Giovanni Battista Calabri

Macrophage activation syndrome/hemophagocytic lymphohistiocytosis and Kawasaki disease

To the Editor: We read with interest the two recent reports on Hemophagocytic Lymphohistiocytosis (HLH) associated with Kawasaki disease (KD) [1,2]. Both are inflammatory conditions and clinical features can overlap, to the point that in one of the two reported cases [1] the diagnosis was uncertain. In patients with rheumatologic disorders, particularly systemic onset Juvenile Idiopathic Arthritis, macrophage activation syndrome (MAS) is sometimes seen. MAS is a systemic inflammatory disorder caused by uncontrolled histiocytic proliferation, hemophagocytosis, activation of macrophages and inflammatory cytokine up-regulation. It can be secondary to several rheumatic diseases, including Kawasaki disease [3–5]. It is thought that reactive HLH and MAS may represent the same disorder [6–8]. We recently diagnosed with KD a patient who at the onset of disease also presented findings suggestive of MAS and would like to add our recent experience. A 20-month-old female presented with a history of fever for 6 days unresponsive to antibiotic treatment. Upon admission she was pale and restless; clinical evaluation showed bilateral conjunctivitis, a diffuse maculopapular rash, oral mucosal changes, and edema of the extremities. Laboratory investigations showed elevation of C-reactive protein (16.3 mg/L) but normal erythrocyte sedimentation rate, hemoglobin of 10.6 g/dl, platelet count 59,000/ l, hyponatremia (133 mEq/L), and elevated AST/ALT (185 and 64 UI/L, respectively). Infections were ruled out. Abdominal ultrasound showed splenomegaly, an abdominal effusion and hydrops of the gallbladder, while echocardiography showed abnormalities of all coronary arteries (with brightness of the left and dilatation of the anterior and right vessels) and a pericardial effusion. Diagnosis of KD was made and treatment with IVIG (2 g/kg) performed. Despite treatment she remained febrile and irritable. Laboratory tests showed further increase of C-reactive protein and liver function tests, hypoalbunimenia, persistent thrombocytopenia, as well as increased levels of d-dimers (2076 mg/dl, n.v. 50–250 ng/ml), lactate dehydrogenase, cholesterol, triglycerides, and ferritin. A second course of IVIG was then administered, with resolution of fever and reduction of laboratory abnormalities and coronary dilatations. The child was discharged 7 days after admission and was subsequently followed, up to complete recovery. Although bone marrow aspiration showing hemophagocytosis was not performed, even if she did not fulfill classical HLH criteria, on the basis of clinical and laboratory findings we diagnosed MAS [9]. Apart from nomenclature issues, we think that a practical point is represented by treatment decisions, in that MAS is usually treated with high steroids +/− cyclosporine only, while HLH is initially treated with more potent medications including etoposide [1]. At least some secondary (reactive) cases appear not to need chemotherapy but can be treated with standard high-dose immunosuppression only [10]. In conclusion, KD can present with criteria that are not included in the official definition, and therefore, can be atypical and/or incomplete; among those non-classic criteria, MAS/HLH can be seen [5].

Recurrent pericarditis in children and adolescents: a multicentre cohort study

Objective Limited data are available about recurrent pericarditis in children. We sought to explore contemporary causes, characteristics, therapies and outcomes of recurrent pericarditis in paediatric patients. Methods A multicentre (eight sites) cohort study of 110 consecutive cases of paediatric patients with at least two recurrences of pericarditis over an 11-year period (2000–2010) [median 13 years, interquartile range (IQR) 5, 69 boys]. Results Recurrences were idiopathic or viral in 89.1% of cases, followed by postpericardiotomy syndrome (9.1%) and familial Mediterranean fever (0.9%). Recurrent pericarditis was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) in 80.9% of cases, corticosteroids in 64.8% and colchicine was added in 61.8%. Immunosuppressive therapies were administered in 15.5% of patients after subsequent recurrences. After a median follow-up of 60th months, 528 subsequent recurrences were recorded (median 3, range 2–25). Corticosteroid-treated patients experienced more recurrences (standardized risk of recurrence per 100 person-years was 93.2 for patients treated with corticosteroids and 45.2 for those without), side effects and disease-related hospitalizations (for all P < 0.05). Adjuvant therapy with colchicine was associated with a decrease in the risk of recurrence from 3.74 per year before initiation of colchicine to 1.37 per year after (P < 0.05). Anakinra therapy (n = 12) was associated with a drop in the number of recurrences from 4.29 per year before to 0.14 per year after (P < 0.05). Transient constrictive pericarditis developed in 2.7% of patients. Conclusion Recurrent pericarditis has an overall favourable prognosis in children, although it may require frequent readmissions and seriously affect the quality of life, especially in patients treated with corticosteroids. Colchicine or anakinra therapies were associated with significant decrease in the risk of recurrence.

