case study on kawasaki disease

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A case report of atypical Kawasaki disease presented with severe elevated transaminases and literature review

Department of Paediatrics, ShaoXing KeQiao Women And Children’s Hospital, ShaoXing, 312030 Zhejiang Province PR China

Chuanxin Zhang

Associated data.

All data generated or analyzed during this study are included in the article.

Kawasaki disease (KD) is the most common cause of acquired heart disease among children in developed countries, in which the resulting coronary artery (CA) abnormalities cause myocardial ischemia, infarction, and death. Prompt diagnosis was essential, and supplemental information should be used to assist the diagnosis when classical clinical criteria are incomplete. The elevated levels of serum transaminases in most KD patients are mild. Herein, a case of atypical KD child with severely elevated transaminase was reported.

Case presentation

A child with clinical manifestations of fever, high C-reactive protein (CRP) and severely elevated transaminases was reported. The treatment effect of antibiotic and liver-protecting drugs was not satisfactory. A bilateral diffuse dilation of the CA was detected on echocardiography on day 5 of the illness; thus, atypical KD was diagnosed. Elevated transaminases declined rapidly to normal after the treatment of intravenous immunoglobulin (IVIG). A 1-month follow-up revealed that CA returned to normal, and 2-month, 6-months, and 1-year follow-up revealed the child was in good general health.

Conclusions

This case highlighted that atypical KD clinical symptoms were diverse, and severely elevated transaminases might provide a clue to healthcare providers for the diagnosis and management of atypical KD.

Kawasaki disease (KD) is an acute vasculitis, which commonly affects children between the age of 6 months and 5 years. Although the precise cause of the disease is yet unknown, a common pathway in many infectious or environmental factors that trigger inflammation of the blood vessels in individuals with a genetic predisposition to this disease could be ascribed as the putative factors [ 1 ]. Elevated serum liver enzymes constituted the typical laboratory tests manifested in the gastrointestinal tract of KD [ 2 ]. However, severely elevated transaminases could not be differentiated from atypical KD and infectious diseases, thereby delaying treatment.

A 1-year-old Han nationality boy was admitted to the Department of Pediatrics, Shaoxing Keqiao Women and Children’s Hospital, Shaoxing, China, due to complaints of fever and cough occasionally for 2 days in March 2019. However, he did not experience breathing difficulty, chills, vomiting, diarrhea, yellowing of skin, convulsions, and rash. Also, the patient had no history of medication except for two 3-mL ibuprofen suspensions. He had always been in good health, and no abnormal findings were detected at birth and in family history. Laboratory findings were as follows: blood routine examination: White blood cell count (WBC): 8.5 (4–10) × 10 9 /L, percentage of neutrophils (N%): 65.5 (40–75), percentage of lymphocyte (L%): 22.8 (40–60), hemoglobin (Hb): 100 (110–150) g/L, platelets (PLT): 240 (100–300) × 10 9 /L), C-reactive protein (CRP): 130.9 (0–8) mg/L. The other test results were as follows: erythrocyte sedimentation rate (ESR): 55 (0–15) mm/h, serum alanine aminotransferase (ALT): 1327 (9–50) U/L, aspartate aminotransferase (AST): 1584 (15–40) U/L, total bilirubin: 7.81 (3.42–20.5) μmol/L, direct bilirubin: 2.60 (0.0–6.84) μmol/L, gamma glutamyl transferase (GGT): 248.9 (10.0–60.0) U/L, and albumin 41.8 (38.0–55.0) g/L. Urinalysis revealed the presence of pyuria. The nitrite test was negative. Serological tests for hepatitis A, B, C, D, E, F, Epstein-Barr virus (EBV), cytomegalovirus, and viruses in the respiratory tract were negative for acute infections. Abdominal ultrasonography showed normal liver, gallbladder, bile ducts, and pancreas. Chest radiographs suggested normal. Ceftriaxone (80 mg/kg.d, qd) was intravenously injected to intervene the possible lung or urinary tract infection. Compound glycyrrhizin injection 20 mL (2 mL/kg, qd) and reduced glutathione 0.3 g (30 mg/kg, qd) were administered to protect the liver. On day 4 post-hospitalization, a large red rash appeared on the chest and back of the child. The results of blood, urine, and throat cultures were negative, respectively, but the fever persisted despite intravenous administration of ceftriaxone for 3 days. The common cause of severely elevated transaminase in children is a viral infection, such as hepatitis A, B, C, D, E, F, EBV, and cytomegalovirus. Since the results for the above tests were negative for the child, and CRP was abnormally elevated, these were deemed incompatible with virus infection and attributed to bacterial infections, such as acute purulent cholecystitis that can cause elevated transaminases. Nonetheless, the child did not show any relevant clinical symptoms. Abdominal ultrasonography was normal, and ceftriaxone had poor anti-infective treatment effect, which further did not support the presence of bacterial infection. Bilateral diffuse dilatation of the CA (2.6 mm left and 3.1 mm right), especially the right, was detected on echocardiography on day 5 post-hospitalization (Fig.  1 ). The Z-scores of the left and right main coronary artery (CA) were 2.13 and 4.13, respectively. According to Z-score classification [ 2 ], the patient had a small CA aneurysm. In summary, the child with fever ≥5 days, CRP 130.9 mg/L, ESR 55 mm/h, Hb 100 g/L, elevated ALT level, urine ≥10 WBC/hpf, CA aneurysm, fulfilled the diagnostic criteria of atypical KD [ 2 ]. Ectasia was frequently detected in the atypical KD than typical KD [ 3 ]. Thus, he was diagnosed as atypical KD and treated with aspirin (35 mg/kg/day from days 5–8 of hospitalization and 4.5 mg/kg/day from day 9 of hospitalization for the following 3 months) and Intravenous immunoglobulin (IVIG) (2 g/kg/day) for 10 h on day 5 of hospitalization. Ceftriaxone was stopped on day 5 of hospitalization. After 24 h of treatment, clinical and laboratory parameters improved rapidly with regression of fever and aminotransferase levels on day 6 post-hospitalization. The trends of temperature and elevated transaminases are shown in Fig.  2 . The child was discharged on day 9 of hospitalization. Also, a gradual regression was observed in the coronary blood vessels when normalized to the echocardiographic findings after 1 month (Fig.  3 ). Moreover, 2-months, 6-months, and 1-year follow-up did not show any recurrence of fever or an additional increase in the CA diameters corresponding to the maintenance dose (4.5 mg/kg/day for 3 months) of aspirin.

Right CA aneurysm (3.1 mm) was detected on echocardiography on day 5 of hospitalization

Trends of transaminases and temperature of the patient during hospitalization

A gradual regression was observed in the CA aneurysm on echocardiography after 1 month

According to literature, elevated serum transaminases or gamma glutamyl transpeptidase is observed in 40–60% KD patients [ 4 ]. The majority of the patients show only a mild increase in transaminases, which is < 2-fold of the upper limit of normal, and only a few patients showed 10-fold of the upper limit of the normal (Table  1 ) [ 9 ]. Although severely elevated transaminase is rare, it could mislead the diagnosis and delay the treatment. Reportedly, high ALT and GGT values in the acute phase are related to IVIG resistance [ 4 ]. However, this phenomenon was not observed in our case. The main purpose of this case report was to acquaint the pediatricians that atypical KD may have masqueraded in various guises, and hence, the variability of this disease should not be ignored. To minimize the diagnostic delay, we investigated the clinical manifestations of atypical KD (Table ​ (Table1 1 ).

Case reports of atypical KD

Since the cause of KD was unknown, it was speculated to be associated with the region, year, gender, season, family history, and genetics. Accumulating evidence linked KD to tropospheric wind patterns, which suggested that the transport of an agent when inhaled by genetically susceptible children, triggers the immunological cascade of KD [ 2 ]. In addition to CA abnormalities, hepatic dysfunction is also a common complication during the acute KD episode. Reportedly, 90.95% of KD patients have at least 1 abnormal liver function test, wherein hypoalbuminemia is the most prevalent type, followed by elevated AST, low total protein, low albumin/globulin ratio, and hyperbilirubinemia; however, the contributing factors are yet unclear and could be associated with inflammatory mediators, infectious agents, therapy, or a combination of the above [ 10 ]. Fei et al. reported continuous veno-venous hemodiafiltration that could rapidly reduce the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and improve the organ function of KD complicated with multiple organ dysfunction syndromes [ 11 ]. This concept provided a rescue therapy in children with KD complicated with severe organ damage. Intriguingly, Sundel et al. suggested a process initiated by an innate immune response to explain the pathophysiology of KD. It involved a reaction mediated by the acquired immune system, resulting in the loss of blood vessel structural integrity, arterial wall dilatation, and aneurysm formation [ 12 ]. Fei and Sundel proposed that the immune response was involved in the pathogenesis of KD [ 11 , 12 ]. Severely elevated transaminases of atypical KD might be related to severe immune damage to the liver.

Hua et al. reported that in patients ≤6-months-old, total fever duration of ≥8 days, delayed diagnosis, and albumin (ALB) ≤35.9 g/L were independent risk factors for acute and subacute KD combined with CA lesions (CAL) [ 13 ]. Shi et al. reported that delayed hospitalization is one of the factors of the increased risk of CAL in patients with atypical KD [ 14 ]. Yunjia et al. demonstrated that patients aged ≤1-year-old receive IVIG treatment after day 10 of illness, and IVIG non-responders were associated with the regression in persistent CA aneurysms (CAA) [ 15 ]. In summary, timely admission to the hospital and prompt treatment for KD patients is essential. Therefore, early recognition of the clinical symptoms of atypical KD, such as severe liver damage, is vital for the treatment of the disease.

KD could lead to severe complications, such as CAAs and thromboembolic occlusions. Thus, early diagnosis of the disease is an urgent requirement. Atypical KD clinical symptoms are diverse. Severely elevated transaminases could be one of the manifestations of atypical KD.

Acknowledgments

This study was partially supported by the Department of Pulmonology, The Children’s Hospital, Zhejiang University School of Medicine.

Abbreviations

Authors’ contributions.

YFR collected the data, reviewed literature, drafted the manuscript, and read and approved the final manuscript. CXZ, XQX, and YY helped with the literature review and data collection. All authors read and approved the manuscript.

Not applicable.

Availability of data and materials

Declarations.

This study was approved by the Research Ethics Committee of Children’s Hospital, College of Medicine, Zhejiang University.

Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. A copy of the written consent is available for review.

The authors declare that they have no competing interests.

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Yifan Ren, Email: moc.361@3121nafiyner .

Chuanxin Zhang, Email: moc.qq@616109372 .

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• Nichkamol Lertamornkitti ,
• Anchalee Wangjirapan
• Department of Pediatrics , Faculty of medicine, Lampang Hospital , Lampang , Thailand
• Correspondence to Dr Anchalee Wangjirapan, cherry_cmu{at}hotmail.com

We report a 3-month-old girl who presented with high-grade fever for 3 days. Her initial physical examination was normal. Investigation showed abnormal white cells in her urine. She was diagnosed with a urinary tract infection and received an antibiotic for 1 day. After that, she developed a generalised maculopapular rash over her body. An adverse drug reaction from the antibiotic was suspected, and the patient was referred to our hospital. On admission, she still had fever and was irritable. She was diagnosed with sepsis and given another broad-spectrum antibiotic for 2 days. However, her fever still persisted. An additional thorough physical examination showed redness of her BCG inoculation scar. Consequently, a diagnosis of Kawasaki disease (KD) was made. After she received intravenous immunoglobulin, her fever diminished straight away. This case highlights an unusual manifestation of KD in an uncommonly young age group.

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The usual incidence of Kawasaki disease (KD) is from 6 months up to 5 years of age. 1 There are only a few reported cases of neonatal KD. 2 An important and distinctive clinical sign that is not included in the classical clinical criteria of KD is a reaction at the BCG inoculation site. BCG redness is found in more than 50% of KD patients aged less than 12 months. 3 The crust formation or redness at the BCG scar should alert the physician to consider KD as a differential diagnosis for any febrile children, even when there are only a few or no classic clinical presentations. 4

Since it is challenging to establish a diagnosis, coronary artery complications occur frequently in infants with KD. 5 To prevent such harmful consequences, paediatricians can treat patients with KD through intravenous immunoglobulin (IVIG) infusion within 10 days of onset of the disease. 6 IVIG can decrease the risk of coronary artery abnormalities from 25% to 5%. 5 Our patient was diagnosed rapidly enough and received IVIG in good time, so she had no residual coronary artery complications.

Persistent fever can be caused by infectious and non-infectious diseases. Infectious diseases may be caused by bacteria, viruses, fungi or parasites. In this case, we gave her broad-spectrum antibiotics, but her symptoms did not improve indicating that bacterial infection was less likely. We therefore also included other micro-organisms and non-infectious diseases such as autoimmune diseases or neoplasm in the differential diagnosis. KD should also be considered as a differential diagnosis in cases of persistent fever especially in children under 5 years. A detailed history and physical examination are required to reveal the cause of persistent fever.

Case presentation

A 3-month-old infant from northern Thailand presented with fever for 3 days. She was a healthy term infant. She received BCG vaccination at birth. Her vaccination was completed according to Thailand’s national immunisation programme. Before she was referred to our hospital, she was admitted to a primary care hospital due to high-grade fever together with poor intake. Investigations for the source of the infection were conducted. Her urine examination showed a concentration of white cells of 20–30 cells/high-power field (hpf). As a result, she was diagnosed with a urinary tract infection. She was given ceftriaxone. After that, she developed a generalised maculopapular rash, so a ceftriaxone allergy was suspected. She was referred to our hospital.

On the first day of admission to our hospital, physical examination revealed high-grade fever (39˚C), a heart rate of 155 beats per minute and a respiratory rate of 32 breaths per minute. She looked irritable. She had erythematous lips and a mildly injected pharynx. She had no erythema of the palms or soles. Other systems were within normal limits. We thought of sepsis, so we gave her meropenem. However, the fever still persisted after 2 days of the antibiotic. We repeated the physical examination and found that she had redness and induration around her BCG scar ( figure 1 ). She had neither conjunctival injection nor cervical lymphadenopathies.

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Redness and induration around her BCG scar.

Investigations

A complete blood count revealed a haemoglobin concentration of 10.7 g/dL, haematocrit of 32.1%, a mean corpuscular volume of 83.1 fL and a white cell count of 23.7 x 10 9 /L  with 66% neutrophils, 22% lymphocytes and 3% monocytes. The platelet count was as high as 450 x 10 9 /L. The erythrocyte sedimentation rate (ESR) was 19 mm/hour. C reactive protein (CRP) was elevated to 130.7 mg/L. The liver function tests revealed a total bilirubin of 0.3 mg/dL, direct bilirubin of 0.1 mg/dL, aspartate aminotransferase of 38 U/L, alanine transaminase of 21 U/L, alkaline phosphatase of 111 U/L, total protein of 5.3 g/dL, albumin of 3.3 gm/dL and globulin of 2 g/dL. Urinary analysis showed a white cell count of 20–30 cells/hpf with 1–2 epithelial cells/hpf. The cerebrospinal fluid profile was normal. All cultures from catheterised urine, blood and cerebrospinal fluid were negative.

Echocardiography showed no anatomical cardiac defect. The coronary arteries were normal sized: the left main coronary artery was 1.7 mm, left anterior descending artery 1.7 mm, left circumflex artery 1.2 mm and the right coronary artery 1.8 mm. There was normal left ventricular function and trivial mitral valve regurgitation without pericardial effusion.

Differential diagnosis

Incomplete KD (two clinical criteria of red lips and polymorphous exanthem). On additional physical examination, erythema induration at BCG inoculation site plus three supplementary laboratory criteria of white cells ≥15 000 cells/mm 3 , urine white cell count ≥10 cells/hpf and platelet count ≥450 000 cells/mm 3 ).

The patient received IVIG 2 g/kg and aspirin 80 mg/kg/day on her seventh day of fever.

Outcome and follow-up

After administration of IVIG and aspirin, the fever dramatically defervesced in the following 24 hours. The infant was discharged 48 hours later. Her vaccination programme was postponed for the next 11 months to avoid live attenuated vaccines. Aspirin was prescribed at an antithrombotic dose for 8 weeks.

A follow-up echocardiography showed normal coronary arteries. The right coronary artery was 1.2 mm, the left main coronary artery was 2 mm and the left anterior descending artery was 1.5 mm. At follow-up examination, she had no periungual peeling of fingers or toes.

Only about 10% of KD occurs in infants who are less than 6 months. 5 Moreover, the incidence of KD in infants less than 3 months in Japan and Korea is only 1.67% and 2.2%, respectively. 7 8 The diagnosis of KD in infants 3 months of age or younger is difficult because very few cases (about 24%) meet 4 out of the 5 classical clinical criteria: changes in lips and oral cavity, polymorphous exanthem, bilateral non-exudative bulbar conjunctivitis, changes in extremities and a cervical lymphadenopathy over 1.5 cm in size. 7 As a consequence, cardiac complications are more common in KD patients less than 6 months of age. 9 IVIG and aspirin remain the mainstay of KD treatment. 10 Prompt diagnosis and administration of IVIG within 10 days, or ideally before day 7 of the disease, is mandated in order to reduce such cardiac complications. 11 Aspirin in the acute inflammatory period is prescribed at either 80–100 mg/kg/day or 30–50 mg/kg/day. Forty-eight to seventy-two hours after cessation of fever, aspirin should be decreased to a low dose (3 to 5 mg/kg/day). Additional therapy may include corticosteroid, infliximab and etanercept. 10

Since diagnosing KD in infants younger than 6 months is difficult, any febrile infants who have fever for 7 days or more without other explanations, even without any clinical clues of KD, should receive a blood analysis of systemic vascular response. If the ESR or CRP is elevated, echocardiography should be performed. 12 However, there are many limitations of echocardiography in the diagnosis of KD. First, it is an operator-dependent imaging. Second, it also requires co-operation from the patient. Third, the growth of children and the increasing body size cause difficulties in visualising the coronary arteries. These could possibly be diagnostic limitations as the sensitivity and specificity of echocardiography to determine coronary artery stenosis are uncertain. 10

There are many studies concentrating on the early diagnostic criteria of infantile KD. 9 13–16 Kang et al reviewed medical records of 64 KD patients from January 2010 to October 2014. Twenty of the analysed KD patients were infants less than 1 year of age. They discovered that infants had higher rates of inflammation at the BCG inoculation site (P<0.001), but lower incidence of changes in the extremities (P=0.029) and cervical lymphadenopathy (P=0.006). They stated that BCGitis is an initial sign that could lead to the diagnosis of incomplete infantile KD. 13 Yoon et al reviewed medical histories of 239 KD patients from January 2013 until June 2015, of which 26 were less than 6 months. They recognised that infants less than 6 months with KD rarely express cervical lymphadenopathy (P=0.005) or non-exudative conjunctival injection (P=0.027) when compared with KD patients aged 6 months or older. 9 Limbach and Lindinger claimed that all infants with KD shared similar characteristics of persistent fever despite administration of antibiotics and a polymorphous skin manifestation. They also revealed that abnormal urinalysis and thrombocytosis were frequently observed in this age group. 16

In our case, the patient was only 3 months. She had BCGitis, polymorphous exanthem, persistent fever even after infusion with several antibiotics, a sterile pyuria and thrombocytosis which provided the clues for a diagnosis. She had neither cervical lymphadenopathy, changes in extremities nor conjunctival injection. Fortunately, IVIG was given within 10 days of the onset of the disease and so she had no coronary artery complications.

Learning points

Kawasaki disease (KD) should be considered in infants less than 6 months even though the incidence is low in this age group.

Careful physical examination is important. If BCGitis is found in febrile children without a source of infection, consideration of KD is warranted.

Early diagnosis of KD and administration of intravenous immunoglobulin could reduce the risk of coronary artery complications.

• Rowley AH ,
• Kagawa J , et al
• Shahmohammadi S
• Igarashi H ,
• Yashiro M , et al
• Park JS , et al
• Chuang CH ,
• Chiu CH , et al
• Hong YM , et al
• McCrindle BW ,
• Newburger JW , et al
• Newburger JW ,
• Seo IA , et al
• Chen SJ , et al
• Choi KM , et al
• Limbach H ,
• Lindinger A

Contributors AW: picked a topic, made an outline and revised the manuscript. NL and AW: researched and wrote the paper.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent Gaurdian consent obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Published: 29 January 2024

Kawasaki disease in neonates: a case report and literature review

• Mingjun Shen 1 , 2   na1 ,
• Die Liu 2   na1 ,
• Fang Ye 2 ,
• Jing Zhang   ORCID: orcid.org/0009-0005-3370-6784 2 &
• Jun Wang 1 , 2  

Pediatric Rheumatology volume  22 , Article number:  23 ( 2024 ) Cite this article

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Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that affects infants and young children but is extremely rare in neonates, especially afebrile KD. We present a case of KD without fever in a neonate and review the literature on KD in neonates.

Case presentation

A newborn female was hospitalized because her peripheral blood leukocytes increased for half a day. The admission diagnosis was considered neonatal sepsis and bacterial meningitis. She had no fever since the admission, but a rash appeared on her face by the 7th day. On day 11 after admission, there was a desquamation on the distal extremities. On day 15 after admission, ultrasound showed non-suppurative cervical lymphadenopathy. Echocardiogram revealed coronary artery aneurysms in both sides. Finally, the patient was diagnosed with incomplete KD (IKD). The follow-up echocardiogram showed that the internal diameter of both coronary arteries returned to normal three months after birth.

Conclusions

Fever, rash, and distal extremity desquamation during the recovery phase are the most common symptoms of IKD. When newborns present with clinical manifestations such as rash, distal extremity desquamation and cervical lymph adenitis and with an increased peripheral blood leukocyte count and progressive increase in platelets simultaneously, the medical staff should be highly alert to the possibility of KD even without fever. The echocardiogram needs to be performed promptly. The incidence of coronary artery lesions is significantly higher if neonatal KD patients miss timely diagnosis and treatment.

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that affects infants and young children [ 1 ], but is extremely rare in neonates, especially afebrile KD. Data on 130,323 patients from the Japanese nationwide surveys of KD (2001–2012) identified 23 neonatal KD cases, representing 0.02% of KD in patients of all ages [ 2 ]. In this study, we present a neonatal case of incomplete KD (IKD) without fever and review the literature on KD in neonates. This report aims to increase awareness of afebrile KD in neonates to reduce the risk of cardiac complications.

A 19-hour-old female patient was transferred to the pediatric ward of China-Japan Friendship Hospital because her peripheral blood leukocytes increased for half a day. She was G1P1, at a gestational age of 40 weeks + 2days, and delivered by cesarean section due to acute intrauterine distress with III-degree contaminated amniotic fluid and slowed fetal heart rate. The Apgar score was 10-point at 1, 5, and 10 min after birth, respectively. The birth weight was 3386 g. The child had no fever, no irritability with a high-pitched cry, no convulsions, and no groans or vomiting after admission. Her temperature was 36.5 ℃, pulse 140/minute, respiration 40/minute, BP 80/55 mmHg, capillary refill less than two seconds. The face and trunk were light yellow. The bregma was bulged and the pressure was slightly higher. The neck resistance was suspiciously positive. The muscular tension in the limbs was normal, and the primitive reflexes were derived.

Laboratory investigations on the day of birth showed white blood cell (WBC) was 41.33 × 10 9 /L (neutrophils 75.3%, lymphocytes 15.4%, monocytes 7.8%), red blood cell (RBC) was 4.65 × 10 12 /L, hemoglobin was 167 g/L, platelet (PLT) was 266 × 10 9 /L, and C-reactive protein (CRP) was 6.86 mg/L. Total bilirubin was 124.11 µmol/L and direct bilirubin was 10.4 µmol/L. The cerebrospinal fluid contained total cells was 15 × 10 6 /L, WBC was 13 × 10 6 /L (multinuclear 85%, mononuclear 15%), protein 0.603 g/L, glucose 4.48 mmol/L (peripheral blood glucose: 5.1 mmol/L), and LDH 96 IU/L. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, treponema pallidum antibody and TORCH were all negative. Rheumatoid factor was normal. Chest X-ray, cranial ultrasound and abdominal ultrasound were unremarkable. Amplitude integration EEG showed no abnormal discharges. The patient was suspiciously diagnosed with neonatal sepsis and bacterial meningitis upon admission. Meropenem and vancomycin were given to control the infection. Mannitol was used to lower the intracranial pressure, and dexamethasone was used to prevent adhesions. On day 2 of hospitalization, intravenous immunoglobulin (IVIG) was used for three days (total dose 2 g/kg) as supportive therapy.

On day 4, cerebrospinal fluid was rechecked and contained total cells 6 × 10 6 /L, WBC 5 × 10 6 /L, protein 0.758 g/L, glucose 2.21 mmol/L (peripheral blood glucose 4.9 mmol/L), and LDH 76 IU/L. She had transient hyponatremia (127 mmol/L). Bacterial cultures from blood and cerebrospinal fluid were sterile.

The patient had no fever since admission, but a rash appeared on her face by the 7th day and lasted for five days. The PLT reached from 603 × 10 9 /L on day 7 to 1345 × 10 9 /L on day 12 (Table  1 ). Distal extremity desquamation began on day 11 and continued for ten days (Fig.  1 ). However, other manifestations including conjunctivitis, erythematous dry lips, red raspberry tongue and swollen extremities did not appeared. Low molecular dextran was given to reduce blood viscosity, enoxaparin sodium was given for anticoagulation, and dipyridamole and low-dose aspirin (5 mg/kg) were administered for anti-platelet aggregation. On the 15th day of the illness, ultrasound showed non-suppurative cervical lymphadenopathy. Echocardiogram showed that the internal diameter of the proximal segment of the left main coronary artery (LMCA) was 5.9 mm (Z = 11.40), the internal diameter of the left anterior descending coronary artery (LAD) was 2.4 mm (Z = 5.19) and the internal diameter of the right coronary artery (RCA) was 3.1 mm (Z = 8.07) (Fig.  2 ). Electrocardiogram was normal. Moreover, no abnormal blood flow was found in the arteries of the upper and lower extremities. No thrombus was found in the deep veins. Finally, the patient was diagnosed with IKD. Low-dose aspirin and dipyridamole were given to prevent platelet aggregation continuously.

Sheet-like desquamation of extremities emerged on day 11. ( A ) Skin on toes peeling. ( B ) Skin on fingers peeling

Echocardiography on 15th day after birth revealed coronary artery aneurysms in the left coronary artery

On 21 days after admission, the blood analyses showed WBC was 10.17 × 10 9 /L (neutrophils was 17.2%, lymphocytes was 61.2%, monocytes was 12.1%), RBC was 2.69 × 10 12 /L, hemoglobin was 90 g/L, PLT was 499 × 10 9 /L, and CRP was < 2.5 mg/L. Echocardiogram revealed LMCA of 2.6 mm (Z = 4.29), LAD of 2.1 mm (Z = 4.13), and RCA of 2.3 mm (Z = 4.95).

The patient was discharged with low-dose aspirin and dipyridamole after 21 days in the hospital. Regular follow-up was carried out every 2–4 weeks after discharge. Echocardiogram revealed LMCA of 2.0 mm (Z = 1.69) and RCA of 1.7 mm (Z = 1.78) three months after birth (Table  2 ).

KD is an acute febrile condition seen in children. The diagnostic criteria for KD are fever, bilateral bulbar conjunctival injection, changes in the lips and oral cavity, rash, changes in the peripheral extremities, and non-suppurative cervical lymphadenopathy. Fever is no longer necessary for the diagnosis of KD, according to the sixth revised edition of the Japanese diagnostic criteria [ 3 ]. Statistically, neonates with KD have a higher risk of incomplete presentation than older children [ 2 ].

