*Viewpoint* **Impact of the COVID-19 Pandemic on Tuberculosis Control: An Overview**

#### **Kefyalew Addis Alene 1,2,\*, Kinley Wangdi 3 and Archie C A Clements 1,2**

Received: 27 May 2020; Accepted: 21 July 2020; Published: 24 July 2020

**Abstract:** Throughout history, pandemics of viral infections such as HIV, Ebola and Influenza have disrupted health care systems, including the prevention and control of endemic diseases. Such disruption has resulted in an increased burden of endemic diseases in post-pandemic periods. The current coronavirus disease 2019 (COVID-19) pandemic could cause severe dysfunction in the prevention and control of tuberculosis (TB), the infectious disease that causes more deaths than any other, particularly in low- and middle-income countries where the burden of TB is high. The economic and health crisis created by the COVID-19 pandemic as well as the public health measures currently taken to stop the spread of the virus may have an impact on household TB transmission, treatment and diagnostic services, and TB prevention and control programs. Here, we provide an overview of the potential impact of COVID-19 on TB programs and disease burden, as well as possible strategies that could help to mitigate the impact.

**Keywords:** COVID-19; pandemic; endemic; tuberculosis; impact; control; overview

### **1. Historical Perspective**

Tuberculosis (TB) is one of the oldest endemic diseases a ffecting humanity, but it remains a significant global public health problem today [1,2]. It is estimated that a quarter of the world's population has latent TB infection (a dormant form of TB) [3]. According to the World Health Organization (WHO) report, an estimated 10 million people develop active TB and more than one million people die due to TB each year [4].

The burden of TB has varied across human history. Major disruptions such as natural disasters, war and infectious disease pandemics have compromised TB programs and led to an increased burden of TB. For instance, during the First and Second World Wars, there were epidemics of TB in many European countries, which accounted for nearly one fourth of the total deaths during this period [5,6].

After World War II, following the discovery of TB medications, and improvements in the socioeconomic status of the population, TB was well controlled in high-income settings with TB burden decreasing dramatically [7]. However, when human immunodeficiency virus (HIV) emerged as a worldwide pandemic disease in the 1980s, TB re-emerged as an opportunistic infection and killed millions of people [8]. With the implementation of several TB prevention programmes and the introduction of anti-retroviral therapy (ART) for HIV, the mortality and morbidity of TB have decreased gradually over the last few decades [9].

More recently, the emergence of major viral disease outbreaks in several parts of the worlds has posed new challenges for global and national TB control e fforts. For instance, the recent outbreak of Ebola in West Africa has severely compromised TB programs in the a ffected countries [10,11]. The outbreaks of Middle East respiratory syndrome coronavirus (MERS-CoV) complicated the control

of TB in Saudi Arabia [12]. The direct and indirect e ffects of these viral outbreaks on TB programs have resulted in an increased burden of TB in the a ffected regions in subsequent years.

The United Nations Sustainable Development Goals (SDGs)include ending the TB epidemic by 2030, and the WHO set ambitious targets, including a 90% reduction in TB incidence and a 95% reduction in TB deaths compared with 2015, and no catastrophic costs due to TB, by 2035 [13]. Although progress continues to be made to achieve these ambitious targets, the current pandemic of coronavirus disease 2019 (COVID-19) could be a major challenge to achieving them.

Given the high levels of global disruption caused by the COVID-19 pandemic, it is critical to consider the potential impact on the control and prevention of common endemic diseases that might be even more devastating to human health than COVID-19 itself. The impact of COVID-19 on other diseases such as cancer and diabetes has been addressed in recent reviews [14,15]. However, there are no published reviews on the impacts of COVID-19 on TB. TB is the leading cause of death due to an infectious disease globally, and it is anticipated that people ill with both TB and COVID-19 may have poorer treatment outcomes. Most importantly, the public health response to COVID-19 to isolate people in their homes for extended periods could facilitate transmission of TB since close household contact, particularly in low-socioeconomic and overcrowded conditions, is a key risk factor for TB. Therefore, understanding the potential impacts of COVID-19 on TB is important for designing prevention strategies. Therefore, we review the potential impact of COVID-19 pandemics on the prevention and control of TB and provide possible strategies that could help to mitigate the impact.

