Virus World

Cardiovascular autonomic dysfunction (CVAD) is a malfunction of the cardiovascular system caused by deranged autonomic control of circulatory homeostasis. CVAD is an important component of post-COVID-19 syndrome, also termed long COVID, and might affect one-third of highly symptomatic patients with COVID-19. The effects of CVAD can be seen at both the whole-body level, with impairment of heart rate and blood pressure control, and in specific body regions, typically manifesting as microvascular dysfunction. Many severely affected patients with long COVID meet the diagnostic criteria for two common presentations of CVAD: postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. CVAD can also manifest as disorders associated with hypotension, such as orthostatic or postprandial hypotension, and recurrent reflex syncope. Advances in research, accelerated by the COVID-19 pandemic, have identified new potential pathophysiological mechanisms, diagnostic methods and therapeutic targets in CVAD.

For clinicians who daily see patients with CVAD, knowledge of its symptomatology, detection and appropriate management is more important than ever. In this Review, we define CVAD and its major forms that are encountered in post-COVID-19 syndrome, describe possible CVAD aetiologies, and discuss how CVAD, as a component of post-COVID-19 syndrome, can be diagnosed and managed. Moreover, we outline directions for future research to discover more efficient ways to cope with this prevalent and long-lasting condition. Cardiovascular autonomic dysfunction (CVAD) is a malfunction of the autonomic control of circulatory homeostasis and is an important component of post-COVID-19 syndrome. In this Review, Fedorowski and colleagues define the major forms of CVAD (including postural orthostatic tachycardia syndrome), and discuss the aetiology, diagnosis and management of post-COVID-19 syndrome-associated CVAD.

Published in Nature Reviews Cardiology Jan.02, 2024: 

https://doi.org/10.1038/s41569-023-00962-3 

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically. The humoral response to SARS-CoV-2 infection has been the focus of intense research, and the role of the innate immune system has received significantly less attention. Here, we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems. We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

Published in Cell. Mol. Immunology (Nov. 20, 2023):

https://doi.org/10.1038/s41423-023-01104-y 

Background

Objectives

Data sources

Study eligibility criteria, participants, and interventions

Methods

Results

Conclusion

It is unclear why people’s immune response to the SARS-CoV-2 coronavirus varies so widely. Tracking patient responses over time sheds light on this issue, and has implications for efforts to predict disease severity. A dysregulated immune response, a cytokine storm and cytokine-release syndrome1,2 are some of the terms used to describe the overexuberant defence response that is thought to contribute to disease severity in certain people who become seriously ill with COVID-19. However, a precise definition of this type of immune dysfunction remains elusive. On page 463, Lucas et al. 3 fill in some gaps in our knowledge.

A holy grail of COVID-19 research is the ability to assess a person’s immune response, to pinpoint early the individuals who have mild symptoms but who are on track to develop the intense defence response that is associated with severe disease. This is important because there is a broad spectrum of clinical disease in people infected with SARS-CoV-2, the coronavirus that causes COVID-19: some infected individuals can be asymptomatic, whereas others are at risk of dying, and require hospitalization in an intensive-care unit and use of a ventilator machine to breathe4,5. Identifying those whose dysregulated immune-response signature predicts the development of severe disease would enable them to be monitored more intensively to minimize disease progression. Lucas and colleagues performed extensive analyses of immune responses over time (longitudinal studies) in 113 people hospitalized with COVID-19 who had moderate or severe disease, and assessed a similar number of SARS-CoV-2- free healthy people as controls. The authors analysed molecules in blood plasma (Fig. 1) and monitored peripheral blood mononuclear cells — white blood cells of the immune system such as CD4 T cells, CD8 T cells and B cells. The longitudinal nature of this study enables conclusions to be drawn that wouldn’t be possible from analysing cross-sectional studies that don’t follow individuals over time. 

The authors found that levels of several molecules that promote inflammation  — immunomodulatory molecules termed cytokines, including IL-1α, IL-1β, IFN-α, IL-17A and IL-12 p70 — were higher in all of the people who had COVID-19 than in the healthy controls, providing a ‘core’ COVID-19 signature. Other cytokines, such as IFN-λ, thrombopoietin (which is associated with abnormalities in blood clotting), IL-21, IL-23 and IL-33, were upregulated to a greater extent in people with severe COVID-19 than in those with moderate...

