key: cord-267003-k7eo2c26 authors: Hendaus, Mohamed A; Jomha, Fatima A; Alhammadi, Ahmed H title: Virus-induced secondary bacterial infection: a concise review date: 2015-08-24 journal: Ther Clin Risk Manag DOI: 10.2147/tcrm.s87789 sha: doc_id: 267003 cord_uid: k7eo2c26 Respiratory diseases are a very common source of morbidity and mortality among children. Health care providers often face a dilemma when encountering a febrile infant or child with respiratory tract infection. The reason expressed by many clinicians is the trouble to confirm whether the fever is caused by a virus or a bacterium. The aim of this review is to update the current evidence on the virus-induced bacterial infection. We present several clinical as well in vitro studies that support the correlation between virus and secondary bacterial infections. In addition, we discuss the pathophysiology and prevention modes of the virus–bacterium coexistence. A search of the PubMed and MEDLINE databases was carried out for published articles covering bacterial infections associated with respiratory viruses. This review should provide clinicians with a comprehensive idea of the range of bacterial and viral coinfections or secondary infections that could present with viral respiratory illness. Viral respiratory tract infections (VRTIs) are very common in children and their presentations vary from simple colds to life-threatening infections. [1] [2] [3] [4] [5] The detection of a respiratory virus does not necessarily infer that the child has only a viral infection, 6 since outbreaks of VRTIs are being linked to increased incidence of bacterial coinfections. 7 The human body is usually capable of eliminating respiratory viral infections with no sequelae; however, in some cases, viruses bypass the immune response of the airways, causing conceivable severe respiratory diseases. 8 Robust mechanical and immunosuppressive processes protect the lungs against external infections, but a single respiratory tract infection might change immunity and pathology. 9 Health care providers often face a dilemma when encountering a febrile infant or child with respiratory tract infection. The reason expressed by many clinicians is the challenge to confirm whether the fever is caused by a virus or bacterium. 10 Acute otitis media (AOM) is a usual bacterial coinfection that occurs in 20%-60% of cases of VRTIs. [11] [12] [13] [14] In addition, almost 60% of children with VRTI have changes in the maxillary, ethmoidal, and frontal sinuses. 11, 12 Moreover, in the year 1918, it was estimated that 40-50 million individuals died from the influenza pandemic, many of which were due to secondary bacterial pneumonia with Streptococcus pneumoniae. 15 A search of the PubMed database and Google was carried out, using different combinations of the following terms: virus, induced, bacteria, pathogenesis, prevention, vaccine, and children. In addition, we searched the references of the identified articles for additional articles. We then reviewed abstracts and titles and included studies that were submit your manuscript | www.dovepress.com Hendaus et al relevant to the topic of interest. Finally, the search was limited to studies of disease in humans that were published in English and Spanish from 1918 to the end of 2014 ( Figure 1 ). The epithelium ( Figure 2) is usually covered by a layer of mucus that functions as a boundary. 16 Mucins, which are charged glycoproteins, are the main components of mucus. 17, 18 MUC5AC and MUC5B are the most common mucins in the human sputum, and they assist the innate immune system through their anti-inflammatory and antiviral properties. 19, 20 In addition, they facilitate trapping and clearance of viruses; however, overproduction of those mucins might have a paradoxical effect. 18, 19 The airway epithelium not only functions as a physical barrier but also recognizes microorganisms through pattern recognition receptors such as Toll-like receptors (TLRs), 18 nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and retinoic acid-inducible gene (RIG)like helicases. 21, 22 TLRs are single, noncatalytic, membrane-spanning receptor proteins used by the innate immune system. 23 Respiratory viruses collaborate with TLR lanes, leading to extended bacterial load in the lungs. 21, 24 In comparison, NLRs and RIG-like helicases activate innate immune responses through cytosolic sensing of viral and bacterial components. 22, 25 Nod1 and Nod2, which are family members of NLRs, are induced by molecules synthesized during the production and/or degradation of bacterial peptidoglycan. [26] [27] [28] [29] In addition, many epithelial cells express the classical antiviral interferons (INFs), especially IFN-α and IFN-β. 30, 31 Moreover, the respiratory virus-infected epithelia facilitates the attraction of inflammatory cells, including natural killer cells, neutrophils, macrophages, and eosinophils from the bloodstream into the infected site. 32 Finally, the airway epithelium consists of many molecules including intercellular adhesion molecule 1 (ICAM-1), carcinoembryonic antigen-related cellular adhesion 1 (CEACAM-1), and platelet-activating factor receptor (PAF-r). 33 Viruses have an effect in modulating these receptors, leading to an increase risk of bacterial adherence; for example, rhinovirus upregulates the expression of PAF-r, leading to the binding of S. pneumoniae to bronchial epithelial cells. 