms and the thick and thin blood smear results for malaria. A total of 1,218 episodes were included. Malaria, arbovirus infection, and diarrhea and other gastrointestinal symptoms caused 102 (8.4%), 68 (5.6%), and 72 (5.9%) episodes, respectively. The median platelet counts in malaria episodes were 89 × 109/L and thrombocytopenia (< 150,000 × 109 platelets/L) yielded a 98% negative predictive value to predict malaria. The median leukocyte counts in arbovirus infection episodes were 3.19 × 109/L and leucopenia (< 4 × 109 leukocytes/L) yielded a 97.9% negative predictive value to predict arbovirus infections. Platelet and leukocyte counts were not significantly altered in episodes caused by diarrhea and other gastrointestinal symptoms. Initial platelet and leukocyte counts might be useful for the clinical differential diagnosis of fever in the returning traveler. Although these results are insufficient to establish a diagnosis, they should be considered in the initial clinical assessment.

Suspected quinine resistant P. falciparum severe malaria possibly acquired in Ivory Coast.

An expatriate to Ivory Coast (supposedly allergic to artemether-lumefantrine) was diagnosed with severe malaria in Spain. Parasitemia increased from 2% up to 21% within 24 h under quinine (10 mg/kg) and clindamycin (450 mg/8 h) combination treatment. Molecular profiling of the patient revealed the presence of molecular markers of quinine and other antimalarials resistance. Additionally, multiple copies of pfpm2 gene were also noticed in the patient sample, despite the absence of piperaquine drug pressure in Ivory Coast. Parasitemia was cleared with artesunate (2.4 mg/kg) under a desensitization protocol. Nevertheless, detection of early treatment failure is needed mainly in cases of suspected antimalarial resistance.

Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory disease caused by TNFRSF1A mutations. Patients with TRAPS suffer from recurrent, long episodes with fever, arthralgia/arthritis, migratory myalgias, abdominal pain, serositis, conjunctivitis and migratory erythematous skin rash. More than 70 different TNFRSF1A mutations have been reported to date, and as consequence of its genetic heterogeneity, TRAPS shows a variable phenotypic expression. Among TNFRSF1A variants, the low-penetrance p.Arg92Gln variant represents the most commonly detected, and is typically associated with mild and short episodes, with a higher tendency to spontaneous resolution, and less familial association than the structural TNFRSF1A mutations. Pericardial involvement is rare but a well-known clinical feature of TRAPS, with a significant increased rate in those adult patients in whom the onset of the disease occurred during adulthood. Moreover, idiopathic recurrent acute pericarditis has also been occasionally described as a clinical presentation of TRAPS. However, cardiac tamponade is an unusual initial manifestation of the disease. Herein, we present a brief review based on the description of the exceptional case of a 35-year-old female patient who presented with recurrent pericardial effusions and cardiac tamponade. TNFRSF1A analyses showed a heterozygous genotype for the low-penetrance p.Arg92Gln variant. Due to disease severity, the patient was treated with the anti-interleukin-1 drug anakinra, showing a prompt resolution of her clinical manifestations.

Risk factors and outcomes of organ-space surgical site infections after elective colon and rectal surgery.

BACKGROUND: Organ-space surgical site infections (SSI) are the most serious and costly infections after colorectal surgery. Most previous studies of risk factors for SSI have analysed colon and rectal procedures together. The aim of the study was to determine whether colon and rectal procedures have different risk factors and outcomes for organ-space SSI. METHODS: A multicentre observational prospective cohort study of adults undergoing elective colon and rectal procedures at 10 Spanish hospitals from 2011 to 2014. Patients were followed up until 30 days post-surgery. Surgical site infection was defined according to the Centers for Disease Control and Prevention criteria. Oral antibiotic prophylaxis (OAP) was considered as the administration of oral antibiotics the day before surgery combined with systemic intravenous antibiotic prophylaxis. RESULTS: Of 3,701 patients, 2,518 (68%) underwent colon surgery and 1,183 (32%) rectal surgery. In colon surgery, the overall SSI rate was 16.4% and the organ-space SSI rate was 7.9%, while in rectal surgery the rates were 21.6% and 11.5% respectively (p < 0.001). Independent risk factors for organ-space SSI in colon surgery were male sex (Odds ratio -OR-: 1.57, 95% CI: 1.14-2.15) and ostomy creation (OR: 2.65, 95% CI: 1.8-3.92) while laparoscopy (OR: 0.5, 95% CI: 0.38-0.69) and OAP combined with intravenous antibiotic prophylaxis (OR: 0.7, 95% CI: 0.51-0.97) were protective factors. In rectal surgery, independent risk factors for organ-space SSI were male sex (OR: 2.11, 95% CI: 1.34-3.31) and longer surgery (OR: 1.49, 95% CI: 1.03-2.15), whereas OAP with intravenous antibiotic prophylaxis (OR: 0.49, 95% CI: 0.32-0.73) was a protective factor. Among patients with organ-space SSI, we found a significant difference in the overall 30-day mortality, being higher in colon surgery than in rectal surgery (11.5% vs 5.1%, p = 0.04). CONCLUSIONS: Organ-space SSI in colon and rectal surgery has some differences in terms of incidence, risk factors and outcomes. These differences could be considered for surveillance purposes and for the implementation of preventive strategies. Administration of OAP would be an important measure to reduce the OS-SSI rate in both colon and rectal surgeries.