The Effect of FOXP3+Regulatory T Cells on Infectious and Inflammatory Diseases

CD4+CD25+FOXP3+regulatory T cells (Tregs) contribute to the maintenance of immune homeostasis and tolerance in the body. The expression levels and functional stability of FOXP3 control the function and plasticity of Tregs. Tregs critically impact infectious diseases, especially by regulating the threshold of immune responses to pathogenic microorganisms. The functional regulatory mechanism and cell-specific surface markers of Tregs in different tissues and inflammatory microenvironments have been investigated in depth, which can provide novel ideas and strategies for immunotherapies targeting infectious diseases.Copyright © 2021. All rights reserved.

Tomato Flu/Fever-An analysis of the Hand Foot and Mouth Disease outbreak reported in India

The term "Tomato Flu” or "Tomato Fever” is the colloquial term in India used to describe multiple diseases that present with a fever and rash, with characteristic red, "tomato” shaped blister that appears on different parts of the body, which begin small and increase in size as disease progresses. Some controversy exists on this ‘new viral "flu” that emerged in May 2022 over a period of 2 weeks in areas in the south of India. Currently, local healthcare workers have been encouraged to address the disease as a variant of Hand Foot and Mouth Disease to avoid unnecessary panic on the emergence of a "new outbreak”. With the circulation of other viruses, inadequate testing and poor-quality surveillance in a low resource setting, where healthcare systems are already burdened with ongoing monkeypox outbreak and COVID-19 pandemic, the use of colloquial terms may cause unnecessary panic in the current hypervigilant climate. Confirmation from Government is required to confirm whether this outbreak is due to a mixed infection or a variant of the highly infectious Hand Foot and Mouth Disease virus. © 2022, The authors.

Acute Myocarditis: Secondary to Viral Infection or Pheochromocytoma?

Background In a young healthy patient, acute cardiogenic shock with a dilated, thickened left ventricle is strongly suggestive of acute myocarditis. Case SM is a 33 year-old healthy man who presented with decompensated heart failure with severe hypervolemia. Notably, he was exposed to Hand-Foot-Mouth disease (HFMD) two weeks prior. B-type natriuretic peptide was elevated at 3,417 pg/mL (normal range < 50 pg/mL), and troponin was elevated. Echocardiogram revealed dilated, severe systolic dysfunction with thickened left ventricular walls. He progressed to cardiogenic shock and multi-organ failure. Right heart catheterization revealed significantly reduced cardiac output and index of 2.36 and 1.2, respectively. His course was complicated by left ventricular thrombus and subacute embolic stroke, acute renal failure and liver failure. He was treated with afterload reduction, inotropes, and diuresis. His shock resolved, and he improved with medical therapy for cardiomyopathy. Decision-making The clinical course is consistent with acute myocarditis leading to cardiogenic shock with multi-organ failure. A broad differential was considered, including viral etiologies, autoimmune diseases, vasculitis, and toxin-mediated myocarditis. Viral labs including COVID-19 and influenza, as well as HIV, and hepatitis B and C viruses were negative. Coxsackie B2 antibody was positive at 1:80, which is consistent with past or current infection. Rheumatology evaluation was unrevealing, and vasculitis was deemed unlikely given normal inflammatory markers. Urine drug screen was unrevealing. However, adrenergic myocarditis remained on the differential given an adrenal nodule noted on imaging. Plasma free metanephrines were significantly elevated, consistent with pheochromocytoma. Conclusion This is a case of acute myocarditis with two likely etiologies. The patient's presentation correlates temporally with exposure to HFMD, suggesting viral myocarditis. However, he had gross hypervolemia and diuresed 50 pounds, which suggests a more indolent course. We propose that he had adrenergic myocarditis and undetected cardiomyopathy which was exacerbated by a second insult, the Coxsackie virus.Copyright © 2023 American College of Cardiology Foundation

Current status of hand-foot-and-mouth disease.

Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age, characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. Over the past two decades, our understanding of HFMD has greatly improved and it has received significant attention. A variety of research studies, including epidemiological, animal, and in vitro studies, suggest that the disease may be associated with potentially fatal neurological complications. These findings reveal clinical, epidemiological, pathological, and etiological characteristics that are quite different from initial understandings of the illness. It is important to note that HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. At present, there is no specific pharmaceutical intervention for HFMD. An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. However, the simultaneous circulation of multiple pathogens and the evolution of the molecular epidemiology of infectious agents make interventions based solely on a single agent comparatively inadequate. Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. Given the substantial impact of HFMD around the world, this Review synthesizes the current knowledge of the virology, epidemiology, pathogenesis, therapy, sequelae, and vaccine development of HFMD to improve clinical practices and public health efforts.

