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The ancient Tuberculosis in the novel COVID-19 scenario

Abstract

Recently, the world has coped with the challenge of the novel SARS-CoV-2 rapid spreading, causing COVID-19. This scenario has overburdened health systems, forced social isolation, and interrupted some services, changing the way how health assistance is provided. The management of chronic infectious diseases such as tuberculosis is a sensitive matter in times when the control strategies are at risk. In this sense, how could a high burden disease such as tuberculosis affect or be affected when combined with the COVID-19 pandemic? Patients with tuberculosis have a social background and lung impairment that represent risks in the pandemic scenario of another widely transmitted respiratory disease. Thus, even with several questions remaining unanswered, research and public policies should be addressed to control the effects of the current highly contagious COVID-19 without forgetting how it will affect the natural progression of patients suffering from tuberculosis.

Keywords:
Tuberculosis; COVID-19; Pandemic

Recently, the world has coped with the challenging and rapid spread of the novel SARS-CoV-2, causing COVID-19. The clinical characteristics of COVID-19 range from asymptomatic status to acute respiratory distress syndrome and multiple organ dysfunctions. The rapid transmissibility and mortality caused by COVID-19 has overburdened staff of health services all around the world. To control the consequences of this health crisis that extends to a pandemic level, social isolation was forced with the maintenance of only essential services, which, in fact, has challenged health providers and the global economy. Given this scenario, it is worth remembering that historically, tuberculosis (TB) has been implied in high rates of morbidity and mortality, killing more than any other infectious disease, being a long-standing public health problem (Alagna et al., 2020Alagna R, Besozzi G, Codecasa LR, Gori A, Migliori GB, Raviglione M, et al. Celebrating World Tuberculosis Day at the time of COVID-19. Eur Respir J. 2020;55(4)2000650. https://doi.org/10.1183/13993003.00650-2020.
https://doi.org/https://doi.org/10.1183/...
). Since the early discovery of antimicrobial therapy, TB has been associated with drug resistance, suffering from the rise of multidrug-resistant Mycobacterium tuberculosis isolates (World Health Organization, 2019World Health Organization. Global Tuberculosis Report. 2019.). Now, we are still in the middle of COVID-19 pandemic; however, in times like these, how could a high burden disease such as TB affect or be affected when combined with the COVID-19 pandemic?

In general, patient retention and the accomplishment of the treatment schema are fundamental to cure TB. However, they are sensitive matters in times of overwhelmed health facilities that could expose fragilities in health systems (Saunders, Evans, 2020Saunders MJ, Evans CA. COVID-19, tuberculosis and poverty: preventing a perfect storm. Eur Respir J . 2020;56(1):2001348. https://doi.org/10.1183/13993003.01348-2020.
https://doi.org/https://doi.org/10.1183/...
). Patients with TB diagnosis should finish the treatment schema unless in exceptional cases this is not possible. If the treatment stops in high burden areas, it could cause further transmission of TB. Mainly in less-developed parts of the world, it is important that public health authorities keep active policies driven to directly observed therapy (DOTs), as recommended by the World Health Organization. Under these circumstances, alternatives for medication provision and patient following might be guaranteed by taking advantage of teleconsultation and a warranted aid of drug supply, supported by all necessary public health nursing, staffing, and appropriate facilities, to avoid losing patient compliance. One of the essential topics associated with TB control is the rapid laboratory diagnosis to deliver the correct identification and drug susceptibility profile of clinical isolates (World Health Organization, 2015World Health Organization. Implementing tuberculosis diagnostics: A policy framework 2015:39. https://doi.org/WHO/HTM/TB/2015.11.
https://doi.org/https://doi.org/WHO/HTM/...
). However, the current situation of overburden staff and facilities, the slow replenishing supplies, and sometimes the lack of investments, could lead to a reallocation of resources that compromise TB diagnosis (Louie et al., 2020Louie JK, Reid M, Stella J, Agraz-Lara R, Graves S, Chen L, et al. A decrease in tuberculosis evaluations and diagnoses during the COVID-19 pandemic. Int J Tuberc Lung Dis. 2020;24(8):860-2.). Initially, this may reflect in delays in test results or unavailable services, which means risks in increasing cases of untreated disease or in numbers associated with multi and extensively resistant TB. In addition, to keep TB stable, public policies should address the social protection of the vulnerable population, because poverty is the main social determinant influencing the background of increases in TB cases (Saunders, Evans, 2020Saunders MJ, Evans CA. COVID-19, tuberculosis and poverty: preventing a perfect storm. Eur Respir J . 2020;56(1):2001348. https://doi.org/10.1183/13993003.01348-2020.
https://doi.org/https://doi.org/10.1183/...
). For example, the impacts of the pandemic in health services are already experienced by slum communities (Ahmed et al., 2020Ahmed SAKS, Ajisola M, Azeem K, Bakibinga P, Chen Y-F, Choudhury NN, et al. Impact of the societal response to COVID-19 on access to healthcare for non-COVID-19 health issues in slum communities of Bangladesh, Kenya, Nigeria and Pakistan: results of pre-COVID and COVID-19 lockdown stakeholder engagements. BMJ Glob Heal 2020;5(8):e003042. https://doi.org/10.1136/bmjgh-2020-003042.
https://doi.org/https://doi.org/10.1136/...
) and maybe by those from remote areas. Together, all these events challenge the Sustainable Development Goals, which part of the targets figures in TB control. However, now this becomes a sensitive matter with potential decrease in cure rates and consequently the increased spread of resistant TB.

