Diagnostic Accuracy of MRI for Detection of Meningitis in Infants.

PURPOSE: To determine the accuracy of MR imaging for diagnosis of meningitis in infants. MATERIALS AND METHODS: Retrospective review of infants less than 1 year of age who underwent a brain MR imaging for meningitis from 2010-2018. Gold standard for diagnosis of bacterial meningitis was a positive bacterial CSF culture or a positive blood culture with an elevated CSF WBC count, and diagnosis of viral meningitis was a positive CSF PCR result and elevated CSF WBC count. Sensitivity, specificity, PPV, NPV, and accuracy for MR imaging diagnosis of meningitis were calculated. RESULTS: Two hundred nine infants with mean age 80 days (range 0-347 days) were included. There were 178 true positives with the most common pathogens being: Group B Streptococcus (58), E. coli (50), Streptococcus pneumoniae (21), H. influenzae (4); Herpes simplex virus 1 or 2 (18); Enterovirus (4); and other (23). There were 31 true negatives. Range of sensitivity, specificity, PPV, NPV, and accuracy of MR imaging for detection of meningitis was 67.4-83.5%, 92.3-95.7%, 95.0-98.6%, 33.3-76.5%, and 71.3-86.5% respectively. MR imaging sensitivity decreased after 10 days from time of presentation while specificity remained stable. Among individual MR imaging findings, leptomeningeal enhancement was the most sensitive finding, while cerebritis, infarction, ventriculitis, abscess, and intraventricular purulent material were the most specific findings. CONCLUSIONS: MR imaging of the brain demonstrates high specificity and moderate sensitivity for diagnosis among infants presenting with signs and symptoms of meningitis. The results reflect current standard of care for imaging of infants with meningitis however a selection bias for imaging of more severe meningitis may affect these results.

Accuracy of MR Imaging for Detection of Sensorineural Hearing Loss in Infants with Bacterial Meningitis.

BACKGROUND AND PURPOSE: Bacterial meningitis most commonly affects young children and can result in critical adverse outcomes, including sensorineural hearing loss (SNHL). The purpose of this study is to determine the diagnostic accuracy of MR imaging for predicting the development of SNHL among infants with bacterial meningitis. MATERIALS AND METHODS: A retrospective review was performed among infants (age <365 days) with bacterial meningitis (n = 115). Independent and consensus blinded review of brain MRIs (n = 239) performed less than 90 days from presentation were conducted. Abnormal appearance of the inner ear was defined as enhancement on postcontrast T1-weighted (T1-weighted+C) sequence and FLAIR hyperintensity. The consensus MR imaging appearance of the inner ear on FLAIR, T1-weighted+C, and combined evaluation was compared with criterion standard audiometric testing to determine the sensitivity and specificity of MR imaging for detecting SNHL. RESULTS: The mean age at diagnosis of bacterial meningitis was 50.6 days (range, 0-338 days) and 24.3% had SNHL. Sensitivity and specificity was 0.61/0.96, 0.50/0.94, and 0.61/0.94 for T1-weighted+C, FLAIR hyperintensity, and combined evaluation, respectively, for prediction of SNHL. There was excellent interobserver agreement for both the T1-weighted+C and FLAIR sequences and combined evaluation for presence of abnormal enhancement and hyperintense signal, respectively. Factors associated with abnormal MR imaging findings on T1-weighted+C and/or FLAIR in patients with SNHL included low CSF glucose (P = .04, .02) and high CSF protein (P = .04, .03). CONCLUSIONS: Abnormal enhancement and/or FLAIR hyperintensity of the inner ear demonstrate high specificity and average sensitivity for prediction of SNHL among infants with bacterial meningitis.

Atherogenic diet-induced hepatitis is partially dependent on murine TLR4.

Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory changes have been poorly characterized. TLR4, a known receptor for LPS, is also a receptor for a variety of endogenous ligands and has been implicated in atheroma formation. Here, we specifically examined the early inflammatory response of the liver to the atherogenic (ATH) diet and the possible contribution of TLR4. Animals fed the high-cholesterol/cholate diet for 3 weeks developed a significant, predominantly mononuclear leukocyte infiltration in the liver, hepatic steatosis, elevated hepatic expression of MCP-1, RANTES, and MIP-2, and increased serum levels of liver enzymes. In TLR4-deleted animals, there was a 30% attenuation in the serum alanine transaminase levels and a 50% reduction in the leukocyte infiltration with a fourfold reduction in chemokine expression. In contrast, hepatic steatosis did not differ from wild-type controls. TLR2 deletion had no effect on diet-induced hepatitis but increased the amount of steatosis. We conclude that the early inflammatory liver injury but not hepatic lipid loading induced by the ATH diet in mice is mediated in part by TLR4.

Comparison of CSF and MRI Findings among Neonates and Infants with E coli or Group B Streptococcal Meningitis.

BACKGROUND AND PURPOSE: Group B Streptococcus and Escherichia coli (E coli) are the 2 most common causes of bacterial meningitis in neonates. The purpose of this study was to determine whether CSF and/or MR imaging findings differ between infants with group B streptococcal or E coli meningitis. MATERIALS AND METHODS: A retrospective review was performed among neonates (younger than 28 days) and infants (younger than 120 days) with proved group B streptococcal (n = 57) or E coli meningitis (n = 50). A CSF or blood culture positive for Streptococcus or E coli and an elevated CSF white blood cell count were used as the criterion standard. Independent, blinded review of brain MRIs obtained within 21 days of presentation were performed by 2 board-certified neuroradiologists. CSF laboratory values and MR imaging findings were compared between the groups. RESULTS: There was no statistically significant difference between the mean age at presentation for patients with group B streptococcal (40 days; range, 2-111 days) versus patients with E coli meningitis (31 days; range, 12-115 days) (P = .18). There was no statistically significant difference in the CSF white blood cell count, glucose, or protein. There was a significant difference between group B streptococcal and E coli meningitis in the frequency of hydrocephalus (0% versus 22%, P = .001) and infarct (40% versus 14%; P = .038), respectively. There was no statistically significant difference in leptomeningeal enhancement, cerebritis, ventriculitis, abscess/granuloma, subdural effusion, extra-axial purulent material, intraventricular purulent material, hemorrhage, and sinus thrombosis. CONCLUSIONS: Although neonates and infants with group B streptococcal or E coli meningitis had similar age and CSF laboratory values, patients with group B streptococcal meningitis more frequently demonstrated infarcts, while those with E coli meningitis more frequently had early onset of hydrocephalus.

Clinical features, diagnosis, and treatment of tuberculosis in infants.

