Abstract
The emergence of novel coronavirus infectious disease-2019 (COVID-19) in
December 2019, caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) has traumatized the whole world with the ongoing
devastating pandemic. After droplet mediated transmission of infectious
virus particle, and subsequent tissue tropism through the upper and
lower respiratory tract, the acute clinical disease is manifested by
severe respiratory illness accompanied by shortness of breath,
progressive pneumonia, multi-organ dysfunction and ultimate death in
SARS-CoV-2 infected patients. The involvement of other microbial
co-infections leading to extortionate ailment in critically ill patients
has not been significantly reviewed along with conclusive reporting on
underlying molecular mechanisms in COVID-19 patients. Although the
incidence of co-infections could be up to 94.2% in laboratory-confirmed
COVID-19 cases, the fate of co-infections among SARS-CoV-2 infected
hosts often depends on the balance between the host’s protective
immunity and immunopathology. The cross-talk between co-pathogens
(especially lung microbiomes), SARS-CoV-2 and host is an important
factor that ultimately increases the difficulty of diagnosis, treatment,
and prognosis of COVID-19, and even increase the symptoms and mortality
of the disease. Simultaneously, co-infecting microorganisms may use new
strategies to escape host defense mechanisms (by altering both innate
and adaptive immune responses) to further aggravate SARS-CoV-2
pathogenesis. This review of literature suggests that clinicians should
rule out SARS-CoV-2 infection by ruling in other respiratory
co-pathogens, and must have a high index of suspicion for co-infection
among COVID-19 patients. Thus, after recognizing the possible pathogens
causing co-infection among COVID-19 patients, and the underlying
molecular mechanisms of co-infections appropriate curative and
preventive interventions can be recommended.
Key Words: COVID-19, SARS-CoV-2, microbial co-infections,
virus, bacteria, archaea, fungi, and molecular pathogenesis.
Introduction
The novel coronavirus infectious
disease-2019 (COVID-19) is a rapidly transmissible pneumonia-like
disease caused by the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) emerged in Wuhan, China in December 2019, and is currently
circulating throughout the world (Hoque,
Chaudhury, Akanda, Hossain, & Islam, 2020;
Rahman et al., 2020)
(Hoque, Chaudhury, et al., 2020;
Rahman et al., 2020). The SARS-CoV-2 is
an enveloped RNA virus which is genetically significantly different from
the previously known coronaviruses, such as SARS-CoV-1 and Middle East
respiratory syndrome coronavirus (MERS-CoV)
(Hoque, Chaudhury, et al., 2020;
Rahman et al., 2020;
N. Zhu et al., 2020). Immediately its
first outbreak in China, this fearsome SARS-CoV-2 has emerged as one of
the deadliest human pathogens in the last hundred years after the
Spanish Flu in 1918-20 (Li et al., 2020;
Reid, Fanning, Hultin, & Taubenberger,
1999). The deadly outbreaks of SARS in 2003 and MERS in 2012, with case
fatality rate 9.6% and 34.4%, respectively were successfully contained
within six months. However, the SARS-CoV-2 infection has become a public
health challenge for all over the world, and thus, the World Health
Organization (WHO) has declared this disease as a public health
emergency of international concern (Hoque,
Chaudhury, et al., 2020; Rahman et al.,
2020). The COVID-19 disease affected total 217 countries and
territories until November 25, 2020, and more than 60,150,606 cases have
been confirmed globally with 14,15.746 deaths. Therefore, this quickly
spreading COVID-19 pandemic highlights the critical need for rapid
development of vaccines and antiviral treatments to reduce the number of
hospitalizations and deaths by this disease
(Mirzaei et al., 2020).
Co-infections and superinfections are common in any respiratory viral
infectious diseases (Mirzaei et al.,
2020; Paget & Trottein, 2019).
Secondary or bacterial co-infections can significantly increase the
mortality rate in patients infected with any viral infections
(Jia et al., 2017;
Mirzaei et al., 2020;
Quah, Jiang, Tan, Siau, & Tan, 2018).
Bacterial co-infections were also reported in MERS-CoV patients
receiving intensive care (Memish, Perlman,
Van Kerkhove, & Zumla, 2020). The co-infection of the SARS-CoV-2 with
other microorganisms is a very important factor in COVID-19 disease that
may complicate proper diagnosis, treatment, prognosis of COVID-19, and
even increase the mortality of the patients
(Hoque, Rahman, et al., 2020) (Ruuskanen
et al., 2011). Clinical trials and metagenomic investigations indicate
the co-presence of other viruses, bacteria, archaea, fungi with
SARS-CoV-2 in COVID-19 patients (N. Chen
et al., 2020; Hoque, Rahman, et al.,
2020; Shen et al., 2020). About 50% of
the patients who died of COVID-19 had secondary bacterial infections
(N. Chen et al., 2020;
Zhou et al., 2020) which further
intensifies the patho-physiological progressions of COVID-19 diseases.
Better understanding of co-infections in COVID-19 is critical for the
effective patient management, treatment and containment of SARS-CoV-2.
It is therefore, necessary to strengthen the investigation of the
co-infection in COVID-19 patients. In the case of COVID-19 disease,
several issues such as useful strategies to prevent disease spread,
collection of appropriate clinical specimens, transmission route, viral
dynamics and effective drug treatments are still largely unknown.
Although, the possibility of co-infection with other respiratory
pathogens including bacteria, archaea, viruses (other than beta
coronavirus) and fungi are not clearly understood, the association of
these secondary pathogens to causing co-infections should be an
important concern for the clinician in the management of COVID-19 cases.
The Centers for Disease Control and Prevention (CDC, USA) endorsed
testing for other respiratory pathogens, suggesting that evidence of
another infection could aid the evaluation of patients with potential
COVID-19 in the absence of widely available rapid testing for SARS-CoV-2
(CDC, 2020).
