Pediatric Viral Respiratory Infections in Saudi Arabia: Narrative and Descriptive Revisits for the Etiology, Epidemiology and Cl

June 2020 KUWAIT MEDICAL JOURNAL 118

Review Article Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology, epidemiology and clinical phenotypes with diagnostic challenges highlights

Ayed A Shati1, Abdelwahid S Ali2, Ahmed M Al-Hakami2, Ali A Asseri1, Saleh M Al-Qahatani1 1Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia 2Department of Microbiology and Clinical Parasitology, College of Medicine, King Khalid University, Abha, Saudi Arabia

Kuwait Medical Journal 2020; 52 (2): 118 - 128

ABSTRACT

Objective: To review, describe and narrate the etiology, Up to 2019, 35 studies were published in the topic. The epidemiology and clinical phenotypes of pediatric viral highest number of reports was for respiratory syncytial respiratory infections (PVRIs) in Saudi Arabia (KSA) viruses (n=17, 48.6%), while bocaviruses are the least Design: A comprehensive electronic search of the reported viruses (n=3, 8.6%). Clinical presentations literature for PVRIs in KSA reported suggested both upper and lower respiratory Setting:An electronic search in PubMed, SCOPUS, Google tract infections. PVRIs were reported from Riyadh, Al- Scholar and MEDLINE Qassim, Jazan, Jeddah, Dammam, Najran, Taif and Subjects: Articles published up till 2019 and those that Abha. Immunofluorescence assays, enzyme-linked dealt with the detection of viruses from clinical specimens immunosorbent assay, polymerase chain reaction and Interventions: Retrieved articles were subtly studied. Data virus isolation were employed. obtained included the virus reported, year of publication, Conclusion(s): In this review communication, we diagnostics, region or city, research purpose, the season of described the etiology, epidemiology and clinical infection and hospital of admission (if any). phenotypes of PVRIs in KSA reported from 1988 through Main outcome measure(s): The etiology, epidemiological 2019. We also showed some challenges associated with features and clinical phenotypes associated with the PVRIs the diagnostic protocols employed. Directions for future in each study were recorded and analyzed. research in this topic, particularly towards diagnostics and Result(s): The first report for PVRIs in KSA was in 1988. preventive medicine, were also recommended.

KEY WORDS: children, Middle East, respiratory infections, Saudi Arabia, viruses

INTRODUCTION infections resulted in far higher mortality rates in It is well-established that respiratory tract children as compared to those in resource- rich infections are major causes of morbidities and countries. Inadequate data about the public health mortalities among children worldwide[1]. A recent impacts and economic losses of these infections in World Health Organization (WHO) report revealed developed countries are available[6-8]. These data that 18% of deaths among children under five years are always critically essential for the design and are attributable to pneumonia[2,3]. Among the different development of efficient protective measures and causes of respiratory infections, viruses were known treatment protocols. The viruses which are known to be to constitute the major etiological factor responsible responsible for ARIs in infants and children included for acute respiratory infections (ARIs) in pediatrics influenza viruses, human respiratory syncytial virus globally[4,5]. In poor and developing countries, these (HRSV), human metapneumovirus (HMPV), human

Address correspondence to: Dr. Ayed Abdullah Shati, Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia. Tel: +966555752063; Mob: +966172417750; E-mail: [email protected] 119 Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology... June 2020 coronaviruses (HCoVs), human parainfluenza viruses from children suffering from ALRTIs. It has been (HPIV), human adenoviruses (HAdVs), and human suggested that the epidemiological parameters of bocaviruses (HBoVs). the infections including incidences, prevalences, Although the burden and public health implications morbidities and mortalities due to HAdVs are highly of influenza infections are yet to be known in many parts virus type dependent[30]. HPIVs were also recognized of the world, particularly in resource-poor countries, it to be associated with URT and LRT illnesses in has been shown that influenza is characterized by high children with their pathology, symptomatology and incidence rates and hospitalizations in the tropics and epidemiology dependent on the virus serotype, age and subtropics[8]. The global incidences and mortalities due season[31]. Among the four genotypes of HBoVs known to influenza in children less than five years was also so far, HBoV-1 is the predominant genotype known to estimated and noted to be significantly high in terms infect the respiratory tract of children[32,33]. Throughout of number of deaths, particularly in the developing the years, human rhinoviruses (HRVs), were known as countries[8-10]. In many epidemiological studies, a significant cause of the “common cold” in children HMPV were recognized as potential etiologic agents and adults worldwide, with considerable economic for acute lower respiratory tract infections (ALRTIs), burdens incurred due to medical visits, schooling and namely bronchopneumonia and bronchiolitis, in work absenteeism[34]. Other viruses causing respiratory children[11-16]. Although the life-threatening effects of infections in children and reported at various points of HMPV infections in children were known in some time include Nipah and Hindra viruses[35]. cases, the fatalities were usually seen associated with Taken all together, viral respiratory infections are other underlying chronic conditions such as chronic considered as major health concerns in pediatric practice lung disease of prematurity, asthma[17], cancer[18] in many parts of the world, particularly in developing and immunosuppression[19,20]. Following intensive and resource-poor countries. As diagnostic testing is literature revisits and personal communications, there improved, more respiratory viruses are expected to be were no obvious distinctions in the epidemiological explored. This review intended to focus on the clinical and clinical patterns between HRSV and HMPV phenotypes and epidemiological pictures of pediatric infections in pediatric patients. Both viruses cause viral respiratory infections (PVRIs) in Saudi Arabia severe and ALRTIs in infants and children, and both (KSA) concerning the previously published reports in represent primary reasons for emergency department that respect. We would also like to cast some light on visits and hospitalization[18,20]. However, HMPV the diagnostic and medical intervention challenges. infections were observed to occur in relatively older children, as compared to HRSV[17]. HCoVs were also METHODS noted, causing numerous seasonal clinical respiratory Search methodology infections in children since ancient times[21]. The In this study, we performed a comprehensive epidemiological patterns of these HCoVs-associated electronic search of the literature for PVRIs in KSA diseases were observed undergoing regular changes in PubMed, SCOPUS, Google Scholar and MEDLINE every time and the respiratory infections attributable databases. The keywords used in the search include to HCoVs were observed not only confined to upper Saudi Arabia, respiratory, children, infants and respiratory tract infections (URTIs), but they are also viruses (the word “virus” was used at times and the seen to cause pneumonia in infants and children[22]. virus name was specified at other times). The search Several reports describing the role of HCoVs in considered articles from ancient times up to 2019. The the lower respiratory tract infections (LRTIs) with retrieved articles were carefully read to help in further their clinical presentations and complications in the search for additional articles. The only considered pediatrics were also published[23-25]. HCoV-severe and documented studies are those that dealt with acute respiratory syndrome (HCoV-SARS) has the detection and/or isolation of viruses from clinical emerged as the first HCoV identified responsible for specimens of the patients and published in peer- severe, acute and fatal respiratory infection in children reviewed journals. in many parts of the world[26,27]. Recently, HCoV- Middle East Respiratory Syndrome (HCoV-MERS) Data retrieval and analysis has also emerged from KSA and proven as a potential The clinical and epidemiological features associated etiologic agent for severe URTIs and LRTIs in children with PVRIs in each study were recorded and analyzed. and young adults[28]. Although HAdVs were primarily The elements recorded included the author(s) who recognized to cause mild URT and LRT infections in conducted the research, year of publication, the virus young children, severe infections of HAdVs during reported to cause the infection, diagnostic technique epidemics were also noted in immunocompromised employed, region or city of the study, the research patients[29]. Several serotypes of HAdVs were isolated purpose, the season of the infection and the hospital June 2020 KUWAIT MEDICAL JOURNAL 120