Tomato Flu-A Review on Existing Scenario

Tomato flu is an infectious disease caused by an unexplained virus. The main symptoms of the infection are tomato-shaped blisters all over the body which enlarges to resemble the shape of a tomato, therefore being named as ‘Tomato flu’. Most commonly affects children below the age of 5 years. Tomato flu is considered a “Hand, Foot and Mouth disease”. The clinical manifestation of most cases is mild. It is a self-limiting infection;which gets resolved on its own in 7-10 days. The diagnosis is based on the clinical history and physical examination, especially in regions where there are outbreaks. This infectious disease etiological agent, its treatment regimen, and vaccination stills remain unknown and is a crucial area of research at present. COVID-19 has taught us lessons for outbreak preparedness and management of cases in emergency conditions by repurposing drugs and vaccines which is also synonymously being tried to curb the condition at present situation.

Viral exanthems Unravelling viral rashes

Common causes of viral exanthems in Australia include herpesviruses, enteroviruses, parvovirus B19, varicella, measles and rubella viruses and mosquito-borne alphaviruses. The cause can often be diagnosed clinically from the rash distribution and morphology, confirmed only when necessary with serological or PCR tests. Most viral exanthems are self-limiting, requiring supportive care alone.

[Overview of Meta-analysis of Lianhua Qingwen preparations in treatment of viral diseases].

This study aims to obtain higher-level evidence by overviewing the Meta-analysis of Lianhua Qingwen preparations in the treatment of viral diseases including influenza, coronavirus disease 2019(COVID-19), and hand, foot and mouth disease(HFMD). CNKI, Wanfang, VIP, China Clinical Trial Registry(ChiCTR), PubMed, EMbase, Web of Science, and Cochrane Library were searched for the Meta-analysis about the treatment of viral diseases with Lianhua Qingwen preparations from the database establishment to April 1, 2022. After literature screening and data extraction, AMSTAR2 and the grading of recommendations assessment, development and evaluations(GRADE) system were used to assess the methodological quality and evidence quality, respectively, and then the efficacy and safety outcomes of Lianhua Qingwen preparations in the treatment of viral diseases were summarized. Thirteen Meta-analysis were finally included, three of which were rated as low grade by AMSTAR2 and ten as very low grade. A total of 75 outcome indicators were obtained, involving influenza, COVID-19, and HFMD. According to the GRADE scoring results, the 75 outcome indicators included 5(6.7%) high-level indicators, 18(24.0%) mediate-level indicators, 25(33.3%) low-level evidence indicators, and 27(36.0%) very low-level indicators.(1)In the treatment of influenza, Lianhua Qingwen preparations exhibited better clinical efficacy than other Chinese patent medicines and Ribavirin and had similar clinical efficacy compared with Oseltamivir. Lianhua Qingwen preparations were superior to other Chinese patent medicines, Oseltamivir, and Ribavirin in alleviating clinical symptoms. They showed no significant differences from Oseltamivir or conventional anti-influenza treatment in terms of the time to and rate of negative result of viral nucleic acid test.(2)In the treatment of COVID-19, Lianhua Qingwen preparation alone or combined with conventional treatment was superior to conventional treatment in terms of total effective rate, main symptom subsidence rate and time, fever clearance rate, duration of fever, time to fever clearance, cough subsidence rate, time to cough subsidence, fatigue subsidence rate, time to fatigue subsidence, myalgia subsidence rate, expectoration subsidence rate, chest tightness subsidence rate, etc. Lianhua Qingwen preparations no difference from conventional treatment in terms of subsiding sore throat, nausea, diarrhea, loss of appetite, headache, and dyspnea. In terms of chest CT improvement rate, rate of progression to severe case, cure time, and hospitalization time, Lianhua Qingwen alone or in combination with conventional treatment was superior to conventional treatment.(3)In the treatment of HFMD, Lianhua Qingwen Granules was superior to conventional treatment in terms of total effective rate, average fever clearance time, time to herpes subsidence, and time to negative result of viral nucleic acid test.(4)In terms of safety, Lianhua Qingwen preparations led to low incidence of adverse reactions, all of which were mild and disappeared after drug withdrawal. The available evidence suggests that in the treatment of influenza, COVID-19, and HFMD, Lianhua Qingwen preparations can relieve the clinical symptoms, shorten the hospitalization time, and improve the chest CT. They have therapeutic effect and good safety in the treatment of viral diseases. However, due to the low quality of available studies, more high-quality clinical trials are needed to support the above conclusions.

