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Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988.

OBJECTIVE: To evaluate the effectiveness of dexamethasone in bacterial meningitis in the subcategories of causative organism and timing and nature of antibiotic therapy. DATA SOURCES: MEDLINE, HEALTHLINE, and AIDSLINE were searched with the Medical Subject Headings "dexamethasone" and "meningitis" in any language. Bibliographies, conference abstracts, and the authors of identified studies were consulted. STUDY SELECTION: Randomized, concurrently controlled trials of dexamethasone therapy in childhood bacterial meningitis published from 1988 to November 1996 were selected. Of 16 studies identified, 5 were not eligible. DATA EXTRACTION: Data were extracted by means of standard outcomes in a protocol sent to all principal authors. DATA SYNTHESIS: Random-effects meta-analysis models were used to obtain summary estimates. As the incidence of severe hearing loss differed significantly by organism among control subjects, organism-specific estimates were used. In Haemophilus influenzae type b meningitis, dexamethasone reduced severe hearing loss overall (combined odds ratio [OR], 0.31; 95% confidence interval [CI], 0.14-0.69). Similar ORs were obtained after studies were stratified by the timing of administration of dexamethasone (before or with antibiotics vs later) or by type of antibiotic (cefuroxime vs other). In pneumococcal meningitis, only studies in which dexamethasone was given early suggested protection, which was significant for severe hearing loss (combined OR, 0.09; 95% CI, 0.0-0.71) and approached significance for any neurological or hearing deficit (combined OR, 0.23; 95% CI, 0.04-1.05). For all organisms combined, the pooled OR suggested protection against neurological deficits other than hearing loss but was not significant (OR, 0.59; 95% CI, 0.34-1.02). Outcomes were similar in studies that used 2 vs more than 2 days of dexamethasone therapy. Adverse effects were not significantly increased with dexamethasone except for secondary fever. The incidence of gastrointestinal tract bleeding increased with longer duration of dexamethasone treatment (0.5% in controls, 0.8% with 2 days of treatment, 3.0% with 4 days of treatment). CONCLUSIONS: The available evidence on adjunctive dexamethasone therapy confirms benefit for H influenzae type b meningitis and, if commenced with or before parenteral antibiotics, suggests benefit for pneumococcal meningitis in childhood. Limiting dexamethasone therapy to 2 days may be optimal.

Adolescent↗

Interleukin-8 levels in children with bacterial, tuberculous and aseptic meningitis.

OBJECTIVE: lnterleukin-8 (IL-8) is produced in monocytes and vascular endothelial cells in response to stimulation with bacteria or lipopolysaccharides, and is released from these cells into blood stream or tissue fluid. METHODS: Cerebrospinal fluid (CSF) levels of interleukin-8 in 56 children with nonbacterial, bacterial and tuberculous meningitis (TBM), and in 15 control subjects were analyzed to evaluate the involvement of this cytokine in the pathogenesis acute bacterial meningitis and their discriminative value between different etiologies of meningitis. The kinetics of IL-8 concentrations during the course of bacterial meningitis was also evaluated in patients. IL-8 levels were significantly higher in bacterial and TBM than in aseptic meningitis and in control subjects (p < 0.0001). RESULTS: There was no difference in the levels of IL-8 between the non-bacterial meningitis and control groups. The analysis of the kinetics of production of IL-8 in patients with bacterial meningitis showed that the SSF concentrations of this cytokine decreased to undetectable values in recovery stage. Conversely in patients with TBM the concentrations of IL-8 were elevated in two weeks after beginning the specific treatment. CONCLUSION: The results suggest that determining IL-8 levels may be useful in the differential diagnosis.

Adolescent↗

[New developments in the diagnosis and therapy of acute bacterial meningitis].