The number of IKD cases increased yearly from 10% to the current level, which is greater than 20% of all KD patients [ 3 ]. Fever, redness, and swelling of the extremities are the most common symptoms of IKD [ 4 ]. We searched case reports of neonatal KD published in English from January 1, 2000 to February 18, 2023 with the search formula: ((“Mucocutaneous Lymph Node Syndrome“[Mesh]) OR (((Kawasaki Syndrome[Title/Abstract]) OR (Lymph Node Syndrome, Mucocutaneous [Title/Abstract])) OR (Kawasaki Disease [Title/Abstract]))) AND ((“Infant, Newborn“[Mesh]) OR (((((((((Infants, Newborn) OR (Newborn Infant)) OR (Newborns)) OR (Newborn)) OR (Neonate)) OR (Neonates)). The inclusion criteria were cases of KD in newborns and the diagnosis met the Revision of diagnostic guidelines for Kawasaki disease (6th revised edition) [ 3 ]. The exclusion criteria were duplication or literature with incomplete case information (no clinical features, no laboratory findings and outcomes). Nineteen cases in 15 papers were analyzed [ 2 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] (Table  3 ). IKD accounted for 68.4% (13/19). The clinical manifestations included rash in 94.7% (18/19), changes in the terminal extremities in 78.9% (15/19), fever in 78.9% (15/19), erythematous changes in the lips and oral mucosa in 68.4% (13/19), bilateral non-purulent conjunctivitis in 42.1% (8/19), cervical lymph adenitis in 10.5% (2/19), and coronary artery lesions (CALs) in 89.5% (17/19). Laboratory tests showed that elevated CRP accounted for 63.2% (12/19) and PLT > 300 × 10 9 /L accounted for 57.9% (11/19) (Table  4 ).

There were four patients with no fever among the 19 neonatal KD cases in our literature review. Only one afebrile patient was diagnosed as IKD purely based on CALs [ 11 ]. The other three afebrile patients [ 9 – 10 ], including the present case, had the same clinical manifestations, such as rash and periungual desquamation. In addition to the above-mentioned manifestations, conjunctival congestion, changes in the lips, and extremity edema were also observed in cases 6 and 7 [ 9 – 10 ] (Table  3 ).

The immune system of newborns is in a special developmental stage, which might lead to heterogeneity in neonatal KD and explain the higher incidence of IKD in neonates than older children. In this case, the patient did not have fever and other clinical manifestations, such as bilateral bulbar conjunctival injection, changes in the lips and oral cavity, probably associated with the early stage of neonate and the impact of early use of IVIG and dexamethasone.

To date, the etiology of KD is not clear. Previous studies suggested that KD is triggered by an infectious agent based on its occurrence in epidemiological clusters, seasonal variation, and a very low risk of recurrence [ 19 ]. Other research suggested that neonatal KD could be associated with sepsis and pneumonia [ 20 , 21 ]. Although the patient’s blood culture and cerebrospinal fluid were all sterile, the infection could not be excluded since abnormally elevated WBC and III-degree contaminated amniotic fluid at birth. We could not distinguish exactly whether this case was a KD secondary to systemic infection or just a KD case from the beginning.

CALs are the primary serious complication affecting the prognosis of KD. Several studies suggested that infants under the age of 6 months not only present more commonly with IKD, but are also at higher risk for coronary artery abnormalities and death [ 8 ]. In the 19 cases of neonatal KD mentioned above, CALs occurred in 89.5% in 19 neonates and 75% in the four cases of afebrile neonatal KD. 61.1% (11/18) of the patients with CALs had a favorable prognosis after using IVIG. Although this patient initially presented with medium to large coronary aneurysms, the internal diameter of the coronary arteries returned to normal after three months by IVIG treatment on 2nd day after birth. The 24th Nationwide Surveillance in Japan reported that approximately 9%, 25%, and 35% of KD patients received the first IVIG treatment on the 3rd, 4th, and 5th days of illness, respectively, and the prevalence of CALs were lower than before [ 3 ]. Consistent with this finding, our case suggests that early use of IVIG might be beneficial for long-term prognosis in KD.

This case report and review of the literature suggest a relatively higher incidence of IKD in neonates. Therefore, when newborns present with rash, terminal changes in the extremities or cervical lymph adenitis, increased peripheral blood leukocyte count and CRP, or progressive increase in platelets, the medical staff should be highly alert to the possibility of KD even without fever. Echocardiogram needs to be performed promptly. The incidence of CALs in neonatal KD is significantly higher. Timely diagnosis and treatment are essential for neonatal KD to improve the prognosis.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Coronary artery aneurysms

Coronary artery lesions

C-reactive protein

Erythrocyte sedimentation rate

Incomplete Kawasaki disease

Intravenous immunoglobulin

• Kawasaki disease

Left anterior descending

Left coronary artery

Procalcitonin

Red blood cell

Right coronary artery

White blood cell

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Mingjun Shen and Die Liu contributed equally to this work.

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Department of Clinical Medicine, Beijing University of Chinese Medicine, Beisanhuan East Road, Chaoyang District, 100029, Beijing, China

Mingjun Shen & Jun Wang

Department of Pediatrics, China-Japan Friendship Hospital, 2 Yinghuayuan East Street, Chaoyang District, 100029, Beijing, China

Mingjun Shen, Die Liu, Fang Ye, Jing Zhang & Jun Wang

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Mingjun Shen, Die Liu and Jing Zhang conceptualized and designed the work, drafted the initial manuscript, and reviewed and revised the manuscript. Fang Ye acquired, analyzed and interpreted patient’s data for diagnosis of KD. Jun Wang reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Jing Zhang or Jun Wang .

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Shen, M., Liu, D., Ye, F. et al. Kawasaki disease in neonates: a case report and literature review. Pediatr Rheumatol 22 , 23 (2024). https://doi.org/10.1186/s12969-024-00959-3

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Article Contents

Introduction, summary figure, lead author biography, supplementary material, data availability.

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Adult Kawasaki disease: a rare and challenging diagnosis—a case report

Conflict of interest: None declared.

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Timothy O’ Connor, Cora McNally, Mark W Kennedy, Adult Kawasaki disease: a rare and challenging diagnosis—a case report, European Heart Journal - Case Reports , Volume 7, Issue 9, September 2023, ytad397, https://doi.org/10.1093/ehjcr/ytad397

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Kawasaki disease (KD) is an acute systemic vasculitis which predominantly occurs in childhood but rarely in adulthood. Diagnosis relies on the presence of typical clinical features; however, patients may present atypically, increasing the challenge of timely diagnosis for physicians.

We report a case of a 40-year-old male presenting with persistent fever, rash, and unilateral neck swelling. Initial investigations were suggestive of necrotizing lymphadenitis, with a presumed infective aetiology. However, extensive microbiology and immunological investigations remained negative. Cardiac injury was evident with elevated troponin T and NT-proBNP; however, left ventricular systolic function was normal. After 4 days, clinical features consistent with KD were noted and the results of a lymph node biopsy supported this diagnosis. Despite timely treatment with intravenous immunoglobulins (IVIG) and high-dose aspirin, follow-up computed tomography (CT) coronary angiography demonstrated two sequential aneurysms (max 6 mm) in the right coronary artery, plus one small subtle aneurysm in the proximal left anterior descending artery (4 mm).

Diagnosis of adult KD remains challenging, as symptoms often present sequentially over time rather than simultaneously and many of the clinical features necessary for diagnosis share commonality with other infectious disease processes.

Adult Kawasaki disease is a rare diagnosis which is classically diagnosed clinically based on the presence of key clinical findings. However, patients can present atypically and clinical findings can present sequentially, making diagnosis challenging.

Delayed or misdiagnosis is associated with an increased incidence of coronary artery aneurysm formation and can have devastating long-term impacts due to myocardial ischaemia from coronary artery thrombosis and stenosis.

Risk stratification and long-term follow-up is advised in those with persistent and regressed coronary aneurysms.

Kawasaki disease (KD) is an acute self-limiting febrile illness and systemic vasculitis of unknown aetiology, predominantly affecting children and rarely adults. 1 This systemic arteritis of medium-sized vessels is the leading cause of acquired heart disease in children due to coronary artery aneurysm formation, occurring in up to 30% of untreated patients. 2 The classical diagnosis of KD is based on the presence of fever for 5 days and at least 4/5 principal clinical findings: bilateral non-exudative conjunctivitis, lip/oral mucosal changes, maculopapular or erythema multiforme–like rash, changes in peripheral extremities with subsequent periungual desquamation in the sub-acute phase, and cervical lymphadenopathy. 3 However, diagnosis remains challenging, particularly in adults, as symptoms often present sequentially rather than simultaneously and the clinical findings necessary for a diagnosis of KD share commonality with other infectious diseases. 2 Delayed or misdiagnosis is associated with an increased incidence of coronary artery aneurysm formation and can have devastating long-term impacts due to myocardial ischaemia from coronary artery thrombosis and stenosis. 3 We present a case of a 40-year-old male with KD who presented atypically and critically unwell.

Case presentation

A 40-year-old male presented with a 4-day history of fever, nausea/vomiting, and an enlarging non-tender left neck swelling. The patient was hypotensive, febrile, and confused. Clinical examination demonstrated a unilateral anterior cervical triangle swelling and an erythematous rash on the left side of his neck and anterior chest wall. Electrocardiogram (ECG) demonstrated sinus rhythm with left anterior fascicular block. Treatment was initially with intravenous fluid resuscitation and broad-spectrum antibiotics. Laboratory findings indicated elevated inflammatory markers [C-reactive protein (CRP) 205 mg/L], and a computed tomography (CT) neck and thorax demonstrated an acute inflammatory process of the left submandibular space, unilateral enlarged lymph nodes (largest 4 cm × 2 cm), and evidence of necrotizing lymphadenopathy.

Rapidly, the patient clinically deteriorated, requiring admission to the intensive care unit (ICU) for septic shock. Laboratory findings showed normal haemoglobin (Hb) and neutrophils (Hb 11.1 g/dL; 6.20 10 9 /L) with elevated inflammatory markers [CRP 205 mg/L; erythrocyte sedimentation rate (ESR) 91 mm/h], lymphopoenia (0.21 10 9 /L), thrombocytopoenia (59 10 9 /L), hyponatraemia (127 mmol/L), hepatitis [alanine aminotransferase (ALT) 275 IU/L; aspartate aminotransferase (AST) 51 U/L; bilirubin 23 umol/L], hypoalbuminaemia (27 g/L), coagulopathy [international normalized ratio (INR) 1.8], and myocarditis (troponin T 1104 ng/L; NT-proBNP 48 412 pg/mL). Viral and bacterial investigations were performed but remained negative throughout hospitalization. Additionally, a vasculitis screen returned negative. Transthoracic echocardiogram demonstrated normal left ventricular function and moderate central mitral regurgitation.

Despite ongoing broad-spectrum antibiotics, the patient remained critically unwell and febrile with no definitive aetiology. An ultrasound-guided biopsy of a left anterior cervical lymph node on Day 3 demonstrated features suggestive of suppurative necrotizing lymphadenitis ( Figure 1 ). On Day 4, clinical assessment noted new erythema of the oral mucosa, fissured lips, strawberry tongue, and bilateral conjunctival injection. Coupled with persistent fever, laboratory findings, and lymph node histology, a possible diagnosis of classic KD was made. Treatment with intravenous immunoglobulins (IVIG) and high-dose aspirin (300 mg) commenced, with dramatic clinical improvement noted within 2 days. On Day 10, acute transient left upper limb weakness occurred. This was investigated by CT angiogram and magnetic resonance imaging (MRI) which excluded vertebral artery dissection or stroke.

Histopathology of lymph node core biopsy. Evidence of areas of necrosis (arrow) which are associated with abundant neutrophils and debris. Occasional fibrin thrombi are noted in small vessels. Features are of suppurative necrotizing lymphadenitis with a wide differential diagnosis including Kawasaki disease.

Given the likely diagnosis of KD, with elevated cardiac enzymes on admission, a computed tomography coronary angiography (CTCA) and cardiac magnetic resonance imaging (CMRI) was undertaken as an outpatient ( Figures 2 and 3 ). A CTCA at 3 months demonstrated two sequential aneurysms (max 6 mm) in the right coronary artery (RCA), with one smaller subtle aneurysm in the proximal left anterior descending (LAD) artery (4 mm). No associated thrombus, mural thickening, coronary plaque, or perivascular fatty changes were noted. Cardiac MRI showed normal left ventricular volumes with preserved function but focal regions of mid-wall fibrosis consistent with previous myocarditis. A follow-up CTCA at 12 months showed resolution of the LAD aneurysm and improvement of the two focal aneurysms in the RCA (3 mm).

Coronary computed tomography angiography shows aneurysms (marked with asterisk) in the right coronary artery and left anterior descending artery 3 months post discharge ( A – C ). Interval improvement in size of aneurysms noted on follow-up imaging at 12 months post discharge ( D – F ) Ao, aorta; RCA, right coronary artery; LAD, left anterior descending artery.

Cardiac magnetic resonance imaging with post contrast (gadolinium) imaging showing a confluent stripe of mid-wall fibrosis in the inferolateral/lateral wall at the basal level ( A ) as well as some patchy inferolateral mid-wall fibrosis at the mid-ventricular level ( B ).

Kawasaki disease is a systemic vasculitis, typically affecting young children, and is the leading cause of acquired heart disease in children in developed countries. Aetiology of the disease remains unknown, but current consensus suggests an infectious trigger initiating an abnormal immune response in genetically predisposed persons. 4 Treatment focuses on prevention of coronary artery aneurysm formation, which occurs in up to 30% of untreated cases and predisposes to stenosis/thrombosis. 2 It is estimated that 5% of acute coronary syndromes (ACS) in adults < 40 years of age results from coronary artery aneurysms from KD. 3 Whilst coronary artery aneurysms receive the majority of attention with regard to cardiovascular complications of Kawasaki disease, myocarditis is more common from a histological perspective and, in a small subset of patients, may result in diffuse myocarditis and fibrosis formation. 2

Adult-onset Kawasaki disease is rare and often misdiagnosed or diagnosed late due to the natural history of the disease, the lack of a specific diagnostic test, and clinical similarities to other more common infectious diseases. 5 According to current guidelines, diagnosis of classic Kawasaki disease requires the presence of fever for 5 days and at least four principal clinical findings. 3 However, in patients whose clinical features do not meet the epidemiological case definition, a diagnosis of atypical Kawasaki disease can be made aided by supporting laboratory findings and imaging studies. As in the current case, Kawasaki disease can rarely manifest with fever and cervical adenopathy before the onset of other clinical signs or may even present with adenopathy dominating the presentation. 6 , 7 Such presentations may be misdiagnosed as bacterial cervical lymphadenitis which may delay a definitive diagnosis of KD and lead to serious cardiac sequale. 6 Indeed, node-first or node-predominant presentations have represented 9–23% of acute KD admissions in some series. 8 , 9

Based on current guidelines, echocardiography is the primary imaging modality for cardiac assessment of Kawasaki disease, but the diagnostic yield is reduced in adults due to inadequate visualization of the coronary arteries. 3 In an adult population, the incidence of abnormal findings on initial echocardiography is low at 44%. 5 Thus, other imaging modalities such as CTCA and CMRI may play a vital role in the diagnosis of adult Kawasaki disease and identify patients at risk of future cardiac adverse sequela. Furthermore, due to the long-term damaging effects to coronary artery function, it is recommended that stress CMRI perfusion be carried out during follow-up of persistent and now regressed coronary aneurysms. 3 , 4

Clinical experience demonstrates that long-term follow-up requires risk stratification to identify those at risk of myocardial ischaemia. This stratification, based on the presence, size, and persistence of aneurysms, allows for individualized long-term management to guide the frequency of clinical follow-up, diagnostic testing, and medical therapy. 3 Whilst therapy with aspirin is well established, statins may play a key role in lowering low-density lipoprotein cholesterol in addition to potential pleiotropic effects on inflammation, endothelial function, platelet aggregation, and fibrinolysis. 3

Kawasaki disease is a rare presentation in adulthood and may have serious long-term cardiac consequences if misdiagnosed. Diagnosis remains challenging; however, an understanding of the typical clinical features and potential atypical presentations may reduce delays in diagnosis and appropriate treatment.

Supplementary material is available at European Heart Journal – Case Reports online.

Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been received from the patient in line with the Committee on Publication Ethics (COPE) guidelines.

Funding: None declared.

The data underlying this article are available in the article and in its online Supplementary material .

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Author notes

• coronary aneurysm
• signs and symptoms
• kawasaki's disease
• persistence

Supplementary data

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• Introduction
• Conclusions
• Article Information

Time series are presented of Kawasaki disease incidence for each age group, normalized by dividing by the mean number of cases in 1987 to 1992 for each age bracket, based on daily smoothed data. To account for the decreasing birth rate in Japan, the incidence rate was computed relative to the population of children and adolescents aged 0 to 14 years for each year. The inset shows the number of patients in each age bracket for the 1970 to 2020 record. The 3 shaded areas in 2014 to 2019 indicate the decrease in cases (middle shaded area) and peaks on either side. For comparison, the time series that is not normalized by the 1987 to 1992 base period is shown in eFigure 1 and eAppendix 1 in Supplement 1 .

The seasonal cycle of daily KD incidence rate per 100 000 individuals younger than age 14 years is presented for 4 age groups for the mean over 1988 to 2019 (A-D) and the mean over successive 4-year periods (E-H). Panels E to H were normalized by the mean incidence rate for the relevant subsets of years. The vertical axis differs for each panel in A to D. Shading in A to D shows the SD of the seasonal cycle between prefectures, with 1 SD above and below the mean. Shaded boxes on H delineate typical periods during which school is in session. Note that not all children between ages 36 and 72 months attend preschool, which has this school schedule. This schedule does not apply to children in day care or at home. Vertical lines on H mark 5 weeks after the start of the school session.

Mean correlations of Kawasaki disease seasonal cycles (1988-2019) between prefectures are presented for 4 age groups. Correlations greater than 0.59 are significant at 95%. The southern island of Okinawa is shown in the inset. Numbers within the map indicate prefecture identifiers.

eAppendix 1. Time Series of Kawasaki Disease Incidence Rate

eFigure 1. Time Series of Kawasaki Disease Incidence Rate by Age Group

eAppendix 2. Significance of Differences Between Seasonal Cycles of Kawasaki Disease Incidence Over Time

eFigure 2. Statistical Tests of Differences Between Seasonal Cycles

eAppendix 3. Correlations of Seasonal Cycles Between Prefectures

eFigure 3. Seasonal Cycle Correlations Between Prefectures (1988-2019)

eAppendix 4. Changing Correlation of Seasonal Cycles Between Prefectures

eFigure 4. Correlation of Daily Incidence Between Regions by Year

eAppendix 5. Changing Attendance in Childcare Institutions

eFigure 5. Number and Percentage of Children Attending Japanese Childcare Institutions

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DeHaan LL , Copeland CD , Burney JA, et al. Age-Dependent Variations in Kawasaki Disease Incidence in Japan. JAMA Netw Open. 2024;7(2):e2355001. doi:10.1001/jamanetworkopen.2023.55001

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Age-Dependent Variations in Kawasaki Disease Incidence in Japan

• 1 Scripps Institution of Oceanography, University of California San Diego
• 2 School of Global Policy and Strategy, University of California San Diego
• 3 Department of Pediatrics, School of Medicine, University of California San Diego
• 4 Rady Children’s Hospital, San Diego, California
• 5 Department Public of Health, Jichi Medical University, Tochigi, Japan

Question   Does the epidemiologic Kawasaki disease (KD) record in Japan yield new clues regarding the mechanism of disease transmission when stratified by age?

Findings   In this cross-sectional study of 422 528 pediatric patients with KD in Japan, there were differences in KD incidence by age group and region, including the rate of increase over the past 3 decades, seasonal cycle, and correlation of the seasonal cycle between prefectures.

Meaning   This study found distinct seasonality and differences in correlations between prefectures of the seasonal cycle of KD incidence across age groups, suggesting different age-related forms of exposure that may need to be accounted for in explanations of KD etiology.

Importance   The etiology of Kawasaki disease (KD) remains elusive, with immunologic and epidemiologic data suggesting different triggers in individuals who are genetically susceptible. KD remains the most common cause of acquired heart disease in pediatric patients, and Japan is the country of highest incidence, with an increasing number of cases.

Objective   To investigate whether an analysis of the epidemiologic KD record in Japan stratified by age and prefecture (subregion) may yield new clues regarding mechanisms of exposure to etiologic agents associated with KD.

Design, Setting, and Participants   This cross-sectional study was conducted using a dataset of patients with KD with detailed information on location and age at onset created through nationwide surveys of hospitals caring for pediatric patients with KD throughout Japan. Pediatric patients hospitalized in Japan for KD from 1970 to 2020 were included. Data were analyzed from January 2022 to January 2024.

Exposure   Pediatric patients with KD.

Main Outcomes and Measures   The KD dataset was analyzed by patient age (infants [aged <6 months], toddlers [aged 6 to <24 months], children aged 2 years [aged 24 to <36 months], and children and adolescents aged 3 years or older [aged ≥36 months]), with investigations of seasonal cycles, interannual variations, and correlations across regions.

Results   Among 422 528 pediatric patients (243 803 males [57.7%] and 178 732 females [42.3%]; median [IQR] age, 23.69 [11.96-42.65] months), infants, toddlers, and patients aged 3 years or older exhibited different rates of increase in KD incidence, seasonality, and degrees of coherence of seasonality across prefectures. Although the mean (SD) incidence of KD among infants remained relatively stable over the past 30 years compared with older patients (1.00 [0.07] in 1987-1992 to 2.05 [0.11] in 2011-2016), the mean (SD) incidence rate for children and adolescents aged 3 years or older increased 5.2-fold, from 1.00 (0.08) in 1987 to 1992 to 5.17 (0.46) in 2014 to 2019. Patients aged 3 years or older saw a reduction in mean (SD) incidence, from peaks of 5.71 (0.01) in October 2014 through June 2015 and July 2018 through March 2019 to 4.69 (0.11) in 2016 to 2017 (17.8% reduction) not seen in younger children. The seasonal cycle varied by age group; for example, mean (SD) incidence peaked in July and August (5.63 [0.07] cases/100 000 individuals) for infants and in December and January (4.67 [0.13] cases/100 000 individuals) for toddlers. Mean (SD) incidence changed dramatically for toddlers beginning in the early 2010s; for example, the normalized mean (SD) incidence among toddlers for October was 0.74 (0.03) in 1992 to 1995 and 1.10 (0.01) in 2016 to 2019. Across Japan, the seasonal cycle of KD incidence of older children and adolescents exhibited mean (SD) correlation coefficients between prefectures as high as 0.78 (0.14) for prefecture 14 among patients aged 3 years or older, while that of infants was much less (highest mean [SD] correlation coefficient, 0.43 [0.23]).

Conclusions and Relevance   This study found distinct temporal signatures and changing spatial consistency of KD incidence across age groups, suggesting different age-related mechanisms of exposure. Some results suggested that social factors may modulate exposure to etiologic agents of KD; however, the increase in KD incidence in older children coupled with the correlation across prefectures of KD incidence suggest that the intensity of an environmental exposure that triggers KD in this age group may have increased over time.

Despite 5 decades of research, the etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children and adolescents, remains a mystery. Tomisaku Kawasaki first described the condition in a landmark publication 1 reporting 50 pediatric patients with fever, rash, mucocutaneous findings, and lymphadenopathy. Without treatment, the acute phase of the illness can last for weeks and then resolve spontaneously. However, 25% of untreated pediatric patients will develop aneurysms of the coronary arteries that may lead to myocardial infarction and death. 2 Treatment with intravenous immunoglobulin within days after the onset of fever reduces the risk of cardiac complications. 3 However, identification of the triggers for KD would be transformative for patient care and would surely lead to improved diagnostics and more specific treatments.

Most authorities believe that KD was a new pediatric disease that emerged in Japan after World War II. Patients meeting the clinical case definition were rare in the 1950s. 4 Nationwide epidemics in 1979, 1982, and 1986 were consistent with new widespread exposure in a highly susceptible population. 5 Subsequent research has revealed an important role for genetic variants that are associated with susceptibility to KD. 6 Japan remains the country of highest incidence, although cases are now diagnosed worldwide. 7 While the etiology remains unknown, a complex interplay of host genetics and environmental factors is suspected.

The epidemiology team at Jichi University has meticulously curated a nationwide survey of KD in Japan since 1970, which has fueled decades of research on KD. Basic features of KD epidemiology in Japan that have been gleaned from this source include the following: incidence with a male-to-female ratio of 1.5:1, 85% of patients younger than age 5 years, an increase in the total number of cases in Japan over time, peak incidence at age 9 months, and a low recurrence rate of 3% to 4%. 8 - 10 Further analyses using the database have identified an overall seasonal structure of KD incidence and spatiotemporal clustering, with similar characteristics noted in North America, the UK, and Western Europe. 11 , 12 A previous analysis of 127 398 Japanese patients with KD explored age-related differences in KD incidence and seasonality. 13 In this study, we add to this investigation by conducting an analysis over a longer period at higher spatial and temporal resolution, enabling a more robust study of age-dependent seasonality and changes in seasonality over decades, as well as spatial coherence of KD incidence.

The nationwide KD survey used in this cross-sectional study was approved by the Bioethical Committee for Epidemiologic Research, Jichi Medical University, Japan. 14 This study was reviewed and a waiver of consent approved by the University of California San Diego Institutional Review Board, which does not require informed consent for any of our activities. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

We hypothesized that different age groups of patients with KD would exhibit differences in KD incidence, seasonal patterns, and spatiotemporal correlations in seasonality across Japan’s 47 prefectures (subregions). To test these hypotheses, we used data compiled from 26 nationwide surveys of patients with KD in Japan, which provided the date of birth, date of onset, and home prefecture of 422 528 patients between 1970 and 2020. Starting in 1970, the survey was conducted every 2 years by questionnaires sent to pediatricians at hospitals with more than 100 beds and at specialized pediatric hospitals. The response rate was more than 70% (eg, 1444 of 1881 facilities [76.8%] reported in the 2015-2016 survey) for the last 2 decades, and most nonresponding hospitals had few or no patients with KD. 15 The diagnosis of patients with KD has been consistent over the period of record based on guidelines created by the Japan Kawasaki Disease Research Committee. Using these data, a 50-year time series of KD incidence rate was computed by counting the number of patients on each date of onset in the record and smoothing that count with a 365-day running mean (the mean was found for the value of each day with the 182 previous days and 182 subsequent days). We smoothed the data with a 365-day running mean to remove the seasonal cycle from the result. To account for the decreasing birth rate in Japan, the incidence rate was computed relative to the population of individuals aged 0 to 14 years from the e-Stat Portal Site of the Government Statistics of Japan. 16 Time-series values were then normalized by dividing incidence rates in each of 6 age brackets (<6 months, 6 to <15 months, 15 to <24 months, 24 to <36 months, 36 to <60 months, and ≥60 months) by the mean number of patients in that age bracket between 1987 and 1992, when the total annual number of patients with KD in Japan was relatively constant ( Figure 1 ). The result is the KD incidence rate for each age bracket relative to the incidence rate from 1987 to 1992. For each age bracket, we performed 2-tailed t tests to compare recent mean incidence rates with those within the stable, 1987 to 1992 postepidemic period and the 2016 to 2017 period of low incidence, with mean rates of peaks on either side, wherein P -values < .05 were considered significant.

We further analyzed data by seasonal cycle using a subset of the Japanese nationwide surveys (1988-2019). The 1979, 1982, and 1986 KD epidemics and the COVID-19 pandemic greatly altered the incidence and seasonality of KD. 17 , 18 Consequently, the record beginning in 1988 and ending in 2019 was used to avoid the influence of the KD epidemics and COVID-19 pandemic. For this analysis, we computed the seasonal cycle of KD incidence rate based on a time series smoothed with a 31-day running mean by finding the mean of the number of KD onsets for each day of the year between 1988 and 2019. We used a 31-day running mean to remove the day-to-day variation in the record. Unique seasonal cycles were computed for 4 age groups and Japan’s 47 prefectures. Age groups were characterized as infants (aged <6 months; 28 147 of 323 530 patients in 1988-2019 [8.7%]), toddlers (aged 6 to <24 months; 131 353 patients [40.6%]), children aged 2 years (aged 24 to <36 months; 56 294 patients [17.4%]), and children and adolescents aged 3 years or older (aged ≥36 months; 107 736 patients [33.3%]). The toddler group combines 2 age groups from Figure 1 based on the similar incidence patterns of those age groups, and likewise the ages 3 years and older group is a combination of 2 groups from Figure 1 . In an analysis of changes in seasonal cycles over 1988 to 2019, incidence rates were normalized by dividing by the mean incidence rate for relevant subsets of years. To test for significant differences between seasonal cycles, we used a random sampling approach, as described in eFigure 2 in Supplement 1 .

