A history of being prescribed controlled substances and risk of drug overdose death.

OBJECTIVE: The abuse of prescription drugs has increased dramatically since 1990. Persons who overdose on such drugs frequently consume large doses and visit multiple providers. The risk of fatal overdose for different patterns of use of opioid analgesics and sedative/hypnotics has not been fully quantified. DESIGN: Matched case-control study. Cases were 300 persons who died of unintentional drug overdoses in New Mexico during 2006-2008, and controls were 5,993 patients identified through the state prescription monitoring program with matching 6-month exposure periods. OUTCOME MEASURES: Death from drug overdose or death from opioid overdose. Exposures were demographic variables and characteristics of prescription history. Crude and adjusted odds ratios (AOR) were calculated. RESULTS: Increased risk was associated with male sex (AOR 2.4, 95% confidence interval [CI] 1.8-3.1), one or more sedative/hypnotic prescriptions (AOR 3.0, CI 2.2-4.2), greater age (AOR 1.3, CI 1.2-1.4 for each 10-year increment), number of prescriptions (AOR 1.1, CI 1.1-1.1 for each additional prescription), and a prescription for buprenorphine (AOR 9.5, CI 3.0-30.0), fentanyl (AOR 3.5, CI 1.7-7.0), hydromorphone (AOR 3.3, CI 1.4-7.5), methadone (AOR 4.9, CI 2.5-9.6), or oxycodone (AOR 1.9, CI 1.4-2.6). Patients receiving a daily average of >40 morphine milligram equivalents had an OR of 12.2 (CI 9.2-16.0). CONCLUSIONS: Patients being prescribed opioid analgesics frequently or at high dosage face a substantial overdose risk. Prescription monitoring programs might be the best way for prescribers to know their patients' prescription histories and accurately assess overdose risk.

Prescription drug monitoring programs and death rates from drug overdose.

OBJECTIVE: Drug overdoses resulting from the abuse of prescription opioid analgesics and other controlled substances have increased in number as the volume of such drugs prescribed in the United States has grown. State prescription drug monitoring programs (PDMPs) are designed to prevent the abuse of such drugs. This study quantifies the relation of PDMPs to rates of death from drug overdose and quantities of opioid drugs distributed at the state level. DESIGN: Observational study of the United States during 1999-2005. OUTCOME MEASURES: Rates of drug overdose mortality, opioid overdose mortality, and opioid consumption by state. RESULTS: PDMPs were not significantly associated with lower rates of drug overdose or opioid overdose mortality or lower rates of consumption of opioid drugs. PDMP states consumed significantly greater amounts of hydrocodone (Schedule III) and nonsignificantly lower amounts of Schedule II opioids. The increases in overdose mortality rates and use of prescription opioid drugs during 1999-2005 were significantly lower in three PDMP states (California, New York, and Texas) that required use of special prescription forms. CONCLUSIONS: While PDMPs are potentially an important tool to prevent the nonmedical use of prescribed controlled substances, their impact is not reflected in drug overdose mortality rates. Their effect on overall consumption of opioids appears to be minimal. PDMP managers need to develop and test ways to improve the use of their data to affect the problem of prescription drug overdoses.

Early detection of illness associated with poisonings of public health significance.

Since September 11, 2001, concern about potential terrorist attacks has increased in the United States. To reduce morbidity and mortality from outbreaks of illness from the intentional release of chemical agents, we examine data from the Toxic Exposure Surveillance System (TESS). TESS, a national system for timely collection of reports from US poison control centers, can facilitate early recognition of outbreaks of illness from chemical exposures. TESS data can serve as proxy markers for a diagnosis and may provide early alerts to potential outbreaks of covert events. We use 3 categories of information from TESS to detect potential outbreaks, including call volume, clinical effect, and substance-specific data. Analysis of the data identifies aberrations by comparing the observed number of events with a threshold based on historical data. Using TESS, we have identified several events of potential public health significance, including an arsenic poisoning at a local church gathering in Maine, the TOPOFF 2 national preparedness exercise, and contaminated food and water during the northeastern US blackout. Integration of poison control centers into the public health network will enhance the detection and response to emerging chemical threats. Traditionally, emergency physicians and other health care providers have used poison control centers for management information; their reporting to these centers is crucial in poisoning surveillance efforts.

The Toxic Exposure Surveillance System (TESS): risk assessment and real-time toxicovigilance across United States poison centers.

