SUBMITTED 14 FEB 23 1 REVISION REQ. 21 MAR 23; REVISION RECD. 5 APR 23 2 ACCEPTED 3 MAY 23 3 ONLINE-FIRST: MAY 2023 4 DOI: https://doi.org/10.18295/squmj.5.2023.033 5 6 The Burden of Human Parechoviruses on Children in Oman 7 A retrospective study 8 Aws Al-Farsi,1 Zaid Alhinai,1 Fatma Ba Alawi,2 Khuloud Al Maamari,2 9 Laila S. Al Yazidi3 10 11 1College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman; 12 Departments of 2Microbiology & Immunology and 3Child Health, Sultan Qaboos University 13 Hospital, Muscat, Oman. 14 *Corresponding Author’s e-mail: lailay@squ.edu.om 15 16 Abstract 17 Objectives: To study the burden, clinical and laboratory features, and outcome of Human 18 Parechoviruses (HPeVs) infection among children managed at Sultan Qaboos University 19 Hospital (SQUH). Methods: This is a retrospective study of children (< 18 years of age) with 20 molecular proven HPeVinfection managed at SQUH between January 2017 and December 21 2019. Data was collected from patients’ medical records and analyzed to describe the 22 demographic, clinical and laboratory features, management and outcome. Results: HPeV was 23 detected in 61 patients, 44 (72%) of whom were males. The median age of these patients was 24 9 months (IQR, 6-15 months). HPeV was detected throughout the year without any 25 significant peaks. The majority of our patients (51; 84%) had co-infection with other viruses. 26 Forty-eight (79%) children with HPeV infection required hospitalization and their median 27 hospital length of stay was 5 days (IQR, 3 - 8 days). Ex-prematurity (10; 16%) was the most 28 common comorbidity seen among this group. Fever (41; 67%) and cough (41; 67%) were the 29 most common presenting symptoms among these children.Two-third of children with HPeV 30 infection in this cohort were managed for lower respiratory tract infection and none for 31 meningitis. Gastroenteritis was not common in our study, only 8 children had diarrhoea. All 32 children had a full recovery. Conclusion: HPeVs does not show a clear seasonality in Oman. 33 Most of the children were < 2 years of age and had a viral co-infection. Outcomes of HPeVs 34 were favorable, with no mortalities, but thorough follow-up of neurological outcomes was 35 lacking. 36 Keywords: Children; Parechovirus; Infection; Outcome; Oman. 37 38 Advances in knowledge 39 - The majority of children infected with HPeV were males, younger than 2 years, and 40 had a viral co-infection. 41 - HPeV does not show a clear seasonality in Oman. 42 - No reported mortality in this group. 43 44 Application to patient care 45 - This study focused on assessing the burden of HPeV infection among children in 46 Oman and describe their clinical and laboratory features. 47 - This study’s findings will help pediatricians understand the complete clinical picture 48 and outcomes of this virus in Oman. 49 50 Introduction 51 Human Parechoviruses (HPeVs) can cause gastrointestinal, severe respiratory tract, and central 52 nervous system infections in children.1,2 They belong to the Picornaviridae family consisting 53 of non-enveloped positive-sense single-stranded RNA viruses3 and are transmitted mainly by 54 the respiratory droplets and faecal-oral routes.4,5 There are two species of HPeVs: Parechovirus 55 A and Parechovirus B.6 Parechovirus A is further divided into 19 genotypes, of which HPeV-56 1, HPeV-3, and HPeV-6 are the most common genotypes associated with human disease.6–8 57 The prevalence and seasonality of the virus differ from one place to another due to the 58 differences in HPeV genotypes and age.6 59 60 HPeV infection is usually asymptomatic or associated with mild respiratory and 61 gastrointestinal symptoms in children.8 Some infants present with fever, irritability, and 62 sometimes rash and they are described as “hot, red, and angry babies”.8 The less common 63 clinical features include seizures, distended abdomen, liver failure, and