A Medication Hiccup: Chlorpromazine-Induced Agranulocytosis in a 72-Year-Old Male.

INTRODUCTION: Agranulocytosis, a severe decrease or absence of neutrophils, is a side effect of several medications, including chlorpromazine. If not promptly recognized, it can lead to overwhelming infection, sepsis, and death. CASE PRESENTATION: A 72-year-old man with adenocarcinoma of the lung status-post recent lobectomy was admitted for postsurgical pain and electrolyte derangement. During his admission, he had intractable hiccups and was started on chlorpromazine 25 mg by mouth 3 times a day. Within a week, he developed pneumonia, type 1 respiratory failure, and a progressive neutropenia. Chlorpromazine-induced agranulocytosis was suspected and chlorpromazine was discontinued; however, the patient expired, with postmortem findings of aspergillus bronchopneumonia as cause of death. DISCUSSION: Chlorpromazine is a well-studied cause of agranulocytosis. This case is novel in its rapid time course of less than 1 week; most cases report the resultant agranulocytosis on the order of weeks rather than days. CONCLUSION: This case highlights an important need to recognize this medication side effect early so the offending agent may be stopped and the patient properly supported, so as to avoid the severe risk of neutropenic infection, sepsis, and death.

Adecuación de la seguridad del metamizol y agranulocitosis / Adequacy of the safety of metamizole and agranulocytosis

Objetivo: Analizar si la nota informativa de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), de 30 de octubre del 2018, sobre agranulocitosis y metamizol contiene la información precisa y necesaria para proteger a los pacientes de la aparición de esta reacción adversa (RA) y si la documentación oficial de los medicamentos con metamizol para médicos, farmacéuticos y población general está adaptada a las directrices de la AEMPS para disminuir el riesgo. Emplazamiento y participantes: Nota informativa, búsqueda bibliográfica, información sobre los medicamentos con metamizol comercializados en España en la Agencia Europea del Medicamento, fichas técnicas, prospectos, base de datos de información sanitaria Bot PLUS y Catálogo de Especialidades Farmacéuticas. Notificación de 4casos de agranulocitosis por metamizol posteriores a la fecha de la nota informativa. Intervenciones y mediciones principales: Comparación de los puntos clave de la nota informativa y de los documentos oficiales sobre metamizol con la bibliografía. Descripción de 4casos de agranulocitosis por metamizol y aplicación del algoritmo de causalidad y gravedad. Resultados: La nota informativa presenta ausencias y dudas respecto a la bibliografía y al uso de metamizol en la práctica asistencial. Los documentos oficiales presentan faltas de actualización, indicaciones no aprobadas y dosis superiores a las recomendadas. La nota informativa no ha frenado la presentación de casos de agranulocitosis por metamizol. Conclusiones: La nota informativa de la AEMPS es mejorable y es necesario actualizar los documentos oficiales de información sobre el metamizol para profesionales sanitarios y pacientes para disminuir el riesgo de agranulocitosis.(AU)

Objective: To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk. Setting and participants: Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued. Main interventions and measurements: Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm. Results: The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole. Conclusions: The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.(AU)

Eosinopenia and neutrophil-to-lymphocyte count ratio as prognostic factors in exacerbation of COPD.

Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPDs) are one of the most important clinical aspects of the disease, and when requiring hospital admission, they significantly contribute to mortality among COPD patients. Our aim was to assess the role of eosinopenia and neutrophil-to-lymphocyte count (NLR) as markers of in-hospital mortality and length of hospitalization (LoH) among patients with ECOPD requiring hospitalization. We included 275 patients. Eosinopenia was associated with in-hospital deaths only when coexisted with lymphocytopenia, with the specificity of 84.4% (95% CI 79.6-88.6%) and the sensitivity of 100% (95% CI 35.9-100%). Also, survivors presented longer LoH (P < 0.0001). NLR ≥ 13.2 predicted in-hospital death with the sensitivity of 100% (95% CI 35.9-100%) and specificity of 92.6% (95% CI 88.8-95.4%), however, comparison of LoH among survivors did not reach statistical significance (P = 0.05). Additionally, when we assessed the presence of coexistence of eosinopenia and lymphocytopenia first, and then apply NLR, sensitivity and specificity in prediction of in-hospital death was 100% (95% CI 35.9-100) and 93.7% (95% CI 90.1-96.3), respectively. Moreover, among survivors, the occurrence of such pattern was associated with significantly longer LoH: 11 (7-14) vs 7 (5-10) days (P = 0.01). The best profile of sensitivity and specificity in the prediction of in-hospital mortality in ECOPD can be obtained by combined analysis of coexistence of eosinopenia and lymphocytopenia with elevated NLR. The occurrence of a such pattern is also associated with significantly longer LoH among survivors.

