A 12-week-old man infant presented to the emergency department with a 4-day history of fever and diarrhea with bright green stools, and a 24-hour history of nonbilious vomiting, lethargy and irritability. He was born to parents of Vietnamese origin at 36-weeks gestation via normal vaginal delivery with a birth weight of 1.8 kg. Serial antenatal ultrasounds for low fetal weight did not reveal any abnormalities. Postnatally, he was admitted to the special care nursery for 2 weeks to monitor growth. Following discharge, he was exclusively breast-fed, weight was tracking along the second percentile, and he had remained well until 4 days before presentation. He had received all routine 8-week immunizations.
On examination, he was irritable, with temperature of 38.5°C, heart rate of 230 beats/min, oxygen saturation of 98% in room air, respiratory rate of 45 breaths/min with mildly increased work of breathing, and blood pressure of 110/80 mm Hg. His fontanelle was normal, pupils were reactive, and he had no nuchal rigidity. His chest was clear and heart sounds were normal with no murmurs. He had marked abdominal distension without guarding or peritonism and normal genital examination and anatomy. He had peripheral mottling with delayed central capillary return but otherwise no rash and normal mucous membranes. He had no lymphadenopathy.
The patient was given 20 mL/kg initial fluid resuscitation and was admitted to the pediatric intensive care unit for inotropic support and intubation due to persistent tachycardia. His baseline laboratory findings revealed microcytic anemia with hemoglobin of 67 g/L (95–135 g/L), mean corpuscular volume 72 (75–100 fL), normal platelet count of 295 × 109/L (150–400 × 109/L), and low total white cell count of 5.1 × 109/L (6.0–18.0 × 109/L) with 39% lymphocytes, 31% neutrophils, 15% monocytes, 13% metamyelocytes and 2% myelocytes. Inflammatory markers were elevated with C-reactive protein (CRP) of 147 mg/L (<8 mg/L) and procalcitonin of 7.35 (<0.06 µg/L). Urea, creatinine and electrolytes were normal, and liver function tests show mildly elevated gamma-glutamyl transferase of 86 IU/L (0–40 IU/L) and alanine aminotransferase (ALT) of 21 IU/L (<50 IU/L), with low albumin of 26 g/L (29–45 g/L). Urine microscopy showed white blood cell count of 400 × 106/L. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) polymerase chain reaction (PCR) on naso- and oropharyngeal swabs were both negative. Combined abdomen and chest radiograph showed a normal thymic shadow, patchy atelectasis in the left lower lobe, an abnormal bowel gas pattern with a markedly dilated loop of bowel in the right flank extending to the mid-abdomen (Fig. 1). There was no gas in the descending colon or rectosigmoid, and no evidence of perforation, raising concern for infectious colitis. Abdominal ultrasound on day 1 of admission showed bilateral slightly echogenic renal parenchyma, mild prominence of the renal pelvis on the left side and no renal abscess.
He was empirically treated with ceftriaxone, flucloxacillin and metronidazole to cover for presumed Gram-negative sepsis with urinary tract or abdominal focus and was subsequently escalated to meropenem when he developed the inotrope requirement.
On day 2 of admission, blood, urine, and stool cultures remained negative. Cerebrospinal fluid (CSF) showed a total WBC of 9 × 106/L (34% polymorphs, 66% lymphocytes), protein of 0.59 g/L (0.20–0.40), glucose of 4.2 mmol/L (2.8–4.0) and no organisms on Gram stain. Pneumocystis jiroveci (PJP) PCR of a tracheal aspirate sample was negative.
CMV PCR on bronchoalveolar lavage (BAL) was positive, as was plasma CMV PCR (8 × 103 copies/mL). Enterovirus PCR on CSF and stool, extended respiratory PCR (includes: influenza A and B, Respiratory syncytial virus, Human parainfluenza virus type 1–4, rhinovirus, seasonal coronavirus, parechovirus, enterovirus, adenovirus, human metapneumovirus, and mycoplasma pneumoniae and bordetella pertussis) and two further SARS-CoV-2 PCR tests on nasopharyngeal aspirate were also negative. Initial immunology investigations including immunoglobulins, lymphocyte subsets and naïve and memory T-cells were normal for age, and HIV serology was negative. Whilst awaiting further immunologic testing and given the presence of colitis in the absence of other positive culture results, empirical ganciclovir was commenced on day 3 of admission.
Further evaluation on day 4 of admission was performed due to persistent daily fevers and progression of abdominal distension. A repeat radiograph showed increased caliber of the single dilated bowel loop. Repeat abdominal ultrasound revealed a new complex and septated fluid collection around bowel loops in the right upper quadrant and flank, measuring up to 3 cm in depth, with some tracking into the gallbladder fossa. Liver enzymes continued to be normal, but hypoalbuminemia (22 g/L) and inflammatory markers (neutrophil count of 14.7 × 109/L and procalcitonin of 16 µg/L) worsened.
