key: cord-0987425-bfmqxvg9 authors: Aghbash, Parisa S.; Eslami, Narges; Shirvaliloo, Milad; Baghi, Hossein B. title: Viral coinfections in COVID‐19 date: 2021-06-12 journal: J Med Virol DOI: 10.1002/jmv.27102 sha: 7691cd9981bdba00d20ed55228642bad0c9f4873 doc_id: 987425 cord_uid: bfmqxvg9 The most consequential challenge raised by coinfection is perhaps the inappropriate generation of recombinant viruses through the exchange of genetic material among different strains. These genetically similar viruses can interfere with the replication process of each other and even compete for the metabolites required for the maintenance of the replication cycle. Due to the similarity in clinical symptoms of most viral respiratory tract infections, and their coincidence with COVID‐19, caused by SARS‐CoV‐2, it is recommended to develop a comprehensive diagnostic panel for detection of respiratory and nonrespiratory viruses through the evaluation of patient samples. Given the resulting changes in blood markers, such as coagulation factors and white blood cell count following virus infection, these markers can be of diagnostic value in the detection of mixed infection in individuals already diagnosed with a certain viral illness. In this review, we seek to investigate the coinfection of SARS‐CoV‐2 with other respiratory and nonrespiratory viruses to provide novel insights into the development of highly sensitive diagnostics and effective treatment modalities. severity of the disease is distinguished by the host immune response to the virus infection. [15] [16] [17] To date, several instances of SARS-CoV and MERS-CoV mixed infection have been reported; however, in the case of COVID-19, coinfection is less frequent. 18 The prevalence of coinfection in different individuals with COVID-19 is thought to vary to a significant extent as only 50% of deaths associated with COVID-19 are suspected to stem from mixed infection. 18 Coinfection can result in the inhibition of host immune response, resistance to antibacterial drugs, and an overall poor prognosis of the disease. 19 One study discovered that 94.2% of people with COVID-19 were also coinfected with several other microorganisms, such as viruses, bacteria, and fungi. 20 Important viral copathogens include the influenza A and B viruses, rhinovirus/enterovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus, human immunodeficiency virus (HIV), dengue virus (DENV), hepatitis B virus (HBV), cytomegalovirus (CMV), Epstein Barr virus (EBV), and other CoVs, among which the influenza A virus and rhinovirus/enterovirus are the most common copathogens. 18, 21 Nonetheless, due to the remarkable advances made in the diagnosis and treatment, influenza is significantly less associated with mortality. 22 Interestingly, the SARS-CoV-2 epidemic in December 2019 coincided with the seasonal outbreak of the influenza virus. 22 An investigation by Xia et al. 23 found high levels of serum procalcitonin in pediatric patients with COVID-19 and other common respiratory infections, suggesting that coinfection with other pathogens might have been responsible for the enhanced inflammatory response. A significant increase in the serum levels of D-dimer (>1 mcg/ml), LDH (lactate dehydrogenase; >350 U/L), and ferritin and troponin (>1000 ng/ml), along with a decline in the lymphocyte count to less than 800, stand among notable laboratory findings in patients with COVID-19, which could be helpful in determining the prognosis of the disease 24, 25 (Table 1) . Nonetheless, there is no definite knowledge regarding the exact coincidence of other diseases with COVID-19. 26 With an emphasis on potential coinfections with SARS-CoV-2, the present review seeks to provide a more clear perspective to facilitate the development of strategies for diagnosis and containment of the disease. 18, 27 1.1 | Coinfection with respiratory viruses and SARS-CoV-2 Identifying coinfections of more than one respiratory virus can help with understanding the various clinical symptoms, longlasting effects on health, and appropriate methods of prevention. In the case of viral respiratory tract infections resulting in pneumonia, a mixed infection can lead to serious disease in individuals with a suppressed immune system. 44 There have been reports of disease exacerbation and hospitalization in children Serum biomarker for COVID- 19 Prognostic value Viral coinfection Correlation with coinfections C-reactive protein Increased levels, especially in the early stages of the disease indicate an acute risk of pulmonary lesions and infection. 23, 28 IL-6 and TNF-α Increased levels predict the progression of the disease to severe forms. 29 DENV 30 CMV 31 Increased in coinfections Lymphocyte count Evaluation of the severity of the disease and the indication of hospitalization in the intensive care unit. It is less than 5% of the normal value in patients with a critical illness. 