Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

<div><p>Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.</p></div

Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: the case of IL-27

Natural killer (NK) cells are characterized by their ability to detect and induce apoptosis of susceptible target cells and by secretion of immunoregulatory cytokines such as IFN-γ. Activation of these effector functions is triggered upon recognition of tumor and pathogen (mostly virus)-infected cells and because of a bidirectional cross talk that NK cells establish with other cells of myeloid origin such as dendritic cells (DC) and macrophages. A common characteristic of these myeloid cells is their ability to secrete different members of the IL-12 family of cytokines such as IL-12, IL-23, and IL-27 and cytokines such as IL-15 and IL-18. Although the effect of IL-12, IL-15, and IL-18 has been characterized, the effect of IL-23 and IL-27 on NK cells (especially human) remains ill-defined. Particularly, IL-27 is a cytokine with dual functions as it has been described as pro- and as anti-inflammatory in different experimental settings. Recent evidence indicates that this cytokine indeed promotes human NK cell activation, IFN-γ secretion, NKp46-dependent NK cell-mediated cytotoxicity, and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC) against monoclonal Ab-coated tumor cells. Remarkably, IL-27 also primes NK cells for IL-18 responsiveness, enhancing these functional responses. Consequently, IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions, which likely contributes to foster the adaptive immune response in different physiopathological conditions.Fil: Zwirner, Norberto Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Ziblat, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Anestesia combinada e métodos não farmacológicos para alívio da dor durante o trabalho de parto e satisfação materna: ensaio clínico randomizado

OBJECTIVE: The objective of this study was to compare maternal satisfaction with childbirth according to whether or not combined spinal-epidural anesthesia (CSE) of pain relief was used during labor. METHODS: A randomized, open clinical trial was performed with 70 pregnant women, 35 of whom received CSE anesthesia while 35 received only non-pharmacological forms of pain relief during labor. The variables evaluated were visual analogue scale (VAS) pain score, maternal satisfaction with the technique of pain relief used during childbirth and with delivery, the patient's intention to request the same technique in a subsequent delivery, and loss of control during delivery. RESULTS: VAS pain score decreased significantly in patients receiving CSE during vaginal delivery. Furthermore, maternal satisfaction with the technique of pain relief and with delivery was higher in the CSE group, and around 97% of the patients would repeat the same technique at future deliveries compared to 82.4% of the women in the group using only non-pharmacological methods. With respect to the women's impressions of their control during delivery, approximately half the women in both groups felt that they had lost control at some point during the process. CONCLUSION: The use of CSE was associated with a significant reduction in VAS pain scores during delivery and with greater maternal satisfaction with the pain relief method and with the childbirth process.OBJETIVOS: Comparar a satisfação materna com o processo do nascimento de acordo com a realização ou não de métodos farmacológicos para alívio da dor do trabalho de parto. MÉTODOS: Realizou-se um ensaio clínico randomizado com 70 parturientes, 35 das quais receberam anestesia combinada (raquidiana e peridural associadas) e 35 receberam métodos não farmacológicos para alívio da dor durante o parto vaginal. As variáveis estudadas foram: escores de dor pela Escala Visual Analógica (EVA), satisfação materna com a técnica analgésica e com o parto, desejo de repetir a técnica analgésica em parto posterior e perda do controle sobre o parto. A análise estatística foi realizada no programa Epi-Info 3.5.3, com base na intenção de tratar. RESULTADOS: Pacientes recebendo anestesia combinada (AC) durante o parto vaginal experimentaram uma diminuição significativa dos escores da EVA e maior satisfação materna com a técnica analgésica e com o parto. A maioria das parturientes, cerca de 97% do grupo da anestesia combinada, repetiu a técnica em partos futuros, contra 82,4% do grupo dos métodos não farmacológicos. No que diz respeito ao sentimento de controle do parto, aproximadamente metade das parturientes dos dois grupos sentiu que em algum momento do parto perdeu o controle deste, não havendo diferença significativa entre os grupos. CONCLUSÃO: O uso da AC está associado a uma significante diminuição dos escores da dor durante o parto, e maior satisfação materna com a técnica analgésica e com o parto.11211

Impacto do estado nutricional e aporte calórico-proteico em pacientes críticos dependentes de ventilação mecânica invasiva/ Impact of nutritional status and caloric-protein intake in critically ill patients dependent on invasive mechanical ventilation