A third analysis was performed to investigate similarities of seasonal cycles among Japan’s 47 prefectures. A seasonal cycle for each prefecture was computed as described previously, and Pearson correlations of seasonal cycles were computed between each pair of prefectures to investigate coherence of KD incidence across regions. The mean of the resulting 46 correlations for each prefecture was then found to give a single value for each prefecture. Pairwise correlations greater than 0.59 were significant at 95%. All computations were performed in MATLAB version R2023a (Mathworks). Data were analyzed from January 2022 to January 2024.

Among 422 528 pediatric patients (243 803 males [57.7%] and 178 732 females [42.3%]; median [IQR] age, 23.69 [11.96-42.65] months), time series of KD incidence rates from 1970 to 2000 for 6 age groups showed that the well-known increase in KD incidence in Japan over time was evident in each age group to varying extents ( Figure 1 ). However, the increase in normalized incidence rates differed among age groups, particularly between infants and children and adolescents aged 3 years and older. After the major KD epidemics in 1979, 1982, and 1986, each age group experienced a period of stable KD incidence until the late 1990s. Thereafter, from 2000 through 2019, incidence increased rapidly. For infants, mean (SD) KD incidence increased by a factor of 2.1 from the base period in 1987 to 1992 (1.00 [0.07]) to the peak years of 2011 to 2016 (2.05 [0.11]) ( P  < .001). In contrast, KD incidence for the children and adolescents aged 3 years and older (ie, the 2 oldest age groups) increased by a factor of 5.2 between the base period in 1987 to 1992 (1.00 [0.08]) and the peak years for this group, 2014 to 2019 (5.17 [0.46]) ( P  < .001). There were 2 marked decreases in KD incidence during this period. The first was in 2016 and 2017. For children and adolescents aged 3 years and older, the decrease, highlighted in the center gray box in Figure 1 (January 2016 through June 2017), was a reduction in the mean (SD) incidence from peaks of 5.71 (0.10) on either side (October 2014 through June 2015 and July 2018 through March 2019) to 4.69 (0.11) ( P  = .005), a 17.8% decrease. The reduction in mean (SD) incidence for children aged 6 to less than 24 months was from peaks of 4.02 (0.06) to 3.74 (0.10) ( P  = .02), and there was no significant reduction for infants. The second decline was a sharp decrease in cases in 2020 that coincided with the COVID-19 pandemic. 17

We analyzed seasonal cycles of KD incidence in each age bracket using a subset of the Japanese nationwide survey (1988-2019, which avoided the KD epidemics and COVID-19 pandemic) with 323 531 patients (186 353 males [57.6%] and 137 177 females [42.4%]; median [IQR] age, 24.26 [12.24-43.56] months). These long-term means ( Figure 2 ) showed different seasonal cycles of KD incidence rates for each age group. Infants experienced a lower overall mean (SD) incidence than other age groups but nonetheless had a discernable peak in July and August of 5.63 (0.07) cases/100 000 individuals that was an increase of nearly 20% over the other 10 months (4.78 [0.31] cases/100 000 individuals, for a 17.8% increase). In contrast, toddlers (patients aged 6 to <24 months) experienced a seasonal peak in mean (SD) incidence in December and January (4.67 [0.13] cases/100 000 individuals), with relatively constant numbers from March through October. Children aged 2 years had a similar winter peak as toddlers but exhibited a pronounced decrease in October. Children and adolescents aged 3 years or older showed the most complex seasonal cycle. The pattern was similar to that of children aged 2 years, with a winter peak and an autumn nadir, but also included secondary peaks in April and June. The typical school calendar shown by the shaded boxes in Figure 2 H highlights that the number of KD cases among children and adolescents aged 3 years or older decreased at the beginning of each school session and then increased after approximately 5 weeks of school attendance.

A more detailed analysis of long-term, 1988 to 2019 means ( Figure 2 A-D) revealed shifts and distortions of the overall seasonal cycle over time, shown by seasonal cycles of normalized KD incidence for successive 4-year periods ( Figure 2 E-H). Most larger differences exceeded the 95th or 99th percentile of statistical odds of random occurrence; for example, toddlers had significantly higher incidence in spring (April, May, and June) in 1988 to 1991 compared with other years (eFigure 2 and eAppendix 2 in Supplement 1 ). Infants, who exhibited the least amount of change over time ( Figure 2 E), had a summer peak that consistently occurred from the early 1990s until 2015. In 2016 to 2019, the summer peak disappeared. Incidence patterns among toddlers changed the most ( Figure 2 F). Toddlers experienced a January peak and an October nadir in the 1990s until the early 2000s, but their seasonal cycle shifted in 2012 to 2015 such that October was no longer a low point, and during 2016 to 2019, October became the peak in the seasonal cycle. The normalized mean (SD) incidence among toddlers for October was 0.74 (0.03) in 1992 to 1995 and 1.10 (0.01) in 2016 to 2019.

Children aged 2 years ( Figure 2 G) had a consistent January peak and October nadir until 2015. However, the October low disappeared during 2016 to 2019 as with toddlers. In comparison with toddlers, children and adolescents aged 3 years and older had a seasonal cycle structure ( Figure 2 H) that was consistent throughout the period. The October nadir occurred throughout the period, as did the January peak. Secondary features of KD incidence in children and adolescents aged 3 years and older were also consistent; peaks in April, June, and September occurred across decades.

To assess whether seasonal cycle varied spatially across Japan, the data record was disaggregated into prefectures and the seasonal cycle for each prefecture was correlated with that of every other prefecture ( Figure 3 ; eFigure 3 and eAppendix 3 in Supplement 1 ). For infants, seasonal cycles of different prefectures showed essentially no correlation with other prefectures; mean (SD) correlation coefficients ranged from 0.02 (0.22) for prefecture 18 to 0.43 (0.23) for prefecture 27 ( Figure 3 A). Seasonal cycles for toddlers and children aged 2 years ( Figure 3 B and Figure 3 C) exhibited higher correlations, with a few prefectures having mean correlations at greater than the 95% significance level. The lowest correlation coefficients for toddlers and children aged 2 years occurred in prefectures on the southern island of Kyushu. Seasonal cycles for children and adolescents aged 3 years and older ( Figure 3 D) exhibited the greatest spatial coherence, with more than 80% of prefecture pairs (38 of 47 pairs [80.9%]) having mean correlations at greater than the 95% significance level; for example, mean (SD) correlation coefficients were as high as 0.78 (0.14) for prefecture 14. Although age groups had different sample sizes, the large difference between the low correlation coefficients of infants and high correlation coefficients of children and adolescents aged 3 years and older across prefectures may reduce concerns about spurious correlations due to small sample size.

There was additional time-varying structure underlying these prefecture-level associations. In earlier years, correlation coefficients across prefectures for toddlers were higher than those for children and adolescents aged 3 years and older. However, in later years there was a decrease in correlation coefficients for toddlers while correlation coefficients for children and adolescents aged 3 years and older increased (eFigure 4 and eAppendix 4 in Supplement 1 ).

Although previous studies have described overall KD incidence in Japan, a sharper and more complex picture emerged when KD incidence was assessed by age groups in this cross-sectional study. Age-associated patterns may add new insights into the epidemiology of KD in Japan and are thus important clues to understanding the etiology of KD. Hypotheses regarding KD etiology must explain the distinctly different epidemiology between infants and older children and adolescents; changing seasonal cycle for toddlers; complex seasonal cycle for children and adolescents aged 3 years and older, with secondary peaks in the spring that aligned across prefectures; and 5-fold increase in incidence rates for older children and adolescents since 1990. These findings argue for both social factors modulating exposure, including person-to-person spread, as well environmental exposures that are increasing over time. The summary of these characteristics, along with the characteristics of previous studies, are listed in the Box . 4 , 10 , 11 , 14 , 17 - 21

Characteristics of KD Incidence in Japan

Previous findings.

New disease after WWII (Shibuya et al, 4 2002)

Male to female incidence, 1.5:1.0; 85% of patients with KD aged <5 y; peak incidence at age 9 mo (Makino et al, 10 2019)

3 Nationwide epidemics followed by annual increase in cases despite decreasing birth rate (Ae et al, 19 2020)

KD cases clustered in time and space in addition to seasonal patterns (Burns et al, 11 2005; Sano et al, 20 2016)

Distinct seasonal cycle with winter peak and fall nadir (Burns et al, 11 2005)

Decrease in KD incidence associated with COVID-19 pandemic (Ae et al, 17 2021; Hara et al, 18 2021)

Birth order observations suggest infants may be exposed from older, school age siblings (Namba et al, 21 2023)

New findings

Infants aged <6 mo had a distinctly different epidemiology than older children and adolescents, with little increase in case numbers over 4 decades, a different seasonal cycle with a modest summer peak, and minimal spatial coherence between prefectures

Toddlers (ages 6 to <24 mo) had a changing seasonal cycle over time, with an October peak in later years

Children and adolescents aged ≥ 3 y were the drivers of the previously described seasonal cycle. Additional peaks in the seasonal cycle in April and June may be associated with the school calendar

The seasonal cycle of KD incidence in children and adolescents aged ≥3 y was correlated across prefectures

Children aged ≥3 y had a >5-fold increase in incidence since 1990

Abbreviation: KD, Kawasaki disease.

For infants, KD incidence increased little over 1987 to 2019 and the seasonal cycle, with a summer peak, showed essentially no coherence across prefectures. It is possible that this distinct difference from the epidemiology of older children and adolescents was associated in part with the tendency of infants to be in the home. A previous analysis 21 of birth order of patients with KD aged 6 to 18 months Japan identified having an older sibling as a risk factor associated with developing KD. The odds ratio was lower when the younger child was in day care. These observations suggest the importance of social factors in KD exposure, including person-to-person transmission from the older sibling to the younger child or increased exposure of the younger child to agents outside the home.

Toddlers exhibited a large change in their seasonal cycle in the mid-2010s in our study, which again suggests potential social or behavioral factors associated with exposure changes. At approximately that same time, the Japanese government launched a number of initiatives to provide increased day care options for families with toddlers. Most notably, the Comprehensive Support System for Children and Childcare was launched in April 2015 and expanded daycare capacity for patients younger than age 3 years (eFigure 5 and eAppendix 5 in Supplement 1 ). While this change in day care use does not completely explain the timing or the change in the seasonal cycle, it is plausible that this change in behavior was a contributor. Spatial correlations demonstrated that these seasonal changes in incidence among toddlers in Kyushu differed from those in other regions in Japan, suggesting that factors associated with these seasonal changes may have differed across regions.

The seasonal cycle of children and adolescents aged 3 years and older consistently exhibited minor peaks in April and June, in addition to a winter peak and an autumn nadir. Nadirs preceding secondary peaks each occurred approximately 5 weeks after the start of a school session, and there was a relative peak at the start of each school session. While it is unclear why KD incidence would decrease for the first 5 weeks of a school session, the consistent pattern suggests that levels of exposure to KD agents may differ according to times when children are in or out of school. Ae et al 22 also found evidence for an association between school attendance and KD incidence in Japan based on the influence of COVID-19 mitigation measures. The connection to the school calendar and the decrease in cases during COVID-19 mitigation measures are both consistent with reduced exposure to aerosols that may trigger KD.

Some KD epidemiologic characteristics suggest that social or behavioral factors modulated KD transmission by person-to-person spread or other mechanisms. However, the large increase in KD incidence since 1990 and the coherence of the seasonal cycle of KD incidence in children and adolescents aged 3 years and older across most of Japan suggest waves of concurrent environmental exposures whose intensity is increasing over time and is associated with disproportionate changes in outcomes among older children and adolescents. The biologic plausibility of these 2 apparently competing mechanisms of transmission deserves consideration. One possibility is that an aerosol carried by regional scale winds harbors an infectious agent 23 that can also be transmitted from person to person, with only individuals who are genetically susceptible manifesting KD. Infants may be exposed in the home environment through contact with older siblings. Alternatively, there could be more than 1 etiology for KD, with infants and older children and adolescents responding to different triggers.

We recognize that there are some limitations of the analysis presented in this study. Japan is the country of highest KD incidence, and the meticulous curation of the country’s dataset ensures that these data accurately reflect the epidemiology of KD in Japan. However, there is no standard test to diagnose KD, so the dataset relies on the clinical diagnosis by experienced physicians. There could thus exist errors in under- and over-diagnosis of KD. In addition, it is unknown if findings discussed in this study also apply to other countries.

In this cross-sectional study of the historical record of KD in Japan, distinct age-specific patterns of KD incidence were revealed that suggested differences in exposures that varied by age group. First, differences in seasonal cycles and different rates of increase over the observational record between age groups suggest that exposure was modulated by social practices, including day care availability and school vacation schedules. Second, the remarkable increase and spatial coherence of KD incidence in children and adolescents aged 3 years and older suggest that environmental factors were associated with increased exposure to a KD trigger. Theories regarding the etiology of KD must account for contrasting KD temporal and spatial patterns associated with different age groups in Japan.

Accepted for Publication: December 5, 2023.

Published: February 6, 2024. doi:10.1001/jamanetworkopen.2023.55001

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 DeHaan LL et al. JAMA Network Open .

Corresponding Author: Laurel L. DeHaan, MS, Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Dr, 0230, La Jolla, CA 92093-0230 ( [email protected] ).

Author Contributions: Mrs DeHaan and Dr Burns had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: DeHaan, Copeland, Burney, Nakamura, Yashiro, Burns, Cayan.

Acquisition, analysis, or interpretation of data: DeHaan, Copeland, Burney, Yashiro, Shimizu, Miyata, Burns.

Drafting of the manuscript: DeHaan, Burney, Nakamura, Yashiro, Burns, Cayan.

Critical review of the manuscript for important intellectual content: DeHaan, Copeland, Burney, Shimizu, Miyata, Burns, Cayan.

Statistical analysis: DeHaan, Copeland, Burney, Yashiro, Cayan.

Obtained funding: Burney, Burns, Cayan.

Administrative, technical, or material support: Burney, Yashiro, Miyata.

Supervision: Burney, Nakamura.

Conflict of Interest Disclosures: Dr Yashiro reported receiving grants from the Japan Kawasaki Disease Research Committee (nonprofit organization) during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported in part by a grant from the Gordon and Marilyn Macklin Foundation to Mrs DeHaan, Mr Copeland, and Drs Burney, Burns, and Cayan.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We thank Ryusuke Ae, MD, PhD (Jichi Medical University Department of Public Health), for providing helpful discussions. He was not compensated for the work.

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• Case report
• Open access
• Published: 23 October 2018

Kawasaki disease: two case reports from the Aga Khan Hospital, Dar es Salaam-Tanzania

• Mariam Noorani   ORCID: orcid.org/0000-0002-6455-1675 1 &
• Nuruddin Lakhani 1  

BMC Pediatrics volume  18 , Article number:  334 ( 2018 ) Cite this article

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Kawasaki disease is a common childhood vasculitis which may result in cardiovascular morbidity if not adequately treated. Its epidemiology in the African region is not well described. Its features may mimic other childhood infections and hemoglobinopathies and it is rarely diagnosed in the East African region. These are the first reports of this disease from Tanzania.

Case presentation

We present two cases of complete Kawasaki disease seen over a 2 year period and diagnosed as per the criteria defined by the American Heart Association. One child was and infant and the other a 3 year old. Both of them presented with a prolonged fever and mucocutaneous findings. None of the children developed coronary artery aneurysms. One was treated with aspirin alone and the other with both aspirin and intravenous immunoglobulin. Both children had complete recovery and did not have any cardiovascular sequelae.

Kawasaki disease may be more common in the East African region than previously thought. It should be considered as a differential diagnosis in children who present with a prolonged fever of greater than 5 days and mucocutaneous findings. More awareness about this condition, its epidemiology, diagnosis and management are required in order to prevent the cardiovascular morbidity associated with it.

Peer Review reports

Kawasaki disease is one of the most common vasculitides in childhood. It occurs predominantly in infants and young children and has long term cardiovascular morbidity due to coronary artery lesions if not adequately treated [ 1 ]. It is the leading cause of acquired heart disease in children in developed countries. The highest incidence is in Asia with almost 1 in a 100 children in Japan having the disease by age 5 [ 2 ]. In Africa, two cases were reported in South Africa in Caucasian children in 1980 but the first case in an African child was reported in Ivory Coast in 1981. Despite of sporadic cases being reported across many countries in Africa, mainly North Africa and the West African region, the epidemiological data for KD is limited for African countries [ 3 , 4 , 5 ].

The etiology of the disease remains unknown and several hypothesis exist in trying to explain the cause. Epidemiologic data suggest that an infectious agent may be causing the disease in genetically susceptible individuals [ 6 ]. The classic presentation of the disease occurs in children below 5 years. This suggests that there is an environmental trigger to which children mount an immune response after which the disease no longer manifests [ 7 ]. Postulated infectious agents include variants of normal flora which are induced by environmental factors such as improved hygiene [ 8 ]. Pathogenetic mechanisms postulated to result in endothelial injury include that of a protein homeostasis system in which immune cells target pathogenic proteins bound to endothelial cells resulting in host cell injury [ 9 ].

The initial symptoms are of a febrile illness lasting longer than 5 days with other mucocutaneous features including a rash, conjuctivitis and adenopathy. Diagnostic criteria exist to make a diagnosis of both complete and incomplete forms of disease [ 10 ]. If left untreated, the symptoms resolve in about 10 days. However, the coronary artery lesions may lead to long term cardiovascular complications including myocardial infarction, heart failure and arrhythmias. Treatment in the acute phase reduces the incidence of coronary artery lesions from 25 to 30% to 3–5% [ 11 ]. Currently, the recommended treatment is intravenous immunoglobulin in addition to acetylsalicylic acid at high doses [ 10 ].

In sub-saharan Africa, children suffer from many tropical and infectious diseases that present with symptoms similar to those of kawasaki disease such as fever, irritability and a rash. Common conditions include malaria, typhoid fever, meningitis and viral exanthems such as measles and roseola infantum. Other conditions that may mimic this disease include sickle cell dactylitis and infection with group A beta hemolytic streptococcus. A high index of suspicion is hence required to identify cases of kawasaki disease and institute early treatment.

We report here 2 cases of kawasaki disease seen at our institution that met diagnostic criteria defined by the American Heart Association. These are the first reports in published literature from the East African region.

Case presentations

A.M was a 3 year old female child of African ethnicity who presented in July 2012 with a 8 day history of high grade fever and a 1 day history of swelling of the hands and feet. (Table  1 – timeline of case 1). She had received oral antibiotics, anti malarials and antihistamines with no improvement in symptoms. Her past medical history had been uneventful and her vaccinations were uptodate.

On examination, she was alert, had dry, red lips and non pitting edema on her hands and feet. She had cervical nodes measuring about 0.5 cm. Her cardiovascular exam was normal. She was admitted for further work up for the cause of her fever.

Her results showed an elevated WBC count of 36,000/μl, Hb of 9.1 g/dl and platelets of 380,000/μl. Her CRP was 173 mg/l. Malaria antigen and slide were both negative. Her urinalysis was normal. She was started empirically on ceftriaxone for presumed bacteremia and blood and urine cultures were sent. A differential diagnosis of sickle cell anaemia with dactylitis was also made and a peripheral smear, reticulocyte count and sickling test were requested. The reticulocyte count was low with a percentage of 0.38. Sickling test was negative and the peripheral smear was normal.

She continued to have fever spikes despite the antibiotics and then developed a maculopapular hyperemic rash on her chest. A diagnosis of incomplete kawasaki disease was now made which met 3 out of the 5 required criteria. An echocardiogram was done which showed normal coronary arteries. High dose aspirin was started at 80 mg/kg/day. IVIG was not available at the institution at that time. A repeat complete blood count showed some improvement in white blood cells (28000/μl) but elevated platelets of 644000/μl. The blood and urine culture were both reported as negative after 48 h.

The child was then flown out to Nairobi, Kenya for IVIG treatment which she received uneventfully. She was discharged on low dose aspirin and subsequent echocardiograms remained normal.

W.I was an 8 month old infant of African ethnicity who presented in August 2013 with a 6 day history of a high grade fever with temperatures upto 39 degrees celsius. (Table 2 – Timeline of case 2). This was associated with redness of the eyes, lips and mouth. He had been treated at various health facilities with antimalarials and 2 antibiotics: cefalexin and coamoxiclav. He had also received paracetamol, ibuprofen and diclofenac injections to control the fever. His past medical history was uneventful and his vaccines were uptodate. He had attained milestones appropriately.

On examination, the child was irritable and difficult to console. He was febrile with a temperature of 38.5 0 C and was not pale. He had dry, cracked, hyperemic lips and conjuctival injection bilaterally. Cervical nodes were not palpable. He had a papular rash on the neck and at the site of the BCG scar. The rest of his physical exam was normal.

A presumptive diagnosis of incomplete kawasaki disease was made meeting 3 of the five criteria required in addition to the fever. A complete blood count showed mild anaemia with normal platelet count. (WBC: 9.07 *10 3 /μl, Hb: 9.3 g/dl, platelets:190,000/μl). Malaria antigen and blood slide were both negative. He was started on high dose aspirin at 90 mg/kg/day as IV IG was not available in our institution at that time. An echocardiogram was done which showed normal coronary arteries and normal cardiac function.

His fever resolved after 72 h and he developed swelling of the hands and feet which now confirmed the diagnosis of complete kawasaki disease. The aspirin dose was reduced to 5 mg/kg/day after the fever subsided. The platelet count was repeated and it showed elevated platelets of 742,000/μl. The CRP was also high: 153 mg/l.

On follow up after a week, the limb swelling had reduced and he had skin exfoliation. His CRP had reduced to 60 mg/l and the platelets were 605,000/μl.

A follow up echo done after 1 month was normal and the aspirin was stopped after the hematological parameters had normalised. He has subsequently remained well with no cardiovascular sequelae.

Discussion and conclusions

Both cases described above presented to us after a prolonged duration of fever and failure to respond to antimalarials and antibiotics. This is a common presentation also described in case reports from Ghana [ 3 ].

The first case was 3 year old child while the second was an infant. This is in keeping with epidemiologic studies from Algeria and Japan which have shown that more than 90% of children are less than 5 years of age [ 2 , 5 ].

The children had the classical mucocutaneous features that are key to making the diagnosis. The first child had limb swelling, a skin rash and oral mucosal changes. The limb swelling was initialy thought to be sickling dactylitis which is a common condition seen in our environment and is one of the presenting signs of sickle cell disease [ 12 ].

The second child had non purulent conjuctivitis, swelling of limbs and the skin rash with involvement of the BCG scar which has been described previously [ 13 ]. Hematologic parameters are not diagnostic of kawasaki disease, however they can assist to confirm or support the diagnosis. Both our children were admitted with normal platelet counts which subsequently became elevated. This is a common finding in the second week of illness and is used as an adjunct in making diagnosis of incomplete kawasaki disease [ 10 ]. The first child had an elevated WBC count leading to a diagnosis of bacteremia and initiation of parenteral antibiotics. However, the blood culture eventually ruled out a bacteremia. The CRP was raised for both the cases as expected and eventually reduced after initiation of aspirin.

The first case was treated with both aspirin and IVIG while the second received only aspirin. The role of aspirin remains uncertain in the current era of use of IVIG, however it still remains as part of the standard treatment protocols. The current treatment: IVIG is an expensive drug that is not readily available or affordable to most families in our population. A single vial of 5 g costs as much as 1 million tanzanian shillings which is about 450 US dollars. This hampers effective treatment which is essential to reduce the cardiovascular sequelae.

Other treatment options that could be considered are use of corticosteroids. A cochrane review of 7 trials showed benefits of reducing cardiac complications by using steroids as adjunct therapy to IVIG early in the course of illness [ 14 ]. Use of steroids alone without IVIG has not been studied. However, in low resource settings where IVIG is not available, steroids could be used to reduce the cardiovascular morbidity [ 15 ]. Other agents such as infliximab have shown promise as adjuncts to IVIG but are also not widely available in sub – saharan Africa [ 16 ].

The echocardiograms for both children were normal at baseline and on subsequent follow ups. This was reassuring since the incidence of coronary abnormalities is as high as 25–30% in patients who are not treated with IVIG [ 11 ]. Echo is a vital modality to follow up the cardiac sequelae in chidlren with kawasaki disease. However, it is not widely available in most resource limited settings and requires specialised training to operate. In Tanzania, it is only available at a few referral hospitals in the cities. This is yet another challenge in providing long-term care to children with kawasaki disease.

Kawasaki disease has not commonly been described in sub-saharan Africa. However, these 2 cases were seen over a 2 year period at a single tertiary institution. This raises concern about how many missed cases there may be which are not diagnosed or managed effectively since the fever and mucocutaneous changes eventually resolve within 3 weeks even without specific treatment. The subsequent devastating cardiovascular morbidity of this condition in children with missed diagnosis remains unknown.

The pattern of disease in the setting of tropical infections like malaria also remains unknown. Kawasaki like syndromes have been described in adults with HIV infection especially with severe immunosupression [ 17 ]. Similar illness in children infected with HIV has not been described but may also occur.

We recommend that a diagnosis of kawasaki disease be entertained for any febrile illness lasting longer than 5 days and presenting with mucocutaneous findings. Any child presenting with a prolonged fever should promptly be referred to and evaluated at a tertiary centre. Doctors and other care providers should be made familiar with this condition in order to diagnose, treat and prevent the cardiovascular morbidity and mortality.

Cases that are seen at other institutions should be published in literature so that the spectrum of the disease, its epidemiologic characteristics and its outcomes in sub-saharan Africa can be described. Equally important is that IVIG be made available at a subsidised and more affordable cost in order to benefit patients with kawasaki disease and other autoimmune conditions where it is indicated.

Abbreviations

Complete blood count

• Intravenous immunoglobulin

White blood cells

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Noorani, M., Lakhani, N. Kawasaki disease: two case reports from the Aga Khan Hospital, Dar es Salaam-Tanzania. BMC Pediatr 18 , 334 (2018). https://doi.org/10.1186/s12887-018-1306-5

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A Doctor’s Lifelong Quest to Solve One of Pediatric Medicine’s Greatest Mysteries

For 40 years, Dr. Jane Burns has been working to find the cause of Kawasaki disease, an illness that can lead to aneurysms and heart attacks. Her work has brought together a most unlikely team.

By Emily Baumgaertner

Photographs by Ariana Drehsler

It looked like a scene from the TV crime show “CSI.” Dr. Jane Burns was peering into a multiheaded microscope at the San Diego County medical examiner’s office, scrutinizing autopsy samples from an array of mysterious deaths.

Listen to this article with reporter commentary

This one was from the heart of a 20-year-old jiu-jitsu fighter who was last seen at the gym and was found dead in his bed two days later. There were no signs of foul play or self-harm.

The blood vessel tissue on the slide looked abnormal. Dr. Burns turned to the examiner: “I think this was likely one of mine.”

Dr. Burns is an expert in a rare childhood illness called Kawasaki disease, which is the most common cause of acquired heart disease in children worldwide. It is also one of pediatric medicine’s greatest mysteries: No one knows what causes it.

And Dr. Burns, who leads the investigations at the University of California San Diego’s Kawasaki Disease Research Center, has devoted her life to solving that mystery.

The condition, which usually occurs in children under 5, is easy to miss: There is no diagnostic test, and its symptoms — a high fever, rash, red cracked lips and a “strawberry tongue” — look to many doctors like scarlet fever, measles or a tick-borne illness, despite its signature distinction of bloodshot eyes.

Kawasaki disease can often resolve itself in a matter of weeks. But without the right treatment, about a quarter of patients develop aneurysms of the coronary arteries, which can lead to sudden heart attacks and death, even years or decades later — as apparently happened to the young man whose tissue Dr. Burns was analyzing.

Dr. Burns and other scientists believe that children inherit some level of susceptibility to it from their parents and that the condition is then brought on by something they breathe in, whether a virus, a bacteria or a toxin. Climate scientists wonder if global warming could also be broadening the disease’s scope.

Her freezers hold the world’s largest biobank of Kawasaki disease samples, and she scours for hints — in both the living and the dead — in hopes of eventually discovering the culprit. She believes that by determining the cause, researchers could then develop diagnostic tests that would lead to more timely treatment and prevent more deaths.

To get there, she has built a most unlikely network of detectives — an oceanographer, a statistician, a cardiologist, a historian, a forensic pathologist, a microbiologist, an anthropologist and others — each with specific expertise. And after 40 years of sleuthing, she believes, the team might just have the tools to complete the mission.

