key: cord-0931484-v37zpnxz
authors: Li, Xin; Liu, Lancong; Yang, Yi; Yang, Xuefeng; Wang, Cengceng; Li, Yan; Ge, Yanyan; Shi, Yuxin; Lv, Ping; Zhou, Hua; Luo, Pei; Huang, Shilong
title: Gender-Associated Difference following COVID-19 virus infection: Implications for Thymosin alpha-1 Therapy
date: 2020-09-18
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2020.107022
sha: e9be527202d17300120f5d317a00e509469fcde3
doc_id: 931484
cord_uid: v37zpnxz

Gender influences clinical presentations, duration and severity of symptoms, and therapy outcome in coronavirus disease 2019 (COVID-19) infection. Whether the immune response to Tα1 treatment for SARS-CoV-2 differs between the sexes, and whether this difference explains the male susceptibility to COVID-19, is unclear. This study aimed to investigate the efficiency and safety of Tα1 treatment and provide a basis for practically identifying gender differences characteristics and features of COVID-19. One hundred twenty-seven patients had COVID-19 symptoms and tested COVID19-positive (female 42.52%) in Wuhan union hospital were enrolled for medication. They were randomly divided into groups Control and Tα1 intervention. Seventy-eight patients received a subcutaneous injection of 1.6mg Tα1, based on supportive treatment for 15 days. The control group included untreated 49 COVID19 patients closely matched for gender and age and received regular supportive treatment. In this retrospective analysis, we found that COVID-19-infected males reported more symptoms than COVID-19-infected females. A high degree of gender differences-related variability was observed in CRP and PCT levels and the cell counts of many lymphocyte subpopulations in the COVID-19 patients after Tα1 intervention. Levels of CRP and IL-6 were higher in Tα1-treated male group than Tα1-treated female group, while the level of PCT was significantly lower in Tα1-treated male group. Gender differences may be a factor in sustaining COVID-19 immunity responded to Tα1, male and female show statistically significant differences in relevance to cytokine production associated with the development of a more significant number of symptoms. This leaves the question of identifying gender-specific risk factors to explain these differences.

127 Besides, comorbidities were classified according to the organ system, including the respiratory 128 system, cardiovascular system, and endocrine system. The endpoint of our study was a synthetic 9 

It has been identified as a zoonotic coronavirus, similar to SARS and 56 MERS coronavirus and named SARS-CoV-2 [1,2] . As of

National Health Commission of the People's Republic of China and State Administration of 61 Traditional Chinese Medicine issued a Diagnosis and Treatment Protocol for Novel Coronavirus

Based on nutritional support, antiviral treatments should 65 be useful in fighting COVID-19. Interferons, intravenous gamma globulin, thymosin-α1, 66 thymopentin, levamisole, cyclosporine A and traditional Chinese medicine are also used for clinical 67 intervention

Tα1 is a thymic peptide that demonstrates a peculiar ability to restore immune system homeostasis in 69 different physiological and pathological conditions acting as multitasking protein depending on the 70 host state of inflammation or immune dysfunction [6] . It is a heat-stable highly acidic molecule 8 156 acquired infection. Respiratory support was provided to 108 patients(71 patients in Tα1 intervention 157 group，37 patients in control group), of which 85.04% were used nasal cannula or face mask and 158 7.87% used high flow nasal cannula or non-invasive mechanical ventilation，with only one patient 159 used invasive mechanical ventilation

45% of 161 patients, and the lymphocyte count was decreased by 62.99% of the patients. On admission, 81.89 % 162 of patients showed pneumonia on chest CT scans

Compared with the Tα1 intervention group, these patients were older and the duration was longer 165 (Table 1)

The 169 average levels of CD3 + T cells, CD8 + T cells and D-Dimer in Tα1 intervention group were 170 significantly higher than those in control group (CD3 + T cells P=0.003 ; CD8 + T cells P=0.010; D-171 dimer P=0.034), and the average levels of NK lymphocytes, IL-2, IL-4, TNF-α and C-reactive protein 172 were significantly lower than those in control group

The Tα1 intervention group's cure rate was higher than 174 that of the control group, and the average level of CRP in Tα1 group was significantly lower than 175 control group. There was no significant difference in PCT and IL-6 between the two groups

