Researchers at Eötvös Loránd University (ELTE) have processed the scientific findings on COVID-19 disease severity, which reveal the risk factors and possible causes of the differential course of the disease.

Researchers at Eötvös Loránd University (ELTE) have processed the scientific findings on COVID-19 disease severity, which reveal the risk factors and possible causes of the differential course of the disease. Their study was published in Viruses. CREDIT Photo: Müller Viktor, Zsichla Levente / Eötvös Loránd University

Researchers at Eötvös Loránd University (ELTE) have processed the scientific findings on COVID-19 disease severity, which reveal the risk factors and possible causes of the differential course of the disease. Their study was published in Viruses.

The COVID-19 pandemic has affected the whole world, but the number of cases and deaths is very unevenly distributed between geographical regions and individual risk has been significantly influenced by the infected individual, the infectious virus strain and some characteristics of the environment.

The clinical course and outcome of COVID-19 is highly variable.

Understanding why some people become asymptomatic while others lose their lives is essential both to cure the disease and to control the epidemic.

Levente Zsichla, a student of the Institute of Biology at ELTE and his supervisor, Dr. Viktor Müller, Associate Professor at the Institute of Biology at ELTE, analysed more than a thousand studies to provide a comprehensive picture of how processes influence the severity of COVID-19 at the individual level.

In their study, they examined in detail the role of demographic factors (age and biological sex, and related pregnancy), the interactions of the disease with other infectious and non-communicable comorbidities, and the influence of genetic polymorphisms, lifestyle, microbiota and established immune memory. In addition, the impact of genetic variation in the coronavirus (SARS-CoV-2) and environmental factors such as air pollution and socioeconomic status were reviewed.

For each factor, the evidence, sometimes conflicting, for the association with COVID-19 outcomes was examined and possible mechanisms of action were outlined. They also reviewed the complex interactions between different risk factors and the feedback effects of epidemic closures on these factors. We review some examples from their study.

WHAT IS ALREADY KNOWN – AGE AND UNDERLYING DISEASES

Advanced age is among the strongest risk factors for COVID-19 mortality. This effect was first reported in early 2020 and has since been confirmed by numerous studies. These findings show that

the risk of death in adults doubles approximately every 6-7 years of life,

and (in the case of the first major wave of the pandemic) has already exceeded 1% in the 65-75 age group. Ageing of lung tissue and the immune system, and the age-related increase in sterile systemic inflammation levels may also be responsible for this phenomenon.

Some chronic diseases also increase the risk of severe COVID-19, but there are exceptions and controversial cases. While obesity, diabetes, hypertension, chronic kidney disease and cardiovascular disease are certainly risk factors, the results for several immunological, neurological and mental diseases are still inconclusive. There is also such controversy within lung diseases. While chronic obstructive pulmonary disease seems to have a clear aggravating effect, in the majority of studies allergic asthma has been found to be a neutral or even risk-reducing underlying condition. This may be because, although both conditions are associated with shortness of breath, chest tightness, wheezing and coughing, the causes and mechanisms of the two conditions are largely different.

MEN ARE MORE VULNERABLE, WOMEN HAVE MORE COMPLICATIONS

Data show that men are at about twice the risk of serious COVID-19 infection, not only among older people but also regardless of age. Similar associations have also been shown for other viral respiratory diseases (e.g. influenza) and infectious pneumonia, so the mechanism is probably not unique to COVID-19. The role of several X-linked genes and the differential expression of other genes that play a key role in the immune system may underlie this phenomenon. In addition, men with severe COVID-19 often have immunological problems involving a family of immune molecules produced against viruses, interferons. In a significant proportion of patients, the production of these interferons is disturbed or the body starts to produce antibodies against them, inactivating the otherwise protective proteins.

Women have a lower risk of severe COVID-19 disease, but a higher rate of post-COVID-19 syndrome. Pregnancy is a particular risk factor for the course of the infection, with pregnant infected women more likely to develop gestational hypertension, more often being admitted to intensive care and the consequences for the foetus/infant.

