Crizanlizumab-Associated Painful Febrile Reaction in Sickle Cell Disease Patients

Background: P-selectin expressed on endothelium and platelets has been implicated in the pathophysiology of vaso-occlusive crises (VOCs) in sickle cell disease (SCD) patients. Crizanlizumab is a humanized monoclonal anti-P-selectin antibody approved by the FDA to reduce the frequency of VOCs. While severe adverse events (AEs) are rare, over 80% of patients most commonly have headache, back pain, nausea, or arthralgia; infusion-related reactions occurred in 3% according to the package insert. We report on 2 patients whose crizanlizumab-associated reactions help shed light on how to manage such events and possible mechanisms. Case reports: Case 1, a 48-year-old woman with hemoglobin SC disease, history of left shoulder replacement due to avascular necrosis and left knee avascular necrosis, pending surgical replacement. Given her frequent pain episodes, she was initiated on crizanlizumab after being intolerant to hydroxyurea (watery diarrhea). She received the first dose of crizanlizumab uneventfully, but at the end of her second infusion, she developed acute bilateral groin pain that radiated to both legs. She was eventually admitted to the hospital with a fever of 38-39°C without evidence of infection. She also received one unit of RBC transfusion for a drop in Hct from 32% to 25%. For her third infusion, we premedicated her with acetaminophen 650mg, diphenhydramine 50mg, ketorolac 1g along with concurrent IV hydration. She tolerated an initial infusion at 20ml/h for the first 15 minutes after which we ramped it up to the regular rate of 200ml/h. Within minutes of that rate increase, the patient developed chest pain and dyspnea, so infusion was stopped immediately. Blood samples taken right after the event revealed tryptase and IgE levels within normal limits, and she chose to discontinue the medication. Case 2, a 20-year-old woman with sickle cell anemia with frequent painful episodes despite hydroxyurea at 25mg/kg/day. The patient preferred to start crizanlizumab over increasing oral medication. She reported having had fever and chills at home after her first crizanlizumab infusion and improved with acetaminophen. About 10 minutes into her second infusion, she developed acute severe migratory pain in her back, moving to her lower limbs, associated with tachycardia. Infusion was immediately discontinued, and she was medicated with diphenhydramine 25mg and methylprednisolone 125mg with no improvement. She progressed with abdominal pain moving into her arms and needed meperidine 25mg and hydromorphone 1mg to achieve pain resolution. She completed the infusion successfully at 50% reduced rate but still reported subjective high fevers and chills again the next day, medicated with acetaminophen. She continues monthly infusions with a slower rate. Discussion: As of October 2020, Novartis (manufacturer of crizanlizumab) informed that, out of 3,500 patients, there have been 22 postmarketing reports of severe pain during or within 24 hours of the infusion. Seven cases reported complications, all of which resolved. Immediate hypersensitivity reactions to monoclonal antibodies can be a cytokine release syndrome, IgE-mediated, or IgG-mediated. One case report has suggested this may be a complement activation-related pseudoallergy (CARPA) as sC5b-9 was mildly elevated in a 17-year-old male patient who developed sudden and severe pain in his back, legs and head within 10 minutes of the infusion, despite having been premedicated with acetaminophen, later developing a fever and need for admission. Differently from that case, our patients developed severe pain with a second exposure of the drug, arguing in favor of an antibody-mediated process. We did not find evidence of mast cell activation or increased IgE production in our patient who needed to discontinue the medication. We therefore hypothesize that crizanlizumab-associated painful febrile reaction may be IgG-mediated. Premedication in our experience was unsuccessful, and symptomatic treatment with acetaminophen was appropriate, but slower infusion rates may prove useful for some patients. Conclusion: While rare, crizanlizumab-associated painful febrile reactions may be observed after a first uneventful infusion and are possibly IgG-mediated. Patients experiencing this reaction may require symptomatic treatment with acetaminophen despite premedication and can be tried on slower infusion rates. Disclosures Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

​Caprine Respiratory Mycoplasmosis (Contagious Caprine Pleuropneumonia CCPP)- A Global Perspective of the Disease, Epidemiology, Diagnosis, Chemotherapy and Immunization: A Review