“This is a quest indeed — a puzzle — but Jane is doggedly persistent,” said Daniel Cayan, a climatologist at the Scripps Institution of Oceanography who has joined Dr. Burns’s team to help investigate how climate variability could be influencing the disease. “Here you have a marvelous organizer and fearless ringleader, pulling on every string and angle, chasing this.”

Answers could not come at a better time. The rate of Kawasaki disease in Japan, where it is most rampant, is increasing at an alarming rate, and doctors in the United States are now seeing a jump in cases after years when the rate remained steady, most likely because some children were protected from exposure during pandemic-era social distancing measures.

This year, doctors at Rady Children’s Hospital-San Diego, which admits the largest number of Kawasaki disease patients in the United States, have seen double the usual number of cases. Hospitals in Boston, Colorado and Chicago have also reported surges.

“Every day in our country, somewhere, a child with K.D. is being misdiagnosed,” Dr. Burns said. “Before now, we didn’t have the tools and the teams and the samples and the data to really attack this disease. Now we do, so let’s get moving.”

She added, “It’s taken a half century to get here, but now we’re ready to roll.”

From a children’s playroom to the atmosphere

Kawasaki disease first captured Dr. Burns’s attention in 1981 when she was a senior medical resident and cared for a feverish 3-month-old baby with mysterious rashes. The baby died. Dr. Burns watched the autopsy and, when the chest was opened, could not believe her eyes: Aneurysms beaded on the surface of the infant’s heart.

The baby’s parents went door to door collecting donations in loose bills and eventually handed $1,500 to Dr. Burns in a brown bag, asking her to research the disease. Dr. Burns persuaded so many senior professors to help her that, for their first meeting, they crammed into the hospital ward’s play space, squatting in children’s chairs to brainstorm a plan: The head of neurology would volunteer a fellow to run electroencephalograms; an immunologist would study the role of T-cells. Dr. Burns’s career as master collaborator was born.

In the early years of her investigation, the epidemiology of Kawasaki disease looked much like a classic infection passed between people. There were three large nationwide epidemics in Japan in the late 1970s and the 1980s, each so drastic that it suggested a novel agent was moving through a highly susceptible population. Each was followed by a plateau period, typically of several years.

But in the 1990s, things began to look strange. The number of school-age children with the disease in Japan kept climbing, despite a falling birthrate, hinting that more and more children were being exposed to its mystery cause each year.

Dr. Burns looked into an array of potential triggers, including carpet cleaning . She and her husband, Dr. John Gordon, a cardiologist treating dozens of adult patients with missed cases of Kawasaki disease, hosted the physician who had first identified the disease, Dr. Tomisaku Kawasaki , at their San Diego home. Dr. Burns went to Japan to interview every living person who had ever been involved in recognizing a new disease there. But there was little funding to pursue such work.

By 2000, a student of Dr. Burns’s noticed that Kawasaki disease cases in San Diego climbed whenever it rained. Dr. Burns partnered with Dr. Cayan, the climatologist, and Japanese researchers to discover that cases in Japan rose and fell with seasonal rhythms and that, in contrast to what is seen with person-to-person outbreaks, the case levels were always oddly consistent across broad swaths of the country .

Later, she and colleagues including a European climate scientist, Xavier Rodó, analyzed records of more than 247,000 patients in Japan to discover that the biggest outbreaks of the disease had something peculiar in common : They had all occurred when large-scale wind currents were blowing in from Central Asia. When those winds reached Hawaii and California, cases climbed there, too.

It was then that Dr. Burns and her colleagues began to argue that whatever was causing Kawasaki disease in children was not just passing from person to person; it was possibly being blown across the world on the wind.

It seemed unlikely to some that living particles could survive a journey through the icy troposphere — but Dr. Burns, who routinely froze viruses to preserve them in the lab, couldn’t shake the theory.

The team waited until the agent was expected to be present in the air and then dispatched an airplane to fly over Japan and collect air samples. With the help of Ian Lipkin, a microbiologist at Columbia, they processed the filters and found a type of fungus called Candida . But it was still just an association — not a sure cause — and funding once again ran dry.

A natural experiment

In recent years, Dr. Burns has recruited new members to her polymathic team, including Dr. Jennifer Burney, an environmental scientist at U.C. San Diego, and Laurel DeHaan, a data analyst, who came aboard to help them analyze the records of almost half a million Kawasaki disease patients in Japan over three decades, stratifying them by age and region.

What they found was bizarre: The rate of cases among children over 3 years old had increased fivefold in recent decades, but the rate among infants had remained relatively flat the whole time. What’s more, the seasonal cycle of cases for the age groups was completely different.

The annual peak for toddlers shifted in the mid-2010s — around the time the Japanese government dramatically expanded day care options for families.

In 2020 came a natural experiment. The dawn of the Covid pandemic brought school closures, and Kawasaki disease among children in the United States fell by 28 percent. But most common respiratory viruses that are transmitted between children faded away almost entirely, and Kawasaki disease did not — in fact, the number of children under 12 months with Kawasaki disease did not change much at all, hinting that some exposure inside homes continued to affect infants.

The atmosphere can be “complicated and chaotic,” said Charles Copeland, the newest recruit, who uses historical records and supercomputer weather models to estimate the globe’s wind patterns for every hour of the day dating back to the 1970s. (He reverse-tracks particles using a program called HYSPLIT, based on a software developed during the cold war to track radioactive particles back to their origins.) The goal, he said in one of the recent team meetings, is to figure out whether seemingly random bursts of Kawasaki disease in history were related to particularly anomalous wind patterns.

“To really try to untangle this and get to the heart of whether this is a wind story, we really have to ask the right questions,” he said. “If you ask the wrong questions — under the wrong assumptions — I think you will get the wrong answer.”

A missed case — or two

At the Kawasaki Disease Clinic at Rady Children’s Hospital-San Diego, led by Dr. Burns, caring for children affected by Kawasaki disease is always linked to the search for the cause.

On a recent Wednesday morning, Dr. Kirsten Dummer, a pediatric cardiologist, was examining the heart scans of a 2-year-old who showed signs of a large aneurysm on the right side of the heart.

“The biggest question from parents is: How did this happen? How did my child get this? In every patient room, that’s what they fundamentally want to know,” she said. “Year after year after year, they come back and ask us, ‘Do you guys know more yet?’”

Dr. Burns, who has continued to see patients herself, said those inquiries motivated her.

“If we were all Ph.D.s in the laboratory working on the etiology of Kawasaki disease,” there would be a different pace to it, Dr. Burns said. “But there’s an urgency to it, because we’re going back and forth, from the lab to the patients, saying, ‘Damn it, I need to answer this question.’ It matters, because it matters to these people.”

Later that morning, Inez Maldonado Diega, a 4-year-old in a mermaid outfit, rolled out balls of Play-Doh with her mother as Dr. Burns broke the news. Seventeen days ago, the girl’s pediatrician’s office had missed her case of Kawasaki disease. A echocardiogram had come back clear — a sign that her heart was so far healthy — but she still had a fever, which meant the disease could be lingering.

“I wish we had seen her sooner,” Dr. Burns said, listening to Inez’s heartbeat. She requested genetic samples for her biobank from both Inez and her mother, explaining that children are believed to inherit a susceptibility to the disease from their parents.

Inez’s mother, Tiara Diega, assured Dr. Burns that she had never had Kawasaki disease as a child — just scarlet fever. Dr. Burns raised her eyebrows and asked Ms. Diega to phone her mother on speakerphone.

Had Ms. Diega had bloodshot eyes during her infection all those years ago, she asked Ms. Diega’s mother? Yes, the mother said. Dr. Burns exhaled slowly.

“That wasn’t scarlet fever,” she said.

For a moment, the room was quiet — Ms. Diega still holding a patty of Play-Doh in midair — as the risks to both mother and daughter sunk in. Then Dr. Burns referred Ms. Diega for a cardiac scan of her own — to see whether a grave danger had been brewing all these years.

Audio produced by Tally Abecassis .

Emily Baumgaertner is a national health reporter for The Times, focusing on public health issues that primarily affect vulnerable communities. More about Emily Baumgaertner

JOHN B. DARBY, MD, AND JENNIFER M. JACKSON, MD

Am Fam Physician. 2021;104(3):244-252

Published online August 12, 2021.

Author disclosure: No relevant financial affiliations.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are inflammatory conditions that present diagnostic and therapeutic challenges to the physician. Although many of their features overlap, they are two distinct conditions. KD is a febrile illness most commonly affecting children younger than five years. It manifests with prolonged fever and at least four of the following features: bilateral bulbar conjunctivitis, mucositis, diffuse maculopapular rash, extremity changes, and cervical lymphadenopathy of 1.5 cm or more in diameter. Patients with MIS-C may have many of the same manifestations but tend to have higher rates of gastrointestinal and neurocognitive symptoms and signs of shock on presentation. Both conditions are associated with cardiac sequelae, including coronary artery aneurysms, although children with MIS-C are at high risk of developing ventricular dysfunction and depressed cardiac output. Lymphocytopenia, thrombocytopenia, elevated troponin, and elevated B-type natriuretic peptide are key laboratory findings of MIS-C that can help distinguish it from KD. The use of intravenous immune globulin is well established in KD and also appears to have a role in the treatment of MIS-C. Aspirin has been used in KD for an anti-inflammatory effect, and low-dose aspirin is recommended for MIS-C to reduce the risk of thrombosis. In addition to supportive care, patients with MIS-C may benefit from immunomodulatory medications, although data on this topic are evolving.

First described in Japan in 1967, Kawasaki disease (KD) is a vasculitis affecting small- and medium-sized vessels; it is predominantly seen in children younger than five years. 1 This febrile illness is characterized by systemic inflammation and is the most common cause of acquired coronary artery disease in children. 2 With the emergence of multisystem inflammatory syndrome in children (MIS-C), a new inflammatory syndrome associated with COVID-19, KD has received increased attention because features of the diseases overlap.

Epidemiology

Although the underlying cause of KD remains unknown, the epidemiology and pathophysiology suggest that it is an inflammatory response in a genetically susceptible host to an infectious or other exogenous trigger. A number of viruses have been implicated as potential triggers for KD, including coronaviruses (non–COVID-19 strains). 3 , 4 KD is an illness predominantly occurring in toddlers, with a mean age of three years in the United States (76% of cases occur in children younger than five years). 5 There is a predilection for children of Asian and Pacific Islander descent, 5 and boys are affected slightly more often than girls (1.5:1). 6

In contrast, MIS-C affects a wider age range, from one week to 20 years with a median age of seven to nine years. 7 – 11 In the United States, 62% of patients are Hispanic or Latino (32%) or non-Hispanic Black (30%)—the ethnic groups disproportionately affected by COVID-19. 7 Similarly to KD, MIS-C occurs more often in boys (60%) than in girls. 7

The clinical features of classic KD are shown in Table 1 . 2 A diagnosis of classic KD is made in patients with prolonged fever (five or more days) and four or more of the following principal features: oral mucosal inflammation; bilateral bulbar conjunctivitis; a diffuse maculopapular rash; extremity changes, including erythema and edema of the hands and feet; and cervical lymphadenopathy of 1.5 cm or more in diameter. 2 Incomplete KD is a diagnosis made when a patient has fewer than four of the major criteria but has sufficient laboratory features or suggestive changes on echocardiography. The 2017 American Heart Association KD guidelines provide a diagnostic algorithm to assist with this often challenging diagnosis 2 ( Table 2 ) .

When diagnosing KD, physicians must have a strong understanding of the features of each major symptom. The conjunctivitis of KD is bilateral, nonexudative, and affects the bulbar conjunctiva but classically spares the limbus ( Figure 1 ) . The rash of KD is typically diffuse and maculopapular, often accentuated in the perineal region ( Figure 2 ) . The oral mucous membrane changes of KD can manifest as erythema of the oropharyngeal mucosa or lips; dryness, cracking, and/or peeling of the lips ( Figure 3 ) ; or a “strawberry” appearance of the tongue. Anterior cervical lymphadenopathy is typically unilateral and involves at least one node larger than 1.5 cm in diameter. In contrast to bacterial lymphadenitis, the lymphadenopathy of KD is typically not associated with marked erythema of the overlying skin and is not exquisitely painful to palpation. Rarely, painful lymphadenopathy is the presenting feature of KD and may be misdiagnosed as bacterial lymphadenitis. 12 The extremity changes of KD manifest as erythema and edema of the palms and soles and, at times, refusal to walk because of painful induration. Subacute extremity changes include periungual desquamation and deep transverse grooves across the nail lines, termed Beau lines. Outside of the major diagnostic criteria, profound irritability is commonly described. Children may also have arthritis or arthralgia, gastrointestinal complaints such as diarrhea and vomiting, or rhinorrhea and cough. Symptoms, physical examination findings, and laboratory evidence of viral infection should not exclude the diagnosis of KD because studies have reported that 30% to 40% of children who meet the diagnostic criteria of KD are also positive for at least one respiratory virus. 3 , 13

The Centers for Disease Control and Prevention case definition of MIS-C is presented in Table 3 . 7 Similarly to KD, fever is the principal diagnostic finding of MIS-C. A shorter duration of fever (24 hours or longer) is used to diagnose MIS-C, which is a significant distinction from KD. Gastrointestinal symptoms, including vomiting, diarrhea, and abdominal pain, are the second most common set of symptoms reported in MIS-C, present in about 80% of cases. 8 Neurocognitive symptoms have been described in approximately one-fifth of patients and include headache, irritability, lethargy, altered mental status, or features of aseptic meningitis. 8 Respiratory symptoms, including cough, congestion, dyspnea, and sore throat, are less common but have also been reported. 8

Of note, the clinical manifestations of MIS-C may have tremendous overlap with those of KD ( Table 4 2 , 6 , 7 , 11 ) . A recent systematic review reported that 36% of patients with MIS-C had symptoms consistent with KD (6% with classic KD and 30% with incomplete KD). 8 The individual symptoms of KD were present with varying frequency in patients with MIS-C: 58% had rash; 40% had conjunctival injection; 23% had red, cracked lips; 4.5% had a strawberry tongue; and 4% had cervical lymphadenopathy. 8

Exposure to or a history of COVID-19 is often noted among patients with MIS-C; however, because COVID-19 can present asymptomatically, this may not be apparent from the history in these patients. Therefore, testing for evidence of COVID-19 is included in the Centers for Disease Control and Prevention's case definition. Among patients with MIS-C, 94% to 99% have tested positive for SARSCoV-2 by reverse transcriptase polymerase chain reaction or for antibodies against this virus. 7 , 8

Cardiac Manifestations

Coronary artery dilation and aneurysm formation are well-known complications of KD. If untreated, 15% to 25% of patients with KD will develop coronary artery abnormalities; the percentage drops to around 5% with prompt treatment. 14 Therefore, echocardiography is important for patients suspected of having KD but should not delay treatment. 2 , 7 For risk stratification, coronary artery lumen diameter is compared with the child's body surface area and normalized as a z score. Scores of at least 2.5 in the left anterior descending branch and proximal right coronary artery are highly specific for KD. 2 Some patients with mild dilation will experience spontaneous resolution, whereas others will develop giant aneurysms ( z score of 10 or more) and can experience significant morbidity, including arterial stenosis, clot formation, and cardiac ischemia or infarction, sometimes requiring cardiac bypass surgery or transplant. 2

Coronary artery changes in KD are not typically symptomatic in the acute phase, and physicians should remain cognizant that the myocardium and endocardium may become inflamed, which could manifest as tachycardia, a hyperdynamic precordium, a gallop rhythm, and accentuation of flow murmurs. 2 Valvular dysfunction has been reported in about 25% of patients with KD (with the mitral valve being the most commonly affected), whereas aortic root dilation has been reported in about 10% of cases. 15 In about 5% of children with KD in the continental United States, intracardiac inflammation can lead to severe tachycardia, hypotension, and cardiovascular collapse, also known as KD shock syndrome. 2

Similarly to KD, MIS-C can have profound cardiac manifestations, the principal of which is shock, which can lead to death. 8 Although shock is rare in KD, most patients with reported MIS-C develop hypotension, likely because of a combination of cardiac dysfunction and systemic vasodilation, 16 and require admission to an intensive care unit. 17 Echocardiography is used to visualize the coronary arteries and to establish the degree of cardiac dysfunction, which has been noted in about 30% of patients with MIS-C in the United States. 16 , 17 Reports have cited a range of rates of coronary artery dilation or aneurysms in MIS-C; one large cohort of 1,733 patients in the United States reported that 16.5% of those with MIS-C developed coronary artery changes, similar to the rate in untreated KD. 17 In addition to echocardiography, electrocardiography has an important diagnostic role in MIS-C because electrocardiographic changes and cardiac arrhythmias, including ST segment changes, premature beats, QTc prolongation, atrioventricular block, and sustained life-threatening arrhythmias, have been well described. 16 , 18

Laboratory Findings

The laboratory findings of KD and MIS-C indicate systemic inflammation; however, some key differences exist. Table 4 provides a comparison of the laboratory values found in an early cohort of patients with MIS-C in England and a large cohort of patients with KD in San Diego, Calif. 2 , 6 , 7 , 11 Diagnostic workup for children with suspected MIS-C should include complete blood count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, and SARS-CoV-2 polymerase chain reaction and/or serologies. Additional workup includes B-type natriuretic peptide, troponin, ferritin, prothrombin time, partial thromboplastin time, d dimer, fibrinogen, lactate dehydrogenase, cytokine panel, electrocardiography, and chest radiography. 19 In KD, inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and d dimer, are most often mildly to moderately elevated. Patients with MIS-C tend to have very high markers of inflammation, especially C-reactive protein values. 11

In complete blood count values, patients with KD typically demonstrate elevated white blood cell counts. 2 Patients with MIS-C present with a low absolute lymphocyte count and frank lymphocytopenia. Both illnesses manifest with mild to moderate anemia, although it tends to be more profound in MIS-C. 11 The platelet count is another area of divergence: Patients with KD classically develop thrombocytosis, with platelet counts of more than 450,000 per μL (450 × 10 9 per L) after seven days of illness, whereas patients with MIS-C tend to develop mild to severe thrombocytopenia. 11

Elevated transaminase and decreased albumin levels can occur in patients with both illnesses. 11 The hypoalbuminemia in KD tends to be mild, but it can be severe in patients with MIS-C and lead to complications, such as pulmonary edema, especially in the setting of aggressive fluid resuscitation.

Finally, the elevation of troponin and B-type natriuretic peptide is a notable difference between patients with MIS-C and those with KD. Troponin and B-type natriuretic peptide levels are not routinely evaluated in KD, but in children with KD whose levels were measured, elevations were minimal. 11

The fundamental goal of treatment for patients with KD and MIS-C is to rapidly reduce systemic inflammation. Intravenous immune globulin (IVIG), 2 g per kg in a single dose, has been a long-established therapy for KD and is an effective way to reduce vascular inflammation, improve symptoms, and reduce risk of coronary artery abnormalities. 2 , 20 – 24 High-dose aspirin (80 to 100 mg per kg per day) has been used for decades for anti-inflammatory effect; however, no evidence supports a reduction in coronary artery abnormalities. 25 , 26 Many clinicians have begun to use medium-dose aspirin (30 to 50 mg per kg per day) or low-dose aspirin (3 to 5 mg per kg per day) during the acute phase to avoid the potential toxicity of high-dose aspirin. 27 Low-dose aspirin provides an antiplatelet effect, given the risk of clotting in patients who develop aneurysms. 2 Systemic corticosteroids for the treatment of KD have been a subject of controversy, but a landmark randomized controlled trial published in 2012 (RAISE study) demonstrated a clear benefit in Japanese children who were at high risk. 28 A subsequent meta-analysis of 16 trials supported the role of corticosteroids as well, especially in early, severe KD. 29 Most of the trials were conducted in Japan, where validated scoring tools are available to identify high-risk patients; thus, results may not be generalizable to other populations, and large practice variation exists. Some centers and KD experts have advocated for the addition of corticosteroids in the treatment of North American patients at high risk of IVIG resistance, including those with coronary artery aneurysms at diagnosis, those younger than 12 months, those with KD shock syndrome, and those who have KD presenting with macrophage activation syndrome. 30 , 31 There is no universally accepted dosing regimen, but corticosteroid courses similar to those used in the RAISE study have been proposed (methylprednisolone or prednisone in a dosage of 2 mg per kg per day for five days, followed by a two-week taper). 31

Treatment for MIS-C is a topic of ongoing research and is based largely on expert opinion and therapies used in KD and other childhood inflammatory conditions. Given the severity of disease, patients with suspected MIS-C in the clinic setting should be quickly referred to the hospital, where a multidisciplinary and multispecialty team can assist with treatment recommendations. 19 Supportive measures, including respiratory support and judicious fluid resuscitation, are critical to prevent patient morbidity and mortality. Many patients also require inotropic support. 8 As in patients with KD, IVIG given at 2 g per kg has been a consensus first-line therapy for those with MIS-C. 19 , 32 Low-dose aspirin is recommended to reduce the risk of thrombosis associated with coronary artery aneurysms. 19 Corticosteroid use to improve outcomes in MIS-C is a topic of ongoing research. Early observational data have suggested that adjunctive systemic corticosteroids can reduce the course of fever in patients with MIS-C. 33 Additional observational studies published in July 2021 had seemingly conflicting results, however, indicating a need for prospective trials using a standardized treatment approach. 34 – 36 Immunomodulators such as anakinra (Kineret), an interleukin-1 receptor antagonist, have been recommended in severe cases, although no robust published data are available on their use. 19

This article updates a previous article on this topic by Saguil, et al. 37

Data Sources: Our review of the literature was conducted by searching PubMed Clinical Queries using the following key terms: pediatric multisystem inflammatory syndrome, SARSCoV-2 related, multisystem inflammatory syndrome in children, Kawasaki disease, mucocutaneous lymph node syndrome. The PubMed MeSH database was also used to search related terms. The search included meta-analyses, randomized controlled trials, clinical trials, reviews, letters to the editor, and case reports. Government disease-tracking websites, such as the Centers for Disease for Control and Prevention website on multisystem inflammatory syndrome in children, were also important sources of information and references. Search dates: January 19 and July 19, 2021.

The authors thank Dr. Lindsay Strowd and the Wake Forest School of Medicine Graham Archives Library for contributing the images included in this work.

Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]. Arerugi. 1967;16(3):178-222.

McCrindle BW, Rowley AH, Newburger JW, et al.; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Epidemiology and Prevention. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association [published correction appears in Circulation . 2019;140(5):e181–e184]. Circulation. 2017;135(17):e927-e999.

Turnier JL, Anderson MS, Heizer HR, et al. Concurrent respiratory viruses and Kawasaki disease. Pediatrics. 2015;136(3):e609-e614.

Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. 2005;191(4):499-502.

Holman RC, Belay ED, Christensen KY, et al. Hospitalizations for Kawasaki syndrome among children in the United States, 1997–2007. Pediatr Infect Dis J. 2010;29(6):483-488.

Holman RC, Curns AT, Belay ED, et al. Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics. 2003;112(3 pt 1):495-501.

Centers for Disease Control and Prevention. Multisystem inflammatory syndrome (MIS). Updated June 25, 2021. Accessed July 14, 2021. https://www.cdc.gov/mis/hcp/index.html

Kaushik A, Gupta S, Sood M, et al. A systematic review of multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection. Pediatr Infect Dis J. 2020;39(11):e340-e346.

Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778.

Cheung EW, Zachariah P, Gorelik M, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City. JAMA. 2020;324(3):294-296.

Whittaker E, Bamford A, Kenny J, et al.; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324(3):259-269.

Kanegaye JT, Van Cott E, Tremoulet AH, et al. Lymph-node-first presentation of Kawasaki disease compared with bacterial cervical adenitis and typical Kawasaki disease. J Pediatr. 2013;162(6):1259-1263.

Kim JH, Yu JJ, Lee J, et al. Detection rate and clinical impact of respiratory viruses in children with Kawasaki disease. Korean J Pediatr. 2012;55(12):470-473.

Freeman AF, Shulman ST. Kawasaki disease: summary of the American Heart Association guidelines. Am Fam Physician. 2006;74(7):1141-1148. Accessed July 5, 2021. https://www.aafp.org/afp/2006/1001/p1141.html

Printz BF, Sleeper LA, Newburger JW, et al.; Pediatric Heart Network Investigators. Noncoronary cardiac abnormalities are associated with coronary artery dilation and with laboratory inflammatory markers in acute Kawasaki disease. J Am Coll Cardiol. 2011;57(1):86-92.

Sperotto F, Friedman KG, Son MBF, et al. Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. Eur J Pediatr. 2021;180(2):307-322.

Belay ED, Abrams J, Oster ME, et al. Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic. JAMA Pediatr. 2021;175(8):837-845.

Choi NH, Fremed M, Starc T, et al. MIS-C and cardiac conduction abnormalities. Pediatrics. 2020;146(6):e2020009738.

Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol. 2021;73(4):e13-e29.

Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gamma-globulin for Kawasaki disease. Lancet. 1984;2(8411):1055-1058.

Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315(6):341-347.

Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr. 1997;131(6):888-893.

Mori M, Miyamae T, Imagawa T, et al. Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease. Mod Rheumatol. 2004;14(5):361-366.

Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2003(4):CD004000.

Baumer JH, Love SJL, Gupta A, et al. Salicylate for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2006(4):CD004175.

Dallaire F, Fortier-Morissette Z, Blais S, et al. Aspirin dose and prevention of coronary abnormalities in Kawasaki disease. Pediatrics. 2017;139(6):e20170098.

Son MBF, Newburger JW. Kawasaki disease. Pediatr Rev. 2018;39(2):78-90.

Kobayashi T, Saji T, Otani T, et al.; RAISE study group investigators. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012;379(9826):1613-1620.

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.

Friedman KG, Gauvreau K, Baker A, et al. Primary adjunctive corticosteroid therapy is associated with improved outcomes for patients with Kawasaki disease with coronary artery aneurysms at diagnosis. Arch Dis Child. 2021;106(3):247-252.

Sundel R. Kawasaki disease: initial treatment and prognosis. UpToDate. Accessed May 1, 2021. https://www.uptodate.com/contents/kawasaki-disease-initial-treatment-and-prognosis

Harwood R, Allin B, Jones CE, et al.; PIMS-TS National Consensus Management Study Group. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process [published correction appears in Lancet Child Adolesc Health . 2021;5(2):e5]. Lancet Child Adolesc Health. 2021;5(2):133-141.

Ouldali N, Toubiana J, Antona D, et al.; French Covid-19 Paediatric Inflammation Consortium. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children [published correction appears in JAMA . 2021;326(1):90]. JAMA. 2021;325(9):855-864.

DeBiasi RL. Immunotherapy for MIS-C—IVIG, glucocorticoids, and biologics [editorial]. N Engl J Med. 2021;385(1):74-75.

McArdle AJ, Vito O, Patel H, et al.; BATS Consortium. Treatment of multisystem inflammatory syndrome in children. N Engl J Med. 2021;385(1):11-22.

Son MBF, Murray N, Friedman K, et al.; Overcoming COVID-19 Investigators. Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med. 2021;385(1):23-34.

Saguil A, Fargo M, Grogan S. Diagnosis and management of Kawasaki disease. Am Fam Physician. 2015;91(6):365-371. Accessed June 28, 2021. https://www.aafp.org/afp/2015/0315/p365.html

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Kawasaki disease as a case study

‘Quality diagnostic reasoning’ curbs medical diagnostic errors.

With my previous focus on the urgency of preventing medical diagnostic errors in Contemporary Pediatrics commentaries (July 2018; August 2018), the article in the October 2018 issue authored by Anne Rowley, MD, professor of  Pediatrics (Infectious Diseases)  and  Microbiology-Immunology at Northwestern University Feinberg School of Medicine, titled “Kawasaki disease: AHA statement and recommendations ” provides valuable insights for the care of children with a suspicion of Kawasaki disease (KD) which, when applied to clinical practice, may prevent medical diagnostics errors.

Thus, for many reasons, Dr. Rowley’s article is a must read for all pediatric healthcare providers. Failure of a timely and accurate diagnosis of KD may result in adverse outcomes for children, including coronary artery abnormalities, dilatation, and aneurysms. Dr. Rowley provides an overview of KD based on the latest 2017 American Heart Association’s (AHA) statement and recommendations for diagnosis and treatment of children who present with prolonged, unexplained fever. Throughout the article, Tables and Figures highlight critical information for the diagnosis and treatment of KD and represent the current best-available evidence. Further studies, both prospective and retrospective, are needed to further clarify diagnostic criteria and treatment options for children of different nationalities because the prevalence and severity of the disease vary based on ethnicity-in particular, for Asian/Japanese children who are aged younger than 5 years.

