Academic Editor: Gustavo Caetano-Anollés
Tuberculosis (TB) and Coronavirus Disease-19 (COVID-19) infection are two
respiratory diseases that are of particular concern epidemiologically.
Tuberculosis is one of the oldest diseases recorded in the history of mankind
dating back thousands of years. It is estimated that approximately one quarter of
the world’s population is infected with latent Mycobacterium tuberculosis (LTBI).
This contrasts with COVID-19, which emerged in late 2019. Data continues to
accumulate and become available on this pathogen, but the long-term side effect
of fibrotic damage in COVID-19 patients evokes parallels between this novel
coronavirus and its ancient bacterial affiliate. This similarity as well as
several others may incite inquiries on whether coinfection of individuals with
latent TB and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lead
to excessive fibrosis in the lungs and thus the emergence of an active TB
infection. While it is well understood how TB leads to structural and
immunological lung complications including granuloma formation, fibrosis, and T
cell exhaustion, less is known about the disease course when coinfection with
SARS-CoV-2 is present. Past and present research demonstrate that IL-10,
TNF-
Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), a highly aerobic bacillus that most commonly colonizes in the lungs. Approximately a quarter of the world’s population is latently infected with tuberculosis. It is one of the top 10 causes of death worldwide and the number one cause of infectious disease deaths worldwide with a rising mortality [1]. Documented incidence in 2020 showed a 20% decrease in TB diagnoses, which is suspected to be the product of many factors. Some of these factors may include reduced access to diagnostic, treatment and preventative services, and misdiagnosis due to the Coronavirus Disease 19 (COVID-19) pandemic [2], as well as a global increase in mask wearing and social distancing. The World Health Organization (WHO) Global Tuberculosis Report 2021 has speculated that the COVID-19 pandemic has reversed years of progress in the effort to globally eradicate TB. The recorded TB diagnosis dropped from 7.1 million in 2019 to 5.8 million in 2020, but it is estimated that approximately 10 million people newly acquired TB in 2020. Drug resistant TB continues to be a threat, making up a statistically significant number of cases. For instance, 132,222 Multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) and 25,681 Extensive and Pre-Extensively drug-resistant tuberculosis (XDR-TB, pre-XDR-TB) were reported globally in 2020, and 150,359 people in total were enrolled in MDR/RR-TB treatment worldwide. This number has decreased 15% from 177,100 in 2019, and it is estimated that only one in three people who develop MDR/RR-TB actually enroll in treatment programs [1].
The COVID-19 pandemic has had significant impacts on global public health and
has adversely affected essential healthcare services. The etiology of the
COVID-19 pandemic is Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2), a rapidly spreading virus which emerged from Wuhan, China in late
2019 resulting in large-scale mortality and morbidity, overwhelming the
healthcare system globally [3]. The condition caused by this virus is
characterized as a whole spectrum of disease ranging from asymptomatic to rapidly
fatal, the severity of which varies greatly based on factors such as viral strain
and host comorbidities. As of October 25, 2021, there have been 243,260,214
confirmed cases and 4,941,039 confirmed deaths reported to the WHO. Despite
extreme vaccination efforts, the course of the pandemic remains unpredictable,
and the challenge to restrain the pandemic is further compounded by the emergence
of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma)
and B.1.617.2 (Delta), which show increased transmissibility and resistance
towards vaccines [4]. As of publication of this review, the world remains
immersed in the COVID-19 pandemic caused by SARS-CoV-2 while the development of
effective antiviral therapies for treating SARS-CoV-2 infection remain in
progress [4]. The effort to understand this novel coronavirus has contributed to
significant research on the subject, but there is still much to be discovered
about the coinfection between this virus and other major morbidities such as
tuberculosis. This article explores the characteristics of coinfection using case
studies and exploration of the major immune system factors Interleukin-10
(IL-10), Tumor Necrosis Factor Alpha (TNF-
Mtb is phagocytosed by macrophages once in the lungs but is not killed by these
immune cells due to its successful blockage of the bridging molecule Early
Endosomal Autoantigen 1 (EAA1), which is required for fusion of the phagosome and
lysosome during pathogen destruction after phagocytosis [10]. This and several
other defense mechanisms prevent the bacterium from destruction and allow
unregulated replication inside the macrophage. Cytokines such as Tumor necrosis
factor alpha (TNF-
TNF
The IFN cytokines are key players in many defense processes against infections
through the stimulation of hundreds of interferon-stimulated genes (ISGs). The
IFN group of cytokines are divided into 3 classes: Class I, II, and III. The
class I IFN family is critical in carrying out various immunoregulatory and
inflammatory processes. This protein family includes 13 IFN
The class II IFN family has one single member: IFN-
T-regs, also known as suppressor T cells, are a subdivision of T cells
responsible for the recognition of self antigens and the prevention of autoimmune
disease. These cells’ control of autoimmunity makes them inherently
immunosuppressive [19, 20]. In the specific context of TB, T-regs change their
role depending on the disease stage. In the early stages of infection, T-regs
contribute to immunosuppression, whereas in the chronic stage, T-regs are helpful
in counter-regulating excessive inflammation, thereby preventing or delaying
disease pathology. T-regs can be broadly classified into Thymic T-regs (tTreg),
or Induced T-regs (iTreg). tTregs are produced in the thymus and are responsible
for maintaining homeostasis and tolerance systemically. iTregs are formed in the
periphery during T cell activation and work locally to dampen antigen-specific
immune responses. Inducible T Regulatory Type 1 cells (IT1) are a subdivision of
iTregs that use cytokine IL-10 to mediate suppressive effects. The key cytokines
involved in the immunosuppressive function of Tregs are IL-10, TGF-
The structures [22, 23, 24] and several functions of key cytokines involved in the immunosuppressive function of T-regs.