The two earlier coronaviruses (SARS-CoV-1 and MERS-CoV), influenza
virus, and SARS-CoV-2 show highly similar respiratory symptoms,
including high fever, cough, headache and even pneumonia
(Assiri et al., 2013;
Cao et al., 2020;
Zahariadis et al., 2006;
T. Zheng et al., 2019). Recent clinical
and in silico studies showed that virus co-infection mainly
includes respiratory viruses such as entero/rhinovirus (hRV), human
metapneumovirus (hMPV), respiratory syncytial virus (RSV),Siphovirus , Alphapapillomavirus , Myovirus ,Tombusvirus , Victorivirus , Partitivirus ,Chrysovirus , Totivirus , and other coronaviruses
(non-COVID-19) (Hoque, Rahman, et al.,
2020; X. Lin et al., 2020). Concurrent
co-infection in COVID-19 can also change the respiratory microbiome
homeostasis, and thus triggers the infection and stimulates immune cells
to produce more severe inflammation
(Hoque, Rahman, et al., 2020;
X. Lin et al., 2020). The gut bacterial
diversity of the COVID-19 patients is also reduced with the increased
relative abundance of opportunistic pathogens, and the lower relative
abundance of the beneficial symbionts
(Guan et al., 2020). Recent metagenomic
studies reveal the concurrent association of bacteria, archaea and
non-COVID viruses in nasal swabs of COVID-19 patient
(Hoque, Rahman, et al., 2020). In the two
earlier coronaviruses (SARS-CoV-1 and MERS-CoV) epidemics, patients
receiving invasive mechanical ventilation were easily developed
co-infections, and had higher mortality rates
(Assiri et al., 2013;
Zahariadis et al., 2006). Therefore,
bacterial co-infection might be a key element that promotes severities
of the disease and mortality rates
(McCullers, 2014). In a recent COVID-19
study, focusing on deceased patients showed that sepsis (100%) acted as
one of the main complications (X. Chen et
al., 2020), indicating that co-infection is of great importance to
prognosis and subsequent treatment of COIVD-19 patients. Furthermore,
co-infection has been associated with more severe outcomes in pandemic
and seasonal influenza (Lansbury, Lim,
Baskaran, & Lim, 2020). It has been suggested that influenza‐related
bacterial infections overall may account for up to 30% of
community-acquired pneumonia (CAP) cases
(Joseph, Togawa, & Shindo, 2013).
Several studies of hospitalized patients with COVID-19 note the empiric
use of antibiotics in a majority of patients
(Lansbury et al., 2020;
D. Wang et al., 2020;
X. Wu et al., 2020). However, there is
an evidence of increased inflammatory serological markers associated
with bacterial infections including procalcitonin and C-reactive protein
in patients with COVID-19 without a corresponding bacterial co-infection
(Lansbury et al., 2020;
Wan et al., 2020). Meanwhile, several
descriptive studies showed that the ecosystem of commensal microbiota
can both regulate and be regulated by invading viruses, facilitating
either stimulatory or suppressive effects
(X. Chen et al., 2020;
Kalantar-Zadeh, Ward, Kalantar-Zadeh, &
El-Omar, 2020; Netea et al., 2020). More
importantly, the coinfected microorganisms may also be a new strategy
for the development of new treatment of SARS-CoV-2 infection. Despite
increasing evidence for its salience to COVID-19 outcomes, the effect of
co-infection clearance on SARS-CoV-2 load has not yet been
systematically reviewed or critically discussed. This systematic review
updates our knowledge on the microbial co-infections associated with
SARS-CoV-2 pandemic, and the possible molecular mechanisms of
co-infections in COVID-19 to emphasize that microbial co-infection.
Rationale and review methodology
To date, thousands of reports on genomics, origin, genome evolution,
molecular diagnosis and vaccine and/or therapeutics of SARS-CoV-2 have
been published. However, a comprehensive review on microbial (virus,
bacteria, fungus, archaea) co-infections associated with COVID-19 and
the impact of its on COVID-19 patients, characterization of
co-infections and underlying molecular mechanisms of co-infections in
COVID-19 patients are lacking. Therefore, we conducted a rigorous
literature survey on the co-infections, identifying of co-infecting
microorganisms and their pathogenesis. The concept and evidence of
co-infection with COVID-19 disease and a rationale of this comprehensive
review are described in the introduction section. Later sections of this
review were arranged coherently from the literature available in the
PubMed central, Google Scholar, ResearchGate, bioRxiv, MedRxiv,
Preprints archives, World Health Organization (WHO) COVID-19 blog,
National Institute of Health (NIH), Centers for Disease Control and
Prevention (CDC, USA), Clinical Trials Registry databases, and COVID-19
vaccine and therapeutics tracker
(https://biorender.com/covid-vaccine-tracker). The original research
articles that discussed the evidence and significance of co-infections
amid COVID-19, detection and possible molecular mechanisms of
co-infections were considered for the content of this review. This
literature survey also included case studies, case series and
observational studies published from the very beginning of COVID-19
outbreak in Wuhan city in China in late December, 2019 to November 15,
2020. The literature search was done through screening of titles,
abstracts and full articles for eligibility. Proposed molecular
mechanisms of co-infections concurrent in SARS-CoV-2 infections have
been represented in Figure 1.
Microbial co-infections in hospitalized patients with
COVID-19
Co-infection refers to the concurrent infection of a cell or host by two
or multiple pathogen species and/or strains, whereas, superinfection is
a scenario where one pathogen infects the host some time before
infection by the second pathogen
(Salas-Benito & Nova-Ocampo, 2015). For
both of these cases, the fate of
the infected host often depends on a balance between the host’s
protective immunity and immunopathology
(Makoti & Fielding,
2020). The universal
pervasiveness or incidence of co-infection among humans is unknown, but
it is thought to be commonplace, sometimes more common than single
infection (E. C. Griffiths, Pedersen,
Fenton, & Petchey, 2011). Coinfecting pathogens can alter the
population of the primary pathogen, as for example, Van der Hoek et al.