A diagnostic laparoscopy on day 4 of admission revealed widespread clear serous fluid throughout the abdomen, edematous omentum in the right upper quadrant, abnormal appearance of liver with generalized inflammation, and normal gall bladder with no purulent fluid or collection evident. Peritoneal fluid obtained at the time of laparoscopy revealed no polymorphs, with lymphocyte count of 710 × 106/L (normal range 0–5 × 106/L) and red cell count of 102,000 × 106/L, and negative bacterial culture.
Due to ongoing fevers and rising inflammatory markers, another test was performed which revealed the diagnosis.
For denouement see p. 1136.
Continued from P. 1135.
On day 7 of admission, despite broad-spectrum antibiotics, daily fevers persisted (day 10 of fever). The procalcitonin rose to 71 µg/L, and blood and urine cultures remained negative. Given the patient’s age and prolonged unexplained fever, Kawasaki disease (KD) was considered. The patient met 4 biochemical criteria for incomplete KD: low albumin, anemia, sterile pyuria and elevated total white cell count on day 3 of admission.1 His echocardiogram (ECHO) revealed normal biventricular size and systolic function with diffusely dilated left coronary arteries, including left main (2.7 mm with Z-score +4.2), left anterior descending (2 mm with Z-score +3.2) and left circumflex (1.8 mm with Z-score +2.7), with no obvious aneurysm, and ectatic proximal right coronary artery (1.5 mm with Z-score +1.5).
The patient was given intravenous immunoglobulin (IVIG) (2 g/kg), aspirin (5 mg/kg) and methylprednisolone (1 mg/kg every 12 hours for 3 days), with subsequent oral prednisolone wean over 14 days. The patient had a dramatic clinical response within 12 hours of completion of IVIG infusion; he became afebrile and less irritable, and abdominal distension improved. He was able to tolerate full feeds on day 2 post-IVIG infusion. Repeat ECHO 5 days after IVIG showed improved Z-scores throughout right coronary artery 1.4 mm (Z score +0.75), left main coronary artery 1.7 mm (Z score +1.03), left anterior descending 1.6 mm (Z score +1.6) and left circumflex 1 mm (Z score 0.07).
SARS-CoV-2 acute (retrospectively added to serum from day 6 of illness) and convalescent (50 days post-IVIG) serologies by immunofluorescent antibody testing were subsequently negative.
KD is an acute childhood vasculitis associated with coronary artery aneurysms and is the leading cause of acquired heart disease in children in many countries.1 In the United States, the mean age at presentation is 3 years.2 Cases of “complete KD” require ≥4 days of fever plus at least 4 diagnostic clinical features: polymorphous rash, extremity changes, nonpurulent conjunctivitis, mucous membrane changes and lymphadenopathy.1
The disease in infants <6 months is well-recognized and has been reported in many countries, but the frequency varies according to region. Over an 8-year period, infants <6 months represented 17% (20/120) of patients presenting with KD in one tertiary hospital in Taiwan,3 and in a larger cohort in Toronto, infants <6 months represented 4% (61/1374) of KD diagnoses over a 17-year period.4 In contrast to older children, infants <6 months tend to present with “incomplete” KD, manifest fewer diagnostic clinical features, and also have a higher incidence of severe coronary artery abnormalities3,4 even when diagnosis is made within the first 10 days of illness.5
In any child with suspected incomplete KD, especially infants <6 months with prolonged or unexplained fever, laboratory criteria should be evaluated and ECHO should be considered early, in accordance with the 2017 American Heart Association guidelines for evaluation of suspected incomplete KD.1 A diagnosis of incomplete KD may be made in infants with fever ≥7 days without other explanation, raised ESR ≥ 40 mm/h or CRP ≥ 3.0 mg/dL, and positive ECHO findings, without meeting other biochemical criteria (anemia for age, thrombocytosis, elevated white cell coun ≥15,000/mm3, elevated ALT and sterile pyuria).1
Our patient presented with features of shock, including tachycardia, poor peripheral perfusion and inotrope requirement, consistent with KD shock syndrome (KDSS). Historically, this manifestation of KD has been rare in children. In their prospective series of consecutive KD patients over a 4-year period, Kanegaye and colleagues reported that only 13 of 187 (7%) children presented with KDSS with a median age of 2.8 years (interquartile range 2.2–5.9 years).6 KDSS is distinguished from classical KD by the presence of systolic hypotension for age or clinical signs of poor perfusion.6 Patients require fluid resuscitation with or without vasoactive support and even though rare in KD, consumptive coagulopathy with thrombocytopenia may also be a feature.6 In practice, it can be challenging to distinguish KSS from septic or toxic shock syndrome (TSS) as several clinical features overlap.7 Maintaining clinical suspicion of KDSS in “culture negative sepsis” or “TSS-like” presentations is key to reducing time to diagnosis and treatment. This is essential in KDSS as it is thought to be associated with a higher incidence of coronary artery abnormalities and IVIG resistance compared with classical presentation.8