Table 1: The reports of different respiratory viruses in Saudi Arabia among pediatric patients from 1988 - 2019

No. of reports Virus Regions of reports Years of reports References Single (%)a Combined (%)b Total (%)c Influenza 2 (28.6) 5 (71.4) 7 (20.0) Riyadh, Jeddah, Madinah, 1988, 1998, 2005, 2010, 2014, 37*- 43 (A & B) Dammam, Najran, Jazan 2017, 2018 HRSV 9 (52.9) 8 (47.1) 17 (48.6) Riyadh, Jazan, Najran, Al- 1988, 1993, 1996, 1998, 2005, 37, 38, 41, 42, Qasim, Abha 2006, 2009, 2014, 2015, 2016, 45- 57 2017, 2018 HMPV 2 (33.3) 4 (66.7) 6 (17.1) Riyadh, Najran, Abha, 2011, 2014, 2016, 2017, 2018, 2019 41, 50, 60- 62 HCoVs 6 (60.0) 4 (40.0) 10 (28.6) Riyadh, Najran, Jazan, 2011, 2012, 2014, 2015, 2016, 28, 41, 42, 50, 60, Jeddah, Dammam 2017, 2019 64- 70 HAdVs 0 (0.0) 8 (100) 8 (22.9) Riyadh, Abha, Al-Qasim, 1988, 1998, 2005, 2014, 2017 37- 39, 41, 47, Najran 51, 53, 73 HPIVs 2 (20.0) 8 (80.0) 10 (28.6) Riyadh, Al-Qasim, Najran 1988, 1998, 2005, 2012, 2013, 37- 39, 41, 47, 2014, 2016 50, 53, 75- 77 HRVs 0 (0.0) 4 (100) 4 (11.4) Najran, Riyadh, Jazan 2014, 2017 41, 42, 51, 73 HBoVs 2 (66.7) 1 (33.3) 3 (08.6) Taif, Najran, Dammam 2013, 2014, 2015 41, 80, 81

HRSV: Human respiratory virus; HMPV: Human metapneumovirus; HCoVs: Human coronaviruses; HAdVs: Human adenoviruses; HPIVs: Human parainfluenza viruses; HRVs: Human rhinoviruses; HBoVs: Human bocaviruses The presented data are expressed as numbers and percentages (%). aSingle report means the study reported only one single virus type; combined report means the study reported more than one virus type. bThe percentages of single and combined reports were calculated from the total number of reports for each virus individually. cThe percentages of the total reports of each virus were calculated from the total number reports for all viruses noticed in this review (35 reports). * The reference number as given in the reference list. of patient admission (if any). A narrative description In another study, a significant percentage of infants of the situations was then generated in this manuscript and children attending the emergency or pediatric using this data. clinics of King Faisal Specialist Hospital (KFSH) in Riyadh also reported positive to influenza viruses in LITERATURE REVIEW 1998[38]. IAV and IBV were also detected in 2005 in the Epidemiology and clinical phenotypes of PVRIs nasopharyngeal secretions of young children admitted The previous reports for the detection of different with acute LRTIs to Buraidah Maternity and Pediatric respiratory viruses among pediatric patients in KSA Hospital (BMPH) in Al-Qasim (central province of from 1988 - 2019 are demonstrated in Table 1. The KSA)[39]. total number of reports of respiratory viruses in Additionally, during the swine flu global pandemic children in different cities of KSA is determined (Fig. in 2009, AlMazroa and co-workers published a 1). The geographical distribution of these infections in comprehensive report showing a significant number the different cities and regions of the country is also of cases affected with swine flu virus (A-H1N1) among retrieved from the data obtained (Fig. 2). Detailed children aged 1 - 10 years in different regions and descriptions for the etiology, epidemiology and clinical localities of KSA. These children included both Saudi features of the PVRIs in infants and children in KSA, as nationals and imported cases, and concluded that retrieved from the previously published research, are influenza A-H1N1 constitute a considerable threat made in the following presentations: to KSA people at the time of the study[40]. In another epidemiological study, six cases of IAV and one case Influenza of IBV were also diagnosed using multiplex RT-PCR Influenza is a highly contagious disease caused among children at Najran Maternity and Children by influenza viruses type A, B and C (IAV, IBV and Hospital (NMCH) in Najran (southern region of ICV). These viruses are characterized by segmented KSA), without adequate description to the clinical RNA genomes and antigenic diversities. They were and epidemiological patterns of these infections being classified with the family Orthomyxoviridae. IAV reported[41]. In a comprehensive surveillance study in causes pandemics and epidemics worldwide; those Jazan (southwestern region of KSA), IAV and IBV were belonging to group B cause epidemics and outbreaks; also detected among pediatric patients without the while those belonging to group C cause sporadic and determination of virus subtypes[42]. In a more recent mild respiratory infections[36]. In KSA, the first report study, the influenza virus A-H1N1 was isolated from for influenza was made in 1988, when a cross-sectional children suspected with HCoV-MERS and presented epidemiological study was carried out to determine the to John Hopkins Aramco Healthcare facilities in viral etiology of tonsillitis among children in Riyadh[37]. Dammam (the eastern region of KSA)[43]. In this study, 121 Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology... June 2020