(2004) reported that in respiratory co-infections, the human coronavirus
(hCoV) load was much lower than for a single infection
(Van Der Hoek, Pyrc, & Berkhout, 2006).
Co-infections may occur by multiple infectious agents of viral,
bacterial, archaeal and fungal origin (Figure 1), and appear to occur
simultaneously with the initial onset of illness
(Bengoechea & Bamford, 2020).
Co-infection morbidity has previously been studied within certain
cohorts (e.g., age and sex), and is often reported to be worse than
single infections (E. Griffiths, Pedersen,
Fenton, & Petchey, 2015). Recently, several observational and cohort
studies reported that pulmonary complications occurred in 51·2%
COVID-19 patients, of which 82.6% accounted for deaths, and independent
risk factors for mortality were male sex, age 65 years or older
(Nepogodiev et al., 2020). However, the
occurrence of co-infection in death across age and sex cohorts of
COVID-19 patients has not been studied yet. We assume that co-infection
associated death may be more common in early adulthood, but it is not
known whether younger adults are more susceptible to co-infection per
se, or more susceptible to fatal co-infection. Therefore, better
understanding of the risk factors and biological interactions associated
with higher case-fatality may help efforts to predict and combat
co-infection mortality.
Viral co-infections in hospitalized patients with COVID-19
Co-infections with other viruses are very common in the viral infections
of respiratory diseases. The prevalence of respiratory virus
co-infection varies from 3.0% to 68.0%
(X. Lin et al., 2020;
Nickbakhsh et al., 2019). Several
clinical studies indicated that viral co-infections of SARS-CoV-2
occurred with other virus from different countries
(X. Chen et al., 2020;
D. Wang et al., 2020). Lin et al. (2020)
reported that in Shenzhen Third People’s Hospital, 3.2% SARS-CoV-2
patients suffered from viral co-infections. Association of other
viruses, bacteria, fungi, with SARS-CoV-2 infection has been reported
(Shen et al., 2020). Bacteriophages are
naturally occurring viruses that use bacteria as hosts, and play an
extremely important part in allowing relatively harmless bacteria to
become pathogens (Hoque et al., 2019;
T. Zheng et al., 2019). The
bacteriophages are overlooked human pathogens that imply in triggering
and worsening of a number of human diseases
(T. Zheng et al., 2019). The COVID-19
causing SARS-CoV-2 strains show neighboring relationship to human
classic coronavirus, the SARS coronavirus isolate Tor2 (SARS-CoV Tor2)
corroborating with the recent findings of Konno et al. (2020)
(Konno et al., 2020). In a recent
metagenomic study, Hoque et al. (2020b) reported that COVID-19 samples
have sole association with 16 viral genera (other thanbetacoronavirus ), and of them, Tombusvirus ,Victorivirus , Partitivirus , Chrysovirus andTotivirus were the most abundant genera associated with
SARS-CoV-2 co-infections (Hoque, Rahman,
et al., 2020).
SARS-CoV-2 and influenza: the disarray
Influenza is an acute and highly contagious respiratory disease that is
responsible for significant morbidity and mortality worldwide. Annually,
influenza can affect approximately 9% of the world’s population, with
up to 1 billion infections, 3 to 5 million severe cases, and 0.3 to 0.65
million deaths (Lambert & Fauci, 2010).
The current COVID-19 pandemic caused by SARS-CoV-2 demonstrates similar
symptoms of influenza such as fever, headache, sore throat and so on.
Although, at the early stage of COVID-19 pandemic, the co-infection of
SARS-CoV-2 and influenza did not draw any significant attention, the
first report of influenza and SARS-CoV-2 co-infection
(X. Zheng et al., 2020) indicated that
only 0.4% influenza positive patients were infected with SARS-CoV-2 in
January, 2020. The incidence of co-infection by influenza viruses in
COVID-19 patients have been reported frequently from different countries
other than China (X. Wu et al., 2020). A
case report of a 78-year old woman in Japan, showed the presence of
Influenza A co-infection with SARS-CoV-2
(Azekawa, Namkoong, Mitamura, Kawaoka, &
Saito, 2020) which intensified the necessity for specific and accurate
detection of etiologic agents considering the travel history and medical
condition of the patients. Another study showed 4.35% presence of
influenza co-infection in hospitalized COVID-19 positive patients
(Ding, Lu, Fan, Xia, & Liu, 2020).
Although no anomalies in hematology screening were reported, all
coinfected patients were clinically cured after treatment with oxygen
inhalation, oseltamivir and antimicrobial agents without any invasive
ventilator, ICU care and extracorporeal membrane oxygenation treatment
(Ding et al., 2020). In another
retrospective study in Jiangsu Province in
China demonstrated that 94.2% of
laboratory-confirmed COVID-19 patients had co-infection, specifically
31% of them had viral co-infections with influenza virus
(X. Zhu et al., 2020). In a recent
retrospective cohort study on COVID-19 patients in a hospital in
Barcelona showed that only 0.4% patients were co-infected with
community-acquired influenza A virus, whereas 3.1% patients infected
with community-acquired bacterial infections, 4.7% of which were
hospital-acquired superinfections
(Garcia-Vidal et al., 2020). However, the
concomitant outbreak of influenza and COVID-19 in the winter season
confirmed the presence of co-infection in multiple cases and inevitably
emphasized the simultaneous laboratory diagnosis facilities for both
SARS-CoV-2 and influenza viruses. The amphipathic symptoms of both
COVID-19 and typical influenza have necessitated the co-diagnosis of
influenza in COVID-positive patients, specifically with recent travel in
influenza-endemic areas.
