Non-comorbid Respiratory Factor and Work of Breathing in Pediatric COVID-19 Patient: How is Their Synergistic Correlation with the Level of Care?

Background: Work of breathing (WOB) and non-comorbidities factors in the respiratory system are the two probable findings in pediatric COVID-19 patients. However, the association of those factors with level of care was not well reported. Purpose: This study aimed to identify the relation between potential predictors including comorbidity, low nutritional fulfillment, infectious disease, shock, cough, O2 saturation reduction, abnormal blood gas analysis and sore throat with the level of care among pediatric COVID-19 patients. We also analyzed the synergistic correlation of non-comorbidities factors in the respiratory system and work of breathing to predict level of care in pediatric COVID-19 patients. Methods: A cross-sectional study was conducted in the six referral hospitals from July to September 2020 in four provinces in Indonesia. An observation checklist was used to collect data from the medical records of pediatric patients with COVID-19, including medical diagnosis, demographic, and clinical manifestation. This study included 423 participants aged from 0 to 18. The multivariate logistic regression was performed to test the adjusted odds ratios (AORs) with the 95% confidence intervals (CIs) of the association between WOB, non-comorbid respiratory, and level of care. Moreover, dummy variables (2x2) were made to analyze synergistic correlation of non-comorbid respiratory disease and WOB. The AOR with the 95% CIs was applied in the association between the complication of non-comorbid respiratory diseases and high work of breathing with level of care among pediatric patients with COVID-19. Results: Results showed that age, presence of comorbidity, nutritional fulfillment, infectious disease, shock, work of breathing, O2 saturation reduction, abnormal blood gas analysis, sore throat, and convulsive meningeal consciousness were significantly associated with the level of care ( p <0.05). Pediatric patients with non-comorbid


Setting and samples
The sample size was estimated using G-Power 3.1 software (El Maniani et al., 2016).The sample size was calculated by employing the effect size of the study based on a previous study with an effect size of 4.89 (Prata-Barbosa et al., 2020) for the level of care among patients with COVID-19.This previous study estimated the determinant factor of invasive mechanical ventilation in the PICU unit.The potential confounding factors were also considered, thus an alpha level (α) = (0.001) was utilized to lowered type I error and 80% power (1-ß) in a two-sided z-test (Cohen, 1988).The minimum sample size needed was 379 and considering an estimated 10% incompletion rate, a total of 423 participants were recruited for this study.
The study was conducted in six COVID-19 referral hospitals to ensure high variety in the pediatric level of care.The actual samples taken in this study using consecutive sampling were a secondary data of medical records with inclusion criteria: medical records of children aged ≤18 years; suspected (suspected) or confirmed (positive) COVID-19.As for the exclusion criteria, medical records suffering from data insufficiency were excluded from the study.
Participants were diagnosed with COVID-19 based on the WHO guidelines (World Health Organization, 2020).For simplicity's sake, the case definition used by the National Clinical Research Center for Child Health, Zhejiang University School of Medicine, whereby the case was classified as (1) suspected or probable case, and (2) confirmed case (Chen et al., 2020).

Measurement and data collection
A structured paper-based questionnaire was used to collect data from the medical records of pediatric patients in the six COVID-19 referral hospitals, Indonesia.Each questionnaire includes three section: (1) demographic data; (2) clinical manifestation; (3) existing diseases, and (4) level of care.The questionnaire was developed through a trial phase in three hospitals, to ensure the questionnaire was easy to understand by data collectors in each centre (Kouame, 2010).Before collecting data, nursing staffs from each centre were trained to use the questionaries.Existing data were tabulated by the research coordinator from each centre into a Google form sent to the principal investigator.Definition for major variables is described below.

