key: cord-0888269-m2w3mmaz authors: Mousquer, Gabriel Tassi; Peres, Alessandra; Fiegenbaum, Marilu title: Pathology of TB/COVID-19 Co-Infection: The phantom menace date: 2020-11-17 journal: Tuberculosis (Edinb) DOI: 10.1016/j.tube.2020.102020 sha: f3c3368d4e6728f5ea7ba7a27c06f0a7ace05164 doc_id: 888269 cord_uid: m2w3mmaz Despite the high number of victims of COVID-19, tuberculosis (TB) remains as the leading cause of death among infectious diseases worldwide. Since the beginning of the pandemic, there is an increasing number of studies trying to elucidate the interactions between Mycobacterium tuberculosis and SARS-CoV-2. The first case reports point to a worsening of respiratory symptoms in co-infected TB/COVID-19 individuals. However, data from the cohort studies has shown some conflicting results. This study proposes to conduct a systematic review on the current literature on TB/COVID-19 co-infection cohorts, evaluating clinical and epidemiological data, focusing on its implications to the immune system. From an immunological perspective, the TB/COVID-19 co-infection has the potential to generate a "perfect storm". The disorders induced by each pathogen to the immune modulation tend to induce an unbalanced inflammatory response, which can promote the progression and worsening of both diseases. Understanding the nature of the interactions between M. tuberculosis and SARS-CoV-2 will be crucial for the development of therapeutic strategies against co-infection. Considered by the World Health Organization (WHO) as the "public enemy number one", 41 coronavirus disease 2019 (COVID-19) brought chaos to the healthcare systems across the globe. Suddenly, 42 humanity was faced with a deadly new pathogen, capable of spreading quickly and aggressively through the 43 host's organism, as among society as well. While the threat of a second wave of COVID-19 haunts nations 44 that already seemed to have overcome the pandemic some countries, like Brazil, are still hostages to SARS-45 CoV-2. In Africa, South America and Southeast Asia, the crisis may become even worse, as COVID-19 may 46 end up converging with another deadly disease: the tuberculosis (TB) [1, 2] . 47 In contrast with COVID-19, which we are just beginning to understand, TB is an ancient threat that 48 menaces mankind since prehistoric ages, for at least 70,000 years [3] . This coevolution has made M. 49 tuberculosis a pathogen highly adapted to coexist and thrive among the humanity. Consequently, it is 50 estimated that around 2 billion people are latently infected with TB worldwide [4] . Each individual with 51 latent TB has approximately a 10% chance of developing the disease in its active form throughout life, 52 however, this risk may vary geographically and rise to 50% in individuals co-infected by the human 53 immunodeficiency virus (HIV) [4] . Currently, TB persists as the leading cause of death among infectious 54 diseases; however, since April 2020 COVID-19 has shown similar numbers of daily deaths worldwide [5] . 55 The convergence between these two deadly diseases raises concern among health authorities, especially in 56 countries endemic for TB. 57 The consequences resultant of the COVID-19 pandemic poses serious challenges to TB control 58 programs, mainly by compromising its diagnosis and treatment. Due to the similarities between TB and 59 COVID-19 symptoms, countries with a precarious diagnostic structure suffer to properly identify these 60 infections. This issue negatively influences in therapeutic decision-making and, therefore, impacts in 61 prognosis of both diseases [6-9]. TB treatment adherence and continuity are also affected by the lack of 62 resources, drugs and hospital supplies, as well as by the reduction of the mobility of patients and healthcare 63 workers; which can result in treatment failure and, consequently, in an increase in incidence of multidrug-64 resistant TB (MDR) [10, 11] . Another crucial aspect is that both diseases have similar social determinants, 4 seropositive individuals. COVID-19 rises now as a new menace, due to its devastating impact on the immune 75 system and, more importantly, to the lung functions [19, 20] . 76 Therefore, becomes clear the urgency for further studies focused on TB/COVID-19 The search strategy was based on the use of the following keywords, combined or separated, always 87 accompanied by "tuberculosis" and "COVID-19" among them: "immune response", "SARS", 88 "mycobacterium", "coronavirus" and "co-infection ". In addition, the bibliography of the reviewed studies 89 was also evaluated to support the results discussion. 90 91 Two authors (GM and MF) carried out the studies selection for this review independently; any 93 divergences were resolved in discussion with the help of the third author (AP). The following selection 94 criteria were applied: 95 • Study design: cohorts and case reports; 96 • Sample size: minimum sample size of 20 cases of TB/COVID-19 co-infection per study; 97 • Study population and assessed outcome: individuals proven to be co-infected with TB and 98 5 The reason for focusing on studies with larger samples and more complete data sets, is because they 106 provide a better representation of the general population, in addition to being more a robust evidence of the 107 relationships between pathogens. 108 109 From the 6 studies that fit to the review selection criteria, the following information was extracted: 111 study design, sample size, clinical features, outcomes, main findings and limitations. Two authors (GM and 112 MF) independently assessed all data, with differences being discussed and solved with a help of a third 113 author (AP). 