Long Term Disruption of Cytokine Signalling Networks are Evident
Following SARS-CoV-2 Infection
Sinead Ahearn-Ford1, Nonhlanhla
Lunjani1, Brian McSharry1,2, John
MacSharry1,2,3, Liam Fanning1,3,
Gerard Murphy4, Cormac Everard4,
Aoife Barry4, Aimee McGreal4, Sultan
Mohamed al Lawati4, Susan
Lapthorne4, Colin Sherlock4, Anna
McKeogh4, Arthur Jackson4, Eamonn
Faller4, Mary Horgan3,4, Corinna
Sadlier4, Liam O’Mahony1,2,3*
1APC Microbiome Ireland, University College Cork,
Cork, Ireland
2School of Microbiology, University College Cork,
Cork, Ireland
3Department of Medicine, University College Cork,
Cork, Ireland
4 Department of Infectious Diseases, Cork University
Hospital, Cork, Ireland
*Corresponding author – liam.omahony@ucc.ie
To the Editor,
The current pandemic caused by the SARS-CoV-2 virus has so far infected
more than 130 million people worldwide, resulting in approximately 3
million deaths. While the current clinical and public health priorities
are designed to limit severe acute and fatal episodes of the disease,
and to quickly roll out vaccines to the general population, it has
become apparent that there may also be significant detrimental long-term
effects following SARS-CoV-2 infection that impact daily functioning and
quality of life1. The mechanisms underpinning the
post-acute sequelae of SARS-CoV-2 infection’s long-lasting symptoms can
include direct effects of the infection (e.g. endothelial damage, lung
fibrosis) or indirect effects associated with changes in the microbiome
or abnormalities in inflammatory and immune signalling pathways
stimulated by the infection2,3.
In order to examine the potential long-term immune changes that occur
following elimination of the primary infection, we examined the levels
of 52 cytokines and growth factors (using MSD multiplex kits) in the
serum of patients that attended follow-up post-COVID infection clinics
at Cork University Hospital, Cork, Ireland (The Clinical Research Ethics
Committee of the Cork Teaching Hospitals approved this study and all
patients provided informed consent). All patients had been hospitalised
for PCR-proven SARS-CoV-2 infection (median in-patient stay of 5.5 days,
range 1 day to 24 days) during the first wave of the pandemic in Ireland
(March-May 2020). 38 serum samples were obtained from 24 patients
(median age 53.5 years, 11 female) at 3-9 months following hospital
discharge. Clinical severity ranged from mild to critical during
hospitalisation and the most common symptoms at follow-up clinics were
fatigue and/or dyspnoea (supplementary Table S1). Sera obtained prior to
the pandemic from 29 healthy volunteers (median age 43.2 years, 14
female) were analysed in parallel.
Of the 52 analytes measured, 19 were significantly elevated in
post-COVID patient sera compared to healthy controls (supplementary
Table S2). These 19 mediators are illustrated as dot plots in Figure 1
and Figure 2. One group of mediators, c-reactive protein (CRP), serum
amyloid A (SAA), Interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-8,
IL-15, IL-16, monocyte chemotactic protein (MCP)-1 and MCP-4, can be
broadly categorised as being associated with ongoing inflammatory
responses (Figure 1a)4. These mediators remained as
elevated in samples taken 6-9 months following hospital discharge as
those levels observed 3-6 months following discharge (p<0.05
versus controls, ANOVA). A second group of mediators, vascular
endothelial growth factor (VEGF-A), soluble tyrosine-protein kinase
receptor Tie-2 (Tie-2), soluble intercellular adhesion molecule (ICAM-1)
and basic fibroblast growth factor (bFGF), can be generally associated
with endothelial dysfunction, remodelling and angiogenesis (Figure
1b)5. The remaining elevated mediators are associated
with patterns of lymphocyte polarisation. Elevated IL-4,
macrophage-derived chemokine (MDC) and thymic stromal lymphopoietin
(TSLP) sera levels indicate activation of TH2 responses
(Figure 2a), while IL-17A, macrophage inflammatory protein (MIP)-3α and
IL-12/23p40 indicate ongoing TH17 activity (Figure 2b).
Other indicators of TH2-associated activities are just
outside statistical significance (IL-5, p=0.06; supplementary Table S2).
While TH1 responses are well described to be upregulated
during acute infection6, the levels of these mediators
(e.g. IFN-γ, IP-10) decrease following elimination of the virus and are
at control levels in our cohort of post-COVID patients (supplementary
Table S2).
Our data suggests that there are long term immunological consequences
following SARS-CoV-2 infection, at least in those that had acute
symptoms severe enough to require hospitalisation. While the relatively
low number of patients included in our study at this stage does not
allow us to perform subgroup analysis, it is possible that these immune
mediators may associate with clinically meaningful disease variables and
ultimately may be of therapeutic value, if findings are replicated in
future studies. Of particular interest is the elevation in
TH2-associated mediators. Could this response be a
component of the mucosal repair mechanisms that occur following viral
damage, or does this indicate new TH2-associated
pathological immune activity that might underpin an increased risk of
developing allergy or asthma? Clearly the potential immune mechanisms
underpinning the emerging post-COVID clinical entities will become
increasingly more important to understand as the health care systems
adapt to caring for large numbers of COVID-19 survivors during the
coming months and years.