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BACKGROUND: The function of polymorphonuclear neutrophils (PMNs) decreases with age, which results in infectious and inflammatory complications in older individuals. The underlying causes are not fully understood. ATP release and autocrine stimulation of purinergic receptors help PMNs combat microbial invaders. Excessive extracellular ATP interferes with these mechanisms and promotes inflammatory PMN responses. Here, we studied whether dysregulated purinergic signaling in PMNs contributes to their dysfunction in older individuals. RESULTS: Bacterial infection of C57BL/6 mice resulted in exaggerated PMN activation that was significantly greater in old mice (64 weeks) than in young animals (10 weeks). In contrast to young animals, old mice were unable to prevent the systemic spread of bacteria, resulting in lethal sepsis and significantly greater mortality in old mice than in their younger counterparts. We found that the ATP levels in the plasma of mice increased with age and that, along with the extracellular accumulation of ATP, the PMNs of old mice became increasingly primed. Stimulation of the formyl peptide receptors of those primed PMNs triggered inflammatory responses that were significantly more pronounced in old mice than in young animals. However, bacterial phagocytosis and killing by PMNs of old mice were significantly lower than that of young mice. These age-dependent PMN dysfunctions correlated with a decrease in the enzymatic activity of plasma ATPases that convert extracellular ATP to adenosine. ATPases depend on divalent metal ions, including Ca2+, Mg2+, and Zn2+, and we found that depletion of these ions blocked the hydrolysis of ATP and the formation of adenosine in human blood, resulting in ATP accumulation and dysregulation of PMN functions equivalent to those observed in response to aging. CONCLUSIONS: Our findings suggest that impaired hydrolysis of plasma ATP dysregulates PMN function in older individuals. We conclude that strategies aimed at restoring plasma ATPase activity may offer novel therapeutic opportunities to reduce immune dysfunction, inflammation, and infectious complications in older patients.

Abstract Background The function of polymorphonuclear neutrophils (PMNs) decreases with age, which results in infectious and inflammatory complications in older individuals. The underlying causes are not fully understood. ATP release and autocrine stimulation of purinergic receptors help PMNs combat microbial invaders. Excessive extracellular ATP interferes with these mechanisms and promotes inflammatory PMN responses. Here, we studied whether dysregulated purinergic signaling in PMNs contributes to their dysfunction in older individuals. Results Bacterial infection of C57BL/6 mice resulted in exaggerated PMN activation that was significantly greater in old mice (64 weeks) than in young animals (10 weeks). In contrast to young animals, old mice were unable to prevent the systemic spread of bacteria, resulting in lethal sepsis and significantly greater mortality in old mice than in their younger counterparts. We found that the ATP levels in the plasma of mice increased with age and that, along with the extracellular accumulation of ATP, the PMNs of old mice became increasingly primed. Stimulation of the formyl peptide receptors of those primed PMNs triggered inflammatory responses that were significantly more pronounced in old mice than in young animals. However, bacterial phagocytosis and killing by PMNs of old mice were significantly lower than that of young mice. These age-dependent PMN dysfunctions correlated with a decrease in the enzymatic activity of plasma ATPases that convert extracellular ATP to adenosine. ATPases depend on divalent metal ions, including Ca2+, Mg2+, and Zn2+, and we found that depletion of these ions blocked the hydrolysis of ATP and the formation of adenosine in human blood, resulting in ATP accumulation and dysregulation of PMN functions equivalent to those observed in response to aging. Conclusions Our findings suggest that impaired hydrolysis of plasma ATP dysregulates PMN function in older individuals. We conclude that strategies aimed at restoring plasma ATPase activity may offer novel therapeutic opportunities to reduce immune dysfunction, inflammation, and infectious complications in older patients.

Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.

Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy. [ABSTRACT FROM AUTHOR]

Introduction Recently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib). Material and methods We present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months. Results There was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary albumin excretion were noted. Neutrophil count increased allowing for reduction or temporary withdrawal of G-CSF treatment. Conclusions Empagliflozin may be new safe treatment in GSD Ib patients with advanced stage of the disease.

