Expanded ILC2s in human infant intestines promote tissue growth.

Early life is characterized by extraordinary challenges, including rapid tissue growth and immune adaptation to foreign antigens after birth. During this developmental stage, infants have an increased risk of immune-mediated diseases. Here, we demonstrate that tissue-resident, interleukin (IL)-13- and IL-4-producing group 2 innate lymphoid cells (ILC2s) are enriched in human infant intestines compared to adult intestines. Organoid systems were employed to assess the role of infant intestinal ILC2s in intestinal development and showed that IL-13 and IL-4 increased epithelial cell proliferation and skewed cell differentiation toward secretory cells. IL-13 furthermore upregulated the production of mediators of type-2 immunity by infant intestinal epithelial cells, including vascular endothelial growth factor-A and IL-26, a chemoattractant for eosinophils. In line with these in vitro findings increased numbers of eosinophils were detected in vivo in infant intestines. Taken together, ILC2s are enriched in infant intestines and can support intestinal development while inducing an epithelial secretory response associated with type 2 immune-mediated diseases.

Generalized Infantile Myofibromatosis with Extensive Small Bowel Involvement in a Neonate.

Infantile myofibromatosis is a rare benign congenital tumour that often regresses spontaneously but may pose therapeutic challenges in its widespread visceral form. We present the case of a full-term neonate with generalized infantile myofibromatosis including ubiquitous subcutaneous and muscular nodules, a tumour in the mastoid and disseminated intestinal involvement. The intestinal tumours led to a mechanical ileus with intestinal perforation within the first days of life. After partial small bowel resection and necessary proximal jejunostomy the boy was dependent on total parenteral nutrition. Chemotherapy with vinblastine and methotrexate was started and was temporarily supplemented with imatinib. Feeding stayed impossible despite tumour shrinkage. At the age of 4.5 months, restoration of intestinal continuity with further stricturoplasties was performed which - for the first time - allowed complete oral feeding. Chemotherapy was continued for further two months. Currently, the child is in good general condition with growth and further disease regression. This report suggests that massive visceral involvement of infantile myofibromatosis may require extensive intestinal surgery, as conservative therapy cannot resolve the disease and its sequelae.

CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation.

Gastrointestinal infections are a major cause for serious clinical complications in infants. The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1++ CD4+ T cells (TFH cells). We investigated the ontogeny of CXCR5+PD-1++ CD4+ T cells in human intestines. While CXCR5+PD-1++ CD4+ T cells were absent in fetal intestines, CXCR5+PD-1++ CD4+ T cells increased after birth and were abundant in infant intestines, resulting in significant higher numbers compared to adults. These findings were supported by scRNAseq analyses, showing increased frequencies of CD4+ T cells with a TFH gene signature in infant intestines compared to blood. Co-cultures of autologous infant intestinal CXCR5+PD-1+/-CD4+ T cells with B cells further demonstrated that infant intestinal TFH cells were able to effectively promote class switching and antibody production by B cells. Taken together, we demonstrate that functional TFH cells are numerous in infant intestines, making them a promising target for oral pediatric vaccine strategies.

Establishment of the German Burn Registry - five years of prospective data collection.

BACKGROUND: From 1991-2014, all major burn centers of the German-speaking countries participated in a multicenter study in which essentially demographic data were collected. Individual patient data was located at the particular burn centers and only cumulated data were summarized annually for presentation. Retrospective statistical analysis of the entire data collection and identification of subgroups was not possible. In 2015 the German Burn Registry was established for prospective collection of individual patient data as a tool for quality management (QM) and for scientific analyses. METHODS: A working group was formed to ensure the development and administration of the registry. From the official start of the German Burn Registry at the beginning of the year 2015 prospective data collection was realized with an individualized, web-based data collection software in a pseudonymized way. Selected data analysis was performed for the first 5 years of data collection. Severely burned adults and all hospitalized children with burn injuries were documented in the registry. RESULTS: The German Burn Registry was successfully established. 64 burn divisions have already been registered. 18,891 patients were documented over 5 years, of which 58% where children (<16 years). Mean ABSI Score was 4 (children: 3, adults: 6) with a mortality rate of 3.8.0% (children: 0.2%, adults: 9.3%). Children were hospitalized for an average of 7 days, whereas adults were discharged after 18 days. CONCLUSION: A registry is mandatory for quality assurance in burn medicine, since realization of randomized studies is difficult due to the heterogeneity of burn injuries. The German Burn Registry already is one of the biggest burn registries in Europe. Several scientific projects, based on the registry database, are in working process or have already been published.

