Jessica Darenberg

Molecular and clinical characteristics of invasive group A streptococcal infection in Sweden

BACKGROUND The incidence and severity of invasive group A streptococcal infection demonstrate great variability over time, which at least, in part, seems to be related to group A streptococcal type distribution among the human population. METHODS An enhanced surveillance study of invasive group A streptococcal infection (746 isolates) was performed in Sweden from April 2002 through December 2004. Noninvasive isolates from either the throat or skin (773 isolates) were collected in parallel for comparison. Clinical and epidemiological data were obtained from 88% of patients with invasive disease and were related to isolate characteristics, including T type, emm sequence type, and the presence of 9 superantigen genes, as well as pulsed-field gel electrophoresis pattern comparisons of selected isolates. RESULTS The annual incidence was 3.0 cases per 100,000 population. Among the patients with invasive disease, 11% developed streptococcal toxic shock syndrome, and 9.5% developed necrotizing fasciitis. The overall case-fatality rate was 14.5%, and 39% of the patients with streptococcal toxic shock syndrome died (P<.001). The T3/13/B3264 cluster accounted for 33% of invasive and 25% of noninvasive isolates. Among this most prevalent type cluster, emm types 89 and 81 dominated. Combined results from pulsed-field gel electrophoresis, emm typing, and superantigen gene profiling identified subgroups within specific emm types that are significantly more prone to cause invasive disease than were other isolates of the same type. CONCLUSIONS This study revealed a changing epidemiology of invasive group A streptococcal infection in Sweden, with emergence of new emm types that were previously not described. The results also suggest that some clones may be particularly prone to cause invasive disease.

Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome – a comparative observational study

BACKGROUND Streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis are the 2 most severe invasive manifestations caused by group A Streptococcus (GAS). Intravenous immunoglobulin (IVIG) therapy has been suggested as adjunctive treatment with a beneficial effect on mortality. However the clinical evidence is limited. Here we aim to further document the clinical efficacy of administered IVIG therapy in a comparative observational study of well-defined patients with STSS. METHODS The effect of IVIG was evaluated in patients with STSS prospectively identified in a nationwide Swedish surveillance study conducted between April 2002 and December 2004. Detailed data on symptoms, severity of disease, treatment, and outcome were obtained from 67 patients. Crude and adjusted analyses with logistic regression were performed. RESULTS Twenty-three patients received IVIG therapy compared with 44 who did not. No significant difference in comorbidities, severity of disease, organ failures, or sex was seen, but the IVIG group was slightly younger and had a higher degree of necrotizing fasciitis (56% vs 14%). The primary endpoint was 28-day survival. Adjusted analysis revealed that factors influencing survival in STSS were Simplified Acute Physiology Score II (odds ratio [OR], 1.1; P = .007), clindamycin (OR, 8.6; P = .007), and IVIG (OR, 5.6; P = .030). CONCLUSIONS This comparative observational study of prospectively identified STSS patients demonstrates that both IVIG and clindamycin therapy contribute to a significantly improved survival in STSS.

Soluble M1 protein of Streptococcus pyogenes triggers potent T cell activation

Streptococcus pyogenes of the M1 serotype is commonly associated with large outbreaks of invasive streptococcal infections and development of streptococcal toxic shock syndrome (STSS). The pathogenesis behind these infections is believed to involve bacterial superantigens that induce potent inflammatory responses, but the reason why strains of the M1 serotype are over‐represented in STSS is still not understood. In the present investigation, we show that a highly purified soluble form of the M1 protein from S. pyogenes, which lacks the membrane‐spanning region, is a potent inducer of T cell proliferation and release of Th1 type cytokines. M1 protein‐evoked T cell proliferation was HLA class II‐dependent but not MHC‐restricted, did not require intracellular processing and was Vβ‐restricted. Extensive mass spectrometry studies indicated that there were no other detectable proteins in the preparation. Taken together, our data demonstrate that soluble M1 protein is a novel streptococcal superantigen, which likely contributes to the excessive T cell activation and hyperinflammatory response seen in severe invasive streptococcal infections.

Effects of PCV7 and PCV13 on invasive pneumococcal disease and carriage in Stockholm, Sweden.