COVID-19 status and level of care
COVID-19 status was determined by collecting samples using a real-time reversetranscriptase polymerase-chain-reaction test (RTPCR) (Dong et al., 2020;Zimmermann & Curtis, 2020).To collect RTPCR sample, health care staffs were trained by the Ministry of Health Republic of Indonesia to ensure the quality of specimens meet a highly quality standard.
Nurse Media Journal of Nursing, 12(3), 2022, 393 Copyright © 2022, NMJN, e-ISSN 2406-8799, p-ISSN 2087-7811 Ward level is usually associated with the level of patient illness severity (Garland et al., 2016).In terms of pediatric COVID-19 severity, it was classified as follows: asymptomatic infection, mild disease, moderate disease, severe disease, and critical illness (Buonsenso et al., 2020;The National Health and Health Commission of & China, 2020).The three types of ward level in line with the COVID-19 severity illness were used as follows: (a) isolation for clients with asymptomatic and mild disease, (b) intermediate level for moderate disease, and (c) intensive isolation for severe and critically ill cases (Carlotti et al., 2020;Mostafa et al., 2020).
Figure 1.Flowchart of participants' recruitment

Demographic characteristics
The age classification was based on Ritchie (2020), divided into 0-9 years and 10-19 years.In addition, it is necessary to add subgroups to the classification of infants aged 0-1 year because the study found that severe COVID-19 cases in children aged ≤1 year are more likely admitted to ICU compared to the older (Bellino et al., 2020)

Presence of comorbid factors
Comorbidity is defined as the co-occurrence of more than one disorder in the same individual (Gulbech Ording & Toft Sørensen, 2013).Currently, there is no agreement on how to describe comorbidity in COVID-19; therefore, data on diabetes, hypertension, cardiovascular disease, Chronic Obstruction Pulmonary Disease (COPD), chronic liver or kidney disease, malignancy, immune-compromised state, obesity (body mass index (BMI) of 30 or higher, sickle cell disease, thalassemia, cerebrovascular disease, Co-existing infection (HIV, sepsis) from various sources were calculated (CDC, 2020;Sanyaolu et al., 2020;Zhou et al., 2020).
Work of breathing (WOB) has been defined as an effort to meet the body's ventilatory demand.In spontaneous breathing, it will represent by respiratory muscles work (Muñoz et al., 2019).Increased breathing definition commonly referred to as respiratory distress (Tulaimat et al., 2014).In this study, increased WOB was noted encompassed dyspnea, tachypnea, rhonchi, rales, grunting, chest wall retraction, nasal flaring, subcostal retraction, head bobbing, and paradox breathing (McCool D, 2012).One criterion above found in the patient, would be classified as an increase in WOB.

Data analysis
The X 2 test was used to analyze the distributions of participant characteristics.Continuous data for instances age has been categorized based on Our World in Data (Roser et al., 2020).The logistic regression analysis was utilized to examine the unadjusted (ORs) with the 95% confidence intervals (CIs) of the association between work of breathing, non-comorbid respiratory with the level of care among pediatric patients with COVID-19.The multivariate logistic regression test was performed to test the adjusted odds ratios (AORs) with the 95% confidence intervals (CIs) of the association between WOB, non-comorbid respiratory with level of care among pediatric with COVID-19 and controlling the covariates including no symptom, sore throat, seizures, abnormal blood gases, decreased oxygen saturation, shock, low nutritional fulfillment, and age.
Further, the synergistic correlation of WOB and non-comorbid respiratory was analyzed after creating four dummy variables for the following four (2x2) (Knol et al., 2007;Kurniasari et al., 2021).The adjusted odds ratio with the 95% confidence intervals (CIs) was applied in the association between the complication of non-comorbid respiratory diseases and high WOB with the level of care among pediatric with COVID-19.The covariates for cough, no symptoms, sore throat, seizures, abnormal blood gases, decreased oxygen saturation, shock, low nutritional fulfillment, and age were controlled, using p-value of <0.05, which was considered statistically significant.All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) ver.25.0 (Chicago, IL, USA).

Sociodemographic characteristics and health status of participants
In total, 423 participants were included with age ranged from 0 to 18 years old.The participants were divided based on the level of care during hospitalization.Among 423 participants, most of them received the level of care in the ward.The majority of them (n=113) were >29 days ~ ≤12 months old, were boys (n=240).Most of the participants had no presence of infection disease (n=348) and a fever (n=264) (Table 1).