pseudo-appendicitis.8 64 It can also be associated with sepsis like-disease and meningoencephalitis.7 A study from Iran 65 showed that HPeVs were a common cause of aseptic meningitis and sepsis like-disease 66 compared to human enteroviruses in children less than 8 years of age between 2009 and 2011.9 67 Another Iranian study reported that HPeV-1 was the main cause of diarrhea among other HPeV 68 genotypes.10 Zhu et al., reported in their study that HPeV infection was more common in 69 children younger than 2 years of age.11 Central nervous system involvement with HPeVs might 70 result in long-term complications including white matter abnormalities, cerebral palsy, and 71 neurodevelopmental sequelae.6,12 Mortality from HPeV infection is rare among healthy 72 children.13 73 74 HPeV infection is common across the globe and is not specific to a particular region. Australia 75 reported 3 epidemics of HPeV-3 between 2013 and 2018.7,8 In several European studies, HPeV 76 infection was seen in about 3-8% of children presenting to the emergency department with a 77 febrile illness.8,14,15 The seasonality of the virus is not very clear but it depends mainly on the 78 most common genotype present in that particular area.6 A study in Iran showed that HPeV-1 79 infection rates peaked during spring and autumn, while on the other hand Rahimi et al., reported 80 that there was no significant difference in seasonality of HPeVs in Iran as it was detected 81 throughout the year.9,10 HPeV-1 infections appear more in the summer and autumn periods of 82 the year in the United States, Denmark and Australia compared to Germany which showed a 83 decrease in the rates in the summer.6,16–18 In Spain, a study showed that the number of HPeV 84 cases increased during both summer and spring.19 In Hong Kong and Northern Ireland, studies 85 showed that the rates of HPeV infection in children were much higher during winter.2,20,21 86 87 There is limited data on the burden and outcome of HPeV infection among Omani children. 88 Little importance has been given to HPeV infection in the Middle East region. Therefore, the 89 results of this study will help pediatricians and healthcare professionals in Oman and in the 90 neighboring countries to get a better understanding of the burden of this virus in the region. 91 The aim of this study was to identify all confirmed cases of HPeV infection among children 92 presenting to Sultan Qaboos University Hospital (SQUH), describe their clinical and laboratory 93 features and their outcome. 94 95 Methods 96 This retrospective study was conducted at SQUH, one of the major tertiary care facilities in 97 Muscat governorate, Sultanate of Oman. The study included all symptomatic children under 98 18 years of age managed at SQUH with a positive HPeV PCR from respiratory and 99 cerebrospinal fluid (CSF) specimens over a period of 3 years (January 2017 - December 2019). 100 Exclusion criteria were age greater than or equal to 18 years, asymptomatic infection, or having 101 insufficient data in the medical records. The patients’ demographics, clinical details, 102 investigation results, treatments, and outcomes of the infection were collected from the SQUH 103 patient electronic medical records (TrakCare®). 104 105 Lower respiratory tract infection (LRTI) was defined as the presence of abnormal lung 106 examination results or infiltrates (new possible or definite) seen in chest x-ray, or oxygen need 107 in conjunction with a diagnosis made by a physician at presentation.22 Secondary bacterial 108 pneumonia was defined as the presence of LRTI with infiltrates on chest x-ray, and physician’s 109 decision to treat the child with antibiotics for 5 days or more.22 Prematurity was defined as a 110 birth that happens before 37 weeks of gestation. The definitions of hypotension, tachycardia 111 and tachypnea was based on the reference ranges of the Pediatric Advanced Life Support 112 (PALS) booklet. Fever was defined as an elevated temperature of 38°C or greater. 