The Swiss National Registry for Primary Immunodeficiencies: report on the first 6 years' activity from 2008 to 2014.

The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care of patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymized clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of 348 patients are registered in Switzerland, indicating an estimated minimal prevalence of 4·2 patients per 100 000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19 091 registered patients: 'predominantly antibody disorders' are the most common diseases observed (n = 217/348, 62%), followed by 'phagocytic disorders' (n = 31/348, 9%). As expected, 'predominantly antibody disorders' are more prevalent in adults than in children (78 versus 31%). Within this category, 'common variable immunodeficiency disorder' (CVID) is the most prevalent PID (n = 98/217, 45%), followed by 'other hypogammaglobulinaemias' (i.e. a group of non-classified hypogammaglobulinaemias) (n = 54/217, 25%). Among 'phagocytic disorders', 'chronic granulomatous disease' is the most prevalent PID (n = 27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high, with a median of 6 years for CVID and more than 3 years for 'other hypogammaglobulinaemias'.

Influence of age, social patterns and nasopharyngeal carriage on antibodies to three conserved pneumococcal surface proteins (PhtD, PcpA and PrtA) in healthy young children.

The acquisition of specific antibodies is paramount to protect children against pneumococcal diseases, and a better understanding of how age, ethnicity and/or Streptococcus pneumoniae (Spn) nasopharyngeal carriage influence the acquisition of antibodies to pneumococcal surface proteins (PSP) is important for the development of novel serodiagnostic and immunisation strategies. IgG antibody titres against three conserved PSP (PhtD, PcpA and PrtA) in the sera of 451 healthy children aged 1 to 24 months from Israel [Jewish (50.1 %) and Bedouin (49.9 %)] were measured by enzyme-linked immunosorbent assay (ELISA), while nasopharyngeal swabs from these children were assessed for the presence of Spn. Globally, anti-PhtD and anti-PrtA geometric mean concentrations (GMC; EU/ml) were high at <2.5 months of age [PhtD: 35.3, 95 % confidence interval (CI) 30.6-40.6; PrtA: 71.2, 95 % CI 60-84.5], was lower at 5-7 months of age (PhtD: 10, 95 % CI 8-12.4; PrtA: 17.9, 95 % CI 14.4-22.1) and only increased after 11 months of age. In contrast, an increase in anti-PcpA was observed at 5-7 months of age. Anti-PcpA and anti-PrtA, but not anti-PhtD, were significantly higher in Bedouin children (PcpA: 361.6 vs. 226.3, p = 0.02; PrtA: 67.2 vs. 29.5, p < 0.001) in whom Spn nasopharyngeal carriage was identified earlier (60 % vs. 38 % of carriers <6 months of age, p = 0.002). Spn carriage was associated with significantly higher anti-PSP concentrations in carriers than in non-carriers (p < 0.001 for each PSP). Thus, age, ethnicity and, essentially, nasopharyngeal carriage exert distinct cumulative influences on infant responses to PSP. These specific characteristics are worthwhile to include in the evaluation of pneumococcal seroresponses and the development of new PSP-based vaccines.

Varicella-zoster immunization in pediatric liver transplant recipients: safe and immunogenic.

Varicella can have a severe course in immunosuppressed patients. Although prevention is fundamental, live-attenuated varicella-zoster (VZV) vaccine is not currently recommended in transplant recipients. Our aims were to (1) evaluate VZV immunity in pediatric liver transplant (LT) recipients; (2) immunize (two doses) seronegative patients post-LT; (3) monitor vaccine safety, (4) assess B and T cell vaccine responses. All patients followed at the Swiss National Pediatric LT Center were approached and 77/79 (97.5%) were enrolled (median age 7.8 years). Vaccine safety was monitored by standardized diary cards and phone calls. VZV-specific serology and CD4(+) T cells were assessed before and after immunization. Thirty-nine patients (51.1%) were seronegative including 14 children immunized pre-LT. Thirty-six of 39 seronegative patients were immunized post-LT (median 3.0 years post LT). Local (54.8%) and systemic (64.5%) reactions were mild and transient. The frequency of VZV-specific CD4(+) T cells and antibody titers increased significantly (respectively from 0.085% to 0.16%, p = 0.04 and 21.0 to 1134.5 IU/L, p < 0.001). All children reached seroprotective titers and 31/32 (97%) patients assessed remained seroprotected at follow-up (median 1.7 years). No breakthrough disease was reported during follow-up (median 4.1 years). Thereby, VZV vaccine appears to be safe, immunogenic and provide protection against disease in pediatric LT patients.

Impaired antibody memory to varicella zoster virus in HIV-infected children: low antibody levels and avidity*.