[Impact and Temporal Evolution of the Corona Pandemic on Pediatric Emergency Care]. / Auswirkungen der Corona Pandemie auf die Notfallversorgung im Kindesalter und die zeitliche Entwicklung im Verlauf der Pandemie.

HINTERGRUND: Die COVID-19 Pandemie hat zu massiven gesellschaftlichen und wirtschaftlichen Einschränkungen geführt. Im Kindesalter wurden elektive Vorsorgeuntersuchung oftmals nicht wahrgenommen und es zeigte sich eine Reduktion der Zahl der Notfallvorstellungen. MATERIAL UND METHODEN: In einer retrospektiven Studie erfolgte eine quantitative Auswertung aller Notfallpatienten der 5 Kindernotaufnahmen Hamburgs und der Kinder- und Jugendarztpraxen der Jahre 2019 und 2020. Zusätzlich erfolgte die detaillierte Analyse der Notfallbehandlungen des Altonaer Kinderkrankenhauses während der ersten Phase der Pandemie im Vergleich zum Vorjahr. Zusammenhänge zu den Eckpunkten der Pandemieentwicklung wurden analysiert. Die Berechnung signifikanter Unterschiede in Bezug auf die demographischen Daten und Krankheitsbilder erfolgte mittels Chi- Quadrat und t-Test. ERGEBNISSE: In allen 5 pädiatrischen Notaufnahmen Hamburgs zeigte sich eine nahezu gleichförmige Abnahme der Patientenvorstellungen während der Pandemie, ähnlich in den Kinder- und Jugendarztpraxen. Die Zahl der Behandlungen verhielt sich dabei nicht streng gegenläufig zu den Neuinfektionen, sondern korreliert eher mit den Mobilitätsdaten und entsprach somit den gesamtgesellschaftlichen Veränderungen. Während der Pandemie stieg der Anteil häuslicher Unfälle an der Gesamtzahl der Vorstellungen signifikant an. Die Analyse der Diagnosen zeigte unter anderem eine relative Abnahme von (viralen) Infektionskrankheiten. Nicht behandlungspflichtige Erkrankungen führten in der Pandemie seltener zur Vorstellung. Diese Phänomene entlasteten einerseits die Notaufnahmen, bergen aber auch die Gefahr, dass Erkrankungen durch Eltern falsch eingeschätzt werden und eine notwendige ärztliche Vorstellung somit zu spät erfolgt.

Markers of neutrophil activation and extracellular trap formation predict appendicitis.

BACKGROUND: Although appendicitis is one of the most frequently occurring pediatric surgery emergencies, current biomarkers for diagnosis are unspecific and have low predictive values. Neutrophils are an essential component of the innate immune system involved during appendicitis. Thus, the current study aimed to evaluate neutrophils and their activation markers in a prospective cohort study. METHODS: The study population included all children with acute abdominal pain who presented to the pediatric surgery department of 2 large clinics between July 2018 and December 2019. All enrolled subjects underwent blood sample collection with an assessment of white blood cell count, C-reactive protein, cell-free DNA, neutrophil elastase, myeloperoxidase, and citrullinated histone H3. If an appendectomy was performed, the appendix was stained for myeloperoxidase, neutrophil elastase, and citrullinated histone H3 using immunofluorescence. RESULTS: In total, 198 subjects were included in the study, of whom 133 had histological verified appendicitis. In those with appendicitis, white blood cell count and C-reactive protein showed a moderate diagnostic value for (noncomplicated and complicated) appendicitis. However, cell-free DNA (area under the curve .87) and citrullinated histone H3 (area under the curve .88) demonstrated excellent predictive power for appendicitis. Most notably, citrullinated histone H3 was able to distinguish (1) noncomplicated from complicated appendicitis, and (2) predict patient outcome. Moreover, the examined biomarkers appear to reflect tissue expression and disease severity. CONCLUSION: Markers of neutrophil activation and extracellular trap formation are excellent biomarkers for appendicitis. In particular, citrullinated histone H3 may be used to identify children with an increased risk of developing complications after appendicitis.

