https://doi.org/10.5812/archcid-128743

The Challenge of Tuberculosis Diagnosis and Management in the Era of the COVID-19 Pandemic and Diabetes Mellitus

authors:

avatar Alireza Esteghamati ORCID 1 , * , avatar Masoud Mardani 2

Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran
Infectious Disease and Tropical Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Archives of Clinical Infectious Diseases: Vol.16, issue 6; e128743
published online: July 9, 2022
article type: Editorial
received: May 31, 2022
accepted: May 31, 2022

how to cite: Esteghamati A, Mardani M. The Challenge of Tuberculosis Diagnosis and Management in the Era of the COVID-19 Pandemic and Diabetes Mellitus. Arch Clin Infect Dis. 2021;16(6):e128743. https://doi.org/10.5812/archcid-128743.

1. Introduction

According to WHO, the COVID-19 pandemic has deleterious effects on global health, including services provided for those with tuberculosis. Tuberculosis (TB) primarily affects the lungs and has clinical similarities with pulmonary SARS-CoV-2 involvement. During the COVID-19 pandemic, the diagnosis and treatment of tuberculosis are negatively affected and mixed with COVID-19 control strategies. Corticosteroids like dexamethasone are one of the main treatment strategies for patients with severe COVID-19 infection, especially those who need hospitalization or oxygen support. Corticosteroids can cause immunosuppression, in addition to their anti-inflammatory properties. During the COVID-19 infection, host immunity alters with corticosteroid therapy, which induces a significant risk for secondary infections or reactivation of dormant infections like latent tuberculosis. Diabetes is also a highly prevalent disease with a severe course and increased mortality rate in those affected by COVID-19. Many patients with concomitant diabetes and severe COVID-19 need dexamethasone treatment, raising the awareness of concealed tuberculosis.

2. Prevalence of Diabetes in the World and Iran

According to the most recent data published in the IDF Atlas, nearly 537 million (10.5%) people aged 20 to 79 have type 2 diabetes (1). Due to this high prevalence, diabetes is a substantial global health burden that needs special attention from multiple stakeholders. In the MENA region, including IRAN, the prevalence of type 2 diabetes is around 16%, the highest in the IDF regions. (1). In Iran, according to national data, the prevalence of diabetes increased from 7.2% in 2007 to 11.3% in 2011 (2). The recent unpublished data from STEPS showed that the prevalence of type 2 diabetes is 14% in Iran, with a significant rise during the last decade.

3. Incidence and Mortality of Tuberculosis

Based on the WHO report, in 2020, nearly 10 million patients developed tuberculosis, while only 5.8 million were diagnosed, with an 18% decrease since 2019. At the same time, roughly 1.5 million deaths occurred due to tuberculosis (3). The deaths caused by TB increased by 0.2 - 0.4 million because of improper diagnosis and treatment associated with the COVID-19 pandemic (4).

4. What Immunological Mechanisms are Impaired in Mycobacterium tuberculosis Infection in Patients with Diabetes Mellitus?

Evidence shows that diabetes is a risk (predisposing) factor for tuberculosis. Although animal studies exploring the mechanisms of immune response in hyperglycemic states against Mycobacterium tuberculosis did not show any definitive findings, the following mechanisms have been suggested:

- Impaired innate immune response of alveolar macrophages in hyperglycemic mice with impaired antimicrobial defense against mycobacterium (5).

- Delayed myeloid cell recruitment to the infection site, induced by hyperglycemia that causes impaired antigen presentation and activation of T cells.

- Another presumptive defect is chemotaxis. Delayed delivery of Mycobacterium to the lymph nodes and defective antigen-specific T-cells activity also occur.

- The other defect is related to neutrophil functions, including migration, bactericidal, and killing abilities.

- Promotion of bacilli replication due to the defects in cytokines and IFN-gamma production (5).

To summarize, in animal models, the hyperglycemic state may alter phagocyte function, microbial killing, T-cell activity, leukocyte function, and chemotaxis with a delay in antigen presentation, creating an opportunity for bacilli boosting (6).

5. Diabetes and Tuberculosis

In patients with diabetes, some types of infections are more prevalent, especially, urinary and respiratory tract and mucocutaneous infections (7). Diabetes is one of the main risk factors for tuberculosis (8, 9), and multiple studies have revealed that up to 30% of patients with TB present with accompanying diabetes (10).

Besides, the incidence and prevalence of tuberculosis are higher in patients with diabetes (11). For example, the risk of developing tuberculosis was nearly twofold higher in patients with diabetes than in patients without diabetes (12).

Some studies have also shown that the prevalence of TB doubles in patients with diabetes, especially those with poor diabetes control and HbA1c greater than 7% (13). Those with concomitant diabetes and tuberculosis usually have a severe course, with more cavitation, increased hospital admission, more antituberculosis drug side effects, and a higher probability of relapse after treatment (14). Moreover, multiple-drug-resistant tuberculosis risk seems to double in patients with diabetes (15, 16). Furthermore, the coincidence of TB and DM increases mortality risk (15).

