A protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions.

BACKGROUND: Management of patients with carboplatin-induced hypersensitivity reactions (HSR) has been complicated by high false-negative rates of carboplatin skin test (ST) results. These patients might be at risk for future carboplatin-induced HSRs. In this article we identify a strategy to improve risk stratification of patients with a history of carboplatin-induced HSRs by using a protocol that includes repeat skin testing and drug desensitization. OBJECTIVE: We sought to identify a management strategy for patients with a history of carboplatin-induced HSRs with negative carboplatin ST results. METHODS: From 2008-2010, patients with carboplatin-induced HSR underwent risk stratification per a protocol using 3 repeat STs with intervening drug desensitizations. RESULTS: Of the 44 patients with carboplatin-induced HSRs, 39 completed the protocol. Patients were classified as having positive ST results (n = 16), having negative ST results (n = 11), or ST converters when the ST result converted to positive after an initial negative result (n = 12). ST converters are more likely to have HSRs during subsequent desensitizations than patients with negative ST results (56.1% vs 4.5%, P < .001). ST converters had a significantly longer time interval between their initial HSR and initial ST evaluation compared with either patients with true-negative ST results (22.1 vs 6.0 months, P = .03) or patients with positive ST results (22.1 vs 1.8 months, P = .001). CONCLUSION: Our experience suggests that repeat STs are necessary for risk stratification in patients with a remote clinical history of HSR and an initial negative ST result because there is a significant rate of conversion to a positive ST result. ST converters have an increased risk of HSRs during subsequent carboplatin treatment.

Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement.

Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management.

BACKGROUND: Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is uncertain. OBJECTIVES: To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin desensitization. METHODS: Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin. RESULTS: Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR (<3 months), 20 of 24 (83%) tested positive, whereas 5 of 14 (36%) with remote HSR (>9 months) tested positive (P < .01). Nineteen carboplatin ST+ and 11 ST- patients underwent desensitization to carboplatin. Seven ST+ patients (37%) had mild HSR during desensitization but completed the desensitization with additional treatment or protocol modification. ST- patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST- with repeated testing. Six of 8 ST- patients (75%) with remote HSR reacted during desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST+ before the second desensitization. Carboplatin desensitization was successfully completed in 105 of 106 (99%) treatment courses. CONCLUSIONS: The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST- patients with a remote history of HSR are at high risk for conversion to ST+ and can develop more severe HSR.

Rituximab Hypersensitivity: Evaluation, Desensitization, and Potential Mechanisms.

BACKGROUND: Rituximab (Rituxan) hypersensitivity (RITS) can be severe and limits the ability to further administer the treatment. Understanding its pattern and desensitization may permit administration in difficult cases. OBJECTIVE: Analyze RITS patient characteristics, hypersensitivity pattern, and desensitization outcomes to optimize management. METHODS: Twenty-five patients with RITS were referred to the Allergy/Immunology Unit at Massachusetts General Hospital over 5 1/2 years. Their clinical reaction patterns were analyzed. Drug desensitizations were performed using 3 related continuous intravenous protocols that were chosen on the basis of clinical history, skin test reactivity, and the patient's previous desensitization outcomes. RESULTS: Of the 25 referred patients, 23 had lymphoma of various types. The 25 patients underwent 170 continuous intravenous desensitizations based on 3 related protocols, with most based on the intermediate protocol. All but 2 desensitizations were completed successfully. Overall 24% of the desensitizations were complicated by hypersensitivity reactions. Two patients with serum sickness and a patient with mast cell disorder were also successfully managed. The average hypersensitivity reaction grade was 3.0 (2-4) before desensitization and 0.41 with desensitization. Skin tests were performed in 18 patients, with 5 patients positive initially and 2 more converted from negative to positive. Skin test status was not helpful for risk stratification for hypersensitivity reactions. Tryptase level was elevated during 21% of desensitizations with reactions but rare among asymptomatic desensitizations. CONCLUSIONS: Nearly all patients with severe sensitivity to rituximab can be successfully desensitized. IgE-mediated mechanism and mast cell degranulation, in addition to cytokine release syndrome and tumor lysis syndrome, may contribute to a significant portion of hypersensitivity reactions among patients with RITS.

