Invasive Group A Streptococcal Infections: Benefit of Clindamycin, Intravenous Immunoglobulins and Secondary Prophylaxis.

Introduction: Mortality associated with invasive group A streptococcal infections (iGAS) remains high among adults, with lower mortality in children. The added value of both clindamycin and immunoglobulins in such treatment is still controversial, as is the need for antibiotic secondary prophylaxis. It is unlikely that conclusive randomized clinical studies will ever definitively end these controversies. Materials and Methods: A clinical and experimental literature review was conducted in Pubmed, Cochrane, and lay literature to determine the benefit of adding clindamycin and immunoglobulins to ß-lactams in the management of iGAS, as well as the need for secondary prophylaxis measures in close contacts. Results: This review includes two meta-analyses, two randomized controlled trials, four prospective studies, five retrospective studies, and microbiological studies. To reduce mortality and morbidity, it appears useful to add clindamycin to ß-lactams in severe clinical presentations, including necrotizing fasciitis or streptococcal toxic shock syndrome, and immunoglobulins for the latter two presentations. The high risk of secondary infection in household contacts justifies the need of taking preventive measures. Conclusions: Both clinical studies and available experimental evidence suggest that adding clindamycin and immunoglobulins as adjunctive therapies in the management of invasive group A streptococcal infections may reduce mortality. Household contacts should be warned about the increased risk of secondary infection, and chemoprophylaxis may be considered in certain situations.

Challenges and Issues of Anti-SARS-CoV-2 Vaccines.

At the beginning of 2021, anti-SARS-CoV-2 vaccination campaigns had been launched in almost 60 countries with more than 500 million doses having been distributed. In addition to the few vaccines already in use, many other candidates are in preclinical phases or experimental stages in humans. Despite the fact that the availability of anti-SARS-CoV-2 vaccine constitutes a major advance and appear to be the only way to control the pandemic, some investigation remains to be carried out, and this is notably concerning the impact on transmissibility, the duration of the conferred protection in the mid- and long term, the effectiveness against present and future viral mutants, or the ideal schedule that should be applied. In this paper, we review the circumstances that facilitated such a rapid development of anti-SARS-CoV-2 vaccines and summarize the different vaccine platforms under investigation as well as their present results and perspectives in different settings. We also discuss the indications of vaccination under special conditions, such as a history of previous COVID-19 infection or belonging to extreme age categories like children and elderly. Overall, this review highlights the multiple challenges to face if aiming to find a global solution to the pandemic through high vaccination coverage all over the world.

Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study.

BACKGROUND: Ten-valent and 13-valent pneumococcal conjugate vaccines (PCVs) have shown important benefits by decreasing invasive pneumococcal disease caused by vaccine serotypes. Belgium had an uncommon situation with sequential use of PCV7, PCV13, and PCV10 in the childhood vaccination programmes between 2007 and 2018. We aimed to analyse the changes in incidence of invasive pneumococcal disease and serotype distribution in children throughout this period. METHODS: Streptococcus pneumoniae isolates were obtained from patients with invasive pneumococcal disease in Belgium between 2007 and 2018 by the national laboratory-based surveillance. Paediatric invasive pneumococcal disease incidence, serotype distribution, and antimicrobial susceptibility were analysed in periods during which PCV7 (2009-10), PCV13 (2013-14), both PCV13 and PCV10 (2015-16), and PCV10 (2017-18) were used. Incidence rates and trends were compared. Vaccination status was collected. For a subset of serotype 19A isolates, multilocus sequence type was identified. FINDINGS: After a decrease in PCV7 serotype invasive pneumococcal disease was observed during the PCV7 period, total paediatric invasive pneumococcal disease incidence significantly declined during the PCV13 period (-2·6% monthly, p<0·0001). During the PCV13-PCV10 period (2015-16), the lowest mean in paediatric invasive pneumococcal disease incidence was achieved, but the incidence increased again during the PCV10 period (2017-18), especially in children younger than 2 years (+1·7% monthly; p=0·028). This increase was mainly due to a significant rise in serotype 19A invasive pneumococcal disease incidence in the PCV10 period compared with the PCV13 period (p<0·0001), making serotype 19A the predominant serotype in paediatric invasive pneumococcal disease in the PCV10 period. Genetic diversity within the 2017-18 serotype 19A collection was seen, with two predominant clones, ST416 and ST994, that were infrequently observed before PCV10 introduction. In 2018, among children younger than 5 years with invasive pneumococcal disease who were correctly vaccinated, 37% (37 of 100) had PCV13 serotype invasive pneumococcal disease, all caused by serotype 19A and serotype 3. INTERPRETATION: After a significant decrease during the PCV13 period, paediatric invasive pneumococcal disease incidence increased again during the PCV10 period. This observation mainly resulted from a significant increase of serotype 19A cases. During the PCV10 period, dominant serotype 19A clones differed from those detected during previous vaccine periods. Whether changes in epidemiology resulted from the vaccine switch or also from natural evolution remains to be further elucidated. FUNDING: The Belgian National Reference is funded by the Belgian National Institute for Health and Disability Insurance and the whole genome sequencing by an investigator-initiated research grant from Pfizer.