In patients with diabetes and tuberculosis, the glycemic control may be poor (17), while good glycemic control could improve immune system function and ultimately better treatment response (18). One recent study found that the INH-resistance or multiple drug resistance occurs more commonly in those with HbA1c greater than 7% (19). In a systematic review of 13 observational studies, the risk of active tuberculosis increased in patients with diabetes mellitus (11). Besides, diabetes increases the risk of cavitary TB and even mortality (13, 20-23). On the contrary, the risk of stress-associated hyperglycemia and insulin resistance increases in those with tuberculosis (24, 25). The risk of infections increases in patients with diabetes due to micro and macrovascular complications, impaired immunity including neutrophil dysfunction, and defects in humoral immunity (26).

6. COVID-19 and Tuberculosis

A study of 46 Chinese patients with COVID -19 showed that both active and latent tuberculosis induced more severe and progressive COVID-19 infections. Moreover, tuberculosis was more common in COVID-19 pneumonia (27). Another cohort of 49 cases also showed concomitant active tuberculosis, its sequelae, and COVID-19, with a 12% fatality rate in patients with co-existed infections (28). Also, pneumonia induced by COVID-19 can increase the progression of tuberculosis in those with latent infection. The immunological environment of the lung induced by COVID-19 infection (e.g., high level of chemokines) can exacerbate tuberculosis immunopathogenesis in patients with latent tuberculosis and induce its progression (29).

Tuberculosis and COVID-19 are linked as syndemic with other comorbid conditions like diabetes, obesity, hypertension, and cardiovascular diseases. These comorbid conditions predispose patients with both TB and COVID-19 to more severe diseases.

7. Corticosteroid Therapy and Tuberculosis

Many north American societies, including the American and Canadian Thoracic Society, Canadian Lung Association, and CDC in the USA, describe that patients with tuberculosis who receive more than 15 mg daily of corticosteroids for two to four weeks are prone to developing active tuberculosis (30, 31). The beneficial effects of corticosteroids in those with tuberculosis are variable and depend on the organ involved in TB, but overall, it reduces mortality.

8. Corticosteroid Treatment for TB Patients with Comorbidities

Population-based studies that used any type of corticosteroids for treatment of COPD and asthma showed a positive association between corticosteroid therapy and active TB due to the immunosuppressive effects of CSTs (32-36).

In a case report of severe COVID-19, the progression of symptomatic tuberculosis occurred in a patient with no comorbidity that used tocilizumab and corticosteroids. The immunosuppression induced by COVID-19 and/or CST treatment was suggested to reactivate latent TB (2).

In a guideline proposed by the Massachusetts General Hospital for COVID-19, it was recommended to screen and document TB before administering more than 20 mg/day prednisone or equivalent dose of dexamethasone. It should be emphasized that when corticosteroids are prescribed for more than two weeks, the risk of reactivation of TB increases.

9. Conclusion

In the COVID-19 pandemic, diabetes is significant comorbidity that increases patients' mortality. Many studies have suggested that tuberculosis flare-ups may occur due to synergistic effects of diabetes, corticosteroid treatment, and pulmonary involvement by COVID-19. Expert consensus solutions and implementation for case findings seem to be very salient. Appropriate control of hyperglycemia and diabetes is of utmost importance. Because there is no global policy for treating latent tuberculosis in those with diabetes, we need more longitudinal clinical and epidemiological studies among those with COVID-19, diabetes, and tuberculosis to answer this vital question.

References

  • 1.

    International Diabetes Federation. IDF Atlas. Brussels, Belgium: International Diabetes Federation; 2021.

  • 2.

    Esteghamati A, Etemad K, Koohpayehzadeh J, Abbasi M, Meysamie A, Noshad S, et al. Trends in the prevalence of diabetes and impaired fasting glucose in association with obesity in Iran: 2005-2011. Diabetes Res Clin Pract. 2014;103(2):319-27. [PubMed ID: 24447808]. https://doi.org/10.1016/j.diabres.2013.12.034.

  • 3.

    World Health Organization. Global tuberculosis report 2021. Geneva, Switzerland: World Health Organization; 2021.

  • 4.

    COVID-19 Treatment Guidelines Panel. The COVID-19 Treatment Guidelines Panel’s Statement on the Emergency Use Authorization of the Bamlanivimab Plus Etesevimab Combination for the Treatment of COVID-19. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Maryland, USA: National Institutes of Health; 2021.

  • 5.

    Martinez N, Kornfeld H. Tuberculosis and diabetes: from bench to bedside and back. Int J Tuberc Lung Dis. 2019;23(6):669-77. [PubMed ID: 31315698]. https://doi.org/10.5588/ijtld.18.0805.

