Introduction
Pediatric urticaria has an estimated incidence of about 3.5%–8%. Acute urticaria is more common with causes being viral, food allergy, and rarely drugs. Chronic urticaria, on the other hand, has a prevalence close to 1.8%, but the risk factors are not precisely known. The latter is defined as occurrence of spontaneous wheals, angioedema, or both lasting for more than equal to six weeks. Chronic urticaria is further divided into two groups: chronic inducible urticaria (CIU) and chronic spontaneous urticaria (CSU).[ 1 ] The point prevalence of CSU in children ranges between 0.1 and 0.3%, and it represents 55.9% of pediatric chronic urticaria cases.[ 2 ]
The pathogenesis of CSU revolves around mast-cell activation. The mediators involved are histamine, platelet-activating factor, leukotrienes, and prostaglandins that induce sensory nerve activation, vasodilatation, and plasma extravasation.[ 3 ] Treatment includes second-generation H1-antihistamines as first-line therapy.In patients with CSU not responding to conventional updosing of second generation H1-antihistaminics, omalizumab, cyclosporine, first-generation H1-antihistamines, and leukotriene antagonists, have been tried but no specific guidelines have been developed in pediatric population.[ 4 ]
Although second-generation antihistaminics are considered the first-line therapy, a recent review concluded that anti-H1 anti-histamine drugs are beneficial in less than 50% of cases.[ 1 ] Therefore, search for a therapeutic modality that can provide extended relief and reduce pill burden is the need of the hour. Autologous serum therapy containing tolerance-generating anti-idiotype antibodies to mast-cell degranulating antigens has been tried for disease remission in the treatment of chronic urticaria. Many studies have depicted efficacy and safety of AST in chronic urticaria with almost negligible side effects.[ 5 ] But all these studies included adult population, and no data is available regarding its safety and efficacy in children.[ 6 ] Our study was aimed to assess the effectiveness and safety of autologous serum therapy (AST) as an adjunctive therapy to standard antihistaminics in chronic spontaneous urticaria in pediatric population.
Materials and Methods
The study was a single-center, prospective pilot study at a tertiary care hospital in Eastern India. Institutional Ethics Committee clearance was obtained prior to study initiation, and written informed consent was taken from patient’s caregivers. Duration of study was from March 2019 to March 2020. All pediatric patients (age between 6 and 16 years) presenting with chronic spontaneous urticaria were screened for eligibility criteria. Chronic spontaneous urticaria was defined as itching and wheals occurring daily/near daily (≥3 times/week) for ≥6 weeks.
Inclusion criteria
Diagnosed case of chronic spontaneous urticaria (itching and wheals occurring daily or near daily[> =3 times per week] for >=6 weeks)
Age between 6 and 16 years.
Exclusion criteria
Patient suffering from immunosuppression from drug and disease
Hepatitis B, C and HIV infection.
Inability to come for regular follow-ups.
Concurrent infections or thyroid dysfunction.
Personal or family history of atopy.
History of physical urticaria or angioedema.
Screening visit
Clinico-demographic data of all patients were recorded. Baseline investigations including complete hemogram, liver function tests, renal function tests, and thyroid panel were performed. Caregivers were instructed to discontinue oral antihistaminics and provided urticaria activity score (UAS) sheet to record and return after 1 week.
Baseline visit
Baseline UAS7 was recorded. UAS was calculated as wheals [0: no wheals; 1: <20 wheals/24 hours; 2: 20-50 wheals/24 hours; 3: >50 wheals/24 hours] and the itch severity scores (0: none, 1: mild (present but not annoying or troublesome), 2: moderate (present and annoying but not interfering with sleep), and 3: severe (present and interfering with sleep). Ease of estimation particularly in children was the reason of preference over use of urticaria total severity score.