BACKGROUND: Acute bacterial meningitis is a medical emergency. Despite advances in the diagnosis and treatment it continues to have a high case-fatality rate and high rates of long-term neurologic sequelae. ETIOLOGY: Since the widespread use of the vaccine for Haemophilus influenzae type B, Streptococcus pneumoniae has replaced it as the most common cause of acute community-acquired bacterial meningitis in industrialized countries. The rising incidence of beta-lactam-resistant pneumococci has to be considered when choosing a regimen for empiric antibiotic therapy. DIAGNOSIS: The clinical diagnosis remains difficult, as absent clinical meningeal signs do not exclude bacterial meningitis. If bacterial meningitis is considered a possible diagnosis, empiric antibiotic therapy should be initiated without any delay. Prior blood cultures and, if not contraindicated, a lumbar puncture should be performed. Based on new evidence, a screening cranial computed tomography to rule out raised intracranial pressure prior to lumbar puncture is recommended only for patients with defined risk factors (age > 60 years; preexisting immunodeficiency, immunosuppression, or neurologic diseases; recent seizures; any pathologic finding in the neurologic examination other than meningism). TREATMENT: Empiric antibiotic therapy should be initiated before cranial computed tomography. Adjuvant dexamethasone therapy initiated with or prior to the antibiotic therapy reduces mortality and morbidity for patients with pneumococcal meningitis without increasing the rate of side effects.

Acute Disease↗

Incidence and etiological agents of bacterial meningitis among children <5 years of age in two districts of Romania.

To expand upon the limited comprehensive population-based data for childhood bacterial meningitis in Eastern Europe, the present study was conducted in the Iasi and Constanta districts of Romania. From March 2000 through March 2002, children <5 years of age hospitalized for bacterial meningitis were enrolled in a prospective surveillance study. A total of 56 cases of bacterial meningitis were identified, including 37 due to Neisseria meningitidis (22 per 100,000 per year), 13 due to Haemophilus influenzae type b (7.6 per 100,000 per year), and six due to Streptococcus pneumoniae (3.5 per 100,000 per year). Of the 31 meningococcal isolates that were serotyped, 12 were serogroup A, eight were serogroup B, and 11 were serogroup C. Among all cases of bacterial meningitis, 25 occurred in children <1 year of age, including those due to meningococci (n=14), H. influenzae type b (n=7), pneumococci (n=3), and Klebsiella pneumoniae (n=1). In Romania the incidence of H. influenzae type b meningitis is similar to that found in other areas of Southern and Eastern Europe during the pre-vaccination era, and the incidence of meningococcal meningitis is one of the highest yet found in Europe. An unexpectedly high proportion of these meningococcal meningitis cases is due to serogroup A. Disease burden could be substantially reduced through the introduction of H. influenzae type b conjugate vaccine and, when available, meningococcal conjugate vaccine protective against serogroups A, B and C.

Age Distribution↗

Performance of a predictive rule to distinguish bacterial and viral meningitis.

OBJECTIVE: Although diagnostic performance has recently improved by using new diagnostic methodologies, acute patient management is usually initiated after considering only fairly elementary findings of CSF examination. Using these early findings it is often difficult to distinguish between bacterial and aseptic (viral) meningitis. In order to help distinguish these two categories, scoring tools have been proposed that are more or less complex and validated. METHODS: The aim of this study was to establish a simple scoring tool and compare it to other available decision making systems. We retrospectively analysed all the meningitis cases from our patients at our institution and established a scoring tool for pediatric meningitis and for meningitis in adults by using categorized analysis tree methodology. RESULTS: Main categories for bacterial etiology were, leucocytosis >15 giga, CSF leucocytes count >1700 per ml, CSF neutrophil percentage >80, CSF protein >2.3g/l and glucose CSF/blood ratio <0.33 for adults and CSF leucocytes count >1800, CSF neutrophil percentage >80, CSF protein >1.2g/l and glucose CSF/blood ratio <0.3 for children. Additionally, our new scoring tool and five published ones were compared using our data and two external data sets; from these scores, three, including ours, exhibited good sensitivity and specificity. We then performed several thousand Monte Carlo simulations of both bacterial and viral meningitis for children and adults. We found that our scoring tool (Meningitest) had very high performances with positive and negative predictive values of 97% and 94%, respectively. CONCLUSION: Thus, from this analysis of five meningitis scoring systems, we believe that our new tool is simple, does not need any complex calculation and is effective in identifying bacterial vs viral meningitis in fully immunocompetent children and adults.

Adult↗

Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe, and seasonal.

