ID

Infection Transmission During Air Travel

May 7, 2014

By Aaron Smith, MD

Peer Reviewed

It’s become a familiar site to travelers: airline passengers wearing respiratory masks to filter pathogens from the cabin air. To those not wearing masks, the fashion trend can be discomfiting. Are the mask-wearers paranoid or prudent? What is the probability of contracting an illness on an airplane? And how unique is the aircraft environment when it comes to disease transmission?

It is clear that due to lower air exchange rates and decreased sunlight, enclosed spaces such as buildings and transport vehicles are more susceptible to the transmission of infectious particles than are the outdoors.[1] Aircraft cabins are particularly worrisome due to high occupant densities and long exposure times. Well-documented outbreaks of tuberculosis, influenza, severe acute respiratory syndrome (SARS), and norovirus are alleged to have occurred during air travel.[2][3][4][5] All of these diseases are transmitted via either large droplets or aerosolization.[6]

Large droplet transmission is a form of contact transmission in which contaminated large droplets (>5 units of measurement), generated when an infected person sneezes, coughs, or talks, are propelled short distances (<1m) and deposited on a susceptible host’s conjunctiva or mucosa. Aerosolization, or airborne transmission, occurs when residual large droplets evaporate to <5 units of measurement in size. These droplets are then dispersed widely and remain suspended in the air indefinitely. Other modes of disease transmission include common vehicle transmission (food- and water-spread illnesses) and vector-borne transmission (via insects). All of these forms of transmission can occur during air travel, but the large droplet and airborne mechanisms probably represent the greatest risk to passengers.[6]

Quantifying the risk of disease transmission for a particular contagion in an aircraft cabin has proven difficult. In a 2005 review published in the Lancet, Mangili et al. argued that there is insufficient data to perform a proper meta-analysis on the risk of transmitting any particular disease.[6] Furthermore, they noted that many of the available epidemiological studies are compromised by reporting bias secondary to incomplete passenger manifests, complicating risk assessment.

In 2012 Gupta et al. performed the most recent in a series of computational fluid dynamics (CFD) simulations to quantify the rate of influenza transmission in an aircraft cabin.[7] A CFD is a computer algorithm that analyzes fluid flow (in this case, airflow within a simulated aircraft cabin). CFD models are very complex, and the aircraft simulation mentioned above took four weeks of computational time over eight parallel processers to simulate just four minutes of airflow. The authors looked at what would happen if one subject infected with influenza coughed, exhaled, and talked on a plane. Using a code called FLUENT, the authors analyzed the dispersion pattern of exhaled droplets emitted from the infected passenger. By inserting this data into a mathematical equation, they attempted to estimate the relative probability of any given passenger on the aircraft becoming infected, accounting for both temporal and spatial variations in the transmission of particles.

To decipher the results of the simulation, it is helpful to understand some basic characteristics of aircraft ventilation. First, air circulation on airplanes is not random or uniform. On most commercial aircrafts, systems are designed so that air circulates in a side-to-side (laminar) pattern, with very little front-to-back or back-to-front (longitudinal) airflow.[8] This means that two passengers breathe the same air if they sit in the same row or in adjacent rows, but not if they sit several rows apart.

Second, the air on airplanes is actively ventilated and filtered. A typical commercial aircraft recirculates 50% of the air delivered to passengers, and this air passes through a high efficiency particle air filter (HEPA) before reentering the cabin.[6] HEPA filters are 99.97% effective at removing particles greater than 0.3 units of measurement in size from the air.[9] These filters effectively remove dust, vapors, bacteria, fungi, and the droplets via which most viruses are spread. The air on a typical aircraft is recirculated more often and filtered more often than the air in a typical office building.[6]

So, what were the results of the CFD simulation? The infected (index) passenger was sitting in seat 4D. When the index passenger coughed, the infected droplets moved backwards to row 5 and then towards the windows. The passengers with the highest risk of exposure were those sitting directly adjacent to the index passenger, and those sitting towards the windows in row 4 (the index row) and row 5. This pattern is consistent with previously described models of airflow in aircraft cabins, in which air is directed from the center towards the sides of the plane.[6]

Respirator masks reduced the probability of a given passenger becoming infected during the simulation. N95 respirators, commonly utilized by health professionals and increasingly worn by the general public, have been shown to be effective barriers to the transmission of airborne and large droplet-borne infections.[10] Gupta et al. calculated the decrease in exposure risk that a respirator would provide by estimating the number of infectious particles in a typical droplet and combining that data with the filtration efficiency of common respirator masks.[1] They estimated that in their simulation, the number of secondary infections would be reduced from three to zero if all of the passengers wore respiratory masks.

Of course, the ubiquity of contemporary air travel poses additional global health challenges. Someone infected with a disease endemic to a particular region, say polio in India, can easily hop on a plane and transmit the disease to a non-endemic region. A well-publicized example of this is alleged to have taken place in the early 1980s, when Gaetan Dugas, a flight attendant and one of the first documented cases of HIV, helped spread the virus throughout North America and Europe.[11] Airplanes can also harbor unwanted, non-human passengers, such as insects and other disease vectors. Cases have been documented of people from Florida and Virginia, without any history of foreign travel, contracting malaria.[12] “Airport malaria,” in which infected mosquitoes hitch a ride on an airplane and infect people in non-endemic countries, usually within the vicinity of an airport, is a real, albeit rare occurrence.

So should you wear a mask on your next flight? Nothing suggests that you are more likely to catch an illness on an airplane than in any other enclosed space. An aircraft cabin actually may even be safer than the average office building because its air is filtrated so frequently. Perhaps the reason people feel vulnerable to infections on airplanes is the same reason people feel vulnerable on airplanes in general: there can be something unnerving about moving five hundred miles per hour, forty thousand feet above the ground. Still, unless you are ready to start wearing an N95 respirator mask in all enclosed spaces, it probably does not make much sense to wear one specifically on an airplane.

Dr. Aaron Smith is a former medical student and now a  1st year  transitional medicine resident at Harbor-UCLA

Peer reviewed by Melanie Maslow, section editor, pharmacology,  Clinical Correlations

Image courtesy of Wikimedia Commons

References:

[1] Gupta JK, Lin C-H, Chen Q. Risk assessment of airborne infectious diseases in aircraft cabins. Indoor Air. 2012;22(5):388–395. doi:10.1111/j.1600-0668.2012.00773.x. http://www.ncbi.nlm.nih.gov/pubmed/22313168

[2] Kenyon TA, Valway SE, Ihle WW, Onorato IM, Castro KG. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N. Engl. J. Med. 1996;334(15):933–938. doi:10.1056/NEJM199604113341501  http://www.ncbi.nlm.nih.gov/pubmed/8596593

[3] Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter DG. An outbreak of influenza aboard a commercial airliner. Am. J. Epidemiol. 1979;110(1):1–6. http://www.ncbi.nlm.nih.gov/pubmed/463858

[4] Olsen SJ, Chang H-L, Cheung TY-Y, et al. Transmission of the severe acute respiratory syndrome on aircraft. N. Engl. J. Med. 2003;349(25):2416–2422. doi:10.1056/NEJMoa031349  http://www.ncbi.nlm.nih.gov/pubmed/14681507

[5] Kirking HL, Cortes J, Burrer S, et al. Likely transmission of norovirus on an airplane, October 2008. Clin. Infect. Dis. 2010;50(9):1216–1221. doi:10.1086/651597 http://www.ncbi.nlm.nih.gov/pubmed/20353365

[6] Mangili A, Gendreau MA. Transmission of infectious diseases during commercial air travel. Lancet. 2005;365(9463):989–996. doi:10.1016/S0140-6736(05)71089-8  http://www.ncbi.nlm.nih.gov/pubmed/15767002

[7] Gupta JK, Lin C-H, Chen Q. Inhalation of expiratory droplets in aircraft cabins. Indoor Air. 2011;21(4):341–350. doi:10.1111/j.1600-0668.2011.00709.x.  http://www.ncbi.nlm.nih.gov/pubmed/21272076

[8] Gerencher CL. TRB Conference Proceedings: Research on the Transmission of Disease in Airports and on Aircraft: Summary of a Symposium. TR News. 2011.  http://trid.trb.org/view.aspx?id=934654

[9] Bull K. Cabin air filtration: helping to protect occupants from infectious diseases. Travel Med Infect Dis. 2008;6(3):142–144. doi:10.1016/j.tmaid.2007.08.004.  http://www.ncbi.nlm.nih.gov/pubmed/18486070

[10] Grinshpun SA, Haruta H, Eninger RM, Reponen T, McKay RT, Lee S-A. Performance of an N95 filtering facepiece particulate respirator and a surgical mask during human breathing: two pathways for particle penetration. J Occup Environ Hyg. 2009;6(10):593–603. doi:10.1080/15459620903120086.  http://www.ncbi.nlm.nih.gov/pubmed/?term=Grinshpun+SA%2C+Haruta+H%2C+Eninger+RM%2C+Reponen+T%2C+McKay+RT%2C+Lee+S-A.+Performance+of+an+N95+filtering+facepiece+particulate+respirator+and+a+surgical+mask+during+human+breathing%3A+two+pathways+for+particle+penetration

[11] Shilts, R. And the Band Played On. London: St. Martin’s Press, 1987.

