Research matters

New tool aids paediatricians in distinguishing viral meningitis from bacterial

A simple algorithm may help doctors distinguish infants and children with viral meningitis from those with bacterial meningitis, potentially reducing unnecessary hospital admissions and prolonged antibiotic treatment.

The suggested guidelines, published in the 3 January issue of the Journal of the American Medical Association, are based on the review of medical charts from thousands of children diagnosed with meningitis at 20 academic medical centers across the United States from January 2001 to June 2004.

“Using a multicenter network of US hospitals that care for acutely ill children, we showed our algorithm effectively identified children with meningitis who are at very low risk of having bacterial meningitis,” said Dr Lise Nigrovic, of the Division of Emergency Medicine at Children’s Hospital Boston and principal investigator of the study. “The finding is important because it gives emergency room physicians a tool to guide their decision-making when caring for children with suspected meningitis.”

Meningitis is usually initially recognised by a higher number of white blood cells in the spinal fluid than normal. While viral infections cause most meningitis cases, approximately one in 25 cases are caused by bacterial or fungal infections, which yield the most severe illness. Although the best course of treatment depends on identifying the strain of infection, definitive test results can take 24 to 72 hours to process, and children are often admitted to hospitals and started on antibiotics while physicians wait for these results.

“Viral or ‘aseptic’ meningitis beyond young infancy is usually a mild disease, while meningitis caused by bacteria can cause serious illness and death,” said Dr Nathan Kuppermann, professor and chair of the Emergency Department at UC Davis Medical Center and a senior author on the study. “Even though most patients will turn out to have viral meningitis, paediatric emergency department physicians usually hospitalise any child with meningitis to receive broad-spectrum antibiotics while waiting two to three days for the bacterial culture results.

“The ability to identify those children who are at very low risk of bacterial meningitis and can be considered for management on an outpatient basis will avoid unnecessary hospitalisation and aggressive antibiotic therapy.”

The Bacterial Meningitis Score classifies patients as being at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/µL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10000 cells/µL, and a history of seizure before or at the time of presentation.Nigrovic developed the algorithm in 2002 with Kuppermann and Dr Richard Malley, of Children’s Divisions of Emergency Medicine and Infectious Diseases at Children’s Hospital Boston and also a senior author on the study.

“The Bacterial Meningitis Score accurately identified patients at very low risk of bacterial meningitis, misclassifying only 0.1% of patients categorised as very low risk,” said Malley. “To our knowledge, this is the first bacterial meningitis prediction model to be externally validated and studied at multiple centers in the era of widespread conjugate pneumococcal immunisation.”

Study limitations include retrospective design subject to potential information bias, blood cultures available for only 90% of the study patients, potential errors in emergency department diagnosis coding, and the possibility that some patients with no predictors of bacterial meningitis have other infections requiring antimicrobial therapy.

“The Bacterial Meningitis Score should be used in concert with careful clinical assessment of the patient, which would include consideration of these other important treatable infections,” the authors conclude.

“In addition, the Bacterial Meningitis Score is designed to serve as an assistive clinical prediction rule to help guide clinical decision making, and not to serve as a directive decision rule that explicitly dictates clinical care. We would particularly caution against the use of the Bacterial Meningitis Score for infants younger than 2 months for whom the Bacterial Meningitis Score may be less accurate, and who may not be appropriate candidates for outpatient management.”

Neurology

New research explores potential relationship between delirium and dementia

Dementia, including Alzheimer’s disease, is one of the most devastating conditions of older age. Currently affecting nearly 24 million people worldwide, dementia leads to total loss of memory and the ability to function independently.

Delirium is an acute confusional state, a common and serious complication in older individuals that often follows surgery or serious illness. Typically accompanied by disorientation, paranoia and hallucinations, delirium develops in 14 to 56% of all hospitalised seniors.

To date, dementia and delirium have typically been viewed as separate and distinct conditions. However a dedicated section of The Journal of Gerontology: Medical Sciences, in the January 2007 edition, examined their interface, asking: ‘Can delirium itself lead to the development of a cognitive disorder? Do delirium and dementia represent opposite ends of the same spectrum of disease, rather than two separate conditions?’

“I have been studying delirium for 20 years,” says Dr Sharon Inouye, a geriatrician at Beth Israel Deaconess Medical Center and Director of the Aging Brain Center at the Institute for Aging Research, Hebrew SeniorLife. “And the more cases I encounter, the more linkages I see with dementia. For a large proportion of older patients, the problem [of delirium] is never resolved. I routinely hear from patients’ families, ‘They went into the hospital, they became very confused, and they never recovered.’”

Inouye, a professor of medicine at Harvard Medical School, together with Dr Luigi Ferrucci, chief of the longitudinal studies section of the National Institute on Aging and editor-in-chief of the journal, examined the relationship between these two widespread conditions during ‘The Aging Brain Center Scientific Symposium: The Interface of Delirium and Dementia’, held last spring.