We prospectively collected laboratory details and outcome data on all patients with laboratory-confirmed cases of meningitis that presented to our unit in Blantyre, Malawi, from 1 April 1998 through 31 March 1999. There were 502 patients with cases of meningitis; the most common causative organisms were Cryptococcus neoformans and Streptococcus pneumoniae. This pattern probably reflects the local human immunodeficiency virus (HIV) seroprevalence (31%) and is different from the pattern in 1974, when Neisseria meningitidis was the most common isolate. There has been an 8-fold increase in the number of meningitis cases per year since 1974, and a doubling of the percentage of medical admissions due to meningitis. The inpatient mortality rate among patients with cases of pneumococcal meningitis was 61%, and in the group as a whole was 41%. Despite the HIV-related pattern of infecting pathogens among these cases of meningitis and the increased incidence of the condition, there was evidence that the typical seasonal pattern of pneumococcal meningitis, which peaks in the cold, dry season, was preserved.

Adult↗

Comparison of the efficacy and safety of ceftriaxone to ampicillin/chloramphenicol in the treatment of childhood meningitis.

Ceftriaxone is a new cephalosporin with a broad spectrum of antibacterial activity and unique serum and CSF pharmacokinetics. The drug was compared in a randomized fashion with ampicillin and chloramphenicol in the treatment of 19 children with Haemophilus influenzae type b meningitis. Ceftriaxone was also administered non-randomly to six other patients including three children with Gram-negative meningitis. Among the children with H. influenzae meningitis, no deaths were noted and the outcomes of the study and the control groups were similar. Ninety per cent of the isolates of H. influenzae were inhibited by 0.0625, 1 and 1 mg/l of ceftriaxone, ampicillin and chloramphenicol respectively. One child with pneumococcal meningitis and two children with meningococcal meningitis recovered rapidly and without incident during ceftriaxone therapy. Three children with Gram-negative meningitis caused by multiply-drug resistant organisms were bacteriologically cured within five days of the onset of therapy. Persistent pleocytosis and neurological disabilities were noted in two at the conclusion of therapy. Ceftriaxone, as a single agent, was comparable in efficacy with traditional antimicrobial therapy usually employed in childhood meningitis.

Adolescent↗

CBC differential profile in distinguishing etiology of neonatal meningitis.

A retrospective study of 72 infants under four weeks of age with meningitis evaluated over almost four years was performed to determine the predictive value of the CBC differential ratio (% lymphocytes + % monocytes/% polymorphonuclear leukocytes + % band forms) profile in distinguishing those with bacterial from those with a nonbacterial etiology. Of 18 neonates with bacterial meningitis, all had a radio lower than one; of 54 neonates with aseptic or viral meningitis, 46 (85%) had a ratio greater than one. The difference between mean ratio values of the two groups was highly significant (P less than 0.001). A CBC differential ratio less than one was more sensitive (100%) in initially identifying neonates with bacterial meningitis than were other traditionally utilized parameters, eg, presence of fever (50%), ill appearance (50%), hypoglycorrhachia (61%), elevated CSF protein (55%), or CSF Gram-stained smear revealing pathogenic organisms (45%). Statistical analysis revealed that a CBC differential ratio less than 1.5 will accurately predict all cases of neonatal bacterial meningitis with a confidence of 99.95%. The CBC differential ratio is an accurate index for distinguishing neonates with bacterial meningitis from those with nonbacterial meningitis. Utilization of this parameter in conjunction with other traditional factors is efficacious in predicting outcome.

Blood Cell Count↗

Neonatal meningitis in England and Wales: 10 years on.

OBJECTIVES: To determine the incidence of neonatal meningitis in England and Wales. DESIGN: A national postal survey using the British Paediatric Surveillance Unit (BPSU) card scheme supplemented by information from other sources. SETTING: England and Wales 1996-1997. SUBJECTS: A total of 274 babies less than 28 days of age who were treated for meningitis. RESULTS: The incidence of neonatal meningitis in England and Wales has not changed since our previous study in 1985-1987. However, the acute phase mortality has fallen from 19.8% in 1985-1987 to 6.6% in this study. Group B streptococci (42%) and Escherichia coli (16%) remain the most common infecting microorganisms. Eight of 69 (12%) babies with group B streptococci and 4/26 (15%) with E coli died. Antibiotic regimens based on the third generation cephalosporins, notably cefotaxime, were most commonly used (84%). The BPSU scheme identified 72% of cases during the study period. Most cases of viral meningitis were not reported through the BPSU. Less than a third of samples from aseptic meningitis were examined for viruses; 56% of these were positive. CONCLUSIONS: Although the incidence of neonatal meningitis remains unchanged, mortality from this infection has fallen significantly. If this improvement is maintained as reflected in the level of sequelae at 5 years of age, then the fear surrounding meningitis during the neonatal period will have been dramatically reduced.

