Drug Allergy in Women.

Across all settings, women self-report more drug allergies than do men. Although there is epidemiologic evidence of increased drug allergy labeling in postpubertal females, the evidence base for female sex as a risk factor for true immune-mediated drug hypersensitivity reactions (DHRs), particularly in fatal drug-induced anaphylaxis, is low. A focus on the known immunologic mechanisms described in immediate and delayed DHR, layered on known hormonal and genetic sex differences that drive other immune-mediated diseases, could be the key to understanding biological sex variations in DHR. Particular conditions that highlight the impact of drug allergy in women include (1) pregnancy, in which a drug allergy label is associated with increased maternal and fetal complications; (2) multiple drug intolerance syndrome, associated with anxiety and depression; and (3) female-predominant autoimmune medical conditions in the context of mislabeling of the drug allergy or increased underlying risk. In this review, we describe the importance of drug allergy in the female population, mainly focusing on the epidemiology and risk, the mechanisms, and the associated conditions and psychosocial factors. By performing a detailed analysis of the current literature, we provide focused conclusions and identify existing knowledge gaps that should be prioritized for future research.

Worldwide Prevalence of Antibiotic-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis.

Importance: Antibiotics are an important risk for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), which are the most severe types of drug hypersensitivity reaction with a mortality rate up to 50%. To our knowledge, no global systematic review has described antibiotic-associated SJS/TEN. Objective: To evaluate the prevalence of antibiotics associated with SJS/TEN worldwide. Data Sources: The MEDLINE and Embase databases were searched for experimental and observational studies that described SJS/TEN risks since database inception to February 22, 2022. Study Selection: Included studies adequately described SJS/TEN origins and specified the antibiotics associated with SJS/TEN. Data Extraction and Synthesis: Two reviewers (E.Y.L. and C.K.) independently selected the studies, extracted the data, and assessed the risk of bias. A meta-analysis using a random-effects model was performed in the studies that described patient-level associations. Subgroup analyses were performed to explore the heterogeneity. The risk of bias was assessed using the Joanna Briggs Institute checklist, and the certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Main Outcomes and Measures: Prevalence of antibiotic-associated SJS/TEN was presented as pooled proportions with 95% CIs. Results: Among the 64 studies included in the systematic review, there were 38 studies that described patient-level associations; the meta-analysis included these 38 studies with 2917 patients to determine the prevalence of single antibiotics associated with SJS/TEN. The pooled proportion of antibiotics associated with SJS/TEN was 28% (95% CI, 24%-33%), with moderate certainty of evidence. Among antibiotic-associated SJS/TEN, the sulfonamide class was associated with 32% (95% CI, 22%-44%) of cases, followed by penicillins (22%; 95% CI, 17%-28%), cephalosporins (11%; 95% CI, 6%-17%), fluoroquinolones (4%; 95% CI, 1%-7%), and macrolides (2%; 95% CI, 1%-5%). There was a statistically significant heterogeneity in the meta-analysis, which could be partially explained in the subgroup analysis by continents. The overall risk of bias was low using the Joanna Briggs Institute checklist for case series. Conclusion and Relevance: In this systematic review and meta-analysis of all case series, antibiotics were associated with more than one-quarter of SJS/TEN cases described worldwide, and sulfonamide antibiotics remained the most important association. These findings highlight the importance of antibiotic stewardship, clinician education and awareness, and weighing the risk-benefit assessment of antibiotic choice and duration.

Interleukin-6 and cytokine release syndrome: A new understanding in drug hypersensitivity reactions.

