Respiratory tract infections in children with allergic asthma on allergen immunotherapy during influenza season

To describle how respiratory tract infections (RTIs) that occurred in children with allergic asthma (AA) on allergen immunotherapy (AIT) during an influenza season. Data including clinical symptoms and treatment history of children (those with AA on AIT and their siblings under 14 years old), who suffered from RTIs during an influenza season (Dec 1st, 2019–Dec 31st, 2019), were collected (by face to face interview and medical records) and analyzed. Children on AIT were divided into 2 groups: stage 1 (dose increasing stage) and stage 2 (dose maintenance stage). Their siblings were enrolled as control. During the study period, 49 children with AA on AIT (33 patients in stage 1 and 16 patients in stage 2) as well as 49 children without AA ( their siblings ) were included. There were no significant differences in occurrences of RTIs among the three groups (p > 0.05). Compared with children in the other two groups, patients with RTIs in stage 2 had less duration of coughing and needed less medicine. Children on AIT with maintenance doses had fewer symptoms and recovered quickly when they were attacked by RTIs, which suggested that AIT with dose maintenance may enhance disease resistance of the body.

www.nature.com/scientificreports/ AA sensitized to house dust mites (HDM) on AIT often suffered from RTIs. The aim of this study was to discuss how RTIs occurred in children with AA sensitized to HDM on AIT by face to face interview and medical records.

Materials and methods
Subjects. Children with AA sensitized to HDM under 14 years old, who were receiving AIT during Dec 1st and Dec 31st of the year 2019 and whose clinical symptoms were well controlled, were included in this research. At the same time, their siblings of the patients who didn't suffer from allergic diseases were also enrolled in this research as control. The diagnosis of AA had to comply with the diagnostic criteria of AA according to the GINA guidelines 14 . All patients enrolled in this study had not received any influenza vaccines. The exclusion criteria were suspected cases of digestive tract infections, chronic RTIs such as tuberculosis, chronic respiratory diseases, immunosuppressive status (e.g., HIV infection, chemotherapy) and leukaemia. Patients with no siblings, or with siblings suffering from allergic diseases, or with siblings under 5 years old, or with siblings older than 14 years old, or accepting any influenza vaccines, or with rhinitis, or with bad controlled asthmas, and or refusing the research were also excluded from this research.  RTIs in children with AA on SCIT and control. During the study period, there were 21 cases, 7 cases and 32 cases with RTIs occurred in stage1, stage 2 and control, respectively. There were no significant differences in occurrences of RTIs among the 3 groups (p > 0.05). The occurrences of lower RTIs, fever, high fever, coughing, wheezing, medicine, seeking medical help, recurrent infections, fluid therapy and hospitalization were lower in stage 2 than those in stage 1 and control, respectively. However, no significant differences were observed in these indicators among the 3 groups (p > 0.05). (Table 1).
Clinical characteristics of children with RTIs. In order to discuss the severity of the RTIs, children with RTIs were divided into 3 groups: stage1, stage 2 and control, respectively. Duration of coughing was significantly less in stage 2 than those in stage 1 and control (p < 0.05), respectively. But no significant difference was observed in duration of coughing between stage 1 and control (p > 0.05). It was suggested that children with RTIs in stage 2 were susceptible to suffer less duration of coughing. The duration of medicine used for RTIs in stage 2 was less than that in stage 1 and control respectively, but there were no significant differences among them (p > 0.05).
No seeking medical help, recurrent infections, fluid therapy and hospitalization occurred in stage 2, which sug- Table1. RTIs in children with AA on SCIT and control. www.nature.com/scientificreports/ gested that patients with dose maintenance treatment may have mild symptoms during influenza season. More frequent seeking medical help were found in stage 1 than in stage 2 and control (p < 0.05), respectively. (Table 2).