32 HIV, 33 BV, 34 54 High rates of interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF-α) were also observed in highrisk groups; thus, the severity of COVID-19 disease can be assessed according to the levels of IL-10 and TNF-α. 7, 17, 55 It has been suggested that the incidence of coinfection with influenza virus in COVID-19 patients is lower than human adenovirus (HAdV) and human rhinovirus (HRV), which is also associated with lower mortality. In spite of low mortality, coinfection with influenza virus may result in a substantial economic burden due to the adverse effects accompanied by either infection. 20 Furthermore, proinflammatory cytokine levels in the blood have been shown to rise considerably in these patients, 35, 71 leading to serious pulmonary sequelae, as well as increased neutrophil and macrophage penetration into the infected region. 71 Furthermore, individuals with ARDS have a higher number of neutrophils in their blood and lungs. 72, 73 Increased neutrophil penetration into the pulmonary tissue, on the contrary, has been linked to lung injury and exacerbation of clinical symptoms in influenza patients. 74 In a study by Ma et al., 69 neutrophil levels and proinflammatory cytokines were shown to be slightly higher in the deceased than in the recovered cases. They also discovered that the amount of D-dimer, which is a risk factor for mortality, was considerably higher in deceased patients than in recovered individuals. 69 Furthermore, D-dimer levels were slightly higher in flu patients than non-flu patients, indicating that these patients had died as the result of local vascular damage, ischemia, and thrombosis caused by a cytokine cascade triggered by virus infection. 75 Besides, according to a report by Wang et al., 76 and HIV has also been demonstrated to be more severe because of immune deficiencies, severe infection, and slower development of antibodies. 76 It has also been documented that the risk of reinfection with SARS-CoV-2 is increased in HIV-infected patients due to immunosuppression, as well as deficiency or failure of the humoral immune response. Thus, it is imperative to avoid any exposure to SARS-CoV-2 in these patients. 90 Studies suggest that the HBV virus is either reactivated or suppressed following coinfection with another viral strain. 91 with coinfection. 33, 107, 108 In the case of HIV infection, factors determining disease severity, including lymphocyte or platelet loss, as well as increased IL-6 AGHBASH ET AL. | 5 levels are associated with reduced CD4 + T-lymphocyte counts. Accordingly, the count of CD4 + T lymphocytes in individuals with severe coinfection with HIV and SARS-CoV-2 appears to be much lower than in patients with moderate symptoms. 33, 35, 109 Despite the lack of any particular association between the CD4 + lymphocytes and COVID-19, inhibition of the immune system might still contribute to the severity of disease, resulting in adverse consequences and persistence of viral infection. 33 Delayed antibody response could be another complication associated with such coinfection, as indicated by a case report regarding a patient with mixed infection of SARS-CoV-2, HIV-1, and HCV. 110 In individuals with SARS-CoV-2 infection, impaired liver function is identified in addition to common symptoms. [116] [117] [118] This inordinate hepatic activity, in turn, contributes to the development of severe disease, and ultimately, death from SARS-CoV-2 infection. However, the exact cause of liver injury in COVID-19 patients has not been explained. [117] [118] [119] Due to the globally high prevalence of hepatitis B, and the high serum levels of HBsAg in these patients, hepatitis B is considered to be a major public health concern. 120 Furthermore, Angiotensin-converting enzyme 2 (ACE2) has been recognized by numerous studies as an important receptor for SARS-CoV-2, which can be found on the surface of the liver cells in the bile ducts. 55, 122 Accordingly, due to the binding of SARS-CoV-2 to ACE2expressing hepatocytes, normal liver function is impaired and the illness is aggravated. Still, increased serum level of alkaline phosphatase (ALP), a bile duct injury marker, was not reported in COVID-19 patients. 39 It has also been shown that elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are related to impaired liver function in COVID-19 patients. There is a possibility for liver damage in COVID-19 patients with moderate symptoms. 118 As a result, the liver is a target organ for SARS- The clinical effects of COVID-19 have been confirmed not to be associated with HBV infection, although some patients might present with elevated liver enzymes. 