Fig 1: Report rates of pediatric respiratory viruses in different cities of KSA Riyadh (central province); Dammam (eastern province); Al- Qasim (northern province); Abha (Asir region, southern province); Jeddah (western province); Najran (Najran region, southern province); Jazan (southwestern region); Taif (western province) Rates were calculated as percentages from number of reports in each region out of the total number of reports in the kingdom (35 reports)

Fig 2: Geographic distribution of viral respiratory infections in children and infants in Saudi Arabia through 1988-2019 HRSV: human respiratory virus; HMPV: human metapneumovirus; HCoVs: human coronaviruses; HAdVs: human adenoviruses; HPIVs: human parainfluenza viruses; HRVs: human rhinoviruses; HBoVs: human bocaviruses June 2020 KUWAIT MEDICAL JOURNAL 122 the authors declared higher incidence among patients Conclusively, the different studies concerning the came from Ras Tanura city (far eastern region of KSA; treatment of children against HRSV using different Fig. 2). types of medicines and regimens in KSA were recently In total, a considerable number of reports about reviewed by Alharbi and co-researchers in 2018[57]. influenza infections among pediatric patients in KSA was noted in the literature. The majority of the Human metapneumovirus (HMPV) available data were those published during the global HMPV was first recognized and described in “avian flu” pandemic in 2005 - 2006 and the global Netherlands in 2001 by van den Hoogen and others[58]. “swine flu” pandemic in 2009 - 2010. Despite all these It is a negative sense, single-stranded RNA enveloped reports, we believe that adequate data pertaining to virus and classified as a member of theParamyxoviridae the virology, clinical phenotypes and epidemiological family, pneumovirinae subfamily and pneumovirus aspects of influenza viruses in KSA, among adult genus[59]. In KSA, HMPV was first detected in 2011 populations in general and children in specific, are among Saudi children hospitalized with ARI in still lacking. Riyadh[60]. Afterward, the virus was also detected among children who presented with ARTIs to NMCH Human respiratory syncytial virus (HRSV) in Najran, with brief explanations of the clinical and HRSV was confirmed in many studies and surveys epidemiological correlates of the infections[41]. The as the leading cause of respiratory tract infections in authors identified the virus in infants in both single infants and young children throughout the world. viral infections and viral co-infections. HMPV was also HRSV is a non-segmented, negative-sense, single- isolated during an investigation in a cohort of children stranded RNA enveloped virus belonging to the suffering severe LRTIs and hospitalized at a tertiary family Pneumoviridae and the genus pneumovirus[44]. As referral center in Riyadh in 2016[50]. The epidemiology compared to influenza, more studies were conducted and some genetic properties of that isolated virus to detect HRSV from children in different cities and were also studied[61]. That is considered the first report regions of KSA, namely Riyadh[37,38,45-51], Najran[41], addressing the HMPV genotypes circulation in the Jazan[42], Al-Qasim[52] and Abha[53]. In all of these KSA. HMPV was also detected in a retrospective study studies, no detailed clinical presentations or specific performed to determine the viral etiological agents epidemiological patterns for HRSV infections were causing RTIs among pediatric patients admitted to the described; however, bronchopneumonia (BP) and Department of Pediatrics, King Abdul-Aziz Medical bronchiolitis were reported as the leading cause of City (KAMC) in Riyadh[51]. morbidities and hospitalization. It was also revealed In a recent publication, we reported the incidence that the infections of HRSV peak in winters and autumn of HMPV in the Aseer region (southern provinces seasons. Deaths attributable to these infections among of KSA) among children who attended the pediatric infants were also recorded, though dearth. The genetic emergency rooms and were hospitalized in Aseer analysis of HRSV group B (HRSV-B) strains circulating Central Hospital with acute bronchiolitis and BP[62]. in KSA was also studied in 2014 by Almajhdi and co- In that study, we reported for the first time the large researchers[54]. This study helped to cast some light on population of virus-infected children in the area, the circulation pattern and molecular characteristics particularly in Abha city and the vicinity. In the of HRSV- B strain in the KSA. previously published articles, reverse transcriptase Medical intervention of HRSV infectivity among PCR (RT-PCR) and direct fluorescent antibody children in KSA remains the most crucial concern to (DFA) test were employed for the detection of the health practitioners and the public. Special attention virus nucleic acid and antigens respectively, in the was particularly directed towards hospitalized RSV- nasopharyngeal secretions from infected children. infected premature infants and children suffering Apart from the previously mentioned reports of from chronic lung disease or congenital heart disease. HMPV infections, the virus was not detected in any Palivizumab (Synagis, Medimmune) is a humanized other region or city of the Kingdom. The role of HMPV monoclonal antibody, which is a combination of in respiratory infections in pediatric medicine in the human (95%) and murine (5%) antibody sequences. In western, eastern and northern regions of KSA was KSA, Palivizumb was used for the prevention of severe not determined yet. The risk factors associated with RSV infections in high-risk groups of children[55,56]. It the severity of HMPV in children in the KSA were not was well-documented that Palivizumb is an effective precisely known up to date. In conclusion, meager agent for the prevention of RSV mortalities and studies regarding the virus distribution, prevalence, fatalities. However, the notable possible drawbacks clinical presentations and medical interventions of associated with this medication include the expense HMPV in KSA were made so far, and much research and extensiveness of use without rationality. work is worthy in these aspects. 123 Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology... June 2020