Prenatal diagnosis and postnatal outcome in patients with absent pulmonary valve syndrome not associated with tetralogy of Fallot: report of one case and review of the literature.

Echocardiographic diagnosis of absent pulmonary valve syndrome and muscular ventricular septal defect was made in a fetus of gestational age 25 weeks referred for marked dilation of the right ventricle at obstetric ultrasound examination. Delivery was planned in a tertiary-level center. The neonate became severely symptomatic for respiratory distress and heart failure during the second day of life. His clinical condition dramatically improved after surgical closure of a large ductus arteriosus. The child is still asymptomatic 30 months later. In the minority of cases with absent pulmonary valve not associated with tetralogy of Fallot, irrespective of the presence of muscular ventricular septal defect, early closure of the ductus may be crucial to improve hemodynamic conditions and postpone surgical correction.

Long-term Outcomes of Pediatric-Onset Hypertrophic Cardiomyopathy and Age-Specific Risk Factors for Lethal Arrhythmic Events

Importance Predictors of lethal arrhythmic events (LAEs) after a pediatric diagnosis of hypertrophic cardiomyopathy (HCM) are unresolved. Existing algorithms for risk stratification are limited to patients older than 16 years because of a lack of data on younger individuals. Objective To describe the long-term outcome of pediatric-onset HCM and identify age-specific arrhythmic risk factors. Design, Setting, and Participants This study assessed patients with pediatric-onset hypertrophic cardiomyopathy diagnosed from 1974 to 2016 in 2 national referral centers for cardiomyopathies in Florence, Italy. Patients with metabolic and syndromic disease were excluded. Exposures Patients were assessed at 1-year intervals, or more often, if their clinical condition required. Main Outcomes and Measures Lethal arrhythmic events (LAEs) and death related to heart failure. Results Of 1644 patients with HCM, 100 (6.1%) were 1 to 16 years old at diagnosis (median [interquartile range], 12.2 [7.3-14.1] years). Of these, 63 (63.0%) were boys. Forty-two of the 100 patients (42.0%) were symptomatic (defined as an New York Heart Association classification higher than 1 or a Ross score greater than 2). The yield of sarcomere gene testing was 55 of 70 patients (79%). During a median of 9.2 years during which a mean of 1229 patients were treated per year, 24 of 100 patients (24.0%) experienced cardiac events (1.9% per year), including 19 LAEs and 5 heart failure–related events (3 deaths and 2 heart transplants). Lethal arrhythmic events occurred at a mean (SD) age of 23.1 (11.5) years. Two survivors of LAEs with symptoms of heart failure experienced recurrent cardiac arrest despite an implantable cardioverter defibrillator. Risk of LAE was associated with symptoms at onset (hazard ratio [HR], 8.2; 95% CI, 1.5-68.4; P = .02) and Troponin I or Troponin T gene mutations (HR, 4.1; 95% CI, 0.9-36.5; P = .06). Adult HCM risk predictors performed poorly in this population. Data analysis occurred from December 2016 to October 2017. Conclusions and Relevance Pediatric-onset HCM is rare and associated with adverse outcomes driven mainly by arrhythmic events. Risk extends well beyond adolescence, which calls for unchanged clinical surveillance into adulthood. In this study, predictors of adverse outcomes differ from those of adult populations with HCM. In secondary prevention, the implantable cardioverter defibrillator did not confer absolute protection in the presence of limiting symptoms of heart failure.

Surgical abdomen with intestinal pseudo-obstruction as presenting feature of atypical Kawasaki disease.

