Coronavirus disease (COVID-19) in children appears to be largely a benign condition. However, there are reports of children presenting significantly unwell across Europe and USA in the last couple of weeks with a new multisystem inflammatory syndrome [1]. We report a child with COVID-19 who had overlapping features of Toxic Shock Syndrome (TSS) and Kawasaki disease (KD).

A previously well, eight-year-old boy presented with fever, cough and throat pain. He was admitted to a local hospital on day 4 of illness in view of high-grade fever spikes. Investigations showed neutrophilic leukocytosis (total white blood cell count 23,000/µL, Neutrophils 89%) with raised acute phase reactants (C-reactive protein, CRP 120 mg/L). Chest X-ray showed right upper and middle lobe infiltrates. Reverse transcriptase polymerase chain reaction (RT-PCR) for severe acute respiratory illness novel coronavirus 2 (SARS-CoV-2) was negative. Treatment was empirically started with ceftriaxone and azithromycin. Despite treatment for three days, he continued to have high fever, worsening respiratory symptoms and was referred to our hospital.

On arrival, he was alert, had respiratory rate of 50/min, intercostal retractions and was maintaining SpO2 in room air. He was febrile with tachycardia (HR 160/min), hypotension (80/31 mm Hg), warm extremities and a capillary refill time of 3 seconds. He was also noted to have a generalized non-pruritic erythematous skin rash, non-purulent bulbar conjunctivitis, cracked lips, strawberry tongue, edema of limbs, tender hepatomegaly and abdominal distention. Investigations in our hospital showed haemoglobin of 8.9 g/dL, neutrophil predominant leukocytosis (total count 17,600/µL, 86% neutrophils), platelet count 3,95,000/µL, markedly raised  CRP (317 mg/L), raised erytherocyte sedimentation rates (115 mm/h), hyper-ferritinemia (Ferritin 1,496 ng/mL), hypoalbuminemia (2.6 g/dL), hyponatremia (133 mEq/L), normal kidney and liver function, and 2+ proteinuria. He was given a fluid bolus and treatment empirically started with piperacillin-tazobactam and doxycycline. When reassessed after 30 minutes, he was febrile, hypotensive and had increased work of breathing. He was shifted to the pediatric intensive care unit. The initial differential diagnoses were pneumonia with septic shock, COVID-19 penumonitis, KD and TSS.  High-flow nasal cannula (HFNC) support was started and antibiotics were modified to meropenem, vancomycin and clindamycin. The blood pressure was stable and urine output was normal. Intravenous Immunoglobulin (IVIG) was given (2 g/kg) with aspirin (75 mg once-a-day). Echocardio-gram did not show any abnormalities and repeat chest X-ray showed increased right-sided infiltrates. Repeat nasopharyngeal COVID-19 RT-PCR was positive. Multiplex PCR of nasopharyngeal aspirate (BioFire FilmArray) detected Coronavirus OC43 and Human Rhino/Enterovirus. As he improved, he was gradually weaned off HFNC. Blood cultures showed no growth and antibiotics were changed to ceftriaxone. In light of the persistent high-grade fever and elevated CRP (121 mg/L), 72 hours after IVIG infusion, he was given tocilizumab (8 mg/kg IV over 2 hours). Twelve hours later, his fever spikes settled, and inflammatory parameters rapidly decreased to baseline (Fig. 1). He was noted to have periungual peeling of skin and recovered completely after two weeks of illness.

 

Fig. 1 Trend of inflammatory markers in a child with hyper-inflammatory syndrome and COVID-19.

The clinical characteristics of COVID-19 disease progression and outcome in children and young adults appear significantly milder compared to older individuals [2]. However, there is now a growing recognition of a small number of children presenting with a multisystem inflammatory syndrome. This rare syndrome shares common features with other pediatric inflammatory conditions, including KD, Staphylococcal/streptococcal toxic shock, bacterial sepsis and macrophage activation syndrome. It can also present with unusual abdominal symptoms with elevated inflammatory markers. Recently 8 children have been reported to present with hyper-inflammatory shock [3]. This has been labelled as Pediatric multisystem inflammatory syndrome temp-orally associated with COVID-19 and a case definition has been suggested [1]: a child presenting with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopenia) and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal or neurological disorder) with additional features, which may include fulfilling full or partial criteria for KD; exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes; and SARS-CoV-2 PCR testing may be positive or negative

Our case fulfils these criteria. It is likely that cytokine storm (CS) is one of the major causes of acute respiratory distress syndrome (ARDS), multi-organ dysfunction and possibly pediatric multisystem inflammatory syndrome [4]. IL-6 is a key cytokine in this process and few studies suggest that CS is positively correlated with disease severity [5]. Various immunomodulators have been discussed and tried for controlling the inflammatory response [6]. Tocilizumab, an IL-6 receptor antagonist approved by the US FDA for treating of Cytokine release syndrome (CRS), is now in clinical trials for treating severe COVID-19 pneumonia [7]. Tocilizumab blocks downstream signal transduction by binding membrane IL-6 receptor and soluble IL-6 receptor and plays a role in the treatment of CS in COVID-19 [8]. High CRP levels seen in our case shows that this inflammatory syndrome is likely mediated by IL-6. Our case suggests that immunomodulation with IVIG and IL-6 blockade can be an effective therapeutic strategy, which has a scientific rationale. It is clear from Europe and the USA that appearance of this syndrome in children follows the peak of infections in affected areas. The immunopathology behind this phenomenon is yet to ascertained. We believe that children across India may present with this inflammatory syndrome related to COVID-19 in the weeks ahead and would like to highlight this to pediatricians across India. Tocilizumab may prove to be an effective second line agent in IVIG refractory children with COVID-19 hyper-inflammatory syndrome

Though most SARS-CoV-2 infections in children are likely to present with mild features, some may develop a hyper-inflammatory syndrome, which may require treatment with IVIG and Tocilizumab. Pediatricians should be aware of such presentation and immuno-modulatory treatment modalities.

Contributors: SB,TMN,BR: took part in treating the patient and preparing the manuscript; AVR: patient management and preparing the manuscript.

Funding: None; Competing interest: None stated.

REFERENCES

1. RCPCH. Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.Available from: https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19. Accessed May 02, 2020.

2. Balasubramanian S, Rao NM, Goenka A, Roderick M, Ramanan AV. Coronavirus Disease (COVID-19) in Children - What We Know So Far and What We Do Not?. Indian Pediatr.2020 Apr 9 [Epub ahead of print]. Available from:https://www.indianpediatrics.net/COVID29.03.2020/SA-00159.pdf. Accessed May 09, 2020.

3. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020 May 07. [Epub ahead of print]. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31094-1/fulltext. Accessed on May 09, 2020.

4. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020 Apr 10. [Epub ahead of print]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194613/pdf/main.pdf. Accessed May 09, 2020.

5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:                             497-506.

6. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393.

7. ClinicalTrials.gov: A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients with Severe COVID-19 Pneumonia. Available from: https://clinicaltrials.gov/ct2/show/NCT04320615. Accessed May 03, 2020.

8.   Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID 19: A single center experience. J Med Virol. 2020 Apr 06 [Epub ahead of print]. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv. 25801. Accessed May 9, 2020.