The association between the major determinant factors with the level of care
Results of the univariate analysis revealed that age, presence of comorbidity, nutritional fulfillment, infectious disease, shock, cough, work of breathing, O2 saturation reduction, abnormal blood gas analysis, sore throat, seizures and non-comorbid respiratory were significantly associated with the level of care (p<0.05)(Table 1).All the significant variables were included into the model using multiple linear regression models.The adjusted β coefficients and 95% CIs of the level of care are presented in Table 2. Participants with work of breathing were more likely to admit to intensive care compared to those who did not present work of breathing after adjustment the covariate and less likely to admit in the low level of care (inward).Additionally, the participants who had non-comorbid respiratory complications were more likely to receive intermediate as well as intensive care compared to those who did not have a non-comorbid respiratory complication.However, after adjusting the covariate, the association was no longer significant (Table 2).

Synergistic correlation of non-comorbid respiratory complication and work of breathing with the level of care
Table 3 shows the synergistic effect of non-comorbid respiratory complication and WOB among pediatric patients.Participants with the presence of both non-comorbid respiratory complication and WOB had synergistically significant to admit the intermediate and intensive level of care compared to those who did not present the symptoms.However, those who present the WOB without non-comorbid respiratory are more likely to admit the intensive care (Table 3).

Discussion
This study aimed to identify the synergistic association of non-comorbidities factors in the respiratory system and work of breathing (WOB) with the level of care of pediatric COVID-19 patient.This study found that both non-comorbid respiratory and increased WOB had a significant relationship with the level of care for pediatric patients with COVID-19.Data showed pediatric patients with no non-comorbid respiratory and increased WOB had a 15.59 times higher risk of requiring PICU care level (p<0.01).These results indicate the highest risk of the overall results of this study.Meanwhile, pediatric patients who experienced both non-comorbid respiratory and increased WOB had a 5.76 times risk of requiring an intermediate level of care (p<0.05), and a 9.32 times higher risk of requiring a PICU level of care (p<0.05).
Patients with high-level WOB were more likely to admit intensive care after adjusting covariate.Based on this study, it was found that pediatric patients with increased WOB had 15.59 times higher risk of requiring intensive care levels.Where the increase in WOB is in line with the increase in the need for respiratory support.These results are in line with the study conducted by Shekerdemian et al. (2020) which found that 48 children with COVID-19 admitted to participating PICUs presented with respiratory symptoms (Shekerdemian et al., 2020).However, these results are in contrast to data from a study conducted by Swann et al., (2020), in which children admitted to critical care were more likely to have presented other clinical signs with diarrhea, conjunctivitis, and altered consciousness/confusion (Swann et al., 2020).
Pediatric patients with non-comorbid respiratory alone were not significantly related to the level of care.This is in line with a study conducted by Chen (2021) which examined respiratory tract infection which is one of the non-comorbid respiratory diseases in children during the COVID-19 pandemic.This study revealed that 73% of pediatric patients were 11% admitted to the ICU.Whereas adult patients who required ICU were likely higher than pediatric (19%) (Chen et al., 2021).Non-comorbid respiratory infections are common in COVID-19 patients in children.Of all research respondents, 56.7% had non-comorbid respiratory.Moreover, acute respiratory infections, ARDS, and pneumonia are among the most common manifestations of COVID-19 in children.This is in line with a study by Souza et al. (2020) which conducted research from a systematic review and metanalysis data from 38 studies (1124 cases) about the clinical manifestation of children with COVID-19 and found that 145 children (36.9%) were diagnosed with pneumonia and 43 children (10.9%) with upper airway infect were reported.Reduced lymphocyte count was reported in 12.9% of cases (Souza et al., 2020).
Pediatric COVID patients with increased WOB and without respiratory comorbidities showed significant correlate to the intensive care admission.In adults, the most common cause of ICU admission is an acute hypoxemic respiratory failure with or without severe hypercapnia due to acute respiratory distress syndrome (ARDS; 60-70%), followed by shock (30%), myocardial dysfunction (20-30%), and acute kidney injury (AKI; 10-30%) (Sun et al., 2020).Meanwhile, about 65-70% of children require treatment in the PICU, 40-60% of vasoactive drugs, and 15-25% require mechanical ventilation.(Gupta et al., 2021).Reports from China state that it takes an average of 8 days for dyspnea to develop and 9 days for pneumonia/pneumonitis to develop (Huang et al., 2020).
Other studies in line with this finding found that among the 66 symptomatic admitted children, 55% required respiratory support, and 17% required critical care.A total of 40 admitted patients had chest radiographs performed on admission, of which 25 (63%) had abnormal findings.Five out of 39 (13%) admitted patients tested with a respiratory pathogen panel had coinfection with an additional respiratory tract virus (Graff et al., 2021).However, a study conducted by Götzinger et al. (2020) found that significant risk factors for requiring ICU admission in multivariate analyses were being younger than one month, male sex, pre-existing medical conditions, and presence of lower respiratory tract infection signs or symptoms at presentation.
COVID-19 patients in children with non-comorbid respiratory and increased WOB synergistically significant with intermediate and intensive care.COVID-19 patients in children who experience both non-comorbid respiratory and increased WOB can occur in some patients with ARDS, pneumonia, or non-comorbid respiratory diseases that can interfere with the respiratory system and have manifestations of increased WOB.In a previous study comparing the main causes of adult and pediatric COVID-19 patients requiring intensive care, it was found that all the adults were admitted to intensive care due to ARDS (Girona-Alarcon et al., 2021).
Another study suggested that the main cause of adult COVID-19 patients requiring intensive care was multi-organ dysfunction syndrome (MODS) with ARDS (67%).Of the ICU admissions, 71% required mechanical ventilation, 35% vasoactive support, 17% renal replacement therapy, and 11% ECMO.Meanwhile, in pediatrics with COVID-19, the high-risk Nurse Media Journal of Nursing, 12(3), 2022, 399 Copyright © 2022, NMJN, e-ISSN 2406-8799, p-ISSN 2087-7811 pediatric population includes children with underlying conditions such as broncho-pulmonary hypoplasia, airway/lung anomalies, severe malnutrition, and congenital heart disease (Yang et al., 2020).This is in line with our findings.Moreover, our study provides more information regarding synergistic correlation of WOB and non-comorbid in the respiratory system.