Autologous serum skin test (ASST) was done at baseline visit. 5 ml venous blood of the patient was drawn with a sterile, disposable syringe from the antecubital vein in sterile BD Vacutainer® (BD, NJ USA) for serum collection. The blood was subjected to centrifugation using centrifuge machine (R-8C laboratory centrifuge, REMI laboratory instruments, Mumbai, India) at the rate of 2000 rpm for 10 min at room temperature. 0.05 ml of the serum thus separated was injected immediately intradermally into the patients’ left flexor forearm 2 inches below the antecubital crease and 0.05 ml sterile normal saline as negative control into right forearm using 31 G sterile disposable 1 ml BD insulin syringe (BD, NJ USA). The beveled end of the needle was kept in the upward direction producing a palpable bleb on the skin. Areas which were involved by spontaneous wheals within last 48 h were avoided. A reading of the weal was taken after 30 min. Patients having weal of more than 1.5 mm perpendicular diameter than that of control were considered to be suffering from autoreactive urticaria (ASST positive). All patients irrespective of ASST result were given autologous serum therapy. 2 ml of the fresh serum separated from the patients’ blood (as stated above) was given deep IM into the upper arm. Patients were asked to take levocetirizine 5 mg tablet on an on-demand basis but not more than 1 tablet/day. Caregivers were given UAS sheets to record disease activity on a daily basis. In case of any untoward side effects, caregivers were instructed to contact the investigator.
Follow-up visits
Patients were given AST therapy at an interval of 2 weeks for a total of eight visits including baseline. UAS7 score was calculated at each visit. UAS7 score was primary effectiveness parameter. Pill burden using a score (0 = none/week, 1 = less than once or once/week, 2 = 2-3 times/week, 3 = daily or almost daily/week) was recorded at each visit. Patient’s Global Assessment scale (PGA) and Physician Global Assessment scale (PHGA) was calculated at each visit using a 5-point Likert scale (0: no improvement, 1: mild improvement, 2: moderate improvement, 3: marked improvement, and 4: excellent improvement). Spontaneously reported adverse effects were noted at each visit. Baseline investigations were repeated at end of eighth visit.
Outcome measures
Primary effectiveness outcome: Reduction in mean UAS7 score between baseline and week 14.
Secondary effectiveness outcome: Comparison of reduction in mean UAS between ASST positive and ASST negative group. Reduction in pill burden and comparison with reduction in UAS7 between baseline and week 14.
Safety outcome parameters: Incidence of spontaneously reported adverse events and incidence of laboratory disturbances between baseline and week 14 were recorded.
Statistical analysis
The sample size of 29 patients was taken over a duration of 1 year. It was a time-bound study, so we recruited patients presenting during that duration. Baseline demographic data, pill burden, and safety data are presented as mean and standard deviation with 95% confidence interval. Urticaria activity score (UAS) is presented as mean with standard deviation at 95% confidence interval and median. Modified intention to treat analysis was carried out in patients reporting for at least one follow-up visit. Last observation was carried forward to address the missing data either due to dropouts or patients who achieved remission. Pre- and post-treatment laboratory values were compared in patients for whom both sets of data were available. All data was analyzed using SPSS version 26.
Results
A total of 29 patients were screened for eligibility criteria, and five patients were excluded (three did not meet eligibility criteria and two did not give consent to participate). Two patients were further lost to follow-up (failing to report for at least one follow-up), and 22 patients were analyzed with modified intention to treat analysis. Out of 22 patients, 12 were females and 10 were males. The mean age of patients was 12.09 ± 2.26 years. The mean duration of chronic spontaneous urticaria was 6.77 ± 2.02 months. The mean weight was 34.18 ± 5.39 kilograms. ASST positivity was seen in 14 out of 22 patients. Both the ASST positive and negative groups were comparable at baseline [Table 1 ].
Table 1: ASST positive Vs ASST negative group
There was statistically significant improvement in the mean UAS7 at week 14 compared to baseline (P < 0.0001). Significant reduction was noted from the fourth visit after initiation of therapy. The reduction in mean UAS7 score correlated positively with the improvement in patient and physician global assessment scale [Figure 1 ]. The reduction in UAS7 was also associated with a simultaneous reduction in the pill burden [Figure 2 ].
