Efficacy and harms of convalescent plasma for treatment of hospitalized COVID-19 patients: a systematic review and meta-analysis

IntroductionWe systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients.Material and methodsRandomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events.ResultsFive RCTs (n = 1067) and 6 cohorts (n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33–1.10) or moderate (RR = 0.60, 95% CI: 0.09–3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49–0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47–1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48–1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82–1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes.ConclusionsIn comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients.     

Schistosoma mansoni Infection Impairs Antimalaria Treatment and Immune Responses of Rhesus Macaques Infected with Mosquito-Borne Plasmodium coatneyi

Malaria and schistosomiasis are the world''s two most important parasitic infections in terms of distribution, morbidity, and mortality. In areas where Plasmodium and Schistosoma species are both endemic, coinfections are commonplace. Mouse models demonstrate that schistosomiasis worsens a malaria infection; however, just as mice and humans differ greatly, the murine-infecting Plasmodium species differ as much from those that infect humans. Research into human coinfections (Schistosoma haematobium-Plasmodium falciparum versus Schistosoma mansoni-P. falciparum) has produced conflicting results. The rhesus macaque model provides a helpful tool for understanding the role of S. mansoni on malaria parasitemia and antimalarial immune responses using Plasmodium coatneyi, a malaria species that closely resembles P. falciparum infection in humans. Eight rhesus macaques were exposed to S. mansoni cercariae. Eight weeks later, these animals plus 8 additional macaques were exposed to malaria either through bites of infected mosquitos or intravenous inoculation. When malaria infection was initiated from mosquito bites, coinfected animals displayed increased malaria parasitemia, decreased hematocrit levels, and suppressed malaria-specific antibody responses compared to those of malaria infection alone. However, macaques infected by intravenous inoculation with erythrocytic-stage parasites did not display these same differences in parasitemia, hematocrit, or antibody responses between the two groups. Use of the macaque model provides information that begins to unravel differences in pathological and immunological outcomes observed between humans with P. falciparum that are coinfected with S. mansoni or S. haematobium. Our results suggest that migration of malaria parasites through livers harboring schistosome eggs may alter host immune responses and infection outcomes.     

Clinical characteristics,management and in-hospital mortality of patients with coronavirus disease 2019 in Genoa,Italy

ObjectivesTo describe clinical characteristics, management and outcome of individuals with coronavirus disease 2019 (COVID-19); and to evaluate risk factors for all-cause in-hospital mortality.MethodsThis retrospective study from a University tertiary care hospital in northern Italy, included hospitalized adult patients with a diagnosis of COVID-19 between 25 February 2020 and 25 March 2020.ResultsOverall, 317 individuals were enrolled. Their median age was 71 years and 67.2% were male (213/317). The most common underlying diseases were hypertension (149/317; 47.0%), cardiovascular disease (63/317; 19.9%) and diabetes (49/317; 15.5%). Common symptoms at the time of COVID-19 diagnosis included fever (285/317; 89.9%), shortness of breath (167/317; 52.7%) and dry cough (156/317; 49.2%). An ‘atypical’ presentation including at least one among mental confusion, diarrhoea or nausea and vomiting was observed in 53/317 patients (16.7%). Hypokalaemia occurred in 25.8% (78/302) and 18.5% (56/303) had acute kidney injury. During hospitalization, 111/317 patients (35.0%) received non-invasive respiratory support, 65/317 (20.5%) were admitted to the intensive care unit (ICU) and 60/317 (18.5%) required invasive mechanical ventilation. All-cause in-hospital mortality, assessed in 275 patients, was 43.6% (120/275). On multivariable analysis, age (per-year increase OR 1.07; 95% CI 1.04–1.10; p < 0.001), cardiovascular disease (OR 2.58; 95% CI 1.07–6.25; p 0.03), and C-reactive protein levels (per-point increase OR 1.009; 95% CI 1.004–1.014; p 0.001) were independent risk factors for all-cause in-hospital mortality.ConclusionsCOVID-19 mainly affected elderly patients with predisposing conditions and caused severe illness, frequently requiring non-invasive respiratory support or ICU admission. Despite supportive care, COVID-19 remains associated with a substantial risk of all-cause in-hospital mortality.     

