Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers.

BACKGROUND: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care. METHODS: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model. RESULTS: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics. CONCLUSIONS: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.

The licorice pentacyclic triterpenoid component 18ß-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus.

This study aimed to identify compounds that enhance the activity of current antibiotics against multidrug-resistant bacteria. Screening of a 350+ compound proprietary small molecules library revealed that the Glycyrrhiza glabra (licorice)-derived triterpenoid 18ß-glycyrrhetinic acid (18ß-GA) potentiated the antibacterial activity of certain antibiotics against Staphylococcus aureus. Here, we evaluated the ability of pentacyclic triterpenoids to potentiate the activity of antibiotics against strains of methicillin-resistant S. aureus (MRSA). Checkerboard assays were used to assess the minimum inhibitory concentration (MIC) of tobramycin and ten pentacyclic triterpenoids against S. aureus. The effect of 18ß-GA on the MIC of different antibiotics against MRSA was also determined in an in vitro airway MRSA infection model. 18ß-GA enhanced the bactericidal activity of the aminoglycosides tobramycin, gentamicin and amikacin, and of polymyxin B against two MRSA strains, reducing the MIC of these antibiotics 32-64-fold [fractional inhibitory concentration index (FICI) of 0.12-0.13]. Other ß-amyrin triterpenoids and α-amyrin triterpenoids did not exert such synergistic effects. 18ß-GA did not enhance the activity of antibiotics from other structural classes against the MRSA strains. In an air-exposed airway epithelial cell culture, 18ß-GA enhanced the bactericidal activity of tobramycin and polymyxin B against the MRSA strain. These data demonstrate the potential of 18ß-GA to synergise with certain types of antibiotics to eliminate strains of MRSA.

Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy.

PURPOSE: To analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions. RESULTS: In the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was 'predominantly antibody disorder (PAD)' (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular 'lymphoma' and 'skin cancer'. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category. CONCLUSIONS: The incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy.

T helper 2 response in allergic bronchopulmonary aspergillosis is not driven by specific Aspergillus antigens.

Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an allergic immunological response to Aspergillus fumigatus. In this study, we investigated whether certain Aspergillus antigens are more allergenic than others, as was postulated previously. We stimulated peripheral blood mononuclear cells from patients with ABPA with the classically described A. fumigatus allergens Aspf1, Aspf2, Aspf3, and Aspf4, as well as two other Aspergillus antigens, Crf1 and Catalase1. Activated CD4+ T cells displayed a T helper 2 phenotype with the production of IL-4 in response to stimulation with several of these different antigens. Immune responses were not limited to the classically described A. fumigatus allergens. In healthy individuals, we demonstrated a similar recognition profile to the different antigens, but in contrast the activated CD4+ T cells exerted a T helper 1 phenotype and mainly produced IFN-γ after stimulation with A. fumigatus antigens. In conclusion, irrespective of the A. fumigatus antigen, the T-cell immune response in patients with ABPA is skewed to a T helper 2 cytokine secretion profile.

Human carriage of ESBL/pAmpC-producing Escherichia coli and Klebsiella pneumoniae in relation to the consumption of raw or undercooked vegetables, fruits, and fresh herbs.

We investigated to what extent the consumption of raw or undercooked vegetables, fruits, and fresh herbs influences carriage rates of ESBL/pAmpC-producing Escherichia coli and Klebsiella pneumoniae (ESBL-E/K) in the general population. We assessed long-term carriage and changes in ESBL-E/K prevalence over time, by comparing the results to findings in the same population 5 years earlier. Between July and December 2021, participants sent in two fecal samples and questionnaires, 3 months apart. Food frequency questionnaires were sent on a monthly basis. Fecal samples were cultured and screened for ESBL-E/K, and phenotypically positive isolates were sequenced. Multivariable logistic regression models were established to assess the association between the consumption of fresh produce and ESBL-E/K carriage. The ESBL-E/K prevalence was 7.6% [41/537; 95% confidence interval (CI): 5.7-10.2] in the first sampling round and 7.0% (34/489; 95% CI: 5.0-9.6) in the second. Multivariable models did not result in statistical significance for any of the selected fruit and vegetable types. Trends for increased carriage rates were observed for the consumption of raspberry and blueberry in the summer period. ESBL-E/K prevalence was comparable with the prevalence in the same cohort 5 years earlier (7.5%; 95% CI: 5.6-10.1%). In six persons (1.2%) a genetically highly homologous ESBL-E/K was found. In conclusion, the contribution of the consumption of raw fruits, vegetables, and herbs to ESBL-E/K carriage in humans in the Netherlands is probably low. Despite COVID-19 containment measures (e.g., travel restrictions, social distancing, and hygiene) the ESBL-E/K prevalence was similar to 5 years earlier. Furthermore, indications for long-term carriage were found.IMPORTANCEESBL-producing bacteria are resistant against important classes of antibiotics, including penicillins and cephalosporines, which complicates treatment of infections. Food is one of the main routes of transmission for carriage of these bacteria in the general population. Although fruits, vegetables, and herbs are generally less frequently contaminated with ESBL-producing bacteria compared to meat, exposure might be higher since these products are often eaten raw or undercooked. This research showed that the contribution of the consumption of raw or undercooked fresh produce to ESBL-E/K carriage in the general Dutch population was low. No specific types of fruit or vegetables could be identified that gave a higher risk of carriage. In addition, we demonstrated the presence of genetically highly homologous ESBL-E/K in six persons after a period of 5 years, indicative for long-term carriage.