KIR3DS1 directs NK cell-mediated protection against human adenovirus infections.

Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1+ NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8+ T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1+/HLA-Bw4+ donor cells compared with children receiving non­KIR3DS1+/HLA-Bw4+ cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

Combination of Side-Swing Flap With Negative-Pressure Wound Therapy Is Superior to Open Excision or Flap Alone in Children With Pilonidal Sinus-But at What Cost?

Background: Pilonidal sinus (PS) disease frequently occurs in adolescents and young adults, and in many cases involves wide excision or local flaps as treatment. These treatments are associated with a significant recurrence rate, a long healing time, and thus absence from school or work. The hybrid technique, which is a combination of side-swing plasty with negative-pressure wound therapy (NPWT) may improve these outcomes. The aim of the study was to compare the latter with other current methods. Methods: Children presenting with a pilonidal sinus to two referral centers for pediatric surgery from January 2017 till June 2019 and subsequent (1) slide-swing plasty, (2) open excision, or (3) slide-swing plasty in combination with NPWT were included in this retrospective study. Type of therapy, number of interventions, duration of hospitalization, complications, and recurrence rate were recorded. In addition, data was retrieved from the national diagnosis-related group for inpatient statistics, for all patients who underwent surgery for pilonidal sinus in 2015 and 2016. Results: In total, 85 children were included, with a mean age of 15 years and a near equal gender distribution (53% female). The minimum follow-up was 1 year. In 56% open resection was performed, while 18% underwent a slide-swing plasty and 26% a slide-swing plasty in combination with NPWT. While the hybrid technique was superior regarding recurrence rate in comparison to open excision (24 vs. 5%, p = 0.047), it had significantly longer hospital stay [17.41 (15.63) vs. 3.65 (1.68) days, p < 0.001] and number of interventions [4.14 (4.07) vs. 1.04 (0.29), p < 0.001]. Conclusions: Management of PS disease using slide-swing plasty in combination with NPWT is an effective treatment and is associated with low recurrence rate and minimal morbidity. However, this type of treatment is accompanied by an elongated hospitalization time and more frequent interventions. A diligent case by case evaluation and thorough patient counseling is thus necessary when choosing the right technique for the treatment of PS disease.

Therapeutic Targeting of Neutrophil Extracellular Traps Improves Primary and Secondary Intention Wound Healing in Mice.

Background: Neutrophils are the first responders in wound healing after injury that mediate pro- and anti-inflammatory activities i.a. through the formation of extracellular traps (NETs). However, excessive NETs presence in wound tissue can cause local hyperinflammation and -coagulation resulting in delayed wound healing. To improve wound healing, we aimed to examine the role of NETs and DNase1 on primary and secondary wound healing. Methods: The study included 93 C57BL/6 mice, with 3 different genotypes: wildtype, Pad4-, and DNase1-Knockout (KO). Pad4-KO mice show limited NETs formation, while DNase1-KO mice cannot disintegrate them. All 3 genotypes were included in (1) a laparotomy group and (2) a thermal injury group. Animals in both groups either received DNase1 or a vehicle i.p. post wound induction and wound assessment and euthanasia were conducted. Laparotomy and burn scars were assessed using the stony brook scar evaluation scale and modified Yeong scale respectively. Tissue was analyzed histologically using H&E staining. Ly6g, Collagen I and III, SMA, and Fibrinogen were visualized and neutrophils activation (NE, MPO) and NETs (H3cit) formation assessed. Results: All animals survived with no complications. DNase1 treatment led to a significantly improved scar appearance in both groups, which was also seen in Pad4-KO mice. In the laparotomy group DNase1 improved collagen deposition and fibrin concentration was significantly reduced by DNase1 treatment. Markers of neutrophil activation were significantly reduced in the treatment and Pad4-KO group. In the thermal injury group wound closure time was significantly reduced after DNase1 treatment and in the Pad4-KO group. Even though inflammation remained high in the thermal injury model over time, neutrophil activation and NETs formation were significantly reduced by DNase1 treatment compared to controls. Discussion: Primary and secondary intention wound healing is improved by targeting NETs through DNase1 treatment or genetic KO, as assessed by wound closure time and scar appearances. Additionally, wound stability was not affected by DNASE treatment. The results suggest that overall wound healing is accelerated and DNase1 appears to be a promising option to reduce scar formation; which should be evaluated in humans.