AHA on incomplete Kawasaki disease

The 2017 AHA statement provides an algorithm for the diagnosis of Incomplete KD (previously termed atypical KD) for any infant aged younger than 1 year with an unexplained fever for 7 days, or in infants with a fever for 5 days and presenting with only 2 or 3 of the principle clinical features of KD. In addition, there are recommendations for laboratory testing to aide in the diagnosis, which may help avoid a medical diagnostic error.

The essential history

The value of a comprehensive history cannot be overemphasized. Parents should be asked specific details related to fever onset, use of antipyretic medications, dosage, and the effect on the infant or child’s fever. Some parents may be hesitant to report how long the infant was at home with a fever, while other parents may not have a means of measuring the temperature of an infant at home and merely “take a guess” concerning the height of the fever.

Dr. Hallas’ Practice Pearls

Parents also should be asked whether the infant or child displayed any of the 5 principle clinical criteria of KD that may have spontaneously resolved. These factors must be considered when making a diagnostic decision about an infant or child presenting with an unexplained fever and fewer than the 5 principle clinical criteria of KD.

Recovery and immunization administration

Another consideration for care of the infant and child after recovery from KD is the administration of immunizations. For an infant aged younger than 12 months who has had a diagnosis of KD or Incomplete KD and received intravenous immunoglobulin (IVIG), the live vaccines, such as measles and varicella-containing vaccines, should not be administered until 11 months after receiving IVIG. 1

Likewise, a child who received the first set of measles and varicella vaccines at 12 months of age and has not received the 4- or 5-year-old doses should not receive the vaccines until 11 months after receipt of the IVIG. The rationale for delaying the vaccines for 11 months postreceipt of IVIG for all children who need the live vaccines is attributed to a possible interference with the development of adequate immune response by the child (AAP). However, readers are referred to the Red Book: 2018 Report of the Committee on Infectious Diseases (AAP) 1 for further details for administration of vaccines to children who are at risk for exposure to measles or varicella and for those children on prolonged aspirin therapy. Infants and children recovering from KD may continue to receive inactivated vaccines per the Centers for Disease Control and Prevention (CDC) 2 and Advisory Committee on Immunization Practices (ACIP) vaccine schedules. 3

Quality diagnostic reasoning

Nurse practitioners and all healthcare providers must remain acutely aware of the diagnostic criteria for KD and Incomplete KD and vigilant when an infant or child presents with a prolonged unexplained fever. Let’s remove the diagnosis of KD from the list of diseases that have an increased likelihood of a medical diagnostic error by applying the scientific evidence throughout the diagnostic and treatment processes. 

References:

1. American Academy of Pediatrics. Section 3: Summary of infectious diseases. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Elk Grove Village, IL: American Academy of Pediatrics; 2018:494-500.

2. Centers for Disease Control and Prevention. Immunization schedules. Available at: https://www.cdc.gov/vaccines/schedules/ . Updated February 6, 2018. Accessed October 20, 2018.

3. Advisory Committee on Immunization Practices. Immunization schedules. Available at: https://www.cdc.gov/vaccines/acip/index.html . Updated October 11, 2018. Accessed October 20, 2018.

Integrating behavioral health within primary care settings

Donna Hallas, PhD, PPCNP-BC, CPNP, PMHS, FAANP, FAAN, shares her thoughts on the latest issue of Contemporary Pediatrics and how these articles can be utilized in the everyday practice of PNPs.

Infants born into a digital world: Are there developmental inequities based on exposure?

Donna Hallas, PhD, PPCNP-BC, CPNP, PMHS, FAANP, FAAN, highlights the April 2024 issue of Contemporary Pediatrics.

This is serious: The results of a measles outbreak have harmful outcomes

Donna Hallas, PhD, CPNP, PPCNP-BC, PMHS, FAANP, FAAN, shares her thoughts on the latest issue of Contemporary Pediatrics.

Fostering healthy eating habits

Donna Hallas shares her perspectives on the most recent issue of Contemporary Pediatrics.

Donna Hallas provides commentary on the latest issue of Contemporary Pediatrics

Donna Hallas, PhD, PPCNP-BC, CPNP, PMHS, FAANP, FAAN, offers her perspective on the latest articles from the November/December issue of Contemporary Pediatrics.

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Donna Hallas, PhD, PPCNP-BC, CPNP, PMHS, FAANP, FAAN, shares her thoughts on the Contemporary Pediatrics' October 2023 vaccine issue.

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Kawasaki Disease and Vaccination: Prospective Case-Control and Case-Crossover Studies among Infants in Japan

Affiliations.

• 1 Kawasaki Disease Center, Fukuoka Children's Hospital, Fukuoka 813-0017, Japan.
• 2 Department of Pediatrics, Japanese Red Cross Fukuoka Hospital, Fukuoka 815-8555, Japan.
• 3 Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
• 4 Department of Pediatrics, Hiroshima City Funairi Citizens Hospital, Hiroshima 730-0844, Japan.
• 5 Department of Pediatrics, Kagoshima City Hospital, Kagoshima 890-8760, Japan.
• 6 Department of Pediatrics, Oita Prefectural Hospital, Oita 870-8511, Japan.
• 7 Department of General Pediatrics, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo 183-8561, Japan.
• 8 Department of Cardiology, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo 183-8561, Japan.
• 9 Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
• 10 Department of Public Health, Research Center for Infectious Disease Sciences, Osaka City University Graduate School of Medicine, Osaka City University, Osaka 558-8585, Japan.
• 11 Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka 812-8582, Japan.
• 12 Department of Public Health, Jichi Medical University, Shimotsuke 329-0498, Japan.
• PMID: 34451964
• PMCID: PMC8402330
• DOI: 10.3390/vaccines9080839

The causal effects of vaccines on Kawasaki disease (KD) remain elusive. We aimed to examine the association between vaccines administered during infancy and the development of KD in Japan. We conducted a multicenter prospective case-control study using questionnaires and compared the vaccination status of infants (age: 6 weeks to 9 months) who developed KD (KD group; n = 102) and those who did not develop KD (non-KD group; n = 139). Next, we performed a case-crossover study of 98 cases in the KD group and compared the status of vaccinations between the case and control periods. We also compared the incidence of KD in children for each 5-year period before and after the addition of new vaccines (2012-2013) using data from the Nationwide Survey of KD. In the case-control study, the vaccination status of the KD and control groups did not differ to a statistically significant extent. Multivariable analysis of the vaccination status and patient backgrounds showed no significant association between vaccination and KD development. In the case-crossover study, the status of vaccinations during the case and control periods did not differ to a statistically significant extent. In the analysis of data from the Nationwide Survey of KD, the incidence of KD in children of ages subject to frequent vaccination showed no significant increases in the latter five years, 2014-2018. Based on these prospective analyses, we confirmed that vaccination in early infancy did not affect the risk of KD.

Keywords: Kawasaki disease; Nationwide Survey of Kawasaki disease in Japan; case-control study; case-crossover study; infant; vaccines.

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Acknowledgement, kawasaki disease in a pediatric intensive care unit: a case-control study.

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Samuel R. Dominguez , Kevin Friedman , Ryan Seewald , Marsha S. Anderson , Lisa Willis , Mary P. Glodé; Kawasaki Disease in a Pediatric Intensive Care Unit: A Case-Control Study. Pediatrics October 2008; 122 (4): e786–e790. 10.1542/peds.2008-1275

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OBJECTIVES. We conducted a case-control study to ascertain the clinical presentations, risk factors, and clinical outcomes of children who had Kawasaki disease and were admitted to the ICU of our children's hospital.

METHODS. We reviewed charts of all children who had a discharge diagnosis of Kawasaki disease and were admitted to the ICU from 1995 through 2007. For each patient, we identified 3 season-matched control subjects who had Kawasaki disease and were not admitted to the ICU.

RESULTS. We identified 423 patients with Kawasaki disease. Of those, 14 (3.3%) were admitted to the ICU and met our inclusion criteria. ICU admission diagnoses were most commonly toxic shock or septic shock. Thirteen (92.8%) of 14 patients who were admitted to the ICU met criteria for complete Kawasaki disease before treatment. There was no significant difference in age in ICU patients compared with season-matched control subjects with Kawasaki disease. ICU patients were significantly more likely to be female and to have higher band counts, lower platelet counts, lower albumin levels, and higher C-reactive protein values. Time from admission to treatment with intravenous immunoglobulin was delayed in ICU patients. ICU patients were more likely to have intravenous immunoglobulin–refractory disease and require therapy with a second dose of intravenous immunoglobulin, infliximab, or steroids.

CONCLUSIONS. We present a case-control study of patients who had Kawasaki disease and presented severely ill, in shock, and requiring admission to the ICU. These patients frequently were misdiagnosed because of failure to appreciate the full spectrum of disease severity seen in patients with Kawasaki disease. These patients' illnesses was often mistaken for toxic or septic shock, leading to a delay in treatment with intravenous immunoglobulin. Patients who have Kawasaki disease and are admitted to the ICU are at increased risk for intravenous immunoglobulin–refractory disease and may be at risk for development of more severe coronary artery disease.

Kawasaki disease (KD) is an acute self-limited vasculitis that occurs in children of all ages. Because of its potential to cause coronary aneurysms, KD has become the leading cause of acquired heart disease in children in the developed world. It is now recognized that patients with KD can present in a variety of ways, and, in recent years, more children are receiving a diagnosis of “incomplete” KD. 1 , 2  

At our institution, we observed a number of children who were admitted to the ICU secondary to hypotension with a presumptive diagnosis of “toxic shock” or “septic shock” and later received a diagnosis of KD. KD was not seriously considered in the initial diagnosis because of the failure to recognize that children with KD could present in shock. Because of these observations, we conducted a case-control study to ascertain the clinical presentations, risk factors, and clinical outcomes of children who had KD and were admitted to the ICU compared with control patients who had KD and were not admitted to the ICU.

Patients with KD were identified from hospital discharge records ( International Classification of Diseases, Ninth Revision code 446.1) from 1995 through 2007. This database included billing codes specific for the ICU at our tertiary care children's hospital. Clinical and demographic information was extracted from the medical chart by retrospective chart review. All patients who were included in the analysis were seen by a pediatric infectious disease specialist during their hospitalization and received a diagnosis of KD. In addition, all charts were retrospectively reviewed independently by 3 infectious disease specialists who concurred with the diagnoses of KD. Subsequently, KD cases were classified as complete or incomplete KD on the basis of published standard clinical criteria. 2  

Case patients were defined as patients who had a discharge diagnosis of KD in their medical chart and who were admitted to the ICU at any time during their initial admission to the hospital. Case patients were excluded when they had positive bacterial cultures from a normally sterile site (blood, urine, or cerebrospinal fluid [CSF]), evidence of focal staphylococcal or streptococcal disease with potential for toxin production (eg, severe sinusitis, pneumonia, cellulitis), or evidence of an alternative diagnosis for their presentation.

Control subjects were defined as patients who had a diagnosis of KD but who were never admitted to the ICU. Three control subjects were chosen for each case patient and matched to the case by date of admission (±3 weeks). Date of admission was chosen as the matching factor to control for the possibility of variations in circulating strains of a potential “Kawasaki” infectious agent. Medical charts of case patients and control subjects were reviewed by using a standardized form to collect demographic data, clinical information, and laboratory test results. Day 1 of illness was defined as the first day of fever. Intravenous globulin (IVIG)-refractory disease was defined as persistence or recrudescence of fever ≥48 hours after completion of IVIG infusion. For patients who had echocardiograms performed before the institution of routine calculation of z scores, a pediatric cardiologist retrospectively calculated a z score on the basis of coronary artery diameter measurements that were obtained at the time of the original study.

Two-tailed Student's t test was used to test for significant differences in the means of continuous variables. Wilcoxon rank-sum test was used for comparing medians in skewed continuous variables. Proportions were compared using Fisher's exact test. Analyses were conducted by using SAS 9.1.3 (SAS Institute, Inc, Cary, NC). Use of clinical data was approved by the Colorado Multiple Institutional Review Board.

Between January 1995 and December 2007, a total of 423 patients were admitted with a discharge diagnosis of KD. Eighteen (4.3%) of these patients were admitted to the ICU sometime during their hospitalization. Fourteen of these patients met criteria for inclusion in the study. Three patients were excluded because they were admitted to the ICU on a subsequent admission that occurred after their initial diagnosis and treatment for KD. One of these patients was admitted to the ICU after an endomyocardial biopsy, and 2 patients were admitted to the ICU with myocardial infarctions within 1 month of their initial discharge. A fourth patient was excluded because subsequently a diagnosis of juvenile rheumatoid arthritis was made. This diagnosis was based on chart review, normal echocardiograms, rheumatology consultation, and response to steroids.

All 14 patients who were admitted to the ICU were initially evaluated by a board-certified pediatric emergency department physician at our institution. Ten (71%) of these 14 patients were directly admitted to the ICU. The 4 remaining patients were admitted initially to the floor and then transferred to the ICU as a result of deteriorating clinical status. Two of these 4 patients had KD as a leading admitting diagnosis. The other 2 patients had leading diagnoses of viral pneumonitis and severe abdominal pain, respectively. The percentage of patients who had KD and were admitted to the ICU ranged from 0% to 10% per year and did not significantly increase or decrease during the course of the 12-year study.

The demographic characteristics of the case patients and control subjects are shown in Table 1 . There were no differences in age between groups even when stratified according to ages of <1 or >6 years.

The clinical characteristics of the case patients and control subjects at time of presentation to the hospital are shown in Table 2 . Patients who were admitted to the ICU presented a median of 2.5 days earlier in the course of their illness than control patients with KD ( P = .01). The majority of ICU and control patients had complete KD, at both time of admission and time of diagnosis. There was no significant difference noted in individual clinical features at time of presentation (eg, rash, lymphadenopathy, conjunctivitis) between case patients and control subjects; however, ICU patients (29%) were less likely to have an admitting diagnosis of KD compared with control subjects (90%; P < .0001). Eleven (78%) of the 14 patients were admitted to the ICU secondary to hypotension; 10 of these 11 patients required ionotropic support. These patients had a presumptive diagnosis of either toxic shock or septic shock. Two patients were admitted to the ICU because of altered mental status, apnea, and CSF pleocytosis with meningitis. One patient was admitted to the ICU because of a gastrointestinal bleed presumably as a result of mesenteric vasculitis. Patients who were admitted to the ICU were significantly more likely to have fluid-refractory hypotension or gallop ( P < .05).

Laboratory values for ICU patients and control subjects are shown in Table 3 . At the time of presentation, patients who were admitted to the ICU had a significantly greater percentage of band counts ( P < .001), lower platelet counts ( P = .001), and lower serum albumin levels ( P = .02). In addition, ICU patients had C-reactive protein (CRP) levels that were on average more than twice those of control patients ( P < .001). These laboratory values remained significant when looked at over the entire course of the hospital admission. Because of the small number of case patients in our data set, we did not have enough power to conduct a highly informative multivariate analysis. Nevertheless, a binary logistic regression analysis showed that a high percentage of band count and low serum albumin levels were independently correlated with a higher likelihood of admission to the ICU (data not shown). Six (43%) of the ICU patients and 3 (7%) of the control patients had a lumbar puncture performed as part of their initial workup because of concerns for meningitis. Of these, 5 (83%) of the 6 ICU patients and 1 (33%) of the 3 control patients who had a lumbar puncture performed had evidence of CSF pleocytosis ( P = .13). On admission, 10 (71%) of the 14 ICU patients had hyponatremia (sodium < 135 mmol/L); 6 (43%) had metabolic acidosis (bicarbonate < 18 mmol/L); 5 (36%) had evidence of acute renal insufficiency with a creatinine level of >1.0 mg/dL, with 1 patient requiring renal dialysis; and 6 (43%) had evidence of coagulopathy. Unfortunately, these laboratory tests were not performed on the majority of the control patients; therefore, a comparison for significance could not be made.

The clinical outcomes of ICU patients versus control patients are shown in Tables 4 and 5 . The median length of stay was 5 days longer for ICU patients compared with control subjects ( P < .001). Patients who were admitted to the ICU were treated with IVIG and high-dose aspirin a median of 2 days later than control subjects from time of their admission to the hospital ( P = .002). Nine (64%) of the 14 ICU patients and 2 (5%) of the 42 control patients had IVIG-refractory disease and required a second therapeutic intervention ( P < .001), consisting of a second dose of IVIG, infliximab, and/or steroids.

All patients had a minimum of 3 echocardiograms performed. The mean ejection fraction of the patients who were admitted to the ICU was 67% (range: 58%–75%; normal: >55%). Only 3 patients, however, had measurements obtained before the administration of IVIG. On qualitative reading of the echocardiogram by a pediatric cardiologist, coronary artery abnormalities (dilatation, ectasia, or aneurysm) were noted on 6 (43%) of 14 ICU patients and 8 (19%) of 42 control patients ( P = .09); 4 (29%) of the 14 ICU patients compared with 3 (7%) of the 42 control patients had coronary artery aneurysms ( P = .06; Table 5 ). On quantitative analysis, 7 (50%) of the ICU patients and 19 (45%) of the control patients had coronary artery z scores ≥2.0 ( P = .5). For patients who had coronary artery involvement, there was a trend toward patients who were admitted to the ICU to have higher z scores, but this did not reach statistical significance (Table 5 ).

Because there is no diagnostic test or pathognomonic clinical feature of KD, clinicians must maintain a high index of suspicion for KD in febrile patients who present with known clinical features of KD. Diagnosis and treatment of patients with KD depends on an awareness of the full spectrum of the disease presentation. It is now becoming recognized that a large number of patients with KD present without fulfilling full clinical criteria (ie, incomplete KD), and up to 20% of patients who are treated for KD have incomplete cases. 1 – 4   We previously reported that delay in diagnosis was primarily related to a dispersion of symptoms over a longer period of time. 5   Several researchers have noted that febrile infants who are younger than 6 months and have KD often present with incomplete criteria and are delayed in receiving a diagnosis because of physicians' failing to consider the diagnosis in this group of patients. 5 – 8  

Several authors have described isolated cases of infants and children who had features of toxic shock syndrome and ultimately had a diagnosis of KD. 9 – 11   Here we report a case-control study of a series of patients who had KD and were admitted to the ICU. This report adds to the expanding spectrum of clinical presentations of children with KD. During a 12-year period, 14 patients with KD at our institution were admitted to the ICU primarily because of hypotension and shock. Despite the fact that the majority of these patients met clinical criteria for KD, KD was not the leading diagnosis in these patients, presumably because of the failure to consider KD in patients who present with hypotension that requires ionotropic support and admission to the ICU. This led to a delay in diagnosis and treatment from their time of presentation to the hospital compared with patients who were not admitted to the ICU.

The cause of severe hypotension in patients with KD is unknown. It is likely multifactorial, and possible explanations include vasculitis with ongoing capillary leak, myocardial dysfunction, and cytokine dysregulation.

Recently, there has been considerable effort and interest in trying to define predictors for IVIG-refractory disease at initial presentation in patients with KD. 12 – 15   We found that two thirds of the patients who had KD and were admitted to the ICU had IVIG-refractory disease compared with only 5% of control patients, indicating that admission to the ICU may be an independent predictor of IVIG-refractory disease.

Similar to studies that examined predictors of IVIG-resistant disease, patients who were admitted to the ICU (our “high-risk” group) were more likely to have a very elevated CRP level (double that of control patients) and lower platelet counts. In contrast to other studies, ICU patients had a higher percentage of band count and lower serum albumin levels than control subjects but did not have any significant difference in other hepatic function tests. It is interesting that age was not associated with ICU admission. Female gender, however, was strongly associated with ICU admission. KD is more commonly a disease of males, 1   but female gender has not previously been reported to be associated with more severe disease. The reason for this finding is unclear but merits additional investigation.

As demonstrated by other researchers, 16 , 17   our data highlight the need for quantitative analysis of coronary artery disease ( z scores) in children with KD, because we found a substantial discrepancy between qualitative and quantitative readings of echocardiograms. We found no difference in the percentage of children who had KD and had coronary artery involvement between those who were admitted to the ICU versus the floor; however, for children who had coronary artery disease, there seemed to be a trend toward those who were admitted to the ICU to have more severe coronary artery involvement/dilation compared with those who were admitted to the floor. Possibly because of our small numbers, this trend did not reach statistical significance. If in fact more severe coronary artery involvement in patients who have KD and are admitted to the ICU is shown by other researchers, then the reasons for having more severe coronary involvement could be related to a more fulminant disease presentation, higher degree of inflammation present (as evidenced by markedly higher CRP levels), and/or a greater degree of myocarditis as evidenced by their presentation in shock. This finding is of importance because these children may be at increased risk for more serious cardiac complications, and diagnosing and treating them promptly may aid in decreasing this risk.

We present the first case-control study in the English literature of patients who had KD and presented severely ill in shock and required admission to the ICU. These patients frequently received a misdiagnosis because of failure to appreciate the full spectrum of disease severity that is seen in patients with KD. These patients were often mistaken for having toxic or septic shock, leading to a delay in treatment with IVIG. Patients who have KD and are admitted to the ICU are at increased risk for IVIG-refractory disease and may be at risk for development of more severe coronary artery disease.

Demographics of ICU and Control Patients

Fisher's exact test.

Two-sample t test for means.

Wilcoxon rank-sum test.

No significant difference in pairwise comparisons.

Clinical Characteristics at Presentation

Laboratory Values of Patients With KD

PMN indicates polymorphonuclear neutrophil; ESR, erythrocyte sedimentation rate; ALT, alanine transaminase; AST, aspartate aminotransferase; GGT, γ -glutamyltransferase; WBC, white blood cell; hpf, high-power field.

Two-sample t test (unless otherwise indicated).

Clinical Outcomes of Patients With KD

Echocardiogram Results of Patients With KD

The most abnormal echocardiogram outcome noted in 3 months after onset of illness.

The authors have indicated they have no financial relationships relevant to this article to disclose.

What's Known on This Subject

Isolated reports of patients who had KD that was confused with toxic shock and were admitted to the ICU were identified in the literature.

What This Study Adds

To our knowledge, this is the first case-control study of a subgroup of patients who had KD and were quite ill with signs of poor perfusion and hypotension and were admitted to the ICU.

We thank Dr James K. Todd for statistical assistance.

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Patient Presentation

Differential diagnosis, examination, investigations, final outcome.

• Case Evaluation - Questions & answers

A previously well 17 month old boy presents with a three day history of fever and a skin rash. No accompanying cough or diarrhoea.

Acknowledgements:

Dr Christiaan Scott and Dr Kate Weakley Webb, Paediatric Rheumatology, Red Cross War Memorial Children’s Hospital, University of Cape Town, South Africa.

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The patient and his family recently moved to South Africa from Burundi (Eastern Africa). His mother reports that prior to this presentation the child has been well. She is unaware of him having any contact with TB or other infectious illnesses.

According to his Road to Health Card he was born full term from a normal vaginal delivery with no complications noted.

He was breast fed for the first 10 months.

He is noted to be HIV unexposed, but no PCR had been done to confirm this.

All growth parameters have been consistent and above the 50 th centile for height and weight.

Past Medical History

• Nothing reported

Past Surgical History

Vaccination History

• BCG given at birth
• No other vaccination history available

Family History

• Lives with both parents and three older siblings aged 3, 5 and 8 in a 1 bedroom apartment with all amenities.

Travel History

• Recent road travel from Burundi to South Africa

Differential diagnosis of an otherwise well child with a rash and fever:

Infections:

• Parainfluenza
• Scarlet fever
• Meningococcus
• Lyme disease
• Post streptococcal
• Kawasaki disease
• Henloch-Schonlein Purpura

In Admission:

• Ill looking child, alert and awake
• Well nourished
• Temperature: 40 o C
• Heart rate: 105
• Respiratory rate: 25
• Normal weight
• No dehydration
• Warm peripheries
• Cervical and axillary lymphadenopathy
• Mild pharyngitis
• Chest clear

Cardiovascular

• Mild tachycardia
• Not distended
• Soft, no generalised tenderness
• No organomegally
• Bowel sounds present

Neurological

• Normal level of consciousness
• Alert and co-operative

Dermatological

• Generalised maculo popular rash

Child was admitted (see investigations), and discharged after 2 days on Amoxil, tobe followed up at out patient clinic in 48 hours to have Mantoux test read

Nine days after initial presentation the patient again presents to hospital

Five days earlier, the patient was started on TB treatment following a positive Mantoux test and a suspicious looking chest X-ray. He now presents again with a fever and 7-day swelling of the face.

On Examination

• Ill looking child
• Temperature 39 o C
• Generalized lymphadenopathy
• Lips swollen, drooling, red tongue and throat.
• Perioral peeling
• Periorbital dryness anderythema
• Warm swollen hands and feet, with painless palpable effusions over the ankles
• Swollen, red BCG vaccination site and red mantoux mark
• Peeling rash on trunk, neck and axillae

Patient was re-admitted, an echocardiogram was performed which was normal and he was treated with 2g polygam, paracetomol and 50mg aspirin daily (see investigations).

He improved and was discharged

10 days later the patient returned to hospital

Although he no longer had a fever his mother was concerned about the persistent rash all over his body and a recurrent swelling of his hands and feet, which had become painful, preventing the child from walking.

• Ill looking child with marked irritability
• Swollen hands, feet and ankles,  with +dactylitis.
• Generalized erythematous macular rash

Patient was readmitted

No repeat polygam given as patient had responded to the first dose

Patient was kept on 20mg daily aspirin , Ibuprofen for pain and sucralfate

TB treatment was continued

(see investigations)

He was discharged home on Aspirin, pain medication and a temperature chart

One month later, patient was seen as an outpatient for a check up

The home temperature chart revealed no fever.

• Lymphadenopathy had resolved
• Hands and feet were still swelling occasionally, but he was able to walk. Some residual desquamation was noted on the hands
• No joint involvement
• BCG and Mantoux sites were normal
• Pain medication was stopped
• TB medication was continued for the full course

Patient was booked for a 3-month repeat Echo

On Presentation

• Chest X-Ray- Widened mediastinum and hilar lymphadenopathy
• Mantoux performed based on CXR finding. Area of induration at 48 hours was >15mm and considered positive.

9 days later

• HIV negative
• ASOT negative
• antiDNAse negative
• TB gastric washings, repeated on three occasions- all negative
• Echocardiogram-normal

2 weeks later

• Repeat echocardiogram- normal
• ESR 75, CRP 15
• ANA negative
• Sickle test negative

This case focuses on an acutely ill 17-month-old baby boy who presented to a paediatric hospital in South Africa having recently moved from Burundi in eastern Africa. His initial presentation was of a rash, fever and pharyngitis, for which he was treated with oral antibiotics. A routine TB work up was done.  Based on the hilar  lymphadenopathy on chest X-ray, and a positive Mantouxtest, he was started on TB treatment, despite not having a definitive microbiological diagnosis. As the paediatric hospital lies in an area with high TB prevalence, treatment is standard protocol. However within a few short days his signs and symptoms worsened.

A diagnosis of Kawasaki Disease (KD) was made and the following discussion will focus on this acute multisystem vasculiticsyndrome of unknown etiology. KD is seen predominantly in infants andchildren younger than 5 years of age and the disease occurs globally, having been first diagnosed in Japan in the 1960s.

KD is characterized by prolonged fever, conjunctivitis, diffuse mucosal inflammation, polymorphous skin rashes, indurative oedema of the hands and feet with an associated peeling of finger tips and non-suppurative lymphadenopathy.The most severe complication in KD is that of acute coronary syndrome, including myocardial infarction and coronary artery aneurysms,which ispathognomonic when identified in the setting of a compatible febrile illness.To date, there are no specific diagnostic tests for KD,instead the diagnosis is made clinically by the presence of fever for five days and 4 out of 5 of the following criteria:

• Non-purulentbilateral conjunctivitis
• Cervical lymphadenopathy of nodes >1.5 cm
• Polymorphous skin rashes
• Strawberry tongue, fissured lips and/or diffuse erythema of the oropharynx
• Oedema of the palms and soles and desquamation of the fingertips.