TGF
The IL-10 family of cytokines has many roles involved with Mtb infection. IL-10,
also known as human Cytokine Synthesis Inhibitory Factor (CSIF), can enhance the
intracellular survival of mycobacterial bacilli through various mechanisms
including: inhibiting phagosomal maturation, reducing nitric oxide production and
blocking IFN-
Tuberculous granulomas will only form if an engulfing macrophage cannot destroy its phagocytosed foreign material. Macrophages infected by TB that are unable to kill their pathogen release cell signals that cause dendritic cells to recruit Th1 cells, which then become activated and aggregate around macrophages.
Released IFN-
Granuloma formation overview.
In post-mortem analysis of a tuberculosis-infected human lung, necrotizing granulomas, or caseum, will be observed. These findings are specific to the tuberculosis pathogen. New caseum reveals a white or yellow cheesy texture. Older caseum becomes grey or chalky. The material is a homogenous, eosinophilic, fine-grained necrosis. Occasionally these granulomas will liquefy and drain, resulting in a cavity. Eventually during the chronic phase of infection, necrotizing granulomas will become invaded with collagenous fibers and solidify into a fibrosed follicle or eventually calcify entirely [32].
SARS-CoV-2 is an enveloped, single stranded positive sense RNA virus belonging
to the Betacoronavirus genus and has a genome up to 80% similar to SARS-CoV-1
[3, 33]. The virion has 4 structural proteins: the Spike (S), Envelope (E),
Membrane (M), and Nucleocapsid (N) proteins. The viral S proteins are Type 1
membrane glycoproteins containing a single transmembrane domain oriented
extracellularly. It is the numerous copies of S protein oriented extracellularly
that give the virus its “crown-like” appearance [34]. For over a decade, it has
been known that the Angiotensin Converting Enzyme 2 (ACE2) protein located in
humans is a receptor for the S protein in many other members of the
Betacoronavirus genus, such as SARS-CoV-1 and MERS-CoV. SARS-CoV-2 is no
exception. The S protein in these Betacoronaviridae species is composed of 2
subunits, one of which (S1) binds to ACE2 and the other of which (S2) anchors the
S protein to the host cell membrane [34]. ACE2 is a protein belonging to the
Angiotensin-Converting Enzyme (ACE) family of dipeptidyl carboxydipeptidases. ACE
converts Angiotensin I into vasoconstricting Angiotensin II, and ACE2 converts
Angiotensin II into vasodilating Angiotensin 1-7 [35]. ACE2 is variably expressed
in multiple organs, such as the kidneys and lungs. While during COVID-19
infection it is a gateway to viral entry into the cell, it is also ironically an
important protein in attenuating inflammatory lung disease [36]. The
immunomodulators TNF-
In general, T-regs are the first line of defense against unregulated inflammatory response during a COVID-19 infection [37]. They are key in manipulating the numbers and expressions of other immune cells in order to maintain self tolerance and immune homeostasis. However, there has been a widely observed variation in T-reg numbers as various studies on the subject have observed that T-reg numbers can be remarkably lower than normal [38, 39] or higher than normal [40]. The lack of consistency in studies suggests that more research is necessary to establish a more substantial conclusion on the correlation between T-reg levels and severity of COVID-19 infection.
