key: cord-0799951-siukg0bc authors: Visca, D.; Ong, C.W.M.; Tiberi, S.; Centis, R.; D’Ambrosio, L.; Chen, B.; Mueller, J.; Mueller, P.; Duarte, R.; Dalcolmo, M.; Sotgiu, G.; Migliori, G. B.; Goletti, D. title: Tuberculosis and COVID-19 interaction: a review of biological, clinical and public health effects date: 2021-01-22 journal: Pulmonology DOI: 10.1016/j.pulmoe.2020.12.012 sha: 73860f8e934b12671897c6929aa945219fdcb54c doc_id: 799951 cord_uid: siukg0bc Evidence is accumulating on the interaction between tuberculosis (TB) and COVID-19. The aim of the present review is to report the available evidence on the interaction between these two infections. Differences and similarities of TB and COVID-19, their immunological features, diagnostics, epidemiological and clinical characteristics and public health implications are discussed. The key published documents and guidelines on the topic have been reviewed. Based on the immunological mechanism involved, a shared dysregulation of immune responses in COVID-19 and TB has been found, suggesting a dual risk posed by co-infection worsening COVID-19 severity and favouring TB disease progression. The available evidence on clinical aspects suggests that COVID-19 happens regardless of TB occurrence either before, during or after an active TB diagnosis. More evidence is required to determine if COVID-19 may reactivate or worsen active TB disease. The role of sequeale and the need for further rehabilitation must be further studied Similarly, the potential role of drugs prescribed during the initial phase to treat COVID-19 and their interaction with anti-TB drugs require caution. Regarding risk of morbidity and mortality, several risk scores for COVID-19 and independent risk factors for TB have been identified: including, among others, age, poverty, malnutrition and co-morbidities (HIV co-infection, diabetes, etc.). Additional evidence is expected to be provided by the ongoing global TB/COVID-19 study. The year 2020 will probably be remembered as the 'COVID-19 (coronavirus disease) year'. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic emerged in January/February, having originated from China in late 2019 [1] [2] [3] . Although continues to dominate both the scientific literature and the media, other communicable diseases including tuberculosis (TB) should not be neglected 4 . Much has been written on the potential interactions between COVID-19 and tuberculosis (TB) following the World Health Organisation (WHO) declaration of COVID-19 as a Public Health Emergency of International Concern 5 , initially based on assumptions, modelling [6] [7] [8] and scientific evidence [9] [10] [11] [12] [13] . The view of the WHO 7 , and the specialized scientific press and newspapers 14, 15 is that an important consequence of the COVID-19 pandemic would be a worsening of the TB epidemic globally, for a variety of reasons, such as additional pressures on health systems by COVID-19 resulting in weakening of the National TB programmes 16 and the potential biological effects of the interaction of the two infections, recalling the concept of 'cursed duet' which in the past was used for TB and HIV 17 . The aim of the present review is to describe the available evidence on the interaction between COVID-19 and TB, starting from differences and similarities, proceeding to describe immunological features, diagnostic implications, epidemiological and clinical characteristics (including impact on mortality) and public health implications (impact on health services). We made a rapid and non-systematic search of the literature using the key-words 'COVID-19', 'tuberculosis', 'immunology', "diagnosis', 'prevention', 'treatment', 'infection control', 'workplace' to identify a minimum set of references from an electronic database (PUBMED), existing guidelines on TB and COVID-19, airborne diseases, and grey literature. This review belongs to the Pulmonology TB series 2021 18 . Recent literature comparing [19] [20] [21] [22] [23] [24] [25] [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 J o u r n a l P r e -p r o o f 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 load 43 and important immune response with subsequent deterioration of the lung damage, respiratory failure (that may require invasivemechanical ventilation) and multi-organ dysfunction [44] [45] [46] [47] . (Figure 1 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 Administration Emergency Authorization [51] [52] [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 . (Figure 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 . 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 infectious 78 . For SARS-CoV-2, the virus requires live eukaryotic cells to replicate, with a minimum turn-around-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 reported 79, 80 . It describes that SARS-CoV2-specific response is detectable in the whole blood and is present during the acute phase 79 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; 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 first 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 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 above 81 the risk of TB death was 1.4 times higher in COVID-19 patients. The findings of a recent study 12 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 study 11 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 coinfected with COVID-19 was 2.17 times higher than in non COVID-19 ones, with a shorter time-todeath. The risk of recovery in these patients was 25% lower than in non COVID-19 ones, with longer time-to-recovery. The GTN suggested several priority research questions to be answered with this global a study and others ones. 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? J o u r n a l P r e -p r o o f 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] [89] [90] [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] [93] [94] Few studies are available on the potential interaction of COVID-19 on the TB health services 9,15 . The GTN global study 9 severe cytokine-storm events that may be fatal. Immunosuppression including steroids used to treat COVID-19 may in future result in TB reactivation. Gold standard diagnostic tests for COVID-19 are PCR, and culture-based methods for TB, but an ideal point-of-care tests that can promptly inform if an individual is actively infectious with TB remains elusive. COVID-19 can occur at any time during a patient's TB journey, with worse outcomes for patients affected by active pulmonary TB disease. More evidence is needed to understand the potential of COVID-19 to favor reactivation of an exisiting TB infection. The aspecific signs and symptoms common to COVID-19 and TB may facilitate a rapid access to imaging services (chest radiography and/or computerized tomography) which may manifest signs of a pre-existing TB. Avaliable data is insuffcient to understand the potential effect of COVID-19 on the TB patients' treatment outcome 11, 12, 86 , as in existing series the majority of these patients are still undergoing treatment. Based on the information available so far, the main determinants of mortality for COVID-19 are age and co-morbidities, including HIV co-infection, poverty, diabetes and malnutrition, all of these also have an impact on TB mortality. We need higher quality prospective studies to really answer the main research questions raised. In the meantime patients who had or have active TB especially people living with HIV co-infection should do their upmost to avoid getting COVID-19 and should be offered suitable vaccination when possible. Funding source: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors While policy development for TB has been slow, countries have been working to adopt and implement national TB strategies and programs, however, a large gap between policy and practice continues to exist due to financial and human resource constraints. Resource mobilisat ion Slow For Covid-19, resource mobilisation has occurred rapidly and through effective multisectoral engagement. Resource mobilisation for tuberculosis has been slow and there continues to be an annual funding deficit for TB research and development of more than $1.6 billion, a shortfall that is exacerbated by a lack of market incentives within the pharmaceutical industry 32 . Economi c impact Huge (rapid) Huge (slow) The economic burden of TB between 2006 and 2015 for twenty-two high-burden countries is estimated be about $3.4 trillion 33 . In May 2020, the Asian Development Bank announced that the COVID-19 pandemic could cost the global economy between $5.8 and $8.8 trillion 34 . Stress on health systems Huge (rapid) Huge (slow) The Covid-19 pandemic put health systems under immense pressure and often stretches hospitals and healthcare providers beyond capacity due to lack of infrastructure and equipment (hospital beds, ventilators) and staff and skills (overworked healthcare workers, lack of intubation skills). An increase in tuberculosis cases in high-burden counties puts additional pressure on already resource strained health systems that are already facing additional epidemics such as HIV. Additionally, new and existing health systems across the globe need to adapt to the rise of resistant forms of tuberculosis to provide better and affordable care. Availabil ity of data Simple and historically complete TB is a slow-moving epidemic and quarterly data is available at the national level. Due to the rapid spread, COVID-19 requires daily data updates, which is often incomplete or inaccurate. 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