[Child abuse-reduction in the estimated number of unreported cases by restructuring a clinical child protection program]. / Kindeswohlgefährdung ­ Ausweitung des Hellfeldes durch Neukonzeption der klinischen Kinderschutzarbeit.

BACKGROUND: Identification of child abuse is a daily challenge in medical work. The estimated number of unreported cases of child abuse and neglect is high. OBJECTIVES: The aim of this study was to investigate the effectiveness of the redesigned clinical child protection program of a major German pediatric hospital and to improve programs in other hospitals for children and physicians through presentation of the advantages of the new structure. METHODS: All cases of child protection at the Altona Children's Hospital were retrospectively analyzed before and after restructuring of the clinic's child protection program for a two-year period each, and a comparison was made. The child protection program was restructured and the new program subsequently managed by a fulltime coordinator. RESULTS: The prevalence of both suspected and substantiated cases of child abuse was significantly higher after restructuring of the child protection program. Before the change, 24 cases were investigated, of which 23 were substantiated; afterward, 124 cases were investigated and 89 were substantiated. Despite the high number of false-positive suspected cases, stigmatization of the families during the clarification progress was avoided by using a very sensitive approach, and the family was not confronted until the suspicion was affirmed. CONCLUSION: The presented concept of child protection in medical clinics seems to facilitate a higher detection rate of child abuse cases. The reduction in the number of undetected cases and thereby prevention of possible escalation of abuse, as well as the decline in the immense social follow-up costs, justifies the increased personnel costs.

Infantile Hepatic Hemangioma: Avoiding Unnecessary Invasive Procedures.

Infantile hepatic hemangioma, the most common vascular tumor of the liver in infancy, can occur with acute postnatal liver and congestive heart failure. Nevertheless, its course is often benign, and many children can be diagnosed and treated without surgical intervention. The distinction from malignant diseases is not always easy and it not clear whether invasive procedures for diagnosis and therapy should be performed. Here we report our experiences in our Center for Pediatric Liver Disease and postulate that large studies are needed to avoid unnecessary invasive procedures for these patients in the future.

The Inhibitory Effect of Curosurf® and Alveofact® on the Formation of Neutrophil Extracellular Traps.

Background: Neutrophil extracellular traps (NETs) are a defense mechanism in which neutrophils cast a net-like structure in response to microbial infection. NETs consist of decondensed chromatin and about 30 enzymes and peptides. Some components, such as neutrophil elastase (NE) and myeloperoxidase (MPO), present antimicrobial but also cytotoxic properties, leading to tissue injury. Many inflammatory diseases are associated with NETs, and their final role has not been identified. Pulmonary surfactant is known to have immunoregulatory abilities that alter the function of adaptive and innate immune cells. The aim of this study was to investigate the hypothesis that natural surfactant preparations inhibit the formation of NETs. Methods: The effect of two natural surfactants (Alveofact® and Curosurf®) on spontaneous and phorbol-12-myristate-13-acetate-induced NET formation by neutrophils isolated by magnetic cell sorting from healthy individuals was examined. NETs were quantitatively detected by absorption and fluorometric-based assays for the NET-specific proteins (NE, MPO) and cell-free DNA. Immunofluorescence microscopy images were used for visualization. Results: Both surfactant preparations exerted a dose-dependent inhibitory effect on NET formation. Samples treated with higher concentrations and with 30 min pre-incubation prior to stimulation with phorbol-12-myristate-13-acetate had significantly lower levels of NET-specific proteins and cell-free DNA compared to untreated samples. Immunofluorescence microscopy confirmed these findings. Conclusions: The described dose-dependent modulation of NET formation ex vivo suggests an interaction between exogenous surfactant supplementation and neutrophil granulocytes. The immunoregulatory effects of surfactant preparations should be considered for further examination of inflammatory diseases.