Anti-Infective Agents↗

Treatment of purulent meningitis with a new cephalosporin-Rocephin (Ro 13-9904). Clinical, bacteriological and pharmacological observations in 24 cases.

In 21 of the 24 cases the diagnosis of purulent meningitis was confirmed by culturing the causal agent and/or by immunological diagnosis. The daily dosage of Rocephin ranged between 15 and 200 mg/kg administered in 2 i.m. injections. A cure was achieved in cases of meningococcal meningitis (1 case with sequelae: blindness in one eye), in 5 out of 6 cases of Haemophilus influenzae meningitis (1 case with severe neuropsychiatric sequelae), in 3 out of 9 cases of pneumococcal meningitis and in 2 out of 4 cases of enterobacterial meningitis. The tolerance was generally excellent. Sterilisation of the cerebrospinal fluid (CSF) was achieved in all 20 cases of meningitis confirmed by culture. The MIC levels are lower than the lowest CSF peak for Rocephin found in this study. The unusual pharmacological behavior of Rocephin makes it possible to achieve and to maintain for a long time highly satisfactory concentration levels in the CSF. These properties of Rocephin should lift the long-standing objections to the use of cephalosporins for the treatment of purulent meningitis.

Adolescent↗

Discrimination between viral and nonviral meningitis by visually analyzed and quantitative electroencephalography.

A prospective study was conducted to assess the ability of the visually analyzed electroencephalogram (VEEG), the quantitative EEG (QEEG) and the Glasgow Coma Scale (GCS) to discriminate between patients with viral and nonviral meningitis. The 55 subjects, aged 14-75 years, fell into one of the following categories: viral (n = 12), bacterial (n = 19), tuberculous (n = 16) or cryptococcal (n = 8) meningitis. EEG recordings and Glasgow Coma Scale (GCS) scores were obtained within 48 hours of admission to hospital. The sensitivity of the VEEG and QEEG for the prediction of patients with nonviral meningitis (true positives in this context) attained reasonably high values of 70% and 80%, respectively. In contrast, the sensitivity of the GCS was only 38%. Each of the three tests achieved high degrees of consistency in this regard with positive predictive values of 94% or better. The specificity for each of the three tests was high, 100% for the VEEG and the GCS and 82% for the QEEG indicating a high probability for the correct prediction of viral meningitis (true negatives). The consistency of this prediction was, however, poor due to negative predictive values of only 53% for the QEEG, 48% for the VEEG and 32% for the GCS. The QEEG results did not reveal any obvious advantages over the VEEG. Rather the assessment of the occurrence of particular VEEG abnormalities showed that patients with delta abnormalities had a very high probability of nonviral meningitis. At the other end of the spectrum, all normal VEEGs occurred in viral meningitis. In important respects the predictive ability of the EEG was superior to that of the GCS. While there was statistically significant agreement between the VEEG and GCS, the degree of agreement was poor. This study indicates that the EEG is a valuable and probably underestimated test in the acute phase of meningitis and provides complementary information to the GCS.

Adolescent↗

Penetration of ciprofloxacin into the spinal fluid in patients with viral and bacterial meningitis.

Cerebrospinal fluid (CSF) concentrations of ciprofloxacin (Ciprobay) were measured by high performance liquid chromatography (HPLC) in 20 patients with varying degrees of meningeal inflammation. Underlying clinical syndromes were viral meningitis (n = 10), convalescent phase of acute bacterial meningitis (n = 9), and acute phase of bacterial meningitis (n = 1). CSF concentrations following an intravenous dose of 200 mg ranged between 0.028 and 0.11 mg/l (5.8-26.8% of corresponding serum levels) in patients with viral meningitis, and between 0.049 and 0.389 mg/l (5.9-77.0% of corresponding serum levels) in patients with bacterial meningitis. Taken together with the findings of other authors, the results indicate a potential usefulness of ciprofloxacin as an alternative agent for treatment of meningitis due to susceptible gram-negative microorganisms.

