Serum IgA contributes to the comprehension of Anisakis simplex associated chronic urticaria.

The phenotype of allergic diseases associated with Anisakis determines the pattern of cytokines related to antibody production. However, the role of serum IgA and the immunomodulatory mechanisms exerted by active infection of L3 or passive mucosal contact with A. simplex specific antigens has not been studied before. We measured serum cytokine by flow cytometry (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-17A, TGF-ß1) and antibody levels (IgE, IgG4, IgA) by ELISA against total and excretory-secretory (ES) antigens, Ani s 3,and the group of major allergens Ani s 1, Ani s 7, and Ani s 13 in sera from 10 patients with gastro-allergic anisakiasis (GAA), 11 Anisakis sensitization associated chronic urticaria (CU+) as well as 17 non-Anisakis-sensitized patients with chronic urticaria (CU-), compared with the urticaria control group (18 subjects). Specific IgE, IgG4 and IgA were high in the GAA, but IgA levels were significantly higher in the CU+ with respect the CONTROL group. We observed higher levels of the ratio IgA/IgG4 in CU+ than GAA group for Ani s 1, Ani s 7, Ani s 13 and ES. Furthermore, chronic urticaria (CU) patients showed significant lower levels of IL-10, IFN-γ and IL-17A than patients without CU. The anti-Ani s 13 IgA/IgG4 ratio correlated positively with pro-inflammatory cytokines and ratios (TNF-α, IL-17A, Th17/Th2, Type1/Type2 and TNF-α/IL-10) in CONTROL group. In general, Anti-Anisakis IgA/G4 ratio was high in CU patients. In conclusion, this study demonstrates the importance of serum IgA because it is associated with chronic urticaria independently of Anisakis sensitization.

Current perspectives and future directions in the management of chronic spontaneous urticaria and their link to disease pathogenesis and biomarkers.

Chronic spontaneous urticaria (CSU) is a relatively common, persistent, debilitating inflammatory skin disorder, having a global point prevalence ~0.5-1%. This disorder considerably worsens the patient's quality of life, and also poses a burden for the society. It is primarily an IgE mediated mast cell disorder, histamine being the principal mediator. So, the current treatment recommendations are aimed at antagonizing the effect of histamine, block mast cell activation by reducing IgE, or immunomodulate the inflammatory response. However, almost one in five CSU patients remain uncontrolled with the current safe treatments comprising antihistamines and add-on anti-IgE omalizumab. Thus, newer and more targeted therapeutic strategies are needed to overcome this unmet need, based on the various interlinked ligands and receptors involved in disease pathogenesis. Considerable progress has been made in understanding the pathogenesis of CSU, beyond the IgE-FceR1-mast cell axis, which has enabled the development of newer and more targeted promising therapeutic strategies. Several biomarkers are also being evaluated which would better define the disease characteristics and foretell treatment outcome even before its initiation. This would enable specific and targeted precision therapy based on disease characteristics, with better effectiveness-safety ratio. The present article discusses the current understanding about CSU, and recent up-to-date perspectives pertaining to disease pathogenesis, emerging treatments, and their link to biomarkers. These authors hope that the article would be helpful for all specialists and CSU treating physicians, in providing optimum care to their patients, based on latest evidence and concepts.

How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19.

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways.

Effects of the immunoglobulin/histamine complex on panic disorder concurrent with chronic spontaneous urticaria: a case report.