#### **2. The Coronavirus Disease 2019 (COVID-19) Pandemic and TB**

The current pandemic of COVID-19 is a global health crisis, causing substantial disruptions to healthcare systems, including TB programs [16]. This section briefly summarizes the clinical features, epidemiological distribution, and transmission and prevention mechanisms of both COVID-19 and TB.

**Clinical features**: COVID-19 is a highly contagious acute viral disease, whereas TB is a chronic bacterial disease. Both COVID-19 and TB a ffect the respiratory system, primarily the lungs, and have similar symptoms such as cough, fever and breathing di fficulty [17], although the severity and duration of the symptoms are varied. Up to 78% of patients with COVID-19 may be asymptomatic and recover spontaneously [18,19].

**Epidemiology**: TB has long been the leading cause of death due to an infectious disease globally, killing more than 1.5 million people, and with an estimated 10 million new cases in 2018 [20]. The COVID-19 pandemic has now become a public health crisis, and COVID-19 has overtaken TB as the infectious disease killing the most people per day [21]. According to the WHO, as of 8 July 2020, there were more than 11.7 million confirmed cases of COVID-19 and over 540,000 deaths globally. COVID-19 has a ffected at least 216 countries, areas and territories around the world. High-burden countries for TB have generally experienced a lower incidence of COVID-19 than countries in Europe and North America, although Russia, Brazil, China and India are amongst the top 20 countries for total numbers of cases and deaths due to COVID-19.

**High-risk groups:** Some population groups are at higher risk of developing severe COVID-19 complications [22]. In particular, a higher number of deaths have occurred in adults aged over 60 years [23], in particular men. Similarly, gender di fferences in TB burden have been reported worldwide, with men more likely to be a ffected by TB than women [24,25]. Patients with underlying chronic diseases such as hypertension, diabetes, lung cancer and chronic obstructive pulmonary disease are at a higher risk of COVID-19-related death and hospital admission, as well as poor outcomes for TB [17,22,26,27].

**Transmission:** While the exact route of transmission for COVID-19 and TB di ffer, the major mode of transmission for both diseases is through close contact with infected people [28,29]. For COVID-19, the source of infection can be both symptomatic and asymptomatic patients, while for TB the main source of infection is symptomatic patients with productive cough. The incubation period for TB

(from infection to active TB) ranges from several months to two years [30], whereas the incubation period for COVID-19 is approximately 5 days [31].

**Prevention**: Various preventive measures have been taken at global, regional and national levels to reduce the risk of transmission of COVID-19 [32]. The common measures taken by countries to prevent the transmission of the disease include early case detection; prompt isolation of confirmed patients; contact tracing and quarantine of all contacts during the incubation period; social distancing; and communitywide containment, including closure of schools and public facilities, maintaining good hand hygiene through regular washing and use of sanitizers, and wearing of personal protective equipment [33,34]. Many countries have also undertaken strict measures, such as banning of public gatherings, complete lock-down of social and economic activities, and closure of borders to prevent importation of cases [35]. While some countries have been able to control transmission of the disease by implementing the aforementioned interventions, the number of new cases reported continues to rise in many countries at the current time [36]. While there are some vaccine trials under development, there is no evidence that any existing vaccine, including the Bacille Calmette-Guérin vaccine (BCG), protects people against infection with COVID-19 virus.

#### **3. The Potential Impact of the COVID-19 Pandemic on Tuberculosis Control**

COVID-19 could impact TB control in several ways, including increasing transmission of TB in the household, delaying the diagnosis and treatment of TB and increasing poor treatment outcomes and risks of developing drug-resistant TB. The direct and indirect effects of COVID-19 on national and global economies will have both short-term and long-term consequences for TB programs.

