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COVID-19’s Profound Impact on Tuberculosis Diagnosis, Treatment, and Research

Global Health Surveillance Human Health

Mtb Diagnoses Are Dropping – Is That Good?

Prior to the onset of the SARS-CoV-2 (COVID-19) pandemic in 2020, Mycobacterium tuberculosis (Mtb) – the causative agent of tuberculosis – was the leading cause of death globally due to an infectious disease. In 2019, approximately 10 million people contracted the disease and it killed 1.4 million of them. Mtb is a bacterium primarily transmitted by aerosol or droplet, and like COVID-19, can be transmitted when a person with an active Mtb infection coughs, sneezes, laughs, or even talks. The disease exists in two forms: an active form capable of being transmitted to others, and a latent form in which the patient is asymptomatic and cannot spread Mtb. Between the two forms, it is estimated that nearly a quarter of the world’s population is infected with Mtb. Following infection, Mtb bacteria most often attack the lungs, but they can also attack the kidney, spine, and brain. Symptoms can include cough, fever, fatigue, night sweats, and weight loss. Several health conditions put an individual at higher risk of contracting Mtb, including malnutrition, HIV/AIDS, and diabetes. These factors result in most infections occurring in low- to middle-income countries with limited resources for an effective response.

Just as COVID-19 has upended daily life around the world, it also impacted all aspects of tuberculosis diagnosis, treatment, and research. Supply chain disruptions and the diversion of healthcare resources to the COVID-19 response have made detection and diagnosis of Mtb more difficult. Similarly, COVID-19 has hampered the months-long treatment regimen of tuberculosis in patients, while causing disruptions to critical clinical trials and research. These impacts have been witnessed first-hand via the National Institutes of Health (NIH-DAIDS) and the NIH funded Mycobacterium tuberculosis Quality Assessment (TBQA) Program at MRIGlobal (Contract Number HHSN272201700001C). The far-reaching effects of COVID-19 on Mtb mitigation efforts highlight the need for novel strategies to prevent future disruptions.

Progress Against Mtb Before COVID-19

Tuberculosis elimination is a top priority for the World Health Organization (WHO) and its partners. As the leading cause of death due to an infectious agent until 2020, Mtb has been heavily targeted by public health strategies. In the United States, the incidence of Mtb steadily declined from 1982 until the start of the COVID-19 pandemic [1]. Though documented rates of infection for Mtb have continued to drop – dramatically in 2020 – that drop is attributed to multiple factors, including service disruptions, failure to seek care, and isolation from the community, and is not a true reduction in incidence [2]. This assumption is supported by Mtb mortality rates in 2020, which indicate an increase in deaths due to Mtb for the first time in 15 years [3].

There are several key components of Mtb control that are critical to reclaiming and then maintaining progress:

  • Early Diagnosis – Patient receives care before disease becomes more complicated
  • Contact Tracing – Close contacts are identified and tested to prevent further spread
  • Therapeutic Intervention – Combinations of multiple antibiotics are administered for a long duration (typically 6-24 months) for active Mtb, often with side effects. Latent Mtb can be treated with either a single antibiotic or a combination therapy before it develops into active Mtb
  • Mtb-Specific Resources – Support is provided through specialized medical staff and clinics, while Directly-Observed-Therapy (DOT) monitors patients for medication compliance

Impact on Diagnosis of Mtb

Mtb diagnosis is the crucial first step in eradicating tuberculosis. Ideally, patients are diagnosed soon after contracting Mtb, but that’s not often the case. Through contact tracing, other potential patients are identified, tested, and treated to prevent further spread. COVID-19 response efforts have posed many challenges to patients needing diagnosis:

  • Restricted Access/Lockdowns – Patients were prevented from seeking care due to lockdowns and the restriction of medical care for emergency only [2]
  • Resources Diverted to COVID-19 – Supplies, clinics, and medical personnel were reassigned to the COVID-19 effort. Mtb-specific medical facilities were often closed or converted to COVID-19 clinics [4,5]
  • Stigma – Patients avoided seeking care for fear of stigma associated with having respiratory symptoms during the COVID-19 pandemic [6]
  • Misdiagnosis – The symptomology of COVID-19 and Mtb is very similar. A positive COVID-19 test could be the end diagnosis without Mtb being considered as a possibility [5,6]
  • Delayed or missed diagnosis results in more complicated and severe Mtb disease and increases the likelihood of transmission to others [2,5].