BACKGROUND: Panic disorder and panic attacks are two of the most common problems in psychiatry. A psychoimmunological correlation between allergic diseases and panic disorder has been strongly suggested. Histamine H1 receptor antagonists have been suggested as alternative drugs for the treatment of panic disorder. Chronic spontaneous urticaria (CSU) and panic disorder improved simultaneously with selective serotonin reuptake inhibitor antidepressants. Panic disorder has also been treated with the antihistamine chlorpheniramine. The immunoglobulin/histamine complex is a histamine-fixed immunoglobulin preparation that was reported to be effective in treating CSU. This case report describes the successful treatment of a patient with concomitant panic disorder and CSU for 23 years using immunoglobulin/histamine complex therapy. CASE PRESENTATION: This report describes a 52-year-old female Korean patient who suffered from CSU with panic disorder for 23 years. Basic allergy tests (blood tests and skin prick tests) were conducted before and after treatment for the evaluation of allergic conditions. A multiple allergosorbent test (MAST) for the detection of allergen-specific IgE levels was also performed. The clinical severity of CSU was evaluated using the urticaria severity score system. Diagnostic interviews systematically assessed the diagnostic criteria outlined by the DSM-V, and the patient was evaluated before, during and after treatment using the Beck Depression Inventory (BDI-2) for depression, the State-Trait Anxiety Inventory (STAI) for anxiety and the Beck Hopelessness Score (BHS) for hopelessness. The patient received 2 ml of Histobulin™ (12 mg human immunoglobulin/0.15 µg histamine complex) once a week by subcutaneous injection for the treatment of CSU. Initial improvement of CSU was achieved after the third injection. After the twenty-seventh injection of Histobulin™, she showed no symptoms or signs and ceased allergic medication use. With the remission of CSU, allergic rhinitis was also completely resolved. The frequency of the common cold was significantly decreased during and after treatment. The medication frequency and development of clinical manifestations of panic disorder changed in parallel with the clinical severity of CSU. Moreover, the patient exhibited no clinical manifestations and ceased medication for panic disorder and sleeping pills for insomnia simultaneously with the remission of CSU. In the psychological evaluation, the BDI, STAI and BHS scores improved accordingly. CONCLUSIONS: The immunoglobulin/histamine complex was effective in treating CSU and concomitant panic disorder in this patient and could be effective in treating some types of panic disorder. Considering the mechanisms of action of histamine and the immunoglobulin/histamine complex together with the patient's clinical progress, histamine seemed to be related to panic disorder in this case. The concept of histamine-mediated syndromes, including allergies and psychiatric disorders, shows that a wider disease identity may be needed. Further studies on the immunopathogenesis of panic disorder and the mechanisms of action of the immunoglobulin/histamine complex are necessary.

Physical urticaria: Clinical features, pathogenesis, diagnostic work-up, and management.

Physical urticaria is a type of urticaria in which recurrent wheals and/or angioedema occur following exposure of the skin to a physical stimulus. It is classified according to its triggers, which may be mechanical (friction, pressure, and vibration), thermal (cold and heat), or solar electromagnetic radiation. Symptoms of different physical urticarias can develop following specific activities that expose patients to an eliciting stimulus and may be variably accompanied by mucosal involvement and systemic symptoms, including nausea, headache, or even anaphylaxis. Differentiation of physical urticaria from other chronic urticarias requires careful clinical assessment and confirmatory provocation testing, which in turn can inform appropriate management. This clinical review provides an evidence-based summary of the epidemiology, clinical features, pathogenesis, diagnostic work-up, and management of physical urticaria.

Chronic Urticaria in Older Adults: Treatment Considerations.

Chronic urticaria is characterized by recurrent wheals and/or angioedema lasting for more than 6 weeks. Chronic urticaria is an extremely disabling disease limiting daily activities, compromising patient quality of life, and frequently associated with psychiatric comorbidities (depression and/or anxiety). Unfortunately, there are still gaps in the knowledge regarding treatment in special populations, especially in older patients. Indeed, there are no specific recommendations for the management and treatment of chronic urticaria in older people; therefore, recommendations for the general population are used. However, the utilization of some medications may be complicated by potential concerns of comorbidities or polypharmacy. Currently, the diagnostic and therapeutic procedures for chronic urticaria in the older patient are the same as those indicated for other age groups. In particular, there is a limited number of blood chemistry investigations for spontaneous chronic urticaria and specific tests for inducible urticaria. With regard to therapy, second-generation anti-H1 antihistamines are used and, in recalcitrant cases, omalizumab (an anti-IgE monoclonal antibody) and possibly cyclosporine A are additional choices. Nonetheless, it should be underlined that in older patients the differential diagnosis can be more difficult, owing to the lower frequency of chronic urticaria and the likelihood of other pathologies that are peculiar for this age group and that can be included in the chronic urticaria differential diagnosis. As far as therapy is concerned, the physiological characteristics of these patients, the possible comorbidities, and the intake of other medications often require a very attentive drug selection for chronic urticaria compared with other age groups. The purpose of this narrative review is to provide an update on the epidemiology, clinical characteristics, and management of chronic urticaria in older patients.

