Immune checkpoint inhibitor-associated hemophagocytic lymphohistiocytosis in a patient with chronic lymphocytic leukemia.

Haemophagocytic lymphohistiocytosis (HLH) is a rare complication of immune checkpoint inhibitor therapy. A 55-year-old male with stable chronic lymphocytic leukemia presented with fevers and symptomatic anaemia after nine cycles of nivolumab for metastatic melanoma. Investigations were consistent with autoimmune haemolytic anemia and corticosteroids were initiated. Thrombocytopenia and elevated liver enzymes without evidence of chronic lymphocytic leukaemia transformation was present. Ferritin was elevated, and thus HLH was considered and subsequently confirmed on a bone marrow biopsy. Corticosteroid monotherapy was continued, with resolution of fevers and improvement in cytopenias and liver enzymes. A six month corticosteroid tapering regimen was initiated, and he remains in HLH remission. This case highlights the importance of prompt recognition of immune checkpoint inhibitor-related HLH in patients with concurrent haematological malignancy.

A 55-year-old man had skin cancer and treatment was started. He also had a blood cancer around the same time that was not causing any problems. The skin cancer treatment started to cause problems many weeks later. His immune system started to react and become more active and so his liver started to suffer. The treatment for his skin cancer was stopped and steroids were started, which eventually improved his condition. These treatments for skin cancer can activate the immune system, but to this extent is not very common. It is important to know that it is possible and needs to be actioned early.

The role of major and minor determinants in penicillin allergy testing: Time to revisit an old friend?

Background: Skin testing is an important step in evaluation of penicillin allergic reactions. It includes testing to the following: amoxicillin, benzyl penicillin, and products generated in vivo after penicillin administration, the major determinant hapten penicilloyl-polylysine (PPL) and the minor determinant mixture (MDM). Although PPL and MDM are available as a commercial kit, their supply and cost remain problematic. Objective: We aimed to evaluate the performance and utility of PPL and MDM in penicillin allergy testing. Methods: A retrospective audit over a 5-year period was undertaken for those with penicillin testing in a tertiary immunology unit. Results: In all, 214 patients were identified. Of those patients, 151 (70.6%) were female and the average age was 58 years. Unspecified penicillin was the most common index drug (n = 127 [59.3%]), followed by amoxicillin (n =3 [24.8%]) and amoxicillin-clavulanic acid (n = 21 [9.7%]). The result of skin testing was positive in 23 patients (10.7%); skin prick testing was positive in 10 patients (4.7%), and intradermal testing (IDT) was positive in 13 patients (6.1%), the majority of whom had identified amoxicillin or amoxicillin-clavulanic acid as the index drug (n = 22 [95.7%]). The result of testing to PPL and/or MDM was positive with IDT only (n=5 [23.8%]). PPL and MDM positivity coexisted with a positive reaction to amoxicillin IDT in 2 patients, 1 of whom passed an amoxicillin challenge. Additionally, 2 positive tests to PPL were present with a negative result for MDM; of these 2 positive results, 1 was positive to amoxicillin IDT. In only 1 case were the results of testing for MDM and PPL both positive, with negative results to all native ß-lactams tested; the patient tolerated an amoxicillin challenge. Overall, the negative predictive value for both skin prick testing and IDT was 89.5%. Conclusion: Benzyl penicillin and amoxicillin alone may be sufficient for in vivo testing in suspected individuals with penicillin allergy.

Tocilizumab in grade 4 hepatitis secondary to immune checkpoint inhibitor: a case report and review of the literature.

First- and second-line treatments for immune checkpoint inhibitor-related hepatotoxicity (IRH) are well established; however, evidence for third-line therapies is limited. We present a 68-year-old female with relapsed metastatic non-small-cell lung carcinoma despite multiple treatments. A fortnight after the second cycle of CTLA-4 inhibitor immunotherapy, she developed scleral icterus and mild jaundice with significant elevation in liver enzymes. A diagnosis of IRH was made, and despite corticosteroids, mycophenolate and tacrolimus, liver enzymes continued to worsen. One infusion of tocilizumab was given, which resulted in a remarkable improvement. Prednisolone and tacrolimus were then tapered over the ensuing months, and mycophenolate was continued. Given the rapid improvement in liver enzymes with tocilizumab, this treatment should be considered as a third-line treatment in IRH.