Hepatitis-B co-infections in COVID-19 patients
Hepatic complications associated with COVID-19 are particularly
concerning among people living with hepatitis B virus (HBV) co-infection
with pre-existing liver complications (e.g., cirrhosis, liver failure,
hepatocellular carcinoma) (Kunutsor &
Laukkanen, 2020; Zhang, Shi, & Wang,
2020). Co-infections among COVID-19 patients with hepatitis symptoms
before developing the respiratory syndromes have been documented in
several studies (Alqahtani & Schattenberg,
2020; Wander, Epstein, & Bernstein,
2020). While our understanding of SARS-CoV-2’s pathogenesis continues
to grow, initial studies suggest that the virus could lead to liver
injury mainly by binding to angiotensin-converting enzyme 2 (ACE2)
receptors on hepatocytes or causing an immune-mediated hepatic injury
through activation of cytokine storm
(Mehta et al., 2020). It is now clear
that COVID-19 could lead to liver injuries and elevate alanine
aminotransferase (ALT), aspartate aminotransferase (AST), and total
bilirubin, particularly among the severe COVID-19 cases who need ICU
(Huang et al., 2020;
Khinda et al., 2020;
G. Zhang et al., 2020). Abnormal liver
functions in COVID-19 patients have also been associated with increased
disease severity and risk of mortality. Interestingly, viral
co-infections caused by non-respiratory infectious agents have been
reported from the Wuhan city in China, which stated the co-incidence of
hepatitis B virus infections in 12.2% patients with acute COVID-19
(X. Chen et al., 2020). The significant
rate of liver cirrhosis and abnormally higher liver functions in severe
COVID-19 patients corroborated with the findings of co-infection with
hepatitis B including elevated alanine aminotransferase (ALT), aspartate
aminotransferase (AST), gamma-glutamyl transferase (GGT) levels
accompanied by moderately elevated prothrombin time (PT), and total
bilirubin (TB) levels in COVID-19 patients
(Ali, 2020;
Cai et al., 2020). The possibilities of
liver impairment in severe COVID-19 patients have been suggested due to
viral tropism to hepatic tissues, drug toxicity and systemic
inflammation (G. Zhang et al., 2020).
Therefore, extensive screening for hepatitis B infections in critical
COVID-19 patients can be more useful for disease progression analysis,
and effective treatment plan application in patients with remarkable
diagnostic indications of abnormalities in liver functions.
SARS-CoV-2 anddengue: the deadly duo
The spread of SARS-CoV-2 in temperate countries such as Switzerland and
France, where arboviral dengue fever is endemic, has been described with
a contemporary travel history (Epelboin,
Blondé, Nacher, Combe, & Collet, 2020). In France, the first
diagnostic test of SARS-CoV-2 RT-PCR revealed negative with a flu-like
syndrome in patients, which became positive a week later with severe
clinical onsets of COVID-19 symptoms like fever, fatigue, loss of
appetite and diarrhea (Epelboin et al.,
2020). The appearance of diffuse maculopapular exanthema made the
clinicians to screen for Leptospira spp., Rift Valley fever
virus, dengue virus and Chikungunya virus infections which indicated
that RT-PCR for type-1 dengue virus was positive. Another report of two
patients from Singapore revealed that rapid serological tests for dengue
can generate false positive results accelerating the respiratory
complications in patients who later became positive for SARS-CoV-2
(Yan et al., 2020). The initially
worsening fever, increasing thrombocytopenia and sero-positivity for
dengue misguided the clinicians who lately found the absence of dengue
specific immunoglobulins, but with positive results from RT-PCR test of
nasopharyngeal swab for SARS-CoV-2. In several countries of South
America, a significant numbers of dengue cases were reported along with
a gradual increase of COVID-19 cases. A study from Brazil depicted the
possibility of under-reporting of dengue cases due to extensive
mobilization of epidemiological sero-surveillance response team for
COVID-19 emergency response, which may indirectly affected the reporting
and treatment of dengue during COVID-19 outbreak
(Lorenz, Bocewicz, et al., 2020). That
study urged the robust integrated national strategy for combined
surveillance, treatment and prevention plan for dengue and COVID-19
management in Brazil. Another study from Columbia analyzed the dual
epidemiological features of dengue and SARS-CoV-2 in the first 20 weeks
of COVID-19 pandemic (Cardona‐Ospina et
al., 2020). The viral interference resulting in blocking entry and
replication of dengue during SARS-CoV-2 infection may also have
contributed to decreased onset of clinical dengue in subclinically or,
mildly COVID-19 infected population (Pinky
& Dobrovolny, 2016). Contemporary reports from Ecuador revealed that
the eco-epidemiological dynamics and high endemic-epidemic transmission
of dengue in large coastal areas can drastically affect the mitigation
campaign and COVID-19 containment measures through extensive loads of
patients on public health facilities for diagnosis, treatment and
preventive actions (Navarro,
Arrivillaga-Henríquez, Salazar-Loor, & Rodriguez-Morales, 2020). These
reports indicated the urgency of sero-surveillance for dengue virus
infections in dwellers and travelers from temperate endemic areas. It
has also been stated that the physical distancing and reduced public
mobility may contribute to the containment of dengue infections amid
COVID-19 (Lorenz, Azevedo, &
Chiaravalloti-Neto, 2020).