Clinical features of patients with chronic spontaneous urticaria associated with autoimmune thyroiditis.

The aim of the study was to focus on children with both chronic spontaneous urticaria (CSU) and autoimmune thyroiditis (AT) as this topic is rarely studied in children although some publications show a higher proportion of antithyroid antibodies in children with CSU. We highlight two cases of children with both CSU and AT and compare their data with reports from the literature. Since only case reports or case series were available, we performed a descriptive analysis of 15 patients. There were 7 (46.7%) cases of hypothyroidism and the rest were euthyroid. Hypothyroidism appears before, during, and after the diagnostic of CSU. One patient with hypothyroidism and one with euthyroidism receiving l-thyroxine experienced remission of urticaria. Three patients over 12 years of age (20%) received omalizumab. Three patients (20%) had another autoimmune disease and seven (58.3%) had a family history of thyroid disease or autoimmune disease. CONCLUSION: Children with CSU need repeated testing for antithyroid antibodies. Children with both CSU and AT require close medical supervision focused on the development of other autoimmune diseases. l-thyroxine may improve urticaria in patients with hypothyroidism, but there is not enough evidence for patients with euthyroidism. Omalizumab may be of benefit in this population but well-controlled studies in children with AT and CSU are needed.

Can chronic spontaneous urticarial produce symptoms of neuropathic pain?

BACKGROUND: Chronic spontaneous urticaria (CSU) is a condition that is associated with recurrent pruritic hives and/or angioedema lasting for more than 6 weeks and is known to affect 1% of the population. Neuropathic pain can be defined as abnormal pain in the peripheral or central nervous system following injury and results from dysfunctions in the peripheral or central nervous system without peripheral nociceptor stimulation. Histamine appears in the pathogenesis of both the CSU and diseases of the neuropathic pain spectrum. OBJECTIVE: To evaluate the symptoms of neuropathic pain in patients with CSU using scales. METHOD: Fifty-one patients with CSU and 47 sex- and age-matched healthy controls were included in the study. RESULTS: The results of the short-form McGill Pain Questionnaire revealed the scores in the sensory and affective domains, Visual Analogue Scale (VAS) scores and pain indices to be significantly higher in the patient group (p < 0.05 for all cases), while the overall pain assessment and sensory assessment based on the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale were also significantly higher in the patient group. Based on the assumption that scores of > 12 indicated neuropathy, 27 (53%) of the patients in the patient group and 8 (17%) in the control group were found to have neuropathy (p < 0.05). STUDY LIMITATIONS: Cross-sectional study, small patient sample and use of self-reported scales. CONCLUSION: In addition to itching, patients with CSU should be aware of the potential for the association of neuropathic pain. In this chronic disease that is known to affect the quality of life, using an integrated approach with the patients and identifying accompanying problems are as important as treating the dermatological disorder.

Alpha-gal syndrome initially misdiagnosed as chronic spontaneous urticaria in a pediatric patient: a case report and review of the literature.

