High-resolution geospatial mapping of zero-dose and under-immunized children following Nigeria's 2021 multiple indicator cluster survey/national immunization coverage survey (MICS/NICS).

BACKGROUND: The "zero-dose" children are those without any routine vaccination or lacking the first dose of the diphtheria-tetanus-pertussis-containing vaccine. As per 2022 WHO/UNICEF estimates, globally, Nigeria has the highest number of zero-dose with over 2.3 million unvaccinated. METHODS: We used data from the 2021 Nigeria Multiple Indicator Cluster Survey - National Immunisation Coverage Survey to identify zero-dose and under-immunized children. Geospatial modelling techniques were employed to determine the prevalence of zero-dose children and predict risk areas with under-immunized at a high resolution of 1x1 km. RESULTS: Both zero-dose and under-immunized children are more prevalent in socially deprived groups. Univariate and multivariate Bayesian analyses showed positive correlations between the prevalence of zero-dose and under-immunized children with factors like stunting, contraceptive prevalence, and literacy. The prevalence of zero-dose and under-immunized children varies significantly by region and ethnicity, with higher rates observed in the country's northern parts. Significant heterogeneity in the distribution of under-vaccinated children was observed. CONCLUSIONS: Nigeria needs to enhance its immunization system and coverage. Geospatial modelling can help deliver vaccines effectively to underserved communities. By adopting this approach, countries can ensure equitable vaccine access and contribute to global vaccination objectives.

Examining the Distribution and Impact of Single-Nucleotide Polymorphisms in the Capsular Locus of Streptococcus pneumoniae Serotype 19A.

Streptococcus pneumoniae serotype 19A prevalence has increased after the implementation of the PCV7 and PCV10 vaccines. In this study, we have provided, with high accuracy, the genetic diversity of the 19A serotype in a cohort of Dutch invasive pneumococcal disease patients and asymptomatic carriers obtained in the period from 2004 to 2016. The whole genomes of the 338 pneumococcal isolates in this cohort were sequenced and their capsule (cps) loci compared to examine their diversity and determine the impact on the production of capsular polysaccharide (CPS) sugar precursors and CPS shedding. We discovered 79 types with a unique cps locus sequence. Most variation was observed in the rmlB and rmlD genes of the TDP-Rha synthesis pathway and in the wzg gene, which is of unknown function. Interestingly, gene variation in the cps locus was conserved in multiple alleles. Using RmlB and RmlD protein models, we predict that enzymatic function is not affected by the single-nucleotide polymorphisms as identified. To determine if RmlB and RmlD function was affected, we analyzed nucleotide sugar levels using ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS). CPS precursors differed between 19A cps locus subtypes, including TDP-Rha, but no clear correlation was observed. Also, significant differences in multiple nucleotide sugar levels were observed between phylogenetically branched groups. Because of indications of a role for Wzg in capsule shedding, we analyzed if this was affected. No clear indication of a direct role in shedding was found. We thus describe genotypic variety in rmlB, rmlD, and wzg in serotype 19A in the Netherlands, for which we have not discovered an associated phenotype.

Trends in measles incidence and measles vaccination coverage in Nigeria, 2008-2018.

