By JD GLOBAL MEDIA
Researchers from the University of Cape Town (UCT), the University of Southampton and international partner institutions have identified 82 genes that may help distinguish children who develop severe COVID-19 from those who experience mild or asymptomatic infection.
The findings, published in BMC Infectious Diseases on 1 October 2026 and highlighted by UCT on 9 October, provide new evidence about how children’s immune systems respond to COVID-19 and other serious respiratory infections. The research examined blood samples from 333 South African children and compared patterns of gene activity across different groups, including children hospitalised with severe COVID-19, children with respiratory syncytial virus (RSV) infections, children with pulmonary tuberculosis and healthy controls.
The study identified thousands of genes whose activity differed across the groups. Among the results were 82 genes that helped distinguish mild or asymptomatic SARS-CoV-2 infection from severe disease, raising the possibility that gene-expression patterns could eventually contribute to identifying children at greater risk of serious illness.
The findings are not a ready-to-use diagnostic test, and the researchers say larger studies are needed before the gene signatures can be assessed for clinical use. Nevertheless, the work addresses an important evidence gap: how children in African settings respond biologically to respiratory infections that can cause severe illness and death.
The research is particularly relevant to South Africa, where lower respiratory tract infections remain an important cause of childhood illness. Understanding why some children become seriously ill while others experience milder symptoms could, over time, help scientists develop better ways to assess risk and investigate potential treatment targets.
What The Researchers Investigated
The research focused on gene expression, the process through which cells use genetic instructions to produce molecules that help regulate their activities. Gene-expression patterns can change when the immune system responds to an infection, offering researchers clues about which biological processes are active during illness.
Rather than looking only at the virus, the team examined how the children’s own bodies responded to infection. The researchers analysed whole-blood transcriptomes, which provide information about the activity of genes across blood cells.
The study compared several groups of children: those with severe COVID-19 who required hospitalisation, those with mild or asymptomatic SARS-CoV-2 infection, children with RSV-related lower respiratory tract illness, children with pulmonary tuberculosis and healthy controls.
The study included 333 South African children in total. The published research describes 127 healthy children, 71 with mild or asymptomatic SARS-CoV-2 infection, 41 hospitalised with severe COVID-19, 47 with RSV-related lower respiratory tract illness and 47 with pulmonary tuberculosis.
By comparing these groups, researchers could investigate which patterns appeared across several serious infections and which were more closely associated with severe COVID-19.
This distinction is important because different infections can produce overlapping symptoms. A child with a serious respiratory illness may experience breathing difficulties, fever or other signs that require clinical assessment, but those symptoms alone do not reveal every biological process taking place inside the body.
The researchers sought to identify patterns in the immune response that might help explain differences in disease severity. Their findings offer a foundation for further investigation, rather than an immediate replacement for existing clinical assessments and laboratory tests.
Eighty-Two Genes May Help Distinguish Severe Disease
One of the study’s key findings was the identification of 82 genes that helped distinguish mild or asymptomatic SARS-CoV-2 infection from severe COVID-19.
The result suggests that the activity of particular genes may contain information about how a child is responding to the virus. If future research confirms that these patterns are reliable, they could potentially contribute to biological markers, also known as biomarkers, for assessing disease severity.
A biomarker is a measurable characteristic that can provide information about a biological process or condition. In infectious disease research, biomarkers may help identify patterns associated with a more serious illness, monitor changes over time or investigate why patients respond differently to the same infection.
However, finding genes associated with severe disease is only an early step. Researchers must establish whether the patterns can reliably distinguish patients in different populations and whether they add useful information beyond existing clinical assessments.
A gene signature that performs well in one research group may not work equally well in every setting. Differences in age, background health, the timing of sample collection, the type of infection and other factors can influence the results.
The 82 genes should therefore not be interpreted as a definitive list that can already predict the outcome for an individual child. The study identifies promising clues for further investigation, not a validated screening tool ready for routine use in clinics.
The research nevertheless provides scientists with a more detailed starting point for studying why severe COVID-19 develops in some children and how the immune system’s response differs between mild and serious infections.
More Than 5,000 Genes Showed Different Activity
The researchers identified more than 5,000 genes whose expression differed across children with severe infections and the comparison groups.
The scale of the finding reflects the complexity of the immune response. Infection does not activate a single isolated mechanism. Instead, many biological processes interact as the body detects pathogens, recruits immune cells, regulates inflammation and attempts to control the infection.
Some of the genes identified were associated with particular infection groups. The published study reported genes linked to severe SARS-CoV-2 infection, including OLFM4, IFI27, CBX7, IGF2BP3 and OTOF. It also identified gene patterns associated with RSV-related respiratory illness and pulmonary tuberculosis.
These findings do not mean that each gene independently causes severe illness. Gene-expression differences may reflect several processes, including the body’s response to infection, changes in the types of cells circulating in the blood and differences in disease severity.
Further work is needed to determine which findings are most useful for understanding the disease and whether any could support clinical decisions.
The researchers also examined biological pathways associated with the observed patterns. In severe COVID-19, these included processes related to neutrophil degranulation, interferon-gamma signalling, ribosomal proteins and changes in immune-response activity.