Part of the risks related to severe disease in COVID-19 are advanced age, hypertension, diabetes, cardiopathies and previous lung impairment. TB manifests as active disease, latent infection, or as sequelae of past disease (World Health Organization, 2018World Health Organization. Global tuberculosis report. Geneva, Switzerland: 2018.). Considering one of the biggest risks, which is previous lung injury, the presence of cases of MDR-TB and XDR-TB should be evaluated. Usually, this group of patients suffers from TB for longer periods. Resistance represents an element for chronification and sequelae, turning the medicines available into a more burdensome administration, with fewer options and more side effects (Datta, Evans, 2019Datta S, Evans CA. Healthy survival after tuberculosis. Lancet Infect Dis. 2019;19(10):1045-7. https://doi.org/10.1016/ S1473-3099(19)30387-1.
https://doi.org/https://doi.org/10.1016/...
). On the other hand, SARS- CoV-2 potentially evolve as viral sepsis and inflammatory-induced lung injury, leading to other complications, which in the case of TB represents a risk of progression from latent infection to active disease. In this sense, research should provide sufficient clinical evidence to point out prognosis and therapeutic strategies in these cases, as little is known about COVID-19 immunology. When considered the severity of the convergence TB/COVID-19, the risk of death could be 2.17 times higher with shorter time-to- death and longer time-to-recovery (Sy et al., 2020Sy KTL, Haw NJL, Uy J. Previous and active tuberculosis increases risk of death and prolongs recovery in patients with COVID-19. Infect Dis (Auckl). 2020;52(12):902-7. https://doi.org/10.1080/23744235.2020.1806353.
https://doi.org/https://doi.org/10.1080/...
), but a limited body of evidence has been presented until this moment (Liu et al., 2020Liu Y, Bi L, Chen Y, Wang Y, Fleming J, Yu Y, et al. Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity. MedRxiv. 2020:2020.03.10.20033795. https://doi.org/10.1101/2020.03.10.20033795.
https://doi.org/https://doi.org/10.1101/...
; Motta et al., 2020Motta I, Centis R, D’Ambrosio L, García-García JM, Goletti D, Gualano G, et al. Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts. Pulmonology. 2020;26:233-40. https://doi.org/10.1016/j.pulmoe.2020.05.002.
https://doi.org/https://doi.org/10.1016/...
; Tadolini et al., 2020Tadolini M, Codecasa LR, García-García JM, Blanc FX, Borisov S, Alffenaar JW, et al. Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases. Eur Respir J . 2020;56(1):2001398. https://doi.org/10.1183/13993003.01398-2020.
https://doi.org/https://doi.org/10.1183/...
). From that perspective, epidemiological data collection could answer if lung impairment caused by TB compromise patients recovering from SARS-CoV-2 infection or what are the best options to manage patients co-infected with TB. Regarding co-infection, the impact of antiviral therapy proposed against SARS-CoV-2 should be assessed over the anti-TB schema, because usually, anti-TB drugs are inactivated or have increased toxicity when co-administered with the drugs purposed to treat COVID-19 (Ong et al., 2020Ong CWM, Migliori GB, Raviglione M, MacGregor-Skinner G, Sotgiu G, Alffenaar JW, et al. Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC). Eur Respir J 2020;56. https://doi.org/10.1183/13993003.01727-2020.
https://doi.org/https://doi.org/10.1183/...
).

