Insights into Patient Experiences with Facilitated Subcutaneous Immunoglobulin Therapy in Primary Immune Deficiency: A Prospective Observational Cohort.

BACKGROUND: Immunoglobulin G replacement therapy (IgRT), intravenous (IV) and subcutaneous (SC) routes, is pivotal in treatment of primary immunodeficiencies (PID). In recent years, facilitated subcutaneous immunoglobulin (fSCIG), a combination of rHuPH20 and 10% IgG has emerged as a delivery method to combine advantages of both IV and SC. METHOD: In an observational prospective cohort, we investigated patient experience with fSCIG in PID patients from 5 PID centers for up to 12 months. We assessed the efficacy and safety of this treatment with patient/caregiver- and physician-reported indicators. Additionally, we analyzed patient treatment satisfaction (TSQM-9) and quality of life (QoL). RESULTS: We enrolled 29 patients (22 pediatric and 7 adults; 14 females and 15 males; (median: 15, min-max: 2-40.9 years) who initiated fSCIG as IgRT-naive (n = 1), switched from conventional rapid-push 10% SCIG (n = 6) or IVIG (n = 22). Among the participants, 19 (65%) exhibited antibody deficiencies, 8 (27%) combined immunodeficiencies, and 2 (7%) immune dysregulations. Remarkably, targeted trough immunoglobulin G levels were achieved under all previous IgRTs as well as fSCIG. No severe systemic adverse drug reactions were documented, despite prevalent local (%86.45) and mild systemic (%26.45) adverse reactions were noted with fSCIG. Due to mild systemic symptoms, 2 patients switched from fSCIG to 10% SCIG. The patient satisfaction survey revealed a notable increase at 2-4th (p = 0.102); 5-8th (p = 0.006) and 9-12th (p < 0.001) months compared to the baseline. No significant trends were observed in QoL surveys. CONCLUSION: fSCIG demonstrates admissable tolerability and efficacy in managing PIDs in addition to notable increase of patients' drug satisfaction with IgRT. The identified benefits support the continuation of this therapy despite the local reactions.

Evaluation of the relationship between mast cell activation and postural orthostatic tachycardia syndrome in children and adolescents.

OBJECTIVE: Postural orthostatic tachycardia syndrome (POTS) is one of the orthostatic intolerance syndromes that are common in young adolescents and impair quality of life. POTS is a multi-systemic disease. Many mechanisms have been defined in POTS etiology, such as autonomic denervation, hypovolemia, hyperadrenergic stimulation, low condition, and hypervigilance. Recently, mast cell activation (MCA) has also been on the agenda in etiology. There are few studies in the literature on the relationship between MCA and POTS in adulthood. However, data on children and adolescents is limited. In light of this information, we aimed to evaluate the relationship between POTS and MCA by measuring serum tryptase levels, a specific marker for MCA. METHODS: This prospective study included patients who were admitted to Kocaeli University Faculty of Medicine Hospital Pediatric Cardiology outpatient clinic for syncope-presyncope between November 2018 and August 2019. Patients who underwent the TILT-table test were enrolled in the study. Patients with structural heart disease or chronic heart disease were not included in this study. Serum tryptase levels were obtained from all patients before the TILT-table test, and serum tryptase levels were re-studied after the test was terminated in patients with positive TILT-table tests for POTS. Patients diagnosed with POTS were classified as Group 1, and other patients were classified as Group 2. RESULTS: Twenty-eight of the 58 patients included in the study (mean: 14.4±2.0 years; 38 girls, 20 boys) were diagnosed with POTS. The remaining 30 patients were diagnosed with vasovagal syncope and included in Group 2. The increase in mean heart rate during the test was 38±6 beats/min and 47.05%±15.65% in patients with POTS. Basal serum tryptase levels were not different between groups (3.2±1.3 ng/ml and 3.84±1.78 ng/ml, respectively; p=0.129), while serum tryptase levels (both baseline and after 45-60 min of the TILT-table test) were higher in patients presenting with symptoms related to MCA compared to others. CONCLUSION: In the literature, MCA was considered to be one of the mechanisms leading to POTS. Although other mechanisms, such as neuropathic and hypovolemic POTS, may be active in the patients, the symptoms of MCA in these patients should be routinely questioned.