Evaluation of the antiviral response to zanamivir administered intravenously for treatment of critically ill patients with pandemic influenza A (H1N1) infection.

A retrospective nationwide study on the use of intravenous (IV) zanamivir in patients receiving intensive care who were pretreated with oseltamivir in the Netherlands was performed. In 6 of 13 patients with a sustained reduction of the viral load, the median time to start IV zanamivir was 9 days (range, 4-11 days) compared with 14 days (range, 6-21 days) in 7 patients without viral load reduction (P = .052). Viral load response did not influence mortality. We conclude that IV zanamivir as late add-on therapy has limited effectiveness. The effect of an immediate start with IV zanamivir monotherapy or in combination with other drugs need to be evaluated.

Effect of amino acid substitutions in the human IFN-γR2 on IFN-γ responsiveness.

Patients with interferon-γ receptor (IFN-γR) null mutations have severe infections with poorly pathogenic Mycobacteria. The IFN-γR complex involves two IFN-γR1 and two IFN-γR2 chains, in which several amino acid substitutions, some linked to disease and some apparently naturally occurring, have been described. We developed a model system to study functional effects of genetic variations in IFN-γR2. We retrovirally transduced wild-type IFN-γR2 and IFN-γR2 carrying presently known amino acid substitutions in various human cell lines, and next determined the IFN-γR2 expression pattern as well as IFN-γ responsiveness. We determined that the T58R, Q64R, E147K and K182E variants of IFN-γR2 are fully functional, although the Q64R variant may be expressed higher on the cell membrane. The R114C, T168N and G227R variants were identified in patients that had disseminated infections with non-tuberculous Mycobacteria. Of these genetic variants, T168N was confirmed to be completely non-functional, whereas the novel variant G227R, and the previously reported R114C, were partial functional. The impaired IFN-γ responsiveness of R114C and G227R is mainly due to reduced receptor function, although expression on the cell membrane is reduced as well. We conclude that the T58R, Q64R, E147K and K182E variants are polymorphisms, whereas the R114C, T168N and G227R constitute mutations associated with disease.

Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis.

Risk stratification-based duration of trimethoprim-sulfamethoxazole (TMP-SMX) chemoprophylaxis to prevent Pneumocystis pneumonia (PCP) in kidney transplant recipients is not a universally adapted strategy and supporting evidence-based sources are limited. We performed a large retrospective study to identify risk factors for PCP in kidney transplant recipients and to define parameters for use in clinical prophylaxis guidelines. Fifty consecutive patients with confirmed PCP and 2 time-matched controls per case were enrolled. All patients were participants of the kidney transplantation program of the Leiden University Medical Center, a tertiary care hospital in the Netherlands. Potential risk factors were compared between groups by uni- and multivariate matched analyses. At transplantation, age >55 years (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.3-5.9) and not receiving basiliximab induction therapy (adjusted OR 4.3, 95% CI 1.1-17.1) predicted development of PCP. In the final multivariate analysis, only cytomegalovirus infection (adjusted OR 3.0, 95% CI 1.2-7.9) and rejection treatment (adjusted OR 5.8, 95% CI 1.9-18) were found to be independently associated with PCP. Using the variables identified by the multivariate analyses, effects of different hypothetical chemoprophylaxis strategies were systematically evaluated. Exploring different scenarios showed that chemoprophylaxis in the first 6 months for all renal transplant patients - and during the first year posttransplantation for patients >55 years of age or those treated for rejection - would result in very low PCP incidence and optimal avoidance of TMP-SMX toxicity. The results provide a rationale for further prospective study on targeted provision of chemoprophylaxis to prevent PCP in kidney transplant patients.

