Hot Topics in Pediatric Dermatology : Indian Journal of Paediatric Dermatology

Secondary Logo

Journal Logo

Hot Topics in Pediatric Dermatology

Hot Topics in Pediatric Dermatology

Barve, Ajit

Author Information
Indian Journal of Paediatric Dermatology: Jul–Sep 2022 - Volume 23 - Issue 3 - p 188-190
doi: 10.4103/ijpd.ijpd_53_22
  • Open

Safety of Propranolol for Infantile Hemangioma in Infants <5-Week Corrected Age

Although propranolol is the therapy of choice for infantile hemangiomas (IHs), its safety has not been established in infants <5-week corrected age. It is as yet not approved by the United States Food and Drug Administration in premature infants with a corrected age of <5 weeks or a corrected gestational age (CGA) of 45 weeks. This is, however, a period when rapid proliferation of IH may occur. In a single-institution retrospective review, Gatts et al. studied patients who were of a corrected age of <5-week or <45-week CGA, when propranolol was initiated for treating IH.[1] A total of 24 patients where propranolol was started prior to 45-week CGA were assessed. The mean age when propranolol was started was 42-week CGA. Other than the age, there were no other contraindications to the use of propranolol. Complete history and examination including cardiac auscultation were carried out prior to starting propranolol. In 88% (21) of these infants, propranolol was started in an outpatient setting. Propranolol was initiated at 1 mg/kg/day in two divided doses in 96% (24) of cases and 88% (21) reached a goal dose of 2 mg/kg/day or higher after 1 week. At the dose of 1–3 mg/kg/day, 92% (22) of patients clearly benefitted from propranolol treatment. Three patients discontinued propranolol. Fussiness and vomiting (n = 1), irritability and sleep disturbances (n = 1), and possible increase in feeding intolerance and irritability (n = 1) were reasons for discontinuing propranolol. In one of these cases, propranolol was restarted after 5 weeks, with favorable response and no adverse effects. There were no serious adverse events such as symptomatic bradycardia, symptomatic hypotension, bronchospasm, or hypoglycemia. The common side effects were sleep disturbance (21%), irritability (17%), and cold hands/feet (13%). Eleven of 24 (46%) had no adverse effects. The study thus found propranolol safe and effective for treatment of IH in infants with a corrected age of <5 weeks. Retrospective nature and small sample size, however, were limitations of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Reference

  1. Gatts JE, Rush MC, Check JF, Samelak DM, McLean TW. Safety of propranolol for infantile hemangioma in infants less than five weeks corrected age. Pediatr Dermatol. 2022 Mar 3. Epub ahead of print.

Rapamycin and Lymphatic Malformations

Slow-flow vascular malformations include capillary malformations, venous malformations (VMs), lymphatic malformations (LMs), or combinations of these malformations. Management of VM and LM includes observation, sclerotherapy, complete or partial resection, physiotherapy, and medical management with mammalian target of rapamycin (mTOR) inhibitors. However, the literature on these therapies is difficult to interpret due to inconsistent use of nomenclature and dearth of clinical trials. The mTOR inhibitor sirolimus (rapamycin) has been increasingly used for treating complicated vascular anomalies. It inhibits mTOR, which is regulated by phosphoinositide-3-kinase and acts as a master switch in numerous cellular processes, such as cell growth and proliferation, angiogenesis, and lymphangiogenesis. Maruani et al. conducted a multicenter, open-label, observational-phase randomized clinical trial (Superficial Slow-Flow Vascular Malformations Treated with Sirolimus) to assess the efficacy and safety of sirolimus for children with complicated slow-flow vascular malformations.[1] Children aged 6–18 years, with a complicated slow-flow vascular malformation extending to underlying tissues (subcutaneous tissue and muscles), confirmed by magnetic resonance imaging (MRI) were included in this study. The study followed a randomized observational-phase design. Participants first underwent an observational period with no treatment and then switched to an interventional period when they received sirolimus. The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient. Sirolimus was administered from the randomized switch time after the observation period until month 12. Treatment was in oral solution or tablets, starting with 0.08 mg/kg/day twice a day, with dose adjustments (maximum 6 mg/day) based on serum levels of sirolimus. Patients underwent MRI thrice once at baseline, at the time of switch from the observation period to the intervention period, and at the end of follow-up. The mean age of participants was 11.6 years. In total, 37.3% (n = 22) had a VM, located mostly on the upper limbs; 30.5% (n = 18) had an LM, located mostly on the head and neck; and 32.2% (n = 19) had a combined malformation, with the most frequent location on the lower limbs.