Human coronaviruses (HCoVs) symptoms, mean age of infection and source of infection Human coronaviruses (HCoVs) are a well-known among pediatric patients were described to an optimal cause for URT and LRT infections in all age groups. level. The various scientific elements of HCoV-MERS They are positive-sense, single-stranded RNA viruses infectivity for children were also recently reviewed by classified in the family Coronaviridae[63]. Before HCoV- Al-Sehaibany in 2017, when he concluded that MERS SARS and HCoV-MERS, which cause severe and is a disease of adults, where few cases among children acute respiratory infections, four other HCoVs were were known with different clinical manifestations recognized to be responsible for mild respiratory and lower mortality rates as compared to infection in infections in adults and children namely HCoV-229E, adults[68]. Conclusively, despite the intensive studies HCoV-OC43, HCoV-NL63 and HCoV-HKU1. The first for detection of HCoV-MERS among adults in KSA and report for HCoVs infections among children in KSA surrounding countries, a limited number of cases were was made by Al-Hajjar and co-workers in 2011[60]. In reported for this virus in children. However, in recent this study, HCoV-NL63 was isolated from children less publications, it had been reported that the proportion than 16 years old hospitalized with ART illness during of asymptomatic cases among pediatric confirmed autumn and winter at KFSH in Riyadh. HCoV-NL63 HCoV-MERS cases was significantly high[69,70]. and HCoV-OC43 were also detected among children presented with acute LRT infections and showing Human adenoviruses (HAdVs) symptoms of bronchiolitis and pneumonia in Najran Human adenoviruses (HAdVs) were known to have region of KSA in 2014[41]. In another cross-sectional a significant contribution in PVRIs. HAdVs infections study carried out to determine the prevalence of viruses were observed as mild and indistinguishable from causing ARTIs among hospitalized children in Riyadh other viral respiratory infections in children on their area, a considerable number of them were diagnosed pathology and clinical grounds[71]. However, acute with HCoVs[50]. The HCoVs serotypes detected in this and severe URT and LRT infections attributable to study were not specified and were most prevalent in HAdVs were also noted among pediatric patients[71,72]. infants less than six months old. Non-MERS HCoVs Since 1988 up to date, only nine studies discussing were also detected in nasopharyngeal swabs collected the incidences and other clinical and epidemiological from asymptomatic outpatients less than 15 years old parameters of adenoviral infections in children in in Jazan province[42]. Despite the wide spread of HCoV- KSA were made. In a serological and virological SARS during the global disease pandemic in 2003, no investigation by Hossain et al in 1988, the first report for single report about the virus infectivity in children in HAdVs infections in children in KSA was made. They KSA was made. As the HCoV-MERS originated from showed that HAdVs were the leading cause of tonsillitis Jeddah (western region of KSA) in 2012[28], plenty among Saudi children during the study period[37]. of reports, thereafter, describing the virological, About ten years later, adenovirus infections were also epidemiological and clinical characteristics of the reported in children who attended the emergency virus were made in KSA at large. Primarily, a single of pediatric wards at KFSH and Research Center in pediatric case (out of 47 sampled patients), laboratory Riyadh[38]. In the same year, HAdVs infections were confirmed positive to HCoV-MERS was identified also detected among Saudi children under five years by Assiri and co-workers throughout KSA as a first who presented to King Khalid University Hospital report, in 2013[64]. Consequently, HCoV-MERS was also (KKUH) in Riyadh with complaints of ARTIs[47]. In reported among eleven pediatric patients in Riyadh in another prospective study, adenoviruses were also 2014[65]. In this report, the clinical presentations and detected in the nasopharyngeal aspirates of children outcomes of the patients were adequately described; hospitalized due to severe bronchiolitis in Abha city[53]. nine cases were asymptomatic, whereas two cases In that study, the clinical features and risk factors of were admitted to the ICUs suffering severe respiratory adenovirus-associated bronchiolitis were described infections, with one of whom died. A case report to an adequate level. They specified the risk factors describing a complicated HCoV-MERS infection in including prematurity, chronic lung diseases, atopic a 9-month-old child admitted to the pediatric ICU of dermatitis, pure formula feeding, passive smoking Prince Sultan Military Medical City in Riyadh, with and age. Also, Meqdam and coauthors reported the infantile nephrotic syndrome that resulted in death, role of HAdVs in the ALRTIs among infants and was also published by Thabet and his team in 2015[66]. young children admitted to BMPH in Al-Qassim[39]. In a comprehensive search in the literature made by Adenoviruses were also identified as a significant cause Al-Tawfiq and co-researchers in 2016; a conclusion was of respiratory infections in children less than five years drawn to indicate that low number of MERS pediatric in Najran city, and mainly observed to be associated cases were evident in KSA and the reasons for this with bronchiolitis and acute wheezing episodes[41]. In low prevalence was unknown[67]. In this report, the two recent epidemiological studies, the role of HAdVs June 2020 KUWAIT MEDICAL JOURNAL 124 in ARTIs among pediatric patients presenting to the stranded RNA genomes, and classified in the family King Fahad City[73] and KAMC[51] in Riyadh was also Picornaviridae and the genus enterovirus[78]. Although confirmed. HRVs were known since early days to cause respiratory infections among pediatric patients in many parts of Human parainfluenza viruses (HPIVs) the world, they have only recently been identified in HPIVs are genetically and antigenically grouped KSA. The first report for HRVs was made in 2014 when into four types namely HPIV-1, HPIV-2, HPIV-3 and recognized as one of the viral etiologies of respiratory HPIV-4. They are enveloped viruses with single- infections in children in Najran in 2014[41]. Later, three stranded, negative-sense RNA genomes and belong to reports were made for HRVs in 2017; two in Riyadh[51,73] the Paramyxoviridae family, paramyxovirinae subfamily and one in Jazan[42]. In all these studies, HRVs had and paramyxovirus genus[74]. HPIV-1, 2 and 3 were seen to constitute the primary cause of RTIs among first reported in KSA among Saudi children below 15 the tested children. Their epidemiological pattern and years of age, who were suffering from acute tonsillitis infectivity was noted to peak in winter, with serious in Riyadh[37]. HPIV-3 was particularly diagnosed clinical consequences in infants and young children. in children presented to KKUH[47], and KFSH and Dual infections with other viruses such as HRSV, Research Center[38] in Riyadh. HPIVs were also HCoVs, HAdVs, HMPV and influenza were more confirmed in another study among children suffering likely to occur, as retrieved from these studies. In acute LRTIs in Al-Qassim, without specification for the conclusion, a limited number of studies discussing the virus type and clinical description of the infection[39]. clinical and epidemiological elements of HPIVs were In Abha city, HPIV-1, HPIV-2 and HPIV-3 were also published in KSA. isolated from children less than two years of age, who were diagnosed with bronchiolitis[53]. The first Human bocaviruses (HBoVs) molecular epidemiological study in KSA was carried HBoV is a parvovirus first identified in 2005 out