INTRODUCTION: Delayed allergy to red meat, also termed alpha-gal syndrome, is increasingly reported in adults and African communities, while pediatric cases remain rare. CASE PRESENTATION: Here, we report on a 7-year-old Caucasian boy presenting with recurrent wheals since the age of 5 years old. Episodes with hives occurred around every 3 weeks, mainly in the evening. One of these episodes was also associated with angioedema. No clear trigger was identified. At the first visit, after excluding an infection and autoimmune thyroiditis, chronic spontaneous urticaria was suspected and symptomatic treatment with antihistamines was prescribed. Six months later, the boy presented at the emergency room with generalized urticaria, dyspnoea, and emesis. Symptoms resolved after administration of epinephrine and antihistamines. A detailed medical history after this event revealed that he had eaten three sausages as well as jelly beans containing gelatine several hours prior to this episode. More precisely, after eating the sausages and jelly beans during the day, he had shown some hives before going to bed, and later developed the other symptoms in the middle of the night, suggesting alpha-gal syndrome. In his history, several tick bites are reported. Immunoglobulin E levels for alpha-gal were clearly elevated, confirming the diagnosis of a delayed-appearing immunoglobulin E-mediated allergic reaction to alpha-gal. Emergency medication was prescribed and avoidance of red meat and gelatine-containing foods was recommended. Under this exclusion diet, the boy remained asymptomatic, with the exception of two accidents in the follow up of 3 years, one developing during a barbecue and the second after exceptionally eating marshmallows. CONCLUSION: A detailed clinical history led to the diagnosis of alpha-gal syndrome. Although alpha-gal syndrome is typically seen in adults, our case illustrates that children can also present with this potentially life-threatening allergy. Since alpha-gal syndrome is rare in Europe, the disease is not well known and often overlooked for several years, especially in children.

Chronic Spontaneous Urticaria in Patients With Interstitial Cystitis/Bladder Pain Syndrome: Insights From Big Data Analyses.

OBJECTIVE: To examine the association between chronic spontaneous urticaria (CSU) and interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A population-based retrospective cross-sectional study was performed using the Clalit Health Services medical database. The prevalence of CSU was compared between patients diagnosed with IC/BPS and age- and gender-matched controls. Univariate analysis was performed using Chi-square and Student t test and a multivariable analysis was performed using a logistic regression model. RESULTS: The study included 681 patients with IC/BPS and 3376 demographically matched controls. The mean age of IC/BPS patients was 60 years old. The prevalence of CSU among patients with IC/BPS was higher as compared to the control group (20% vs 13.7%; P <.001). The adjusted OR for CSU in patients with IC/BPS was 1.58 (95% CI 1.28-1.97). Female gender and Jewish ethnicity were associated with the coexistence of these disorders (OR 1.7 95% CI 1.36-2.13, and 1.6 95% CI 1.28-2, respectively). CONCLUSION: A significant association was found between IC/BPS and CSU. This finding may support the presence of allergic/immune components in the pathogenesis of IC/BPS.

Retrospective evaluation of patients with chronic spontaneous urticaria using omalizumab during the COVID-19 pandemic.

INTRODUCTION: Omalizumab (OMZ) is a monoclonal anti-immunoglobulin E antibody used in patients with chronic spontaneous urticaria (CSU). The data about using OMZ during the coronavirus disease 19 (COVID-19) pandemic are limited. The aim of this study was to evaluate the status of having COVID-19 and relationships between COVID-19, vaccination, and urticaria symptoms of CSU patients on OMZ. METHOD: We conducted a retrospective cohort study of 36 adult CSU patients treated with OMZ. Demographic data, the results of COVID-19 real-time polymerase chain reaction (RT-PCR), and vaccination status were recorded from the electronic medical records. RESULTS: Thirty-six patients, 23 women, and 13 men were evaluated. The mean age was 45.81 years. Two patients were diagnosed with COVID-19 while using OMZ. Four patients interrupted their OMZ treatment during the pandemic, and OMZ treatments were restarted in all patients. There were 28 patients who had at least one dose of vaccine (inactive and/or mRNA vaccine). Only one patient had an urticaria exacerbation after the first dose of mRNA vaccine. CONCLUSION: As a result, our findings have shown that omalizumab treatment in CSU patients during the COVID-19 pandemic does not increase the risk of COVID-19 infection and omalizumab can be used safely.

