Evaluation of infectious morbidity due to BTK inhibitors in indolent B-cell lymphomas: latest research findings and systematic analysis.

INTRODUCTION: Randomized clinical trials (RCTs) have suggested that BTK inhibitors (BTKis) might increase infectious disease (ID) risk. Systematic analysis of this topic as derived from RCTs and clinical practice is needed. AREAS COVERED: An extensive Medline, Embase, and Cochrane search of peer-reviewed sources reporting on ID morbidity in patients on BTKis was performed (1 January 2014 - 31 December 2013). Contribution of intrinsic immune defects in indolent B-cell lymphomas to this morbidity was carefully considered. EXPERT OPINION: Patients with indolent B-cell lymphomas display a wide range of innate and adaptive immune defects. In addition, BTKi use is linked with an increased signal of upper respiratory tract infections (URTIs) and pneumonias, mainly grade 1-2. These agents also increase the risk of rare invasive fungal infections (IFIs), mainly due to Cryptococcus and Aspergillus spp. with a peak within several months after the start of therapy. More than half of these IFIs are fatal. Research suggests a similar ID risk across 1st, 2nd and 3rd generations of BTKis, all causing B-cell dysfunction due to BTK inhibition, along with off-target functional neutrophil/macrophage alterations. Expanding the knowledge base on ID morbidity in patients on BTKis would facilitate timely diagnosis and treatment, and improve clinical outcomes.

Clinical and biochemical footprints of inherited metabolic diseases. XII. Immunological defects.

Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Combined Immune Defect in B-Cell Lymphoproliferative Disorders Is Associated with Severe Infection and Cancer Progression.

B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan-Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.

[Role of genetic factors in pneumonia and COVID-19]. / Bedeutung der Genetik für die Pneumonie und COVID-19.

Pneumonia causes the highest mortality of all infectious diseases worldwide. The most common pathogens are bacteria but there are also epidemic or pandemic lung infections caused by influenza or coronaviruses, such as the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the occurrence of antibiotic resistance and immune pathologies, such as in sepsis, important challenges lie in considering the susceptibility of individual patients. Here, age, medication and comorbidities are considered; however, there is also clear evidence of genetic influences on the individual risk of developing pneumonia or developing a severe course of the disease. This article discusses the genetic influences on pneumonia and the clinical significance.

Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune "Defects" in the Tumor Microenvironment.

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed with the treatment of pancreatic cancer and all other immunogenic "cold" tumors. This prompts the need for a better understanding of the complexity of the cold tumor microenvironment (TME) of pancreatic cancer and what are truly the "defects" in the TME making the cancer unresponsive to immune checkpoint inhibitors. Here we discuss four major immune defects that can be recognized in pancreatic cancer, including lack of high-quality effector intratumoral T cells, heterogeneous dense stroma as a barrier to effector immune cells infiltrating into the tumor, immunosuppressive tumor microenvironment, and failure of the T cells to accomplish tumor elimination. We also discuss potential strategies for pancreatic cancer treatment that work by correcting these immune defects.

Candidemia in critically ill immunocompromised patients: report of a retrospective multicenter cohort study.

BACKGROUND: Immunocompromised critically ill patients constitute a population with the high risk of candidemia. This retrospective study aimed to assess the outcome of immunocompromised critically ill patients with candidemia. Secondary objectives were to describe clinical phenotypes of these patients, Candida ecology, and factors associated with mortality. RESULTS: Overall, 121 patients were included in this study. Median delay from candidemia to first antifungal therapy was 3 days, in line with the observed delay of blood culture positivity. Candia albicans was the main Candida specie identified (54%), and susceptibility of Candida to fluconazole and echinocandins was of, respectively, 70% and 92%. Hospital mortality was of 60%. After adjustment for confounders, severity as assessed by the need for vasopressors (HR 1.8, CI95% 1.1-3.1), need for mechanical ventilation (HR 2.0, CI95% 1.1-3.8) and allogenic stem cell transplantation (HR 2.5, CI95% 1.1-6.0) were independently associated with poor outcome. Candida specie, susceptibility and treatment strategies were not associated with outcome. CONCLUSIONS: Candidemia in immunocompromised critically ill patients is associated with a grim outcome. Despite the high prevalence of Candida non-albicans species, neither C. species nor its susceptibility was associated with outcome. Conversely, severity and preexisting allogeneic stem cell transplantation were independently associated with poor outcome. Despite antifungal prophylaxis and use of preemptive antifungal therapy in neutropenic patients, antifungal therapy was initiated three days after symptoms onset suggesting needs for specific strategies aiming to reduce this delay.

