The-Scientist.com, June 17, 2010, by Jef Akst – An increasing amount of data is showing that the cellular battle between pathogens and hosts needs much more than a simple military metaphor to describe it—think undercover infiltration, front organizations, and forced suicide.

When searching for an appropriate description of the mammalian immune system, the vast majority of scientists settle on the metaphor of a war. It’s a battle scene, with the foot soldiers of the immune system (e.g., killer T cells) battling the bacterial or viral particles in an open field (the host’s body). Painting a picture in such strong terms is a good way to attract attention (and funding), and in many ways, it is a good fit—one paper I stumbled on as a graduate student that elegantly modeled the conflict generated nearly identical equations to those used in traditional models of warfare, which predict that military losses are proportional to the size of enemy forces.

Over the last several years, however, scientists have begun to realize that the molecular interactions between a pathogen and its host are quite a bit more complex than simple open field battle, where the power of one’s army is measured by bodies alone. The immune system is a multifaceted defense system, and pathogens have evolved numerous molecular strategies to evade its wrath, including methods that resemble more the devious tactics of organized crime than those of traditional warfare, such as setting up fronts to conduct covert operations, going undercover to infiltrate the opposing gang, and terrifying the enemy into admitting defeat (or committing Seppuku).

Pathogen – The white plague type II pathogen is a new genus and species of bacteria, with a proposed name of Aurantimonas coralicida. It is an obligately aerobic gram negative heterotroph.

In the late 1990s, the discovery of pathogenicity islands—large regions of bacterial and viral genomes unique to pathogenic species—led researchers to recognize that many pathogens were involved in some complex racketeering, says immunologist and microbiologist Igor Brodsky of Yale University. Encoding specialized systems to inject virulence proteins into cells, pathogens are able to manipulate cellular processes in the host for their own benefit, such as initiating immune cell death and blocking a continued immune response.

This prompted the field to start identifying specific virulence factors important for a particular pathogen—either by mining databases for genes that might be behind those factors, knocking them out, and observing the effects on the pathogen’s ability to infect its host, or doing random mutagenesis. Once scientists identified some factors important for virulence, “then the question was what were these genes or proteins doing,” Brodsky says.

Pathogens have evolved molecular strategies to escape the immune system that resemble more the tactics of organized crime than traditional warfare.

In the last 4 or 5 years, Brodsky says, researchers have begun to answer that question thanks to a growing interest in the field, as well as new tools and reagents. “People have made a lot of progress in figuring out what these genes do and how they target host cell biology.” They’ve found, for instance, that bacteria employ a variety of techniques to infiltrate and assassinate undetected, such as innovative camouflages and coaxing hosts to abandon their fight.

“There certainly has been a rapid pace of discovery in the area of the host–pathogen interaction,” agrees cell and molecular biologist John Reed of the Sanford-Burnham Institute for Medical Research in La Jolla, Calif. Like many fields in the life sciences, he adds, the quickly advancing field of “genomics is a big part of that,” as well as the “development of algorithms that allow us to search for hypothetical candidate genes [and] other research technologies [that] keep getting more and more powerful.”

Researchers say that the study of host–pathogen interactions has also benefited from the coming together of two historically distinct disciplines—immunology and microbiology—allowing the two fields to feed off each other in a way that further accelerates the science. “Initially they were sort of kept separate—you had the bacterial pathogenesis folks and then you had the immunologists,” says leukocyte biologist Scott Kobayashi of NIAID’s Rocky Mountain Labs. “I think now really those two areas are starting to merge, [and] more people are focusing in on bridging that gap.”

1. Set up a front organization

Whether it’s “waste management” or a massage parlor, the first step in avoiding capture is to find a way to conduct business undetected. Indeed, while organisms have evolved numerous cellular sensors to identify an infection—which, when bound to a pathogen, elicit a profound immune response that eliminates most invading microorganisms—many pathogens have evolved to escape such detectors.

One of the most prevalent classes of tools that hosts use to spot pathogens is the Toll-like receptor (TLR) family. The TLR pathway is “a, if not the, central [pathogen] recognition system we have,” says Thomas Miethke of the Technische Universität München. TLR4, for example, specializes in recognizing a key component of the outer membrane of most Gram-negative bacteria known as lipopolysaccharide (LPS), while TLR5 senses a conserved region of flagellin, the main structural protein in bacterial flagella.