Implications and limitations
Though non-comorbid respiratory has never been reported affecting the severity of pediatric patients with COVID-19, our study highlights its presence together with increased WOB, and this condition would likely increase the risk of the higher level of care.This study showed that nurses and doctors can perform more accurate triage of the patient's condition through a comprehensive assessment, one of which is through increased WOB.Accurate mapping of the level of care can also be useful in increasing the effectiveness and efficiency of patient care while in the hospital and impacting patient outcomes.Our existing data were taken from six COVID-19 referral in four provinces which may sufficiently represent COVID-19 cases in the Indonesian pediatric population.This study had several strengths, but it also had some limitations.Our study did not assess the biological marker of the diseases mechanism which is important to examine its relationship with the level of care among COVID-19 patients.Thus, further research involving the complex mechanism including biological aspect is highly recommended.Also, although our data represent the level of care among COVID-19 patients across Indonesia in a time, however, follow-up data in the longer time is also recommended to examine the outcome of patients during hospitalization.

Conclusion
In conclusion, it was found that both non-comorbid respiratory and increased WOB had a significant relationship with the level of care for pediatric patients with COVID-19.In particular, an increase in breathing is one of the most important clinical signs in increasing the level of care for pediatric patients with COVID-19.However, the existence of non-comorbid respiratory did not correlate significantly with a higher risk of level of care.These results suggest the crucial role of the pediatric nurse in detecting the increased work of breathing in pediatric COVID-19 admitted to the hospital.

Table 1 .
Table 1 also provides bivariate analysis to select the potential variable that included in multivariate analysis.Sociodemographic characteristics and health status based on level of care (n=423)

Table 2 .
The major determinant factor of the level of careamong pediatric patients withThe OR was calculated with a binary logistic regression test.The AOR was calculated by a multiple logistic regression test and adjusted for cough, no symptoms, sore throat, seizures, abnormal blood gases, decreased oxygen saturation, shock, low nutritional fulfillment age.
* Indicates a significant difference in values between groups at p<0.05.** Indicates a significant difference in values between groups at p<0.01

Table 3 .
Synergistic correlation of non-comorbid respiratory complication and work of breathing on level of care among pediatric patient with