Symptoms predictive of Fusobacterium necrophorum pharyngotonsillitis - an observational study of cases presenting to hospitals in Southern Sweden.

OBJECTIVES: Fusobacterium necrophorum is a common cause of pharyngotonsillitis. However, no guidelines exist on when to diagnose or treat it. We aimed to investigate associations between clinical criteria and F. necrophorum-positivity in pharyngotonsillitis and assess the predictive potential of a simple scoring system. METHODS: Pharyngotonsillitis patients who were tested for F. necrophorum (PCR) and presented to hospitals in the Skåne Region, Sweden, between 2013-2020 were eligible. Data were retrieved from electronic chart reviews and registries. By logistic regression we investigated associations between F. necrophorum-positivity and pre-specified criteria: age 13-30 years, symptom duration ≤ 3 days, absence of viral symptoms (e.g. cough, coryza), fever, tonsillar swelling/exudate, lymphadenopathy and CRP ≥ 50 mg/L. In secondary analyses, associated variables were weighted by strength of association into a score and its predictive accuracy of F. necrophorum was assessed. RESULTS: Among 561 cases included, 184 (33%) had F. necrophorum, which was associated with the following criteria: age 13-30, symptom duration ≤ 3 days, absence of viral symptoms, tonsillar swelling/exudate and CRP ≥ 50 mg/L. Age 13-30 had the strongest association (OR5.7 95%CI 3.7-8.8). After weighting, these five variables had a sensitivity and specificity of 68% and 71% respectively to predict F. necrophorum-positivity at the proposed cut-off. CONCLUSION: Our results suggest that F. necrophorum cases presenting to hospitals might be better distinguished from other pharyngotonsillitis cases by a simple scoring system presented, with age 13-30 being the strongest predictor for F. necrophorum. Prospective studies, involving primary care settings, are needed to evaluate generalisability of findings beyond cases presenting to hospitals.

Low usefulness of reporting tonsillar PCR Ct-values in pharyngeal infections with Fusobacterium necrophorum.

Tonsillar Fusobacterium necrophorum PCR Ct-values were higher in participants with asymptomatic tonsillar carriage than patients with pharyngeal infections. However, Ct-values were not associated with severity of disease or predictive of development of complications and hence lacked clinical usefulness. The reporting of F. necrophorum Ct-values in clinical samples is not recommended.

Associations Between Findings of Fusobacterium necrophorum or ß-Hemolytic Streptococci and Complications in Pharyngotonsillitis-A Registry-Based Study in Southern Sweden.

BACKGROUND: Most pharyngotonsillitis guidelines focus on the identification of group A streptococci (GAS), guided by clinical scores determining whom to test with a rapid antigen detection test. Nevertheless, many patients testing negative with this test are evaluated for group C/G streptococci (GCS/GGS) and Fusobacterium necrophorum, yet their importance remains debated. Our primary aim was to evaluate associations between complications and findings of F. necrophorum, GAS, or GCS/GGS in pharyngotonsillitis. METHODS: This was a retrospective, registry-based study of pharyngotonsillitis cases tested for F. necrophorum (polymerase chain reaction) and ß-hemolytic streptococci (culture) in the Skåne Region, Sweden, in 2013-2020. Patients with prior complications or antibiotics (within 30 days) were excluded. Data were retrieved from registries and electronic charts. Logistic regression analyses were performed with a dichotomous composite outcome of complications as primary outcome, based on International Classification of Diseases, Tenth Revision, codes. Cases with negative results (polymerase chain reaction and culture) were set as reference category. Complications within 30 days were defined as peritonsillar or pharyngeal abscess, otitis, sinusitis, sepsis or septic complications, recurrence of pharyngotonsillitis (after 15-30 days) or hospitalization. RESULTS: Of 3700 registered cases, 28% had F. necrophorum, 13% had GCS/GGS, 10% had GAS, and 54% had negative results. The 30-day complication rates were high (20%). F. necrophorum (odds ratio, 1.8; 95% confidence interval, 1.5-2.1) and GAS (1.9; 1.5-2.5) were positively associated with complications, whereas GCS/GGS were negatively associated (0.7; 0.4-0.98). CONCLUSIONS: Our results indicate that F. necrophorum is a relevant pathogen in pharyngotonsillitis, whereas the relevance of testing for GCS/GGS is questioned. However, which patient to test and treat for F. necrophorum remains to be defined.