Simultaneous assessment of cytotoxic T lymphocyte responses against multiple viral infections by combined usage of optimal epitope matrices, anti- CD3 mAb T-cell expansion and "RecycleSpot"

The assessment of cellular anti-viral immunity is often hampered by the limited availability of adequate samples, especially when attempting simultaneous, high-resolution determination of T cell responses against multiple viral infections. Thus, the development of assay systems, which optimize cell usage, while still allowing for the detailed determination of breadth and magnitude of virus-specific cytotoxic T lymphocyte (CTL) responses, is urgently needed. This study provides an up-to-date listing of currently known, well-defined viral CTL epitopes for HIV, EBV, CMV, HCV and HBV and describes an approach that overcomes some of the above limitations through the use of peptide matrices of optimally defined viral CTL epitopes in combination with anti-CD3 in vitro T cell expansion and re-use of cells from negative ELISpot wells. The data show that, when compared to direct ex vivo cell preparations, antigen-unspecific in vitro T cell expansion maintains the breadth of detectable T cell responses and demonstrates that harvesting cells from negative ELISpot wells for re-use in subsequent ELISpot assays (RecycleSpot), further maximized the use of available cells. Furthermore when combining T cell expansion and RecycleSpot with the use of rationally designed peptide matrices, antiviral immunity against more than 400 different CTL epitopes from five different viruses can be reproducibly assessed from samples of less than 10 milliliters of blood without compromising information on the breadth and magnitude of these responses. Together, these data support an approach that facilitates the assessment of cellular immunity against multiple viral co-infections in settings where sample availability is severely limited.

Optimization of methods to assess human mucosal T-cell responses to HIV infection.

The majority of HIV-1 infections occur via sexual transmission at mucosal epithelia lining the vagina, cervix or rectum. Mucosal tissues also serve as viral reservoirs. However, our knowledge of human mucosal T-cell responses is limited. There is a need for reliable, sensitive, and reproducible methods for assessing mucosal immunity. Here we report on the collaborative efforts of two laboratories to optimize methods for processing, culturing, and analyzing mucosal lymphocytes. Rectal biopsy tissue was obtained by flexible sigmoidoscopy, which is rapid, minimally invasive, and well tolerated. Of the four methods compared for isolating mucosal mononuclear cells (MMC), collagenase digestion reproducibly yielded the most lymphocytes (4-7 x 10(6)). Furthermore, 0.5-1 x 10(6) MMC could be polyclonally expanded to yield 17 x 10(6) CD8+ T cells allowing mapping of responses to overlapping peptides spanning the HIV-1 genome using IFN-gamma enzyme-linked immunospot (ELISpot). Expansion also reduced the spontaneous IFN-gamma production normally detected in fresh MMC. Piperacillin-tazobactam and amphotericin B reduced contamination of MMC cultures to 4%. Taken together, these methods will be useful for studies of mucosal immunity to HIV-1 and other pathogens during natural infection and following vaccination.

Oxaliplatin hypersensitivity: evaluation, implications of skin testing, and desensitization.

