Bob Meek

Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis.

Inconclusive evidence for the efficacy of infliximab in sarcoidosis hinders the global use of this potentially beneficial drug. To study infliximab efficacy in a clinical setting, we performed a prospective open-label trial in patients refractory to conventional treatment. Patients (n=56) received eight infusions of 5 mg·kg-1 infliximab. Pulmonary function, disease activity measured by 18F-fluorodeoxyglucose (FDG) by positron emission tomography (PET) and quality of life were part of the clinical work-up. Infliximab levels were measured before every infusion. After 26 weeks of infliximab treatment, mean improvement in forced vital capacity (FVC) was 6.6% predicted (p=0.0007), whereas in the 6 months before start of treatment, lung function decreased. Maximum standardised uptake value (SUVmax) of pulmonary parenchyma on 18F-FDG PET decreased by 3.93 (p<0.0001). High SUVmax of pulmonary parenchyma at baseline predicted FVC improvement (R=0.62, p=0.0004). An overall beneficial response was seen in 79% of patients and a partial response was seen in 17% of patients. No correlation between infliximab trough level (mean 18.0 µg·mL-1) and initial response was found. In conclusion, infliximab causes significant improvement in FVC in refractory 18F-FDG PET positive sarcoidosis. Especially in pulmonary disease, high 18F-FDG PET SUVmax values at treatment initiation predict clinically relevant lung function improvement. These results suggest that inclusion of 18F-FDG PET is useful in therapeutic decision-making in complex sarcoidosis. Infliximab is highly effective in refractory 18F-FDG PET positive sarcoidosis patients http://ow.ly/JoxhL

Recombinant low-seroprevalent adenoviral vectors Ad26 and Ad35 expressing the respiratory syncytial virus (RSV) fusion protein induce protective immunity against RSV infection in cotton rats.

RSV is an important cause of lower respiratory tract infections in children, the elderly and in those with underlying medical conditions. Although the high disease burden indicates an urgent need for a vaccine against RSV, no licensed RSV vaccine is currently available. We developed an RSV vaccine candidate based on the low-seroprevalent human adenovirus serotypes 26 and 35 (Ad26 and Ad35) encoding the RSV fusion (F) gene. Single immunization of mice with either one of these vectors induced high titers of RSV neutralizing antibodies and high levels of F specific interferon-gamma-producing T cells. A Th1-type immune response was indicated by a high IgG2a/IgG1 ratio of RSV-specific antibodies, strong induction of RSV-specific interferon-gamma and tumor necrosis factor-alpha cytokine producing CD8 Tcells, and low RSV-specific CD4 T-cell induction. Both humoral and cellular responses were increased upon a boost with RSV-F expressing heterologous adenovirus vector (Ad35 boost after Ad26 prime or vice versa). Both single immunization and prime-boost immunization of cotton rats induced high and long-lasting RSV neutralizing antibody titers and protective immunity against lung and nasal RSV A2 virus load up to at least 30 weeks after immunization. Cotton rats were also completely protected against challenge with a RSV B strain (B15/97) after heterologous prime-boost immunization. Lungs from vaccinated animals showed minimal damage or inflammatory infiltrates post-challenge, in contrast to animals vaccinated with formalin-inactivated virus. Our results suggest that recombinant human adenoviral Ad26 and Ad35 vectors encoding the RSV F gene have the potential to provide broad and durable protection against RSV in humans, and appear safe to be investigated in infants.

⁹⁹mTc-anti-TNF-α antibody for the imaging of disease activity in pulmonary sarcoidosis.

Infliximab, a monoclonal antibody directed against tumour necrosis factor (TNF)-α, is used in the treatment of refractory sarcoidosis. However, the clinical response is variable and a tool to select responders beforehand is highly desirable. In this study we evaluated scintigraphy with technetium-99m (99mTc)-labelled infliximab for the imaging of disease activity in patients with pulmonary sarcoidosis. 10 patients were studied using single photon emission computed tomography/computed tomography (CT) 6 h and 20 h after intravenous administration of 370 MBq of 99mTc-infliximab. Correlation analysis was performed between tissue accumulation of 99mTc-infliximab and laboratory parameters (including soluble interleukin-2 receptor and angiotensin-converting enzyme), lung function parameters (including forced expiratory volume in 1 s and the diffusing capacity of the lung for carbon monoxide) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Analysis showed selective and variable accumulation of 99mTc-infliximab in the target tissue. Accumulation correlated positively with all four laboratory parameters and negatively with all four lung function parameters, yielding better correlations than serum TNF-α levels or 18F-FDG PET/CT. 99mTc-infliximab accumulation reflects the in situ TNF-α expression in an individual patient and therefore provides valuable information on the presence of the biological target for anti-TNF-α therapy. 99mTc-TNF-α antibody accumulation reflects presence of the biological target for anti-TNF therapy in sarcoidosis http://ow.ly/V92cz

Mannose-binding lectin and L-ficolin polymorphisms in patients with community-acquired pneumonia caused by intracellular pathogens

