Surveillance for Dengue Virus and Other Pathogens in Patients with Acute Undifferentiated Febrile Illnesses in Yucatan, Mexico, During the Final Phase of the Coronavirus Disease 2019 Pandemic.

Etiological diagnosis of febrile illnesses in returning travelers is a great challenge, particularly when presenting with no focal symptoms [acute undifferentiated febrile illnesses (AUFI)], but is crucial to guide clinical decisions and public health policies. In this study, we describe the frequencies and predictors of the main causes of fever in travelers. Prospective European multicenter cohort study of febrile international travelers (November 2017-November 2019). A predefined diagnostic algorithm was used ensuring a systematic evaluation of all participants. After ruling out malaria, PCRs and serologies for dengue, chikungunya and Zika viruses were performed in all patients presenting with AUFI ≤ 14days after return. Clinical suspicion guided further microbiological investigations. Among 765 enrolled participants, 310/765 (40.5%) had a clear source of infection (mainly traveler's diarrhea or respiratory infections), and 455/765 (59.5%) were categorized as AUFI. AUFI presented longer duration of fever (p < 0.001), higher hospitalization (p < 0.001) and ICU admission rates (p < 0.001). Among travelers with AUFI, 132/455 (29.0%) had viral infections, including 108 arboviruses, 96/455 (21.1%) malaria and 82/455 (18.0%) bacterial infections. The majority of arboviral cases (80/108, 74.1%) was diagnosed between May and November. Dengue was the most frequent arbovirosis (92/108, 85.2%). After 1month of follow-up, 136/455 (29.9%) patients with AUFI remained undiagnosed using standard diagnostic methods. No relevant differences in laboratory presentation were observed between undiagnosed and bacterial AUFI. Over 40% of returning travelers with AUFI were diagnosed with malaria or dengue, infections that can be easily diagnosed by rapid diagnostic tests. Arboviruses were the most common cause of AUFI (above malaria) and most cases were diagnosed during Aedes spp. high season. This is particularly relevant for those areas at risk of introduction of these pathogens. Empirical antibiotic regimens including doxycycline or azithromycin should be considered in patients with AUFI, after ruling out malaria and arboviruses.

BackgroundSeroprevalence studies provide information on the true extent of infection and capture demographic and geographic differences, indicating the level of immunity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We sought to provide local evidence of SARS-CoV-2 exposure in school-aged children during in-class teaching in Maputo City and Province, Mozambique.MethodsBetween August and November 2022, we performed a cross-sectional study in school-aged children in four schools in rural, peri-urban, and urban areas of Maputo City and Province. A point-of-care test was used to evaluate SARS-CoV-2 antigens and anti-SARS-CoV-2-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies. Descriptive statistics were used to estimate the prevalence of the antigens and antibodies. Multiple logistic regression models were used to estimate the adjusted odds ratio (AOR) for the factors associated with anti-SARS-CoV-2 antibodies.ResultsA total of 736 school-aged children were analyzed. The prevalence of the SARS-CoV-2 antigen was 0.5% (4/736). The prevalence of SARS-CoV-2 antigens was 0.0% (0/245), 0.8% (2/240) and 0.8% (2/251), in the rural, peri-urban and urban areas respectively. The overall seroprevalence of the anti-SARS-CoV-2 antibodies (IgG or IgM) was 80.7% (594/736). In rural area anti-SARS-CoV-2 IgG or IgM antibodies were detected in 76.7% (188/245), while in peri-urban area they were detected in 80.0% (192/240) and in urban area they were detected in 85.3% (214/251). In the adjusted logistic regression model, school-aged children from the urban area were more likely to have anti-SARS-CoV-2 IgG or IgM antibodies than were school-aged children from the rural area (adjusted odds ratio: 1.679; 95% CI: 1.060–2.684; p-value = 0.028).ConclusionsDuring the in-class teaching period, active SARS-CoV-2 cases in school-aged children were observed. More than half of the school-aged children were exposed to SARS-CoV-2, and SARS-CoV-2 was significantly more common in the schools at the urban area than in the school in the rural area at Maputo City and Province.

