Acute Kawasaki Disease With Concomitant Adenovirus Infection

Abstract

Background

Adenovirus infection is the most common condition in the differential diagnosis of acute Kawasaki disease (KD), but it may also occur as a concomitant infection, the relevance of which has been incompletely defined.

Methods

A prospectively maintained, single-center database of all presenting patients with acute KD was queried. Patients with laboratory evidence of adenovirus infection were compared with patients with no laboratory evidence of any concomitant infection of any type. We sought to determine differences in demographics, clinical and laboratory features, treatment received, and coronary artery (CA) outcomes.

Results

From 1997 to 2023, a total of 1442 patients who had no laboratory evidence of concomitant infection and 39 patients positive for adenovirus were compared. There were no differences regarding demographics and few differences regarding clinical features at presentation, with 72% in each group meeting guideline criteria for a diagnosis of complete KD. Patients positive for adenovirus were less likely to have rash (69% vs 88%; P < 0.001), were more likely to have respiratory (61% vs 20%; P < 0.001) and gastrointestinal symptoms (47% vs 27%; P = 0.007), and had less severe laboratory abnormalities. Adenovirus positivity was not associated with an increased risk of resistance to intravenous immunoglobulin. CA involvement was not observed in any patient in the adenovirus group (P = 0.049).

Conclusions

The presence of positive evidence of adenovirus in the setting of acute KD does not appear to confound the diagnosis of KD, the response to which should be prompt initiation of immunomodulatory treatment. CA outcomes appear to be excellent.

Kawasaki disease (KD) is an acute self-limited vasculitis affecting young children, the important sequela of which is the development of coronary artery (CA) aneurysms.^1,2 The diagnosis is made using a set of clinical criteria, although laboratory features and the presence of CA involvement can support the diagnosis when these criteria are insufficiently present. Although KD is not a diagnosis of exclusion, the differential diagnosis includes certain common and rare infectious illnesses, including adenovirus infection. Adenovirus infection is common in children less than 5 years of age, with most children having had at least 1 infection episode by 10 years of age.³ Although the age distribution is similar, KD is rare, particularly in non–East Asian countries.⁴ The majority of children with adenovirus infection have mild symptoms, commonly upper respiratory symptoms, gastroenteritis, and conjunctivitis.³ In contrast, patients with KD appear very irritable and acutely ill. Nonetheless, clinical features can overlap, making differentiation challenging. Adenovirus infection can be confirmed with specific laboratory testing, now commonly polymerase chain reaction (PCR) of respiratory secretions; this is not the case for KD.

Approximately one-third of patients with acute KD have evidence of concomitant infections, including adenovirus.^5,6 It is not clearly known if this is coincidental or part of an inciting stimulus of a pathophysiologic pathway that leads to immune system dysregulation and hyperinflammation in susceptible individuals, which manifests as KD.^7,8 There have been some case reports of patients with acute KD and concomitant adenovirus infection.9, 10, 11 Whether patients meeting KD criteria with concomitant adenovirus detection have similar features, clinical course, response to treatment, and CA outcomes remains poorly defined. We sought to compare demographics, clinical features, laboratory findings, treatment patterns, and CA outcomes of patient diagnosed with acute KD with concomitant adenovirus infection vs those without evidence of any type of infection.

Methods

From 1997 to 2023, a total of 2697 patients were assessed and diagnosed with acute KD at the Hospital for Sick Children, Toronto, and the information was abstracted and entered into a prospectively maintained database. Of these patients, 405 lacked sufficient laboratory information to verify the presence or absence of concomitant infections and hence were excluded. Of the remainder, 811 had laboratory evidence of concomitant infections other than adenovirus and were likewise excluded. This left 2 groups, including 1442 patients without concomitant infection and 39 with laboratory evidence for adenovirus (viral culture, rapid antigen detection, and PCR). The exact test used was not recorded. Data regarding patient demographics, clinical features, laboratory values at presentation, treatment received, and CA outcomes were included in the analysis. CA dimensions abstracted from echocardiogram reports were converted to body surface area–corrected z scores based on published regression equations from a normal population.¹² The z scores were further categorized as normal, dilation, and aneurysm based on published z-score categories.¹ Group comparisons were performed using χ² or Fisher exact tests for categorical variables and Kruskal-Wallis analysis of variance for continuous variables, as appropriate, with statistical significance defined as P < 0.05.