Lidocaine-Epinephrine-Tetracaine Gel Is More Efficient than Eutectic Mixture of Local Anesthetics and Mepivacaine Injection for Pain Control during Skin Repair in Children: A Prospective, Propensity Score Matched Two-Center Study.

INTRODUCTION: Skin lacerations are common in children and their repair is a very unpleasant experience for a child. While pain management has been recognized as a key element of high-quality patient care, recent studies report that pain management in the pediatric emergency departments is still suboptimal. Lidocaine-epinephrine-tetracaine (LET) gel could potentially improve the traumatic experience caused by skin repair as it obviates the need for infiltration. Thus, the aim of the current study was to compare local eutectic mixture of local anesthetics (EMLA) plus mepivacaine infiltration with topical anesthetics (LET-gel). MATERIALS AND METHODS: Prospective, propensity score-matched multicenter study including all children between 3 and 16 years presented at two centers. After anesthetics (LET vs. EMLA and infiltration) standardized skin repair was performed. Pain assessment was performed using the faces pain rating scale or visual analogue scale. Follow-up, performed 2 weeks after initial presentation, assessed wound infection rates and overall satisfaction. RESULTS: Of 73 subjects 59 children (37 LET vs. 22 EMLA) were included after propensity score matching. Groups had similar baseline characteristics. Pretreatment was significantly less painful in LET versus local anesthetics group. Pain during skin repair was similar between groups (LET and EMLA with mepivacaine infiltration) and both groups demonstrated similar efficacy (procedure time, need for secondary infiltration, infection rate). Ultimately, pain levels during pretreatment and the surgical procedure were perceived significantly higher by the children than estimated by parents or surgeons. CONCLUSION: In conclusion, it appears that LET is superior to conventional anesthesia including mepivacaine infiltration in the pediatric emergency departments. Pretreatment with LET is significantly less painful but equally effective. Hence, we recommend LET as a topical anesthetic in the pediatric emergency department.

Multidisciplinary long-term care and modern surgical treatment of congenital melanocytic nevi - recommendations by the CMN surgery network.

In recent years, our knowledge of congenital melanocytic nevi (CMN) has greatly expanded. This has led to a paradigm shift. The present article represents a commentary by an interdisciplinary group of physicians from German-speaking countries with extensive experience in long-term care and surgical treatment of children and adults with CMN (CMN surgery network, "Netzwerk Nävuschirurgie", NNC). The authors address aspects such as the indication for treatment as well as treatment planning and implementation under these new premises. Adequate counseling of parents on conservative and/or surgical management requires an interdisciplinary exchange among physicians and individualized planning of the intervention, which frequently involves a multi-stage procedure. Today, the long-term aesthetic outcome is at the center of any therapeutic endeavor, whereas melanoma prevention plays only a minor role. The premise of "removal at any cost" no longer holds. Potential treatment-related adverse effects (hospitalization, wound healing disorders, and others) must be carefully weighed against the prospects of a beneficial outcome. In this context, the use of dermabrasion in particular must be critically evaluated. At a meeting of the NNC in September 2018, its members agreed on a consensus-based position on dermabrasion, stating that the procedure frequently leads to impaired wound healing and cosmetically unfavorable or hypertrophic scarring. Moreover, dermabrasion is considered to be commonly associated with considerable repigmentation that usually occurs a number of years after the procedure. In addition, the NNC members saw no benefit in terms of melanoma prevention. In the future, physicians should therefore thoroughly caution about the potential risks and often limited cosmetic benefits of dermabrasion.

Extensive Spinal Adhesive Arachnoiditis After Extradural Spinal Infection-Spinal Dura Mater Is No Barrier to Inflammation.