OBJECTIVE: HIV-infected children have impaired antibody responses after exposure to certain antigens. Our aim was to determine whether HIV-infected children had lower varicella zoster virus (VZV) antibody levels compared with HIV-infected adults or healthy children and, if so, whether this was attributable to an impaired primary response, accelerated antibody loss, or failure to reactivate the memory VZV response. METHODS: In a prospective, cross-sectional and retrospective longitudinal study, we compared antibody responses, measured by enzyme-linked immunosorbent assay (ELISA), elicited by VZV infection in 97 HIV-infected children and 78 HIV-infected adults treated with antiretroviral therapy, followed over 10 years, and 97 age-matched healthy children. We also tested antibody avidity in HIV-infected and healthy children. RESULTS: Median anti-VZV immunoglobulin G (IgG) levels were lower in HIV-infected children than in adults (264 vs. 1535 IU/L; P<0.001) and levels became more frequently unprotective over time in the children [odds ratio (OR) 17.74; 95% confidence interval (CI) 4.36-72.25; P<0.001]. High HIV viral load was predictive of VZV antibody waning in HIV-infected children. Anti-VZV antibodies did not decline more rapidly in HIV-infected children than in adults. Antibody levels increased with age in healthy (P=0.004) but not in HIV-infected children. Thus, antibody levels were lower in HIV-infected than in healthy children (median 1151 IU/L; P<0.001). Antibody avidity was lower in HIV-infected than healthy children (P<0.001). A direct correlation between anti-VZV IgG level and avidity was present in HIV-infected children (P=0.001), but not in healthy children. CONCLUSION: Failure to maintain anti-VZV IgG levels in HIV-infected children results from failure to reactivate memory responses. Further studies are required to investigate long-term protection and the potential benefits of immunization.

Successful serology-based intervention to increase protection against vaccine-preventable diseases in liver-transplanted children: a 19-yr review of the Swiss national reference center.

As children referred for OLT in Switzerland were not vaccinated optimally, new guidelines were developed and recommended to base catch-up immunization on serum antibody titers against vaccine-preventable diseases, before and after OLT. We measure the results of this serology-based intervention by comparing vaccine coverage and antibody titers in the pre- (1990-2002, P1) and post-intervention (2003-2008, P2) cohorts in a quality control project. Forty-four P1 and 30 P2 children were evaluated. At pre-OLT visit, D, T, SPn, and MMR serologies were checked more frequently in P2 than P1 (p < 0.05). More P2 children were up-to-date for DTaP and MMR (p < 0.05) or had received ≥1 dose of HBV, HAV, SPn, and VZV vaccines (p < 0.05). One yr post-OLT, DT, SPn, MMR, and VZV serologies were more frequently checked (p < 0.05), and antibody titers were higher for DT and HAV (p < 0.05) in P2. Gender, age, or diagnosis did not explain these differences. Among P2 patients, pre- and post-OLT titers for D, T, Hib, HBV, SPn14, and SPn19 were correlated (p < 0.05 for all). Protection against vaccine-preventable diseases of high-risk children like OLT patients can be significantly improved by serology-based intervention for vaccine-preventable diseases.

[Management of childhood malaria in Switzerland]. / Prise en charge du paludisme chez l'enfant en Suisse.

Imported malaria is a rare condition in current paediatric practice in Switzerland but should be suspected in all febrile children returning from a malaria-endemic region. Immediate treatment is essential to decrease the risk of complications and mortality. Severity criteria must always be searched for. We suggest a diagnostic strategy based on the use of microscopy and rapid antigen-detection tests. Treatment depends on the Plasmodium species and the severity of illness. For uncomplicated malaria, a drug combination that includes an artemisinin derivative should be used in priority. Atovaquone/proguanil represents an alternative. Chloroquine can be used in most cases of malaria caused by another Plasmodium species. Severe malaria must be treated intravenously with quinine and soon with artesunate.

Postural tachycardia syndrome among adolescents.

Postural tachycardia syndrome (PoTS) is a polymorphic clinical syndrome that is underdiagnosed, especially in adolescents. It is a form of dysautonomia, but its exact physiopathology remains elusive. Several pathologies can mimic PoTS; it is characterized by heterogeneous symptoms that accompany a disproportionate tachycardia upon the upright position. It can significantly impact the patients' quality of life. Only a Schellong test is useful for making the diagnosis. Treatment in PoTS is primarily symptomatic with the main goal being to restore the patient's condition as quickly as possible. We report here the diagnosis and management of seven adolescents, aged 11-16, who have been followed up since 2015.

[Group B meningococcal invasive infections: an unresolved public health problem]. / Infections invasives à méningocoque de groupe b: un problème de santé publique non résolu.

