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Picornaviridae family is an extensive group of viruses causing enteric, neurological, and respiratory diseases. Members of this family including rhinoviruses A, B and C, coxsackievirus, echovirus, and enterovirus are responsible for important pediatric enteric and respiratory diseases. Several reports have shown that rhinovirus C is associated with asthma exacerbations.1, 2, 3, 4 Non‐polio enteroviruses such as coxsackievirus A16 and enterovirus 71 have been associated with hand, foot and mouth disease in the United States and Asia,5 whereas coxsackievirus A24 and enterovirus 70 have been related to conjunctivitis outbreaks and echoviruses 13, 18, and 30 have caused outbreaks of viral meningitis in the United States.6
In the late summer of 2014, clusters of severe respiratory infections due to enterovirus D68 had been reported in children throughout the United States, Canada, and the Netherlands.7 These children presented with asthma exacerbation and were generally characterized by low‐grade or absent fever, wheezing, dyspnea, and hypoxia.8, 9 Severe cases of the disease needed mechanical ventilation, and on rare occasions, children developed acute focal limb weakness with non‐enhancing spinal cord lesions following the respiratory illness.8, 9
The purposes of this report were to describe the clinical findings of an EV‐D68 infection outbreak in Mexico City and identify genetic relationship with the strains reported in United States, Europe, and Asia. During September, we detected an increase in enterovirus/rhinovirus identification on respiratory samples from hospitalized children with pneumonia or asthma exacerbation (none with paralysis), of which 24 were EV‐D68‐positive.
Acute respiratory infections (ARIs) are a main cause of morbidity and mortality in children, with viruses being responsible for more than 80% of ARIs worldwide.12) Clinical manifestations of ARI can hardly differentiate bacterial from viral etiologies, which can lead to the unnecessary use of antibiotics. Recent development of the multiplex reverse transcription polymerase chain reaction (RT-PCR) assay makes noninvasive identification of respiratory pathogens possible. However, a more accurate diagnosis of causative ARI pathogens does not decrease hospital admissions or antibiotic use in children with ARI.3) Since viruses are often detected in asymptomatic children,4) identification of a virus by RT-PCR does not always imply that it is the culprit for a current ARI. Because these viruses are sometimes asymptomatic carriers and sometimes pathogens, a diagnosis should not be based solely on viral identification in respiratory samples. Moreover, new respiratory viruses have been increasingly recognized, but their clinical significance remains unclear.56) Thus, in addition to multiplex RT-PCR assays, a better understanding of these viruses is required to improve clinical management.
In this study, we assessed the viral epidemiology of ARI in hospitalized children under age of 15 years, and we characterized the virus-specific clinical and laboratory profiles as well as clinical outcomes. Together with RT-PCR results, this data will help us understand the clinical course of viral ARI and to establish more effective preventive and therapeutic strategies.
Between September and November of 2014, a total of 126 children with respiratory disease were hospitalized at our institute. There was a 90% increase in admission for respiratory symptoms compared with the corresponding months in 2012 and 2013 based on overall admission.13
At least one respiratory virus was detected in 78 (62%) of NPS from the enrolled patients. The most common were enterovirus/rhinovirus (EV/RV) in 40 (31·7%) patients, followed by RSV (11·9%), HMPV (8·7%), HPIV (4·0%), adenovirus (2·4%), and influenza A and coronavirus OC43 (both with 1·6% each). Single viral infections were detected in 70 samples (55·5%), while double viral infections were found in 8 samples (6·3%).
Of the 40 patients positive for enterovirus/rhinovirus, EV‐D68 was identified in 24 patients (19%) and rhinoviruses B and C were identified in 16 patients (12·7%); EV‐D68 was identified in 12 patients in September, 10 in October, and 2 in November 2014.
Median age of patients infected with EV‐D68 was 5·2 years (IQR 1·75–7·8), and 13 (54·2%) of them were female. Common features of the hospitalized patients included cough, rhinorrhea, dyspnea, and wheezing (Table 2). Among all hospitalized patients with respiratory infection, individuals with an EV‐D68 infection had significantly greater neutrophilia (80·9%, 95% CI 65·0–92·2, P = 0·001) and lymphopenia (13·9% 95% CI 5·3–24·5; P = 0·0002) when compared with those negative for enterovirus/rhinovirus infection, but not when compared with those positive for rhinovirus infection (Table 3). Other parameters such as O2 saturation on room air, partial oxygen and carbon dioxide pressure, bicarbonate, oxygen saturation, and leukocyte, monocyte, eosinophil and basophil levels did not show any significant differences (Table 3). To find a relationship between EV‐D68 infection and wheezing/asthma or pneumonia diagnoses, we classified patients into two groups. Among the 24 patients positive for EV‐D68 infection, nine (37·5%) were admitted because of wheezing or asthma exacerbation with no lung opacities in the chest roentgenogram and 15 (62·5%) had opacities (pneumonia), and we found no significant difference between both groups.
Sixteen of the 24 EV‐D68‐positive children (67%) were febrile. No neurological signs or symptoms as such acute flaccid paralysis, encephalitis, or aseptic meningitis were observed in the hospitalized children included in this study.
The length of hospital stay for all the EV‐D68‐infected patients was 6 days (median), IQR (4–7), while the whole evolution period (considered from the symptom onset until disease resolution) was 11 days (median), IQR (7–21). Regarding respiratory parameters, most admitted children required significant levels of respiratory support. Patients with EV‐D68 infection were significantly more likely to progress to hypoxemia than those with rhinovirus infection or those who were enterovirus/rhinovirus‐negative (P = 0·044) (Figure 1).
The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus two (SARS-CoV 2), is a member of Betacoronaviruses, like the former human coronaviruses SARS coronavirus (SARS-Cov) and the Middle East respiratory syndrome (MERS). Human coronaviruses are positive-sense, long (30,000 base pairs) single-stranded RNA viruses. COVID-19 was first detected in humans towards the end of 2019 and the first cases were traced back to Wuhan city (Hubei province) in China. The virus appears to spread via human to human transmission in a similar fashion to influenza and several viruses causing upper respiratory infections, i.e., through contact with secretions from infected individuals. There is also concern regarding airborne transmission as well as oro-fecal transmission. The virus predominantly replicates in the respiratory system during the prodromal period, which further contributes to the transmission of the disease as patients may still be harboring the infection in the absence of symptoms. After the initial reports of infection, in the following several weeks, COVID-19 outbreaks were reported in South Korea, Iran, and Italy. This was quickly followed by several other European, Asian, and North and South American countries reporting cases. COVID-19 was declared a pandemic by the World Health Organization (WHO) on March 11, 2020.
Compared to adults, there have been significantly less reported cases of COVID-19 in the pediatric population. As of February 2020, 2.4% of the 75,465 cases (confirmed and suspected) in China were reported in the pediatric population. This article looks to review specific epidemiological factors, symptomatology, laboratory, and imaging workup and other relevant metrics derived from the limited published literature that are specific to the pediatric population to provide a review for the pediatric practitioner and guide in part towards the creation of an interim algorithm for the management of COVID-19 in the pediatric population.