**Impact of COVID-19 on household transmission of TB:** One of the measures undertaken by countries to prevent the spread of COVID-19 is advising or requiring people to stay at home until the situation comes under control [33,34]. While this measure has several advantages in reducing the communitywide transmission of COVID-19, it may also facilitate household transmission of TB. Prolonged contact at household level is one of the risk factors that increases the transmission of TB [37]. A recent modelling study showed that a 3-month lockdown due to COVID-19 would cause an additional 1.65 million TB cases and 438,000 TB deaths in India over the next 5 years [38]. Another study conducted in Brazil showed that intensity of household exposure increased the risk of TB infection and disease among household members [37]. Previous studies have also shown that the prevalence of TB among children in household contact with adult patients is higher than in the general population [39,40], and the risk of household infection is significantly increased with prolonged household contact with sputum positive adults [39,41]. Since TB has a long incubation period, the impact of increased household transmission of TB is only likely to be observed in future years, when an increase in numbers of TB cases may be observed [42,43]. For instance, following the global pandemic of HIV, epidemics of TB were observed in several countries such as South Africa [44,45], which suggests that future public health vigilance is advisable.

**Impact of COVID-19 on TB treatment and diagnostic services:** Overwhelming of health care systems by COVID-19 cases is likely to impact on TB treatment and diagnostic services in several ways: (1) diversion of resources (including human and financial) away from routine services, to manage the pandemic; (2) health service and political leadership, the media and the public focusing on pandemic management and response with limited oversight and accountability of TB programmes; (3) health care personnel experiencing stress and anxiety, key predictors of errors and poor quality of care; (4) health care personnel being required to quarantine, or becoming ill or dying, and therefore not being available for routine services; and (5) stigma and fear of COVID-19 infection at health care facilities, discouraging people from visiting TB services. All of these factors will contribute to delays in the diagnosis and commencement of treatment. As untreated pulmonary TB is the main source of TB infection, late diagnosis and treatment of TB may increase the risk of transmission, especially the household transmission of TB as many people are currently at home. Late diagnosis and inappropriate treatment of TB can also increase the risk of poor treatment outcomes and development of drug-resistant TB. Misdiagnosis and under-detection of TB are ongoing problems for TB programs [4]. It was estimated that globally 3 million TB cases were un-detected in 2018 [4]. This number is likely to increase due the current COVID-19 pandemic.

**Impact of COVID-19 on the prevention and control of TB:** Prevention and control strategies for TB have already been compromised due to the COVID-19 pandemic. Many fora for exchanging TB research and information, such as seminars, workshops and annual conferences, have not been conducted in 2020. For instance, the World Tuberculosis Day, which is celebrated on March 24 each year, to build public awareness about the prevention and control of TB and to raise funding to support TB control efforts, has been cancelled in several countries. Vaccination programs, including the BCG vaccination that has been given to prevent childhood TB, have been negatively affected by COVID-19 [46]. Furthermore, TB preventive therapy, which is often given to high-risk groups to prevent the progression of latent TB to active TB, may also be affected by COVID-19 [47].

The worldwide pandemic of COVID-19 may affect the global strategy of ending TB by 2035 in several ways. Many of the factors affecting diagnostic and testing services also affect prevention and control programmes. Shortages of resources, either directly due to diversion towards pandemic management or indirectly due to broader economic consequences of the pandemic and stretched national budgets, are likely to impact on routine public health programmes. Currently, the attention of the public, government, media and health professions is diverted to COVID-19. Prioritization of TB and other endemic diseases is likely to be less than pre-pandemic levels as a result.

**Impact of COVID-19 on late reactivation of TB:** The impact of COVID-19 on the health status of individuals, including on the functioning of the immune system [48,49], might be associated with a higher risk of developing active TB disease. Pneumonia and respiratory failure caused by COVID-19 might cause long-lasting damage to the respiratory system, particularly the lungs, which might increase the risk of TB [50]. Previous studies have shown that infections with viruses such as HIV and influenza play a role in the development of active TB disease, either directly after exposure to TB or through reactivation of latent TB infection [51–53].

Moreover, the COVID pandemic will severely damage global and national economies. The crisis will have a disproportionate impact on the poor, through job losses, loss of remittances, rising prices, and disruptions to services such as education and health care [54]. The World Bank estimates that the global extreme poverty rate could rise by 0.3 to 0.7 percentage points, to around 9 percent in 2020, and around 40 million to 60 million people will fall into extreme poverty in 2020 as a result of COVID-19. This will have a long-term impact on the burden of TB [55], because poverty is widely recognised as an important risk factor for being infected and developing active TB [55–57].

