A study has identified subtle changes in how immune cells respond to different severe febrile illnesses in children, which could lead to improved treatments.
A range of pathogens and inflammatory triggers could cause severe febrile illnesses in children, researchers wrote in the journal Nature Communications, however it was difficult for clinicians to identify the exact cause as the illnesses tended to share clinical features.
Diagnosis required time-consuming microbiological testing, which could lead to delays in clinicians starting appropriate treatment, the UK research team said.
Using immunophenotyping with mass cytometry and cell stimulation experiments, they followed the path of immune dysfunction in a group of 128 children: 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, eight with Kawasaki disease and a further 42 controls.
They further explored the findings using gene expression data from whole blood RNA sequencing in a separate cohort of 500 children with these severe febrile illnesses and 134 healthy controls.
The study found that neutrophil activation and apoptosis were prominent in MIS-C, and that this was partially shared with bacterial infection.
In addition, memory T cells from patients with MIS-C and those with bacterial infection were exhausted.
In contrast, viral infection was characterised by a distinct signature of decreased interferon signalling and lower interferon receptor gene expression.
‘Our data support an important role for neutrophil and monocyte activation in the pathology of MIS-C and highlight T cell exhaustion upon presentation of MIS-C,’ the researchers concluded.
‘Neutrophil activation and features of T cell activation and exhaustion were shared with severe bacterial infection, while severe viral infection was characterised by downregulated STAT signalling pathways, highlighting shared and distinct features of immune dysregulation in these disparate severe febrile illnesses of childhood,’ they added.
Study co-author Professor Michael Levin, chair in paediatrics and international child health from the Department of Infectious Disease at Imperial College London, said: ‘For decades we have been working to unpick the granular detail of febrile illnesses, so we can improve treatments and reduce the impact these conditions have on children.
‘As clinicians, we may often see a child in the hospital or clinic with a fever and no other real defining symptoms, making an accurate diagnosis and targeted treatment difficult.’
By providing a clearer picture of the immune mechanisms in febrile illnesses, this study and others like it might ultimately help clinicians to diagnose and treat children earlier, he said.
The team was motivated to investigate immune dysfunction in febrile illnesses after an increase in the number of children being admitted to hospitals worldwide with MIS-C – a life-threatening condition following SARS-CoV-2 exposure characterised by symptoms including fevers, rash, conjunctival infection, severe cardiac dysfunction, multi-organ involvement and intense inflammation.
They noted that clinically MIS-C shared similarities with severe bacterial infection, including toxic shock syndrome and Kawasaki disease, adding that both MIS-C and Kawasaki disease could cause coronary artery aneurysms.
Study co-author Dr Michael Carter, from King’s College London and the Evelina London Children’s Hospital, said: ‘We saw that severe bacterial infection and MIS-C overlapped immunologically, although they are caused by very different things.
‘In the clinic currently, our treatments for dysfunctional immunity are poor and not targeted to individual children. Going forwards, by looking at the immune system in much more detail, we hope we’ll be able to develop therapies that can treat the immune response in a much more targeted way and improve outcomes for our patients.’
The latest findings build on related work led by Imperial College London researchers which aimed to develop a blood test to rapidly diagnose the cause of paediatric febrile illnesses by using the differences in the levels of expression of 161 genes in patients’ blood to distinguish between 18 infectious and inflammatory diseases.