Autoimmune Hemolytic Anemia Due to Spondyloenchondrodysplasia with Spastic Paraparesis and Intracranial Calcification due to Mutation in ACP5.

Spondyloenchondrodysplasia (SPENCD) is a rare spondylometaphyseal skeletal dysplasia with characteristic lesions mimicking enchondromatosis and resulting in short stature. A large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders. SPENCD is caused by loss of tartrate-resistant acid phosphatase activity, due to homozygous mutations in ACP5 , playing a role in nonnucleic-acid-related stimulation/regulation of the type I interferon pathway. In this article, we presented a 19-year-old boy with SPENCD, presenting with recurrent autoimmune hemolytic anemia episodes since he was 5 years old. He had short stature, platyspondyly, metaphyseal changes, intracranial calcification, spastic paraparesis, and mild intellectual disability. He also had recurrent pneumonia attacks. The clinical diagnosis of SPENCD was confirmed by sequencing of the ACP5 gene, and a homozygous c.155A > C (p.K52T) variation was found, which was reported before as pathogenic. In conclusion, in early onset chronic autoimmune cytopenias an immune dysregulation may often have a role in the etiology. Associating findings and immunologic functions should be carefully evaluated in such patients in the light of the literature. The present case shows the importance of multisystemic evaluation for the detection of SPENCD that has a monogenic etiology.

Prospective evaluation of tolerance to unheated milk-boiled egg after baked milk-egg tolerance under 2 years.

BACKGROUND: The time to acquisition of tolerance to unheated milk and regular egg after achievement of tolerance to baked goods is not known. OBJECTIVE: To determine the time to acquisition of unheated-milk-regular-egg tolerance, after the tolerance of the baked forms, in children younger than 2 years. METHODS: An initial oral food challenge with baked milk (BM) and baked egg (BE) was performed on patients who were reactive to unheated milk-regular egg, respectively. Patients who were BM-BE tolerant were offered unheated-milk-regular-egg challenges, and patients who were BM-BE reactive were offered BM-BE challenges at an average of 3-month intervals. Food-induced atopic dermatitis was included. RESULTS: Thirty-six children with unheated-milk allergy (median age, 7.3 months [interquartile range (IQR), 6.0-13.5]) and 65 with regular-egg allergy (median age, 7 months [IQR, 5.8-11.0]) were included. Seven of 13 children who were BM tolerant acquired unheated-milk tolerance after a median 4.0 months (IQR, 2.0-7.0). Twelve of 23 children who were BM reactive acquired unheated-milk tolerance after a median 5.0 months (IQR, 3.0-8.0) after BM tolerance. Twenty-one of 29 children who were BE tolerant acquired regular-egg tolerance after a median 3.0 months (IQR, 1.0-6.0). Sixteen of 36 children who were BE reactive acquired regular-egg tolerance after a median 4.0 months (IQR, 2.0-6.8) after BE tolerance. CONCLUSION: Different tolerance rates were determined for baked products at different time points in the first 2 years of life. Unheated-milk-regular-egg allergy resolved in up to 65.5% and 75.5% of cases, respectively, in an average 4 to 5 months after acquisition of BM-BE tolerance. Baked-milk-baked-egg tolerance may be regarded as a precursor of tolerance.

Angioedema-like presentation as the presenting finding of juvenile myositis and juvenile dermatomyositis in 2 patients.