Comprehensive profiling and characterization of cellular microRNAs in response to coxsackievirus A10 infection in bronchial epithelial cells.

Coxsackievirus A10 (CV-A10), the causative agent of hand, foot, and mouth disease (HFMD), caused a series of outbreaks in recent years and often leads to neurological impairment, but a clear understanding of the disease pathogenesis and host response remains elusive. Cellular microRNAs (miRNAs), a large family of non-coding RNA molecules, have been reported to be key regulators in viral pathogenesis and virus-host interactions. However, the role of host cellular miRNAs defensing against CV-A10 infection is still obscure. To address this issue, we systematically analyzed miRNA expression profiles in CV-A10-infected 16HBE cells by high-throughput sequencing methods in this study. It allowed us to successfully identify 312 and 278 miRNAs with differential expression at 12 h and 24 h post-CV-A10 infection, respectively. Among these, 4 miRNAs and their target genes were analyzed by RT-qPCR, which confirmed the sequencing data. Gene target prediction and enrichment analysis revealed that the predicted targets of these miRNAs were significantly enriched in numerous cellular processes, especially in regulation of basic physical process, host immune response and neurological impairment. And the integrated network was built to further indicate the regulatory roles of miRNAs in host-CV-A10 interactions. Consequently, our findings could provide a beneficial basis for further studies on the regulatory roles of miRNAs relevant to the host immune responses and neuropathogenesis caused by CV-A10 infection.

Trends of morbidity and mortality of hand foot and mouth disease in China, 2008-2017

Objective: To analyze the trends of morbidity and mortality of hand foot and mouth disease (HFMD) in China from 2008 to 2017, and provide scientific evidence for the development of HFMD prevention and control strategies.

Epidemiological characteristics of associated epidemics in Tongzhou district, Beijing, 2015-2020

Objective: To analyze the characteristics of the associated epidemics in Tongzhou district of Beijing from 2015 to 2020, identify the risk factors and provide scientific basis for the early warning, prevention and control of infectious disease epidemics.

Relationship between meteorological factors, air pollutants and hand, foot and mouth disease from 2014 to 2020.

BACKGROUND: Meteorological factors and air pollutants have been reported to be associated with hand, foot, and mouth disease (HFMD) epidemics before the introduction of vaccine. However, there is limited evidence for studies with long-term dimensions. METHODS: We collected the daily HFMD counts, weather and air pollution data from 2014 to 2020 in Chengdu. Distributed lag non-linear models (DLNM) were used to assess the associations of meteorological factors and air pollutants on HFMD cases. RESULTS: From 2014-2020, high relative humidity and precipitation and extremely high and low levels of PM10, O3, SO2 and CO increased the risk of HFMD. In pre-vaccination period, extreme high and low temperatures, PM10 and NO2, low precipitation and high concentrations of PM2.5 and O3 significantly increase the risk of HFMD; In post-vaccination period, high relative humidity and low level of CO can significantly increase the incidence of HFMD; During the period of COVID-19, only low temperature will significantly increase the risk of HFMD; Low concentration of air pollutants has the greatest impact on the 6-14 age group, while the high concentration of air pollutants has the greatest impact on the 0-1 age group. CONCLUSIONS: Our study suggest that high relative humidity and precipitation and extremely high and low levels of PM10, O3, SO2 and CO increased the risk of HFMD from 2014 to 2020. The results of this study provide a reference for local authorities to formulate intervention measures and establish an environment-based disease early warning system.