[12] Huang Z, Tatem AJ. Global malaria connectivity through air travel. Malar J. 2013;12(1):269. doi:10.1186/1475-2875-12-269.  http://www.ncbi.nlm.nih.gov/pubmed/23914776

 

 

Proton Pump Inhibitors and Clostridium Difficile Infection

March 20, 2014

By Aaron Smith, MD

Peer Reviewed

First introduced in the late 1980s, proton pump inhibitors (PPIs) have revolutionized the treatment of gastric acid-related disorders and have been described as a miracle drug by patients and physicians alike. As is often the case with miracle drugs, however, long-term use of PPIs has led to unforeseen adverse effects. Chief among the purported side effects of PPI use is an association with Clostridium difficile infection (CDI). CDI, an enterocolitis that leads to voluminous and potentially fatal diarrhea, was first described in the 1970s but in recent years has become a true epidemic.[1] Although antibiotic exposure is the most well-established risk factor for CDI [2], prevention of nosocomial CDI is critical to improving hospital safety, and therefore the potential association between CDI and PPI use has become a prominent, albeit controversial, issue. Some argue that PPIs are overprescribed and lead to preventable CDI, while others maintain that PPIs are invaluable weapons in the fight against peptic ulcer disease and that their use should not be curtailed. In February 2012 the Food & Drug Administration weighed in and issued a warning that PPI use may predispose to CDI.[3]

The association between PPI use and CDI was first suggested in 1982, when Gurian et al. demonstrated that gastric juices killed C. difficile and neutralized its toxin in a dose dependent manner. Given that PPIs neutralize the gastric juices proven to kill C.difficile, PPIs were theorized to increase vulnerability to CDI[4] More recently, Kaur et al. showed that mice receiving PPI therapy had similar susceptibility to CDI as mice receiving antibiotics.[5] Unfortunately, there has been no randomized, prospective study examining PPI use and CDI susceptibility to date. Most experts agree that a randomized trial enrolling thousands of patients to either PPI or placebo and then prospectively monitoring them for CDI would be both impractical and unethical.[6] For this reason, all of the clinical studies available to examine the association between PPI use and CDI susceptibility have thus far been observational.

The largest study conducted to date was published in The Archives of Internal Medicine in 2010.[7] In it, Howell et al. performed a retrospective analysis of data collected from 101,796 discharged patients from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, from January 1, 2004, to January 31, 2008. The primary exposure of interest was acid suppression therapy, and patients were classified into four groups of acid suppression (no suppression, histamine2-receptor antagonist [H2RA] therapy, daily PPI treatment, and PPI treatment more frequently than daily). As the level of suppression increased, the risk of nosocomial CDI increased in turn, from 0.3% in patients not receiving acid suppression, to 0.6% in those receiving H2RA therapy, to 0.9% in those receiving daily PPI treatment, and to 1.4% in those receiving more frequent PPI therapy. The risk of CDI increased stepwise as acid suppression increased in a dose responsive manner [8]

The retrospective design of the Howell study has considerable limitations. Most importantly, retrospective studies have difficulty controlling for confounding variables. Were the patients who received frequent PPI treatment more prone to CDI because they were taking PPIs? Or were they just sicker patients who needed more medicine and therefore more prone to CDI because of their overall weakened states? Howell et al. attempted to control for confounding variables by performing advanced statistical analyses including propensity scores and cohort propensity score matching; however, the authors admit that no amount of statistical manipulation is as convincing as a strong, randomized, prospective trial. The Howell study and similar retrospective analyses do the best they can with the data available, but they cannot provide any definitive answers.

Two recent meta-analyses from The American Journal of Gastroenterology looked at the link between PPIs and CDI. The first, by Janarthanan et al., included 23 studies totaling close to 300,000 patients.[9] The authors found a 65% increase (relative risk 1.69, p<0.001) in the incidence of CDI among patients on PPIs. They also performed a subgroup analysis based on study design and saw an increased incidence of CDI among PPI users in both case–control studies (relative risk 1.48, p<0.001) and cohort studies (relative risk 2.31, p<0.001). The second meta-analysis, by Kwok et al., included 42 studies totaling 313,000 patients.[10] This study showed a 1.74 odds ratio (p< 0.001) for patients receiving PPI therapy to develop CDI as compared with patients not taking PPIs.

These two meta-analyses used different statistical methods to look at many of the same studies and arrived at the same conclusion: PPI use is strongly associated with CDI. Although meta-analyses look at a great deal of data, they cannot correct for biases within their constituent studies. If all of the trials included in a meta-analysis are biased and of poor quality, the meta-analysis will be of poor quality as well. The Janarthanan and Kwok meta-analyses make the most of the available data, but they can not provide a definitive answer as their constituent studies are observational and retrospective.

Does PPI use increase the risk of CDI? Despite limitations with the available studies, there is a moderate body of evidence to suggest that it does. Providers should use this evidence when weighing the risks and benefits of PPI therapy in their patients.

Dr. Aaron Smith is a former medical student and now a  1st year  transitional medicine resident at Harbor-UCLA

Peer reviewed by Ilseung Cho, MD, Medicine (Gastroenterology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] John G. Bartlett; Narrative Review: The New Epidemic of Clostridium difficile–Associated Enteric Disease. Annals of Internal Medicine. 2006 Nov;145(10):758-764. https://annals.org/article.aspx?articleid=730466

[2] Johnson S, Clabots CR, Linn FV, et al. Nosocomial Clostridium difficile colonisation and disease. Lancet. 1990;336(8707):97–100. http://www.sciencedirect.com/science/article/pii/014067369091605A

[3] http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm

[4] Gurian L, Ward TT, Katon RM. Possible foodborne transmission in a case of pseudomembranous colitis due to Clostridium difficile: influence of gastrointestinal secretions on Clostridium difficile infection. Gastroenterology. 1982;83(2):465-469. http://www.gastrojournal.org/article/S0016-5085(82)70089-7

[5] Kaur S, Vaishnavi C, Prasad KK, Ray P, Kochhar R. Comparative role of antibiotic and proton pump inhibitor in experimental Clostridium difficile infection in mice. Microbiol Immunol. 2007;51(12):1209-1214.

[6] Leontiadis GI, Miller MA, Howden CW. How much do PPIs contribute to C. difficile infections? The American Journal of Gastroenterology. 2012;107(7):1020–1021. http://www.nature.com/ajg/journal/v107/n7/full/ajg2012174a.html

[7] Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch. Intern. Med. 2010;170(9):784–790. http://archinte.jamanetwork.com/article.aspx?articleid=415908

[8] Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295-300. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898525/

[9] Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. The American Journal of Gastroenterology. 2012;107(7):1001–1010. http://www.nature.com/ajg/journal/v107/n7/full/ajg2012179a.html

[10] Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. The American Journal of Gastroenterology. 2012;107(7):1011–1019. http://www.nature.com/ajg/journal/v107/n7/full/ajg2012108a.html

 

West Nile Virus: Just How Bad Is It?

March 5, 2014

By Julian Horwitz

Peer Reviewed

As of mid-August 2012, the CDC had reported 1118 cases of West Nile virus (WNV) infections and 41 related deaths, which, pro rata, made 2012 the most prolific year for WNV in the United States [1]. Although West Nile’s classification as a public health crisis remains debatable, the lack of treatment and vaccination options make associated severe infections a real threat.