Mycoplasma infection of the respiratory tract of goats is prevalent worldwide including the South Asian sub-continent. Owing to intensive and large scale goat farming, the incidence of the disease is on an increase. Among various species of mycoplasma, Mycoplasma capricolum subspecies Capri pneumoniae is increasingly incriminated in Contagious Caprine Pleurapneumonia (CCPP) in goat populations with considerable economic fallout in the form of high morbidity and mortality. The disease manifestations in caprines are recorded as anorexia, high febrile reaction and respiratory embarrassment in the shape of clinical dyspnoea, polypnea, paroxysmal cough and sero-purulent nasal discharges. The disease is thus contracted by the healthy animals through aerosol, contaminated feed and water sources in the herd premises, without a protective immunity and that the conferred immunity in recovered cases being short-lived. The true lesions of CCPP are confined to the lung alveolar tissues of infected goats, which distinguish it from other respiratory diseases of small ruminants caused by the members of the Mycoplasma mycoides cluster. Atypical pneumonia caused by the mycoplasma infection of goats, also known as Contagious Caprine Pleuropneumonia (CCPP) has been more often reported from Africa and Asia than Europe. Classical, acute CCPP attributed to Mycoplasma capricolum subsp. Capri pneumoniae, originally known asthe F38 biotype (World Organisation for Animal Health, 2008) causes heavy kid mortality. Two other organisms in this group, M. mycoides subsp. capri and M. mycoides subsp. mycoides large-colony type, can cause disease in small ruminants that clinico-pathologically mimics CCPP but may have extra pulmonary signs and lesions, sometimes. Mycoplasma Capri pneumoniae and other members of the M. mycoides cluster cross-react in serological tests and share biochemical and genetic similarities. The most favourable epidemiological scenario in the Sub-continent is the hot humid climate during monsoons. The diversity and multi-etiological subspecies involved in the disease is detrimental in the development of an effective vaccine even though in some places a liquid vaccine is presently in use. At other places, anti-mycoplasmal antibiotics of aminoglycoside and fluoroquinolone and perhaps the macrolide groups remain to be the main option in preventing flock mortalities.

Febrile reaction after hematopoietic stem cell infusion is more frequent if no steroid premedicaton is given which results in more frequent use of antibiotics in early post-transplant phase

Background: There is no consensus as to the need for steroid premedication before fresh product hematopoietic stem cell (HSC) infusion. In case of febrile reaction post-HSC infusion, on-call staff frequently prescribe antibiotics empirically. Considering the recent data on the value of microbiota and its influence on GVHD incidence, we analysed the frequency of febrile reactions and the use of antibiotic after HSC infusion in 149 consecutive patients. Methods: In the time period between 1/2018 and 10/2019, 149 patients were subject to transplantation in our institution. Per institutional standard operating procedure (SOP), all the patients received premedication before hematopoietic stem cell infusion consisting of 20 mg chloropyramine-chlorid iv, and in case of ABO incompatible graft 1 mg/kg methylprednisolone iv. Retrospective data was collected by using patient charts. Survival probability was calculated by applying Kaplan-Meier method. Results: Fifty-two patients received steroids, 12 patients (23%) developing fever after graft infusion, 46 patients received no steroids, 26 of them (57%) developed fever (p<0.001). There was no difference in the number of patients having positive blood cultures. Nine (17%) and 16 (35%) patients received IV antibiotics in the “steroid” and no-steroid” group, respectively (p<0.05). There was no difference in survival between “steroid” and “no-steroid” group. Conclusions: Even with no difference in the frequency of febrile episodes caused by systemic infection, a significantly more patients not receiving steroid premedication develop fever and are treated with IV antibiotics, which could potentially have further implications on transplantation outcomes due to its influence on microbiota early post-transplant.

Convalescent plasma as potential therapy for severe COVID-19 pneumonia.

At the beginning of the COVID-19 pandemic, there was high mortality and a lack of effective treatment for critically ill patients. Build on the experience in argentine hemorrhagic fever with convalescent plasma, we incorporated 90 patients into a multicenter study, and 87 were evaluable. We collected 397 donations from 278 convalescent donors. Patients received plasma with an IgG concentration of 0.7-0.8 (measured by Abbott chemiluminescence) for every 10 kg of body weight. Survival during the first 28 days was the primary objective. 77% were male, age 54 (+/-15.6 y/o (range 27-85); body mass index 29.7 +/-; 4,4; hypertension 39% and diabetes 20%; 19.5% had an immunosuppression condition; 23% were healthcare workers. Plasma was administered to 55 patients (63%) on spontaneous breathing with oxygen supplementation (mainly oxygen mask with reservoir bag in 80%), and 32 patients (37%) were infused on mechanical ventilation. The 28-day survival rate was 80%, with 91% in patients infused on spontaneous breathing and 63% in those infused on mechanical ventilation (p = 0.0002). There was a significant improvement in the WHO pneumonia clinical scale at 7 and 14 days, and in PaO2 / FiO2, ferritin and LDH, in the week post-infusion. We observed an episode of circulatory volume overload and a febrile reaction, both mild. Convalescent plasma infusions are feasible, safe, and potentially effective, especially before requiring mechanical ventilation, and are an attractive clinical option for treating severe forms of COVID-19 until other effective therapies become available.

In Vivo Demonstration of the Superior Replication and Infectivity of Genotype 2.1 with Respect to Genotype 3.4 of Classical Swine Fever Virus by Dual Infections

In Taiwan, the prevalent CSFV population has shifted from the historical genotype 3.4 (94.4 strain) to the newly invading genotype 2.1 (TD/96 strain) since 1996. This study analyzed the competition between these two virus genotypes in dual infection pigs with equal and different virus populations and with maternally derived neutralizing antibodies induced by a third genotype of modified live vaccine (MLV), to simulate that occurring in natural situations in the field. Experimentally, under various dual infection conditions, with or without the presence of maternal antibodies, with various specimens from blood, oral and fecal swabs, and internal organs at various time points, the TD/96 had consistently 1.51−3.08 log higher loads than those of 94.4. A second passage of competition in the same animals further widened the lead of TD/96 as indicated by viral loads. The maternally derived antibodies provided partial protection to both wild type CSFVs and was correlated with lower clinical scores, febrile reaction, and animal mortality. In the presence of maternal antibodies, pigs could be infected by both wild type CSFVs, with TD/96 dominating. These findings partially explain the CSFV shift observed, furthering our understanding of CSFV pathogenesis in the field, and are helpful for the control of CSF.