Some bacteria, however, have mastered the art of disguise. Helicobacter pylori, for instance, has evolved ways to be essentially invisible to both these TLR pathways, despite the fact that it is a Gram-
negative bacterium with four to six flagella. To hide from TLR4, H. pylori’s lipid A—the part of the LPS protein that anchors it to the outer part of the bacterial envelope and the domain sensed by TLR4—has taken on a slightly different structure. While TLR4 recognizes lipid A molecules with six acyl chains attached, each 12 to16 carbons in length, the H. pylori lipid A has only five acyl groups, each with up to 6 more carbons. Similarly, amino acid differences in the terminal domain of H. pylori’s flagellin protein allow the bacteria to evade detection by TLR5.1

Other pathogens take a different approach to camouflaging their presence: Rather than disguise the proteins that the host is on the lookout for, some bacteria species have chosen to eliminate them altogether. For example, Anaplasma phagocytophilum—which causes a tick-borne disease known as human granulocytic anaplasmosis—has lost all genes for the biosynthesis of LPS and most genes for the biosynthesis of peptidoglycan, another component of the bacterial cell wall that hosts recognize as a sign of infection. As a result, these pathogens do not trigger an effective innate immune response.

“By removing these LPS and peptidoglycan [proteins], the macrophages and neutrophils cannot recognize these bacteria as a pathogen, so they can enter into [the cells] like stealth pathogens,” says molecular microbiologist Yasuko Rikihisa of the College of Veterinary Medicine at The Ohio State University. “Without being recognized, they can enter, survive, and replicate, and kill the leukocytes eventually.”

The lack of these key cell membrane components, however, is not without consequences, Rikihisa adds. Without LPS and peptidoglycan, “their membrane structure becomes more fragile,” she says. To compensate, the bacteria take up cholesterol from host cells, which stabilizes their membranes. In fact, Rikihisa and her colleagues found that A. phagocytophilum infection rates were 10 times higher in mice fed a high-cholesterol diet than in those on a normal diet.2 “So the cholesterol is helping [the pathogen],” she says.

“Initially, [immunology and microbiology] were sort of kept separate. I think now really those two areas are starting to merge.” —Scott Kobayashi

Further experimentation by Rikihisa and colleagues last year revealed that A. phagocytophilum actually coaxes the host cell to take up more low-density lipoprotein (the so-called “bad”) cholesterol by increasing the expression of the LDL receptor on infected cells, thereby gaining access to the cholesterol it needs to promote infection.3 This represents yet “another subversion mechanism of this bacterium,” Rikihisa says—one that compensates for its initial effort to avoid detection in the first place.

2. Go undercover

If the host successfully detects the presence of a pathogen, it initiates signaling cascades that kick off a variety of immune responses. Eight years ago, in the course of his studies on the Toll/interleukin-
1 receptor (TIR) domain and its role in TLR immune signaling in response to infection, Miethke started searching the National Center for Biotechnology Information database for additional eukaryotic TIR-containing proteins. What he found gave him a bit of a shock. Instead of finding eukaryotic proteins with TIR homology, “I found, to my surprise, bacterial proteins which also have a TIR domain,” he recalls. “When you see that, fantasy immediately starts up. If they have this TIR domain, maybe they interfere with this main signaling cascade,” he says. Because several components of the host TLR signaling pathway interact at their TIR domains, bacteria encoding similar domains may be able to divert this entire cascade by binding to and blocking those components.

Before Miethke had much time to investigate these bacterial proteins that contain TIR domains (known as bacterial TIR-domain-containing proteins, or Tcps), a paper emerged from Reed’s lab at the Burnham Institute that confirmed Miethke’s suspicion.4 A Tcp dubbed TlpA from Salmonella enteritidis blocked NF-kB—a downstream target of the TLR signaling pathway that triggers the expression of cytokines and recruits white blood cells to the site of infection.

Reed and his collaborators had also scoured the databases, and identified more than 200 bacterial TIR homologs. Choosing one to start with, the team cloned and overexpressed TlpA in mammalian cells and demonstrated that it likely blocks NF-kB activation by somehow interfering with a TIR-containing protein called myeloid differentiation factor 88 (MyD88), used by most TLRs to activate NF-kB.

Like mobsters who send their subordinates undercover to infiltrate enemy gangs, pathogens with such TIR-containing proteins can thus evade the disciplinary actions of the host. Using this “molecular mimicry strategy,” Reed says, the bacterium “is able to go in more stealth mode and hang out in the cell,” allowing it to “replicate intracellularly [and] get a foothold before the immune system” knocks it down.

The finding was initially met with “a fair amount of skepticism,” Reed admits, which is why he was “delighted” when Miethke published the results of his first experiments on Tcps 2 years later.5 Using a similar strategy of cloning the TIR-domain-containing genes, expressing them in host cells, and looking for any biological defects they might cause, Miethke confirmed that two more Tcps—TcpC in Escherichia coli and TcpB in Brucella melitensis—interfered with MyD88. Miethke further showed that TcpC bound to MyD88, suggesting it directly inhibits the host protein—and the entire pathway it activates.

Another growing example of pathogen mimicry comes from viruses, which target the host ubiquitin system. Once thought to be little more than a tag for protein degradation, in the last 5 or 6 years, “it’s become very, very clear that ubiquitylation plays a major role in controlling activity of proteins,” including those involved in immunity, says virologist Adolfo García-Sastre of the Mount Sinai School of Medicine. “Once we know that, then it doesn’t become so surprising that pathogens are intersecting with the ubiquitin and ubiquitin-like pathways for their own benefit.”