Summary of national data of class A, B and C communicable diseases in China, September 2021

In September 2021 (from 00:00, 1 September to 24: 00, 30 September), a total of 500 929 cases of notifiable communicable diseases, including 2 172 deaths, were reported in China (except Hong Kong, Macao Special Administrative Regions and Taiwan Province, the same below). In communicable diseases in class A, no case and no death were reported. In communicable diseases in class B, no cases and no deaths of severe acute respiratory syndrome, poliomyelitis, human infection with highly pathogenic avian influenza virus, diphtheria and human infection with avian influenza A(H7N9) virus were reported. For the remaining 22 communicable diseases in class B, 272 332 cases were reported, a decrease of 0.9% compared with last month (274 917 cases) and a decrease of 5% compared with the same period in 2020 (287 923 cases). The first 5 diseases in terms of reported case number were viral hepatitis, pulmonary tuberculosis, syphilis, gonorrhea and brucellosis, accounting for 94% of the total reported cases in class B. A total of 2 172 deaths were reported, an increase of 5% (95 deaths) compared with last month (2 077 deaths) and a decrease of 5% compared with the same period in 2020 (2 291 deaths). According to the website of the National Health Commission of China, a total of 1 264 confirmed COVID-19 cases were reported, without death, by 31 provinces (municipalities, autonomous regions) and Xinjiang Production and Construction Corps from 00:00, 1 September to 24: 00, 30 September, 2021. In class C communicable diseases, a total of 228 597 cases were reported, an increase of 10% compared with last month (207 153 cases) and a decrease of 7% compared with the same period in 2020 (247 112 cases). The first 3 diseases in terms of reported case number were other infectious diarrhea, hand foot and mouth disease (HFMD) and influenza, accounting for 93% of the total reported cases in class C. Compared with last month, except filariasis, visceral leishmaniasis, leprosy and other infectious diarrhea which decreased by 1 case, 11 cases (39%), 12 cases (33%) and 12 747 cases (12%) respectively, the reported cases of all other diseases increased, the diseases with obvious case increases were HFMD (15 352 cases, 22%), influenza (14 160 cases, 66%) and mumps (4 253 cases, 51%). Compared with the same period in 2020, the diseases with reported case increases were influenza (17 269 cases, 95%), visceral leishmaniasis (4 cases, 31%), rubella (19 cases, 27%) and typhus fever (32 cases, 18%), filariasis had no incidences in both years, and the diseases with obvious reported case decreases were HFMD (26 506 cases, 23%). other infectious diarrhea (5 628 cases, 6%) and mumps (523 cases, 4%). No death caused by class C communicable diseases was reported, same to the last month and a decrease of 3 deaths compared with the same period in 2020 (3 deaths).

Risk assessment of public health emergencies concerned in the mainland of China, September 2021

Objective: To assess the risk of public health emergencies, both the indigenous ones and the imported ones, which might occur in the mainland of China in September 2021.

A large-scale outbreak of hand, foot and mouth disease, France, as at 28 September 2021.

We report a large-scale outbreak of hand, foot and mouth disease (HFMD) in France. As at 28 September 2021, 3,403 cases have been reported (47% higher than in 2018-19). We prospectively analysed 210 clinical samples; 190 (90.5%) were enterovirus-positive. Most children presented with atypical HFMD. Coxsackievirus (CV)A6 (49.5%; 94/190) was predominant; no enterovirus A71 was detected. Dermatological and neurological complications of HFMD justify prospective syndromic and virological surveillance for early detection of HFMD outbreaks and identification of associated types.

Response of Severe EV71-Infected Patients to Hyperimmune Plasma Treatment: A Pilot Study.

Hand, foot, and mouth disease (HFMD) is highly prevalent in East and Southeast Asia. It particularly affects children under five years of age. The most common causative agents are coxsackieviruses A6 and A16, and enterovirus A71 (EV71). The clinical presentation is usually mild and self-limited, but, in some cases, severe and fatal complications develop. To date, no specific therapy or worldwide vaccine is available. In general, viral infection invokes both antibody and cell-mediated immune responses. Passive immunity transfer can ameliorate the severe symptoms of diseases such as COVID-19, influenza, MERS, and SARS. Hyperimmune plasma (HIP) from healthy donors with high anti-EV71 neutralizing titer were used to transfuse confirmed EV71-infected children with neurological involvement (n = 6). It resulted in recovery within three days, with no neurological sequelae apparent upon examination 14 days later. Following HIP treatment, plasma chemokines were decreased, whereas anti-inflammatory and pro-inflammatory cytokines gradually increased. Interestingly, IL-6 and G-CSF levels in cerebrospinal fluid declined sharply within three days. These findings indicate that HIP has therapeutic potential for HFMD with neurological complications. However, given the small number of patients who have been treated, a larger cohort study should be undertaken. Successful outcomes would stimulate the development of anti-EV71 monoclonal antibody therapy.