ABSTRACT
PURPOSE: Patients treated with cytotoxic chemotherapy are at risk of neutropenia, neutropenic fever and neutropenic sepsis. We hypothesised that pre-existing neutrophil function dysfunction may increase susceptibility to neutropenic fever in paediatric patients receiving cytotoxic chemotherapy. METHODS: Prospective cohort study recruited patients at Alder Hey Children's NHS Foundation Trust, United Kingdom. We measured neutrophil phagocytic function using a validated flow cytometric whole blood phagocytosis assay in paediatric patients (n = 16) with oncological disease before and after chemotherapy in a prospective cohort study. We recruited healthy children as a control comparator (n = 10). RESULTS: We found significantly decreased phagocytic function in oncology patients compared to healthy participants. In five patients who developed neutropenic fever, we observed increased pre-dose neutrophil respiratory burst. CONCLUSION: With further validation, measurement of neutrophil function could potentially be used to personalise appropriate prophylactic antimicrobial administration for patients receiving cytotoxic chemotherapy.
Subject(s)
Neoplasms/immunology , Neutrophils/physiology , Adolescent , Biomarkers , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Neoplasms/drug therapy , Phagocytosis , Prospective StudiesABSTRACT
OBJECTIVE: To refine and validate a neutrophil function assay with clinical relevance for patients with community-acquired pneumonia (CAP). DESIGN: Two phase cross-sectional study to standardise and refine the assay in blood from healthy volunteers and test neutrophil phagocytic function in hospital patients with CAP. PARTICIPANTS: Phase one: Healthy adult volunteers (n = 30). Phase two: Critical care patients with severe CAP (n = 16), ward-level patients with moderate CAP (n = 15) and respiratory outpatients (no acute disease, n = 15). RESULTS: Our full standard operating procedure for the assay is provided. Patients with severe CAP had significantly decreased neutrophil function compared to moderate severity disease (median phagocytic index 2.8 vs. 18.0, p = 0.014). Moderate severity pneumonia neutrophil function was significantly higher than control samples (median 18.0 vs. 1.6, p = 0.015). There was no significant difference between critical care and control neutrophil function (median 2.8 vs. 1.6, p = 0.752). CONCLUSIONS: Our whole blood neutrophil assay is simple, reproducible and clinically relevant. Changes in neutrophil function measured in this pneumonia cohort is in agreement with previous studies. The assay has potential to be used to identify individuals for clinical trials of immunomodulatory therapies, to risk-stratify patients with pneumonia, and to refine our understanding of 'normal' neutrophil function in infection.
Subject(s)
Community-Acquired Infections/blood , Neutrophils/physiology , Phagocytosis/physiology , Adult , Aged , Aged, 80 and over , Biological Assay , Critical Illness , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Severity of Illness IndexABSTRACT
Epidemiological and immunological evidence suggests that some vaccines can reduce all-cause mortality through nonspecific changes made to innate immune cells. Here, we present the first data to describe the nonspecific immunological impact of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a. We vaccinated healthy adults with Ty21a and assessed aspects of innate and adaptive immunity over the course of 6 months. Changes to monocyte phenotype/function were observed for at least 3 months. Changes to innate and adaptive immune cell cytokine production in response to stimulation with vaccine and unrelated nonvaccine antigens were observed over the 6-month study period. The changes that we have observed could influence susceptibility to infection through altered immune responses mounted to subsequently encountered pathogens. These changes could influence all-cause mortality.
Subject(s)
Polysaccharides, Bacterial/immunology , Salmonella typhi/immunology , Typhoid Fever/prevention & control , Typhoid-Paratyphoid Vaccines/immunology , Vaccination , Vaccines, Attenuated/immunology , Administration, Oral , Adult , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Female , Healthy Volunteers , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Polysaccharides, Bacterial/administration & dosage , Typhoid Fever/immunology , Typhoid Fever/metabolism , Typhoid-Paratyphoid Vaccines/administration & dosage , Vaccines, Attenuated/administration & dosage , Young AdultABSTRACT
Alveolar macrophages (AM) are critical to the homeostasis of the inflammatory environment in the lung. Differential expression of surface markers classifies macrophages to either classically (M1) or alternatively activated (M2). We investigated the phenotype of human alveolar macrophages (AM) in adults living in two different geographical locations: UK and Malawi. We show that the majority of AM express high levels of M1 and M2 markers simultaneously, with the M1/M2 phenotype being stable in individuals from different geographical locations. The combined M1/M2 features confer to AM a hybrid phenotype, which does not fit the classic macrophage classification. This hybrid phenotype may confer to alveolar macrophages an ability to quickly switch between M1 or M2 associated functions allowing for appropriate responses to stimuli and tissue environment.
Subject(s)
Antigens, CD/biosynthesis , Macrophage Activation/physiology , Macrophages, Alveolar/metabolism , Phenotype , Adolescent , Adult , Antigens, CD/genetics , Biomarkers/metabolism , Cohort Studies , Gene Expression , Humans , Macrophages, Alveolar/immunology , Middle Aged , United Kingdom , Young AdultABSTRACT
The ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal immunoglobulin G (IgG) to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating. Passive immunization with this antiserum was ineffective to block acquisition of colonization compared to agglutinating antisera raised against the encapsulated parent strain. In the human challenge model, samples were collected from PCV and control-vaccinated adults. In PCV-vaccinated subjects, IgG levels to CPS were increased in serum and nasal wash (NW). IgG to the inoculated strain CPS dropped in NW samples after inoculation suggesting its sequestration by colonizing pneumococci. In post-vaccination NW samples pneumococci were heavily agglutinated compared with pre-vaccination samples in subjects protected against carriage. Our results indicate that pneumococcal agglutination mediated by CPS-specific antibodies is a key mechanism of protection against acquisition of carriage. Capsule may be the only vaccine target that can elicit strong agglutinating antibody responses, leading to protection against carriage acquisition and generation of herd immunity.
Subject(s)
Agglutination , Antibodies, Bacterial/metabolism , Pneumococcal Infections/immunology , Pneumococcal Vaccines/immunology , Streptococcus pneumoniae/immunology , Adolescent , Adult , Animals , Bacterial Capsules/immunology , Carrier State , Female , Humans , Immunization, Passive , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pneumococcal Infections/prevention & control , Vaccination , Vaccines, Conjugate , Young AdultABSTRACT
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