Objetivo: avaliar o impacto do estado nutricional e o aporte calórico-proteico de pacientes críticos internados na Unidade de Terapia Intensiva (UTI) de um hospital de Recife-PE. Métodos: estudo do tipo coorte, prospectivo, observacional, com pacientes internados em UTI, sob ventilação mecânica invasiva (VMI) e terapia nutricional enteral (TNE). Para diagnóstico nutricional foi realizado o exame físico e aferido as medidas antropométricas. Para definição das necessidades nutricionais foram utilizadas as fórmulas de bolso recomendadas por guidelines atuais. As demais variáveis coletadas foram: o tempo em VMI; a quantidade de calorias e gramas de proteínas consumidas por dia, o tempo em uso de drogas vasoativas e sedativos, o Simplified Acute Physiology Score e o desfecho clínico. Resultados: foram acompanhados 40 pacientes, 52,5% (n=21) do sexo masculino e 47,5%(n=19) do sexo feminino, idade média de 76,4 anos (Desvio-Padrão-DP = 10 anos). A média do percentual calórico administrada foi de 63,4% (DP = 27%) e protéico 59,8% (DP=26,2%). Da amostra total, 65% (n=26) não receberam a quantidade recomendada de calorias e proteínas por quilograma, apenas 35% (n=14) atingiram a recomendação. A média de permanência sob VMI foi 11,9 dias, 55% (n=22) dos pacientes apresentaram desmame prolongado. A média de dias em uso de drogas vasoativas e sedativas foi 5,5 e 8,3, respectivamente. Apresentaram associação com o desmame de VMI apenas a “Adequação PTN/kg” (p=0,048), o uso de drogas e sedação, p=0,002 e p=0,001, respectivamente. Conclusão: Não foi verificado associação entre a adequação da terapia nutricional e o desmame de VMI, assim também como não houve associação com o estado nutricional

Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

National estimates of emergency department visits for pediatric severe sepsis in the United States

Objective. We sought to determine the characteristics of children presenting to United States (US) Emergency Departments (ED) with severe sepsis. Study design. Cross-sectional analysis using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). Using triage vital signs and ED diagnoses (defined by the International Classification of Diseases, Ninth Revision codes), we identified children <18 years old presenting with both infection (triage fever or ICD-9 infection) and organ dysfunction (triage hypotension or ICD-9 organ dysfunction). Results. Of 28.2 million pediatric patients presenting to US EDs each year, severe sepsis was present in 95,055 (0.34%; 95% CI: 0.29–0.39%). Fever and respiratory infection were the most common indicators of an infection. Hypotension and respiratory failure were the most common indicators of organ dysfunction. Most severe sepsis occurred in children ages 31 days–1 year old (32.1%). Most visits for pediatric severe sepsis occurred during winter months (37.4%), and only 11.1% of patients arrived at the ED by ambulance. Over half of severe sepsis cases were self-pay or insured by Medicaid. A large portion (44.1%) of pediatric severe sepsis ED visits occurred in the South census region. ED length of stay was over 3 h, and 16.5% were admitted to the hospital. Conclusion. Nearly 100,000 children annually present to US EDs with severe sepsis. The findings of this study highlight the unique characteristics of children treated in the ED for severe sepsis

Impaired Release of Antimicrobial Peptides into Nasal Fluid of Hyper-IgE and CVID Patients

Patients with primary immunodeficiency (PID) often suffer from frequent respiratory tract infections. Despite standard treatment with IgG-substitution and antibiotics many patients do not improve significantly. Therefore, we hypothesized that additional immune deficits may be present among these patients.To investigate if PID patients exhibit impaired production of antimicrobial peptides (AMPs) in nasal fluid and a possible link between AMP-expression and Th17-cells.Nasal fluid, nasopharyngeal swabs and peripheral blood mononuclear cells (PBMCs) were collected from patients and healthy controls. AMP levels were measured in nasal fluid by Western blotting. Nasal swabs were cultured for bacteria. PBMCs were stimulated with antigen and the supernatants were assessed for IL-17A release by ELISA.In healthy controls and most patients, AMP levels in nasal fluid were increased in response to pathogenic bacteria. However, this increase was absent in patients with common variable immunodeficiency (CVID) and Hyper-IgE syndrome (HIES), despite the presence of pathogenic bacteria. Furthermore, stimulation of PBMCs revealed that both HIES and CVID patients exhibited an impaired production of IL-17A.CVID and HIES patients appear to have a dysregulated AMP response to pathogenic bacteria in the upper respiratory tract, which could be linked to an aberrant Th17 cell response

Dual requirement of cytokine and activation receptor triggering for cytotoxic control of murine cytomegalovirus by NK cells

Natural killer (NK) cells play a critical role in controlling murine cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein by Ly49H is sufficient for effective control of MCMV infection. Additionally, during the host response to infection, distinct immune and non-immune cells elaborate a variety of pleiotropic cytokines which have the potential to impact viral pathogenesis, NK cells, and other immune functions, both directly and indirectly. While the effects of various immune deficiencies have been examined for general antiviral phenotypes, their direct effects on Ly49H-dependent MCMV control are poorly understood. To specifically interrogate Ly49H-dependent functions, herein we employed an in vivo viral competition approach to show Ly49H-dependent MCMV control is specifically mediated through cytotoxicity but not IFNγ production. Whereas m157 induced Ly49H-dependent degranulation, efficient cytotoxicity also required either IL-12 or type I interferon (IFN-I) which acted directly on NK cells to produce granzyme B. These studies demonstrate that both of these distinct NK cell-intrinsic mechanisms are integrated for optimal viral control by NK cells