Immediate drug hypersensitivity reactions (DHRs) are historically thought to be because of immunoglobulin E (IgE) cross-linking, causing mast cell degranulation and release of mediators like tryptase and histamine. With the increasing use of monoclonal antibodies, it has become apparent that some patients present atypical features during immediate DHRs, including occurrence in initial exposure, a lack of urticaria and angioedema, and the presence of fever, chills, rigors and musculoskeletal pain as the predominant symptoms. This observation led to the recognition of a novel phenotype of immediate DHRs called cytokine release syndrome (CRS). Other types of immediate DHRs include infusion-related reactions (which present similarly to CRS), and mixed reactions (which share overlapping features of both type 1 reactions and CRS). Desensitization to culprit drugs can be a lifesaving option in patients who develop immediate DHRs to first-line treatment. Whereas robust data are supporting the safety and efficacy of drug desensitization, breakthrough reactions can still occur and CRS seems to be a more common cause than type 1 reactions. Tryptase has been the only available biomarker for immediate DHRs and is associated with type 1 reactions. Emerging evidence consistently found the association between increased serum interleukin 6 level and DHR-related CRS, suggesting that interleukin 6 can be a novel biomarker, in addition to tryptase, to distinguish various types of DHRs. In the era of precision medicine, phenotyping and endotyping hypersensitivity reactions to chemotherapy and monoclonal antibodies using validated biomarkers should be part of routine drug allergy care.

Monitoring patients with uncomplicated common variable immunodeficiency: a systematic review.

BACKGROUND: Non-infectious complications have become a major cause of morbidity and mortality in patients with Common Variable Immunodeficiency (CVID). The monitoring of patients with CVID prior to the development of non-infectious complications is not well defined. OBJECTIVE: Our objectives were to systematically review the current literature on the monitoring of CVID patients without non-infectious complications and to develop recommendations for such monitoring. METHODS: MEDLINE and EMBASE were searched from January 1st, 2000 to March 25th, 2021. Studies on any aspects of CVID monitoring were included. Studies that included only children, on monitoring CVID patients with existing non-infectious complications, or in the format of case reports were excluded. RESULTS: Nine studies on CVID monitoring, including 3 cohort studies, 3 experts' opinions, 2 consensus statements and a single guideline report were identified. These studies revealed that clinical assessment and bloodwork were preformed every 6 to 12 months in asymptomatic patients. Some centers performed computerized tomography scan of the chest every 2-5 years to identify chronic lung disease, although the majority did chest imaging in accordance with clinical indications. Pulmonary function tests were done annually at most centers. Most studies did not address the role of abdominal imaging to screen for liver diseases or endoscopy to screen for gastric cancer in asymptomatic patients with uncomplicated CVID. CONCLUSIONS: There is paucity of evidence-based information to guide the routine monitoring of CVID patients without non-infectious complications. Prospective studies are needed to determine the best monitoring practices in this group of patients.

Demographic and clinical characteristics of patients with hereditary angioedema in Canada.

BACKGROUND: Data on the clinical and demographic features of Canadian patients with hereditary angioedema (HAE) are lacking. OBJECTIVE: To describe the clinical and demographic features in a large Canadian HAE cohort and compare them with patients with HAE in other countries. METHODS: An online questionnaire was distributed to the members of 2 Canadian HAE patient groups to collect information on demographics and HAE clinical characteristics. All participants 18 years of age or older with HAE type I or II were eligible. Frequency, location, prodromes, and triggers of HAE attacks, including types of HAE treatment, were characterized. RESULTS: Among the 90 participants who completed the online survey, 57% self-identified as having HAE type 1 and 26% HAE type II. The average diagnostic delay was 11 years. In the preceding 6 months, 24% of the participants had no attacks and 35% experienced greater than 5 attacks. The most frequently affected regions of the body were the abdomen (83%), arms orlegs (63%), face (41%), and larynx or throat (41%). Approximately 87% of the participants reported having access to C1 inhibitor at home, and 69% reported using it for long-term prophylaxis. CONCLUSION: Canadian patients with HAE share common clinical characteristics with patients with HAE in other countries. They had a delay in HAE diagnosis and a high burden of disease, as indicated by the high frequency of attacks in the preceding 6 months. This study provides a better understanding of the demographic and clinical characteristics of Canadian patients with HAE.

Characterizing telemedicine use in clinical immunology and allergy in Canada before the COVID-19 pandemic.