Results

There were no significant differences between the groups regarding sex or age (Table 1). Regarding typical KD clinical features, the groups did not differ significantly regarding the presence of conjunctivitis, extremity changes, and oral changes (Table 2). Patients positive for adenovirus were significantly less likely to have rash and were somewhat more likely to have cervical adenopathy. The proportion of patients meeting American Heart Association criteria for complete KD was identical between the groups. However, patients positive for adenovirus were significantly more likely to have associated respiratory and gastrointestinal symptoms. Severe presentations with shock and intensive care unit admission were rare in both groups and did not differ significantly.

Table 1.

Demographics

Variable∗	Adenovirus negative (n = 1442)	Adenovirus positive (n = 39)	P value
Sex: male, n (%)	893 (62)	21 (54)	0.30
Age at admission (y), median (IQR)	3.0 (1.6, 5.1)	3.7 (2.4, 5.8)	0.09

IQR, interquartile range (values at the 25th and 75th percentile).

^∗For ethnicity, there are insufficient data to compare groups.

Table 2.

Clinical features

Variable	n	Adenovirus negative (n = 1442)	n	Adenovirus positive (n = 39)	P value
Conjunctivitis, n (%)	1410	1229 (87%)	39	33 (85)	0.64
Cervical lymphadenopathy, n (%)	1410	791 (56)	39	28 (72)	0.051
Rash, n (%)	1416	1239 (88)	39	27 (69)	<0.001
Extremities changes, n (%)	1414	1092 (77)	39	28 (72)	0.43
Oral mucosal changes, n (%)	1408	1216 (86)	39	34 (87)	0.89
Meet AHA criteria for complete KD, n (%)	1406	1010 (72)	39	28 (72)	1.00
Respiratory symptoms, n (%)	1416	283 (20)	38	23 (61)	<0.001
Abdominal symptoms, n (%)	1421	388 (27)	38	18 (47)	0.007
Shock, n (%)	1074	10 (1)	37	0 (0)	1.00∗
ICU admission, n (%)	1343	18 (1)	39	0 (0)	1.00∗

AHA, American Heart Association; ICU, intensive care unit; KD, Kawasaki disease.

^∗From the Fisher exact test.

Laboratory features at presentation did not differ significantly regarding hemoglobin, lymphocyte and basophil counts, and C-reactive protein or erythrocyte sedimentation rate (Table 3). Patients positive for adenovirus had significantly lower counts of white blood cells, neutrophils, eosinophils, and platelets. They also had significantly lower levels of alanine aminotransferase but not aspartate aminotransferase. Albumin levels were not significantly different between the groups.

Table 3.

Laboratory values at presentation

Variable∗	n	Adenovirus negative (n = 1442)	n	Adenovirus positive (n = 39)	P value
Hemoglobin (g/L)	1038	114 (105, 121)	32	114 (110, 120)	0.51
White blood cell count (×109/L)	1038	12.7 (9.6, 16.6)	32	9.6 (7.3, 13.9)	0.007
Neutrophils (×109/L)	776	7.3 (4.7, 10.4)	29	5.5 (4.0, 8.0)	0.034
Lymphocytes (×109/L)	774	2.9 (1.8, 4.3)	29	2.6 (1.7, 4.0)	0.49
Basophils (×109/L)	475	0.05 (0.01, 0.11)	16	0.05 (0.03, 0.08)	0.83
Eosinophils (×109/L)	687	0.25 (0.11, 0.50)	19	0.03 (0.01, 0.10)	<0.001
Platelet count (×109/L)	1032	355 (274, 459)	32	227 (223, 379)	0.004
C-reactive protein (mg/L)	877	40 (27, 88)	31	38 (23, 58)	0.15
Erythrocyte sedimentation rate (mm/h)	945	69 (40, 95)	32	61 (43, 79)	0.22
Alanine aminotransferase (U/L)	956	30 (19, 68)	31	18 (12, 25)	<0.001
Aspartate aminotransferase (U/L)	855	37 (28, 55)	28	35 (31, 43)	0.94
Albumin (g/L)	673	37 (34, 41)	23	38 (34, 42)	0.29

^∗Median with interquartile range (values at the 25th and 75th percentile).

Although patients positive for adenovirus were significantly more likely to receive initial intravenous immunoglobulin (IVIG), they were not different regarding the need for additional IVIG doses or intravenous or oral steroids (Table 4). No patients positive for adenovirus received inotropic agents.

Table 4.

