1. INTRODUCTION
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease, COVID-19, was initially reported in Wuhan, China on December 31, 2019 and has been declared a global pandemic by the World Health Organization (WHO). The outbreak of COVID-19 pandemic had led to increased mortality rate and economic loss day by day all around the world. Current treatment option for COVID-19 is dependent on antibiotics and preventive measures such as vaccination, social distancing and hand hygiene practices. It is likely that during the COVID-19 pandemic there are higher possibilities of antimicrobial resistance especially among hospitalized patients as they are vulnerable to various nosocomial pathogens or due to the usage of broad spectrum antibiotics for treatment. Secondary bacterial infections and co-infections are considered common in pandemics due to viruses (Manohar et al., 2020). There are several studies that shows bacterial co-infection or secondary infections in critically ill COVID-19 patients especially who are immunocompromised, thus further increasing the rate of mortalities. Coinfections have been reported in cases of various respiratory viral infections caused by MERS-CoV, SARS-CoV, H1N1 influenza and SARS-CoV-2. For example, during H1N1 pandemic in 2009 about 30% hospitalized patients and 12% of non-hospitalized patients were tested positive for secondary bacterial infection, pneumonia. In 1918 influenza pandemic, almost 50 million patients were killed due to secondary bacterial pneumonia. Recent COVID-19 pandemic has around 50% death records due the secondary infections in critically ill patients involving bacterial and fungal co-infections as well (Hendaus & Jomha, 2020; Mazumder et al., 2021). There is inadequate knowledge about the pathogenesis of the secondary bacterial infections in COVID-19 but some evidences from research suggests that dysfunction of host’s immune system, damage in the respiratory airway epithelium and dysbiosis caused by the invading virus predisposes the host to opportunistic secondary bacterial infections. The better knowledge about epidemiology and pathogenesis of the secondary bacterial infection during COVID-19 would require a proper understanding of the interactions between host, virus and bacteria. Bacteria often encountered during the secondary bacterial infections includes Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis, Haemophilus influenzae, Klebsiella pneumoniae and members of species of Enterobacter, Citrobacter and Proteus (Handel et al., 2009). Furthermore, secondary bacterial infections can be acquired from the hospital ward and typically involve bacteria that are multidrug resistant including drug resistant Mycobacterium, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin resistant Enterococci (VRE), drug-resistant Streptococcus, Enterobacteriaceae (CRE), Colistin-resistant Klebsiella, Carbapenemase producing Pseudomonas aeruginosa, and Carbapenemase producing Acinetobacter baumannii (Manohar et al., 2020). Considering the current scenario of COVID-19 and secondary bacterial infections, we must focus on providing patients with most suitable and structured diagnostic tool to efficiently differentiate the secondary bacterial infection from COVID-19 followed by the usage of narrow-spectrum antibiotics or alternative treatment approaches in order to prevent emergence of drug resistant pathogens and mortality. Through the present study, we wish to learn about the pathophysiology and immunological changes that occur during secondary bacterial infections in COVID-19 disease mediated by SARS-CoV-2, as well as explore alternate therapeutic options.
2. METHODOLOGY
A wealth of information for this technical writing has been published as it is a current subject of career interest in medical care. Several online databases were searched using Google Scholar, PubMed, Mendeley, and ResearchGate to locate relevant scholarly papers.
Secondary bacterial infections, co-infections, COVID-19 superinfections, pathophysiology of superinfections, airway epithelium immunity, antimicrobial stewardship, diagnosis of co-infections, biomarkers, and phage therapy were among the descriptive search terms used to search from online databases. To narrow down the search results, the boolean operator “AND” was used.
The majority of the cited references were published during the last five years. A few references from the previous decade were included to define underlying concepts that are still in use today. The initial resources were selected by screening titles and article abstracts, and then deciding whether or not the contents were applicable to the keywords.