INTRODUCTION: All WHO regions have set measles elimination objective for 2020. To address the specific needs of achieving measles elimination, Nigeria is using a strategy focusing on improving vaccination coverage with the first routine dose of (monovalent) measles (MCV1) at 9 months, providing measles vaccine through supplemental immunization activities (children 9-59 months), and intensified measles case-based surveillance system. METHODS: We reviewed measles immunization coverage from population-based surveys conducted in 2010, 2013 and 2017-18. Additionally, we analyzed measles case-based surveillance reports from 2008-2018 to determine annual, regional and age-specific incidence rates. FINDINGS: Survey results indicated low MCV1 coverage (54.0% in 2018); with lower coverage in the North (mean 45.5%). Of the 153,097 confirmed cases reported over the studied period, 85.5% (130,871) were from the North. Moreover, 70.8% (108,310) of the confirmed cases were unvaccinated. Annual measles incidence varied from a high of 320.39 per 1,000,000 population in 2013 to a low of 9.80 per 1,000,000 in 2009. The incidence rate is higher among the 9-11 months (524.0 per million) and 12-59 months (376.0 per million). Between 2008 and 2018, the incidence rate had showed geographical variation, with higher incidence in the North (70.6 per million) compare to the South (17.8 per million). CONCLUSION: The aim of this study was to provide a descriptive analysis of measles vaccine coverage and incidence in Nigeria from 2008 to 2018 to assess country progress towards measles elimination. Although the total numbers of confirmed measles cases had decreased over the time period, measles routine coverage remains sub-optimal, and the incidence rates are critically high. The high burden of measles in the North highlight the need for region-specific interventions. The measles program relies heavily on polio resources. As the polio program winds down, strong commitments will be required to achieve elimination goals.

Measles outbreak in complex emergency: estimating vaccine effectiveness and evaluation of the vaccination campaign in Borno State, Nigeria, 2019.

BACKGROUND: From January to May 2019, large measles outbreaks affected Nigeria. Borno state was the most affected, recording 15,237 suspected cases with the state capital of Maiduguri having 1125 cases investigated and line-listed by March 2019. In Borno state, 22 of the 27 Local Government Areas (LGAs or Districts), including 37 internally displaced persons (IDPs) camps were affected. In response to the situation, an outbreak response immunization (ORI) campaign was conducted in the 13 most affected LGAs. In addition to conventional vaccination teams, special teams were deployed in security compromised areas, areas with migrants, and for nomadic and IDPs. Here we describe the outbreak and the ORI campaign. We also assess the measles-containing vaccine (MCV) coverage and vaccine effectiveness (VE) in order to quantify the population-level impact. METHODS: We reviewed the ORI activities, and conducted an analysis of the surveillance and the outbreak investigation reports. We assessed VE of MCV by applying the screening-method. Sensitivity analyses were also conducted to assess the effect of final classification of cases on the VE of MCV. The MCV coverage was assessed by a post-campaign coverage survey after completion of the ORI through a quantitative survey in the 12 LGAs that were accessible. RESULTS: Of the total 15,237 reported measles cases, 2002 cases were line-listed and investigated, and 737 were confirmed for measles by week 9 of 2019. Of the investigated cases 67.3% (n = 1348) were between 9 and 59 months of age. Among the 737 confirmed cases, only 9% (n = 64) stated being vaccinated with at least 1 dose of MCV. The overall VE for MCV was 98.4% (95%CI: 97.8-98.8). No significant differences were observed in the VE estimates of lab-confirmed and epi-linked cases when compared to the original estimates. The aggregated weighted vaccination coverage was 85.7% (95% CI: 79.6-90.1). CONCLUSION: The experience in Borno demonstrates that adequate VE can be obtained in conflict-affected areas. In complex emergencies affected by measles outbreaks, health authorities may consider integration with other health strategies and the engagement of security personnel as part of the ORI activities.

Impact and effectiveness of the 10-valent pneumococcal conjugate vaccine on invasive pneumococcal disease among children under 5 years of age in the Netherlands.

