Thymosin alpha 1 (Tα1) reduces the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells
clinical drug discovery/repurposing immunology/immunity
Authors: Lui Y …. Chen Y.
Journal/ Pre-Print: Clinical Infectious Diseases
Tags: Immunology/Immunity, Clinical trial, Drug discovery/Drug repurpose
1. Severe and critical COVID-19 patients treated with Thymosin α 1 (10mg daily for >7 days) had a lower mortality rate and less need of mechanical ventilation than patients without Thymosin α 1.
2. Tα1 treatment was associated with an increase in T lymphocyte counts, evident in the most lymphopenic patients.
3. The course of Tα1 treatment was associated with an increase in recent thymic emigrants and a corresponding drop in the proportion of CD8+ T cells expressing exhaustion markers (PD-1 and TIM-3).
The daily administration of thymosin alpha 1 (Tα1) to 36 severe and critical COVID-19 patients was assessed for potential clinical and immunological benefit in this retrospective study. Treatment with 10mg Thymosin alpha 1 daily for > 7 days was associated with lower mortality (11% vs 30%) and less patients requiring mechanical ventilation (5% vs 28%). No side effects associated with Tα1 were reported in this patient cohort
Tα1 treatment was associated with an increase in T lymphocyte counts in the most lymphopenic patients. This effect was also noticeable in the elderly and those with pre-existing conditions. The increase in T cell counts correlated with an increase in recent thymic emigrants and a corresponding drop in the proportion of CD8+ T cells expressing exhaustion markers, such as PD-1 and TIM-3.
Impact for SARS-CoV2/COVID19 research efforts
Treatment of SARS-CoV2/COVID19 positive individuals
· Clinical Cohort study (e.g. drug trials)
Strengths and limitations of the paper
Novelty: This early retrospective study suggests that Tα1 could be a clinically viable and well tolerated COVID-19 treatment, ahead of upcoming findings from larger clinical trials.
Standing in the field: Thymosin alpha 1 has been postulated as a potential repurposed therapy1,2, yet data on its benefit in COVID-19 patients is still being collected.
Appropriate statistics: The statistical tests are not described.
Viral model used: SARS-CoV-2 PCR confirmed severe/critical patients from Wuhan from December 2019 and March 2020.
Translatability: Tα1 may confer some clinical benefit in severe COVID-19 cases. This initial data needs to be validated by larger cohorts in formal clinical trials.
- Small cohorts throughout the study: seventy-six severe or critical COVID-19 patients (thirty-six received Tα1 and forty did not); thirty-four patients in T cell count analysis; twelve patients in exhaustion analysis, with only 9 in TREC analysis.
- Variation within the ‘severe’ and ‘critical’ cohorts is not reported, and the co-morbidities of participants are not detailed. These should be in declared in Table 1 alongside the variance of treated and non-treated cohorts.
- As a retrospective cohort study, this study constitutes a lower level of evidence than if it had been designed as a randomised, controlled trial3.
- Mortality is the sole clinical outcome; this should be measured in conjunction with other outcomes, such as ‘time to extubation’. .
- The labelling of Figure 2 is inverted. In its current state it would suggest patients that received Tα1 treatment were more likely to be ventilated.
- The labelling in Figure 3 should be more explicit in order to demonstrate how many patients are represented in each graph, and the demographics of those patients. For example, what proportion of the patients involved in the analysis are over the age of sixty.
- The authors conclude that their study demonstrates treatment with Tα1 reverses exhaustion of T cells. This conclusion is limited in at least two ways. First, there is no evidence presented to suggest that the apparent reversal of exhaustion is de to dilution of these exhausted T cells with naïve T cells. Second, it is tenuous to claim that the T cells measured are exhausted on the basis of a single stain for a debatable marker of exhaustion. Further evidence should be provided to support the conclusions. Additionally, it is unclear whether the changes in immunological parameters were due solely to therapy and not disease progression. Thus, it would have been useful to have followed the untreated patients in the same way as the treated patients.
1. Iino, S. et al. The efficacy and safety of thymosin alpha-1 in Japanese patients with chronic hepatitis B; results from a randomized clinical trial. J. Viral Hepat. 12, 300–306 (2005).
2. Naylor, P. H. & Mutchnick, M. G. Immunotherapy for hepatitis B in the direct acting antiviral era: Reevaluating the thymosin α1 efficacy trials in the light of a combination therapy approach. J. Viral Hepat. 25, 4–9 (2018).
3. Phillips, B. et al. Levels of Evidence. Centre for Evidence Based Medicine. (2009).