Since finding severe acute respiratory syndrome (SARS) to occur due to infection by coronaviruses (CoVs),12 researchers have become more interested in human coronaviruses (HCoVs). Along with the outbreak of Middle East Respiratory Syndrome (MERS) in the Republic of Korea this year, HCoVs continue to impact global health.34 There are four respiratory HCoV species: 229E, NL63, OC43, and HKU1. In particular, subtypes 229E and OC43 are known to cause upper respiratory illness with relatively mild symptoms or even asymptomatic infections; however, these two subtypes still heavily impact the elderly and patients with cardiopulmonary disease.5
HCoV infections can occur anytime, anywhere, and in anybody. However, there are differences in geographic prevalence and age specificity. Among the four known respiratory HCoVs, typically only one, or at least a predominant type, is found at a particular time and in a particular area. In early childhood, OC43 and NL63 are detected at a younger age and more frequently.56
In the Republic of Korea, a single HCoV infection was detected every month in 2013, except June through September, in Seoul. The most detected virus was rhinovirus, and HCoVs were minor pathogens.7 From 2010 to 2012, HCoV-OC43 was the most prevalent subtype.8 Interestingly, however, in 2014, HCoV positive rates were lower than in other years, and HCoV caused fewer respiratory infections requiring admission, especially in children. While studies on HCoVs with lower respiratory tract infections (LRTIs) have been conducted in other countries,91011 there are no reports on HCoVs affecting LRTIs. In this study, we reviewed clinical presentations of HCoV infection during the 2014 winter season in Korea.
This retrospective cohort study was approved by the Institutional Review Board of Korea University Guro Hospital (KUGH). Hospitalized patients under 15 years of age with a discharge diagnosis of ARI from January 2013 to December 2015 were enrolled. ARI was diagnosed based on one of symptoms or signs; fever of more than 37.8℃, cough, rhinorrhea, sore throat, tonsillar injection, wheezing, crackle, chest wall retraction.
Nasopharyngeal aspirates from all patients were obtained within 48 hours of admission for multiplex RT-PCR assay to detect the following 15 common respiratory viruses: influenza virus A and B (IFA, IFB), respiratory syncytial virus A and B (RSV A, RSV B), parainfluenza virus 1-4 (PIV 1, PIV 2, PIV 3, PIV 4), human coronavirus 229E and OC43 (hCV-229E, hCV-OC43), human rhinovirus (hRV), human enterovirus (hEV), adenovirus (AdV), human bocavirus (hBV), and human metapneumovirus (hMPV). Only a single sample was taken from the patients during the admission. RT-PCR results were used to evaluate the incidence of respiratory viruses. Laboratory parameters on the first day of admission, as well as overall clinical profiles including baseline characteristics, presenting symptoms and signs, treatments and clinical outcomes, were analyzed in patients with single-virus infections. Any possible bacterial coinfections were excluded by sputum and blood culture and clinical course. Mycoplasma coinfections were excluded by sputum PCR or by a serial increase of antibody titer or a high initial IgM titer without history of recent respiratory disease.
This study was performed at Severance Children’s Hospital in Seoul, Korea. Outpatient clinic, emergency room, and inpatient ward data were collected. From October 1 to December 31 in 2014, 504 patients under the age of 18 years with episodes of respiratory infection received nasopharyngeal swabs. All clinical data were collected by retrospective review of an electric medical record system.
We defined LRTIs as pneumonia or bronchiolitis. When a patient had abnormal lung sounds, such as rales or crackles, with local infiltration or consolidation on chest X-ray, we diagnosed the patient with pneumonia. When lower airway obstruction signs, such as wheezing, decreased lung sounds, or chest retractions, with either a normal or hyperinflation chest X-ray were present, we diagnosed the patient with bronchiolitis.
The swab specimens were sent to a virology laboratory in the Department of Laboratory Medicine at Yonsei University Medical Center for respiratory virus detection. DNA or RNA of respiratory viruses was extracted by TANBead Smart LabAssist-32 (BioKett, Taipei, Taiwan). Then the AdvanSure™ Respiratory Virus real-time RT-PCR Kit (LG Life Science, Seoul, Korea) was used to analyze all 504 samples. Using this kit, we were able to detect 14 types of viruses: respiratory syncytial virus (RSV) types A and B, influenza A and B, parainfluenza types 1, 2, and 3, rhinovirus A, metapneumovirus, HCoV-229E, HCoV-OC43, HCoV-NL63, and bocavirus.
Acute bronchiolitis (AB), which is the most common acute lower respiratory system disease in infants, is often caused by a viral infection. It is especially the leading cause of hospitalization in infants under 6 months of age.1,2 Epidemic peaks of AB are frequently seen during the winter season. Respiratory syncytial virus (RSV) is usually the cause of 50% to 80% of the cases, but other viruses including adenovirus, influenza virus, and parainfluenza virus have also been reported to cause AB as the sole pathogen or as coinfection with or without RSV.3,4 With various polymerase chain reaction (PCR) techniques, possible new agents like rhinovirus, human metapnomovirus, human bocavirus, Bordatella pertussis, and atypical pathogens were also described as the leading causes of AB.5-7 Having a cardiovascular disease, chronic pulmonary disease, immunodeficiency, and premature birth increase the risk of AB-associated respiratory failure, or even death.8 The World Health Organization has reported that RSV is the causative pathogen for over 30 million new acute lower respiratory infection episodes in children under 5 years of age and it gives rise to more than 3.4 million hospital admissions and 160 000 deaths every year.9,10
The diagnosis of AB is made based on typical history with wheezing and characteristic clinical features such as tachypnea, nasal flaring, chest retractions, and wheezing and/or rales followed by a viral upper respiratory infection in infants. The American Academy of Pediatrics (AAP) 2006 Clinical Practice Guidelines for the Diagnosis and Management of Bronchiolitis described AB as the first episode of wheezing in children under 24 months of age who have respiratory findings during the viral infection episode.11 Chest radiographs and laboratory studies may be thought of on clinical suspicion after evaluating the differential diagnosis for secondary or comorbid bacterial infection, complications, or other conditions. Viral diagnosis methods including antigen detection or immunofluorescence of nasal secretion wash or nasal aspiration, rapid antigen tests, and PCR are only suggested for identifying specific viral agents in children with bronchiolitis if the results will determine discontinuation of palivizumab prophylaxis, initiation or continuation/discontinuation of antibiotic therapy.12-15
Majority of studies have recently researched the burden of respiratory viral tract infection agents in AB with larger groups. In these studies, epidemiological, clinical, and risk factors of AB have also been defined. So, it can be said that AB is frequent in infancy and that there is an increase in the number of admissions to hospitals and bronchiolitis-related morbidity.
