Among all patients admitted to this multicenter cohort that analyzed data from 37 Brazilian hospitals, the frequency of tuberculosis was small, with a ratio of 6:1000 individuals. Nevertheless, our records allowed the comparison of individuals with a previous history of TB and its respective matched control group. In our data we have found significant differences between both groups, since the presence of COPD, psychiatric diseases, hypertension, previous solid organ transplant and the use of illicit drugs were higher in the TB group. These are known risk factors for tuberculosis. It was also possible to observe a substantial difference between the use of medications such as immunosuppressants, oral and inhalatory corticoids, which were also higher in the case group. We did not find significant differences in the outcomes such as in-hospital mortality, IMV requirement, need for dialysis and ICU admission.
One of these differences was a higher frequency of COPD in patients with previous TB. The organism’s inflammatory response against Mycobacterium tuberculosis leads to cytokine and chemokine releases, which can cause lung damage, resulting in COPD [7]. This can be corroborated by the findings of the study, since patients with a history of tuberculosis had a higher incidence of COPD when compared to the control group (15% vs 3.2%, p <0.001). However, even with the higher rate of COPD patients in our case group, the frequency of dyspnea (58.8% vs 65.2%, p=0.347) and cough (62.5% vs 53.8%, p=0.203) were similarly reported by both groups in the acute phase of the disease.
The awareness of the differences in study patients regarding the presence of comorbidities, such as COPD, and their role in the prognosis of Covid-19 in these subjects may be fundamental to improve patient care. Patients with COPD and Covid-19 have a higher risk of developing severe pneumonia, and the pathophysiological mechanism explaining this may be related to the greater availability of angiotensin-converting enzyme 2 (ACE2) receptors in the small airways [19]. SARS-CoV 2 has an invasion mechanism into the body cells by the recognition of the virus Spike protein predominantly by ACE2 receptors [20]. Another mechanism that explains the greater propensity to develop severe cases of pneumonia is the tissue damage caused by the disease itself, which results in poor underlying lung reserves [20]. However, ACE2 receptors appear to be more abundant in older male individuals, [21] which in itself may be a risk factor for developing severe forms of Covid-19 [22]. This study did not show tough a difference in outcomes of case and control groups, as far as acute phase is concerned. We have no information about the severity of COPD, which could have been relevant.
It should be noted that patients in the case group also had higher rates of solid organ transplants (5% vs 0.9%, p =0.033). Tuberculosis is one of the most frequent complications of solid organ transplantation [23,24], mainly because the prevalence of latent TB is high Brasil [25].
The reports of hypertension were smaller in patients with history of TB when compared with controls (35% vs 48%, p=0.048). A metanalysis points out that there is no correlation between hypertension in TB and non-TB patients, studies shown a higher and lower frequency of TB [26]. Hypertension is risk factor for mortality in TB patients [27], however it was not found as an independent risk factor for Covid mortality [28]. In this study we found no difference in admission systolic blood pressure levels between groups (128 vs 123 mm/Hg, p =0.823).
The rate of psychiatric diseases at baseline was also higher in patients with history of TB when compared to control (10% vs 3.5%, p=0.034). Despite the fact that the role of psychiatric diseases as a risk factor for developing TB is still under debate, schizophrenia and depression have shown to be possible risk factors for its development [29]. Both diseases share a strong relationship with social determinants, such as homelessness and poverty [29]. Unfortunately, our data did not retrieve social and economic variables to try to explore these issues in Covid-19 patients and those with a history of TB, but the association between psychiatric diseases and TB can reinforce that theory.
Illicit drug use was also higher at baseline in patients with a history of TB. Illicit drugs are a risk for TB infection [29], the use of illicit drugs facilitate close physical contact and also is higher in the homeless population, a group also at risk for TB [30]. The use of powder or crack cocaine can lead to pulmonary edema, pneumonia, alveolar hemorrhage and other lung damage. This damage, associated with cocaine effect reducing alveolar macrophage response and proinflammatory responses facilitate the infection from M. tuberculosis [31]. The relation of illicit drugs and Covid-19 was pointed out by Wang et al (2021), substance abuse was related to an increase in hospitalization and death rates in Covid-19 patients. However, there was no difference between these outcomes in our groups [32].
Besides psychiatric diseases and illicit drug use, chronic kidney disease (CKD) also presented a higher frequency in our case group at baseline, compared with controls (11.2% vs 2.8% p=0.004). Chronic kidney disease leads to malnutrition, oxidative stress, and inflammation, which impairs cell-mediated immunity. This state of immunosuppression can result in the reactivation of latent tuberculosis infections and even new TB infections. Consequently, TB incidence is higher in CKD patients than in non-CKD [33].
Furthermore, CKD is found as a risk factor for Covid hospitalization, severity, and mortality [34]. Data published by the Brazilian Covid-19 Registry shows that elevated blood urea nitrogen at admission is a risk for death in COVID patients [35] and higher creatinine levels at admission lead to greater chances for renal replacement therapy [36]. This evidence reinforces that kidney impairment is a risk factor for COVID severity, however little is known of the physiopathology of CKD and COVID severity [34]. Since CKD is a risk factor for TB infection, we advise that the population at risk for CKD should have priority in vaccination and boosts shots against COVID and clinicians have to better screen these patients for the presence or a history of TB and other infections [37].
Patients with a history of TB had significantly higher home use of inhaled corticosteroids and oral corticosteroids than the control group at baseline. The higher rate inhaled and oral corticosteroids use may explain better outcomes than those expected, since the use of specific corticosteroids can lead to better outcomes such as lower rate of need for ventilatory support [38,39]. In-hospital use of corticosteroids did not differ between groups (77.5 vs 81.8, p=0.477). However, further studies are necessary to support that home use of corticosteroids can contribute to better outcomes in patients with previous diagnosis of TB.
For this study, a few limitations were observed. First, all of our patients were retrieved through medical data, which resulted in a low number of patients with a history of TB. Second, this study was retrospective, this can lead to report bias from the medical records. In order to lessen the burden of this potential bias, data collected was audited for possible errors.