Hamid Jafari

Dexamethasone therapy in bacterial meningitis.

We enrolled 200 infants and older children with bacterial meningitis in two prospective double-blind, placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime (Study 1) or ceftriaxone (Study 2). Altogether, 98 patients received placebo and 102 received dexamethasone (0.15 mg per kilogram of body weight every six hours for four days). At the beginning of therapy, the clinical and demographic characteristics of the patients in the treatment groups were comparable. The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo (glucose, 2.0 vs. 0.4 mmol per liter [36.0 vs. 6.9 mg per deciliter], P less than 0.001; lactate, 4.0 vs. 2.1 mmol per liter [38.3 vs. 19.8 mg per deciliter], P less than 0.001; and protein, 0.64 vs. 0.25 g per liter [64.0 vs. 25.3 mg per deciliter], P less than 0.05). One patient in the placebo group in Study 1 died. As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P less than 0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P less than 0.01). Twelve patients in the two placebo groups (14 percent) had severe or profound bilateral hearing loss requiring the use of a hearing aid, as compared with 1 (1 percent) in the two dexamethasone groups (P less than 0.001). We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis, particularly in preventing deafness.

Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis.

Antiinflammatory therapy has been shown to reduce the adverse pathophysiological consequences that occur in bacterial meningitis and to improve outcome from disease. In the present study, modulation of two principal steps of the meningeal inflammatory cascade was accomplished by concomitant administration of dexamethasone to diminish overproduction of cytokines in response to a bacterial stimulus and of a monoclonal antibody directed against adhesion-promoting receptors on leukocytes to inhibit recruitment of white blood cells into the subarachnoid space. Dexamethasone and antibody therapy produced a marked attenuation of all indices of meningeal inflammation and reduction of brain water accumulation after H. influenzae-induced meningitis in rabbits compared with results of each agent given alone and of untreated animals. In addition, the enhanced hosts meningeal inflammatory reaction that follows antibiotic-induced bacterial lysis was profoundly ameliorated when dual therapy was administered without affecting clearance rates of bacteria from cerebrospinal fluid and vascular compartments. The combination of both therapeutic approaches may offer a promising mode of treatment to improve further the outcome from bacterial meningitis.

Immunogenicity of supplemental doses of poliovirus vaccine for children aged 6-9 months in Moradabad, India: a community-based, randomised controlled trial

BACKGROUNDnThe continued presence of polio in northern India poses challenges to the interruption of wild poliovirus transmission and the management of poliovirus risks in the post-eradication era. We aimed to assess the current immunity profile after routine doses of trivalent oral poliovirus vaccine (OPV) and numerous supplemental doses of type-1 monovalent OPV (mOPV1), and compared the effect of five vaccine formulations and dosages on residual immunity gaps.nnnMETHODSnWe did a community-based, randomised controlled trial of healthy infants aged 6-9 months at ten sites in Moradabad, India. Serum neutralising antibody was measured before infants were randomly assigned to a study group and given standard-potency or higher-potency mOPV1, intradermal fractional-dose inactivated poliovirus vaccine (IPV, GlaxoSmithKline), or intramuscular full-dose IPV from two different manufacturers (GlaxoSmithKline or Panacea). Follow-up sera were taken at days 7 and 28. Our primary endpoint was an increase of more than four times in antibody titres. We did analyses by per-protocol in children with a blood sample available before, and 28 days after, receiving study vaccine (or who completed study procedures). This trial is registered with Current Controlled Trials, number ISRCTN90744784.nnnFINDINGSnOf 1002 children enrolled, 869 (87%) completed study procedures (ie, blood sample available at day 0 and day 28). At baseline, 862 (99%), 625 (72%), and 418 (48%) had detectable antibodies to poliovirus types 1, 2, and 3, respectively. In children who were type-1 seropositive, an increase of more than four times in antibody titre was detected 28 days after they were given standard-potency mOPV1 (5/13 [38%]), higher-potency mOPV1 (6/21 [29%]), intradermal IPV (9/16 [56%]), GlaxoSmithKline intramuscular IPV (19/22 [86%]), and Panacea intramuscular IPV (11/13 [85%]). In those who were type-2 seronegative, 42 (100%) of 42 seroconverted after GlaxoSmithKline intramuscular IPV, and 24 (59%) of 41 after intradermal IPV (p<0·0001). 87 (90%) of 97 infants who were type-3 seronegative seroconverted after intramuscular IPV, and 21 (36%) of 49 after intradermal IPV (p<0·0001).nnnINTERPRETATIONnSupplemental mOPV1 resulted in almost total seroprevalence against poliovirus type 1, which is consistent with recent absence of poliomyelitis cases; whereas seroprevalence against types 2 and 3 was expected for routine vaccination histories. The immunogenicity of IPV produced in India (Panacea) was similar to that of an internationally manufactured IPV (GSK). Intradermal IPV was less immunogenic.