“Better understanding of delirium may represent a new window of opportunity for the prevention of dementia,” explains Ferrucci. “We decided to approach the subject from a multidisciplinary perspective, exploring delirium and dementia from a number of vantage points.” Findings spawned from the symposium make up the five articles featured in the special issue of the journal, including:

• Biomarkers

“There is currently no way of identifying delirium save for the observations of an astute clinician,” notes Inouye. In this review article, geriatrician Edward Marcantonio, of Beth Israel Deaconess Medical Center (BIDMC), examines a number of promising biomarkers for delirium, including serum chemistries, genetic markers, serum anticholinergic activity, neurotransmitters, inflammatory markers and cortisol.

• Role of neuroimaging.

Physicist David Alsop, PhD, of BIDMC’s Department of Radiology, describes major advances in neuroimaging, including methods using magnetic resonance (MR) imaging, positron emission tomography (PET) and single photo emission computed tomography (SPECT). These methods offer the possibility of using highly sensitive imaging techniques to detect changes in the brain following episodes of delirium and thereby investigate the mechanisms and networks involved in its onset and consequences.

• Use of SPECT scanning to assess cerebral perfusion changes in patients with delirium.

Led by Dr Tamara Fong, of BIDMC’s Department of Neurology, this paper describes a study examining a group of hospitalised patients, which shows that frontal or parietal cerebral perfusion abnormalities occur in cases of delirium. These results suggest localised involvement in the brain’s frontal and parietal lobes with delirium, which may correlate with the clinical findings and long-term outcomes.

• The link between anaesthesia and development of long-term delirium.

Dr Zhongcong Xie, together with senior author Dr Rudolph Tanzi of the Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, demonstrate that the commonly used anaesthetic isoflurane results in neuronal cell death, and enhancement of A-beta oligomerization. For the first time, this provides a direct link between the acute effects of inhalational anaesthetics (recognised risk factors for delirium) and the hallmark mechanisms of Alzheimer’s disease neuropathogenesis.

• The potential role for cognitive reserve.

Inouye, together with BIDMC gerontologist Richard Jones, ScD, an investigator in the Institute for Aging Research at Hebrew SeniorLife, report their findings showing that hospitalised older persons with lower levels of education may be at increased risk for delirium relative to older persons with more education.

“People have varying degrees of cognitive reserve, the capability to withstand insults and stresses to their system [such as might occur in a hospital setting],” explains Inouye. “Our study shows that amount of education correlates with brain resiliency, perhaps by building greater numbers of neuronal pathways.”

In a 1999 study in The New England Journal of Medicine, Inouye demonstrated that delirium can be decreased by 40% by implementing a number of straightforward interventions while patients are hospitalised. These include making sure that patients are oriented and hydrated, that they are up and walking, that they are using their hearing aids and vision aids, and that they avoid the use of sleep medications.

“Our goal now is to better understand the fundamental changes that cause delirium and determine whether they result in permanent injury to the brain, in order to better devise ways to intervene and prevent this injury,” concludes Inouye. “Knowing that our population is rapidly aging, these figures are only going to increase unless we do something now. We hope to eventually be able to identify at-risk individuals before they develop delirium, so that we can intervene before it escalates to a chronic condition.”

Oncology

Survey reveals need for standardised oral chemotherapy prescribing practices

Despite the widespread use of prescribing safeguards for infusion chemotherapy, few of those measures have been implemented with oral chemotherapy, according to a study led by researchers at the US-based Dana-Farber Cancer Institute.

In the 13 January issue of the British Medical Journal, Dr Saul N. Weingart, vice president for patient safety at Dana-Farber, and his colleagues report that a survey of National Cancer Institute-designated comprehensive cancer centers found few organisations with standardised prescribing practices for oral chemotherapy.

“Given how quickly oral chemotherapies have become standard care for a growing number of cancers, we were not surprised to find variations in how organisations prescribe and monitor the use of these agents,” said Weingart. “It was surprising, however, that few of the safeguards used with infusion chemotherapy have been adopted for oral chemotherapy.”

The researchers sent a survey on the current practices for prescribing, coordinating and monitoring, dispensing, and educating patients about oral chemotherapy to 54 NCI-designated comprehensive cancer centers, of which 42 centers responded.

Weingart said the survey revealed significant variations in the manner prescriptions were generated at most centers and in the amount of information required to complete them.

Nearly 70% of the centers (29) used handwritten orders for the majority of oral chemotherapy prescriptions, 5% (2) used pre-printed paper prescriptions, and 14% (6) used computer-based prescription order entry systems.

An analysis of the information required to order prescriptions for six oral chemotherapies found that few centers mandated the inclusion of the patient’s diagnosis (26%), the treatment’s schedule and duration (9%), or the patient’s body surface area (BSA) calculation, which is used to determine appropriate and safe drug dosage level, and only 21% of the centers required a second physician to review and approve the chemotherapy order. More than half of the centers had no required elements for oral chemotherapy prescriptions, noted Weingart.

The respondents also reported that between 2004 and 2005 at least one serious adverse drug event related to oral chemotherapy occurred at 10 centers, and 13 centers experienced a ‘serious near miss’.