BACKGROUND: In 2011, the 7-valent pneumococcal conjugate vaccine (PCV7) was replaced by the 10-valent vaccine (PCV10) in the Netherlands. We report on impact and effectiveness against invasive pneumococcal disease (IPD) in children aged under 5 years by switching from PCV7 to PCV10. METHOD: We included IPD cases between 2004 and 2019 in children aged < 5 years reported via the national surveillance system. To assess the impact of the PCV10 vaccination program we compared IPD incidence 6-8 years after PCV10 introduction (2017-2019) to the two years just before the switch to PCV10 (2009-2011). We estimated vaccine effectiveness (VE) using the indirect cohort method, comparing vaccination status (at least two vaccine doses) in IPD-cases caused by PCV10 serotypes (cases) to non-PCV10 IPD cases (controls), in children eligible for PCV10. RESULTS: The overall incidence decreased from 8.7 (n = 162) in 2009-2011 to 7.3 per 100.000 (n = 127) in 2017-2019 (Incidence rate ratio (IRR) 0.83, 95%CI: 0.66; 1.05). IPD caused by the additional serotypes included in PCV10 declined by 93% (IRR 0.07, 95%CI: 0.02; 0.23). Incidence of non-PCV10 IPD showed a non-significant increase (IRR 1.25, 95%CI: 0.96; 1.63). Among 231 IPD-cases eligible for PCV10, the overall VE was 91% (95%CI: 67; 97) and did not differ by sex or age at diagnosis. Effectiveness against non-PCV10 serotype 19A IPD was non-significant with an estimate of 28% (95%CI:-179; 81). CONCLUSION: PCV10 is highly effective in protecting against IPD in Dutch children under 5 years with limited serotype replacement after switching from PCV7 to PCV10. We found no evidence for significant cross-protection of PCV10 against 19A serotype IPD.

Immunoglobulin A deficiency in children, an undervalued clinical issue.

Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of defense against invasion of pathogenic micro-organisms. The reported prevalence rate of complete IgA deficiency in healthy children ranges from 1:170 to 1:400, and as a solitary condition, it is often considered of limited clinical importance. However, patients with IgA deficiency can develop recurrent respiratory and gastrointestinal infections, as well as allergic and autoimmune diseases. In children referred for recurrent respiratory tract infections, the observed prevalence rate increases more than tenfold. This review discusses several aspects of IgA deficiency in children, including immunologic and microbiome changes in early childhood and the potential consequences of this condition in later life. It illustrates the importance of early identification of children with impaired IgA production who deserve appropriate clinical care and follow-up.

Impact of infant pneumococcal conjugate vaccination on community acquired pneumonia hospitalization in all ages in the Netherlands.

BACKGROUND: The long-term impact of pneumococcal conjugate vaccines on pneumonia hospitalizations in all age-groups varies between countries. In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was implemented for newborns in 2006 and replaced by PCV10 in 2011. We assessed the impact of PCVs on community-acquired pneumonia (CAP) hospitalization rates in all age-groups. METHODS: A time series analysis using Poisson regression was performed on 155,994 CAP hospitalizations. Hospitalization rates were calculated using the total number of hospitalizations as denominator. The time trend in the pre-PCV period (1999-2006) was extrapolated to predict the hospitalization rate in the post-PCV period (2006-2014) if PCV had not been implemented. Rate ratios over time were calculated by comparing observed and predicted time trends. RESULTS: In children <5 years of age, the observed hospitalization rates during the post-PCV period were significantly lower than predicted if PCV had not been implemented (0-6 months: 0.62, 95% CI: 0.41-0.96; 6 months - 1 year: 0.67, 95% CI: 0.50-0.90; 2-4 years: 0.78, 95% CI: 0.61-0.97). In all other age-groups, rate ratios declined over time but did not reach statistical significance. CONCLUSIONS: After introduction of PCV, CAP hospitalizations declined in young children but no clear impact of PCV on CAP hospitalizations was seen in other age-groups.

Severe underestimation of pertussis related hospitalizations and deaths in the Netherlands: A capture-recapture analysis.