One example comes from the “congo” virus, the devastating cause of Crimean-Congo hemorrhagic fever. Searching its sequence for homologous domains, García-Sastre and his colleagues found a couple of interest. One was a viral protein domain that belongs to the family of ovarian tumor (OTU)–like proteases. In mammals, OTU proteases dissociate ubiquitin from its specific target proteins. The reverse process—the addition of ubiquitin or ubiquitin-like molecules, such as interferon-stimulated gene product (ISG15), to target proteins—can initiate antiviral responses, leading García-Sastre to suspect the viral OTU-like proteases may be messing with the normal host immune response.

“Having in mind that ubiquitylation and ISGylation are required for innate immunity, we decided to test whether this domain from ‘congo’ will deconjugate ubiquitin and ubiquitin-like molecules and disarm host innate responses,” García-Sastre explains. Sure enough, expression of the congo virus OTU-like proteases actively detached ISG15 and ubiquitin from their target proteins, and by doing so, prevented two different antiviral pathways.6

This deubiquitylating strategy “most likely represents one of the ways viruses can regulate ubiquitylation inside cells,” García-Sastre says, but it is not the only one. Some viruses encode their own ubiquitin and ubiquitin-like proteins; others encode their own E3 ligases—necessary enzymes for ubiquitin conjugation—and still others encode adaptor proteins that recruit host E3 ligases. Just last year, García-Sastre and his colleagues published one of the first examples of a viral protein that inhibits an E3 ligase to prevent antiviral responses.7 The targeting of the ubiquitin system by viruses to evade the host immune response is turning out “to be a common theme,” García-Sastre says.

3. Forced suicide

Another way to survive is to simply destroy an opponent, which is where Tommy guns and Molotov cocktails come in. Many pathogens do this, of course, killing the host immune cells. But some bacteria, such as the Yersinia family, which includes the causative agent of the plague, have a hard balance to strike—kill enough macrophages to prevent the normal immune response, but not too many that it signals the host to mount an inflammatory immune response. “It’s a little paradoxical in a sense that in some infections, [cell death] is protective, and in some it’s pathogenic,” says molecular biologist Jim Bliska of Stony Brook University in New York. Yersinia’s solution: induce the macrophages to quietly kill themselves.

Yersinia bacteria achieve their mission by secreting factors known as Yersinia outer proteins (Yops) into macrophages to inhibit two key immune signaling pathways—both involved in the suppression of apoptosis following infection. These Yops (YopJ in Y. pestis and Y. pseudotuberculosis; YopP in Y. enterocolitica) block the activation of two kinases (MAPKK and IkB kinase), preventing the action of MAPK and NF-kB and the subsequent expression of genes that suppress cell death, causing the macrophages to undergo apoptosis. Thus, the Yersinia bacterium successfully kills the immune cell without allowing it to tip off the rest of the body that there has been an invasion, preventing the specific immune action of the macrophage (present antigens) as well as a larger immune response.

Although the exact mechanism by which Yops cause apoptosis remains “controversial,” Bliska says, the Yops may alter the host’s proteins, which prevents the activation of antiapoptotic genes. On MAPKK, for example, the Yops may add an acetyl group to the part of the protein normally activated by phosphorylation, thus preventing phosphorylation (and activation). Alternatively, YopJ may induce apoptosis by acting on the ubiquitin system.

By inhibiting these pathways and thus the expression of host antiapoptotic genes, Yersinia effectively stimulates the macrophages to peacefully surrender: They undergo apoptosis without inducing an inflammatory response often caused by other types of cell death. At the same time, inhibiting the function of these immune cells by killing them off essentially “handcuffs the macrophages’ ability to present antigens and also to direct the immune response as well,” Kobayashi says.

Interestingly, while Yersinia also induces low levels of apoptosis in other types of immune cells, such as dendritic cells, this February Kobayashi and his colleagues found that the bacteria have the opposite effect in neutrophils—the most abundant type of white blood cells in mammals.8 Instead of inducing apoptosis, the bacteria postpone normal neutrophil death by inhibiting the production of reactive oxygen species that normally cause rapid cell death following infection. Under normal infection conditions, these apoptotic neutrophils are then digested by macrophages, thereby eliminating the pathogen.

The benefit to Yersinia of preventing neutrophil cell death is still a bit unclear, Kobayashi says, but “the assumption is that anything that survives within these phagocytes is probably helping to promote pathogenesis.” Thus, prolonging the lifespan of the neutrophil “buys the bug time to replicate in the neutrophil and survive,” he says. “There [are] many different ways a cell can die,” Kobayashi adds, “and I think people are starting to recognize that pathogens may differently alter that course of death.”