Abstract Background Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma. Results We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort. Conclusion We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research.

Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.

BackgroundGlycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients.MethodsOff-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment.ResultsA 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18–24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter.ConclusionsRepurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.

Abstract Glycogen storage disease type Ib (GSDIb) is characterized by hepatomegaly and fasting hypoglycaemia as well as neutropaenia and recurrent infections. We conducted a retrospective observational study on a cohort of patients with GSDIb across England. A total of 35 patients, with a median age of 9.1 years (range 1‐39 years), were included in the study. We examined the genotype and phenotype of all patients and reported 14 novel alleles. The phenotype of GSDIb in England involves a short fasting tolerance that extends into adulthood and a high prevalence of gastrointestinal symptoms. Growth is difficult to manage and neutropaenia and recurrent infections persist throughout life. Liver transplantation was performed in nine patients, which normalized fasting tolerance but did not correct neutropaenia. This is the first natural history study on the cohort of GSDIb patients in England.

Background: Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma.Results: We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort.Conclusion: We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim Innate immune disarray is a key component in the development and progression of acute on chronic liver failure (ACLF) and predisposition to infections. We evaluated the neutrophil dysfunction and its impact on outcomes in patients with ACLF. Methods Forty patients with acute decompensation of cirrhosis (10 each of grades 0, 1, 2, and 3 ACLF) and 10 healthy controls were prospectively evaluated for neutrophil immunophenotype (NP), neutrophil phagocytic capacity (NPC), and oxidative burst (OB) in both resting and stimulated conditions. The patients were followed up for 90 days or until death or transplant, whichever was earlier. Results NP was normal (in %) and NPC (in mean fluorescence intensity [MFI]) was better in controls compared to patients with ACLF (83.74 ± 12.38 vs 63.84 ± 22.98; P = 0.007 and 98.33 ± 130.60 vs 18.73 ± 17.88, P = 0.001, respectively). Resting OB was higher in patients with ACLF compared to controls (97 ± 4.9% vs 91 ± 9%; P = 0.034), but it failed to increase further after stimulation, suggesting an immune exhaustion. NP was normal (in %) and NPC (in MFI) was better in 90‐day survivors compared to nonsurvivors (78 ± 11.9 vs 62.2 ± 24.11, P = 0.02 and 33.3 ± 22.7 vs 16.36 ± 13.3; P = 0.004, respectively). Phenotypically normal neutrophils >71.7% had 78.6% sensitivity and 65.4% specificity with an area under receiver operating curve (AUROC) of 0.70 (95% confidence interval [CI]: 0.55–0.90); P = 0.017, and NPC >17.32. MFI had 71.4% sensitivity and 69.6% specificity with an AUROC of 0.73 (95% CI: 0.54–0.86), P = 0.035, in predicting 90‐day survival. Conclusion Neutrophils have impaired bactericidal function in patients with ACLF compared to healthy adults. Neutrophil phenotype and phagocytic capacity may be used to predict 90‐day survival in patients with ACLF.

Abstract Background Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolism due to mutations in SLC37A4. Besides a severe form of fasting intolerance, the disorder is usually associated with neutropenia and neutrophil dysfunction causing serious infections, inflammatory bowel disease, oral, urogenital and perianal lesions as well as impaired wound healing. Recently, SGLT2 inhibitors such as empagliflozin that reduce the plasma levels of 1,5-anhydroglucitol have been described as a new treatment option for the neutropenia and neutrophil dysfunction in patients with GSD Ib. Results We report on a 35-year-old female patient with GSD Ib who had been treated with G-CSF for neutropenia since the age of 9. She had a large chronic abdominal wound as a consequence of recurrent operations due to complications of her inflammatory bowel disease. Treatment with 20 mg empagliflozin per day resulted in normalisation of the neutrophil count and neutrophil function even after termination of G-CSF. The chronic abdominal wound that had been unchanged for 2 years before the start of empagliflozin nearly closed within 12 weeks. No side effects of empagliflozin were observed. Conclusion SGLT2 inhibitors are a new and probably safe treatment option for GSD Ib-associated neutropenia and neutrophil dysfunction. We hypothesize that restoration of neutrophil function and normalisation of neutrophil apoptosis leads to improvement of wound healing and ameliorates symptoms of inflammatory bowel disease.