Agranulocytosis leads to intestinal Echinococcus multilocularis oncosphere invasion and hepatic metacestode development in naturally resistant Wistar rats.

Susceptibility to Echinococcus multilocularis infection considerably varies among intermediate (mostly rodents) and dead-end host species (e.g. humans and pig), in particular regarding intestinal oncosphere invasion and subsequent hepatic metacestode development. Wistar rats are highly resistant to infection and subsequent diseases upon oral inoculation with E. multilocularis eggs, however, after immunosuppressive treatment with dexamethasone, rats become susceptible. To address the role of the cellular innate immunity, Wistar rats were individually or combined depleted of natural killer (NK) cells, macrophages (MΦ) and granulocytes (polymorphonuclear cells, PMN) prior to E. multilocularis egg inoculation. Although NK cell and MΦ depletion did not alter the resistance status of rats, the majority of PMN-depleted animals developed liver metacestodes within 10 weeks, indicating that PMN are key players in preventing oncosphere migration and/or development in Wistar rats. In vitro studies indicated that resistance is not caused by neutrophil reactive oxygen species or NETosis. Also, light microscopical examinations of the small intestine showed that oral inoculation of E. multilocularis eggs does not elicit a mucosal neutrophil response, suggesting that the interaction of oncospheres and neutrophils may occur after the former have entered the peripheral blood. We suggest to consider granulocytes as mediators of resistance in more resistant species, such as humans.

Presentación de un caso de agranulocitosis por propiltiouracilo / Presentation of a case of agranulocytosis caused by propylthiouracil

Se estudió una paciente de 33 años de edad con antecedentes patológicos de Bocio tiroideo difuso desde hace 8 años, que acude al cuerpo de guardia por presentar falta de aire, fiebre de 39-40 °C, dolor de garganta y palpitaciones hace alrededor de tres días. Al examen físico se le constató exoftalmos, mucosas hipocoloreadas y faringe purulenta y punteada de color blanquecina, artralgia y taquicardia. Referente a los exámenes complementarios presentó anemia, leucopenia y pancitopenia luego de haber consumido propiltiouracilo (50mg) por un período prolongado; por lo que se concluye como agranulocitosis como consecuencia de una reacción adversa al propiltiouracilo. Luego de ser tratada la paciente se recupera de su gravedad con el uso de factores estimulantes de colonias de granulocitos(AU)

A female 33-year-old patient with an 8-year history of diffuse thyroid goiter presents at the emergency service with shortness of breath, a 39-40ºC fever, a sore throat and palpitation of 3 days' evolution. Physical examination revealed exophthalmos, hypopigmented mucosas, a purulent pharynx dotted with whitish spots, arthralgia and tachycardia. Complementary tests found anemia, leukopenia and pancytopenia upon consumption of propylthiouracil (50 mg) for a long period. The diagnosis is agranulocytosis resulting from an adverse reaction to propylthiouracil. After being treated the patient recovered from her severe status with the use of granulocyte colony stimulating factors(AU)

[Clinical Features of Nosocomial Infections in Agranulocytosis Patients with Hematological Malignancies and Analysis of Risk Factors].