OBJECTIVE: Despite the recent resurgence of tuberculosis among children in the United States, no series of infants < 1 year of age with tuberculosis has been reported in the last 20 years. This study was undertaken to describe the epidemiology, clinical, and radiographic manifestations, and response to therapy in infants < 1 year of age with tuberculous disease. METHODS: The medical records were reviewed for all infants age 12 months or less with a diagnosis of tuberculosis and cared for at the Children's Tuberculosis Clinic at Ben Taub General Hospital in Houston, Texas between January 1, 1985 and June 30, 1992. RESULTS: Of the 47 infants identified, 51% were female. The median age at diagnosis was 8 months (range 3.5 to 12 months). Fifty-one percent of the infants were African-American and over one-third were Hispanic. All patients were born in the United States. Diagnosis resulted from the examination of an ill infant in 79% of cases, a case contact investigation of an adult suspected of having tuberculosis in 19%, and routine tuberculin skin testing in 2%. An adult with infectious tuberculosis who had contact with the infant was identified in 68% of cases. Intrathoracic disease alone was present in 70% of cases. Fourteen (30%) infants had extrapulmonary tuberculosis (11 central nervous system disease, 2 disseminated disease, and 1 cervical adenitis). Gastric aspirate cultures yielded Mycobacterium tuberculosis from 75% of the infants with isolated intrathoracic disease. Forty-five infants successfully completed therapy and only one death was directly related to tuberculosis. Forty-eight percent of the infants with pulmonary tuberculosis were treated with a 6-month regimen consisting of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide. Eighteen infants received some twice weekly directly observed therapy mainly due to documented or suspected nonadherence. Treatment was well-tolerated; one patient (2%) developed hepatotoxicity due to isoniazid. No infant had a relapse or recurrence of disease in 6 months to 7 years follow-up for a median of 3 years (range, 6 months to 7 years). CONCLUSION: Most infants with tuberculosis are symptomatic at the time of diagnosis, and bacteriologic confirmation was obtained in 70% of cases. A contact investigation of the household should be initiated immediately when an infant is suspected of having tuberculosis because valuable information needed to establish the diagnosis and guide therapy in the infant may be obtained. Intensive 6-month and twice weekly directly observed therapy appear to be well-tolerated and effective for the treatment of pulmonary tuberculosis in infants.

Tuberculosis and pregnancy.

After decades of decline, tuberculosis case rates are again increasing in the United States. The increases have been most dramatic among minority young adults of childbearing age. The availability of adequate chemotherapy means that the outcome for both mother and child in pregnancy complicated by tuberculosis should be good. Complete case finding and screening of high-risk adults is essential to bring tuberculosis under control again.

Intrathoracic tuberculosis in children.

After decades of decline, tuberculosis case rates are increasing again in the United States. Primarily because of increases in tuberculosis among persons of child-bearing years and diminished performance by some health departments, substantial increases in reported cases of tuberculosis in children have occurred since 1985. Although the clinical/radiographic presentation of intrathoracic tuberculosis in children has not changed significantly, major changes have occurred in the treatment of tuberculous disease over the past decade. This article will review the current epidemiology, diagnosis, and treatment of childhood tuberculosis.

Roles of the bacterial cell wall and capsule in induction of tumor necrosis factor alpha by type III group B streptococci.

Group B streptococci (GBS) are the major cause of sepsis and fatal shock in neonates in the United States. The precise role of tumor necrosis factor alpha (TNF-alpha) in the development of human GBS sepsis has not been defined; however, whole GBS have been shown to induce the production of this inflammatory cytokine. We sought to determine which bacterial cell wall components of GBS are responsible for triggering TNF-alpha production. Human cord blood monocytes were stimulated with encapsulated (COH1) or unencapsulated (COH1-13) whole type III GBS or with purified bacterial components, including type III capsular polysaccharide (III-PS), group B polysaccharide (GB-PS), lipoteichoic acid (LTA), or peptidoglycan (PG). Lipopolysaccharide from Escherichia coli served as a control. Supernatants were harvested at specific timed intervals, and TNF-alpha levels were measured by enzyme-linked immunosorbent assay. Monocytes exposed to COH1 and COH1-13 induced similar amounts of TNF-alpha. III-PS, GB-PS, LTA, and PG each induced TNF-alpha in a time- and concentration-dependent manner. However, TNF-alpha release was significantly greater after stimulation by the GB-PS or PG than after stimulation by III-PS or LTA (P < 0.05). Our findings indicate that GB-PS and PG are the bacterial cell wall components primarily evoking TNF-alpha release. These, alone or in concert with other factors, may be responsible for septic shock accompanying GBS sepsis.

Treatment of meningitis and other infections due to ampicillin-resistant Haemophilus influenzae type b in children.

