Airway and Blood Monocyte Transcriptomic Profiling Reveals an Antiviral Phenotype in Infants With Severe Respiratory Syncytial Virus Infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection. METHODS: Tracheobronchial aspirates and blood samples were collected from control patients (n = 9) and those infected with RSV (n = 14) who were admitted to the pediatric intensive care unit. Monocytes (CD14+) were sorted and analyzed by RNA sequencing for transcriptomic profiling. RESULTS: Peripheral blood and airway monocytes of patients with RSV demonstrated increased expression of antiviral and interferon-responsive genes as compared with controls. Cytokine signaling showed a shared response between blood and airway monocytes while displaying responses that were more pronounced according to the tissue of origin. Airway monocytes upregulated additional genes related to migration and inflammation. CONCLUSIONS: We found that the RSV-induced interferon response extends from the airways to the peripheral blood. Moreover, RSV induces a migration-promoting transcriptional program in monocytes. Unraveling the monocytic response and its role in the immune response to RSV infection could help the development of therapeutics to prevent severe disease.

Measles seroprevalence in pregnant women in Soweto, South Africa: a nested cohort study.

OBJECTIVES: Measles infection causes particularly severe disease in young children who, prior to vaccination, are dependent on maternal antibodies for protection against infection. Measles vaccination was introduced into the South African public immunization programme in 1983 and became widely available in 1992. The aim of this study was to determine measles-specific immunoglobulin G (IgG) levels in pregnant women living with and without HIV born before and after measles vaccine introduction in South Africa. METHODS: Measles IgG antibody level from blood obtained at the time of delivery was compared between women who were born before 1983 (n = 349) and since 1992 (n = 349). Serum samples were tested for measles IgG antibody using an enzyme-linked immunosorbent assay. Geometric mean titres (GMTs) and the proportion with seronegative (<200 mIU/mL) or seropositive titres (≥275 mIU/mL) were compared. RESULTS: Women born since 1992 had lower GMTs [379.7 mIU/mL (95% CI 352.7-448.6)] and fewer were seropositive (55.9%, 195/349) than women born before 1983 [905.8 mIU/mL (95% CI 784.7-1045.5); 76.8%, 268/349], for both comparisons p < 0.001. CONCLUSIONS: We found an association between measles vaccine implementation into the public immunization program in South Africa and peri-partum maternal measles immunity, where women born before vaccine introduction had higher measles IgG antibody titres and were more likely to be seropositive. These findings suggest a need to reconsider the infant measles immunization schedule in settings where women have derived immunity mainly from measles vaccine rather than wild-type virus exposure.

Post-trial Access in Maternal Vaccine Trials.

Provisions for post-trial access (PTA) of the experimental intervention are required before the start of a clinical trial. Although there has been ample attention for PTA in the context of preventive vaccine research, discussions on PTA barely include maternal vaccine trials in which mother-infant pairs are exposed to the intervention. In maternal vaccination trials, specific PTA arrangements are required because pregnancy is transient and PTA may apply to the next pregnancy or the child. In this article, we examine the application and adherence to PTA in the context of maternal vaccine trials. We focused on differences between publications before and after 2000 when international ethical guidance documents formalized PTA requirements. Randomized maternal vaccine trials were included after a systematic search for clinical trials in phases II and III with a maternal vaccine as intervention. We used PTA as defined at the time of publication in the World Medical Association's Declaration of Helsinki (DoH) or in the ethical guidelines of the Council for International Organizations of Medical Sciences (CIOMS). In addition, we investigated whether PTA was included in the trial design. Therefore, we contacted principal investigators (PI's) of the publications found in the review to fill out a questionnaire regarding provisions for PTA. Before and after 2000, no trial articles examined in the systematic review described PTA in their trial publication (0/7, 0% and 0/17, 0%, respectively). In addition, more than half of the PI's of the trials found were not familiar with PTA recommendations in international ethical guidelines. Most cases of PTA included making knowledge available by publishing the results of the trial. The revision of the DoH in 2002 and the CIOMS ethical guidelines in 2002 has not resulted in increased PTA provisions for maternal vaccination trials. PTA is a shared responsibility of various stakeholders including sponsors, Institutional Review Boards, regulators, political entities, and researchers. Inclusion of PTA provisions in trial protocols and publications on maternal vaccination trials is essential to increase transparency on the form and content of these provisions.