It has also been noted that in countries where newborn babies receive Bacillus Calmette-Guerin (BCG) vaccination, KD canbe associated with erythematousinduration or even ulceration of BCG scars in one-third of cases. The patient in this case study had received BCG at birth and during the course of his illness presented with BCG scar reactivation and a positive Mantoux test with a reading of >15mm.

Although the aetiology of KD is not well understood, with the aid of our case study and graphics we will explore the ways in which immune-mediated destruction of the vascular system occurs following the introduction of a yet to be identified immunogenic agent. We will also discuss the role that genetics has to play in this disease by looking specifically at two of the genes that have been implicated. We will also explain how this vasculitic syndrome may be connected to BCG scar reactivation and a positive Mantoux test in the absence of TB infection.

To better understand Kawasaki disease, let’s first look at the precipitating inflammatory response

It is thought that KD may develop in genetically susceptible individuals following an initial inflammatory response to a potentially inhaled immunogenic agent. Although no specific agent has been identified, prior infection by one of a number of viruses and bacterial species has been associated with the development of KD. These include EBV, HIV, measles , Staph. aureus, Strep. pyogenes and Mycoplasmapneumoniae, to name a few. A primary immune response to the agent occurs in the mucosal lymphoid tissues by activation of T and B cells, which is then thought to be followed by a translocation of the agent or possibly transport of the agent via trafficking phagocytic cells into the systemic circulation. A systemic immune response is then initiated and in genetically susceptible hosts this may lead to the uncontrolled systemic inflammation and immune-mediated damage of blood vessels or vasculitis.

What are the signs of this developing vasculitis in Kawasaki Disease?

The ensuing vasculitisis thought to be mediated by uncontrolled activation of CD4 + T cells and antigen-presenting cells and subsequent cytokine-mediated activation of medium vessel endothelial cells. The increased levels of cytokines such as IL-1 ,TNF-alpha and IL-6   cause the prolonged fever as seen in this patient. Along with IFN-g, these pro-inflammatory cytokines promote endothelial cells to up-regulate cell-adhesion molecules and secrete cytokines that recruit additional immune cells. Extravasation of immune cells into the subendothelium leads to immune-mediated damage to the elastic lamina and smooth muscle cells.  This weakens the blood vessel wall that in time can progress to aneurysm formation and scarring. When coronary arteries are involved it can result in ischaemic heart complications (not present in this patient). Excessive inflammatory responses to antigens in the skin also occur because there is increased trafficking of immune cells from cutaneous blood vessels into the dermis.  This can result in a persistent generalized rash and BCG scar activation, as seen during the course of illness in our patient.

As we know KD is a multisystem vasculitic syndrome. In the acute stage, numerous immunologic factors including CD4+ T cell activation, cytokine production and enhanced adhesion molecule expression by endothelial cells mediatesthe vasculitis. These various processes are further discussed here.

Lets look more closely at the activation of medium vessel endothelial cells

The activated CD4+ T cells secrete IFN-g that enhances the activity of phagocytic cells such as macrophages. Activated macrophages secrete TNF-a and IL-1 that together with IFN-g activates vascular endothelial cells. Endothelial cells also express CD40 receptors, which engage with CD40L (CD154) present on the surface of activated CD4+ T cells.

The resulting tethered CD4+ cells to the vascular endothelium secrete cytokines, which further activates the endothelial cells and induces them to express further cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and secreteIL-1, TNF-a and IFN-g. Genetic susceptibility is thought to play a role in the development of Kawasaki disease. In particular, polymorphisms in two genes encoding the T cell regulatory protein ITPKC and Caspase-3. We will uncover these specific events towards the end of our discussion.

Activated endothelial cells also secrete IL-6 in sufficient amounts to promote fever by acting on the hypothalamus and to induce the liver to synthesize acute phase proteins (such as CRP). MCP-1 is a chemo-attractant for monocytes and VEGF promotes vascular permeability and enhances extravasation of immune cells into the sub-endothelium.

Recruitment of monocytes and neutrophils to the endothelium

Activated monocytes, recruited to the sub-endothelium by interacting with the adhesion molecules (ICAM-1 and VCAM-1) on endothelial cells, mature into macrophages and secrete pro-inflammatory cytokines such as IL- 1, IL-6 and TNF-a.

The recruitment of CD4+ T cells to the endothelium occurs in a similar way

Additional CD4+ T cells in the circulation that express cell adhesion molecules LFA-1 and VLA-4 bind to ICAM-1 and VCAM-1 that are expressed on activated endothelial cells. This CD4+ T cell interactionfacilitates extravasation into the subendotheliumwhere they further secrete IFN-g, which in turn, enhances the maturation of monocytes into macrophages with increased phagocytic and antigen presenting abilities.

Recruitment of IgA-secreting B cells to the endothelium

Immune-mediated damage leading to aneurysm and scarring

The result of this mass movement of activated cells and the effects of cytokines is damage and dissolution of the subendothelium tissues. The elastic lamina is degraded by the action of elastases and matrix metalloproteases and these enzymes also digest extracellular matrix proteins that disrupt the smooth muscle architecture resulting in necrosis of smooth muscle cells. Disrupted endothelial cell barriers allow the influx of erythrocytes into the subendothelium causing aneurysm and the development of thrombosis.

The exposed collagen activates platelets, which express CD40L(CD154). The engagement of CD40L with CD40 expressed by endothelial cells results in platelets secreting IL-1 and soluble CD40L.The release of both these solutes causes further activation of endothelial cells and severe inflammation. At the same time activated fibroblasts secrete extracellular matrix proteins, such as collagen, that promotes scarring which results in vessel stiffness. When this occurs in coronary arteries, the damage may contribute to heart disease.

What leads to skin inflammation?

Alongside the well-documented vasculitis, skin inflammation is also often observed in patients with KD. This is seen predominantly as a polymorphous skin rash and is one of the diagnostic criteria for the disease. It is likely that the generalized skin involvement is a consequence of increased infiltration of immune cells through activated endothelium of cutaneous blood vessels into the dermis where an immune response to skin antigens can be mounted. This inflammatory response is excessive due the dysregulation of CD4+ T cells, probably leading to a predominance of Th17 cells, and the high activation state of antigen-presenting cells.  It has been noted that in regions where BCG vaccination is in use, up to a third of patients who succumb to KDalso have a reactivation of their BCG scar, along with the usual skin rash.

What is the association between Kawasaki disease and BCG scar reactivation?

Since BCG vaccination is usually given at birth and susceptible children show clinical evidence of KD months to years later, it seems likely that the immune response is directed towards antigens present in the vaccine that have persisted in the skin over time. Due to cytokine stimulation, increased numbers of T cells and antigen presenting cells infiltrate the skin (via cutaneous blood vessels) and memory BCG-specific CD4+ T cells become re-activated and clonally expand in numbers. In KD, genetic susceptibility genes that affect negative-regulation of activated CD4+ T cells may promote an excessive immune response by increased pro-inflammatory cytokine production.

In our case study, the patient had both a reactivation of his BCG scar and a (presumed) false positive Mantoux test. While it is well recognized that children who have received BCG vaccination can sometimes have a false-positive Mantoux test due to cross-reactive immune responses to Mycobacterium tuberculosis antigens, there are also some reports of a false-positive Mantoux test in children with KD who were never BCG vaccinated. The Mantoux test involves intradermal administration of Mycobacterium tuberculosis protein antigens.   It is likely that a combination of underlying genetic defects that affect negative regulation of CD4+ T cells, an increased infiltration of CD4+ T cells into the skin and the high activation state of antigen presenting cells all lead to an excessive localized immune response in patients with KD. A true-positive Mantoux test relies on activation of memory Mycobacterium tuberculosis -specific T cells, but in this case, a small pool of naïve CD4+ T cells responding to enhanced antigen presentation may be sufficient to promote an inflammatory response causing an induration to develop. In severe cases of KD, macrophage activation syndrome may even be present, due to the highly-activated state of macrophages.

Along with the immune mediated causes for Kawasaki Disease, as discussed, we will also discuss how a genetic predisposition in the patient together with immune dysregulation plays an important role in susceptibility to KD. We explain this using our graphics below.

A detailed look at CD4+ T cell NFAT activation pathway

As discussed above, KD is associated with uncontrolled activation of CD4+ T cells and over-stimulation of antigen presenting cells. Following T cell receptor (TCR) stimulation after engagement with the MHC class II-peptide complex on the surface of macrophages, one of the intracellular signaling pathways that is activated results in the translocation to the nucleus of NFAT transcription factors that mediate gene transcription. This pathway depends on phospholipase C gamma-2 production of IP3 that opens calcium ion channels in the cell membrane or in the endoplasmic reticulum. Calcium ions bind to calmodulin-calcineurin complexes. Calcineurin dephosphorylates cytoplasmic NFAT, which enters the nucleus and activates gene transcription, such as cytokines and membrane proteins. NFAT is later re-phosphorylated and recycled back to the cytoplasm. There are two mechanisms of negative regulation of NFAT activation that may play a role in Kawasaki disease.

1) Negative regulators of T cell activation: ITPKC

NFAT activation is negatively regulated by ITPKC proteins in the cytoplasm of T cells. IP3 produced by phospholipase C gamma-2 following TCR signal transduction is a substrate of ITPKC and is converted to IP4, which inactivates it. This limits the binding of IP3 to calcium channels to increase intracellular calcium ions needed to activate NFAT via calmodulin-calcineurin complexes. In Kawasaki Disease, gene variants of ITPKC that lead to lower protein levels have been associated with risk of disease development. It is thought that lower levels of ITPKC leads to longer persistence of IP3 following TCR signaling and prolonged activation of NFAT.  This results in prolonged and uncontrolled CD4+ T cell activation resulting in release of higher levels of pro-inflammatory cytokines and over-excitation of antigen-presenting cells. Excessive activation of endothelial cells leads to immune-mediated damage to blood vessels that have been described.

2) Negative regulators of T cell activation: Caspase-3

The NFAT activation pathway is also regulated by caspase-3 found in the cytoplasm of activated T cells. TCR signaling induces transcription of the caspase-3 gene. One of the functions of caspase-3 is to proteolytically degrade cytoplasmic NFAT proteins.

This reduces the amount of NFAT that can be activated by the calmodulin-calcineurin complex. In Kawasaki Disease, gene variants of caspase-3 have been associated with lower transcription levels. Lower levels of cytoplasmic caspase-3 activity leads to increased levels of cytoplasmic NFAT and prolonged CD4+ T cell activation, higher levels of pro-inflammatory cytokines and increased activation of antigen presenting cells. Systemic inflammation can then develop following an antigenic stimulus.

Although the aetiology of Kawasaki Disease remains largely undetermined, understanding the immunology and genetics behind the mechanisms leading to this condition have been identified and provides insights into our patient’s presentation. Thus, in light of our better understanding of this disease it is most likely that this patient was in fact TB negative at presentation. However due to the high incidence of TB in this geographic location, along with his suspicious clinical and laboratory findings and positive Mantoux test, it remained prudent to provide standard TB medication to this patient.

Download images for this case

Kawasaki disease.

Patient was treated for 6 months on standard TB treatment

Five days after starting TB treatment, the patient received the standard Kawasaki Disease regimen – 2g polygam, paracetamol and 50mg aspirin daily.

Polygam was not repeated.

Aspirin was continued at a lower dose, 20mg daily, and ibuprofen was given for pain until all symptoms resolved.

Skin rash and joint involvement resolved

At 3 months, echocardiogram was repeated and was normal

Cassidy, Petty et al. (2011) Textbook of Pediatric Rheumatology. (Sixth edition). Elsevier Inc ISBN: 978-1-4160-6581-4

Link to article

Rodó X, Ballester J, Cayan D (2011). Association of Kawasaki disease with tropospheric wind patterns. Science Reports . Nov 10; 1:152. Epub

Lee KY, Rhim JW, Kang JH (2012). Kawasaki disease: laboratory findings and an immunopathogenesis on the premise of a “protein homeostasis system”. Yonsei Med J. Mar;53(2):262-75.

Link to abstract

Jia S, Li C, Wang G, Yang J, Zu Y (2010). The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease. Clin Exp Immunol. Oct;162(1):131-7. doi: 10.1111/j.1365-2249.2010.04236.x.

Onouchi Y, Ozaki K, Burns JC et al.(2010). A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet. Mar 25;44(5):517-21.

Lee YC, Kuo HC, Chang JS et al. (2012). Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet . Mar 25;44(5):522-5.

Scuccimarri R.(2012). Kawasaki disease., PediatrClin North Am . Apr;59(2):425-45.

Takahashi K, Oharaseki T, Yokouchi Y (2011) Pathogenesis of Kawasaki disease. Clin Exp Immunol .  May;164Suppl 1:20-2.

Alexoudi I, Kanakis M, Kapsimali V, Vaiopoulos G (2011). Kawasaki disease: current aspects on aetiopathogenesis and therapeutic management. Autoimmun Rev .  Jul;10(9):544-7.

Evaluation – Questions & answers

What was the final diagnosis?

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Which cytokines are known to cause the prolonged fever present in Kawasaki disease?

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Which genetic variants are thought to play a role in susceptibility to Kawasaki Disease?

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Outbreak of Human Trichinellosis — Arizona, Minnesota, and South Dakota, 2022

Weekly / May 23, 2024 / 73(20);456–459

Shama Cash-Goldwasser, MD 1 ; Dustin Ortbahn, MPH 2 ; Muthu Narayan, DO 3 ; Conor Fitzgerald, MPH 4 ; Keila Maldonado 5 ; James Currie, MD 6 ; Anne Straily, DVM 7 ; Sarah Sapp, PhD 7 ; Henry S. Bishop 7 ; Billy Watson, PhD 7 ; Margaret Neja 7 ; Yvonne Qvarnstrom, PhD 7 ; David M. Berman, DO 8 ; Sarah Y. Park, MD 8 ; Kirk Smith, DVM, PhD 9 ; Stacy Holzbauer, DVM 9 ,10 ( View author affiliations )

What is already known about this topic?

Human trichinellosis cases in the United States are rare and are usually acquired through consumption of wild game.

What is added by this report?

Among eight persons who shared a meal that included the meat of a black bear harvested in Canada and frozen for 45 days, six trichinellosis cases were identified. The meat was grilled with vegetables and served rare; two cases occurred in persons who ate only the vegetables. Motile freeze-resistant Trichinella nativa larvae were identified in remaining meat frozen for >15 weeks.

What are the implications for public health practice?

Cooking meat to an internal temperature of ≥165°F (≥74°C) is necessary to kill Trichinella spp. parasites. Trichinella -infected meat can cross-contaminate other foods, and raw meat should be kept and prepared separate from other foods to prevent cross-contamination.

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Trichinellosis is a parasitic zoonotic disease transmitted through the consumption of meat from animals infected with Trichinella spp. nematodes. In North America, human trichinellosis is rare and is most commonly acquired through consumption of wild game meat. In July 2022, a hospitalized patient with suspected trichinellosis was reported to the Minnesota Department of Health. One week before symptom onset, the patient and eight other persons shared a meal that included bear meat that had been frozen for 45 days before being grilled and served rare with vegetables that had been cooked with the meat. Investigation identified six trichinellosis cases, including two in persons who consumed only the vegetables. Motile Trichinella larvae were found in remaining bear meat that had been frozen for >15 weeks. Molecular testing identified larvae from the bear meat as Trichinella nativa , a freeze-resistant species. Persons who consume meat from wild game animals should be aware that that adequate cooking is the only reliable way to kill Trichinella parasites and that infected meat can cross-contaminate other foods.

Investigation and Results

Index patient notification.

In July 2022, the Minnesota Department of Health was notified of a man aged 29 years who was hospitalized with fever, severe myalgias, periorbital edema, eosinophilia, and other laboratory abnormalities ( Table ); health care providers suspected trichinellosis. The patient had sought care for his symptoms, which commenced in early July, four times and had been hospitalized twice over a 17-day period. During his second hospitalization, providers obtained a history of bear meat consumption, and empiric albendazole treatment for probable trichinellosis was initiated. An investigation was launched to confirm the diagnosis, identify additional cases, and ascertain the source of infection to prevent future cases. The index patient’s diagnosis was confirmed by a positive Trichinella immunoglobulin (Ig) G antibody test result.

Potential Exposure Source Identification

Six days before symptom onset in the index patient, he and eight extended family members from three states (Arizona, Minnesota, and South Dakota) had gathered for several days in South Dakota and shared a meal that included kabobs made from the meat of a black bear ( Ursus americanus ), which had been harvested by one of the family members in northern Saskatchewan, Canada in May 2022. The hunting outfitter had recommended freezing the meat to kill parasites. The meat was frozen in a household freezer* for 45 days until being thawed and grilled with vegetables. The meat was initially inadvertently served rare, reportedly because the meat was dark in color, and it was difficult for the family members to visually ascertain the level of doneness. After some of the family members began eating the meat and noticed that it was undercooked, the meat was recooked before being served again. The family reunion concluded before onset of illness in the index patient.

Laboratory Investigation and Case Definition

Public health authorities in Arizona, Minnesota, and South Dakota interviewed eight of the nine persons who had attended the implicated meal. The ninth attendee was a person aged <18 years whose exposure status could not be confirmed; however, that person reportedly remained healthy. Testing of paired acute and convalescent sera for Trichinella IgG antibodies was recommended for the eight exposed persons and was completed for six. Pathogen-agnostic microbial cell-free metagenomic DNA sequencing ( 1 ) was performed on plasma samples from the index patient and one other person who had sought care twice before being hospitalized with fever, myalgias, abdominal pain, periorbital edema, and laboratory abnormalities. Trichinellosis cases were classified according to the 2014 case definition from the Council for State and Territorial Epidemiologists (CSTE), † (i.e., the presence of clinically compatible symptoms in a person who had consumed an epidemiologically implicated meal or meat in which the parasite was demonstrated [probable] or had a positive serologic test result for Trichinella antibodies [confirmed]). Samples of frozen bear meat were obtained from the household freezer and sent to CDC for artificial tissue digestion and microscopic examination for larvae and molecular testing for Trichinella spp.

Additional Case Detection and Exposure Source Confirmation

Among the eight interviewed persons, five consumed the bear meat, and eight consumed the vegetables that had been cooked with it. Six of the eight persons who attended the meal, including four who consumed the bear meat and the vegetables, and two who consumed only the vegetables (but no meat), had symptoms consistent with trichinellosis, and met case criteria (two confirmed and four probable). Patients with trichinellosis ranged in age from 12 to 62 years and lived in three states: Arizona (one), Minnesota (four), and South Dakota (one). All cases were diagnosed in the patients’ state of residence. Three of the six symptomatic persons, two of whom sought care at least twice before being offered treatment, were hospitalized. The three hospitalized persons received trichinellosis-directed treatment with albendazole. § All six symptomatic persons recovered; the nonhospitalized patients did not receive trichinellosis-directed treatment because their symptoms had resolved with supportive care only, and the benefit of treatment after larval invasion of muscle is unclear ( 2 ). Six persons submitted a serum sample, each collected within 4 weeks of symptom onset; two specimens tested positive for Trichinella IgG antibodies by enzyme-linked immunosorbent assay. Two persons submitted a plasma sample for microbial cell-free DNA sequencing during hospitalization for trichinellosis-compatible symptoms, and both plasma samples tested positive for Trichinella spp. DNA. Microscopy identified motile Trichinella larvae (>800 larvae/g) in samples of bear meat that had been frozen for 110 days in a household freezer ( Figure ). Real-time multiplex polymerase chain reaction testing ( 3 ) of the bear meat was positive for T. nativa and whole genome sequencing identified mitochondrial sequences 100% identical to T. nativa.

Public Health Response

The family member who harvested the bear and provided meat samples for testing was advised to discard any remaining meat. All identified trichinellosis cases were reported to appropriate state health departments and to CDC. CDC notified the Public Health Agency of Canada of the outbreak and the confirmed source of infection. This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy. ¶

Trichinellosis is rarely reported in the United States. As a result of changes in pork production practices from historical norms that fostered transmission, most cases reported in recent years are attributed to consumption of meat from wild game ( 4 ). During January 2016–December 2022, seven U.S. trichinellosis outbreaks, including 35 probable and confirmed cases, were reported to CDC; bear meat was the suspected or confirmed source of infection in the majority of those outbreaks (CDC, unpublished data, 2022). Estimates of Trichinella infection prevalence among wild animal host species vary widely. A Trichinella infection prevalence range of at least 1% to 24% among black bears in Canada and Alaska has been reported, and even higher prevalences of Trichinella infection are reported among species of predators that are strict carnivores (e.g., polar bear, wolverine, and cougar) ( 5 ). The frequency with which black bear meat is the implicated source of human infection might be driven by hunting practices, ecological factors, and the relatively high parasite density observed in the muscle of infected black bears compared with that of other species ( 6 , 7 ).

Because symptoms of trichinellosis are typically nonspecific, diagnosis of infection requires a high index of suspicion; however, periorbital edema and certain laboratory abnormalities (e.g., eosinophilia and elevated creatine kinase levels) can provide etiologic clues. In this outbreak, two of the hospitalized patients sought care multiple times before receiving a diagnosis. Four of the six patients met clinical and epidemiologic criteria and thus were considered probable cases. Laboratory confirmation can be challenging because of the limited sensitivity of antibody testing early in illness ( 8 ); in this investigation, acute Trichinella IgG test results were positive in only two of six tested patient specimens. The clinical utility of trichinellosis test results obtained after acute illness is limited, and historically, public health investigators have had difficulty obtaining convalescent serum samples from persons who have recovered. Laboratory criteria in the current CSTE trichinellosis case definition do not include nucleic acid testing of human specimens. The sensitivity of such assays to detect Trichinella DNA in blood is uncharacterized; however, plasma samples from both patients tested by metagenomic sequencing ( 1 ) yielded positive results for Trichinella DNA. As demonstrated in this outbreak, pathogen-agnostic molecular assays can be useful for detection of rare diseases when standard workup is unrevealing and if other diagnostic tests lack sensitivity.

Implications for Public Health Practice

Although freezing kills Trichinella species commonly implicated in pork-associated outbreaks, freeze-resistant Trichinella species, including T. nativa and the T6 genotype ( 9 ), predominate in Arctic and sub-Arctic regions ( 6 ). Larval motility was observed in bear meat that had been frozen for nearly 4 months (110 days). Persons who consume game meat, especially that harvested in northern latitudes, should be informed that adequate cooking is the only reliable way to kill Trichinella parasites. Cooking wild game meat to an internal temperature of ≥165°F (≥74°C) is recommended by public health authorities**; temperatures should be verified with a meat thermometer. As demonstrated in this outbreak, the color of meat is not a good indicator of cooking adequacy. Safe handling of raw meat (i.e., separating raw or undercooked meat and its juices from other foods) is recommended to prevent trichinellosis; this investigation and previous investigations suggest that Trichinella -infected meat can cross-contaminate other foods ( 10 ). Government and private entities that oversee and organize hunting should educate hunters about these risks and effective preventative measures.

Acknowledgments

The persons affected by this outbreak; Lauren Ahart, Sue Montgomery, Parasitic Diseases Branch, CDC.

Corresponding author: Shama Cash-Goldwasser, [email protected] .

1 Epidemic Intelligence Service, CDC; 2 South Dakota Department of Health; 3 University of Minnesota, Minneapolis, Minnesota; 4 Arizona Department of Health Services; 5 Maricopa County Department of Public Health, Phoenix, Arizona; 6 Lakeview Clinic, Waconia, Minnesota; 7 Division of Parasitic Diseases and Malaria, Center for Global Health, CDC; 8 Medical Affairs, Karius, Inc., Redwood City, California; 9 Minnesota Department of Health; 10 Division of State and Local Readiness, Center for Preparedness and Response, CDC.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. David M. Berman reports that he is a paid laboratory medical consultant for Precision Health Solutions and reports ownership of company shares in Karius, Inc. No other potential conflicts of interest were disclosed.

* The temperature of the freezer is not known.

† https://ndc.services.cdc.gov/case-definitions/trichinellosis-2014/

§ https://www.cdc.gov/trichinellosis/hcp/clinical-care/index.html

¶ 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.

** https://www.cdc.gov/trichinellosis/prevention/index.html

• Blauwkamp TA, Thair S, Rosen MJ, et al. Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nat Microbiol 2019;4:663–74. https://doi.org/10.1038/s41564-018-0349-6 PMID:30742071
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• Harms NJ, Larivee M, Scandrett B, Russell D. High prevalence and intensity of Trichinella infection in Yukon American Black ( Ursus americanus ) and Grizzly ( Ursus arctos ) bears. J Wildl Dis 2021;57:429–33. https://doi.org/10.7589/JWD-D-20-00135 PMID:33822166
• Yang Y, Cai YN, Tong MW, et al. Serological tools for detection of Trichinella infection in animals and humans. One Health 2016;2:25–30. https://doi.org/10.1016/j.onehlt.2015.11.005 PMID:28616474
• Pozio E. Adaptation of Trichinella spp. for survival in cold climates. Food Waterborne Parasitol 2016;4:4–12. https://doi.org/10.1016/j.fawpar.2016.07.001
• Hall RL, Lindsay A, Hammond C, et al. Outbreak of human trichinellosis in Northern California caused by Trichinella murrelli . Am J Trop Med Hyg 2012;87:297–302. https://doi.org/10.4269/ajtmh.2012.12-0075 PMID:22855761

Abbreviations: eos = eosinophils; F = female; M = male; NA = not applicable; ND = not done; WBC = white blood cell. * Initial results are from hospitalization during which trichinellosis was suspected. Reference ranges varied among different laboratories that conducted testing. † Reference range = 4–88. § Reference range = 39–208. ¶ Consumed vegetables that were cooked and served with the bear meat. ** Reference range = 39–308.

FIGURE . Microscopic examination of encapsulated larvae in a direct black bear meat muscle squash prep (A), larvae liberated from artificially digested bear meat (B), and motile larvae viewed with differential interference contrast microscopy (C and D)* from black bear meat suspected as the source of an outbreak of human Trichinella nativa infections — Arizona, Minnesota, and South Dakota, 2022

Photos/Division of Parasitic Diseases and Malaria, Center for Global Health, CDC

* Scale bars = 100 µ m.

Suggested citation for this article: Cash-Goldwasser S, Ortbahn D, Narayan M, et al. Outbreak of Human Trichinellosis — Arizona, Minnesota, and South Dakota, 2022. MMWR Morb Mortal Wkly Rep 2024;73:456–459. DOI: http://dx.doi.org/10.15585/mmwr.mm7320a2 .

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• Published: 27 May 2024

Exploring shared molecular signatures and regulatory mechanisms in nonalcoholic steatohepatitis and inflammatory bowel disease using integrative bioinformatics analysis

• Zixuan Zhong 1 , 2 ,
• Minxuan Xu 1 , 2 , 3 ,
• Chenxu Ge 1 , 2 , 3 &
• Jun Tan 1 , 2  

Scientific Reports volume  14 , Article number:  12085 ( 2024 ) Cite this article

Metrics details

• Genetic markers
• Mechanisms of disease

The co-existence of inflammatory bowel disease (IBD) and non-alcoholic steatohepatitis (NASH) has raised interest in identifying shared molecular mechanisms and potential therapeutic targets. However, the relationship between these two diseases remains unclear and effective medical treatments are still lacking. Through the bioinformatics analysis in this study, 116 shared differentially expressed genes (SDEGs) were identified between IBD and NASH datasets. GO and KEGG pathway analyses revealed significant involvement of SDEGs in apoptotic processes, cell death, defense response, cytokine and chemokine activity, and signaling pathways. Furthermore, weighted gene co-expression network analysis (WGCNA) identified five shared signature genes associated specifically with IBD and NASH, they were CXCL9, GIMAP2, ADAMTS5, GRAP, and PRF1. These five genes represented potential diagnostic biomarkers for distinguishing patients with diseases from healthy individuals by using two classifier algorithms and were positively related to autophagy, ferroptosis, angiogenesis, and immune checkpoint factors in the two diseases. Additionally, single-cell analysis of IBD and NASH samples highlighted the expression of regulatory genes in various immune cell subtypes, emphasizing their significance in disease pathogenesis. Our work elucidated the shared signature genes and regulatory mechanisms of IBD and NASH, which could provide new potential therapies for patients with IBD and NASH.

