NIHR Signal Corticosteroids given early reduce risk of heart problems in children with Kawasaki disease

Published on 14 February 2017

Early treatment with corticosteroids on top of standard therapy reduces the risk of serious heart problems in children under five with the rare vascular disease, Kawasaki disease.

The disease needs to be recognised early, but can be hard to spot outside specialist care because it is so rare. It is now the commonest cause of acquired heart disease in children and delayed diagnosis can have serious consequences. Blood vessels supplying the heart become inflamed, increasing the risk of heart attack and death in later life. The disease is about 20 times more common in people of Japanese origin.

This summary of the evidence found that adding corticosteroids early to standard treatment within five days of onset of symptoms reduced the risk of serious abnormalities in the heart arteries by more than two thirds.

Corticosteroids were not effective when used as rescue treatment after standard treatment had failed.

Increasing awareness of the presenting symptoms of children with Kawasaki disease should ensure children are referred early for treatment. Specialist clinicians may want to consider adding corticosteroids to standard treatment with immunoglobulin and aspirin as initial treatment for Kawasaki disease.

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Why was this study needed?

The main features of Kawasaki disease are fever, peeling of the skin on the hands and feet and mouth ulcers. It is more common in Japan, where there are 138 cases per 100,000 children younger than five years, than in the UK, where there are 8.1 cases per 100,000 children. In 2016, NHS Improvement reported two serious cases of missed diagnosis.

Kawasaki disease can cause serious abnormalities, such as a bulge in a coronary artery. Between 15% and 25% of untreated children experience serious coronary artery abnormalities and 2% and 3% of untreated patients die. Children who develop coronary artery abnormalities from Kawasaki disease are at increased risk of severe heart problems as adults.

Intravenous immunoglobulin and aspirin are used to treat Kawasaki disease, but this does not prevent abnormalities for between 20% and 40% of children. Some studies suggest that adding corticosteroids may help prevent heart problems, but the prior evidence was mixed.

What did this study do?

Researchers systematically reviewed studies on the use of corticosteroids in children with Kawasaki disease, and pooled results in a meta-analysis. They included studies where corticosteroids were used as initial therapy along with standard therapy using intravenous immunoglobulin, and studies which added corticosteroids after failure of standard therapy.

They compared how many children had coronary artery abnormalities (assessed by Japanese criteria) after standard treatment alone or additional corticosteroids.

They identified 16 studies including 2,746 children, 861 of whom received corticosteroids and 1885 who received conventional therapy. Most of the studies were conducted in Japan and more than half had less than 100 participants. The studies varied moderately in terms of which corticosteroid was used (dexamethasone, methylprednisolone or presnisolone) and the dose and length of treatment.

What did it find?

  • Combining the results of all 16 trials showed that corticosteroid therapy on top of standard therapy more than halved the risk of coronary artery abnormalities compared with standard therapy alone (odds ratio [OR] 0.42, 95% confidence interval 0.27 to 0.67).
  • Subgroup analyses showed that corticosteroids were only effective when used as initial therapy (OR 0.32 for initial treatment, 95% CI 0.18 to 0.56). Initial therapy was started on average within 4.7 days of the onset of illness. This result was based on 10 studies with 2,363 children.
  • Corticosteroids were not effective when used as “rescue” treatment after standard therapy had failed. Rescue treatment was started on average 7.2 days after onset of illness (OR 0.85, 95% CI 0.47 to 1.6,). This result was based on six studies with 383 children.
  • Fewer than one in 10 children in the corticosteroid group (8%) and the standard treatment group (7.7%) experienced adverse effects from treatment (OR 1.31, 95% CI 0.49 to 3.48).

What does current guidance say on this issue?

UK guidance on management of Kawasaki disease (published in 2014) recommends treatment with aspirin (30-50 mg/kg a day) and intravenous immunoglobulin (2 g/kg in a single infusion), usually within 10 days of symptom onset.

It says that steroid treatment should be restricted to children who have received two or more infusions of immunoglobulin but still have fever and acute inflammation, or who have the most severe disease, or serious cardiovascular complications. The evidence is not conclusive on when to give steroids or which is the best treatment regimen to use.

What are the implications?

Clinicians may want to consider adding corticosteroids to immunoglobulin and aspirin in children who present within five days of onset of Kawasaki disease.

Adding corticosteroids might not reduce the risk of heart problems if given late or as rescue treatment, e.g. more than a week from starting immunoglobulins.

Clinicians should be aware that children with Japanese ancestry presenting with fever and the other specific symptoms may have Kawasaki disease and refer the patient quickly for early treatment to prevent heart problems.