The purpose of this study was to evaluate the frequency of pathogens and to determine the differences in clinical and microbiological features among patients under 24 months of age, who were hospitalized with AB in Ege University Children’s Hospital.
Avian infectious bronchitis virus (IBV) is a member of the Coronaviridae family, which includes many human and animal pathogens of global concern, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome virus (MERS-CoV), and mouse hepatitis virus(MHV). IBV has a major economic impact on the global poultry industry because this prototype coronavirus considerably decreases hen egg production by impairing the upper respiratory and reproductive tracts of chickens. IBV is an enveloped positive-stranded RNA virus with a 27–30 kb genome that encodes several polyproteins. The polyproteins of IBV are cleaved by viral proteases into at least 15 nonstructural proteins (NSPs). Four structural proteins, namely, spike protein (S), nucleocapsid protein (N), membrane protein (M), and small envelope protein (E), are encoded by subgenomic RNA species. The binding and entry of IBV into host cells require interactions between cellular surface receptors and viral structural proteins that are involved in the attachment stage. Nearly all IBV field isolates can only be propagated in embryonated chicken eggs or transiently proliferated in primary chicken embryo kidney cells. However, the Beaudette strain, a cell-adapted strain, replicates efficiently in various cultured mammalian cell lines, including African green monkey kidney cells (Vero), human liver cancer cells, lung cancer cell lines, and baby hamster kidney cells through serial passages [5–8]. However, the detailed mechanism underlying virus-host interactions during viral attachment and entry remains uninvestigated. Here, we used the Beaudette strain as an in vitro model to study the mechanism of IBV infection.
As functional membrane microdomains, lipid rafts contain abundant cholesterol and sphingolipids, which are also termed detergent-insoluble glycolipid-enriched complexes or detergent-resistant membranes because of their significant features, such as composition and detergent resistance. Specific microdomains exist in biological membranes; however, the existence of lipid rafts in living cells still remains controversial. Lipid rafts are involved in some important cellular processes, including signal transduction, cell migration, and axonal guidance [12–15]. In addition, numerous studies have revealed that lipid rafts are important during viral infection. For example, lipid rafts are critical in multiple stages of the life cycles of dengue and hepatitis C viruses. Furthermore, lipid rafts are involved in the binding and entry of host cells for several enveloped and non-enveloped viruses, including human immunodeficiency virus, poliovirus, human herpes virus 6, West Nile virus, foot-and-mouth disease virus, and simian virus 40. Moreover, lipid rafts are involved in the assembly and egress of some viruses, including rotavirus, measles virus, Newcastle disease virus, influenza virus, Ebola virus, and Marburg virus [23–26].
Coronaviruses also require lipid rafts for cellular entry. Some studies showed that drug-mediated cholesterol depletion inhibited human coronavirus 229E and MHV entry into host cells. In a previous study, we reported that lipid rafts are crucial for SARS–CoV entry into Vero E6 cells. Moreover, changes in the lipid component of cellular membranes affect the outcome of IBV infection. Intriguingly, the efficiency of IBV-induced membrane fusion considerably varies among different cell lines. In this study, we investigated the direct role of lipid rafts during IBV infection in Vero cells. Lipid rafts were disrupted by depleting cellular cholesterol with two pharmacological agents, methyl-β-cyclodextrin (MβCD) and Mevastatin. The results showed that the structural proteins of IBV are required for attachment to Vero cells. However, lipid rafts may not be involved in the replication and release of IBV. These results revealed that lipid rafts are required during the early stages of IBV infection.
Reviewing published literature, Jiehao et al., in their case series of 10 children with the 2019 novel coronavirus, reported that the age group of patients affected was between three and 131 months with a mean age of 74 months with a male to female ratio of 1:1.5.
Xia et al. noted 65% of the affected patients to be male within their subset of 20 pediatric inpatients with COVID-19 infection. The age range within this group of affected patients was one day to 14 years with a median age of two years. Seventy percent of the affected patients within this subset were under the age of three years. One of the patients had a history of epilepsy as a sequela of previous viral encephalitis and two patients had a history of atrial septal defect (ASD) repair surgery. The authors noted five further patients with a history of congenital or acquired diseases (unspecified within the reported study), which the authors purported to indicate that children with underlying diseases would have a greater susceptibility to COVID-19. Jiehao et al. noted within their study that the mean incubation period in their set of pediatric patients from household exposure to a symptomatic adult case was six and a half days, which they noted to be suggestive of a longer incubation period than what is being reported in adults.
Dong et al., in their pre-publication release data looking at the epidemiology of COVID-19 among children in China, reviewed 2143 cases of which 731 were laboratory confirmed and 1412 were suspected cases. They found the median age among these cases to be seven years with 56.6% of the cases being boys.
Overall, the epidemiological data suggests a slightly higher percentage of affected cases to be male. The age range of affected patients is wide, with concern regarding a higher propensity of illness in patients with pre-existing diseases. This may represent either worse symptoms resulting in a higher rate of testing or may indicate an increased susceptibility to illness with underlying disease.
Xia et al. noted in their study of pediatric COVID-19 cases that eight (80%) patients had a fever, six (60%) had a cough, four (40%) had a sore throat, three (30%) had a stuffy nose, and two (20%) had sneezing and rhinorrhea. None of the patients had diarrhea or dyspnea during the course of their illness.
Xia et al. report the presence of fever, which was defined as axillary temperature over 37.3°C in 12 cases (12/20, 60%), cough in 13 cases (13/20, 65%), diarrhea in three cases (3/20, 15%), nasal discharge in three cases (3/20, 15%), sore throat in one case (1/20, 5%), vomiting in two cases (2/20, 10%), tachypnea in two cases (2/20, 10%), and fatigue in one case (1/20, 5%). They also further noted physical exam findings when assessed by medical personnel to be rales in three cases (3/20, 15%), retraction signs in one case (1/20, 5%), and cyanosis in one case (1/20, 5%).
Dong et al. characterized, in looking at their data of 2143 pediatric patients with laboratory diagnosed and/or clinically suspicious cases of COVID-19 infection, the severity of illness as asymptomatic, mild (predominantly upper respiratory tract infectious symptoms with no frank respiratory distress), moderate (presence of pneumonia, frequent fever and cough but with no obvious hypoxemia), severe (presence of dyspnea with central cyanosis, oxygen saturation <92% with other hypoxia manifestations) and critical (acute respiratory distress syndrome (ARDS), respiratory failure, shock, encephalopathy, myocardial injury, heart failure, coagulation dysfunction, and organ dysfunction). With these clinical parameters, they found 4.4% of cases to be asymptomatic, 50.9% of cases to be mild, and 38.8% of the cases to be in the moderate range accounting for 94.1% of all cases. They also noted the proportion of severe and critical cases to be inversely proportional to the age range, with the age group of less than one year old having 10.6% of the severe and/or critical cases.