Tricky Tactic: Target the head honchos or the subordinate hit men

Pathogens have many different effects on and interactions with their hosts. While some, such as Bacillus anthracis, cause acute and often lethal host disease, others, such as Mycobacterium tuberculosis, can maintain long-term persistent infections. As a result, acute pathogens tend to focus on replication and transmission with no regard for their host’s health, while chronic pathogens depend on the survival of their hosts for their own continued existence.

The nature of these different approaches to life came up in a meeting of the Ruslan Medzhitov lab at Yale University. “Very acute severe pathogens like anthrax don’t have a requirement for long-term interactions with the host, and the kinds of things they target are going to be extremely disruptive to host physiology,” says immunologist and microbiologist Igor Brodsky, a postdoc in the lab. “In contrast, persistent pathogens can’t afford to do that because they would eliminate their own biological niche. The nature of the requirements for an acute infection differ fundamentally [from] chronic or persistent infection.”

This discussion led the group to an idea: Perhaps acute pathogens target more central players in the host immune system, often with devastating consequences to the host, while chronic or persistent pathogens merely pick away at the peripheral components to avoid being eliminated from the host while causing minimal disease.

“The idea of nodes and hubs in signaling networks and biological networks is not a new idea,” says Brodsky, who wrote a review with Medzhitov on the topic last year,9 but for how pathogens interact with their hosts, “it’s a relatively new concept.”

The concept makes sense, researchers agree, but the evidence for it is still limited. “The idea is certainly interesting and a lot of the aspects are true,” says molecular biologist Jim Bliska of Stony Brook University in New York. “Obviously more work has to be done to validate this model, and there’s probably going to be examples of pathogens that cause chronic infections that do target central hubs, and certainly pathogens that cause acute infections will also affect the peripheral networks.”

In addition, many chronic pathogens can alternate between a latent stage, with little or no effect on host health, to an active infection, says cell and molecular biologist John Reed of the Burnham Institute for Medical Research in La Jolla, Calif., in which case the same pathogen might target different aspects of the host immune system at different points in its life cycle. “We don’t know a lot yet about the circumstances that would tell bacteria to turn on or off certain genes,” Reed says. The host–pathogens interactions “might have a big role for when they are expressed and how that manifests in the context of clinical disease.”

References:

1. E. Andersen-Nissen et al., “Evasion of Toll-like receptor 5 by flagellated bacteria,” Proc Natl Acad Sci, 102:9247–52, 2005.

2. Q. Xiong et al., “High-cholesterol diet facilitates Anaplasma phagocytophilum infection and up-regulates macrophage inflammatory protein-2 and CXCR2 expression in apolipoprotein E-deficient mice,” J Infect Dis, 195:1497–1503, 2007.

3. Q. Xiong et al., “Cholesterol-dependent Anaplasma phagocytophilum exploits the low-density lipoprotein uptake pathway,” PLoS Pathog 5:e1000329, 2009.

4. R.M. Newman et al., “Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins,” Infect and Immun, 74:594–601, 2006.

5. C. Cirl et al., “Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins,” Nat Med, 14:399–406, 2008.

6. N. Frias-Staheli et al., “Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses,” Cell Host & Microbe, 2:404–16, 2007.

7. M.U. Gack et al., “Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I,” Cell Host & Microbe, 5:439–49, 2009.

8. J.L. Spinner et al., “Neutrophils are resistant to Yersinia YopJ/P-induced apoptosis and are protected from ROS-mediated cell death by the type III secretion system,” PLoS One, 5:e9279, 2010.

9. I.E. Brodsky, R. Medzhitov, “Targeting of immune signalling networks by bacterial pathogens,” Nat Cell Bio, 11:521–26, 2009.

Read more: – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/article/display/57467/#ixzz0r8UfmEBr

A wide range of germs, parasites, and other unwanted organisms can enter the human body where they attempt to grow, reproduce, and wreck havoc by triggering dozens of defensive responses from the immune system.

We feel a cold coming on because the cold germ was observed by the immune system. To retaliate against the invading pathogen, histamine is produced and body temperature is raised in hope that this unwanted virus or bacteria may give up and die from the extra heat.

 

If immunity has been weakened, the invading germ multiplies and enjoys a cozy host, drawing free nutrients and taking over without pity. We say we’ve got a cold, or pneumonia, or bronchitus, or sticky phlem, or runny noses.

Pathogen” is a general term similar to “germ
referring to any of the unwanted diseases in the organized list below.

Microscopic View of Pathogens, below

Forbes.com, June 17, 2010, by Mike Stobbe, ATLANTA — For the first time, emergency room visits from the abuse of medicines have become as common as those from illegal drugs.

According to a new government report, ERs in 2008 saw about 1 million visits from the abuse of prescription or over-the-counter medicines – mostly painkillers and sedatives. That was about the same number of visits from people overdosing on heroin, cocaine and other illegal drugs.

Health officials are not sure why painkiller abuse is increasing so dramatically, but the number of prescriptions has been increasing.