“The growing availability of effective oral chemotherapy, especially the new class of ‘targeted biologic therapies,’ is one of the wonderful recent advances in cancer care, as it has given cancer patients unprecedented convenience compared to intravenous infusion therapy,” said paper co-author Dr Lawrence Shulman, chief medical officer at Dana-Farber and an associate professor of medicine at Harvard Medical School. “However, these findings underline the importance of forging a consensus in the oncology field on standardised safeguards and practices for prescribing and monitoring the use of these drugs.”

Oncology

New angiogenesis inhibitor shows promise for treating glioblastomas

Researchers from the Massachusetts General Hospital (MGH) Cancer Center have found that AZD2171 (Recentin), a new angiogenesis inhibitor, can significantly reduce the size of glioblastomas and could potentially improve the effectiveness of other therapeutic techniques.

The Phase 2 clinical trial also found that AZD2171 treatment can alleviate edema, a debilitating symptom in many brain cancer patients that currently can be treated only with steroid drugs. Appearing in the January 2007 issue of Cancer Cell, the study is too preliminary to determine whether this new drug may have an impact on overall patient survival.

“Patients with recurrent glioblastomas desperately need new, effective treatment alternatives,” says Dr Tracy Batchelor, chief of neuro-oncology in the MGH Cancer Center and the study’s lead author. “While these are preliminary results of an initial trial, it’s looking like these agents may play an increasingly important role in the treatment of patients whose tumours have recurred and perhaps in newly diagnosed patients as well.”

Glioblastoma is the most malignant form of brain tumour and has a very poor prognosis. Standard treatments, including surgery, chemotherapy and radiation therapy, may delay tumour growth, but patients usually survive for little more than a year. There are currently no effective options for patients whose tumours recur, and the vast majority die within six months.

Angiogenesis inhibitors suppress the growth of blood vessels supplying a tumour and have received a lot of attention as potential oncology agents. While the earliest clinical trials did not meet expectations that these drugs would ‘starve’ tumours, the agents did improve patient survival when combined with traditional anticancer therapies. Three such drugs have received FDA approval for the treatment of certain tumours, and several others are currently under investigation.

An oral medication, AZD2171 is a potent inhibitor of the three primary receptors for angiogenesis factor VEGF, known to be present on glioblastoma blood vessels. AZD2171 is currently available only to participants in clinical trials.

The MGH trial, sponsored by the National Cancer Institute, was designed to assess whether AZD2171 could benefit patients with recurrent glioblastomas and also, to examine whether the drug might normalise tumour vasculature. Blood vessels that develop around and within tumours are leaky and disorganised, potentially blocking the delivery of chemotherapy drugs or the effectiveness of radiation therapy, which requires an adequate supply of oxygen to the tumour. The fact that combining angiogenesis inhibitors with other therapies improved survival for some patients supports a theory developed by Rakesh Jain, PhD, director of the Steele Laboratory in the MGH Department of Radiation Oncology, that the agents temporarily ‘normalise’ blood vessels, creating a period during which chemotherapy and radiation treatment can be more effective. Jain is the senior author of the Cancer Cell article.

The paper reports on the first 16 patients to enter the clinical trial, which began in January 2006. All had glioblastomas that had resumed growing despite prior radiation or chemotherapy. Participants took a daily oral dose of AZD2171, which started at 45 mg and could be reduced in those experiencing negative side effects, including fatigue, diarrhea and hypertension. Participants were followed with regular physical, neurological, and MR imaging exams during the six-month study period.

Imaging studies showed that tumours began to shrink in most participants within 28 days of the initial AZD2171 dose. Overall, the tumours shrank by at least 25% in three-quarters of the study participants and by 50% or more in half of the patients. Factors indicating a normalisation of the tumours’ blood vessels, including reduction in size and a decrease in permeability, were seen almost immediately in most participants and continued for at least 28 days, with some features persisting up to four months. These results are the first to define how long the period of vascular normalisation might last, which may establish a window of time during which applying additional therapies would be most effective.

The advanced MR imaging techniques used in this report, developed at MGH, showed the vascular normalisation to be very rapid, beginning after the first dose in some patients. Other MGH-pioneered MRI techniques showed that AZD2171 treatment led to a rapid decrease in brain edema, an effect that continued as long as the medication was taken. The alleviation of edema allowed several study participants to reduce or even discontinue steroid treatment.

Analysis of potential biomarkers identified several that may indicate when the period of vascular normalisation is ending or which patients’ tumours are most likely to become resistant to AZD2171 treatment. These findings suggest that the imaging and biomarker studies will be important scientific tools for future assessment of therapy with AZD2171 and other drugs. “This small group of patients needs to be followed for a longer period of time, but we are cautiously optimistic that this trial and future studies will lead to positive long-term outcomes for some patients,” says Jain.

The researchers expect that the complete results of this trial, which enrolled a total of 31 patients, will be available later this year. They also are exploring additional trials to further define the role of AZD2171 in glioblastoma treatment and hope to study the drug in combination with traditional therapies and in newly diagnosed patients.