Chest radiographs revealed a unilateral patchy infiltrate in four (40%) of 10 patients with COVID-19 reported by Jiehao et al.. Xia et al. further looked to examine the chest CT findings at various stages of the COVID 19 process. At the early stage of the disease, they noted six patients presented with unilateral pulmonary lesions (6/20, 30%), 10 with bilateral pulmonary lesions (10/20, 50%), and one pediatric patient and three neonates had no abnormalities on chest CT (4/20, 20%). Sub-pleural lesions with localized inflammatory infiltration were found in all children. Ten patients (10/20, 50%) were noted to have “halo sign” consolidation, 12 patients (12/20, 60%) had ground-glass opacities, four patients (4/20, 20%) had “fine mesh shadows,” and tiny nodules were detected in three patients (3/20, 15%). No patients were noted to have signs of pleural effusion and lymphadenopathy on CT scan.
Jiehao et al. noted within their laboratory findings: median white blood cell count (WBC) 7.35×109/L, C-reactive protein (CRP) 7.5 mg/L, procalcitonin (PCT) 0.07 ng/dL, creatine kinase-myocardial band (CK-MB) 23 U/L, alanine aminotransferase (ALT) 18.5 U/L, aspartate aminotransferase (AST) 27.7 U/L, urea 3.1 mmol/L, creatinine 35.5 μmol/L, lactate dehydrogenase (LDH) 25 U/L, and D-dimer 0.45 μg/mL; influenza virus A and B were negative. The study also showed that all patients had 2019-nCoV RNA detected in nasopharyngeal and throat swabs within four to 48 hours after the onset of symptoms and 2019-nCoV RNA in nasopharyngeal or throat swabs was no longer detectable within six to 22 days (with a mean of 12 days) after the onset of illness. Six of these patients had fecal samples tested, and 5 (83.3%) were positive for 2019-nCoV RNA. The authors also noted with concern that the five patients still had 2019-nCoV RNA detected in feces within 18-30 days after illness onset at the time of publication of their findings. Five patients also had serum and urine samples tested and were negative for 2019-nCoV RNA.
For Xia et al. (per their reference ranges used), WBC was normal (5.5-12.2) in 14 cases (14/20, 70%), decreased (<5.5) in four cases (4/20, 20%), and increased (>12.2) in two cases (2/20, 10%); ALT increased (>40 IU/L) in five cases (5/20, 25%),CK‐MB increased in 15 cases (15/20, 75%), and PCT (>0.05) increased in 16 cases (16/20, 80%). Eight patients were co-infected with other pathogens (8/20, 40%), including influenza viruses A and B, mycoplasma, respiratory syncytial virus (RSV), and cytomegalovirus (CMV). Further, four cases had abnormal electrocardiogram (EKG) events, including atrial arrhythmia, first-degree atrioventricular (AV) block, atrial and ventricular premature beats, and incomplete right bundle branch block.
Elevations in CK-MB and EKG changes are of particular concern, as they may be indicative of myocarditis as a potential complication of COVID-19. Lippi et al., in their electronic data review (which was not specific for pediatric patients), also noted the cardiac Troponin I value significantly increased in patients with severe COVID-19 infection.
Jiehao et al. noted the mean number of secondary symptomatic cases in the household exposure setting was 2.43, which is indicative of the basic reproductive number for pediatric COVID-19 cases and proof of direct transmission. Xia et al. noted within their subset of 20 cases that 13 pediatric patients (13/20, 65%) had an identified history of close contact with COVID‐19 diagnosed family members, again supporting proof of direct transmission.
A particular source of concern is the paucity of data on the vertical transmission potential of COVID-19 pneumonia in pregnant women. Chen et al. retrospectively reviewed the medical records for nine pregnant women with laboratory-confirmed COVID-19. The evidence of intrauterine vertical transmission through testing for the presence of SARS-CoV-2 in amniotic fluid, cord blood, and neonatal throat swab samples was assessed. Breastmilk samples were also collected and tested from patients after the first lactation.
They reported that within this subset of patients nine live-births delivered via cesarian section were recorded. No neonatal asphyxia was observed in the newborn babies. All nine newborns had a one-minute Apgar score of eight to nine and a five-minute Apgar score of nine to 10. Six patient’s amniotic fluid, cord blood, neonatal throat swab, and mother’s breastmilk samples were tested for SARS-CoV-2, and all samples tested negative for the virus. They noted within this subset of patients that the clinical characteristics of the disease were similar in pregnant and non-pregnant adults and that they did not note any evidence of intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy.
At the time of publication of this article, the U.S. Food and Drug Administration (FDA) currently has no approved medications to treat patients with COVID-19. As such, management algorithms, particularly for the pediatric patient, are based at least in part on clinical opinion. Partially based on the data reviewed above and partially upon the opinion of the authors of the article, looking specifically at pediatric COVID-19, we recommend the investigation and management pathway as displayed in Figure 1.
Acute respiratory infections (ARIs) are the leading cause of mortality in children worldwide, particularly in developing countries. It represents an important public health problem in early development, with high mortality and morbidity among children under five years of age.1 ARIs are classified as upper respiratory tract infections or lower respiratory tract infections (LRTIs) depending on the airways predominately involved.2
Although ARIs can be caused by bacteria or fungi, viral infections are responsible for most of them. Several viruses have been consistently identified during ARIs: influenza virus, human parainfluenza virus (HPIV), human rhinovirus (HRV), adenovirus (ADV), coronavirus (HCoV), enterovirus, human metapneumovirus (HMPV), and respiratory syncytial virus (RSV).3
Moreover, viral infections are one of the many risk factors associated with wheezing illnesses and exacerbation of respiratory diseases in children of all ages.4 HRV has been associated with these exacerbations, including cough, wheezing, shortness of breath, oxygen use, and length of hospital stay.5,6 In addition, asthma inception and exacerbation had been associated with HRV7–9 and HMPV infection,10 with some reports estimating that approximately 60% of cases are associated with HRV infection.11
Human rhinovirus have been classified into two genetic species: HRV-A (including 76 serotypes) and HRV-B (including 25 serotypes). However, recently, HRV-C has been included. HRV-A and HRV-B are associated with the common cold, whereas the role of HRV-C is relatively unknown, but recent reports suggest that HRV-Cs may be more pathogenic than other HRVs.12–14
Virus identification and molecular characterization is fundamental for epidemiological surveillance and control, but also for diagnostic purposes that may lead to specific therapy and an adequate response to treatment because clinical manifestations of virus and bacteria associated with ARI overlap considerably except in epidemic situations.15
The aim of this study was to determine the association of each type of respiratory viruses with acute hypoxemic respiratory disease mainly asthma acute exacerbation or pneumonia in children admitted to a reference respiratory center in Mexico City during three different seasons.