COVID-19 patients with chronic viral diseases: HIV and HCV
The triple burden of COVID-19,
human immunodeficiency virus (HIV)
and hepatitis C virus (HCV) is one of the major and persistent global
health challenges of the twenty-first century. The HIV, HCV and newly
emerging infectious diseases such as coronavirus epidemics are expected
to overlap in high HIV and HCB or HCV burden countries
(Tamuzi et al., 2020). How COVID-19 will
manifest itself in persons co-infected with HIV/HCV is still unclear
(Tamuzi et al., 2020). Populations
infected with HIV and HCV may be at elevated risk for severe responses
if they are infected with COVID-19. In the future, lung lesions
associated with COVID-19 may increase the risk of HIV or HCV, which
induces a truly vicious circle of HIV-HCV-COVID-19 co-infections
(Soriano & Barreiro, 2020;
Tamuzi et al., 2020). While COVID-19
continues to spread across the world, many areas face the risk of
infection with SARS-CoV-2 and the obstacles and challenges to sustaining
the continuum of HIV and HCV treatment in high-burden HIV/HCV countries
are increasing (Tamuzi et al., 2020). In
fact, the pathogenicity of COVID-19 could be accelerated in people
living with HIV, who have compromised immunity
(Soriano & Barreiro, 2020). Recent
evidence has indicated a substantial association between
coronavirus-related lower respiratory tract infections (LRTIs) and
increased risk of death in immuno-compromised individuals
(Tamuzi et al., 2020). Co-infections of
HIV and SARS-CoV-2 in five individuals—three male and two transgender
patients in Spain has been reported
(Makoti & Fielding, 2020).
Interestingly, the HIV/SARS-CoV-2 patients had similar clinical,
laboratory and radiographical features to the HIV-negative patients
infected with SARS-CoV-2. During the current SARS-CoV-2 pandemic, this
lack of information is a concern in countries with high HIV cases,
especially in Sub-Saharan Africa, where 70% of people living with HIV
infection (Makoti & Fielding, 2020). As
the patient had the history of co-infection with HIV-1 and HCV before 4
years, the follow-up study of anti-SARS-CoV-2 immune response revealed
the delayed antibody response but with repeatedly negative RT-PCR test
for SARS-CoV-2 RNA (Tang et al., 2020).
However, the compromised immune status of the patient caused the delayed
humoral response development against the SARS-CoV-2, but the anti-HIV
therapeutics and elevated level of activated IFN-γ due to anti-HIV
agents may be suppressed to SARS-CoV-2 infection leading to persistently
undetectable RNA in RT-PCR tests (Tang et
al., 2020). Therefore, history of viral co-infection with
immuno-compromised status and antiviral therapeutics may lead to delayed
antibody response along with indistinct COVID-19 diagnosis.
SARS-CoV-2 with hCoV-HKU1
The endemic human coronaviruses (hCoVs) have been known to cause
co-infections, sequential infections or can be co-detected with each
other or with other respiratory viruses, including influenza A/B,
respiratory syncytial virus (RSV), metapneumovirus, enterovirus, and
adenovirus (Chaung, Chan, Pada, &
Tambyah, 2020). A critical case of co-infection by
human coronavirus HKU1 in a
COVID-19 patient, reported from Indonesia, indicated the sequential
infections by hCoV-HKU1 and SARS-CoV-2, which was confirmed by a
FilmArray Respiratory Panel (RP) test
(Chaung et al., 2020). Thus, clinicians
need to be aware of hCoV co-infections among COVID-19 patients. A high
degree of suspicion in this rapidly evolving outbreak is required to
make the diagnosis, and thereby, to contain and control the spread of
the COVID-19.
Bacterial, archaeal and fungal co-infections in hospitalized
patients with COVID-19
Like other well studied respiratory viral infections including the 1918
influenza outbreak (Reid et al., 1999),
and 2009 H1N1 pandemic (MacIntyre et al.,
2018), the current pandemic outbreak of SARS-CoV-2 is also reported to
associate with secondary microbial infections
(N. Chen et al., 2020;
Hoque, Rahman, et al., 2020;
Manna, Baindara, & Mandal, 2020).
Bacterial co-infections were previously reported for respiratory
diseases including SARS-CoV, MERS-CoV and influenza patients receiving
intensive care (Langford et al., 2020;
Memish et al., 2020). Several
retrospective studies showed that during the 1918 Spanish flu pandemic,
bacterial pneumonia was a major cause of morbidity and mortality
(Morens, Taubenberger, & Fauci, 2008).
In a previous study, the prevalence of bacterial co-infections during
the pandemic of influenza A (H1N1) between 2009 to 2012 was 23.0%
(MacIntyre et al., 2018). Recent study
reported that about 65% of laboratory-confirmed cases of influenza
infection are known to be complicated by bacterial co-infections
(Klein et al., 2016).
Bacterial co-infections develop in patients amid or after the primary
infection initiated by an infectious agent. Bacterial co-infections also
play a significant role during COVID-19 and are associated with an
increasing rate of disease severity and case fatality
(Bengoechea & Bamford, 2020). However,
till now a limited number of studies have been reported the
prevalence/incidence of bacterial co-infections with confirmed cases of
severe respiratory illness caused by SARS-COV-2 infection. The
prevalence rate of bacterial co-infections in critically ill
hospitalized COVID-19 patients was around 14% revealed by a
meta-analysis (Bassetti, Kollef, &
Timsit, 2020). Co-infections with Streptococcus pneumoniae,
Staphylococcus aureus , or other colonizing bacteria during the
patho-physiology of COVID-19 impairs both innate and adaptive
antibacterial host defenses and temporarily compromise the physical and
immunological barrier to cause secondary bacterial pneumonia, leading to
severe and deadly disease in people with pre-existing comorbidities and
previously healthy people (Ginsburg &
Klugman, 2020). Data regarding bacterial co-infections in COVID-19
pneumonia are still emerging, but an association has been made between
the detection of bacterial pathogens in samples with disease severity in
COVID-19 patients. The incidence of co-infection associated with
bacterial pneumonia ranged between 11% and 35% among the patients who
had been infected with respiratory viruses
(Klein et al., 2016). Recently, Fu et al.
