key: cord-0906166-xe53rn0p authors: Arslan Gulen, Tugba; Bayraktar, Muhammet; Yaksi, Nese; Kayabas, Uner title: Is the course of COVID‐19 associated with tuberculin skin test diameter? A retrospective study date: 2021-10-29 journal: J Med Virol DOI: 10.1002/jmv.27414 sha: 23e3ddc9f678863bdb2128f5fefc44f44cd7f711 doc_id: 906166 cord_uid: xe53rn0p The pathogenesis of coronavirus disease 2019 (COVID‐19) is still not fully understood. As severe acute respiratory syndrome coronavirus 2 (SARS‐COV‐2) has a similar pathogenetic pathway to Mycobacterium tuberculosis, it has been reported that there may be a relationship between Bacille Calmette–Guérin (BCG) vaccination rate and COVID‐19 severity. This study investigated the relationship between tuberculin skin test (TST) induration diameter and the clinical course of COVID‐19. Of 1963 adult patients who underwent TST, 76 patients with SARS‐COV‐2 infection confirmed by RT‐PCR analysis of respiratory tract samples were included in the study. Relationships between COVID‐19 clinical severity and TST positivity, induration size, and other clinical parameters were analyzed. Of the 76 patients, TST results were negative for 53 patients (69.7%) and positive for 23 patients (30.3%). COVID‐19 severity was mild in 47 patients (61.8%), moderate in 22 patients (28.9%), and severe in seven patients (9.3%). All TST‐positive patients had mild disease. Patients with mild disease had a significantly higher TST positivity rate (p < 0.001) and larger induration diameter (p < 0.001). The area under the receiver operating characteristic (ROC) curve of TST induration size for the differentiation of mild with moderate and severe disease was 0.768 (p < 0.001). The maximum Youden J index value was 0.522 at an induration diameter of 6.5 mm, which had a sensitivity of 66.0% and specificity of 86.2%. COVID‐19 patients with positive TST showed a significantly higher rate of mild disease than those with negative TST. TST positivity is favorably associated with the course of COVID‐19. Since December 2019, the world has been fighting coronavirus disease 2019 , caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and scientists worldwide have been working intensively to elucidate the pathogenesis. Although descriptive studies show that the public has complied with the numerous measures recommended by authorities for disease prevention, they also reflect an increase in people's perceived stress levels since the start of the pandemic. 1 As the course of COVID-19 varies from person to person, identifying the factors affecting the clinical course has been a primary concern. Various risk factors have been identified in relation to the complications and severity of COVID-19, but there is still much that remains unclear about the virus. The dominant opinion remains that the host immune response affects the outcome of the disease. SARS-CoV-2 causes mild disease in most infected patients; however, high proinflammatory cytokine levels have been associated with a more severe clinical course and systemic complications in some patients. 2 Nuclear factor-kappa B (NF-κB) is a ubiquitous dimeric transcription factor whose activity is regulated by various cytokines and J Med Virol. 2021; 1-7. wileyonlinelibrary.com/journal/jmv © 2021 Wiley Periodicals LLC | 1 other external stimuli. NF-κB plays a role in the activation of immune cells by increasing the expression of many cytokines required for immune system activation. 3 NF-κB activation is known to play a role in the pathogenesis of Mycobacterium tuberculosis infection [4] [5] [6] and was also shown to have a key role in the pathogenesis of SARS-CoV infection. [7] [8] [9] Similar pathogenetic properties of these etiological agents gave rise to hypotheses that Bacille Calmette-Guérin (BCG) immunization may protect against COVID-19 or reduce its severity, and various studies have been conducted to test these hypotheses. [10] [11] [12] In a large-scale study evaluating the correlation between total COVID-19 deaths and BCG vaccine coverage across 173 countries, it was observed that COVID-19-related mortality is lower in countries with high BCG vaccination rates. 13 BCG immunization has been shown to induce histone modifications and epigenetic reprogramming of innate immune cells and lead to a more active natural immune response to restimulation and reduced susceptibility to respiratory tract infections due to trained immunity. 14, 15 To further investigate the possibility that BCG immunization may TSTs were interpreted as recommended by the Centers for Disease Control and Prevention (CDC). Cases were considered TST positive if the induration was 10 mm or larger in individuals without BCG vaccination and those living or working in high-risk collective environments, 15 mm or larger in BCG vaccinees, and 5 mm or larger in immunocompromised individuals with radiological findings suggestive of previous TB infection. 16 The clinical classification of COVID-19 was based on the fol- Continuous variables that met the assumptions for parametric tests were presented as mean ± SD, and those that did not were presented as median (minimum-maximum) values. χ 2 and Fisher's exact significance tests were used in the analysis of categorical variables. Differences between pairs of groups were evaluated using Kruskal-Wallis H with post hoc analysis using Dunn's test. Receiver operating characteristic (ROC) analysis was used to determine the value of TST diameter in the prediction of COVID-19 severity and identify a cut-off point. The power of the study was calculated as 87% by performing a power analysis with the OpenEpi program. The population in Nigde province is approximately 350,000. Between and showed that COVID-19 incidence and fatality rates were lower in countries with a high TB incidence when compared with countries with low TB incidence and especially in low-TB countries with higher BCG vaccine coverage when compared with low-TB countries with lower BCG vaccine coverage. 26 There were no BCG scars in three patients, two of whom were in the severe and one in the moderate patient group. In correlation with the results of many studies on BCG vaccination in the literature, at least one BCG scar was detected in all patients in the mild disease group. These results suggest that in BCG vaccinees, the course of COVID-19 may be milder due to the immune response to SARS-CoV-2, which has a pathogenetic effect on the same pathway of CD4+ cell-mediated trained immunity activation. In a study investigating the effect of TB contact and BCG vaccination on the course of COVID-19 in healthcare workers, it was found that the rate of BCG vaccination was higher in those with a history of COVID-19-related hospitalization, in contrast to many studies in the literature and our results. In the same study, higher mean TST results were found in outpatients compared to inpatients, although there was no significant difference. 30 We observed that patients with positive TST results were significantly more likely to have mild COVID-19 disease compared to those with negative TST, too. The results of ROC analysis to examine the relationship between high specificity helps rule out the disease, while a positive result in a test with high sensitivity is useful in determining that the disease exists in the patient being tested. 32 Accordingly the high specificity values observed for TST induration sizes greater than 9.5 mm were also consistent with the finding discussed above, that patients with TST induration size of 10 mm and larger had significantly milder disease than patients with indurations smaller than 10 mm. As a result of the comparison of the lymphocyte counts of the patients in terms of the severity of COVID-19, it was revealed that there was a statistically significant difference between the mild and severe patient groups. These results support the literature data. The present study has some limitations. As the data were collected retrospectively and the study sample was small, we could not use To summarize our findings, COVID-19 patients with positive TST showed a significantly higher rate of mild disease than those with negative TST. It is possible to say that TST positivity is favorably associated with the course of COVID-19. The authors declare that there are no conflicts of interest. 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