OJECTIVE: Despite vaccination, pertussis has remained endemic, sometimes leading to severe disease. We aimed to quantify the completeness of reporting (CoR) of pertussis hospitalizations and deaths in the Netherlands. STUDY DESIGN: CoR was estimated using capture-recapture analyses. Hospitalizations (2007-2014) from the National Registration Hospital Care (hospital data) were matched to the notifiable Infectious Disease case registry (notifications) providing (month and) year of birth, gender and postal code. Deaths (1996-2014) from Statistics Netherlands (death registry) were matched to notifications using gender, age, year of death and notification date. Cases <2years (y) and ≥2y were analysed separately. Chao's estimator estimated the total population, which was used to calculate CoR. RESULTS: Using strict matching criteria, we found 461 matches among 876 (hospital data) and 757 (notifications) hospitalizations <2y. The population estimate of hospitalized infants was 1446, resulting in CoR between 52% and 61%. For hospitalizations ≥2y (246; hospital data and 264; notifications) 43 matches were found, with a population estimate of 1512 and CoR between 16.5% and 22%. Among thirteen (death registry) and eight (notifications) deaths <2y, seven cases overlapped. The population estimate was 16. CoR of the two sources was 50-81%. With two (death registry) and eight (notifications) deaths ≥2y without overlap, the population estimate was 26 and CoR 8-31%. CONCLUSION: Results showed substantial underestimation of pertussis hospitalizations and deaths. This has to be taken into account in evaluation of current and future immunization programs.

Meningococcal carriage in Dutch adolescents and young adults; a cross-sectional and longitudinal cohort study.

OBJECTIVES: Current information on rates and dynamics of meningococcal carriage is essential for public health policy. This study aimed to determine meningococcal carriage prevalence, its risk factors and duration in the Netherlands, where meningococcal C vaccine coverage is >90%. Several methods to identify serogroups of meningococcal carriage isolates among adolescent and young adults were compared. METHODS: Oropharyngeal swabs were collected from 1715 participants 13-23 years of age in 2013-2014; 300 were prospectively followed over 8 months. Cultured isolates were characterized by Ouchterlony, real-time (rt-) PCR or whole-genome sequencing (WGS). Direct swabs were assessed by rt-PCR. Questionnaires on environmental factors and behaviour were also obtained. RESULTS: A meningococcal isolate was identified in 270/1715 (16%) participants by culture. Of MenB isolates identified by whole genome sequencing, 37/72 (51%) were correctly serogrouped by Ouchterlony, 46/51 (90%) by rt-PCR of cultured isolates, and 39/51 (76%) by rt-PCR directly on swabs. A sharp increase in carriage was observed before the age of 15 years. The age-related association disappeared after correction for smoking, level of education, frequent attendance to crowded social venues, kissing in the previous week and alcohol consumption. Three participants carried the same strain identified at three consecutive visits in an 8-month period. In these isolates, progressively acquired mutations were observed. CONCLUSIONS: Whole genome sequencing of culture isolates was the most sensitive method for serogroup identification. Based upon results of this study and risk of meningococcal disease, an adolescent meningococcal vaccination might include children before the age of 15 years to confer individual protection and potentially to establish herd protection.

Bacteraemic and non-bacteraemic/urinary antigen-positive pneumococcal community-acquired pneumonia compared.

The diagnosis of invasive pneumococcal pneumonia is based mainly on bacteraemia. Episodes without bacteraemia, but with a positive urinary antigen test (UAT), are considered non-invasive. We determined differences in outcome between patients with bacteraemic and non-bacteraemic/UAT-positive pneumococcal community-acquired pneumonia (CAP). Adult patients with clinical and radiological evidence of CAP with blood cultures and UAT tests performed at presentation in three Dutch laboratories between June 2008 and May 2010 were included. Clinical characteristics were retrospectively extracted from hospital records. Overall, 168 patients had non-bacteraemic/UAT-positive pneumococcal CAP and 123 had bacteraemic pneumococcal CAP. The day-30 mortality was 9% and 13% for non-bacteraemic/UAT-positive and bacteraemic pneumococcal CAP patients, respectively [risk difference -4%, 95% confidence interval (CI) -11% to +3%, p = 0.28]. In a multivariable logistic regression model, age ≥ 65 years, admission to the intensive care unit/coronary care unit (ICU/CCU) and presence of an immunocompromising condition were associated with day-30 mortality. A non-significant association with mortality was found for bacteraemia [odds ratio (OR) 2.21, 95% CI 0.94-5.21, p = 0.07). No such trend was found for UAT positivity. The median lengths of hospital stay were 8 [interquartile range (IQR) 5-14] and 10 (IQR 6-18) days for non-bacteraemic/UAT-positive and bacteraemic pneumococcal CAP patients, respectively (p = 0.05). As compared to non-bacteraemic/UAT-positive pneumococcal CAP, bacteraemic pneumococcal CAP has a stronger association with day-30 mortality.

