Flavio De Maio1,2, Delia Mercedes Bianco2 and Giovanni Delogu2,3.
di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico
Universitario “A. Gemelli”, IRCCS, Rome, Italy.
Dipartimento di Scienze biotecnologiche di base, cliniche
intensivologiche e perioperatorie – Sezione di Microbiologia,
Università Cattolica del Sacro Cuore, Rome, Italy.
3 Mater Olbia Hospital, Olbia, Italy.
Correspondence to: Flavio
De Maio. Dipartimento di Scienze di Laboratorio e Infettivologiche,
Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, Rome, Italy.
ublished: March 1, 2022
Received: September 20, 2021
Accepted: February 11, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022021 DOI 10.4084/MJHID.2022.021
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
the emergence of Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) at the end of 2019, a number of medications have been used
to treat the infection and the related Coronavirus disease – 19
Some of the administered drugs were tested or used
in practice only on the basis of biological plausibility; a promising
strategy was to target the host immune response, with host directed
therapies (HDTs), to reduce systemic hyperinflammation and
hypercytokinemia responsible for additional tissue damage.
We summarize the treatments against SARS-CoV-2 and underline their possible effects on Mycobacterium tuberculosis (Mtb) infection. Both SARS-CoV-2 and Mtb
respiratory infections impair the host’s immune response. Furthermore,
little research has been conducted on the impact of medicaments used to
counteract COVID-19 disease in patients with Latent Tuberculosis
Infection (LTBI). A number of these drugs may modulate host immune
response by modifying LTBI dynamic equilibrium, favoring either the
host or the bacteria.
pandemic has shown a significant disruptive impact on Tuberculosis (TB)
services, with negative effects on prompt diagnosis, treatment and
immunization.[1,2] Pressure on laboratories and
pharmaceutical industries led to the readaptation of many TB labs to
detect SARS-CoV-2 as well as Bacillus Calmette-Guérin (BCG) shortages
and consequent decrease of newborn vaccinations. Estimates indicate a 25% drop in the global BCG coverage and an increase in pediatric deaths ranging from 0.5% to 17%.
several countries, reports suggest a decline in case notification in
the last few months due to massive cancellation of routine health
services in many
settings.[5-7] Although it has
been noted that many of the preventive measures implemented to reduce
SARS-CoV-2 incidence also have a clear benefit on reducing Mycobacterium tuberculosis (Mtb)
transmission, 2020 saw the first year-over-year increase in TB deaths
from 2005, regardless of physical distancing and PPE (personal
protective equipment) wearing measures.[2,8]
Canada, the pandemic significantly affected latent TB infection (LTBI)
and active TB treatment, leading to ineffective measures for TB
elimination. In Spain, newly diagnosed TB
patients had more extended pulmonary disease, moreover there was a rise
in household transmission probably due to anti-COVID-19 measures.
Also, in England, it has been observed a fall in rates of TB treatment
initiation during the period of government-imposed lockdown (March
23–May 10, 2020), and an increase of cases of disseminated TB during
the COVID-19 pandemic. All this makes it
important to evaluate the measures against COVID-19 globally and not
only considering the pathologies related to SARS-CoV-2,
COVID-19 emergence prompted the scientific community to focus on
determining the mechanisms of transmission, the identification of
virulence factors of SARS-CoV-2 and the development of suitable
therapies. Therapeutical management of COVID-19
is in constant change, and treatment guidelines are readily updated
based on scientific evidence and experts’ opinion (National Institutes
of Health, n.d.) as we entered in an era of “hype-based medicine”,
the long forgotten eminence-based medicine regained importance as the
number of trials on possible therapies multiplied, some of them causing
overnight changes in the management of COVID-19 patients.
The lack of antiviral therapies and the rapid spread of the
infection convinced investigators and pharmaceutical companies to focus
on the development of vaccines, able to
induce neutralizing antibodies against SARS-CoV-2 Spike protein in
naive subjects. The developed vaccines do not only trigger a humoral
response against the protein, but they impact all the components of the
As most of the therapies used against COVID-19
disease therapies do not target SARS-CoV-2, but aim to regulate the
host immune response[16,17] it is reasonable to consider the long-term effects of these therapies on subjects with latent TB infection (LTBI).
