Reactivation of BCG inoculation site in a child with febrile exanthema of 3 days duration: an early indicator of incomplete Kawasaki disease

Abstract

The aetiology of febrile exanthems in children is often difficult to distinguish clinically. A diagnosis of Kawasaki disease (KD) should be considered in infants with exanthematous fever. More perplexing is the increasing incidence of an atypical form of KD. Pathogenesis of KD remains unclear even though an aberrant response of the immune system to an unidentified pathogen is often hypothesised. A 30-fold increase in the incidence of KD in Italy during the SARS-CoV-2 pandemic suggests an immune response to a viral trigger. We report an infant clinically diagnosed with high probability as incomplete KD, who presented with reactivation of the BCG injection site even though fever with rash was only less than 3 days duration. Echocardiography confirmed coronary artery abnormalities and prompt treatment with intravenous immunoglobulin facilitated rapid recovery. Physicians should consider a diagnosis of KD if BCG site reactivation is noted in children presenting with febrile exanthema.

Background

The distinctive characteristics of febrile exanthema in children are numerous. As such, a thorough history and full physical examination is critical to making an accurate diagnosis. More often than not, the characteristics of the rash give us diagnostic clues helpful to determine the aetiology of the illness. Maculopapular rashes, which occur most commonly in viral infections, has been described in measles, rubella, exanthemas subitum, erythema infectiosum and so on.¹ Of the non-infectious causes, Kawasaki disease (KD), a vasculitis of medium calibre vessels with detrimental cardiovascular complications, remains an important consideration.²

In 2017, the American Heart Association (AHA) published a scientific statement intended to improve the clarity of diagnosis, treatment and long-term management of KD. The diagnostic criteria for classic KD include persisting fever for at least 5 days and the presence of four of the following five principal clinical features.

1. Erythema or cracking of the lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa.

2. Bilateral bulbar conjunctival injection without exudate.

3. Rash: maculopapular, diffuse erythroderma or erythema multiforme-like.

4. Erythema of the hands and feet in acute phase and/or periungual desquamation in subacute phase.

5. Cervical adenopathy (≥1.5 cm diameter), usually unilateral.

AHA advised that experienced clinicians may establish diagnosis of KD even with 3 days of fever. They recommended the evaluation of patients who lack full clinical features of classic KD as a case of incomplete KD (IKD). If coronary artery abnormalities are detected in cardiac evaluation, diagnosis of IKD is considered confirmed in most cases.³ AHA also clarified that even though the presence of fever for ≥4 days along with four of the five principal clinical findings establish IKD, these criteria do not identify all cases in children. KD should be considered in any child with prolonged fever in association with any of the principal features of the disease and a confirmation of diagnosis can be made in the presence of echocardiographic evidence of coronary artery aneurysms. Further, IKD is more common in infants and has a higher predilection for coronary artery involvement in those who presented with prolonged fever as the sole clinical finding.^{2 3} Even though erythema and induration of the previous BCG vaccination site occur during the course of illness in children with KD, AHA has not included BCGitis in the diagnostic criteria. This may be due to non-inclusion of BCG in the immunisation schedule of several countries in the world.⁴

Case presentation

Here we report the case of a fully immunised 11-month-old male infant of Chinese origin with IKD wherein, BCG site reactivation helped us to make the diagnosis on day 3 of fever with rash. He was born at 39 weeks and had an uneventful neonatal period. He was vaccinated as per national primary childhood immunisation schedule which included BCG at birth. Measles, mumps and rubella vaccine is due at 1 year of age. He did not have any other significant medical history.

The patient arrived at the Children’s emergency department of KK Women’s and Children’s Hospital, Singapore in early January 2020 with a history of high unremitting fever for 3 days, with temperature ranging between 39°C and 39.5°C. There were no gastrointestinal symptoms but the infant was refusing even oral fluids. Other observed features included a widespread polymorphous maculopapular rash over the face, torso, and legs, bilateral conjunctival injection with no discharge and erythematous lips and tongue. He was noted to have a 2×2 cm area of erythema and induration at the previous healed BCG inoculation site, at the left deltoid region (figure 1). Since there are no specific diagnostic tests or pathognomonic clinical features, the appearance of BCG reactivation proved to be particularly useful to strongly suspect IKD especially in the background of only 3 days of fever and rash.

Figure 1.

Erythema at previous BCG site on left deltoid region on day 3 of fever.

Investigations

On admission, sepsis workup was performed. Full blood count was unremarkable although raised platelet count (516–588×10⁹/L) was present throughout the illness. C reactive protein showed a rise from 11 mg/L to 21 mg/L from day 1 to 2 and an erythrocyte sedimentation rate (ESR) of 81 mm/hour, both indicating an ongoing inflammatory process. Liver function test (LFT) showed significant transaminitis; alanine aminotransferase, 418 U/L and aspartate transaminase (AST), 1195 U/L. Coagulation profile and renal function tests were unremarkable.