BACKGROUND: Spinal adhesive arachnoiditis (SAA) is an inflammatory process of the meninges. Cystic changes and cicatrization may lead to neurologic deficits and immobilization. Therapy is difficult and often unsatisfactory. We describe 8 cases of extensive SAA after extradural spinal infection. METHODS: A total of 238 patients with epidural abscess or osteomyelitis were treated at our institution between 2011 and 2018. We identified 8 patients who developed extensive SAA on follow-up. Different forms of the disease, radiologic changes, and potential treatment options are described. RESULTS: Eight patients developed extensive SAA after either spontaneous epidural infection in 4 cases (50%) or after surgery or steroid injection (50%). Initial treatment for epidural infection was surgery without dural injury in 87.5%. One patient was treated conservatively. SAA was diagnosed 1 month to 8 years after the initial infection, not only in the index region but throughout the whole spine, with varying clinical symptoms. Treatment options such as corticosteroids (n = 4), thecaloscopy (n = 1), syringe-subarachnoid shunting (n = 1), and focal or multilevel arachnolysis (n = 5) were applied. In 2 patients (25%), a rare complication of internal malabsorptive hydrocephalus had to be treated. Patients showed diverse outcomes at last follow-up (mean, 37 months). CONCLUSIONS: The prognosis for extensive SAA is poor. Surgical interventions may improve radiologic findings and clinical presentation at least temporarily. Even extradural infection can lead to severe SAA. Early surgery with local reduction of the epidural infection might reduce the risk of inflammation passing the dural sac and causing SAA.

Integra®-Dermal Regeneration Template and Split-Thickness Skin Grafting: A Therapy Approach to Correct Aplasia Cutis Congenita and Epidermolysis Bullosa in Carmi Syndrome.

The association of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) and aplasia cutis congenita (ACC) was described by El Shafie et al. (J Pediatr Surg 14(4):446-449, 1979) and Carmi et al. (Am J Med Genet 11:319-328, 1982). Most patients die in the first weeks of life, and no curative treatment options are available so far. We describe a patient with JEB-PA and ACC (OMIM # 226730) who was treated for extensive areas of ACC by Integra®-Dermal Regeneration Template and split-thickness skin grafting (STSG). Clinically, the dermal template changed into well-vascularized neodermis, and after STSG, full take of the transplants was detected. No infections of the huge ACC areas were seen. Further studies must validate this treatment option in severe and acute cases of JEB-PA with ACC. Based on clinical findings, we postulate that placement of Integra®-Dermal Regeneration Template with STSG could be a new treatment option for patients having JEB-PA with ACC to prevent severe infection, compartment-syndrome-like conditions, and deformities. Based on literature findings, we assume that Integra®-Dermal Regeneration Template with STSG could even be able to prevent new blistering and thereby be a treatment option in cases of ACC and JEB.

Topical Timolol for Infantile Hemangiomas: Evidence for Efficacy and Degree of Systemic Absorption.

BACKGROUND: Topical use of timolol for infantile hemangiomas has recently emerged with promising results. It is unknown whether topical ß-blockers act locally or if their effect is partly due to systemic absorption. This study investigates whether topically applied timolol is absorbed and reports on the efficacy of this treatment. METHODS: We treated 40 infants with small proliferating hemangiomas with topical timolol gel 0.5% twice daily and assessed urinary excretion and serum levels in a proportion of patients. Clinical response was evaluated on a visual analog scale of standardized photographs after 1, 2, 3, and 5 months. RESULTS: Forty infants with a median age of 18 weeks (range 2-35 wks) were included; 23 (58%) had superficial and 17 (42%) mixed-type hemangiomas. The median size was 3 cm(2) (range 0.1-15 cm(2) ) and nine hemangiomas were ulcerated. The hemangiomas improved significantly during treatment, with a median increase in visual analog scale of 7 points after 5 months (p < 0.001). Urinalysis for timolol was performed in 24 patients and was positive in 20 patients (83%). In three infants, serum levels of timolol were also measured and were all positive (median 0.16 ng/mL [range 0.1-0.18 ng/mL]). No significant side effects were recorded. CONCLUSION: Topical therapy with timolol is effective for infantile hemangiomas, but systemic absorption occurs. Serum levels in our patients were low, suggesting that using timolol for small hemangiomas is safe, but caution is advised when treating ulcerated or large hemangiomas, very young infants, or concomitantly using systemic propranolol.