Association between the severity of chronic spontaneous urticaria and sleep-disordered breathing.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common mast cell-driven disease, presenting with wheals, angioedema, or both. Sleep-disordered breathing (SDB) is also a common condition and contributes to various diseases by causing chronic inflammation. Recent studies have suggested an association between CSU and SDB. METHODS: To determine the association between the severity of SDB and that of CSU, we studied consecutive patients with CSU who visited the Sagamihara National Hospital allergy department or dermatology department between April 1 and October 31, 2018. The severity of CSU and SDB was evaluated based on the urticaria activity score 7 (UAS7) and peripheral arterial tone apnea-hypopnea index (pAHI) derived from out-of-center sleep testing (OCST) findings, respectively; their correlation was examined. RESULTS: Of the 37 patients studied, 19 had symptom-free-to-mild CSU (UAS7 ≤15) and 18 had moderate-to-severe CSU (UAS7 ≥16). The pAHI in the latter group was significantly higher than that in the former group (18 vs. 4.2, p = 0.001). In multivariate logistic analysis, moderate-to-severe SDB (pAHI ≥15) was significantly associated with moderate-to-severe CSU even after adjusting for the BMI (adjusted odds ratio 22 [95% confidence interval, 1.7-285]). CONCLUSIONS: The severity of SDB is correlated with that of CSU independently of the BMI. Physicians should consider comorbid SDB when treating patients with CSU.

Clinical difference between single subtype and mixed subtype chronic urticaria: A retrospective study.

BACKGROUND: The subtypes of chronic urticaria share a common clinical expression, but may show differences phenotypically. Meanwhile, two or more different subtypes of chronic urticaria can coexist in any given patient which may involve different phenotypes. AIMS: The study aims to compare the two phenotypes in terms of demographics, clinical profile and treatment response. METHODS: In this retrospective study, 2678 chronic urticaria patients were divided into the single subtype chronic urticaria group and mixed subtype chronic urticaria group as was appropriate.The differences in the clinical features, possible causes, urticaria activity score of seven days, dermatology life quality index score, laboratory investigations and response to treatments were evaluated among the two groups. RESULTS: An obvious female predominance was detected in chronic urticaria, especially in mixed subtype chronic urticaria patients. Of the 2678 chronic urticaria patients, there were 837(31.25%) mixed subtype chronic urticaria. Chronic spontaneous urticaria combined with symptomatic dermographism was the most common group in the mixed subtype chronic urticaria. Patients with mixed subtype chronic urticaria were more likely to have associated chest tightness/shortness of breath and showed greater urticaria activity. In patients with single subtype chronic urticaria, the positive rate of family history with allergic rhinitis, asthma or urticaria was lower. Based on evaluation of the treatment, control with second-generation antihistamines at licensed doses was achieved in only 38.83% of mixed subtype chronic urticaria patients, compared with 56.32% of patients with single subtype. LIMITATIONS: First, this study was a single-center design retrospective study. Second, omalizumab treatment was not included. Third, the differences between different subtypes of mixed subtype chronic urticaria were not discussed in detail. CONCLUSION: This study showed that mixed subtype chronic urticaria had some distinct features. Comprehensive knowledge about it may help us define effective therapeutic strategies and improve symptom control and the quality of life for chronic urticaria patients.

A case report of hypocomplementemic urticarial vasculitis presenting with membranoproliferative glomerulonephritis.

BACKGROUND: Hypocomplementemic urticarial vasculitis syndrome is an infrequent condition characterized by ocular, renal, gastrointestinal and pulmonary involvement with low serum complement levels and autoantibodies. Renal manifestations vary from microscopic hematuria to nephrotic syndrome and acute kidney injury. Accordingly differing histologic patterns have been reported. CASE PRESENTATION: We present the case of a 65 years old woman with a history of chronic uveitis who presented with arthralgias, urticarial rush, nephrotic syndrome, glomerular hematuria and low serum complement. Kidney biopsy revealed an immune-complex membranoproliferative glomerulonephritis. The patient received induction therapy with steroids, cyclophosphamide and hydroxychloroquine followed by rapid clinical improvement and remission of proteinuria. Maintenance treatment consisted of rituximab pulses. CONCLUSIONS: The majority of hypocomplementemic urticarial vasculitis syndrome cases is idiopathic, although an association to drugs, infections or other autoimmune disorders has been recorded. Given the rarity and heterogeneity of the disease, no standard treatment is established.

Characteristics and determinants of patient burden and needs in the treatment of chronic spontaneous urticaria.

