Management of Dengue: An Updated Review.

Dengue is an important public health problem with a wide clinical spectrum. The World Health Organization classifies dengue into probable dengue, dengue with warning signs, and severe dengue. Severe dengue, characterized by plasma leakage, severe bleeding, or organ impairment, entails significant morbidity and mortality if not treated timely. There are no definitive curative medications for dengue; management is supportive. Judicious fluid resuscitation during the critical phase of dengue is the cornerstone of management. Crystalloids are the initial fluid of choice. Prophylactic platelet transfusion is not recommended. Organ involvement in severe dengue should be carefully looked for and managed. Secondary hemophagocytic lymphohistiocytosis is a potentially fatal complication of dengue that needs to be recognized, as specific management with steroids or intravenous immunoglobulin may improve outcomes. Several compounds with anti-dengue potential are being studied; no anti-dengue drug is available so far.

COVID-19 Antibodies as Predictor of Severe Dengue among Hospitalized Children with Dengue Illness in the Post-third-wave Period of COVID-19 Infection in India.

BACKGROUND: There were widespread unconfirmed reports about the increased severity of dengue post-second wave of the COVID-19 pandemic in India. It is known that a second dengue infection with a different strain in an individual can trigger antibody-dependent enhancement (ADE). A similar phenomenon is hypothesized for severe COVID-19 infection since both dengue and COVID-19 are viral diseases with different and varying strains. However, much research is needed to confirm this hypothesis. In this context, we intended to assess the severity of dengue illness in relation to previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, possibly the role of COVID-19 antibodies as an early predictor of severe dengue illness. OBJECTIVE: To assess the utility of COVID-19 antibodies for early identification of severe dengue illness among children in the post-third-wave period of COVID-19 infection in India. MATERIALS AND METHODS: All hospitalized children with dengue illness were categorized as severe (shock and/or hemorrhage and/or multi-organ dysfunction) and non-severe dengue illness (dengue with or without warning signs) as per WHO definition. COVID-19 antibody titers were estimated in both groups. Clinical features and seroprevalence of COVID-19 antibodies were compared in both groups. RESULT: A total of 31 children were studied (13 severe and 18 non-severe dengue illnesses). The most common symptoms prior to presenting to the hospital included fever (100% in both groups), vomiting (85% in severe and 63% in non-severe), abdominal pain (85% in severe and 50% in non-severe), poor feeding (54% in severe and 28% in non-severe), and skin rashes (15% in severe and none in non-severe). The mean duration from the onset of fever to the first hospital visit was 4.6 days in severe illness and 5.3 days in non-severe dengue illness. The mean duration of hospitalization was 9.7 days in severe dengue illness and 4.1 days in non-severe dengue illness. While 92.3% of all severe dengue had significantly higher COVID-19 antibody titers, it was found elevated only in 44.4% of the children with non-severe dengue illness (p-value 0.0059; Yates' corrected p-value 0.0179). CONCLUSION: Clinical symptoms prior to presenting to the hospital were fever, vomiting, abdominal pain, poor oral feeding, and skin rashes. While fever, vomiting, and abdominal pain were seen commonly in both severe and non-severe dengue illnesses, the presence of skin rash during febrile phase is associated with severe dengue illness only. Hospitalized children having severe dengue had increased seroprevalence of COVID-19 antibodies (92.3%) compared to children with non-severe dengue (44.4%). However, there is no corelation of the severity of dengue illness with absolute values of COVID-19 antibody levels. Therefore, the presence of COVID-19 antibodies (previous COVID-19 infection) can be a predictor of severe illness in children with dengue especially if associated with poor oral feeding and skin rashes. The limitation of the study is its lesser sample size to conclude any definitive statement; nevertheless, the study paves way for a similar cohort of a larger sample size to draw conclusions.

Efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever in patients with acute dengue: A randomised, double blind, placebo-controlled trial.

