Recent literature comparing,19–26 COVID-19 and TB are summarised with key similarities and differences in Table 1.

The main difference is that TB is curable, while definite evidence on effective anti-viral agents or other drugs for COVID-19 is still lacking.35,36

Research on new and effective vaccines is ongoing for both diseases: vaccination for COVID-19 has now started while for TB several candidates are under evaluation to replace the old BCG.37

Both COVID-19 and TB have the capacity to stress health systems, they are airborne transmissible diseases, can be diagnosed rapidly (although implementation of rapid testing is not yet available in all settings), they cause stigma and need public awareness and cooperation to allow prevention, diagnosis and treatment to be effective. Although surveillance is able to report on TB and viral diseases separately, in the vast majority of countries the information on COVID-19 is still incomplete and information on TB do not contain many clinical and immunological parameters, which would be useful to better understand the interaction between the two diseases. Moreover COVID-19 pandemic has led to a significant fall in TB notifications.9

In terms of funding, although health systems can be considered relatively underfunded even in resource rich countries (a debate is ongoing in these countries on the adequacy of prevention services and on the needed number of intensive care unit beds) human and economic resources for TB are historically sub-optimal at the global level, while resources have been rapidly mobilised against COVID-19 following the wave(s) of the emergency.19,20,38

A long story of prevention and control exists for TB, with the development of: a) national TB control programmes and b) prevention, diagnosis and treatment policies and guidelines in almost all countries of the world (although they are not always correctly implemented). On the COVID-19 side, the policy guidance is under continuous development, following the growing evidence available with the first and subsequent waves.

COVID-19 is a communicable disease caused by SARS-CoV-2, a member of the beta Coronaviridae family, which also includes SARS-CoV-1 (severe acute respiratory syndrome coronavirus 1) and MERS-CoV (Middle East respiratory syndrome coronavirus).39 The SARS-CoV-2 genome is up to 80% similar to SARS-CoV-1 and 50% similar to MERS-CoV.39,40 The coronavirus spike (S) glycoprotein, common to all these viruses, belongs to the class-I viral fusion proteins and upregulates and engages angiotensin-converting enzyme 2 (ACE2) as the entry receptor into humans.41,42 However, not all people exposed to SARS-CoV-2 are infected and not all infected patients develop severe respiratory illness.3 Accumulating evidence indicates that COVID-19 can be roughly divided into three stages: stage 1, an asymptomatic incubation period with or without detectable virus; stage 2, non-severe symptomatic period with the presence of virus; stage 3, severe respiratory symptomatic stage with high viral load43 and important immune response with subsequent deterioration of the lung damage, respiratory failure (that may require invasive-mechanical ventilation) and multi-organ dysfunction.44–47 (Fig. 1

Fig. 1.

Schematic representation of the progression of COVID-19 infection and potential adjuvant interventions.

IFNa: Interferon alpha; IV: Intravenous; HAS2: Hyaluronan Synthase 2.

Created with BioRender.com.

(0.34MB).

It has been shown that a broad and coordinated SARS-CoV-2 antigen-specific adaptive immune responses (ADIMs) among CD4, CD8 and B cells are associated with lower COVID-19 disease severity, while absent or minimal adaptive immunity is associated with more severe COVID-19 disease. In particular SARS-CoV-2-specific CD4 + T cells are associated with protective immune responses.48 Significant redundancy or compensation may exist between the protective actions of neutralizing antibodies, SARS-CoV-2-specific CD4 T cells, and SARS-CoV-2-specific CD8 T cells.48

CD4 + T lymphocytes are rapidly activated to become pathogenic T helper (Th) 1 cells and generate granulocyte-macrophage colony stimulating factor (GM-CSF). The cytokine environment induces CD14+CD16+ monocytes with high expression of IL-6 and accelerates inflammation. Also, over-activation of T cells, manifested by the increase in Th17 and high cytotoxicity of CD8 + T cells in the peripheral blood of a patient with severe COVID-19, have been reported.49 Although the pathophysiology of SARS-CoV-2 is not yet fully understood, it seems there are similarities with that of SARS-CoV-1.50

Certain therapeutic interventions are under evaluation for the incubation and early stages of SARS-CoV-2 infection; these include convalescent plasma, pegylated IFNa (Interferon alpha), zinc, vitamin B3 and/or specific antivirals like remdesivir and Regeneron’s casirivimab/imdevimab antibody cocktail and bamlanivimab (Eli Lilly), some of which have already US Food and Drug Administration Emergency Authorization.51–53 However, the treatment with hydroxychloroquine and lopinvir/ritonavir has not been significantly associated with differences in hospital mortality.54,55

For patients with severe COVID-19, mostly immunosuppressive therapeutic options have been proposed, with dexamethasone being recommended for use and others currently being evaluated including HAS2 (Hyaluronan Synthase 2) inhibitors as well as activated MSCs (mesenchymal stromal /stem cells).44,56,57 (Fig. 1). Lung and tissue damage, which can occur with hypoxia even in TB,58 have also been described as sequelae to COVID-19 infection,59 as well as thrombosis and pulmonary emboli.47