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Introduction.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder closely related to insulin resistance, obesity, and metabolic syndrome 1 , 2 . It encompasses a spectrum of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH is characterized by fat accumulation, inflammation, and fibrosis, which can progress to cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC) 3 , 4 , 5 . The activation of innate immunity in the liver is a pivotal factor in triggering and promoting the inflammatory response, driving the progression of NAFLD to NASH and probably contributing to liver fibrosis in NASH 6 .

Inflammatory Bowel Disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammatory condition primarily targeting the gastrointestinal tract. The intricate interplay involving the genetic factors, immune system dysregulation, environmental influences, and microbial components results in persistent intestinal inflammation of IBD 7 , 8 . IBD may serve as a precursor to various complex ailments, including hepatic steatosis, hepatic amyloidosis, sclerosing cholangitis, autoimmune hepatitis, and liver abscess 9 , 10 , 11 . Additionally, the presence of obesity and overweight conditions, observed in NAFLD and NASH, is also prevalent among individuals diagnosed with IBD 12 , 13 , 14 .

Recent studies have demonstrated an elevated prevalence of NAFLD and NASH within the IBD patients cohort, with reported incidences ranging from 8 to 59% 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . Despite the lack of complete understanding of this association, a recent retrospective study conducted by Sourianarayanane et al . confirmed that approximately one-third of individuals diagnosed with IBD globally have developed NAFLD, with a two-fold increased risk of NAFLD occurrence in IBD patients compared to those without IBD 16 . Furthermore, Bessissow et al. 20 found that the emergence of incident NAFLD is a common occurrence among IBD patients, and these individuals may subsequently progress to an advanced state of liver fibrosis characteristic of NASH. Magrì et al . suggested that metabolic syndrome serves as a specific risk factor for advanced liver fibrosis among IBD patients concurrently afflicted with NAFLD 22 . Besides the metabolic syndrome, IBD-specific risk factors encompass malnutrition, intestinal inflammation, steroid exposure, drug-induced hepatotoxicity, and gut dysbiosis, all potentially contribute to the pathogenesis of NASH 8 , 15 , 16 . However, further studies are required to clarify these risk factors. Although accumulating evidence suggests that the pathogenesis of both NASH and IBD involves intricate interplay among genetic predisposition, immune system dysfunction, environmental factors, and metabolic disorders 7 , 23 , 24 , 25 , 26 , 27 , 28 , the biomolecular mechanisms and crucial signaling molecules commonly shared by NASH and IBD remain unknown.

In this study, we aimed to elucidate the shared genetic markers and key molecular pathways that contribute to the progression of NASH and IBD by employing advanced computational methods and integrated bioinformatics analyses. Our findings may uncover the potential connection and shared molecular signatures between NASH and IBD, offering insights into the pathophysiology of both diseases and potentially paving the way for novel therapeutic strategies benefiting patients with overlapping conditions of NASH and IBD.

Materials and methods

Data collection.

We searched the GEO database ( https://www.ncbi.nlm.nih.gov/geo/ , Access Date: 2023.05) using the terms “Inflammatory Bowel Disease” and “Nonalcoholic Steatohepatitis” to identify gene expression profiles associated with NASH. The following criteria were applied as filters to ensure data quality and reliability: (1) Inclusion of array-based expression profiling or high-throughput mRNA sequencing. (2) Inclusion of both case and control groups in all datasets, with each group containing no fewer than 6 samples. (3) The number of samples in each group was required to be a minimum of 10 for WGCNA analysis. Finally, the four GEO datasets GSE59071, GSE36807, GSE89632, and GSE164760 were selected.

GSE59071 and GSE36807 are IBD datasets, while GSE89632 and GSE164760 are NASH datasets. The GSE59071 dataset included 116 samples, of which 8 active CD samples, 74 active UC samples, and 11 healthy samples were used in this study. The GSE36807 datasets included 35 samples, of which 13 CD samples, 15 UC samples, and 7 healthy samples were used in this study. The GSE89632 dataset included 63 samples, of which 19 NASH samples and 24 healthy samples were used in this study. The GSE164760 dataset included 170 samples, of which 74 NASH samples and 6 healthy samples were used in this study. The GSE164985 and GSE190487 datasets were also downloaded from GEO database for single-cell analysis. The specific information of all datasets was detailed in Table 1 .

Identification of differentially expressed genes

To identify the common genetic effects of NASH and IBD, the ‘limma’ (version 3.44.3) R package with P value < 0.05 and |Fold change (FC)|> 1.5 were used to explore the differentially expressed genes (DEGs) in GSE59071 and GSE89632. Then, the DEGs of NASH and IBD were visualized using the ‘complexheatmap’ (version 3.1.2) and ‘ggplot2’ (version 3.3.3) R packages to generate the heat maps and volcano maps, respectively. The overlapping DEGs in NASH and IBD were calculated using R-language, and these shared differentially expressed genes (SDEGs) with consistent up-regulated or down-regulated trends were retained for subsequent analysis.

Analysis of functional classification and pathway enrichment

To obtain the common biological functions and signaling pathways underpinning the initiation and progression of the two diseases, the SDEGs between the IBD dataset GSE59071 and NASH dataset GSE89632 were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) 12 pathway enrichment using “ClusterProfiler” (version3.16.1), ‘org.Hs.eg.Db’(version 3.11.4), and ‘GOplot’ (version 1.0.2) R packages, P value < 0.05 was set for enrichment.

Protein–protein interaction network analysis

The STRING database ( http://string-db.org , Access Date: 2023.06) was employed to predict and delineate potential protein interactions, thereby facilitating the construction of a protein–protein interaction (PPI) network. Within this network, PPI pairs with a reliability score > 0.4 were considered to be statistically significant. Cytoscape (version 3.8.0) was used for visualizing molecular interaction networks. Subsequently, the identification of pivotal hub genes, characterized by top ten genes with highest connectivity within the PPI networks, was conducted employing the Maximal Clique Centrality (MCC) method through the cytoHubba plugin within the Cytoscape platform. Furthermore, to identify and delineate the most influential clusters within the PPI network, we applied the Molecular Complex Detection (MCODE) plugin available in Cytoscape software.

WGCNA for co-expression network construction

To obtain WGCNA modules of NASH and IBD, the ‘WGCNA’ (version 1.70.3) R package 29 was applied to the IBD dataset GSE59071 and NASH dataset GSE89632. First, the variance for each gene expression value was calculated and a filtering process was employed to eliminate genes exhibiting absolute deviations exceeding 25% in relation to the median value. Furthermore, potential outlier samples were addressed by employing the “hclust” function for hierarchical clustering analysis. Samples exhibiting outlier characteristics were excluded using the ‘goodSampleGenes’ function (Supplementary Fig.  1 A, B). To construct scale-free networks, β value was evaluated using the “pickSoftThreshold” function and a soft threshold β of 14 was identified as suitable for both NASH and IBD datasets (Supplementary Fig.  2 A, B). Subsequently, hierarchical clustering dendrograms were constructed and similar genes were grouped into distinct modules, with a minimum of 30 genes per module. Analogous modules were consolidated based on a Module Eigengenes Dissimilarity Threshold (MEDissThres) = 0.2. Finally, a Pearson correlation analysis was conducted to establish the association between modules and the specific disease phenotypes of interest. Our analysis focused on modules demonstrating remarkable correlations with the targeted phenotypic attributes. From these disease-related modules, genes were selected for subsequent analysis.

Identification of SWDEGs in NASH and IBD

Firstly, the hub modules displaying strong association with NASH and IBD were screened out (absolute correlation coefficient \(\ge \hspace{0.17em}\) 0.6 and P value < 0.001) based on the module trait correlation and the significance levels of eigengenes in relation to phenotypic traits within each module. Then, the shared genes in hub modules positively related to the two diseases and up-regulated SDEGs were identified using the Jvenn online tool ( http://jvenn.toulouse.inra.fr/app/example.html , Access Date: 2023.06) 30 , and these genes were considered as shared gene signatures (SWDEGs). Finally, the expression levels of SWDEGs between patients with IBD and normal controls in validation datasets GSE36807, NASH and normal controls in validation datasets GSE164760 were confirmed and represented using box plots respectively.

Validation of diagnostic capacity of SWDEGs for NASH and IBD

Two classification algorithms including support vector machine (SVM) 31 and logistic regression (LR) 32 were employed to assess the diagnostic validity of SWDEGs for NASH and IBD. Both algorithms are widely used methods for binary classification problems. The area under the ROC curve (AUC) was calculated based on SWDEGs expression in GSE59071, GSE89632, GSE36807, and GSE164760, respectively using ‘pROC’ (version 1.18.0), ‘e1071’ (version 1.7.9), and ‘rms’ (version 6.2.0) R packages. The training set obtained 70% of the total samples, and the test set obtained 30% of the total samples for two classifier algorithms.

Transcription factors and miRNAs analysis

The SWDEGs in NASH and IBD have been considered in this analysis. The miRNAs-SWDEGs interaction networks and transcription factors (TFs)–SWDEGs interaction networks were identified using Network Analyst ( https://www.networkanalyst.ca/ , Access Date: 2023.07) 33 . TarBase v.8 database ( https://dianalab.e-ce.uth.gr/html/diana/web/index.php?r=tarbasev8 , Access Date: 2023.07) was used for discovering miRNAs-DEGs interaction networks 34 , and JASPAR 2022 ( https://jaspar.genereg.net/ , Access Date: 2023.07) was used for TFs–SWDEGs interaction network analysis 35 . Both TFs–SWDEGs and miRNAs–SWDEGs interaction networks were visualized in Cytoscape.

Correlation analysis of SWDEGs with ferroptosis, autophagy, angiogenesis, and immune

A total of 304 ferroptosis-related genes (FRGs) were obtained from the FerrDb V2 database ( http://www.zhounan.org/ferrdb/current/ , Access Date: 2023.07), 222 autophagy-related genes (AURGs) were obtained from HADb (Human Autophagy Database, http://www.autophagy.lu/index.html , Access Date: 2023.07), 36 angiogenesis-related genes (ANRGs) were obtained from the MSigDB Team (Hallmark Gene set) and 79 immune checkpoint-related genes (ICRGs) according to a previous paper 36 . Pearson’s correlation analysis was used to reveal the relationships between SWDEGs and four gene sets (FRGs, AURGs, ANRGs, and ICRGs). Then, the top 10 genes of high correlation values with SWDEGs in each gene set were extracted and visualized them using ChiPlot ( https://www.chiplot.online/ , Access Date: 2023.07).

Single‑cell sequencing analysis

The GSE164985 and GSE190487 datasets were first processed using the ‘Seurat’ (version 4.0.2) R package 16 , and then UMAP method analysis was employed to identify the spatial associations among the various clusters present within the datasets. 'SingleR' (version 1.2.4) and 'celldex' (version 1.11.1) R packages were utilized to provide coprehensive annotation 37 . In tandem, we performed a manual validation of cell type annotation utilizing CellMarker ( http://xteam.xbio.top/CellMarker/ , Access Date: 2023.07). The marker gene identification for each distinct cell subtype was achieved through the application of the FindAllMarkers function, employing a log-fold change (logfc) threshold of 0.25. Genes with P value < 0.05 were chosen as separate marker genes for each cell cluster (Supplementary Table S1 ).

Collection of human clinical samples

Human liver tissue samples of NASH group (n = 5) and non-steatosis group (n = 5) used in the current study were collected from adult patients as our previously reported 38 . The liver samples with a NASH activity score (NAS) of 0 were classified as non-steatosis group, and samples with a NAS ≥ 5 or a NAS of 3–4 but showing fibrosis were included in the NASH group. All procedures associated with human subjects used in this study were based on the Declaration of Helsinki, and completely approved by the Academic Research Ethics Committee in Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region and other participating units. According to the research approved by IRB/IEC, written informed consents were required and samples were then collected from the donors.

Human colon tissue samples from patients with CD or UC were obtained from the Department of Gastrointestinal Surgery and the Clinical Trial Research Center at Shandong Cancer Hospital and Institute. The diagnosis of UC or CD was confirmed through radiological, clinical, and endoscopic evaluations, and histological data analysis. The samples with and without UC or CD phenotype were categorized into the IBD group (n = 5) and non-IBD group (n = 5), respectively. All patients and donors provided informed consent for the use of their samples in this study, which was approved by the Institutional Research Ethics Committees of Shandong First Medical University & Shandong Academy of Medical Sciences and Chongqing University of Education (Ethics Approval Number: CQUE202014EA02).

Immunofluorescence examination

Immunofluorescence analysis was carried out as described previously 38 , 39 . In brief, 5 µm thick frozen tissue sections were placed for 20 min at room temperature and then washed with PBS for three times. The tissue sections were blocked using a solution containing 10% goat serum (Beyotime) and 0.3% Triton X-100 (Beyotime) for 1 h at room temperature and then incubated with primary antibodies against CXCL9, GIMAP2, ADAMTS5, GRAP, PRF1 and F4-80 (Invitrogen) at 4 °C overnight in the indicated groups. After three times of PBS washes, the tissue slides were incubated with the corresponding goat anti-mouse or anti-rabbit IgG antibodies (Abcam) at room temperature in the dark for 1 h. Finally, the sections were stained with 2-(4-Amidinophenyl)-6-indole-carbamidine dihydrochloride (DAPI, Beyotime) solution for nuclei staining. All the histological procedure was performed in accordance with the standard procedures as indicated in reagent specifications. Images were visualized and captured under fluorescence microscopy (Olympus, Japan).

Statistical analysis

Statistical analysis was performed using R programming language (version 4.0.5). The PPI network, miRNAs-SWDEGs and TFs-SWDEGs interaction networks were visualized in Cytoscape (version 3.8.0). A threshold of P value < 0.05 was considered to indicate statistical significance.

Ethics statement

The studies involving human participants were approved by the Academic Research Ethics Committee in Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region and Chongqing University of Education.

Identification of common DEGs between NASH and IBD

The workflow of the study was displayed in Fig.  1 . The IBD dataset GSE59071 and NASH dataset GSE89632 were downloaded from the NCBI GEO database, and 1581 up-regulated and 1177 down-regulated DEGs were identified in the GSE59071 dataset, 925 up-regulated and 1158 down-regulated DEGs were identified in GSE89632 with P value < 0.05 and |Fold change|> 1.5. The visualization of DEGs within the two datasets was facilitated through the utilization of volcano plots and heatmap analyses (Fig.  2 A–D). According to the result, 116 shared DEGs (SDEGs) between GSE59071 and GSE89632 were identified (Fig.  2 E,F), in which 58 SDEGs were up-regulated and 58 SDEGs were down-regulated in NASH and IBD datasets.

Flow chart of this study.

Identification and analysis of shared DEGs (SDEGs) in IBD dataset GSE59071 and NASH dataset GSE89632. ( A ) Volcano plot of the DEGs in IBD. ( B ) Volcano plot of the DEGs in NASH. ( C ) Heatmap of DEGs in IBD. ( D ) Heatmap of DEGs in NASH. ( E ) Venn diagram of up-regulated SDEGs in NASH and IBD. ( F ) Venn diagram of down-regulated SDEGs in NASH and IBD.

GO and KEGG pathway analysis of SDEGs

GO and KEGG pathway enrichment analyses were performed to gain deeper insights into the biological functions of the SDEGs. Following screening using a threshold of P value < 0.05, we identified and selected significantly enriched GO terms and KEGG terms (Fig.  3 A–D). In the biological process category, SDEGs predominantly participated in crucial processes such as the apoptotic process, cell death, defense response, cytokine response, and regulation of signaling. In the cellular component category, SDEGs displayed notable associations with membrane, plasma, and T-cell receptors. In the molecular function category, SDEGs were mainly involved in receptor-ligand and regulator activity, cytokine and chemokine activity, and chemokine receptor binding. Moreover, the KEGG pathway enrichment analysis revealed that SDEGs were significantly enriched in the pathways of cancer, hematopoietic cell lineage, and multiple signaling pathways, including PI3K-Akt, Rap1, PPAR, and Toll-like receptor signaling pathways.

GO function analysis of SDEGs in ( A ) biological progress, ( B ) cellular component, and ( C ) molecular function. ( D ) KEGG pathway analysis of SDEGs. The enrichment significance gradually increases from red to blue, and the dot size represents the number of genes contained in the corresponding pathway.

PPI network analysis and hub genes selection

The 116 SDEGs of NASH and IBD were subjected to analysis within the STRING database. The outcomes of this analysis were then imported into Cytoscape software for visual examination (Fig.  4 A). Thereafter, Cytoscape plug-in cytoHubba was utilized to screen out the top 10 of the important genes in the PPI network based on the MCC algorithm, including CD2, PRF1, CXCL11, IFI44, USP18, IFIT3, TRIM22, IFIT2, CXCL9 and GBP5 (Fig.  4 B). All 10 hub genes were up-regulated in both NASH and IBD patients. The MCODE plug-in was used to identify significant gene cluster modules from the PPI network. Module 1 network included 8 nodes and 24 edges with a cluster score of 6.857, 8 out of 10 hub genes obtained by cytoHubba were also highlighted in the module 1 network by MCODE (Fig.  4 C), which could be key drug targets and biomarkers in NASH and IBD associated with various biological mechanisms.

PPI network construction and hub genes identification of SDEGs. ( A ) PPI network of SDEGs. Red and blue circle nodes indicate up- and down-regulated SDEGs, respectively. ( B ) Identification of the top ten hub SDEGs by the MCC algorithm in cytoHubba. The color and size of the circular node depend on the degree of the node. ( C ) The No.1 cluster extracted using the MCODE plug-in.

Identification of SWDEGs in NASH and IBD via WGCNA

In GSE59071, thirteen distinct modules were identified via WGCNA, each module denoted by a unique color scheme (Fig.  5 A, C). Five modules labeled as ‘MEblack’ (r = 0.81, P  = 3e−22), ‘MEyellow’ (r = 0.83, P  = 4e−24), ‘MEblue’ (r = 0.57, P  = 3e−09), ‘MEgrey’(r = 0.51, P  = 2e−07) and ‘MEturquoise’ (r = 0.68, P  = 6e−14) exhibited a high correlation with IBD. Notably, the 'MEblack’, ‘MEyellow’, ‘MEblue’, and ‘MEgrey’ modules demonstrated a positive correlation with IBD, while the ‘MEturquoise’ module displayed a negative correlation. The top three positively correlated modules ‘MEblack’, ‘MEyellow’, and ‘MEblue’ were identified as IBD-related modules, and a total of 1898 genes from the three modules were subsequently subjected to further analyses. Similarly, eight modules from the GSE89632 dataset were identified via WGCNA (Fig.  5 B, D), two modules ‘MEbrown’ (r = 0.75, P  = 2e−08) and ‘MEblue’ (r = 0.89, P  = 3e−15) exhibited a high correlation with NASH. The ‘MEbrown’ module showed a positive correlation with NASH, while the 'MEblue’ module displayed a negative correlation. The positively correlated module ‘MEbrown’, containing 529 genes, was identified as a NASH-related module.

Identification of SWDEGs in NASH and IBD via WGCNA. ( A ) The dendrogram of the co-expressed gene cluster in IBD dataset GSE59071. ( B ) The dendrogram of the co-expressed gene cluster in NASH dataset GSE89632. ( C ) Correlation analysis between expression of module genes and disease phenotypes in IBD dataset GSE59071. ( D ) Correlation analysis between expression of module genes and disease phenotypes in NASH dataset GSE89632. ( E ) Venn diagram of five SWDEGs screened from the intersection of up-regulated SDEGs and gene modules positively related NASH and IBD.

A total of five SWDEGs (CXCL9, GIMAP2, ADAMTS5, GRAP, and PRF1) were screened from the intersection of SDEGs, IBD positively correlated gene modules (‘MEblack’, ‘MEyellow’, and ‘MEblue’) and NASH positively related gene module (‘MEbrown’) (Fig.  5 E). To validate the significance of the five SWDEGs beyond the GSE59071 and GSE89632 datasets, we extended our analyses to additional two datasets—GSE36807 for IBD and GSE164760 for NASH (Fig.  6 A–D). The gene expressions of the five SWDEGs within the NASH and IBD groups were consistently elevated in comparison to the control group. This collective exploration underscored the potential involvement of these genes in the pathogenesis of both NASH and IBD.

Gene expression level of five SWDEGs in ( A ) GSE59071, ( B ) GSE89632, ( C ) GSE36807, and ( D ) GSE164760.

Assessment of the diagnostic validity of SWDEGs for NASH and IBD

Furthermore, the diagnostic efficacy of five SWDEGs was assessed across four datasets (GSE59071, GSE89632, GSE36807, and GSE164760) by constructing different five-SWDEG prediction models based on SVM and LR algorithms. As is shown in Fig.  6 , all datasets exhibited high AUC values on the ROC curves using two classifier algorithms. The AUC values of the SVM model in GSE59071, GSE89632, GSE36807, and GSE164760 were 0.944, 0.971, 0.938, and 0.957 respectively (Fig.  7 A–D). The AUC values of LR model in GSE59071, GSE89632, GSE36807, and GSE164760 were 0.970, 0.987, 0.918, and 0.966 respectively (Fig.  7 E–H), which suggested that high diagnostic potential of five SWDEGs to discriminate between IBD and non-IBD patients, or NASH and non-NASH patients. Besides, each gene of five SWDEGs also showed high AUC values in four datasets of NASH and IBD (Supplementary Fig.  3 A–D).

The ROC curves estimating the diagnostic performance of the five-SWDEGs prediction model. ( A ) IBD dataset GSE59071 by SVM algorithm, ( B ) NASH dataset GSE89632 by SVM algorithm, ( C ) IBD validation dataset GSE36807 by SVM algorithm, ( D ) NASH validation dataset GSE164760 by SVM algorithm, ( E ) IBD dataset GSE59071 by LR algorithm, ( F ) NASH dataset GSE89632 by LR algorithm, ( G ) IBD validation dataset GSE36807 by LR algorithm, ( H ) NASH validation dataset GSE164760 by LR algorithm.

Prediction of TFs and miRNAs associated with SWDEGs

To comprehensively elucidate the intricacies of gene expression alterations at the transcriptional level and gain a profound understanding of the regulatory influence exerted by miRNAs on the SWDEGs in NASH and IBD, NetworkAnalyst was utilized to predict the involvement of TFs and miRNAs in interaction with the five SWDEGs and Cytoscape to visualize the TFs-SWDEGs and miRNAs-SWDEGs regulatory network (Fig.  8 A,B). In the TF-SWDEGs network, two pivotal TFs (YY1 and FOXC1) exhibited interactions with four SWDEGs (CXCL9, GIMAP2, GRAP, and PRF1). In the miRNA-SWDEGs network, seven miRNAs (mir-26b-5p, mir-26a-5p, mir-124-3p, mir-128-3p, mir-10b-5p, mir-20a-5p, and mir-671-5p) associated with ADMTS5 also exhibited interactions with other four SWDEGs (CXCL9, GIMAP2, GRAP, and PRF1). These seven miRNAs might be crucial for regulating the expression of SWDEGs.

Interaction networks of ( A ) TFs-SWDEGs and ( B ) miRNAs-SWDEGs. The highlighted red ellipse nodes indicate SWDEGs, purple rhombus nodes indicate TFs and blue triangle nodes indicate miRNAs.

Correlation between SWDEGs and genes related to key regulatory mechanism

We performed correlation analysis of four gene sets (FRGs, AURGs, ANRGs, and ICRGs) with five SWDEGs in NASH and IBD respectively, and extracted the top 10 genes with high positive relevance scores in each gene set (Fig.  9 A–H). We noticed a stronger correlation between SWDEGs (CXCL9, GIMAP2, ADAMTS5, GRAP, and PRF1) and four gene sets in GSE59071 than that in GSE89632. Moreover, GIMAP2 had a significant correlation with the autophagy-related gene ATG4C in both diseases. For ICRGs, ADORA2A, CD226, and CD40 were correlated with five SWDEGs with different significance in both diseases.

Relationship of SWDEGs and key regulatory genes. ( A – D ) Correlation of SWDEGs with angiogenesis-, autophagy-, ferroptosis-, and immune checkpoint-related genes in IBD dataset GSE59071. ( E – H ) Correlation of hub genes with angiogenesis-, autophagy-, ferroptosis-, and immune checkpoint-related genes in NASH dataset GSE89632The color and size of the circular node depend on the correlation value. * P  < 0.05; ** P  < 0.01; *** P  < 0.001; ns, non-significant.

Analysis of regulatory gene expression in single cells

We obtained the two distinct single-cell sequencing datasets, GSE164985 for IBD and GSE190487 for NASH, and subjected them to single-cell analysis utilizing the ‘Seurat’ package. Employing the UMAP algorithm, we performed cellular clustering, and subsequently capitalized on the HumanPrimaryCellAtlasData and BlueprintEncodeData as our primary reference for cellular annotation, each cluster was annotated via the ‘SingleR’ package (Supplementary Table S2 ). Within the GSE164985 dataset, all cells were classified into five categories: B cells, T cells, epithelial cells, NK cells, and monocytes (Fig.  10 A). Similarly, the cells within the GSE190487 dataset were classified into four primary categories: B cells, T cells, NK cells, and monocytes (Fig.  10 B).

Single-cell analysis of NASH and IBD. ( A ) Cellular subtypes of IBD single-cell sequencing dataset GSE164985 and ( B ) NASH single-cell sequencing dataset GSE19048.

In pursuit of a comprehensive understanding of the cellular landscape within NASH and IBD, we explored the expression levels of genes related to immune responses, ferroptosis, autophagy, and angiogenesis within various cell categories. The results indicated a consistent expression pattern of these regulatory genes across various immune cell subtypes in NASH and IBD (Fig.  11 A–H).

Expression profiles of regulatory genes in single cells of NASH and IBD. ( A – D ) Bubble plot of the expression of angiogenesis-, autophagy-, ferroptosis-, and immune checkpoint-related genes in IBD single-cell sequencing dataset GSE164985. ( E – H ) Bubble plot of the expression of angiogenesis-, autophagy-, ferroptosis-, and immune checkpoint-related genes in NASH single-cell sequencing dataset GSE19048.

Immunofluorescence analysis of SWDEGs in human liver and colon samples

To verify the enhanced expression patterns of five SWDEGs in NASH and IBD patients, immunofluorescence analysis was conducted to examine the expression of CXCL9, ADAMTS5, GIMAP2, GRA, PRF1, and F4/80 (a marker for macrophages) in our collected human samples. Notably, the similar results we obtained from bioinformatic analysis were further observed and confirmed in the liver tissues with NASH and non-steatosis phenotype (Fig.  12 A–C) and colon tissues with IBD and non-IBD phenotype (Fig.  13 ).

Representative immunofluorescence staining images of five SWDEGs and F4/80 expression in the liver samples of human donors with non-steatosis phenotype and NASH phenotype. ( A ) The co-expression of GIMAP2 and PRF1. ( B ) The co-expression of ADAMTS5 and GRAP. ( C ) The co-expression of CXCL9 and F4/80.

Representative immunofluorescence staining images of five SWDEGs expression in the colon samples of human donors with non-IBD phenotype and IBD phenotype.

NASH and IBD are states of chronic inflammation, and the co-existence of the two diseases is becoming increasingly recognized, suggesting the potential presence of shared underlying pathogenic mechanisms and therapeutic targets between them. However, until now, the relationship between NASH and IBD remains unclear, and there is still a lack of effective medical treatments for the two diseases, underscoring the urgent need for the identification and validation of novel biomarkers capable of tracking NASH and IBD progression 40 , 41 , 42 . In this study, we aimed to identify shared signature genes between NASH and IBD for potential biomarker discovery and drug target identification.

Firstly, 116 shared differentially expressed genes (SDEGs) between NASH and IBD datasets were identified through bioinformatics analysis. Then, GO and KEGG pathway enrichment analyses of the SDEGs provided insight into the biological functions and signaling pathways shared by NASH and IBD. Notably, these SDEGs were significantly enriched in biological processes of the apoptotic process, cell death, defense response, cytokine response, and regulation of signaling pathways. Importantly, the enriched signaling pathways, including PI3K-Akt, Rap-1, PPAR, and Toll-like receptor (TLR) signaling, have been closely linked to the development and pathogenesis of NAFLD/NASH and IBD 43 , 44 , 45 , 46 , 47 , 48 . Particularly, the TLR signaling pathway emerged as a prominent signal, leading to the activation of the innate immune system, upregulation of inflammatory cytokines, and activation of downstream inflammatory pathways 49 , 50 , 51 . Similarly, PPAR signaling pathway plays an essential role in regulating gene expression involved in various cellular processes, including lipid metabolism, inflammatory and immune response, cell proliferation, and fibrosis, which has significant effects on the progression of both NASH and IBD 52 , 53 . Additionally, PPI network analysis identified 10 hub genes within the SDEGs, such as CD2, PRF1, CXCL11, IFI44, USP18, IFIT3, TRIM22, IFIT2, CXCL9, and GBP5, all up-regulated in NASH and IBD patients, underlining their importance in the pathogenesis of two diseases. These hub genes may serve as key regulators of biological processes and potential biomarkers for disease diagnosis and prognosis.

