The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19

Schultheiß, Christoph; Willscher, Edith; Paschold, Lisa; Gottschick, Cornelia; Klee, Bianca; Henkes, Svenja-Sibylla; Bosurgi, Lidia; Dutzmann, Jochen; Sedding, Daniel; Frese, Thomas; Girndt, Matthias; Höll, Jessica I.; Gekle, Michael; Mikolajczyk, Rafael; Binder, Mascha

doi:10.1016/j.xcrm.2022.100663

Cited by 273 publications

(301 citation statements)

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“…Several studies have demonstrated a prolonged SARS-CoV-2 shedding in the respiratory tract, faeces, and intestinal biopsies, even in asymptomatic patients [ 47 , 48 ]. This could lead to an exacerbated immune response resulting in increased levels of proinflammatory cytokines, including interleukin (IL)-6, IL-1β, and TNF [ 49 , 50 ]. A persistent proinflammatory state could explain organ damage and prolonged symptoms, such as fatigue, headache, and smell impairment [ 46 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Prevalence and clinical presentation of long COVID in children: a systematic review

et al. 2022

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A systematic literature review was conducted up to 15th February 2022 to summarize long COVID evidence and to assess prevalence and clinical presentation in children and adolescents. Articles reporting long COVID prevalence and symptoms based on original data in the paediatric population were included. Case series quality was assessed through the JBI Critical Appraisal Checklist. For observational studies, adherence to STROBE checklist was evaluated. Twenty-two articles were included: 19 observational studies (12 cohort/7 cross-sectional) and 3 case series. Nine studies provided a control group. We found a high variability in terms of prevalence (1.6–70%). The most frequently reported symptoms were fatigue (2–87%), headache (3.5–80%), arthro-myalgias (5.4–66%), chest tightness or pain (1.4–51%), and dyspnoea (2–57.1%). Five studies reported limitations in daily function due to long COVID. Alterations at brain imaging were described in one study, transient electrocardiographic abnormalities were described in a minority of children, while most authors did not evidence long-term pulmonary sequelae. Older age, female sex, and previous long-term pathological conditions were more frequently associated with persistent symptoms. Conclusion : Long COVID evidence in children is limited, heterogeneous, and based on low-quality studies. The lockdown consequences are difficult to distinguish from long COVID symptoms. High-quality studies are required: WHO definition of long COVID should be used, controlled clinical studies should be encouraged, and the impact of new variants on long COVID prevalence should be investigated to ensure an objective analysis of long COVID characteristics in children and a proper allocation of healthcare system resources. What is Known: • Children rarely develop a severe respiratory disease in the acute phase of COVID-19. • A limited number of patients develop a multisystem inflammatory condition that can lead to multiorgan failure and shock. What is New: • Persistent symptoms after SARS-CoV-2 infection are reported in children and limitations in daily function due to long COVID symptoms affect school attendance. • Functional complaints of post-acute COVID are difficult to be distinguished from those due to social restrictions. Supplementary Information The online version contains supplementary material available at 10.1007/s00431-022-04600-x.

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Section: Discussionmentioning

confidence: 99%

Prevalence and clinical presentation of long COVID in children: a systematic review

et al. 2022

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“…IL6 secretion from B cells correlates with the severity of humoral autoimmune disease [ 30 ], and IL6 is involved in the pathogenesis of IgAN by promoting IgA production [ 17 , 31 ]. In addition, sustained IL-6 activity also affects the development of ME/CFS and neuropsychiatric symptoms of Long COVID [ 14 , 18 , 32 ]. It is thought that one of the causes is that IL-6, which is an inflammatory cytokine, crosses the blood–brain barrier and affects the energy metabolism of neurons [ 18 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis

Nishi

Yoshimoto

Nishi

et al. 2022

IJMS

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The epipharynx, located behind the nasal cavity, is responsible for upper respiratory tract immunity; however, it is also the site of frequent acute and chronic inflammation. Previous reports have suggested that chronic epipharyngitis is involved not only in local symptoms such as cough and postnasal drip, but also in systemic inflammatory diseases such as IgA nephropathy and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID. Epipharyngeal Abrasive Therapy (EAT), which is an effective treatment for chronic epipharyngitis in Japan, is reported to be effective for these intractable diseases. The sedation of chronic epipharyngitis by EAT induces suppression of the inflammatory cytokines and improves systemic symptoms, which is considered to be one of the mechanisms, but there is no report that has proved this hypothesis. The purpose of this study was to clarify the anti-inflammatory effect of EAT histologically. The study subjects were 8 patients who were not treated with EAT and 11 patients who were treated with EAT for chronic epipharyngitis for 1 month or more. For immunohistochemical assessment, the expression pattern of IL-6 mRNA, which plays a central role in the human cytokine network, was analyzed using in situ hybridization. The expression of IL-6 in the EAT-treated group was significantly lower than those in the EAT nontreated group (p = 0.0015). In addition, EAT suppressed the expression of tumor necrosis factor alpha (TNFα), a crucial proinflammatory cytokine. As a result, continuous EAT suppressed submucosal cell aggregation and reduced inflammatory cytokines. Thus, EAT may contribute to the improvement of systemic inflammatory diseases through the suppression of IL-6 expression.

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“…A not yet published study showed a long-lasting cytokine signature in patients with prior COVID-19 where IL-1β, IL-6, and TNF-α showed a significant correlation with post-acute COVID-19. Bronchoalveolar lavage fluid of patients with acute COVID-19 indicated that these cytokines were concentrated in the pro-inflammatory subset of lung macrophages [ 255 ]. Further, a follow-up prospective study of 113 patients who developed ARDS during admission for COVID-19 found that 81% had persistent symptoms eight months post-infection suggesting that COVID-19-related ARDS is associated with long-term consequences of COVID-19 [ 233 ].…”

Section: Long-term Complications Of Covid-19mentioning

confidence: 99%

Virus Infection and Systemic Inflammation: Lessons Learnt from COVID-19 and Beyond

Faist

Janowski

Kumar

et al. 2022

Cells

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Respiratory infections with newly emerging zoonotic viruses such as SARS-CoV-2, the etiological agent of COVID-19, often lead to the perturbation of the human innate and adaptive immune responses causing severe disease with high mortality. The responsible mechanisms are commonly virus-specific and often include either over-activated or delayed local interferon responses, which facilitate efficient viral replication in the primary target organ, systemic viral spread, and rapid onset of organ-specific and harmful inflammatory responses. Despite the distinct replication strategies, human infections with SARS-CoV-2 and highly pathogenic avian influenza viruses demonstrate remarkable similarities and differences regarding the mechanisms of immune induction, disease dynamics, as well as the long-term sequelae, which will be discussed in this review. In addition, we will highlight some important lessons about the effectiveness of antiviral and immunomodulatory therapeutic strategies that this pandemic has taught us.

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The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19

Cited by 273 publications

References 100 publications

Prevalence and clinical presentation of long COVID in children: a systematic review

Prevalence and clinical presentation of long COVID in children: a systematic review

Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis

Virus Infection and Systemic Inflammation: Lessons Learnt from COVID-19 and Beyond

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