Is Novel Corona Virus Truly a Trigger for Kawasaki Disease in Infants?– Reporting the First Asian Case

SARSCov2 pandemic has hit the world this year with alarming consequences in most of the continents. There are relatively few reported cases of COVID-19 infection in children, compared to the total number of cases in the general population. Children are battling the infection more positively unless they have pre-existing morbidity. Interestingly an inammatory condition is being reported from western world in this COVID 19 era with increased risk of mortality. We report the rst Asian infant with orid features of Kawasaki Disease who eventually tested positive for Novel Corona virus.


Introduction
The present pandemic of COVID 19 has threatened the world with extreme morbidity and mortality. The paediatric population was so far not affected as dreadfully as the elderly fraternity. Severe COVID-19 in children is rare. To date, the largest review of children with COVID-19 included 2143 children in China.
Only 5·8% had severe disease (de ned as hypoxia) and only 0·6% children developed respiratory or multiorgan failure or acute respiratory distress syndrome (ARDS) (1). But recently, a new in ammatory pathology manifesting as Kawasaki Disease or Kawasaki like shock syndrome has been described in children above 4 years of age from the western world during this pandemic era. (2,3). However, no such clinical scenario has been reported from the Asian (including Chinese) Paediatric population. Here we report a unique case presenting with fever and clinical manifestations of Kawasaki Disease eventually screening positive for COVID 19.
Case Report A 4-month-old baby, born of non-consanguineous parents with uneventful antenatal and postnatal history; so far healthy and well grown, presented with high-grade fever for 4 days. Fever was spiking 6-8 hourly reaching 39 0 C. He developed an erythematous macular rash over the trunk, palm and sole on 2 nd day. His birth-weight was 2.7 kg and presently was weighing 5.6kg. There was no symptomatic COVID 19 case in the family and the child was con ned at home since the lockdown imposed in the country 38days back. On admission the child was haemodynamically stable and was breastfeeding normally. He had red lips and red congested throat with small cervical lymphadenopathy. He was very cranky and irritable which elicited a suspicion of meningitis with or without sepsis. He did not have any cough or nasal congestion. On auscultation, his chest was clear and heart rate was 110 to 120/min and regular. He was maintaining a saturation of 97-98% in air. Initial investigations revealed a haemoglobin of 9.9gm/dL, total leucocyte count (TLC) of 14770/mm3 with 50% neutrophil, platelet count 4.25lac/µL C Reactive protein (CRP) of 115.6mg/L (Normal up to 9.9mg/L), normal liver enzymes with albumin 30g/L and globulin of 22g/L. He had a normal chest X-ray. His nasopharyngeal swab was sent for COVID 19 RT-PCR and other viral PCR tests. The infant was started with broad spectrum antibiotics after sending blood and urine culture but fever continued to spike up to the third day of admission and he developed nonpurulent conjunctivitis with left subconjunctival haemorrhage. Repeat CRP showed a higher value of 178.2mg/L.
With evolving clinical signs simulating Kawasaki Disease, an echocardiography was performed while awaiting the viral PCR report. His viral swab was negative for any virus or bacteria. Echocardiography showed normal left ventricular function, perivascular brightness and diffuse ectasia of coronary arteries with left middle coronary artery (LMCA) of 2.7mm(z score +2.6) [Fig 1], left anterior descending artery of 2mm (Zscore +2.9) and proximal right coronary artery (RCA) of 2.4mm (z score+3.6) [Fig 2]. He was started with oral Aspirin (80mg/kg/day) and intravenous gamma globulin (2gm/kg). He stayed stable clinically and did not need intensive care. Fever subsided after 24hours of nishing gamma globulin and child became playful. Subsequently COVID 19 PCR showed a positive result and was shifted to a COVID designated hospital. All cultures were negative till 7days. Repeat blood test revealed a downward trend of CRP (148mg/L). To date the baby is stable, afebrile, and is kept under observation in the Paediatric ward.
Later his mother was found positive for SARS CoV2 as well.