124 Accordingly, a few theories can be considered in such situations: 1. Long-term use of HBV antiviral medications has been linked to the progression of COVID-19 disease, as have nucleoside analogs, such as entecavir, tenofovir, and others. As a result, tenofovir binds to the RNA-dependent RNA polymerase (RdRp) enzyme of SARS-CoV-2, halting the synthesis of its RNA. 125, 126 As a consequence, during the COVID-19 pandemic, nucleotide analogs might be considered as potential therapeutic agents. 124 2. Immune system dysfunction plays a key role in the development of COVID-19 in individuals with chronic HBV infection. It has been shown that the persistence of viral genes can lead to a decrease in CD4 + and CD8 + T cells in these patients. 127, 128 In this case, a disruption in the proinflammatory cytokine secretion, such as IL-2 and TNF-α, may result in repressed antiviral function. 129 Furthermore, the release of IL-2, IL-6, and TNF-α is suggested to be corre- DNA is present in the peripheral blood. [133] [134] [135] As a consequence, an important risk factor for HBV reactivation following COVID-19 could be the disequilibrium of the immune system and virus replication. 124 Accordingly, there is a possibility of SARS-CoV-2/HBV coinfection in individuals with COVID-19. 21 One of the most significant public health concerns in Asian countries is DENV, 116 which is more prevalent in rainy seasons, causing conditions varying from mild dengue fever (DF) to severe hemorrhagic DF and dengue shock syndrome. 136 only been documented in patients with classic DF. 144 The number of lymphocytes in the peripheral blood may increase in the mixed infection of DENV and SARS-CoV-2, hence, the reports of impaired innate and acquired immune systems in these patients. 145 It should be noted that coinfection with SARS-CoV-2 and DENV are associated with elevated blood glucose levels, which favor replication of SARS-CoV-2. 146 Therefore, it is necessary to utilize the fastest and most sensitive serological tests, such as antibodies against the nonstructural glycoprotein 1 (NS1), secreted by all flaviviruses, at the appropriate time after the onset of symptoms (5 days after onset of fever), especially in endemic areas. 147 Increased IL-6 levels in DENV infection are associated with enhanced severity of symptoms. 30 However, serum studies of cases with acute symptoms of COVID-19 revealed increased amounts of proinflammatory cytokines (TNF-α, IL-1, and IL-6). 148 One of the markers facilitating the identification of individuals suspected to have COVID-19 is lymphocytopenia, which may incapacitate the immune system against DENV infection. 61, 149 Bleeding disorders have been identified in a few cases during ACE2 is the major receptor mediating the entry of SARS-CoV-2 into the host cells, which is expressed in large amounts in organs, such as the kidneys and lungs. 159 Patients with renal insufficiency due to immunosuppression stand among the most sensitive groups and are at risk of death from COVID-19. 160 Carll et al. 161 activity has also been associated with serious pulmonary complications. 166 As a consequence, immune modulators, according to reports, might play a key role in the development of CMV coinfection. [167] [168] [169] CMV is the most common viral infection among patients with kidney failure, especially kidney transplant recipients. 170 Coinfections, compared with single infections, may lead to changes in transmission of the pathogen, progression of clinical symptoms, and the adverse effects associated with any given infection, which ultimately determines the management of infectious diseases. [182] [183] [184] [185] The inability of conventional methods to detect coinfection, in the absence of sufficient evidence, in turn, can result in underdiagnosis of coinfections. 186 Coinfections or mixed infections have been reported to negatively affect the efficiency of diagnostic methods used for detection of SARS-CoV-2; for instance, RT-PCR may not be the optimal diagnostic test for diagnosis of COVID-19 in patients with influenza A virus coinfection. 18 In contrast, nucleic acid amplification test would be a suitable method for detection of influenza virus RNA in the case of coinfection with SARS-CoV-2. 78 Similarly, a proper diagnosis of DENV and SARS-CoV-2 coinfection in countries endemic to DF can only be made through the adoption of reliable laboratory tests, such as the PCR of the nasopharyngeal swab and anal swab, NS1 DENV, immunoglobulin (Ig) M and IgG assays. 187 It is also necessary to develop new strategies to better understand the clinical signs of coinfections and discover suitable therapeutic options for them. 188 Accordingly, early detection of coinfections is important due to the discrepancies in treatment and appropriate prognosis. 189 Considering the fact that there is more than one mechanism involved in the occurrence of coinfections, one might hypothesize that the mere existence of a virus and its impact on the immune system may Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 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