Observational multi-centre, prospective study to characterize novel pathogen-and host-related factors in hospitalized patients with lower respiratory tract infections and/or sepsis - the "TAILORED-Treatment" study.

BACKGROUND: The emergence and spread of antibiotic resistant micro-organisms is a global concern, which is largely attributable to inaccurate prescribing of antibiotics to patients presenting with non-bacterial infections. The use of 'omics' technologies for discovery of novel infection related biomarkers combined with novel treatment algorithms offers possibilities for rapidly distinguishing between bacterial and viral infections. This distinction can be particularly important for patients suffering from lower respiratory tract infections (LRTI) and/or sepsis as they represent a significant burden to healthcare systems. Here we present the study details of the TAILORED-Treatment study, an observational, prospective, multi-centre study aiming to generate a multi-parametric model, combining host and pathogen data, for distinguishing between bacterial and viral aetiologies in children and adults with LRTI and/or sepsis. METHODS: A total number of 1200 paediatric and adult patients aged 1 month and older with LRTI and/or sepsis or a non-infectious disease are recruited from Emergency Departments and hospital wards of seven Dutch and Israeli medical centres. A panel of three experienced physicians adjudicate a reference standard diagnosis for all patients (i.e., bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. Nasal swabs and blood samples are collected for multi-omics investigations including host RNA and protein biomarkers, nasal microbiota profiling, host genomic profiling and bacterial proteomics. Simplified data is entered into a custom-built database in order to develop a multi-parametric model and diagnostic tools for differentiating between bacterial and viral infections. The predictions from the model will be compared with the consensus diagnosis in order to determine its accuracy. DISCUSSION: The TAILORED-Treatment study will provide new insights into the interplay between the host and micro-organisms. New host- or pathogen-related biomarkers will be used to generate a multi-parametric model for distinguishing between bacterial and viral infections. This model will be helpful to better guide antimicrobial therapy for patients with LRTI and sepsis. This study has the potential to improve patient care, reduce unnecessary antibiotic prescribing and will contribute positively to institutional, national and international healthcare economics. TRIAL REGISTRATION: NCT02025699 . Registration Date: January, 1, 2014.

[Infection prevention in newborns through maternal vaccination: current insights and developments]. / Infectiepreventie bij zuigelingen door maternale vaccinatie.

- In the first few months of life, newborns are vulnerable to infections.- Vaccination of the pregnant mother leads to transplacental antibody transfer, resulting in the best possible protection of the newborn.- Maternal vaccination has long been given for the prevention of tetanus in developing countries, and for the prevention of pertussis and influenza in developed countries, such as the United States, England and Belgium. These vaccinations give newborns good protection and, to date, no adverse effects are known for the foetus or the pregnancy.- Currently, phase 3 trials during pregnancy are ongoing following maternal vaccination against group B streptococci and respiratory syncytial virus. Here, again, no risks to mother or child have been reported.- Recently, the Dutch Health Council advised that all pregnant women in the Netherlands be vaccinated against pertussis in a vaccination programme.- This paper gives an overview of effectiveness, safety and practicalities of maternal vaccination.

Value of cone-beam computed tomography in the process of diagnosis and management of disorders of the temporomandibular joint.