BACKGROUND: Oxaliplatin hypersensitivity (OXS) presents a challenge in the treatment of oxaliplatin-sensitive malignancies. OBJECTIVE: To analyze patient characteristics of patients with OXS, skin test results, and desensitization outcomes to optimize management. METHODS: Over 5 years, 48 patients with OXS were referred to the allergy/immunology unit at Massachusetts General Hospital. Their clinical reaction patterns were analyzed. Immediate hypersensitivity skin testing was used for risk stratification, and drug desensitizations were performed by using 3 related continuous intravenous protocols that were chosen based on clinical history, skin test reactivity, and the patients' previous desensitization outcomes. RESULTS: OXS occurred in both sexes, with mostly gastrointestinal-related tumors. Hypersensitivity reaction (HSR) onset had occurred during any course of therapy (course nos. 1-28), with a median onset at course no. 8. HSR to oxaliplatin was similar to those observed with cisplatin and carboplatin, including cutaneous, cardiovascular, pulmonary, and gastrointestinal symptoms. However, neurologic symptoms, including tingling, and systemic symptoms, including fever and chills, occurred more often in patients with OXS. Unique to OXS, 2 patients developed drug-induced thrombocytopenia; 1 patients also developed drug-induced hemolytic anemia. Skin testing was positive for the majority of patients with OXS (27/46 [59%]) and correlated with a greater likelihood of developing an HSR during subsequent desensitizations. We safely performed 200 desensitizations in 48 patients with OXS. CONCLUSION: OXS is common with much similarity to other platin agents but also have distinct differences in the onset of hypersensitivity, sex, tumor type, drug-induced hemolytic anemia, and drug-induced thrombocytopenia. Skin testing was helpful for risk stratification. All of the desensitizations were completed successfully.

Ten-year study of causes of moderate to severe angioedema seen by an inpatient allergy/immunology consult service.

The causes of angioedema are not well described, especially in the inpatient setting. The purpose of this study was to examine the causes of moderate to severe angioedema in patients requiring inpatient treatment. We performed a retrospective review in patients requiring inpatient consultation by the Division of Allergy and Immunology at our institution between 1995 and 2004. We focused on potential interactions among medications that elicited life-threatening angioedema requiring intubation. The allergy/immunology service was consulted on 69 patients with moderate to severe angioedema. Medications were the most common cause of angioedema (n = 64, 93%). In most cases (n = 46, 67%), the angioedema was attributed to two or more medications. Patients previously stable on ACE inhibitors (ACEI), aspirin (ASA), or non-steroidal anti-inflammatory drugs (NSAIDs) appeared more likely to develop angioedema soon after the addition of another drug (i.e., ACEI, ASA/NSAIDs, direct mast cell degranulators, and antibiotics). ACEI, ASA/NSAID, and direct mast cell degranulators were contributing causes in 36 patients (56%), 45 patients (70%), and 23 patients (36%), respectively. Twenty patients required intubation, 14 (70%) patients were on ACEI, 12 (60%) patients were on ASA/NSAID, and 7 (35%) patients were on direct mast cell degranulators. ACEI, ASA/NSAID, or direct mast cell degranulators were a cause in 95% (n = 19) of patients requiring intubation. The combination of ACEI and ASA/NSAID was the most frequent cause of angioedema among all patients (n = 17, 25%) and those requiring intubation (n = 8, 40%). Moderate to severe angioedema often is a result of interactions between two or more medications involved in different pathways causing angioedema. In particular, combinations of ACEI, ASA/NSAID, or direct mast cell degranulators may lead to life-threatening angioedema requiring intubation.

Differential immunogenicity of vaccinia and HIV-1 components of a human recombinant vaccine in mucosal and blood compartments.

Mucosal immune responses induced by HIV-1 vaccines are likely critical for prevention. We report a Phase 1 safety and immunogenicity trial in eight participants using the vaccinia-based TBC-3B vaccine given subcutaneously to determine the relationship between HIV-1 specific systemic and gastrointestinal mucosal responses. Across all subjects, detectable levels of blood vaccinia- and HIV-1-specific antibodies were elicited but none were seen mucosally. While the vaccinia component was immunogenic for CD8(+) T lymphocyte (CTL) responses in both blood and mucosa, it was greater in blood. The HIV-1 component of the vaccine was poorly immunogenic in both blood and mucosa. Although only eight volunteers were studied intensively, the discordance between mucosal and blood responses may highlight mechanisms contributing to recent vaccine failures.