to screen HPVI-3 in nasopharyngeal secretions and known as a causative agent of respiratory tract collected from children hospitalized in Riyadh with infections[32]. Four HBoV subtypes were recognized acute respiratory diseases using nested RT-PCR[75]. In so far, namely HBoV-1, HBoV-2, HBoV-3 and HBoV- another similar study, HPIV-2 was also isolated from 4. HBoV-1 was isolated from infants with respiratory children in Riyadh[76]. Al-Ayed and co-workers also manifestations including cough, dyspnea, wheezing identified HPIV-1 and HPIV-3 in children less than five and suffering from rhinitis, pharyngitis, pneumonia years old with ARTIs in Najran[41]. Although HPIVs and otitis media. HBoVs are classified with the family were widely seen as infectious to URT, in a retrospective Parvoviridae, subfamily Parvovirinae, genus Bocavirus[79]. study performed at the Departments of Pediatrics, Following a systematic search in the literature, only Pathology and Microbiology of KKUH in Riyadh, a three reports for HBoV infections among pediatric small portion of children less than one-year-old were patients in KSA were noticed. The first report for HBoV observed as suffering bronchiolitis and pneumonia in KSA was made by Abdel-Moneim and co-workers due to HPIV-1, 2 and 3 infections[77]. In another in 2013 in Taif city (western region of KSA) when epidemiological investigation among hospitalized they detected the virus in 22% of the tested children children at a tertiary referral center in Riyadh, HPIVs with respiratory distress[80]. In that study, the authors were also detected in the nasopharyngeal aspirates confirmed that the circulating HBoV genotype among using monoplex RT-PCR[50]. In that study, HPIVs were the tested patient was HBoV-1. They also showed that seen mostly prevalent in infants less than six months co-infection with other viruses was seen in the majority during winter. of samples. The second report was from Najran in In conclusion, HPIV-1 and HPIV-3 were the most 2014[41], while the third report for HBoV in KSA was commonly observed viruses causing RTIs among made by Bubshait and his group in 2015 among children in KSA. There were many factors reported children admitted to King Fahad University Hospital to predispose the children to these infections, such as in Dammam. They reported five positive cases for overcrowding, non-breast feeding and environmental HBoV, with their clinical presentations varying from smoke. Symptoms associated with HPIVs have also mild to severe disease[81]. been correlated with the age of the child and virus type. Diagnostic challenges The PVRIs in KSA have been reported for Human rhinoviruses (HRVs) thirty years. Several methods and techniques were HRVs were first identified in the 1950s and known employed for the diagnosis of these infections. as the most predominant cause of URTIs. HRVs are Viral antigen detection using DFA, ELISA and virus non-enveloped viruses, with positive-sense, single- propagation in cell cultures were the commonly 125 Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology... June 2020 performed methodologies[37,38,53,77]. However, in the previously published work in the topic, the epidemiological studies for investigations of viral following elements should have special emphasis in etiologies of respiratory tract infections later relied future research attempts: mainly on the PCR and RT-PCR for detection of · Detailed description of the epidemiological DNA and RNA viruses, respectively[41,42,50,81]. These patterns of these viruses among different molecular methods were seen to significantly increase populations of children should be documented. the viral detection sensitivities and specificities. · Nationwide surveillance studies to reveal A great debate for the reliability of these tests was the exact prevalence of these viruses among raised, since positive reactions for asymptomatic newborns, infants and children in the country are patients were observed. The debate was also raised recommended. due to positive reactions observed for bronchiolitis · The exact morbidities and long-term consequences cases associated with viruses which were well known of the early life infection with these viruses, to cause URTIs[51]. especially among the high-risk groups (e.g., One of the great difficulties and challenges children with chronic lung disease and high risk associated with the diagnostic concerns in the of pulmonary asthma) should be determined. different regions of KSA was convincing the children, their parents, or representatives with sampling ACKNOWLEDGMENT (pharyngeal swabs and aspirates, blood), particularly Conflict of interest: The authors declare no conflict for research purposes. Another significant concern for of interest. health specialists and practitioners is the distribution of diagnostic logistics among the different regions and Funding: The research was funded by the deanship provinces of the kingdom. More focus and attention, of scientific research, King Khalid University, Abha, as per the diagnostic facilities, are directed towards the Saudi Arabia with project No. 190. central province of the kingdom (Riyadh area) with limited resources available at the peripheral regions. Authors Contribution That had been obvious and affected the screening AAS: literature search, data extraction and program during the HCoV-MERS epidemic in 2012 recording, manuscript writing and revision, tables & 2013, when samples for virus detection had to be and figures preparation. ASA: literature search, data sent to central laboratories in Riyadh. Challenges extraction and recording, manuscript writing and associated with the availability of diagnosticians revision. AMH: manuscript writing and revision. and laboratory technical staff were also raised on AAA: manuscript revision, editorial and language. many occasions, since the qualified personnel are not SMA: manuscript revision, editorial and language. available in all regions. REFERENCES CONCLUSIONS · A total number of 35 studies were retrieved 1. Tregoning JS, Schwarze J. Respiratory viral infections from the literature that reported the detection of in infants: causes, clinical symptoms, virology, and respiratory viruses in infants and children in KSA immunology. Clin Microbiol Rev 2010; 23(1):74-98. from 1988 until 2019. 2. Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood HRSVs are the most commonly reported virus · pneumonia. Bull World Health Organ 2008; 86(5):408- involved in respiratory infections among pediatric 416. patients in KSA, while HBoVs are the least 3. Black RE, Cousens S, Johnson HL, Lawn JE, Rudan reported viruses. I, Bassani DG, et al. Global, regional, and national · The highest number (68.6%) of reports for PVRIs causes of child mortality in 2008: a systematic was observed from Riyadh region (including analysis. Lancet 2010; 375(9730):1969-1987. Riyadh city). This is presumably attributable to 4. Tsolia MN, Psarras S, Bossios A, Audi H, Paldanius M, the fact that Riyadh, as the capital city of KSA, Gourgiotis D, et al. Etiology of community-acquired encompasses a high number of hospitals and pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin medical cities as compared to other regions. Infect Dis 2004; 39(5):681-686. Additionally, better diagnostic and research 5. Arnold JC, Singh KK, Spector SA, Sawyer facilities are available in the research centers and MH. Undiagnosed respiratory viruses in university laboratories in Riyadh. children. Pediatrics 2008; 121(3):e631-e637. 6. Williams BG, Gouws E, Boschi-Pinto C, Bryce J, Dye Directions for future research C. Estimates of world-wide distribution of child After careful analysis and subtle investigations deaths from acute respiratory infections. Lancet Infect Dis 2002; 2(1):25-32. June 2020 KUWAIT MEDICAL JOURNAL 126