In this commentary, we aim to summarize treatments against SARS-CoV-2 and underline their possible effects on Mtb
infection highlighting likely “side” effects that could help to contain
virus-mediated damage and, conversely, prompt mycobacterial replication
in both early infection or during Mtb latency.
Therapies Against SARS-CoV-2 Infection
represents the biggest therapeutic challenge of our century. At
present, approximately 2900 clinical trials have been registered, designing new molecules and repurposing existing drugs based on the virus biology and pathogenesis.
approaches range from convalescent plasma of people who have recovered
from COVID-19, to medications which are commonly used to treat
autoimmune or inflammatory diseases as well as drugs used to treat
for COVID‑19 target different pathogenetic mechanisms, with the aim of
a) blocking viral replication, summarized in points 1-3 of the Figure 1, and b) reducing tissue damage, modulating the immune responses, and preventing over-inflammation (Figure 1, points 4-6).
||Figure 1. Schematic
representation of the pharmaceuticals used against SARS-CoV-2
infection. The first class of molecules includes antivirals to prevent
viral entry (point 1); the second class includes compounds that inhibit
gene transcription (point 2) and the third class accounts molecules
that prevent proteolytic processing and block viral docking (point 3).
The points 4-6 described medications that reduce tissue damage,
modulating the immune responses or preventing over-inflammation.
The first class includes antivirals to prevent spike-protein-mediated cell fusion, thus blocking viral entry (Figure 1, point 1), inhibit gene transcription (Figure 1, point 2) or prevent proteolytic processing and block viral docking (Figure 1, point 3), as explained in Table 1.[20-23]
Interestingly, several agents show no effects on SARS-CoV-2 even
though they were described to have activity against other infections.
||Table 1. Summary reporting
experimental evidence of the impact of drugs used against SARS-CoV-2
infection on Mycobacterium tuberculosis infection.
infection causes an overproduction of type I interferons triggering the
transcription of several genes and the recruitment of CD4+ T helper
lymphocytes, responsible for the Th1/Th2 response.
For this reason, immunomodulators (corticosteroids, interferons,
monoclonal antibodies against inflammatory cytokines) have been
suggested, and largely used, to reduce the over-inflammation that is
responsible for several systemic disease manifestations.
the NHS Panel failed to evaluate the real role of some of these
therapies due to insufficient evidence to recommend either for or
against their use.
Examples of drugs in this category are IL-1 inhibitors, colchicine, the antiparasitic agent ivermectin, and thalidomide. Some others are currently recommended as IL-6 inhibitors and Janus Kinase inhibitors (refer to Table 1 and Figure 1, point 4 to 6).
the use of immunomodulatory treatments had an immediate impact on the
care of patients infected with SARS-CoV-2, their long-term effects are
Impact of the Therapies Against SARS-CoV-2 on Mycobacterium tuberculosis
infection represents a classical model of persistent infection, a
situation in which a microorganism can persist indefinitely within the
host,[28,29] establishing an equilibrium between the
pathogen and the host immune response whose modification could increase
the risk of relapse and disease. Indeed, host immune response can
limit Mtb spread, after macrophages killing evasion, creating a multicellular structure known as granuloma, which entraps mycobacteria that persist in a heterogeneous range of states. In the last decades, to deal with the emergence of Mtb strains resistant anti-TB drugs (MDR/RR-Mtb and XDR-Mtb), a novel approach has been proposed targeting the host and so named host directed therapies (HDTs).[32–35]
HDTs can support antimycobacterial host response at different stages:
a) perturbating granuloma integrity to enhance drug penetration; b)
modifying autophagy or phagosome maturation to increase intracellular
killing; c) promoting cell-mediated response; d) inducing antimicrobial
peptides and controlling inflammation response by avoiding tissue
damage. While the use of HDTs seem to support anti-TB treatment in symptomatic individuals, no data nor anecdotal knowledge support the use of such therapies in people with asymptomatic or subclinical infection.
In other words, it is undeniable that some immunomodulatory treatments may alter the host-Mtb
equilibrium, favoring either the host or the bacteria. In this
scenario, we cannot exclude that those immunomodulatory therapies used
against COVID-19 may have a negative effect on infected individuals
causing symptomatic TB.