BACKGROUND: Rupatadine was previously shown to reduce endothelial dysfunction in vitro, reduced vascular leak in dengue mouse models and to reduce the extent of pleural effusions and thrombocytopenia in patients with acute dengue. Therefore, we sought to determine the efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever (DHF) in patients with acute dengue. METHODS AND FINDINGS: A phase 2, randomised, double blind, placebo controlled clinical trial was carried out in patients with acute dengue in Sri Lanka in an outpatient setting. Patients with ≤3 days since the onset of illness were either recruited to the treatment arm of oral rupatadine 40mg for 5 days (n = 123) or the placebo arm (n = 126). Clinical and laboratory features were measured daily to assess development of DHF and other complications. 12 (9.7%) patients developed DHF in the treatment arm compared to 22 (17.5%) who were on the placebo although this was not significant (p = 0.09, relative risk 0.68, 95% CI 0.41 to 1.08). Rupatadine also significantly reduced (p = 0.01) the proportion of patients with platelet counts <50,000 cells/mm3 and significantly reduced (p = 0.04) persisting vomiting, headache and hepatic tenderness (p<0.0001) in patients. There was a significant difference in the duration of illness (p = 0.0002) although the proportion of individuals who required hospital admission in both treatment arms. Only 2 patients on rupatadine and 3 patients on the placebo developed shock, while bleeding manifestations were seen in 6 patients on rupatadine and 7 patients on the placebo. CONCLUSIONS: Rupatadine appeared to be safe and well tolerated and showed a trend towards a reducing proportion of patients with acute dengue who developed DHF. Its usefulness when used in combination with other treatment modalities should be explored. TRIAL REGISTRATION: International Clinical Trials Registration Platform: SLCTR/2017/024.

COVID-19 Vaccine Hesitancy and Confidence in the Philippines and Malaysia: A Cross-sectional Study of Sociodemographic Factors and Information-Seeking (preprint)

With the emergence of the highly transmissible Omicron variant, large-scale vaccination coverage is crucial to the national and global pandemic response, especially in populous Southeast Asian countries such as the Philippines and Malaysia. Little is known, however, about predictors of COVID-19 vaccine hesitancy and vaccine confidence among unvaccinated individuals in these regions. An internet-based cross-sectional survey was conducted from May 2021 to September 2021. Data from a total of 2558 participants from the Philippines (N = 1002) and Malaysia (N = 1556) were analysed. Results showed that Filipino (vs. Malaysian) participants indicated higher prevalence of COVID-19 vaccine hesitancy (56.6 vs. 22.9%, p = 0.001). However, there were no significant differences in ratings of vaccine confidence between Filipino (45.9%) and Malaysian (49.2%) participants (p = 0.105). Predictors associated with greater vaccine hesitancy included females (p = 0.029) and rural dwellers (p = 0.015) among Filipino participants, whereas females (p = 0.004), 25-34 year olds (p = 0.027), Christians (p < 0.001), and social media use (p < 0.001) were associated with hesitancy among Malaysian participants. Predictors associated with lower confidence included females (p = 0.026) and information seeking (p < 0.001) among Filipino participants, whereas predictors associated with lower confidence among Malaysian participants included residing in a rural community (p = 0.004), Christians (p < 0.001), online information seeking (p < 0.001), and determining relevance of online information (p = 0.013). Efforts to improve uptake of COVID-19 vaccination must be centred upon targeting specific communities using local authorities and for the masses through social media. Efforts should focus on determining effective interventions to decrease vaccination hesitancy and increase the uptake of COVID-19 vaccination, particularly in light of the Dengvaxia crisis in the Philippines.

Prognostic indicators associated with progresses of severe dengue.

