Issue 46
May 2023
COVID-19 SPECIAL
By Thong Pei Min, PhD student, Chong Hai Tarng, Master student, Anabel Chang, Bsc student and Assistant Professor Catherine Ong from the Infectious Diseases Translational Research Programme
The urgent mobilisation of limited healthcare resources and personnel to combat the pandemic has hindered the management of other communicable and non-communicable diseases.
The Coronavirus Disease 2019 (COVID-19) had a devastating impact on global health. The urgent mobilisation of limited healthcare resources and personnel to combat the pandemic has hindered the management of other communicable and non-communicable diseases1. Tuberculosis (TB) among many others has seen a rise in cases. Due to difficulties in accessing TB services, an 18% decline in notifications of newly-diagnosed TB disease was observed between 2019 and 2020, with an increase in TB deaths the following year2,3. This is further exacerbated by the fact that both TB and COVID-19 are airborne infectious diseases which primarily affects the lungs, making differential diagnosis a challenge. The pandemic also disrupted the control of chronic diseases such as diabetes (DM), a leading cause of deaths in adults4. The disruptions to global health brought about by the pandemic raises the need to re-evaluate healthcare strategies to better deal with COVID-19 comorbidities.
DM is an established risk factor for COVID-19 mortality5. It was first reported in China that DM patients had a higher COVID-19 mortality rate compared to non-diabetic individuals, with similar phenomenon observed in the US and England6,7,8. As DM patients are relatively immunocompromised, their risk and severity of COVID-19 infection9 is increased. The reasons DM drives more severe COVID-19 infections remains unclear. Some possible mechanisms include increased oxidative stress and inflammatory cytokines production10.
18%
decline in
notifications of
newly-diagnosed
TB disease was
observed between
2019 and 2020
The relative risk
of developing
DM after
COVID-19 was
1.62 TIMES
higher
Approximately
10 million
new and
relapsed TB
diseases globally
in 2019
While DM could increase one’s risk for COVID-19 infection, COVID-19 patients are also at risk of developing diabetes. Compared to non-COVID-19 patients, the relative risk of developing DM after COVID-19 was 1.62 times higher11. The situation was worse in younger patients, with the risk of developing DM doubled compared to those without COVID-19 or with other respiratory infections12. In a separate study comprising 453 hospitalised COVID-19 patients in China, the reported prevalence of newly-diagnosed DM was 20.8%13. These studies show that COVID-19 is a risk factor for new-onset DM.
The mechanisms of COVID-19-induced DM are not well understood. Some proposed mechanisms include (1) direct pancreatic beta cell damage by SARS-CoV2 leading to impaired insulin secretion, (2) indirect pancreatic beta cell damage via autoimmune response against beta cells, (3) overproduction of cytokines leading to insulin resistance, (4) enhanced glucose synthesis due to increased secretion of glucogenic factors by SARS-CoV2-infected hepatocytes, (5) steroid-induced DM for those treated for severe COVID-19, and (6) adoption of sedentary lifestyle due to stay-at-home orders14,15. Studying the mechanisms underlying COVID-19-induced DM is crucial as the global incidence of DM is expected to increase drastically.
TB is a leading infectious killer, with approximately 10 million new and relapsed TB diseases globally in 2019. The emergence of the COVID-19 pandemic resulted in a reallocation of healthcare resources and staff to support COVID-19 operations, potentially disrupting the provision of health services, including services for TB care and management. We conducted a study that involved 43 TB centres from 19 countries and reported a substantial decline in the number of newly diagnosed TB infection, TB disease, drug-resistant TB and TB deaths in 2020 compared to 201916. Since TB and COVID-19 share similar clinical manifestations due to the nature by which both are primarily respiratory infections, differential diagnosis is challenging, which may explain missed TB diagnoses and decreased TB notifications during this period. This is further exacerbated by the lockdown measures in many countries, which hinder patients from seeking care and treatment. The consequence is an increase in contact time between infected individuals and family members, thereby resulting in TB transmission within the family. Accordingly, a modelling study of high TB burden countries (India, Kenya and Ukraine) predicted that a three-month suspension of TB services could result in an additional 1.2 million TB cases in the next five years17. This could lead to increased TB deaths and incidence, which has already been reported by the World Health Organization in their Global Tuberculosis Report 202218.
