Heleen van Velzen-Blad

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial

BACKGROUND Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. METHODS In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. FINDINGS Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). INTERPRETATION Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. FUNDING None.

A family with complement factor D deficiency

A complement factor D deficiency was found in a young woman who had experienced a serious Neisseria meningitidis infection, in a deceased family member with a history of meningitis, and in three relatives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified factor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. The gene encoding factor D was found to contain a point mutation that changed the TCG codon for serine 42 into a TAG stop codon. This mutation was found in both alleles of the five completely factor D-deficient family members and in one allele of 21 other members of the same family who had decreased or low-normal factor D levels in their serum. The gene sequence of the signal peptide of human factor D was also identified. Our report is the first, to our knowledge, to document a Factor D gene mutation. The mode of inheritance of factor D deficiency is autosomal recessive, in accordance with the localization of the Factor D gene on chromosome 19. Increased susceptibility for infections in individuals with a partial factor D deficiency is unlikely.

Mannose-Binding Lectin Genotypes in Susceptibility to Community-Acquired Pneumonia

BACKGROUND Community-acquired pneumonia (CAP) is most frequently caused by Streptococcus pneumoniae, Haemophilus influenzae, atypical pathogens, and respiratory viruses. Susceptibility to CAP can be increased by single-nucleotide polymorphisms (SNPs) within the mannose-binding lectin (MBL) gene. We questioned whether MBL polymorphisms are associated with the susceptibility to and outcome of CAP and its most common pathogens. METHODS All adult patients presenting with CAP in a 23-month period were included in this study. Frequencies of SNPs were determined for the promoter X/Y and the three coding SNPs in exon 1 (A/0). Six genotypes were constructed representing patients with sufficient and deficient serum levels of MBL. The results of the patients with CAP were compared with control subjects. RESULTS In 199 patients and 223 control subjects, MBL genotypes were determined. There were no differences in MBL genotype frequencies between patients with CAP in general, pneumonia caused by S pneumoniae or H influenzae, and control subjects. The frequency of sufficient MBL genotypes was nonsignificantly higher in patients with pneumonia with Legionella sp and Mycoplasma pneumoniae. In Legionella spp, the sufficient YA/YA genotype was significantly more frequent than in control subjects (odds ratio [OR], 5.43; confidence interval [CI], 1.32 to 22.41; p = 0.02). The frequency of the MBL-deficient genotype was significantly higher in patients with viral (co)infections (OR, 2.36; CI, 1.06 to 5.26; p = 0.03) and nonsignificantly higher in patients with pneumococcal pneumonia and viral (co)infections. MBL genotypes had no effect on outcome. CONCLUSIONS MBL genotypes play a limited role in pneumococcal pneumonia. Sufficient MBL genotypes were more frequently found in a small group of patients with atypical pneumonia, and MBL-deficient genotypes were more frequently found in patients with viral (co)infections.

Evaluation of CD103 as a cellular marker for the diagnosis of pulmonary sarcoidosis

A high CD4(+)/CD8(+) ratio in bronchoalveolar lavage fluid is indicative for the diagnosis pulmonary sarcoidosis but this ratio only does not fully discriminate pulmonary sarcoidosis from other interstitial lung diseases. Recently, the integrin CD103 has been implicated in the diagnostic evaluation of sarcoidosis. CD103 is expressed on intraepithelial lymphocytes in mucosal areas, including bronchi, and is possibly involved in the retention of lymphocytes to the mucosa. The Dutch BAL working party initiated an investigation to evaluate the diagnostic value of relative number of CD103 expressing CD4(+) T-lymphocytes in the BAL fluid of patients with a variety of interstitial lung diseases. The expression of CD103 was examined on bronchoalveolar lavage cells from 119 patients including 56 patients with pulmonary sarcoidosis. We redefined criteria for alveolar CD4(+) T-cell lymphocytosis and for the relative enumeration of CD103 expressing CD4(+) T-lymphocytes in the BAL fluid. Our data demonstrate that the combined use of the CD103(+)CD4(+)/CD4(+) ratio (<0.2) and the BAL CD4(+)/CD8(+) ratio (>3) or the relative alveolitis CD4(+)/CD8(+) BAL/PB ratio (>2) provides a specific tool for discriminating sarcoidosis, also without a clear CD4(+) alveolitis, from other interstitial lung diseases.