Incidence, aetiology and temporal trend of bloodstream infections in southern Sweden from 2006 to 2019: a population-based study.

BackgroundBloodstream infections (BSI) are a public health concern, and infections caused by resistant bacteria further increase the overall BSI burden on healthcare.AimTo provide a population-based estimate of BSI incidence and relate this to the forthcoming demographic ageing western population change.MethodsWe retrieved positive blood cultures taken from patients in the Skåne region, southern Sweden, 2006-2019 from the Clinical Microbiology Department database and estimated incidence rates (IR), stratified by age (0-49, 50-64, 65-79, ≥ 80 years), sex, year, and species and described antimicrobial susceptibility for Enterobacterales.ResultsWe identified 944,375 blood culture sets, and 129,274 (13.7%) were positive. After deduplication and removal of contaminants, 54,498 separate BSI episodes remained. In total, 30,003 BSI episodes (55%) occurred in men. The overall IR of BSI was 307/100,000 person-years, with an average annual increase of 3.0%. Persons ≥ 80 years had the highest IR, 1781/100,000 person-years, as well as the largest increase. Escherichia coli (27%) and Staphylococcus aureus (13%) were the most frequent findings. The proportion of Enterobacterales isolates resistant to fluoroquinolones and third generation cephalosporins increased from 8.4% to 13.6%, and 4.9% to 7.3%, (p for trend < 0.001), with the largest increase in the oldest age group.ConclusionWe report among the highest BSI IRs to date worldwide, with a higher proportion among elderly persons and males, including resistant isolates. Given expected demographic changes, these results indicate a possible substantial future BSI burden, for which preventive measures are needed.

Epidemiology, aetiology and clinical characteristics of clostridial bacteraemia: a 6-year population-based observational study of 386 patients.

The objective of this study is to provide a population-based clinical, epidemiological and microbiological overview of clostridial bacteraemia. All cases of bacteraemia in the Skåne Region between 2014 and 2019 with a species currently belonging to the Clostridium genus were identified in the regional clinical microbiology database. Clinical data were retrieved by medical chart-review. A total of 386 unique episodes of clostridial bacteraemia were found resulting in an incidence rate of 4.9/100.000 person-years. The median age was 76 with 56% males. The incidence rate ratio was 34.3 for those aged 80 + vs 0-59. The minimum inhibitory concentrations varied between species but were universally low for metronidazole and carbapenems. Malignancy was the most common co-morbidity, in 47% of patients and most pronounced for C. septicum. Criteria for sepsis and septic shock were met in 69% and 17%, respectively. The 28-day mortality was 26%. High age, absence of fever, high C-reactive protein and high SOFA-score were all significantly associated with mortality. We present the highest incidence rate of clostridial bacteraemia to date. Clostridial bacteraemia is a severe condition with acute onset, affecting elderly with co-morbidities, most pronounced malignancies. Mortality is related to acute manifestations rather than to background factors.

Short blood culture time-to-positivity in Fusobacterium necrophorum bacteremia is associated with Lemierre's syndrome.

The usefulness of blood culture time-to-positivity (TTP) in the diagnosis of endovascular infections has previously been shown. Here, we investigated TTP in 41 patients with F. necrophorum bacteraemia and found an association between short TTP and Lemierre's syndrome (p = 0.026).

Geographical differences in tonsillar carriage rates of Fusobacterium necrophorum - A cross-sectional study in Sweden and Zambia.