Household transmission of haemolytic uraemic syndrome associated with Escherichia coli O104:H4 in the Netherlands, May 2011.

Following the outbreak of haemolytic uraemic syndrome (HUS) and haemorrhagic colitis in Germany, two patients returning from a stay in Germany developed HUS due to Escherichia coli O104:H4 in the Netherlands. The index case developed symptoms eight days, and her child 15 days after their return. It is very likely that transmission resulted from secondary spread from mother to child. Recommendations should be made to prevent secondary transmission within households.

Predicting the need for radiologic imaging in adults with febrile urinary tract infection.

BACKGROUND: Radiologic evaluation of adults with febrile urinary tract infection (UTI) is frequently performed to exclude urological disorders. This study aims to develop a clinical rule predicting need for radiologic imaging. METHODS: We conducted a prospective, observational study including consecutive adults with febrile UTI at 8 emergency departments (EDs) in the Netherlands. Outcomes of ultrasounds and computed tomographs of the urinary tract were classified as "urgent urological disorder" (pyonephrosis or abscess), "nonurgent urologic disorder," "normal," and "incidental nonurological findings." Urgent and nonurgent urologic disorders were classified as "clinically relevant radiologic findings." The data of 5 EDs were used as the derivation cohort, and 3 EDs served as the validation cohort. RESULTS: Three hundred forty-six patients were included in the derivation cohort. Radiologic imaging was performed for 245 patients (71%). A prediction rule was derived, being the presence of a history of urolithiasis, a urine pH ≥7.0, and/or renal insufficiency (estimated glomerular filtration rate, ≤40 mL/min/1.73 m(3)). This rule predicts clinically relevant radiologic findings with a negative predictive value (NPV) of 93% and positive predictive value (PPV) of 24% and urgent urological disorders with an NPV of 99% and a PPV of 10%. In the validation cohort (n = 131), the NPV and PPV for clinically relevant radiologic findings were 89% and 20%, respectively; for urgent urological disorders, the values were 100% and 11%, respectively. Potential reduction of radiologic imaging by implementing the prediction rule was 40%. CONCLUSIONS: Radiologic imaging can selectively be applied in adults with febrile UTI without loss of clinically relevant information by using a simple clinical prediction rule.

Mycobacterium bovis BCG-itis and cervical lymphadenitis due to Salmonella enteritidis in a patient with complete interleukin-12/-23 receptor beta1 deficiency.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder with predisposition to severe, sometimes lethal, disease caused by otherwise poorly virulent, non-tuberculous environmental mycobacteria and poorly virulent salmonellae. In patients with MSMD, mutations have been identified in five genes that encode for the proteins IL-12/IL-23p40, IL-12/ IL-23Rbeta1, IFN-R1, IFN-gammaR2 and STAT1. These proteins play important roles in the type-1 cytokine pathway, which is crucial for human host defence against intracellular pathogens such as mycobacteria and salmonellae. We report a girl with mild Mycobacterium bovis Bacille Calmette-Guérin (BCG) disease and Salmonella enteritidis cervical lymphadenitis. Despite treatment, she has remained a fecal carrier of S. enteritidis for the past 14 years. She was found to have complete IL-12/IL-23Rbeta1 deficiency. A homozygous r.518G>C IL12RB1 mutation was identified, leading to a non-functional R173P substitution in the IL-12/IL-23Rbeta1 protein. This mutation abrogated IL-12/IL-23Rbeta1 cell-surface expression and resulted in complete lack of T cell responsiveness to both IL-12 and IL-23.

[Rise and threat of infectious diseases]. / Opkomst en dreiging van infectieziekten.

In 2019, 1 in 4 deaths was caused by infectious diseases. In addition to the big 3 - HIV, malaria and tuberculosis - these diseases are mainly respiratory infections, infectious diarrhoea and sepsis. The burden of disease caused by infections also remains high in the Netherlands. This could still get worse because of several factors: ageing, 'vaccination doubts', increased use of immunosuppressive drugs, increased mobility of people and globalisation of food chains. Global warming also affects the spread of pathogens and disease vectors. Pathogens have an impressive ability to adapt and, for example, to develop resistance to antimicrobial agents. In order to cope with these threats, we would do well to consider the emergence of new infectious diseases as well as the threat of old ones. What can we learn from decades past? Why do new infections keep emerging? What does the future look like?