Objective: Leukocytes play an important role in the body's immune system. The aim of this study was to assess alterations in neutrophil phenotype and function in pump‐assisted circulation in vitro. Methods: Human blood was circulated for four hours in three circulatory flow loops with a CentriMag blood pump operated at a flow of 4.5 L/min at three rotational speeds (2100, 2800, and 4000 rpm), against three pressure heads (75, 150, and 350 mm Hg), respectively. Blood samples were collected hourly for analyses of neutrophil activation state (Mac‐1, CD62L, CD162), neutrophil reactive oxygen species (ROS) production, apoptosis, and neutrophil phagocytosis. Results: Activated neutrophils indicated by both Mac‐1 expression and decreased surface expression of CD62L and CD162 receptors increased with time in three loops. The highest level of neutrophil activation was observed in the loop with the highest rotational speed. Platelet‐neutrophil aggregates (PNAs) progressively increased in two loops with lower rotational speeds. PNAs peaked at one hour after circulation and decreased subsequently in the loop with the highest rotational speed. Neutrophil ROS production dramatically increased at one hour after circulation and decreased subsequently in all three loops with similar levels and trends. Apoptotic neutrophils increased with time in all three loops. Neutrophil phagocytosis capacity in three loops initially elevated at one hour after circulation and decreased subsequently. Apoptosis and altered phagocytosis were dependent on rotational speed. Conclusions: Our study revealed that the pump‐assisted circulation induced neutrophil activation, apoptosis, and functional impairment. The alterations were strongly associated with pump operating condition and duration. [ABSTRACT FROM AUTHOR]

Myeloperoxidase (MPO) is found in the lysosomes of monocytes and neutrophils, serving as a crucial component in the elimination of infections through the process of phagocytosis via neutrophils. Consequently, individuals with MPO deficiency exhibit a significantly heightened susceptibility to serious infections and chronic inflammatory diseases. In a clinical case, a 37-year-old Iranian woman presented with a chronic history of bacterial and fungal infections dating back to her childhood. She has no family history of similar diseases and has used antibiotics and antifungal medications. A comprehensive clinical assessment revealed that she is well-nourished and without acute distress, neurological symptoms, or cutaneous manifestations. A complete blood count (CBC) with differential white blood cell (WBC) count showed a decreased number of neutrophils despite normal WBC counts, and peripheral blood smear (PBS) revealed reduced neutrophil granulation, abnormal neutrophil morphology, decreased chromatin condensation, and cytoplasmic hypogranulation. So, the patient was diagnosed with MPO deficiency, a rare condition requiring early diagnosis and management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mousavi et al.)