Coronaviruses (CoVs) are enveloped viruses with a long single-stranded RNA ranging from 26 to 32 kilobases (kb) in size 1. CoVs belong to the family Coronaviridae in the order Nidovirales, and have been organised into 3 groups: α-CoVs, β-CoVs, and γ-CoVs 2. Two of the β-CoVs including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) caused severe acute respiratory disease outbreaks in China in 2002-2003 and in the Middle East in 2012, respectively 3.
In December 2019, a novel CoV outbreak, identified and named as severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) started in Wuhan, Hubei province, China. The SARS-CoV-2 spread very quickly in China and then to the many other countries, causing coronavirus disease-19 (COVID-19). The clinical futures of COVID-19 mainly include fever, cough and pneumonia 4. Up to date, it has already infected more than 90,000 people worldwide and killed more than three thousand patients, mainly in Wuhan, China. SARS-Cov-2 shares a high sequence identity (around 80%) with SARS- CoV and a 96.2% sequence identity with BatCoV RaTG13, a bat CoV 5. Although some initial cases were linked to a local seafood market in Wuhan, its origin, intermediate hosts and how it was transmitted to humans are still largely unknown 4.
In this mini-review, we will mainly focus on β-CoV, which is inclusive of SARS-CoV, MERS-CoV, and the current emerging SARS-CoV-2 to discuss the implication of the endocytic pathway and autophagy process in the infection of these pathogenic CoVs and therapeutic potential of targeting these processes. This review will also include the well-studied mouse hepatitis virus (MHV) since it is often used as a safe mode to study CoV infection.
Viruses with RNA genomes are major causes of emerging deadly infectious diseases and represent the most ever-present and everlasting changing cellular parasites known. There are many different alterations of genetic elements occurring during RNA genome replication. This plasticity is fundamental and caused by infidelity of the replication process. Evolution of RNA viruses is basically unpredictable due to the stochastic nature of the mutation and recombination events, as well as environmental factors. A fundamental concern regarding RNA viruses is their high mutation rate. RNA viruses exist as quasispecies which are the result of pressure, mutation, and selection, in ways which are poorly understood. These mutations could affect the binding capability of the virus to both neutralizing antibodies and host receptors which could result in emergence of new viral host ranges. The chance that defined molecules may promote selection of escape mutants or a particular detection tool may fail to detect the virus is high.
The mechanisms of viral infection and prevention are the most difficult investigations in virology research. Virus tropism and neutralizing antibodies are the major crucial steps in virus life cycles and vaccine development respectively. To better understand the molecular pathways of infection and prevention, we must utilize synthetic biology. Synthetic biologists would simplify and engineer complex artificial biological systems that investigate natural biological phenomena.
The current generation of synthetic vaccines, diagnostic reagents (monoclonal antibodies (mAbs), peptide antigens, oligonucleotides, etc.) and therapeutics may be very adequate to prevent, detect and cure infections due to DNA viruses. Unfortunately, these fail to address RNA viruses. This is largely due to the vast number of circulating quasispecies associated with RNA pathogens. The dynamics of viral quasispecies mandates careful consideration. In reality, prevention and therapy of infection due to an RNA virus should rely on multicomponent vaccines and antiviral agents that address the complexity of the RNA quasispecies mutant spectra. This can be accomplished using the RNA Qβ coliphage display peptide library.
Phage display technology has been developed, applied extensively and proven to have success in exposing functional peptides on the exterior surface of phage. A novel display system which exploits the high mutation rate of RNA replicase has been developed. A small peptide library has been presented on this RNA phage surface and selected against the SD6 mAbs of the foot-and-mouth disease virus (FMDV). The membrane-proximal external region (MPER) of the human immunodeficiency virus type-1 (HIV-1) was engineered on the surface of Qβ as well. These studies use the Qβ phage for its large population and high mutation rate. The novel pipeline proposed herein takes into consideration the quasispecies nature of these pathogenic RNA viruses. This review will present a detailed structural and functional synopsis of the Qβ platform and emphasize the methodologies and medical applications associated with the system.
Human rhinovirus (HRV), a single-stranded positive-sense RNA virus, belongs to the genus Enterovirus and family Picornaviridae, and is classified as HRV-A, -B, or -C. HRV-A and HRV-B were discovered in the 1950s (Price, 1956), while HRV-C was identified using molecular techniques in 2006 (Lamson et al., 2006; Lau et al., 2007). According to the 2017 International Committee on the Taxonomy of Viruses (ICTV) release1, a total of 168 HRV genotypes (80 HRV-A, 32 HRV-B, and 56 HRV-C) are recognized (Kuroda et al., 2015).
Human rhinovirus genomic RNA is approximately 7.2 kb that consisting of a single open reading frame (ORF) encodes 11 proteins, with 5′ and 3′ untranslated regions (UTR) at both end, respectively. The ORF encodes a poly-protein which is cleaved by viral proteases to produce 11 proteins including four structural viral proteins (VP) 1 to 4. Compared to the rest of the HRV genome, the capsid proteins exhibit a high degree of heterogeneity resulting in a wide range of antigenic diversity. RT-PCR assays targeted the 5′-UTR are usually used for HRV clinical detection. HRV species and types are classified almost exclusively now based on VP1 or VP4/VP2 sequence alignments (Wisdom et al., 2009).
Human rhinovirus is a frequently detected respiratory virus in children with mild acute respiratory infection (ARI), but may also lead to more-severe respiratory tract symptoms, such as pneumonia, bronchiolitis, and asthma. HRV is, after respiratory syncytial virus (RSV), the second most frequent viral cause of community-acquired pneumonia and other severe acute respiratory infections (SARIs) (Honkinen et al., 2012; Esposito et al., 2013). HRV-C is more frequently associated with wheezing episodes, asthma exacerbations, and lower respiratory tract infections compared with HRV-A and -B (Linsuwanon et al., 2009; Gern, 2010; Bizzintino et al., 2011). However, there is reportedly no relationship between disease severity and HRV species (Lee et al., 2012; Chen et al., 2015; van der Linden et al., 2016).
Data on the genotypic diversity and epidemiology of HRVs in children with SARI are sparse. Thus, we evaluated the predominant HRV species and genotypes, and their associations with the clinical characteristics, of 1,003 children hospitalized with SARI from 2013 to 2015 in Shanghai, China.
Streptococcus suis serotype 2 (S. suis 2, SS2) is an important zoonotic pathogen that causes severe porcine infectious diseases, including arthritis, meningitis, and pneumonia. Virulent strains of SS2 can also be transmitted to humans (especially abattoir workers and pork handlers) by direct contact, causing meningitis, permanent hearing loss, septic shock, and even death. Two large-scale outbreaks of severe SS2 epidemics occurred in China in 1998 and 2005, causing great economic losses in the swine industry. These two outbreaks also posed serious public health risks from the newly emerging streptococcal toxin shock syndrome (STSS), which claimed 52 lives. Over the past decade, considerable attention has been given to the study of virulence factors (e.g., CPS, MRP, EF, and suilysin) and the pathogen-host interaction in this emerging pathogen. However, comparative studies at the whole-genome level had little done to decipher the evolutionary aspects by which the virulence and environmental adaptation of SS2 are shaped.