Such pathways help scientists understand the broader biological systems involved, rather than viewing each gene as an isolated result.
For clinicians and researchers, this wider perspective may be important because severe illness can arise from complex interactions between pathogens and the body’s defence mechanisms. A better understanding of those interactions could eventually help identify new avenues for diagnosis or treatment research.
What The Study Found Across Different Respiratory Infections
The research did not focus exclusively on COVID-19. It also compared gene-expression patterns associated with RSV-related lower respiratory tract illness and pulmonary tuberculosis.
RSV is a respiratory virus that can cause serious illness, particularly in infants and young children. Pulmonary tuberculosis affects the lungs and remains an important infectious disease in South Africa.
Although these infections have different causes, they can all affect the lower respiratory tract and lead to significant illness. Comparing them can help researchers identify which immune-response patterns are shared and which may be more closely associated with a particular infection.
The study identified 10 groups of genes whose expression patterns were correlated across different lower respiratory tract infections. These groups were associated with immune responses, cell regulation and other biological processes involved in infection.
The result suggests that some parts of the body’s response to serious respiratory illness may be shared across different pathogens.
That does not mean COVID-19, RSV and tuberculosis are biologically identical or should be managed in the same way. Each infection has its own causes, transmission patterns, diagnostic requirements and treatment considerations.
Instead, shared gene-expression patterns may help scientists understand common aspects of the body’s response to infection. At the same time, the differences between the groups may offer clues about biological processes more closely associated with individual diseases.
This comparison is useful because it places severe COVID-19 within the wider context of childhood respiratory illness. It may help future researchers determine whether a biological marker is specific to one infection or reflects a more general response to severe disease.
Why Severe COVID-19 In Children Needs Further Study
Most children infected with SARS-CoV-2 experience mild illness or no noticeable symptoms, but a minority develop severe disease.
Understanding why outcomes differ is a major research question. Clinical observations can identify factors associated with serious illness, but they do not always explain the underlying biological mechanisms.
The UCT-led study contributes to this field by examining gene activity in South African children and comparing it with patterns observed in other respiratory infections.
Professor Heather Zar, the study’s principal investigator and chairperson of UCT’s Department of Paediatrics and Child Health, said research examining biological responses to these infections in African children has been limited.
The study also draws on children from the Drakenstein Child Health Study, a birth-cohort research programme that has helped build evidence about childhood health in South Africa.
The involvement of South African children is important because research findings from one population cannot automatically be assumed to apply identically to every other population. Differences in environmental exposure, underlying health, access to healthcare and other factors may influence how disease presents and progresses.
The study does not establish that children in South Africa have a unique immune response compared with children elsewhere. Rather, it adds evidence from an African setting to an area where the researchers say the available data have been limited.
Expanding this evidence base may help scientists assess whether findings from different populations are consistent and determine how broadly potential biomarkers could be used.
The Role Of International Collaboration
The project brought together researchers from UCT, the University of Southampton and other partner institutions, including scientists associated with South African infectious-disease research.
Such collaboration allows specialists in paediatrics, immunology, respiratory disease, genetics and data analysis to contribute different forms of expertise.
The study involved researchers with links to the South African Medical Research Council’s Unit on Child and Adolescent Health, the National Institute for Communicable Diseases, the University of the Witwatersrand and several international academic institutions.
The collaboration also demonstrates how locally collected clinical samples can contribute to broader scientific questions when combined with advanced laboratory analysis and international research expertise.
Professor John W Holloway of the University of Southampton described the work as a foundation for further research into why some children develop severe infections.
Dr Negusse Kitaba, the study’s lead researcher, said the findings provide new insights into biological pathways associated with disease severity and highlight genes that warrant further investigation as possible biomarkers and therapeutic targets.
The statements reflect the study’s potential scientific contribution, but they do not mean that a new treatment has already been developed. Identifying a possible target is different from demonstrating that changing that target will improve a patient’s outcome.
Any future treatment based on these findings would require extensive investigation, including evidence that the proposed approach is safe and effective.
Could The Findings Lead To A New Test?
The possibility of using gene-expression patterns to help identify children at risk of severe disease is one of the most significant implications of the study.
A future test based on validated biomarkers might, in principle, provide additional information about a child’s biological response to infection. Depending on how such a test performs, it could potentially complement existing clinical assessments or help researchers investigate disease progression.
However, the present findings do not establish that a practical test is available. The research team says larger groups of children will be needed to determine whether the identified gene signatures can be developed for clinical use.
A test intended for clinical decision-making must be assessed for accuracy, reliability and usefulness in the settings where it would be used. Researchers need to determine whether it can distinguish children with different levels of disease severity, how often it produces misleading results and whether the information improves decisions compared with existing methods.
Practical considerations also matter. A test may require laboratory equipment, trained personnel, sample-processing procedures and a reliable way to return results quickly enough to inform care.
In resource-constrained settings, affordability and accessibility would be particularly important. A sophisticated test that is available only at a small number of specialist laboratories may have limited value for routine care if it cannot reach the facilities where children are assessed.