West Nile virus, a single-stranded RNA virus of the Flavivirus family, was first isolated in Uganda in 1937 [2]. Since its emergence in the United States in 1999, there have been approximately 33,000 cases and 1,200 deaths. The virus is maintained in an enzootic cycle between over 300 avian species and Culex mosquitos, which act as the transmission vector. It is believed that only birds can maintain high enough viral loads to be infectious hosts, as humans and other mammals result in “dead-end” infections [2].

Upon viral inoculation via an infected mosquito, WNV initially infects local dendritic cells in the skin, followed by viral amplification in regional lymph nodes. Subsequently, a mild viremia, which is cleared in approximately 1 week by a rapid IgM response, results in a multi-organ infection as well as highly variable systemic symptoms [2]. Only 20-40% of individuals who are infected will become symptomatic after the virus’s 2-14 day incubation period. The majority of these individuals develop a mild, flu-like, self-limiting illness known as West Nile fever [3].

Less than 1% of infected patients, however, will develop severe neuroinvasive disease. The manifestations of these severe infections include meningitis, encephalitis, and acute flaccid paralysis. WNV infection of the central nervous system can be definitively diagnosed by the presence of West Nile IgM in the cerebrospinal fluid, detectable in greater than 90% of patients with neuroinvasive disease by day 8 of presentation [4]. Of clinical significance, serum WNV IgM false-positives are possible with recent yellow fever or Japanese encephalitis vaccination or a recent infection with a Flavivirus (St. Louis encephalitis or dengue). Supplemental testing with plaque-reduction neutralization testing and nucleic acid amplification testing can increase the specificity and accuracy, respectively, of serum IgM detection [4].

In neuroinvasive disease, viral entry into the CNS is likely mediated by both an increase in blood-brain barrier permeability, secondary to local TNF-alpha production, and by retrograde transmission via peripheral neurons [2]. West Nile meningitis, which represents 40% of West Nile neuroinvasive disease, is associated with a favorable prognosis with <1% mortality [5]. Approximately 50% of neuroinvasive infections, especially in the elderly and immunocompromised, are characterized as West Nile encephalitis. These infections result in a 20% in-hospital mortality rate as well as persistent Parkinsonian symptoms in up to 40% of survivors [5]. Finally, the most devastating disease variant is West Nile acute flaccid paralysis (WNP), which accounts for approximately 10% of neuroinvasive disease [5]. Interestingly, WNP is not a transient demyelinating process, as seen with infection-mediated Guillain-Barré syndrome; rather, the paralysis is due to irreversible anterior horn neuronal damage consistent with poliomyelitis [3]. The extent of paralysis can range form monoplegia to quadriplegia with neuromuscular respiratory failure, which results in mortality rates ranging from 10-50% [5]. In addition to short-term morbidity and mortality, neuroinvasive West Nile disease is associated with persistent fatigue, weakness, ataxia, and cognitive dysfunction in nearly 50% of survivors in long-term follow-up studies [5].

Although the probability of severe disease is <1% of the relatively small number of total West Nile infections, there is currently no specific approved therapy for WNV. Therapeutic candidates for WNV such as ribavirin, mycophenolic acid, and interferon-alpha have demonstrated efficacy in vitro, but they have failed to show a clinical benefit [6]. Passive immunity with anti-WNV antibodies has demonstrated reduction in mortality in animal models as well as improvement in neuroinvasive disease in small human trials, particularly among elderly and immunocompromised patients who have high viral titers [6]. This promising therapeutic option is currently undergoing phase 2 clinical trials. Another experimental treatment approach involves small-interfering RNA (siRNA) to target intracellular viral RNA, thus limiting viral translation and subsequent replication. While this form of treatment is efficacious in early-diagnosed infections, advances in the delivery system technology for siRNA will be a required next step before widespread clinical use [6].

Until the establishment of a WNV vaccine or effective treatment, the single most important (and least expensive) intervention is prevention, which is particularly important in the peak months of July through September [4]. The CDC recommends DEET-based insect repellents and mosquito nets for personal protection, especially at night and near sources of still water. At the community level, some areas are adopting strategically timed low-volume insecticide applications, which appear to effectively decrease WNV transmission [4]. The CDC also uses local authorities to track bird deaths in order to assess for avian WNV infections, thus better identifying high-risk locations [7].

While WNV may present as an incurable neuroinvasive disease (as is often portrayed by the media), statistically speaking, over 99% of infections range from asymptomatic to a self-limiting flu-like illness, especially in immunocompetent individuals. Regardless of the favorable probabilities, appropriate precautions and continued antiviral research will hopefully soon eliminate 100% of this annual viral threat.

Julian Horwitz is a 4th year medical student at NYU School of Medicine

Peer Reviewed by Harold Horowitz, MD, Medicine,  NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Kaiser J. Public health. Outbreak pattern stymies vaccine work. Science. 2012:337(6098):1030.  http://www.sciencemag.org/content/337/6098/1030.short

[2] Ulbert S. West Nile virus: the complex biology of an emerging pathogen. Intervirology. 2011:54(4):171-184.  http://www.ncbi.nlm.nih.gov/pubmed/21576931

[3] Kramer LD, Li J, Shi PY. West Nile virus. Lancet Neurol. 2007:6(2):171-181.  http://www.ncbi.nlm.nih.gov/pubmed/17239804

[4] Peterson LR, Brault AC, Nasci RS. West Nile virus: review of the literature. JAMA. 2013:310(3):308-315.  http://www.ncbi.nlm.nih.gov/pubmed/23860989

[5] Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis. 2007:44(12):1617-1624.   http://cid.oxfordjournals.org/content/44/12/1617.full

[6] Diamond MS. Progress on the development of therapeutics against West Nile virus. Antiviral Res. 2009:83(3):214-227.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759769/

[7] Centers for Disease Control and Prevention. Epidemic/epizootic West Nile virus in the United States: guidelines for surveillance, prevention, and control. http://www.cdc.gov/westnile/resources/pdfs/wnvguidelines.pdf.  Revised June 14, 2013. Accessed February 19, 2014.

Can Young Patients Get Diverticular Disease?

January 23, 2014

By Aaron Smith, MD

Peer Reviewed

Case: A 35 year-old, overweight female presents to the emergency room with five days of left lower quadrant abdominal pain. The pain is 10/10 in severity and accompanied by nausea, bloating, and loss of appetite.

Diverticulosis, the presence of small colonic outpouchings thought to occur secondary to high pressure within the colon, is an extremely common condition in elderly patients. Recent data suggests that up to 50% of people over the age of 60 have colonic diverticula.[1] When a colonic diverticulum becomes inflamed, the result is diverticulitis, a painful condition that can result in colonic obstruction, perforation, or abscess formation. Diverticulitis is a very common cause of acute abdominal pain in elderly individuals, especially in the United States.[1]

Traditionally, diverticulosis and diverticulitis, together falling under the heading of “diverticular disease,” have been considered diseases of the elderly. That stereotype may have to change. A 2009 study by Etzioni et al. used a 1998 to 2005 nationwide inpatient sample to analyze the care given to 267,000 patients admitted with acute diverticulitis.[2] During this eight-year period, admissions for acute diverticulitis increased by 26%. During the same period, admissions in the 18 to 44 year-old age group increased by 82%, far more rapidly than in the older group. For the younger group, the incidence of diverticulitis necessitating inpatient admission increased from 1 in 6600 to 1 in 4000.

Etzioni et al. offer several potential explanations for the rapid rise of diverticulitis cases in young patients. One is that increased use of computed tomography (CT) scanning may have led to a higher rate of detection. This would mean that the actual incidence of diverticulitis has remained stable, but that more cases have been diagnosed. A second possible explanation is that an influx of a specific racial or ethnic group with a high rate of diverticulitis, likely Hispanics, may have increased in number between 1998 and 2005, affecting the results. (It has been suggested that Hispanics are prone to a particularly virulent form of diverticulitis at a young age, but the data are scarce.)[3] The dataset used for the study did not include race or ethnicity, and therefore the authors could not examine racial or ethnic data and could not exclude the possibility of a demographic shift affecting the numbers. The authors rightly note, however, that there is a distinct possibility that from 1998 to 2005 there was a real and dramatic increase in the rate of diverticulitis in younger patients. Why? Diverticulitis has been linked to obesity, poor fiber intake, and the western lifestyle in general, and so its increased incidence is mostly likely related to America’s current obesity epidemic.[3-5]

Two lessons can be gleaned from the data presented in this paper. First is a reminder of that favorite medical axiom, “common things are common.” When a disease is highly prevalent in the overall population, it may be highly prevalent in subsets of the population not stereotypically associated with the disease. Take diverticular disease as an example. According to the Etzioni study, diverticulitis is roughly ten times more common in patients above the age of 75 than in patients aged 18 to 44. It is therefore tempting to dismiss diverticulitis as a potential diagnosis in young patients, because diverticulitis is so much more common in the elderly. This would be a mistake. With a prevalence of 1 in 4000, diverticular disease in young patients is more common than rare causes of abdominal pain classically associated with young people. Symptomatic intestinal malrotation, for example, is classically considered a disease of the young, but is less common than diverticulitis, with a prevalence of 1 in 6000.[6] Decades of high colonic pressure in the elderly increase the chances of diverticula formation, and diverticulitis is certainly less common in the young than it is in the elderly. Still, less common does not equal uncommon.