Many studies have revealed that patients with severe COVID-19 infections have
higher levels of cytokines (TNF-
It has been proposed that TGF-
Class I and III interferons have a critical role in the defense against viral infections. When Pattern Recognition Receptors (PRR) on immune cells recognize Pathogen Associated Molecular Proteins (PAMPs) affiliated with many viral infections, IFN cytokines will be secreted. Interferons are critical for both the innate and adaptive immune responses because once they are activated, they in turn will activate hundreds of different interferon-stimulated genes (ISGs) that increase the immune response against viral infections [14]. Class I IFNs were first discovered through recognition of their strong response against the influenza virus, and the numerous signaling pathways that IFN cytokines trigger continue to be studied today. The viral inhibition mechanisms are extremely diverse and include mechanisms that target the viral life cycle at almost every step. Some ISGs operate as viral sensors (RIG-I, PKR, IFI16, cGAS), some deter viral entry (IFITM), some impede viral genome replication (Mx), and some block viral release and dissemination (BST-2/CD137) [45].
Addionally, interferons have been implicated in the cytokine storm that affects
the host’s system during SARS-CoV-2 infection. SARS-CoV-2 infection produces the
increase of inflammatory molecules such as IL-6 and IFN-
In post-Mortem analysis of a COVID-19-infected human lung, the major histopathological finding is disseminated Diffuse Alveolar Damage (DAD) at different stages, detectable in all lung lobes but not homogeneously effected. The middle and lower lung fields are most heavily affected. Characteristics of DAD include fibroblastic proliferation, fibrosis, and pneumocyte hyperplasia leading to alveolar collapse [46]. Other non-universal findings that may be observed include signs of pulmonary embolism, alveolar hemorrhage, and bronchopneumonia with or without typical features of DAD [47].
Co-infection with latent TB and COVID-19 is of particular concern for various reasons, including potential for missed diagnosis due to nonspecific overlapping clinical features, potential for drug-drug interactions, and increased severity of disease with post-TB sequelae [48]. Our review aimed to analyze current literature on whether COVID-19 may reactivate latent TB. There is emerging evidence that patients with Latent Mycobacterium Tuberculosis Infection (LMTBI) and TB disease have an increased risk of the SARS-CoV-2 infection and predisposition towards developing severe COVID-19 pneumonia, although evidence is not conclusive [49]. In a study by Petrone et al. [50], it was demonstrated that COVID-19 patients, either TB or LMTBI, have a low ability to build an immune response to SARS-CoV-2 while retaining the ability to respond to Mtb-specific antigens. Another study reported that long term impact of COVID-19 may activate latent TB post-pandemic, given the history of tuberculosis as a key bacterial infection in past viral pandemics [51].
In the first published cohort study analyzing co-infection of TB and COVID-19
across 8 countries, 49 cases of co-infection were explored and it was found that
a diagnosis of COVID-19 may occur before, simultaneously, or after a diagnosis of
tuberculosis [52] A case report of a 40 year old female diagnosed with COVID-19
and TB suggested that CD4
In a retrospective analysis by Diao et al. [38], the number of total T
cells, CD4
In a study conducted by Riou et al. [55] they found that acute
SARS-CoV-2 infection may not immediately result in progression of latent Mtb to
subclinical or active TB disease but found a significant reduction of
Mtb–specific CD4
Some have inspected the possibility of unintentional activation of LMTB with
anti-inflammatory agents intended to lower inflammation caused by another
pathogen. COVID-19 is an inflammatory lung disease, and treatment with
anti-inflammatory agents would be a logical step in COVID-19 treatment.
Anti-inflammatories, however, do by definition attenuate the pro-inflammatory
cytokines responsible for the inflammatory process, including TNF-
Both COVID-19 and TB are primarily respiratory illnesses that can be transmitted in the air, eliciting hyperinflammatory state in the lung. It is thus reasonable to speculate that the hyperinflammatory milieu induced by COVID-19 could accelerate TB disease progression and vice versa [56]. A major concern of co-infection with active TB in addition to poorer treatment outcomes is the potential for overlooking diagnosis of TB due to overlapping clinical features. It is also important to consider the prevalence of drug resistant strains of TB in co-infections. More studies are currently required, but it has been previously observed that variables related to mortality in DR-TB probably do not differ dramatically from those of the general population [58].