A lady had cancer of the lung. A new medication was started but the liver became damaged. Three medications were tried to help the liver. None of these worked. Another drug (called tocilizumab) was tried and worked. The liver got better.

Lenalidomide Desensitization for Delayed Cutaneous Reaction: A Case Series and Review of the Literature.

BACKGROUND: Lenalidomide is commonly used for treatment of multiple myeloma (MM) as well as other hematological disorders. Cutaneous adverse reactions occur frequently and withholding lenalidomide treatment may have implications for prognosis. OBJECTIVE: To evaluate the role of lenalidomide desensitization in patients with cutaneous adverse reactions. METHODS: A retrospective review of patients referred for lenalidomide desensitization between May 2019 and May 2022 at a tertiary hospital. All patients underwent a 6-week outpatient desensitization with premedication. RESULTS: There were 12 patients: 10 males and 2 females with a median age of 65 years. All had MM with autologous stem cell transplantation and lenalidomide 10 mg daily added for maintenance therapy. Most patients (n = 8) had a generalized maculopapular exanthem with or without pruritus. All patients had delayed cutaneous reactions; the median time to onset was 14 days (range 2-28 d). Six patients tolerated desensitization: 5 on the first attempt and 1 after 3 attempts and supplementary oral prednisolone. Four patients underwent multiple (≤3) attempts at desensitization owing to breakthrough symptoms. In patients who failed desensitization, recurrence of symptoms occurred variably, either early (within days), within weeks, or delayed by more than 1 month. CONCLUSIONS: Lenalidomide desensitization is worthwhile and allows continuation of treatment. In our MM cohort, lenalidomide desensitization was successful in only 50% of cases, including some cases in whom ongoing symptoms were mitigated by cotreatment with antihistamine.

Can C-reactive protein be used as a surrogate marker of IL-6 in a broad array of clinical entities?

Background: C-reactive protein (CRP) is commonly performed, whereas cytokine testing is limited to research. Aims: To determine CRP correlation to cytokines IL-6, IL-1ß and TNF-α. Results: Consecutive samples (n = 307) were collected over 24 h. Ninety-six patients (31%) had acute infections, and 23 patients (7.5%) had autoimmune or inflammatory disease presentations. A strong correlation between CRP and two IL-6 assays (r = 0.74 and r = 0.71; p < 0.001) was present. CRP did not correlate with IL-1ß and TNF-α across the data set. Bacterial infection had a significantly higher CRP and IL-6 (p < 0.001), while only CRP was elevated in inflammatory and autoimmune diseases (p < 0.001). Discussion: CRP may be used as a surrogate marker of IL-6 levels in the routine diagnostic laboratories.

AstraZeneca ChAdOx1-S COVID-19 vaccine can be safely administered in patients with EDTA allergy.