Cefotaxime and other cephalosporins were retrospectively evaluated for the treatment of meningitis and non-central nervous system (CNS) infections due to ampicillin-resistant Haemophilus influenzae type b (Hib). Between January 1985 and February 1989, 45 cases of meningitis and 27 cases of non-CNS infection due to ampicillin-resistant Hib were documented at Texas Children's Hospital in Houston. Of the 45 children with meningitis, 26 (57.8%) were treated with cefotaxime, 11 (24.4%) with chloramphenicol, and three (6.7%) with cefuroxime; five children (11.1%) were initially given chloramphenicol but later received cefotaxime instead. In addition, 14 chloramphenicol-treated patients from a previous study were included in this analysis. There were no significant differences in terms of neurologic sequelae or other complications (except diarrhea) between the cefotaxime and chloramphenicol groups. The efficacy of cefotaxime was equivalent to that of chloramphenicol for the treatment of ampicillin-resistant Hib meningitis. Cefuroxime was as safe and effective as chloramphenicol or cefotaxime for the treatment of non-CNS infections due to ampicillin-resistant Hib.

Demonstration of circulating group B streptococcal immune complexes in neonates with meningitis.

Group B streptococci are the major cause of sepsis and fatal shock in neonates in the United States. Although a number of clinical features have been associated with enhanced severity of disease, the role of soluble immune complex formation in group B streptococcal infection has not been evaluated. We determined the frequency with which circulating immune complexes occurred in 16 infants with nonfatal type III, group B streptococcal meningitis, using an immunoglobulin-specific C1q enzyme immunoassay. Ten healthy, age-matched infants served as a control group. Elevated levels of immunoglobulin M (IgM)-containing immune complexes were present in the sera of four (25%) patients with group B streptococcal meningitis. Group B antigen was detected in precipitated IgM immune complexes from each of these four infants by competitive enzyme-linked immunosorbent assay. In addition, IgG-containing immune complexes were present in 56% of sick and 60% of control infants. Group B antigen was demonstrated in the serum of a sick neonate containing only IgG immune complexes but not in controls. Our findings indicate that a subset of infants with type III, group B streptococcal meningitis develop IgM immune complexes containing group B-specific antigen, and these may persist for up to 3 months in some patients.

Interleukin-6 production by human neonatal monocytes stimulated by type III group B streptococci.

The subcellular components of type III group B streptococci (GBS) that contribute to the host inflammatory response were determined by measuring production of the proinflammatory cytokine interleukin (IL)-6 by cord blood monocytes. Monocytes were stimulated with encapsulated (COH1) or unencapsulated (COH1-13) whole type III GBS or with purified GBS components, including type III capsular polysaccharide (III-PS), group B antigen (GB-Ag), lipoteichoic acid (LTA), or Escherichia coli lipopolysaccharide. Monocytes exposed to COH1 and COH1-13 released similar amounts of IL-6. GBS III-PS, GB-Ag, and LTA each induced IL-6. However, IL-6 release by monocytes was significantly greater after stimulation by GB-Ag than by III-PS or LTA (P < .05). Sera from 16 neonates with systemic GBS disease had IL-6 levels of 8 pg/mL to 4.28 ng/mL. GB-Ag is a potent inducer of IL-6 and may play an important role in tissue inflammation during GBS infection.

Nonopsonic binding of type III Group B Streptococci to human neutrophils induces interleukin-8 release mediated by the p38 mitogen-activated protein kinase pathway.