Cerebral malaria caused by Plasmodium vivax in adult subjects

Cerebral malaria is a diffuse encephalopathy associated with seizures and status epilepticus which can occur in up to one-third of patients with severe malaria, particularly that caused by Plasmodium falciparum.In this article, we report three cases of Plasmodium vivax malaria (all adult male patients) complicated by seizures and symptoms of diffuse meningoencephalitis. Two patients had predominantly meningeal signs, while in the third patient the features were purely of encephalitis All cases were treated with artesunate. Usually, cerebral malaria is caused by P. falciparum, and rarely, cerebral malaria is a presenting complication or occurs during the course of P. vivax infection.     

Incidence and Mortality Associated with Cardiovascular Medication among Hypertensive COVID-19 Patients in South Korea

PurposeWe aimed to investigate whether the use of cardiovascular drugs in coronavirus disease 2019 (COVID-19) patients with hypertension as a comorbidity has a significant effect on the incidence and associated mortality rate of COVID-19.Materials and MethodsData covering the period between January 1, 2020 and June 4, 2020 were extracted from The National Health Insurance Service-COVID-19 (NHIS-COVID-19) database in South Korea and analyzed as a population-based cohort study.ResultsA total of 101657 hypertensive adults aged 20 years or older were included for final analysis. Among them, 1889 patients (1.9%) were diagnosed with COVID-19 between January 1, 2020 and June 4, 2020, and hospital mortality occurred in 193 patients (10.2%). In a multivariable model, the use of beta-blockers was associated with an 18% lower incidence of COVID-19 [odds ratio (OR): 0.82, 95% confidence interval (CI): 0.69–0.98; p=0.029]. Among 1889 hypertensive patients diagnosed with COVID-19, the use of a calcium channel blocker (CCB) was associated with a 42% lower hospital mortality rate (OR: 0.58, 95% CI: 0.38–0.89; p=0.012). The use of other cardiovascular drugs was not associated with the incidence of COVID-19 or hospital mortality rate among COVID-19 patients. Similar results were observed in all 328374 adults in the NHIS-COVID-19 database, irrespective of the presence of hypertension.ConclusionIn South Korea, beta-blockers exhibited potential benefits in lowering the incidence of COVID-19 among hypertensive patients. Furthermore, CCBs may lower the hospital mortality rate among hypertensive COVID-19 patients. These findings were also applied to the general adult population, regardless of hypertension.     

Invasive fungal infections among critically ill adult COVID-19 patients: First experiences from the national centre in Hungary

IntroductionData suggests that invasive fungal infections (IFI) might complicate COVID-19. Our goal was to describe characteristics of IFI among critically ill COVID-19 adults.MethodsA retrospective observational case-series analysis was done between March–July 2020. Consecutive patients with critical COVID-19 were eligible, and have been included when proven or putative/probable IFI could be confirmed during their course. For COVID-19 diagnosis, ECDC definitions and WHO severity criteria were followed. Candidaemia was diagnosed according to the ESCMID 2012 guideline. Invasive pulmonary aspergillosis (IPA) was defined following EORTC/MSG, ECMM/ISHAM and modified AspICU criteria. Outcome variables were rates of IFIs, in-hospital all-cause mortality, rate and time to negative respiratory SARS-CoV-2 PCR.ResultsFrom 90 eligible patients, 20 (22.2%) fulfilled criteria for IFI. Incidence rate for IFI was 2.02 per 100 patient-days at ICU. Patients were mostly elderly males with significant comorbidities, requiring mechanical ventilation because of ARDS. IFI could be classified as candidaemia in 7/20 (40%), putative/probable IPA in 16/20 (80.0%). Isolated species of candidaemia episodes were Candida albicans (4/9, 44.4%), Candida glabrata (3/9, 33.3%), Candida parapsilosis (1/9, 11.1%), Candida metapsilosis (1/9, 11.1%). Mold isolates from lower respiratory tract were Aspergillus fumigatus, BAL galactomannan positivity was prevalent (16/20, 80.0%). Mortality was 12/20 (60.0%) with a median time to death of 31.0±37.0 (5–89) days. Only 9/20 (45.0%) patients reached SARS-CoV-2 PCR negativity after a median time of 20.0±12.0 (3–38) days.ConclusionIn this small cohort of critically ill COVID-19 adults, morbidity and mortality related to invasive fungal infections proved to be significant.     