The objective of this study was to assess the value of cone-beam computed tomographic (CT) images in the primary diagnosis and management of 128 outpatients with disorders of the temporomandibular joint (TMJ). Before a diagnosis was made and treatment planned, the history was taken, physical examination made, and the orthopantomogram studied. After assessment of the cone-beam CT, the oral and maxillofacial surgeon (specialist or resident) was allowed to revise the provisional primary diagnosis and management. The degree of certainty was rated by the clinician before and after the cone-beam CT had been assessed. The primary diagnosis was changed in 32 patients (25%), additional diagnostic procedures were changed in 57 (45%), and the treatment was changed in 15 (12%) (in 4 the treatment was changed to a (minimally) invasive procedure). A total of 74 patients (58%) had their diagnosis and management changed after the cone-beam CT had been assessed. Changes in diagnosis and management were clinically relevant in 9/32 and 9/61 patients, respectively. The clinician's certainty about the primary diagnosis increased after the cone-beam CT had been assessed in 57 patients. Logistic regression analysis showed that the odds in favour of changes in primary diagnosis and management increased when limited mandibular function was a primary symptom, the patient was taking medication for pain, and the articular eminence could not be assessed on OPT. Assessment of cone-beam CT led to changes in primary diagnosis and management in more than half the patients with disorders of the TMJ.

Vitamin D-binding protein haplotype is associated with hospitalization for RSV bronchiolitis.

BACKGROUND: Between 75 000 and 125 000 U.S. infants are hospitalized for respiratory syncytial virus (RSV) bronchiolitis every year. Up to half will be diagnosed with asthma in later childhood. Vitamin D deficiency has been associated with susceptibility to asthma and respiratory infections. Measured vitamin D is largely bound to vitamin D-binding protein (VDBP); VDBP levels are influenced by its gene (GC) haplotype. OBJECTIVE: We assessed the relationship between polymorphisms rs7041 and rs4588, which define haplotypes GC1s, GC1f, and GC2, and RSV bronchiolitis susceptibility and subsequent asthma. METHODS: We retrospectively recruited 198 otherwise healthy children (93% White) hospitalized for severe RSV bronchiolitis in Boston and 333 parents into a follow-up study to assess asthma diagnosis. Data were analysed using family-based genetic association tests. We independently validated our results in 465 White children hospitalized with RSV bronchiolitis and 930 White population controls from the Netherlands. RESULTS: The rs7041_C allele (denoting haplotype GC1s) was overtransmitted (P = 0.02, additive model) in the entire Boston cohort, in Whites (P = 0.03), and especially in children subsequently diagnosed with asthma (P = 0.006). The GC1f haplotype was undertransmitted in the asthma subgroups (all races and White, both P < 0.05). The rs7041_C allele was also more frequent in the RSV bronchiolitis group compared with controls (OR 1.12, 95% CI 1.02, 1.4, P = 0.03) in the Netherlands, especially in mechanically ventilated patients (P = 0.009). CONCLUSION AND CLINICAL RELEVANCE: GC1s haplotype carriage may increase the risk of RSV bronchiolitis in infancy and subsequent asthma development. The GC1s haplotype is associated with higher VDBP levels, resulting in less freely available vitamin D. KEY MESSAGES: Vitamin D-binding protein (VDBP) haplotypes influence free vitamin D levels. We report an association between a VDBP haplotype and hospitalization for RSV bronchiolitis in infancy in two independent cohorts.

Respiratory syncytial virus in critically ill adult patients with community-acquired respiratory failure: a prospective observational study.

The incidence of respiratory syncytial virus (RSV) and influenza virus infection was determined during three RSV seasons in 158 adult patients consecutively admitted to the intensive care unit with community-acquired respiratory failure. Nasopharyngeal swabs were tested for the presence of RSV and influenza virus by real-time polymerase chain reaction. Six patients (4%) were positive for RSV and all recovered. This finding was in sharp contrast to influenza (23 (15%) patients, 4 (17%) deaths). In conclusion, even in the midst of the RSV season, RSV is an infrequent cause of respiratory failure in adults admitted to the intensive care unit.

Arthroscopic cauterization of retrodiscal tissue as a successful minimal invasive therapy in habitual temporomandibular joint luxation.