Adult↗

Acute bacterial meningitis in children in Hefei, China 1990-1992.

OBJECTIVE: To obtain etiologic and epidemiologic information about bacterial meningitis, especially the H influenza type B (Hib), from a medium-sized city, Hefei, China. METHODS: Data were collected prospectively over 3 years, from 1990 to 1992 by a well-organized group including 13 hospitals. All children with a clinical diagnosis of acute bacterial meningitis were enrolled and the specimens were taken for the etiologic studies. CSF and blood were tested by standard bacteriologic technique. CSF, blood and concentrated urine were tested directly for detection of antigen by countercurrent immuno-electrophoresis (CIE). Data were analyzed by epidemiologic methods. RESULTS: Bacterial culture and CSF Gram's staining were positive only in 13.3% and 11.7%, respectively. Bacterial antigen detection was positive in up to 90% by CIE which was more sensitive than bacterial culture (chi 2 = 67.7, P < 0.005). The annual incidence of acute bacterial meningitis in the city is calculated as 9.3 cases/100,000 children from 1 month to 15 years of age and 19.2 cases/100,000 children from 1 month to 5 years of age. Hib meningitis accounted for 51.7%, N. meningitis (Nm) for 38.3%, and S. pneumoniae (Sp) for 8.3%. There was no significant seasonal variation. Of the patients, 76.7% were children under 5 years of age, and 51.7% under 1 year of age. The case fatality rate was 11.7% for all bacterial meningitis, 9.7% for Hib, 17.4% for Nm and 20% for Sp. A total of 22.6% of survivors suffered from neurological or psychological problems. CONCLUSIONS: Using antigen detection combined with bacterial culture, we could make an etiologic diagnosis in up to 90% of the patients in this group. Hib, Nm and Sp were the predominant pathogens, which was similar to the findings in other countries. Hib was the most common cause of bacterial meningitis, but the incidence was much lower than in most parts of the world.

Child↗

[Epidemiology of bacterial meningitis in France in 1999].

In France, two sources of data, the mandatory notification and the laboratory network EPIBAC, allow the health authorities to follow the incidence of bacterial meningitis (BM) and to assess the relative frequency of the micro-organisms responsible for such infection. In 1999, more than 1,000 cases of BM were notified in France. The more common micro-organisms were: Streptococcus pneumoniae 46%, Neisseria meningitidis 32% and Streptococcus agalactiae(or Streptococcus B) 11%. Listeria monocytogenes and Haemophilus influenzae accounted for 6% and 5% of the cases respectively. In 1999, the incidence per 100,000 inhabitants of meningitis due to pneumococci (0.81), to streptococci B (0.19) and tuberculosis meningitis (0.17) were stable since 1995. The incidence rate of meningitis due to Listeria (0.10) and to H. influenzae (0.08) shows a regular decrease since 1992. The impact of preventive measures of meningitis due to Listeria and H. influenzae B has been clearly demonstrated through the dramatic decrease of meningitis due to these micro-organisms.

Adolescent↗

Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine.

Migraine is among the most common types of pain, but its mechanisms are poorly understood. A growing body of evidence points to a critical role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine headache. During migraine, CGRP is thought to be released from peripheral endings of perivascular meningeal nociceptors primary and to promote vasodilatation. A current hypothesis suggests that peripheral CGRP and its related meningeal vasodilatation results in activation and sensitization, leading to the generation of migraine headache. However, direct evidence supporting this idea is lacking. Here, using electrophysiological, extracellular, single-unit recording combined with laser-Doppler flowmetry measurements of dural blood flow (DBF), we examined whether CGRP and meningeal vasodilatation promote activation or sensitization of meningeal nociceptors. Changes in (DBF), ongoing discharge, and responsiveness to mechanical stimulation of the dura were studied after either topical administration or intravenous infusion of rat alpha-CGRP in anesthetized rats. Both topical and systemic administration of CGRP caused a significant increase in dural blood flow; however, neither method of CGRP administration resulted in activation or sensitization of meningeal nociceptors. The results of this study suggest that CGRP effects in the meninges, including meningeal vasodilatation, are not sufficient to activate or sensitize meningeal nociceptors.