Published in Nature (August 20, 2020):

https://doi.org/10.1038/d41586-020-02379-1 

Here are some of the things we have learned about Covid-19, and some of the pressing questions that we still need answered. he “before times” seem like a decade ago, don’t they? Those carefree days when hugging friends and shaking hands wasn’t verboten, when we didn’t have to reach for a mask before leaving our homes, or forage for supplies of hand sanitizer. Oh, for the days when social distancing wasn’t part of our vernacular. In reality, though, it’s only been about seven months since the world learned a new and dangerous coronavirus was in our midst. In the time since Chinese scientists confirmed the rapidly spreading disease in Wuhan was caused by a new coronavirus and posted its genetic sequence on line, an extraordinary amount has been learned about the virus, SARS-CoV-2, the disease it causes, Covid-19, and how they affect us.Here are some of the things we have learned, and some of the pressing questions we still need answered. 

Covid and kids: It’s complicated 

Early in the pandemic, it looked like there was a silver lining to the disease cloud sweeping across the world. Children, it seemed, didn’t develop the severe symptoms that were sending adults to hospitals struggling for breath, and they very rarely died. It even seemed that kids didn’t contract the disease at the same rates as adults did. But everything Covid is complex, and kids are no exception. While deaths among children and teens remain low, they are not invulnerable. And they probably contribute to transmission of SARS-CoV-2, though how much remains unclear. We’ve learned younger children and teenagers shouldn’t be lumped together when it comes to Covid. Teens seem to shed virus — emit it from their throats and nasal passages — at about the same rates as adults. Kids under 5 have high levels of virus in their respiratory tracts, but it’s still not clear how much they spread it or why they don’t develop symptoms as often as adults do. A recently published report from a Georgia sleep-away camp shows how quickly the virus can spread among kids. The camp had to be closed within 10 days of starting its orientation for camp staffers, because within days of children arriving, kids and staff started getting sick. (The campers ranged in age from 6 to 19.) The camp did not require campers to wear face masks. A recent report on Covid infections in children from the Centers for Disease Control and Prevention showed that while they remain low, U.S. hospitalization rates for Covid-19 in children have risen since the pandemic started. And one in three children hospitalized with the disease ends up in intensive care. The highest rate of hospitalizations in children was among those under 2 years of age. Black and Latino children were hospitalized at higher rates than white children. And like adults, children with other health conditions — obesity, chronic lung diseases, or infants who were born premature — are at higher risk than otherwise healthy children...

Six months into the outbreak, Nature looks at the pressing questions that researchers are tackling. In late December 2019, reports emerged of a mysterious pneumonia in Wuhan, China, a city of 11 million people in the southeastern province of Hubei. The cause, Chinese scientists quickly determined, was a new coronavirus distantly related to the SARS virus that had emerged in China in 2003, before spreading globally and killing nearly 800 people. Six months and more than ten million confirmed cases later, the COVID-19 pandemic has become the worst public-health crisis in a century. More than 500,000 people have died worldwide. It has also catalysed a research revolution, as scientists, doctors and other scholars have worked at breakneck speed to understand COVID-19 and the virus that causes it: SARS-CoV-2. 

They have learnt how the virus enters and hijacks cells, how some people fight it off and how it eventually kills others. They have identified drugs that benefit the sickest patients, and many more potential treatments are in the works. They have developed nearly 200 potential vaccines — the first of which could be proved effective by the end of the year. But for every insight into COVID-19, more questions emerge and others linger. That is how science works. To mark six months since the world first learnt about the disease responsible for the pandemic, Nature runs through some of the key questions that researchers still don’t have answers to.

One of the most striking aspects of COVID-19 is the stark differences in experiences of the disease. Some people never develop symptoms, whereas others, some apparently healthy, have severe or even fatal pneumonia. “The differences in the clinical outcome are dramatic,” says Kári Stefánsson, a geneticist and chief executive of DeCODE Genetics in Reykjavik, whose team is looking for human gene variants that might explain some of these differences....