OBJECTIVE: To explore the clinical features and risk factors for nosocomial infections in agranulocytosis patients with hematological malignancies so as to provide basis for clinical prevention and treatment of nosocomial infections. METHODS: The clinical data of 725 patients with agranulocytosis in the First Hospital of Lanzhou University from May 2015 to May 2018 were retrospectively analyzed, including sex, age, primary disease, treatment stage, agranulocytosis degree, agranulocytosis duration, nosocomial infection, infectous site, average length of stay and average days of infection. Univariate analysis (Chi-square test) and multivariate analysis (non-conditional Logistic regression models) were used to analyze the risk factors of nosocomial infection. RESULTS: The most common sites of nosocomial infection in agranulocytosis patients with hematological maliguancies were upper respiratory tract, accounting for 24.0%, followed by lung (16.2%) and blood stream (13.8%). In disease composition, acute leukemia holded the first place, accounting for 82.1%, among which the acute myeloid leukemia had the highest infection rate, accounting for 73.3%, followed by acute lymphoblastic leukemia. The infection rates were 68.0% and 66.7% for multiple myeloma, 79.3% and 84.5% for acute leukemia at the initial induction and relapse stages, respectively. 184 pathogenic bacteria were isolated clinically, of which 126 were a Gram-negative bacteria, 23 were Gram-positive bacteria and 35 were fungi, accounting for 68.48%, 12.50% and 19.02%, respectively. It was found that age, primary disease, degree and duration of granulocyte deficiency, chemotherapy, glucocorticoid use and disease status all associated with nosocomial infection (P＜0.05). Multivariate unconditional logistic regression analysis showed that acute leukemia, absolute count of neutrophils＜0.2×109/L, chemotherapy and disease unremitting were the main risk factors of nosocomial infection. CONCLUSION: The patients with malignant hematological agranulocytosis are a high-risk population of nosocomial infection. Nosocomial infection rate is still high, especially in patients with acute leukemia who have received chemotherapy or without complete remission or neutrophil absolute count less than 0.2×109/L. Thus early intervention measures should be taken to reduce the incidence of nosocomial infection and mortality.

Treatment of invasive fungal diseases in cancer patients-Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

BACKGROUND: Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects. OBJECTIVES: Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFDs) towards pre-emptive therapy of probable IFD. METHODS: The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. MEDLINE was systematically searched for English-language publications from January 1975 up to September 2019 using the key terms such as 'invasive fungal infection' and/or 'invasive fungal disease' and at least one of the following: antifungal agents, cancer, haematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis and mucormycosis. RESULTS: AFT of IFDs in cancer patients may include not only antifungal agents but also non-pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (eg licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials. CONCLUSIONS: Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarised in tables to give the reader rapid access to key information.

Early intervention with supplemental parenteral nutrition reduces the incidence of granulocytopenia-related infections in patients with lung cancer: a retrospective cohort study.

BACKGROUND AND OBJECTIVES: The optimal timing for initiating supplemental parenteral nutrition in chemotherapy- induced severe granulocytopenia in patients with lung cancer remains uncertain. METHODS AND STUDY DESIGN: A retrospective study was conducted among patients with lung cancer from February 2016 to June 2018. In total, 182 eligible patients were included and divided into 2 groups according to the time of supplemental parenteral nutrition intervention: early initiation (within 72 hours of development of granulocytopenia) and late initiation (over 72 hours). The primary outcomes of the study were bacterial infection and fungal infection, and the secondary outcomes were duration of absolute neutrophil count less than 1.0×109 cells/L, length of hospital stay, mortality rate, and rate of chemotherapy (4 cycles) completion. RESULTS: The incidence rates of bacterial infection and fungal infection were significantly lower among patients who received supplemental parenteral nutrition early than among patients who received it late. No significant difference in mortality was observed between the groups. In addition, compared with late supplemental parenteral nutrition, early supplemental parenteral nutrition was associated with a higher rate of completion of 4 chemotherapy cycles and shorter hospital stays and leukocyte recovery periods in our cohort. Univariate and multivariate logistic regression analyses revealed that the subgroup of patients with an NRS-2002 score of 2 benefited from early supplemental parenteral nutrition. CONCLUSIONS: Early supplemental parenteral nutrition after chemotherapy-induced severe granulocytopenia could reduce the risk of infection, improve the likelihood of chemotherapy completion, and shorten hospital stays and leukocyte recovery times.