Management of varicella in neonates and infants.

In countries where vaccination is not implemented, varicella is a common ubiquitous disease offering a broad range of clinical presentations. Whereas mother-to-child perinatal transmission of varicella zoster virus (VZV) can lead to disseminated life-threatening diseases in unimmunised newborns, postnatal acquisition will be generally a source of milder infections. The pattern and severity of the disease are known to be partly determined by the timing of VZV acquisition during pregnancy with the highest risk period located around delivery. Management of youngest children after contact with a varicella case remains difficult for clinicians not only because of unawareness of varicella natural history and risks factors for serious complications, but also because of the lack of consensus from experts available in the literature. This state of uncertainty often leads to overconsumption of healthcare resources with systematic hospitalisation and unjustified antiviral intravenous therapies. After a concise literature review, this article proposes pragmatic recommendations considering newborns in various scenarios following a contact with VZV, taking into account the timing and mode of virus transmission, the maternal immunological status, the baby's gestational age and the presence of other underlying conditions.

Prospective Cohort Study Investigating the Safety and Efficacy of Ambulatory Treatment With Oral Cefuroxime-Axetil in Febrile Children With Urinary Tract Infection.

Aims: To assess the safety and efficacy of ambulatory oral cefuroxime-axetil treatment in children presenting with first febrile urinary tract infection (UTI) in terms of resolution of fever, antibiotics tolerance, bacterial resistance, and loss to ambulatory follow-up. Methods: Two-year prospective single-center evaluation of the local protocol of oral ambulatory treatment of children presenting first febrile urinary tract infection (UTI). Results: From October 2013 to October 2015, 82 children were treated ambulatory with oral cefuroxime-axetil. The median age was 8 months. When analyzing those 82 children treated orally, 51 (62%) completed oral treatment, 14 (17%) missed their scheduled follow-up visits (3 patients at day 2 and 11 patients at week 2), and 17 (21%) were switched to IV therapy for the following reasons: vomiting in 9, persistent fever in 5, antibiotic resistance in 2 and bacteremia in 1. Six children (8%) presented recurrent UTI after a median of 5 months of follow-up. Conclusions: This 2-year evaluation suggests that oral treatment with cefuroxime-axetil in febrile UTI is feasible but should be implemented with caution. Home-treated children require reevaluation during treatment since 21% of our cohort had to be temporarily switched to parenteral therapy and 17% did not attend scheduled follow-up visits during oral treatment.

Varicella paediatric hospitalisations in Belgium: a 1-year national survey.

BACKGROUND: Varicella universal vaccination (UV) has been implemented in many countries for several years. Nevertheless, varicella UV remains debated in Europe and few data are available on the real burden of infection. We assessed the burden of varicella in Belgium through analysis of hospitalised cases during a 1-year period. METHODS: Data on children admitted to hospital with varicella were collected through a national network from November 2011 to October 2012. Inclusion criteria were either acute varicella or related complications up to 3 weeks after the rash. RESULTS: Participation of 101 hospitals was obtained, covering 97.7% of the total paediatric beds in Belgium. 552 children were included with a median age of 2.1 years. Incidence of paediatric varicella hospitalisations reached 29.5/10(5) person-years, with the highest impact among those 0-4 years old (global incidence and odds of hospitalisation: 79/10(5) person-years and 1.6/100 varicella cases, respectively). Only 14% (79/552) of the cohort had an underlying chronic condition. 65% (357/552) of children had ≥1 complication justifying their admission, 49% were bacterial superinfections and 10% neurological disorders. Only a quarter of children (141/552) received acyclovir. Incidence of complicated hospitalised cases was 19/10(5) person-years. Paediatric intensive care unit admission and surgery were required in 4% and 3% of hospitalised cases, respectively. Mortality among Belgian paediatric population was 0.5/10(6) and fatality ratio 0.2% among our cohort. CONCLUSIONS: Varicella demonstrated a substantial burden of disease in Belgian children, especially among the youngest. Our thorough nationwide study, run in a country without varicella UV, offers data to support varicella UV in Belgium.

Virulence Factors of Streptococcus pneumoniae. Comparison between African and French Invasive Isolates and Implication for Future Vaccines.

