Violeta Régnier Galvão

Hypersensitivity to biological agents-updated diagnosis, management, and treatment.

Biological agents are used in the treatment of neoplastic, autoimmune, and inflammatory diseases and their clinical applications are becoming broader. Following their increased utilization, hypersensitivity reactions linked to these drugs have become more frequent, sometimes preventing the use of first-line therapies. The clinical presentation of hypersensitivity reactions to biological agents ranges from mild cutaneous manifestations to life-threatening reactions. In this scenario, rapid desensitization is a groundbreaking procedure that enables selected patients to receive the full treatment dose in a safe way, in spite of their immediate hypersensitivity reaction to the drug, and protects them against anaphylaxis. The aim of this review is to update and discuss some of the main biological agents used in clinical practice (rituximab, trastuzumab, cetuximab, ofatumumab, tocilizumab, brentuximab, omalizumab, and tumor necrosis factor alpha inhibitor agents) and their associated hypersensitivity reactions, including clinical presentations, diagnosis, and treatment in the acute setting. In addition, novel management options with rapid desensitization are presented.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions

BACKGROUND The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Womens Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Current Knowledge and Management of Hypersensitivity Reactions to Monoclonal Antibodies

Hypersensitivity reactions (HSRs) to monoclonal antibodies (mAbs) are increasingly frequent as this class of therapeutic agents is rapidly expanding. Immediate and nonimmediate HSRs have been reported with mAbs. Immediate HSRs can be explained by 3 main mechanisms: cytokine release syndrome, IgE-mediated, and IgG-mediated reactions. Importantly, IgE-mediated reactions can occur on first exposure due to preformed specific IgEs, as shown for cetuximab. Almost all patients with an immediate HSR can be safely re-exposed either through desensitization or challenge depending on the severity and mechanism of the initial reaction. An algorithm detailing the general approach to these HSRs and the preferred method of re-exposure is presented in this review. Also, the mAbs that are most frequently implicated in HSRs are discussed individually.

Clinical and laboratory improvement after intravenous immunoglobulin in drug reaction with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also called drug-induced hypersensitivity syndrome, is a severe adverse drug reaction associated with immunologic abnormalities and viral reactivation. DRESS is difficult to diagnose because the symptomsmimic several other diseases and can appear long after initial drug exposure. RegiSCAR, a diagnostic tool developed to diagnose DRESS, is based on evaluating 7 criteria, including fever >38.8 C, acute skin rash, lymphadenopathy, internal organ involvement, and blood cell count abnormalities. Diagnosis is confirmed in individuals who exhibit 3 or more of the 7 criteria. Affected patients are treated with corticosteroids, and full recovery is achieved in up to 90% of cases; however, the mortality rate can be as high as 10%-20%, which correlates with the degree of hepatic or renal involvement. DRESS can have a variable effect on the immune system. Although leukocytosis with atypical lymphocytes and eosinophilia of varying degrees are prominent features, leukopenia and lymphopenia can precede the development of leukocytosis in some cases. With regard to humoral immunity, reduced B cell numbers and dramatically decreased serum IgG, IgA, and IgM levels have been described. Recently, a significantly decreased number of circulating natural killer cells at disease onset was reported, which might be associated with subsequent reactivation of viruses, mainly within the herpesvirus family. Although human herpesvirus (HHV) 6 is the most common virus reactivated during this severe reaction, other reactivated viruses have also been observed, such as EBV, cytomegalovirus, and HHV-7. Although the role of viruses in the pathogenesis of DRESS syndrome is unknown, analysis of the data shows that HHV-6 reactivation is associated with poor prognosis and a prolonged course of disease. The current treatment for severe DRESS cases is limited to systemic corticosteroids and supportive care. The use of intravenous immunoglobulin (IVIG) to treat DRESS is currently anecdotal and controversial, and its mechanism of action is unknown. In this case report, we describe that viral clearance and clinical recovery occurred after IVIG administration to a 45-year-old female patient who presented with severe corticosteroid-refractory DRESS. The patient initially appeared in the emergency department with a maculopapular rash, and it was determined that she had been using phenytoin for 1 month for seizure prophylaxis after a subarachnoid hemorrhage (Figure 1). The patient was hospitalized, and systemic corticosteroid (prednisolone, 0.75 mg/kg/d) was administered. Results of initial laboratory tests showed normal liver enzyme levels and mild eosinophilia (Table I). After the patient’s improvement, prednisolone was tapered on day 4 of hospitalization. However, symptoms worsened 2 days after lowering the corticosteroid dose, and the patient developed purpuric skin lesions, oral lesions, lymphadenopathy, and fever (Figure 1). Blood analysis indicated the presence of eosinophilia, atypical lymphocytosis, thrombocytopenia, increased liver enzyme levels, and hypergammaglobulinemia (Table I); moreover, a skin biopsy revealed lymphocytic and eosinophilic infiltration with spongiosis. Prednisolone thus was adjusted up to 1 mg/kg/d on day 8 of hospitalization. While investigating an episode of gastrointestinal bleeding on day 7 of hospitalization, a macroscopic pattern typical of eosinophilic esophagitis was observed. An esophageal biopsy specimen revealed an eosinophilic infiltrate of >20 eosinophils per high power field, which supported the diagnosis (Figure 1). Serologic tests showed the presence of specific IgG antibodies to EBV, cytomegalovirus, and hepatitis A but not to HHV-6. The patient’s serum was also positive for EBV DNA by PCR analysis. The DRESS diagnosis was confirmed from these test results, with a RegiSCAR score of 8 (>5 is considered a definite case). After 6 days without significant improvement despite the increased systemic corticosteroid dose, on day 14 of hospitalization, she received IVIG (1 g/kg/d) for 3 days and subsequently presented clinical and laboratory improvement. Her purpuric rash and lymphadenopathy improved, quantitative EBV DNA became undetectable, liver enzyme levels progressively returned to baseline, and eosinophil counts (already decreasing, probably due to the corticosteroid) continued to drop (Figure 2). The patient was discharged 3 weeks after hospitalization with a prescription for oral prednisone (0.75 mg/kg/d). Before discharge, detectable quantitative EBV DNA had returned. Although the clearance of viremia was transient, it might have occurred at a crucial time for patient recovery. In terms of outpatient treatment, corticosteroids were tapered slowly over 6 months until discontinuation, with only 1 episode of mild recrudescence of the rash. At present, the patient has had no additional DRESS signs or symptoms, and results of her laboratory tests continue to be normal while off corticosteroids (Table I). Few reports exist about IVIG use in DRESS. The presented case here is the first report to our knowledge that shows that IVIG is

Carboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation

Deleterious germline BRCA 1/2 mutation was described as an independent risk factor for carboplatin hypersensitivity reactions (HSRs). In 2013, Moon et al observed in a retrospective study that most patients who developed carboplatin HSR had deleterious BRCA 1/2 mutations (93% [27 of 29]), versus 50% (29 of 58) in patients without HSR (P < .0001). The studied population was composed of 87 patients with ovarian, fallopian tube, or primary peritoneal cancer. This study also found that patients with BRCA 1/2 mutations developed an HSR to carboplatin with a lower cumulative dose. Patients who are allergic to platinum-based agents can benefit from rapid drug desensitization (RDD). RDD to carboplatin protects patients against severe HSR, with more than 90% of them presenting no or mild reactions during the procedure, including those with an initial anaphylactic reaction. The overall prevalence of the BRCA 1/2 mutation in patients with tubo-ovarian cancer is 13% to 17%, and its prevalence in patients with breast cancer treated at the Dana Farber Cancer Institute is 6.1%. BRCA 1/2 mutation prevalence among carboplatin-allergic patients is unknown. We hypothesized that patients undergoing carboplatin RDD would present a high prevalence of BRCA 1/2 mutations, and evaluated the impact of BRCA mutations on the type of initial HSR and on reactions during RDD. We reviewed 239 consecutive records of patients treated at the Dana Farber Cancer Institute and enrolled in the Brigham and Women’s Hospital Desensitization Program between January 2011 and October 2015 who underwent RDD to carboplatin. BRCA 1/2 mutation status was reported in 138 patients, who had tubo-ovarian, peritoneal, breast, or endometrial cancer. Data are presented as mean SD, unless otherwise stated. Categorical variables were compared using chi-square and Fisher exact tests. Continuous variables were compared using t test, and a P value of less than .05 was considered statistically significant. The mean age was 60.6 10 years, and no significant difference was found between BRCA-positive (59.1 8 years) and BRCA-negative patients (61.2 11 years). Most patients presented with tubo-ovarian cancer (91.3% [n 1⁄4 126]), followed by breast (3.6% [n 1⁄4 5]), peritoneal (2.1% [n 1⁄4 3]), peritoneal þ ovarian (2.1% [n 1⁄4 3]), and endometrial cancer (0.7% [n 1⁄4 1]). The overall prevalence of the BRCA mutation was 34% (n 1⁄4 47): 66% (n 1⁄4 31) with BRCA 1 and 34% (n 1⁄4 16) with BRCA 2 mutation. The mean number of lifetime exposures before the allergic reaction in BRCA-positive patients was 9.9 4.5 versus 9.1 4.7 for BRCA-negative patients (P 1⁄4 .37). BRCA-positive patients had more initial immediate HSR than did BRCA-negative patients (Figure 1, A; P 1⁄4 .03). No statistical difference was found between BRCA-positive and BRCAnegative patients regarding the severity of the initial reaction (Figure 1, B; P 1⁄4 .22). Most patients were desensitized using the 12 steps/3 bags protocol (92% [n 1⁄4 127]), while 8% (n 1⁄4 11) used the 16 steps/4 bags protocol. Reactions during RDD occurred in 51% of patients with the BRCA 1/2 mutation versus 27% of patients without the mutation (Figure 2, A; P < .01). The severity of RDD reactions had a similar distribution between groups (Figure 2, B; P 1⁄4 .72). Serum tryptase levels were obtained during initial HSR or RDD reaction in 14 BRCA-negative patients and in 15 BRCApositive patients. In both groups, mean tryptase levels were elevated (BRCA positive, 13.4 13.1 mg/L; BRCA negative, 13.6 13.4 mg/L; normal value, <11.4 mg/L). Tryptase levels obtained during RDD reactions were higher in BRCA-positive patients (16.2 12.9 mg/L) than in BRCA-negative patients (13.3 12 mg/L), but this difference was not statistically significant (Figure 2, C; P 1⁄4 .62). Skin test results were positive in 94% (n 1⁄4 44) of BRCApositive patients versus 89% (n 1⁄4 81) of BRCA-negative patients (P 1⁄4 .33). When subdividing skin test results into negative or positive at prick 10 mg/dL, intradermal 1 mg/mL, or intradermal 10 mg/dL levels, BRCA-positive and BRCA-negative patients presented a similar distribution (P 1⁄4 .33). Our studied population (n 1⁄4 138) was found to be comparable to the patients who were not evaluated for BRCA mutation (n 1⁄4 101) in terms of age, sex, grade of initial HSR, number of lifetime exposures to carboplatin, frequency of desensitization reactions, and severity of these reactions (data not shown). BRCA 1/2 mutation was highly represented in patients with gynecologic malignancies undergoing RDD to carboplatin. The average prevalence of this mutation in tubo-ovarian cancer population is 13% to 17%, but when considering only allergic patients to carboplatin enrolled in the RDD program, we identified a prevalence of 34%. This corroborates the finding of the BRCA mutation as an independent risk factor for HSR to carboplatin, because its prevalence is notably increased in our population. We found that BRCA 1/2-positive patients receiving carboplatin presented more immediate HSR as their initial clinical presentation than did BRCA-negative patients (Figure 1, A). This observation prompts enhanced surveillance during carboplatin administration for this group of patients because