Background and Aim: Innate immune disarray is a key component in the development and progression of acute on chronic liver failure (ACLF) and predisposition to infections. We evaluated the neutrophil dysfunction and its impact on outcomes in patients with ACLF. Methods: Forty patients with acute decompensation of cirrhosis (10 each of grades 0, 1, 2, and 3 ACLF) and 10 healthy controls were prospectively evaluated for neutrophil immunophenotype (NP), neutrophil phagocytic capacity (NPC), and oxidative burst (OB) in both resting and stimulated conditions. The patients were followed up for 90 days or until death or transplant, whichever was earlier. Results: NP was normal (in %) and NPC (in mean fluorescence intensity [MFI]) was better in controls compared to patients with ACLF (83.74 ± 12.38 vs 63.84 ± 22.98; P = 0.007 and 98.33 ± 130.60 vs 18.73 ± 17.88, P = 0.001, respectively). Resting OB was higher in patients with ACLF compared to controls (97 ± 4.9% vs 91 ± 9%; P = 0.034), but it failed to increase further after stimulation, suggesting an immune exhaustion. NP was normal (in %) and NPC (in MFI) was better in 90‐day survivors compared to nonsurvivors (78 ± 11.9 vs 62.2 ± 24.11, P = 0.02 and 33.3 ± 22.7 vs 16.36 ± 13.3; P = 0.004, respectively). Phenotypically normal neutrophils >71.7% had 78.6% sensitivity and 65.4% specificity with an area under receiver operating curve (AUROC) of 0.70 (95% confidence interval [CI]: 0.55–0.90); P = 0.017, and NPC >17.32. MFI had 71.4% sensitivity and 69.6% specificity with an AUROC of 0.73 (95% CI: 0.54–0.86), P = 0.035, in predicting 90‐day survival. Conclusion: Neutrophils have impaired bactericidal function in patients with ACLF compared to healthy adults. Neutrophil phenotype and phagocytic capacity may be used to predict 90‐day survival in patients with ACLF. [ABSTRACT FROM AUTHOR]

Neutrophils, the most abundant circulating leukocyte, are critical for host defense. Granulopoiesis is under the control of transcriptional factors and culminates in mature neutrophils with a broad armamentarium of antimicrobial pathways. These pathways include nicotinamide adenine dinucleotide phosphate oxidase, which generates microbicidal reactive oxidants, and nonoxidant pathways that target microbes through several mechanisms. Activated neutrophils can cause or worsen tissue injury, underscoring the need for calibration of activation and resolution of inflammation when infection has been cleared. Acquired neutrophil disorders are typically caused by cytotoxic chemotherapy or immunosuppressive agents. Primary neutrophil disorders typically result from disabling mutations of individual genes that result in impaired neutrophil number or function, and provide insight into basic mechanisms of neutrophil biology. Neutrophils can also be activated by noninfectious causes, including trauma and cellular injury, and can have off-target effects in which pathways that typically defend against infection exacerbate injury and disease. These off-target effects include acute organ injury, autoimmunity, and variable effects on the tumor microenvironment that can limit or worsen tumor progression. A greater understanding of neutrophil plasticity in these conditions is likely to pave the way to new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3–0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation. [ABSTRACT FROM AUTHOR]

Abstract Background Mounting evidence suggests that sepsis-induced morbidity and mortality are due to both immune activation and immunosuppression. Resistin is an inflammatory cytokine and uremic toxin. Septic hyperresistinemia (plasma resistin >20 ng/ml) has been associated with greater disease severity and worse outcomes, and it is further exacerbated by concomitant acute kidney injury (AKI). Septic hyperresistinemia disturbs actin polymerization in neutrophils leading to impaired neutrophil migration, a crucial first-line mechanism in host defense to bacterial infection. Our experimental objective was to study the effects of hyperresistinemia on other F-actin-dependent neutrophil defense mechanisms, in particular intracellular bacterial clearance and generation of reactive oxygen species (ROS). We also sought to examine the effects of hemoadsorption on hyperresistinemia and neutrophil dysfunction. Methods Thirteen patients with septic shock and six control patients were analyzed for serum resistin levels and their effects on neutrophil migration. In vitro, following incubation with resistin-spiked serum samples, Pseudomonas aeruginosa clearance and ROS generation in neutrophils were measured. Phosphorylation of 3-phosphoinositide-dependent protein kinase-1 (PDPK1) was assessed using flow cytometry. In vitro hemoadsorption with both Amberchrome™ columns (AC) and CytoSorb® cartridges (CC) were used to test correction of hyperresistinemia. We further tested AC for their effect on cell migration and ROS generation and CC for their effect on bacterial clearance. Results Patients with septic shock had higher serum resistin levels than control ICU patients and showed a strong, negative correlation between hyperresistinemia and neutrophil transwell migration (ρ= − 0.915, p