RATIONALE: There exists a geographic barrier to access CIA care for patients who live in rural communities; telemedicine may bridge this gap in care. Herein we characterized the use of telemedicine in CIA at a population-based level and single centre. METHODS: Before the COVID-19 pandemic, telemedicine care was provided via the Ontario Telemedicine Network (OTN) in Ontario, Canada. Descriptive data were collected from the OTN administrative database and from electronic medical records at a single academic centre during 2014 to 2019. The potential distance travelled and time saved by telemedicine visits were calculated using postal codes. RESULTS: A total of 1298 telemedicine visits was conducted over OTN, with an average of 216 visits per year. Only 11% of the allergists/immunologists used telemedicine to provide care before the COVID-19 pandemic. In the single centre that provided the majority of the telemedicine care, 66% patients were female and the overall mean age was 46. The most common diagnosis was immunodeficiency (40%), followed by asthma (13%) and urticaria (11%). Most patients required at least one follow-up via telemedicine. The average potential two-way distance travelled per visit was 718 km and the average potential time travelled in total was 6.6 h. CONCLUSION: Telemedicine was not widely used by allergists/immunologists in Ontario, Canada before the COVID-19 pandemic. It could offer a unique opportunity to connect patients who live in remote communities and allergists/immunologists who practice in urban centres in Canada. Independent of the current pandemic, our study further highlights the need for more physicians to adopt and continue telemedicine use as well as for healthcare agencies to support its use as a strategic priority once the pandemic is over.

Immediate hypersensitivity reaction followed by successful oral desensitization to ursodiol.

BACKGROUND: Immediate hypersensitivity reaction to ursodiol is rare and there is no previously published protocol on ursodiol desensitization. CASE PRESENTATION: A 59-year-old woman with primary biliary cholangitis (PBC) developed an immediate hypersensitivity reaction to ursodiol-the first-line treatment for PBC. When she switched to a second-line treatment, her PBC continued to progress. As such, she completed a novel 12-step desensitization protocol to oral ursodiol. She experienced recurrent pruritus after each dose following desensitization, which subsided after a month of being on daily ursodiol. CONCLUSION: Immediate hypersensitivity reaction to ursodiol is uncommon. Our case demonstrated that this novel desensitization protocol to ursodiol could be safely implemented when alternative options are not available or have proven inferior in efficacy.

Quality of life in patients with hereditary angioedema in Canada.

BACKGROUND: Hereditary angioedema (HAE) is associated with decreased quality of life (QoL), which has typically been measured using a generic non-disease-specific questionnaire. OBJECTIVE: We aimed to assess the QoL in patients with HAE type I and II in Canada using a previously validated HAE-specific questionnaire. METHODS: An online questionnaire was sent to the members of two Canadian HAE patient groups to collect data on demographics, HAE clinical course, and QoL scores. All patients 18 years of age or older with HAE type I or II were eligible. The impact of the available clinical factors on the QoL scores was evaluated. Multiple linear regression was performed using clinically relevant factors to predict HAE QoL outcome. RESULTS: Among the 72 patients in the study, the mean total HAE QoL score was 102 (±23) (SD) on a scale of 25 to 135, with higher scores indicating better QoL. Although the total QoL scores correlated positively with patients' level of satisfaction and perceived control (P < .001 for both), it correlated negatively with the number of acute attacks (P = .03). Yet, the types of treatment did not have an impact on the QoL. Predictors, including sex, comorbidities, and the number of attacks, only explained 12% of the variance in the total QoL scores. CONCLUSION: HAE continues to impair QoL in Canadian patients despite receiving recommended treatment. Although the frequency of attacks affects QoL, patients' experience with their HAE care also affects QoL substantially. The study highlights the importance of considering patients' experience with their HAE care as physicians develop an appropriate management plan.

Characterization of Patients with Ibuprofen Hypersensitivity.