Treatment

Variable	n	Adenovirus negative (n = 1442)	n	Adenovirus positive (n = 39)	P value
Received any IVIG, n (%)	1430	1254 (88)	39	39 (100)	0.02∗
Received 2 or more IVIG doses, n (%)	1239	206 (16)	38	4 (11)	0.39∗
Received IV steroids, n (%)	1440	80 (6)	39	0 (0)	0.27∗
Received oral steroids, n (%)	1440	73 (5)	39	0 (0)	1.00∗
Received inotropes, n (%)	1072	8 (1)	37	0 (0)	1.00∗

IV, intravenous; IVIG, intravenous immunoglobulin.

^∗From the Fisher exact test.

CA dilatation or aneurysms were significantly less likely for patients positive for adenovirus, with lower maximum CA z-score in any branch and lower maximum CA z-score category (Table 5). All patients positive for adenovirus had normal CA dimensions and z scores.

Table 5.

Coronary artery involvement

Variable	n	Adenovirus negative (n = 1442)	n	Adenovirus positive (n = 39)	P value
CA abnormality	1423		38		0.049
Normal, n (%)		1268 (89)		38 (100)
Dilation, n (%)		29 (2)		0 (0)
Small CAA, n (%)		59 (4)		0 (0)
Medium CAA, n (%)		31 (2)		0 (0)
Large CAA, n (%)		36 (3)		0 (0)
Maximum z score for any CA branch∗		0.41 (0.18, 0.88)		0.31 (0.06, 0.51)	0.032‡

CA, coronary artery; CAA, coronary artery aneurysm.

^∗Median with interquartile range.

^†From the Mantel-Haenszel χ² test.

Discussion

In this comparison of patients with acute KD who were positive for adenovirus vs those with no evidence of concomitant infection, there were few significant differences regarding demographics, clinical and laboratory features, and treatment received. An identical proportion of patients in each group met American Heart Association criteria for a diagnosis of complete KD. Those patients positive for adenovirus were significantly more likely to have associated respiratory and gastrointestinal symptoms, which can be hallmarks of adenovirus infection. The most notable difference was the absence of CA involvement for those patients positive for adenovirus.

Clinical overlap of acute KD with adenovirus infection

Adenovirus infection is a very common childhood illness, sometimes asymptomatic, often associated with upper respiratory symptoms, gastrointestinal symptoms, or conjunctivitis, and rarely associated with serious consequences including pneumonia, myocarditis, and meningoencephalitis.³ It is perhaps the most common condition cited in the differential diagnosis of acute KD.¹ Several adenoviral syndromes, such as pharyngoconjunctival fever, adenoviral exanthem, and adenoviral gastroenteritis with systemic inflammation, may closely mimic KD, contributing to diagnostic uncertainty, particularly when adenovirus is detected by PCR. The most common overlapping clinical features include prolonged fever, conjunctivitis, cervical lymphadenopathy, oral/pharyngeal changes, rash (less frequent), and elevated inflammatory markers.

There have been attempts to identify differentiating features between KD and adenovirus infection. Choi et al.¹³ compared patients with KD with patients with acute adenovirus infection and noted that patients with KD were younger and had higher levels of N-terminal pro–brain natriuretic peptide. This biomarker has been shown to be a useful diagnostic tool for KD.^14,15 Fabi et al.¹⁶ compared patients with adenovirus infection with those with either acute KD or multisystem inflammatory syndrome in children (MIS-C), and noted that the patients with adenovirus were younger, more likely to have pharyngotonsillitis, cough, or rhinorrhea, but less likely to have conjunctivitis, oral changes, skin rash, or extremity changes. They developed a clinical scoring system that differentiated patient groups with a sensitivity of 100% and a specificity of 80%. Kim et al.¹⁷ noted that, compared with patients with adenovirus infection, patients with KD who were positive for adenovirus were more likely to have oral changes, sterile pyuria, and higher C-reactive protein.

Concomitant infections in the setting of acute KD

Although adenovirus infection may mimic acute KD, the 2 conditions are not mutually exclusive. Concomitant infections are common in patients presenting with acute KD. Baker et al.¹⁸ reported that in the 10 days preceding a diagnosis of acute KD, 61% of patients had gastrointestinal symptoms and 35% had respiratory symptoms, suggesting the presence of concomitant infection. An initial single-center study reported by Benseler et al.⁵ noted that 33% of patients with KD had 1 or more confirmed concomitant infections, but that the presence of infection was not associated with either IVIG resistance or CA involvement. Dionne et al.⁶ noted a 38% prevalence of concomitant infection, with an increased risk of IVIG resistance, but not CA involvement. Hachisuka et al.¹⁹ noted a temporal correlation between PCR positivity for respiratory pathogens and the incidence of KD, with patients with KD having evidence of concomitant infection having a greater odds of IVIG resistance. Neubauer et al.²⁰ performed a meta-analysis including 18 observational studies and noted a mean prevalence of 30% for concomitant viral infections, with adenovirus accounting for 10%. They noted no association with either IVIG resistance or CA involvement.