Increased prevalence of gastrointestinal viruses and diminished secretory immunoglobulin a levels in antibody deficiencies.

PURPOSE: Gastrointestinal disease occurs frequently in antibody deficiencies. This study aims to explore the relation between gastrointestinal infections and mucosal homeostasis in patients with antibody deficiencies. METHODS: We performed an observational study including 54 pediatric antibody deficient patients (48 % CVID, 41 % CVID-like, 11 % XLA) and 66 healthy controls. Clinical symptom scores and stool samples were collected prospectively. Stool samples were evaluated for bacteria, parasites, viruses, secretory IgA- and for calprotectin levels. Results were compared between patients and controls. RESULTS: 24 % of antibody deficient patients versus 9 % of healthy controls tested positive for gastrointestinal viruses (p = 0.028). Fecal calprotectin levels were significantly higher in virus positive patients compared to virus negative patients (p = 0.002). However, in controls, fecal calprotectin levels were similar between virus positive and virus negative controls. Moreover, gastrointestinal virus positive patients had low serum IgA levels in 13/14 cases (94 %) versus 40/62 (62 %) patients in the virus negative patient group (p = 0.04). The virus positive patient group also displayed significantly lower secretory IgA levels in stool (median 13 ug/ml) than patients without gastrointestinal viruses detected or healthy controls (median 155 ug/ml) (p = 0.046). CONCLUSION: We here report an increased prevalence of gastrointestinal viruses and gastrointestinal complaints in antibody deficient patients. Patients that tested positive for gastrointestinal viruses showed diminished serum- and secretory IgA levels, and only in patients, virus positivity was associated with signs of mucosal inflammation. These findings suggest that particularly patients with low IgA are at risk for longstanding replication of gastrointestinal viruses, which may eventually result in CVID-related enteropathy.

Increased incidence of serotype-1 invasive pneumococcal disease in young female adults in The Netherlands.

Analysis of the Dutch national invasive pneumococcal disease (IPD) surveillance data by sex reveals an increase in the incidence of serotype-1 disease in young female adults in The Netherlands after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the national immunization schedule. This has led to an overall increase in IPD in women aged 20-45 years, which was not observed in men of the same age. No other differences in serotype shifts possibly induced by the introduction of PCV7 were observed between the sexes in this age group. Serotype 1 is a naturally fluctuating serotype in Europe and it has been associated with disease in young healthy adults before. It remains uncertain whether or not there is an association between the observed increase in serotype-1 disease in young female adults and the implementation of PCV7 in The Netherlands.

Human herpes virus 6 reactivation: important predictor for poor outcome after myeloablative, but not non-myeloablative allo-SCT.

Hematopoietic SCT (HSCT) is often complicated by viral reactivations. In this retrospective cohort study (January 2004-August 2008), predictors for human herpes virus 6 (HHV6)-reactivation and associations between HHV6-reactivation and clinical outcomes after allogeneic HSCT were studied. HHV6 DNA load in plasma was monitored weekly by quantitative real-time PCR. Associations between the main end point HHV6-reactivation and other end points, that is, acute GVHD (aGVHD) and NRM were analyzed using Cox proportional hazard models. In total, 108 patients receiving either a myeloablative (MA; n=60) or non-myeloablative (NMA; n=48) conditioning regimen were included. Median age was 40 years (range 17-65); median follow-up was 20 months (range 3-36). In 16/60 (27%) patients with MA conditioning regimen, a HHV6 reactivation was observed (mean viral load 50 323 cp/mL) compared with 2/48 (4%) patients with a NMA conditioning regimen with low viral load (mean 1100 cp/mL). In multivariate analysis, MA conditioning was the only predictor for HHV6 reactivation (P=0.02). In addition, HHV6 reactivation was associated with grades 2-4 aGVHD (P<0.001) and NRM (P=0.03). Regular monitoring of HHV6 reactivation after HSCT might be important in MA HSCT patients to enable early initiation of antiviral treatment or to anticipate aGVHD, all of which may improve clinical outcome.