Asymptomatic Wild-Type Poliovirus Infection in India among Children with Previous Oral Poliovirus Vaccination

BACKGROUNDnMucosal immunity induced by oral poliovirus vaccine (OPV) is imperfect and potentially allows immunized individuals to participate in asymptomatic wild-type poliovirus transmission in settings with efficient fecal-oral transmission of infection.nnnMETHODSnWe examined the extent of asymptomatic wild-type poliovirus transmission in India by measuring the prevalence of virus in stool samples obtained from 14,005 healthy children who were in contact with 2761 individuals with suspected poliomyelitis reported during the period 2003-2008.nnnRESULTSnWild-type poliovirus serotypes 1 and 3 were isolated from the stool samples of 103 (0.74%) and 104 (0.74%) healthy contacts, respectively. Among contacts of individuals with laboratory-confirmed poliomyelitis, 27 (12.7%) of 213 and 29 (13.9%) of 209 had serotypes 1 and 3, respectively, isolated from their stool samples. The odds ratio of excreting serotype 1 wild-type poliovirus was 0.13 (95% confidence interval, 0.02-0.87) among healthy children reporting 6 doses of OPV, compared with children reporting 0-2 doses. However, two-thirds of healthy children who excreted this virus reported >or=6 doses, and the prevalence of this virus did not decrease with age over the sampled range.nnnCONCLUSIONSnAlthough OPV is protective against infection with poliovirus, the majority of healthy contacts who excreted wild-type poliovirus were well vaccinated. This is consistent with a potential role for OPV-vaccinated children in continued wild-type poliovirus transmission and requires further study.

Global Polio Eradication Initiative: Lessons Learned and Legacy

The world is on the verge of achieving global polio eradication. During >25 years of operations, the Global Polio Eradication Initiative (GPEI) has mobilized and trained millions of volunteers, social mobilizers, and health workers; accessed households untouched by other health initiatives; mapped and brought health interventions to chronically neglected and underserved communities; and established a standardized, real-time global surveillance and response capacity. It is important to document the lessons learned from polio eradication, especially because it is one of the largest ever global health initiatives. The health community has an obligation to ensure that these lessons and the knowledge generated are shared and contribute to real, sustained changes in our approach to global health. We have summarized what we believe are 10 leading lessons learned from the polio eradication initiative. We have the opportunity and obligation to build a better future by applying the lessons learned from GPEI and its infrastructure and unique functions to other global health priorities and initiatives. In so doing, we can extend the global public good gained by ending for all time one of the worlds most devastating diseases by also ensuring that these investments provide public health dividends and benefits for years to come.

Effects of antifungal therapy on inflammation, sterilization, and histology in experimental Candida albicans meningitis.

To assess the effects of antifungal therapy on the course of Candida albicans central nervous system infection and inflammation, we inoculated intracisternally 10(5) CFU of C. albicans into rabbits. Fluconazole (10 mg/kg of body weight) or amphotericin B (1 mg/kg) was infused intravenously daily for 14 days. Treatment was initiated 24 h or 5 days after infection. Cerebrospinal fluid (CSF) was repeatedly obtained to culture the organisms, assess the level of inflammation, and measure drug concentrations. Brain tissue was obtained at the end of therapy for culture, drug concentration determinations, and histopathology. The median number of days of treatment required to sterilize CSF cultures was 4 days for fluconazole therapy and 1 day for amphotericin B therapy (P = 0.037). There was a significant reduction in tumor necrosis factor alpha and leukocyte concentrations in the CSF of animals treated early versus those in untreated control animals (P < 0.05 and P < 0.001, respectively; analysis of variance). Compared with treated animals, a higher proportion of cultured CSF samples from untreated animals were positive for Candida (P < 0.001). A cultured brain sample from 1 of the 12 animals treated early with amphotericin B was positive for C. albicans (P < 0.01 versus controls); cultures of brain samples from 3 of 12 animals treated early with fluconazole were positive, whereas cultures of brain samples from 10 of 12 controls were positive (P < 0.05). The mean density of C. albicans was lower in the single culture-positive amphotericin B recipient (1 x 10(1) CFU/g of brain tissue) than in those treated with fluconazole (1 x 10(3) CFU/g) and in controls (8 x 10(4) CFU/g). In animals treated late, the density of C. albicans in the brain in relation to the number of days of therapy was significantly lower in amphotericin B recipients than in those treated with fluconazole (P < 0.01) and untreated controls (P < 0.01; analysis of covariance). By histopathology, a larger proportion of untreated animals compared with those treated early demonstrated features of severe infection such as perivasculitis, ventriculitis, and evidence of fungal organisms. Compared with amphotericin B-treated rabbits, those given fluconazole had a trend toward more severe pathologic lesions. Reduced susceptibility to both fluconazole and amphotericin B was observed in the C. albicans organisms isolated from the brain of one fluconazole-treated animal. These data suggest that amphotericin B is the preferred treatment for C. albicans infections of the central nervous system.

