Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was medically challenging to health systems worldwide ^[1][2][3][4][1,2,3,4]. Due to respiratory complications, some patients needed to be hospitalized, and in more severe cases required mechanical ventilation in intensive care units ^[5][6][5,6]. High rates of mortality were observed, mainly in the elderly or in adults with serious comorbidities [7].

During outbreaks of respiratory infection, treatment usually focuses on the viral infection itself and its complications, but there always remains risk of secondary infections [8]. Viral respiratory infections predispose patients to bacterial infections that worsen outcomes of the original viral infection [9]. One such example documented in microbiological studies suggests that most deaths associated with the influenza pandemic of 1918–1919 were due to secondary infections ^[10][11][12][10,11,12]. Bacterial, viral, and fungal infections are common complications that have also been reported in other influenza virus pandemics ^{[13][14][15][16]}[13,14,15,16]. As with other viral outbreaks, questions began to be asked about whether this novel coronavirus is associated with super pathogens or co-pathogens ^[17][18][17,18]. However, with thousands of cases diagnosed in a short period of time, many clinical decisions were made without scientific evidence. One such decision was the use of antibiotics. Although COVID-19 is a viral disease, 70% of ICU patients received antibiotics in addition to immunomodulatory drugs ^{[19][20][21][22]}[19,20,21,22]. Coinfections describe simultaneous viral infection, while secondary infections typically refer to bacterial secondary infection, and both have been described in COVID-19 patients ^[23][24][23,24]. It is believed that the high mortality rates in severely ill COVID-19 patients are due to superinfections and viral replication, leading to severe lung injury and acute respiratory distress syndrome (ARDS) ^{[25][26][27][28][29][30][31][32]}[25,26,27,28,29,30,31,32]. However, there is a lack of data regarding the frequency of superinfections in COVID-19 patients. As the diagnosis and treatment approaches for superinfections are not clear, some clinicians have argued for the use of empirical antibiotics while others have called for sampling severely ill patients for early detection and treatment [33].

2. The Virus: Classification and Possible Origin

SARS-CoV-2 is an enveloped and positive-sense single stranded RNA (+ssRNA) virus [34]. It belongs to the betacoronavirus family, one of the four groups of the coronoviridae [35], which also includes two highly pathogenic viruses, Severe Acute Respiratory Syndrome Human Coronavirus (SARS-CoV) and the Middle Eastern Respiratory Syndrome Coronavirus (MERS-Cov) [34]. SARS-CoV-2 is a novel human-infecting betacoronavirus, genetically different from but related to SARS-CoV and MERS-CoV. Another study found a very close relation (96.2% genome identity) with the bat coronavirus BaTCoV RaTG13 detected in rhinolofus affinis. This almost identical genome suggests bats as a possible origin of the virus [35].

3. SARS-CoV-2 Transmission and Immune Response

SARS-CoV-2 is transmitted mainly by the person-to-person route, which was confirmed by infected clusters of medical staff and family members, in addition to the animal-to-human transmission route which was seen early in the epidemic [36]. Once infected, the spike protein which covers the SARS-CoV-2 surface binds to the host cell’s angiotensin converting enzyme-2 (ACE2) receptor, mediating viral entry [37]. The next challenge for the virus is to encounter the innate immune response. Unfortunately, it is still unknown how SARS-CoV2 evades the immune response and drives its pathogenesis [28]. The inflammation and cellular anti-viral activity caused by the immune response is critical in inhibiting the viral replication. However, an exaggerated response affects the host, resulting in severe pneumonia which can rapidly deteriorate to acute respiratory distress syndrome (ARDS) [38]. When the immune reaction does not resolve after completing its mission, it becomes chronic or hyperinflammed, which can result in organ failure and tissue damage. COVID-19 is manifested by uncontrolled production of inflammatory cytokines such as IL-6, G-CSF, IP10 (Interferon gamma-induced protein 10), MCP-1 (Monocyte chemoattractant protein-1), MIP-1α (Macrophage inflammatory protein-1 alpha), TNF-α, IL-10, IL-7, and IL-2 ^[39][40][39,40]. In addition, in ICU patients, GSCF, MCP, and TNF-a values are significantly higher than in non-ICU patients, suggesting that the cytokine storm is closely related to the severity and mortality of the disease [38]. Depletion of CD4+ T cells in COVID-19 patients has been shown to reduce pulmonary lymphocyte recruitment and production of cytokines and antibodies, processes that lead to severe pneumonitis and delayed clearance of the virus [41]. One study demonstrated that the viral replication in lungs continues for 10 days post-infection. However, lung inflammation was more intense after clearance of the virus, peaking at 14 days and remaining until day 28, suggesting that the early inflammation phase is dependent on viral replication, but the later stages are viral independent and are caused by the hyperinflammatory response [42].