Citation and Funding

Chen S, Dong Y, Kiuchi MG, et al. Coronary artery complication in Kawasaki disease and the importance of early intervention: a systematic review and meta-analysis. JAMA Pediatr. 2016;170(12):1156-1163.

No funding information was provided for this study.

Bibliography

Eleftheriou D, Levin M, Shingadia D, et al. Management of Kawasaki disease. Archives of Disease in Childhood. 2014;99(1):74-83.

Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747-71.

NHS Choices. Kawasaki disease. London: Department of Health; 2016.

NHS Improvement. Risk of death and serious harm from failure to recognise acute coronary syndromes in Kawasaki disease patients. Patient Safety Alert. Stage 1: Warning. Alert reference number: NHS/PSA/W/2016/004. London: NHS Improvement; 2016.

Sundel R. Clarifying the role of corticosteroids in Kawasaki disease. JAMA Pediatr. 2016;170(12):1140-42.

Why was this study needed?

The main features of Kawasaki disease are fever, peeling of the skin on the hands and feet and mouth ulcers. It is more common in Japan, where there are 138 cases per 100,000 children younger than five years, than in the UK, where there are 8.1 cases per 100,000 children. In 2016, NHS Improvement reported two serious cases of missed diagnosis.

Kawasaki disease can cause serious abnormalities, such as a bulge in a coronary artery. Between 15% and 25% of untreated children experience serious coronary artery abnormalities and 2% and 3% of untreated patients die. Children who develop coronary artery abnormalities from Kawasaki disease are at increased risk of severe heart problems as adults.

Intravenous immunoglobulin and aspirin are used to treat Kawasaki disease, but this does not prevent abnormalities for between 20% and 40% of children. Some studies suggest that adding corticosteroids may help prevent heart problems, but the prior evidence was mixed.

What did this study do?

Researchers systematically reviewed studies on the use of corticosteroids in children with Kawasaki disease, and pooled results in a meta-analysis. They included studies where corticosteroids were used as initial therapy along with standard therapy using intravenous immunoglobulin, and studies which added corticosteroids after failure of standard therapy.

They compared how many children had coronary artery abnormalities (assessed by Japanese criteria) after standard treatment alone or additional corticosteroids.

They identified 16 studies including 2,746 children, 861 of whom received corticosteroids and 1885 who received conventional therapy. Most of the studies were conducted in Japan and more than half had less than 100 participants. The studies varied moderately in terms of which corticosteroid was used (dexamethasone, methylprednisolone or presnisolone) and the dose and length of treatment.

What did it find?

  • Combining the results of all 16 trials showed that corticosteroid therapy on top of standard therapy more than halved the risk of coronary artery abnormalities compared with standard therapy alone (odds ratio [OR] 0.42, 95% confidence interval 0.27 to 0.67).
  • Subgroup analyses showed that corticosteroids were only effective when used as initial therapy (OR 0.32 for initial treatment, 95% CI 0.18 to 0.56). Initial therapy was started on average within 4.7 days of the onset of illness. This result was based on 10 studies with 2,363 children.
  • Corticosteroids were not effective when used as “rescue” treatment after standard therapy had failed. Rescue treatment was started on average 7.2 days after onset of illness (OR 0.85, 95% CI 0.47 to 1.6,). This result was based on six studies with 383 children.
  • Fewer than one in 10 children in the corticosteroid group (8%) and the standard treatment group (7.7%) experienced adverse effects from treatment (OR 1.31, 95% CI 0.49 to 3.48).

What does current guidance say on this issue?

UK guidance on management of Kawasaki disease (published in 2014) recommends treatment with aspirin (30-50 mg/kg a day) and intravenous immunoglobulin (2 g/kg in a single infusion), usually within 10 days of symptom onset.

It says that steroid treatment should be restricted to children who have received two or more infusions of immunoglobulin but still have fever and acute inflammation, or who have the most severe disease, or serious cardiovascular complications. The evidence is not conclusive on when to give steroids or which is the best treatment regimen to use.

What are the implications?

Clinicians may want to consider adding corticosteroids to immunoglobulin and aspirin in children who present within five days of onset of Kawasaki disease.

Adding corticosteroids might not reduce the risk of heart problems if given late or as rescue treatment, e.g. more than a week from starting immunoglobulins.

Clinicians should be aware that children with Japanese ancestry presenting with fever and the other specific symptoms may have Kawasaki disease and refer the patient quickly for early treatment to prevent heart problems.

Citation and Funding

Chen S, Dong Y, Kiuchi MG, et al. Coronary artery complication in Kawasaki disease and the importance of early intervention: a systematic review and meta-analysis. JAMA Pediatr. 2016;170(12):1156-1163.

No funding information was provided for this study.

