Hu

Kawasaki disease (KD) is a common childhood disease that primarily affects small- and medium-sized arteries, particularly the coronary arteries, causing severe cardiovascular disease. It is generally accepted that KD is an autoimmune disorder activated by various microbial agents.[1-4]
Previous research found that roughly one-third of children with KD developed respiratory symptoms.[5,6] Before confirming the diagnosis of KD, febrile children with respiratory symptoms undergo laboratory testing to identify respiratory viruses.[5,6] Human rhinoviruses (HRV), a common cause of the common cold, can lead to various clinical manifestations beyond the typical upper respiratory symptoms, ranging from exacerbations of underlying lung diseases to extrapulmonary complications.[7] There have been isolated case reports tentatively suggesting a potential association between HRV infections and KD in children.[8,9] However, convincing evidence from well-designed epidemiological studies is still lacking, and the mechanisms behind this putative association remain elusive.
This study aimed to investigate the possible role of HRV infection in the development of KD. Children with KD who tested negative for respiratory viruses and those who tested positive for other respiratory viruses served as controls. By analyzing and comparing the three groups' demographic, clinical, and laboratory characteristics, this study attempted to gain further insight into the potential contribution of HRV infection to the pathogenesis of KD.

Patient selection. According to the American Heart Association, KD is distinguished by a 5-day fever and at least four of the five primary clinical characteristics of KD.[9] Between January 2022 and December 2022, children hospitalized with KD who tested positive for HRV were enrolled as the study subjects. At the same time, children with KD who tested positive for other respiratory viruses and those with negative respiratory virus tests were enrolled as control groups for comparison.
Laboratory tests. In addition to Mycoplasma pneumoniae and Chlamydia, a panel of respiratory viruses, including Flu A (H1N1 and H3N2) and B, respiratory syncytial virus (RSV), human parainfluenza virus (HPIV), HRV, human metapneumovirus (HMPV), human coronavirus (HCoV: NL63, OC43, 229E, and HKU1), human adenovirus (HAdV), and human bocavirus (HBoV)were detected in these specimens using commercial polymerase chain reaction (PCR) –capillary electrophoresis kits (Ningbo Haiers Gene Technology Co., Ltd., China).
Exclusion criteria. The exclusion criteria included the following: (1) patients with potential chronic diseases (e.g., congenital anomalies; genetic disorders; immunodeficiency; and autoimmune, cardiovascular, endocrinologic, hematological, hepatobiliary tract, or respiratory diseases), (2) coinfection with bacteria or other pathogens, and (3) patients with insufficient clinical data.
Statistical analyses. The statistical analyses were performed using SPSS ver. 21.0 software (SPSS, Inc., Chicago, IL, USA). Chi-square or Fisher's exact tests were used to compare group frequency distributions. Normally distributed continuous data are presented as mean ± standard deviation. The mean values between groups were compared using the independent sample t-test. A P value of <0.05 was considered statistically significant.

Demographic information and basic clinical features of the cases. A total of 21 children with KD tested positive for respiratory viruses, including 11 who were positive for HRV and 10 who were positive for other respiratory viruses: 5 for HCoV, 1 for HBoV, 2 for RSV, 1 for HAdV, and 1 for HMPV. Of the 11 KD children with HRV infection, 4 (36.4%) were admitted with respiratory tract infection, and 6 (54.5%) were admitted with KD accompanied by respiratory tract infection. In the discharge diagnosis, four cases (36.4%) had upper respiratory tract infections (URIs), one (9.1%) had tracheitis, and six (54.5%) had pneumonia. The demographic information and basic clinical features of the cases are listed in Table 1.

Table 1. The baseline characteristics of KD patients with respiratory viral infection.

Comparison of the clinical characteristics between KD patients with HRV infection and with other respiratory viral infections. The clinical characteristics between KD patients with HRV infection and other respiratory viral infections are listed in Table 2. Patients with HRV infection had the highest rate of clinical presentation as oral mucosal changes (p = 0.035) and cervical lymphadenopathy (p = 0.008).