Although it has been controversial, initial observations suggest that there may be a link between vaccination with bacillus Calmette-Guérin (BCG) and a likely decrease in severe outcomes due to infection with SARS-CoV-2 (Miller et al., 2020Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv 2020; Preprint https://doi.org/10.1101/2020.03.24.20042937.
https://doi.org/https://doi.org/10.1101/...
). While studies are being conducted, BCG has arisen discussions on its role as a booster to the immune system, preparing it for other infections than those caused by M. tuberculosis (Belicchi-Ferrari et al., 2010Belicchi-Ferrari M, Bisceglie F, Buschini A, Franzoni S, Pelosi G, Pinelli S, et al. Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N4-ethylmorpholine thiosemicarbazonates. J Inorg Biochem. 2010;104(2):199-206. https://doi.org/10.1016/j.jinorgbio.2009.11.002.
https://doi.org/https://doi.org/10.1016/...
). Apparently, after BCG vaccination, a trained non-specific immunostimulatory response by monocytes and NK cells is prepared to deal with infectious diseases other than TB, sounding like a “memory” from innate immunological cells, crucial for the antiviral immune response (Maheshwari, Jain, 2020Maheshwari N, Jain A. Is There a Rationale for Using Bacillus Calmette-Guerin Vaccine in Coronavirus Infection? Viral Immunol 2020;00:1-7. https://doi.org/10.1089/vim.2020.0079.
https://doi.org/https://doi.org/10.1089/...
; Yitbarek et al., 2020Yitbarek K, Abraham G, Girma T, Tilahun T, Woldie M. The effect of Bacillus Calmette-Guérin (BCG) vaccination in preventing sever infectious respiratory diseases other than TB: Implications for the COVID-19 pandemic. Vaccine 2020;38($1):6374-80. https://doi.org/10.1016/j.vaccine.2020.08.018.
https://doi.org/https://doi.org/10.1016/...
). In this sense, some countries which have left the BCG vaccination have started clinical studies to evaluate the potential of BCG protecting against SARS-CoV-2. Even not being an effective strategy in TB combat, now BCG gains credit as an alternative to prepare the immune system against infectious diseases other than TB, so, its role as a compulsory vaccination has once again been discussed.

Another important point applied to TB management that could be suggested to COVID-19 diagnosis is the implantation of the GeneXpert platform. GeneXpert has been used in TB diagnosis detecting not only the presence of M. tuberculosis but also resistance to rifampicin for the presumptive detection of MDR-TB. The molecular basis of the method provides high sensitivity and specificity, and it is an easy performance tool for TB diagnosis. Using GeneXpert to detect SARS-CoV-2 could provide the availability of rapid results within a few hours, while the symptoms and radiological findings of COVID-19 are non-specific and could induce misdiagnosis. Moreover, it is a safe device to manage the high transmissibility of SARS-CoV-2. Due to the pandemic, in cases of severe complications of TB, the testing for COVID-19 should be endorsed as a precaution to the correct management of the case when both conditions are present (World Health Organization, 2020World Health Organization. Note: Tuberculosis and COVID-19. 2020.).

The rapid evolution of respiratory diseases such as COVID-19 in some cases associated with misinformation could trigger social stigma and panic that individually and collectively jeopardize the measures of control proposed for the disease. In this sense, it could be learned from TB control strategies that correct information about etiology transmission/prevention, diagnosis, and treatment, which will certainly have a positive impact on the population, improving their comprehension and acting to help in the process of dealing with the pandemic.