Figure 1 Unadjusted risk of the level of T lymphocyte subsets, cytokines, D-dimer, C-reactive protein, 187 procalcitonin and homocysteine were comparing Tα1 intervention group with control group

A high 192 degree of gender differences-related variability was observed in the cell counts of many lymphocyte 193 subpopulations in the COVID-19 patients' group after Tα1 intervention

Tα1-treated male group. Meanwhile, levels of B lymphocytes (14.92 ± 9

85pg/ml) and CD4+ T cells to CD8+ T cell ratio (2.14 ± 0.90 vs 198 1.69 ± 0.87) were significantly lower in Tα1-treated male group (Figure 2 A)

93 ± 2.16 pg/ml vs 2.02 ± 0.83 pg/m) and CRP (43.66 ± 43.07 mg/L vs 25.53 ± 30.18 mg/L) were 203 significantly lower in Tα1

Tα1 intervention and age on gender differences-related. CD8+ T cells 205 (28.47 ± 9.46% vs 23.86 ± 8.51%), NK lymphocytes (9.48 ± 5.99% vs 6.52 ± 4.54%), IL-6 (13.70 ± higher in males than females with Tα1 intervention group. While CD4+ T cells

± 9.90% vs 46.77 ± 9.31 %)

The CRP level decreased after the Tα1 intervention both males and females, and Tα1-treated female 211 group significantly lower than control group. The level of IL-6 decreased in Tα1-treated female group 212 compared to control group, but the difference was not significant. The level of IL-6 was higher in T 213 α1

This is how we discovered that age was a factor influencing CRP and IL-6 elevation in males. Levels 215 of CD8+ T cells (30.66 ± 12

Coronaviridae Study Group of the International Committee on Taxonomy of

COVID-19: 286 consider cytokine storm syndromes and immunosuppression

State Administration of Traditional Chinese Medicine. Diagnosis 289 and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 4

Potential interventions for novel coronavirus in China: A 291 systematic review

Thymosin alpha 1 and HIV-1: recent advances and future perspectives

The origin, transmission and clinical 296 therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status. Military 297

Thymosin alpha1: isolation and sequence 299 analysis of an immunologically active thymic polypeptide

Pathogenic human coronavirus infections:causes and 312 consequences of cytokine storm and immunopathology

Induction of pro-inflammatory cytokines (IL-1 and 315 IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory 316 strategies

Liver injury in COVID-19: management and 318 challenges

The use of anti-inflammatory drugs in the 320 treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of 321 clinical immunologists from China

Clinical characteristics of 50466 hospitalized patients with 2019-nCoV 323 infection

Pathological findings of COVID-19 associated with acute 325 respiratory distress syndrome

Clinical investigation of outbreak of nosocomial severe acute 327 respiratory syndrome

Characteristics and prognostic factors of disease 329 severity in patients with COVID-19: The Beijing experience

The laboratory tests and host 332 immunity of COVID-19 patients with different severity of illness

Abnormal Hemostatic Parameters and Risk of

Gender Differences in Patients 337 With COVID-19: Focus on Severity and Mortality

Preliminary study on sex-related 339 inflammatory reactions in mice infected with Schistosoma mansoni

The influence of age and sex on the cell counts of 342 peripheral blood leukocyte subpopulations in Chinese rhesus macaques

Macrophages: regulators 345 of sex differences in asthma?

Sex Differences in Susceptibility to Viral Infection

Sex Hormones and Immunity to Infection

Sex influences immune responses to viruses, and efficacy of prophylaxis 349 and therapeutic treatments for viral diseases

Therapeutic strategies for critically ill patients with COVID-19

What we know so far: COVID-19 current clinical knowledge and research

Sruthi Acute ST Elevation Myocardial Infarction

Evaluation of procalcitonin, C-358 reactive protein, interleukin-6 & serum amyloid A as diagnostic biomarkers of bacterial infection 359 in febrile patients

Andrés Martínsepsis from non-infectious systemic inflammatory response syndrome

Cellular 367 proteostasis: a new twist in the action of thymosin α1

The effect of thymosin α1 for prevention of 370 infection in patients with severe acute pancreatitis

Historical review of thymosin α 1 in infectious 373 diseases

An experimental trial of 375 recombinant human interferon alpha nasal drops to prevent COVID-19 in medical staff in an 376 epidemic area