34 Different mechanisms might contribute to the debilitation in host defense of the respiratory tract against bacteria following viral infection. Some of the mechanisms have been extrapolated from studies conducted in animal models of sequential infections by respiratory viruses and several bacterial pathogens. Mammalian cells are prone to bacterial attachment during a viral illness. 8, 35 Viruses can debilitate the mucociliary clearance structure, leading to the increased attachment of bacteria to mucins and colonization; moreover, the condensed mucus will impede the penetration of antibacterial material and immune cells. 36 Viruses like the respiratory syncytial virus (RSV) can damage ciliated cells, resulting in ciliostasis and, therefore, deterioration of mucociliary clearance. 37 The same concept applies to an influenza virus infection, leading to decreased tracheal mucociliary velocity and clearance of S. pneumoniae. 35, 38 Moreover, virus-induced cell death debilitates the mechanical elimination of the attached pathogens and displays novice receptors for bacterial adherence. 39 Studies have shown that the RSV virus induces the adherence of S. pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenza to airway epithelial cells. [40] [41] [42] [43] In addition, adenovirus and rhinovirus play the same role in the adherence of S. pneumoniae to the airway epithelial cells; 8, 44 however, the measles virus decreases the risk of adherence of streptococcal bacteria, implying that every virus has a specific mode of changing the host cell membrane. 44 Moreover, bacterial adhesion might also be a result of the upregulation of surface receptors including PAF-r, which is involved in pneumococcal invasion. 45, 46 In patients with cystic fibrosis, bacterial adherence forms a biofilm, creating permanent airway colonization with P. aeruginosa. 47 Viruses such as RSV, rhinovirus, and influenza virus also lead to pneumococcal biofilm formation on the airway lining. 48 Furthermore, RSV increases the risk of adherence of Staphylococcus aureus and Bordetella pertussis to Hep-2 (human epidermoid cancer) epithelial cells. 49, 50 virus effect on the immune system Post-viral sustained desensitization of lung sentinel cells to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with viral infection. For instance, TLR4 and TLR5 pathways are altered after influenza virus infection, resulting in decreased neutrophil attraction, thereby leading to increased attachment of S. pneumonia and P. aeruginosa to the airway epithelial cells. 25 The interrelation between host cells and microorganisms during an infection induces immune responses that include the generation of proinflammatory molecules. Despite their crucial role as a bactericidal, proinflammatory cytokines such as TNF-α produced in response to infection could be detrimental to the host cells. 51 During a viral infection, TLR and RIG-I-like receptor activation induces production of type I IFNs, which can augment the inflammatory response to TLR ligands including lipopolysaccharide (LPS). 52, 53 In addition, certain bacteria such as S. aureus integrate into the A549 respiratory epithelial cells (adeno-carcinomic α β Hendaus et al human-alveolar basal-epithelial cells) during a respiratory viral infection by increasing the expression of ICAM-1. 54 RSV differs from influenza virus in that the former upregulates cellular receptors including CEACAM-1 and ICAM-1, which eventually leads to bacterial infection. 45 Finally, interaction between type I IFNs and Nod1/Nod2 signaling leads to bacterial recognition, but indicts harmful effects in the virally infected host. 55 Another study showed that the rates of bacteremia and OM were 18% and 44%, respectively, in children with viral-induced bronchiolitis. 11 The highest incidence of AOM is usually 2-5 days after an upper respiratory infection. 64, 65 Isolation of viruses alone from sinus aspirates or in concomitance with bacteria proposes the role of viruses in the induction of bacterial sinusitis, 62 with rhinovirus and parainfluenza viruses being the culprits. 66 The rate of bacteremia in children with acute bronchiolitis ranges from 0.2% to 1.4%. [67] [68] [69] [70] [71] [72] [73] [74] [75] In addition, the rate of bacterial urinary tract infection (UTI) in children with bronchiolitis can be as high as 11.4%. 67 In a recent study, Hendaus et al 76 The human myxovirus resistance protein 1 (MxA) is an important intermediary of the IFN-induced antiviral response against a variety of viruses. MxA expression is firmly modified by type I and type III IFNs, which also requires signal transducer and activator of transcription 1 signaling. Additionally, MxA has many characteristics similar to the superfamily of large guanosine triphosphatases. 78 MxA analysis could be beneficial to differentiate between bacterial and viral infections. Engelmann et al 79 conducted a prospective, multicenter cohort study in different pediatric emergency departments in France on the role of MxA in the diagnosis of viral infections. MxA blood values were calculated in infants and children with verified bacterial or viral infections, uninfected controls, and infections of unknown origin. A receiver operating characteristic analysis was used to verify the diagnostic performance of MxA. The study, which included 553 children, showed that MxA was significantly higher in children with viral versus bacterial infections and uninfected controls (P0.0001). Additionally, MxA levels were significantly higher in children with clinically diagnosed viral infections than in those with clinically diagnosed bacterial infections (P0.001). 79 Other authors have also reported the usefulness of blood MxA testing in patients with viral infections. 