The effects of pneumococcal conjugated vaccines (PCVs) need to be investigated. In Stockholm County, Sweden, PCV7 was introduced in the childhood immunisation programme in 2007 and changed to PCV13 in 2010. Over 90% of all invasive isolates during 2005–2014 (n=2336) and carriage isolates, 260 before and 647 after vaccine introduction, were characterised by serotyping, molecular typing and antibiotic susceptibility, and serotype diversity was calculated. Clinical information was collected for children and adults with invasive pneumococcal disease (IPD). The IPD incidence decreased post-PCV7, but not post-PCV13, in vaccinated children. Beneficial herd effects were seen in older children and adults, but not in the elderly. The herd protection was more pronounced post-PCV7 than post-PCV13. PCV7 serotypes decreased. IPD caused by PCV13 serotypes 3 and 19A increased post-PCV7. Post-PCV13, serotypes 6A and 19A, but not serotype 3, decreased. The serotype distribution changed in carriage and IPD to nonvaccine types, also in nonvaccinated populations. Expansion of non-PCV13 serotypes was largest following PCV13 introduction. Serotype diversity increased and nonvaccine clones emerged, such as CC433 (serotype 22F) in IPD and CC62 (serotype 11A) in carriage. In young children, meningitis, septicaemia and severe rhinosinusitis, but not bacteraemic pneumonia, decreased. Pneumococcal vaccination leads to expansion of new or minor serotypes/clones, also in nonvaccinated populations. New or minor serotypes/clones expanded, also in nonvaccinated populations, affecting future vaccine strategies http://ow.ly/VA9EO

Clinical manifestations of invasive pneumococcal disease by vaccine and non-vaccine types.

Pneumococcal conjugated vaccines (PCVs) have shown protection against invasive pneumococcal disease by vaccine serotypes, but an increase in non-vaccine serotype disease has been observed. Type-specific effects on clinical manifestation need to be explored. Clinical data from 2096 adults and 192 children with invasive pneumococcal disease were correlated to pneumococcal molecular serotypes. Invasive disease potential for pneumococcal serotypes were calculated using 165 invasive and 550 carriage isolates from children. The invasive disease potential was lower for non-PCV13 compared to vaccine-type strains. Patients infected with non-PCV13 strains had more underlying diseases, were less likely to have pneumonia and, in adults, tended to have a higher mortality. Furthermore, patients infected with pneumococci belonging to clonal serotypes only expressing non-PCV13 capsules had a higher risk for septicaemia and mortality. PCV vaccination will probably lead to a decrease in invasive pneumococcal disease but an alteration in the clinical manifestation of invasive pneumococcal disease. Genetic lineages causing invasive pneumococcal disease in adults often express non-vaccine serotypes, which can expand after vaccination with an increased risk of infection in patients with underlying diseases. Pneumococcal non-vaccine type strains cause severe disease, but with different spectrums of clinical manifestations http://ow.ly/ABYnz

Comparison of the Impact of Pneumococcal Conjugate Vaccine 10 or Pneumococcal Conjugate Vaccine 13 on Invasive Pneumococcal Disease in Equivalent Populations

Abstract Background Pneumococccal conjugated pneumococcal vaccine (PCV10) and pneumococcal conjugate vaccine 13 (PCV13), are used in childhood immunization programs worldwide, but direct comparisons of impacts against invasive pneumococcal disease (IPD) in equivalent populations have not been performed. We compared the vaccines (prevaccination 2007–2009 vs postvaccination 2013–2016) in Sweden, where the 21 counties use either PCV10 or PCV13 (introduced 2009–2010). Methods All IPD episodes (n = 16992) were recorded in Sweden during 2005–2016. Of 14186 from 2007–2016, 13468 (94.9%) were characterized with serotyping and 12235 (86.2%) with antibiotic susceptibility. Poisson models assessed changes in incidence over time. Results Invasive pneumococcal disease incidences decreased between 2005 and 2016 in vaccinated children (by 68.5%), and in the whole population (by 13.5%), but not among the elderly (increased by 2%), due to a substantial increase of non-vaccine types (NVTs). In 2016, NVTs constituted 72% of IPD cases in the elderly. Serotype 6A declined in PCV10 and PCV13 counties, whereas serotype 19A increased in PCV10 counties. There was no effect against serotype 3. Cross-protection was found between 6B and 6A, but not between 19F and 19A. Serotype 6C increased in PCV10 counties, but not in PCV13 counties, suggesting cross-protection with 6A, which is included in PCV13. In the elderly, the increase of NVTs excluding 6C, was more pronounced in PCV13 counties. Conclusions The overall impact of IPD incidences was not statistically different irrespective of vaccine used. The incidence of serotypes, where the effect of the vaccines differed, will influence the cost-effectiveness of which vaccine to use in immunization programs. The dominance of NVTs suggests a limited effect of current pediatric PCVs against IPD in the elderly.