BACKGROUND: Many surface proteins thought to promote Streptocococcus pneumoniae virulence have recently been discovered and are currently being considered as future vaccine targets. We assessed the prevalence of 16 virulence genes among 435 S. pneumoniae invasive isolates from France and the "African meningitis belt" region, with particular focus on serotype 1 (Sp1), to compare their geographical distribution, assess their association with site of infection and evaluate their potential interest as new vaccine candidates. METHODS: Detection by PCR of pspA (+families), pspC (+pspC.4), pavA, lytA, phtA,B,D,E, nanA,B,C, rrgA (Pilus-1), sipA (Pilus-2), pcpA and psrp was performed on all isolates, as well as antibiotic resistance testing and MLVA typing (+MLST on 54 representative strains). Determination of ply alleles was performed by sequencing (Sp1 isolates). RESULTS: MLVA and virulence genes profiles segregated Sp1 isolates into 2 groups that followed continent distribution. The ply allele 5 and most of the genes that were variable (nanC, Pilus-2, psrp, pcpA, phtD) were present in the French Sp1 isolates (PMEN clone Sweden(1)-28, ST306) but absent from the African ones. Whereas all African Sp1 isolates clustered into a single MLST CC (CC217), MLVA distinguished two CCs that followed temporal evolution. Pilus-2 and psrp were more prevalent in bacteraemic pneumonia yielded isolates and phtB in meningitis-related isolates. Considering vaccine candidates, phtD was less prevalent than anticipated (50%) and pcpA varied importantly between France and Africa (98% versus 34%). Pilus-1 was carried by 7-11% of isolates and associated with ß-lactams resistance. CONCLUSIONS: Most virulence genes were carried by the European ST306 clone but were lacking on Sp1 isolates circulating in the African meningitis belt, where a more serious pattern of infection is observed. While virulence proteins are now considered as vaccine targets, the geographical differences in their prevalence could affect the efficacy expected from future vaccines.

The ABC of pneumococcal infections and vaccination in patients with chronic kidney disease.

BACKGROUND: In the general population, pneumococcal polysaccharide vaccines (PPV) decrease the incidence of invasive pneumococcal disease (IPD) whereas the impact on the prevention of noninvasive pneumococcal disease is less clear. As compared with PPV, pneumococcal conjugate vaccines (PCV) provoke a higher, longer-lasting immune response resulting in a 45% decreased incidence in vaccine-type pneumonia, and a 75% decrease in vaccine-type IPD. METHODS: Literature review on pneumococcal vaccination in end-stage renal disease. RESULTS: As compared with the general population, patients with chronic kidney disease (CKD) suffer increased mortality and morbidity from pneumococcal disease (PD), being up to 10-fold for those treated with dialysis. Numerous, usually small and methodological heterogeneous studies demonstrate that PPV provokes a serological response in dialysis patients, kidney transplant recipients, children with nephrotic syndrome and CKD patients receiving immunosuppressive medication. This response is of less intensity and duration than in healthy controls. Similar observations were made for the PCV. The protective value of these vaccine-elicited anti-pneumococcal antibodies in the CKD population remains to be substantiated. For patients treated with dialysis, epidemiological data demonstrate a correlation-which does not equal causality-between pneumococcal vaccination status and a slightly decreased total mortality. Clinical outcome data on the effectiveness of pneumococcal vaccination in the prevention of morbidity and mortality in the CKD population are lacking. CONCLUSIONS: Awaiting better evidence, pneumococcal vaccination should be advocated in all patients with CKD, as early in their disease course as possible. The ACIP schedule recommends a PCV-13 prime vaccination followed by a PPV-23 repeated vaccine at least 8 weeks later in pneumococcal non-vaccinated patients, and a PCV-13 vaccine at least 1 year after the latest PPV vaccine in previously vaccinated patients. In the UK, vaccination with PPV-23 only is recommended. There exist no good data supporting re-vaccination after 5 years in the dialysis population.

HIV transmission through breastfeeding: still possible in developed countries.

We describe here the case of a 13-month-old boy who acquired HIV infection postnatally through breastfeeding in a developed country in 2012. His mother had regular pregnancy follow-up and was found to be seronegative for HIV on 2 consecutive screening tests (during pregnancy and just after delivery). However, 1 year later, diagnosis of HIV infection arose in both of them after a pediatric emergency department visit for bronchitis when unexplained hepatosplenomegaly and inflammatory syndrome were noted. The negative maternal viral load found just after delivery confirmed that the mother's seroconversion occurred postnatally, which allowed for active HIV transmission during lactation and lack of the efficient preventive measures that have implemented in Belgium for years. We discuss this uncommon but still existing mode of HIV transmission in industrialized countries and highlight the importance of implementing new targeted health education interventions in addition to constant clinicians' awareness.

[Chronic granulomatous disease: pathogenesis and therapy of associated fungal infections]. / Infections fongiques et granulomatose septique chronique - De la physiopathologie aux nouvelles perspectives thérapeutiques.