What are the positive drivers and potential barriers to implementation of hospital at home selected by low-risk DECAF score in the UK: a qualitative study embedded within a randomised controlled trial.

OBJECTIVE: Hospital at home (HAH) for chronic obstructive pulmonary disease exacerbation selected by low-risk Dyspnoea, Eosinopenia, Consolidation, Acidaemia and atrial Fibrillation (DECAF) score is clinical and cost-effective; DECAF is a prognostic score indicating risk of mortality. Up to 50% of admitted patients are suitable, a much larger proportion than earlier services. Introduction of new models of care is challenging, but may be facilitated by informed engagement with stakeholders. This qualitative study sought to identify facilitators and barriers to implementation of HAH. DESIGN: Semistructured interviews, data were analysed using thematic-construct analysis. SETTING: Interviews were conducted within patients' homes and hospitals in North East England. PARTICIPANTS: 89 participants were interviewees; 44 patients, 15 carers, 15 physicians, 11 specialist nurses and 4 managers. RESULTS: Facilitators include the following: (1) availability of home comforts and maintaining independence (with positive influences on perceived rate of recovery, sleep quality and convenience for friends, family and carers) and (2) confidence in the continuity of HAH care. Barriers include the following: (1) fear of being alone at home; (2) privacy issues and not wanting visitors and (3) resistance to change. Clinician concerns occasionally delayed return home, principally during the early phase of the trial. Nurses cited higher workload and greater responsibility, but with additional resource and training; overall, they viewed HAH positively. Operational concerns included keeping medical records in a patient's home and inability to capture activity within current payment systems. CONCLUSION: HAH selected by DECAF was preferred to inpatient care by most patients and their families. Implementation in other hospitals will require education, training and service planning, tailored to overcome the identified barriers. TRIAL REGISTRATION NUMBER: ISRCTN29082260.

Severe acute pancreatitis with blood infection by Candida glabrata complicated severe agranulocytosis: a case report.

BACKGROUND: Blood infection with Candida glabrata often occurs in during severe acute pancreatitis (SAP). It complicate severe agranulocytosis has not been reported. CASE PRESENTATION: We present a case where a SAP patient presenting with a sudden hyperpyrexia was treated for 19 days. We monitored her routine blood panel and CRP levels once or twice daily. The results showed that WBC count decreased gradually. And the lowest level of WBC was appeared at the 21st day of treatment. WBC 0.58 × 109/L(4.0-10.0 × 109/L), neutrophils 0.1 × 109/L [2.20%] (2.5-7.5 × 109/L). During treatment, Candida glabrata was identified as the infecting agent through blood culture, drainage tubes culture and gene detection. During anti-infection therapy, the patient had severe agranulocytosis. With control of the infection, her WBC and granulocyte counts gradually returned to the normal range. CONCLUSIONS: Blood infection with Candida glabrata can complicate severe agranulocytosis.

Recurrent Levamisole-Induced Agranulocytosis Complicated by Bowel Ischemia in a Cocaine User.

BACKGROUND Levamisole is a common adulterant of cocaine and up to 69% of seized cocaine in United States contains levamisole. It is a synthetic imidazothiazole derivative which was previously used as an immunomodulating agent for treatment of various connective tissue disorders and colorectal carcinoma. However, it was withdrawn later from the market due to significant toxicity associated with it. CASE REPORT We present the case of a 59-year-old male patient with a history of active cocaine use who presented to the hospital with febrile neutropenia and agranulocytosis. He underwent extensive work-up for neutropenia and was suspected to have it secondary to levamisole-adulterated cocaine. He was treated with antibiotics and granulocyte-stimulating factor. His white cell count improved and he was discharged home. He continued to use cocaine after discharge from the hospital. He returned to the hospital 3 weeks later with recurrent neutropenia and agranulocytosis complicated by septic shock and bowel necrosis which required prolonged antibiotics and a bowel resection. CONCLUSIONS Levamisole-induced agranulocytosis should be considered in patients who present with neutropenia and a history of cocaine use. Physicians should have high clinical suspicion and consider it a potential etiology of agranulocytosis when other causes have been excluded.