The study showed that sirolimus treatment had no effect on volume changes detected on MRI scans of slow-flow vascular malformations overall associated with the duration period in slow-flow vascular malformations but significantly decreased the volume of LM. Complete regression was not observed in any case. Sirolimus treatment also had positive effects on end points associated with symptoms such as pain (especially in combined malformations), bleeding, oozing, and quality of life. LMs seem to be the best indication as per the authors as they found evidence of an effect of sirolimus treatment on decreasing LM volume, oozing, and bleeding and improving quality of life. In combined malformations, sirolimus treatment significantly reduced pain, oozing, and bleeding.

During the intervention, 89 adverse events were deemed probably associated with sirolimus treatment, of which 5 were serious adverse events including 1 case of viral ileitis, 1 case of septic arthritis of the toe, 1 case of sepsis due to Pseudomonas aeruginosa, 1 case of fecaloma, and 1 deep vein thrombosis of the leg. There were no pneumocystis infections, although no patients received pneumocystis prophylaxis during the study. Among nonserious adverse events likely associated with sirolimus treatment, the most frequent were oral ulcers, upper respiratory infections, and headaches. Most of the nonserious adverse events resolved spontaneously. In total, five patients discontinued treatment because of adverse effects. Laboratory test results found a slight transitory elevation of liver enzyme activity in two patients and hypercholesterolemia in two patients (did not require stopping treatment); after the 12-month study period, sirolimus was continued in 45.7% (27 out of 59) of participants.

However, the study was not blinded and did not include children <6 years of age.

The authors state that finding the optimal age to initiate sirolimus to potentially prevent an increase in the volume of vascular malformations and duration of treatment are questions needing further exploration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Reference

  1. Maruani A, Tavernier E, Boccara O, Mazereeuw-Hautier J, Leducq S, Bessis D, et al. Sirolimus (Rapamycin) for slow-flow malformations in children: The observational-phase randomized clinical PERFORMUS Trial. JAMA Dermatol 2021;157:1289-98.

New Insights into Acne Pathogenesis

In the past few years, researchers have found that following Staphylococcus aureus skin invasion, fibroblasts can undergo localized proliferation and differentiation into a preadipocyte lineage. This process is called reactive adipogenesis. Reactive adipogenesis is characterized by an increased expression of preadipocyte factor 1 (PREF1/DLK1) during preadipocyte proliferation.[123] Reactive adipogenesis helps in host defense as it is accompanied by an acute and transient increase of the expression of the antimicrobial peptide cathelicidin (Camp) and other genes with immunologic functions. Cathelicidin expression during reactive adipogenesis restricts bacterial growth. Impairment of reactive adipogenesis or deletion of Camp from cultured fibroblasts was found to result in increased S. aureus growth. Reactive adipogenesis also takes place in the gut in response to injury, and suppression of reactive adipogenesis leads to increased penetration of microbial products into the blood. Fibroblasts in the subepithelial stroma play an important immunological function.

On these lines, O'Neill et al. studied the role of fibroblasts in acne.[4] They performed single-cell RNA sequencing on human acne lesions and mouse skin challenged by Cutibacterium acnes. A transcriptome consistent with adipogenesis was observed within specific fibroblast subsets from human acne and mouse skin lesions infected with C. acnes. Perifollicular dermal preadipocytes in human acne and mouse skin lesions showed colocalization of PREF1, an early marker of adipogenesis, and cathelicidin (Camp), an antimicrobial peptide.

The study found that dermal fibroblasts in acne lesions display a response consistent with reactive adipogenesis. The study showed that retinoids may exert their action in acne because of the ability of retinoids to inhibit lipid synthesis and increase the expression of cathelicidin. Adipogenic fibroblasts can be a potential target in acne treatment. The authors showed that dermal perifollicular fibroblasts play a role in the pathogenesis of acne.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

REFERENCES

1. Chen SX, Zhang LJ, Gallo RL. Dermal white adipose tissue: A newly recognized layer of skin innate defense J Invest Dermatol. 2019;139:1002–9
2. Zhang LJ, Guerrero-Juarez CF, Hata T, Bapat SP, Ramos R, Plikus MV, et al Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection Science. 2015;347:67–71
3. Zhang Z, Shao M, Hepler C, Zi Z, Zhao S, An YA, et al Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice J Clin Invest. 2019;129:5327–42
4. O'Neill AM, Liggins MC, Seidman JS, Do TH, Li F, Cavagnero KJ, et al Antimicrobial production by perifollicular dermal preadipocytes is essential to the pathophysiology of acne Sci Transl Med. 2022;14:eabh1478
© 2022 Indian Journal of Paediatric Dermatology | Published by Wolters Kluwer – Medknow