These are future questions, not shortcomings that invalidate the current research. The study is an early scientific step that identifies patterns worth testing in larger and more diverse groups.
For now, healthcare professionals should continue to rely on established clinical guidance and appropriate diagnostic procedures when assessing children with respiratory symptoms.
Potential Implications For Treatment Research
The study’s findings may also guide further research into the biological processes associated with severe infection.
By identifying gene-expression patterns and pathways that differ between groups, researchers can investigate which mechanisms are most closely linked to serious illness. Some of these mechanisms may offer possible targets for future therapies.
However, a gene associated with disease severity is not necessarily a cause of the disease, and targeting a biological pathway can have effects beyond the intended outcome.
The immune system depends on carefully regulated interactions. A response that helps control an infection in one context may contribute to inflammation or tissue damage in another. Scientists must therefore establish whether modifying a particular pathway would be beneficial, harmful or ineffective.
The findings may help researchers prioritise questions for laboratory studies and subsequent clinical investigation. They do not establish that a medicine based on the 82 genes is ready for development or that any particular treatment should be changed.
The research is best understood as a contribution to the early stages of understanding disease mechanisms. Its potential value lies in helping scientists identify which biological processes deserve closer attention.
Limitations And The Need For Larger Studies
As with any research study, the findings need to be interpreted in light of the methods and population examined.
The analysis involved 333 South African children divided into several comparison groups. Although the study identified substantial differences in gene expression, the number of participants in each group limits the extent to which the results can automatically be generalised to every child.
The researchers have specifically stated that larger studies are required to determine whether the identified gene signatures can be developed for clinical use.
Future research will need to assess whether the patterns are reproduced in independent groups, whether they remain informative across different settings and whether they provide reliable information about disease severity.
Researchers may also need to examine how the timing of sample collection affects results. Gene expression can change during the course of an infection, meaning that the same patient may show different patterns at different stages of illness.
The study’s early publication status is another consideration. The journal describes the paper as an accepted research article made available before the final version of record, allowing readers to access the work sooner while further editorial processing may still occur.
These qualifications do not erase the findings. They clarify the difference between identifying a promising biological signal and establishing a tool that can be used confidently in routine clinical practice.
What The Findings Mean For Parents And Caregivers
For parents and caregivers, the study offers an important scientific development but should not be interpreted as a new way to diagnose severe COVID-19 at home.
The research does not provide a simple symptom checklist, a commercially available gene test or a reason to change a child’s treatment without professional advice.
Children who develop breathing difficulties, unusual drowsiness, signs of dehydration or other concerning symptoms should receive appropriate medical assessment. The urgency of care depends on the child’s condition, and caregivers should follow advice from qualified healthcare professionals.
The gene-expression findings are intended to help researchers understand biological differences between mild and severe infections. They are not a substitute for clinical assessment or established diagnostic procedures.
The study also does not suggest that every child who contracts COVID-19 will develop severe illness. The researchers examined differences across groups precisely because the severity of infection varies.
For families, the immediate value of the research is that it contributes to a longer-term effort to understand why some children become seriously ill and how future research might improve the assessment and management of respiratory disease.
Any eventual clinical application will depend on additional evidence and appropriate validation.
Strengthening African Evidence In Childhood Health
The study adds to the body of research examining childhood respiratory infections using data from South Africa.
Its focus on gene-expression patterns addresses a question that has implications beyond COVID-19: how the immune system responds to different infections and why the clinical course can vary between children.
Research conducted with African participants can help reduce gaps in the global evidence base and support the development of scientific findings that are tested in populations relevant to the settings where they may eventually be used.
The international collaboration also demonstrates the importance of linking clinical research, laboratory science and data analysis. Each discipline contributes to understanding different aspects of a complex disease.
Further research will need to establish whether the identified gene patterns can be replicated, whether they have practical value in clinical settings and whether they can support the development of useful biomarkers or therapeutic approaches.
Those steps may take time. Scientific findings do not become routine healthcare tools immediately, particularly when they involve complex biological measurements and decisions about children’s treatment.
Nevertheless, identifying promising pathways is an important part of the process through which researchers develop a better understanding of disease.
The Road Ahead
The UCT-led research has identified 82 genes that may help distinguish mild or asymptomatic COVID-19 from severe disease in children, alongside thousands of other gene-expression differences associated with serious respiratory infections.
The study also found shared patterns across COVID-19, RSV-related illness and pulmonary tuberculosis, suggesting that some immune-response mechanisms may be common to different infections while other patterns may help distinguish between them.
For South Africa, the work provides additional evidence from local children and contributes to international research into childhood respiratory disease.
The findings do not yet offer a validated diagnostic test or a new treatment. Larger studies are required to determine whether the gene signatures can be used reliably in clinical practice, and further research will be needed before any potential treatment targets can be translated into patient care.
The next phase will involve confirming the findings in larger groups, assessing their clinical relevance and determining whether the information adds value to existing methods of assessing children with respiratory illness.
The research nevertheless marks a meaningful step in understanding the biology of severe COVID-19 in children. By examining how the immune system responds to infection, scientists are building a more detailed picture of why outcomes differ and which questions should guide future investigations.
JD GLOBAL MEDIA
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