INDIRECT EFFECTS OF THE ENVIRONMENT

Poor socioeconomic status, including poverty, poor housing conditions or belonging to an ethnic minority, has been shown to be a risk factor in many countries. It also affects people’s lifestyle, nutrition, exposure to air pollution and infectious respiratory diseases, and the availability and quality of health care. Unsurprisingly, and supported by research evidence, regular physical activity and a healthy diet are beneficial for overall health and COVID-19 outcomes, while excessive alcohol consumption increases the risk of serious disease. Even more surprisingly, the impact of smoking, which significantly impairs respiratory function, on the clinical outcome of SARS-CoV-2 infection remains undetermined. In contrast, a growing body of research links long-term exposure to high concentrations of particulate matter with severe coronavirus disease.

SIGNIFICANCE OF THE REVIEW

There have been several summaries of factors influencing the outcome of COVID-19, but these have either covered a small area or provided only a sketchy summary of a wider range of risk factors. The new study provides the most comprehensive overview of risk factors,

highlighting the dominant role of age, biological sex, certain chronic underlying diseases, previously acquired specific immunity, and the infectious virus strain in the course of the disease.

If you take the time to read it – and we recommend it to our brave and persistent readers – you will see how complex the science is and how often it is difficult to draw clear conclusions. It also reveals the amazing scientific collaboration that has taken place over the past few years as the international scientific community has joined forces to find answers and solutions to the pandemic threatening the world. Fortunately, with the development of effective vaccines and the immunity of those who have been affected, the pandemic has gradually been pushed into the background. Nevertheless, as the virus is expected to be with us for a long time to come, the conclusions of this study will be needed well into the future.

The mild disease does not lead to substantial long-term illness in most infected individuals, say researchers.

Most symptoms or conditions that develop after mild covid-19 infection linger for several months but return to normal within a year finds a large study from Israel published by The BMJ today.

In particular, vaccinated people were at lower risk of breathing difficulties – the most common effect to develop after mild infection – than unvaccinated people.

These findings suggest that, although the long covid phenomenon has been feared and discussed since the beginning of the pandemic, the vast majority of mild disease cases do not suffer serious or chronic long term illness, say the researchers.

Long covid is defined as symptoms persisting or new symptoms appearing more than four weeks after initial infection. In March 2022, an estimated 1.5 million people in the UK (2.4% of the population) reported long covid symptoms, mainly fatigue, shortness of breath, loss of smell, loss of taste, and difficulty concentrating.

But the clinical effects of long covid one year after mild infection and their association with age, sex, covid-19 variants, and vaccination status are still unclear.

To address this, researchers compared the health of uninfected individuals with those who had recovered from mild covid-19 for a year after infection.

They used electronic records of a large public healthcare organisation in Israel, in which almost 2 million members were tested for covid-19 between 1 March 2020 and 1 October 2021. Over 70 long covid conditions were analysed in a group of infected and matched uninfected members (average age 25 years; 51% female).

They compared conditions in unvaccinated people, with and without covid-19 infection, controlling for age, sex and covid-19 variants, during early (30-180 days) and late (180-360 days) time periods after infection. Conditions in vaccinated versus unvaccinated people with covid-19 were also compared over the same time periods.

To ensure only mild disease was assessed, they excluded patients admitted to hospital with more serious illness. Other potentially influential factors, such as alcohol intake, smoking status, socioeconomic level, and a range of pre-existing chronic conditions were also taken into account.

Covid-19 infection was significantly associated with increased risks of several conditions including loss of smell and taste, concentration and memory impairment, breathing difficulties, weakness, palpitations, streptococcal tonsillitis and dizziness in both early and late time periods, while hair loss, chest pain, cough, muscle aches and pains and respiratory disorders resolved in the late period.

For example, compared with non-infected people, mild covid-19 infection was associated with a 4.5-fold higher risk of smell and taste loss (an additional 20 people per 10,000) in the early period and an almost 3-fold higher risk (11 per 10,000 people) in the late period. 

The overall burden of conditions after infection across the 12-month study period was highest for weakness (an additional 136 people per 10,000) and breathing difficulties (107 per 10,000).

When conditions were assessed by age, breathing difficulties were the most common, appearing in five of the six age groups but remaining persistent throughout the first year post-infection in the 19-40, 41-60, and over 60 years age groups. 

Weakness appeared in four of the six age groups and remained persistent in the late phase only in the 19-40 and 41-60 age groups.

Male and female patients showed minor differences, and children had fewer outcomes than adults during the early phase of covid-19, which mostly resolved in the late period. Findings were similar across the wild-type, Alpha and Delta covid-19 variants.

Vaccinated people who became infected had a lower risk of breathing difficulties and similar risk for other conditions compared with unvaccinated infected patients.