The Toxic Exposure Surveillance System (TESS) is a uniform data set of US poison centers cases. Categories of information include the patient, the caller, the exposure, the substance(s), clinical toxicity, treatment, and medical outcome. The TESS database was initiated in 1985, and provides a baseline of more than 36.2 million cases through 2003. The database has been utilized for a number of safety evaluations. Consideration of the strengths and limitations of TESS data must be incorporated into data interpretation. Real-time toxicovigilance was initiated in 2003 with continuous uploading of new cases from all poison centers to a central database. Real-time toxicovigilance utilizing general and specific approaches is systematically run against TESS, further increasing the potential utility of poison center experiences as a means of early identification of potential public health threats.

Influenza pandemics: can we prepare for the unpredictable?

Although no viruses are better understood or more intensively studied than the viruses of influenza, if the next influenza pandemic occurs within the next 5-10 years its control will depend on innovations in vaccine production developed more than 40 years ago, but not yet applied to the full extent demanded by our present hard-won knowledge of the epidemiology of the disease. We have become so enamored of the brilliant advances made in the interim in understanding the molecular biology of both virus and host that common sense and inexpensive implementation of proven and older methods of control have been neglected as an interim barricade. In this review, I have advocated a return to first principles, while embracing the promise and returns of contemporary research. With the assumption that the next pandemic virus will contain one of the 13 influenza A virus hemagglutinin subtypes not currently causing epidemic human disease, high-yield reassortant viruses of each of these subtypes should be produced with all dispatch and, in collaboration with industry, tested for production stability and immunogenicity in humans. From this archive, an appropriate reassortant could be selected within days or weeks, and production could ensue. If not a perfect match with the imminent pandemic virus, this "barricade vaccine" could stand as a first line of defense until supplanted by a definitive "rampart vaccine," matching better the emergent, potentially pandemic virus.

The Spanish toxic oil syndrome 20 years after its onset: a multidisciplinary review of scientific knowledge.

In 1981, in Spain, the ingestion of an oil fraudulently sold as olive oil caused an outbreak of a previously unrecorded condition, later known as toxic oil syndrome (TOS), clinically characterized by intense incapacitating myalgias, marked peripheral eosinophilia, and pulmonary infiltrates. Of the 20,000 persons affected, approximately 300 died shortly after the onset of the disease and a larger number developed chronic disease. For more than 15 years, a scientific committee supported by the World Health Organization's Regional Office for Europe and by the Institute of Health Carlos III in Madrid has guided investigation intended to identify the causal agent(s), to assess toxicity and mode of action, to establish the pathogenesis of the disease, and to detect late consequences. This report summarizes advances in research on this front. No late mortality excess has been detected. Among survivors, the prevalence of some chronic conditions (e.g., sclerodermia, neurologic changes) is high. Attempts to reproduce the condition in laboratory animals have been unsuccessful, and no condition similar to TOS has been reported in the scientific literature. Laboratory findings suggest an autoimmune mechanism for TOS, such as high levels of seric soluble interleukin-2 receptor. Epidemiologic studies integrated with chemical analyses of case-related oils have shown that the disease is strongly associated with the consumption of oils containing fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP). These chemicals have also been found in oils synthesized under conditions simulating those hypothesized to have occurred when the toxic oil was produced in 1981. Whether PAP esters are simply markers of toxicity of oils or have the capability to induce the disease remains to be elucidated.

Rapid confirmation by RFLP of transfer to vaccine candidate reassortment viruses of the principal 'high yield' gene of influenza A viruses.

Influenza vaccines must be revised constantly on almost a yearly basis because of the sequential mutations (antigenic drift) that occur as the virus responds to immunologic pressure. New, high yield (hy) reassortant viruses have proved essential to meet production needs for the supply of new vaccines. We have devised a method for simple, rapid and precise identification of the principal influenza A virus RNA segment (RNA 7) associated with hy and transferred from the hy donor virus, A/PR/8/34 (H1N1). The method entails the use of a single restriction enzyme, Bsgl, in analysis by restriction fragment length polymorphism (RFLP) of reverse transcriptase-polymerase chain reaction (RT-PCR)-generated DNA amplicons. The method clearly distinguishes the RNA coding for the M proteins of the donor virus from that of representative and epidemiologically significant human wild type viruses of the past 60 years. In the course of this methodological study further evidence has been found of the variability of the so-called 'invariant' and stable M1 and M2 proteins of the virus. Another finding of potentially basic significance that merits further study is the occurrence of a consistent change at the same amino acid (aa) site of the donated RNA 7 upon its transfer to reassortant viruses.

Immunization with 1976 swine H1N1- or 2009 pandemic H1N1-inactivated vaccines protects mice from a lethal 1918 influenza infection.