(2020) reported that among ICU admitted COVID-19 patients, 13.9% were
suffering from bacterial co-infections. Despite having a varying rate of
bacterial co-infections among COVID-19 patients, the rate of prevalence
could be as high as 50% among the non-survivors
(Fu et al., 2020). A series of
retrospective case studies on SARS-COV-2 confirmed that severely and
non-severely ill patients had 7.7% and 3.2%, bacterial and fungal
co-infections, respectively (G. Zhang et
al., 2020). In Italy, a study conducted among 16,654 patients with
critical condition, who died of SARS-CoV-2 infection depicted that 11%
of those cases were associated with bacterial and fungal co-infections
(Lai, Wang, & Hsueh, 2020).
The most commonly identified coinfected bacterial pathogens include,Acinetobacter baumannii, Klebsiella pneumoniae, Mycoplasma
pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, andClamydia pneumoniae (Hoque, Rahman,
et al., 2020; Khatiwada & Subedi, 2020;
Langford et al., 2020;
Peddu et al., 2020), whileAspergillus flavus, Candida glabrata , and Candida albicansare the most common coinfected fungi
(Bassetti et al., 2020). In addition,
bacterial pathogens such as Staphylococcus aureus, Haemophilus
influenzae, Klebsiella pneumoniae, Streptococcus pneumoniae, Neisseria
meningitides (Khatiwada & Subedi, 2020;
Peddu et al., 2020) as well as some
genera of Proteus, Enterobacter, and Citrobacter species have
also been reported in hospitalized COVD-19 patients (Rawson et al.,
2020). In a recent microbiome study, Hoque et al. reported 527 and 306
bacterial genera in COVID-19 patients of Bangladesh and China,
respectively (Hoque, Rahman, et al.,
2020). In the recent outbreaks, Pseudomonas aeruginosa andE. coli are the most frequently isolated multi-drug resistant
(MDR) pathogens to be associated with hospital acquired superinfections
(Garcia-Vidal et al., 2020). Remarkably,
SARS-CoV-2 RNA has also been detected in fecal samples of COVID-19
patients. It raises the question of gastrointestinal infection of
SARS-CoV-2 and a possible fecal-oral route of disease transmission
(Gao, Chen, & Fang, 2020;
Xiao et al., 2020). Moreover, high
expression levels of ACE2 mRNA in the gastrointestinal system revealed a
strong interaction of SARS-CoV-2 with the gastrointestinal system that
has high microbiome diversity and possible chances of immune suppression
and bacterial co-infections (Gao et al.,
2020; Xiao et al., 2020). The role of
SARS-CoV-2 in modulation of microbiome diversity in the gastrointestinal
tracts is an important question for further research.
A study on hospitalized COVID-19 patients with oropharyngeal candidiasis
(OPC) showed that C. albicans was found to be the most prevalent
pathogen, which was counted for 70.7%, followed by other fungi
including C. glabrata (10.7%), C. dubliniensis (9.2%),C. tropicalis (3%), and C. krusei (1.5%)
(Salehi, Abedi, Balakrishnan, &
Gholamrezanezhad, 2020). On the other hand, Chen et al. (2020b)
reported 5% prevalence of fungal co-infections in 99 COVID-19 patients
in China, including one case of Aspergillus flavus , one case
of Candida glabrata and three cases of C. albicans(X. Chen et al., 2020). Yang et al.
(2020) found that 5.8% (3/52) of the critically COVID-19 patients had
fungal co-infections with A. flavus , A.
fumigatus and C. albicans (X.
Yang et al., 2020). In addition, 8-15% incidence of
non-specific co-infections among COVID-19 patients were reported in
different studies from China, but it is not clear whether it is
bacterial or fungal infections (Huang et
al., 2020; Song, Liang, & Liu, 2020).
A significant percentage of the SARS-CoV-2 infected patients developed
co-infections associated with MDR typically from nosocomial pathogens
(Clancy, Buehrle, & Nguyen, 2020). An
appreciable minority cases of superinfection, most commonly pneumonia
and bacteremia can be developed due to MDR bacterial pathogens and
fungus specially Aspergillus spp. Fungal originated co-infections
including pulmonary aspergillosis and candidiasis were reported to
complicate SARS-CoV-2 infection
(Garcia-Vidal et al., 2020). To date
COVID-19-associated pulmonary aspergillosis (CAPA) has been documented
in >30% of the cases
(Bassetti et al., 2020).
Until now, most of the reported respiratory tract co-infections are
limited to viral, bacterial, and fungal pathogens
(Bassetti et al., 2020;
Díaz-Muñoz, 2017;
Li et al., 2020;
Song et al., 2020), while a plethora of
other concomitant microbial components including archaea could also be
found (Contou et al., 2020;
Hoque, Rahman, et al., 2020). Unlike
bacteria, the incidence, diversity and composition of these co-pathogens
always remain much lower compared to the infectious agent of COVID-19.
Metagenomic investigations confirmed presence of Methanosarcina ,Methanocaldococcus , Thermococcus ,Methanothermobacter , Haloarcula , Staphylothermus ,Natronomonas , Ferroglobus , Caldivirga ,Halobacterium , Natrialba , Methanosphaerula andPicrophilus as the archaeal genera in samples of COVID-19
(Hoque, Rahman, et al., 2020).