The second lesson to be learned is that due to increases in obesity and sedentary lifestyle, clinicians should rethink which conditions are diseases of the elderly and which are not. Type II diabetes used to be called adult-onset diabetes until it became so common in children and adolescents that the term became a misnomer. Like type II diabetes, diverticular disease is associated with obesity and sedentary lifestyle, and its increased prevalence can be thought of as a correlate to the increased prevalence of other diseases of the western lifestyle (diabetes, hypertension, coronary artery disease…). If the population of the United States continues to grow more obese and inactive, diverticular disease may become more common.

The patient described in the introduction received a CT scan and was diagnosed with acute diverticulitis. Even after imaging confirmed the diagnosis, the patient’s primary physician was hesitant to accept that diverticulitis was the cause of the patient’s abdominal pain, because she was “too young” to have diverticulitis. The Etzioni paper and other recent studies suggest that this mode of thinking may need to be reexamined.[7] Diverticulitis is a diagnosis that should be considered in all patients with abdominal pain, and not just in the elderly. Remember: common things are common, even in young people.

Dr. Aaron Smith is a former medical student and now a  1st year  transitional medicine resident at Harbor-UCLA

Peer reviewed by Michael Poles, MD, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

[1] Weizman AV, Nguyen GC. Diverticular disease: epidemiology and management. Can. J. Gastroenterol. 2011;25(7):385–389. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174080/

[2] Etzioni DA, Mack TM, Beart RW Jr, Kaiser AM. Diverticulitis in the United States: 1998–2005. Annals of Surgery. 2009;249(2):210–217. http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2009&issue=02000&article=00006&type=abstract

[3] Zaidi E, Daly B. CT and clinical features of acute diverticulitis in an urban U.S. population: rising frequency in young, obese adults. AJR Am J Roentgenol. 2006;187(3):689–694. http://www.ajronline.org/doi/abs/10.2214/AJR.05.0033

[4] Aldoori W, Ryan-Harshman M. Preventing diverticular disease: review of recent evidence on high-fibre diets. Can Fam Physician. 2002;48:1632–1637. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213940/

[5] Hjern F, Johansson C, Mellgren A, et al. Diverticular disease and migration–the influence of acculturation to a western lifestyle on diverticular disease. Aliment Pharmacol Ther. 2006;23:797–805. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2006.02805.x/abstract;jsessionid=E566F268C85EEE5067FA4E1664437630.d03t02

[6] Berseth CL. Disorders of the intestines and pancreas. In: Avery’s Diseases of the Newborn, 7th, Taeusch WH, Ballard RA (Eds), WB Saunders, Philadelphia 1998. 918.

[7] van de Wall BJ, Poerink JA, Draaisma WA, Reitsma JB, Consten EC, Broeders IA. Diverticulitis in young versus elderly patients: a meta-analysis. Scand J Gastroenterol. 2013. http://informahealthcare.com/doi/abs/10.3109/00365521.2012.758765

Who Should We Screen for Hepatitis C: By Risk Or Birth Cohort?

January 8, 2014

By Jung-Eun Ha

Peer Reviewed

Over the last few years major changes have occurred in the diagnosis and treatment of hepatitis C. In 2011 the U.S. Food and Drug Administration (FDA) approved a rapid finger stick antibody test for hepatitis C virus (HCV) infection [1]. The FDA also approved the protease inhibitors telapravir (Incivek; Vertex Pharmaceuticals, Cambridge, Massachusetts; Johnson & Johnson, New Brunswick, New Jersey) and boceprevir (Victrelis; Merck, Whitehouse Station, New Jersey), for the treatment of genotype 1 hepatitis C [1]. In August 2012, the Centers for Disease Control & Prevention recommended one-time screening for hepatitis C in all persons born between 1945 and 1965 [2}. In June 2013, the U.S. Preventive Services Task Force (USPSTF) also recommended screening for HCV infection in high-risk individuals and one-time screening in individuals born between 1945 and 1965 (“B” recommendation) [3]. The birth-cohort recommendation exponentially expands the size of the screening population, which was previously limited to high-risk individuals: ever IV drug users, blood transfusion or organ transplant recipients before 1992, those ever on hemodialysis, healthcare workers exposed to HCV-infected blood, children born to HCV-positive mothers, and sexual partners of HCV-positive persons.

The update affects about 82 million Americans born between 1945 and 1965 [4]. The1999-2008 National Health and Nutrition Examination Survey revealed that HCV antibody prevalence in this cohort is 3.25%, or 2.7 million people, as opposed to 0.88% prevalence in people born outside of the cohort [2]. The prevalence is about 1.6% in the general population [5]. More than two-thirds of the chronically infected belong to the 1945-1965 baby-boomer cohort. Many of them were inadvertently exposed to HCV-infected blood before the discovery of HCV in 1989 and the development of a screening test in 1992. HCV incidence was highest during the 1980s. Given the slow progression from chronic HCV infection to cirrhosis and hepatocellular carcinoma over decades [6], now is the time to screen this birth cohort before complications start to appear. Advanced fibrosis of the liver shows poor response to HCV treatment, and is also more costly to treat [7].

Relying solely on risk-based screening in this birth cohort is not sufficient, as up to 45% of people ever infected with HCV may not recall any exposure risk and thus will not likely volunteer to get screened [2]. Fifty to eighty percent of the infected don’t know their HCV status [8]. The number of people born between 1945 and 1965 needed to screen to prevent one HCV-related death is 607.

Overall, one-time HCV screening of this birth cohort is estimated to cost around $15,700 per quality-adjusted life year (QALY) [9]. By comparison, screening for colorectal cancer with colonoscopy can cost about $10,000 to $25,000 per QALY [10], and requires repeated studies. HCV screening of the 1945-1965 cohort is likely a one-time screening event, as HCV incidence has decreased drastically over the years, thanks to effective blood screening and increased awareness of HCV transmission among IV drug users. Morbidity and mortality from chronic HCV infection will be even lower, with a number of direct acting antivirals in the pipeline [11-12]. A recent proof-of-concept study of vaccine against single strain of HCV [13] suggests that mass screening may not even be necessary in the future if, and hopefully when, primary prevention is possible and feasible.

Commentary by Dr. Vin Pham of the Division of Infectious Diseases

The rationale for identifying persons earlier in the course of their disease includes having a greater likelihood of achieving successful outcome after treatment. The registrational studies for interferon-based hepatitis C therapies have consistently shown lower rates of sustained virologic response for subjects with fibrosis scores of 3 or 4, demonstrating the need to identify and treat people in the earlier stages of fibrosis. Ironically, the development of an effective vaccine against HCV may further expand the need for testing for HCV infection, since obviously vaccine would only be offered to those not already infected.

Jung-Eun Ha is a 4th year medical student at NYU School of Medicine

Peer reviewed by Vinh Pham, MD, Infectious Disease, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Getchell JP, Wroblewski KE, DeMaria A, et al. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62(18):1-4.  http://www.medscape.com/viewarticle/804472

[2] Smith BD, Morgan RL, Beckett GA, et al. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.  http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm

[3] U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htm Published June 25, 2013. Accessed August 12, 2013.

[4] Centers for Disease Control and Prevention. Population projections, United States, 2004 – 2030, by state, age and sex. http://wonder.cdc.gov/population-projections.html.  Published 2005. Updated June 26, 2009. Accessed May 18, 2013.