BACKGROUND: Juvenile dermatomyositis (JDM) is the most common subtype of idiopathic inflammatory myopathies in childhood. Gottron's papules, shawl sign, periorbital heliotrope rash, and periungual telengiectasis are characteristic skin findings of the disease. Besides characteristic skin involvement, some other skin findings, such as angioedema, may be seen prior or in the course of the disease. The presence of angioedema in JDM is emphasized in this report. CASE PRESENTATIONS: We present 2 unrelated girls, aged 2 (case 1) and 12 years (case 2), who had developed symmetrical weakness in the proximal muscles, muscle pain, elevated muscle enzymes and angioedema. Both cases had abnormal muscle magnetic resonance imaging findings, suggestive of inflammatory myositis. Muscle biopsy was performed only in case 1, and major histocompatibility complex-1 expression on myofibers was shown consistent with JDM. Cases were diagnosed as probable and definite JDM, respectively. Angioedema was prominent, particularly in the lips and extremities of both cases, without laboratory evidence of C1 inhibitor deficiency or capillary leak syndrome, and absence of family history. Mast cell-mediated, acquired angioedema was the most likely diagnosis. In both cases, skin and muscle findings improved significantly with steroid treatment. CONCLUSION: We suggest that angioedema may be among the characteristic skin findings in JDM, and may be included in subsequent definitions.

A Prospective Assessment of Clinical Characteristics and Responses to Dietary Elimination in Food Protein-Induced Allergic Proctocolitis.

BACKGROUND: Some aspects of diagnostic elimination/challenge diets in food protein-induced allergic proctocolitis (FPIAP) are still poorly defined. OBJECTIVE: This study investigated the symptom spectrum, time required for resolution of each symptom, triggering foods, and risk factors for multiple food allergies (MFA) in FPIAP. METHODS: Infants referred with visible blood in stool were enrolled after etiologies other than FPIAP had been excluded. Laboratory evaluation, clinical features, and elimination/challenge steps were performed prospectively during diagnostic management. RESULTS: Ninety-one of 102 infants (53 boys) were diagnosed with FPIAP. Eleven children did not bleed during challenges. Visible blood in stool began before 2 months of age in 63.6% of the infants not diagnosed with FPIAP, compared with 18.9% of the patients with FPIAP (P = .003). Offending foods were identified as cow's milk (94.5%), egg (37.4%), beef (10.9%), wheat (5.5%), and nuts (3.3%). MFA was determined in 42.9% of patients. Multivariate logistic regression analysis identified atopic dermatitis (AD) (odds ratio [OR]: 2.98, 95% confidence interval [CI]: 1.18-7.55, P = .021) and an eosinophil count ≥300 cells/µL (OR: 2.72, 95% CI: 1.09-6.80, P = .032) as independent risk factors for MFA. Blood and mucus in stool disappeared in a median 3 days (interquartile range [IQR]: 1-14.5 days) and 30 days (IQR: 8-75 days), respectively. CONCLUSIONS: A tendency to transient bleeding occurs in infants who present with bloody stool before 2 months of age. A 2-week duration of elimination for blood in stool is sufficient to reach a judgment of suspected foods for FPIAP. Mucus in stool is the last symptom to disappear. Concurrent AD suggests a high probability of MFA in FPIAP.

Are large local reactions a marker for systemic reactions to subcutaneous immunotherapy in children?

BACKGROUND: Previous studies involving predominantly adults concluded that the patients developing frequent large local reactions (LLRs) might be at greater risk for systemic reactions (SRs) during subcutaneous allergen immunotherapy (SCIT). OBJECTIVE: To determine the rate of side effects to SCIT and evaluate frequency of LLR among pediatric patients with SRs. METHODS: The retrospective study included pediatric patients receiving SCIT. Data on the demographic features, season at onset of SCIT, the indication for treatment, additional allergic diseases, laboratory results, the allergens applied, side effects after injection, grade of SRs, and the total number of injections for each patient were collected retrospectively from the medical records and injection charts. RESULTS: A total of 19,562 injections were administered to 261 patients with conventional SCIT. The incidence LLRs was 0.2% per injection; 1.15% of all patients (n = 3) experienced LLRs on at least two consecutive visits. Systemic side effects were seen in 1% of all SCIT injections. No grade 3 or grade 4 SRs were observed. Logistic regression analysis showed that having an LLR was 3.32 times (95% CI, 1.313-8. 440; P = 0.011) and initiation of SCIT in summer and spring was 4.309 and 3.056 times than autumn (95% CI, 1.527-12.157, P = 0.006; 95% CI, 1.358-6.849, P = 0.007), respectively, increased risk for an SR. CONCLUSIONS: Having LLRs might predict the risk of SRs at any time during immunotherapy in also pediatric patients. Knowing the risk factors is important for developing a personalized protocol in these patients.