Commonly Abused Prescription Drugs

Concerned about misuse of prescription drugs? View the pictures of Rx medications and click on images of drugs for medical information about proper uses.

Centers for Disease Control and Prevention – Your Online Source for Credible Health Information

Emergency Department Visits Involving Nonmedical Use of Selected Prescription Drugs — United States, 2004–2008

 

Morbidity and Mortality Weekly Report

June 18, 2010 / 59(23);705-709

Rates of overdose deaths involving prescription drugs increased rapidly in the United States during 1999–2006 (1). However, such mortality data do not portray the morbidity associated with prescription drug overdoses. Data from emergency department (ED) visits can represent this morbidity and can be accessed more quickly than mortality data. To better understand recent national trends in drug-related morbidity, CDC and the Substance Abuse and Mental Health Services Administration (SAMHSA) reviewed the most recent 5 years of available data (2004–2008) on ED visits involving the nonmedical use of prescription drugs from SAMHSA’s Drug Abuse Warning Network (DAWN). This report describes the results of that review, which showed that the estimated number of ED visits for nonmedical use of opioid analgesics increased 111% during 2004–2008 (from 144,600 to 305,900 visits) and increased 29% during 2007–2008. The highest numbers of ED visits were recorded for oxycodone, hydrocodone, and methadone, all of which showed statistically significant increases during the 5-year period. The estimated number of ED visits involving nonmedical use of benzodiazepines increased 89% during 2004–2008 (from 143,500 to 271,700 visits) and 24% during 2007–2008. These findings indicate substantial, increasing morbidity associated with the nonmedical use of prescription drugs in the United States during 2004–2008, despite recent efforts to control the problem. Stronger measures to reduce the diversion of prescription drugs to nonmedical purposes are warranted.

DAWN is a public health information system that tracks the impact of drug use, misuse, and abuse in the United States by monitoring drug-related hospital ED visits. In a manner similar to the National Electronic Injury Surveillance System,* DAWN uses a sample of EDs to estimate national ED visit rates (2). DAWN collects data from a stratified, simple random sample of approximately 220 nonfederal, short-stay, general hospitals that operate 24-hour EDs in the United States. DAWN’s sampling frame is based on the American Hospital Association annual survey database and is updated annually to reflect new, closed, merged, and demerged hospitals, and to give new hospitals an opportunity to be selected into the sample.

The DAWN sample is designed to produce estimates and trends for individual metropolitan areas (12 in 2008) and the United States overall (2). To achieve this, the selected metropolitan areas are oversampled. The oversampled hospitals and a supplementary sample of hospitals outside those areas together capture ED visits in all 50 states and the District of Columbia. Trained DAWN reporters review the medical charts of all patients treated in the participating hospital EDs to identify visits for conditions induced by or related to drug use. DAWN reporters record de-identified information from the ED medical records using standard abstraction forms. DAWN does not conduct interviews or follow-up with clinicians, patients, or family members. Rates presented in this report are based on the numbers of ED visits weighted so that they are representative of the U.S. population. Denominators for this report were based on U.S. Census postcensal estimates. Differences between counts and between rates were tested using two-sided t tests.†

DAWN defines nonmedical use of a prescription or over-the-counter drug as taking a higher-than-recommended dose, taking a drug prescribed for another person, drug-facilitated assault, or documented misuse or abuse, all of which must be documented in the medical record. DAWN classifies suicide attempts, patients seeking detoxification, and unintentional ingestions in other categories.

For 2008, a total of 231 hospitals submitted data that were used for estimation. The overall weighted hospital response rate was 32.9% (response rates have been stable from year to year). In 2008, DAWN recorded 351,697 drug-related ED visits. On average, a DAWN member hospital submitted 1,522 DAWN cases.

DAWN estimated 1.6 million ED visits for the misuse and abuse of all drugs in 2004 and 2.0 million in 2008. Among these, illicit drugs such as cocaine and heroin were involved in 1.0 million visits in both 2004 and 2008, whereas prescription or over-the-counter drugs used nonmedically were involved in 0.5 million visits in 2004 and 1.0 million visits in 2008. The estimated number of ED visits involving nonmedical use of opioid analgesics§ increased from 144,600 in 2004 to 305,900 in 2008 (111%, p<0.001), whereas rates increased from 49.4 per 100,000 to 100.6 per 100,000, an increase of 104% (p<0.05).