Group B meningococcal infections represent 64% of the invasive meningococcal infections in Switzerland. While conjugate vaccine against group C meningococcus is part of the additional vaccinations of the Swiss vaccinal calendar and quadrivalent vaccines protect against serogroups A, C, Y, and W135, there is presently no available vaccine against group B meningococcus in Switzerland. The use of the capsular polysaccharide from the group B meningococcus is ineffective and possibly dangerous because of its similarity with an adhesion molecule of the human neuronal cells. Development of new vaccines with other antigenic targets gives hope for an optimal protection not only against group B meningococcus, but also against other serogroups that share same antigenic determinants.

Development of a real-time PCR for the specific detection of Waddlia chondrophila in clinical samples.

Waddlia chondrophila is considered as an emerging human pathogen likely involved in miscarriage and lower respiratory tract infections. Given the low sensitivity of cell culture to recover such an obligate intracellular bacteria, molecular-based diagnostic approaches are warranted. We thus developed a real-time PCR that amplifies Waddlia chondrophila DNA. Specific primers and probe were selected to target the 16S rRNA gene. The PCR specifically amplified W. chondrophila but did not amplify other related-bacteria such as Parachlamydia acanthamoebae, Simkania negevensis and Chlamydia pneumoniae. The PCR exhibited a good intra-run and inter-run reproducibility and a sensitivity of less than ten copies of the positive control. This real-time PCR was then applied to 32 nasopharyngeal aspirates taken from children with bronchiolitis not due to respiratory syncytial virus (RSV). Three samples revealed to be Waddlia positive, suggesting a possible role of this Chlamydia-related bacteria in this setting.

Prevalence and diversity of Chlamydiales and other amoeba-resisting bacteria in domestic drinking water systems.

A growing number of human infections incriminate environmental bacteria that have evolved virulent mechanisms to resist amoebae and use them as a replicative niche. These bacteria are designated amoeba-resisting bacteria (ARB). Despite the isolation of these ARB in various human clinical samples, the possible source of infection remains undetermined in most cases. However, it is known that the ARB Legionella pneumophila, for instance, causes a respiratory infection in susceptible hosts after inhalation of contaminated water aerosols from various sources. The Chlamydiales order contains many ARB, such as Parachlamydia acanthamoebae or Simkania negevensis, previously implicated in human respiratory infections with no identified contamination sources. We thus investigated whether domestic water systems are a potential source of transmission of these Chlamydiales to humans by using amoebal culture and molecular methods. Other important ARB such as mycobacteria and Legionella were also investigated, as were their possible amoebal hosts. This work reports for the first time a very high prevalence and diversity of Chlamydiales in drinking water, being detected in 35 (72.9%) of 48 investigated domestic water systems, with members of the Parachlamydiaceae family being dominantly detected. Furthermore, various Legionella and mycobacteria species were also recovered, some species of which are known to be causal agents of human infections.

Comparative analysis of viral shedding in pediatric and adult subjects with central nervous system-associated enterovirus infections from 2013 to 2015 in Switzerland.

BACKGROUND: Several enterovirus (EV) genotypes can result in aseptic meningitis, but their routes of access to the central nervous system remain to be elucidated and may differ between the pediatric and adult populations. OBJECTIVE: To assess the pattern of viral shedding in pediatric and adult subjects with acute EV meningitis and to generate EV surveillance data for Switzerland. STUDY DESIGN: All pediatric and adult subjects admitted to the University Hospitals of Geneva with a diagnosis of EV meningitis between 2013 and 2015 were enrolled. A quantitative EV real-time reverse transcriptase (rRT)-PCR was performed on the cerebrospinal fluid (CSF), blood, stool, urine and respiratory specimens to assess viral shedding and provide a comparative analysis of pediatric and adult populations. EV genotyping was systematically performed. RESULTS: EV positivity rates differed significantly between pediatric and adult subjects; 62.5% of pediatric cases (no adult case) were EV-positive in stool and blood for subjects for whom these samples were all collected. Similarly, the EV viral load in blood was significantly higher in pediatric subjects. Blood C-reactive protein levels were lower and the number of leucocytes/mm3 in the CSF were higher in non-viremic than in viremic pediatric subjects, respectively. A greater diversity of EV genotypes was observed in pediatric cases, with a predominance of echovirus 30 in children ≥3 years old and adults. CONCLUSION: In contrast to adults, EV-disseminated infections are predominant in pediatric subjects and show different patterns of EV viral shedding. This observation may be useful for clinicians and contribute to modify current practices of patient care.

Control of a cluster of community-associated, methicillin-resistant Staphylococcus aureus in neonatology.