80, 81 The use MxA in diagnosing viral infection is very promising, especially in patients who are at risk of infectious complications. Two separate studies have shown that blood MxA is beneficial in differentiating between viral illness and acute graft-versushost disease after allogenic stem cell transplantation. 82, 83 It has been recommended that treatment or prevention of a viral disease may be a superior method for diminishing 62 It has also been published that live attenuated influenza vaccine is effective in reducing the incidence of all-cause AOM [86] [87] [88] and pneumonia 89 compared to placebo in children. In addition, the intranasal influenza vaccine can reduce OM by 44%. 90 Moreover, studies have shown that a combined influenza/pneumococcal vaccine is efficient in the prevention of OM in children and pneumonia. 91, 92 However, the credit of protection was awarded to the influenza vaccine since studies have shown that pneumococcal vaccine has no benefit in the reduction of AOM. 93, 94 In addition, the pneumococcal polysaccharide vaccine showed no efficacy in the prevention of pneumonia in adults. 95 Treatment of viral infection is anticipated to prevent bacterial superinfections. Currently, the only respiratory virus that is pharmacologically treatable is the influenza viruses (Type A and B). 62 Neuraminidase inhibitors can potentially diminish the morbidity related to influenza. 96 Oseltamivir can reduce the incidence of AOM in preschool children, 97 and the reduction rate can be up to 44%. 98 A meta-analysis review showed that oral oseltamivir reduces the rate of hospitalization by 25% and morbidity by 75%. 99 In addition, its use can reduce the use of antibiotics by up to 50%, 100, 101 The same concept of protection applies to vaccines that prevent against RSV infections. 62 The vaccine available for RSV is palivizumab (MedImmune, Gaithersburg, MD, USA), a humanized monoclonal antibody that perceives the fusion protein of RSV. The other monoclonal antibody that is under clinical trials is motavizumab (MedImmune), which has a higher affinity for RSV fusion protein than palivizumab and can prevent against medically attended lower respiratory tract infection. 102 The rate of concurrent serious bacterial infections with viral illness is appreciable. Similar emphasis must be given to the prevention and treatment of viral illnesses, especially in young children. Furthermore, health care providers should emphasize to parents on the importance of clinical follow-up of infants and young children diagnosed with VRTI. Moreover, the introduction of MxA in the diagnosis of viral illnesses in children is promising. The authors declare no conflicts of interest in this work. Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology Paediatric Respiratory Research Group. Viral etiology of acute respiratory infections with cough in infancy: a community-based birth cohort study Respiratory viral infections in adults Emerging respiratory agents: new viruses for old diseases? Respiratory pathogens in children with and without respiratory symptoms Asthma exacerbations in children associated with rhinovirus but not human metapneumovirus infection How do viral infections predispose patients to bacterial infections? The airway epithelium: soldier in the fight against respiratory viruses Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis: a systematic review Bacterial coinfections in children with viral wheezing Epidemiology of documented viral respiratory infections and acute otitis media in a cohort of children followed from two to twenty-four months of age Acute otitis media and respiratory viruses Detection of respiratory viruses in nasopharyngeal secretions and middle ear fluid from children with acute otitis media Influenza infection and COPD Mucins, mucus, and sputum Structure and function of the polymeric mucins in airways mucus Respiratory tract mucin genes and mucin glycoproteins in health and disease Regulation of mucin genes in chronic inflammatory airway diseases Airway mucus obstruction: mucin glycoproteins, MUC gene regulation and goblet cell hyperplasia Pathogen recognition by innate immunity and its signaling Pathogen recognition and innate immunity Intracellular NOD-like receptors in host defense and disease Toll to be paid at the gateway to the vessel wall Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection CATERPILLER: a novel gene family important in immunity, cell death, and diseases An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease Viruses and the type I interferon antiviral system: induction and evasion Viruses and interferon: a fight for supremacy Host defense function of the airway epithelium in health and disease: clinical background Effects of rhinovirus infection on the adherence of Streptococcus pneumoniae to cultured human airway epithelial cells Influenza virus infection decrease stracheal mucociliary velocity and clearance of Streptococcus pneumoniae The biology of bacterialcolonization and invasion of the respiratory mucosa Respiratory syncytial virus and human bronchial epithelium The platelet activating factor receptor is not required for exacerbation of bacterial pneumonia following influenza Airway epithelial cell-pathogen interactions Non typeable Haemophilus influenzae and Streptococcus pneumoniae bind respiratory syncytial virus glycoprotein The effects of disodium cromoglycate on enhanced adherence of Haemophilus influenzae to A549 cells infected with respiratory syncytial virus Direct binding of respiratory syncytial virus to pneumococci: a phenomenon that enhances both pneumococcal adherence to human epithelial cells and pneumococcal invasiveness in a murine model RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells Rhinovirus enhances various bacterial adhesions to nasal epithelial cells simultaneously Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species-and cell type-dependent manner Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor Pseudomonas aeruginosa biofilm infections in cystic fibrosis: insights into pathogenic processes and treatment strategies Bacterial biofilm in upper respiratory tract infections Developmental and environmental factors that enhance binding of Bordetella pertussis to human epithelial cells in relation to sudden infant death syndrome (SIDS) Factors enhancing adherence of toxigenic Staphylococcus aureus to epithelial cells and their possible role in sudden infant death syndrome Toll-like receptors in the pathogenesis of human disease Viral infection causes rapid sensitization to lipopolysaccharide: central role of IFN-alpha beta A role for IFN-alpha beta in virus infection-induced sensitization to endotoxin Rhinoviruses promote internalisation of Staphylococcus aureus into non-fully permissive cultured pneumocytes Viral infection augments Nod1/2 signaling to potentiate lethality Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection The role of respiratory viral infections among children hospitalized for communityacquired pneumonia in a developing country Etiology of community-acquired pneumonia in 254 hospitalized children Community acquired pneumonia and influenza in children Nasopharyngeal carriage of Streptococcus pneumoniae in Finnish children younger than 2 years old A longitudinal study of respiratory viruses and bacteria in the etiology of acute otitis media with effusion Respiratory viruses predisposing to bacterial infections: role of neuraminidase Acute otitis media and respiratory virus infections Time to development of acute otitis media during an upper respiratory tract infection in children Temporal development of acute otitis media during upper respiratory tract infection Mandell, Douglas and Bennett's Principles and Practices of Infectious Diseases Concurrent serious bacterial infections in 2396 infants and children hospitalized with respiratory syncytial virus lower respiratory tract infections Low risk of bacteremia in febrile children with recognizable viral syndromes A prospective study of the risk for serious bacterial infections in hospitalized febrile infants with or without bronchiolitis Office-based treatment and outcomes for febrile infants with clinically diagnosed bronchiolitis Diagnostic testing for serious bacterial infections in infants aged 90 days or younger with bronchiolitis Sepsis evaluations in hospitalized infants with bronchiolitis Multicenter RSV-SBI Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics Sepsis workup in febrile infants 0-90 days of age with respiratory syncytial virus infection Risks for bacteremia and urinary tract infections in young febrile children with bronchiolitis Risk of urinary tract infection in infants and children with acute bronchiolitis Diagnosis and outcomes of enterovirus infections in young infants Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity Diagnosis of viral infections using myxovirus resistance protein A (MxA) MxA-based recognition of viral illness in febrile children by a whole blood assay New sandwich-type enzymelinked immunosorbent assay for human MxA protein in a whole blood using monoclonal antibodies against GTP-binding domain for recognition of viral infection MxA expression in patients with viral infection after allogeneic stem cell transplantation MxA RNA quantification in febrile patients who underwent hematopoietic cell transplantation for primary immunodeficiency Current strategies for management of influenza in the elderly population Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae Effectiveness of intranasal live attenuated influenza vaccine against all-cause acute otitis media in children The role of new vaccines in the prevention of otitis media Prevention of otitis media by vaccination Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens Efficacy of intranasal virosomal influenza vaccine in the prevention of recurrent acute otitis media in children Additive preventive effect of influenza and pneumococcal vaccines in elderly persons Effects of a largescale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study Pneumococcal conjugate vaccines for preventing otitis media Vaccine Safety Datalink. Effectiveness of pneumococcal polysaccharide vaccine in older adults Neuraminidase inhibitors: zanamivir and oseltamivir Neuraminidase inhibitors for preventing and treating influenza in children Oral oseltamivir treatment of influenza in children Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial: US Oral Neuraminidase Study Group Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial Publish your work in this journal Submit your manuscript here: http://www.dovepress.com/therapeutics-and-clinical-risk-management-journal Therapeutics and Clinical Risk Management is an international, peerreviewed journal of clinical therapeutics and risk management, focusing on concise rapid reporting of clinical studies in all therapeutic areas, outcomes, safety, and programs for the effective, safe, and sustained use of medicines. This journal is indexed on PubMed Central, CAS, EMBase, Scopus and the Elsevier Bibliographic databases. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.