Molecular mechanism of co-infection in COVID-19
Co-infections can augment the pathogenesis, morbidity and mortality in
most of the respiratory viral diseases
(Bengoechea & Bamford, 2020). The Table
1 discusses the commonly reported microbial co-pathogens amid COVID-19,
their transmission pattern, possible mechanism of co-infections and
outcomes. Co-infections in COVID-19 patients may also complicate the
clinical outcomes of the disease. The SARS-CoV-2 enters human cells by
binding to the ACE2 protein of the cells lining the upper and lower
airways. Recently, Lee et al. (2020) reported that the ACE2 receptor
protein robustly localizes within the motile cilia of airway epithelial
cells, which likely represents the initial or early subcellular site of
SARS-CoV-2 viral entry during host respiratory transmission. However,
the ciliary ACE2 expression in the upper airway is influenced by patient
demographics (age, sex and smoking), clinical characteristics,
comorbidities/co-infections or medication use
(Lee et al., 2020). Remarkably, specific
molecular kinetics of these additional infections in COVID-19 patients
are still remained unclear although a few studies proposed some models
for the co/superinfections in COVID-19 patients in different countries
(D. Wang et al., 2020). Based on
available literature, we propose a plausible mechanism of co-infection
in COVID-19 patients (Figure 1, Table 1).
Respiratory viruses are frequently collaborated by secondary bacterial
infections due to the outgrowth of opportunistic bacterial pathogens.
Although the specific molecular mechanisms of co-infections in COVID-19
patients remain unclear, it may include virus-induced airway damage,
cell loss, goblet cell hyperplasia, altered mucus secretion, reduced
ciliary beat frequency, function and clearance, reduced oxygen exchange,
and damage to the immune system (X. Wu et
al., 2020; You et al., 2017;
X. Zhu et al., 2020). Co-infection
increases the levels of C-reactive protein (CRP) and procalcitonin (PCT)
(Li et al., 2020). Viral infections
damage the respiratory airway both histologically and functionally
(Avadhanula et al., 2006;
Manna et al., 2020).
The co-infection mechanisms
include virus-induced airway damage, cell loss, goblet cell hyperplasia,
altered mucus secretion, reduced ciliary beat frequency, reduced
mucociliary clearance, dis-coordinated mucociliary functions, reduced
oxygen exchange, and damage to the immune system
(Avadhanula et al., 2006;
Manna et al., 2020;
Vareille, Kieninger, Edwards, & Regamey,
2011). Viral co-infection can also facilitate bacterial adhesion,
disrupt the tight junction and epithelial barrier integrity favoring
paracellular transmigration of bacteria, and alter both innate and
adaptive immune responses that render the lung more vulnerable to
SARS-CoV-2 infections ((X. Lin et al.,
2020; Nickbakhsh et al., 2019). Since
many viruses can destroy the airway epithelium, which facilitates other
viral co-infection (Denney & Ho, 2018).
The COVID-19 patient having co-infected with HIV had a longer
progression of the disease and slower generation of specific antibody
because of the collapse of immune system
(Wang, Luo, Bu, & Xia, 2020).
SARS-CoV-2 infection may cause liver damage
(Li et al., 2020), and thus, drug-induced
liver injury (DILI) is more likely to occur in patients who already have
certain viral infections including HCV and HIV
(X. Chen et al., 2020). Therefore, the
development and outcome of SARS-CoV-2 associated co-infections with
other viruses are highly dependent on the host immune response,
especially in the elderly (X. Chen et al.,
2020). The co-infection of viruses is associated with different
molecular mechanisms by which the predisposition of the virus occurs in
the respiratory tract that promotes simultaneous bacterial infection.
The epithelial cells of the respiratory tract help bacterial adherence
using different mechanisms during viral infection, while the disease
severity varies upon virus, bacterial strain, other co-pathogens and
hosts immunity. Respiratory viruses can up-regulate the expression of
host cell membrane protein to facilitate their binding
(Manna et al., 2020). Respiratory
syncytial virus (RSV) reported to bind directly with Haemophilus
influenzae and Staphylococcus pneumonia , and thus, favoring
bacterial proximity to the epithelial monolayer and supplementing
attachment to the host cell receptors. Moreover, the expression and
localization of the RSV glycoprotein on the host cell membrane during
infection can further act as bacterial receptors for pneumococcal
binding (Iverson et al., 2011). Previous
studies demonstrated that influenza virus can make mice susceptible to
pneumonia caused by S. aureus where both virus and bacterial load
increased during co-infection (Iverson et
al., 2011; Smith et al., 2013). Several
respiratory viruses such as RSV, parainfluenzavirus-3, and influenza
viruses reported to increase the bacterial adherence upon infection, in
both primary and immortalized epithelial cells
(Manna et al., 2020). The surface
glycoprotein adhesion molecule-1 (ICAM-1) expression is upregulated
during RSV and adenovirus infection, and thereby, increases adherence
for S. pneumoniae in human nasopharyngeal cells (HEp-2) and
pneumocyte type II cells (A549). The enhanced pneumococcal adherence in
epithelial cells results in bacterial accumulation which may facilitates
other bacterial co-infections (Manna et
al., 2020; Nguyen et al., 2015).
Methanogenic archaea coexist and interact closely with anaerobic
bacteria (Hoque et al., 2019).
Methanogenic archaea utilize low molecular weight compounds, such as
H2 + CO2, formic acid, or acetate, and
therefore, have symbiotic relationships with the producers of these
substrates. It is reasonable to assume that the presence or increase in
level of methanogenic archaea modulates the composition of the
polymicrobial community and changes the virulence property of the
microflora (Hoque et al., 2019) (Maeda et
al., 2013). Although, several earlier studies stated that archaeal
co-infection is frequently detected in viral and bacterial hosts
(Díaz-Muñoz, 2017;
Roux et al., 2014), the systematic tests
of the factors explaining variation in viral co-infection across
different taxa and environments are still lacking.
Recent studies suggested that COVID-19 patients having microbial
co-infections are characterized by lymphopenia and enhanced levels of
proinflammatory cytokines including interleukin-6 (IL-6) and IL-1β as
well as MCP-1, IP-10, and granulocyte colony-stimulating factor (G-CSF)
in the plasma. It has been proposed that high levels of proinflammatory
cytokines might lead to shock as well as respiratory failure or multiple
organ failure, and several trials to assess inflammatory mediators are
under way (Arunachalam et al., 2020).