Coronavirus:
Coronavirus is the primary causal agent of the ongoing pandemic Covid-19 which has claimed about 154 million lives worldwide. India is currently the second affected country by Covid-19 after US (Goel et al., 2021). Coronaviruses, a member of coronaviridae family are spherical, enveloped, and consists of positive-strand RNA genome. They have a helical nucleocapsid symmetry. Spike proteins are found in the virion envelope and play a key role in the virion binding to the host cell receptor and also in membrane fusion. These glycoprotein projections gives virion a Crown-like appearance and hence the origin of its name coronavirus (Hendaus & Jomha, 2020). Coronavirus is about 65-125 nm in diameter and its RNA genome size range is 26-32 kb. Its family is divided into four groups: alpha (α), beta (β), gamma (ϒ) and delta (δ). Moreover β coronaviruses are further divided into subgroups: A, B, C and D (Goel et al., 2021).
Coronavirus symptoms are often similar to the symptoms of influenza flu which includes dry cough, sore throat, high fever, malaise, breathing difficulties and loss of smell & taste. Although in severe cases the symptoms can be ranging from acute respiratory disease (ARD) or even death. Most appropriate treatment option in order to cure COVID-19 is currently not available but precautionary measures to control the spreading of novel coronavirus are considered under the contemporary treatment approach (Hendaus & Jomha, 2020).
Figure 1 : Structure of coronavirus (SARS-CoV-2) which causes COVID-19
Case studies :
Secondary bacterial infections were found to be common in COVID-19 patients in recent studies. Zhou et al showed in his study that a total of 191 COVID patients were admitted to the hospital in China out of which 28 (15%) patients were reported with secondary bacterial infections. And out of this 28 patients 27 had died (Zhou et al., 2020).
In another study by Chen et al showed that among 99 COVID patients, two patients had co-infection out of which the respiratory sample of one patient was identified to be co-infected with drug resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Aspergillus flavus. Additionally one patient was co-infected with Candida glabrata (N. Chen et al., 2020).
Zhu et al (Zhu et al., 2020) reported in a study that out of a total 257 Covid 19 patients, 243 (94.2%) had coinfections. Majority of such co-infection was due to bacteria in 236 patients (91.8%) followed by viruses in 81 patients (31.5%) and fungi in 60 patients (23.3%). Bacteria which commonly caused secondary bacterial infections were mostly Streptococcus pneumoniae and then Klebsiella pneumoniae and Haemophilus influenzae. Even though they were conditionally pathogenic, they could be pathogenic in Covid 19 patients with reduced immunity. Severe and critically ill patients were reported to be co-infected with bacteria and fungi. Thus co-infection with multiple pathogens increases difficulty in diagnosis as well as treatment and such problem requires simultaneous screening of other respiratory pathogens along with SARS-CoV-2 detection in order to design proper diagnostic methods and provide suitable treatment to the patient .
He et al (He et al., 2020) studied a total of 2216 patients, selecting 194 of 292 COVID-19 positive pneumonia patients and 212 of 1924 COVID-19 negative pneumonia patients for secondary bacterial co-infection analysis. According to this study, 50% of COVID-19 positive individuals had co-infections. Bordetella pertussis was much more common in COVID-19 patients than in COVID-19 negative patients. B.pertussis increases pathogen spreading in the air through cough and is known to cause respiratory disorders by suppressing the function of host’s immune system. Bacteria such as Moraxella catarrahlis and Mycoplasma pneumonia were exclusively detected in COVID-19 negative patients. Both COVID-19 positive as well as negative individuals were identified with bacteria including Pseudomonas aeruginosa, Streptococcus pneumoniae, Bordetella pertussis, Streptococcus pyogenes, Staphylococcus aureus, N. meningitides, Haemophius influenzae and Neisseria meningitidis. Pseudomonas aeruginosa was the dominant among them and it causes secondary infection in pulmonary diseases being an opportunistic pathogen. Thus, one or many pathogens whenever gain access to the upper respiratory tract or cause some damage then it paves a way for a new pathogen to cause its infection challenging the diagnostic and treatment methods. But this study could not provide the clarification for increased Bordetella pertussis infection in COVID-19 patients .