A recent paper highlighted the relationship between SARS-CoV-2 and Mtb
infection, showing that asymptomatic SARS-CoV-2 seropositive
individuals with a positive IGRA exhibited heightened levels of
humoral, cytokine production, and systemic inflammation compared to
individuals negative for Mtb infection. Mtb
is apparently able to modulate the host immune response in
SARS-CoV-2-infected individuals. Furthermore, various clinical cases
describe TB reactivation following SARS-CoV-2 infection confirming the
concerns that COVID-19 associated CD4+ T-cell depletion or altered
T-cell function can have similar implications as HIV for TB disease
progression, promoting the development of active TB.[25,40] Moreover, some studies highlighted a higher probability to develop severe disease in patients with SARS-CoV-2 / Mtb co-infection compared to COVID-19 patients.[41,42] Unfortunately, we have little information on TB occurrence after COVID-19 treatments.
On the other hand, there was a delay in the onset of the pandemics in
many countries endemic for TB. Moreover, those countries showed lower
COVID-19’s severe cases and SARS-CoV-2 related-mortality. Intriguingly, one of the variables that was mathematically linked to COVID-19 low spread was BCG vaccination,
which is known to stimulate non-specific heterologous immune responses
inducing cross-protective effects toward non-tuberculosis-related
diseases, included SARS-CoV-2.[15,46,47]
Indeed, numerous clinical trials are currently registered to update on
the benefits of BCG vaccinations against SARS-CoV-2 exposure.[15,47]
We can classify therapies used against COVID-19 based on their activity on Mtb infection in four main drug classes: a) drugs acting directly on Mtb (Figure 2, point 1); b) drugs that modify phagosome acidification (Figure 2, point 2); c) drugs with adjuvant function that can indirectly modulate the infection (Figure 2, point 3) and d) drugs with immunomodulatory activity (Figure 2, point 4). Although many anti-COVID-19 pharmaceutics appeared to impair mycobacterial growth in in vitro experiments, (Figure 2, point 1),[48–51] we focus our attention on their immunomodulatory effects (Table 1).
||Figure 2. Schematic
representation of the medications used against SARS-CoV-2 with effects
on Mycobacterium tuberculosis infection. Therapies used against
COVID-19 are classified based on their activity on Mtb
infection in four main classes: drugs acting directly on mycobacteria
(point 1) or indirectly showing ability to modify phagosome
acidification (point 2), to modulate the infection with adjuvant
functions (point 3) and to regulate hose immune response (point 4).
Hydroxychloroquine inactivates mycobacterial NAD+ dependent DNA ligase A
and modulates phagolysosome, reducing intracellular mycobacterial
growth. Similarly, chlorpromazine, an antipsychotic drug, has been
observed to have antimycobacterial activity and to promote macrophagic
killing by increasing phagosome acidification. Acidification may though differently affect phagosomes at different stages of maturation. Moreover, Mtb itself can influence phagosome maturation potentially counteracting these drugs.
Nitazoxanide, which has been also suggested to modulate immune response inducing interferon-γ,[50,56] inhibits intracellular Mtb growth while amplifying Mtb-induced gene expression.
Thalidomide represents a compound that has been tested against Mtb
infection showing a detrimental effect on infection control due to
TNF-α inhibition with consequent increase in mycobacterial replication[57,58] (Figure 2 and Table 1).
Interestingly, several drugs that have been proposed against SARS-CoV-2 have not been tested in vitro against Mtb infection (Table 1).
This is true for several molecules that act on the host immune system
to prevent over inflammation (which has been observed as a critical
point for the progression of SARS-CoV-2 infection). These compounds,
that dampen pro-inflammatory cytokines, could impair the fine
equilibrium between Mtb
replication and the host immune system response, thus promoting active
disease. Among them, monoclonal antibodies such as IL-6 antagonists and
antivirals have been observed to significantly modulate host cytokine
response and potentially alter host immune response versus Mtb replication. Interestingly, Mtb
regulates IL-6 secretion to inhibit type I interferon signaling and
causes disease progression which appears to be associated to sigH gene expression. For this reason, IL-6 antagonist could have important implications during Mtb infection.
Another example are corticosteroids that are beneficial in hospitalized COVID-19 patients,[61,62] but, conversely, could increase the risk of LTBI reactivation or progression of sub-clinical TB.
the specific effect of COVID-19 on T-cells and for anti-COVID-19
treatments on LTBI, clinicians should consider monitoring patients with
both previous COVID-19 infection and LTBI to rapidly identify active
disease and prevent Mtb transmission.
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