The global threat of contagious infectious diseases, particularly tuberculosis (TB), has long concerned authorities in charge of public health policies. Most data and all predictions concerning global epidemiology of TB are based on “
TB remains of great significance for the public health in Eastern Europe (e.g., Romania), which has the highest TB incidence in the European Union (EU) (4 times higher than the average), accounting for a quarter of the TB burden in the EU [
Influenza infection may promote the progression of latent
This deleterious synergism of viral and bacterial infections increases the risk of influenza-associated mortality, and patients with PTB may increase the severity of influenza disease and death due to chronic lung disease and immunosuppression. Epidemiologic data suggest an increased rate of influenza or severe influenza-associated disease in patients with TB during influenza pandemics [
Individuals with chronic respiratory infections, including TB, are first to experience the adverse effects of a pneumotropic pandemic, especially in the healthcare setting [
Therefore, we aimed to review the available literature in order to predict the impact of COVID-19 pandemic on patients with latent TB and TB sequelae based on the data available from the past influenza pandemic and seasonal influenza outbreaks (considering similar or more severe outcomes in the current pandemic) underline possible clinical particularities and diagnostic errors on these patients evaluate possible different therapeutic approaches on TB patients (latent, sequelae, or active) given that current COVID-19 treatment may induce mycobacterial proliferation [
The electronic database of PubMed was systematically searched for relevant articles from the inception until March 2020. The search terms used were [“
In order to identify emerging coinfection particularities of novel coronavirus SARS-CoV-1, we queried the COVID-19 Open Research Dataset (CORD-19), the current largest open dataset available with over 47000 scholarly articles, including over 36000 with full text about COVID-19, SARS-CoV-2, and other coronaviruses. The CORD-19 dataset is available at
Articles were exported from CORD-19 and merged locally for further processing. Articles of interest were retrieved by administering the query “COVID” OR “COVID-19” OR “2019-nCoV” OR “SARS-CoV-2” OR “Novel coronavirus” OR “Tuberculosis” OR “
Study selection process and number of papers included.
For a better understanding of managing a novel coronavirus pandemic, one needs to understand the experience. Since the first discovery of coronaviruses in 1960, there have been described three human coronaviruses known to cause fatal respiratory diseases: The severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV, now known as SARS-CoV-1) that led to a global epidemic in 2002 [ The Middle-East respiratory syndrome coronavirus (MERS-CoV) which was discovered in 2012 and still affects people from 27 countries [ Most recently, the novel coronavirus (SARS-CoV-2), whose outbreak led to an ongoing pandemic with thousands of new cases being confirmed each day and a growing number of reported deaths worldwide [
It has to be added that while SARS-CoV-1 was associated in 37 countries with 8096 cases and 774 deaths during the entire nine months of the epidemic [
Known and possible interactions between MTB and coronaviruses.
Its high transmissibility rate reminds of the 1918-19 influenza pandemic when it has been estimated that almost a third of the world’s population is affected with a mortality rate of 2.5% [
Some studies have shown that, in a patient with TB, induction of type I interferons (IFNs) determined by influenza infection could be detrimental [
During the 2002-03 SARS-CoV-1 epidemic, it was highlighted that to contain the epidemic, the correct management of symptomatic patients (within and outside the hospital) was critical [
TB in SARS patients has been reported in several studies from TB endemic countries such as Singapore, China, or Taiwan [
During an epidemic, many measures are taken (especially in hospitals) to limit the transmission of the disease to naïve patients. However, overcrowding hospitals are prone to mistakes. Known-TB patients from China supposedly acquired SARS due to exposure to SARS patients from the same hospital wards. Hence, coinfection could have been avoided [
When dealing with a possible SARS patient from an endemic TB region, one should never forget TB as a coexisting pathology. In April 2003, a SARS-related hospital screening from Taipei (Taiwan) resulted in discovering 60 TB cases among healthcare workers [
Influenza pandemic/seasonal outbreaks and other coronaviruses epidemics might have a negative impact on TB patients. Transmission prevention was crucial for containing the epidemics. In order to decrease the opportunity of SARS-CoV-2 spreading among TB cases, hospital treatment for TB patients should be limited to severe cases.
Although the pathophysiology of SARS-CoV-2 is not fully understood, it seems most likely similar to the one of SARS-CoV-1. Substantial evidence suggests that SARS-CoV-2 infection could initiate an aggressive inflammation by increasing cytokines secretion such as interleukin-1
Immune system hyperreaction was also described in the 1918–1919 influenza pandemic, which was the first known pandemic to report an excess risk of death among individuals 25–35 years old [
Cytokines have an essential role in host resistance to TB infection, being first demonstrated in murine infection models [
Since the SARS-CoV-2 is a newly discovered pathogen (first infection being reported in December 2019) [
On the contrary, 20 patients with TB and COVID-19 had a rather benign clinical course of the coinfection, with only one patient that died. TB lesions at chest X-ray were not aggravated, and only four patients had signs of newly developed pneumonia [
One should keep in mind that the existence of underlying conditions, autoimmune diseases, poor hygiene, and overcrowding is all known as risk factors for developing one, another, or both diseases [
Another serious problem posed by the COVID-19 pandemic is the treatment continuity of TB patients. The nature of the disease, with extended treatment regimens and poor outcomes with drug resistance resulting from therapy discontinuation, are significant problems even in regular times, all the more in a pandemic context with numerous and stringent isolation measures [
Cytokines seem to play an essential role in both COVID-19 and TB, their plasma level being associated with disease’s severity. Immune system hyperreaction could explain a more unfortunate outcome in people 25–35 years old. Although there is limited data on MTB and COVID-19 coinfection, one could reasonably presume that their coexistence might have a more severe evolution for the patient.
