From the Guidelines
The severity of Coronavirus disease (COVID-19) is significantly influenced by an imbalance between T helper 1 (Th1) and T helper 2 (Th2) immune responses, with severe cases characterized by an excessive Th1 inflammatory response and inadequate Th2 responses, as evident from the most recent and highest quality study published in the European Respiratory Journal in 2021 1.
Key Findings
- The imbalance between Th1 and Th2 immune responses contributes to the pathophysiology of severe COVID-19, where initial viral replication is followed by dysregulated immune responses rather than effective viral clearance.
- Patients with pre-existing conditions that affect immune regulation, such as autoimmune diseases or certain metabolic disorders, may be predisposed to more severe Th1/Th2 imbalances when infected with SARS-CoV-2.
- Therapeutic approaches targeting this imbalance include corticosteroids like dexamethasone, which have shown benefit in severe cases by dampening excessive inflammation, and immunomodulators like tocilizumab (an IL-6 receptor antagonist) that specifically target components of the cytokine storm, as supported by the European Respiratory Society living guideline published in 2021 1.
Mechanisms and Implications
- The Th1/Th2 imbalance in COVID-19 is characterized by elevated levels of pro-inflammatory cytokines like IL-6, TNF-α, and IFN-γ, which can lead to a hyperinflammatory state and damage to lung tissue and other organs.
- The use of anti-inflammatory treatments, such as corticosteroids and immunomodulators, can help mitigate this imbalance and improve outcomes in severe COVID-19 cases, as demonstrated by the UK RECOVERY trial and other studies 1.
- Understanding the immunological imbalance in COVID-19 can help explain why some individuals experience mild disease while others develop life-threatening complications, and inform the development of targeted therapeutic approaches to improve outcomes and reduce morbidity and mortality.
From the Research
Role of T helper 1 (Th1)/T helper 2 (Th2) imbalance in COVID-19
The imbalance of T helper type 1 (Th1) or T helper type 2 (Th2) cells has been well documented among populations who have suffered as a result of the COVID-19 pandemic, and who are at maximum risk of infection and mortality 2.
Th1 and Th2 cytokine endotypes
Studies have investigated the association of Th1 and Th2 cytokine/chemokine endotypes with cell-mediated immunity via multiplex immunophenotyping, single-cell RNA-Seq analysis of peripheral blood mononuclear cells, and analysis of the clinical features of COVID-19 patients 3.
- Two prominent clusters were of interest and could be used as prognostic reference for a targeted treatment of severe COVID-19 cases.
- Cluster III reflected severe/critical pathology and was characterized by decreased in CCL17 levels and increase in IL-6, C-reactive protein CXCL9, IL-18, and IL-10 levels.
- Cluster II showed mild to moderate pathology and was characterized by predominated CXCL9 and IL-18 levels, levels of IL-6 and CRP were relatively low.
Early Th1 response
An early Th1 response is a key factor for a favorable COVID-19 evolution 4.
- Asymptomatic SARS-CoV-2 infected individuals showed a potent and robust Th1 immunity, with a lower Th17 and less activated T-cells at the time of sample acquisition compared not only with symptomatic patients, but also with healthy controls.
- Severe COVID-19 patients presented with Th17-skewed immunity, fewer Th1 responses and more activated T-cells.
- The Th1 response was an independent protective factor for the prevention of hospitalization and severe forms of the disease.
Early Th2 inflammation
Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids has been investigated 5.
- Individuals with COVID-19 who clinically deteriorated showed an early blunted respiratory interferon response and pronounced and persistent Th2 inflammation, mediated by CC chemokine ligand (CCL)-24, compared with those with COVID-19 who did not clinically deteriorate.
- Budesonide treatment modulated inflammation in the nose and blood and was shown to decrease IL-33 and increase CCL17.
Melatonin as an adjunctive treatment
Melatonin has been evaluated as an adjunctive treatment for COVID-19, with a focus on its effects on Th1 and Th2 mediated cellular and humoral immunity 6.
- Adjuvant therapy with melatonin controlled and reduced inflammatory cytokines in patients with COVID-19.
- Melatonin also controlled and modulated the dysregulated genes that regulate the humoral and cellular immune systems mediated by Th1 and Th2.