Transience of vaccine-induced HIV-1-specific CTL and definition of vaccine "response".

Many vaccine approaches emphasize producing HIV-1-specific CD8+ T-lymphocyte (CTL) responses. Towards this goal, many studies simply classify vaccinees as "responders" or "nonresponders," based on arbitrary cutoff criteria. HIV-1-uninfected participants receiving the TBC-3B vaccine were assessed for HIV-1-specific CTL by interferon-gamma ELISpot, and compared to HIV-1-infected control subjects not on antiretroviral therapy. Vaccinees also were tested for HIV-1-specific antibody responses and generalized CD8+ T-lymphocyte activation. Different criteria for vaccine "responder" status were applied to the measured CTL values. The vaccinees showed evidence of vaccine exposure by CD8+ T-lymphocyte activation and HIV-1-specific antibodies. Considering any single positive HIV-1-specific CTL measurement a vaccine "response," all vaccinees could be classified as "responders," but even slight increases in the stringency of response criteria resulted in a steep decline of the "response" rate. In contrast, HIV-1-infected persons were clearly "responders" against the same proteins by the same criteria. Quantitative assessment of CTL demonstrated low and transient HIV-1-specific CTL compared to natural infection. These analyses emphasize the pitfalls of summarizing vaccine study results using simple cutoff criteria to define response rates, and suggest the utility of more comprehensive descriptions to describe vaccine immunogenicity and persistence of responses.

Parallel human immunodeficiency virus type 1-specific CD8+ T-lymphocyte responses in blood and mucosa during chronic infection.

Gut-associated lymphoid tissue is the major reservoir of lymphocytes and human immunodeficiency virus type 1 (HIV-1) replication in vivo, yet little is known about HIV-1-specific CD8+ T-lymphocyte (CTL) responses in this compartment. Here we assessed the breadth and magnitude of HIV-1-specific CTL in the peripheral blood and sigmoid colon mucosa of infected subjects not on antiretroviral therapy by enzyme-linked immunospot analysis with 53 peptide pools spanning all viral proteins. Comparisons of blood and mucosal CTL revealed that the magnitude of pool-specific responses is correlated within each individual (mean r2 = 0.82 +/- 0.04) and across all individuals (r2 = 0.75; P < 0.001). Overall, 85.1% of screened peptide pools yielded concordant negative or positive results between compartments. CTL targeting was also closely related between blood and mucosa, with Nef being the most highly targeted (mean of 2.4 spot-forming cells [SFC[/10(6) CD8+ T lymphocytes/amino acid [SFC/CD8/aa]), followed by Gag (1.5 SFC/CD8/aa). Finally, comparisons of peptide pool responses seen in both blood and mucosa (concordant positives) versus those seen only in one but not the other (discordant positives) showed that most discordant results were likely an artifact of responses being near the limit of detection. Overall, these results indicate that HIV-1-specific CTL responses in the blood mirror those seen in the mucosal compartment in natural chronic infection. For protective or immunotherapeutic vaccination, it will be important to determine whether immunity is elicited in the mucosa, which is a key site of initial infection and subsequent HIV-1 replication in vivo.

Reactions to radiocontrast media.

Adverse reactions to radiocontrast media (RCM) occur unexpectedly and may be life-threatening. This article describes an anaphylactoid reaction (AR) in one patient. The term AR refers to a syndrome clinically similar to anaphylaxis, but these reactions are independent of immunoglobulin E antibody-mediated mast cell or basophil degranulation. This article briefly reviews the literature regarding RCMs and types of reactions to RCM. The risk factors for AR to RCM infusions will be discussed along with current concepts of the pathogenesis of RCM-induced ARs. This article also describes the therapeutic management of patients who have had a previous adverse reaction to RCM and provides an approach to patients who have breakthrough reactions despite adequate premedication, but require additional radiographic studies.