To shed light on the evolution of pathogenicity and potential genomic polymorphisms of SS2, several virulent strains were subjected to whole-genome sequencing and comparative genomic studies. Comparative analysis of the whole-genomic DNA sequence of the European S. suis strain P1/7 (by the Sanger Institute) and two representative highly virulent strains (98HAH12 and 05ZYH33) isolated from STSS patients during the two epidemic outbreaks in China uncovered a candidate pathogenicity island (PAI) named 89K, which has been confirmed to undergo horizontal gene transfer (HGT) by our recent work. Further analysis based on PCR amplification revealed that 89K exclusively present in the epidemic strains in these two Chinese SS2 outbreaks but not in other domestic clinical isolates or international virulent strains. However, analysis of the unfinished genomic sequence of SS2 strain 89/1591 (by the DOE Joint Genome Institute) revealed that a partial 89K sequence (~30 kb) is present in this typical North American virulent strain. Similarly, results from a recently published work suggest that S. suis strain BM407, which was isolated from a human meningitis case in Vietnam in 2004, contains two regions with extended similarity to 89K. These findings led us to hypothesize that the genome of SS2 would be highly polymorphic among different strains.
In this study, we employed the comparative genome re-sequencing (CGS) approach developed by Roche NimbleGen Systems to investigate genomic diversity in a collection of 18 SS2 strains, including isolates from the two outbreaks in China, other virulent strains from China (isolated before these outbreaks), virulent strains from European countries, and several avirulent strains. Although CGS cannot identify recently gained genes due to technical limitations, the DNA microarray-based comparative genome sequencing technique allows high resolution detection of sequence polymorphisms based on a reference genome. Using this technology, we identified a number of novel genetic polymorphisms in SS2 strains and several candidate virulence factors that may contribute to STSS. Our results provide new insight into the virulence mechanisms and genome dynamics of SS2, which will help to elucidate the evolution of SS2 strains and better monitor the incidence and spread of epidemic strains.
CoVs are a group of large enveloped RNA viruses under the Coronaviridae family. Together with Artierivirdae and Roniviridae, Coronaviridae is classified under the Nidovirale order. As proposed by the International Committee for Taxonomy of Viruses, CoVs are further categorized into four main genera, Alpha-, Beta-, Gamma- and Deltacoronaviruses based on sequence comparisons of entire viral genomes. These CoVs can infect a wide variety of hosts, including avian, swine and humans. HCoVs are identified to be either in the Alpha- or Betacoronavirus genera, including Alphacoronaviruses, HCoV-229E and HCoV-NL63, and Betacoronaviruses, HCoV-HKU1, SARS-CoV, MERS-CoV and HCoV-OC43 (Table 1).
Under the electron microscope, the CoV virions appear to be roughly spherical or moderately pleomorphic, with distinct “club-like” projections formed by the spike (S) protein. Within the virion interior lies a helically symmetrical nucleocapsid that encloses a single-stranded and positive sense RNA viral genome of an extraordinarily large size of about 26 to 32 kilobases. The positive sense viral genomic RNA acts as a messenger RNA (mRNA), comprising a 5′ terminal cap structure and a 3′ poly A tail. This genomic RNA acts in three capacities during the viral life cycle: (1) as an initial RNA of the infectious cycle; (2) as a template for replication and transcription; and (3) as a substrate for packaging into the progeny virus. The replicase-transcriptase is the only protein translated from the genome, while the viral products of all downstream open reading frames are derived from subgenomic mRNAs. In all CoVs, the replicase gene makes up approximately 5′ two-thirds of the genome and is comprised of two overlapping open reading frames (ORFs), ORF1a and ORF1b, which encodes 16 non-structural proteins. The final one-third of the CoV genomic RNA encodes CoV canonical set of four structural protein genes, in the order of spike (S), envelope (E), membrane (M) and nucleocapsid (N). In addition, several accessory ORFs are also interspersed along the structural protein genes and the number and location varies among CoV species (Figure 1).
Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses belonging to the family Coronaviridae within the order Nidovirales. Based on its properties, this family can be divided into four distinct genus: alpha, beta, delta, and gamma. Coronaviruses infect a wide variety of birds and mammals, including humans, livestock, and companion animals [1–3]. Human coronaviruses (HCoVs) are associated mainly with relatively mild upper and lower respiratory tract disease; however, emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in the winter of 2002–2003 in China, and more recently Middle East respiratory syndrome coronavirus (MERS-CoV) in the Middle East, demonstrates the potential threat posed by zoonotic coronaviruses [2–4].
Canine respiratory coronavirus (CRCoV) was first identified in 2003 in samples obtained from the respiratory tracts of dogs with canine infectious respiratory disease (CIRD; also known as kennel cough) that were housed in animal shelters in the United Kingdom. CIRD is a contagious disease with high morbidity but low mortality; it usually occurs in densely housed dog populations (e.g., rehoming centers, veterinary hospitals). Characterized by a dry, hacking cough, the disease is generally mild and self-limiting. However, it can progress to a potentially fatal bronchopneumonia [6, 7]. CIRD is considered a complex infection, with a multifactorial etiology in which a number of organisms (including Bordetella bronchiseptica, canine parainfluenza virus, canine adenovirus type 1 and 2, canine herpesvirus, Mycoplasma spp., canine pneumovirus, and influenza viruses) are involved [6, 8]. It is believed that CRCoV plays a role in the early stages of CIRD by limiting ciliary clearance of the upper airways. Consequently, infection leads to reduced respiratory clearance and sensitization to secondary infections [5–7].
CRCoV is closely related to two other betacoronaviruses, bovine coronavirus (BCoV) and HCoV-OC43 (97.3% nucleotide identity in the spike gene for BCoV and 96.9% for OC43 as reported by Erles et al.), but is clearly distinct from Canine Enteric Coronavirus (CECoV, previously known as Canine Coronavirus) [5, 7]. CRCoV is a difficult pathogen to work with because the only confirmed susceptible cell line is a human rectal tumor cell line (HRT-18) and its derivative HRT-18G. No canine cell line supports replication of the virus. Furthermore, CRCoV does not produce a cytopathic effect in HRT-18 cells.