The Fcγ Receptor IIA-R/R131 Genotype Is Associated with Severe Sepsis in Community-Acquired Pneumonia

ABSTRACT Community-acquired pneumonia (CAP) can be caused by a variety of microorganisms but is most frequently associated with Streptococcus pneumoniae and gram-negative bacteria like Haemophilus influenzae. Encapsulated bacteria are able to escape phagocytosis, unless they are bound by immunoglobulin G2 subclass antibodies. These antibodies interact with Fcγ receptor IIa (Fcγ-RIIa), thereby facilitating opsonophagocytosis of the encapsulated bacteria. We studied the relationship between the Fcγ-RIIa-R/H131 polymorphism and the clinical course of CAP and pathogen-specific susceptibility. Regarding methodology, the Fcγ-RIIa genotype R/H131 was determined in 200 patients with CAP and in 313 healthy controls and was correlated with the clinical course, laboratory parameters, and causative microorganism. The Fcγ-RIIa-R/R131 genotype was found more frequently in patients with severe sepsis (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.30 to 5.00; P < 0.01). The majority of patients in this group suffered from invasive pneumococcal disease. The duration of hospital stay was longer for patients with the Fcγ-RIIa-R/R131 genotype. Fcγ-RIIa genotypes were not associated with an increased risk of CAP in general; however, the Fcγ-RIIa-R/R131 genotype was found more frequently in patients with CAP caused by H. influenzae than in controls (OR, 3.03; CI, 1.04 to 9.09; P < 0.05). In conclusion, the Fcγ-RIIa-R/R131 genotype is associated with severity of CAP and is more frequent in CAP caused by H. influenzae.

Increased Expression of CD16, CD69, and Very Late Antigen-1 on Blood Monocytes in Active Sarcoidosis

BACKGROUND Different types of immune cells are involved in the formation of granulomas, a hallmark of pulmonary sarcoidosis. Proinflammatory monocytes are activated circulating monocytes thought to be related to the initial events of granuloma formation. We tested the hypothesis that peripheral blood monocytes in patients with active pulmonary sarcoidosis have an activated phenotype and, secondly, that measuring this activation status can provide a new tool for monitoring disease activity. METHODS Blood was collected of 23 steroid-naive patients presenting with pulmonary sarcoidosis and 10 healthy control subjects. Expression of CD16 (Fc-gamma type III receptor), CD69 (a general activation marker of cells of the hematopoietic lineage), and the integrin very late antigen (VLA)-1 (on interaction with extracellular matrix compounds mediates cell adhesion) was measured by flow cytometry. RESULTS Percentages of monocytes expressing CD16, CD69, and VLA-1 in patients vs control subjects were 56.2 +/- 4.1% vs 12.2 +/- 2.4% (p < 0.0001), 87.3 +/- 2.1% vs 8.6 +/- 3.3% (p < 0.0001), and 66.5 +/- 3.6% vs 11.2 +/- 2.3% (p < 0.0001), respectively. Moreover, the CD69+VLA-1+ monocyte subset, abundantly present at disease presentation, was found to decrease to normal levels during follow-up with disease remission. CONCLUSIONS Peripheral blood monocytes from patients with pulmonary sarcoidosis show a highly activated phenotype. Phenotyping circulating monocytes might be a promising tool for monitoring sarcoidosis disease activity but needs further investigation.

(18)F-FDG PET patterns and BAL cell profiles in pulmonary sarcoidosis.

PurposeBronchoalveolar lavage (BAL) and 18F-fluorodeoxyglucose (18F-FDG) PET can both demonstrate sarcoid activity. To assess whether metabolic activity imaged by 18F-FDG PET represents signs of disease activity as reflected by BAL, 18F-FDG PET patterns were compared with BAL cell profiles.MethodsIn this retrospective analysis, 77 newly diagnosed pulmonary sarcoidosis patients underwent BAL and 18F-FDG PET. Based on 18F-FDG PET, patients were diagnosed with exclusively mediastinal/hilar activity (group A) and activity in the lung parenchyma (group B). Per group, BAL lymphocytes (%), CD4/CD8 ratio, CD103+CD4+/CD4+ ratio and neutrophils (%) were compared with the extent of metabolic activity expressed as the maximum standardized uptake value (SUVmax). Additionally, SUVmax and BAL parameters per radiographic stage were analysed.ResultsOverall, the SUVmax in the lung parenchyma correlated with neutrophils and SUVmax of the mediastinum/hila correlated with the CD4/CD8 ratio. In both groups, a significant, negative correlation between the SUVmax of the mediastinum/hila and the CD103+CD4+/CD4+ ratio was found. In group B, the SUVmax of the mediastinum/hila correlated with the CD4/CD8 ratio, while the SUVmax in the lung parenchyma correlated with the CD103+CD4+/CD4+ ratio and neutrophils. Significant differences were found in the SUVmax, CD4/CD8 ratio, CD103+CD4+/CD4+ ratio and neutrophils between the radiographic stages. The SUVmax of the lung parenchyma was positively related to the radiographic stage, while the SUVmax of the mediastinum/hila and CD4/CD8 ratio were inversely related.Conclusion18F-FDG PET correlates with the CD4/CD8 ratio and neutrophils, suggesting that 18F-FDG PET represents this specific cell profile in BAL. High SUVmax values of the lung parenchyma may therefore correlate with more severe parenchymal involvement, particularly when accompanied by a low SUVmax of the mediastinum/hila.

