Sherief R. Janmohamed

The proactive wet-wrap method with diluted corticosteroids versus emollients in children with atopic dermatitis: A prospective, randomized, double-blind, placebo-controlled trial

BACKGROUND Wet-wrap treatment (WWT) has been advocated as a relatively effective treatment in children with severe atopic dermatitis (AD). WWT often serves as crisis intervention for AD. OBJECTIVES We sought to evaluate the use of WWT with diluted corticosteroids in comparison with emollient in children with severe AD during 4 weeks in a proactive schedule during which the frequency of corticosteroid applications was tapered. METHODS A randomized, double-blind, placebo-controlled study was performed in children aged 6 months to 10 years with severe AD (objective SCORAD at least 40 ± 5), comparing WWT with diluted corticosteroids (1:3 mometasone furoate 0.1% ointment and for the face 1:19 mometasone furoate 0.1% ointment under a mask) with emollient (petrolatum 20% in cetomacrogol cream). The primary outcome was improvement of the objective SCORAD; secondary outcomes included Patient-Oriented Eczema Measure and quality-of-life index. RESULTS WWT with diluted corticosteroids acted faster and was more efficacious than WWT with emollients. Best results were obtained in age groups 6 to 9 years and 0 to 3 years. The difference in efficacy evaluated by objective SCORAD was significant at all measuring points. This also applied to the quality-of-life index. LIMITATIONS The study group was relatively small. CONCLUSIONS WWT for severe AD is an effective therapy option for at least a period of 4 weeks.

Scoring the proliferative activity of haemangioma of infancy: the Haemangioma Activity Score (HAS)

Background.  Haemangioma of infancy (HOI) is the most frequently occurring benign tumour of infancy. A good, reliable and objective scoring system for haemangioma activity is not yet available.

Educational paper: therapy of infantile haemangioma—history and current state (part II)

AbstractInfantile haemangioma (IH) is the most frequent tumour of infancy. Although it is benign and self-limiting, severe complications can arise due to localisation and fast tumour growth. Also, IHs leave scars after regression in more than half of the cases. Management and therapy of IH have changed greatly after 2008. This update provides an overview of the older therapy options before 2008, which mainly consisted of the administration of corticosteroids, and discusses the modern management with new therapy options such as β-blockers (both systemically and topically). Conclusion: β-blockers are promising and are currently preferred above corticosteroids, but β-blockers still do not give a definitive treatment.

Educational paper: pathogenesis of infantile haemangioma, an update 2014 (part I)

AbstractInfantile haemangioma (IH) is the most frequent childhood tumour. Although it is benign and self-limiting, severe complications can arise due to localisation and fast tumour growth. Management and therapy of IH has changed greatly after 2008 with propranolol. However, the pathogenesis remains elusive. This update provides an overview of all possible mechanisms currently considered. We discuss the possibility that several mechanisms act together, although local hypoxia seems to be important. Clinically, in about half of the cases, an IH is preceded by an anaemic macula (local ischaemia) or a so-called precursor lesion. Laboratory findings indicate stabilisation and an increased transcription activity of hypoxia-inducible factor 1 alpha (HIF1α), leading to up-regulation of its downstream target genes (such as vascular endothelial growth factor (VEGF)), which normally occurs in cases of hypoxia. Conclusion: Three main hypotheses have been proposed, namely (1) the theory of tissue hypoxia, (2) the theory of embolization of placental endothelial cells and (3) the theory of increased angiogenic and vasculogenic activity.

Multiple cutaneous infantile haemangiomas and the risk of internal haemangioma

Infantile hemangioma (IH) is a frequently occurring tumor in infancy of which the pathogenesis is not completely understood. Although IHs are self-limiting, they can cause problems during their active growth and therapy may then be indicated. Generally, screening for internal hemangiomas is recommended when five or more cutaneous IHs are present. This recommendation, however, is lacking solid scientific evidence. In this chapter, we discuss some controversies regarding the prevalence of IH, the nomenclature of “hemangiomas,” the nomenclature of multiple hemangiomas/hemangiomatosis, the therapy of IH, and the abovementioned screening recommendation. Since 1993, children with IHs have been evaluated in outpatient consultations by the working group on vascular anomalies Rotterdam (WEVAR), using an approach protocol. This protocol aimed at determining the relation between number of IHs and the occurrence of internal hemangiomas. We included all patients presenting with five or more cutaneous IHs in the period of 1993–2011. These patients had all been referred for an ultrasound study for internal hemangiomas. We distinguished between children with ten or more IHs (hemangiomatosis group, group 1) and children with five to nine IHs (multiple IH group, group 2). Forty-three patients were included, 27 in group 1 and 16 in group 2. Nine infants in the hemangiomatosis group 1 showed internal hemangiomas versus none in group 2. Further examination for internal hemangiomas in children with fewer than ten cutaneous IHs is controversial and does not seem to be necessary. However, we do recommend ultrasound examination for children with ten or more cutaneous IHs.