113 114 Respiratory specimens were collected by nasopharyngeal aspirate (NPA), throat or nasal 115 swabs. Real-time multiplex polymerase chain reaction (real time-PCR) for respiratory and 116 cerebrospinal viruses were used to detect HPeV nucleic acid. FTD respiratory pathogens 21 117 kits were used to test respiratory samples for the following targets: human coronaviruses 118 (OC43, HKU1, NL63 and 229E), HPeVs, human bocavirus, parainfluenza viruses (1, 2, 3 and 119 4), influenza viruses (A and B), rhinovirus, RSV, human metapneumovirus, adenovirus, 120 enteroviruses, and mycoplasma pneumonia. HPeV can cause meningitis as well. CSF samples 121 for all children with impression of meningoencephalitis during the study period were tested for 122 herpes simplex viruses 1 &2 (HSV 1/2), varicella zoster virus (VZV), HPeVs, enteroviruses 123 and mumps using FTD Viral Meningitis kits. 124 125 The Statistical Package for the Social Sciences software (SPSS, version 25) was used to 126 analyze data collected from all children who had met the inclusion criteria. To compare two 127 categorical variables, Chi-square or Fisher's exact test was used. For non-normally distributed 128 continuous variables, Mann-Whitney U test was used. A P-value of less than 0.05 was 129 considered significant. Comparison was done between children with isolated HPeV and those 130 with infection with co-viruses to see if those with co-infection have more severe disease and 131 subsequently worse outcome. 132 133 Ethical approval was obtained from the Medical Research Ethics Committee (MREC) at the 134 College of Medicine and Health Sciences (CoMHS) in May 2020 (MREC#2109). 135 136 Results 137 Sixty-one children were managed for symptomatic HPeV infection during the study period, 138 among whom 44 (72%) children were males. All patients were of Omani nationality and the 139 median age was 9 months (IQR, 6-15 months). 140 141 The results revealed that 48 (79%) patients were hospitalized and their median hospital length 142 of stay was 5 days (IQR, 3-8 days). Most of these patients 24 (39%) were admitted to the 143 regular ward while only 7 (12%) were admitted to the pediatric intensive care unit (PICU) for 144 respiratory support. The most common comorbidity seen among HPeV infected patients was 145 ex-prematurity as shown in table 1. Eight of the preterm babies (80%) required Oxygen therapy 146 and either admission to high dependency or PICU admission. 147 Figure 1 shows that HPeV infection was detected throughout the year. 148 149 All positive specimens for HPeVs were respiratory specimens. The majority of these specimens 150 were nasopharyngeal aspirates (48 specimens; 79%) followed by throat swabs (11 specimens; 151 18%). A lumbar puncture was not performed to any of these cases, as there was no suspicion 152 of meningitis or encephalitis. HPeV PCR is part of our CSF viral multiplex PCR panel and 153 none of the patients who were investigated for meningitis during the study period had HPeV 154 meningitis. 155 156 Fever (41 cases, 67%) and cough (41 cases, 67%) were the most common presenting symptoms 157 in our patients with HPeVs. Seven children had rash. Two-third of children with HPeVs were 158 managed for LRTI. Gastroenteritis was not common; only eight children had diarrhea. HPeV 159 PCR is not part of gastrointestinal panel in our hospital but we assumed that HPeV causes the 160 diarrhea in patients with confirmed HPeV from respiratory tract. There were no cases of 161 meningitis or encephalitis. Tachypnea (49 cases, 80%), tachycardia (27 cases, 44%) and 162 wheezing (36 cases, 59%) were the most common findings on clinical examination. Apnea, 163 stridor and hypoxia were reported in 4 (7%), 6 (10%) and 28 (46%) children respectively. 