key: cord-299918-0ahvoak4
authors: Aykac, Kubra; Karadag‐Oncel, Eda; Tanır Basaranoglu, Sevgen; Alp, Alpaslan; Cengiz, Ali Bulent; Ceyhan, Mehmet; Kara, Ates
title: Respiratory viral infections in infants with possible sepsis
date: 2018-09-24
journal: J Med Virol
DOI: 10.1002/jmv.25309
sha: 
doc_id: 299918
cord_uid: 0ahvoak4

BACKGROUND: Knowledge of infections leading to sepsis is needed to develop comprehensive infection prevention and sepsis, as well as early recognition and treatment strategies.The aim of this study was to investigate the etiology of sepsis and evaluate the proportion of respiratory viral pathogens in infants under two years of age with possible sepsis. METHODS: The prospective study was performed in two years. Multiplex reverse transcriptase polymerase chain reaction (RT‐PCR) was performed to detect viral pathogens. All patients who were included in this study had sepsis symptoms as defined by the Surviving Sepsis Campaign. RESULTS: We compared 90 patients with sepsis into three groups as patients (n = 33) who had only viral positivity in nasopharyngeal swab, patients (17) had proven bacterial infection with or without viral infection, and patients (40) without the pathogen detection. Human rhinovirus (16.7%) and influenza (7.8%) were the most commonly seen viruses. A cough was more common in the viral infection group than other groups ( P = 0.02) and median thrombocyte count was lower in the bacterial infection group than the others ( P = 0.01). Patients having bacterial sepsis had the longest duration of hospitalization than the other groups ( P = 0.04). During winter and spring seaons, patients with sepsis had more viral infection; however, in summer and autumn period, patients were mostly in a state that we could not prove infection agents ( P = 0.02). CONCLUSIONS: Our results suggest that respiratory tract viruses may play an important role in patients with sepsis and they should be kept in mind, especially during winter and spring seasons. In overall infection, viral respiratory viruses as a single pathogen with a detection rate of 36.6% in sepsis etiology.

Sepsis results from a wide spectrum of infectious agents and is a very common cause of mortality and morbidity worldwide. It leads to 7.5 million annual deaths in children under 5 years of age. 1, 2 Previously, in 2012, sepsis was defined as systemic inflammatory response syndrome (SIRS) in the presence of or as a result of suspected or proven infection by the Surviving Sepsis Campaign. Infection could be bacterial, viral, or fungal. Culture and nonculture-based diagnostic methods might be helpful for identification of these pathogens. 3 Various viruses could cause sepsis, which are influenced by age and underlying immune status. [4] [5] [6] [7] Respiratory viral infections (RVIs) among infants can cause morbidity and mortality. 8 Limited data exist on their proportion in sepsis. Numerous cases of clinical deterioration sepsis remain without bacterial evidence. Thus, viruses may also be considered as causative pathogens. [4] [5] [6] Respiratory viruses are ubiquitous in the surroundings of the children and are the most common source of respiratory infection among healthy and immunocompromised individuals. Several respiratory viruses may also cause severe respiratory disease mainly in infants but also in children. These viruses are well known as influenza viruses, respiratory syncytial virus (RSV), coronavirus (CoV), human metapneumovirus (hMPV), parainfluenza viruses type 1 to 3 (PIV 1-3), adenovirus (AV), enteroviruses (EV), human rhinovirus (hRV), and human bocavirus (hBoV). 9, 10 Despite their clinical expansiveness, RVIs are usually not considered to be of clinical significance among septic patients. Influenza is one of the most common causes of viral sepsis in children with the highest rate of hospitalizations and the number of death. 11 The management of pediatric sepsis should be arranged according to the age, the immune capacity of child and severity, site, and the source of the infection. 1 Currently, there are few studies about the etiology of nosocomial or community-acquired sepsis in children. 12, 13 The aim of the current study was to evaluate the proportion of respiratory viral pathogens in infants under two years of age with possible sepsis. 

Statistical analyses were performed using IBM SPSS for Windows version 20.0 (Chicago, Illinois). Descriptive statistics were used to summarize the participants' baseline characteristics, including medians, minimum-maximum for continuous variables and numbers, and total percentages for categorical variables. The Kruskal-Wallis test was used to compare the baseline characteristics of categorical variables (age, duration of hospital day, and laboratory findings in Tables). Comparisons between groups for categorical variables (season, gender, and symptoms and clinical findings in Tables) were made using the Chi-square (χ 2 ) test. Statistical significance was defined as P values less than 0.05. Since we could not predict the patient count for the study at the beginning, we did a power analysis at the end of the study. When assessed for the presence of factors among seasons, the power was 84.5%.

Total of 90 infants with sepsis were enrolled in this study during the 24-months study period. Nasopharyngeal swabs were collected from all the patients. We compared patients among three groups as patients (n = 33) who had only viral positivity in nasopharyngeal swab, patients (n = 17) who had proven bacterial infection (bacteremia and meningitis) with or without viral infection, and patients (n = 40) without pathogen detection (viral or bacterial). No patient had a urinary tract infection. The median age of the groups were 5 months (minimum-maximum; 1-23), 6 months (minimum-maximum; 1-20), and 3.5 months (minimum-maximum; 1-21), respectively. Most patients were male in all three groups. No statistically significant differences were found between the groups in terms of gender (P = 0.19) and age (P = 0.36) ( Table 1) .