Nonopsonic interaction of host immune cells with pathogens is an important first line of defense. We hypothesized that nonopsonic recognition between type III group B streptococcus and human neutrophils would occur and that the interaction would be sufficient to trigger neutrophil activation. By using a serum-free system, it was found that heat-killed type III group B streptococci bound to neutrophils in a rapid, stable, and inoculum-dependent manner that did not result in ingestion. Transposon-derived type III strain COH1-13, which lacks capsular polysaccharide, and strain COH1-11 with capsular polysaccharide lacking terminal sialic acid demonstrated increased neutrophil binding, suggesting that capsular polysaccharide masks an underlying binding site. Experiments using monoclonal antibodies to complement receptor 1 and to the I domain or lectin site of complement receptor 3 did not inhibit binding, indicating that the complement receptors used for ingestion of opsonized group B streptococci were not required for nonopsonic binding. Nonopsonic binding resulted in rapid activation of cellular p38 and p44/42 mitogen-activated protein kinases. This interaction was not an effective trigger for superoxide production but did promote release of the proinflammatory cytokine interleukin-8. The release of interleukin-8 was markedly suppressed by the p38 mitogen-activated protein kinase inhibitor SB203580 but was only minimally suppressed by the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059. Thus, nonopsonic binding of type III group B streptococci to neutrophils is sufficient to initiate intracellular signaling pathways and could serve as an arm of innate immunity of particular importance to the immature host.

Hepatosplenic abscesses due to Brucella melitensis: report of a case involving a child and review of the literature.

Suppurative disease of the liver and/or spleen is a rare and serious complication of human brucellosis. In the English-language literature, only nine cases have been reported, all involving adults with chronic infection. We report the case of a young child in whom abscesses of the liver and spleen developed during acute brucellosis. Brucella melitensis was cultured from an aspirate of the liver and from the bone marrow. After percutaneous drainage of the liver abscess, the patient responded to a 56-day course of antimicrobial therapy. To our knowledge, this is the first reported case of hepatosplenic abscess due to a Brucella species in a child.

Group B Streptococcus induces TNF-alpha gene expression and activation of the transcription factors NF-kappa B and activator protein-1 in human cord blood monocytes.

It has been postulated that production of TNF-alpha is central to the pathogenesis of septic shock induced by group B Streptococcus (GBS). In vitro studies using human cord blood monocytes have demonstrated that GBS induces TNF-alpha secretion, but little is known about the intracellular signaling pathways of TNF-alpha induction. In this report we show that heat-killed serotype III GBS induces host cell signal transduction pathways that lead to activation of the transcription factors NF-kappaB and AP-1. Using adenoviral transfer of IkappaBalpha (IkappaBalpha overexpression), the production of TNF-alpha induced by whole GBS was inhibited by only 20%. We also show that the p38 mitogen-activated protein kinase (MAPK) pathway is involved in GBS-induced TNF-alpha secretion, because TNF-alpha protein and mRNA levels in the presence of a specific inhibitor of p38 MAPK, SB 202190, were dramatically diminished. EMSAs showed that SB 202190 inhibited GBS-induced AP-1 activation, but had no effect on NF-kappaB-DNA binding activity. These results indicate that both NF-kappaB and AP-1 (via p38 MAPK) are involved in the regulation of TNF-alpha production in GBS-stimulated neonatal monocytes. Therefore, disrupting the signal transduction pathways induced by GBS has the potential to attenuate the production of immune response mediators, thereby halting or possibly reversing the course of this potentially fatal disease.

In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4.

Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and nitric oxide (NO) may play a role in lipopolysaccharide (LPS)-induced cardiac depression. Toll-like receptor-4 (TLR-4) mediates the cytokine response to LPS in immune cells. TLR-4 also is expressed in human and murine myocardial tissue. Therefore, the hypothesis that LPS induces proinflammatory cytokines in the heart via TLR-4 was tested. C3H/HeJ (TLR-4 deficient) and C3HeB/FeJ mice were studied. LPS induced a robust increase in myocardial TNF-alpha and IL-1beta mRNA in C3HeB/FeJ mice. The response in C3H/HeJ mice was blunted and delayed. Myocardial TNF-alpha and IL-1beta protein levels were higher in C3HeB/FeJ mice, as were inducible NO synthase protein and NO production. Activation of myocardial NF-kappaB was observed within 30 min in C3HeB/FeJ mice but not in C3H/HeJ mice. These findings suggest that myocardial TLR-4 is involved in signaling cytokine production within the heart during endotoxic shock.