Food-induced anaphylaxis in early childhood and factors associated with its severity.

Background: Several factors that increase the risk of severe food-induced anaphylaxis have been identified. Objective: We aimed to determine the demographic, etiologic, and clinical features of food-induced anaphylaxis in early childhood and also any other factors associated with severe anaphylaxis. Methods: We carried out a medical chart review of anaphylaxis cases from 16 pediatric allergy and immunology centers in Turkey. Results: The data of 227 patients with 266 food-induced anaphylaxis episodes were included in the study. The median (interquartile range) age of the first anaphylaxis episode was 9 months (6-18 months); 160 of these patients were boys (70.5%). The anaphylaxis episodes were mild in 75 cases (28.2%), moderate in 154 cases (57.9%), and severe in 37 cases (13.9%). The most frequent food allergens involved were cow's milk (47.4%), nuts (16.7%), and hen's egg (15.8%). Epinephrine was administered in only 98 (36.8%) of these anaphylaxis episodes. A logistic regression analysis revealed two statistically significant factors that were independently associated with severe anaphylaxis: the presence of angioedema and hoarseness during the anaphylactic episode. Urticaria was observed less frequently in patients who developed hypotension. In addition, confusion and syncope were associated with 25.9- and 44.6-fold increases, respectively, in the risk of concomitant hypotension. Conclusion: Cow's milk, nuts, and hen's egg caused the majority of mild and moderate-to-severe anaphylaxis episodes. The presence of angioedema and hoarseness in any patient who presents with a history of food-induced anaphylaxis should alert clinicians that the reaction may be severe. In addition, the presence of confusion, syncope, or stridor probably indicates concomitant hypotension.

Proven Food-Induced Acute Urticaria and Predictive Factors for Definitive Diagnosis in Childhood.

BACKGROUND: Urticaria can be the only sign of a food allergy or can be seen together with other signs and symptoms of a food allergy. OBJECTIVE: To determine the demographic, etiologic, and clinical features of food-induced acute urticaria in childhood. METHODS: Patients suspected of food-induced acute urticaria were included in this prospective cross-sectional multicenter study. RESULTS: Two hundred twenty-nine urticaria cases were included in this study. Seventeen patients who did not meet the inclusion criteria of the study were excluded. Of the 212 included cases, 179 (84.4%) were diagnosed with definitive food-induced acute urticaria. The most common foods causing acute urticaria were cow's milk, hen's eggs, and nuts in 56.4, 35.2, and 19% of cases, respectively. The positive predictive value of a history of milk-induced acute urticaria together with a milk-specific IgE >5 kU/L for cow's milk-induced acute urticaria was 92% (95% CI: 81-96%). A history of cow's milk-induced and/or hen's egg-induced acute urticaria was consistent with a definitive diagnosis of food-induced urticaria (Chen's kappa: 0.664 and 0.627 for milk and eggs, respectively). Urticaria activity scores were higher in patients with food-induced acute urticaria (p = 0.002). CONCLUSION: Cow's milk, hen's eggs, and nuts were the most common allergens in the etiology of childhood food-induced acute urticaria. Although the urticaria activity score provides guidance for diagnosis, an oral food challenge is often essential for the definitive diagnosis of a patient with a history of food-induced acute urticaria.

Utility of fresh egg skin prick test and egg yolk specific immunoglobulin E for outgrowth.