Estimation of Excess All-cause Mortality during COVID-19 Pandemic in Korea

BackgroundExcess all-cause mortality is helpful to assess the full extent of the health impact, including direct and indirect deaths of coronavirus disease 2019 (COVID-19). The study aimed to estimate overall and regional excess all-cause mortality during the pandemic in Korea.MethodsWe obtained all-cause death data and population statistics from January 2010 to December 2020. The expected mortality in 2020 was estimated using a quasi-Poisson regression model. The model included death year, seasonal variation, cold wave (January), average death counts in the previous month, and population. Excess mortality was defined as the difference between the observed mortality and the expected mortality. Regions were classified into three areas according to the numbers of COVID-19 cases.ResultsThere was no annual excess all-cause mortality in 2020 at the national and regional level compared to the average death for the previous ten years. The observed mortality in 2020 was 582.9 per 100,000 people, and the expected mortality was 582.3 per 100,000 people (95% confidence interval, 568.3–596.7). However, we found monthly and regional variations depending on the waves of the COVID-19 pandemic in Korea. While the mortality in August, October, and November exceeded the expected range, the mortality in September was lower than the expected range. The months in which excess deaths were identified differed by region.ConclusionOur results show that the mortality in 2020 was similar to the historical trend. However, in the era of the COVID-19 pandemic, it would be necessary to regularly investigate COVID-19-related mortality and determine its direct and indirect causes.     

New-onset diabetes in COVID-19 and clinical outcomes: A systematic review and meta-analysis

BACKGROUNDDiabetes mellitus (DM) is associated with adverse clinical outcomes and high mortality in patients with coronavirus disease 2019 (COVID-19). The relationship between diabetes and COVID-19 is known to be bidirectional.AIMTo analyze the rate of new-onset diabetes in COVID-19 patients and compare the clinical outcomes of new-onset diabetes, pre-existing diabetes, hyperglycemic, and non-diabetes among COVID-19 patients.METHODSWe used the Meta-analysis of Observational Studies in Epidemiology statement for the present meta-analysis. Online databases were searched for all peer-reviewed articles published until November 6, 2020. Articles were screened using Covidence and data extracted. Further analysis was done using comprehensive meta-analysis. Among the 128 studies detected after thorough database searching, seven were included in the quantitative analysis. The proportion was reported with 95% confidence interval (CI) and heterogeneity was assessed using I².RESULTSAnalysis showed that 19.70% (CI: 10.93-32.91) of COVID-19 patients had associated DM, and 25.23% (CI: 19.07-32.58) had associated hyperglycemia. The overall mortality rate was 15.36% (CI: 12.57-18.68) of all COVID-19 cases, irrespective of their DM status. The mortality rate was 9.26% among non-diabetic patients, 10.59% among patients with COVID-19 associated hyperglycemia, 16.03% among known DM patients, and 24.96% among COVID-19 associated DM patients. The overall occurrence of adverse events was 20.52% (CI: 14.21-28.70) among COVID-19 patients in the included studies, 15.29% among non-diabetic patients, 20.41% among patients with COVID-19 associated hyperglycemia, 20.69% among known DM patients, and 45.85% among new-onset DM. Meta-regression showed an increasing rate of mortality among new hyperglycemic patients, known diabetics, and new-onset DM patients in comparison to those without diabetes.CONCLUSIONA significantly higher rate of new onset DM and hyperglycemia was observed. Higher mortality rates and adverse events were seen in patients with new-onset DM and hyperglycemia than in the non-diabetic population.     

Antibody-free rapid diagnosis of malaria in whole blood with surface-enhanced Raman Spectroscopy using Nanostructured Gold Substrate