164 165 Co-infection with other viruses was common. Fifty-one children (84%) had a co-infection with 166 other viruses including 34 (56%) with only one virus, 10 (16%) with two viruses, five (8%) 167 with three viruses and two (3%) with four viruses. Rhinovirus (30 cases; 49%) followed by 168 adenovirus (14 cases; 23%) were the most common viruses causing co-infection with HPeVs. 169 170 Children with isolated HPeV and those co-infected with other viruses were compared. Sodium 171 level was lower in children with isolated HPeV (median 137, IQR 135-138 vs 139, IQR 136-172 141, P = 0.024). Wheezing showed a lower frequency trend among children with isolated 173 HPeV, however it did not reach a statistical significance (P = 0.075) as shown in table 2. 174 175 None of our patients developed sepsis, acute kidney injury or liver dysfunction. Two children 176 ( 7-month and 12-month old) presented with febrile seizure during the HPeV infection. All 177 patients with HPeVs in this cohort had full recovery. No long-term follow-up provided for 178 these children, so we could not comment on their neurological outcome. 179 180 Discussion 181 The results of this study highlight the burden of HPeV infection on our health care system, as 182 the majority needed hospital admission. In our cohort, 44 (72%) of HPeV infected patients 183 were males which is a similar finding in studies from Iran, China and USA.2,10,13 The median 184 age of children managed for HPeV infection in our study was 9 months (IQR, 6-15 months) 185 which is similar to what has been described recently by an Australian study that found a median 186 age of 8 months (IQR, 6.0-11.7 months).18 This increase in susceptibility to HPeV infection 187 after 6 months of age might be due to the waning of immunity provided by maternal 188 antibodies.18 The most common comorbidities seen among children with HPeVs in our cohort 189 was ex-prematurity (10; 16%). Premature birth was also identified as a risk factor for HPeV 190 and its complications in a study from Australia.12 191 192 When compared to RSV infection in our institution, (48; 79%) of HPeV infections required 193 hospitalization compared to (57; 94%) of RSV infection (unpublished data) which highlights 194 the virus’s burden on the healthcare facilities. In addition, 7 (12%) of children with HPeV in 195 our cohort required admission to the PICU for respiratory support, which again shows that 196 HPeV can cause severe infection in children. An Australian study presented similar findings 197 with their patients having a median length of stay of 4 days (IQR, 2-13 days) and 15 (25%) of 198 the children in their cohort were admitted to the intensive care unit.7 199 200 Viral co-infection was very common in our cohort as 51 (84%) of our patients with HPeV 201 infection have co-infection with other viruses which is similar to what other studies have 202 shown.2,13,18 Rhinovirus was the most common virus causing co-infection in our patients and 203 this agrees with the findings of two previous studies.2,13 204 205 HPeV infection was detected throughout the year, with a relative increase in cases in the fall 206 and winter months. The relative increase in HPeV cases during fall and winter might be because 207 of the opening of schools and the probability of having different HPeV genotypes circulating 208 in Oman, which results in different seasonality patterns. In addition, this rise might be due to 209 the decrease in temperatures from late summer to winter. The seasonality of HPeV described 210 in our study is similar to what has been described by Rahimi et al., in Iran which showed that 211 the virus appears throughout the year without any significant differences between the various 212 seasons.9 This could be because of the close proximity of Oman to Iran and relatively similar 213 weather and might share similar viral genotypes. Studies from Hong Kong and Australia 214 showed very clear seasonality compared to what we see in Oman.2,7,20 215 216 The majority of our patients with HPeVs were managed for LRTI. Few patients (8; 13%) had 217 gastroenteritis and none were managed for meningitis. This might be because of the HPeV 218 genotypes, which is present in Oman. HPeV-1 causes respiratory and mild gastrointestinal 219 infection in children compared to HPeV-3 which usually causes severe central nervous system 220 infection in neonates.2 Therefore, it is likely that HPeV-1 is the main circulating genotype in 221 our setting since no cases of meningitis were seen among our cohort and most of the children 222 were older than 6 months. 