A case series of 7 patients with co-infection in Saudi Arabia was reported with each case showing signs of TB prior to confirmation of co-infection through microbiological testing [59]. Although the patients had differing presentations of disease, they were all found to have atypical imaging characteristics for COVID-19 that raised suspicion for alternative pulmonary disease. While COVID-19 is likely to show a bilateral, diffuse, infiltrative pattern, TB is likely to show a unilateral upper-zone opacity. Immune mediators and pathways that perhaps drive necrosis and cavitation during TB may lead to subsequent fibrosis [60] and affect the function of the respiratory tract, increasing the risk of pneumonia and respiratory failure. All patients demonstrated improved outcomes except for one 30-year-old female with no known prior medical conditions who passed away due to extensive disease. Another case series reported 4 migrant workers residing in dormitories in Singapore who were co-infected and also had atypical radiographic features [61]. A case report of a 28-year-old man described co-infection with COVID-19 with lung infiltrates and disseminated TB, with lesions found in the liver and a tuberculoma excised from the brain [62].
While many co-infection cases have shown good outcomes with treatment, fatal cases of co-infection have been reported. One reported fatal case is of a 38-year-old-male without significant medical history who presented with symptoms of low-grade fever, cough with expectorations, and shortness of breath for a month and a half; SARS-CoV-2 testing was positive through Reverse Transcription-Polymerase Chain Reaction (RT-PCR) [63]. Even with treatment including IV antibiotics, hydroxychloroquine sulfate, and oxygen supplementation, the patient remained symptomatic. With prolonged and untreated symptoms, sputum samples for TB were sent. Despite empirical treatment for TB, the patient rapidly deteriorated and died: diagnosis of TB was confirmed post mortem [63]. An additional fatal case of coinfection has been reported in a 3-month-old infant in Botswana who presented with fever and respiratory distress in the setting of failure to thrive [64]. The patient’s rapid clinical decline could not be explained by TB alone, and presence of diffuse microthrombi on autopsy together suggested a likely synergistic pathophysiologic effect of co-infection. A study by Sy et al. [65] explored co-infection cases in the Philippines, comparing risk of death and recovery in COVID-19 patients with and without TB. They found that patients with TB had 2.17 times higher risk of death than those without and risk of recovery in patients with TB was 25% lower than in those without [65]. The final matched sample consisted of 530 patients, with 106 cases with TB. Majority of cases were male patients with hypertension and/or DM II and most of the deaths seen were among older individuals with several comorbidities. Their results are consistent with an additional preliminary cohort study conducted by Davies which concluded COVID-19 patients with a current TB diagnosis had a 2.5 times higher risk of death, and those with previous TB had a 50% higher risk [66].
Age, poverty, malnutrition, and co-morbidities such as TB indicate higher risk of more severe COVID-19 [33]. Low income populations have a tendency to become more vulnerable to infectious disease due to several factors including reduced access to adequate healthcare and sub-optimal living conditions. Moreover, coinfection with both tuberculosis and COVID-19 is of special concern to these populations where tuberculosis is already a risk of higher significance.
The pandemic affected efforts to eradicate tuberculosis. Consequently, there has been an 18% decline in newly diagnosed TB cases and an increase in TB deaths, which is speculated to be a side effect of recent lack of access to diagnosis and treatment resources for TB. In an effort to better fund COVID-19 eradication efforts, many countries have reduced their resources allotted to other healthcare objectives such as the infrastructure in place to combat TB [1]. In addition to a reduced emphasis on TB healthcare, symptomatic patients may have been reluctant to seek medical attention leading to a delay or lack of active TB diagnosis and thus worsening of their condition [67]. Asymptomatic individuals who have had known contact with TB patients may delay seeking medical attention during the COVID-19 pandemic, thus leading to reduced diagnosis of LMTBI as well.
There are many reasons why a host’s immune system may be rendered inadequate enough to maintain granulomatous retention of LTBI and thus cause activated TB. This review compares the characteristics of different immune signaling molecules in the specific context of COVID-19 and whether co-infection with LTBI or active TB can lead to more deadly complications, whether it be because of the co-infection itself or the management, or lack thereof, of the co-infection due to lack of knowledge of the condition or healthcare infrastructure changes due to the pandemic.
IL-10 levels will see an increase during TB infection. Some of its key functions in TB are to suppress phagosomal maturation and nitrous oxide production, which are both functions that do not aid in the suppression of the disease. IL-10 can therefore aid in the reactivation of TB and disease progression. In COVID-19 infection, it is seen to be upregulated during a cytokine storm and a consistent correlation between disease severity and IL-10 levels has been observed.