BACKGROUND: Ibuprofen is the most frequently used over-the-counter nonsteroidal anti-inflammatory drug (NSAID) in North America. While it has been commonly implicated in drug-induced hypersensitivity reactions, there is limited literature specifically on ibuprofen hypersensitivity. OBJECTIVES: To characterize the demographics and clinical course of hypersensitivity reactions in a cohort of patients with ibuprofen allergy. METHODS: A retrospective chart review of patients diagnosed with ibuprofen allergy was conducted between 2008 and 2016 in an allergy clinic at a tertiary care academic institution. Demographics and clinical information were obtained, and severity of reactions was assessed by a standardized grading system. RESULTS: A total of 41 patients were included of whom 27 were female. The mean age at first reaction to ibuprofen was 33 ± 13.9 years. The medi an time from the first reaction to the time of diagnosis was 1 year (0-3). The median time from ibuprofen exposure to the onset of symptoms was 30 min (16-101). The median duration of symptoms was 180 min (60-1,440). Urticaria and angioedema were seen in 90% of patients. The reactions were either mild (46%) or moderate (51%) in severity, but 1 patient had severe anaphylaxis. Cross-reactivity to other NSAIDs or acetaminophen was seen and presented with mostly mild reactions. CONCLUSION: In our cohort of patients, ibuprofen hypersensitivity affected females more commonly than males, and presented with mainly cutaneous manifestations. Onset of symptoms was rapid (< 60 min). Reactions typically ranged in severity from mild to moderate although there was a risk of severe anaphylaxis. There was potential cross-reactivity with other NSAIDs or acetaminophen. The results of our study contribute to the understanding of the demographics and clinical course of ibuprofen hypersensitivity reactions.

What is hidradenitis suppurativa?

OBJECTIVE: To provide family physicians with an understanding of the epidemiology, clinical features, diagnosis, and management of hidradenitis suppurativa (HS). SOURCES OF INFORMATION: A PubMed literature search was performed using the MeSH term hidradenitis suppurativa. MAIN MESSAGE: Hidradenitis suppurativa is a chronic, recurrent, and debilitating skin condition. It is an inflammatory disorder of the follicular epithelium, but secondary bacterial infection can often occur. The diagnosis is made clinically based on typical lesions (nodules, abscesses, sinus tracts), locations (skin folds), and nature of relapses and chronicity. Multiple comorbidities are associated with HS, including obesity, metabolic syndrome, inflammatory bowel disease, and spondyloarthropathy. Although the lack of curative therapy and the recurrent nature makes HS treatment challenging, there are effective symptomatic management options. CONCLUSION: Family physicians should be suspicious of HS in patients presenting with recurrent skin abscesses at the skin folds. Family physicians play an important role in early diagnosis, initiation of treatment, and referral to a dermatologist before HS progresses to debilitating end-stage disease.

Qu'est-ce que l'hidradénite suppurée?

OBJECTIF: Permettre aux médecins de famille de comprendre l'épidémiologie, le tableau clinique, le diagnostic et la prise en charge de l'hidradénite suppurée. SOURCES D'INFORMATION: Une recherche de la littérature a été effectuée sur PubMed à l'aide des mots-clés MeSH hidradenitis suppurativa. MESSAGE PRINCIPAL: L'hidradénite suppurée est une affection cutanée chronique, récidivante et incapacitante. C'est un trouble inflammatoire de l'épithélium folliculaire, bien qu'une infection bactérienne secondaire se produise souvent. Le diagnostic, posé en clinique, repose sur les lésions typiques (nodules, abcès, tractus sinusal), le siège (plis cutanés), la nature des rechutes et le caractère chronique. De nombreuses comorbidités sont associées à l'hidradénite suppurée, y compris l'obésité, le syndrome métabolique, la maladie intestinale inflammatoire et la spondylarthropathie. Même si l'absence de traitement curatif et la nature récidivante de l'hidradénite suppurée en compliquent le traitement, il existe des options efficaces pour prendre en charge les symptômes. CONCLUSION: Les médecins de famille doivent soupçonner l'hidradénite suppurée chez les patients qui présentent des abcès cutanés récidivants dans les plis cutanés. Les médecins de famille jouent un rôle important dans le diagnostic précoce, l'instauration du traitement et la recommandation en dermatologie avant que l'hidradénite suppurée ne progresse vers une atteinte terminale incapacitante.

Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection.