BACKGROUND: Dengue usually progress abnormally, especially in the critical phase. The main causes of death were shock, severe bleeding and organ failure. The aim of our study was to evaluate prognostic indicators of severe dengue according to the phases of the disease progression. METHODS: A cross-sectional study was conducted from July to December 2017 at the National Hospital for Tropical Diseases and the Hospital for Tropical Diseases of Ho Chi Minh City. 326 patients, aged 6 years and over, including 99/326 patients with severe dengue and 227/326 patients with non-severe dengue, hospitalized in the first 3 days of illness, confirmed Dengue virus by the RT-PCR assay have been registered for the study. Clinical manifestations were monitored daily. The hematocrit, white blood cells, platelet, serum albumin, ALT, AST, bilirubin, prothrombin time (PT%, PTs), fibrinogen, aPTT, INR and creatinine were evaluated at two times: febrile phase and critical phase. RESULTS: Independent factors associated with severe dengue were identified on multivariate logistic regression models. During the first 3 days of the disease, the prognostic indicators were platelet count ≤ 100 G/L (OR = 2.2; 95%CI: 1.2-3.9), or serum albumin < 35 g/L (OR = 3.3; 95%CI: 1.8-6.1). From day 4-6, the indicator were AST > 400 U/L (OR = 3.0; 95%CI: 1.1-7.9), ALT > 400 U/L (OR = 6.6; 95%CI: 1.7-24.6), albumin < 35 g/L (OR = 3.0; 95%CI: 1.5-5.9), and bilirubin total >17 µmol/L (OR = 4.6; 95%CI: 2.0-10.4). CONCLUSION: To predict the risk of patients with severe dengue, prognostic laboratory indicators should be indicated consistent with the progression of the disease. During the first 3 days of illness, prognostic indicators should be platelet count, or serum albumin. From the 4th - 6th day of illness, prognostic indicators should be AST, ALT, albumin, or bilirubin total.

Dengue infection: Global importance, immunopathology and management.

Dengue is an arboviral infection that is hyperendemic in tropical and subtropical climates. Clinical manifestations of dengue can range from asymptomatic infection to severe infection with multi-organ failure. Dengue haemorrhagic fever (DHF) is a subcategory in dengue infection with a hallmark of plasma leak (ie critical phase). The plasma leak in DHF is selective (pleuroperitoneal spaces), transient and dynamic, and needs careful monitoring and meticulous fluid resuscitation. In addition, dengue fever may present with extended and unusual manifestations affecting any organ, including the heart, liver, kidney and brain. Studies on vaccine development and vector control are ongoing to prevent this infection of global importance. In this article, the clinicopathological features and management aspects of dengue are discussed.

Omicron variant of SARS-COV-2 gains new mutations in New Zealand and Hong Kong (preprint)

SARS-COV-2 evolution is a key factor that drives the pandemic. As the previous four variants of concern, omicron variant arose from complete obscurity and have rapidly become the prominent pandemic driver around the world. After initial identification in November 2021, this variant has yielded three different subvariants, BA.1, BA.2 and BA.3. Among them, BA.1 is dominant around the world although BA.2 is gradually taking over this role. BA.1 has acquired spike R346K and yielded a sub-lineage known as BA.1.1. An important question is how these variants continue their evolution. To address this question, I analyzed new SARS-COV-2 genomes identified in Oceania and Asia, where there are many ongoing pandemic hotspots. This analysis revealed that together with BA.2, two different BA.1.1 strains are dominant in New Zealand. Each of them carries two new substitutions, with L133F of NSP10 as the common one. This residue is located at an unstructured C-terminal tail, so the impact of L133F is not obvious. The other new substitutions are T1368I of NSP3 and R289H of NSP14. While T1368I of NSP3 is located close to its first transmembrane domain, R289H of NSP14 is right at a key motif of the binding pocket for S-adenosyl methionine, a cofactor required for the guanine-N7 methyltransferase activity. Analysis of SARS-COV-2 genomes from New Zealand also identified a delta subvariant with over ten new mutations (including spike N481K and R765H), but the subvariant is still negligible in driving the pandemic. Analysis of SARS-COV-2 genomes from Hong Kong uncovered a predominant BA.2 subvariant with three new substitutions: I1221T of spike protein (located at the transmembrane domain), T725I of NSP3 (within the C-terminal third of a SARS-unique domain) and T145I of NSP8 (at a surface area away from the site for interaction with NSP7 and NSP12). By contrast, no dominant mutations are obvious in omicron genomes from Australia, Indonesia, Singapore, Malaysia, Thailand, Japan and South Korea, suggesting that emergence of the dominant omicron subvariants in New Zealand and Hong Kong is of random nature. These findings partly explain the current situation in these two pandemic hotspots and reiterate the importance to continue tracking SARS-COV-2 evolution.

