Immune cell insights in childhood febrile illnesses could improve targeted treatments

29th October 2024

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.

Immunogenicity occurs in pregnant and lactating women after COVID-19 vaccination

17th May 2021

Real-world data indicate that both pregnant and breast-feeding women are able to generate a satisfactory immune response after vaccination against COVID-19.

With pregnant women excluded from the COVID-19 vaccination trials, it remained uncertain whether those who were either pregnant or breast-feeding would develop satisfactory immunogenicity, especially given the evidence of more severe outcomes after infection in those who are pregnant. While there are some data to indicate that vaccination against other viruses such as influenza confers immunity, much less is known about COVID-19 vaccination and the efficacy in lactating mothers. In addition, with the emergence of an increasing number of COVID-19 variants, there is an urgent need to examine whether a sufficient antibody titre against COVID-19 and new variants is generated within these two patient cohorts. Consequently, a team from the Department of Obstetrics and Gynaecology, Boston, US, set out to answer this question prospectively following up on a number of women who received a COVID-19 vaccination between December 2020 and March 2021. The team also included a group of pregnant/non-pregnant women/unvaccinated women who had been previously infected with COVID-19 and who provided serum samples for comparative purposes.

Findings
A total of 103 participants were enrolled in the study comprising 57 who were non-pregnant, 30 pregnant and 16 lactating women. The median age of the pregnant and lactating women was 35 years and the majority (over 80%) were of white ethnicity. Most (63%) pregnant women had received the mRNA-1272 (Moderna) vaccine whereas the majority of lactating mothers (69%) had the BNT162b vaccine. Serum samples were taken a median of 21 days after the second vaccination dose for non/pregnant individuals and 26 days for lactating mothers. In addition, nine women gave birth and contributed infant cord blood. The level of receptor-binding domain (RBD) antibody titres in non-pregnant, pregnant and lactating were similar but higher than among those who had a prior COVID-19 infection, irrespective of pregnancy status. In cord samples, the levels of RBD antibodies were similar in mothers compared to cord samples (14,953 vs 19,873) among those who had been vaccinated but lower in non-vaccinated, but previously infected women (1342 vs 635). Interestingly, there were higher median levels of antibodies in breast milk among those who had a prior infection compared to vaccinated women (203 vs 97). Although RBD antibodies to the wild-type COVID-19 were comparable across the different groups, there was a 3.5-fold lower titre against the B.1.1.7 (UK variant) and a 6-fold lower titre for the B.1.351 (South African variant). Despite these lower titre levels, responses to non-neutralising antibodies and T-cell responses were preserved in both pregnant and non-pregnant women to the variants of concern, suggesting that cellular immune responses may be important for protection.

Commenting on these results, the authors noted how their data confirm other findings of a higher vaccine-induced antibody response compared to prior infection.

They concluded that while the results are based on a small sample size, the presence of neutralising antibodies in both cord and breast milk samples reveals how newborns are protected by maternal vaccination.

Citation
Collier AY et al. Immunogenicity of COVID-19 mRNA vaccines in pregnant and lactating women. JAMA 2021