The researchers point to some limitations, such as incomplete measurement within medical records, so data might not fully reflect diagnoses and outcomes reported. And they can’t rule out the possibility that covid-19 patients may use healthcare services more frequently, resulting in higher reporting and increased screening for potential covid-related outcomes in these patients.

Nevertheless, this was a large detailed analysis of health records across a diverse population, representing one of the longest follow-up studies in patients with mild covid-19 to date. And findings should apply to similar western populations worldwide.

“Our study suggests that mild covid-19 patients are at risk for a small number of health outcomes and most of them are resolved within a year from diagnosis,” say the researchers.

“Importantly, the risk for lingering dyspnoea was reduced in vaccinated patients with breakthrough infection compared with unvaccinated people, while risks of all other outcomes were comparable,” they add.

Prof. Jan Felix Drexler (left) and co-author Dr. Anges Yadouleton (center) in the Laboratory of Viral Hemorrhagic Fever (LFHB) in Benin © Charité | Anna-Lena Sander

First discovered a year ago in South Africa, the SARS-CoV-2 variant later dubbed “Omicron” spread across the globe at incredible speed. It is still unclear exactly how, when and where this virus originated. Now, a study published in the journal Science* by researchers from Charité – Universitätsmedizin Berlin and a network of African institutions shows that Omicron’s predecessors existed on the African continent long before cases were first identified, suggesting that Omicron emerged gradually over several months in different countries across Africa.

Since the beginning of the pandemic, the coronavirus has been constantly changing. The biggest leap seen in the evolution of SARS-CoV-2 to date was observed by researchers a year ago, when a variant was discovered that differed from the genome of the original virus by more than 50 mutations. First detected in a patient in South Africa in mid-November 2021, the variant later named Omicron BA.1 spread to 87 countries around the world within just a few weeks. By the end of December, it had replaced the previously dominant Delta variant worldwide.

Since then, speculations about the origin of this highly transmissible variant have centered around two main theories: Either the coronavirus jumped from a human to an animal where it evolved before infecting a human again as Omicron, or the virus survived in a person with a compromised immune system for a longer period of time and that’s where the mutations occurred. A new analysis of COVID-19 samples collected in Africa before the first detection of Omicron now casts doubt on both these hypotheses.

The analysis was carried out by an international research team led by Prof. Jan Felix Drexler, a scientist at the Institute of Virology at Charité and the German Center for Infection Research (DZIF). Other key partners in the European-African network included Stellenbosch University in South Africa and the Laboratory of Viral Hemorrhagic Fever (LFHB) in Benin. The scientists started by developing a special PCR test to specifically detect the Omicron variant BA.1. They then tested more than 13,000 respiratory samples from COVID-19 patients that had been taken in 22 African countries between mid-2021 and early 2022. In doing so, the research team found viruses with Omicron-specific mutations in 25 people from six different countries who contracted COVID-19 in August and September 2021 – two months before the variant was first detected in South Africa.

To learn more about Omicron’s origins, the researchers also decoded, or “sequenced,” the viral genome of some 670 samples. Such sequencing makes it possible to detect new mutations and identify novel viral lineages. The team discovered several viruses that showed varying degrees of similarity to Omicron, but they were not identical. “Our data show that Omicron had different ancestors that interacted with each other and circulated in Africa, sometimes concurrently, for months,” explains Prof. Drexler. “This suggests that the BA.1 Omicron variant evolved gradually, during which time the virus increasingly adapted to existing human immunity.” In addition, the PCR data led the researchers to conclude that although Omicron did not originate solely in South Africa, it first dominated infection rates there before spreading from south to north across the African continent within only a few weeks.

“This means Omicron’s sudden rise cannot be attributed to a jump from the animal kingdom or the emergence in a single immunocompromised person, although these two scenarios may have also played a role in the evolution of the virus,” says Prof. Drexler. “The fact that Omicron caught us by surprise is instead due to the diagnostic blind spot that exists in large parts of Africa, where presumably only a small fraction of SARS-CoV-2 infections are even recorded. Omicron’s gradual evolution was therefore simply overlooked. So it is important that we now significantly strengthen diagnostic surveillance systems on the African continent and in comparable regions of the Global South, while also facilitating global data sharing. Only good data can prevent policymakers from implementing potentially effective containment measures, such as travel restrictions, at the wrong time, which can end up causing more economic and social harm than good.”