  • 6.

    Ayelign B, Negash M, Genetu M, Wondmagegn T, Shibabaw T. Immunological Impacts of Diabetes on the Susceptibility of Mycobacterium tuberculosis. J Immunol Res. 2019;2019:6196532. [PubMed ID: 31583258]. [PubMed Central ID: PMC6754884]. https://doi.org/10.1155/2019/6196532.

  • 7.

    Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AI, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41(3):281-8. [PubMed ID: 16007521]. https://doi.org/10.1086/431587.

  • 8.

    American Diabetes Association. Standards of medical care in diabetes-2018. 41. USA: American Diabetes Association; 2018.

  • 9.

    World Health Organization. Global tuberculosis report 2019. Geneva, Switzerland: World Health Organization; 2019.

  • 10.

    Ruslami R, Aarnoutse RE, Alisjahbana B, van der Ven AJ, van Crevel R. Implications of the global increase of diabetes for tuberculosis control and patient care. Trop Med Int Health. 2010;15(11):1289-99. [PubMed ID: 20955495]. https://doi.org/10.1111/j.1365-3156.2010.02625.x.

  • 11.

    Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008;5(7). e152. [PubMed ID: 18630984]. [PubMed Central ID: PMC2459204]. https://doi.org/10.1371/journal.pmed.0050152.

  • 12.

    Antonio-Arques V, Franch-Nadal J, Cayla JA. Diabetes and tuberculosis: A syndemic complicated by COVID-19. Med Clin (Engl Ed). 2021;157(6):288-93. [PubMed ID: 34541325]. [PubMed Central ID: PMC8433042]. https://doi.org/10.1016/j.medcle.2021.04.006.

  • 13.

    Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lonnroth K, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 2011;9:81. [PubMed ID: 21722362]. [PubMed Central ID: PMC3155828]. https://doi.org/10.1186/1741-7015-9-81.

  • 14.

    Moreno-Martinez A, Casals M, Orcau A, Gorrindo P, Masdeu E, Cayla JA, et al. Factors associated with diabetes mellitus among adults with tuberculosis in a large European city, 2000-2013. Int J Tuberc Lung Dis. 2015;19(12):1507-12. [PubMed ID: 26614193]. https://doi.org/10.5588/ijtld.15.0102.

  • 15.

    Huangfu P, Ugarte-Gil C, Golub J, Pearson F, Critchley J. The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis. Int J Tuberc Lung Dis. 2019;23(7):783-96. [PubMed ID: 31439109]. https://doi.org/10.5588/ijtld.18.0433.

  • 16.

    Salindri AD, Kipiani M, Kempker RR, Gandhi NR, Darchia L, Tukvadze N, et al. Diabetes Reduces the Rate of Sputum Culture Conversion in Patients With Newly Diagnosed Multidrug-Resistant Tuberculosis. Open Forum Infect Dis. 2016;3(3):ofw126. [PubMed ID: 27419188]. [PubMed Central ID: PMC4942763]. https://doi.org/10.1093/ofid/ofw126.

  • 17.

    Kumpatla S, Sekar A, Achanta S, Sharath BN, Kumar AM, Harries AD, et al. Characteristics of patients with diabetes screened for tuberculosis in a tertiary care hospital in South India. Public Health Action. 2013;3(Suppl 1):S23-8. [PubMed ID: 26393064]. [PubMed Central ID: PMC4463146]. https://doi.org/10.5588/pha.13.0035.

  • 18.

    Song C, Xie W, Gong L, Ren M, Pan P, Luo B. The relationship between HbA1c control levels and antituberculosis treatment effects: a meta-analysis. J Chin Med Assoc. 2019;82(12):915-21. [PubMed ID: 31800532]. https://doi.org/10.1097/JCMA.0000000000000205.

  • 19.

    Lyu M, Wang D, Zhao J, Yang Z, Chong W, Zhao Z, et al. A novel risk factor for predicting anti-tuberculosis drug resistance in patients with tuberculosis complicated with type 2 diabetes mellitus. Int J Infect Dis. 2020;97:69-77. [PubMed ID: 32474202]. https://doi.org/10.1016/j.ijid.2020.05.080.

  • 20.

    Shewade HD, Jeyashree K, Mahajan P, Shah AN, Kirubakaran R, Rao R, et al. Effect of glycemic control and type of diabetes treatment on unsuccessful TB treatment outcomes among people with TB-Diabetes: A systematic review. PLoS One. 2017;12(10). e0186697. [PubMed ID: 29059214]. [PubMed Central ID: PMC5653348]. https://doi.org/10.1371/journal.pone.0186697.

  • 21.