The monocyte-dependent immune response to bacteria is suppressed in smoking-induced COPD.

COPD patients have an increased susceptibility to bacterial airway infections that can induce exacerbations. In response to infections, circulating monocytes become recruited to the infected tissue and secrete cytokines. We hypothesized that this cytokine response is reduced in COPD. Cultured peripheral blood monocytes of never smokers (NS) and smokers without (S) and with COPD (3 study populations, n = 36-37) were stimulated with extracts of Haemophilus influenzae, Staphylococcus aureus, or Streptococcus pneumoniae or with four different pathogen-associated molecular patterns (PAMPs). Four cytokines and 9 PAMP-related signaling molecules were measured and compared between the groups. Granulocyte-macrophage-colony-stimulating-factor responses to all stimulants were reduced in S and COPD compared to NS. Tumor-necrosis-factor-α responses to all bacterial extracts, peptidoglycan, and lipopolysaccharide were reduced in S and/or COPD. Interleukin-10 responses to S. aureus and lipoteichoic acid were increased in COPD. Correlations to pack-years and lung function were found. The peptidoglycan-receptor NOD2 and the mRNA of the lipopolysaccharide-receptor TLR4 were reduced in S and COPD. Cytokine responses of monocytes to bacteria are suppressed by smoking and in COPD possibly due to NOD2 and TLR4 reduction and/or interleukin-10 increase. This might help to explain the increased susceptibility to bacterial infections. These systemic molecular pathologies might be targets for therapeutic strategies to prevent infection-induced exacerbations. KEY MESSAGES: COPD subjects have an increased susceptibility to bacterial infections. This implies defects in the immune response to bacteria and is critical for disease progression. The cytokine response of monocytes to bacteria is reduced in COPD. This might be due to a reduced NOD2 and TLR4 and an increased IL-10 expression. This can explain the increased susceptibility to infections and help to identify drug targets.

The Pattern of Malignancies in Down Syndrome and Its Potential Context With the Immune System.

The immune surveillance theory of cancer posits that the body's immune system detects and destroys randomly occurring malignant cells. This theory is based on the observation of the increased frequency of malignancies in primary and secondary immunodeficiencies, and is supported by the successful demonstration of immune augmentation in current oncological immune therapy approaches. We review this model in the context of Down syndrome (DS), a condition with a unique tumor profile and various immune defects. Children and adults with DS are more prone to infections due to anatomical reasons and a varying degree of T- and B-cell maturation defects, NK cell dysfunction, and chemotactic or phagocytic abnormalities. However, despite an increased incidence of lymphoblastic and myeloblastic leukemia of infants and children with DS, individuals with DS have a globally decreased incidence of solid tumors as compared to age-adjusted non-DS controls. Additionally, cancers that have been considered "proof of immune therapy principles," such as renal carcinoma, small cell lung carcinoma, and malignant melanoma, are less frequent in adults with DS compared to the general population. Thus, despite the combination of an increased risk of leukemia with detectable immune biological abnormalities and a clinical immunodeficiency, people with DS appear to be protected against many cancers. This observation does not support the immune surveillance theory in the context of DS and indicates a potential tumor-suppressive role for trisomy 21 in non-hematological malignancies.

Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory Condition.

Rosacea is a chronic cutaneous inflammatory disease that affects the facial skin. Clinically, rosacea can be categorized into papulopustular, erythematotelangiectatic, ocular, and phymatous rosacea. However, the phenotypic presentations of rosacea are more heterogeneous. Although the pathophysiology of rosacea remains to be elucidated, immunologic alterations and neurovascular dysregulation are thought to have important roles in initiating and strengthening the clinical manifestations of rosacea. In this article, we present the possible molecular mechanisms of rosacea based on recent laboratory and clinical studies. We describe the genetic predisposition for rosacea along with its associated diseases, triggering factors, and suggested management options in detail based on the underlying molecular biology. Understanding the molecular pathomechanisms of rosacea will likely aid toward better comprehending its complex pathogenesis.

Overview of Immunodeficiency Disorders.

The spectrum of primary immunodeficiency disorders (PIDs) is expanding. It includes typical disorders that primarily present with defective immunity as well as disorders that predominantly involve other systems and show few features of impaired immunity. The rapidly growing list of new immunodeficiency disorders and treatment modalities makes it imperative for providers to stay abreast of the latest and best management strategies. This article presents a brief overview of recent clinical advances in PIDs.