From January 1 to February 6, 2020, Wang et al evaluated COVID-19 patients over the age of 60 at Renmin Hospital in Wuhan. A total of 339 COVID-19 patients were studied, with average age of 71 years and 173 females (51%) were investigated in which usually encountered symptoms were fever (90%) , cough (53%), dyspnea (40.8%) and fatigue (39.9%). In this study, 143 (42.8%) of the 339 COVID-19 patients had a bacterial infection, followed by 96 cases (28.7%) of hypertransaminasemia and 71 cases (21%) of acute respiratory distress syndrome (ARDS) (Wang et al., 2020).
In a multicenter research comprising 476 COVID-19 patients, secondary bacterial infections were found to be substantially associated with outcome severity. In that report, patients were separated into three groups (moderately ill, severely ill, and critically ill). Critically sick patients exhibited the highest percentage (34.5%) of bacterial co-infection compared to individuals in the mildly ill and seriously ill categories (3.9 % and 8.3 % respectively) . Despite the fact that the majority of critical patients (92.9%) received antibiotic treatment, compared to 59.4 percent and 83.3 percent in the moderately ill and seriously ill groups, respectively, critically ill patients had a higher proportion of co-infections (Vaillancourt & Jorth, 2020).
Finally, Goncalves Mendes Neto et al in a retrospective study showed that among 242 positive COVID-19 patients, 46 cases (19%) were co-infected with bacteria. Bacterial co-infection was found more in older patients. E.coli was the dominant organism in the bacterial co-infections. Most common bacterial co-infection was genitourinary infection (57%) followed by skin infections (10%) and respiratory (8%). Moreover this study also showed that patients with bacterial co-infection acquired steroid in a significantly higher rates (Goncalves Mendes Neto et al., 2021).
Secondary bacterial infections in COVID-19
Secondary bacterial infections lead to higher rates of morbidity and mortality in patients when they develop during or after initial viral infections . In contrast to secondary infections, which develop after the main infection, co-infections are caused by many pathogens of viral, bacterial, or fungal origin and occur concurrently at the same time. There is a heavy emphasis on a single pathogen rather than a mix of pathogens, especially for viral-bacterial infections that are more commonly found in patients.(Manohar et al., 2020).
Due to the likelihood of severity and hospitalization for certain COVID-19 infections, admission to a hospital or clinic raises the risk of nosocomial infections to some extent.. Antibiotic treatment that is empiric, strong, or prolonged increases the chances or risk of acquiring nosocomial infections in hospitals (Cimolai, 2021).
COVID-19 patients are usually kept on invasive mechanical ventilation and are maintained for long periods which increases the risk of acquiring infections from the hospital and ventilator.
Antibiotics have been overused and exploited for decades, resulting in the rise of multi-drug-resistant bacteria (MDR). Because there are typically no antibiotics available to treat such diseases, particularly secondary infections, therefore, multidrug resistance is a global health issue.(Manohar et al., 2020).
As a result, early detection of co-infection and secondary bacterial infection is needed, preferably using methods that can detect a wide range of potential pathogens and antimicrobial resistances, followed by infection monitoring. In managing and treating the most serious COVID-19 cases, the rapid characterization of co-infection is essential for saving lives and improving antimicrobial stewardship during the entire pandemic (Cox et al., 2020).
Protections provided by airway epithelial cells against respiratory viruses
Airway epithelium has a coating of mucus that acts as barrier between the airway epithelium and the rest of the body. Mucus is made up primarily of mucins, which are charged glycoproteins (Hendaus & Jomha, 2020).
Many respiratory viruses stimulates the production of airway mucin. Although increased mucus production allows an improved mucus trapping and the removal of viruses but overproduction of mucin and excessive mucus formation, on the other hand, may trigger airway obstruction and worsen preexisting airway disease, turning a strong innate cleansing protection system into a harmful mechanism (Vareille et al., 2011).
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