ß-blocker therapy for infantile hemangioma.

INTRODUCTION: Fifteen percent of proliferating infantile hemangioma (IH) require intervention because of the threat to function or life, ulceration, or tissue distortion. Propranolol is the mainstay treatment for problematic proliferating IH. Other ß-blockers and angiotensin-converting enzyme (ACE) inhibitors have been explored as alternative treatments. AREAS COVERED: The demonstration of a hemogenic endothelium origin of IH, with a neural crest phenotype and multi-lineage differentiation capacity, regulated by the renin-angiotensin system, underscores its programmed biologic behavior and accelerated involution induced by propranolol, other ß-blockers and ACE inhibitors. We review the indications, dosing regimens, duration of treatment, efficacy and adverse effects of propranolol, and therapeutic alternatives including oral atenolol, acebutolol, nadolol, intralesional propranolol injections, topical propranolol and timolol, and oral captopril. EXPERT OPINION: Improved understanding of the biology of IH provides insights into the mechanism of action underscoring its accelerated involution induced by propranolol, other ß-blockers and ACE inhibitors. More research is required to understand the optimal dosing and duration, efficacy and safety of these alternative therapies. Recent demonstration of propranolol's actions mediated by non-ß-adrenergic isomer R-propranolol on stem cells, offers an immense opportunity to harness the efficacy of ß-blockers to induce accelerated involution of IH, while mitigating their ß-adrenergic receptor-mediated adverse effects.

Damp mouldy housing and early childhood hospital admissions for acute respiratory infection: a case control study.

INTRODUCTION: A gap exists in the literature regarding dose-response associations of objectively assessed housing quality measures, particularly dampness and mould, with hospitalisation for acute respiratory infection (ARI) among children. METHODS: A prospective, unmatched case-control study was conducted in two paediatric wards and five general practice clinics in Wellington, New Zealand, over winter/spring 2011-2013. Children aged <2 years who were hospitalised for ARI (cases), and either seen in general practice with ARI not requiring admission or for routine immunisation (controls) were included in the study. Objective housing quality was assessed by independent building assessors, with the assessors blinded to outcome status, using the Respiratory Hazard Index (RHI), a 13-item scale of household quality factors, including an 8-item damp-mould subscale. The main outcome was case-control status. Adjusted ORs (aORs) of the association of housing quality measures with case-control status were estimated, along with the population attributable risk of eliminating dampness-mould on hospitalisation for ARI among New Zealand children. RESULTS: 188 cases and 454 controls were studied. Higher levels of RHI were associated with elevated odds of hospitalisation (OR 1.11/unit increase (95% CI 1.01 to 1.21)), which weakened after adjustment for season, housing tenure, socioeconomic status and crowding (aOR 1.04/unit increase (95% CI 0.94 to 1.15)). The damp-mould index had a significant, adjusted dose-response relationship with ARI admission (aOR 1.15/unit increase (95% CI 1.02 to 1.30)). By addressing these harmful housing exposures, the rate of admission for ARI would be reduced by 19% or 1700 fewer admissions annually. CONCLUSIONS: A dose-response relationship exists between housing quality measures, particularly dampness-mould, and young children's ARI hospitalisation rates. Initiatives to improve housing quality and to reduce dampness-mould would have a large impact on ARI hospitalisation.

Elevated Serum Levels of Alpha-Fetoprotein in Patients with Infantile Hemangioma Are Not Derived from within the Tumor.

AIMS: The embryonic-like stem cell origin of infantile hemangioma (IH) and the observed elevated serum levels of alpha-fetoprotein (AFP) in patients with hepatic IH led us to investigate if this tumor was the source of AFP. MATERIALS AND METHODS: We measured serial serum levels of AFP in patients with problematic proliferating IH treated with surgical excision or propranolol treatment. We also investigated the expression of AFP in extrahepatic IH samples using immunohistochemical staining, mass spectrometry, NanoString gene expression analysis, and in situ hybridization. RESULTS: Serum levels of AFP normalized following surgical excision or propranolol treatment. Multiple regression analysis for curve fittings revealed a different curve compared to reported normal values in the general populations. AFP was not detected in any of the IH samples examined at either the transcriptional or translational levels. CONCLUSION: This study demonstrates the association of proliferating IH with elevated serum levels of AFP, which normalized following surgical excision or propranolol treatment. We have shown that IH is not the direct source of AFP. An interaction between the primitive mesoderm-derived IH and the endogenous endodermal tissues, such as the liver, via an intermediary, may explain the elevated serum levels of AFP in infants with extrahepatic IH.

PHACE(S) Syndrome With Absent Intracranial Internal Carotid Artery and Anomalous Circle of Willis.

