key: cord-0973614-44qyodl5 authors: Civljak, Rok; Tot, Tatjana; Falsey, Ann R.; Huljev, Eva; Vranes, Jasmina; Ljubin‐Sternak, Suncanica title: Viral pathogens associated with acute respiratory illness in hospitalized adults and elderly from Zagreb, Croatia, 2016 to 2018 date: 2019-03-04 journal: J Med Virol DOI: 10.1002/jmv.25437 sha: dd2131284ce2adc9d0eabb475fa89900f4dc6991 doc_id: 973614 cord_uid: 44qyodl5 AIMS: To investigate the viral etiology of acute respiratory infection (ARI) in hospitalized adults and elderly patients in Croatia, compare the prevalence of detected viruses, and to determine clinical characteristics and seasonal occurrence of investigated infections. METHODS: From January 2016 to June 2018, a total of 182 adult patients presented with symptoms of ARI and admitted to the hospital were tested for 15 respiratory viruses by multiplex reverse‐transcription polymerase chain reaction. Clinical data were collected by retrospective analysis of the patient's chart. RESULTS: A virus was identified in 106 (58.5%) of the patients. The most commonly detected virus was influenza virus (41.5%), followed by respiratory syncytial virus (13.8%), human metapneumovirus (13.0%), parainfluenza viruses (12.2%), rhinoviruses (11.4%), adenovirus and coronaviruses with equal frequencies (3.3%), and enterovirus (1.6%). The serum level of C‐reactive protein and white blood cell count were significantly lower in patients with respiratory viruses identified when compared with those in whom no virus was detected (P < 0.001 and P = 0.007, respectively). There were no differences in clinical symptoms according to the type of the detected virus, except for more frequent illness exposure recall for influenza infection ( P = 0.010). Influenza, parainfluenza, and pneumoviruses were detected mostly in winter months, while rhinoviruses in autumn and spring. CONCLUSIONS: In addition to influenza, pneumoviruses, rhinoviruses, and parainfluenza viruses play an important role in etiology of ARIs in adults. Fast and accurate laboratory diagnosis for respiratory viruses in routine practice is needed for clinicians optimally manage patients with ARI and potentially avoid the unnecessary use of antimicrobial drugs. Acute respiratory infections (ARIs) are the most common infections in humans of all ages. The disease burden from ARIs is substantial and thus their prevention and treatment are a priority for public health agencies. 1 Moreover, current data regarding patterns of unnecessary antimicrobial use in adult patients showed that ARIs are among most frequent indications for antimicrobial use. 2, 3 Children and older adults are the most vulnerable groups of the population, and ARIs are the most common cause of their hospitalization worldwide. 4, 5 Older adults are at increased risk of morbidity and mortality due to ARIs because of coexisting chronic diseases and immune senescence. 6 Although bacteria, fungi, and parasites can cause and human rhinovirus (HRV) strains. 7 Influenza is a well-recognized cause of ARIs in adults 8, 9 but substantial adult disease is also caused by other respiratory viruses, 10 particularly RSV and HMPV. [11] [12] [13] [14] Both viruses belong to the new family Pneumoviridae within order Mononegavirales, 15 and have similar clinical features. 16, 17 The clinical and epidemiological characteristics of ARIs in children caused by RSV and HMPV in Croatia are well described. [18] [19] [20] In contrast, for adult populations in Croatia, data are limited primarily on influenza viruses due to laboratory use of direct methods (isolation, antigen detection, or molecular methods) for routine diagnosis of respiratory viruses. Influenza diagnosis is performed in the Croatian Institute of Public Health, acting as a National Influenza Centre, that collects samples from several local, regional, and national institutions for the purpose of the influenza surveillance. Therefore, this Centre performs diagnosis of influenza for our hospitals with the results available to clinicians within 24 to 72 hours, depending on the time of sampling. The diagnosis of other respiratory viruses has been neglected and their incidence and role in the etiology of ARI in adults in Croatia is unknown. Also, in the past the burden of noninfluenza respiratory viruses was underestimated due the insensitivity of older microbiologic tests and the inability to get certain types of clinical specimens. 21 In addition to inclusion criteria, exclusion criteria were: (1) presumed bacterial respiratory infection, including, otitis, sinusitis, Normality of data was tested using Kolmogorov-Smirnov test. Multiple comparisons between the groups were tested using χ 2 and Kruskal-Wallis' test with post hoc Dunn's testing when appropriate. A value of P < 0.05 was set. In addition, P was corrected to < 0.001 for post hoc comparisons between multiple groups. Statistical software on which all calculations were made was "R." test P = 0.709). Distribution of tested patients by age, with proportion of those positive for respiratory virus is presented in Figure S1 . Overall there were 59 (32%) females and 123 (68%) males tested, of whom 59% of females and 57% of males were positive for respiratory virus. All respiratory virus-positive patients were hospitalized; 71 of 106 (67.0%) patients with a respiratory virus detected were hospitalized onward, with mean length of stay of 11.0 ± 4.9 days, while others were treated in our day hospital. More than two-thirds of respiratory virus-positive patients (73 of To evaluate laboratory characteristics of viral infections, the serum level of C-reactive protein (CRP) and white blood cell (WBC) count were compared for those who were infected with single virus, those who were infected with two or more viruses, and those in who no virus was detected ( Figure S2a Coronaviruses and adenoviruses monoinfection was not included in analysis due to low frequencies of detection (three and two cases, respectively). b χ 2 test except for age and hospital stays where the Kruskal-Wallis test is used; a value of P < 0.05 was considered significant and presented in bold. Other recent studies using molecular diagnostics highlight the role of HRV as the most prevalent noninfluenza respiratory virus with detection rates of 11.5% in adults greater than 18 years. 27 In this study HRV was detected as the fifth most common virus after Flu, RSV, HMPV, and PIVs, with detection rate of 7.7% (14 of 182). HCoV and AdV in this study were detected with equal frequencies (4 of 182; 2.2%) and the low AdV frequency is similar to the other previously mentioned adult studies (1.6%), 25 whereas, the incidence of HCoV is lower than prior reports ranging from 3% to 14%. 