BACKGROUND: In children younger than 2 years, studies evaluating the value of skin prick tests (SPTs) and specific immunoglobulin E (sIgE) results to predict persistence or resolution of egg allergy (EA) are limited. In addition, the value of egg yolk (EY) sIgE and fresh egg (FE) SPTs has not been well characterized. OBJECTIVE: To investigate the optimal decision points (ODPs) for outgrowing allergy with SPTs and sIgE tests for egg allergen preparations. METHODS: SPTs for FE, egg white (EW), and EY, sIgE tests for EW and EY, and oral food challenges (OFCs) were performed in children with suspected EA. Reactive patients strictly avoided all dietary egg. After 1 year, EA was reevaluated with addition OFCs, SPTs, and sIgE tests. RESULTS: A total of 81 children (median age, 7 months; age range, 2-24 months) were enrolled. Notably, 4 children with a history of anaphylaxis and 60 of 77 children with a positive challenge result underwent egg elimination. The 1-year follow-up OFC test was performed on 59 children. A total of 27 reacted to egg. No persistent patient had a follow-up SPT result for FE of 4 mm or less (positive predictive values of 100% and negative predictive value of 56% for outgrowth). The diameters of the initial SPT for FE decreased 50% or more in half of the patients who outgrew EA. The ODPs for outgrowing allergy for follow-up sIgE tests for EY and EW were 2.1 kU/L or less (positive predictive value of 86.2%) and 4.0 kU/L or less (positive predictive value of 84.6%), respectively. CONCLUSION: A SPT diameter for FE of 4 mm or less and sIgE values of 2.1 kU/L or less for EY and 4.0 kU/L or less for EW have a good positive predictive value for outgrowth of EA in children younger than 2 years.

Mutational landscape of severe combined immunodeficiency patients from Turkey.

Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.

Two approaches for diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity in children.

BACKGROUND: The oral provocation test (OPT) with culprit drug is the gold standard in the diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity (NSAID-H). Some authors have proposed that the total number of OPTs required to diagnose NSAID-H is much lower with acetyl salicylic acid (ASA) provocations, regardless of patients' reaction history, and less time consuming. OBJECTIVE: This study aims to evaluate the total number of OPTs required to confirm NSAID-H according to the drugs (ASA or culprit NSAID) used in the initial OPT. METHODS: The study included patients with a history of NSAID-H. Data on the demographic and clinical features, coexisting chronic or allergic disease, and laboratory results were collected from medical records. The drug used for the initial OPT (ASA or culprit NSAID), results of the OPT, and the total number of OPTs were reviewed. RESULTS: We included 56 children with suspected hypersensitivity reaction to NSAIDs. NSAID-H was confirmed in 21 children (37.5%). We calculated that if all OPTs were performed with culprit drugs as an initial choice, the number of OPTs required for diagnosis would be 3 or more in 85.7% of positive cases. The number of episodes was an independent risk factor for NSAID-H by multiple logistic regression analysis (odds ratio, 4.3; 95% confidence interval, 1.48-12.24; P = .007). CONCLUSION: Performing an initial OPT with ASA regardless of patients' reaction history can result in much lower numbers of OPT to diagnose NSAID-H and can improve patient compliance.

Suspected Reaction with Cephalosporin May Be a Predictive Factor for ß-Lactam Allergy in Children.

BACKGROUND: Most children diagnosed with ß-lactam allergy based only on history are not truly allergic, and mislabeling leads to use of less effective and more costly alternative broader-spectrum antibiotics, significantly increasing drug resistance. OBJECTIVE: To determine the frequency and risk factors of confirmed allergy in patients with ß-lactam allergy reported by parents or their doctors and evaluate cross-reactivity between ß-lactams in children with confirmed allergy. METHOD: Sixty-seven children with suspected ß-lactam allergy were evaluated via history, sIgE measurements, skin tests, and drug provocation tests over a period of 5 years. RESULTS: ß-Lactam allergy was confirmed in 10 (14.9%) patients. Six patients had a positive intradermal test result to one or more of the penicillin skin test materials or ceftriaxone, 4 patients with negative skin test results had positive test results with suspected drugs. Age, gender, time interval between evaluation and the initial reaction, personal history of atopy, parental history of drug allergy, reaction type, and multiple drug allergy history were not significantly different between allergic and tolerant patients. For culprit drugs, there was a significant different between the 2 groups; the rate of confirmed diagnosis was significantly higher for cephalosporins such as ceftriaxone, cefuroxime, and cefprozil (p = 0.03). Three patients with allergy to penicillin tolerated cefuroxime; in 4 patients with selective allergy to ceftriaxone tolerated cephalosporins with a dissimilar side chain (cefadroxil, cefuroxime, cefaclor, and cefdinir). CONCLUSION: Our study indicates that most patients with a suspected ß-lactam allergy tolerated this drug. An appropriate diagnostic allergy workup may prevent the use of less effective and more expensive alternatives.