The patient’s blood culture and two consecutive urine cultures were sterile. Urine microscopy showed white cell count of 67/µL, indicating sterile pyuria. Antistreptolysin O titres were negative (<100 IU/mL). Serological screening for viral causes included measles, respiratory virus multiplex PCR, Epstein-Barr virus and herpes simplex virus, all of which were negative.

A 2D echocardiography was performed, which revealed coronary arteritis. There was dilation of the patient’s left main coronary artery (LMCA) measuring 2.45/2.70/2.60 mm, 2.58 mm (mean), Z score +2.4 (Kobayashi) and right coronary artery (RCA) measuring 2.52/2.66/2.62 mm, 2.6 mm (mean), Z score +3.2 (Kobayashi). Left anterior descending and circumflex arteries were unaffected. The echo findings of LMCA and RCA were consistent with the diagnosis of IKD.

Differential diagnosis

Measles, scarlet fever and KD shares many clinical features (figure 2). Even though BCG site reactivation has been reported in one specific case of an infant with measles, its presence is more consistent with a diagnosis of KD.^{4 5} In our reported case, real - time reverse transcription polymerase chain reaction (rRT PCR) test for measles was negative. Exanthem subitum characterised by fever of 2 days followed by an evanescent rash lasting for a day or 2 was ruled out with negative herpes virus 6 PCR in the serum. Among exanthematous fevers, scarlet fever shares some of the clinical features of KD. Primary clinical features differentiating scarlet fever from KD and measles is that there are no clear signs of upper respiratory inflammation, and the area around the mouth looks pale and both cheeks look eryhthematous.¹

Figure 2.

Clinical features of measles, scarlet fever and Kawasaki disease.

Meningococcal sepsis can mimic KD. Akin to that in KD, early characteristic features of meningococcal septicemia are fever with a non-blanching, petechial rash on the trunk and lower extremities and signs of haemorrhage in the soft palate, ocular or palpebral conjunctiva. Our child did not have a petechial rash or any evidence of bleeding. On further laboratory investigations, elevated platelet counts and negative blood cultures pointed against meningococcal sepsis. Other differential diagnoses to be considered include toxic shock syndrome, leptospirosis and systemic onset of juvenile rheumatoid arthritis based on age, sex and local prevalence of the diseases.

Treatment

On admission, after obtaining blood and urine sample for culture the patient was empirically started on intravenous ampicillin 100 mg/kg/day in divided doses. In keeping with the diagnosis of IKD, he was started on intravenous immunoglobulin (IVIG) infusion at 2 g/kg over 12 hours according to our institutional guidelines. Antiplatelet therapy (clopidogrel 1 mg/kg) was initiated due to the presence of thrombocytosis. LFTs normalised over a week and clopidogrel was stopped and aspirin was initiated. The patient’s fever, rash and erythema over the BCG scar site had subsided over the next 2 days. Blood and urine cultures were negative and intravenous antibiotic was stopped and continued orally for a week.

The patient remained afebrile prior to discharge on day 6 of admission. A multidisciplinary approach to care was crucial in the management of this patient, involving emergency physicians, cardiologists, infectious disease specialists and paediatricians. The patient’s caregivers were advised to delay administration of live vaccines for 11 months post-IVIG and to return to the emergency department if any symptoms recurred.

Outcome and follow-up

A repeat 2D echocardiography 2 weeks after discharge showed resolution of the earlier aneurysmal dilatations of the LMCA. However, proximal RCA remained dilated, measuring 2.41/2.43/2.47 mm, 2.44 mm (mean), Z score +2.6 (Kobayashi). Cardiac follow-up 6 weeks later showed complete resolution of coronary artery aneurysms. Further physical examination at 20 months of age revealed an active child with no pertinent physical findings. His growth parameters included the following: weight 12.5 kg (90th cent); height 83.5 cm (75th cent) and head circumference 49 cm (75th cent). When last reviewed in October 2020, he was neuro-developmentally appropriate for age.

Discussion

The first report of KD was established in 1967 in Dr Tomisaku Kawasaki’s seminal paper, delineating the clinical features of KD and its associated coronary sequelae. KD has been recognised in more than 60 countries across various continents owing to its high incidence in young children less than 5 years of age.^{6 7} Incidence in USA is ≈25 cases per 100 000 children<5 years old.³ In Asia alone, Japan, South Korea, China and Taiwan have reported 10–30 times higher incidence than European countries and the USA.⁸ To date, KD is considered the leading cause of acquired heart disease in children.³ As such, clinching the diagnosis of KD is crucial in order to prevent coronary artery aneurysms and its long-term complications. This is especially pertinent as the diagnosis of IKD has been increasingly common.^9–11 Men are affected more than women’s ≈1.5:1. The case fatality rate is <0.1% in Japan, but recurrence rate is ≈3%.³

In infants, a higher prevalence of IKD (40%) when compared with older children (10%–12%) has been reported.¹² Recently, Mastrangelo et al reported higher rate of IKD in 68.7% of 113 infants with KD and cardiac involvement was detected in 59% of them. The mean time to diagnosis was longer in IKD, 8±4 days in their cohort conversely our case was diagnosed on day 3.²