[5] Armstrong G, Wasley A, Simard E, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705–714. http://www.ncbi.nlm.nih.gov/pubmed/16702586

[6] Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006;3(2):47–52.  http://www.medsci.org/v03p0047

[7] Prati GM, Aghemo A, Rumi MG, et al. Hyporesponsiveness to PegIFNalpha2B plus ribavirin in patients with hepatitis C-related advanced fibrosis. J Hepatol. 2012;56(2):341-347.

[8] Hagan H, Campbell J, Thiede H, et al. Self-reported hepatitis C virus antibody status and risk behavior in young injectors. Public Health Rep. 2006;121(6):710-719.  http://www.ncbi.nlm.nih.gov/pubmed/17278406

[9] Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156(4):263-270.  http://www.ncbi.nlm.nih.gov/pubmed/22056542

[10] Pignone M, Saha S, Hoerger T, Mandelblatt J. Cost-effectiveness analyses of colorectal cancer screening: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137(2):96-104.  http://www.ncbi.nlm.nih.gov/pubmed/12118964

[11] Schaefer E, Chung R. Antihepatitis C virus drugs in development. Gastroenterology 2012;142(6):1340–1350.  http://www.ncbi.nlm.nih.gov/pubmed/22537441

[12] Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat. 2012;19(7):449–464.  http://www.ncbi.nlm.nih.gov/pubmed/22676357

[13] Law JL, Chen C, Wong J, et al. A hepatitis C virus (HCV) vaccine comprising envelope glycoproteins gpE1/gpE2 derived from a single isolate elicits broad cross-genotype neutralizing antibodies in humans.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602185/

 

 

 

Barriers to Translating Evidence into Clinical Care: the Zoster Vaccine

December 13, 2013

Zachary Elkin

Faculty Peer Reviewed

There are more than a million cases of herpes zoster (HZ) in the US annually [1-3]. The incidence of HZ, or shingles, has been rising in the US since the 1990s [2,4-7]. One third of all people in the US will get HZ, with the highest incidence in people aged 50 to 79 [2,5]. As a result of the Shingles Prevention Study (SPS), the U.S. Food and Drug Administration (FDA) and Advisory Committee on Immunization Practices (ACIP) approved the Zostavax vaccine (Merck & Co Inc, Whitehouse Station, New Jersey) for the prevention of HZ in 2006 for immunocompetent patients aged 60 and above [8]. The FDA extended the approval to patients aged 50 to 59 in March 2011 [9].

Despite strong evidence of efficacy, the uptake of zoster vaccination among eligible patients has been significantly less than other standard adult vaccines [1,10-13]. CDC estimates show that only 15.8% of eligible patients received the vaccine in 2011, up from 14.4% in 2010, 10% in 2009, and 6.7% in 2008 [13,14]. The 2011 rates were even lower in African Americans (7.9%) and Hispanics (8.0%). Our 2011 survey at NYU found that that only 66% of general internal medicine physicians responded that HZ vaccination was an important clinical priority, and 48% reported that less than 10% of their patients received the HZ vaccine [15]. Why has this evidence-based medicine not been translated into standard clinical care?

Evidence behind the efficacy of the HZ vaccine

Published in 2005, the Shingles Prevention Study demonstrated that HZ vaccine reduced the burden of illness by 61%, the incidence of post-herpetic neuralgia by 66.5%, and incidence of zoster by 51.3% [16]. Since then, the HZ vaccine has repeatedly been shown to be safe and efficacious. A 2012 study reported the efficacy of preventing HZ in persons 50-59 to be 69.8% [17] and another found the hazard ratio of recurrent HZ in patients under 70 to be 0.39 among vaccinated patients compared with unvaccinated patients [18]. A Cochrane Review of 3 randomized controlled studies of HZ vaccination efficacy found a risk ratio for HZ to be 0.49 in all vaccinated patients [19]. Furthermore, the 4-year follow-up to the SPS showed continued reductions in burden of illness of 50.1% [20].

Current barriers to the use of the HZ vaccine

Most of the barriers to HZ vaccination use are related to difficulties distributing the vaccine and a lack of physician recommendation. Hurley and colleagues identified the top barriers for physicians to be the perceived cost to patients, reimbursement difficulties, and the up-front cost of stocking the vaccine [11]. Patients with Medicaid (which covers the vaccine) and those without insurance have overall lower HZ coverage and greater difficulty accessing adult vaccines [1,21].

Additional studies have described a lack of strong physician recommendation as a major barrier to patient adherence with national guidelines [11,12]. Hurley reported that only 41 percent of physicians strongly recommended the zoster vaccine [11]. A study in the Netherlands by Opstelten and colleagues found that a lack of strong physician recommendations accounted for an odds ratio of 4.0 for patients refusing the HZ vaccine when offered free with a yearly influenza vaccine [12]. Correspondingly, a study estimated that 95.1% of unvaccinated patients had at least one missed opportunity to be offered the zoster vaccine at an outpatient visit [1]. Even when the HZ vaccine was offered for free by ophthalmologists at the Bellevue Eye Clinic during regularly scheduled appointments, 47% of patients who refused the vaccine reported wanting to speak to their primary care physician [22]. None returned to receive the vaccine.

Framework to overcome barriers in translating evidenced-based medicine into clinical practice

Cabana and colleagues described that to overcome barriers to physician adherence to evidence-based practice, there must first be a change in knowledge, then attitude [23]. Knowledge can be limited by lack of awareness of the published guidelines. Attitude can be affected by disagreement with guidelines, a lack of clinical priority, or insecurity in performing the task. Finally, physician behaviors can be affected by patient adherence and structural barriers within the health system.

All of these issues must be addressed through interventions to increase adherence to national vaccination guidelines. System supports can be implemented to improve physician attitudes towards HZ vaccination. Chaudhry and colleagues evaluated clinical decision support software as part of the electronic medical record at the Mayo Clinic and found an increase in vaccine utilization of 43% and 54% at two clinics [24]. Loo and colleagues described a statistical increase in pneumococcal vaccination and influenza vaccination at Beth Israel Deaconess following implementation of EMR reminders [25]. Physician reminders can be more successful when combined with patient reminders [26] or nurse-initiated reminders [27]. 

However, time and general changes in the healthcare system are also needed to increase utilization. For example, in 2011, 62.3% of eligible patients in the US received the pneumococcal vaccine [14]. Interventions to increase use of that vaccine started in 1981 with Medicare covering it, but by 1989 only 14.1% of eligible adults 65 and older were vaccinated [28]. The HZ vaccine was only approved for immunocompetent patients 60 and older in 2006, and healthcare system-wide changes have only begun. New York State began to allow certified pharmacists to administer the HZ vaccine with a prescription in October 2012, and Merck began a marketing campaign about shingles that year as well. More time may be needed to see overall changes in patient and provider behaviors.

In a commentary in 2003 in the New England Journal of Medicine, Lenfant described how healthcare providers and the public were not applying the vast wealth of clinical knowledge gained in the 20th century to clinical practice [29]. He explained that there were structural, economic, and motivational barriers to the adoption of evidence-based medicine; however, a major problem is that research rarely focuses on translating knowledge to public use. Simple interventions like the ones described and demonstration of cost effectiveness can go a long way to improving physician and patient adherence. More operational research is needed to describe which interventions work best in varied clinical settings. This may be the best approach to increase use of the HZ vaccine.

Commentary by Dr. Michael Simberkoff

There were specific problems with the shingles vaccine that hampered initial enthusiasm for its use. These include the cost of the vaccine compared to others that are commonly available, the mechanism that was set up for reimbursement (Medicare Part D), the difficulty of shipment and storage of the vaccine in a frozen state until it is used, and the shortages of vaccine due to production problems that led to shortages of the vaccine at a time when its use should have been promoted. Many of these issues have been resolved, but they slowed acceptance of an otherwise useful vaccine. The author suggests that more widespread use of the EMR will improve adherence to guidelines. I would agree that the EMR can provide reminders about good clinical practices, but remain skeptical that these will translate into sustainable improvements unless they are coupled with incentives for providers.

Dr. Zachary Elkin is a 4th year medical student at NYU School of  Medicine

Peer reviewed by Michael Simberkoff, MD, Infectious Diseases, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Lu PJ, Euler GL, Harpaz R. Herpes zoster vaccination among adults aged 60 years and older, in the U.S., 2008. Am J Prev Med. 2011;40(2):e1-6. http://www.ncbi.nlm.nih.gov/pubmed/21238856

2. Rimland D, Moanna A. Increasing incidence of herpes zoster among Veterans. Clin Infect Dis. 2010;50(7):1000-1005.

3. Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011;305(2):160-166.

4. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341-1349.

5. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med. 2005;20(8):748-753.

6. Ghaznawi N, Virdi A, Dayan A, et al. Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. Ophthalmology. 2011;118(11):2242-2250.

7. Yawn BP, Wollan PC, Kurland MJ, St Sauver JL, Saddier P. Herpes zoster recurrences more frequent than previously reported. Mayo Clin Proc. 2011;86(2):88-93.

8. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30.

9. Harpaz R, Hales CM, Bialek SR. Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep. 2011;60(44):1528.  http://www.ncbi.nlm.nih.gov/pubmed/22071592

10. Freed GL, Clark SJ, Cowan AE, Coleman MS. Primary care physician perspectives on providing adult vaccines. Vaccine. 2011;29(9):1850-1854.

11. Hurley LP, Lindley MC, Harpaz R, et al. Barriers to the use of herpes zoster vaccine. Ann Intern Med. 2010;152(9):555-560. http://www.ncbi.nlm.nih.gov/pubmed/20439573

12. Opstelten W, van Essen GA, Hak E. Determinants of non-compliance with herpes zoster vaccination in the community-dwelling elderly. Vaccine. 2009;27(2):192-196.

13. Williams WW, Peng-Jun L, Singleton JA, etal. Adult vaccination coverage-United States, 2010. MMWR. 2012;61(04):66-72. http://www.cdc.gov/mmwr/preview/mmwrhtml/su6102a11.htm

14. Williams WW, Peng-Jun L, Greby S, et al. Noninfluenza vaccination coverage among adults–United States, 2011. MMWR. 2013;62(04):66-72.

15. Elkin Z, Cohen E, Goldberg J, et al. Studying physician knowledge, attitudes, and practices regarding the herpes zoster vaccine to address perceived barriers to vaccination. Cornea. 2013;32(7):976-981.

16. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284.  http://www.ncbi.nlm.nih.gov/pubmed/15930418

17. Schmader KE, Levin MJ, Gnann JW, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis. 2012;54(7):922-928.

18. Tseng HF, Chi M, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population. J Infect Dis. 2012;206(2):190-196.

19. Gagliardi AM, Gomes Silva BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst Rev. 2012;10:CD008858.  http://www.ncbi.nlm.nih.gov/pubmed/23076951

20. Schmader KE, Oxman MN, Levin MJ, et al. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis. 2012;55(10):1320-1328.

21. Orenstein WA, Mootrey GT, Pazol K, Hinman AR. Financing immunization of adults in the United States. Clin Pharmacol Ther. 2007;82(6):764-768.

22. Jung JJ, Elkin ZP, Li X, et al. Increasing use of the vaccine against zoster through recommendation and administration by ophthalmologists at a city hospital. Am J Ophthalmol. 2013;155(5):787-795.  http://www.ncbi.nlm.nih.gov/m/pubmed/23394910/

23. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282(15):1458-1465.

24. Chaudhry R, Schietel SM, North F, Dejesus R, Kesman RL, Stroebel RJ. Improving rates of herpes zoster vaccination with a clinical decision support system in a primary care practice. J Eval Clin Pract. 2013;19(2):263-266. http://www.ncbi.nlm.nih.gov/pubmed/22304668 

25. Loo TS, Davis RB, Lipsitz LA, et al. Electronic medical record reminders and panel management to improve primary care of elderly patients. Arch Intern Med. 2011;171(17):1552-1558.

26. Thomas RE, Russell M, Lorenzetti D. Interventions to increase influenza vaccination rates of those 60 years and older in the community. Cochrane Database Syst Rev. 2010(9):CD005188.

27. Rhew DC, Glassman PA, Goetz MB. Improving pneumococcal vaccine rates. Nurse protocols versus clinical reminders. J Gen Intern Med. 1999;14(6):351-356. http://www.ncbi.nlm.nih.gov/pubmed/10354255

28. Koch JA. Strategies to overcome barriers to pneumococcal vaccination in older adults: an integrative review. J Gerontol Nurs. 2012;38(2):31-39.

29. Lenfant C. Clinical research to clinical practice–lost in translation? New Engl J Med. 2003;349(9):868-874.

From The Archives: The Polymyxins: Why am I using them all the time, and what are they?

November 21, 2013

Please enjoy this post from the archives dated December 8, 2010

By Jon-Emile S Kenny

Faculty Peer Reviewed

A 65-year-old female with locally advanced rectal cancer is admitted to the ICU, hypotensive and febrile. Her PICC line is removed and blood cultures drawn. Fourty-eight hours later all cultures return ESBL Klebsiella with susceptibility only to polymyxin.

I sat on the venerable call-room couch staring mindlessly at the cluttered, nauseating walls repeating the word ‘polymyxin’ like an endless antimicrobial mantra. What strange dosing it has, and an even more peculiar name.

The polymyxins (B and E – the latter also known as Colistin), were developed in the 1950s as anti-pseudomonal agents [1]. In the long evolutionary struggle between gram positives and gram negatives, Bacillus Polymyxa (a gram positive) began secreting cyclic peptides with long hydrophobic chains that selectively bind to gram-negative lipopolysaccharide (LPS). These polymyxins cause rapid destabilization of gram-negative outermembranes, permeability changes, and cell death [2]. Chemical modification of the polymyxins (e.g. treatment with formaldehyde and sodium bisulfate) have rendered these chemicals safe for intravenous use [5].

Resistance, however, can occur. Gram-negatives sensitive to polymyxin have their LPS molecules bridged, and stabilized by divalent cations (e.g. Magnesium). The hydrophobic tail of polymyxin promotes its intercalation into the outermembrane, while the cyclic peptide portion binds to the divalent cation and disrupts membrane architecture [3]. However, in resistant gram-negatives, the divalent cation is replaced by a positively charged H1 protein that is hardy to polymyxin’s mechanism of action [4].

There is a general paucity of data for the pharmacokinetics and pharmacodynamics of the polymyxins, and dosing is confusing [5]. The dose of polymyxin depends on the type (i.e. Polymyxin B vs. Colistin) and with regards to the latter, the formulation. This information would be best gleaned from a friendly infectious disease fellow, hospital pharmacist or Micromedex. Of note, dosage alterations must be made based on a patient’s renal function and it is usually a twice-daily infusion over one hour [5]. Interestingly, recent pharmacodynamic studies with Pseudomonas suggest that the bacteriocidal activity of Polymyxin B is related to the ratio of the area under the concentration-time curve to MIC [6]. This suggests that it may be the total daily dose, and not the frequency of administration that is important (1).

As the mechanism of action detailed above alluded, synergism between the polymyxins and other antibiotics including: rifampin, azithromycin, imipenem have been reported against pan-resistant Klebsiella, Acinetobacter, and Pseudomonas [5].

The overuse of broad-spectrum antibiotics has led to increasing antibiotic resistance, rendering many typical antimicrobials ineffective. The use of polymyxin is reserved for patients with severe sepsis caused by multi-drug resistant gram negative bacteria. Consequently, intravenous polymyxin B is used frequently for the treatment of a myriad of nosocomial infections including: bacteremia, postoperative wound infections, urinary tract infections and intra-abdominal infections [1]. However, Polymyxin – due to its large molecular size, and ionic charge – has poor pleural penetration and does not have adequate efficacy for severe pulmonary infections by itself, but may be used synergistically with other antimicrobials [7]. Interestingly, lipid emulsification of Polymyxin has been shown to increase its penetration into pulmonary tissue in animal models [8].

Polymyxins were originally abandoned due to nephro- and neurotoxicities, the latter including neuromuscular blockade and need for mechanical ventilation [5]. However, contemporary studies have found the rates and degrees of these side-effects to be less concerning even after four weeks of therapy [9]. While nephrotoxicity is still common, it is roughly two times more likely in patients with baseline renal insufficiency [3].

My trance was broken quite suddenly when a nurse opened the door to the call room. She informed me that a patient’s potassium level was 3.2 on an ABG. I looked at the intern and he motioned to order some repletion.