The coronavirus disease 2019 (COVID-19) pandemic has been ongoing for more than 3 years, with an enormous impact on global health and economies. In some patients, symptoms and signs may remain after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which cannot be explained by an alternate diagnosis; this condition has been defined as long COVID. Long COVID may exist in patients with both mild and severe disease and is prevalent after infection with different SARS-CoV-2 variants. The most common symptoms include fatigue, dyspnea, and other symptoms involving multiple organs. Vaccination results in lower rates of long COVID. To date, the mechanisms of long COVID remain unclear. In this narrative review, we summarized the clinical presentations and current evidence regarding the pathogenesis of long COVID.

Published Dec. 2023:

https://doi.org/10.1016/j.pccm.2023.10.003 

The AIDS epidemic has been a global public health issue for more than 40 years and has resulted in ~40 million deaths. AIDS is caused by the retrovirus, HIV-1, which is transmitted via body fluids and secretions. After infection, the virus invades host cells by attaching to CD4 receptors and thereafter one of two major chemokine coreceptors, CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte, as it replicates. If unchecked this can lead to an immune-deficient state and demise over a period of ~2–10 years. The discovery and global roll-out of rapid diagnostics and effective antiretroviral therapy led to a large reduction in mortality and morbidity and to an expanding group of individuals requiring lifelong viral suppressive therapy. Viral suppression eliminates sexual transmission of the virus and greatly improves health outcomes.

HIV infection, although still stigmatized, is now a chronic and manageable condition. Ultimate epidemic control will require prevention and treatment to be made available, affordable and accessible for all. Furthermore, the focus should be heavily oriented towards long-term well-being, care for multimorbidity and good quality of life. Intense research efforts continue for therapeutic and/or preventive vaccines, novel immunotherapies and a cure. In HIV infection, the virus invades and destroys the immune system of the host. This Primer by Bekker and colleagues summarizes the epidemiology, mechanisms, diagnosis and treatment of HIV infection, and discusses patient quality of life and open research questions for this condition.

Published August 17, 2023:

https://www.nature.com/articles/s41572-023-00452-3 

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations.

Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process. Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.

Published in Nat Rev Microbiol (Jan. 2023):

https://doi.org/10.1038/s41579-022-00846-2

The UNAIDS estimates that 38 million people currently live with human immunodeficiency virus (HIV) infection. Combination antiretroviral treatment has had great success in saving lives but is also associated with numerous medical and public health challenges. Vaccination remains the best and most cost-effective option for controlling HIV infection across the world. Professor Tomáš Hanke jointly from the University of Oxford, UK, and Kumamoto University, Japan, designs vaccines and coordinates clinical programs testing the most advanced vaccine candidates developed by his team in the UK, Europe, U.S. and Africa.

Ending AIDS with vaccination

Human immunodeficiency virus (HIV) type 1 represents 95% of all HIV infections worldwide and is responsible for the global HIV pandemic. If untreated, HIV-infected patients develop acquired immunodeficiency syndrome—better known as AIDS—that manifests as a progressive failure of their immune system. As a result, patients eventually succumb to opportunistic infections. Combination antiretroviral treatment (cART) has transformed the lives of people living with HIV, and dramatically decreased AIDS-related mortality and onward transmission of HIV. Unfortunately, the provision of cART to everybody who needs it faces many obstacles particularly in low- and middle-income countries. The cost, complexity of the treatment, necessity of regular monitoring of patients, threat of drug resistance, side effects, social stigma and the use of cART to prevent HIV infections (or pre-exposure prophylaxis), which further stretches the cART supply, make cART a suboptimal therapeutic and an unlikely stand-alone tool to end the HIV epidemic. Therefore, an effective vaccine for both prevention and cure of HIV is urgently needed. 