Community‐acquired pneumonia (CAP) is the leading infectious disease requiring hospitalization in the western world. Genetic variability affecting the host response to infection may play a role in susceptibility and outcome in patients with CAP. Mannose‐binding lectin (MBL) and l‐ficolin (l‐FCN) are two important activators of the complement system and they can enhance phagocytosis by opsonization. In a prospective cohort of 505 Dutch patients with CAP and 227 control participants we studied whether polymorphisms in the MBL (MBL2) and FCN (FCN2) genes influenced susceptibility and outcome. No difference in frequency of these genotypes was found between patients with CAP in general and controls. However, the +6424G>T single nucleotide polymorphism (SNP) in FCN2 was more common in patients with a Coxiella burnetii pneumonia (P = 0·014). Moreover, the haplotypes coding for the highest MBL serum levels (YA/YA and YA/XA) predisposed to atypical pneumonia (C. burnetii, Legionella or Chlamydia species or Mycoplasma pneumoniae) compared with controls (P = 0·016). Furthermore, patients with these haplotypes were more often bacteraemic (P = 0·019). It can therefore be concluded that MBL2 and FCN2 polymorphisms are not major risk factors for CAP in general, but that the +6424G>T SNP in the FCN2 gene predisposes to C. burnetii pneumonia. In addition, patients with genotypes corresponding with high serum MBL levels are at risk for atypical pneumonia, possibly caused by enhanced phagocytosis, thereby promoting cell entry of these intracellular bacteria.

Pneumococcal conjugate vaccination response in patients after community-acquired pneumonia, differences in patients with S. pneumoniae versus other pathogens

OBJECTIVES The goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease. METHODS Hospitalised adult CAP patients who participated in two trials (2004-2006 (n=201) and, 2007-2009 (n=304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3-4weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients. RESULTS We vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (≥9/13 serotypes with concentration≥1300ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration≥1300ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p=0.02). For serotype 1, total IgG and IgG2/IgG1 subset post-vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP. CONCLUSIONS Our results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients. ClinicalTrials.gov Identifier: NCT02141009.

YKL-40, CCL18 and SP-D predict mortality in patients hospitalized with community-acquired pneumonia.

The aim of this study was to investigate the prognostic value of four biomarkers, YKL‐40, chemokine (C‐C motif) ligand 18 (CCL18), surfactant protein‐D (SP‐D) and CA 15‐3, in patients admitted with community‐acquired pneumonia (CAP). These markers have been studied extensively in chronic pulmonary disease, but in acute pulmonary disease their prognostic value is unknown.

Course of SP-D, YKL-40, CCL18 and CA 15-3 in adult patients hospitalised with community-acquired pneumonia and their association with disease severity and aetiology : A post-hoc analysis

Background and aim SP-D, YKL-40, CCL18 and CA 15–3 are pulmonary markers that have been extensively investigated in different chronic pulmonary diseases. However, in acute pulmonary diseases, such as community-acquired pneumonia (CAP), little is known about the course of these markers and their relationship with the aetiological agent. The aim of this study was to investigate the course of these four markers in CAP and to study influence of disease severity, aetiology and antibiotic use prior to admission on their course. Methods We included 291 adult patients hospitalised with CAP and 20 healthy controls. Measurements were performed in serum of day 0, 2, and 4, and at least 30 days after admission. Results Our most important results were: 1) At all time-points, including 30 days after admission, YKL-40 and CCL18 levels were higher in CAP patients compared to healthy controls; and 2) Patients with CAP caused by an intracellular, atypical bacterium had lower YKL-40 and especially CCL18 levels on and during admission in comparison with other or unknown CAP aetiology. Conclusions Our findings suggest that these pulmonary markers could be useful to assess CAP severity and, especially YKL-40 and CCL18 by helping predict CAP caused by atypical pathogens.

Can intermediate monocytes predict response to infliximab therapy in sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown origin that can cause a variety of symptoms, but most often affects the lungs [1]. Because sarcoidosis is self-limiting in the majority of patients, not all patients require therapy [2]. In case of severe sarcoidosis, first-line therapy consists of prednisone, with methotrexate or azathioprine being the most commonly used second-line options [3]. Infliximab, a monoclonal anti-tumour necrosis factor (TNF) drug, is an effective third-line therapeutic for severe sarcoidosis [4, 5]. Responders to infliximab therapy have more intermediate monocytes at baseline compared with non-responders http://ow.ly/fMLp300oVrO

Determination of Pneumococcal Antibodies in Serum with Multiplex Technology

Ger T Rijkers1*, Bob Meek2 and Ben de Jong3 1Medical Immunologist, Roosevelt Academy, Middelburg, The Netherlands 2Medical Immunologist in Training, Roosevelt Academy, Middelburg, The Netherlands 3Research Technician, Roosevelt Academy, Middelburg, The Netherlands *Corresponding author: Ger T Rijkers, Head of Science Department, Roosevelt Academy, Middelburg, The Netherlands, Tel: 31 118 655 500; E-mail: g.rijkers@antoniusziekenhuis.nl

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Current laboratory investigation of patients with suspected immunodeficiency or immune-mediated disease includes extensive analysis of lymphocyte subsets, T-cell receptor use, antibody profiles, cytokine profiles and genetic polymorphisms of relevant genes, all in all: big data. Clinical immunology clearly has entered the omics era, generating more and more data.