Commentary by Melanie J. Maslow, M.D., F.A.C.P., Associate Professor of Clinical Medicine

Years back, as an Infectious Diseases Fellow, I participated in a study of Ro-139904, now known to providers as ceftriaxone. Ceftriaxone was one of the earlier third generation cephalosporins, which now include cefotaxime and ceftazidime. At last, there was an alternative to the standard therapy of the time for resistant gram-negatives, polymyxin B. Thirty years later, a new generation of physicians is paying the price for decades of overusing extended-spectrum antibiotics and selection of multidrug resistant gram-negative bacilli, including species of Pseudomonas, Acinetobacter, and Klebsiella. As the author discusses, the new dosing regimens appear to be better tolerated with less renal toxicity than we observed but there is intrinsic resistance to this drug. Providers should be aware that polymyxin B is inactive against some organisms, including Proteus spp., Providencia spp., and most Serratia spp. The take home message here is that overuse of broad-spectrum antibiotics has brought us back to the era of using a “detergent” to treat multidrug resistant bacterial infections.

Dr. Kenny is a chief resident at NYU Langone Medical Center

Peer reviewed by Melanie Maslow, section editor, pharmacology, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

(1) Yuan and Tam Polymyxin B: a new strategy for multidrug-resistant Gram-negative organisms. Expert Opin Investig Drugs. 2008 May;17(5):661-8. http://www.ncbi.nlm.nih.gov/pubmed/18447592

(2) LaPorte et al. Inhibition of Escherichia coli growth and respiration by polymyxin B covalently attached to agarose beads. Biochemistry 1977 ; 16 : 1642 -8

(3) Zavascki et al. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. Journal of Antimicrobial Chemotherapy (2007) 60, 1206–1215. http://jac.oxfordjournals.org/content/60/6/1206.abstract

(4) Brown MR, Watkins WM. Low magnesium and phospholipid content of cell walls of Pseudomonas aeruginosa resistant to polymyxin. Nature 1970 ; 227 : 1360 -1

(5) Landman et al. Polymyxins Revisited. Clinical Microbiology Reviews , July 2008, p. 449–465. http://cmr.asm.org/cgi/content/short/21/3/449

(6) Tam et al. Pharmacodynamics of polymyxin B against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005 ; 49 : 3624 -30

(7) Sobieszczyk et al. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother 2004 ; 54 : 566 -9

(8) Omri A, et al. Enhanced activity of liposomal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection. Biochem Pharmacol 2002 ; 64 : 1407 -13

(9) Falagas et al Toxicity after prolonged (more than four weeks) administration of intravenous colistin. 2005 BMC Infect. Dis. 5:1–8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC547910/

Barriers to Translating Evidence into Clinical Care: the Zoster Vaccine

October 10, 2013

By Zachary Elkin

Faculty Peer Reviewed

There are more than a million cases of herpes zoster (HZ) in the US annually [1-3]. The incidence of HZ, or shingles, has been rising in the US since the 1990s [2,4-7]. One third of all people in the US will get HZ, with the highest incidence in people aged 50 to 79 [2,5]. As a result of the Shingles Prevention Study (SPS), the U.S. Food and Drug Administration (FDA) and Advisory Committee on Immunization Practices (ACIP) approved the Zostavax vaccine (Merck & Co Inc, Whitehouse Station, New Jersey) for the prevention of HZ in 2006 for immunocompetent patients aged 60 and above [8]. The FDA extended the approval to patients aged 50 to 59 in March 2011 [9].

Despite strong evidence of efficacy, the uptake of zoster vaccination among eligible patients has been significantly less than other standard adult vaccines [1,10-13]. CDC estimates show that only 15.8% of eligible patients received the vaccine in 2011, up from 14.4% in 2010, 10% in 2009, and 6.7% in 2008 [13,14]. The 2011 rates were even lower in African Americans (7.9%) and Hispanics (8.0%). Our 2011 survey at NYU found that that only 66% of general internal medicine physicians responded that HZ vaccination was an important clinical priority, and 48% reported that less than 10% of their patients received the HZ vaccine [15]. Why has this evidence-based medicine not been translated into standard clinical care?

Evidence behind the efficacy of the HZ vaccine

Published in 2005, the Shingles Prevention Study demonstrated that HZ vaccine reduced the burden of illness by 61%, the incidence of post-herpetic neuralgia by 66.5%, and incidence of zoster by 51.3% [16]. Since then, the HZ vaccine has repeatedly been shown to be safe and efficacious. A 2012 study reported the efficacy of preventing HZ in persons 50-59 to be 69.8% [17] and another found the hazard ratio of recurrent HZ in patients under 70 to be 0.39 among vaccinated patients compared with unvaccinated patients [18]. A Cochrane Review of 3 randomized controlled studies of HZ vaccination efficacy found a risk ratio for HZ to be 0.49 in all vaccinated patients [19]. Furthermore, the 4-year follow-up to the SPS showed continued reductions in burden of illness of 50.1% [20].

Current barriers to the use of the HZ vaccine

Most of the barriers to HZ vaccination use are related to difficulties distributing the vaccine and a lack of physician recommendation. Hurley and colleagues identified the top barriers for physicians to be the perceived cost to patients, reimbursement difficulties, and the up-front cost of stocking the vaccine [11]. Patients with Medicaid (which covers the vaccine) and those without insurance have overall lower HZ coverage and greater difficulty accessing adult vaccines [1,21].

Additional studies have described a lack of strong physician recommendation as a major barrier to patient adherence with national guidelines [11,12]. Hurley reported that only 41 percent of physicians strongly recommended the zoster vaccine [11]. A study in the Netherlands by Opstelten and colleagues found that a lack of strong physician recommendations accounted for an odds ratio of 4.0 for patients refusing the HZ vaccine when offered free with a yearly influenza vaccine [12]. Correspondingly, a study estimated that 95.1% of unvaccinated patients had at least one missed opportunity to be offered the zoster vaccine at an outpatient visit [1]. Even when the HZ vaccine was offered for free by ophthalmologists at the Bellevue Eye Clinic during regularly scheduled appointments, 47% of patients who refused the vaccine reported wanting to speak to their primary care physician [22]. None returned to receive the vaccine.

Framework to overcome barriers in translating evidenced-based medicine into clinical practice

Cabana and colleagues described that to overcome barriers to physician adherence to evidence-based practice, there must first be a change in knowledge, then attitude [23]. Knowledge can be limited by lack of awareness of the published guidelines. Attitude can be affected by disagreement with guidelines, a lack of clinical priority, or insecurity in performing the task. Finally, physician behaviors can be affected by patient adherence and structural barriers within the health system.

All of these issues must be addressed through interventions to increase adherence to national vaccination guidelines. System supports can be implemented to improve physician attitudes towards HZ vaccination. Chaudhry and colleagues evaluated clinical decision support software as part of the electronic medical record at the Mayo Clinic and found an increase in vaccine utilization of 43% and 54% at two clinics [24]. Loo and colleagues described a statistical increase in pneumococcal vaccination and influenza vaccination at Beth Israel Deaconess following implementation of EMR reminders [25]. Physician reminders can be more successful when combined with patient reminders [26] or nurse-initiated reminders [27].

However, time and general changes in the healthcare system are also needed to increase utilization. For example, in 2011, 62.3% of eligible patients in the US received the pneumococcal vaccine [14]. Interventions to increase use of that vaccine started in 1981 with Medicare covering it, but by 1989 only 14.1% of eligible adults 65 and older were vaccinated [28]. The HZ vaccine was only approved for immunocompetent patients 60 and older in 2006, and healthcare system-wide changes have only begun. New York State began to allow certified pharmacists to administer the HZ vaccine with a prescription in October 2012, and Merck began a marketing campaign about shingles that year as well. More time may be needed to see overall changes in patient and provider behaviors.

In a commentary in 2003 in the New England Journal of Medicine, Lenfant described how healthcare providers and the public were not applying the vast wealth of clinical knowledge gained in the 20th century to clinical practice [29]. He explained that there were structural, economic, and motivational barriers to the adoption of evidence-based medicine; however, a major problem is that research rarely focuses on translating knowledge to public use. Simple interventions like the ones described and demonstration of cost effectiveness can go a long way to improving physician and patient adherence. More operational research is needed to describe which interventions work best in varied clinical settings. This may be the best approach to increase use of the HZ vaccine.