Cytotoxic CD8(+) T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. T cell 'exhaustion' is a hallmark of chronic persistent viral infections including HIV. The inhibitory regulatory molecule, T cell Immunoglobulin and Mucin domain containing 3 (Tim-3) is induced on HIV-specific T cells in chronic progressive infection. These Tim-3 expressing T cells are dysfunctional in terms of their capacities to proliferate or to produce cytokines. In this study, we evaluated the effect of Tim-3 expression on the cytotoxic capabilities of CD8(+) T cells in the context of HIV infection. We investigated the cytotoxic capacity of Tim-3 expressing T cells by examining 1) the ability of Tim-3(+) CD8(+) T cells to make perforin and 2) the direct ability of Tim-3(+) CD8(+) T cells to kill autologous HIV infected CD4(+) target cells. Surprisingly, Tim-3(+) CD8(+) T cells maintain higher levels of perforin, which was mainly in a granule-associated (stored) conformation, as well as express high levels of T-bet. However, these cells were also defective in their ability to degranulate. Blocking the Tim-3 signalling pathway enhanced the cytotoxic capabilities of HIV specific CD8(+) T cells from chronic progressors by increasing; a) their degranulation capacity, b) their ability to release perforin, c) their ability to target activated granzyme B to HIV antigen expressing CD4(+) T cells and d) their ability to suppress HIV infection of CD4(+) T cells. In this latter effect, blocking the Tim-3 pathway enhances the cytotoxcity of CD8(+) T cells from chronic progressors to the level very close to that of T cells from viral controllers. Thus, the Tim-3 receptor, in addition to acting as a terminator for cytokine producing and proliferative functions of CTLs, can also down-regulate the CD8(+) T cell cytotoxic function through inhibition of degranulation and perforin and granzyme secretion.

HIV-specific IL-21 producing CD4+ T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control.

We examined the role of CD4(+) T cell IL-21 production in viral control of HIV infection. HIV-infected individuals had greater circulating IL-21-producing CD4(+) T cells in blood compared with uninfected volunteers. HIV-specific IL-21-producing CD4(+) T cells were detected in blood during untreated acute and chronic HIV infection, and elevated frequencies of these cells correlated with relative viral control. These cells had an effector memory or end effector phenotype and expressed CXCR5. HIV-specific CD8(+) T cells exhibited high levels of IL-21R, indicating sensitivity to IL-21. Low or aviremic long-term nonprogressors, however, showed absent or low HIV-specific IL-21 CD4(+) T cells, but more easily detectable HIV-specific IL-2-producing CD4(+) T cells, suggesting changing requirements for particular gamma-chain cytokines depending on Ag abundance. Thus, IL-21-producing CD4(+) T cells are induced in viremic HIV infection and likely contribute to viral control by affecting CD8(+) T cell maintenance.

Clinical and immunologic features of an atypical intracranial mycobacterium avium complex (MAC) infection compared with those of pulmonary MAC infections.

Members of the Mycobacterium avium complex (MAC) may cause chronic pulmonary infections in otherwise healthy elderly persons but rarely invade parts of the body outside of the lungs in immunocompetent hosts. We present a case of an isolated intracranial MAC infection in an apparently immunocompetent individual and review previous reports. We studied the T-cell and monocyte responses in healthy volunteers, individuals with a pulmonary MAC infection, and one individual with an isolated intracranial MAC infection. Genomic DNA from the individual with the brain MAC infection was studied for gamma interferon (IFN-gamma) receptor mutations. Individuals with localized pulmonary MAC infections showed increased activation of monocytes and enhanced monocyte and T-cell tumor necrosis factor alpha (TNF-alpha) production in response to lipopolysaccharide and MAC antigens but defects in T-cell IFN-gamma secretion. The individual with an intracranial MAC infection showed a lack of monocyte activation and deficiencies in both monocyte and T-cell TNF-alpha production and monocyte interleukin-12 (IL-12) production but had preserved T-cell IFN-gamma production. Mutations or deletions in the IFN-gamma receptor were not detected in the individual with the intracranial MAC infection. Our data suggest that distinct immune defects characterize two different manifestations of MAC infection. A relative defect in IFN-gamma production in response to MAC may predispose an individual to localized but partially controlled lung disease, whereas defects leading to reduced IL-12 and TNF-alpha production may allow the dissemination of MAC. Further studies delineating the potential role of TNF-alpha in limiting the spread of MAC outside the lung are warranted.