To control an outbreak of community-associated MRSA (CA-MRSA) in a neonatology unit, an investigation was conducted that involved screening neonates and parents, molecular analysis of MRSA isolates and long-term follow-up of cases. During a two-month period in the summer of 2000, Panton-Valentine leukocidin (PVL)-producing CA-MRSA (strain ST5-MRSA-IV) was detected in five neonates. The mother of the index caseshowed signs of mastitis and wound infection and consequently tested positive for CA-MRSA. A small cluster of endemic, PVL-negative MRSA strains (ST228-MRSA-I) occurred in parallel. Enhanced hygiene measures, barrier precautions, topical decolonization of carriers, and cohorting of new admissions terminated the outbreak. Four months after the outbreak, the mother of another neonate developed furunculosis with the epidemic CA-MRSA strain. One infant had persistent CA-MRSA carriage resulting in skin infection in a sibling four years after the outbreak. In conclusion, an epidemic CA-MRSA strain was introduced by the mother of the index case. This spread among neonates and was subsequently transmitted to another mother and a sibling. This is the first report of a successfully controlled neonatology outbreak of genetically distinct PVL-producing CA-MRSA in Europe.

[Whooping cough: a diagnosis one shouldn't forget]. / La coqueluche: une maladie a ne pas oublier.

Reports of whooping cough, due to Bordetella pertussis, have been increasing worldwide for the last two decades in all age groups. Infants are especially at risk for severe disease, but older children and adolescents can have a great disease burden as well. Diagnosing pertussis is difficult due to atypical symptoms, and frequent lack of laboratory confirmation. This article reviews the reasons for epidemiologic changes, clinical manifestations, diagnostic tools, treatment and prevention strategies, especially vaccination which will most certainly focus in the future on decreasing susceptible pools by immunizing adolescents and young adults. This strategy would not only protect these individuals from whooping cough, but most importantly protect, by herd immunity, the infants too young to be (fully) immunized.

[Recurrent lower respiratory tract infection in children: when and how should they be investigated?]. / Infections récurrentes des voies respiratoires inférieures de l'enfant: quand et comment les investiguer?

Children with recurrent lower respiratory tract infections are often a challenge for their physicians. This article reviews the differential diagnosis of recurrent cough, bronchopneumonia and/or pneumonia in children and emphasizes on the necessity of preventing long-term complications of these infections. It also suggests a step-wise immunological work-up, which includes investigating a possible immune maturation delay or deficiency which could explain these symptoms. This work-up focuses on measuring antibody responses to pneumococci, followed by immunization when necessary, to rule out B cell dysfunction. Finally, this article also describes an upcoming study in Switzerland which will evaluate in 2005 the clinical and immunological outcome of these young patients.

Dolutegravir-based antiretroviral therapy in a severely overweight child with a multidrug-resistant human immunodeficiency virus infection. A case report and review.

The management of multidrug-resistant human immunodeficiency virus (MDR HIV) infections in children is particularly challenging due to the lack of experience with new drugs. Dolutegravir, combined with an optimized antiretroviral background therapy, is promising for the treatment of MDR HIV and has been approved recently for adults and adolescents. Data for children are extremely limited. We describe the efficacy, safety and plasmatic levels of a dolutegravir-based, complex active antiretroviral treatment regimen in a severely overweight 11-year-old child infected with an MDR HIV strain.

Corrigendum to "Dolutegravir-based antiretroviral therapy in a severely overweight child with a multi-drug resistant human immunodeficiency virus infection. A case report and review" [New Microbes New Infect] 6 (2015) 1-4].

[This corrects the article DOI: 10.1016/j.nmni.2015.02.003.].

Enterovirus and Parechovirus viraemia in young children presenting to the emergency room: Unrecognised and frequent.

BACKGROUND: Human Enterovirus (EV) and Parechovirus (HPeV) are well recognised as agents causing disease in neonates, but their importance is poorly described in the general paediatric population consulting with a suspicion of infection. OBJECTIVE: We investigated the prevalence of EV- or HPeV-associated infections in children presenting to a paediatric emergency department with a suspicion of infection. STUDY DESIGN: Plasma specimens collected in our paediatric emergency room for clinical reasons were screened by specific real-time RT-PCR for the presence of EV and HPeV. RESULTS: Based on an analyses of 233 plasma specimens, up to 6.9% and 2.6% were positive for EV and HPeV, respectively. Amongst the population <3y.o, prevalence of EV and HPeV viraemia was 11% and 3.7%, respectively. Importantly, 56.3% of positive EV specimens were detected in infants >3 months of age. CONCLUSION: The prevalence of EV and HPeV viraemia in children <3 years old is largely underestimated. Our results confirm that EV should be suspected and included in the work-up in children >3 months of age and not restricted to neonates.