Microvascular changes on nailfold capillaroscopy in acute stage of Kawasaki disease: a new diagnostic paradigm for an enigmatic condition

Abstract

Objectives

Kawasaki disease (KD) is a medium vessel vasculitis with a predilection to involve coronary arteries. However, there is a paucity of literature on microvascular changes in patients with KD.

Methods

Children diagnosed with KD based on American Heart Association guidelines 2017 were enrolled prospectively. Demographic details and echocardiographic changes in coronaries were recorded. Nailfold capillaries were assessed using Optilia Video capillaroscopy and data were analysed using Optilia Optiflix Capillaroscopy software at acute (prior to IVIG administration) and subacute/convalescent phase.

Results

We enrolled 32 children with KD (17 boys) with a median age of 3 years. Nailfold capillaroscopy (NFC) was performed in 32 patients in the acute phase (compared with 32 controls) and in 17 during the subacute/convalescent phase at a median follow-up of 15 (15–90) days after IVIG treatment. The following findings were seen in NFC in the acute phase of KD: reduced capillary density (n = 12, 38.6%), dilated capillaries (n = 3, 9.3%), ramifications (n = 3, 9.3%) and capillary haemorrhages (n = 2, 6.2%). Capillary density was reduced significantly in the acute phase of KD (38.6%) as compared with the subacute/convalescent phase (25.4%) (P-value <0.001) and controls (0%) (P-value = 0.03). We observed no correlation between coronary artery involvement and mean capillary density (P = 0.870).

Conclusion

Results show that patients with KD have significant nailfold capillary changes in the acute phase. These findings may provide a new diagnostic paradigm for KD and a window to predict coronary artery abnormalities.

Introduction

Kawasaki disease (KD) is a medium vessel vasculitis with a predilection to involve coronary arteries [1]. Although coronary artery involvement is the hallmark complication in patients with KD, involvement of systemic arteries (e.g. axillary, brachial, femoral and popliteal arteries) has also been reported [2]. However, there is a paucity of literature on microvascular changes in patients with KD. Of the various techniques available for the assessment of microcirculation, nailfold capillaroscopy (NFC) is a simple, non-invasive, rapid and sensitive tool [3]. NFC has been used for the detection of microvascular changes in several rheumatological illnesses such as juvenile SSc (JSSc), JDM and SLE [4, 5]. Assessment of nailfold capillary changes is an important diagnostic tool and may indicate disease severity and response to treatment in JSSc and JDM. However, NFC has rarely been utilized in patients with KD. Huang et al. reported nailfold capillary abnormalities in patients with KD during the convalescent phase of the disease [6]. Because of the paucity of literature on microvascular changes in KD, we planned to assess the nailfold and nail bed capillary changes during the acute phase of KD. We also tried to correlate the presence of nailfold capillary changes with the risk of coronary artery aneurysms (CAAs). To the best of our knowledge, this is the first study to assess the follow-up of microvascular changes based on a standard algorithm for the assessment of nailfold capillary changes using high-resolution dynamic NFC in the acute and subacute/convalescent phases of KD.

Patients and methods

We performed a single-centre prospective case control study between July 2020 and June 2021. Standard diagnostic criteria were used to diagnose KD in children. These include American Heart Association (AHA) 2017 guidelines [7]. Children with KD who had already been given treatment with IVIG before enrolment were excluded from the study. All consecutive cases diagnosed to have KD and who fulfilled the criteria for enrolment were included in the study. Age and sex-matched healthy (afebrile) controls were included from the paediatric outpatient department and vaccination clinic. The study protocol was approved by the Institute’s Ethics Committee and informed written consent was obtained from the parents of the children included in this study. A written informed assent was signed by all participants above the age of 7. This study was performed in line with the principles of the Declaration of Helsinki.

Demographic details, clinical findings, laboratory investigations, 2D echocardiography findings and treatment details were recorded on a predesigned Excel sheet. Dermatological manifestations in all patients with KD were recorded separately at the time of enrolment.

Assessment of nailfold capillaroscopy

The nailfold capillaries were assessed using a high-resolution dynamic nailfold capillaroscope (Optilia Video Capillaroscope OP-120 111 (Vällingby, Sweden), equipped with a 200$×$ magnification high-resolution lens) taking all aseptic precautions. Standard-defined protocols were used for the assessment of nailfold capillaries [3, 8].

All assessments were carried out in-house.

• The patients were asked to sit in a room with a temperature of ∼24°C for 20 minutes.