Cytokine storm, or hypercytokinemia, describes hyperactivation of the
immune system that may be provoked or worsened by co-infections. This
can lead to devastating and irreparable destruction of lung tissue as
proinflammatory cytokines damage the alveoli, tiny sacs in the lungs
responsible for gas exchange and oxygenation (Kwon et al., 2020). Damage
to lung tissues caused by SARS-CoV-2 may explore the receptors for other
pathogenic or opportunistic microorganisms facilitating secondary
infections. Specific domains in
which viruses play such facilitating role including enhancement of
bacterial adhesion by unmasking cryptic receptors and upregulation of
adhesion proteins, disruption of tight junction integrity favoring
paracellular transmigration of bacteria and loss of epithelial barrier
integrity, increased availability of nutrients, such as mucins and iron,
alteration of innate and adaptive immune responses, and disabling
defense against bacteria, and lastly, changes in airway microbiome that
render the lung more vulnerable to pathogens
(Rossi, Fanous, & Colin, 2020).
Moreover, SARS-CoV-2 infection can damage lymphocytes, especially B
cells, T cells, and NK cells, which will lead to the immune system’s
impairment during the period of disease
(D. Wang et al., 2020). The decrease of
lymphocytes and host immune function may be the main reason for further
super- or secondary infection (Luo et al.,
2019). The mortality is more significant in severe cases compared with
the non-severe group (Qin et al., 2020)
due to the higher co-infection rate in severe patients
(Luo et al., 2019;
Qin et al., 2020) (Luo et al., 2019; Qin
et al., 2020). The mechanistic evidence of influenza and pneumococcal
co-infections showed that influenza virus causes a depletion of alveolar
macrophage which allows a smaller inoculum of bacteria to establish
productive infection (Smith & Smith,
2016), and consequent severity of the bacterial co-infection is
exacerbated by preexisting host factors such as obesity
(McArdle, Turkova, & Cunnington, 2018).
For more severely ill patients, they are more likely to receive
treatment with invasive catheters, resulting in increased sensitivity to
co-infections with multidrug-resistant pathogens such asAcinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa,
and Enterococcus species (Rawson et al., 2020). In addition, during the
patho-physiology of COVID-19, SARS-CoV-2 viruses can interact with a
large number of cellular proteins (virus-host interactome) and
protein-protein interactions between unrelated viruses, bacteria,
archaea and fungi are also possible
(Kumar, Sharma, Barua, Tripathi, & Rouse,
2018). Co-infections may result in genetic exchange among heterologous
viruses, and/or agents (Roux et al.,
2013) leading to the generation of recombinant or chimeric pathogens,
and this recombination effects can influence viral evolution, disease
dynamics, sensitivity to antiviral therapy, and eventually the fate of
the host (Kumar et al., 2018) Though not
studied yet, similar mechanistic events may be found in SARS-CoV-2 and
associated co-infections aggravating the patho-physiology of COVID-19.
In addition, four factors including host ecology, host taxonomy or
phylogeny, host defense mechanisms, and the interactions of co-pathogens
with SARS-CoV-2 are likely to play vital role in the patho-physiology
and severity of COVID-19 disease. The relevance and importance of these
are likely to vary for cross-infectivity, culture co-infection, and
single-cell co-infection (Díaz-Muñoz,
2017). Overall, due to some risk factors associated including the
epithelial lung damage, immune system dysregulation, prolonged period of
hospitalization etc., the possible development of superinfections is
somewhat expected in severely ill COVID-19 patients
(Bassetti et al., 2020). However, the
actual scenario of prevalence, incidence and characteristics of
microbial co-infections in SARS-CoV-2 infected patients is yet to be
elucidated and analyzed. This review highlights that understanding the
immunological mechanisms of co-infections underlying the diverse
clinical presentations of COVID-19 is a crucial step in the design of
rational therapeutic strategies. Therefore, the effect of SARS-CoV-2
replication and induction of innate immune response on the composition
of the human or animal upper respiratory tract (URT) microbiome remains
to be elucidated and analyzed in depth on a community wide scale.
Further extensive investigation is warranted for a better understanding
and evaluating the risk factors associated and the disease spectrum of
co/secondary and superinfection in critically ill patients suffering
from SARS-CoV-2 infection.
Conclusions and perspectives
Co-infections with various microorganisms are commonly found in COVID-19
patients that significantly influences the severity and mortality of
COVID-19 patients. However, our understanding about co-infecting
organisms and their cross-talks and ultimate interactions with the hosts
are poor. The COVID-19 co-infections can be associated with multiple
domains of microorganisms including viruses, bacteria, fungi and
archaea. Although the specific molecular events of co-pathogenesis in
SARS-CoV-2 patho-physiology is yet unknown, the coinfecting pathogens
may participate to damage the respiratory airway, cell loss, goblet cell
hyperplasia, alter mucus secretion, reduced ciliary beat frequency,
function and clearance, reduced oxygen exchange, and damage the immune
system. Furthermore, viral co-infection facilitates bacterial adhesion,
disrupt the tight junction and epithelial barrier integrity favoring
paracellular transmigration of bacteria, and alter both innate and
adaptive immune responses that render the lung more vulnerable to
SARS-CoV-2 infections. Although this review provides a comprehensive
scenario of co-infection in COVID-19 patient, further studies are needed
to focus the epidemiology and clinical and laboratory characteristics of
coinfecting pathogens among diverse group of COVID-19 patients from
different geo-climatic conditions, and assess the effect of co-infecting
microorganisms on the outcome of COVID-19 patients.