Erythema multiforme induced by clindamycin diagnosed by patch test

Results A 17 years of age male was admitted in a University Hospital In Sao Paulo, Brazil, because he had been a victim of a car accident in May 2012. He suffered a tibia open fracture and was submitted to a surgical treatment. Three days after the procedure he developed face rash, cutaneous itching, target lesions in oropharynx and lower limbs peeling. He was being treated with Clindamycin, Ciprofloxacin, Dipyrone, Ketoprofen and Tramadol. The patient evolved with fever and leucocytosis, without eosinophilia. This reaction was diagnosed as EM major by Dermatology Unit and he was successfully treated with antihistamines and corticosteroids, besides suspected drugs substitution. After been discharged the patient was referred to the Allergy Unit to perform a drug hypersensitivity investigation. He was submitted to patch test with all the suspected drugs diluted in petrolatum 10%. Only the clindamycin patch test was positive, which was confirmed with a second patch test. The patient also presented reactivation of previous lesions. Conclusions As far as we know, this is the first patient who had developed erythema multiforme due to clindamycin. The patch test was essential to confirm the diagnosis and the use of all other drugs which were present at the time of the reaction could be released.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE): two atypical case reports

Background The symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a delayed-type hypersensitivity drug reaction (HDR) that causes symmetrical erythematous lesions in flexural areas, including buttocks and groin, which arise following exposure to drugs, especially beta-lactams. The involvement of palms and soles is rare and, until now, it has only been described after exposure of amoxicillin. We hereby report a patient with SDRIFE and involvement of the palms and soles after taking cephalexin and another patient who developed SDRIFE after exposure to doxycyclin.

Basophil activation test in allergic patients to platins undergoing rapid desensitization

Background Desensitization (DST) has become a cornerstone in the management of immediate hypersensitivity reactions (HSRs) to chemotherapic agents. It is the only effective procedure for overcoming HSRs to first-line therapy, thus representing an important advance in patients’ treatment and prognosis. Nevertheless, there are still no good biomarkers to monitor DST safety and effectiveness. The basophil activation test (BAT) has greater applicability in difficult cases with inconclusive diagnosis and when other diagnostic tests (skin tests and serum specific IgE) have not been standardized, as in drug-induced reactions. The main goal of our study was to assess BAT as a test to monitor rapid DST in patients allergic to platins. Method We studied 7 oncologic patients who presented platin allergy and 4 healthy volunteers who had never been exposed to platins. We performed the BAT immediately before DST to platins, assessing CD 203c and CD63 expression on basophils. All patients were evaluated at least in 2 different DST. Results BAT was positive in 6 patients (85.7%), with increased expression of CD203c and CD63 in 6 and 3 patients, respectively. Subsequent BAT analysis in different DST procedures showed that the test remained positive with an even greater expression of CD203c and CD63 on basophils after platins exposure. Some patients with positive BAT reacted during DST, in spite of being premedicated, showing the correlation between BAT results and clinical outcomes. Further investigation is necessary to determine BAT predictive values and its clinical applicability. Conclusion We developed a BAT to platins that presented good sensitivity in our study. Short-term DST to platinum drugs does not induce persistent hyporresponsiveness on basophils, highlighting the need to maintain DST in allergic patients to platins.