• The patient was asked to sit in their parent’s lap or on the chair.

• Nailfold capillaries were assessed using high-resolution dynamic nailfold video capillaroscopy.

• The fingers to be examined were held over the table in the prone position and a drop of immersion oil was applied on the nailfold to maximize the translucency of keratin layers and the capillaroscope was placed over the nailfold.

• Excluding the thumb, the rest of the fingers were examined with a capillaroscope at a magnification of 200$×$⁠. The images were captured from individual fingers.

• The images were stored and analysed using Optilia’s Optifix capillaroscopy software with a platform for hand mapping and marking the images to the corresponding finger and position. The software can assess capillary morphology, capillary density, capillary width and arrangement.

• Capillary image analysis included number of capillaries per millimetre, diameter of afferent and efferent limb of capillaries, presence of giant capillaries, presence of torturous capillaries and presence of dropouts and haemorrhages.

• Control subjects had undergone the same procedure once.

• Nailfold capillaroscopy was repeated in patients with KD during the subacute/convalescent phase (10–14 days after giving IVIG).

• Dermatoscopy was performed to visualize the nail bed capillaries in patients with KD in the acute phase and during the subacute/convalescent phase (10–14 days after giving IVIG) and in control subjects using a dermatoscope with 10$×$ magnification.

The following findings in the NFC were considered abnormal [3, 8] (Fig. 1A shows a normal NFC pattern):

• Abnormal capillary shape: absence of inverted U or safety pin appearance.

• Dilated capillaries: afferent limb diameter >15 µm or efferent limb diameter >20 µm.

• Giant capillaries: diameter >50 µm

• Reduced capillary density: no. of capillaries per mm <7.

• Microhaemorrhages: reddish-brown lesions in the nail bed.

• Capillary ramification: branching of capillaries.

No treatment modification was done for the purpose of this study and all children were managed as per the standard guidelines.

Statistical analysis

Statistical analysis was performed using the SPSS software (version 20, IBM Corp., USA) Briefly, variables were expressed as mean (s.d.) [parametric data] or median (Q1, Q3) [non-parametric data]. The data were checked for normal distribution using the Shapiro–Wilk test and assessment of Q-Q plots. Comparisons between patients with KD and control subjects were carried out using Student’s t test (parametric data) or the Mann–Whitney U test (non-parametric data) and a P-value of <0.05 was considered significant. Pearson correlation analysis was carried out when both variables were normally distributed while Spearman correlation analysis was performed when either of the variables had a non-parametric distribution.

Results

Demographic profile

We included 32 patients with KD (53% boys). Median age at diagnosis of KD was 3.0 (1.1, 5.0) years and 37.5% had complete KD. Recurrent KD was seen in 3/32 (9%). Median age of the control group was 54 months. There was no statistically significant difference in the median age of patients with KD and the control group.

Clinical manifestations

At the time of hospitalization, rash, oral-mucosal changes, extremity changes and conjunctival injection were noted in 59%, 81%, 47%, and 34% of the patients, respectively (Supplementary Table S1, available at Rheumatology online). Of the 32 patients with KD, 30 received IVIG while IVIG was not given in two as these patients became afebrile before presenting to us and their inflammatory parameters were normal.

Treatment

All children with KD were treated with aspirin in low doses (4–5 mg/kg/day). IVIG resistance was seen in 3/32 (9.37%) patients. Corticosteroids, infliximab, ciclosporin, etoposide and tocilizumab were used in these patients as per the unit protocols.

Laboratory investigations

Laboratory investigations at diagnosis of KD showed anaemia (<110 g/l) (n = 22), leucocytosis (n = 18), thrombocytosis(n = 18), thrombocytopenia(n = 3), elevated C-reactive protein (CRP) (n = 29), high erythrocyte sedimentation rate (ESR) (n = 15), elevated N-terminal pro-B-type natriuretic peptide (BNP) (n = 21) and elevated transaminases (n = 8) (Supplementary Table S2, available at Rheumatology online).

NFC findings

NFC was performed in 32 patients with acute KD (prior to administration of IVIG) and 32 controls. We performed NFC and dermatoscopy during follow-up (subacute/convalescent phase) in 17/32 patients (Supplementary Fig. S1, available at Rheumatology online). This was performed at a median follow-up of 15 days after giving IVIG treatment (range 15–90 days).