7. Cashat-Cruz M, Morales-Aguirre JJ, Mendoza-Azpiri 22. Sizun J, Soupre D, Legrand MC, Giroux JD, Rubio S, M. Respiratory tract infections in children in developing Chastel C, et al. Pathogen role of coronavirus in pediatric countries. Semin Pediatr Infect Dis 2005; 16(2):84-92. intensive care: retrospective analysis of 19 positive 8. Nair H, Brooks WA, Katz M, Roca A, Berkley JA, Madhi samples with indirect immunofluorescence. Arch SA, et al. Global burden of respiratory infections due Pediatr 1994; 1(5):477-480. to seasonal influenza in young children: a systematic 23. Sizun J, Soupre D, Legrand MC, Giroux JD, Rubio review and meta-analysis. Lancet 2011; 378(9807):1917- S, Cauvin JM, et al. Neonatal nosocomial respiratory 1930. infection with coronavirus: a prospective study in 9. Viboud C, Alonso WJ, Simonsen L. Influenza in tropical a neonatal intensive care unit. Acta Paediatr 1995; regions. PLoS Med 2006; 3(4):e89. 84(6):617-620. 10. Brooks WA, Steinhoff M. Epidemiology of Influenza 24. Gagneur A, Sizun J, Vallet S, Legr MC, Picard B, in Tropical and Subtropical Low-Income Regions. In: Talbot PJ, et al. Coronavirus-related nosocomial viral Rappuoli R, Giudice GD, editors. Influenza Vaccines for respiratory infections in a neonatal and pediatric the Future. 2nd Ed. Basel, Switzerland: Springer; 2011. p intensive care unit: a prospective study. J Hosp 55-75. Infect 2002; 51(1):59-64. 11. Boivin G, Abed Y, Pelletier G, Ruel L, Moisan D, Cote 25. Prill MM, Iwane MK, Edwards KM, Williams JV, S, et al. Virological features and clinical manifestations Weinberg GA, Staat MA, et al. Human coronavirus associated with human metapneumovirus: a new in young children hospitalized for acute respiratory paramyxovirus responsible for acute respiratory-tract illness and asymptomatic controls. Pediatr Infect Dis J infections in all age groups. J Infect Dis 2002; 186(9):1330- 2012; 31(3):235-240. 1334. 26. Drosten C, Gunther S, Preiser W, van der Werf S, 12. Bastien N, Ward D, Van Caeseele P, Brandt K, Lee SHS, Brodt HR, Becker S, et al. Identification of a novel McNabb G, et al. Human metapneumovirus infection coronavirus in patients with severe acute respiratory in the Canadian population. J Clin Microbiol 2003; syndrome. N Engl J Med 2003; 348(20):1967-1976. 41(10):4642-4646. 27. Van der Hoek L, Pyrc K, Jebbink MF, Vermeulen-Oost 13. Williams JV, Harris PA, Tollefson SJ, Halburnt-Rush W, Berkhout RJ, Wolthers KC, et al. Identification of LL, Pingsterhaus JM, Edwards KM, et al. Human a new human coronavirus. Nat Med 2004; 10(4):368- metapneumovirus and lower respiratory tract disease 373. in otherwise healthy infants and children. N Engl J Med 28. Zaki, AM, van Boheemen S, Bestebroer TM, Osterhaus 2004; 350(5):443-450. AD, Fouchier RA, et al. Isolation of a novel coronavirus 14. Bosis S, Esposito S, Niesters HG, et al. Impact of human from a man with pneumonia in Saudi Arabia. N Engl J metapneumovirus in childhood: comparison with Med 2012; 367(19):1814-1820. respiratory syncytial virus and influenza viruses. J Med 29. Lynch JP 3rd, Kajon AE. Adenovirus: Epidemiology, Virol 2005; 75:101-104. global spread of novel serotypes, and advances in 15. Lu G, Li J, Xie Z, Liu C, Guo L, Vernet G, et al. Human treatment and prevention. Semin Respir Crit Care metapneumovirus associated with community- Med 2016; 37(4):586-602. acquired pneumonia in children in Beijing, China. J Med 30. Tabain I, Ljubin-Sternak S, Cepin-Bogović J, Virol 2012; 85(1):138-143. Markovinovic L, Knezovic I, Mlinaric-Galinovic G. 16. Panda S, Mohakud NK, Pena L, Kumar S. Human Adenovirus respiratory infections in hospitalized metapneumovirus: review of an important respiratory children: clinical findings in relation to species and pathogen. Int J Infect Dis 2014; 25:45-52. serotypes. Pediatr Infect Dis J 2012; 31(7):680-684. 17. Williams JV. Human Metapneumovirus: An important 31. Denny FW Jr. The clinical impact of human respiratory cause of respiratory disease in children and adults. Curr virus infections. Am J Respir Crit Care Med 1995; Infect Dis Rep 2005; 7(3):204-210. 152(4 Pt 2):S4-12. 18. Williams JV, Martino R, Rabella N, Otegui M, Parody R, 32. Allander T, Tammi MT, Eriksson M, Bjerkner A, Heck JM, et al. A prospective study comparing human Tiveljung-Lindell A, Andersson B. Cloning of metapneumovirus with other respiratory viruses in a human parvovirus by molecular screening of adults with hematologic malignancies and respiratory respiratory tract samples. Proc Natl Acad Sci tract infections. J Infect Dis 2005; 192(6):1061-1065. USA 2005; 102(36):12891-12896. 19. Englund JA, Boeckh M, Kuypers J, Nichols WG, 33. Guido M, Tumolo MR, Verri T, Romano A, Serio F, Hackman RC, Morrow RA, et al. Brief communication: De Giorgi M. Human bocavirus: Current knowledge fatal human metapneumovirus infection in stem-cell and future challenges. World J Gastroenterol 2016; transplant recipients. Ann Intern Med 2006; 144(5):344- 22(39):8684-8697. 349. 34. Park SW, Kwon MJ, Yoo JY, Choi HJ, Ahn YJ. Antiviral 20. Martin ET, Kuypers J, Heugel J, Englund JA. Clinical activity and possible mode of action of ellagic disease and viral load in children infected with respiratory acid identified in Lagerstroemia speciosa leaves syncytial virus or human metapneumovirus. Diagn toward human rhinoviruses. BMC Complement Microbiol Infect Dis 2008; 62(4):382-388. Altern Med 2014; 14:171. 21. McIntosh K, Chao RK, Krause HE, Wasil R, Mocega 35. Williams JV. The clinical presentation and outcomes HE, Mufson MA. Coronavirus infection in acute lower of children infected with newly identified respiratory respiratory tract disease of infants. J Infect Dis 1974; tract viruses. Infect Dis Clin North Am 2005; 19(3):569- 130:502-507. 584. 127 Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology... June 2020