Our patient represents a large proportion of IKD cases, wherein the ‘bullseye’ appearance of BCG site reactivation was a highly specific diagnostic marker that allowed us to clinically distinguish KD from other infectious febrile illnesses even on day 3 of fever. Various mechanisms of BCG reactivation in KD has been described. One of the earliest mechanisms proposed by Yokota involves the augmentation of immune response by heat shock proteins (HSPs). HSPs are produced when a cell is subjected to stressors, such as raised temperature, viral infections and exposure to oxidative stress or hypoglycemia. HSPs serve as common antigenic determinants in numerous infections. More specifically, exogenous HSP 65 kDa (HSP 65) is involved in triggering endogenous immune response. Through activation of polyclonal T cells, antibody production and subsequently high circulating levels of interleukins, HSP 65 serves as a potent factor in activating immunocompetent cells, resulting in the endothelial damage seen in the initial phase of KD.¹³ Sireci et al¹⁴ have further confirmed this hypothesis, theorising that crossreactivity between mycobacterial HSP 65 and human homologue HSP 63 results in hyperreactivity to BCG in patients with KD. The primary exposure to bacterial HSP 65 induces immune activation and simultaneous autologous HSP 63 expression.¹⁴ Lastly, Lin et al¹⁵ have proposed an association between the C allele of inositol 1,4,5-trisphosphate 3-kinase C gene (rs28493229) polymorphism and reactivation of BCG. These researchers in Taiwan found that 71.4% of patients carrying the C allele and younger than 20 months had such BCG reactivation. Enhanced T cell activation would augment the hyper-reactivity of BCG-recognising T cells emigrated at the BCG inoculation site.^{15 16} Rezai and Shahmohammadi have done a review and found that BCG reactivation was more prevalent than cervical lymphadenopathy and rash, and it can be a useful criterion for the diagnosis of IKD. Their review concluded that reactivation at the BCG inoculation site was an early sign suggestive of KD, especially IKD among children younger than 5 years of age.¹⁷ Conversely, Hsieh et al reported that even though BCG site reactivation is a useful diagnostic tool, it might not be a predictor of coronary artery ectasia.¹⁸

More recently, there have been reports of a rise in cases of severe Kawasaki-like disease and paediatric multisystem inflammatory syndrome that is temporally related to the COVID-19 pandemic.^{19 20} Our patient presented in early January 2020, before the first case of COVID-19 was reported in Singapore on 23 January 2020, hence he was not tested for SARS-CoV-2.

Diagnosis of KD and IKD is based on the AHA criteria. Unexplained fever in an infant with rash but no other features described by AHA should be subjected for an echo and if coronary artery changes are detected diagnosis of IKD can be confirmed,³ as noted in our patient. BCGitis was a good indicator in our case, prompting urgent cardiac assessment. Supplementary laboratory criteria include normal or elevated white cell count, elevated C reactive protein and erythrocyte sedimentation rate, low serum sodium and albumin, elevated liver enzymes and sterile pyuria. Thrombocytosis is common after second week of onset of fever. Our patient had raised acute phase reactants, liver enzymes and thrombocytosis on day 3 of fever. AST levels were also markedly higher in IKD,² as noted in our case.

IVIG remains the mainstay of treatment in patients with KD and has shown to reduce the coronary artery abnormalities. Additional therapies include antiplatelet drugs like aspirin or clopidogrel and repeat doses of IVIG±corticosteroids in IVIG-resistant cases. Monoclonal antibody, infliximab has been approved for use in resistant KD to bind the high levels of cytokine tumor necrosis factor (TNF)-α.^{3 21}

In conclusion, incidence of IKD is increasing especially in infants. The pathophysiology of KD is not well understood. Reactivation of BCG inoculation site has been shown to facilitate early suspicion of KD especially in infants with febrile exanthem. A precise diagnostic test remains elusive. Presence of echocardiographic evidence of coronary artery aneurysm alone in the presence any of the five principal clinical features put forth by AHA in a febrile child can confirm IKD. Early IVIG therapy has been efficacious in reducing cardiac morbidity.

Patient’s perspective.

Mother’s perspective: I am happy that my sons’ medical condition, Kawasaki disease was diagnosed quickly, and gamma globulin was given. He became afebrile in 1–2 days and was discharged home on day 6 of admission. His follow-up echo tests were normal. We are happy that he is doing well.

Learning points.

• Kawasaki disease (KD) remains as one of the top differentials in a child presenting with febrile exanthema. Diagnosis of incomplete KD is still perplexing.

• Reactivation of BCG can manifest as erythema, induration, ulceration or crust formation at a previous BCG inoculation site, and can be considered as a feature of classic and incomplete KD in a febrile child with rash.

• Prompt diagnosis of KD allows for timely intervention with intravenous immunoglobulin and antiplatelet therapy, reducing the time-sensitive risk of coronary sequelae.

• We highlighted the usefulness of BCG reactivation in the timely diagnosis of a child with suspected KD.