PurposeThe aim of this study is to establish a rapid antibody-free diagnostic method of malaria infection with Plasmodium falciparum and Plasmodium vivax in whole blood with Surface-enhanced Raman Spectroscopy using Nanostructured Gold Substrate.Materials and methodsThe blood samples collected from patients were first lysed and centrifuged before dropping on the gold nano-structure (AuNS) substrate. Malaria diagnosis was performed by detecting Raman peaks from Surface Enhanced Raman Spectroscopy (SERS) with a 532 nm laser excitation.ResultsRaman peaks at 1370 cm⁻¹, 1570 cm⁻¹, and 1627 cm⁻¹, known to have high specificity against interference from other mosquito-borne diseases such as Dengue and West Nile virus infection, were selected as the fingerprint markers associated with P. falciparum and P. vivax infection. The limit of detection was 10⁻⁵ dilution, corresponding to the concentration of parasitized blood cells of 100/mL. A total number of 25 clinical samples, including 5 from patients with P. falciparum infection, 10 with P. vivax infection and 10 from healthy volunteers, were evaluated to support its clinical practical use. The whole assay on malaria detection took 30 min to complete.ConclusionsWhile the samples analyzed in this work have strong clinical relevance, we have clearly demonstrated that sensitive malaria detection using AuNS-SERS is a practical direction for rapid in-field diagnosis of malaria infection.     

Evaluation of the OptiMAL Test for Rapid Diagnosis of Plasmodium vivax and Plasmodium falciparum Malaria

The development of rapid and specific diagnostic tests to identify individuals infected with malaria is of paramount importance in efforts to control the severe public health impact of this disease. This study evaluated the ability of a newly developed rapid malaria diagnostic test, OptiMAL (Flow Inc., Portland, Oreg.), to detect Plasmodium vivax and Plasmodium falciparum malaria during an outbreak in Honduras. OptiMAL is a rapid (10-min) malaria detection test which utilizes a dipstick coated with monoclonal antibodies against the intracellular metabolic enzyme parasite lactate dehydrogenase (pLDH). Differentiation of malaria parasites is based on antigenic differences between the pLDH isoforms. Since pLDH is produced only by live Plasmodium parasites, this test has the ability to differentiate live from dead organisms. Results from the OptiMAL test were compared to those obtained by reading 100 fields of traditional Giemsa-stained thick-smear blood films. Whole-blood samples were obtained from 202 patients suspected of having malaria. A total of 96 samples (48%) were positive by blood films, while 91 (45%) were positive by the OptiMAL test. The blood films indicated that 82% (79 of 96) of the patients were positive for P. vivax and 18% (17 of 96) were infected with P. falciparum. The OptiMAL test showed that 81% (74 of 91) were positive for P. vivax and 19% (17 of 91) were positive for P. falciparum. These results demonstrated that the OptiMAL test had sensitivities of 94 and 88% and specificities of 100 and 99%, respectively, when compared to traditional blood films for the detection of P. vivax and P. falciparum malaria. Blood samples not identified by OptiMAL as malaria positive normally contained parasites at concentrations of less than 100/μl of blood. Samples found to contain P. falciparum were further tested by two other commercially available rapid malaria diagnostic tests, ParaSight-F (Becton Dickinson, Cockeysville, Md.) and ICT Malaria P.f. (ICT Diagnostics, Sydney, Australia), both of which detect only P. falciparum. Only 11 of the 17 (65%) P. falciparum-positive blood samples were identified by the ICT and ParaSight-F tests. Thus, OptiMAL correctly identified P. falciparum malaria parasites in patient blood samples more often than did the other two commercially available diagnostic tests and showed an excellent correlation with traditional blood films in the identification of both P. vivax malaria and P. falciparum malaria. We conclude that the OptiMAL test is an effective tool for the rapid diagnosis of malaria.     

Clinico-pathological studies of Plasmodium falciparum and Plasmodium vivax — malaria in India and Saudi Arabia

Malaria is one of the most devastating diseases of tropical countries with clinical manifestations such as anaemia, splenomegaly, thrombocytopenia, hepatomegaly and acute renal failures. In this study, cases of thrombocytopenia and haemoglobinemia were more prominent in subjects infected with Plasmodium falciparum (Welch, 1897) than those with Plasmodium vivax (Grassi et Feletti, 1890). However, anaemia, jaundice, convulsions and acute renal failure were significantly high (3–4 times) in subjects infected with P. falciparum than those infected with P. vivax. The incidence of splenomegaly and neurological sequelae were 2 and 6 times higher in P. falciparum infections compared to the infections of P. vivax. Both in P. vivax and P. falciparum malaria, the cases of splenomegaly, jaundice and neurological sequelae were almost double in children (<10 years) compared to older patients. The liver enzymes were generally in normal range in cases of low and mild infections. However, the AST, ALT, ALP activities and serum bilirubin, creatinine, and the urea content were increased in P. falciparum and P. vivax malaria patients having high parasitaemia, confirming liver dysfunction and renal failures in few cases of severe malaria both in India and Saudi Arabia.     