Chronic granulomatous disease is a genetic disorder responsible for a defect in the NADPH oxidase of phagocytic cells. It impairs the oxidative burst necessary to the intracellular inactivation of microorganisms and predisposes to an increased risk of infections by various microorganisms, including fungi like Aspergillus spp. and other less frequently encountered or emerging fungal species. Here we review the genetic basis, pathogenesis and clinical presentation associated with fungal infections in chronic granulomatous disease as well as the current prophylaxis and newly available therapies.

Pandemic A/H1N1v influenza 2009 in hospitalized children: a multicenter Belgian survey.

BACKGROUND: During the 2009 influenza A/H1N1v pandemic, children were identified as a specific "at risk" group. We conducted a multicentric study to describe pattern of influenza A/H1N1v infection among hospitalized children in Brussels, Belgium. METHODS: From July 1, 2009, to January 31, 2010, we collected epidemiological and clinical data of all proven (positive H1N1v PCR) and probable (positive influenza A antigen or culture) pediatric cases of influenza A/H1N1v infections, hospitalized in four tertiary centers. RESULTS: During the epidemic period, an excess of 18% of pediatric outpatients and emergency department visits was registered. 215 children were hospitalized with proven/probable influenza A/H1N1v infection. Median age was 31 months. 47% had ≥ 1 comorbid conditions. Febrile respiratory illness was the most common presentation. 36% presented with initial gastrointestinal symptoms and 10% with neurological manifestations. 34% had pneumonia. Only 24% of the patients received oseltamivir but 57% received antibiotics. 10% of children were admitted to PICU, seven of whom with ARDS. Case fatality-rate was 5/215 (2%), concerning only children suffering from chronic neurological disorders. Children over 2 years of age showed a higher propensity to be admitted to PICU (16% vs 1%, p = 0.002) and a higher mortality rate (4% vs 0%, p = 0.06). Infants less than 3 months old showed a milder course of infection, with few respiratory and neurological complications. CONCLUSION: Although influenza A/H1N1v infections were generally self-limited, pediatric burden of disease was significant. Compared to other countries experiencing different health care systems, our Belgian cohort was younger and received less frequently antiviral therapy; disease course and mortality were however similar.

Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey.

BACKGROUND: Invasive fungal infection (IFI) represents a life-threatening condition for patients with chronic granulomatous disease (CGD) and causes one-third of deaths in this population. This study offers a descriptive review of invasive mold infection (mIFI) in children with CGD over an extended period of time. METHODS: In a cohort of patients with CGD registered in the French National database for Primary Immunodeficiency, we performed a retrospective review of proven mIFI episodes (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group 2008 criteria) occurring from 1984 through 2009. RESULTS: Twenty-nine proven mIFIs were identified in 24 patients. Thirteen (54%) of 24 children were receiving itraconazole prophylaxis. Seven episodes were caused by Aspergillus fumigatus, 10 by Aspergillus nidulans, 2 by Aspergillus species, and 6 by other opportunistic molds (4 patients only had positive pathological examination findings). First proven mIFI occurred later in the group that received itraconazole than in the group without (median time to mIFI, 10 vs 4 years; P < .01), with a higher proportion of infections due to A. nidulans and other opportunistic molds (P < .05). Course of IFI was complex, with the median duration of therapy and hospitalization reaching 446 and 153 days, respectively. Combined antifungal therapy was commonly used. Four patients received geno-identical hematopoietic stem cell transplantation as salvage therapy. Global cure rate among the cohort reached 75%, but sequelae were frequent. Prognosis has improved over time (43% mortality during 1985-1990 vs 6% thereafter; P = .06). Mortality tended to be lower in the group that recieved itraconazole prophylaxis but at the cost of a longer duration of therapy among cured patients. CONCLUSIONS: Management of mIFI remains challenging in patients with CGD, but significant improvements have been made over the past decade.

Enteroviral infection of a cardiac prosthetic device.

BACKGROUND: Identification of the causative pathogen may be challenging in culture negative infective endocarditis (IE). METHODS: A 4 month-old 21-trisomic boy with congenital atrioventricular septal defect presented 3 episodes of dehiscence of his prosthetic patch, attributed to IE. He presented heart failure, but neither fever, nor inflammatory syndrome. RESULTS: Surgical and histopathological findings confirmed the diagnosis of IE, but blood cultures remained sterile. Extensive work up failed to demonstrate bacterial or fungal etiology. Coxsackie B2 virus was cultured from the excised patch, nasopharyngeal secretions and stools. CONCLUSIONS: Viral IE has only been described in animal models. This case is the first reported probable human viral IE. We suggest that a viral etiology should be considered in case of culture negative IE.