Experience of establishing severe acute respiratory surveillance in the Netherlands: Evaluation and challenges.

The 2009 influenza A (H1N1) pandemic prompted the World Health Organization (WHO) to recommend countries to establish a national severe acute respiratory infections (SARI) surveillance system for preparedness and emergency response. However, setting up or maintaining a robust SARI surveillance system has been challenging. Similar to other countries, surveillance data on hospitalisations for SARI in the Netherlands are still limited, in contrast to the robust surveillance data in primary care. The objective of this narrative review is to provide an overview, evaluation, and challenges of already available surveillance systems or datasets in the Netherlands, which might be used for near real-time surveillance of severe respiratory infections. Seven available surveillance systems or datasets in the Netherlands were reviewed. The evaluation criteria, including data quality, timeliness, representativeness, simplicity, flexibility, acceptability and stability were based on United States Centers for Disease Control and Prevention (CDC) and European Centre for Disease Prevention and Control (ECDC) guidelines for public health surveillance. We added sustainability as additional evaluation criterion. The best evaluated surveillance system or dataset currently available for SARI surveillance is crude mortality monitoring, although it lacks specificity. In contrast to influenza-like illness (ILI) in primary care, there is currently no gold standard for SARI surveillance in the Netherlands. Based on our experience with sentinel SARI surveillance, a fully or semi-automated, passive surveillance system seems most suited for a sustainable SARI surveillance system. An important future challenge remains integrating SARI surveillance into existing hospital programs in order to make surveillance data valuable for public health, as well as hospital quality of care management and individual patient care.

Severe acute respiratory infections surveillance for early signals in the community.

BACKGROUND: Surveillance of acute respiratory infections (ARI) in the Netherlands and other European countries is based mostly on primary care data, with little insight into the severe spectrum of the disease. We compared time-trends for ARI in secondary care with influenza-like illness (ILI), ARI and pneumonia in primary care, and crude mortality, in order to assess the value of routinely collected data on respiratory infections in hospitals and the added value of severe acute respiratory infections (SARI) surveillance. METHODS: We calculated incidence of ARI in secondary care, ILI, ARI, and pneumonia in primary care, and crude mortality using five historical databases (2008-2016). RESULTS: Over eight years, seasonal incidence peaks of ARI in secondary care occurred earlier than ILI and ARI incidence peaks in primary care, except during the 2009 influenza A(H1N1) pandemic and post-pandemic season. The median time-lag between ARI in secondary care and ILI, ARI and pneumonia in primary care was 6.5 weeks, 7 weeks, and 1 week, respectively. Crude mortality lagged a median 5 weeks behind ARI in secondary care. CONCLUSION: This observational study demonstrates that routinely collected data can be used for describing trends of ARI in secondary care and may be suitable for near real-time SARI surveillance. In most seasons, the incidence peaks for ARI in secondary care preceded the peaks in primary care and crude mortality with a considerable time-lag. It would be of great value to add microbiological test results to the incidence data to better explain the difference in time-lag between these surveillance systems.

[No scientific lower threshold for compulsory vaccination]. / Geen wetenschappelijke ondergrens voor verplicht vaccineren.

The national vaccination rate in young children in the Netherlands has decreased in recent years. This has led to social and political discussions, for instance about compulsory vaccination for children in child-care. The national commission on child-care and vaccination has advised that vaccination should be made compulsory when the rate of vaccination has declined to a pre-determined lower threshold, to be determined by the government. A frequently quoted lower threshold is 95%. The idea behind this is the concept of a critical vaccination rate, a threshold needed for elimination of an infection in a large, well-mixed population. In this article we argue why the critical vaccination rate does not offer a scientific basis for a lower threshold to the national vaccination rate.

Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP.