Furthermore, WGCNA was employed to identify co-expressed modules specifically associated with NASH and IBD. The categorization of these modules as IBD-related and NASH-related modules provides insights into the genes specifically linked to each disease. Notably, five co-expressed SWDEGs (CXCL9, GIMAP2, ADAMTS5, GRAP, and PRF1) derived from the intersection of SDEGs and gene modules with positive correlations hold potential as diagnostic biomarkers, with the capability to discriminate patients with NASH and IBD from healthy individuals. Among these, CXCL9 is a chemokine that plays a crucial role in recruiting specific immune cell populations (T cells and natural killer cells) to sites of inflammation, promoting chronic inflammation and immune-mediated tissue damage, which could be a biomarker for NASH and IBD 54 , 55 . GIMAP2 is a member of the GTPase family and involved in the regulation of apoptotic pathways, immune cell survival, and homeostasis 56 , however, the exact function of GIMAP2 in NASH and IBD is not fully understood. ADAMTS5 has been linked to inflammatory processes in various conditions, its activity could contribute to the release of pro-inflammatory mediators and cytokines, and exacerbate tissue inflammation 57 . Few studies have elucidated that the absence of ADAMTS5 could preserve liver integrity in diet-induced NASH models 58 , 59 . GRAP is an adaptor protein involved in Ras signaling 60 , it may participate in various signaling cascades triggered by cell surface receptors 61 , potentially influencing immune responses, inflammation, and cellular processes in the two diseases. PRF1 is primarily known for its role in the immune system, specifically in the cytotoxic function of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells 62 , 63 . Thus, PRF1-expressing CTLs and NK cells may be involved in immune-mediated cytotoxicity, targeting and killing infected or damaged cells in the condition of two diseases. Notably, CXCL9 and PRF1 were also hub SDEGs in the PPI network and interacted with each other by connecting with the same cytokines and chemokines, such as CXCL11, CXCL12, XCL1 and CCL5 (Supplementary Fig.  4 ). In addition, the high diagnostic potential of five SWDEGs for NASH and IBD has been validated across four datasets (GSE59071, GSE89632, GSE36807, and GSE164760) by using SVM and LR algorithms, indicating that these SWDEGs could serve as promising therapeutic targets for both diseases.

Moreover, the prediction of transcript factors (TFs) and miRNAs associated with the five SWDEGs through network analysis offered valuable insights into gene expression changes at the transcriptional level and potential regulatory networks that may modulate the expression of SWDEGs in NASH and IBD. From the TFs-SWDEGs network, two TFs (YY1 and FOXC1) showed a high interaction with four SWDEGs (CXCL9, GIMAP2, GRAP, and PRF1). YY1 is associated with inflammation and immune responses 64 , suggesting a potential role in modulating immune-related gene expression during IBD, and it also has been associated with the progression of NAFLD and NASH 65 . FOXC1 has been identified for its role in promoting the invasion and metastasis of HCC through the PI3K/Akt/HIF-1α signaling pathway 66 , and it emerges as a pivotal TF implicated in the pathogenesis of colitis-associated colon cancer (CAC) 67 . In the miRNAs-SWDEGs network, both mir-26a-5p and mir-26b-5p are involved in the suppression of colorectal cancer 68 . Particularly, mir-26a-5p plays a crucial role in regulating fatty acid and cholesterol homeostasis, protecting against the progression of NAFLD 69 . The mir-20a-5 serves as a key regulator in inflammation-driven liver fibrosis 70 , and it is also involved in the prevention of CD development by improving the intestinal epithelial barrier function 71 . Additionally, the other four key miRNAs in this network are mir-124-3p, mir-128-3p, mir-10b-5p, and mir-671-5p, they all play a potential role in immune regulation or affecting the infiltration of immune cells, as reported in previous studies 72 , 73 , 74 , 75 . The identified TFs and miRNAs may serve as key regulators of SWDEGs expression in NASH and IBD, presenting opportunities for targeted therapeutic interventions.

According to previous studies, the pathogenesis of both NASH and IBD was associated with autophagy, ferroptosis, angiogenesis, and immune response 76 , 77 , 78 , 79 , 80 , 81 , which are all key regulatory mechanisms in inflammation and immune-related diseases. A correlation analysis of five SWDEGs with FRGs, AURGs, ANRGs, and ICRGs was performed to unravel the underlying mechanisms of autophagy, ferroptosis, angiogenesis, and immune response in the two diseases. The results showed that the expression patterns of SWDEGs in NASH and IBD had distinct degrees of correlation with genes related to autophagy, ferroptosis, angiogenesis, and immune checkpoint, with stronger correlations observed in IBD datasets, suggesting the importance of these regulatory mechanisms in the pathogenesis of IBD. Additionally, three ICRGs (ADORA2A, CD226, and CD40) showed differently significant correlation with five SWDEGs in both diseases, which provided further insights into potential biological interactions and immune regulatory mechanisms underlying NASH and IBD.

Finally, two single-cell sequencing datasets from NASH and IBD samples were downloaded for single-cell annotation analysis. The annotated cell types were mainly B cells, T cells, NK cells, and monocytes in both diseases. These four cell types are all important components of the immune system and play distinct roles in the pathogenesis of NASH and IBD 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , in which FRGs, AURGs, ANRGs, and ICRGs were expressed to varying degrees. Notably, ICRGs were expressed in four cell types, whereas FRGs, AURGs, and ANRGs were mainly expressed in monocytes of two diseases. Monocytes can differentiate into macrophages and play a crucial role in IBD pathogenesis, contributing to tissue damage and inflammation by releasing inflammatory mediators and participating in immune responses 86 . A recent study indicated that monocytes were also involved in fibrogenesis and related to fibrosis progression in NASH 85 . Furthermore, Kotsiliti et al .  revealed that gastrointestinal B cells contributed to T cell–driven inflammation and aggravated hepatic fibrosis in mice and patients with NASH, providing a potential target in the gut-liver axis for NASH 83 . The annotation of different cell clusters and the expression levels of FRGs, AURGs, ANRGs, and ICRGs provided valuable information about the cellular heterogeneity and potential molecular pathways in the two diseases.

In general, our study provides novel insights into the connection of NASH and IBD through identification of co-expressed gene modules and analysis of regulatory networks involving five SWDEGs with diagnostic potential, and the elevated expression of these five SWDEGs in NASH and IBD patients was also confirmed by our immunofluorescence analysis. Notably, apart from CXCL9, the other four SWDEGs (GIMAP2, ADAMTS5, GRAP, and PRF1) have not been extensively explored their roles in the pathogenesis of NASH and IBD in previous studies, which could be new potential biomarkers and targets for therapeutic interventions of the two diseases. Moreover, the regulatory mechanisms involving autophagy, ferroptosis, angiogenesis, and immune responses were found to play pivotal roles in both diseases, particularly in IBD, suggesting that targeting these mechanisms could offer novel therapeutic strategies for both diseases.

However, some limitations in this study need to be addressed. Firstly, the functional roles of SWDEGs and their regulatory mechanisms need experimental validation. Secondly, although single-cell analysis provides an overview of gene expression in specific cell types, further investigations are needed to elucidate the functional relevance of specific cell subtypes in the pathogenesis of NASH and IBD.

In conclusion, this study represents the first attempt to examine shared signature genes and potential regulatory mechanisms between NASH and IBD. The findings showed significant implications for understanding the pathogenesis of two diseases and hold promise for the development of novel diagnostic biomarkers and therapeutic targets for NASH and IBD.

Data availability

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

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Acknowledgements

This work was supported by (1) National Natural Science Foundation of China (NSFC Grant No.: 81703527); (2) Science and Technology Research Program of Chongqing Education Commission (Grant No.: KJQN202301609-2) (3) School-level Research Program of Chongqing University of Education (Grant No.: 2023BSRC006).

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Zhong, Z., Xu, M., Ge, C. et al. Exploring shared molecular signatures and regulatory mechanisms in nonalcoholic steatohepatitis and inflammatory bowel disease using integrative bioinformatics analysis. Sci Rep 14 , 12085 (2024). https://doi.org/10.1038/s41598-024-62310-w

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Integration of case-based learning and three-dimensional printing for tetralogy of fallot instruction in clinical medical undergraduates: a randomized controlled trial

• Jian Zhao 1   na1 ,
• Xin Gong 1   na1 ,
• Jian Ding 1 ,
• Kepin Xiong 2 ,
• Kangle Zhuang 3 ,
• Rui Huang 1 ,
• Shu Li 4 &
• Huachun Miao 1  

BMC Medical Education volume  24 , Article number:  571 ( 2024 ) Cite this article

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Case-based learning (CBL) methods have gained prominence in medical education, proving especially effective for preclinical training in undergraduate medical education. Tetralogy of Fallot (TOF) is a congenital heart disease characterized by four malformations, presenting a challenge in medical education due to the complexity of its anatomical pathology. Three-dimensional printing (3DP), generating physical replicas from data, offers a valuable tool for illustrating intricate anatomical structures and spatial relationships in the classroom. This study explores the integration of 3DP with CBL teaching for clinical medical undergraduates.

Sixty senior clinical medical undergraduates were randomly assigned to the CBL group and the CBL-3DP group. Computed tomography imaging data from a typical TOF case were exported, processed, and utilized to create four TOF models with a color 3D printer. The CBL group employed CBL teaching methods, while the CBL-3DP group combined CBL with 3D-printed models. Post-class exams and questionnaires assessed the teaching effectiveness of both groups.

The CBL-3DP group exhibited improved performance in post-class examinations, particularly in pathological anatomy and TOF imaging data analysis ( P  < 0.05). Questionnaire responses from the CBL-3DP group indicated enhanced satisfaction with teaching mode, promotion of diagnostic skills, bolstering of self-assurance in managing TOF cases, and cultivation of critical thinking and clinical reasoning abilities ( P  < 0.05). These findings underscore the potential of 3D printed models to augment the effectiveness of CBL, aiding students in mastering instructional content and bolstering their interest and self-confidence in learning.

The fusion of CBL with 3D printing models is feasible and effective in TOF instruction to clinical medical undergraduates, and worthy of popularization and application in medical education, especially for courses involving intricate anatomical components.

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Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease(CHD) [ 1 ]. Characterized by four structural anomalies: ventricular septal defect (VSD), pulmonary stenosis (PS), right ventricular hypertrophy (RVH), and overriding aorta (OA), TOF is a focal point and challenge in medical education. Understanding anatomical spatial structures is pivotal for learning and mastering TOF [ 2 ]. Given the constraints of course duration, medical school educators aim to provide students with a comprehensive and intuitive understanding of the disease within a limited timeframe [ 3 ].

The case-based learning (CBL) teaching model incorporates a case-based instructional approach that emphasizes typical clinical cases as a guide in student-centered and teacher-facilitated group discussions [ 4 ]. The CBL instructional methods have garnered widespread attention in medical education as they are particularly appropriate for preclinical training in undergraduate medical education [ 5 , 6 ]. The collection of case data, including medical records and examination results, is essential for case construction [ 7 ]. The anatomical and hemodynamic consequences of TOF can be determined using ultrasonography, computed tomography (CT), and magnetic resonance imaging techniques. However, understanding the anatomical structures from imaging data is a slow and challenging psychological reconstruction process for undergraduate medical students [ 8 ]. Three-dimensional (3D) visualization is valuable for depicting anatomical structures [ 9 ]. 3D printing (3DP), which creates physical replicas based on data, facilitates the demonstration of complex anatomical structures and spatial relationships in the classroom [ 10 ].

During the classroom session, 3D-printed models offer a convenient means for hands-on demonstration and communication, similar to facing a patient, enhancing the efficiency and specificity of intra-team communication and discussion [ 11 ]. In this study, we printed TOF models based on case imaging data, integrated them into CBL teaching, and assessed the effectiveness of classroom instruction.

Research participants

The study employed a prospective, randomized controlled design which received approval from the institutional ethics committee. Senior undergraduate students majoring in clinical medicine at Wannan Medical College were recruited for participation based on predefined inclusion criteria. The researchers implemented recruitment according to the recruitment criteria by contacting the class leaders of the target classes they had previously taught. Notably, these students were in their third year of medical education, with anticipation of progressing to clinical courses in the fourth year, encompassing Internal Medicine, Surgery, Obstetrics, Gynecology, and Pediatrics. Inclusion criteria for participants encompassed the following: (1) proficient communication and comprehension abilities, (2) consistent attendance without absenteeism or truancy, (3) absence of failing grades in prior examinations, and (4) capability to conscientiously fulfill assigned learning tasks. Exclusion criteria were (1) absence from lectures, (2) failure to complete pre-and post-tests, and (3) inadequate completion of questionnaires. For their participation in the study, Students were provided access to the e-book “Localized Anatomy,” authored by the investigators, as an incentive for their participation. Voluntary and anonymous participation was emphasized, with participants retaining the right to withdraw from the study at any time without providing a reason.

The study was conducted between May 1st, 2023, and June 30, 2023, from recruitment to completion of data collection. Drawing upon insights gained from a previous analogous investigation which yielded an effect size of 0.95 [ 10 ]. Sample size was computed, guided by a statistical consultant, with the aim of 0.85 power value, predicated on an effect size of 0.8 and a margin of error set at 0.05. A minimum of 30 participants per group was calculated using G*Power software (latest ver. 3.1.9.7; Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany), resulting in the recruitment of a total of 60 undergraduate students. Each participant was assigned an identification number, with codes placed in boxes. Codes drawn from the boxes determined allocation to either the CBL group or the CBL-3DP group. Subsequently, participants were randomly assigned to either the CBL group, receiving instruction utilizing the CBL methodology, or the CBL-3DP group, which received instruction integrating both CBL and 3D Printed models.

Printing of TOF models

Figure  1 A shows the printing flowchart of the TOF models. A typical TOF case was collected from the Yijishan Hospital of Wannan Medical College. The CT angiography imaging data of the case was exported. Mimics Research 20.0 software (Mimics Innovation Suite version 20, Materialize, Belgium) was used for data processing. The cardiovascular module of the CT-Heart tool was employed to adjust the threshold range, independently obtain the cardiac chambers and vessels, post-process the chambers and vessels to generate a hollow blood pool, and merge it with the myocardial volume to construct a complete heart model. The file was imported into Magics 24.0 software (version 24.0; Materialize, Belgium) for correction using the Shell tool page. After repairs, the model entered the smoothing page, where tools such as triangular surface simplification, local smoothing, refinement and smoothing, subdivision of components, and mesh painting were utilized to achieve varying degrees of smoothness. Finally, optimized data were obtained and exported as stereolithography (STL) files. An experienced cardiothoracic surgeon validated the anatomical accuracy of the digital model.

The STL files were imported into a 3D printer (J401Pro; Sailner 3D Technology, China) for model printing. This printer can produce full-color medical models using different materials. The models were fabricated using two distinct materials: rigid and flexible. Both materials are suitable for the observational discussion of the teaching objectives outlined in our study. From the perspective of observing pathological changes in the TOF, there is no significant difference between the two materials.

Experimental flow chart of this study. A TOF model printing flow chart. B The instructional framework

Teaching implementation

Figure  1 B illustrates the instructional framework employed in this study. One week preceding the class session, all the students were tasked with a 30-minute self-study session, focusing on the theoretical content related to TOF as outlined in the Pediatrics and Surgery textbooks, along with a review of pertinent academic literature. Both groups received co-supervision from two basic medicine lecturers boasting over a decade of teaching experience, alongside a senior cardiothoracic surgeon. Teaching conditions remained consistent across groups, encompassing uniform assessment criteria and adherence to predefined teaching time frames, all conducted in a Project-Based Learning (PBL) classroom at Wannan Medical College. Additionally, a pre-course examination was administered to gauge students’ preparedness for self-study.

In adherence to the curriculum guidelines, the teaching objectives aimed to empower students to master TOF’s clinical manifestations, diagnostic modalities, and differential diagnoses, while acquainting them with treatment principles and surgical methodologies. Additionally, the objectives sought to cultivate students’ clinical reasoning abilities and problem-solving skills. the duration of instruction for the TOF theory session was standardized to 25 min. The didactic content was integrated with the TOF case study to construct a coherent pedagogical structure.

During the instructional session, both groups underwent teaching utilizing the CBL methodology. Clinical manifestations and case details of TOF cases were presented to stimulate students’ interest and curiosity. Subsequently, the theory of TOF, including its etiology, pathogenesis, pathologic anatomy, clinical manifestations, diagnostic methods, and therapeutic interventions, was briefly elucidated. Emphasis was then placed on the case, wherein selected typical TOF cases were explained, guiding students in analysis and discussion. Students were organized into four teams under the instructors’ supervision, fostering cooperative learning and communication, thereby deepening their understanding of the disease through continuous inquiry and exploration (Fig.  2 L). In the routinely equipped PBL classroom with standard heart models (Fig.  2 J, K), all students had prior exposure to human anatomy and were familiar with these models. Both groups were provided with four standard heart models for reference, while the CBL-3DP group received additional four 3D-printed models depicting TOF anomalies, enriching their learning experience (Fig.  2 D, G). After the lesson, summarization, and feedback sessions were conducted to consolidate group discussions’ outcomes, evaluate teaching effectiveness, and assess learning outcomes.

Heart models utilized in instructional sessions. A External perspective of 3D digital models. B, C Cross-sectional views following trans-septal sagittal dissection of the 3D digital model (PS: Pulmonary Stenosis; OA: Overriding Aorta; VSD: Ventricular Septal Defect; RVH: Right Ventricular Hypertrophy). D External depiction of rigid 3D printed model. E, F Sagittal sections of the rigid 3D printed model. G External portrayal of flexible 3D printed model. H, I Sagittal sections of the flexible 3D printed model. J, K The normal heart model employed in the instruction of the CBL group. L Ongoing classroom session

Teaching effectiveness assessment

Following the instructional session, participants from the two groups underwent a theoretical examination to assess their comprehension of the taught material. This assessment covered domains such as pathological anatomy, clinical manifestations, imaging data interpretation, diagnosis, and treatment relevant to TOF. Additionally, structured questionnaires were administered to evaluate the efficacy of the pedagogical approach employed. The questionnaire consisted of six questions designed to gauge participants’ understanding of the teaching content, enhancement of diagnostic skills, cultivation of critical thinking and clinical reasoning abilities, bolstering of confidence in managing TOF cases, satisfaction with the teaching mode, and satisfaction with the CBL methodology.

The questionnaire employed a 5-point Likert scale to gauge responses, with 5 indicating “strongly satisfied/agree,” 4 for “satisfied/agree,” 3 denoting “neutral,” 2 reflecting “dissatisfied/disagree,” and 1 indicating “strongly dissatisfied/disagree.” It comprised six questions, with the initial two probing participants’ knowledge acquisition, questions 3 and 4 exploring satisfaction regarding enhanced competence, and the final two assessing satisfaction with teaching methods and modes. Additionally, participants were encouraged to provide suggestions at the end of the questionnaire. To ensure the questionnaire’s validity, five esteemed lecturers in basic medical sciences with more than 10 years of experience verified its content and assessed its Content Validity Ratio and Content Validity Index to ensure alignment with the study’s objectives.

Statistical analysis

Statistical analyses were conducted utilizing GraphPad Prism 9.0 software. Aggregate score data for both groups were presented as mean ± standard deviation (x ± s). The gender comparisons were analyzed with the chi-square (χ2) test, while the other variables were compared using the Mann-Whitney U test. The threshold for determining statistical significance was set at P  < 0.05.

Three-dimensional printing models

After configuring the structural colors of each component (Fig.  2 A, B, C), we printed four color TOF models using both rigid and flexible materials, resulting in four life-sized TOF models. Two color TOF models were created using rigid materials (Fig.  2 D, E, F). These models, exhibiting resistance to deformation, and with a firm texture, smooth and glossy surface, and good transparency, allowing visibility of the internal structures, were deemed conducive to teaching and observation. We also fabricated two color TOF models using flexible materials (Fig.  2 G, H, I), characterized by soft texture, opacity, and deformability, allowing for easy manipulation and cutting. It has potential utility beyond observational purposes. It can serve as a valuable tool for simulating surgical interventions and may be employed to create tomographic anatomical specimens. In this study, both material models were suitable for observation in the classroom. The participants were able to discern the four pathological changes characteristic of TOF from surface examination or cross-sectional analysis.

Baseline characteristics of the students

In total, 60 students were included in this study. The CBL group comprised 30 students (14 males and 16 females), with an average age of (21.20 ± 0.76) years. The CBL-3DP group consisted of 30 students (17 males and 13 females) with an average age of 20.96 years. All the students completed the study procedures. There were no significant differences in age, sex ratio, or pre-class exam scores between the two groups ( P  > 0.05), indicating that the baseline scores between the two groups were comparable (Table  1 ).

Theoretical examination results

All students completed the research procedures as planned. The post-class theoretical examination encompassed assessment of pathological anatomy, clinical presentations, imaging data interpretation, diagnosis, and treatment pertinent to TOF. Notably, no statistically significant disparities were observed in the scores on clinical manifestations, diagnosis and treatment components between the cohorts, as delineated in Table  2 . Conversely, discernible distinctions were evident whereby the CBL-3DP group outperformed the CBL group notably in pathological anatomy, imaging data interpretation, and overall aggregate scores ( P  < 0.05).

Results of the questionnaires

All the 60 participants submitted the questionnaire. Comparing the CBL and CBL-3DP groups, the scores from the CBL-3DP group showed significant improvements in many areas. This included satisfaction with the teaching mode, promotion of diagnostic skills, bolstering of self-assurance in managing TOF cases, and cultivation of critical thinking and clinical reasoning abilities (Fig.  3 B, C, D, E). All of which improved significantly ( P  < 0.05 for the first aspects and P  < 0.01 for the rest). However, the two groups were not comparable ( P  > 0.05) in terms of understanding of the teaching content and Satisfaction with the CBL methodology (Fig.  3 A, F).

Upon completion of the questionnaires, participants were invited to proffer recommendations. Notably, in the CBL group, seven students expressed challenges in comprehending TOF and indicated a need for additional time for consolidation to enhance understanding. Conversely, within the CBL-3DP group, twelve students advocated for the augmentation of model repertoire and the expansion of disease-related data collection to bolster pedagogical efficacy across other didactic domains.

Five-point Likert scores of students’ attitudes in CBL ( n  = 30) and CBL-3DP ( n  = 30) groups. A Understanding of teaching content. B Promotion of diagnostic skills. C Cultivation of critical thinking and clinical reasoning abilities. D Bolstering of self-assurance in managing TOF cases. E Satisfaction with the teaching mode. F Satisfaction with the CBL methodology. ns No significant difference, * p  < 0.05, ** p  < 0.01, *** p  < 0.001

TOF presents a significant challenge in clinical practice, necessitating a comprehensive understanding for effective diagnosis and treatment [ 12 ]. Traditional teaching methods in medical schools have relied on conventional resources such as textbooks, 2D illustrations, cadaver dissections, and radiographic materials to impart knowledge about complex conditions like TOF [ 13 ]. However, the limitations of these methods in fully engaging students and bridging the gap between theoretical knowledge and practical application have prompted a need for innovative instructional approaches.

CBL has emerged as a valuable tool in medical education, offering students opportunities to engage with authentic clinical cases through group discussions and inquiry-based learning [ 14 ]. By actively involving students in problem-solving and decision-making processes, CBL facilitates the application of theoretical knowledge to real-world scenarios, thus better-preparing students for future clinical practice [ 15 ]. Our investigation revealed that both groups of students exhibited comparable levels of satisfaction with the CBL methodology, devoid of discernible disparities.

CHD presents a formidable challenge due to the intricate nature of anatomical anomalies, the diverse spectrum of conditions, and individual variations [ 16 ]. Utilizing 3D-printed physical models, derived from patient imaging data, can significantly enhance comprehension of complex anatomical structures [ 17 ]. These models have proven invaluable in guiding surgical planning, providing training for junior or inexperienced pediatric residents, and educating healthcare professionals and parents of patients [ 18 ]. Studies indicate that as much as 50% of pediatric surgical decisions can be influenced by the insights gained from 3D printed models [ 19 ]. By providing tangible, anatomically accurate models, 3D printing offers a unique opportunity for people to visualize complex structures and enhance their understanding of anatomical intricacies. Our study utilized full-color, to-scale 3D printed models to illustrate the structural abnormalities associated with TOF, thereby enriching classroom sessions and facilitating a deeper comprehension of the condition.

Comparative analysis between the CBL-3DP group and the CBL group revealed significant improvements in post-test performance, particularly in pathological anatomy and imaging data interpretation. Additionally, questionnaire responses indicated higher levels of satisfaction and confidence among students in the CBL-3DP group, highlighting the positive impact of incorporating 3D printed models into the learning environment, improving the effectiveness of CBL classroom instruction. Despite the merits, our study has limitations. Primarily, participants were exclusively drawn from the same grade level within a single college, possibly engendering bias owing to shared learning backgrounds. Future research could further strengthen these findings by expanding the sample size and including long-term follow-up to assess the retention of knowledge and skills. Additionally, the influence of the 3D models depicting a normal heart on the learning process and its potential to introduce bias into the results warrants consideration, highlighting a need for scrutiny in subsequent studies.

As medical science continues to advance, the need for effective teaching methods becomes increasingly paramount. Our study underscores the potential of combining active learning approaches like CBL with innovative technologies such as 3D printing to enhance teaching effectiveness, improve knowledge acquisition, and foster students’ confidence and enthusiasm in pursuing clinical careers. Moving forward, further research and integration of such methodologies are essential for meeting the evolving demands of medical education, especially in areas involving complex anatomical understanding.

Conclusions

Integrating 3D-printed models with the CBL method is feasible and effective in TOF instruction. The demonstrated success of this method warrants broad implementation in medical education, particularly for complex anatomical topics.

Data availability

All data supporting the conclusions of this research are available upon reasonable request from the corresponding author.

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Acknowledgements

We extend our sincere appreciation to the instructors and students whose invaluable participated in this study.

This paper received support from the Education Department of Anhui Province, China (Grant Numbers 2022jyxm1693, 2022jyxm1694, 2022xskc103, 2018jyxm1280).

Author information

Jian Zhao and Xin Gong are joint first authors.

Authors and Affiliations

Department of Human Anatomy, Wannan Medical College, No.22 West Wenchang Road, Wuhu, 241002, China

Jian Zhao, Xin Gong, Jian Ding, Rui Huang & Huachun Miao

Department of Cardio-Thoracic Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China

Kepin Xiong

Zhuhai Sailner 3D Technology Co., Ltd., Zhuhai, China

Kangle Zhuang

School of Basic Medical Sciences, Wannan Medical College, Wuhu, China

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Contributions

Jian Zhao and Huachun Miao designed the research. Jian Zhao, Xin Gong, Jian Ding, Kepin Xiong designed the tests and questionnaires. Kangle Zhuang processed the imaging data and printed the models. Xing Gong and Kepin Xiong implemented the teaching. Jian Zhao and Rui Huang collected the data and performed the statistical analysis. Jian Zhao and Huachun Miao prepared the manuscript. Shu Li and Huachun Miao revised the manuscript. Shu Li provided the Funding acquisition. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Shu Li or Huachun Miao .

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This investigation received ethical approval from the Ethical Committee of School of Basic Medical Sciences, Wannan Medical College (ECBMSWMC2022-1-12). All methodologies adhered strictly to established protocols and guidelines. Written informed consent was obtained from the study participants to take part in the study.

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Zhao, J., Gong, X., Ding, J. et al. Integration of case-based learning and three-dimensional printing for tetralogy of fallot instruction in clinical medical undergraduates: a randomized controlled trial. BMC Med Educ 24 , 571 (2024). https://doi.org/10.1186/s12909-024-05583-z

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Received : 03 March 2024

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Published : 24 May 2024

DOI : https://doi.org/10.1186/s12909-024-05583-z

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