36. Poon LL, Song T, Rosenfeld R, Lin X, Rogers MB, Zhou of 72bp Duplication Group A and 60bp Duplication B, et al. Quantifying influenza virus diversity and Group B Respiratory Syncytial Virus (RSV) Strains in transmission in humans. Nat Genet 2016; 48(2):195- Riyadh, Saudi Arabia during 2014. PLoS One 2016; 200. 11(11):e0166145. 37. Hossain A, Bakir TF, Zakzouk SM, et al. Tonsillitis and 50. Amer HM, Alshaman MS, Farrag MA, Hamad respiratory infections of viral etiology in a developing ME, Alsaadi MM, Almajhdi FN. Epidemiology of country. Ann Trop Paediatr 1988; 8(2):108-111. 11 respiratory RNA viruses in a cohort of hospitalized 38. Al-Hajjar S, Akhter J, Al Jumaah S, Hussain Qadri children in Riyadh, Saudi Arabia. J Med Virol 2016; SM. Respiratory viruses in children attending a major 88(6):1086-1091. referral centre in Saudi Arabia. Ann Trop Paediatr 1998; 51. Eifan SA, Hanif A, AlJohani SM, Atif M, et al. Respiratory 18(2):87-92. tract viral infections and coinfections identified by 39. Meqdam MM, Subaih SH, Thwiny IR. Rapid detection Anyplex™ II RV16 detection kit in pediatric patients at and clinical features of influenza and parainfluenza a Riyadh Tertiary Care Hospital. Biomed Res Int 2017; in infants and young children hospitalized with 2017:1928795. acute lower respiratory illnesses. J Trop Pediatr 2005; 52. Meqdam MM, Subaih SH. Rapid detection and clinical 51(3):160-165. features of infants and young children with acute lower 40. AlMazroa MA, Memish ZA, AlWadey AM. respiratory tract infection due to respiratory syncytial Pandemic influenza A (H1N1) in Saudi Arabia: virus. FEMS Immunol Med Microbiol 2006; 47(1):129- description of the first one hundred cases. 133. Ann Saudi Med 2010; 30(1):11-14. 53. Al-Shehri MA, Sadeq A, Quli K. Bronchiolitis in Abha, 41. Asaad AM, Al-Ayed MSZ, Qureshi MA, Ameen MS. Southwest Saudi Arabia: viral etiology and predictors Viral etiology of respiratory infections in children in for hospital admission. West Afr J Med 2005; 24(4):299- southwestern Saudi Arabia using multiplex reverse- 304. transcriptase polymerase chain reaction. Saudi Med 54. Almajhdi FN, Farrag MA, Amer HM. Group B strains J 2014; 35(11):1348-1353. of human respiratory syncytial virus in Saudi Arabia: 42. Abdulhaq AA, Basode VK, Hashem AM, Alshrari molecular and phylogenetic analysis. Virus Genes 2014; AS, Badroon NA, Hassan AM, et al. Patterns 48(2):252-259. of Human Respiratory Viruses and Lack of MERS- 55. Al-Alaiyan S, Pollack P, Notario GF. Safety and Coronavirus in Patients with Acute Upper Respiratory pharmacokinetics of extended use of palivizumab in Tract Infections in Southwestern Province of Saudi Saudi Arabian infants and children. Drugs Context 2015; Arabia. Adv Virol 2017; 2017:4247853. 4. pii: 212270. 43. Rabaan AA, Alshaikh SA, Bazzi AM. Influenza A 56. Fahad A, Al-Hajjar S, Latifa BM, et al. Guidelines for (H1N1) pdm09 epidemiology in the Eastern Province palivizumab prophylaxis in infants and young children of Saudi Arabia. J Infect Public Health 2018; 11(5):636- at increased risk for respiratory syncytial virus infection 639. in Saudi Arabia. Inter J Pediatr Adolescent Med 2016; 44. Chanock R, Roizman B, Myers R. Recovery from 3(1):38-42. infants with respiratory illness of a virus related to 57. Alharbi AS, Alqwaiee M, Al-Hindi MY, Mosalli R, Al- chimpanzee coryza agent (CCA). I. Isolation, properties Shamrani A, Alharbi S, et al. Bronchiolitis in children: and characterization. Am J Hyg 1957; 66(3):281-290. The Saudi initiative of bronchiolitis diagnosis, 45. Jamjoom GA, Al-Semrani AM, Arab Board, Al- management and prevention (SIBRO). Ann Thorac Frayh AR, Artz F, Al-Mobaireek KF. Respiratory Med 2018; 13(3):127-143. syncytial virus infection in young children hospitalized 58. Van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de with respiratory illness in Riyadh. J Trop Pediatr 1993; Groot R, Fouchier RA, et al. A newly discovered human 39(6):346-349. pneumovirus isolated from young children with 46. Chowdhury D, Al-Howasi M, Ramia S, Al-Frayh respiratory tract disease. Nat Med 2001; 7(6):719- 724. ARS, Khalil M, Chowdhury S. Respiratory syncytial 59. Domachowske JB. Human metapneumovirus: A newly virus in Saudi patients admitted to hospital with described respiratory pathogen of humans. Clin Micro bronchiolitis: Use of direct fluorescent antibody tests as Newsletter 2003; 25(3):17-20. a rapid diagnostic tool. Ann Saudi Med 1996; 16(1):90- 60. Al Hajjar S, Al Thawadi S, Al Seraihi A, Al Muhsen S, 92. Imambaccus H. Human matapneumovirus and human 47. Bakir TM, Halawani M, Ramia S. Viral aetiology coronavirus infection and pathogenicity in Saudi and epidemiology of acute respiratory infections Arabia children hospitalized with acute respiratory in hospitalized Saudi children. J Trop Pediatr 1998; illness. Ann Saudi Med 2011; 31(5):523-527. 44(2):100-103. 61. Amer HM. Molecular epidemiology of human 48. Al-Majhdi FN, Al-Jarallah A, Elaeed M, Latif A, metapneumovirus in Riyadh Province, Saudi Arabia. J Gissmann L, Amer HM. Prevalence of respiratory Mol Microbiol Biotechnol 2016; 26(6):414-421. syncytial virus infection in Riyadh during the winter 62. Ali MA, Abdelwahid SA, Ahmed MA et al. Human season 2007-2008 and different risk factors impact. Inter Metapneumovirus in Pediatric Acute Respiratory Tract J Virol 2009; 5(4):154-163. Infections in Aseer Region of Saudi Arabia: A Role in 49. Ahmed A, Haider SH, Parveen S, Arshad M, Clinical Outcomes and Complications. Saudi J Med Alsenaidy HA, Baaboud AO, et al. Co-Circulation Med Sc 2019; 6(5):80-85. June 2020 KUWAIT MEDICAL JOURNAL 128