114 115 All the data collected from the reviewed studies were critically analyzed by the authors and 117 summarized in Table 1 .0. Some of the information, regarding the clinical characteristics of the TB/COVID-118 19 co-infection, was not described in a standardized manner in their respective articles, therefore, not all the 119 data presented in Table 1 .0 can be paired between the studies. In addition, some of the mentioned studies 120 were published before the outcome information's could be evaluated, therefore, they do not present this data. 121 122 The results of this review are described in Table 1 .0. In summary, most of the evaluated studies point 124 to an association between TB and COVID-19. Both active TB and a previous history of TB seem to be 125 related to an increased risk for the development of COVID-19, as well as worsening the infection prognosis 126 The first cohort evaluating the association between TB and COVID-19 consisted of international 142 cooperation, grouping 49 cases of co-infection from 8 different countries; this study identified a higher 143 mortality among elderly people with a previous history of TB, however, regional differences in the COVID- Recently, two reviews, including a meta-analysis, were conducted with data from case reports and 159 cohorts of co-infected TB/COVID-19 individuals [12, 28] . Both studies did not identify a direct association 160 of TB with the worsening of COVID-19, however, it should be noted that these reviews only evaluated the 161 literature available until then, not including the results of the South African cohort, for example [27] . An 162 assessment conducted by a task force composed of specialists in immunology and microbiology, concluded 163 that despite the current lack of data on co-infection, it is quite likely that there is indeed a relationship 164 between TB and the worsening prognosis of COVID-19, as well as COVID-19 with the progression of TB. 165 However, there has not yet been time for these analyzes to be properly conducted [29] . Over time, more 166 studies describing TB/COVID-19 should be published, confirming these hypotheses. Even so, the lack of 167 data from TB endemic countries and with a high incidence of COVID-19, such as Brazil and India, remains 168 intriguing. What can already be established as a consensus is that co-infection is particularly dangerous for 169 people in conditions of social vulnerability, the elderly and people with other comorbidities, such as diabetes 170 and hypertension. Considering that a significant part of the individuals who develop active TB is part of this 171 group highlights the need for special attention to these populations during the pandemic. The potential 260 impact of COVID-19-related disruption on tuberculosis burden COVID-19, tuberculosis and poverty: Preventing a perfect storm Co-evolution of Mycobacterium tuberculosis and Homo sapiens Life and death in the granuloma: Immunopathology of tuberculosis Understanding Latent Tuberculosis: A Moving Target Up-regulation of IL-6 and TNF-␣ induced by SARS-coronavirus spike protein in murine macrophages via NF-B pathway The granuloma in tuberculosis: Dynamics of a host-pathogen collusion Cell Pyroptosis, a Potential Pathogenic Mechanism of 2019-nCoV Asymptomatic SARS-CoV-2 Infection Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis Mycobacterium tuberculosis: An adaptable pathogen associated with 355 multiple human diseases Macrophages and control of granulomatous inflammation in tuberculosis Induction of Th1 / Th17 immune response by Mycobacterium 360 tuberculosis: role Induction of Th1 / Th17 immune response by Mycobacterium tuberculosis : role of Functional exhaustion of antiviral 373 lymphocytes in COVID-19 patients Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus 376 Disease Expression 378 of IFN-γ -inducible protein ; monocyte chemotactic proteins 1 , 3 , and 4 ; and eotaxin in T H 1-and 379 T H 2-mediated lung diseases On the alert for cytokine 382 storm: Immunopathology in COVID-19 Pro-and anti-inflammatory cytokines in tuberculosis: 385 A two-edged sword in TB pathogenesis SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene 388 in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues IL-4 / IL-13 Remodeling Pathway 391 of Covid-19 Lung Injury The IL-13 / IL-393 4R ? axis is involved in tuberculosis-associated pathology Neutrophils in Tuberculosis-Associated Inflammation and Lung Neutrophil-to-lymphocyte ratio as an 398 independent risk factor for mortality in hospitalized patients with COVID-19 HIV-infected individuals Lung Remodeling in Pulmonary The Significance of Bronchiectasis Associated with Pulmonary Tuberculosis The role of tuberculosis and other forms of bronchopulmonary necrosis 409 in the pathogenesis of bronchiectasis Cytokine Networks in the Regulation of Inflammation and Fibrosis in the Lung Correlation of 413 virulence, lung pathology, bacterial load and delayed type hypersensitivity responses after infection 414 with different Mycobacterium tuberculosis genotypes in a BALB/c mouse model Endobronchial Tuberculosis Before and Early After Antituberculosis Chemotherapy Chronic pulmonary function impairment caused by initial and 420 recurrent pulmonary tuberculosis following treatment Tuberculosis and lung damage: From 423 epidemiology to pathophysiology Corticosteroids in tuberculosis Associated With Pulmonary Tuberculosis in Patients With Chronic COVID-19: Immunology and treatment 440 options IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy New diseases and old threats: lessons 444 from tuberculosis for the COVID-19 response Impact of COVID-19 on tuberculosis control in China