BACKGROUND: Treatment of chronic spontaneous urticaria (CSU) is founded on evidence-based guidelines. However, specific patient needs and benefits of therapy have not been outlined at the guideline level. OBJECTIVES: The aim of this study was to characterise the specific needs and treatment goals in chronic spontaneous urticaria from the patient's perspective. MATERIALS AND METHODS: This cross-sectional study was conducted in four German outpatient dermatology clinics. Patient needs and potential therapy goals were determined with the validated Patient Needs Questionnaire (PNQ) using a specific version for chronic urticaria. Further instruments to characterise the link between patient needs and disease burden were disease-specific (CU-Q2oL), skin-generic (DLQI) and health-generic (EQ VAS) scales. RESULTS: Data from 103 patients were analysed (age: 43.92 ± 14.96 years; 71.4% female). Among the most important therapeutic goals were the absence of visible skin lesions (92.3% important/very important), to be free of itching (91.5%) and the desire to be healed of all skin defects (89.5%). All 26 items were found to be quite important/very important by at least 30% of the respondents. Specific profiles of patient needs were found to be related to sex and disease duration. CONCLUSION: Innovative drugs and patient-centred individualised treatment may increase overall benefits. Regardless of the treatment chosen, shared decision making in the management of the disease should be a goal.

Efficacy and Safety of Omalizumab for Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Omalizumab has been proposed as a possible effective treatment of chronic spontaneous urticaria (CSU). STUDY QUESTION: We aimed to access the efficacy and safety of omalizumab in the treatment of CSU based on qualified, randomized controlled trials (RCTs). DATA SOURCES: PubMed, the Cochrane library, and Embase databases. STUDY DESIGN: Computerized search by index words was performed to identify qualified RCTs, and relevant literature sources were also searched. RESULT: Nine RCTs were included in the meta-analysis with 1612 patients in the omalizumab group and 1251 patients in the placebo group. Compared with the placebo group, omalizumab significantly decreased the weekly itch score after therapy [Weighted Mean Difference (WMD), -3.94; 95% confidence interval (CI), -4.64 to -3.24], the weekly hive score (WMD, -5.27; 95% CI, -6.17 to -4.38), the dermatology life quality index (DLQI; WMD, -3.58; 95% CI, -4.66 to -2.50), and the urticaria activity score over 7 days (UAS7; WMD, -9.51; 95% CI, -10.94 to -8.08). There was no significant difference in the incidence of adverse events (AE) [relative risk (RR), 1.01; 95% CI, 0.91-1.12], serious AE (RR, 0.85; 95% CI, 0.57-1.27), and severe AE (RR, 0.83; 95% CI, 0.60-1.14) between the 2 groups. Compared with the placebo, omalizumab significantly decreased the weekly itch score and weekly hive score after therapy in patients receiving 75, 150, and 300 mg omalizumab, respectively. DLQI was significantly reduced in patients receiving 150 and 300 mg of omalizumab, respectively. In all the subgroup of UAS7, omalizumab significantly decreased the score compared with the placebo. Only patients receiving 600-mg omalizumab had a significantly higher AE incidence versus placebo. There was no significant difference in serious and severe AE between the 2 groups. CONCLUSION: Omalizumab caused a significantly greater reduction in weekly itch score, weekly hive score, DLQI, and UAS7 in CSU patients than the placebo. However, high-quality, multicenter RCTs with a larger sample size are needed to confirm the safety of omalizumab, and whether AEs are caused by omalizumab or other factors.

Celiac disease in the context of airborne allergen-associated chronic vulvo-vaginitis.

We present a woman with a three-year history of severe chronic urticaria and recurrent vulvo-vaginal Candidiasis in the setting of seasonal allergic rhinitis. Her past medical history was significant only for Bell's palsy in her childhood. Her review of systems was otherwise negative (specifically: no history of diarrhea, weight loss, malabsorption, anemia, nor eczema). Extensive testing revealed seasonal sensitivities to outdoor allergens and celiac disease. Repeating the evaluation six months after initiating a wheat-free diet, her vulvo-vaginal symptoms resolved.