Intestinal pseudo-obstruction is also infrequent in KD, noted in 7/310 (2.2%) of patients with KD in a historical Japanese cohort.9 Overall 49 cases of intestinal involvement with KD have been reported in the literature between 1979 and 2017,10 with the mean age of 3.29 years (SD 2.59); 38 of these cases had imaging findings consistent with pseudo-obstruction. The most commonly associated symptoms were fever (82%), abdominal pain (69%), vomiting (49%) and diarrhea (29%), with other signs of KD appearing after abdominal symptoms.10 In 29% of cases, similar to our case, only abdominal symptoms were present. Coronary artery aneurysms were noted at the time of diagnosis in 21 of 49 cases, and in 7 of these, the abnormalities persisted.10 Children with KD presenting with an acute abdomen often undergo abdominal surgery, at least an exploratory laparotomy, before receiving the KD diagnosis and effective medical treatment.7 This delay may contribute to the high rate of coronary artery aneurysms noted in reports of KD with intestinal pseudo-obstruction.9 To avoid diagnostic delay and unwarranted invasive procedures, KD should be considered in patients presenting with fever and intestinal pseudo-obstruction without definable cause.11
This patient presented 2 weeks after the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic, when there were 2793 cases of COVID-19 in Australia. Since then, there have been emerging international reports of a KD-like syndrome following or associated with SARS-CoV-2, termed Pediatric Inflammatory Multi-system Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS) or Multisystem Inflammatory Syndrome in Children (MIS-C).12–15 Early in the pandemic, these cases were labeled as KD when in reality, they may have been cases of PIMS-TS or MIS-C. Verdoni et al described 10 patients with KD in Bergamo between February 18 and April 20, 2020 (peak of the COVID-19 pandemic in this province), 50% of whom presented with shock16 and there have been similar reports in Paris and South London.17,18 Because of their overlapping clinical features, clinicians should consider testing for SARS-CoV-2 in patients with complete or incomplete KD, with multiple PCR tests and pre-treatment serology, and should also consider storing pre-treatment serum and plasma in addition to reporting suspected or confirmed cases to the WHO Global COVID-19 Clinical Data Platform.14 While our case fit many features of the preliminary case definition of PIMS-TS,14 multiple PCR tests as well as acute and convalescent serologies for SARS-CoV-2 were negative.
We present a case of incomplete KD in a 12-week-old male infant presenting as KDSS with intestinal pseudo-obstruction. KD in a 12-week-old infant is uncommon, and KDSS and intestinal pseudo-obstruction are both rare associations. It is important to maintain high diagnostic suspicion for KD and its uncommon variants, especially in young infants who lack classical KD features.
1. 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; and 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. Circulation. 2017;135:e927–e999.
2. 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;29:483–488.
3. Chang FY, Hwang B, Chen SJ, et al. Characteristics of Kawasaki disease in infants younger than six months of age. Pediatr Infect Dis J. 2006;25:241–244.
4. Manlhiot C, Yeung RS, Clarizia NA, et al. Kawasaki disease at the extremes of the age spectrum. Pediatrics. 2009;124:e410–e415.
5. Cameron SA, Carr M, Pahl E, et al. Coronary artery aneurysms are more severe in infants than in older children with Kawasaki disease. Arch Dis Child. 2019;104:451–455.
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8. Yim D, Ramsay J, Kothari D, et al. Coronary artery dilatation in toxic shock-like syndrome: the Kawasaki disease shock syndrome. Pediatr Cardiol. 2010;31:1232–1235.
9. Miyake T, Kawamori J, Yoshida T, et al. Small bowel pseudo-obstruction in Kawasaki disease. Pediatr Radiol. 1987;17:383–386.
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12. Health RCoPaC. Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. 2020; Available at: https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf
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14. WHO. Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. 2020. Available at: https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19
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15. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324:259–269.
16. 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;395:1771–1778.
17. Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395:1607–1608.
18. Toubiana J, Poirault C, Corsia A, et al. Outbreak of Kawasaki disease in children during COVID-19 pandemic: a prospective observational study in Paris, France. BMJ. 2020;369:m2094.