Although viral respiratory infections and TB impair the host’s immune responses little evidence is available about co-infection of SARS-CoV-2 and Mycobacterium tuberculosis. TB status might play a role in the development of COVID-19 infection and exacerbation of the course of the disease for the co-infected population considering cases studied in China and India60 and the evidence provided by a study performed on a systematic transcriptomic evaluation of immune signatures associated with COVID-19 clinical severity and the spectrum of asymptomatic and symptomatic TB.17 In particular the results of this study performed on the transcriptomic evaluation of whole blood (WB), peripheral blood mononuclear cell (PBMC) and bronchoalveolar lavage fluid (BALF) signatures suggest that subclinical and active TB (ATB) increase the risk of severe COVID-19 disease, due to increased abundance of circulating myeloid subpopulations which are also found in the lungs of severe COVID-19 patients.17 The increased IFN production and the type I and III IFN responses signatures are significantly upregulated in severe disease in both COVID-1961 and TB62 and may lead to disease progression and severe/fatal outcomes. COVID-19 may therefore pose the biggest threat to ending the TB epidemic.6

Also, the use of immunosuppressive drugs in severe and critical COVID-19 patients, although done for a limited period of time, may result in increased likelihood of active TB caused by reactivation or new infection of M. tuberculosis63,64 even in post-pandemic times.

A range of diagnostic tests is available for both TB and COVID-19. For both pathogens, nucleic acid detection tests, and antigen-based tests are available while culture-based and smear methods apply to Mycobacterium tuberculosis and serology for SARS-CoV-2 (Table 2).

The WHO has described the ASSURED criteria (Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free and Deliverable to end-users), relevant to both Mycobacterium tuberculosis and SARS-Cov-2, to identify the most appropriate diagnostic tests for most settings.77 However, a key limitation to all available tests, independent of the pathogen, is the inability to promptly declare if the pathogen is viable and infectious78 For SARS-CoV-2, the virus requires live eukaryotic cells to replicate, with a minimum turn-arou.nd-time of one week to determine viability. For Mycobacterium tuberculosis, culture results to determine viability require a minimum of 6 weeks. Even in this age of state-of-the-art technology, rapid information on the state of infectiousness of these two pathogens remains elusive. An interesting experimental approach to evaluate SARS-CoV2-specific response in the whole blood has been recently reported79,80. It describes that SARS-CoV2-specific response is detectable in the whole blood and is present during the acute phase79 as well as in the convalescents.80

In a first meta-analysis of six studies from China on a few patients,81 the TB prevalence among COVID-19 patients ranged between 0.47 to 4.47%. The TB prevalence was higher among patients with severe COVID-19 than in non-severe ones (1.47%, 10/680 vs 0.59%, 10/1703; OR: 2.1; P = 0.24).

In a cohort from eight countries (Belgium, Brazil, France, Italy, Russia, Singapore, Spain and Switzerland)11 TB and COVID-19 were studied in 49 patients during the initial wave of the pandemic. TB was diagnosed before COVID-19 in 26 patients (53.0%), COVID-19 was diagnosed before TB in 14 ones (28.5%) while the diagnosis was concomitant in 9 patients (18.3%) (within the same week). Forty-two patients (85.7%) had active TB while 7 (14.3%) suffered post-cure TB sequelae. The authors concluded the following:

• 1)

  COVID-19 can occur before, simultaneously or after the diagnosis of TB;

• 2)

  The role of COVID-19 in boosting the development of active TB is yet to be established;

• 3)

  The role of TB sequelae in COVID-19 evolution is also unclear, potentially being a risk factor for worsening outcomes;

• 4)

  Further studies are needed to enable analysis of interactions and determinants of outcomes in patients with both diseases.

These findings have been confirmed by a similar study conducted in India.82

In an interesting clinical study conducted in a reference TB centre in Northern Italy, the Sondalo Hospital,13 detection of Sars-Cov2 was made in 20 patients (the majority being young migrants without co-morbidities) following nosocomial transmission. All patients received hydroxychloroquine and no antiviral drug was administered, with oxygen administered to 4 patients at admission and 3 during their hospital stay. A single elderly patient with advanced pulmonary TB and cachexia developed COVID-19 pneumonia and died 6 days after admission. The other 19 patients had a good clinical outcome. TB lesions at chest radiography did not worsen and only 4 patients had signs of newly developed pneumonia.

The data reported suggest the following:

• 1

  Low rate of clinical and radiological deterioration may be associated to young age of most patients, low frequency of co-morbidities, good quality of healthcare service

• 2

  Impact of COVID-19 on active TB appears to be manageable with proper care. Rigorous infection control and personal protection devices are crucial to prevent the risk of in-hospital transmission.83

In the meta-analysis mentioned above81 the risk of TB death was 1.4 times higher in COVID-19 patients. The findings of a recent study12 on 69 patients from 8 countries suggest the following:

• 1)

  The case fatality rate in the overall cohort was 11.6% (8/69); 14.3% (7/49) in the 8 countries study11 and 5% (1/20, the single old patient with comorbidities) in the Sondalo Hospital study.13

• 2)

  Mortality is likely to occur in elderly patients with co-morbidities;

• 3)

  TB might not be a major determinant of mortality;

• 4)

  Migrants experienced lower mortality, probably due to their younger age and lower number of co-morbidities. However, the authors commented that in patients with severe TB and/or with a disease caused by resistant strains of Mycobacterium tuberculosis, a higher mortality rate can be expected also in younger individuals.

