Clinical presentation of invasive disease caused by Neisseria meningitidis serogroup Y in Sweden, 1995 to 2012.

Over the period 1995-2012, the incidence of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y (NmY) increased significantly in Sweden. This is mainly due to the emergence of a predominant cluster named strain type YI subtype 1, belonging to the ST-23 clonal complex (cc). The aim of this study was to examine the clinical picture of patients with invasive disease caused by NmY and to analyse whether the predominant cluster exhibits certain clinical characteristics that might explain the increased incidence. In this retrospective observational study, the medical records available from patients with IMD caused by Nm serogroup Y in Sweden between 1995 and 2012 were systematically reviewed. Patient characteristics, in-hospital findings and outcome were studied and differences between the dominating cluster and other isolates were analysed. Medical records from 175 of 191 patients were retrieved. The median age was 62 years. The all-cause mortality within 30 days of admission was 9% (15/175) in the whole material; 4% (2/54) in the cohort with strain type YI subtype 1 and 11% (12/121) among patients with other isolates. Thirty-three per cent of the patients were diagnosed with meningitis, 19% with pneumonia, 10% with arthritis and 35% were found to have bacteraemia but no apparent organ manifestation. This survey included cases with an aggressive clinical course as well as cases with a relatively mild clinical presentation. There was a trend towards lower mortality and less-severe disease in the cohort with strain type YI subtype 1 compared with the group with other isolates.

Betamethasone and dexamethasone in adult community-acquired bacterial meningitis: a quality registry study from 1995 to 2014.

Acute bacterial meningitis (ABM) is a highly lethal disease. Available data support the use of corticosteroids in high-income countries, but the effect on mortality is still controversial. The effects of corticosteroids on mortality and sequelae were evaluated in the national Swedish quality registry. In total, during 1995-2014 1746 adults with ABM were included, of whom 989 were treated with corticosteroids (betamethasone, n = 766; dexamethasone, n = 248; methylprednisolone, n = 2), 498 were not given corticosteroids and in 259 patients data for corticosteroids were missing. Fatal outcome was observed in 8.9% of the patients in the corticosteroid-treated group vs. 17.9% in the non-corticosteroid-treated group (p <0.001), resulting in an odds ratio (OR) of 0.57 with a 95% confidence interval (CI) of 0.40-0.81 adjusted for age, sex, mental status, and door-to-antibiotic time. In patients with meningitis caused by S. pneumoniae, mortality was 10.2% in the corticosteroid-treated group and 21.3% in the non-corticosteroid-treated group (p <0.001) with an adjusted OR of 0.50 (95% CI 0.31-0.80). In ABM patients with non-pneumococcal aetiology the adjusted OR was 0.71 (95% CI 0.40-1.26). Lower mortality was observed in the corticosteroid-treated group with impaired mental status, whereas no significant difference was found in patients with unaffected mental status. The adjusted ORs for betamethasone and dexamethasone were 0.49 (95% CI 0.28-0.84) and 0.61 (95% CI 0.37-1.01), respectively. Corticosteroid treatment decreases mortality in ABM and should be administered initially with antibiotics in adult ABM patients with impaired mental status regardless of presumed aetiology. Betamethasone seems to be at least as effective as dexamethasone.

Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians.

Acute bacterial meningitis (ABM) is challenging for the admitting physician because it is a rare but fulminant disease, usually presenting without typical symptoms, and rapid treatment is pivotal. The purpose of this study was to evaluate the effect of initial management by infectious diseases (ID) physicians vs. non-ID physicians. A total of 520 consecutive adults (>17 years old), 110 with initial ID management and 410 with non-ID management, registered in the Swedish quality registry for community-acquired ABM January 2008 to December 2013, were analysed retrospectively. Primary outcome was appropriate treatment with antibiotics and corticosteroids <1 hour from admission. Secondary analyses were mortality during hospital stay and persisting neurological and hearing deficits at follow-up after 2 to 6 months. Differences in diagnostic treatment sequences also were analysed. Appropriate treatment <1 hour from admission was achieved significantly more often (41%) by ID physicians vs. non-ID physicians (24%) with an odds ratio (OR) of 2.4 (95% confidence interval [CI]: 1.40 to 4.14; p < 0.01) adjusted for confounders. The door-to-antibiotic time was significantly shorter, and significantly more patients were administered corticosteroids together with the first doses of antibiotics in the ID group. A trend of decreased mortality (4.5% vs. 8.0%) and sequelae at follow-up (24% vs. 44%; adjusted OR 0.55: 95% CI 0.31 to 1.00; p 0.05) were observed in the ID group vs. the non-ID group. Antibiotics were started without prior neuroimaging more often in the ID group (86% vs. 57%; p < 0.001). Initial management at the emergency department by ID physicians is associated with earlier appropriate treatment, more appropriate diagnostic treatment sequences and favourable outcome.

Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-blind, randomized controlled trial.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis. Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications. METHODS: One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned to placebo (n = 51) or 0.5 g of valacyclovir twice daily (n = 50) for 1 year after initial treatment with 1 g of valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome was time until recurrence of meningitis. The patients were followed up for 2 years. RESULTS: The first year, no significant difference was found between the valacyclovir and placebo groups. The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.06-10.21]). One-third of the patients experienced 1-4 meningitis episodes during the study period. A considerable morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was found in both groups. CONCLUSIONS: Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could be interpreted as a rebound phenomenon.

[Enterovirus diagnosis is important, but should be used cautiously]. / Enterovirusdiagnostik angelägen men bör bedrivas med urskillning.

While the enterovirus diagnostic test positive rate is very low in Sweden, many enterovirus diagnoses are probably missed, owing to inappropriate testing, in patients with acute aseptic meningitis. In the article it is recommended that the cerebrospinal fluid PCR (polymerase chain reaction) test should be performed routinely in cases of acute aseptic meningitis. Serology and virus isolation in stool are indicated in cases of acute pericarditis or myocarditis, or certain chronic heart diseases. The PCR test should be performed in serum in the few cases of sepsis-like diseases in newborns or patients with hypogammaglobulinaemia. Otherwise, enterovirus diagnosis is very seldom justified on clinical grounds. For the purpose of poliovirus surveillance, enterovirus isolation may be important for virus typing, especially in cases of paralytic conditions.

Multicenter evaluation of the Amplicor Enterovirus PCR test with cerebrospinal fluid from patients with aseptic meningitis. The European Union Concerted Action on Viral Meningitis and Encephalitis.

The Amplicor Enterovirus PCR test was compared with viral culture for the detection of enteroviruses in cerebrospinal fluid (CSF) specimens. In a multicenter study in which nine laboratories participated, a total of 476 CSF specimens were collected from patients with suspected aseptic meningitis. Sixty-eight samples were positive by PCR (14.4%), whereas 49 samples were positive by culture (10.4%), demonstrating that the Amplicor Enterovirus PCR test was significantly more sensitive than culture (P < 0.001). After discrepancy analysis the sensitivity and specificity of the Amplicor Enterovirus PCR test obtained by using viral culture as the "gold standard" were 85.7 and 93.9%, respectively. Our results with the CSF specimens collected in different countries demonstrate that the Amplicor test is capable of detecting a large variety of enterovirus serotypes and epidemiologically unrelated isolates in CSF specimens from patients with aseptic meningitis. The Amplicor Enterovirus PCR test is a rapid assay which can be routinely performed with CSF samples and is an important improvement for the rapid diagnosis of enteroviral meningitis.

Interferon-gamma in cerebrospinal fluid from patients with viral and bacterial meningitis.

Interferon (IFN)-gamma was analysed immunologically in cerebrospinal fluid (CSF) sampled in the acute phase from 27 patients (15-66 years) with viral meningitis and from 18 patients (0.5-90 years) with bacterial meningitis. Increased CSF concentrations were observed in 19/27 viral and in 13/18 bacterial cases. CSF-IFN-gamma did not distinguish between viral and bacterial meningitis. Five of 8 patients with meningitis due to herpes simplex virus type 2 (HSV-2) had CSF-IFN-gamma levels above the highest found in enteroviral meningitis. Thus, a markedly increased CSF-IFN-gamma value in patients with suspected viral meningitis ought to indicate HSV-2 etiology. The patients with Streptococcus pneumoniae meningitis (6 adults and 1 child) had significantly higher levels than the 7 children with Haemophilus influenzae meningitis. This may indicate that S. pneumoniae induces more IFN-gamma secretion than H. influenzae, and/or that during meningitis, adults are more apt to react with IFN-gamma production, than are children.

Diagnosis of enteroviral meningitis with IgG-EIA using heat-treated virions and synthetic peptides as antigens.