Habitual temporomandibular joint (TMJ) luxation is a serious condition for the patient, and is often managed by extensive open joint surgery. Arthroscopic eminoplasty is an alternative, but this technique could also cause concomitant damage to the articular surface. The aim of this study was to evaluate the therapeutic effects and side effects of arthroscopic electrocautery of retrodiscal tissues in habitual TMJ luxation. All patients with habitual TMJ luxations who needed surgical management from 1 January 2000 to 31 December 2009 in the authors' institution in The Netherlands, were included in this study. All patients were primarily treated with arthroscopic electrocautery. Pre- and postoperative evaluation parameters were: TMJ luxations, maximum mouth opening, translatory capacity, pain and joint noises. Sixteen patients with habitual luxation were treated with arthroscopic electrocautery. Patient reluxation occurred in one. None of the patients had joint pain or mobility restrictions. The overall success rate was 95%. After 86 months there was a high success rate for this therapy. No other morbidity was seen, in contrast with open joint surgery or using sclerosing agents. The authors conclude that arthroscopic eletrocautery of retrodiscal tissues is a highly successful minimal invasive therapy in habitual TMJ luxation without side effects.

Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on dental side effects.

OBJECTIVES: This study aimed to assess possible dental side effects associated with long-term use of an adjustable oral appliance compared with continuous positive airway pressure (CPAP) in patients with the obstructive sleep apnea syndrome and to study the relationship between these possible side effects and the degree of mandibular protrusion associated with oral appliance therapy. MATERIALS AND METHODS: As part of a previously conducted RCT, 51 patients were randomized to oral appliance therapy and 52 patients to CPAP therapy. At baseline and after a 2-year follow-up, dental plaster study models in full occlusion were obtained which were thereupon analyzed with respect to relevant variables. RESULTS: Long-term use of an oral appliance resulted in small but significant dental changes compared with CPAP. In the oral appliance group, overbite and overjet decreased 1.2 (±1.1) mm and 1.5 (±1.5) mm, respectively. Furthermore, we found a significantly larger anterior-posterior change in the occlusion (-1.3 ± 1.5 mm) in the oral appliance group compared to the CPAP group (-0.1 ± 0.6 mm). Moreover, both groups showed a significant decrease in number of occlusal contact points in the (pre)molar region. Linear regression analysis revealed that the decrease in overbite was associated with the mean mandibular protrusion during follow-up [regression coefficient (ß) = -0.02, 95 % confidence interval (-0.04 to -0.00)]. CONCLUSIONS: Oral appliance therapy should be considered as a lifelong treatment, and there is a risk of dental side effects to occur. CLINICAL RELEVANCE: Patients treated with the oral appliance need a thorough follow-up by a dentist or dental-specialist experienced in the field of dental sleep medicine.

Inhibitory receptor expression on neonatal immune cells.

Neonates are born with quantitative and qualitative defects in both adaptive and innate immune responses. The immune system is regulated by several mechanisms, including the signalling of inhibitory receptors. Increased expression of inhibitory receptors may result in a higher threshold for activation and suppressed function of neonatal cells. The aim of this study was to determine whether the expression of seven inhibitory receptors is increased on neonatal immune cells compared to adult immune cells. In a healthy birth cohort, we examined the expression of seven inhibitory immune receptors on neonatal neutrophils, monocytes, natural killer (NK) cells, CD4(+) and CD8(+)T cells. The expression of leucocyte-associated immunoglobulin (Ig)-like receptor-1 (LAIR-1), signal inhibitory receptor on leucocytes-1 (SIRL-1), CD31, signal-regulatory protein alpha (SIRPα), Siglec-9, CD200R, immune receptor expressed on myeloid cells-1 (IREM-1) and the membrane-bound ligand CD200 was studied by flow cytometry on leucocytes in cord blood (n = 14), neonatal venous blood (n = 24) and adult venous blood (n = 22). Expression of LAIR-1, CD31 and CD200 was increased consistently across all neonatal T cell subsets. Neonatal monocytes exhibited decreased expression of LAIR-1 and IREM-1 compared to adults. Furthermore, cord blood and neonatal venous blood samples contained a distinct LAIR-1-positive neutrophil population, which was not detected in adult blood. We demonstrated distinct expression of inhibitory receptors on neonatal peripheral blood immune cells in a healthy birth cohort. This is the first evidence that inhibitory receptors play a role in regulation of the neonatal immune system. Consistently increased inhibitory receptor expression on T cells may be an important mechanism in preventing the development of allergy and autoimmunity.