Agranulocitosis en niña de 6 años. ¿Qué hay detrás? / Agranulocytosis in a 6 year-old girl. What's behind it?

El síndrome de Kabuki (SK) es una rara enfermedad genética que cursa con importantes alteraciones cardiacas e inmunológicas. La mayoría de los pacientes son diagnosticados en los primeros años de vida pese a que la edad de inicio no está bien definida. Los pacientes afectos presentan infecciones de repetición debido a su inmunosupresión pudiendo llegar a un estado de agranulocitosis. Aunque su pronóstico es bastante favorable, su esperanza de vida viene condicionada por este tipo de complicaciones. Por ello, conocer sus características analíticas particulares resulta interesante desde el punto de vista del laboratorio de hematología para contribuir en su orientación diagnóstica y en el seguimiento de los mismos. Presentamos el caso de un paciente diagnosticado de SK

Kabuki syndrome (KS) is a rare genetic disease that usually involves significant cardiac and immunological disorders. Most patients are diagnosed in the first years of life, despite the fact that the age of onset is not well-defined. Affected patients have recurrent infections due to their immunosuppression, and may reach a state of agranulocytosis. Although their prognosis is quite favourable, their life expectancy is determined by these types of complications. Therefore, to understand its particular analytical characteristics is interesting from the point of view of the Haematology Laboratory to contribute to their diagnosis and follow-up. The case is presented of a patient diagnosed with KS

Enfermedad de Graves en un paciente de 3 años con agranulocitosis asociada a fármacos antitiroideos: terapia ablativa con radioyodo como una alternativa eficaz / Graves’ disease in a 3 year-old patient with agranulocytosis due to anti-thyroid drugs: radioiodine ablation therapy as an effective alternative

Se presenta el caso de una niña de 3 años pluripatológica, con una enfermedad genética mitocondrial (encefalomiopatía necrosante subaguda o síndrome de Leigh), insuficiencia renal crónica estadio v por una esclerosis mesangial difusa y alteraciones del desarrollo, que fue diagnosticada de hipertiroidismo autoinmune por enfermedad de Graves-Basedow. A las 6 semanas del inicio terapéutico con neocarbimazol, la paciente presentó un cuadro de agranulocitosis severa que obligó a suspender la medicación con fármacos antitiroideos, motivo por el cual fue tratada de manera eficaz con terapia metabólica con 131I. La relevancia del artículo radica en la infrecuencia de la enfermedad de Graves en niños prepuberales (especialmente menores de 6 años), las complicaciones en el desarrollo derivadas de un posible diagnóstico tardío, la aparición de agranulocitosis como efecto adverso potencialmente grave tras el uso de antitiroideos y los pocos casos reportados de terapia ablativa con 131I a esta edad, que otorgan singularidad al caso (AU)

The case is presented of a 3 year-old girl with mitochondrial disease (subacute necrotizing encephalomyelopathy of Leigh syndrome), v-stage chronic kidney disease of a diffuse mesangial sclerosis, as well as developmental disorders, and diagnosed with hyperthyroidism Graves-Basedow disease. Six weeks after starting the treatment with neo-carbimazole, the patient reported a serious case of agranulocytosis. This led to stopping the anti-thyroid drugs, and was treated successfully with 131I ablation therapy. The relevance of the article is that Graves’ disease is uncommon in the paediatric age range (especially in children younger than 6 years old), and developing complications due to a possible late diagnosis. Agranulocytosis as a potentially serious adverse effect following the use of anti-thyroid drugs, and the few reported cases of ablation therapy with 131I at this age, makes this case unique (AU)

An infant with concurrent serotype 6C invasive pneumococcal disease and infectious mononucleosis.