63. Lai MMC, Perlman S, Anderson LJ. Coronaviridae, U.S. children. N Engl J Med 2015; 372(9):835-845. In: Fields BN, Knipe DM, Howley PM editors. Field 73. Fagbo SF, Garbati MA, Hasan R, Al Shahrani Virology. 5th Ed. Philadelphia: Lippincott Williams & D, Al-Shehri M, AlFawaz T, et al. Acute Wilkins Press; 2007. P 1305-1335. viral respiratory infections among children in MERS- 64. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah endemic Riyadh, Saudi Arabia, 2012-2013. J Med FA, Al-Hajjar S, Al-Barrak A, et al. Epidemiological, Virol 2017; 89(2):195-201. demographic, and clinical characteristics of 47 cases of 74. Gisela Enders. Paramyxoviruses: General Concepts, Middle East respiratory syndrome coronavirus disease Chapter 59. In: Samuel Baron editors. Medical from Saudi Arabia: a descriptive study. Lancet Infect Microbiology. 4th Ed. University of Texas Medical Dis 2013; 13(9):752-761. Branch at Galveston, 1996. 65. Memish ZA, Al-Tawfiq JA, Assiri A, et al. Middle 75. Almajhdi FN, Alshaman MS, Amer HM. Molecular East respiratory syndrome coronavirus disease in characterization and phylogenetic analysis children. Pediatr Infect Dis J 2014; 33:904-906. of human parainfluenza virus type 3 isolated 66. Thabet F, Chehab M, Bafaqih H, Al Mohaimeed S. from Saudi Arabia. J Med Virol 2012; 84(8):1304-1311. Middle East respiratory syndrome coronavirus in 76. Almajhdi FN, Alshaman MS, Amer HM. Human children. Saudi Med J 2015; 36(4):484-486. parainfluenza virus type 2 hemagglutinin- 67. Al-Tawfiq JA, Kattan RF, Memish ZA. Middle East neuramindase gene: sequence and phylogenetic respiratory syndrome coronavirus disease is rare in analysis of the Saudi strain Riyadh 105/2009. Virol children: An update from Saudi Arabia. World J Clin J 2012; 9:316. Pediatr 2016; 5(4):391-396. 77. Bukhari EE, Elhazmi MM. Viral agents causing acute 68. Al-Sehaibany FS. Middle East respiratory syndrome lower respiratory tract infections in hospitalized in children. Dental considerations. Saudi Med J 2017; children at a tertiary care center in Saudi Arabia. 38(4):339-343. Saudi Med J 2013; 34(11):1151-1155. 69. Al-Tawfiq JA, Gautret P. Asymptomatic Middle East 78. Hamparian VV, Colonno RJ, Cooney MK, Dick EC, Respiratory Syndrome Coronavirus (MERS-CoV) Gwaltney JM Jr, Hughes JH, et al. A collaborative report: infection: Extent and implications for infection control: rhinoviruses--extension of the numbering system from A systematic review. Travel Med Infect Dis 2019; 27:27- 89 to 100. Virology 1987; 159(1):191-192. 32. 79. Jartti T, Hedman K, Jartti L, Ruuskanen O, Allander T, 70. Alfaraj SH, Al-Tawfiq JA, Altuwaijri TA, Memish ZA. Soderlund-Venermo M. Human bocavirus-the first 5 Middle East respiratory syndrome coronavirus in years. Rev Med Virol 2012; 22(1):46-64. pediatrics: a report of seven cases from Saudi Arabia. 80. Abdel-Moneim AS, Kamel MM, Al-Ghamdi AS, Al- Front Med 2019; 13(1):126-130. Malky MIR. Detection of bocavirus in children suffering 71. Edmond K, Scott S, Korczak V, Ward C, Sanderson from acute respiratory tract infections in Saudi Arabia. C, Theodoratou E, et al. Long term sequelae from PLoS One 2013; 8(1):e55500. childhood pneumonia; systematic review and meta- 81. Bubshait DK, Albuali WH, Yousef AA, Obeid OE, analysis. PLoS ONE 2012; 7(2):e31239. Alkharsah KR, Hassan MI, et al. Clinical description 72. Jain S, Williams DJ, Arnold SR, Ampofo K, of human bocavirus viremia in children with LRTI, Bramley AM, Reed C, et al. Community acquired Eastern Province, Saudi Arabia. Ann Thorac Med 2015; pneumonia requiring hospitalization among 10(2):146-149.