Impact on Treatment of Mtb

Mtb treatment involves a long course of antibiotic therapy involving multiple drugs. Patient adherence is often monitored through Directly-Observed-Therapy (DOT) and supportive care is given to navigate the long and difficult treatment. Patients often suffer severe side effects, social isolation, and stigma. COVID-19 mitigation strategies and their subsequent effects have had a strong negative impact on Mtb treatment:

  • Lockdowns – Lockdowns restricted patient travel, making it difficult to obtain consistent treatment [2,6]
  • Resources Diverted to COVID-19 – Mtb-specific medical facilities were often closed or converted to COVID-19 clinics. Supportive care essential to treatment success was often diverted to COVID-19 response [6]
  • Supply Chain Disruptions – Failures in the supply chain led to lapses in medical supplies, including medications
  • Monitoring Interrupted – DOT relies on a healthcare worker observing patients in person. Some DOT was conducted virtually where resources permitted, while other DOT healthcare workers were diverted to COVID-19 response [6]

Impact on Mtb Clinical Trials and Research

The execution of clinical trials has been negatively impacted by the pandemic, with lockdowns and travel restrictions hindering studies already in progress and preventing new studies from being initiated. Supply chain disruptions have also limited access to necessary study materials. STREAM (evaluation of a Standardized Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant tuberculosis) is a large-scale, multi-country clinical trial funded initially by the USAID, and it, too, has been negatively impacted by the pandemic [7]. Other clinical trials, such as TB-PRACTECAL conducted by Médecins Sans Frontières (MSF), have experienced similar COVID-19 consequences [8].

General Mtb laboratory research has also been impeded as laboratory operations were reduced, in part due to limitations on the number of staff permitted in the lab. Reduced operations also resulted from COVID-19 infection among staff, forcing them to take some time away from the lab. Supply chain shortages added another layer of difficulty, as research facilities struggled to find the materials necessary to conduct studies.

Impact on Transmission of Mtb

Because the COVID-19 pandemic is still with us in mid-2022, it is too early to measure the full scope of its impact on Mtb transmission. Most public health practitioners agree, however, that Mtb transmission has been worsened by the pandemic. Delayed diagnosis, for instance, has likely increased the opportunity for transmission [2]. Some COVID-19 mitigation measures, such as mask-wearing and social distancing, may have prevented Mtb transmission as the diseases are similarly transmitted [2,4]. Conversely, COVID-19 lockdowns may have promoted Mtb transmission among those in households who had to share living space for an extended time [2,6].

Co-Infection of Mtb and COVID-19

Patients living with Mtb have diminished lung function, putting them at greater risk of secondary lung infections, such as what results with COVID-19. The most severe COVID-19 complications occur when lung capacity is severely weakened [9]. Consequently, COVID-19 infection makes it more challenging for the lungs of Mtb patients to quickly recover, even after the resolution of the viral infection. 

A study in South Africa found that 61 percent of rifampicin-resistant Mtb patients who contracted COVID-19 died of the complications [10]. The association of current Mtb infection and COVID-19 was further reported in another study in the same country, resulting in poor outcomes [11].

Lessons Learned Could be Derailed by Continued Crises

The COVID-19 pandemic has undoubtedly disrupted years of effort to eradicate Mtb. Public health measures such as lockdowns and the diversion of resources to the pandemic response have directly and indirectly impacted all aspects of the Mtb fight. Patients lost access to healthcare support and have been more likely to suffer from complicated co-infection with COVID-19. Additionally, the long-term goal of eliminating Mtb has been impacted by delays and interruptions to crucial clinical trials and research. 

While there has been significant ground lost toward the goal of eradicating Mtb, there have been some valuable lessons learned. The pandemic helped identify gaps in the healthcare system. Strategies employed for COVID-19 response, including digital health, home delivery of medications, and data dashboards, can be leveraged in the efforts against Mtb [12]. Globally, laboratories scaled up their molecular testing capabilities, which could be utilized for Mtb testing. Finally, the rapid developments of mRNA vaccines could serve as a model for developing a more efficacious vaccine against Mtb and help eradicate it going forward. 

Unfortunately, geopolitical instability, natural disasters, or a new pandemic could again derail the fight against Mtb. Consideration of Mtb should be included in all future crisis preparedness planning. The current war in Ukraine – a high burden drug-resistant Mtb country – highlights the serious challenge posed to the global community. Learning from COVID-19 responses in a coordinated and global way should be our priority to attain our common goal of eradicating tuberculosis.

References

  1. https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm (accessed 20Apr2022)
  2. Front Pub Health, 2021; DOI: 10.3389/fpubh.2021.644536
  3. WHO Global Tuberculosis Report, 2021. https://www.who.int/publications/i/item/9789240037021
  4. Arch Bronconeumol, 2021, 57(S2):5-6; DOI: 10.1016/j.arbres.2020.11.016
  5. Clin Infect Dis, 2021, 73(S1):S74-6; DOI: 10.1093/cid/ciab387
  6. Ther Adv Infect Dis, 2021, 8; DOI: 10.1177/20499361211016973
  7. Trop Med Infect Dis, 2020, 5(2):86; DOI:10.3390/tropicalmed5020086
  8. Trials, 2021, 22, 371; DOI: 10.1186/s13063-021-05331-4
  9. Clin Microbiol Infect, 2021, 27(6):892-6; DOI: 10.1016/j.cmi.2021.02.019
  10. Int J Tuberc Lung Dis 25(5):409-12; DOI: 10.5588/ijtld.21.0010
  11. Clin Infect Dis, 2021, 73(7):e2005-15. DOI: 10.1093/cid/ciaa1198
  12. N Engl J Med, 2022; DOI: 10.1056/NEJMp2118145

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