One of the most effective ways to prevent diseases caused by pathogens, like bacteria or viruses, proved to be vaccination [
Since 1921 a vaccine is used widely for TB prevention, a live-attenuated strain of the bovine tubercle bacillus named bacillus Calmette–Guerin (BCG) [
Although one might argue that the lack of widespread BCG vaccination in the United States may be influencing the course of their pandemic compared to countries with broad spread vaccination, one should also keep in mind that the United States delayed the implementation of infection control strategies (that could avoid superspreading events). There still is a reluctance of face masks wearing when out in public, a measure that has been proven to slow and stop the spread of the virus [
There is data suggesting that BCG vaccination of adults could increase the capacity of producing proinflammatory cytokines such as Il-1
Considering these facts, the BCG vaccine is contemplated as a potential candidate against respiratory viruses [
Given the high TB burden, especially in emerging economies and the high global threat of SARS-CoV-2, a vaccine that may be beneficial in combating TB and COVID-19 would be of high interest.
Adenoviral vectors have previously been used to improve immunogenicity with excellent results in the enhancement of both humoral and cellular immunity [
The University of Oxford appears to be repurposing this viral-based TB vaccine for use against SARS-CoV-2 by changing the immunogenetic antigen expressed. ChAdOx1 nCoV-19 (more recently known as AZD1222) is a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein. In rhesus macaques, ChAdOx1 nCoV-19 induced both humoral and cellular immune responses after one single dose. In humans, the preliminary results demonstrated an acceptable safety profile and spike-specific T cell responses as early as day 7, peaking on day 14, and maintained up to day 56 [
It is noted that SARS-CoV-2 envelope spike (S) protein has a decisive role for determining host tropism and transmission capacity [
Novel methods are emerging such as reverse vaccinology that refers to the process of constructing vaccines by detecting viral antigens through genomic analysis using bioinformatics tools. Reverse vaccinology has successfully been applied to fight against the Zika virus or Chikungunya virus. One study proposed reverse vaccinology and immunoinformatics methods to design potential subunit vaccines against SARS-CoV-2 using the highly antigenic viral proteins and epitopes. Suggested vaccine constructs appeared to confer good immunogenic response through various computational studies. Three vaccine constructs were designed, and the best one was selected through molecular docking study. Another study proposes a specific synthetic vaccine epitope and peptidomimetic agent, identified through bioinformatics methods [
Currently, there are 15 potential vaccine candidates for SARS-CoV-2 in the pipeline globally developed using various technologies (messenger RNA, synthetic DNA, synthetic, and modified virus-like particles) [
SARS-CoV-2 genome is up to 80% similar to SARS-CoV-1 and 50% similar to MERS-CoV. No SARS vaccine was approved for clinical use (in 18 years of research). Ongoing trials on the SARS-CoV-2 vaccine are on the highest interest.
TB and COVID-19 are mainly respiratory diseases that primarily affect the lungs; however, the onset of TB is often slow compared to COVID-19, which seems to develop in a few days from exposure [
Tuberculin skin test (TST) and with a greater sensibility and specificity, the interferon-gamma release assays (IGRAs) are widely used for TB screening [
It has been observed that high CRP and low peripheral lymphocyte counts could occur within a few days of exposure to SARS-CoV-2 [
As SARS-CoV-2 has not been identified for a few months in humans, there is no specific treatment [
With the urge of identifying the radiological features of SARS-CoV-2 infection, with the community transmission present in most countries, and with its nonspecific clinical onset (fever, dry cough, dyspnoea and radiological findings of bilateral infiltrates, and even pleural effusion and cavitation) [
Considering the sudden onset of the SARS-CoV-2 pandemic, countries struggled to quickly find a possible treatment to prevent respiratory failures and deaths, especially among patients with respiratory comorbidities. Also, since its fatal dynamics, there is no time to carry out new drug development in the traditional manner. Therefore, screening for already available drugs (for any activity against SARS-CoV-2) [
Coinfection of TB and SARS-CoV-2 may be challenging to diagnose. SARS-CoV-2 infection may mask the clinical and radiological active TB. Patients receiving the proposed treatment for COVID-19 may be at risk for the infection with NTM.
Because viral respiratory infections and TB impede the host’s immune responses, their lethal synergism can be assumed to contribute to more severe clinical evolution. Coinfection most likely affects both sides of these patients: rapid development of severe acute respiratory syndrome through cytokine-mediated immune response and increased risk of tuberculosis reactivation. As a lesson from previous outbreaks, hospital treatment for patients with tuberculosis should be limited to severe cases, to prevent the spread of SARS-CoV-2 in TB cases. Despite the rapidly increasing number of cases, the data needed to predict the impact of the COVID-19 pandemic on patients with latent TB and TB sequelae and to guide management in this particular context still lies ahead.
Data used to support the findings of this study are available from the corresponding author upon request.
Cristina Grigorescu has the same contribution as the first author.
The authors declare that there are no conflicts of interest regarding the publication of this article.
This study was funded by the Romanian Academy of MedAcademy of Medical Sciences and European Regional Development Fund (MySMIS 107124: Funding Contract 2/Axa 1/31.07.2017/107124 SMIS).