4. Clinical Features: Mortality and Morbidity

The incubation period in every case defined as COVID-19 is 14 days [43]. Viral infection was mostly seen in adult males with median ages of 32–72 [44]. Those most affected by the virus were the immunocompromised and the vulnerable, such as those with cardiovascular or cerebrovascular diseases ^[45][46][45,46]. Clinically, the virus has a wide spectrum of symptoms ranging from asymptomatic infections to patients suffering from cytokine storms. Mild disease is defined as presenting various symptoms of COVID-19, such as fever, cough, sore throat, malaise, headache, and muscle pain, with no pneumonia or dyspnoea. Moderately ill patients have evidence of clinical and radiologic pneumonia or lower respiratory disease, but O₂ saturation is preserved above 93% in room air. Severely ill patients are those who have one of the following: Spo2 < 94% in room air, a respiratory rate above 30 breaths per minute, or PaO2/FiO2 < 300 mmHg. Critically ill patients have one of the following: respiratory failure, septic shock, or multiple organ dysfunction and failure ^{[47][48][49][50][51][52][53]}[47,48,49,50,51,52,53].

5. Complications

The hospitalization and mortality rate for COVID-19 in China was up to 10% in adults, with men being more likely to develop severe complications [54]. Complications reported included increased coagulopathy, necrotizing pneumonia with staphylococcus aureus that was usually fatal cardiovascular complications (pericarditis, left ventricular dysfunction, myocardial infarction, arrythmias), ARDS (approximately 5% of COVID-19 patients) ventilation associated pneumonia, massive pulmonary embolism with right heart failure, sepsis, septic shock with multiple organ failure, and higher mortality risk especially with severe hyperglycaemic disease, heart failure, or the use of high doses of corticosteroids ^{[55][56][57][58]}[55,56,57,58].

6. Diagnosis and Definitions of Superinfections

Superinfection can be diagnosed when a patient exhibits clinical symptoms and signs of bacteraemia or pneumonia, with a positive culture from blood samples or lower respiratory tract samples taken at least 48 h following admission [59]. One new and potential future first-line method for detecting superinfection and helping to decide the use of antimicrobials is metagenomic sequencing, as reported by Qing Miao et al. [60]. A gold standard is yet to be attained for diagnosis of ventilator-acquired pneumonia (pneumonia developing in a person on a ventilator), but reasonable criteria to diagnose VAP would be new or progressive radiographic consolidation or infiltration, with at least two of the following: temperature >38 °C, leucocytosis > 12,000 cells/mm³, leukopenia < 4000 cells/mm³, and the presence of purulent secretions [61]. Sepsis and septic shock are defined based on the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Sepsis is also represented by an increase in sequential organ failure assessment (SOFA) score of two or more. Septic shock is identified by maintaining mean arterial pressure (MAP) of 65 mmHg or more with vasopressors or serum lactate greater than 2 mmol/L in the absence of hypovolemia [62]. Catheter-associated UTI is defined as a new appearance of bacteriuria or funguria with more than 10³ CFU/mL.