Clinical features of Kawasaki disease initially mimicking retropharyngeal abscess: a retrospective analysis

Kawasaki disease (KD), which was previously called cutaneous mucosal lymph node syndrome, is an acute, self-limiting vasculitis that predominantly affects children less than 5 years of age. KD mainly involves the middle and small arteries, especially the coronary artery, and can cause a serious incidence of cardiovascular complications, including coronary artery aneurysms (CAAs) and coronary artery stenosis or thrombosis [1]. KD has had increasing incidence worldwide, with the highest rates seen among Asian/Pacific Islanders at 29.8 per 100,000 children < 5 years. KD has various clinical presentations, and typical clinical manifestations include the presence of a fever lasting five or more days, bilateral conjunctival injection, oral changes such as cracked and erythaematous lips and strawberry tongue, cervical lymphadenopathy, extremity changes such as erythema or palm and sole desquamation, and polymorphous rash [1, 2]. Its diagnosis mainly relies on clinical manifestations due to the lack of reliable objective indicators. It is not difficult to diagnose KDs when they have a typical clinical manifestation. However, the diagnosis of incomplete KD (IKD) can be difficult. Some IKD cases initially presented as retropharyngeal abnormalitys, without the additional clinical criteria for the diagnosis of classic KD. They are very rare and are prone to misdiagnosis and missed diagnosis, often leading to poor prognosis. Most patients were misdiagnosed as retropharyngeal abscess because retropharyngeal abscess also mainly affects children, causing fever, cervical lymphadenopathy, leukocytosis, and elevated serum C-reactive protein (CRP) [3, 4]. Because the treatments of the two diseases are quite different and the diseases can be fatal if an appropriate treatment is not provided, distinguishing them is important. However, only a few case reports or case series have been reported in the literature [5‐12], and very few retrospective case–control studies have been conducted in this regard. Here, our retrospective study afforded the unique opportunity to describe and compare IKD patients initially presenting with retropharyngeal abnormalities, typical KD patients without retropharyngeal abnormalities and retropharyngeal abscess patients from a single centre. We sought to identify clinical, laboratory, and imaging features that distinguish patients with IKD initially presenting as retropharyngeal abnormalitys and retropharyngeal abscesss. To increase knowledge and awareness of this intriguing disease and to avoid delays in treatment and unnecessary surgery in KD children initially presenting with retropharyngeal abnormalities.

Kawasaki disease is an acute febrile systemic vasculitis of unknown aetiology, and its incidence is increasing yearly [13, 14]. As the aetiology of KD is unknown and there is a lack of specific laboratory indicators for KD, diagnosis still depends primarily on clinical manifestations. Fever, rash, hyperaemia in the bulbar conjunctiva, changes in the lip and oral cavity, peripheral extremity changes, and cervical lymphadenopathy are the main clinical presentations in KD patients. It is not difficult to diagnose KDs when they have a typical clinical manifestation. However, the incidence of IKD has been increasing annually in recent years [15‐17]. IKD has fewer characteristic clinical features than KD, causing delays in diagnosis, missed diagnosis or misdiagnosis. Some IKD cases initially presented as only fever and cervical lymphadenopathy and accompanying retropharyngeal low-density areas on CT, mimicking deep neck infection [7, 8, 18]. These cases are frequently misdiagnosed as retropharyngeal abscesss due to atypical symptomatology. However, the treatments of the two diseases are dramatically different, and some cases have been diagnosed when peripheral desquamation occurs in the recovery period, so the incidence of coronary artery disease (CAD) in them is high, which is related to delays in diagnosis [9, 18, 19]. To the best of our knowledge, this is the first retrospective case–control study that has compared the clinical characteristics of IKD patients initially presenting with retropharyngeal abnormalities to both KD patients without retropharyngeal abnormalities and retropharyngeal abscess patients.