As shown in our study, the concomitant infection may be adenovirus. Song et al.²¹ noted that patients with adenovirus infection and features mimicking KD had fewer KD features, predominance of adenovirus B and E, and a greater viral load when compared with patients with KD and concomitant adenovirus detection. Jaggi et al.²² noted a prevalence of adenovirus detection in 8.8% of patients with complete KD and 35% with incomplete KD, with a lower viral load for those with complete KD. They further suggested that molecular typing of the adenovirus detected may differentiate adenovirus B infection mimicking KD vs KD with concomitant adenovirus detection, representing persistence of adenovirus C in tonsillar tissue rather than infection and suggesting that adenovirus may be a confounding bystander.

The role of infections in the etiology of KD

Although the etiology of KD has long been hypothesized to be related to an infectious trigger, no single agent has been consistently identified. During the recent COVID-19 pandemic, the emergence of MIS-C as a delayed hyperinflammatory response to prior SARS-CoV-2 infection reinvigorated interest in this hypothesis. It was observed that MIS-C had important clinical features overlap with KD, including cardiac involvement, and a similar response to immunomodulatory treatment.²³ This led to debate as to whether MIS-C was a distinct illness possibly with some shared pathophysiologic features or a specific form of KD whereby there was a single and known etiologic trigger.^24,25 Interestingly, coronavirus had been a hypothesized etiologic agent in the past.26, 27, 28 With this in mind, detection of adenovirus in children meeting KD clinical criteria may reflect either a potential trigger for inflammation or an incidental finding, rather than a uniform causal agent.

Further evidence of an etiologic, albeit ecologic, link between KD and respiratory viruses, specifically adenovirus, comes from epidemiologic studies. Valtuille et al.²⁹ used administrative data in France to perform a time-series analysis, and concluded that approximately 35% of KD might be attributable to seasonal infections, with adenovirus being implicated for 24.4%. A molecular epidemiologic study reported by Marutani et al.³⁰ noted that of patients who had PCR testing for respiratory pathogens, patients with KD had increased evidence of prior infection, including adenovirus, compared with controls. An epidemiologic study by Low et al.⁷ using population-wide administrative data showed a significant association of an increased incidence of KD and viral intestinal infections, but not specifically for adenovirus infection.

Limitations

Given that the data were abstracted into a prospectively maintained database over a period of many years, changes in definitions and methods may have occurred over time. Missing values may introduce bias. The lack of information regarding which test was used to diagnose the presence of adenovirus in the affected patients is a recognized limitation. Information regarding adenovirus type and viral load would have been most helpful. Although we were unable to distinguish if positive adenovirus testing was due to active vs past infection, we presume that most had active infection given the high prevalence of respiratory and gastrointestinal symptoms. In addition, there was no protocol for testing for concomitant infections, and various investigations were not applied uniformly. Patients included in the group without concomitant infections may not have had complete testing, and some may have had missed infections. These various factors may have introduced misclassification bias, which may have influenced our comparison.

Conclusions

KD patients with vs without concomitant adenovirus infection have similar demographics and similar patterns of typical KD clinical features. Those with concomitant adenovirus are more likely to have additional associated respiratory and gastrointestinal symptoms, with a less remarkable clinical presentation and lesser laboratory abnormalities, together with no evidence of CA involvement. These findings may suggest that these patients likely had adenovirus infection with a KD-like clinical presentation vs an attenuated form of KD etiologically linked to adenovirus exposure, although uncertainty remains. Given this uncertainty, the presence of adenovirus detection alone should not be considered sufficient to exclude a diagnosis of KD but may be associated with a lower risk of CA involvement.

Ethics Statement

Institutional research ethics board approval was obtained and maintained for this study, with a waiver of patient consent granted.

Patient Consent

The authors confirm that patient consent is not applicable to this article. A waiver of patient consent was granted.

Funding Sources

The authors have no funding sources to declare.

Disclosures

BWM is a consultant for Chiesi, Esperion, and Ultragenyx, and a speaker for Ultragenyx. The other authors have no conflicts of interest to disclose.