Up to 45% of febrile returning travellers remain undiagnosed after a thorough diagnostic work-up, even at referral centres. Although metagenomic next-generation sequencing (mNGS) has emerged as a promising tool, evidence of its usefulness in imported fever is very limited. Travellers returning with fever were prospectively recruited in three referral clinics from November 2017 to November 2019. Unbiased mNGS optimised for virus detection was performed on serum samples of participants with acute undifferentiated febrile illness (AUFI), and results were compared to those obtained by reference diagnostic methods (RDM). Among 507 returned febrile travellers, 433(85.4%) presented with AUFI. Dengue virus (n = 86) and Plasmodium spp. (n = 83) were the most common causes of fever. 103/433(23.8%) AUFI remained undiagnosed at the end of the follow-up.Metagenomic next-generation sequencing unveiled potentially pathogenic microorganisms in 196/433(38.7%) AUFI. mNGS identifications were more common in patients with a shorter duration of fever (42.3% in ≤5days vs 28.7% in >5days, P = 0.005). Potential causes of fever were revealed in 25/103(24.2%) undiagnosed AUFI and 5/23(21.7%) travellers with severe undiagnosed AUFI. Missed severe aetiologies included eight bacterial identifications and one co-infection of B19 parvovirus and Aspergillus spp.Additional identifications indicating possible co-infections occurred in 29/316(9.2%) travellers with AUFI, and in 11/128(8.6%) travellers with severe AUFI, who had received a diagnosis through RDM. The most common co-infections detected in severe AUFI were caused by Gram-negative bacteria. Serum mNGS was unable to detect >50% of infectious diagnoses achieved by RDM and also yielded 607 non-pathogenic identifications. mNGS of serum can be a valuable diagnostic tool for selected travellers with undiagnosed AUFI or severe disease in addition to reference diagnostic techniques, especially during the first days of symptoms. Nevertheless, mNGS results interpretation presents a great challenge. Further studies evaluating the performance of mNGS using different sample types and protocols tailored to non-viral agents are needed.

SARS-CoV-2 transmission dynamics in the urban-rural interface

Serological identification of past and recent SARS-CoV-2 infection through antibody screening in Luanda, Angola.

Even though extreme containment and mitigation strategies were implemented by numerous governments around the world to slow down the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the number of critically ill patients and fatalities keeps rising. This crisis has highlighted the socioeconomic disparities of health care systems within and among countries. As new CoVID policies and responses are implemented to lessen the impact of the virus, it is imperative (1) to consider additional mitigation strategies critical for the development of effective countermeasures, (2) to promote long-term policies and strict regulations of the trade of wildlife and live animal markets, and (3) to advocate for necessary funding and investments in global health, specifically for the prevention of and response to natural and manmade pandemics. This document considers some of these challenges.

Few studies have examined the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rural areas and clarified rural–urban differences. Moreover, the effectiveness of non-pharmaceutical interventions (NPIs) relative to vaccination in rural areas is uncertain. We addressed this knowledge gap through using an improved statistical stochastic method based on the Galton–Watson branching process, considering both symptomatic and asymptomatic cases. Data included 1136 SARS-2-CoV infections of the rural outbreak in Hebei, China, and 135 infections of the urban outbreak in Tianjin, China. We reconstructed SARS-CoV-2 transmission chains and analyzed the effectiveness of vaccination and NPIs by simulation studies. The transmission of SARS-CoV-2 showed strong heterogeneity in urban and rural areas, with the dispersion parameters k = 0.14 and 0.35, respectively (k < 1 indicating strong heterogeneity). Although age group and contact-type distributions significantly differed between urban and rural areas, the average reproductive number (R) and k did not. Further, simulation results based on pre-control parameters (R = 0.81, k = 0.27) showed that in the vaccination scenario (80% efficacy and 55% coverage), the cumulative secondary infections will be reduced by more than half; however, NPIs are more effective than vaccinating 65% of the population. These findings could inform government policies regarding vaccination and NPIs in rural and urban areas.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third virus that caused coronavirus-related outbreaks over the past 20 years. The outbreak was first reported in December 2019 in Wuhan, China, but rapidly progressed into a pandemic of an unprecedented scale since the 1918 flu pandemic. Besides respiratory complications in patients with COVID-19, clinical characterization of severe infection cases showed several other comorbidities, including multiple organ failure, and septic shock. To better understand the systemic pathogenesis of COVID-19, we interrogated the virus's presence in the peripheral blood cells, which might provide a form of trafficking or hiding to the virus. By analyzing >2 billion sequence reads of high-throughput transcriptome sequence data from 180 samples of patients with active SARS-CoV-2 infection or healthy controls collected from 6 studies, we found evidence of traces of SARS-CoV-2 RNA in peripheral blood mononuclear cells in two samples from two independent studies. In contrast, the viral RNA was abundant in bronchoalveolar lavage specimens from the same patients. We also devised a “viral spike-to-actin” RNA normalization as a metric to compare across various samples and minimize errors caused by intersample variability in total human RNA abundance. Our observation suggests immune presentation and discounts the possibility of extensive viral infection of lymphocytes or monocytes.

Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: Two Different Illnesses with Overlapping Clinical Features

Opsonizing antibodies mediated SARS‐CoV‐2 entry into monocytes leads to inflammation

Pathogenesis of severe acute respiratory syndrome

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019. Several studies reported that SARS-CoV-2 infections may produce false-positive reactions in dengue virus (DENV) serology tests and vice versa. However, it remains unclear whether SARS-CoV-2 and DENV cross-reactive antibodies provide cross-protection against each disease or promote disease severity. In this study, we confirmed that antibodies against the SARS-CoV-2 spike protein and its receptor-binding domain (S1-RBD) were significantly increased in dengue patients compared to normal controls. In addition, anti-S1-RBD IgG purified from S1-RBD hyperimmune rabbit sera could cross-react with both DENV envelope protein (E) and nonstructural protein 1 (NS1). The potential epitopes of DENV E and NS1 recognized by these antibodies were identified by a phage-displayed random peptide library. In addition, DENV infection and DENV NS1-induced endothelial hyperpermeability in vitro were inhibited in the presence of anti-S1-RBD IgG. Passive transfer anti-S1-RBD IgG into mice also reduced prolonged bleeding time and decreased NS1 seral level in DENV-infected mice. Lastly, COVID-19 patients’ sera showed neutralizing ability against dengue infection in vitro. Thus, our results suggest that the antigenic cross-reactivity between the SARS-CoV-2 S1-RBD and DENV can induce the production of anti-SARS-CoV-2 S1-RBD antibodies that cross-react with DENV which may hinder dengue pathogenesis.

Purpose Acute undifferentiated febrile illness (AUFI) and acute encephalitis syndrome (AES) continue to be major public health concerns, particularly in rural areas with limited healthcare facility. We investigated the aetiological agents responsible for seasonal sporadic AUFI and AES cases in Northern India. Method The study included 4200 patient samples (April 2022 to March 2024), fulfilling the AUFI or AES case definition. Clinical samples were tested for IgM antibodies against dengue, chikungunya, Japanese encephalitis, scrub typhus, and leptospirosis. Further, Leptospira IgM ELISA positives (n = 79) were also tested by microscopic agglutination test (MAT) assay. Results In AUFI cases, scrub typhus was the predominant bacterial aetiology (24.6%, 593/2407) followed by leptospirosis (12.4%, 266/2151). Dengue (23.0%, 321/1398) was the leading cause among viral aetiologies. Similarly, among AES cases, scrub typhus (36% in cerebrospinal fluid and 34.3% in serum) remained the most common bacterial aetiology followed by leptospirosis (5.42%, 11/203). Whereas, chikungunya was the predominant viral cause (5.4%, 17/314) behind AES cases. Further, using MAT assay, 7.6% (6/79) of the AUFI samples tested positive for leptospirosis. The prevalent serogroups identified included L. interrogans serovars Australis, Pomona, Hebdomadis, Pyrogenes and Djasiman, and L. borgpetersnii serovar Tarassovi. Housewives constituted the primary risk group for leptospirosis infection, followed by individuals engaged in various farming practices. Conclusion This study identifies scrub typhus as the predominant and leptospirosis as the second most common infection in sporadic cases of AUFI and AES. Therefore, continuous monitoring of changing aetiologies is crucial for the effective implementation of targeted control and preventive measures for neglected tropical diseases.

Author response: Phylodynamics of SARS-CoV-2 in France, Europe, and the world in 2020

Editor's evaluation: Phylodynamics of SARS-CoV-2 in France, Europe, and the world in 2020