Our IKD cases initially appeared both clinically and radiographically as a retropharyngeal space infectious process, and it was not until the other classic clinical manifestations of KD were noted that the correct diagnosis of KD was established. In our study, the incidence of IKD initially presenting as retropharyngeal abnormality in patients with KD was 0.66%; however, the exact incidence has not been defined because cervical imaging studies are not a routine examination for diagnosing KD, and some cases may be misdiagnosed as deep neck infection and resolved with antibiotic and corticosteroid treatment. Tona et al. [3] retrospectively reviewed 277 KD patients and found that low-density lesions in the retropharyngeal space were identified by contrast-enhanced CT in 3.6% of KD patients. A US report with population-based retrospective analysis of serial cross-sectional datasets using the Kids’ Inpatient Database described 20,787 patients with Kawasaki disease, of whom 0.6% (130 cases) had deep neck space involvement, which was similar to our study. However, they included some patients with a previous diagnosis of KD who had deep neck space involvement. The incidence of IKD initially presenting as retropharyngeal abnormality in patients who were suspected to have retropharyngeal infection was 7.52% in our study. Lim et al. [20] retrospectively reviewed the medical records of children diagnosed with parapharyngeal and retropharyngeal cellulitis or abscess using CT at a single institution over a 3-year period. They found that 11 (23.4%) patients were eventually diagnosed with KD. Therefore, if a patient has fever, lymphadenopathy, and oedema of the retropharyngeal space, retropharyngeal infection might be initially suspected, but IKD initially presenting as retropharyngeal abnormality should also be considered.

Although no sex difference was observed in the IKD initially presenting as retropharyngeal abnormality patients, the patients with retropharyngeal low-density lesions were older than those without, suggesting that the more mature mucosal immune system in older patients might result in a more intense inflammatory response. In the early phase of the clinical course, the symptoms of IKD initially presenting as retropharyngeal abnormality include fever, sore throat, neck pain, torticollis or limitation of motion, neck irritation and lymphadenopathy. Some patients had dysphagia, dyspnoea, salivation and hoarseness. Severe cases can lead to wheezing and upper airway obstruction. It is still difficult to distinguish children with IKD initially presenting as retropharyngeal abnormality from children with retropharyngeal abscess in the early phase of the clinical course. On the day of admission, the two diseases had similar early clinical presentations, and there were no significant differences in any major signs or symptoms between the two groups. The rate of hoarseness in the group A, group B and group C was 20.00, 15.00 and 12.50%, respectively. However, there was no significant group difference, which was probably related to the small sample size. Previous studies revealed that hoarseness was found to be prevalent as a presenting sign of acute KD in younger children, it might be related to viral infection and immunological diseases, and hoarseness was presented in 11.6–30.0% patients [21, 22]. However, in children with retropharyngeal abscess, hoarseness often be caused by compression of nerves by abscesses or inflammatory edema in the glottic region, the incidence of hoarseness was relatively low [23, 24]. This symptom might be an important diagnostic clue of KD, but it needs to be confirmed by further large sample studies. However, after admission, fever subsided within 3 days of antibiotic therapy in most children with retropharyngeal abscess, while fever persisted for 3 days or longer in most children with IKD initially presenting as retropharyngeal abnormality despite antibiotic therapy. However, the number of major KD clinical symptoms gradually appeared over time as the course progressed, implying the importance of close observation for the development of new KD signs and symptoms.

In addition, the patients could be distinguished by careful in-depth analysis of laboratory parameters and neck radiological findings. Our study shows that AST, ALT and CRP levels were significantly higher and WBC levels were significantly lower in IKD initially presenting as retropharyngeal abnormalities than in retropharyngeal abscesses. This may be because IKD is a systemic disease and might involve liver injury. ALT and AST are indices of liver function damage. The exact etiology of abnormalities of liver function tests in IKD has not been established. Hypotheses included generalized inflammation, vasculitis, congestive heart failure secondary to myocarditis, nonsteroidal anti-inflammatory antipyretics, toxin-mediated effects, or a combination of these events [25]. And retropharyngeal abscess is more a local infection, this does not appear to affect liver function. In some previous reports, these laboratory findings also differed slightly between the two diseases, but the difference did not reach statistical significance [20, 26]. Furthermore, neck radiological findings, such as the presence of ring enhancement and mass effects on the airway, are also useful tools for distinguishing these two diseases. In all of our IKD children, the main finding was retropharyngeal low density without ring enhancement and mass effects on the airway. Roh et al. [27] reported that the majority of the 34 (61%) of 56 patients with retropharyngeal low density were diagnosed with KD, and retropharyngeal low density without rim enhancement was seen in all KD patients. However, whether the CT number of retropharyngeal abnormalities is useful in distinguishing the two diseases remains controversial. Sasaki et al. reported that they could distinguish lesions from true abscesses by measuring their Hounsfield unit values. However, previous studies and the present study found that there was no difference in the CT number of retropharyngeal abnormalities [26, 28]. Among the types of retropharyngeal inflammation, retropharyngeal low density without rim enhancement indicates retropharyngeal cellulitis, and the circumferential rim of enhancement and mass effects are the hallmarks of an abscess [3, 27]. Neck radiological findings are often performed in children with fever and restricted neck movements. However, whether MRI or CT and whether plain or contrast are selected for imaging is dependent on hospital resources and policy. Plain CT seems to be the modality of choice in the majority of hospitals. However, recommended imaging for suspected KD initially presenting as retropharyngeal abnormality includes contrast-enhanced CT or MR of the neck, and unnecessary surgery for drainage can be avoided.