Increased incidence of invasive group A streptococcal infections in Sweden, January 2012-February 2013.

The incidence of invasive group A streptococcal infections in Sweden was 6.1 per 100,000 population in 2012, the highest since the disease became notifiable in 2004. Furthermore, January and February 2013 marked a dramatic increase of cases notified, partly explainable by an increase of emm1/T1 isolates, a type previously shown to cause severe invasive disease more often than other types. Healthcare providers in Sweden and health authorities in neighbouring countries have been informed about this increase.

Pneumococcal Carriage in Children under Five Years in Uganda-Will Present Pneumococcal Conjugate Vaccines Be Appropriate?

Background Pneumonia is the major cause of death in children globally, with more than 900,000 deaths annually in children under five years of age. Streptococcus pneumoniae causes most deaths, most often in the form of community acquired pneumonia. Pneumococcal conjugate vaccines (PCVs) are currently being implemented in many low-income countries. PCVs decrease vaccine-type pneumococcal carriage, a prerequisite for invasive pneumococcal disease, and thereby affects pneumococcal disease and transmission. In Uganda, PCV was launched in 2014, but baseline data is lacking for pneumococcal serotypes in carriage. Objectives To study pneumococcal nasopharyngeal carriage and serotype distribution in children under 5 years of age prior to PCV introduction in Uganda Methods Three cross-sectional pneumococcal carriage surveys were conducted in 2008, 2009 and 2011, comprising respectively 150, 587 and 1024 randomly selected children aged less than five years from the Iganga/Mayuge Health and Demographic Surveillance Site. The caretakers were interviewed about illness history of the child and 1723 nasopharyngeal specimens were collected. From these, 927 isolates of S. pneumoniae were serotyped. Results Overall, the carriage rate of S. pneumoniae was 56% (957/1723). Pneumococcal carriage was associated with illness on the day of the interview (OR = 1.50, p = 0.04). The most common pneumococcal serotypes were in descending order 19F (16%), 23F (9%), 6A (8%), 29 (7%) and 6B (7%). One percent of the strains were non-typeable. The potential serotype coverage rate for PCV10 was 42% and 54% for PCV13. Conclusion About half of circulating pneumococcal serotypes in carriage in the Ugandan under-five population studied was covered by available PCVs.

Reply to Arends and Harkisoen

To the Editor—We thank Arends and Harkisoen [1] for their thoughtful comments relating to our article on the efficacy of polyspecific intravenous immunoglobulin (IVIG) in streptococcal toxic shock syndrome (STSS). As detailed in our article [2], 75 STSS patients were identified through a national Swedish active surveillance study of invasive group A streptococcal (GAS) infections, in which a total of 746 invasive cases were included [3]. The study was designed to focus entirely on STSS cases and not on the heterogeneous group of patients with invasive (GAS) infections, the rationale being that IVIG has been suggested as adjunctive therapy in STSS with a beneficial effect on survival in these patients with pronounced systemic toxicity. The mortality often exceeds 40% in STSS cases compared with <15% for invasive cases. Among the 746 invasive GAS cases, 26 patients in total received IVIG, and as expected, the vast majority had an STSS diagnosis (n = 23). The question of whether the timing of IVIG administration differed between STSS patients with or without necrotizing fasciitis (NF) and therefore could be a confounder influencing mortality is a valid concern. The reported timing of IVIG administration in patients with or without NF showed that the majority of patients received IVIG within 24 hours after their STSS diagnosis (Table ​(Table1).1). However, as we acknowledge in the article, presence of NF might lead to a more rapid diagnosis and consequently a more rapid aggressive therapy including also IVIG. Table 1. Timing of Intravenous Immunoglobulin Administration in Patients With Streptococcal Toxic Shock Syndrome In the article, we discuss the fact that although the IVIG and non-IVIG groups were well matched with respect to several baseline characteristics, including among others the Simplified Acute Physiology Score (SAPS II), they did differ significantly with respect to age (60 vs 65 years), presence of NF (56.5% vs 13.6%), and erysipelas (4.3% vs 34.1%). As Arends and Harkisoen point out, the data also show some differences, albeit nonsignificant, in underlying conditions. However, the number of patients affected by specific underlying conditions was too small to allow for further statistical analyses. In addition, the SAPS II score, in which some chronic underlying conditions such as metastatic cancer, hematological malignancy, and AIDS are represented, was included in the analytical plan as a possible confounder. Even when clindamycin treatment, surgery, and SAPS II scores were taken into account, IVIG remained a significant factor for survival with an odds ratio of 5.6.