BACKGROUND: Immediate hypersensitivity reactions to COVID-19 vaccines have been postulated to be linked to their excipients, such as polyethylene glycol (PEG) in Pfizer Comirnaty, or polysorbate 80 and ethylenediaminetetracetic acid (EDTA) in AstraZeneca ChAdOx1-S [recombinant] (Vaxzevria). These excipients are found in a range of other products, including injectable and oral medications as well as intravenous radiocontrast media (RCM) and various cosmetic products. Patients with proven excipient allergy may be advised to avoid a COVID-19 vaccine containing that excipient and/or potentially cross-reactive excipients. This may result in individual patients not receiving vaccines, especially if an alternate option is not available, and on a broader level contribute to vaccine hesitancy. We present two cases of previously confirmed EDTA anaphylaxis with positive intradermal testing, who had negative Vaxzevria vaccine in-vivo testing and subsequently tolerated the vaccine. CASE 1: A patient with history of anaphylaxis to RCM and local anaesthetics (LA) had positive intradermal test (IDT) to EDTA nine years earlier. Skin testing to Vaxzeria vaccine (up to 1:10 IDT), Comirnaty vaccine (up to 1:10 IDT) and EDTA 0.3 mg/mL IDT were negative. However, following EDTA 3 mg/ml IDT, he developed immediate generalised urticaria without anaphylaxis. Basophil activation testing was negative to disodium EDTA, Vaxzevria and Cominarty vaccines. Given the negative in-vitro and in-vivo testing to Vaxzevria vaccine, he proceeded to Vaxzevria immunisation and tolerated both doses. CASE 2: A patient with history of anaphylaxis to RCM had positive skin testing to EDTA and RCM containing EDTA six years earlier. Following referral to COVID19 vaccine clinic, Vaxzevria vaccine (1:10 IDT) and Cominarty vaccine (1:10 IDT) were negative whilst EDTA was positive at 0.3 mg/mL IDT. He subsequently tolerated both Vaxzevria vaccinations. CONCLUSION: Excipient allergy does not necessarily preclude a patient from receiving a vaccine containing that excipient. Allergy testing can help identify excipient-allergic patients who may still tolerate vaccination, which is important in situations where COVID-19 vaccination options are limited.

Rituximab hypersensitivity reactions and tolerance of ofatumumab therapy.

B-cell depleting agents play a key role in a variety of disease entities. Rituximab, a murine-human chimeric anti-CD20 monoclonal antibody, as one of these major agents, has been associated with hypersensitivity reactions, which not only include the classic hypersensitivity ranging from immediate (type 1) to delayed (type IV), but also infusion-related reactions (IRRs). Whilst these typical hypersensitivity reactions occur in the setting of prior exposure, IRRs may occur in first exposure. Factors to consider include chimeric composition of agent, for example, rituximab with murine component, which may be responsible for such hypersensitivity reactions. In these individuals, alternate anti-CD20, such as oftatumumab, a fully human monoclonal antibody may be used. We report three cases of rituximab hypersensitivity in patients with auto-immune disease, and in whom ofatumumab therapy was given and subsequently tolerated.

Anakinra desensitisation in patients with cryopyrin-associated periodic syndromes.

Cryopyrin-associated periodic syndrome (CAPS) is rare and patients experience rashes, arthralgias and fevers despite supportive treatment. In these cases, anakinra subcutaneous therapy is indicated which provides symptom control. However, adverse reactions notably injection-site related, are common resulting in treatment cessation in these patients. Ongoing symptoms lead to morbidity and predispose patients to complications such as amyloidosis. We describe our experience with anakinra desensitisation in two cases with CAPS who had injection-site related reactions. We also propose a 34-day outpatient desensitisation protocol.

The role of immunological testing and intervention in reproductive medicine: A fertile collaboration?

Advances in reproductive medicine have significantly increased the success of fertility treatments. Nevertheless, some women experience recurrent implantation failure (RIF) after in-vitro fertilization (IVF) or recurrent pregnancy loss (RPL). Imbalances in the immune system and failure to achieve immune tolerance to the foetus have been implicated as potentially modifiable causes of idiopathic RIF and RPL. As such, women are increasingly being treated with immunomodulatory agents in an attempt to achieve a successful pregnancy. This systematic review examines the published evidence on immune changes in these patients, the use of immunomodulation therapies and diagnostic testing modalities to guide their use or to identify patient subsets most likely to benefit. The PubMed database was searched for the terms "recurrent implantation failure" and "recurrent pregnancy loss" in conjunction with T-helper (Th) cells and their subsets in particular; Th1, Th2, Th17 and T-regulatory (Treg) cells, natural killer (NK) cells, cytokine imbalance as well as immune modulators and immune suppressants. The reference lists of articles were examined to identify additional articles. There remains limited data on the immunological changes in cytokine and cellular profiles during the hormonal cycle as well as prior to, during and after implantation in health as well as idiopathic RIF and RPL. There is a need to advance immunological diagnostics to match the clinical need in this emerging field and to guide clinicians to make optimal and safe therapeutic choices. It is also imperative that the well-being of the infants conceived after such intervention is monitored.