To initiate infection, enveloped viruses fuse with host cell membrane prior to delivering genetic material. This process may occur at the cell surface (e.g., human immunodeficiency virus, herpes simplex virus); otherwise prior internalization is required [2, 9]. To enter the cell, viruses hijack a number of different endocytic pathways, including macropinocytosis and clathrin-mediated, caveolin-mediated, and clathrin- and caveolin-independent routes [2, 9, 10]. For example, SARS-CoV uses clathrin-dependent, lipid raft-mediated, and clathrin- and caveolae-independent entry pathways [2, 11–13]. In addition, feline infectious peritonitis virus (FIPV) uses clathrin- and caveolin-independent endocytic routes, whereas HCoV-229E uses caveolae-dependent endocytosis. Furthermore, some human respiratory coronaviruses may utilize protease activation to modulate the route of entry [16–18]. Generally, within each of these endocytic pathways, vesicles are formed through interaction of certain protein networks. Early vesicles provide a starting point for trafficking, which leads to endosome maturation and allows sorting of incoming cargo [19, 20]. Some internalized vesicles are recycled back to the cell surface, while others are converted, for example to lysosomes. Sorting of cargo is regulated by Rab GTPases, which serve as molecular hallmarks of different routes [19–21].
Here, we studied internalization of CRCoV into HRT-18G cells. The results clearly demonstrated that CRCoV entry into HRT-18G cells requires endocytic internalization prior to membrane fusion, a process that requires caveolin-1 and dynamin. Furthermore, fusion of the viral and cellular membranes occurs before the endosome progresses to the late phase.
Between April 2013 and April 2016, a total of 316 infants hospitalized with AB were included in this prospective study. The mean age was 7 ± 6.5 months; 201 (63.6%) were male (Table 1). The most frequent age range of infants with AB was 1 to 6 months, accounting for 63.6% of all included cases. Most of the patients had cough and runny nose on admission to hospital. Nearly half of the infants diagnosed with AB were exposed to passive smoking. There was a history of atopy in 12% of all the infants.
Table 2 shows the clinical data and laboratory findings, disease severity scores, hospitalization rates, and duration of hospitalizations of the infants. The most common complaint of the patients was cough (100%), and fever was present only in 88 (27.8%) of all the cases on admission to hospital. On examination, the percentage of infants with wheezing was 58. Ninety-six (30.4%) infants needed oxygen supplementation, and the mean length of hospitalization duration was 7.5 days. More than half of the infants had moderate bronchiolitis and the mean respiratory score was 5.3.
All aspects of the study were performed in accordance with the national ethics regulations and approved by the Ethics Committee of the Children’s Hospital of Fudan University (Jun Shen; CHFU2013016) as well as the Ethics Committee of National Institute for Viral Disease Control and Prevention (RL; IVDC2013022). Participants were received “Written Informed Consent” on the study’s purpose and of their right to keep information confidential. Written consent was obtained from all participants or their guardians.
Acute HEV infections in immunocompetent individuals usually culminate in spontaneous clearance of the virus after a certain time period. However, in severe cases leading to decreased liver functioning, administration of ribavirin was found to help in prompt clearance of the virus and inhibition of further liver damage.38 It remains unclear if ribavirin intake can arrest the progress towards complete liver failure (fulminant hepatitis). Till date, liver transplantation from appropriate donors remains the only choice for such patients.39 For treatment of transplantation patients suffering from chronic infection with HEV, the following course of action is usually undertaken post-transplantation. The first step involves the reduction of immunosuppression, which has been shown to have a 25% clearance rate.40 If this is unsuccessful, the next step usually involves monotherapy with ribavirin for an initial period of 90 days.39,41,42 Administration of Peg-IFN-α is also an option; however, due to its many side-effects and complications in solid organ transplantation recipient patients, it is not preferred.39 HEV infection in pregnant women is associated with significant complications like stillbirths, abortions, premature distribution and maternal or fetal death.43 Interestingly, significant differences exist in the severity of complications caused by HEV infection in diverse endemic populations. For instance, while the infection typically has severe outcomes in pregnant women from northern India, it follows a fairly benign course in populations from Egypt and western countries.44,45 Studies suggest that poor prenatal care and nutrition may constitute major contributory factors for such severe outcomes in selected populations.46 Efforts are ongoing to develop an effective vaccine against HEV, and currently a promising candidate (trade name: Hecolin) is in Phase IV of clinical trials (clinicaltrials.gov database).
This retrospective descriptive study took place at the paediatric wards of Hamad General Hospital (HGH), a 603- bed, tertiary-care facility in Doha, for two consecutive years, 2010 and 2011. The institutional review board at Hamad Medical Corporation approved the study, IRB number 12054.
The study population included children aged between 2 weeks- 2 years admitted to the paediatric ward at HGH with a diagnosis of acute bronchiolitis defined according to International Classification of Disease (ICD) code 466.1 in the 9th revision of the ICD. Based on recorded clinical diagnosis, an episode of acute bronchiolitis was determined by a constellation of clinical signs and symptoms including fever, rhinitis, tachypnoea, cough, wheezing, crackles, use of accessory muscles and possible chest X ray findings of hyperinflation of the lungs, peri-bronchial thickening, collapsed segment or a lobe of the lung and increase interstitial markings. Due to the potential for an atypical natural history of bronchiolitis, children with the following diagnoses were excluded: born prematurely, defined as <37 weeks of gestation, those with low birth weight, defined as birth weight <2.5 kg, with underlying chronic lung disease or neurological disease or congenital heart disease, and those immunocompromised or with hospital-acquired bronchiolitis.