In addition, coinfection of TB/COVID-19 was associated with higher risk of mortality19. This may due to (1) ineffective mounting of immune response to SARS-CoV-2 antigen, (2) reduction in Mycobacterium tuberculosis (M.tb)-specific CD4+ T cell response in COVID-19 patients, or (3) uncontrolled production of inflammatory cytokines in the lungs in response to both SARS-CoV-2 and M.tb, leading to extensive lung injury20,21.
Since TB and COVID-19 share similar clinical manifestations due to the nature by which both are primarily respiratory infections, differential diagnosis is challenging, which may explain missed TB diagnoses and decreased TB notifications during this period. This is further exacerbated by the lockdown measures in many countries, which hinder patients from seeking care and treatment.
Additionally, there is an increased risk of TB reactivation among COVID-19 patients. A study showed that infection of a virus from the same genus as SARS-CoV-2 reactivated dormant TB infections, providing evidence of SARS-CoV2-induced TB reactivation22. Overall, coinfection of TB/COVID-19 is associated with higher mortality and increased risk of TB reactivation resulting in increased TB burden globally.
Figure 1: The global incidence of tuberculosis (TB) and diabetes (DM) is set to rise and can disrupt TB control. (A) Estimated incidence of TB and DM co-occurrence. Top ten countries with the highest TB incidence in 2021 are labelled. High incidence of TB and DM are expected in South Asia and China. (B) Compared to TB patients without DM, patients with TB and DM exhibit a worsened clinical phenotype. This include (I) Delayed Mycobacterium tuberculosis (M.tb) clearance and altered immune response, (II) Higher prevalence of drug and multi-drug resistant M.tb, (III) Higher mycobacterial burden due to poor glycaemic control and (IV) More severe lung cavitary and parenchymal lesion. Figure created with BioRender.com.
Halting the rise
in DM incidence
would prevent
6 million
TB cases and
1.1 million
TB deaths in
high TB burden
countries in the
next 20 years
DM is a risk factor for TB; three-quarters of DM burden is found in low- and middle-income countries where TB is prevalent (Figure 1A). The presence of DM is associated with more severe TB manifestations (Figure 1B) and delayed sputum sterilisation, translating to a longer period of infectiousness within the community23,24. Findings from animal studies and humans suggest that innate and adaptive immune responses were impaired in DM host, leading to delayed mycobacteria clearance from the lungs. Consequentially, TB-DM patients would experience higher levels of inflammation and slower resolution25. This aligns with the human data showing higher systemic matrix metalloproteinases (MMPs), angiogenic factors and pro-inflammatory cytokines in TB-DM patients compared to TB patients26,27,28. However, the underlying mechanism remains to be elucidated and would be imperative in managing TB-DM.
The management of TB-DM patients is challenging due to increased risk of drug-drug interactions, higher pill burden and longer treatment duration. Several studies have shown that TB-DM patients have lower plasma TB drug concentration than TB patients, suggesting that vascular integrity and drug delivery may be compromised29,30. This is backed up by a study done in TB zebrafish, where treatment with anti-angiogenic agent showed reduced vascular leakiness and mycobacterial burden, with further suppression of mycobacterial growth when in combination with rifampicin31. Anti-angiogenic agent could thus potentially be used as adjuvants in TB treatment. Another potential adjunctive therapy is doxycycline, a broad-spectrum MMP inhibitor32. Doxycycline works by improving TB drug delivery and/or retention by reducing vascular leakage33. Taken together, these studies suggest that there is a need to refine existing TB treatment regimen to improve treatment outcomes of TB-DM patient.
The increasing incidence of COVID-19 induced DM, and heightened risk of TB reactivation in COVID-19 patients has threatened global TB control. Coinfection of DM and TB are often associated with more severe disease and poorer treatment outcomes. Although the underlying mechanisms remain to be elucidated, optimal glucose control could potentially lower the risk of developing TB disease in DM patients and improving TB treatment outcomes. A modelling study evaluating the impact of DM on 13 high TB burden countries suggests that halting the rise in DM incidence would prevent six million TB cases and 1.1 million TB deaths in these countries in the next 20 years34. Measures to prevent TB-DM should therefore be taken at a national level, especially in countries with high TB and DM burdens. Some approaches include bidirectional screening for early detection of DM and/or TB diseases and increased government funding in TB research.
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