Challenges of dengue and coronavirus disease 2019 coinfection: two case reports.

BACKGROUND: Dengue fever and coronavirus disease 2019 have now begun to overlap within tropical and subtropical regions. This is due to the high prevalence of dengue fever in these regions and the current severe acute respiratory syndrome coronavirus 2 pandemic situation. The similarity of symptoms between the two diseases can confuse diagnoses, but coinfection can also occur. CASE PRESENTATION: We present two cases of patients with dengue and severe acute respiratory syndrome coronavirus 2 coinfection. The first case is that of a 24-year-old Hispanic woman with acute fever, odynophagia, and diarrhea, without respiratory symptoms and with positive molecular tests for both dengue and severe acute respiratory syndrome coronavirus 2. The second case is that of a 59-year-old Hispanic male patient with fever and respiratory symptoms of 2 weeks duration, negative molecular tests, and positive serological tests for both viruses. The clinical and epidemiological characteristics of both viral infections can help elucidate diagnoses and prognoses. CONCLUSIONS: Severe dengue infection is common in young adults, while coronavirus disease 2019 is generally asymptomatic. In older people, the severity of dengue fever will depend on their comorbidities or the infectious serotype, but coronavirus disease 2019 is consistently more severe in this group. The accurate diagnosis of both infections can better guide clinical management, as well as public health actions in transmission control, now especially important during the coronavirus disease 2019 pandemic.

Influence of the COVID-19 Pandemic and Bystander-victim Relationship on the Willingness of Thai Healthcare Providers and Laypersons to Perform Cardiopulmonary Resuscitation: a Cross-sectional Online Survey (preprint)

Background: Out-of-hospital cardiac arrest (OHCA) is a significant health problem in many Asian countries. Bystander cardiopulmonary resuscitation (CPR) can reduce mortality from OHCA. The willingness of bystanders to initiate aid is also critical. During the COVID-19 pandemic, CPR eases to spread of COVID-19 with negatively affect the decision. The objectives were to study the influence of the COVID-19 pandemic and bystander-victim relationship on the willingness of Thai healthcare providers (HCPs) and laypersons to perform CPR and associated factors. Methods: : The cross-sectional online survey was conducted between August to November 2020 in a Thai population. A structured questionnaire was developed and given to volunteers as an online survey. We recorded participant characteristics and willingness to perform compression-only CPR (W-COC) and conventional CPR (W-CC) on family members, acquaintances, and strangers during the pandemic and in a non-pandemic situation and analyzed associated factors. Results: : We included 419 laypersons and 716 HCPs. Lay-participants expressed less W-COC on acquaintances and strangers (risk ratio [RR] 0.74-0.85), but not on family members. By contrast, the HCPs were less W-COC across the board (RR 0.84-0.92). Both groups were less W-CC on all recipients (RR 0.43-0.54). There was no difference in participants’ W-COC and W-CC on family members and acquaintances, except that HCPs expressed greater W-CC on family members. Participants in all groups were less W-COC and W-CC on strangers. W-COC was correlated with CPR knowledge (Odds ratio [OR] 2.32), self-efficacy (OR 1.96), single marital status (OR 1.91), and being an HCP (OR 2.00). W-CC on family members was related to CPR knowledge (OR 2.16). Conclusion: Participants were less willing during the COVID-19 pandemic on all groups except family members of lay participants. The victim’s relationship to the participant was more important in conventional CPR than compression-only CPR, especially in HCPs. CPR knowledge, self-efficacy, single marital status, and being an HCP related to higher willingness. Trial registration: TCTR20210330003 (Thai Clinical Trials Registry)

Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.

Potential severe pediatric SARS-CoV-2-induced multisystem inflammatory syndrome resembles dengue infection.