Patients with decompensated cirrhosis are highly susceptible to develop bacterial infections and these can trigger multiorgan failure associated with high in-hospital mortality. Neutrophils from patients with decompensated cirrhosis exhibit marked alterations that may explain the susceptibility of these patients to develop bacterial infections. These neutrophil alterations include marked defects in intracellular signaling pathways involving serine/threonine kinases such as protein kinase B (AKT), p38-mitogen-activated protein kinase (MAPK), and the MAP kinases1/2; activation of the NADPH oxidase complex; myeloperoxidase (MPO) release; and bactericidal activity of neutrophils stimulated by the bacterial peptide formyl-Methionine-Leucine-Phenylalanine (fMLF). Impaired activity of the NADPH oxidase 2 (NOX2) complex is also related to reduced levels of expression of its major components through post-transcriptional mechanisms. In addition, the catalytic NOX2 component gp91phox is subject to degradation by elastase highly present in patients' plasma. A defect in the protein kinase B (AKT) and p38 MAPK-mediated signaling pathways may explain the decrease in phosphorylation of p47phox (an important component of the NADPH oxidase complex) and MPO release, in response to neutrophil stimulation by fMLF. Most of these alterations are reversible ex vivo with TLR7/8 agonists (CL097, R848), raising the possibility that these agonists might be used in the future to restore neutrophil antibacterial functions in patients with cirrhosis.

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils. [ABSTRACT FROM AUTHOR]

Objective: Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection. In this article, we reviewed the correlation between neutrophil dysfunction and sepsis. Data Sources: Articles published up to May 31, 2016, were selected from the PubMed databases, with the keywords of “neutrophil function”, “neutrophil dysfunction”, and “sepsis”. Study Selection: Articles were obtained and reviewed to analyze the neutrophil function in infection and neutrophil dysfunction in sepsis. Results: We emphasized the diagnosis of sepsis and its limitations. Pathophysiological mechanisms involve a generalized circulatory, immune, coagulopathic, and/or neuroendocrine response to infection. Many studies focused on neutrophil burst or cytokines. Complement activation, impairment of neutrophil migration, and endothelial lesions are involved in this progress. Alterations of cytokines, chemokines, and other mediators contribute to neutrophil dysfunction in sepsis. Conclusions: Sepsis represents a severe derangement of the immune response to infection, resulting in neutrophil dysfunction. Neutrophil dysfunction promotes sepsis and even leads to organ failure. Mechanism studies, clinical practice, and strategies to interrupt dysregulated neutrophil function in sepsis are desperately needed.