Streptococcosis is regarded as a leading infectious disease in the swine industry, that clinically features with meningitis, septicemia, or arthritis and annually results in significant economic loss worldwide.1
Streptococcus suis (S. suis) that was initially reported in 19542 has been demonstrated as an etiological agent for this kind of frequently-occurring bacterial infection.1,3 Indeed, S. suis, a complex population consisting of heterogeneous strains,4 can be classified into 35 serotypes (1–34, 1/2) based on the differentiation of capsule antigens.1,3 Based on the varied virulence of these bacteria, they may be categorized into highly-pathogenic, weakly-pathogenic (hypo-virulent), and nonpathogenic (avirulent) strains.1 Generally, serotype 2 of S. suis (SS2) is considered to be the most virulent, and is frequently isolated from clinically-diseased piglets.1 In fact, serotype 9 of S. suis is also one of the most important serotypes in several countries. Of particular note, SS2 seems to be a previously neglected but recently emerging human pathogen,5 whose infection has become increasingly potent, especially in the southeast Asian countries like Thailand,6 Vietnam,7 and China.8,9
As the primary agent of meningitis, septicemia, arthritis and as an opportunistic pathogen in the case of pneumonia,1,5
S. suis have been reported to have spread over 30 countries and/or regions (Fig. 1) and has claimed no less than 1600 human cases, some of which were fatal.2 Also, similar clinical symptoms including bacterial meningitis, septicemia, and arthritis are frequently observed in human SS2 infections.2,3 Occasionally, serotypes other than SS2, including SS1,10 SS4,10 SS5,11,12 SS14,13,14 SS16,15,16 and SS2411 can also be found to function as the causative agents responsible for sporadic cases of human S. suis infection.3 Of note, two big outbreaks of human SS2 endemics which occurred in China, in 1998 and 2005, respectively,9,17,18 have raised serious concerns in public health and have challenged the conventional opinion that human SS2 infections are only present in sporadic cases.2,8,19 Unfortunately, no specific/effective human therapeutics or vaccine against SS2 infections is available thus far. Considering the severity (high mortality and modality) of SS2 infection in humans,5,8 it is important to develop a method for convenient and quick diagnosis, which can be applied toward local SS2 detection.4,18
Over the past four decades, significant progress has been made toward better understanding the highly infectious clones of S. suis. At the time of formulating this review, 1104 articles were available in PubMed regarding S. suis (http://www.ncbi.nlm.nih.gov/pubmed/?term=Streptococcus+suis).Totally, over 20 bacterial virulence-associated factors have been identified that include capsular polysaccharides (CPS),20 Muramidase-released protein (MRP),21 and Suilysin (SLY).22 To date, genomic sequences of a collection of S. suis strains are available (Fig. 2), the majority of which are derived from SS2 species,23,24 except two newly-released genomes which correspond to SS325 and SS14,26 respectively. Genomic mining combined with bacterial genetics have elucidated that Chinese epidemic strains of highly pathogenic S. suis 2 carry a specific 89K PAI (pathogenicity island).23,27 Further studies suggested that 89K PAI with a transposon-like essence can undergo GI-type T4SS-mediated horizontal transfer in epidemic SS2 species.28 The systematic elucidation of the of S. suis pathogenesis in the Omics Era was illustrated by functional definition of a collection of other new genes or putative orthologs (such as Zur, a zinc uptake regulator,29 CovR, an orphan response regulator,30 and Rgg-like transcription factor31) following the release of the genome sequence of SS2 (e.g., 05ZYH33).23 Although we have gained a partial glimpse of the molecular mechanism underlying the high pathogenicity of SS2 itself, we are still lacking further insights into the interface between the SS2 pathogen and the host it infects.3,8
In this review, we aim to describe an updated but partial picture of SS2 as an emerging infectious agent, which centers on five aspects: global epidemiology/distribution, clinical diagnostics/typing, pathogenesis, protective antigen/candidate vaccine, and zoonotic potential.
We compared individuals with a demonstrated single viral infection in the absence of bacterial infection with those with no viral infection detected by logistic regression models, searching for an association between viral infections and clinical symptoms. As shown in Table3, HRV infections were significantly associated with wheezing (P = 0·00 003; OR: 3·58 [95% CI: 1·9–6·7]), supraesternal retraction (P = 0·019; OR: 1·97 [95% CI: 1·11–3·49]), xiphoid retraction (P = 0·029; OR: 2·87 [95% CI: 1·14–7·2]), and with the absence of fever (P = 0·0001; OR: 0·36 [95% CI: 0·21–0·61]) and crackles (P = 0·036; OR: 0·57 [95% CI: 0·34–0·97]). Other viruses such as RSV were mostly related with the presence of crackles (P = 0·009; OR: 2·27 [95% CI: 1·21–4·25]), hyporexia (P = 0·036; OR: 2·02 [95% CI: 1·04–3·93]), and diarrhea (P = 0·002; OR: 4·63 [95% CI: 1·8–11·7]), while influenza A infection presented more malaise (P = 0·003; OR: 3·22 [95% CI: 1·45–7·15]) and postnasal drip (P = 0·008; OR: 3·38 [95% CI: 1·4–8·07]; Table3).
As shown in Table3, wheezing disorders and asthma were common in those with HRV infection (P = 0·000 003; OR: 3·65 [95% CI: 2·09–6·36]) and less likely in those with RSV (P = 0·005; OR: 0·40 [95% CI: 0·21–0·77]) and HMPV infection (P = 0·018; OR: 0·19 [95% CI: 0·04–0·87]), whereas pneumonia was likely in RSV infection (P = 0·003; OR: 2·64 [95% CI: 1·38–5·05]) and more uncommon in HRV infection (P = 0·000 009; OR: 0·29 [95% CI: 0·17–0·51]).
The 115 samples positive to HRV infection were typified, and 49·4% of the samples were classified as HRV-C. To determine the influence of comorbidities and other factors such as age, bacterial, and viral coinfections, multivariate logistic regression was realized. Remarkably, the relationship between HRV-C and asthma is maintained (P = 0·02; OR=2·53 [95% CI: 1·14–5·59]). The rest of types and subtypes of respiratory viruses and comorbidities such as gastroesophageal reflux were not associated with asthma either in the univariate analysis or in the adjusted analysis (data not shown).
Individuals with HMPV infection had prolonged hospital stays in days [7 (5–16·5); P = 0·015], and those with HRV infection had the shortest hospital stays [5 (4–6); P = 0·006].
Due to the mostly asymptomatic nature of acute HCV infection, treatment options are limited. However, studies have reported that interferon-based treatment at an early stage might be helpful.34 Individuals exhibiting HCV RNA and antibodies at detectable levels in their blood after more than 6 months post-infection are considered to be cases of chronic HCV infection. A combination therapy of ribavirin and Peg-IFN-α (pegylated interferon α), for a duration of either six months or one year, was the accepted treatment regimen for chronic cases of HCV infection up until 2011.35 However, achievement of a sustained virological response (SVR), which is the key to cure, was observed to vary between genotypes and populations.36 Western European patients infected with HCV genotype 1 reportedly achieve a higher SVR (50%) than the North American patient population (40%). The SVR achieved with this treatment in case of patients infected with genotypes 2, 3, 5 and 6 was observed to be higher in general compared to genotype 1-infected patients (SVR of up to 80%). In particular, genotype 2 was the found to be most susceptible (SVR > 80%).36 Direct-acting antivirals (DAAs) such as telaprevir and boceprevir (first-wave, first generation), which target the HCV NS3-4A serine protease, were introduced in 2011 for treating infections caused by HCV genotype 1.37 Phase III clinical trials on treatment-naïve patients found that administration of telaprevir and boceprevir in conjunction with ribavirin and Peg-IFN-α (triple-combination) was effective in achieving a SVR in the range between 65% and 75%.37 However, this treatment regimen comes with its own set of disadvantages, including significant side-effects and not being cost-effective in the case of patients with advanced fibrosis.37 Since 2011, the following DAAs have been approved which can be used either independently or in combination with Peg-IFN-α and/or ribavirin. These DAAs are (a) sofosbuvir (nucleotide analogue), (b) simeprevir (NS3-4A protease inhibitor), (c) daclatasvir (NS3-4A protease inhibitor), (d) paritaprevir (NS3-4A protease inhibitor), (e) ombitasvir (NS5A inhibitor), (f) asunaprevir (NS3-4A protease inhibitor), (g) grazoprevir (NS3-4A protease inhibitor) and (h) elbasvir (NS5A replication complex inhibitor).35 The rate of SVR achieved depends on the combination used, the genotype, the presence of resistant strains and the disease severity. Finally, attempts to create an effective vaccine against HCV have not been successful till date due to the extreme sequence variation of the virus genome.