The authors present a case of PHACE(S) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies, and sternal cleft or supraumbilical raphe) syndrome with a right-sided segmental infantile hemangioma, and describe in detail, the associated absent ipsilateral intracranial internal carotid artery and anomalous Circle of Willis. Propranolol therapy led to accelerated, complete involution. Nadolol may reduce the theoretical risk of treating PHACE(S) patients with ß-blockers.

Low-dose propranolol regimen for infantile haemangioma.

AIMS: Propranolol, now the preferred treatment for problematic proliferating infantile haemangioma (IH), at an empirical cardiovascular dosage of 2-3 mg/kg/day is associated with variable complication rates. A meta-analysis shows complications in 31% of patients at a mean dosage of 2.12 mg/kg/day. This study reports on the minimal dosage and duration of treatment to achieve accelerated involution and side effects using a stepwise escalation regimen. METHODS: Consecutive patients with problematic proliferating IH treated with propranolol were identified from our vascular anomalies database. Propranolol was commenced at 0.5 mg/kg/day in two divided doses and increased to 1 mg/kg/day after 24 h. The patients were reviewed after 1 week, and the dosage was increased to 1.5 mg/kg/day. The dosage was further increased by 0.5 mg/kg/day, if necessary, to achieve accelerated involution. RESULTS: Forty-four patients, aged 3 weeks to 11 months (mean, 3.8 months), received propranolol therapy for problematic proliferating IH. The minimal dosage required to achieve accelerated involution was 1.5-2 mg/kg/day. Treatment was maintained for an average of 9.3 months and discontinued at an average age of 14.2 months. Rebound growth occurred in the first patient of this series when propranolol was withdrawn at 7.5 months of age, requiring reinstitution of treatment. Slight rebound growth following cessation of treatment was observed in four other patients, but reinstitution of propranolol was not required. Minor complications were observed in three (6.8%) patients. CONCLUSIONS: Propranolol at 1.5-2 mg/kg/day, administered in divided doses with stepwise escalation, is safe and effective for treating problematic proliferating IH. Treatment is continued to an average age of 14.2 months.

Pharmacologic therapies for infantile hemangioma: is there a rational basis?

BACKGROUND: Infantile hemangioma is the most common tumor of infancy. The majority of cases are managed conservatively, but intervention is necessary in approximately 10 percent of cases because of the threat to life or function or because of tissue distortion or destruction. The mainstay treatment for these problematic proliferating infantile hemangiomas is pharmacologic therapy, mostly discovered serendipitously. METHODS: This review examines the rational basis of the hitherto empirical pharmacologic therapies for the enigmatic infantile hemangioma, in light of new knowledge regarding its biology, including the critical roles of stem cells and the renin-angiotensin system. RESULTS: Steroids have remained the first-line therapy for problematic infantile hemangioma for over 40 years despite their known side effects and failure rates. Vincristine has emerged as an alternative to interferon for steroid-resistant cases because of interferon's adverse effects, especially neurotoxicity. ß-Blockers are now the preferred first-line therapy for problematic cases. There is increasing evidence that infantile hemangioma is a disorder of aberrant proliferation and differentiation of primitive mesoderm-derived neural crest phenotypic cells. This primitive phenotype that gives rise to a hemogenic endothelium intermediate has the ability to undergo primitive erythropoiesis and terminal mesenchymal differentiation. CONCLUSIONS: The recent discovery of the crucial role of stem cells and the inferred role of the renin-angiotensin system in the biology of infantile hemangioma underscores the possibility of even more targeted therapies, by using modulators of the renin-angiotensin system, on infantile hemangioma. The observation of the potential role of these traditional antihypertensive agents in stem cell biology may lead to better understanding of developmental biology and tumor stem cell growth.

Steroid therapy for problematic proliferating haemangioma.

AIM: To evaluate the effectiveness and the safety of systemic and intralesional steroid therapy for problematic proliferating haemangioma. METHOD: 233 patients with haemangioma were identified from our vascular anomalies database 1996-2007. 46 (36%) out of 129 patients with proliferating haemangioma required intervention. 24 of these patients received steroid therapy. Indications for steroid therapy, the response and side effects of treatment and the need for other treatment were recorded. Intralesional triamcinolone up to 4 mg/kg/injection was preferred for small, localised non-periorbital lesions in 5 patients and oral prednisolone 2.0-2.5 mg/kg/day was used for larger lesions, especially around the periorbital region in 19 patients. RESULTS: Accelerated regression of the haemangioma was observed in four of the five patients who received intralesional triamcinolone and there was no complication. Overall, the haemangioma in 17 (89%) of the 19 patients responded to high dose oral prednisolone with accelerated regression noted in 10 (53%) patients. Rebound growth was observed in 5 patients during dose tapering, requiring dose increment in three patients and debulking surgery in one patient. Three patients developed growth retardation during treatment but this normalised 3-10 months following cessation of steroid therapy. Other side effects included mild Cushingoid features (n=2), irritability (n=2), increased appetite (n=3). CONCLUSION: Intralesional and systemic steroid are relatively safe and effective in treating problematic proliferating haemangioma. Systemic steroid therapy is associated with few short-term side effects. A multidisciplinary management is essential. Propranolol is likely to replace steroid as the first-line treatment for problematic proliferating haemangioma.

Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function.

We report here the case of an infant with multiple hepatic and cutaneous infantile hemangiomas (IHs) associated with deranged liver function who was treated successfully with low-dose propranolol. We also discuss our recent data that show that IH is a developmental anomaly of hemogenic endothelium derived from primitive mesoderm with a neural crest-cell phenotype. We previously presented evidence that this hemogenic endothelium is governed by the renin-angiotensin system, which we propose can account for both the action of propranolol and the process of spontaneous involution of IH. We further speculate on the possibility of using inhibitors of angiotensin-converting enzyme and that of angiotensin II receptor 2 as potential alternative therapies.

Low-dose propranolol for infantile haemangioma.

In 2008, propranolol was serendipitously observed to cause accelerated involution of infantile haemangioma. However, the mechanism by which it causes this dramatic effect is unknown, the dosage empirical and the optimal duration of treatment unexplored. This study determines the minimal dosage and duration of propranolol treatment to achieve accelerated involution of problematic infantile haemangioma. Consecutive patients with problematic proliferating infantile haemangioma treated with propranolol were culled from our prospective vascular anomalies database. The patients were initially managed as inpatients and commenced on propranolol at 0.25 mg kg(-1) twice daily, and closely monitored. The dosage was increased to 0.5 mg kg(-1) twice daily after 24 h, if there was no cardiovascular or metabolic side effect. The dosage was increased further by 0.5 mg kg(-1) day(-1) until a visible effect was noticed or up to a maximum of 2 mg kg(-1) day(-1), and was maintained until the lesion had fully involuted or the child was 12-months old. A total of 15 patients aged 3 weeks to 8.5 months (mean, 11 weeks) underwent propranolol treatment for problematic proliferating infantile haemangioma, which threatened life (n=1) or vision (n=2) or nasal obstruction (n=3) and/or caused ulceration (n=6) and/or bleeding (n=2) and/or significant tissue distortion (n=12). The minimal dosage required to achieve accelerated involution was 1.5-2.0 mg kg(-1) day(-1). Rebound growth occurred in the first patient when the dose was withdrawn at 7.5 months of age requiring reinstitution of treatment. No rebound growth was observed in the remaining patients. No other complications were observed. Propranolol at 1.5-2.0 mg kg(-1) day(-1), administered in divided doses with gradual increase in the dose, is effective and safe for treating problematic proliferating infantile haemangioma in our cohort of patients. Treatment should be maintained until the lesion is completely involuted or the child is 12-months old. Larger scale studies confirming the safety and efficacy of propranolol may broaden the indications of treatment of proliferating infantile haemangioma.

Rotavirus hospitalisation in New Zealand children under 3 years of age.

OBJECTIVE: To describe the epidemiology of severe rotavirus gastroenteritis and to estimate the hospitalisation rates of this illness in New Zealand children under 3 years of age. METHODS: Children under 3 years of age with acute diarrhoea admitted to 1 of 8 study hospitals between 1 May 1998 and 30 April 2000 were surveyed. Their socio-demographic, treatment and length-of-stay data were recorded and stool samples tested by a rotavirus-specific enzyme-linked immunoassay. National hospital discharge data for infectious diarrhoea (International Classification of Diseases, ninth revision, 003-009) were reviewed, allowing population-based estimates for rotavirus-related hospitalisation in New Zealand. RESULTS: Of 2019 enrolled children, 1138 (56.4%) provided stools for testing, and of these 485 (42.6%) tested rotavirus positive. Rotavirus detection varied significantly by age (26.8% for 0 to 5 months, 42.5% for 6 to 11 months and 52.1% for children aged 12 to 35 months; P < 0.001), and by season (51.2% in winter/spring vs. 24.5% in summer/autumn; P < 0.001). While those infected with rotavirus were more likely to be dehydrated (50.6% vs. 37.4%; P < 0.001), their median hospital stay was similar (1.0 vs. 2.0 days; P = 0.09) to other children with acute gastroenteritis. The estimated national hospitalisation rate for rotavirus diarrhoea in children under 3 years, standardised for age and season, was 634 (95% CI 597, 672) per 100,000. In New Zealand, rotaviruses result in 1 in 52 children being hospitalised by 3 years of age. CONCLUSIONS: Rotavirus diarrhoea is an important, potentially vaccine-preventable cause of hospitalisation in New Zealand children, especially during winter and spring seasons.