High risk for RSV bronchiolitis in late preterms and selected infants affected by rare disorders: a dilemma of specific prevention.

Respiratory syncytial virus (RSV) is the most frequent aetiologic agent that causes bronchiolitis and lower respiratory tract infection in infants. These infections may be severe and even life-threatening in selected high-risk populations. Traditional, well-established, high-risk populations are preterm infants with or without chronic lung disease and children with congenital heart disease. For these children, RSV prophylaxis using palivizumab, a monoclonal anti-RSV humanised antibody against the F-protein of RSV, has proven safe and efficacious in preventing RSV-related hospitalisation. Recently, a number of rare medical conditions have been associated with the risk of severe RSV infections. Evidence of safety and efficacy of RSV prophylaxis in these populations is lacking. Given the low incidence of these conditions, randomised trials are not feasible. A practical, opinion-based approach to this dilemma is offered in this paper. It is proposed that these rare disorders may qualify for RSV prophylaxis if the association between a specific condition and the risk of severe RSV infection is confirmed in at least 3 independent publications, of which at least 1 includes a prospective cohort study. To facilitate pharmaco-economic analyses, at least one of the three studies must also report on the absolute risk of severe RSV infection in the specified illness. The authors believe that qualification criteria will enable caregivers to target RSV prophylaxis more effectively in children with rare conditions and the proposed approach provides direction for future epidemiological studies on the risk of severe RSV infection in children with these uncommon, medical illnesses.

Breastfeeding modulates neonatal innate immune responses: a prospective birth cohort study.

BACKGROUND: Neonatal Toll-like receptor (TLR) responses are biased toward Th2-polarizing responses at birth and rapidly mature toward more balanced responses during the first month of life. Postnatal TLR maturation may be guided by environmental exposure. AIMS: To determine the environmental determinants of neonatal TLR function. MATERIALS AND METHODS: A prospective birth cohort study was performed in 291 healthy term neonates. Mode of delivery, breastfeeding, birth month, siblings, pets and parental smoking were analyzed in relation to neonatal innate immune parameters at the age of 1 month. Whole blood concentrations of innate immune cells were measured by flow cytometry. In vitro TLR-mediated cytokine production was determined by ELISA. RESULTS: Breastfeeding was the major determinant of neonatal innate immunity, associated with 5 (31%) of neonatal innate immune parameters, of which the association with TLR7-mediated IL-10 production was most significant (76 pg/ml in breastfed neonates vs. 293 pg/ml in formula-fed neonates, p = 0.001). Of innate immune variables, TLR3-mediated IL-12p70 production was highly associated with environmental exposures (pets, breastfeeding and mode of delivery), whereas TLR9-mediated cytokine responses were not associated with any environmental factor. CONCLUSION: Neonatal innate immune responses are differentially modulated by environmental exposure in the first month of life. The protective effect of breastfeeding against subsequent infections and atopy might be explained by its innate immune modulatory effects in the first month of life.