A 31⁄2-year-old previously healthy Caucasian girl presented to a local hospital with a 1-day history of fever and severe abdominal pain. On admission, she was febrile with tender abdomen; physical examination was otherwise unremarkable. Blood exams revealed haemoglobin 120 g/L, white blood cell count (WBC) of 18 × 10/L with neutrophilia (83,7%), platelets count of 217 × 10/L, C-reactive protein (CRP) of 85 mg/L (normal 5 mg/L), whereas urea, creatinine, serum electrolytes, transaminases and urinalysis were all normal. On day two after admission, blood exams showed increased CRP and abdominal ultrasound demonstrated peri-appendicular effusion and normal gallbladder. Appendicitis was suspected and laparotomy with appendectomy was performed showing very mildly inflamed appendix. Thereafter, she was treated with intravenous antibiotics without improvement. During the next few days, the girl remained irritable, febrile, with painful abdomen. The abdominal distension worsened and she presented vomit and occasionally watery stools. Thus, she was transferred to our paediatric surgical ward on the fifth day of her illness. Abdomen examination did not reveal signs of peritonitis. Laboratory testing revealed further increasing WBC and CRP (22 × 10/L and 230 mg/L, respectively). Blood, urine and stool cultures were negative as well as viruses in stools. Serial plain abdominal films revealed multiple water and gas levels in the ileum, prompting the diagnosis of small bowel pseudo-obstruction (Figs 1,2). An abdominal ultrasound confirmed findings compatible with paralytic ileus. As the plain abdomen X-ray did not demonstrate any intestinal perforation, an oral contrast study was performed showing the barium running freely round the stomach and the duodenum up to the small bowel where a very slow transit and dilated loops were noted. A true mechanical obstruction was excluded and a conservative management with bowel rest, intravenous antibiotics (meropenem and teicoplanin) and rehydration was chosen. Nevertheless, the child continued to be febrile and to complain of marked abdominal pain and deterioration of her general conditions. On day eight after admission, she was transferred to our general paediatrics ward where she still remained febrile and presented bilateral injected non-purulent conjunctivae, red dry fissured lips, erythematous maculopapular rash on trunk and erythema of palms and soles. In light of prolonged fever, conjunctivitis, rash, hands and feet erythema, and cheilitis, the diagnosis of Kawasaki disease (KD) was entertained. Echocardiography revealed minimal epi-pericardial effusion and electrocardiography was found normal. Intravenous immunoglobulin (IVIG) at the dose of 2 g/kg was initiated on day nine of illness, associated with aspirin (80 mg/kg/day) prompting a rapid resolution of abdominal pain and of all the signs of the disease. After 3 days, a periungual desquamation of her fingers and toes appeared. Repeated blood counts showed decreased CRP, normalised WBC and mild thrombocytosis (platelet count: 560,000/ mL). Subsequent echocardiography and electrocardiography were normal. Bowel dilatation disappeared on abdominal ultrasound. She was discharged on day fifteen in a stable condition with low-dose aspirin (5 mg/kg/day). At 1 and 2 months followup the patient remained stable.

Kawasaki shock syndrome: a case report

Kawasaki disease is the second most common systemic vasculitis of childhood and may result in life-threatening coronary artery abnormalities in up to 25% of untreated patients. Adolescents often present with an atypical/incomplete presentation of KD with a delayed diagnosis. Kawasaki Shock syndrome (KDSS) is a rare KD presentation and has been recently defined as the presence of any of the following conditions: systolic hypotension ( 20% or clinical signs of poor perfusion with accompanying features of KD [1].

Clinical profile and outcome of cardiac involvement in MELAS syndrome

BACKGROUND Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like (MELAS) syndrome is a rare condition with heterogeneous clinical presentation. Cardiac involvement commonly develops during adulthood, comprising both structural and conduction/arrhythmic abnormalities; early paediatric onset has rarely been reported. We describe the clinical profile, outcome and clinical implication of MELAS-associated cardiomyopathy at a tertiary referral centre. METHODS From 2000 to 2016 we enrolled 21 patients affected by genetically-proven MELAS. Patients were followed-up at least annually over a mean of 8.5 years. RESULTS All patients carried the MT-TL1 3243A>G mutation. Cardiac involvement was documented in 8 (38%) patients (three <18 years; five ≥18 years), including 6 (75%) with hypertrophic cardiomyopathy, 1 (12.5%) with dilated cardiomyopathy, and 1 (12.5%) with persistent pulmonary hypertension. During follow-up, 3 patients died, all with cardiac onset <18 years. The cause of death, however, was non-cardiac (infections, respiratory failure, stroke). Neither events nor cardiac progression were recorded among patients with onset ≥18 years. Adult cardiologists were responsible for 5/8 of referrals, even in patients with long-standing extra-cardiac involvement. CONCLUSIONS Cardiac involvement was found in over 1/3 of patients with MELAS syndrome, and exhibited a bimodal age-related distribution with distinct final outcomes. Paediatric-onset cardiomyopathy represented a hallmark of systemic disease severity, without being the main determinant of outcome. Conversely, adult-onset cardiomyopathy appeared to represent a mild and non-progressive mid-term manifestation. Adult cardiologists played an important role in the diagnostic process, triggering suspicion of MELAS in most of patients diagnosis >18 years.