While Fusobacterium necrophorum historically has been considered normal tonsillar flora, recent studies from Europe and the US have suggested that carriage occur transiently in adolescence and young adulthood. However, no studies originating from Africa exist. In this cross-sectional study of tonsillar carriage of F. necrophorum, we aimed to investigate geographical differences in tonsillar carriage rates of F. necrophorum in healthy participants aged 15-25 years in Sweden and Zambia and further investigate the age distribution of tonsillar carriage in Zambia. Specimens were obtained by tonsillar swabs and analyzed with real-time PCR for F. necrophorum. In participants aged 15-25 years, tonsillar carriage was more common in Sweden 21/100 (21%) than in Zambia 6/192 (3%), p < 0.001. In Zambian participants aged above 25 years tonsillar carriage was rare 1/76 (1%). In conclusion, the high rate of tonsillar carriage in participants aged 15-25 years in Sweden has implications on the interpretation of tonsillar findings in patients with pharyngotonsillitis. Interestingly, a geographical difference was found with tonsillar carriage rarely identified in Zambia.

Sublethal Lead Exposure Alters Movement Behavior in Free-Ranging Golden Eagles.

Lead poisoning of animals due to ingestion of fragments from lead-based ammunition in carcasses and offal of shot wildlife is acknowledged globally and raises great concerns about potential behavioral effects leading to increased mortality risks. Lead levels in blood were correlated with progress of the moose hunting season. Based on analyses of tracking data, we found that even sublethal lead concentrations in blood (25 ppb, wet weight), can likely negatively affect movement behavior (flight height and movement rate) of free-ranging scavenging Golden Eagles (Aquila chrysaetos). Lead levels in liver of recovered post-mortem analyzed eagles suggested that sublethal exposure increases the risk of mortality in eagles. Such adverse effects on animals are probably common worldwide and across species, where game hunting with lead-based ammunition is widespread. Our study highlights lead exposure as a considerably more serious threat to wildlife conservation than previously realized and suggests implementation of bans of lead ammunition for hunting.

Three variants of the leukotoxin gene in human isolates of Fusobacterium necrophorum subspecies funduliforme.

Leukotoxin is a well-known virulence factor of animal isolates of Fusobacterium necrophorum subspecies necrophorum, and is also expressed by animal isolates of subspecies funduliforme, whereas its presence in isolates from humans has not been fully established. In this study we found that the leukotoxin gene was present in all tested F. necrophorum isolates from humans. Three sequence variants were found, two of which have not been described previously. The sequence types correlated to source of infection. Further studies are needed to examine the role of the leukotoxin in human infections.

The role of Fusobacterium necrophorum in pharyngotonsillitis - A review.

Fusobacterium necrophorum is a gram-negative anaerobic bacterium that is the causative agent of the invasive disease Lemierre's syndrome. In addition, it is also associated with peritonsillar abscess formation and otitis media in small children. Recent research has shown that F. necrophorum may be involved in pharyngotonsillitis especially in adolescent and young adults and that it may be the second most common bacterial cause of pharyngotonsillitis after Streptococcus pyogenes (Group A streptococci). Peritonsillar abscesses and Lemierre's syndrome due to F. necrophorum are also found in this age group, suggesting that they may be complications of F. necrophorum pharyngotonsillitis. In this review we present the present knowledge about the role of F. necrophorum in pharyngotonsillitis with special emphasis on the age distribution. We argue that F. necrophorum is an important pathogen involved in pharyngotonsillitis in the age group of 13-40 years of age and we urge clinical microbiology labs to set up the appropriate techniques to be able to detect F. necrophorum from throat swabs.

Eubacterium bacteremia - a retrospective observational study of a seldom found anaerobic pathogen.