Bibliography

Eleftheriou D, Levin M, Shingadia D, et al. Management of Kawasaki disease. Archives of Disease in Childhood. 2014;99(1):74-83.

Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747-71.

NHS Choices. Kawasaki disease. London: Department of Health; 2016.

NHS Improvement. Risk of death and serious harm from failure to recognise acute coronary syndromes in Kawasaki disease patients. Patient Safety Alert. Stage 1: Warning. Alert reference number: NHS/PSA/W/2016/004. London: NHS Improvement; 2016.

Sundel R. Clarifying the role of corticosteroids in Kawasaki disease. JAMA Pediatr. 2016;170(12):1140-42.

Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention : A Systematic Review and Meta-analysis

Published on 18 October 2016

Chen, S.,Dong, Y.,Kiuchi, M. G.,Wang, J.,Li, R.,Ling, Z.,Zhou, T.,Wang, Z.,Martinek, M.,Purerfellner, H.,Liu, S.,Krucoff, M. W.

JAMA Pediatr , 2016

Importance: The timing and selection of patients with Kawasaki disease for corticosteroid use to prevent coronary artery complications remain controversial. Objective: To evaluate the effect of corticosteroid therapy in KD. Data Sources: Databases of Medline, The Cochrane Library, and the Clinicaltrials.gov website until July 2015. We used the key words ["Kawasaki disease"] and ["steroid" OR "corticosteroid"] to retrieve potentially relevant studies in the databases of Medline, the Cochrane Library, and the Clinicaltrials.gov website until July 2015. Both English and non-English literature was identified. Titles and abstracts were reviewed by 2 authors (S.C. and Y.D.) to determine suitability for inclusion. Relevant articles were reassessed by reviewing the full text. Discrepancies in study inclusion were resolved by consensus (M.G.K.). Study Selection: Clinical studies that compared corticosteroids plus intravenous immunoglobulin (IVIG) therapy with IVIG therapy alone in treating patients with KD. Studies either using corticosteroids as initial therapy or as rescue therapy were included. Data Extraction and Synthesis: Investigators independently extracted the data information. Data were quantitatively synthesized using random-effects analysis. Main Outcomes and Measures: Rate of coronary artery abnormalities. Results: Sixteen comparative studies characterizing 2746 patients were analyzed. The duration of illness before corticosteroids therapy was significantly shorter in the initial corticosteroids subset than in the rescue corticosteroids subset. The rate of coronary artery abnormalities was significantly lower in adjunctive corticosteroids therapy than in IVIG therapy (odds ratio [OR], 0.424; 95% CI, 0.270-0.665). Meta-regression based on known variables demonstrated that the overall efficacy was negatively correlated with the duration of illness before corticosteroid therapy (P < .001). Subgroup analysis, including studies using corticosteroids plus IVIG as initial therapy, showed a more advantageous effect than IVIG alone regarding coronary artery abnormality prevention (OR, 0.320; 95% CI, 0.183-0.560), whereas this benefit was not found in a subgroup of studies using corticosteroids as rescue therapy. Further analysis found that patients predicted at baseline to be at high risk of IVIG resistance seemed to obtain the greatest benefit from adjunctive corticosteroid therapy regarding coronary artery abnormality prevention (OR, 0.240; 95% CI, 0.123-0.467). The fever duration was significantly reduced in the corticosteroids group. The favorable effects of corticosteroids were conferred without an increased risk of adverse events. Conclusions and Relevance: This study highlights the importance of timing to prevent coronary artery complication in treating KD. High-risk patients with KD benefit greatly from a timely and potent adjunctive corticosteroid therapy strategy.

NICE guidance on fever in under 5s (2013), recommends considering a diagnosis of Kawasaki disease in children with fever that has lasted longer than 5 days and who have 4 of the following 5 features:

  • bloodshot eyes
  • change in the lining of the upper respiratory tract (for example, dry cracked lips or a red tongue)
  • change in the hands and feet (for example, swelling, redness or skin peeling)
  • rash
  • swollen neck glands.

Expert commentary

In this review the effect was more marked when corticosteroids were given with immunoglobulin (IVIG) as initial therapy, and patients at high risk of coronary artery complications showed most benefit.

Most data was from Japanese studies using Japanese criteria for disease severity and may not be directly applicable to Kawasaki disease in other regions.

No significant differences in adverse effects were recorded between the corticosteroid group versus IVIG only group though details were not given regarding which specific adverse effects were monitored.

Initial treatment with IVIG and steroids would add no benefit to the 60-80% of Kawasaki disease patients who respond to IVIG alone.

Dr Paul Heaton, Consultant Paediatrician, Yeovil Hospital