223 224 Our study suggests that HPeV infection is a benign infection in children as we reported no 225 mortality in any of our patients similar to what has been described recently in the United 226 States.13 We could not comment on the neurological outcomes as long-term follow-up was 227 lacking in our cohort. 228 229 This study has several limitations. The first limitation is the relatively small sample size. This 230 might be because data was collected from only one center (SQUH) and because not all the 231 children with respiratory symptoms are tested for HPeVs, which makes it likely that there is an 232 underestimation of the number of HPeV infections reported in our study. As such, results from 233 our study may not necessarily reflect the experience in other tertiary, secondary, and primary 234 healthcare settings. Another limitation of this study is that HPeV genotypes were not identified 235 and hence not possible to compare the severity of infections among the different genotypes and 236 the seasonal distribution of infection with other communities. Furthermore, the retrospective 237 design of the study was another limitation because some patients had incomplete medical data. 238 In addition, presence of co-infection in most of our patients makes it difficult to make sure that 239 the clinical picture is fully explained by HPeV infection in these patients. Finally, this study 240 might not completely assess the burden of HPeV infections in Omani primary healthcare 241 facilities but we believe it is a good representation of the burden of this virus among children 242 in a tertiary healthcare setting. 243 244 Future work includes conducting a multicenter study in Oman to assess the burden of HPeV 245 infections among children especially neonates to assess the severity. In addition, studies on 246 HPeV genotypes are also recommended in order to have a complete understanding of the 247 burden of HPeVs on Oman healthcare facilities. 248 249 Conclusion 250 HPeVs does not show a clear seasonality in Oman. Most of the children were < 2 years of age 251 and had a viral co-infection. Outcomes of HPeVs were favorable, with no mortalities, but 252 thorough follow-up of neurological outcomes was lacking. 253 254 Conflicts of Interest 255 The authors declare no conflict of interests. 256 257 Funding 258 No funding was received for this study. 259 260 Authors’ Contribution 261 LY conceptualized the study and supervised the work. AA collected the data. ZA analyzed the 262 data. FBA and KAM interpreted the virology data. AA, FBA and KAM drafted the manuscript. 263 ZA, FBA, KAM and LY revised the manuscript. All authors approved the final version of the 264 manuscript. 265 266 References 267 1. Benschop KSM, Schinkel J, Minnaar RP, Pajkrt D, Spanjerberg L, Kraakman HC, et 268 al. Human parechovirus infections in Dutch children and the association between 269 serotype and disease severity. Clin Infect Dis. 2006;42(2):204–10. 270 2. Chiang GPK, Chen Z, Chan MCW, Lee SHM, Kwok AK, Yeung ACM, et al. 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J Pediatric Infect Dis Soc. 2019;8(1):21–8. 