BACKGROUND: Human infections due to Eubacterium are rare and knowledge of the condition is limited. This study aimed to describe clinical characteristics and outcome in patients with Eubacterium bacteremia. METHODS: Episodes of Eubacterium bacteremia were identified through the clinical microbiology laboratory in Lund, Sweden. Medical records were retrospectively reviewed. Blood isolates of Eubacterium were collected and antibiotic susceptibility testing was performed with agar dilution. RESULTS: Seventeen patients with Eubacterium bacteremia were identified of whom six had monomicrobial bacteremia. The incidence was 1.7 cases of Eubacterium bacteremia per million inhabitants and year. The median age was 67 years (interquartile range 63-79 years), and six patients had some form of malignancy. Most of the patients an abdominal focus of infection and the 30-day mortality was low (n = 1). CONCLUSIONS: Invasive infections with Eubacterium have a low incidence. The condition has a low mortality and an abdominal focus of infection, and malignancy, is common.

Proteomic Characterization of Plasma in Lemierre's Syndrome.

BACKGROUND: The underlying mechanisms of thrombosis in Lemierre's syndrome and other septic thrombophlebitis are incompletely understood. Therefore, in this case control study we aimed to generate hypotheses on its pathogenesis by studying the plasma proteome in patients with these conditions. METHODS: All patients with Lemierre's syndrome in the Skåne Region, Sweden, were enrolled prospectively during 2017 to 2021 as cases. Age-matched patients with other severe infections were enrolled as controls. Patient plasma samples were analyzed using label-free data-independent acquisition liquid chromatography tandem mass spectrometry. Differentially expressed proteins in Lemierre's syndrome versus other severe infections were highlighted. Functions of differentially expressed proteins were defined based on a literature search focused on previous associations with thrombosis. RESULTS: Eight patients with Lemierre's syndrome and 15 with other severe infections were compared. Here, 20/449 identified proteins were differentially expressed between the groups. Of these, 14/20 had functions previously associated with thrombosis. Twelve of 14 had a suggested prothrombotic effect in Lemierre's syndrome, whereas 2/14 had a suggested antithrombotic effect. CONCLUSION: Proteins involved in several thrombogenic pathways were differentially expressed in Lemierre's syndrome compared to other severe infections. Among identified proteins, several were associated with endothelial damage, platelet activation, and degranulation, and warrant further targeted studies.

Binding and activation of plasminogen at the surface of Fusobacterium necrophorum.

Fusobacterium necrophorum is a gram-negative, anaerobic bacterium, which has been suggested to be a normal inhabitant of the oral flora. In rare cases, it can invade the tonsils and deeper tissues, causing the serious condition Lemièrre's syndrome. Recruitment of host plasminogen is a well-known bacterial virulence mechanism, and plasmin activity at the bacterial surface is thought to be important for bacterial invasion. Herein we show that plasminogen can be recruited to the surface of F. necrophorum, that surface-bound plasminogen is more easily converted to active plasmin than plasminogen in buffer, and that bound plasminogen is protected against inactivation by α2-antiplasmin. These findings add to the understanding of the pathogenesis of Lemièrre's syndrome.

Ophthalmic complications of Lemierre syndrome.

PURPOSE: Lemierre syndrome is a life-threatening condition characterized by head/neck bacterial infection, local suppurative thrombophlebitis and septic embolic complications in a range of sites of distant organs. No prior study focused on the course and characteristics of ophthalmic complications of Lemierre syndrome. METHODS: We analysed data of 27 patients with ophthalmic complications from a large cohort of 712 cases with Lemierre syndrome reported globally between 2000 and 2017. We focused on initial manifestations, early (in-hospital) course and long-term ophthalmic deficits at the time of hospital discharge or during postdischarge follow-up. The study protocol was registered in the International Prospective Register of Systematic Reviews PROSPERO (CRD42016052572). RESULTS: Nine (33%) patients were women; the median age was 20 (Q1-Q3: 15-33) years. Fusobacterium spp. was involved in 56% of cases. The most prevalent initial manifestations were decreased vision (35%) and periocular oedema (38%), followed by impaired eye movements/nerve palsy (28%) and proptosis (28%). Venous involvement, notably cerebral vein thrombosis (70%) and ophthalmic vein thrombosis (55%), explained the symptomatology in most cases. Septic embolism (7%), orbital abscesses (2%) and carotid stenosis (14%) were also present. Ophthalmic sequelae were reported in 9 (33%) patients, often consisting of blindness or reduced visual acuity, and nerve paralysis/paresis. CONCLUSION: Ophthalmic complications represent a severe manifestation of Lemierre syndrome, often reflecting an underlying cerebral vein thrombosis. Visual acuity loss and long-term severe complications are frequent. We call for an interdisciplinary approach to the management of patients with Lemierre syndrome and the routine involvement of ophthalmologists.