ED visit rates for opioid analgesics were highest for oxycodone, hydrocodone, and methadone during the entire study period (Figure 1). Estimated ED visits involving oxycodone increased from 41,700 to 105,200 (p<0.001), and rates increased from 14.2 per 100,000 to 34.6 per 100,000, an increase of 144% (p<0.05). The estimated number of ED visits involving nonmedical use of benzodiazepines increased from 143,500 in 2004 to 271,700 in 2008 (89%, p=0.01), and rates increased from 49.0 to 89.4 per 100,000, an increase of 82% (p<0.05). The increases in numbers of ED visits during 2004–2008 for individual benzodiazepines were significant: alprazolam (125%, p=0.01), clonazepam (72%, p<0.001), diazepam (70%, p=0.02), and lorazepam (107%, p=0.006), as was the increase for the sleep aid zolpidem (121%, p=0.002). Carisoprodol-related visits also increased significantly (132%, p=0.04). The estimated number of visits for alprazolam in 2008 (104,800) was more than twice the number for the next most common benzodiazepine, clonazepam (48,400).

Although women had more benzodiazepine-related visits than men (Table), this difference was not statistically significant. Among opioid analgesic–related visits, 38% did not involve any other drug (including alcohol); the corresponding figure was 21% for benzodiazepine-related visits. Benzodiazepines were involved in 26% of opioid analgesic–related visits. Alcohol was involved in 15% and 25% of visits for opioids and benzodiazepines, respectively. Approximately one in four patients was admitted. For the year 2008, rates for both types of drugs increased sharply after age 17 years, peaked in the 21–24 years age group, and declined after age 54 years (Figure 2). The largest increases during 2004–2008 occurred among persons aged 21–29 years.

Reported by

R Cai, MS, E Crane, PhD, K Poneleit, MPH, Office of Applied Studies, Substance Abuse and Mental Health Services Admin. L Paulozzi, MD, Div of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC.

Editorial Note

The number of ED visits involving nonmedical use of prescription or over-the-counter drugs increased rapidly during 2004–2008, and by 2008 matched the number of ED visits involving illicit drugs. ED visits involving such pharmaceuticals accounted for all of the growth in overall drug misuse/abuse rates during 2004–2008. ED visits involving opioids or benzodiazepines were the largest contributors to the increase in ED visits involving the nonmedical use of prescription or over-the-counter drugs.

Notably, results from 2008 indicate that in addition to the large increase in visits compared with 2004, peak visit rates for both opioids and benzodiazepines appear to have shifted into the 21–24 and 25–29 years age groups and away from the 30–34 and 35–44 years age groups. As late as 2006, the peak mortality rate for fatal drug overdoses involving opioid analgesics had been in the 35–54 years age group (1).

The 5-year increase in ED visit rates reflects, in part, substantial increases in the prescribing of these classes of drugs (3). The increase also might reflect an increase in the rate of nonmedical use of prescription drugs per 1,000 prescriptions, as has been observed for selected opioids (4). In the 2008 National Survey of Drug Use and Health (NSDUH), 4.6% of persons aged ≥18 years reported past-year nonmedical use of prescription pain relievers, and 2.1% reported nonmedical use of tranquilizers, a category that includes benzodiazepines (5).

In contrast to the results of this study, NSDUH results have shown no increase in self-reported rates of nonmedical use of selected pharmaceuticals since 2004 (5). Increasing ED visit rates in the context of stable self-reported nonmedical use rates might indicate that persons seen in EDs are different from typical respondents to NSDUH; a shift toward riskier types of pain relievers and benzodiazepines, riskier modes of use, more frequent or heavier use; and/or an increased tendency to seek emergency care because of greater awareness of the serious consequences of nonmedical use of such drugs. However, changes in health-seeking behavior would not affect changes in drug-related deaths, and DAWN ED visit trends are consistent with medical examiner data from six states also tracked by DAWN (Maine, Maryland, New Hampshire, New Mexico, Utah, and Vermont). In these states, the number of nonsuicidal deaths related to benzodiazepines increased 64.2%, and the number related to opioid analgesics other than methadone increased 47.4% during 2004–2007 (6).

The relative magnitudes of the rates shown generally reflect prescription volumes. For example, the benzodiazepine with the highest number of ED visits, alprazolam, was the most prescribed benzodiazepine in the United States in 2008, with an estimated 44 million prescriptions (7). However, some exceptions exist: hydrocodone was prescribed nearly 124 million times and oxycodone nearly 45 million times in 2008, but hydrocodone ED rates were not higher than oxycodone ED rates. The high frequency of multidrug involvement is a reflection of the tendency of persons who abuse drugs to combine them to moderate or enhance their effects. The lower proportion of single-drug ED visits among benzodiazepine ED visits compared with opioid analgesic visits is consistent with the relative rarity of a benzodiazepine being the sole drug involved in a fatal overdose (6,8).

The findings in this report are subject to at least four limitations. First, the drugs involved in ED visits might not all be identified and documented. The extent to which ED staff members document drug involvement might have increased over time. Second, information on the motivation for use might be incomplete; some of the ED visits might have represented suicide attempts. Third, rates based on population cannot be used to determine risk per patient or per prescription. Finally, distinguishing drugs taken for nonmedical and medical reasons is not always possible, especially when multiple drugs are involved.