Two recently developed enzyme immunosorbent assays (EIA) for the detection of significant titre increases in enteroviral IgG-antibodies were evaluated as diagnostic tools in 127 etiologically well-characterized patients with aseptic meningitis. One assay was based on heat-treated virions (H-EIA) and one on synthetic peptides (P-EIA) as antigens. The sensitivities, with virus isolation as reference method, were 0.67 by H-EIA and 0.62 by P-EIA, which were higher than by a routinely used complement fixation test (CFT, 0.51) but somewhat lower than the sensitivities found by two previously presented IgM-assays, mu-capture EIA, and solid-phase reverse immunosorbent test (SPRIST). The specificities of the two IgG-EIA techniques and CFT were apparently high, whereas the two IgM-assays showed positive reactions in some non-enteroviral cases. A relatively rapid increase in enteroviral IgG-antibodies was apparent using H-EIA and P-EIA. The two IgG-EIA tests contributed with considerable additional etiological information since significant IgG-rises were obtained in 13 patients by H-EIA and in 19 by P-EIA, respectively, out of the 56 individuals in whom enterovirus isolation was negative and a non-enteroviral diagnosis was not found. Thus, detection of enteroviral IgG-antibodies by H-EIA and P-EIA seems to be a valuable alternative to CFT for the routine diagnosis of enteroviral meningitis. The IgM-assays, mu-capture EIA, and SPRIST, may allow a relatively rapid report of an enteroviral infection. However, since both the IgM-tests are hampered by incomplete specificities, a confirmation of positive results by an IgG-assay should be carried out.

Tumor necrosis factor-alpha (TNF alpha) in cerebrospinal fluid from patients with meningitis of different etiologies: high levels of TNF alpha indicate bacterial meningitis.

The levels of tumor necrosis factor (TNF)-alpha in cerebrospinal fluid (CSF) were analyzed in 139 patients with meningitis and in 20 control subjects. Elevated concentrations were observed in 42 (82%) of 51 patients with purulent bacterial meningitis (18/24 Haemophilus influenzae, 13/14 Streptococcus pneumoniae, 7/7 Neisseria meningitidis, and 4/6 with other purulent bacterial etiology). In contrast, elevated levels were found in only 5 of 78 individuals with nonbacterial meningitis (2/8 with herpes simplex type 2, 3/3 with varicella-zoster virus). Thus, the positive and negative predictive values were 0.89 for indicating a purulent bacterial meningitis. Raised CSF TNF alpha levels were observed in 7 of 8 patients with purulent bacterial meningitis in whom the routinely used parameters did not unequivocally indicate the diagnosis. Moderately increased levels were seen in 5 of 6 patients with Mycobacterium tuberculosis meningitis and in 1 of 4 cases of Borrelia burgdorferi. Thus, the present study indicates that concentrations of TNF alpha in CSF usually can discriminate between purulent bacterial and nonbacterial meningitis. These findings may contribute diagnostic guidance with routinely used CSF parameters.

Detection of enteroviral RNA by polymerase chain reaction in cerebrospinal fluid from patients with aseptic meningitis.

An assay based on a 2-step (semi-nested) polymerase chain reaction (PCR) was developed and evaluated for detection of enterovirus-specific RNA in cerebrospinal fluid (CSF) from patients with aseptic meningitis of different etiology. The limit of detectability of enteroviral RNA was equivalent to about 0.25 tissue culture infective doses 50%. In samples, stored at -70 degrees C, analyzed without repeated thawing, enteroviral RNA was demonstrable in 21/22 CSF specimens from which an enterovirus had been isolated. Enteroviral RNA was shown to be degraded during freeze-thawing of the samples. In repeatedly freeze-thawed samples from 134 consecutive patients with aseptic meningitis, a lower sensitivity (34/48 = 0.71) was observed. In the latest phase of the study, comprising 35 consecutive patients, the PCR was performed in CSF stored at -20 degrees C without thawing. In this material, the PCR yielded positive results in 19 patients, whereas enteroviruses were isolated from 6 cases only. In the total clinical material of 169 patients, 67 (40%) were found positive by PCR, whereas an enterovirus was isolated from CSF in 54 (32%) cases. All the 13 isolated enterovirus serotypes found in the study were demonstrable by PCR, indicating that the assay is broad-reacting within the enterovirus group. The specificity appeared to be high, since all of 21 patients with non-enteroviral diagnoses were negative by the PCR test, except 1 with an Epstein-Barr virus infection. As serological evidence of enteroviral etiology was found in this patient, a dual infection seemed probable. This study indicates that enteroviral RNA can be detected in CSF by a 2-step PCR in meningitis caused by enterovirus and that the technique has the potential to become a screening method for routine diagnosis of enteroviral meningitis.

Detection of enteroviral RNA by polymerase chain reaction in faecal samples from patients with aseptic meningitis.