Compared to KD patients without retropharyngeal abnormalities, we observed that IKD patients initially presenting with retropharyngeal abnormalities were older, ranging in age from 33 to 110 months. This finding may suggest retropharyngeal abnormalities that might be related to the age of KD patients. The more mature mucosal immune system in older patients might result in a more intense inflammatory response, which is why they had higher CRP levels.

The retropharyngeal abscess is serious, potentially lifethreatening deep neck infections in children. The incidence has been reported to have 0.22 cases per 10,000 [29]. Retropharyngeal infections are not rare, and they are far more numerous than IKD initially presenting as retropharyngeal abnormality [29, 30]. Therefore, physicians shouldn’t hesitate to use antibiotics at presentation as retropharyngeal abscess can be fatal. The initial misdiagnosis could be explained by the onset of the disease when the clinical picture was still incomplete. However, the fact that successive antibiotic treatment may not be effective was often interpreted as inefficiencies of treatments. A therapeutic escalation rather than a questioning of the diagnosis could be responsible for a delayed diagnosis. In addition, the rash, when it appeared secondarily, may sometimes be interpreted as an allergic reaction to antibiotics. Corticosteroids were associated with lower odds of surgical drainage among children with retropharyngeal abscess [31], so some children received corticosteroid treatment, which may mask the symptoms of KD and then delay diagnosis. In caring for children with suspected retropharyngeal abscess, particularly when they are not responding to antibiotics, clinicians should evaluate them for the possibility of KD. Fever duration after antibiotics treatment is significantly shorter in retropharyngeal abscess as it indicates the good response to antibiotics in real infection, and not good response to antibiotics should be an alter to look for other etiology including KD.

Currently, the specific mechanisms of KD-induced retropharyngeal abnormalities remain unclear. However, the clinical, operative details, and retropharyngeal abnormality of all cases disappeared following immunoglobulin treatment rather than antibiotic therapy, suggesting that inflammation and oedema were likely the main mechanism, consistent with previously reported literature [8, 9, 18]. In our reported cases and previous cases, surgical exploration of the retropharyngeal area did not reveal areas of fluctuance or abscess, and cultures of the inflammatory exudate were sterile [3‐5, 32]. Additionally, it is important to note that there are no reported cases of KD with coexisting retropharyngeal abscess. The retropharyngeal space is anterior to the prevertebral muscles and lies posterior to the pharynx and oesophagus [33]. This space extends from the skull base to the superior mediastinum (the T1-T6 vertebrae) [34, 35]. There is loose connective tissue and abundant lymph nodes within the retropharyngeal space. Lymphadenopathy can lead to lymphatic circulation disorders, accumulation of lymph in the posterior pharyngeal wall, formation of hypodense oedematous areas, and imaging findings similar to posterior pharyngeal abscess, which could explain why the retropharyngeal low-attenuation area seen in neck radiological findings is its extension without significant ring enhancement and mass effects on the airway. The inflammatory responses in the mucosal immune system produce excess levels of inflammatory cytokines during the acute phase of KD [35, 36]. Retropharyngeal low-density lesions in IKD might be caused by a similar mechanism, which could explain why they are seen in older patients whose mucosal immune systems are more mature. Furthermore, previous studies have reported that the retropharyngeal abnormality is likely to be associated with hypoalbuminemia and hyponatremia, but no visible difference was detected between Group A and Group B in our study.

The present study has some limitations, including a small sample size, single-centre design and retrospective design. The location of the study may affect the results of the study as well because KD is more common in the northeastern Asian population [36]. These facts may restrict the generalizability of the present findings.

Although IKD initially presenting as retropharyngeal abnormality is rare, the careful observation of the signs and symptoms of this disease and the comprehensive analysis of the laboratory tests and the neck radiological findings could detect the disease early and then reduce the unnecessary use of antibiotics, reduce unnecessary invasive procedures such as surgical aspiration, and avoid the occurrence of serious complications. The possibility of KD should be considered in children showing deep neck inflammation unresponsive to empirical antibiotic therapy after 3 days and low-density cervical lesions demonstrating minimal to no enhancement. When children initially present with retropharyngeal abnormalities, paediatricians, otolaryngologists, and radiologists should be aware of it as an atypical presentation of KD.