Streptococcus pneumoniae is a main causative agent of serious invasive bacterial infections. However, concurrent infection with invasive pneumococcal disease (IPD) and viral infectious mononucleosis (IM) is rare. We report an infant with serotype 6C infection causing IPD occurring simultaneously with IM. A previously healthy 11-month-old girl referred to our hospital because of fever, leukopenia, and elevated C-reactive protein presented to us with disturbance of consciousness, tachycardia, tachypnea and agranulocytosis. Other findings included tonsillitis with purulent exudates and white spots, bilateral cervical adenopathy, and hepatosplenomegaly. We diagnosed her illness as sepsis and administered a broad-spectrum antibiotic, an antiviral agent, and granulocyte transfusions. After treatment was initiated, fever gradually decreased and general condition improved. IPD was diagnosed based upon isolation of S. pneumoniae of serotype 6C from blood cultures obtained on admission. Concurrently the girl had IM, based upon quantitation of Epstein-Barr viral DNA copies in blood and fluctuating serum antibody titers. Although simultaneous IPD and IM is a rare occurrence, this possibility is important to keep in mind.

[DRESS syndrome and agranulocytosis, a rare combination]. / Syndrome d'hypersensibilité médicamenteuse et agranulocytose, une association rare.

INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe toxidermia that can lead to death from multivisceral failure. We report a case of DRESS associated with febrile agranulocytosis in a child. OBSERVATION: An 8-year-old child was hospitalized for diffuse maculopapular exanthema with edema of the extremities and face associated with cheilitis and febrile agranulocytosis. This symptomatology began 1month after the introduction of carbamazepine for partial epilepsy. The clinical picture was a multisystemic disease with colitis, interstitial pneumonitis, hepatic cytolysis, and hepatocellular insufficiency. HHV7 viral reactivation and increased eosinophils (20%) in the myelogram were demonstrated, providing the diagnosis of DRESS. The progression was favorable after carbamazepine therapy was stopped and systemic corticosteroids were administered. DISCUSSION: DRESS syndrome is a disorder that is unfamiliar to pediatricians. Its association with agranulocytosis is rare and the absence of hypereosinophilia contributed to diagnostic difficulties in this case. The multisystemic failure, the reactivation of HHV7, the increase of eosinophils in the myelogram, and the favorable progression under systemic corticosteroid therapy contributed greatly to the diagnosis. A cutaneous biopsy was not considered necessary for the diagnosis in the case reported herein. CONCLUSION: DRESS syndrome is rarely associated with agranulocytosis, but its diagnosis must be quickly raised so that the incriminated drug can be interrupted.

[Leukopenia with unclear fever]. / Leukopenie mit unklarem Fieber.

We report on a 77-year-old male patient with neutropenic fever as a result of a newly diagnosed agranulocytosis. The patient was taking metamizole, which is a well known cause of agranulocytosis. The diagnosis of metamizole-induced agranulocytosis as an underestimated side-effect of metamizole could be confirmed by a bone marrow biopsy. The bone marrow and the blood count recovered completely after stopping the therapy with metamizole and administration of granulocyte colony-stimulating factor (G-CSF).

A Concise Review of Autoimmune Cytopenias in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune complications such as autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, and autoimmune granulocytopenia. It is critical to diagnose cytopenias from these secondary complications of CLL accurately, since prognosis and therapy are substantially different from patients who have cytopenias due to extensive bone marrow infiltration by CLL. The pathogenesis of autoimmune cytopenias in CLL is complex; and it involves antigen presentation by CLL cells to polyclonal B cells resulting in production of autoantibody, and alteration of the T cell milieu tilting the balance in favor of an autoimmune response. Traditional therapy of autoimmune complications in CLL consists of immunosuppression with corticosteroids and/or anti-CD20 monoclonal antibodies. In patients who have a suboptimal response, treating the underlying CLL is generally effective in ameliorating secondary cytopenias. Although novel oral therapies such as ibrutinib, idelalisib, and venetoclax have been shown to be extremely effective in the management of CLL, prospective data from larger numbers of patients with longer follow-up are needed prior to recommending their routine use in the management of autoimmune cytopenias in CLL.

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.