An assay based on the polymerase chain reaction (PCR) for detection of enteroviral RNA in stool samples was carried out using specimens from 74 patients with aseptic meningitis. The primer pair and probe were derived from the highly conserved 5' non-coding enterovirus genomic region. Enteroviral RNA was detected in faeces of all 36 patients in whom an enterovirus was isolated from stool. The PCR assay yielded positive results in additionally 3/6 cases where enterovirus diagnoses were obtained by virus isolation from cerebrospinal fluid and/or serological tests. Thus, the positive outcome of the PCR assay was 39 (93%) among the 42 patients with enterovirus diagnoses. Furthermore, 7/19 (37%) cases with an etiology that was not established by other means were positive in the test indicating that the PCR assay may give considerable additional etiological information in patients with aseptic meningitis. The limit of RNA detectability in the PCR assay was about 100 TCID50 when highly cytopathogenic enterovirus types (coxsackievirus type B5 and echovirus type 11) were tested. The PCR was negative in all 13 patients with non-enterovirus diagnoses except in one case with a herpes simplex virus type 2 infection. Since enterovirus-specific IgM antibodies could be detected in this case a dual infection seemed probable. All the negative controls, included in the study, were PCR-negative and no contamination was encountered. This study proves the usefulness of the PCR assay for detection of enteroviral RNA in stool samples and suggests that the test may be an alternative to virus isolation for rapid enterovirus diagnosis in patients with aseptic meningitis.

Early diagnosis of enteroviral meningitis by detection of specific IgM antibodies with a solid-phase reverse immunosorbent test (SPRIST) and mu-capture EIA.

A solid-phase reverse immunosorbent test (SPRIST) and a mu-capture enzyme immunosorbent assay (EIA) for detection of enterovirus-specific IgM antibodies were evaluated for enterovirus diagnosis of aseptic meningitis in 160 consecutive patients from whom enterovirus (11 different serotypes) were isolated in 64. In patients with an enterovirus isolate and/or four-fold titre rise in the complement fixation test (CFT) for enterovirus, specific enterovirus IgM antibodies were detected on the day of admission to hospital in 48% by SPRIST and in 50% by EIA and 4-6 days after onset of symptoms in 71% by SPRIST and 79% by EIA. A significant increase in titre was observed between serum sampled on the day of admission and 2 days later in 38% by SPRIST and in 41% by EIA. These results indicate that the IgM antibody response appears early in the course of aseptic meningitis. Since both SPRIST and EIA provide rapid results the tests may be of differential diagnostic value and the IgM antibody kinetics may be utilized for diagnosis during the acute phase of aseptic meningitis. With optimized serum sampling the positive outcome was 76% in SPRIST and 82% in EIA among patients with positive virus isolation and/or CFT for enterovirus. In 67 patients virus isolation and CFT for enterovirus yielded negative results as well as all non-enteroviral diagnostic tests. Thirty-eight of these patients were positive by SPRIST and/or EIA and in half of these 38 a significant titre rise and/or fall in SPRIST and/or EIA was recorded. The majority of these IgM-positive patients became ill in the late summer or autumn, i.e., the "enterovirus season."(ABSTRACT TRUNCATED AT 250 WORDS)

Early diagnosis of enteroviral meningitis by a solid-phase reverse immunosorbent test and virus isolation.

45 cases of aseptic meningitis/meningoencephalitis were studied with regard to enteroviral etiology by virus isolation and solid-phase reverse immunosorbent test (SPRIST), a cross-reacting test for enterovirus IgM. An etiological diagnosis was reached in 37/45 (82%) patients. Etiological diagnoses other than enteroviruses were found in 8 patients: Borrelia burgdorferi in 4, varicella-zoster virus in 2, herpes simplex virus in 1 and mumps virus in 1 patient. Enteroviruses (echovirus 6, 21 and 30) were isolated from cerebrospinal fluid (CSF) in 26/37 (70%) and from stool samples of 20/21 (95%) of patients with no other etiology. Altogether enteroviruses were isolated from CSF and/or faecal samples in 29 patients. Echovirus 30 dominated as etiologic agent. In 34/40 (85%) of the samples with an enterovirus, a cytopathogenic effect was observed in cell culture within 4 days. In patients with an enterovirus isolate a SPRIST IgM response to echovirus 3, 5, 7 and/or coxsackievirus B3 was detected in 6/13 (46%) sera sampled 3-4 days after the onset of meningeal symptoms and in altogether 17/25 patients (68%). In 4 out of these virus isolation positive and SPRIST negative patients a single serum for SPRIST was available less than 4 days after onset of meningeal symptoms. Antigen from echovirus 5 gave the highest diagnostic yield. The SPRIST IgM test was positive in 2 cases where virus isolation, complement fixation and neutralization tests were negative. Epidemiological data however supported an enteroviral diagnosis in both of them. In conclusion, both SPRIST and virus isolation seem to be valuable for the early diagnosis of enteroviral meningitis.

Septicemia caused by Staphylococcus saprophyticus.

Staphylococcus saprophyticus is a common cause of acute urinary tract infection (UTI) in young women. Septicemia has not been reported in patients without signs of immunodeficiency. We report 2 such cases in previously healthy 19- and 33-year-old women. Thus, this microbe may give rise to invasive infection and should be considered when coagulase-negative staphylococci are isolated from blood cultures in patients with symptoms of UTI.