Background: Mounting evidence suggests that sepsis-induced morbidity and mortality are due to both immune activation and immunosuppression. Resistin is an inflammatory cytokine and uremic toxin. Septic hyperresistinemia (plasma resistin >20 ng/ml) has been associated with greater disease severity and worse outcomes, and it is further exacerbated by concomitant acute kidney injury (AKI). Septic hyperresistinemia disturbs actin polymerization in neutrophils leading to impaired neutrophil migration, a crucial first-line mechanism in host defense to bacterial infection. Our experimental objective was to study the effects of hyperresistinemia on other F-actin-dependent neutrophil defense mechanisms, in particular intracellular bacterial clearance and generation of reactive oxygen species (ROS). We also sought to examine the effects of hemoadsorption on hyperresistinemia and neutrophil dysfunction. Methods: Thirteen patients with septic shock and six control patients were analyzed for serum resistin levels and their effects on neutrophil migration. In vitro, following incubation with resistin-spiked serum samples, Pseudomonas aeruginosa clearance and ROS generation in neutrophils were measured. Phosphorylation of 3-phosphoinositide-dependent protein kinase-1 (PDPK1) was assessed using flow cytometry. In vitro hemoadsorption with both Amberchrome™ columns (AC) and CytoSorb® cartridges (CC) were used to test correction of hyperresistinemia. We further tested AC for their effect on cell migration and ROS generation and CC for their effect on bacterial clearance. Results: Patients with septic shock had higher serum resistin levels than control ICU patients and showed a strong, negative correlation between hyperresistinemia and neutrophil transwell migration ( ρ= − 0.915, p < 0.001). In vitro, neutrophils exposed to hyperresistinemia exhibited twofold lower intracellular bacterial clearance rates compared to controls. Resistin impaired intracellular signaling and ROS production in a dose-dependent manner. Hemoadsorption with AC reduced serum concentrations of resistin and restored neutrophil migration and generation of ROS to normal levels. Hemoadsorption with CC also corrected hyperresistinemia and reconstituted normal intracellular bacterial clearance. Conclusions: Septic hyperresistinemia strongly correlates with inhibition of neutrophil migration in vitro. Hyperresistinemia itself reversibly impairs neutrophil intracellular bacterial clearance and ROS generation. Hemoadsorption therapy with a clinically approved device corrects hyperresistinemia and neutrophil dysfunction. It may therefore provide a therapeutic option to improve neutrophil function during septic hyperresistinemia and ultimately alleviate immunosuppression in this disease state. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type Ib (GSD-Ib) is characterized by impaired glucose homeostasis, neutropenia and neutrophil dysfunction. Mass spectrometric glycomic profiling of GSD-Ib neutrophils showed severely truncated N-glycans, lacking galactose. Experiments indicated the hypoglycosylation of the electron transporting subunit of NADPH oxidase, which is crucial for the defense against bacterial infections. In phosphoglucomutase 1 (PGM1) deficiency, an inherited disorder with an enzymatic defect just one metabolic step ahead, hypogalactosylation can be successfully treated by dietary galactose. We hypothesized the same pathomechanism in GSD-Ib and started a therapeutic trial with oral galactose and uridine. The aim was to improve neutrophil dysfunction through the correction of hypoglycosylation in neutrophils. The GSD-Ib patient was treated for 29 weeks. Monitoring included glycomics analysis of the patient's neutrophils and neutrophil function tests including respiratory burst activity, phagocytosis and migration. Although no substantial restoration of neutrophil glycosylation was found, there was partial improvement of respiratory burst activity. [ABSTRACT FROM AUTHOR]

HSCT is a lifesaving procedure for children with malignant and non-malignant conditions. The conditioning regimen renders the patient severely immunocompromised and recovery starts with neutrophil ( PMN) engraftment. We hypothesize that children demonstrate minimal PMN dysfunction at engraftment and beyond, which is influenced by the stem cell source and the conditioning regimen. Peripheral blood was serially collected from children at 1 to 12 months following allogeneic HSCT. PMN superoxide ( [ABSTRACT FROM AUTHOR]

Malnutrition in childhood continues to be one of the most important risk factor for secondary immunodeficiency in the world; therefore one should think of existence of malnutrition in a child suffering of frequent infections, not only in developing country, rarely but still possible in developed country also. Undernourishment in the early childhood is a trigger for starting a vicious cycle of impaired immunity, recurrent infections, and worsening malnutrition. Taking out from that cycle is an urgent and complex process, in which in parallel the infection should be controlled and the nutritional status solved out, and then, slowly follows the restoration of the immune system. We present a patient at the age of 13 months, with marasmic kwashiorkor accompanied by severe infection manifested with sepsis. The laboratory investigations revealed severe anaemia, hypoproteinemia and impaired immunological response, first of all neutrophil dysfunction with decreased oxidative metabolic response during the phagocytosis, paralyzed first line of defense of the organism and open possibility for bacterial or fungal invasion, multiorgan failure and high risk for fatal outcome. Because malnutrition and infections had many causes, only multiple and synergistic interventions embedded in true multisectoral programs, fortunately, were effective and got positive outcome. [ABSTRACT FROM AUTHOR]