Correlation between Objective SCORAD and Three-Item Severity Score used by physicians and Objective PO-SCORAD used by parents/patients in children with atopic dermatitis.

Background: A self-assessment rating scale (SAS) is a good tool to assess the fluctuating disease severity and quality of life (QoL) in children with atopic dermatitis (AD). The European Task Force on Atopic Dermatitis created an SAS based on the Scoring Atopic Dermatitis (SCORAD) index, called the Patient-Oriented SCORAD (PO-SCORAD). Objective: The aim of our study was to measure the correlation between alternative systems such as the Objective SCORAD, the Three-Item Severity (TIS) score and the Objective PO-SCORAD. We also investigated the correlations between the objective severity assessments and QoL. Methods: In a specialized outpatient clinic, an observational prospective study was performed with children ≤16 years with AD. Results: Seventy-five children were included. A good and significant correlation was shown between Objective SCORAD and Objective PO-SCORAD: Spearmans ρ correlation (rs) = 0.63 (p < 0.001). The correlation with QoL was moderate, but still significant (rs = 0.41-0.61, p < 0.001). Conclusion: The Objective PO-SCORAD can be used for the evaluation of fluctuating AD and correlates significantly with the Objective SCORAD and the less time-consuming TIS score.

Do we have to check glucose in patients with haemangioma of infancy treated with beta-blockers?

Editor From the day that Léauté-Labrèze et al. published their well known report until now, there is a growing number of publications describing the efficacy and effectiveness of oral propranolol in the treatment of haemangioma of infancy (HOI). Recently, propranolol ointment (1% and 5%) and other beta-blockers such as timolol (ophthalmic solution 0.5% or gel 0.1%) are also found to be effective. Further investigation has to focus on the mechanism of action and the optimal dosage and duration of therapy. Also, side effects that are however rare, have to be considered. The most common serious side effects of propranolol include bradycardia and hypotension. Bronchospasm can be seen in patients with reactive airway diseases. Hypoglycaemia is another side effect. However, it is well known that this occurs mostly in the neonatal period. Older infants and children are considered to be at low risk, and HOI therapy is generally started after the neonatal period. So, why do most doctors (and reviewers) stress out to check glucose? Probably because of the available case reports published after the discovery of Léauté-Labrèze et al., describing side effects (hypoglycaemia) in children with HOI, treated with propranolol. However, when reading all the cases thoroughly, it can be seen that most patients who were hypoglycaemic, had an underlying condition, often they are ill or have fever (rectal temperature <36 or >38.5 degrees Celsius) and were in state of fasting (bad oral intake due to the fever). This has been summarized by Holland et al. The mechanism by which hypoglycaemia develops, aside from less oral intake, is not completely understood. Also, normal glucose homeostasis is thought to be impaired through inhibition of adrenergic mediated glycogenolysis, gluconeogenesis and lipolysis. Children (and infants) seem to be at a higher risk for this adverse effect because their glucose use is higher while fasting (attributed partly to their greater brain mass relative to their body weight). In addition, glycogen stores are lower in infants and children compared with adults, leading to a reduced fasting ability. Thus, when treating healthy infants with beta-blockers, hypoglycaemia normally does not occur. Therefore, it is not necessary to check the glucose level frequently. Especially when treating with topical beta-blockers: there is a minimal use and the penetration through the skin is also minimal. This is in line with our experiences; in healthy patients we have never seen hypoglycaemia. We recommend the following: • Beta-blockers are safe in terms of hypoglycaemia. • We check the glucose level only one time at the start of therapy (fasting glucose level after three doses of propranolol). When it is normal, there is no need to check it again at a later time if the child remains healthy. • We inform the parents that in case of an illness or fever, their child is not allowed to fast. Parents have to see to it that their child has a sufficient intake or else they have to come to the hospital. Of course, glucose control is then indicated. • There is no need to check glucose in patients treated with topical beta-blockers. In very large, non-alarming HOI, treated with topical beta-blockers, we check glucose once. • Pay special attention on concomitant medication also causing hypoglycaemia!