We describe a child with acute fever and abdominal pain who developed rash and edema of extremities. Blood test revealed thrombocytopenia, lymphopenia, positive dengue-IgM, and hypoalbuminemia with elevated procalcitonin. Right pleural effusion revealed from chest x-ray. Diagnosed as dengue hemorrhagic fever (DHF) grade 1, however, at 7th day of illness, altered mental status, respiratory and circulatory failure occurred. Laboratory examination showed marked thrombocytopenia, transaminitis, metabolic acidosis, elevated D-dimer, decrease fibrinogen, and elevated cardiac marker (troponin I and CKMB). The patient then developed catecholamine-resistant shock and did not survive after 48 hours. Although rapid test of SARS CoV-2 infection was negative, rapid deterioration with some unusual clinical feature suggest multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 infection. This case raises an awareness of MIS-C that clinical features resemble dengue infection.

Case Report: Severe COVID-19 and Dengue in an Indonesian Infant.

We report a case of a 10-month infant with dual severe infection of COVID-19 and dengue fever who was admitted to the hospital with an influenza-like illness. The patient experienced severe conditions of COVID-19 and dengue fever with shock followed by disseminated intravascular coagulation. The standard of COVID-19 care was given coupled with fluid resuscitation and blood transfusion. The pitfalls of this case are how to differentiate the clinical manifestation of dengue fever in a patient with confirmed COVID-19; the difficulty to monitor the dengue course of illness of the patient in the COVID-19 isolation room; and to differentiate the severe dengue from the multisystem inflammatory syndrome-C when the patient was in critical condition. The infant recovered without sequale, but the management of new probable cases must be improved more thoroughly, especially during dengue peak period in tropical and developing countries such as Indonesia.

Effects of chloroquine or hydroxychloroquine treatment on non-SARS-CoV2 viral infections: A systematic review of clinical studies.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.

Analyzing and Forecasting Thai Macroeconomic Data Using Mixed-Frequency Approach (preprint)

Macroeconomic data are an important piece of information in decision making for both the public and private sectors in Thailand. However, the release of key macroeconomic data, usually in a lower frequency such as quarterly, is not always in a timely manner. Using the higher frequency data such as monthly and daily to analyze or forecast the lower frequency data can mitigate the release timing effect. This study applies the mixed-frequency data approach to analyze and forecast Thai key macroeconomic data. The mixed data sampling regressions with various specifications are employed and implemented through some macroeconomic data such as gross domestic product and inflation. The results show that in most cases the mixed-frequency models outperform the autoregressive integrated moving average model, which we used as the benchmark model, evenduring the COVID-19 period. Some policy implications can also be drawn from the analysis.

COVID-19 with dengue shock syndrome in a child: coinfection or cross-reactivity?

COVID-19, caused by SARS-CoV-2, has spread globally. Coinfection with other endemic viruses is likely to complicate the clinical presentation and outcome. Information on clinical manifestations and management strategies on COVID-19 coinfection with endemic diseases in children is yet to evolve. The risk of dengue infection exists in 129 countries and it is endemic in more than 100 countries. The SARS-CoV-2 pandemic might overlap with the dengue epidemics in tropical countries. We report the first paediatric case to the best of our knowledge of COVID-19 encephalitis with dengue shock syndrome. This clinical syndrome could be attributed to serological cross-reactivity, incidental coinfection or perhaps a warning for dengue-endemic regions to face the unique challenge of differentiating and managing two disease entities together. Enhanced understanding of potential COVID-19 and dengue coinfection warrants immediate attention of researchers and international health policy makers.

A Review of Piezoelectric and Magnetostrictive Biosensor Materials for Detection of COVID-19 and Other Viruses.