These increases in nonmedical use of pharmaceuticals suggest that previous prevention measures, such as provider and patient education and restrictions on use of specific formulations, have not been adequate. Given the societal burden of the problem, additional interventions are urgently needed, such as more systematic provider education, universal use of state prescription drug monitoring programs by providers, the routine monitoring of insurance claims information for signs of inappropriate use, and efforts by providers and insurers to intervene when patients use drugs inappropriately (9,10). This report also reinforces the value of timely, population-based national surveillance for nonmedical use of drugs, which can be used to assess the effect of such interventions.

References

  1. Warner M, Chen LJ, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999–2006. NCHS data brief, no 22. Hyattsville, MD: National Center for Health Statistics; 2009.
  2. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2007: national estimates of drug-related emergency department visits. Available at http://dawninfo.samhsa.gov/files/ed2007/dawn2k7ed.pdf  . Accessed June 10, 2010.
  3. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Safety 2006;15:618–27.
  4. Dormitzer C. Summary of drug abuse “rates” in the United States. Available at http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4356s1-04-fda-corepresentations.ppt  . Accessed June 10, 2010.
  5. Substance Abuse and Mental Health Services Administration. Results from the 2008 National Survey on Drug Use and Health: national findings. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2009. HHS publication no. SMA 09-4434. Available at http://www.oas.samhsa.gov/nsduh/2k8nsduh/2k8results.cfm . Accessed June 10, 2010.
  6. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2007: area profiles of drug-related mortality. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2009. HHS publication no. SMA 09-4407. Available at http://dawninfo.samhsa.gov/pubs/mepubs . Accessed June 10, 2010.
  7. SDI/Verispan. 2008 top 200 generic drugs by total prescriptions. Available at http://drugtopics.modernmedicine.com/top200gen . Accessed June 10, 2010.
  8. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA 2008;300:2613–20.
  9. Kraman P. Drug abuse in America—prescription drug diversion. Lexington, KY: Council of State Governments; 2004. Available at http://www.csg.org/knowledgecenter/docs/ta0404drugdiversion.pdf  . Accessed June 10, 2010.
  10. CDC. CDC’s issue brief: unintentional drug poisoning in the United States. Available at: http://www.cdc.gov/homeandrecreationalsafety/poisoning/brief.htm. Accessed June 10, 2010.

 

* U.S. Consumer Product Safety Commission. NEISS All Injury Program: sample design and implementation. Washington, DC: U.S. Consumer Product Safety Commission; 2001.

† To minimize the effect of nonresponse, the DAWN weighting plan includes nonresponse adjustment factors for within-hospital nonresponse and hospital nonresponse; the weighting plan also includes a poststratification adjustment factor that reconciles the weighted number of total visits for responding hospitals with the number of total visits from the most recent American Hospital Association Annual Survey Database. Estimates for all DAWN-eligible hospitals in the United States are produced by applying poststratified weights to the data received from the sampled hospitals. Estimates (and their associated rates and confidence intervals) are suppressed if based on an unweighted count of fewer than 30 cases, if the estimate is less than 30, or if the relative standard error is greater than 50%. The DAWN data collection protocol aims for 100% chart review but accepts any percentage above 90% as complete. In EDs where chart subsampling has been implemented, reporters review 100% of the charts for sampled days. Chart subsampling is employed at large facilities with more than 3,500 visits per month. In these facilities, charts are typically reviewed every other day. Additional information about DAWN is available in appendix C at http://dawninfo.samhsa.gov/files/ed2007/dawn2k7ed.pdf 

§ An additional 60,900 visits involving “opiates/opioids unspecified” were not included because some might have involved heroin.

What is already known on this topic?

Deaths involving the nonmedical use of prescription drugs increased in the United States through 2006.

What is added by this report?

Emergency department visits involving nonmedical use of two types of prescription drugs, opioid analgesics and benzodiazepines, more than doubled during 2004–2008 in the United States; visits for misused prescription and over-the-counter drugs are now as common as emergency department visits for use of illicit drugs.

What are the implications for public health practice?

Recent public health and law enforcement measures intended to prevent nonmedical use of such drugs have not prevented rate increases, and additional measures are needed urgently.

TABLE. Estimated number and rate of emergency department visits for nonmedical use of opioid analgesics and benzodiazepines, by selected characteristics — United States, 2008
Characteristic Opioid analgesics Benzodiazepines
No. Rate* 95% CI No. Rate 95% CI
Total 305,900 100.6 (75.6–125.6) 271,700 89.4 (61.6–117.1)
Sex            
Male 150,800 100.6 (74.9–126.3) 119,600 79.7 (57.1–102.4)
Female 155,000 100.6 (75.1–126.1) 152,100 98.7 (64.8–132.5)
No. of drugs (including alcohol)            
One drug 116,800 38.4 (31.4–45.4) 56,900 18.7 (15.1–22.3)
Multidrug 189,000 62.2 (42.8–81.6) 214,800 70.6 (45.9–95.4)
Alcohol involvement 46,200 15.2 (10.9–19.5) 68,600 22.6 (14.6–30.6)
Admitted to hospital 72,700 23.9 (15.7–32.1) 81,300 26.8 (14.5–39.0)
Source: Substance Abuse and Mental Health Services Administration (SAMHSA)’s Drug Abuse Warning Network (DAWN), 2004–2008. Additional information available in appendix C at http://dawninfo.samhsa.gov/files/ed2007/dawn2k7ed.pdf  .