Low neonatal Toll-like receptor 4-mediated interleukin-10 production is associated with subsequent atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) and respiratory syncytial virus lower respiratory tract infection (RSV LRTI) are common diseases during early life. Impaired Th1-cell polarizing Toll-like receptor (TLR) responses play an important role in the pathogenesis of both diseases. Neonatal TLR-mediated production of Th1-type cytokines is decreased at birth, but rapidly increases during the first month of life. OBJECTIVE: To determine whether decreased TLR-mediated production of Th1-polarizing cytokines, at the age of 1 month is associated with subsequent AD or RSV LRTI. METHODS: A prospective healthy birth cohort study was performed. Whole blood concentrations of innate immune cells and TLR-mediated cytokine responses were measured at the age of 1 month in 291 neonates. AD was determined by a physician questionnaire at the age of 1 year and RSV LRTI was defined as parent-reported respiratory symptoms and presence of RSV RNA in a nose-throat specimen. RESULTS: Of participating neonates, 45 (15%) developed AD and 41 (14%) developed RSV LRTI. Risks of AD and RSV LRTI were not associated (χ(2) , P = 1.00). AD was associated with decreased concentrations of basophils (7.6 vs. 14.0 × 10(6) /mL, P = 0.002) and plasmacytoid dendritic cells (17.0 vs. 20.5 × 10(6) /mL, P = 0.04), increased concentrations of NK-cells (79.7 vs. 45.1 × 10(6) /mL, P = 0.03), and twofold lower TLR4-mediated IL-10 production (P = 0.001). In contrast, RSV LRTI was associated neither with neonatal concentrations of innate immune cells, nor with TLR-mediated TNF-α, IL-12p70, IL-10 or IFN-α production. CONCLUSIONS AND CLINICAL RELEVANCE: Atopic dermatitis, but not RSV LRTI, is associated with distinct pre-symptomatic differences in the innate immune system. We hypothesize that decreased neonatal IL-10-mediated immune regulation during early life might play a causal role in the initiation of AD.

[Dissertations 25 years after date 28. Degenerative diseases of the temporomandibular joint]. / Proefschriften 25 jaar na dato 28. Degeneratieve aandoeningen van het kaakgewricht.

In 1985, the dissertation 'Temporomandibular joint. Articular cartilage structure and function' was published. Much was known at the time concerning the (clinical) pathogenesis of osteoarthrosis of the temporomandibuIar joint, the associated radiographical characteristics and the results of non-surgical treatment. Little was known, however, concerning the processes that lead to the loss of bone tissue and other degenerative changes. The current idea that osteoarthrosis was histopathologically characterized by defects in the joint surfaces did not seem to apply to temporomandibular joints. In temporomandibular joints, the phenomenon was recognized of degenerative changes in the deeper layers of the articular cartilage and the subchondral bone, while the articular surface could be microscopically intact. A dislocated articular disc was seen as part of the disease osteoarthrosis. Clear insight into the origins of osteoarthrosis was not achieved.

Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African children.

Respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Disease severity has been linked to host immune responses and polymorphisms in genes associated with innate immunity. A large-scale genetics study of single nucleotide polymorphisms (SNPs) in children in the Netherlands identified SNPs in the vitamin D receptor (VDR) and JUN genes which have a strong association with an increased risk of developing bronchiolitis following the first respiratory syncytial virus (RSV) infection. The Toll-like receptor 4 (TLR4) gene has two SNPs which have been associated previously with RSV disease severity in various populations. The aim of this study was to determine if these SNPs may be associated with RSV disease in African children in South Africa. RSV patient (n = 296) and control (n = 113) groups were established (median ages: 3 and 3.5 months) and DNA extracted from the collected specimens. Real-time polymerase chain reaction using hydrolysis probes was used to screen for SNPs in the VDR (Thr1Meth; rs10735810), TLR4 (Asp299Gly; rs4986790 and Thr399Ile; rs4986791) and JUN (c.750G/A; rs11688) genes. Carriers of the VDR (Thr1Meth) SNP minor T allele were more prone to RSV disease than individuals in the control group. The TLR4 (Asp299Gly), TLR4 (Thr399Ile), and JUN (c.750G/A) SNPs showed no significant association with RSV disease. It is concluded that children carrying the minor T allele of the VDR (Thr1Meth) SNP may be predisposed to RSV disease, as this SNP was identified as a risk factor for severe RSV disease in South African children, confirming the findings in the Netherlands.