In viral infection group, 30.3% (n = 10) of patients had no underlying disease, the most frequent underlying disease was prematurity (24%, n = 8). In the bacterial infection group, gastrointestinal and immunodeficiency diseases were commonly seen at the same rate (23.5%, n = 4) and only %11.8 of patients had no underlying disease. In no proven infection agent group, neurological (25%, n = 10) and immunodeficiency (20%, n = 8) disease were most common underlying disease and only 12.5% of patients had no underlying disease.

According to seasonal distribution, in winter and spring, patients with sepsis mostly had viral infection; however, in summer and autumn, patients were mostly in which we could not prove infection agents. The seasonal distribution was significantly different between the three groups (P = 0.02). Empirical therapy was started to all patients and switched according to the test results and clinical status of patients. Patients with bacterial sepsis had the longest duration of hospitalization (median; 28 days), although pediatric intensive care unit (PICU) stay rates and infection-related mortality rates were not different between groups. Overall mortality rate was 18.8% (n = 17) and the infection-related mortality rate was 12.2% (n = 11). Four patients with RVIs, five patients with no confirmed infection, and two patients with both bacteremia and RVI died. However, there was a statistically significant difference between groups in terms of duration of hospitalization (P = 0.04; Table 1 ).

Symptoms and clinical findings of patients are presented in Table 2 . A cough was the only symptom that had statistical significance between groups (P = 0.02), with the highest rate in the viral infection group (36.4%, P = 12). In laboratory findings of patients, median thrombocyte count was lower in the bacterial infection group than the others (P = 0.01). There was no difference in other parameters (white blood cell count, active prothrombin time, international normalized ratio, d-dimer, and C-reactive protein; Table   3 In addition, we evaluated patients in two groups as HAS (40%, n = 36) and CAS (60%, n = 54). No difference was found between two group in terms of age, sex distribution, season, duration of hospitalization, PICU stay, infection-related mortality rate, and viral infection rate.

However, 31.5% (n = 17) of patients in the CAS group had no underlying disease, and in the HAS group all the patients had several underlying diseases such as prematurity (27.8%) and neurological diseases (19.4%).

There was the statistically significant difference between groups with regard to bacterial bloodstream infection rate (P = 0.001). In the HAS group 33.3% (n = 12) patients had bacteremia, whereas in the CAS group only 5.6% (n = 3) patients had bacterial infection. Viral infection rates were equal in groups (Table 4 ). Twenty-seven (30%) patients received antibiotics before the sepsis diagnosis.

We prospectively evaluated a group of infants for RVIs from one month to two years with possible sepsis in our tertiary hospital.

Virus detection in pediatric departments is an important issue, which has been considered to contribute to successful antibiotic infections, mostly in winter, could be explained due to respiratory virus epidemics, which are often seen in winter-like influenza and photoperiodicity influence on leukocyte function and relative D vitamin deficiency in wintertime which has an important role in the modulation of both innate and cellular immune responses. [23] [24] [25] We found that RV infections were seen throughout the year, especially in autumn and spring when we evaluated only patients with RV infection. Studies from our country indicated that RV infections were seen during all year. Gülen et al found that RV infections were detected especially winter and spring and in another study RV infections seen more frequently in early spring and winter. 26, 27 The causes of sepsis are so important for the duration of hospitalization and the severity of the disease. In our study, patients had bacterial sepsis who had the longest duration of hospitalization (median; 28 days), although pediatric intensive care unit (PICU) stay rates and infection-related mortality rates were not different between groups. There was the statistically significant difference between groups in terms of duration of hospitalization (P = 0.04).

This could be related that patients with bacteremia had longer antibiotic treatment duration. In addition to this, patients with RVIs had same infectious mortality rate and PICU stay rate showed us that we should consider patients with sepsis in terms RVIs due to the same rate of mortality and PICU stay. Miggins et al investigated critically ill patients in the USA and detected that viral infections may play a significant yet unrecognized role in overall outcomes of ICU patients. 28 In our study, hRV and influenza were the most commonly seen viruses with the rate of 16.7% and 7.8%, respectively ( Figure 1) . It was reported that influenza causes an increased risk of sepsis in the literature. 28 Also, we know that hRV are associated with severe respiratory infections in patients with immunocompromised or chronic lung disease. 29 Twenty-seven (30%) patients received antibiotics before the sepsis diagnosis. This could interfere with blood culture tests for bacteria and for this reason we had found, CDC recommends to obtain cultures before starting antimicrobial therapy.

Our study has also some limitations including the small sample size and one-center results because viral infection rates appear to vary substantially between different centers based upon limited prior reports in infants. Another limitation is that detection of nucleic acid from the respiratory tracts of infants could represent false-positive results, prolonged shedding from a precede infection, or even colonization rather than acute infection. Another limitation is that we did not obtain respiratory samples specifically at the beginning of clinical findings of sepsis in our outpatient population, we were able to collect the specimens upon admission to the emergency department. Despite many of these limitations, this is the first infant population study that has documented RVIs among patients with sepsis from our country.

Identification of the causative pathogen provides an opportunity to select the ideal treatment that improves survival rates, overall patient outcomes, reduces hospitalization duration, and overall hospital costs. 33 As well as further research should focus place of RVIs in sepsis, whether viruses are a cause of sepsis or are they colonization in the nasopharynx. This could solve with a prospective study with serial quantitative PCR analyses in asymptomatic, septic, and ill but nonseptic children. We believe that our conclusion, which is having significant viral etiology in patients with sepsis is underdiagnosed by clinicians, is warranted. Diagnosing RVIs early may be of help for the clinical decision and treatment strategies.

The authors have stated explicitly that there are no conflicts of interest in connection with this study.

Kubra Aykac http://orcid.org/0000-0002-0974-4765

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How to cite this article

Respiratory viral infections in infants with possible sepsis