The spread of the severe acute respiratory syndrome coronavirus has changed the lives of people around the world with a huge impact on economies and societies. The development of wearable sensors that can continuously monitor the environment for viruses may become an important research area. Here, the state of the art of research on biosensor materials for virus detection is reviewed. A general description of the principles for virus detection is included, along with a critique of the experimental work dedicated to various virus sensors, and a summary of their detection limitations. The piezoelectric sensors used for the detection of human papilloma, vaccinia, dengue, Ebola, influenza A, human immunodeficiency, and hepatitis B viruses are examined in the first section; then the second part deals with magnetostrictive sensors for the detection of bacterial spores, proteins, and classical swine fever. In addition, progress related to early detection of COVID-19 (coronavirus disease 2019) is discussed in the final section, where remaining challenges in the field are also identified. It is believed that this review will guide material researchers in their future work of developing smart biosensors, which can further improve detection sensitivity in monitoring currently known and future virus threats.

Immunological Mechanisms Explaining the Role of Vaccines, IgE, Mast Cells, Histamine, Elevating Ferritin, IL-6, D-dimer, VEGF Levels in COVID-19 and Dengue, Potential Treatments Such as Mast Cell Stabilizers, Antihistamines: Predictions and Confirmations (preprint)

A novel coronavirus, SARS-CoV-2 was identified in Wuhan, China. The disease caused by the virus can range in severity from asymptomatic to acute respiratory distress syndrome (ARDS) and death.Primary dengue infection results in IgE mediated sensitization against dengue virus proteins. These IgE bind to receptors on mast cells. Upon subsequent exposure to the antigen recognized by the IgE, mast cell degranulation occurs releasing mediators such as histamine. Therefore secondary dengue infection results in urticaria, increased vascular permeability, hypotension, dengue hemorrhagic fever and dengue shock syndrome. A case of “slow rolling anaphylaxis”.Vaccines contain proteins derived from coronavirus infected animals as well as other proteins with high homology to SARS-CoV-2. So one could develop IgE mediated sensitization to SARS-CoV-2-like proteins. Therefore, receipt of such vaccines acts like a dengue “primary infection”. It results in IgE mediated sensitization. Subsequent SARS-CoV-2 infection becomes a “secondary dengue infection” that has a severe course due to IgE mediated mast cell degranulation and the immune cascade that follows.There are many common observations between COVID-19 and dengue. Elevated levels of ferritin, interleukin-6, vascular endothelial growth factor, D-dimer, coagulopathy, urticaria and ARDS are reported in both diseases. Numerous teams have now confirmed this mechanism that was predicted in Jan 2020, upon analyzing the 2019-nCoV proteome.There are many indicators that mast cell degranulation and histamine release have a major role in COVID-19, dengue and influenza severity. Mast cell stabilizers, antihistamines and anti-parasite treatments may address different aspects of this cascade and thus reduce disease severity.

After the honeymoon, the divorce: Unexpected outcomes of disease control measures against endemic infections.

The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control-the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.

ADE and hyperinflammation in SARS-CoV2 infection- comparison with dengue hemorrhagic fever and feline infectious peritonitis.

The COVID-19 pandemic has rapidly spread around the world with significant morbidity and mortality in a subset of patients including the elderly. The poorer outcomes are associated with 'cytokine storm-like' immune responses, otherwise referred to as 'hyperinflammation'. While most of the infected individuals show minimal or no symptoms and recover spontaneously, a small proportion of the patients exhibit severe symptoms characterized by extreme dyspnea and low tissue oxygen levels, with extensive damage to the lungs referred to as acute respiratory distress symptom (ARDS). The consensus is that the hyperinflammatory response of the host is akin to the cytokine storm observed during sepsis and is the major cause of death. Uncertainties remain on the factors that lead to hyperinflammatory response in some but not all individuals. Hyperinflammation is a common feature in different viral infections such as dengue where existing low-titer antibodies to the virus enhances the infection in immune cells through a process called antibody-dependent enhancement or ADE. ADE has been reported following vaccination or secondary infections with other corona, Ebola and dengue virus. Detailed analysis has shown that antibodies to any viral epitope can induce ADE when present in sub-optimal titers or is of low affinity. In this review we will discuss ADE in the context of dengue and coronavirus infections including Covid-19.