Enzyme immunoassay for detection of antigen in acutePlasmodium falciparum malaria

A monoclonal antibody specific for an epitope of a 50 kDa Plasmodium falciparum antigen was used in an enzyme immunoassay for detection of the corresponding exo-antigen in culture supernatant and in the sera of 31 patients suffering from acute malaria. The assay was specific for Plasmodium falciparum and did not appear to be strain restricted. A parasitaemia level below 0.001 % could be detected.     

New Scoring System for Predicting Mortality in Patients with COVID-19

PurposeWe aimed to develop a novel mortality scoring system for inpatients with COVID-19 based on simple demographic factors and laboratory findings.Materials and MethodsWe reviewed and analyzed data from patients who were admitted and diagnosed with COVID-19 at 10 hospitals in Daegu, South Korea, between January and July 2020. We randomized and assigned patients to the development and validation groups at a 70% to 30% ratio. Each point scored for selected risk factors helped build a new mortality scoring system using Cox regression analysis. We evaluated the accuracy of the new scoring system in the development and validation groups using the area under the curve.ResultsThe development group included 1232 patients, whereas the validation group included 528 patients. In the development group, predictors for the new scoring system as selected by Cox proportional hazards model were age ≥70 years, diabetes, chronic kidney disease, dementia, C-reactive protein levels >4 mg/dL, infiltration on chest X-rays at the initial diagnosis, and the need for oxygen support on admission. The areas under the curve for the development and validation groups were 0.914 [95% confidence interval (CI) 0.891–0.937] and 0.898 (95% CI 0.854–0.941), respectively. According to our scoring system, COVID-19 mortality was 0.4% for the low-risk group (score 0–3) and 53.7% for the very high-risk group (score ≥11).ConclusionWe developed a new scoring system for quickly and easily predicting COVID-19 mortality using simple predictors. This scoring system can help physicians provide the proper therapy and strategy for each patient.     

Association between antecedent statin use and severe disease outcomes in COVID-19: A retrospective study with propensity score matching

BackgroundStatins have been associated with a reduction in inflammatory markers and improved endothelial function. Whether statins offer any benefit in COVID-19 needs to be elucidated.ObjectiveTo determine the association between antecedent statin use and severe disease outcomes among COVID-19 patients.MethodsA retrospective cohort study on 1014 patients with confirmed COVID-19 diagnosis. Outcomes were mortality, need for mechanical ventilation, and intensive care admission. Patients were classified into statin-users vs statin non-users based on antecedent use of statins. Multivariable regression analysis was performed adjusting for confounders such as age, sex, race, BMI, smoking, insurance, and comorbidities. Propensity score matching was performed to achieve a 1:1 balanced cohort.ResultsA total of 1014 patients (Median age 65 (IQR 53–73); 530 (52.3%) males; 753 (74.3%) African Americans; median BMI 29.4 (IQR 25.1–35.9); 615 (60.7%) with Medicare insurance) were included in the study. About 454 patients (44.77%) were using statins as home medication. Antecedent statin use was associated with significant decrease in mortality in the total cohort (OR, 0.66; 95% CI, 0.46 – 0.95; p = 0.03). Among the propensity score matched (PSM) cohort of 466 patients (233 statin users and 233 statin non-users), all the baseline characteristics had similar distribution among the two groups. Statin users had significant reduction in mortality in the PSM cohort as well (OR, 0.56; 95% CI, 0.37 – 0.83; p = 0.004).ConclusionsStatin use was associated with significant reduction in mortality among COVID-19 patients. These findings support the pursuit of randomized clinical trials to explore the possible benefits of statins in COVID-19.     

Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study

ObjectivesTo describe the burden, epidemiology and outcomes of co-infections and superinfections occurring in hospitalized patients with coronavirus disease 2019 (COVID-19).MethodsWe performed an observational cohort study of all consecutive patients admitted for ≥48 hours to the Hospital Clinic of Barcelona for COVID-19 (28 February to 22 April 2020) who were discharged or dead. We describe demographic, epidemiologic, laboratory and microbiologic results, as well as outcome data retrieved from electronic health records.ResultsOf a total of 989 consecutive patients with COVID-19, 72 (7.2%) had 88 other microbiologically confirmed infections: 74 were bacterial, seven fungal and seven viral. Community-acquired co-infection at COVID-19 diagnosis was uncommon (31/989, 3.1%) and mainly caused by Streptococcus pneumoniae and Staphylococcus aureus. A total of 51 hospital-acquired bacterial superinfections, mostly caused by Pseudomonas aeruginosa and Escherichia coli, were diagnosed in 43 patients (4.7%), with a mean (SD) time from hospital admission to superinfection diagnosis of 10.6 (6.6) days. Overall mortality was 9.8% (97/989). Patients with community-acquired co-infections and hospital-acquired superinfections had worse outcomes.ConclusionsCo-infection at COVID-19 diagnosis is uncommon. Few patients developed superinfections during hospitalization. These findings are different compared to those of other viral pandemics. As it relates to hospitalized patients with COVID-19, such findings could prove essential in defining the role of empiric antimicrobial therapy or stewardship strategies.     

Impact of prior statin use on clinical outcomes in COVID-19 patients: data from tertiary referral hospitals during COVID-19 pandemic in Italy

BackgroundEpidemiological evidence suggests that anti-inflammatory and immunomodulatory properties of statins may reduce the risk of infections and infection-related complications.ObjectiveWe aimed to assess the impact of prior statin use on coronavirus disease (COVID-19) severity and mortality.MethodsIn this observational multicenter study, consecutive patients hospitalized for COVID-19 were enrolled. In-hospital mortality and severity of COVID-19 assessed with National Early Warning Score (NEWS) were deemed primary and secondary outcomes, respectively. Propensity score (PS) matching was used to obtain balanced cohorts.ResultsAmong 842 patients enrolled, 179 (21%) were treated with statins before admission. Statin patients showed more comorbidities and more severe COVID-19 (NEWS 4 [IQR 2–6] vs 3 [IQR 2–5], p < 0.001). Despite having similar rates of intensive care unit admission, noninvasive ventilation, and mechanical ventilation, statin users appeared to show higher mortality rates. After balancing pre-existing relevant clinical conditions that could affect COVID-19 prognosis with PS matching, statin therapy confirmed its association with a more severe disease (NEWS ≥5 61% vs. 48%, p = 0.025) but not with in-hospital mortality (26% vs. 28%, p = 0.185). At univariate logistic regression analysis, statin use was confirmed not to be associated with mortality (OR 0.901; 95% CI: 0.537 to 1.51; p = 0.692) and to be associated with a more severe disease (NEWS≥5 OR 1.7; 95% CI 1.067–2.71; p = 0.026).ConclusionsOur results did not confirm the supposed favorable effects of statin therapy on COVID-19 outcomes. Conversely, they suggest that statin use should be considered as a proxy of underlying comorbidities, which indeed expose to increased risks of more severe COVID-19.     

Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice

Cerebral malaria (CM) is the most severe complication of human infection with Plasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM is Plasmodium berghei ANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome of PbANKA infection in mice previously infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodent Plasmodium parasites in experimental coinfection models. We found that concomitant M. tuberculosis infection did not change the clinical course of PbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected with PbANKA. Our data suggest that M. tuberculosis coinfection is not able to change the outcome of PbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected with M. tuberculosis.     

Evaluation of Concurrent Malaria and Dengue Infections among Febrile Patients

Context: Despite a wide overlap between endemic areas for two important vector-borne infections, malaria and dengue, published reports of co-infections are scarce till date. Aims: To find the incidence of dengue and malaria co-infection as well as to ascertain the severity of such dengue and malaria co-infection based on clinical and haematological parameters. Setting and Design: Observational, retrospective cross-sectional study was designed including patients who consulted the tertiary care hospital of Ahmedabad seeking treatment for fever compatible with malaria and/or dengue. Subjects and Methods: A total of 8364 serum samples from clinically suspected cases of fever compatible with malaria and/or dengue were collected. All samples were tested for dengue NS-1 antigen before 5 days of onset of illness and for dengue IgM after 5 days of onset of illness. In all samples, malaria diagnosis was based on the identification of Plasmodium parasites on a thin and thick blood films microscopy. Results: Only 10.27% (859) patients with fever were tested positive for dengue and 5.1% (434) were tested positive for malaria. 3.14% (27) dengue cases show concurrent infection with malarial parasites. Hepatomegaly and jaundice 37.03% (10), haemorrhagic manifestations 18.51% (5) and kidney failure 3.7% (1), haemoglobin <12 g/dl 100% (27) and thrombocytopenia (platelet count <150,000/cmm) 96.29% (26) were common in malaria and dengue co-infections and were much more common in Plasmodium falciparum infections. Conclusion: All febrile patients must be tested for malaria and dengue, both otherwise one of them will be missed in case of concurrent infections which could lead to severe diseases with complications.     