Convalescent plasma treatment in severely immunosuppressed patients hospitalized with COVID-19: an observational study of 28 cases.

BACKGROUND: Immunosuppressed patients are particularly vulnerable to severe infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), risking prolonged viremia and symptom duration. In this study we describe clinical and virological treatment outcomes in a heterogeneous group of patients with severe immunosuppression due to various causes suffering from COVID-19 infection, who were all treated with convalescent plasma (CCP) along with standard treatment. METHODS: We performed an observational, retrospective case series between May 2020 to March 2021 at three sites in Skåne, Sweden, with a population of nearly 1.4 million people. All patients hospitalized for COVID-19 who received CCP with the indication severe immunosuppression as defined by the treating physician were included in the study (n = 28). RESULTS: In total, 28 severely immunocompromised patients, half of which previously had been treated with rituximab, who had received in-hospital convalescent plasma treatment of COVID-19 were identified. One week after CCP treatment, 13 of 28 (46%) patients had improved clinically defined as a decrease of at least one point at the WHO-scale. Three patients had increased score points of whom two had died. For 12 patients, the WHO-scale was unchanged. CONCLUSION: As one of only few studies on CCP treatment of COVID-19 in hospitalized patients with severe immunosuppression, this study adds descriptive data. The study design prohibits conclusions on safety and efficacy, and the results should be interpreted with caution. Prospective, randomized trials are needed to investigate this further.

Activation of the contact system at the surface of Fusobacterium necrophorum represents a possible virulence mechanism in Lemièrre's syndrome.

Fusobacterium necrophorum causes Lemièrre's syndrome, a serious disease with septic thrombophlebitis of the internal jugular vein, pulmonary involvement, and systemic inflammation. The contact system is a link between inflammation and coagulation, and contact activation by the bacteria could therefore contribute to the abnormal coagulation and inflammation seen in patients with Lemièrre's syndrome. In this study, F. necrophorum was found to bind radiolabeled high-molecular-weight kininogen (HK), a central component of the contact system. Binding was inhibited by the addition of unlabeled HK and domain D5 of HK but not other components of the contact system, indicating a specific interaction mediated through the D5 region. Binding of HK was significantly reduced after pretreatment of the bacteria with trypsin, suggesting that surface proteins are involved in HK binding. Incubation of the bacteria with human plasma resulted in an HK breakdown pattern suggestive of bradykinin release, and bradykinin was also detected in the supernatant. In addition, we show that factor XI (FXI), another component of the contact system, binds to F. necrophorum and that the bound FXI reconstitutes the activated partial thromboplastin time of FXI-deficient plasma. Thrombin activity was detected at the surface of the bacteria following incubation with plasma, indicating that the intrinsic pathway of coagulation is activated at the surface. This activity was completely blocked by inhibitors of the contact system. The combined results show that the contact system is activated at the surface of F. necrophorum, suggesting a pathogenic role for this system in Lemièrre's syndrome.

Jugular Vein Thrombosis and Anticoagulation Therapy in Lemierre's Syndrome-A Post Hoc Observational and Population-Based Study of 82 Patients.