Clinical features predicting failure of pathogen identification in patients with community acquired pneumonia

Community acquired pneumonia (CAP) is caused by a variety of microorganisms. By identifying patients at risk for failure of pathogen identification, it is possible to make an early decision on the extent of diagnostic procedures to be performed. This is especially important in patients with severe CAP. The aim of this study was to identify these patients by using clinical and laboratory features. In 201 patients hospitalized for CAP, clinical and laboratory variables were collected. Pathogen identification was performed by culture of sputum and blood, urine antigen tests, polymerase chain reaction of sputum, serological testing and viral culture of the pharynx. In 128 patients a respiratory microorganism was identified. In both univariate and multivariate analysis, failure of pathogen identification was predicted by pre-hospital antibiotic therapy, a medical history of hypertension and a low C-reactive protein. We conclude that patients with pre-hospital antibiotic therapy, a medical history of hypertension and a relatively low C-reactive protein are at risk for failure of pathogen identification. These predictors should be confirmed in a larger population. Invasive testing in high-risk patients with CAP in the presence of these predictors should be considered at an early phase of hospitalization.

Dexamethasone Downregulates the Systemic Cytokine Response in Patients with Community-Acquired Pneumonia

ABSTRACT The influence of adjunctive corticosteroids on the cytokine response in community-acquired pneumonia (CAP) is largely unknown. In this study, we analyzed the effect of dexamethasone on the cytokine response in patients with CAP and evaluated whether this effect is dependent on the causative microorganism. We hypothesized that dexamethasone has a larger effect on the cytokine response in patients with pneumococcal pneumonia than in patients with pneumonia caused by an atypical bacterium. A total of 304 hospitalized, nonimmunocompromised patients with CAP were randomized to an adjunctive 4-day course of 5 mg dexamethasone once a day (n = 151) or a placebo (n = 153). Serum concentrations of interleukin-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-10, IL-17, tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), macrophage inflammatory protein-1 alpha (MIP-1α), and monocyte chemotactic protein-1 (MCP-1) were measured on days 0, 1, 2, and 4 and at a control visit. Overall, the concentrations of IL-6 (P < 0.01), IL-8 (P < 0.01), MCP-1 (P < 0.01), and TNF-α (P < 0.01) were significantly lower on day 2 in the dexamethasone group than in the placebo group. In patients with pneumococcal pneumonia (n = 72), both treatment groups showed a rapid decrease of cytokine concentrations; only the concentration of TNF-α (P = 0.05) was significantly lower in the dexamethasone group on day 2. In patients with CAP caused by an atypical pathogen (Legionella pneumophila, Chlamydophila species, Coxiella burnetii, or Mycoplasma pneumoniae; n = 58), IL-1Ra (P < 0.01), IL-6 (P < 0.01), and MCP-1 (P = 0.03) decreased more rapidly in the dexamethasone group than in the placebo group. In conclusion, dexamethasone downregulates the cytokine response during CAP. This effect seems to be dependent on the causative microorganism. This study provides insight into which patients with CAP might benefit most from adjunctive dexamethasone.

Longitudinal Analysis of Pneumococcal Antibodies during Community-Acquired Pneumonia Reveals a Much Higher Involvement of Streptococcus pneumoniae than Estimated by Conventional Methods Alone

ABSTRACT In up to half of all cases of community-acquired pneumonia (CAP), no pathogen can be identified with conventional diagnostic methods. The most common identified causative agent is Streptococcus pneumoniae. In this study, pneumococcal antibody responses during CAP were analyzed to estimate the contribution of the pneumococcus to all cases of CAP for epidemiological purposes. Pneumococcal antibodies against 14 different serotypes were measured in serum of hospitalized CAP patients. Patients participated in one of two consecutive clinical trials in a general 600-bed teaching hospital in the Netherlands (between October 2004 and June 2009). A significant pneumococcal immune response was defined as at least a 2-fold increase in antibody concentrations against a single serotype between an early (day 1) and a late (day 30) serum sample of each patient with an end concentration above 0.35 μg/ml. A total of 349 adult CAP patients participated in two consecutive clinical trials. For 200 patients, sufficient serum samples were available to determine antibody responses: 62 pneumococcal pneumonia patients, 57 nonpneumococcal pneumonia patients, and 81 patients with an unidentified causative agent. A significant immune response was detected in 45% (28/62 patients) of pneumococcal pneumonia patients, in 5% (3/57) of nonpneumococcal pneumonia patients, and in 28% (23/81) of patients with an unidentified causative agent. The estimated contribution of pneumococci in patients with an unidentified causative agent was calculated to be 57% (95% confidence interval, 36 to 86%). A substantial fraction of pneumococcal pneumonia patients do not elicit a serotype-specific immune response.