Professor Tomáš Hanke and his team at the Jenner Institute at the University of Oxford, UK, together with their collaborators at the Joint Research Center for Human Retrovirus Infection, Kumamoto University, Japan, are studying T cell responses to HIV to inform vaccine development. In addition, Professor Hanke oversees Experimental Medicine trials of his leading T-cell vaccine candidates in healthy and HIV-positive people at several global sites and collaborates with prestigious universities and organizations such as the International AIDS Vaccine Initiative, IrsiCaixa AIDS Research Institute-HIVACAT in Spain, Imperial College London, the Kenya AIDS Vaccine Initiative-Institute for Clinical Research and National Institute of Allergy and Infectious Diseases. He also co-ordinates the "Globally Relevant AIDS Vaccine Europe-Africa Trials Partnership" consortium, acronymed GREAT, which builds research capacity and tests vaccine candidates in Eastern and Southern Africa, and is one of the principal investigators of the European AIDS Vaccine Initiative 2020.

A key goal to controlling COVID-19 is developing an effective vaccine. Development of a vaccine requires knowledge of what constitutes a protective immune response and also features that might be pathogenic. Protective and pathogenic aspects of the response to SARS-CoV-2 are not well understood, partly because the virus has infected humans for only 6 months.

However, insight into coronavirus immunity can be informed by previous studies of immune responses to non-human coronaviruses, to common cold coronaviruses, and to SARS-CoV and MERS-CoV. Here we review the literature describing these responses and discuss their relevance to the SARS-CoV-2 immune response.

Original review  available at Immunity (July 14, 2020):

https://doi.org/10.1016/j.immuni.2020.07.005

This year was full of fascinating discoveries. New viruses were identified, and others were associated with new and old diseases. Milestones were reached in the battle against viral diseases, and yet viral outbreaks continued to frighten the world. Scientists uncovered novel technologies to diagnose viral infections, and to deliver gene therapies that achieved results we could not imagine decades ago. Virologists learned more about the role the human microbiome plays in viral infection. This is the year in review with the findings that shaped 2019 in the field of viruses.

New diseases and viruses

A new polio-like disease outbreak (acute flaccid myelitis, or “AFM”) emerged in the United States in the last years, with more than 500 cases reported by CDC. AFM brought us back memories and fears from the early 1940s in the US, where after a few years of small polio outbreaks in American children, many more episodes would come in the following years paralyzing more than 50,000 children at the peak of the1952 epidemic. In 2019, epidemiological and immunological studies associated the new polio-like disease with other picornaviruses, enterovirus D68 and A71. Human herpesviruses 6 (HHV-6) and Epstein-Barr virus (EBV) were associated with multiple sclerosis in humans. HHV-6 and HHV-7 were also linked to Alzheimer’s disease. Adenovirus C was associated with type I diabetes, and human papillomavirus infection correlated with increased odds of breast carcinoma. An entire new family of viruses, the redondoviridae, was found in the human lung during metagenomic analyses. The “medusavirus”, was identified in a hot spring in Japan. The medusavirus infects amoeba cells and its genome is among the largest and more complexed viral genomes ever found, with genes encoding all types of histones. Scientists demonstrated for the first time that a non-enveloped insect RNA virus, “Providence virus”, can also infect plants and mammalian cells, suggesting that plants could act as reservoirs of human viruses. Another study reported that more viruses than previously elucidated (about 30 different viral species) can be found in human semen.  The list included viruses of known routes of sexual transmission, such as HIV or HTLV-1, and also others like Lassa, Zika or Dengue. Proof of sexual transmission of dengue virus was confirmed in 2019 for the first time.

New viral therapies

This was not a great year for FDA approvals for antiviral therapies. 54 new drugs were approved by the FDA in 2019, included 48 new small-molecules. None of them target viral diseases. Xofluza (baloxavir marboxil), an inhibitor of the influenza virus polymerase acidic endonuclease, was approved in October 2018 for the treatment of acute uncomplicated influenza, in healthy people 12 years and older. In October 2019 Xofluza was also approved for the treatment of people at high risk of influenza complications, including those with asthma, chronic lung disease, diabetes, heart disease and obesity. During 2019 we heard great news about the first anti-influenza drug approved in more than 20 years. Therapy with Xofluza was found useful at preventing flu transmission in the household environment, reducing the chances of transmission in individuals under the same house by over 85%. However, in November, results from a study reported alarming rates of baloxavir-resistant strains, especially in children. The appearance of drug-resistance is common among RNA viruses, but the study found the troublesome ability of the virus to mutate without compromising its "viral fitness". Some scientists questioned the use of the antiviral in children, where resistant rates were significantly higher......