AIMS/HYPOTHESIS: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As monocytes may contribute to the excessive inflammatory responses in such wounds, this study focussed on the effects of maggot secretions on the pro-inflammatory activities of these cells. METHODS: Freshly isolated monocytes were incubated with a range of secretions for 1 h and then stimulated with lipopolysaccharides (range 0-100 ng/ml) or lipoteichoic acid (range 0-5 microg/ml) for 18 h. The expression of cell surface molecules, cytokine and chemokine levels in culture supernatants, cell viability, chemotaxis, and phagocytosis and killing of Staphylococcus aureus were measured. RESULTS: Maggot secretions dose-dependently inhibited production of the pro-inflammatory cytokines TNF-alpha, IL-12p40 and macrophage migration inhibitory factor by lipopolysaccharides- and lipoteichoic acid-stimulated monocytes, while enhancing production of the anti-inflammatory cytokine IL-10. Expression of cell surface receptors involved in pathogen recognition remained unaffected by secretions. In addition, maggot secretions altered the chemokine profile of monocytes by downregulating macrophage inflammatory protein-1beta and upregulating monocyte chemoattractant protein-1 and IL-8. Nevertheless, chemotactic responses of monocytes were inhibited by secretions. Furthermore, maggot secretions did not affect phagocytosis and intracellular killing of S. aureus by human monocytes. Finally, secretions induced a transient rise in the intracellular cyclic AMP concentration in monocytes and Rp-cyclic AMPS inhibited the effects of secretions. CONCLUSIONS/INTERPRETATION: Maggot secretions inhibit the pro-inflammatory responses of human monocytes through a cyclic AMP-dependent mechanism. Regulation of the inflammatory processes by maggots contributes to their beneficial effects on chronic wounds.

Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients.

Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell (TH1) responses and interferon-gamma (IFN-gamma) production. IL-12 binds to high-affinity beta1/beta2 heterodimeric IL-12 receptor (IL-12R) complexes on T cell and natural killer cells. Three unrelated individuals with severe, idiopathic mycobacterial and Salmonella infections were found to lack IL-12Rbeta1 chain expression. Their cells were deficient in IL-12R signaling and IFN-gamma production, and their remaining T cell responses were independent of endogenous IL-12. IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain. The lack of IL-12Rbeta1 expression results in a human immunodeficiency and shows the essential role of IL-12 in resistance to infections due to intracellular bacteria.

Interferon-gamma release assays in immigrant contacts and effect of remote exposure to Mycobacterium tuberculosis.

OBJECTIVE: To assess the association between remote exposure to tuberculosis (TB) and results of the tuberculin skin test (TST), and two interferon-gamma release assays (IGRAs)-QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB-in immigrant contacts of sputum smear-positive TB patients. METHODS: Immigrants aged >or=16 years in close contact with smear-positive TB patients were included. QFT-GIT and T-SPOT.TB were performed if the TST induration size was >or=5 mm. Associations between test results and origin from an endemic country were assessed. RESULTS: Of 433 close contacts, 322 (74%) had TST >or=5 mm, of whom, 282 (88%) had valid test results for all assays. Positive QFT-GIT results were obtained for 152/282 (54%) and positive T-SPOT.TB for 168/282 (60%). After adjustment for age, sex and recent contact, positive IGRA results and TST results >/=10 mm were found to be more frequent among immigrants who originated from Africa, in particular sub-Saharan Africa. CONCLUSION: When IGRAs are used to determine latent TB infection in foreign-born individuals, positive findings not only relate to recent TB infection, but also reflect prior TB exposure in the country of origin. This late reactivity will limit their usefulness in contact investigations among immigrants originating from endemic areas.

Marburg haemorrhagic fever in returning travellers: an overview aimed at clinicians.

Marburg virus haemorrhagic fever (MARV HF) is a dramatic disease that can occur in a traveller returning from an area where the virus is endemic. In this article, we provide an overview of MARV HF as an imported infection with an emphasis on clinical aspects. Although late features such as rash, signs of haemorrhagic diathesis and liver necrosis may point to the diagnosis, the initial clinical picture is non-specific. If in this early phase the patient's epidemiological exposure history is compatible with MARV HF, the patient should be isolated and managed according to viral haemorrhagic fever protocol and RT-PCR should be performed on the patient's blood as soon as possible to rule out MARV HF (or other possible viral haemorrhagic fevers). In severe cases, direct electron microscopy of blood in specialized centres (e.g. Bernhard-Nocht Institute in Hamburg, Germany) may be considered if the result of the RT-PCR is not readily available. Adequate diagnostics and empirical treatment for other acute life-threatening illnesses should not be withheld while test results are awaited, but all management and diagnostics should be weighed against the risks of nosocomial transmission.