28, 29 HEV was rarely detected (2 of 182; 1%) and was always in codetection with another respiratory virus ( Figure 2 ). Previously published long-term studies on pneumoviruses seasonality based on the monitoring in children 18, 19 reported that pneumoviruses in Croatia show biannual cycles characterized by a large RSV winter season followed by a late spring outbreak of HMPV one year, and a winter HMPV outbreak and RSV spring outbreak the following year. 19 Large RSV epidemics in winter months appeared in the odd years, and large HMPV epidemics in occurred even years. The current study conducted in adults, did not confirm biennial RSV cycles, although conclusions about biennial occurrence is not possible in a 2.5-year study. Interestingly, high HMPV epidemic waves were still observed in even years ( Figure 2 ). HRV mostly occurred in the spring and fall months although other studies reported its occurrence during colder months. 38 To the best of our knowledge this is the first report for HRV epidemiology in Croatia since laboratory diagnosis for HRV in Croatia was not possible until this study. Meta-analysis studies are being performed to make global estimates of seasonality and burden of disease and require the input specific viral activity data from different countries to make accurate estimates. 39 In addition, new adult vaccines for RSV are in active clinical development. 40 As new products become available, health ministries will need accurate local viral activity and seasonality data for optimal deployment. There are several limitations of our study which includes low enrollment rate, allowance of clinicians to rule out possible bacterial infection, exclusion of persons in ICU (most severe disease), but also outpatients (mildest disease) which may have affected the viruses detected as well as the clinical features. Bacterial coinfection can be difficult to diagnose and conclusions about the frequency of this occurrence should be cautious. Lastly, our study was relatively short and future studies over multiple seasons are needed to generate comprehensive seasonality data. In conclusion, a variety of respiratory viruses are associated with serious illness leading to hospitalization in older Croatian adults. Implementation of rapid and sensitive diagnostics such as multiplex PCR that covers not only Flu but also other common respiratory viruses in clinics and public health laboratories could help clinicians and general practitioner's treatment decisions regarding antiviral agents and antibiotics. In addition, physician and public awareness of the importance of noninfluenza respiratory viruses will help policy on the use of new antivirals and vaccines for other viruses under development. Lung infection-a public health priority Antibiotic prescription and clinical management of common infections among general practitioners in Latvia, Lithuania, and Sweden: a pilot survey with a simple protocol Vital signs: improving antibiotic use among hospitalized patients Hospitalization of children under five years of age due to avoidable causes Infectious disease-related emergency department visits of elderly adults in the United States Aging of the immune system as a prognostic factor for human longevity Identification of new respiratory viruses in the new millennium Should clinical case definitions of influenza in hospitalized older adults include fever? Influenza Other Respir Viruses Viral pathogens among elderly people with acute respiratory infections in Shanghai, China: preliminary results from a laboratory-based surveillance Rhinovirus and coronavirus infection-associated hospitalizations among older adults Respiratory syncytial virus infection in adult populations Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness The role of human metapneumovirus in the critically ill adult patient Respiratory syncytial virus infection in elderly adults Taxonomy of the order mononegavirales: update 2016 Detection of genetic lineages of human metapneumovirus in Croatia during the winter season 2005 Human metapneumovirus (HMPV) associated pulmonary infections in immunocompromised adultsinitial CT findings, disease course and comparison to respiratorysyncytial-virus (RSV) induced pulmonary infections Eleven consecutive years of respiratory syncytial virus outbreaks in Croatia Seasonal occurence of human metapneumovirus infections in Croatia Etiology and Clinical characteristics of single and multiple respiratory virus infections diagnosed in croatian children in two respiratoy seasons Polymicrobial communityacquired pneumonia: An emerging entity Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden Respiratory syncytial virus infection in older adults: an under-recognized problem Respiratory viral detection in children and adults: comparing asymptomatic controls and patients with community-acquired pneumonia Use of multiple imputation to estimate the proportion of respiratory virus detections among patients hospitalized with community-acquired pneumonia Age-related prevalence of common upper respiratory pathogens, based on the application of the FilmArray Respiratory panel in a tertiary hospital in Greece Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease Clinical impact of human coronaviruses 229E and OC43 infection in diverse adult populations Human bocavirus in nasopharyngeal secretion of hospitalized children with acute respiratory tract infection-first year results of four-year prospective study Lack of sensitivity of rapid antigen tests for the diagnosis of respiratory syncytial virus infection in adults Diagnosis of respiratory syncytial virus infection: comparison of reverse transcription-PCR to viral culture and serology in adults with respiratory illness Comparative evaluation of six commercialized multiplex PCR kits for the diagnosis of respiratory infections Multiplex respiratory virus testing for antimicrobial stewardship: a prospective assessment of antimicrobial use and clinical outcomes among hospitalized adults Viral diagnostics: only half the battle Serum procalcitonin measurement and viral testing to guide antibiotic use for respiratory infections in hospitalized adults: a randomized controlled trial Procalcitonin to initiate or discontinue antibiotics inacute respiratory tract infections Impact and seasonality of human rhinovirus infection in hospitalized patients for two consecutive years Respiratory syncytial virus seasonality: a global overview The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates The authors declare that there are no conflict of interests.