Discussions
AA is a multi-factorial disease of the airway that precipitates from genetic predisposition and environmental triggers. The World Health Organization estimates that 235 million people have asthma and an additional 100 million people will develop the disease over the next 15 years 15,16 . Patients with AA are susceptible to suffer from RTIs due to an impaired antimicrobial defence [17][18][19][20] . A prospective study during the 2009 influenza pandemic showed that H1N1 preferentially infected asthmatics more than non-asthmatics 21 . AA exacerbations could be caused by RTIs frequently 22 . However, subsequent studies noted that asthmatics had fewer severe outcomes (including reduced bacterial pneumonia) compared to non-asthmatics [23][24][25][26][27] , which may be explained by the accelerated clearance of viruses in patients with AA 15,28 . But it was regretful that we could get few children with AA qualified who didn't receive AIT in allergy clinic. So we could not acquire medical data of RTIs in this kind of patients for comparison during the study period in this research. RTIs including common cold, acute tonsillitis, acute rhinosinusitis, flu-like illness, acute bronckitis, and pneumonia are the most common diseases in human beings 29 . Typical symptoms of patients with RTIs include sneezing, nasal congestion and discharge, sore throat, cough, fever, headache, and malaise, which were similar to those of patients with allergic rhinitis and asthma. RTIs are usually diagnosed clinically, based on symptoms. In this research, fever or sore throat was necessary in the diagnosis of RTIs. RTIs consist of upper RTIs and lower RTIs. Compared with upper RTIs, lower RTIs such as pneumonia is considered more severe. Most RTIs occur in winter days in northern hemisphere 30 . In our research, RTIs outbreak occurred in December, which suggested an influenza season. During that time, many patients with AA who were receiving AITs also suffered from RTIs. In order to discuss how RTIs occurred in children with AA who were receiving AIT, the research on RTIs in children with AA sensitized to HDM on AIT as well as their siblings in December of 2019 were conducted.
In the research, the occurrences of RTIs in patients with AA were similar to those in patients without AA, which was not consistent with the previous report 21 . And the occurrences of lower RTIs, fever, high fever, coughing, wheezing, medicine, seeking medical help, recurrent infections, fluid therapy and hospitalization in children with AA receiving dose maintenance treatment were less than those in patients with AA receiving dose increasing treatment and in patients without AA, which suggested that AIT with dose maintenance treatment may enhance RTIs resistance of the body. It was difficult to explain the phenomenon and further study should be needed.

Table2.
Clinical characteristics of children with RTIs. a Comparison between stage1 and stage2, p < 0.05; b Comparison between stage2 and control, p < 0.05. www.nature.com/scientificreports/ Frequent seeking medical help, recurrent infections, fluid therapy and hospitalization were important indicators in evaluating the severity of RTIs. In our research, no seeking medical help, recurrent infections, fluid therapy and hospitalization occurred in children with AA on dose maintenance SCIT. Especially, the duration of coughing in children with AA on dose maintenance SCIT was significantly less than those in children with AA on dose increasing SCIT and their siblings. All those above suggested that children with AA on dose maintenance SCIT were prone to have mild symptoms after RTIs attack. The explanation may be that SCIT can play important role in the protection of children from RTIs, which was consistent with the previous results 31 . Frequent seeking medical help was very high in children with AA on dose increasing SCIT. For guardians of the children with AA often worried about the health of children. They couldn't stop visiting doctors for medical help at the beginning of SCIT. The occurrence of RTIs in children with AA on dose increasing SCIT was similar to that in children without AA, which suggested that SCIT at dose increasing treatment could not protect the children from RTIs attacks.
However, this research still had some limitations. First, the number of the patients was limited.. And many variables couldn't get statistical significances. Second, limited to our research equipment, we couldn't detect the microbes of the RITs in laboratory. The influenza season was judged by the number of children with RTIs visiting our hospital and clinical experiences. Third, it was a retrospective research. Many data couldn't be acquired. Fourth, almost all the patients who came to allergy clinic for SCIT, no enough children with AA qualified who didn't accept SCIT could be acquired for comparison. Fourth, diagnoses were based on clinical symptoms; however, that is a rule in general practice 29 .
In summary, Children on AIT with maintenance dose had fewer symptoms and recovered quickly when they were attacked by RTIs, which suggested that AIT with dose maintenance may enhance disease resistance of the body.