* Per 100,000 population

† Confidence interval.

 

FIGURE 1. Rates of emergency department (ED) visits* for nonmedical use of selected opioid analgesics, by type — United States, 2004–2008

Source: Substance Abuse and Mental Health Services Administration (SAMHSA)’s Drug Abuse Warning Network (DAWN), 2004–2008. Additional information available in appendix C at http://dawninfo.samhsa.gov/files/ed2007/dawn2k7ed.pdf  .

* Per 100,000 population.

† 95% confidence interval.

§ Rate significantly less than the rate in 2008, by two-sided t test (p<0.05).

¶ Drug types include combination products (e.g., combinations of oxycodone and aspirin).

Alternate Text: The figure above shows rates of emergency department (ED) visits for nonmedical use of selected opioid analgesics, by type, in the United States during 2004-2008. ED visit rates for opioid analgesics were highest for oxycodone, hydrocodone, and methadone during the entire study period.

FIGURE 2. Age-specific rates of emergency department visits* for nonmedical use of opioid analgesics (OAs) and benzodiazepines (BZDs) — United States, 2004 and 2008

Source: Substance Abuse and Mental Health Services Administration (SAMHSA)’s Drug Abuse Warning Network (DAWN), 2004–2008. Additional information available in appendix C at http://dawninfo.samhsa.gov/files/ed2007/dawn2k7ed.pdf  .

* Per 100,000 population.

The-Scientist.com, June 17, 2010, by Alison McCook  –  The mother of young twins with a rare genetic disease is seeking approval from the U.S. Food and Drug Administration to administer a non-prescription compound directly into the brains of her girls based on recent findings showing the compound dramatically improves cats with the disease.

It may seem unusual for a parent to fill out such an application to the FDA, but Chris Hempel, who has two 6-year old children suffering from Niemann-Pick Type C (NPC), has practice. Last month, the FDA approved her orphan drug designation application for the compound in question, cyclodextrin, widely employed by the food and chemical industries, and used as a drug solubilizer. “I’m so excited,” Hempel told The Scientist. “It’s been a long process.”

Hempel has been giving her twin girls regular intravenous infusions of cyclodextrin to stop or stall the progression of NPC, a rare fatal disease that disrupts cholesterol trafficking (see the twins’ story in our November, 2008 issue). She sought orphan status in order to obtain tax credits towards human research, enable scientists to obtain grants to move clinical trials forward, and help get the word out about cyclodextrin to other families with NPC kids. “Cyclodextrin needs to have the visibility,” she said.

The compound works, in theory, by depleting cells of cholesterol. Indeed, recent evidence has suggested it may help in other diseases that depend on cholesterol to progress, such as HIV. Hempel hopes cyclodextrin will stop or reverse some of the effects of NPC, such as dementia, and difficulty walking and speaking.

Hempel’s twins Addi and Cassi are test subjects of sorts, as each receive a “whopping dose” of cyclodextrin every week — 2500 milligrams per kilogram over 8 hours. The FDA-approved infusions have taken place over the course of a year, and the girls haven’t shown signs of kidney toxicity or hearing damage (some animals that receive high doses go deaf), and their lungs seem clear. And the compound is doing something — when the girls had to skip 3 weeks’ worth of infusions, their walking was so bad they had to stay in bed. After their infusions, their walking improves, their appetite is better, and they generally seem more engaged, Hempel said. “I feel that it is helping them.”

Still, the girls continue to deteriorate, so Hempel plans to ask for approval to deliver cyclodextrin directly into their brains. This could require a much smaller dose, and get the drug right where it needs to go, she reasoned, adding she plans to submit the new protocol and an approval request to the FDA in a few weeks.

Hempel’s optimism stems from recent findings out of Charles Vite’s lab at the University of Pennsylvania, where the neuroscientist studies NPC positive cats, which typically die of the disease at 24 weeks old. But when Vite injected cyclodextrin directly into the spinal fluid of 3 NPC cats, “at 24 weeks of age, they looked clinically normal,” he said. Vite is now examining their brains, and applying for an R01 to see how long the NPC cats can live when given these infusions. “I think it’s kind of astonishing that giving it directly in spinal fluid has such a positive effect,” Vite told The Scientist.

For now, Hempel is still celebrating the victory of cyclodextrin’s designation as an orphan drug. “In giving us their approval, the FDA is agreeing that this is a drug.”

Read more: Good news for rare disease? – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57495/#ixzz0r8N2rvoV