The present study demonstrates higher age, decrease in Hb%, haematocrit and increase in TLC, polymorph count, monocyte count & serum ferritin level in severely ill patients which reflect acute phase response in viral infection. Lower lymphocyte counts in peripheral blood are a consistent finding in patients with severe Covid-19 2 as was seen in our study as well. Not only lymphocyte depletion, there was a severity dependant decrease in response to mitogen stimulation of lymphocytes also (Table 1). T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in viral infections as well as cancerand is often described with severe covid-19 patients.15,16 In addition to decrease in count, T cells exhaustion is identified with loss of interleukins in a hierarchical manner where (IL)-2 and tumor necrosis factor (TNF) are always decreased significantly followed by interferon (IFN)-γ and beta-chemokine production.17,18 COVID-19 patients however have shown very high levels of IL- 2, IL-7, IL-10, TNF-α, G-CSF, IP-10, MCP-1, and MIP-1A 2,19 which is in contradiction to the exhausted status of T cells with decreased levels of (IL)-2, (TNF) and (IFN)-γ.17,18 Moreover, T cell exhaustion is described to effect antigen-specific T cells due to excessive and persistent antigenic exposure.18 The present study however demonstrated poor response to even mitogen which stimulate a large proportion of normal lymphocytes to respond in a manner similar to their response by specific antigens. It could therefore be concluded that there exists a dysregulated immune response in all critically ill Covid-19 patients. However, whether the mechanism to evoke such compromised immunity is T cell exhaustion or T cell anergy which is failure of T cells to proliferate and to produce cytokines preferentially in Th1 cells20 remains to be proved. All critically ill Covid-19 patients showed severe unresponsiveness by the mycobacterium specific T cells while they remain high on IL-6 level. These patients are also seen to have increased level of IL-10 which is known to be involved in the induction of anergy in CD4 + T cells by selectively impairing signalling through the TCR/CD3 complex21 thus favouring later to be more probable.
Fifty percent of our study population of healthy volunteers or asymptomatic/mild Covid-19 patients was strongly positive for Mtb IGRA depicting good community exposure to tubercular antigen. The 95% of remaining half of the study group had BCG scar and evidently had Mtb antigenic exposure to their immune system sometime in past. Not only the distribution of Quantiferon TB gold test positivity was lowest (3 out 20 in gr S vs 10 out of 20 in gr A) in group S (table 1), but Quantiferon TB gold test positivity was associated with increased survival also in severe COVID-19 (table2). All these findings indicate that latent TB or recent TB exposure might have some beneficial effect with reference to severity and mortality in COVID-19. Similar observations were made authors who reported strong correlation between the BCG index, an estimation of the degree of universal BCG vaccination deployment in a country, and COVID- 19 mortality in different socially similar European countries (r2 = 0.88; P = 8 × 10−7).12
COVID-19−related deaths are significantly higher in countries with higher quality of life, contradicting the expectation of lower rates of mortality in countries with improved health care systems.12 Though India has become the third highest country with maximum number of Covid-19 patients, it continues to shows significantly lower prevalence of the disease, both in terms of disease and deaths per million population in comparison to other top 15-20 countries.22 Natural course for most of Covid-19 patients in Th1 predominant population may be to remain asymptomatic or minimally symptomatic which is reflected in the epidemiological reports from India and other similar countries like south America etc.12 Patients with moderate to severe symptoms from such a population, probably have pre-existing low immunity due to malnutrition or an associated co-morbidity. An unforeseen Th2 predominance due to worm infestation, subtle autoimmune or allergic disorder etc. affecting these patients could be another compounding factor and deserves further exploration.
None of the subject from our study group had ever been administered an influenza vaccine showing its nearly negligible prevalence. Consequently, frequent affection to common cold, common habit of eating spicy food, relative unhygienic environment, a common religious practice of performing Hawan and Arti etc. which involves sublimating mixture of wood with odoriferous and medicinal herbs in the fire exposing nasal, respiratory and gut mucosa to many irritants of ancient unproven qualities23 could possibly be contributing to an enhanced innate immunity among the Indian population. Besides its role in building up of innate immunity, the medicinal smoke from performing Hawan has been found to reduce bacterial counts also by 94% in 60 minutes and was seen to be maintained for 24 hours.24 Strong Th1 immunity can be attributed to lower worsening or progression of the disease in Covid-19 patients. This however is unlikely to cause lower infectivity of the disease among the population, which could only be obtained through measure like social distancing, tracking and quarantine the patients etc. or some unrecognized biological sentinels in the respiratory passage as pointed above.
D-dimer levels have been reported as a reliable prognostic marker for in-hospital mortality in patients admitted for Covid-19.25 75% patients in group A had D-dimer levels much above the cut off value of 2000 ng/ml25 which qualify them for initiating an anticoagulant therapy. None of such patients were prescribed with any anticoagulants and had no untoward incident for at least 8 weeks after the discharge from the hospital. Interestingly, patients in group S of severe disease with 70% mortality also showed raised D-dimer levels but of lesser magnitude than the Group A. Such observations dictate to hypothesize that increased D-dimer level may be an independent risk factor for producing state of hypercoagulability but is likely to benefit patients through T cell independent immune mechanism. Various Th2 cytokines IL-4, IL- 10 and IL-13 have been shown to deactivate monocytes and macrophages and also to downregulate fibrinogen biosynthesis.26 Higher fibrinogen degradation products and D-dimer are reported in patients with tuberculosis than community acquired pneumonia.27 It may therefore be inferred that Th1 immunity predisposes to increased fibrinogen or D-dimer level. D-dimer is reported to stimulate peripheral blood monocytes to secrete IL-6 and TNF-α28 thus creating an additional pathway for inducing early innate immunity. This is supported by previous studies which suggested cytokine release not to originate from T cells but to trigger from monocytes and macrophages in COVID-19 patients.3 Such an altered pattern of D-dimer levels in our population and its pathogenesis deserves to be substantiated with further studies.
The present study is constrained by its smaller sample size and lack of a detailed corroborating cytokine profile of all subjects. BCG vaccine has been suggested to be used as prophylaxis against Covid-19. It has merit theoretically but is difficult to be established due to BCG vaccine’s long preparatory period and known poor efficacy in adult population.12 The present work probably establishes a direct correlation between Mtb induced Th1 immunity and protection against Covid-19. The restoration of Th1/Th2 imbalance may be a more natural strategy to fight against Covid-19. The novel and explicit results should stimulate researchers to explore treatment options with broad and long-term benefits than to develop a highly specific but short-lived prophylaxis.