The relationship between RSV bronchiolitis and recurrent wheeze: the chicken and the egg.

Respiratory syncytial virus bronchiolitis is the most frequent cause of infant hospitalization. RSV bronchiolitis is often followed by recurrent episodes of wheeze. Pathogenesis of RSV bronchiolitis as well as post-bronchiolitis wheeze are incompletely understood. The aim of this review is to provide a brief overview of our current understanding of the complex pathogenesis of RSV bronchiolitis and post-bronchiolitis wheeze. Two non-exclusive hypotheses exist, which are paraphrased for this review as "the chicken and the egg". First, we reviewed the pre-existent genetic, pulmonary and immunological mechanisms of RSV bronchiolitis and post-bronchiolitis wheeze. Second, RSV as the causative virus of long-term airway morbidity is reviewed. Clearly, RSV infection is capable of causing direct damage to the airways and/or inducing long-term inappropriate immune responses to respiratory viruses or aero-allergens. It is concluded that intervention trials aimed at preventing RSV infections are required to establish the relative contribution of both RSV-induced and pre-existent mechanisms to the development of long-term airway disease following RSV bronchiolitis.

Viruses and bacteria in acute asthma exacerbations--a GA² LEN-DARE systematic review.

A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.

Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community.

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, with remarkable variability in disease severity. Factors determining severity of disease in previously healthy infants are still unclear. It was hypothesized that disease severity is correlated with viral load in primary RSV infection. Infants of a healthy birth cohort were included at signs of their first respiratory tract infection. Nasopharyngeal aspirate was obtained within 48-96 hr and disease severity was assessed with a previously published severity scoring model. PCR was applied to test the aspirates in a semi-quantitative way for the presence of 10 respiratory pathogens. In case of multiple infection, the pathogen with the highest load was defined as the primary pathogen. The correlation between disease severity and viral load was analyzed. A total of 82 infants were included over a period of 2 years. Median age at first respiratory tract infection was 3 months. Pathogens were detected in 77 (94%) infants; more than one pathogen was detected in 35 (43%) infants. RSV was present in aspirates of 30 infants; in 16 aspirates RSV was the primary pathogen. A negative correlation between RSV CT-value and disease severity was found in all RSV cases (rho = -0.52, P = 0.003) and in cases with RSV as the primary pathogen (rho = -0.54, P = 0.03). In conclusion, this is the first report on viral loads in previously healthy infants with RSV infection in the community. Disease severity correlated positively with viral load during primary RSV infection.

Complaints related to mandibular function impairment after closed treatment of fractures of the mandibular condyle.

This study analysed the relationship between complaints and mandibular function after closed treatment of fractures of the mandibular condyle in a prospective study. In a 1-year follow-up, complaints were assessed during physical examination and function was assessed using the mandibular function impairment questionnaire (MFIQ), scoring range 0-68. Data from 114 patients (41 women, 73 men), mean age 28.1 years (SD 13.3), were available. On average the MFIQ scores were low 3.4 (SD 7.3). Ten patients (9%) experienced pain and 45 (39%) patients had a MFIQ score > 0. Mean mouth opening was 51.9 mm (SD 8.4). Occlusion was perceived as moderate or poor by 24% of the patients. In the logistic regression analysis mandibular function impairment (MFIQ score > 0) was entered as a dependent variable. Risk factors for mandibular function impairment were: pain, perceived occlusion (moderate or poor), absolute difference between left and right horizontal movements and age. A protective factor was mouth opening. The results of this study show that complaints (i.e. pain, perceived occlusion, reduced mouth opening, difference between left and right lateral movements and increased age) are predictors of mandibular function impairment after closed treatment of fractures of the mandibular condyle.