Assessing Population Immunity in a Persistently High-Risk Area for Wild Poliovirus Transmission in India: A Serological Study in Moradabad, Western Uttar Pradesh

BACKGROUNDnMoradabad district in Uttar Pradesh reported the highest number of paralytic polio cases in India during 2001-2007. We conducted a study in Moradabad in 2007 to assess seroprevalence against poliovirus types 1, 2, and 3 in children 6-12 and 36-59 months of age to guide future strategies to interrupt wild poliovirus transmission in high-risk areas.nnnMETHODSnChildren attending 10 health facilities for minor illnesses who met criteria for study inclusion were eligible for enrollment. We recorded vaccination history, weight, and length and tested sera for neutralizing antibodies to poliovirus types 1, 2, and 3.nnnRESULTSnPoliovirus type 1, 2, and 3 seroprevalences were 88% (95% confidence interval [CI], 84%-91%), 70% (95% CI, 66%-75%), and 75% (95% CI, 71%-79%), respectively, among 467 in the younger age group (n=467), compared with 100% (95% CI, 99%-100%), 97% (95% CI, 95%-98%), and 93% (91%-95%), respectively, among 447 children in the older age group (P<.001 for all serotypes).nnnCONCLUSIONSnThis seroprevalence study provided extremely useful information that was used by the program in India to guide immunization policies, such as optimizing the use of different OPV formulations in vaccination campaigns and strengthening routine immunization services. Similar surveys in populations at risk should be performed at regular intervals in countries where the risk of persistence or spread of indigenous or imported wild poliovirus is high.

Pharmacokinetics and antibacterial efficacy of cefpirome (HR 810) in experimental Escherichia coli and Haemophilus influenzae type b meningitis.

Cefpirome (HR 810) is a new cephalosporin related to cefotaxime that has potent bactericidal activity against a broad spectrum of gram-negative and gram-positive organisms. The pharmacokinetics and bacteriological efficacy of cefpirome administered as a single intravenous dose were assessed in rabbits with experimental Haemophilus influenzae type b and Escherichia coli K1 meningitis. The mean penetrations into the cerebrospinal fluid (CSF) in relation to the amount of drug in serum of animals infected with H. influenzae and E. coli were 25 and 54%, respectively. The median CSF bactericidal titers were 1:128 against both organisms at 1 h of uninfected animals, the mean penetration was 4.5%. There was a significant reduction in the concentrations of bacteria in CSFs of both groups of animals treated with cefpirome compared with that in untreated groups. Mortality was also significantly lower in treated animals than it was in untreated animals. Intravenous administration of dexamethasone before the cefpirome dose did not compromise penetration, bactericidal titers, or antibacterial activity of cefpirome in CSF.

Prevalence of Asymptomatic Poliovirus Infection in Older Children and Adults in Northern India: Analysis of Contact and Enhanced Community Surveillance, 2009

BACKGROUNDnIn 2009, enhanced poliovirus surveillance was established in polio-endemic areas of Uttar Pradesh and Bihar, India, to assess poliovirus infection in older individuals.nnnMETHODSnIn Uttar Pradesh, stool specimens from asymptomatic household and neighborhood contacts of patients with laboratory-confirmed polio were tested for polioviruses. In Bihar, in community-based surveillance, children and adults from 250 randomly selected households in the Kosi River area provided stool and pharyngeal swab samples that were tested for polioviruses. A descriptive analysis of surveillance data was performed.nnnRESULTSnIn Uttar Pradesh, 89 of 1842 healthy contacts of case patients with polio (4.8%) were shedding wild poliovirus (WPV); 54 of 85 (63.5%) were ≥5 years of age. Shedding was significantly higher in index households than in neighborhood households (P<.05). In Bihar, 11 of 451 healthy persons (2.4%) were shedding WPV in their stool; 6 of 11 (54.5%) were ≥5 years of age. Mean viral titer was similar in older and younger children.nnnCONCLUSIONSnA high proportion of persons≥5 years of age were asymptomatically shedding polioviruses. These findings provide indirect evidence that older individuals could have contributed to community transmission of WPV in India. Polio vaccination campaigns generally target children<5 years of age. Expanding this target age group in polio-endemic areas could accelerate polio eradication.