Increased proportion of perforin-expressing CD8+T-cells indicates control of herpesvirus reactivation in children after stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is frequently complicated by viral reactivations. Early diagnosis of viral reactivations and preemptive therapy relies on frequent viralload monitoring. An easy marker of effective cytotoxicity in lymphopenia is lacking and therefore we studied perforin-expression in CD8+T-cells in children following HSCT. Prospectively, we weekly monitored viral loads and perforin-expression of CD8+T-cells in whole blood by FACS, until 4months after HSCT in children. 27 patients were included (median age 4,3, range 0.3-20,1years) of whom 19 developed viral reactivations. These patients showed higher percentages of perforin-expressing CD8+T-cells (17,2%, range 0-63%) than those without (6,8%; range 0-16%) (p=0.001). The increased percentage of perforin-expressing CD8+T-cells coincided with a decrease in viral load with a median interval between maximum viral load and maximum level of perforin-expression of 0,4weeks (range 0.1-7.1). We conclude that perforin-expression in CD8+T-cells may be a marker for effective antiviral T-cell reconstitution early after HSCT in children.

Stem cell source-dependent reconstitution of FOXP3+ T cells after pediatric SCT and the association with allo-reactive disease.

In adult patients, regulatory CD4+FOXP3+ T cells are suggested to have a role in the control of allo-reactive disease after hematopoietic SCT (HSCT). We compared CD4+FOXP3+ T-cell reconstitution after unrelated cord blood (UCB), matched unrelated donor (MUD) and matched sibling donor (MSD) HSCT in children, starting as early as 1 week after transplantation, and analyzed the association with allo-reactive disease. A total of 30 children were included who underwent a myeloablative-conditioning regimen followed by UCB (12/30), MUD (7/30) or MSD (11/30) HSCT. These three patient groups showed significant differences in FOXP3+ T-cell reconstitution pattern. Early after UCB and MSD, but not after MUD, HSCT a peak in FOXP3+ T cells was observed. There were significant differences in activation status and Ki67 expression of the FOXP3+ T cells after UCB and MSD, respectively. FOXP3+ T-cell proportions early after HSCT and in the graft were inversely correlated with allo-reactivity. This study indicates that FOXP3 reconstitution after HSCT is dependent on the type of graft used. Furthermore, in children evaluation of FOXP3+ T-cell numbers early after HSCT and in the graft may be used to judge the risk of developing allo-reactivity after HSCT.

[Prevention of severe infections in patients with hyposplenism or asplenia]. / Voorkómen van ernstige infecties bij patiënten met hypo- of asplenie.

Each year, up to a 1000 splenectomies are performed in the Netherlands. Aside from patients without a spleen, there is also a large group of patients with hyposplenism or functional asplenia due to other primary diseases. All these patients are at risk of developing severe infections, such as post-splenectomy sepsis (PSS), which is associated with very high mortality. However PSS can partly be prevented by taking simple measures such as immunizations and prophylactic or early use of antibiotics. Healthcare professionals in first and secondary care in the Netherlands are generally not well informed about which preventive measures should be taken to prevent these infections, resulting in often suboptimal management of patients. In this article, recommendations are given on vaccination and administration of antibiotics to prevent severe infections such as PSS in this group of patients.