Discussion
Children of all ages can acquire COVID-19, although they appear to be affected less commonly than adults (1,4,5,6,7). However, compared to the numbers in adult series reported from Chinese, European and American populations Paediatric data is dismal. In a systematic literature review (from January 1 through March 18, 2020), children accounted for 1 to 5 percent of diagnosed COVID-19 cases (8). In USA, infants accounted for 15 percent of con rmed cases till 2 nd April. The proportion of all cases that have occurred in infants (0.27 percent) is less than the proportion of the United States population that is <1 year of age (6). The present infant with hyperin ammatory disease is the 1 st case with severe disease reported in this part of the globe without any immediate symptomatic contacts.
The most common symptoms in paediatric SARS CoV2 infection are fever and cough as described in different series from Chinese and American experience (4.6). This infant also presented with fever characterised by extreme irritability conspicuous by the absence of respiratory symptoms.
In the Chinese series, 5.8% of children had severe and critical disease(1) However, in the same series, among infants approximately 11 percent had severe or critical diseases.(1). The discussed infant was never critical throughout the period of hospitalisation though considering the in ammatory features associated with his disease it could have been critical.
There have been few reports of children with COVID-19 and clinical features that are similar to those of toxic shock syndrome and atypical Kawasaki disease (eg, abdominal pain, gastrointestinal symptoms, myocarditis) and laboratory ndings associated with increased in ammation (eg, elevated CRP, erythrocyte sedimentation rate, and ferritin) (3). Royal College of Paediatric and Child Health(UK) published this new in ammatory entity as "Paediatric multisystem in ammatory syndrome temporarily associated with COVID 19" (9). Case de nitions include persistent fever, in ammation (neutrophilia, elevated CRP, and lymphopenia) and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurological disorder). This may include children ful lling full or partial criteria for Kawasaki disease. Other microbial causes which may give rise to these features should be excluded. The discussed case had markedly raised CRP without any neutrophilia or lymphopenia or organ dysfunction though ful lled criteria for Kawasaki Disease.
Jones et al. in this pandemic period, published the rst case of a 6-month-old female admitted and diagnosed with classic Kawasaki disease (KD), who tested positive for COVID 19. Our case was very similar to theirs but the 6-month-old had most of the clinical features of KD without any echocardiographic ndings though the girl had persistent tachycardia (200/min). In contrast the present infant had diffuse coronary arterial ectasia, perivascular brightness with normal left ventricular function despite having normal heart rate. Like our case, Jones et al also treated the infant with IV gamma globulin and high dose Aspirin which gave dramatic relief as happens usually in typical KD.
A recent literature search revealed a case series of 8 previously healthy children above 4 years of age from southeast England admitted in Paediatric Intensive care with a hyperin ammatory shock like atypical KD, Kawasaki Shock Syndrome or Toxic Shock Syndrome. One child died after a massive cerebral infarction despite optimal management. All of them have common clinical features with persistent fever (38-40°C), variable rash, conjunctivitis, peripheral oedema, and generalised pain with signi cant gastrointestinal symptoms. All progressed to warm, vasogenic shock, refractory to volume resuscitation and eventually requiring noradrenaline and milrinone for haemodynamic support. They had minimal or no respiratory symptoms. Only three of them had positive COVID 19 results (3). Our case, the other KD case, and these children most likely had similar pathogenesis with varied severity but need further research to de ne it. How much SARS CoV 2 is responsible for this in ammatory pathology and through which pathway it is activating the immune phenomena are still not clear. Cytokine storm and shock suggesting hyper in ammation had been described in adult series from China but particular Kawasaki Disease like presentation or Kawasaki Shock Syndrome had not been described (10,11). Very recently one such case from Southern part of India has been reported in an eight year oid child (12).
Ferritin, troponin and IL6 levels would be the right parameters to monitor in this infant which are not available while submitting this report.
Aetiology of KD is still not known but a viral association had been suspected in many studies. Infection by a ubiquitous agent(? RNA virus) had been suggested as the initiating factor in the pathogenetic model by Rowley et al (13). Whether Coronavirus 19 is acting as that agent in these patients causing vasculitis is still to be proved. More research will be needed to unveil this hyperin ammatory phenomenon in the midst of this pandemic.
India is still in the early stage of this pandemic and had not yet experienced many severe cases occurring in children. To the best of our knowledge, this 4-month-old child represents the rst case, among the Asian Paediatric population of COVID 19 presenting as full blown Kawasaki Disease. This novel case is an eye-opener for our awareness of the hyperin ammatory manifestations caused by the novel Coronavirus in Indian vis-a-vis Asian children.  Ectasia of RCA