Support for the hypoxia theory in the pathogenesis of infantile haemangioma.

The pathogenesis of infantile haemangioma (IH) is unknown. Several mechanisms have been proposed, including hypoxia, which triggers upregulation and stabilization of hypoxia‐inducible factor (HIF)1α. HIF1α stimulates downstream transcription of target genes that enhance angiogenesis.

Minimizing differences in treatment: expert- and evidence-based guidelines for propranolol treatment of infantile haemangiomas in the U.K. and beyond

Despite the high incidence of infantile haemangiomas (IHs) and their potential complications, there are currently no unified U.K. guidelines concerning the treatment with oral propranolol because of uncertainties and partly controversial opinions. In 2013 and 2015, U.S. and European guidelines were published to standardize the use of propranolol for the treatment of complicated IHs. However, U.S. recommendations did not follow a Delphi and anonymous voting approach, and the European study did not include a survey of current practice. Solman and colleagues therefore used a Delphi technique to provide unified and evidence-based guidelines for the treatment of IHs with oral propranolol in order to assist clinical decision-making and standardizing of care. These guidelines are published in this issue of the BJD. A European treatment survey had already indicated differing approaches to the management of IHs. Also, many U.K. dermatologists formulated their own guidelines. U.K. experts performed a systematic review of the literature using these data. This led to the formulation of 70 statements, which were subsequently discussed and voted on. Finally, consensus was achieved on 47 statements. According to the authors, statements about the indication for hospitalization, starting dose of propranolol, and indication for glucose measurements led to extensive discussion. These issues are also much debated outside the U.K., and hypoglycaemia is an important one, but I agree with the statement: in healthy children, propranolol does not lead to hypoglycaemia. As long as parents are instructed to stop when intake is hampered (illness/vomiting/diarrhoea), there is no need to be afraid and it is not warranted to hurt children with glucose measurements for your own (false) sense of safety. Although the guidelines are for oral propranolol, there is mention of topical timolol for ulcerated IHs. It should be emphasized that although there are publications showing improvement, the effect is probably due to systemic absorption and therefore oral propranolol (at a lower dose) is preferred with proper (pretreatment) investigations, even in older babies. In the U.K., only generic propranolol is available but as these guidelines will also be read by people outside the U.K. one should know that side-effects due to dosing errors by pharmacists or formulation do occur. The commercial formulation has been developed especially to minimize these problems, and pharmacokinetic studies showed that two daily doses are sufficient. In addition, scoring systems can be used in the management of IHs. The Haemangioma Severity Scale (HSS), for example, assesses the severity and might help in deciding which IHs need systemic treatment, while the Haemangioma Activity Score (HAS) measures the activity and can be used over time to assess the response to treatment (or natural evolution). In the last 10 years many children have been treated with oral propranolol. Nevertheless, we are still in a period that sees different approaches in the same country, and even in the same city. Unified and simplified evidence-based guidelines are necessary. Therefore, these guidelines, based on an international survey, a systematic review of the literature, a face-to-face multidisciplinary panel meeting, and anonymous voting, are important for physicians in the U.K. and even beyond.

Intractable vascular autonomic dysregulation (Harlequin phenomenon) in two brothers: another indication for propranolol?

Vascular autonomic dysregulation, in the most extreme presentation known as Harlequin phenomenon, is a rare condition. It manifests as a sudden and brief paroxystic change in skin color, resulting in two different colors on the body. It is supposed that this condition occurs due to a vasomotor instability. This again is caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn. Typically, there is spontaneous regression. We describe two brothers who both had this condition in their first life years. Clinical symptoms included frequent attacks of discoloration of extremities (up to four times per day) accompanied with terrifying crying fits, interpreted by the parents as pain. These patients were treated with propranolol, a nonselective beta‐blocker, resulting in improvement of symptoms: only occasional attacks were seen. Beta‐blockers act on β1‐adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. We hypothesize that propranolol, which is very lipophilic and therefore also acts on β‐receptors of the central nervous system, acts on the sympathetic system.