BACKGROUND: Zoonotic infections with H1N1 influenza viruses that evolved initially from the 1918 virus (1918) and adapted to swine threatened a pandemic in 1976 (1976 swH1N1) and a novel reassortant H1N1 virus caused a pandemic in 2009-2010 (2009 pH1N1). Epidemiological and laboratory animal studies show that protection from severe 2009 pH1N1 infection is conferred by vaccination or prior infection with 1976 swH1N1 or 1918. OBJECTIVES: Our aim was to demonstrate cross-protection by immunization with 2009 pH1N1 or 1976 swH1N1 vaccines following a lethal challenge with 1918. Further, the mechanisms of cross-protective antibody responses were evaluated. METHODS: Mice were immunized with 1976 swH1N1, 2009 pH1N1, 2009 seasonal trivalent, or 1918 vaccines and challenged with 1918. Cross-reactive antibody responses were assessed and protection monitored by survival, weight loss, and pathology in mice. RESULTS AND CONCLUSIONS: Vaccination with the 1976 swH1N1 or 2009 pH1N1 vaccines protected mice from a lethal challenge with 1918, and these mice lost no weight and had significantly reduced viral load and pathology in the lungs. Protection was likely due to cross-reactive antibodies detected by microneutralization assay. Our data suggest that the general population may be protected from a future 1918-like pandemic because of prior infection or immunization with 1976 swH1N1 or 2009 pH1N1. Also, influenza protection studies generally focus on cross-reactive hemagglutination-inhibiting antibodies; while hemagglutinin is the primary surface antigen, this fails to account for other influenza viral antigens. Neutralizing antibody may be a better correlate of human protection against pathogenic influenza strains and should be considered for vaccine efficacy.

Influenza pandemics of the 20th century.

Three worldwide (pandemic) outbreaks of influenza occurred in the 20th century: in 1918, 1957, and 1968. The latter 2 were in the era of modern virology and most thoroughly characterized. All 3 have been informally identified by their presumed sites of origin as Spanish, Asian, and Hong Kong influenza, respectively. They are now known to represent 3 different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2, respectively. Not classified as true pandemics are 3 notable epidemics: a pseudopandemic in 1947 with low death rates, an epidemic in 1977 that was a pandemic in children, and an abortive epidemic of swine influenza in 1976 that was feared to have pandemic potential. Major influenza epidemics show no predictable periodicity or pattern, and all differ from one another. Evidence suggests that true pandemics with changes in hemagglutinin subtypes arise from genetic reassortment with animal influenza A viruses.

The total influenza vaccine failure of 1947 revisited: major intrasubtypic antigenic change can explain failure of vaccine in a post-World War II epidemic.

Although vaccine-induced immunity to influenza A virus is continually challenged by progressively selected mutations in the virus's major antigens (antigenic drift), virus strains within a subtype (e.g., H1N1) are antigenically cross-reactive. Although cross-immunity diminishes as further mutations accumulate, necessitating frequent changes in vaccine strains, older vaccines are usually partially protective. The post-World War II epidemic of 1947 is notable for the total failure of a vaccine previously effective in the 1943-44 and 1944-45 seasons. We have combined extensive antigenic characterization of the hemagglutinin and neuraminidase antigens of the 1943 and 1947 viruses with analysis of their nucleotide and amino acid sequences and have found marked antigenic and amino acid differences in viruses of the two years. Furthermore, in a mouse model, vaccination with the 1943 vaccine had no effect on infection with the 1947 strain. These findings are important, because complete lack of cross-immunogenicity has been found previously only with antigenic shift, in which antigenically novel antigens have been captured by reassortment of human and animal strains, sometimes leading to pandemics. Although the 1947 epidemic lacked the usual hallmarks of pandemic disease, including an extensive increase in mortality, it warns of the possibility that extreme intrasubtypic antigenic variation (if coupled with an increase in disease severity) could produce pandemic disease without the introduction of animal virus antigens.

Protection of mice with recombinant influenza virus neuraminidase.

Contemporary influenza vaccines are standardized with respect to their content of hemagglutinin, the major virus antigen. Although the immunizing effect of viral neuraminidase--the less abundant of the 2 major surface glycoproteins--has been well documented in experimental animals, the importance of the purified recombinant protein has not yet been adequately assessed in animals or humans. We demonstrate that different lots of a baculovirus-derived recombinant N2 protein, in the absence of other influenza virus proteins, can induce neuraminidase-specific antibodies, reduce the replication of both homologous and heterovariant virus in mice, and suppress disease, as it is manifested by total body weight loss.