BACKGROUND: Lemierre's syndrome is typically caused by Fusobacterium necrophorum where an oropharyngeal infection is followed by septic internal jugular vein thrombophlebitis with subsequent septic embolization. Yet, the pathogenesis of septic thrombophlebitis, differences dependent on the presence of jugular vein thrombosis, and the role of anticoagulant therapy are insufficiently understood. METHODS: Patients with invasive infection with F. necrophorum and Lemierre's syndrome who had been investigated for jugular vein thrombosis were included from a previous population-based observational study in Sweden. Medical records were reviewed and compared in patients with and without jugular vein thrombosis. Then, patients with jugular vein thrombosis were compared by exposure to therapeutic, prophylactic, or no anticoagulation. Outcomes examined were thrombosis progression, early or late peripheral septic complications, chronic major sequelae, 30-day mortality, and major bleeding. RESULTS: Fifty-one of 82 (62%) radiologically investigated patients with Lemierre's syndrome had jugular vein thrombosis. Patients with jugular vein thrombosis had lower platelet levels (median, 76 vs 112 ×109/L; P = .04) on presentation and more days to defervesence (12 vs 7 days; P = .03) yet similar rates of major sequelae and 30-day mortality. No significant differences in outcomes were seen between patients with jugular vein thrombosis exposed to therapeutic, prophylactic, or no anticoagulation therapy, yet study outcomes were rare. CONCLUSIONS: Patients with Lemierre's syndrome with jugular vein thrombosis were more severely affected, yet had similar prognosis. Most patients with jugular vein thrombosis recovered well without therapeutic anticoagulation therapy, though adverse events were similarly rare in anticoagulated patients. The observational design and rarity of study outcomes require cautious interpretation.

Convalescence plasma treatment of COVID-19: results from a prematurely terminated randomized controlled open-label study in Southern Sweden.

OBJECTIVE: Convalescent plasma has been tried as therapy for various viral infections. Early observational studies of convalescent plasma treatment for hospitalized COVID-19 patients were promising, but randomized controlled studies were lacking at the time. The objective of this study was to investigate if convalescent plasma is beneficial to hospitalized patients with COVID-19. RESULTS: Hospitalized patients with confirmed COVID-19 and an oxygen saturation below 94% were randomized 1:1 to receive convalescent plasma in addition to standard of care or standard of care only. The primary outcome was number of days of oxygen treatment to keep saturation above 93% within 28 days from inclusion. The study was prematurely terminated when thirty-one of 100 intended patients had been included. The median time of oxygen treatment among survivors was 11 days (IQR 6-15) for the convalescent plasma group and 7 days (IQR 5-9) for the standard of care group (p = 0.4, median difference -4). Two patients in the convalescent plasma group and three patients in the standard of care group died (p = 0.64, OR 0.49, 95% CI 0.08-2.79). Thus no significant differences were observed between the groups. Trial registration ClinicalTrials NCT04600440, retrospectively registered Oct 23, 2020.

Adapting a peer-led self-management program for breast cancer survivors in Switzerland using a co-creative approach.

OBJECTIVE: The peer-led Cancer Thriving and Surviving Program (CTS) has demonstrated improved health outcomes for cancer survivors. We describe a co-creative process for adapting the CTS for breast cancer survivors in Switzerland and integrating the program into the clinical pathway of Swiss breast centers. METHODS: A co-creative approach was employed. Breast cancer survivors and health care professionals (total n = 81) participated in three workshops, an online rating, and a consensus conference. An iterative cycle (evidence, ideas, refining, rating, and synthesis) guided the adaptation process. RESULTS: Survivors involvement in the adaptation process allowed to tailor the self-management program to the psychosocial needs identified as the highest priority. New contents "Being a woman", "Breast cancer and my (working) life" and "My exercise" were added to the CTS. Program duration was expanded from 6 to 7 weeks. Transition to follow-up care was considered as the optimal time point for program integration into the clinical pathway. CONCLUSION: The co-creative process may serve as a model in adapting supportive interventions for cancer. A subsequent pilot testing examined the feasibility and preliminary efficacy. PRACTICE IMPLICATIONS: Combining expertise of health care professionals and patients to co-create a peer-led breast cancer self-management program may enhance acceptability and adoption.