#### **4. Possible Strategies to Mitigate the Impact of COVID-19 on TB Control**

Several strategies can be implemented to mitigate the impact of COVID-19 on TB control (Table 1). For example, to limit household transmission of TB, basic infection prevention and control measures, recommended by the WHO for health care facilities and high-risk settings, can be implemented at home [58]. To avoid TB diagnosis and treatment delay due to COVID-19, use of virtual care and digital health technologies, decentralising TB treatment to community health workers, and supporting private health sectors and academic research institutions to provide TB testing and treatment might all be required.

**Table 1.** Possible strategies to mitigate the impact of COVID-19 on tuberculosis (TB) control.


**1. Introduction**

In recent decades, the need to increase hatchery efficacy is increasing with demand for quality chicks. Therefore, during incubation, new techniques which are associated with embryo management are increasing with this demand. A possible reason is that the newly developed broiler genotypes have diverged considerably compared to traditional genotypes in terms of the biological, physiological, and biochemical requirements [1]. Thus, manipulation of different incubation conditions to meet the requirements of modern broiler genotypes is under continuous investigation. Incubation conditions have a significant effect on hatchability, chick quality and post-hatch performance in chicken. In addition, while the first quarter of incubation is critical to chicken embryogenesis [2], the last quarter is very significant to hatch and post hatch performance [3].

Incubation temperature is the most significant incubation condition [4] and there has been an increase in studies regarding thermal manipulation (TM). TM (i.e., increasing or lowering incubation temperature) and broiler chicken embryogenesis has been deeply studied by Collin A, Tzschentke B, Piestun Y, Yahav S, and Halevy O, and the technique enhances chick quality through improved body weight gain, increased expression of genes in the breast muscle, and thermotolerance. Earlier studies laid the foundation for implementation of TM between different days of embryogenesis in addition to key factors such as duration and strength of TM to enhance the chick's ability to cope with environmental challenges of cold and heat stress during post-hatch period [5–10].

In an earlier study, Yahav et al. [11] reported that TM at 39.5°C for 3 hours (h)/day (d) from embryonic age (E) E11–E16 improves the chicks' thermotolerance acquisition. A similar effect was confirmed by [12–16] with TM at 39.5°C for 12 h/d from E7 to E16. Recent studies have also confirmed a long-lasting effect on thermotolerance acquisition in chicks at hatch or 1-day-old chicks, for instance, Piestun et al. [17] and David et al. [18] both with TM at 39.5°C for 12 h/d from E7 to E16, Al-Zghoul et al. [19] with TM at 38.5, 39, 39.5 and 40°C for 18 h/d from E12 to E18 and Al-Zghoul et al. [20] with TM at 39°C for 18 h/d from E10 to E18.

The effect of TM on hatchability in several studies has been reported to differ extensively, with hatchability after TM being higher [11, 21, 22], reduced [9, 12, 13, 23, 24], and not affected [25, 26]. Also, studies from different researchers have shown contradicting results on chick quality parameters, and hatch or chick weight after TM exposure was increased [22, 23, 27], decreased [28], and not affected [21, 25, 29].

Production of optimal quality chicks depends on controlling incubation conditions and understanding the insights into the complex interaction among them. Although various studies have reported the benefits of TM, results are still contradicting and depend on timing, duration, and level of TM. With this background, we systematically reviewed the recent literature regarding the effect of thermal manipulation on embryonic development, hatchability, and hatching quality of broiler chicks.


**3.2 Treatment strategy**

There are some complications of type 2 DM that affect the brain; it is believed that diabetes treatment may have beneficial effects on cognition. Three different trials reported that intensive glycaemic control alleviate microvascular complications but does not alleviate macrovascular complications in geriatric patients with long-duration of type 2 diabetes and high cardiovascular risk [62–64]. The intensive treatment of type 2 DM leads to hypoglycaemia which may contribute to cognitive decline and eliminate the benefits of intensive treatment [63, 65, 66]. Hypoglycaemia is more common in intensive glycaemic control than in standard glycaemic control [67].

**Table 1.**

*Cognitive domains affected by type 1 and type 2 DM (with strong supporting data).*

**Table 2.**

*Cognitive domains affected by type 1 and type 2 DM (with less supporting data).*