Figure 1: Co-relation between reduction in mean UAS7 and PGA and PHGA, PGA: Patient’s Global Assessment scale, PHGA: Physician Global Assessment scale, 5-point Likert scale (0: no improvement, 1: mild improvement, 2: moderate improvement, 3: marked improvement, 4: excellent improvement)
Figure 2: Comparison between mean UAS7 and pill burden; pill burden, 0 = none/week, 1 = less than once or once/week, 2 = 2–3 times/week, 3 = daily or almost daily/week
Reduction in UAS7 between baseline and week 14 was statistically significant in both the ASST positive and ASST negative groups (P = 0.001, ASST positive group) (P = 0.005, ASST negative test) [Figure 3 ]. However, intergroup comparison revealed no statistically significant difference between the two groups (P < 0.05) [Table 2 ].
Figure 3: Mean UAS7 between baseline and week 14 in ASST positive and ASST negative groups
Table 2: Table of P value of mean UAS7 between baseline and week 14 in ASST positive and ASST negative groups
Injection site pain was the most commonly reported adverse effect in 50% of patients. None of the parents reported any cognitive impairment during the autologous serum therapy. Laboratory parameters at the baseline and eighth visit were comparable.
Discussion
A subset of adult and pediatric patients (40%) with chronic urticaria has a type IIb autoimmune basis for their disease pathogenesis. It is hypothesized that autoantibodies to the high-affinity IgE receptor are responsible for the mast cell and basophil degranulation via cross-linking of IgE receptors.[ 7 ] This subgroup is termed as autoimmune urticaria whose prevalence ranges from 27 to 61%.[ 6 ] There are two methods of detecting these autoantibodies by either an in vivo test such as the autologous serum skin test (ASST) or in vitro test such as the basophil histamine assay.[ 8 ] In children with chronic urticaria, ASST positivity rates have been found in the range of 35–47%.[ 9 , 10 ] In our study, a slightly higher incidence of 63% was found.
Children with chronic urticaria suffer from the high disease morbidity due to the irritable itch and wheals and are also subjected to a huge antihistamine pill burden. Several studies reported that, in children with CU, discomfort caused by itching, aesthetic aspect, and unpredictability of manifestations can lead to anxiety and a higher risk of depression. The unpredictability disease course, high pill burden, and impaired quality of life associated with CSU in children warrants the need for adjuvant therapies so as to reduce the morbidity associated with the disease. Autologous serum therapy is a promising therapeutic option that has been explored in the adult population for chronic urticaria. It works on the principle of induction of anti-idiotypes to counteract the autoantibodies in patients with autoimmune urticaria and also by possibly shifting Th2 response to Th1 type in patients with ASST positivity.[ 11 ] Debberman et al . and Karn et al . have reported that weekly injections of intramuscular AST in adult patients with chronic urticaria show statistically significant improvement compared to placebo.[ 6 , 12 ] A study comparing intramuscular and subcutaneous AST therapy in adult chronic urticaria patients has reported that subcutaneous injection is not inferior to intramuscular route of administration.[ 13 ] In our pilot, we found encouraging results in the use of AST in pediatric patients with chronic urticaria. There was statistically significant improvement in UAS7 score from the fourth visit onward after initiation of two weekly AST therapies. The reduction in UAS7 score was also associated with improvement in both the patient and physical global assessment score and a significant reduction in the antihistaminic pill burden.
Although, traditionally, the AST therapy was assumed to have a role only in those subset of chronic urticaria patients with ASST positivity, many studies have documented efficacy in ASST negative patients as well.[ 6 , 12 ] The underlying pathomechanism, however, remains to be understood. In our study as well, we found that both the ASST positive and ASST negative groups both responded to the AST therapy; however, there was no statistically significant difference between the two groups.
The safety parameters were encouraging with no deleterious cognitive impairments reported to the therapy among children in our study. The laboratory parameters were also comparable compared to baseline. These findings corroborate to studies in the adult counterpart.[ 14 ]
Limitations
There was no control group and there was no followup after completion of the study period.
Conclusion
In conclusion, two weekly AST therapies represent a viable option for children with CSU not responding to conventional antihistaminic up dosing. Apart from being efficacious in pediatric CSU, autologous serum therapy helps to reduce pill burden without any deleterious side-effects to the child’s development. This study has explored the efficacy and safety of autologous serum therapy in the pediatric CSU patients with promising results. Both ASST positive and ASST negative groups respond to AST therapy and help reduce pill burden. A comparative study with a placebo group may be a future research prospect to confirm findings noted in our study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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