In sum, due to the chronic evolution of TB, at this moment, it is early to measure the effects of pandemic on its epidemiology. Indeed, the world has currently suffered from the economic slowdown and the impacts of pandemic in health systems, which could compromise diagnostic, treatment, and, hence, threaten the TB-focused strategies to control spreading and drug-resistance. Additionally, patients with TB have a social background and lung impairment that represents risks in the pandemic scenario of another widely transmitted respiratory disease. Thus, even with several questions remaining unanswered, research and public policies should be addressed to control the effects of the current highly contagious COVID-19 without forgetting how it will affect the natural progression of patients suffering from TB, as the rise/decline of TB depends on economic and social transformations related to health care.

ACKNOWLEDGEMENTS

To the Brazilian Coordination of Superior Level Staff Improvement (CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and to the Laboratory for Teaching and Research in Clinical Analysis of the State University of Maringá (LEPAC/ UEM - Laboratório de Ensino e Pesquisa em Análises Clínicas)

REFERENCES

  • Ahmed SAKS, Ajisola M, Azeem K, Bakibinga P, Chen Y-F, Choudhury NN, et al. Impact of the societal response to COVID-19 on access to healthcare for non-COVID-19 health issues in slum communities of Bangladesh, Kenya, Nigeria and Pakistan: results of pre-COVID and COVID-19 lockdown stakeholder engagements. BMJ Glob Heal 2020;5(8):e003042. https://doi.org/10.1136/bmjgh-2020-003042.
    » https://doi.org/https://doi.org/10.1136/bmjgh-2020-003042
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    » https://doi.org/https://doi.org/10.1183/13993003.00650-2020
  • Belicchi-Ferrari M, Bisceglie F, Buschini A, Franzoni S, Pelosi G, Pinelli S, et al. Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N4-ethylmorpholine thiosemicarbazonates. J Inorg Biochem. 2010;104(2):199-206. https://doi.org/10.1016/j.jinorgbio.2009.11.002.
    » https://doi.org/https://doi.org/10.1016/j.jinorgbio.2009.11.002
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  • Louie JK, Reid M, Stella J, Agraz-Lara R, Graves S, Chen L, et al. A decrease in tuberculosis evaluations and diagnoses during the COVID-19 pandemic. Int J Tuberc Lung Dis. 2020;24(8):860-2.
  • Maheshwari N, Jain A. Is There a Rationale for Using Bacillus Calmette-Guerin Vaccine in Coronavirus Infection? Viral Immunol 2020;00:1-7. https://doi.org/10.1089/vim.2020.0079.
    » https://doi.org/https://doi.org/10.1089/vim.2020.0079
  • Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv 2020; Preprint https://doi.org/10.1101/2020.03.24.20042937.
    » https://doi.org/https://doi.org/10.1101/2020.03.24.20042937
  • Motta I, Centis R, D’Ambrosio L, García-García JM, Goletti D, Gualano G, et al. Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts. Pulmonology. 2020;26:233-40. https://doi.org/10.1016/j.pulmoe.2020.05.002.
    » https://doi.org/https://doi.org/10.1016/j.pulmoe.2020.05.002
  • Ong CWM, Migliori GB, Raviglione M, MacGregor-Skinner G, Sotgiu G, Alffenaar JW, et al. Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC). Eur Respir J 2020;56. https://doi.org/10.1183/13993003.01727-2020.
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    » https://doi.org/https://doi.org/10.1080/23744235.2020.1806353
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    » https://doi.org/https://doi.org/10.1183/13993003.01398-2020
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  • World Health Organization. Global tuberculosis report. Geneva, Switzerland: 2018.
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    » https://doi.org/https://doi.org/WHO/HTM/TB/2015.11
  • Yitbarek K, Abraham G, Girma T, Tilahun T, Woldie M. The effect of Bacillus Calmette-Guérin (BCG) vaccination in preventing sever infectious respiratory diseases other than TB: Implications for the COVID-19 pandemic. Vaccine 2020;38($1):6374-80. https://doi.org/10.1016/j.vaccine.2020.08.018.
    » https://doi.org/https://doi.org/10.1016/j.vaccine.2020.08.018

Publication Dates

  • Publication in this collection
    06 Jan 2023
  • Date of issue
    2022

History

  • Received
    10 Sept 2020
  • Accepted
    26 Dec 2020
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br