    Faurholt-Jepsen D, Range N, PrayGod G, Jeremiah K, Faurholt-Jepsen M, Aabye MG, et al. Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania. Trop Med Int Health. 2013;18(7):822-9. [PubMed ID: 23648145]. https://doi.org/10.1111/tmi.12120.

  • 22.

    Moreira J, Castro R, Lamas C, Ribeiro S, Grinsztejn B, Veloso VG. Hyperglycemia during tuberculosis treatment increases morbidity and mortality in a contemporary cohort of HIV-infected patients in Rio de Janeiro, Brazil. Int J Infect Dis. 2018;69:11-9. [PubMed ID: 29253707]. https://doi.org/10.1016/j.ijid.2017.12.014.

  • 23.

    Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet. 2009;373(9677):1798-807. [PubMed ID: 19465235]. [PubMed Central ID: PMC3144755]. https://doi.org/10.1016/S0140-6736(09)60553-5.

  • 24.

    Kubjane M, Berkowitz N, Goliath R, Levitt NS, Wilkinson RJ, Oni T. Tuberculosis, Human Immunodeficiency Virus, and the Association With Transient Hyperglycemia in Periurban South Africa. Clin Infect Dis. 2020;71(4):1080-8. [PubMed ID: 31557282]. [PubMed Central ID: PMC7428387]. https://doi.org/10.1093/cid/ciz928.

  • 25.

    Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab. 2012;16 Suppl 1:S27-36. [PubMed ID: 22701840]. [PubMed Central ID: PMC3354930]. https://doi.org/10.4103/2230-8210.94253.

  • 26.

    Chen Y, Wang Y, Fleming J, Yu Y, Gu Y, Liu C, et al. Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity. medRxiv. 2020;Preprint. https://doi.org/10.1101/2020.03.10.20033795.

  • 27.

    Tadolini M, Garcia-Garcia JM, Blanc FX, Borisov S, Goletti D, Motta I, et al. On tuberculosis and COVID-19 co-infection. Eur Respir J. 2020;56(2). [PubMed ID: 32586888]. [PubMed Central ID: PMC7315815]. https://doi.org/10.1183/13993003.02328-2020.

  • 28.

    Esmail H, Lai RP, Lesosky M, Wilkinson KA, Graham CM, Horswell S, et al. Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis. Proc Natl Acad Sci U S A. 2018;115(5):E964-73. [PubMed ID: 29339504]. [PubMed Central ID: PMC5798330]. https://doi.org/10.1073/pnas.1711853115.

  • 29.

    Peoples M. Canadian Tuberculosis Standards. Winnipeg, Canada: Public Health Agency of Canada; 2014.

  • 30.

    No authors listed. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221-47. [PubMed ID: 10764341]. https://doi.org/10.1164/ajrccm.161.supplement_3.ats600.

  • 31.

    Chung WS, Chen YF, Hsu JC, Yang WT, Chen SC, Chiang JY. Inhaled corticosteroids and the increased risk of pulmonary tuberculosis: a population-based case-control study. Int J Clin Pract. 2014;68(10):1193-9. [PubMed ID: 24838040]. https://doi.org/10.1111/ijcp.12459.

  • 32.

    Kim JH, Park JS, Kim KH, Jeong HC, Kim EK, Lee JH. Inhaled corticosteroid is associated with an increased risk of TB in patients with COPD. Chest. 2013;143(4):1018-24. [PubMed ID: 23079688]. https://doi.org/10.1378/chest.12-1225.

  • 33.

    Huang TM, Kuo KC, Wang YH, Wang CY, Lai CC, Wang HC, et al. Risk of active tuberculosis among COPD patients treated with fixed combinations of long-acting beta2 agonists and inhaled corticosteroids. BMC Infect Dis. 2020;20(1):706. [PubMed ID: 32977747]. [PubMed Central ID: PMC7519522]. https://doi.org/10.1186/s12879-020-05440-6.

  • 34.

    Lee CH, Kim K, Hyun MK, Jang EJ, Lee NR, Yim JJ. Use of inhaled corticosteroids and the risk of tuberculosis. Thorax. 2013;68(12):1105-13. [PubMed ID: 23749841]. https://doi.org/10.1136/thoraxjnl-2012-203175.

  • 35.

    Lee CM, Heo J, Han SS, Moon KW, Lee SH, Kim YJ, et al. Inhaled Corticosteroid-Related Tuberculosis in the Real World Among Patients with Asthma and COPD: A 10-Year Nationwide Population-Based Study. J Allergy Clin Immunol Pract. 2019;7(4):1197-1206 e3. [PubMed ID: 30339858]. https://doi.org/10.1016/j.jaip.2018.10.007.

  • 36.

    Sasson A, Aijaz A, Chernyavsky S, Salomon N. Pulmonary Cavitary Tb in a Patient with SARS-COV-2 Pneumonia. Chest. 2020;158(4):A560-1. https://doi.org/10.1016/j.chest.2020.08.528.