TNF-
IFN-
TGF-
Not every molecule in this article has been found to have significant actions
taken during both TB infection and COVID-19 infection. ACE-2 does not appear to
have a significant contribution to TB infection, but is the host receptor for the
COVID virus’ Spike protein. In TB infection, iTreg cells work locally to mediate
suppressive effects through the use of IL-10, IL-35, and TGF-
Currently there is no available experimental data on immunopathological effects of TB/COVID-19 co-infection. However, given our current understanding of the etiology of TB and COVID-19 independently as well as reviewing current literature on co-infection, we can postulate the interactions of these airborne diseases with co-infection. A thorough understanding of the immunological and clinical similarities and differences of these pathogens and further investigation of their interactions may lead to a hopeful improved system of therapeutic strategies for co-infection as well as improved prevention measures. Several studies explored in this review have suggested a synergistic or additive effect when Mtb and SARS-CoV-2 share the same host, leading to increased severity of disease, especially if presenting with comorbidities such as DM II, HTN, and obesity.
There are several mechanisms that have been proposed that may explain why
co-infection between TB and COVID-19 causes a synergistic effect. One popular
proposed mechanism involves the combined effect of TB and COVID-19 infection
likely causing a pronounced lymphocytopenia and consequently a
CD4
COVID-19 is an inflammatory lung disease, and it follows that treatment with anti-inflammatory agents would be a logical step in COVID-19 treatment. Therefore, the use of immunomodulators should be carefully considered in individuals given their clinical history, especially in areas with high TB incidence as the use of blocking pro-inflammatory cytokines that maintain the structural integrity of the granuloma may lead to activation of latent TB. Understanding how pathogens interact with the same host pulmonary microenvironment and the biomolecular effects of these contributors to pathogenicity is fundamental for prevention and treatment of TB/COVID-19 co-infection. A summary of these contributors to pathogenicity of TB and COVID-19 has been summarized in Table 1. As great effort and focus is placed into stopping the ongoing COVID-19 pandemic globally, it is of utmost importance to not neglect TB, one of the oldest and deadliest infectious diseases of mankind which is both preventable and treatable.
Cytokines and modulators | Mycobacterium tuberculosis | SARS-CoV-2 |
IL-10 | ||
TNF- |
||
IFN- |
||
Class I and III IFN | ||
TGF- |
||
ACE-2 | ||
Treg | ||
IL-35 | ||
Our search was conducted through the PubMed database. Our search criteria
included the following keywords, both combined and separated: “COVID-19”,
“Latent TB”, “Active TB”, “Tuberculosis”, “SARS”, “MERS”, “immune
response”, “anti-inflammatory agents”, “epidemiology”, “bronchiectasis”,
“fibrosis”, “cavitation”, “TB treatment”, “IL-10”, “TNF-
LTBI, Latent Tuberculosis Infection; TB, Tuberculosis; Mtb, Mycobacterium tuberculosis; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; COVID-19, Coronavirus Disease-19; IL, Interleukin; TNF, Tumor Necrosis Factor; IFN, Interferon; TGF, Transforming Growth Factor; Treg, Regulatory T Cells; DR-TB, Drug-Resistant tuberculosis; MDR/RR-TB, Multidrug and rifampicin-resistant Tuberculosis; XDR-TB, Extensively Drug Resistant TB; MERS, Middle East Respiratory Syndrome; EAA1, Early Endosomal Autoantigen 1; PGE2, Prostaglandin E2; ISG, Interferon-Stimulated Genes; Th, Helper T cell; RT-PCR, Reverse Transcription Polymerase Chain Reaction; HIV, Human Immunodeficiency Virus; iTreg, Induced Regulatory T Cells; tTreg, Thymic Regulatory T Cells; IT1, Inducible T Regulatory Type 1 Cells; DMII, Diabetes Mellitus Type 2; CVD, Cardiovascular Disease; COPD, Chronic Obstructive Pulmonary Disease; ACE, Angiotensin Converting Enzyme; PAMP, Pathogen Associated Molecular Protein; PRR, Pattern Recognition Receptor; DAD, Diffuse Alveolar Damage.
Not applicable.
Not applicable.
Data sharing not applicable. No new data were created or analyzed in this study. Data sharing is not applicable to this article.
EL, KS, and GS have contributed to drafting this review. VV conceived the framework, provided guidance and assistance, and made edits to the draft. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
We appreciate the funding support from National Institutes of Health (NIH) award RHL143545-01A1.
The authors declare no conflict of interest.