Objective/Aim: To evaluate the safety of transfusing pooled, whole blood-derived granulocytes in additive solution and plasma (GASP) in 30 recipients. Background: Demand for granulocytes in England has increased five-fold. With the advantages of reduced red cell, plasma and overall volume, GASP maintains function in vitro. Methods and Materials: Observations were recorded prior to and post transfusion. Increments were recorded at 1 h and the following morning. Leucocyte antibody screening was undertaken prior to and at 1-6 months following transfusion. Results: Thirty patients aged between 8 months and 68 years received 221 GASP in 148 transfusion episodes. GASP contained an average of 1·0 ×1010 granulocytes in 207 mL. Adults usually received two packs and children 10-20 mL kg-1. Children and adults received a median [interquartile range (IQR)] dose of 12·5 (9·1-25·3) and 19·7 (12·0-25·8) ×109 granulocytes per transfusion, respectively. There was one episode of transfusion-associated circulatory overload (TACO) in a patient with chronic cardiac failure following 600 mL of unpooled granulocytes, other fluids and one GASP. New leucocyte alloimmunisation occurred in 3/30 recipients 10%. No other significant reactions were reported. Median peripheral blood neutrophil increments at 1 h post transfusion were 0·06 (IQR, 0·01-0·17) in children and (0·03) (IQR, 0-0·16) in adults. Conclusion: GASP has a similar safety profile to other sources of granulocytes for patients with refractory infection or in need of secondary prophylactic transfusion. Further studies are required to clarify the role of GASP in the treatment of neutropenic patients. [ABSTRACT FROM AUTHOR]

The functions of neutrophils obtained from 3 calves affected with chronic and recurrent pneumonia, with marked neutrophilia, were examined. Their functions were compared with those of normal calves. Neutrophils from the three calves showed a markedly decreased phagocytosis, bacterial killing activity, NBT reduction activity, luminol-dependent chemiluminescence and chemotactic response. These findings show that the 3 calves had defective neutrophils; the disorder was diagnosed as bovine granulocytopathy syndrome. Zusammenfassung Bovines Granulozytopathie-Syndrom: Dysfunktion der neutrophilen Granulozyten bei Holstein-Friesian-Kälbern: Es wurde die Funktion von neutrophilen Granulozyten geprüft, die von 3 Kälbern mit chronischer recurrenter Pneumonie und ausgeprägter Neutrophilie stammten. Zum Vergleich wurde auch die Funktion neutrophiler Granulozyten von normalen Kälbern untersucht. Die von den drei kranken Kälbern stammenden neutrophilen Granulozyten zeigten eine herabgesetzte Phagozytose, eine verringerte Bakterien-Abtötungs-Aktivität, eine verringerte NBT-Reduktions-Aktivität, eine herabgesetzte Luminol-abhängige Chemohumineszenz sowie eine reduzierte chemotaktische Antwort. Nach diesen Befunden hatten die 3 Kälber defekte neutrophile Granulozyten; die Störung wurde als bovines Granulozytopathie-Syndrom diagnostiziert. [ABSTRACT FROM AUTHOR]

A 4-year-old girl presented with recurrent infections. Immunoglobulin deficiency (serum and secretory IgA, serum IgG3) neutropenia and neutrophil dysfunction (defective spontaneous migration and chemotaxis) were found. T-lymphocyte counts were normal and they responded to phytohaemagglutinin but were not stimulated by Concanavalin A, pokeweed mitogen and microbial antigens in vitro. Delayed cutaneous hypersensitivity testing to purified protein derivative and candidin was negative. Despite bacille Calmette-Guérm vaccination and candidiasis, near normal beta-2-micro-globulin and human leucocyte antigen (HLA) class I concentrations were detected on mononuclear cells and phytohaemagglutinin-induced lymphoblasts. HLA class II antigens (HLA-DP, -DQ, -DR) were not expressed. These observations indicated a bare lymphocyte syndrome (BLS) type II. This is the first time neutrophil dysfunction has been noted in association with BLS. [ABSTRACT FROM AUTHOR]