Characteristics and predictors of death among 4035 consecutively hospitalized patients with COVID-19 in Spain

ObjectivesTo analyse the characteristics and predictors of death in hospitalized patients with coronavirus disease 2019 (COVID-19) in Spain.MethodsA retrospective observational study was performed of the first consecutive patients hospitalized with COVID-19 confirmed by real-time PCR assay in 127 Spanish centres until 17 March 2020. The follow-up censoring date was 17 April 2020. We collected demographic, clinical, laboratory, treatment and complications data. The primary endpoint was all-cause mortality. Univariable and multivariable Cox regression analyses were performed to identify factors associated with death.ResultsOf the 4035 patients, male subjects accounted for 2433 (61.0%) of 3987, the median age was 70 years and 2539 (73.8%) of 3439 had one or more comorbidity. The most common symptoms were a history of fever, cough, malaise and dyspnoea. During hospitalization, 1255 (31.5%) of 3979 patients developed acute respiratory distress syndrome, 736 (18.5%) of 3988 were admitted to intensive care units and 619 (15.5%) of 3992 underwent mechanical ventilation. Virus- or host-targeted medications included lopinavir/ritonavir (2820/4005, 70.4%), hydroxychloroquine (2618/3995, 65.5%), interferon beta (1153/3950, 29.2%), corticosteroids (1109/3965, 28.0%) and tocilizumab (373/3951, 9.4%). Overall, 1131 (28%) of 4035 patients died. Mortality increased with age (85.6% occurring in older than 65 years). Seventeen factors were independently associated with an increased hazard of death, the strongest among them including advanced age, liver cirrhosis, low age-adjusted oxygen saturation, higher concentrations of C-reactive protein and lower estimated glomerular filtration rate.ConclusionsOur findings provide comprehensive information about characteristics and complications of severe COVID-19, and may help clinicians identify patients at a higher risk of death.     

Age-Dependent IgG Subclass Responses to Plasmodium falciparum EBA-175 Are Differentially Associated with Incidence of Malaria in Mozambican Children

Plasmodium falciparum blood-stage antigens such as merozoite surface protein 1 (MSP-1), apical membrane antigen 1 (AMA-1), and the 175-kDa erythrocyte binding antigen (EBA-175) are considered important targets of naturally acquired immunity to malaria. However, it is not clear whether antibodies to these antigens are effectors in protection against clinical disease or mere markers of exposure. In the context of a randomized, placebo-controlled trial of intermittent preventive treatment in infants conducted between 2002 and 2004, antibody responses to Plasmodium falciparum blood-stage antigens in a cohort of 302 Mozambican children were evaluated by immunofluorescence antibody test and enzyme-linked immunosorbent assay at 5, 9, 12, and 24 months of age. We found that IgG subclass responses to EBA-175 were differentially associated with the incidence of malaria in the follow-up period. A double amount of cytophilic IgG1 or IgG3 was associated with a significant decrease in the incidence of malaria (incidence rate ratio [IRR] = 0.49, 95% confidence interval [CI] = 0.25 to 0.97, and P = 0.026 and IRR = 0.44, CI = 0.19 to 0.98, and P = 0.037, respectively), while a double amount of noncytophilic IgG4 was significantly correlated with an increased incidence of malaria (IRR = 3.07, CI = 1.08 to 8.78, P = 0.020). No significant associations between antibodies to the 19-kDa fragment of MSP-1 (MSP-1₁₉) or AMA-1 and incidence of malaria were found. Age, previous episodes of malaria, present infection, and neighborhood of residence were the main factors influencing levels of antibodies to all merozoite antigens. Deeper understanding of the acquisition of antibodies against vaccine target antigens in early infancy is crucial for the rational development and deployment of malaria control tools in this vulnerable population.