Total numbers of fingers analysed in NFC were as follows: acute phase of KD: 209; healthy controls: 192; and subacute/convalescent phase of KD: 114. Mean linear capillary density (capillaries/mm) of all fingers combined in patients with KD during acute phase (6.71 [1.37]) was significantly lower than the mean linear capillary density in healthy controls (7.89 [1.18], P-value <0.001) (Table 1). Mean linear capillary density in patients with KD was also lower than in healthy controls when each finger was analysed and compared individually (Table 1). Mean linear capillary density in patients with KD during acute phase was significantly less than the mean linear capillary density in the subacute/convalescent phase (Table 2). Patients with the acute phase of KD (38.6%) were substantially more likely to have reduced capillary density than controls (0%) and subacute/convalescent (25.4%) phase patients (Fig. 1B).

We observed capillary haemorrhage in 2/32 (6.2%) patients with KD during acute phase (Fig. 1B) as compared with none in control subjects. Dilated capillaries were seen in three (9.3%) patients with KD in acute phase while only one (3.1%) healthy control had dilated capillaries. Ramification of capillaries was seen in three (9.3%) cases with KD in acute phase (Fig. 1C) whereas this finding was not seen in any of the controls. None of the patients with KD had giant capillaries or scleroderma pattern on NFC. Capillary dilatation, haemorrhages and ramification of capillaries were not observed in patients with KD in the subacute/convalescent phase.

There was no difference in the mean linear capillary density in patients with KD without CAAs (6.69 [1.40], n = 30) as compared with those with CAAs (6.695 [1.399], n = 2) (P-value 0.870).

In patients with acute KD, mean linear capillary density did not correlate significantly with haemoglobin concentration, total leucocyte count, absolute neutrophil count, platelet count, ESR, CRP levels and N-terminal pro-BNP levels. Besides, average linear capillary density was similar in patients with acute KD when stratified by the presence or absence of complete KD or mucocutaneous findings, namely: rash, oromucosal changes, acute extremity changes and conjunctival injection.

Dermatoscopy findings

Dermatoscopy was performed in 32 patients with KD in acute phase, 17 patients with KD in subacute/convalescent phase and 32 healthy controls. Among cases, six showed dilated capillaries (18.75%) during acute phase as compared with none in controls. Of these six patients, three had chromonychia (orange-brown discolouration) on inspection.

Discussion

KD is an acute febrile medium vessel vasculitis of childhood with the hallmark complication of development of CAAs. Rarely, KD may also affect large vessels [7]. However, there is a paucity of literature on the microvascular changes of KD. It is believed that oedema of extremities and erythema of mucosal membranes, the two common manifestations of KD, may be because of microcirculatory changes [6]. The present study is a first of its kind where in nailfold capillary changes were assessed in patients with KD during the acute and subacute/convalescent phases and compared with healthy controls.

Of the 32 cases enrolled in the present study, 12 (37.5%) had complete KD while the rest had incomplete KD. Proportion of incomplete KD constitutes ∼20–50% of all patients with KD in different studies [9].

KD is predominantly a disease of young children (<5) and boys are affected more frequently than girls. In Japan, the mean age of onset of KD is 6–11 months, 2–3 years in the United States, and 5 years in India [10]. Male-to-female ratio has been reported as between 1.3:1 and 2:1 [7]. In the present study, the median age at diagnosis was 36 months (3 years) and male-to-female ratio was 1.13:1.

Dermatological and mucocutaneous manifestations, if carefully looked for, can serve as vital clues for the timely diagnosis of KD [1]. In the present study, rash, oromucosal changes, extremity changes, conjunctival injection and cervical lymphadenopathy were noted in 59%, 81%, 47%, 34% and 40.6% of the patients, respectively, which is similar to what has been reported previously in the literature [11–14].

KD predominantly involves coronary arteries and is the leading cause of acquired cardiac disease in children in developed countries. CAAs may develop in up to 15–25% of untreated patients with KD. The risk is higher in infants, adolescents, those with delay in diagnosis and patients with IVIG resistance. Early treatment with IVIg has been found to reduce the risk of CAAs from 15–25% to <5% [15]. In the present study, two of the 32 patients with KD had CAAs (6%).

In the present study, 3/32 (9.37%) children had IVIg resistance. Corticosteroids, infliximab, ciclosporin, etoposide and tocilizumab were used in these patients. The rate of IVIg resistance in the present study is similar to those previously reported in the literature [16].

Mortality in patients with KD in Japan is 0.1% and 0.17% in the USA [17]. One patient died in the present cohort. The cause of death was fulminant macrophage activation syndrome and multi-organ dysfunction. KD with macrophage activation syndrome has a mortality rate of 10–40% and occurs in the acute phase of KD [18].