333 334 335 336 Table 1: Demographic features of HPeV patients managed at Sultan Qaboos University 337 during the study period: 338 Table 1: Demographic features of HPeV patients (N=61) Gender Male, n (%) 44 (72%) Female, n (%) 17 (28%) Governorate Muscat, n (%) 24 (39%) Al Batinah, n (%) 20 (33%) Ash Sharqiyah, n (%) 9 (15%) Ad Dakhiliya, n (%) 7 (12%) Dhofar, n (%) 1 (2%) Nationality Omani, n (%) 61 (100%) Non-Omani, n (%) 0 (0%) Age (months) Median 9 months IQR 6-15 months Site of sample NPA, n (%) 48 (79%) Throat swab, n (%) 11 (18%) Nasal swab, n (%) 2 (3%) Admission Admitted, n (%) 48 (79%) Regular ward, n (%) 24 (39%) High dependency unit, n (%) 17 (28%) Paediatric intensive care unit, n(%) 7 (12%) Length of hospital stay (days), n=48 Median 5 days IQR 3-8 days Co-morbidities Premature birth, n (%) 10 (16%) Asthma, n (%) 7 (12%) Other atopic disease, n (%) 3 (5%) Immunocompromised, n (%) 6 (10%) Neurological impairment, n (%) 6 (10%) Sickle cell trait, n (%) 4 (7%) Congenital heart disease, n (%) 3 (5%) NPA: nasopharyngeal aspirate 339 340 Table 2: Comparison of clinical, laboratory and radiological features between isolated 341 HPeV and co-infected HPeV managed at Sultan Qaboos University during the study 342 period: 343 344 Table 2: Comparison between isolated HPeV and HPeV with coinfection Only Parechovirus N = 10 Coinfection N = 51 P value Missing Male gender, n (%) 5 (50%) 39 (77%) 0.12 0 Age, months, median (IQR) 10 (6-15) 9 (6-15) 0.82 0 Weight, kg, median (IQR) 7.6 (4.9-9.9) 8.0 (6.0-9.2) 0.85 2 Length of stay, days, median (IQR) 7 (5-44) 5 (3-8) 0.13 13 WBC, median (IQR) 10.3 (9.2-13.7) 12.2 (7.9-16.1) 0.85 6 ANC, median (IQR) 3.7 (2.3-6.2) 4.7 (2.8-8.9) 0.25 6 ALC, median (IQR) 5.6 (5.3-6.3) 4.5 (2.9-7.4) 0.66 6 Platelet, median (IQR) 430 (279-645) 371 (279-471) 0.21 6 CRP, median (IQR) 38.5 (9.8-86) 23 (9-58.5) 0.28 10 ALT, median (IQR) 17.5 (10.3-21) 18.5 (15-46.3) 0.37 47 Total Bilirubin, median (IQR) 4 (3- ) 3.5 (3-5) 0.81 48 Albumin, median (IQR) 37 (26.3-42.5) 39 (36.8-43.3) 0.30 39 Sodium, median (IQR) 137 (135-138) 139 (136-141) 0.024 7 Creatinine, median (IQR) 19 (17.8-25.8) 20.5 (18-23) 0.62 7 CXR infiltrates, n (%) 4 (50%) 26 (68%) 0.42 15 Documented fever, n (%) 8 (80%) 33 (64.7%) 0.47 0 Maximum temperature, °C, median (IQR) 38.9 (37.8- 39.4) 38.3 (37.6-39.1) 0.53 1 Lowest oxygen saturation, %, median (IQR) 96 (90.3-99) 95 (89-97) 0.37 0 Tachypnea, n (%) 10 (100%) 39 (78%) 0.18 1 Tachycardia, n (%) 4 (40%) 23 (45.1%) 1.0 0 Premature birth, n (%) 2 (40%) 8 (26.7%) 0.61 26 Sickle cell, n (%) 0 (0%) 1 (2%) 1.0 0 Preceding duration of symptoms, median (IQR) 3.5 (2.3-4.8) 3 (1-4) 0.38 7 Nasal congestion, n (%) 7 (70%) 36 (70.6%) 1 0 Cough, n (%) 6 (60%) 41 (80.4%) 0.22 0 Wheezing, n (%) 3 (30%) 33 (64.7%) 0.075 0 Retractions, n (%) 4 (40%) 26 (51.0%) 0.731 0 Crackles/Crepitations, n (%) 4 (40%) 27 (52.9%) 0.51 0 Apnea, n (%) 1 (10%) 3 (5.9%) 0.52 0 Cyanosis, n (%) 3 (30%) 4 (7.8%) 0.08 0 Stridor, n (%) 1 (10%) 5 (9.8%) 1 0 Diarrhea, n (%) 1 (10%) 7 (13.7%) 1 0 Rash, n (%) 2 (20%) 5 (10%) 0.32 0 LRTI, n (%) 5 (50%) 36 (70.6%) 0.27 0 Secondary pneumonia, n (%) 4 (40%) 20 (39.2%) 1 0 Highest level of care needed Admitted, n (%) 9 (90%) 39 (76.5%) 0.67 0 PICU, n (%) 1 (10%) 6 (11.8%) 1 0 Highest level of respiratory support needed Oxygen, n (%) 6 (60%) 21 (41.2%) 0.32 0 HFNC, n (%) 0 (0%) 4 (7.8%) 1 0 NIV, n (%) 1 (10%) 11 (22%) 0.32 0 Invasive ventilation, n (%) 0 (0%) 3 (5.9%) 1 0 Antibiotics, n (%) 9 (90%) 33 (64.7%) 0.15 0 Antiviral, n (%) 3 (30%) 21 (41.2%) 0.73 Seizure, n (%) 0 (0%) 2 (3.9%) 1 0 Encephalopathy, n (%) 0 (0%) 0 (0%) - 0 Hypotension/Shock, n (%) 0 (0%) 0 (0%) - 0 Acute kidney injury, n (%) 0 (0%) 0 (0%) - 0 Acute liver failure, n (%) 0 (0%) 0 (0%) - 0 Readmission within 28 days, n (%) 1 (10%) 3 (5.9%) 0.52 0 Chronic morbidity, n (%) 0 (0%) 0 (0%) - 0 Death, n (%) 0 (0%) 0 (0%) - 0 Abbreviations: WBC: White blood cells; IQR: Interquartile range; ANC: Absolute neutrophil count; ALC: 345 Absolute lymphocyte count; CRP:C-reactive protein; ALT: Alanine transaminase; CXR: Chest x-ray; LRTI: 346 Lower respiratory tract infection. 347 348 349 350