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)

Background Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. Methods This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). Results Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. Conclusions In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. Clinical trials registration NCT02511405

Features of feverish reaction in children with herpes virus infection

One of the most persistent and striking manifestations of herpes virus infections is fever. The feverish reaction is different and depends from the child's age and the effect on the child's body of pyrogenic substances. The main biological and pathogenetic feature of herpesviruses is the long-term presence in the body of the child pathogens, which are present in different tissues. This causes the polymorphism of clinical manifestations and the severity of certain infectious diseases. The aim of our work was the analysis of modern scientific data regarding herpes infection and the observation of children in whom the fever lasted three or more days. We examined 86 children aged 1–7 years with herpesvirus infection in whom fever was observed. Verification of the diagnosis and clarification of herpes virus infection was carried out within 1–3 days from the moment of hospitalization by determining the polymerase chain reaction, Ig M and G to herpes viruses of types 1, 2, cytomegalovirus, Epstein-Barr virus and type 6 and 7 herpes viruses in blood and smears-prints of tonsils. The degree of activity of the inflammatory process in hepatocytes was evaluated by the level of alanine aminotransferases (ALT). To determine the extent of damage to hepatocytes used the indirect method — the Ritz coefficient. We used absolute and relative statistics using Microsoft Excel on an IBM PC/AT computer to evaluate the study results. In our study, 55.8% of children had pyretic fever (temperature above 39°C).The duration of the febrile reaction in 52.32% of patients was acute from 6 to 7 days. In 88.37% of children of the first 3 years of life with herpesvirus infection, a febrile reaction was accompanied by a general intoxication syndrome and manifestations of emotional lability, increased irritability, tearfulness, sleep disturbance, negative reaction to examination, and rapid fatigue. A rash on skin and mucous membranes was observed in 27.9% of children and an increase in the size of liver was recorded in 79.05% of patients.

Unusual Drug Fever Caused by Imipenem/Cilastatin and a Review of Literature

Introduction: Drug fever is a febrile reaction caused by initiation of one drug or varieties of drugs and often disappears after cessation of the drug(s). Clinically, drug fever is frequently induced by antibiotics, anticonvulsants, and antineoplastics. There are few previous reports about drug fever caused by imipenem/cilastatin. Case Presentation: Here, we described a 66-year-old man undergoing the Ivor Lewis esophagectomy for esophageal carcinoma, who developed drug fever. The patient had a high temperature with shivering after administration of imipenem/cilastatin for 7 days. Furthermore, his temperature came down after discontinuing imipenem/cilastatin and receiving steroids. Body temperature increased rapidly 4 hours after intravenous readministration of imipenem/cilastatin and rapidly decreased to normal after discontinuing imipenem/cilastatin and administering steroids. Conclusion: Thorough history, blood tests, physical examination, and computed tomography (CT) did not reveal any evidence of fever. Drug fever caused by imipenem/cilastatin was considered. We also present a review of relevant literature and provide a point of reference for the clinical diagnosis and therapy of patients with drug fever.

Efficacy of Oral Acetaminophen and Intravenous Chlorpheniramine Maleate versus Placebo to Prevent Red Cell Transfusion Reactions in Children and Adolescent with Thalassemia: A Prospective, Randomized, Double-Blind Controlled Trial

Background. Thalassemia is a common congenital hemolytic disorder. In severe cases, regular blood transfusion is essentially required. The role of premedications to prevent transfusion reactions is varied among institutions with no standard guideline. Objective. To prospectively compare the risk of transfusion reactions in thalassemia patients premedicated with acetaminophen and chlorpheniramine maleate (CPM) versus placebo prior to blood transfusion. Material and Method. A randomized, double-blinded, placebo-controlled transfusion reaction study of 147 eligible patients was analyzed. All administered red blood cell (RBC) products were leukoreduced blood products. Patients were monitored and followed for the development of transfusion reactions for 24 hours after RBC transfusion. Results. A total of 73 patients randomized to receive active drugs consisting of acetaminophen and CPM were compared to 74 patients receiving placebo. The overall incidences of febrile reaction and urticarial rash were 6.9% and 22% in the patients randomized to receive active drugs comparing with 9.5% and 35.2% in the patients receiving placebo with no significant differences between two groups. However, delayed development of urticarial rash at 4-24 hours after RBC transfusion was significantly higher in female and patients receiving placebo. Conclusion. Administration of premedications in thalassemia patients receiving RBC transfusion without a history of transfusion reactions does not decrease the overall risk of transfusion reactions. However, the use of CPM might be beneficial to prevent delayed urticarial rash in those patients especially in females (Thai Clinical Trial Registry (TCTR) study ID: 20140526001).