There is a paucity of literature on microvascular abnormalities in patients with KD. Huang et al. studied the microvascular abnormalities in patients with KD noninvasively using laser Doppler flowmetry and dynamic capillaroscopy [6]. This study, however, was conducted during the afebrile (subacute) phase and convalescent phase, and patients were not included in the acute phase and included 100 subjects: 64 KD patients and 36 healthy controls. Amongst patients with KD, 33 were in the afebrile phase, i.e. after 10–12 days of onset of symptoms, and 31 were in the convalescent phase, i.e. after 8–12 months of the onset of fever. It must be noted that patients with KD in the afebrile and convalescent phases were not the same. In patients with KD, the capillary morphology was found to be abnormal with larger arterial and venous limb diameters and increased intercapillary distance both during afebrile and convalescent phases in patients with KD as compared with controls. These findings were statistically significant despite the fact that the mean intercapillary distance, the diameters of the arterial and venous limbs in all three groups were within the normal range. The capillary density was found to be reduced in the afebrile phase (5.16 [0.13]) and in the convalescent phase (6.12 [0.12]) when compared with healthy controls (7.56 [0.19]). Authors did not include cases in the acute phase in this study. Authors also compared abnormal loop percentage in all three groups. Abnormal loop percentages were significantly higher in patients with KD compared with normal controls. All children with KD underwent echocardiography and none had CAAs (Table 3).

In a recent case-control study, Sedaghat et al. found that 45% of patients with KD in the acute phase had reduced capillary density, 67.7% had abnormal capillary diameter, 35% had irregular dilatation and 25% had capillary architecture distortion. Ramification was seen in 13% of patients compared with 6.7% in the control group, but the difference was not statistically significant. Authors also observed a positive correlation between coronary artery involvement and abnormal capillaroscopy findings [19]. However, capillary changes were not assessed in the convalescent phase in this study.

In the present study, we observed that the mean number of capillaries/mm were significantly less in the acute phase compared with controls and the subacute/convalescent phase of KD. Our study is the first of its kind to compare NFC findings in the acute (before giving IVIg) and subacute/convalescent phase of KD. Mean number of capillaries/mm was significantly less in all fingers in the acute phase of KD as compared with controls. The present study showed no statistically significant difference in capillary density in patients with and without CAAs. However, only two patients had CAAs in the present study. Hence, studies with a larger number of patients need to be performed to analyse the association of NFC with CAA.

We also carried out dermatoscopy of the nail tips in the patients with KD in the acute phase and subacute/convalescent phase of KD and in healthy controls. In dermatoscopy, we observed dilated capillary loops in the nail tip in 6/32 (18.75%) cases and none in the controls. We have reported previously that dermatoscopy findings in patients with KD may show dilated capillaries at nail tips [20]. These dilated capillaries may be a reason for grossly visible chromonychia in these patients. However, these results need to be validated further.

The strengths of this study are that this is the first study to analyse and compare nailfold capillary changes in acute and convalescent phases of KD and the same group of children was also followed up in the convalescent phase to show improvement in NFC findings. Diagnosis of KD in all cases was based on the standard criteria, strict inclusion/exclusion criteria were followed, and patients in whom IVIg treatment had already been initiated were excluded from the study. The fact that NFC findings showed improvement between the acute and subacute/convalescent phases of KD may be a pointer towards these changes being a surrogate marker of coronary inflammation. We have also carried out dermatoscopy assessment of nail tips to demonstrate dilated vessels at nail tip in patients with KD. Limitations of the study include a small sample size and all patients who were enrolled in the acute phase of KD could not be followed up in the convalescent phase. Only two patients in this study had CAAs. As a result, we could not demonstrate any correlation between nailfold capillaroscopy and CAAs.

To conclude, the results of the study suggest that microvascular abnormalities in the acute phase of KD are a fact and need further work. NFC changes may represent the footprint of microvascular morbidities of KD and coronary artery vasculitis. However, no strong evidence supports that NFC changes may represent coronary artery vasculitis. These findings may provide an important diagnostic paradigm in patients with KD. Further studies with larger sample sizes are needed to evaluate whether these changes correlate with the disease severity or the risk of development of CAAs. Based on studies on NFC in patients with SSc, NFC findings in KD may provide an important diagnostic and prognostic indicator. This is, as yet, an unexplored area of KD.

Supplementary material

Supplementary material is available at Rheumatology online.

Data availability

Data available on request.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.

References