First analysis of human herpesvirus 6T-cell responses: specific boosting after HHV6 reactivation in stem cell transplantation recipients.

Early human herpesvirus 6 (HHV6) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with poor survival. We characterized HHV6 immuneresponses in HSCT patients during lymphopenia. Prospectively, HHV6 DNA-load was measured weekly by realtime-PCR. Numbers of IFNγ-producing HHV6-T-cells were retrospectively determined by enzyme-linked immunospot assay 2 months after HSCT. HHV6-specific T-cell proliferative capacity was analyzed with a newly developed assay using antigen-presenting autologous HHV6-infected PBMC. Fifty-six patients were included (median age 4.6 years; range 0.2-21.2 years). HHV6-reactivation occurred in 29/56 (52%) patients with a median time of 14 (range 1-41) days after HSCT. The median number of IFN-γ producing HHV6-specific T-cells at 2 months and the HHV6-specific CD8+ T-cell proliferative capacity at 6 months after HSCT was increased after HHV6-reactivation compared to non-reactivating patients (P=0.006 and p=0.019). In conclusion, HHV6-specific immuneresponses can be initiated during lymphopenia early after HSCT, which implicates a potential window for development of HHV6-specific (immuno)therapy.

Trends in primary-care consultations, comorbidities, and antibiotic prescriptions for respiratory infections in The Netherlands before implementation of pneumococcal vaccines for infants.

The burden of respiratory infections is mainly seen in primary healthcare. To evaluate the potential impact of new preventive strategies against respiratory infections, such as the implementation of pneumococcal conjugate vaccines for infants in 2006 in The Netherlands, we conducted a baseline retrospective cohort study of electronic primary-care patient records to assess consultation rates, comorbidities and antibiotic prescription rates for respiratory infections in primary care. We found that between 1995 and 2005, overall registered consultation rates for lower respiratory tract infections had increased by 42·4%, upper respiratory infections declined by 4·9%, and otitis media remained unchanged. Concomitantly, there was a steady rise in overall comorbidity (75·7%) and antibiotic prescription rates (67·7%). Since Dutch primary-care rates for respiratory infections changed considerably between 1995 and 2005, these changes must be taken into account to properly evaluate the effect of population-based preventive strategies on primary-care utilization.

Airway and interstitial lung disease are distinct entities in paediatric common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a common primary immune deficiency, caused by undefined defects in lymphocyte function, and is treated routinely by immunoglobulin substitution. CVID complications include airway disease (AD) and interstitial lung disease (ILD). It was not known if AD and ILD in CVID have a common immunological aetiology and should be considered separate features of the same disease, or as distinct syndromes that require specialized monitoring and treatment. We used high-resolution computed tomography (CT) to diagnose AD or ILD in paediatric CVID patients. Spirometry and body plethysmography did not differentiate between ILD and AD. Patients with AD (n = 11, 20%) developed more pneumonias while children with ILD (n = 8, 15%) showed immune dysregulation characterized by autoimmune complications, more severe memory B cell reduction and expansion of non-naive cytotoxic T cells. In conclusion, ILD and AD in CVID have dissimilar clinical and immunological characteristics, suggesting distinct aetiology requiring tailored monitoring and treatment of these patient subgroups.

Expression of CD64 (FcγRI) in skin of patients with acute GVHD.

GVHD remains a major problem in allo-SCT. We explored the presence of APC in skin biopsies of GVHD patients, using the IgG receptor CD64 expression as a hallmark for activated APC. By immunohistochemistry we demonstrated CD64 to be upregulated on host APC in skin biopsies of patients with acute GVHD and, less prominently, in chronic GVHD. Double staining for CD32 polymorphism revealed CD64-positive cells to be mainly of host origin. The majority of CD64-positive cells coexpressed CD68, indicating a macrophage phenotype. Given its very restricted cellular distribution, CD64 may represent an excellent target for APC-directed therapies in GVHD.