In a recent modelling study based on data from the Philippines,84 the risk of death in TB patients co-infected with COVID-19 was 2.17 times higher than in non COVID-19 ones, with a shorter time-to-death. The risk of recovery in these patients was 25% lower than in non COVID-19 ones, with longer time-to-recovery.

A study from South Africa85 showed that while HIV-TB co-infection doubled the risk of death of TB patients compared to HIV-uninfected individuals, TB (both drug-susceptible and drug resistant) increased the hazard of COVID-19 death of 2.7. A lower increase (1.51) was reported in those with previous TB.

A global study on TB and COVID patients, coordinated by the Global Tuberculosis Network (GTN) and supported by the World Health Organization (WHO) is going on at present to improve the description of the interaction between the two diseases. As of October 13th 2020, 36 Countries/Regions joined the global study, with 132 Centres from 27 Countries/Regions having already provided data for 597 individual patients.86 The primary objective of the study is to describe the characteristics of patients with COVID-19 and TB (current or past), including diagnostic tests and prescribed therapies. The secondary objectives are: 1. To evaluate the logistic and organizational feasibility of a global repository for patients with COVID-19 and TB and 2) to describe the clinical outcomes (outcomes of COVID-19 disease, as well as interim and final treatment outcomes of TB patients).86

The GTN suggested several priority research questions to be answered with this global a study and others ones.

They include:

• 1

  Does COVID-19 increase the risk of developing TB disease in individuals with TB infection?

• 2

  What is the COVID-19 attributable risk on TB mortality?

• 3

  What are the other determinants of mortality in TB−COVID-19 co-infected patients?

• 4

  Is BCG vaccination protective for COVID-19?87

• 5

  Do TB/COVID-19 co-infected patients require different management? (or in other words, which additional services are needed for these patients?)

• 6

  What impact will COVID-19 have on TB services over the coming years, considering also the increasing effects of its second wave?

• 7

  Are patients with post-TB sequelae a higher risk group for COVID? Do they suffer increased mortality or delayed cure? Do these patients require specific rehabilitation services?

According to recent studies, a high proportion of cases with post-TB treatment sequelae suffer from lung function impairment and poor Quality of Life (QoL). Preliminary data suggest that pulmonary rehabilitation is effective in patients with a previous history of TB.88–91

In addition, it has been well described that severe acute respiratory syndrome is the dominant finding of the acute phase of COVID-19 infection whilst functional impairment of patients surviving the COVID-19 acute phase has been poorly described. Recent studies suggested that early, post-hospitalization rehabilitative interventions should be recommended.92–94

Few studies are available on the potential interaction of COVID-19 on the TB health services.9,15

The GTN global study9 evaluated patient attendances in TB health care units in 33 centres from 16 countries comparing the volume of TB-related healthcare activities in the first 4 months of the COVID-19 pandemic (January–April 2020) to the same period in 2019.9 The majority of the centres experienced reductions during their national lockdowns in the first 4 months of 2020, in TB-related hospital discharges, of newly diagnosed cases of active TB, of the total active TB outpatient visits, and of the new latent TB infections diagnosed (and related outpatient visits). In some centres, personnel initially attributed for TB service provision were re-prioritised to COVID-19. In addition, the decreased attendance to TB clinics was associated with patient fear of exposure to COVID-19 in the community or with disruptions of the services or struggle in accessing health services during lockdown. Conversely, national lockdowns favoured the increased use of telemedicine. In the TB centres surveyed in Australia, Russia, India, and the United Kingdom, telehealth service use increased.

A study carried out in Sierra Leone10 compared the number of patients assessed for presumptive TB and the number of those confirmed sputum smear positive in the first 4 months of 2020 with the number of cases reported in 2018 and 2019. The results show a significant drop of confirmed TB cases. Furthermore, the number of presumptive TB decreased in March/April 2020, with no treatment supervised nor cases of TB/COVID-19 coinfection or childhood TB detected in April 2020. The study shows the indirect impact of COVID-19 on TB care in a low-resource high TB-burden setting. The study suggests that Africa needs economic and technology support to strengthen its response to COVID-19 pandemic. Otherwise, all results achieved in recent years in the fight against TB may be lost.

Similar findings have been observed in Brazil,95 China,96 India,7,97 Iran,98 Nigeria99 and United States (migrants).100 A similar experience was reported on children in South Africa.101 In Korea, on the contrary, the impact of COVID-19 on the performances of the TB private sector project (PPM) was not observed.102 Repeat lockdowns of varying degrees are reported in countries which have recurrent COVID-19 waves, and severe consequences to TB services are therefore expected.26