Table 2. Comparison of the clinical characteristics between KD patients with HRV infection and other respiratory virus infections.

Comparison of the clinical characteristics between KD patients with and without respiratory viral infection. The results presented in Table 3 indicated that the rate of conjunctival injection was lower in the KD group with HRV infection than in the group of KD patients who tested negative for respiratory viruses (p = 0.028). The KD group with other respiratory viral infections had significantly lower conjunctival injection (p = 0.006), oral mucosal changes (p < 0.001), extremity changes (p = 0.008), cervical lymphadenopathy (p = 0.009), and white blood cell count (p = 0.043). In contrast, coronary artery lesions (p = 0.002) were substantially elevated.

Table 3. Comparison of the clinical characteristics between KD patients with and without respiratory viral infection.

Of the 11 KD children with HRV infection, 36.4% had a respiratory tract infection at the time of admission, and 54.5% had KD and a respiratory tract infection. While this study could not conclusively establish the sequence of events leading from HRV respiratory infection to KD onset, the association suggests that HRV infection likely contributes to the risk of developing KD, at least in some children. HRV infection may act as a co-factor that, in concert with other genetic and environmental factors, plays a role in the pathogenesis of KD in susceptible individuals. According to recent studies, one-half of patients with KD were positive for a respiratory virus by PCR, and a large proportion of patients with KD presented with concurrent respiratory symptoms.[5,11,12]
We found that children with HRV-associated KD had a much higher incidence of oral mucosal changes and cervical lymphadenopathy than children with KD related to other viruses. Even though numerous respiratory viruses display similar symptoms, they can have contrasted clinical manifestations.[13,14] In other words, while various respiratory viruses appear to trigger a generally comparable syndrome known as KD with overlapping symptoms and signs, differences remain in the precise clinical manifestations between instances linked to separate viruses. The observed clinical differences could stem from intrinsic HRV tropism for upper respiratory tissues or divergent immune responses provoked by HRV during KD pathogenesis compared to mechanisms of other respiratory viruses triggering KD.
In this study, children with Kawasaki disease linked to respiratory virus infection (virus-positive KD group) exhibited significantly lower rates of conjunctival injection, oral mucosal changes, extremity changes, and swollen lymph nodes than children without detectable respiratory virus (virus-negative KD group). However, coronary artery lesions were significantly more common in the virus-positive KD group, particularly in the subset of children with HCoV (3 cases) or HMPV (1 case) detected. These results suggest that:
1. Respiratory virus-associated KD may represent a clinically distinct subset with a different symptom profile due to distinct disease mechanisms.
2. HCoV and HMPV, in particular, may be linked to a very severe course of KD with a higher propensity for coronary lesions, potentially due to differences in viral tropism or host response. These viruses could more readily infect tissues involved in coronary damage or elicit an immune reaction promoting vasculitis. Genetics may also play a role in disease severity.
3. Larger scale studies are still needed to validate links between individual respiratory viruses and KD severity, as this study has limited power due to small sample sizes, especially for HMPV (1 case).
4. Longer follow-up is also needed to determine longer-term outcomes, as the degree of initial coronary changes does not necessarily directly correlate with the need for intervention or resolution of disease. Some cases with less initial coronary damage could progress over time, while others remain stable. Furthermore, studies have indicated that IVIG can stave off coronary artery abnormalities but has limited efficacy when treating existing coronary damage.[15] All patients with coronary artery anomalies in our study, both in the case and control groups, were given IVIG within two days of being diagnosed with KD. Only one case with concurrent HRV infection showed no response to IVIG treatment. As a result, this element has little impact on our conclusions.
Our study also has some limitations. First, this is a retrospective study, and not all KD patients underwent respiratory pathogen testing, so some potential positive cases may have been missed. Second, the number of positive cases is relatively small, which may lead to statistical bias. Finally, pathogen testing only involved the detection of common respiratory pathogens. In the control group, some infected KD cases may have had potential infections from non-respiratory viruses. Further large-scale, multi-center prospective studies are warranted to validate and extend these findings.

Possible Involvement of Infection with Human Rhinoviruses in Children with Kawasaki Disease