Determination of Dietary Status as a Risk Factor of Cardiovascular Heart Disease in Turkish Elderly People.

This study was performed to determine the status of diet as a risk factor of cardiovascular heart disease in a group of Turkish elderly people. We performed a cross-sectional study using the data of voluntary participants aged between 65-74 years old. Participants completed 3-day diet records. Of participants, 64.1% of the men and 62.2% of the women reported their daily dietary fat intake as being > 30% of total energy (p > .05). More than 20% of these elderly respondents' daily intakes of vitamin E, vitamin B6, vitamin B12, and folate were found to be under the recommended values. As a result, the total fat intake of these elderly people was found to be high; while their intake of fiber and vitamin B6, vitamin B12 were found to be low, compared to American Heart Association recommendations. In conclusion, it is recommended that developing sufficient and balanced diets may decrease cardiovascular risk factors.

The relationship between height and arm span, mid-upper arm and waist circumferences in children.

BACKGROUND: Height is a significant parameter in assessment of growth, development, and nutritional status. OBJECTIVE: The aim of this study was to assess the relationship between height and arm span, mid-upper arm and waist circumferences in Turkish children. SUBJECTS AND METHODS: Height, arm span, mid-upper arm and waist circumferences were measured in 1145 boys and 1372 girls aged 7-14 years old from metropolitan Ankara schools in Turkey. RESULTS: Among the children aged between 7 and 14 years old the arm span was determined to be shorter than height. The correlation coefficient between height and arm span of children aged 7-10 years old was 0.92 for boys and 0.90 for girls, and was 0.89 for boys and 0.85 for girls aged 11-14 years old. The correlation between height and arm span was high in both genders at the age group of 7-10 years old. Moreover, significant correlations were found between the height, the mid-upper arm and waist circumferences. CONCLUSIONS: Arm span was found to be strongly correlated with height. Although mid-upper arm and waist circumferences were moderately correlated, waist circumference was not detected as a predictor for height in girls and boys.

Body dysmorphic disorder in university students with skin diseases compared with healthy controls.

Body dysmorphic disorder appears relatively frequently in dermatological and cosmetic surgery settings; in fact, dermatologists may be the type of practitioner most often consulted by patients with body dysmorphic disorder. The aim of this study was to evaluate body dysmorphic disorder symptoms in Turkish university students with skin diseases. A total of 107 outpatients diagnosed with any skin disease and 109 age- and sex-matched healthy subjects recruited from the students of the same university were enrolled in the study. Subjects in both the patient and the control groups completed the Beck Depression Inventory and the Body Dysmorphic Symptoms Scale (BDSS). Groups differed on the basis of BDSS scores (t = 3.74, p = 0.001), with higher scores in the group with skin diseases compared with those for healthy controls. Subjects with skin diseases and higher BDSS scores had higher Beck Depression Inventory scores compared with those with lower BDSS scores (z = 4.13, p = 0.001). This study suggests that patients with skin disease have higher body dysmorphic disorder scores compared with healthy controls.

Body image satisfaction and anxiety of a Turkish sample of university students with skin diseases.

The aim of this study was to evaluate perception of body image and anxiety of 221 university students presenting to the dermatology outpatient clinic with a skin disease and 205 students without skin disease. Analysis of anxiety and body image scores yielded differences by sex and age in both groups. The group with skin disease had lower scores on body image. Acne vulgaris seems to be the most disturbing among the skin diseases, and this was more prominent in younger patients.