Action Potentials↗

Spinal perineurial and meningeal cysts.

Perineurial cysts may be responsible for clinical symptoms and a cure effected by their removal. They do not fill on initial myelography but may fill with Pantopaque some time, days or weeks, after Pantopaque has been instilled into the subarachnoid space. Perineurial cysts arise at the site of the posterior root ganglion. The cyst wall is composed of neural tissue. When initial myelography fails to reveal an adequate cause for the patient's symptoms and signs referable to the caudal nerve roots, then about a millilitre of Pantopaque should be left in the canal for delayed myelography which may later reveal a sacral perineurial cyst or, occasionally, a meningeal cyst. Meningeal diverticula occur proximal to the posterior root ganglia and usually fill on initial myelography. They are in free communication with the subarachnoid space and are rarely in my experience responsible for clinical symptoms. Meningeal diverticula and meningeal cysts appear to represent a continuum. Pantopaque left in the subarachnoid space may convert a meningeal diverticulum into an expanding symptomatic meningeal cyst, as in the case described. Many cases described as perineurial cysts represent abnormally long arachnoidal prolongations over nerve roots or meningeal diverticula. In general, neither of the latter is of pathological significance. Perineurial, like meningeal cysts and diverticula, may be asymptomatic. They should be operated upon only if they produce progressive or disabling symptoms or signs clearly attributable to them. When myelography must be done, and this should be done only as a preliminary to a probable necessary operation, then patient effort should be made to remove the Pantopaque.

Adolescent↗

[Diagnosis of meningitis with reagent strips]

OBJECTIVE: To determine the usefulness of reagent strips in the evaluation of pleocytosis, cerebrospinal fluid glucose and protein levels for early and rapid diagnosis of meningitis in children. METHODS: We included cerebrospinal fluid samples of 164 children admitted to the outpatient clinic of Communicable Diseases of the General Pediatric Center (Fundação Hospitalar do Estado de Minas Gerais, CGP-FHEMIG) during the daytime hours from May of 1997 to May 1999, and who presented with clinical suspicion of meningitis. Patients ranged in age from one month to 12 years (median 12 months). Results from the cytological and biochemical assay (cellularity, cerebrospinal fluid glucose and protein levels) were obtained from 154 patients. These results were subsequently compared with the reaction of cerebrospinal fluid in reagent strips. RESULTS: The cytological and biochemical assay identified 43 cases of probable bacterial meningitis, 19 of probable viral meningitis, and 83 with no alterations. According to the reagent strips, there were 41 cases of probable bacterial meningitis, 2 of probable viral meningitis, and 71 with no alterations. By comparing the results of reagent strips and those of the cytological and biochemical assay, we obtained values for sensitivity, specificity, positive and negative predictive values, and accuracy (respectively 90.7; 98.1; 95.1; 96.4; and 96.1). Statistical analysis using McNemer test did not indicate significant differences between the two methods in the diagnosis of bacterial meningitis (P=0.68). Kappa statistics indicated a high level of agreement between the tests (P<0.0001). CONCLUSIONS: Our results suggest that reagent strips may be a useful additional resource in the diagnosis of bacterial meningitis, especially when it is difficult to collect a sufficient amount of cerebrospinal fluid or to indicate the initial treatment.

Journal Article↗

Vasopressin levels in infants during the course of aseptic and bacterial meningitis.

We measured urine vasopressin (VP) once daily on days 1 through 3 in 18 patients hospitalized with meningitis. Urine VP values were 215 +/- 100, 116 +/- 44, and 69 +/- 23 pg/mL on days 1 through 3, respectively, for children with bacterial meningitis and 34 +/- 14, 20 +/- 4, and 15 +/- 4 pg/mL for those with aseptic meningitis. Urinary VP levels of infants with bacterial meningitis were significantly greater than those of healthy ambulatory subjects (n = 18) on all three study days; VP values of infants with bacterial meningitis were also greater than those of infants with aseptic meningitis on study days 2 and 3. The VP levels for the subjects with aseptic meningitis were significantly greater than those of the controls on day 1 only. None of the infants exhibited the clinical syndrome of inappropriate antidiuretic hormone secretion.

Bacterial Infections↗