Commentary by Dr. Michael Simberkoff

There were specific problems with the shingles vaccine that hampered initial enthusiasm for its use. These include the cost of the vaccine compared to others that are commonly available, the mechanism that was set up for reimbursement (Medicare Part D), the difficulty of shipment and storage of the vaccine in a frozen state until it is used, and the shortages of vaccine due to production problems that led to shortages of the vaccine at a time when its use should have been promoted. Many of these issues have been resolved, but they slowed acceptance of an otherwise useful vaccine. The author suggests that more widespread use of the EMR will improve adherence to guidelines. I would agree that the EMR can provide reminders about good clinical practices, but remain skeptical that these will translate into sustainable improvements unless they are coupled with incentives for providers.

Dr. Zachary Elkin is a 4th year medical student at NYU School of Medicine

Peer reviewed by Michael Simberkoff, MD, Chief of Staff, Deparment of Veterans Affairs, New York Harbor Healthcare System, Professor of Medicine (Infectious Diseases), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Lu PJ, Euler GL, Harpaz R. Herpes zoster vaccination among adults aged 60 years and older, in the U.S., 2008. Am J Prev Med. 2011;40(2):e1-6.  http://www.ncbi.nlm.nih.gov/pubmed/21238856

2. Rimland D, Moanna A. Increasing incidence of herpes zoster among Veterans. Clin Infect Dis. 2010;50(7):1000-1005.

3. Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011;305(2):160-166.

4. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341-1349.  http://www.ncbi.nlm.nih.gov/pubmed/17976353

5. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med. 2005;20(8):748-753.

6. Ghaznawi N, Virdi A, Dayan A, et al. Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. Ophthalmology. 2011;118(11):2242-2250.

7. Yawn BP, Wollan PC, Kurland MJ, St Sauver JL, Saddier P. Herpes zoster recurrences more frequent than previously reported. Mayo Clin Proc. 2011;86(2):88-93.  http://www.ncbi.nlm.nih.gov/pubmed/21220354

8. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30.  http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm

9. Harpaz R, Hales CM, Bialek SR. Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep. 2011;60(44):1528.  http://www.ncbi.nlm.nih.gov/pubmed/22071592

10. Freed GL, Clark SJ, Cowan AE, Coleman MS. Primary care physician perspectives on providing adult vaccines. Vaccine. 2011;29(9):1850-1854.

11. Hurley LP, Lindley MC, Harpaz R, et al. Barriers to the use of herpes zoster vaccine. Ann Intern Med. 2010;152(9):555-560.

12. Opstelten W, van Essen GA, Hak E. Determinants of non-compliance with herpes zoster vaccination in the community-dwelling elderly. Vaccine. 2009;27(2):192-196.  http://www.cabdirect.org/abstracts/20093090353.html;jsessionid=9CFCCF3008A615DD6B3D63AEA35E874A?freeview=true

13. Williams WW, Peng-Jun L, Singleton JA, etal. Adult vaccination coverage-United States, 2010. MMWR. 2012;61(04):66-72.  http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6104a2.htm

14. Williams WW, Peng-Jun L, Greby S, et al. Noninfluenza vaccination coverage among adults–United States, 2011. MMWR. 2013;62(04):66-72.

15. Elkin Z, Cohen E, Goldberg J, et al. Studying physician knowledge, attitudes, and practices regarding the herpes zoster vaccine to address perceived barriers to vaccination. Cornea. 2013;32(7):976-981.

16. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284.

17. Schmader KE, Levin MJ, Gnann JW, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis. 2012;54(7):922-928.  http://cid.oxfordjournals.org/content/54/7/922.abstract

18. Tseng HF, Chi M, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population. J Infect Dis. 2012;206(2):190-196.

19. Gagliardi AM, Gomes Silva BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst Rev. 2012;10:CD008858.

20. Schmader KE, Oxman MN, Levin MJ, et al. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis. 2012;55(10):1320-1328.

21. Orenstein WA, Mootrey GT, Pazol K, Hinman AR. Financing immunization of adults in the United States. Clin Pharmacol Ther. 2007;82(6):764-768.

22. Jung JJ, Elkin ZP, Li X, et al. Increasing use of the vaccine against zoster through recommendation and administration by ophthalmologists at a city hospital. Am J Ophthalmol. 2013;155(5):787-795.

23. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282(15):1458-1465.

24. Chaudhry R, Schietel SM, North F, Dejesus R, Kesman RL, Stroebel RJ. Improving rates of herpes zoster vaccination with a clinical decision support system in a primary care practice. J Eval Clin Pract. 2013;19(2):263-266.  http://www.ncbi.nlm.nih.gov/pubmed/22304668

25. Loo TS, Davis RB, Lipsitz LA, et al. Electronic medical record reminders and panel management to improve primary care of elderly patients. Arch Intern Med. 2011;171(17):1552-1558.

26. Thomas RE, Russell M, Lorenzetti D. Interventions to increase influenza vaccination rates of those 60 years and older in the community. Cochrane Database Syst Rev. 2010(9):CD005188.

27. Rhew DC, Glassman PA, Goetz MB. Improving pneumococcal vaccine rates. Nurse protocols versus clinical reminders. J Gen Intern Med. 1999;14(6):351-356.  http://www.ncbi.nlm.nih.gov/pubmed/10354255

28. Koch JA. Strategies to overcome barriers to pneumococcal vaccination in older adults: an integrative review. J Gerontol Nurs. 2012;38(2):31-39.

29. Lenfant C. Clinical research to clinical practice–lost in translation? New Engl J Med. 2003;349(9):868-874.

 

 

 

Diagnostic Dilemma-Poststreptococcal Reactive Arthritis in a Pregnant Woman

September 18, 2013

By Bryan Stierman and Todd Cutler, MD

Faculty Peer Reviewed

Case Presentation

A 35-year-old Hispanic woman presented to the emergency room with severe joint pain and swelling for one week.

The patient had a history of hypothyroidism and hepatitis C which was treated with interferon therapy two years prior. She was recently discovered to be pregnant and, at the time of presentation, was in her tenth week of pregnancy. Three weeks prior to admission she developed a sore throat. She saw an outside care provider who diagnosed her with streptococcal pharyngitis. Her symptoms resolved shortly after starting a ten-day course of penicillin.

Two weeks prior to admission the patient developed pain in her ankles that, over the following days, successively spread to her knees, hips, shoulders, elbows, wrists and hands. The pain did not improve in any affected joints. By the day of admission, the patient had resorted to using a wheelchair and, when she visited her obstetrician, she was sent to the emergency department. For the last two days, her pain had prevented her from walking or using her hands.

On arrival to the emergency room, the patient was in great distress. She was afebrile with tachycardia. She had exquisite pain and decreased range of motion in her ankles, knees, hips, shoulders, elbows, wrists and finger joints. She also had mild erythema and swelling in the affected joints—most notably in the left ankle. She had a soft, systolic murmur over the right upper sternal border. Her laboratory studies were most notable for an elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) of 214 mg/L and 136 mm/hr, respectively, and a normocytic anemia with a hemoglobin of 9.0 g/dl. Her EKG showed sinus tachycardia. She was given opiates for pain with minimal improvement and was admitted to medicine for further management.

An active infection was thought to be unlikely. Instead, her presentation appeared to be consistent with a post-infectious reactive arthritis and, given her recent history, a post-streptococcal arthritis was high on the differential diagnosis. Further laboratory studies were significant for an elevated anti-streptolysin O (ASO) titer of 703 units/ml, an elevated C3 of 256 mg/dl, an elevated C4 of 58 mg/dl, a negative anti-nuclear antibody, a negative rheumatoid factor, a negative anti-cyclic citrullinated peptide antibody and an absence of cryoglobulinemia. An echocardiogram was unremarkable.

Given these findings, 20mg of daily oral prednisone were started on the evening of day one. The following morning the patient reported a vast improvement in her pain and, over the following ten days, her symptoms continued to improve to the point where she could ambulate with minimal difficulty. Her ESR and CRP normalized and her ASO titer decreased to 604 units/ml. On the day of discharge, she had mild residual tenosynovitis in her right wrist. She was prescribed 20mg prednisone twice daily to be tapered as an outpatient.

Discussion

The presentation of arthritis following streptococcal pharyngitis is often considered to be a manifestation of acute rheumatic fever (ARF). Poststreptococcal reactive arthritis (PSRA) is a clinically distinct entity from ARF and can often manifest with arthritis alone. Much like ARF, development of PSRA is less common in the context of a properly treated streptococcal infection.[1] Given that the distinction in diagnoses may have important ramifications in treatment and surveillance of these diseases, it is important to understand the following clinical question: What is post-streptococcal reactive arthritis and how does it differ from acute rheumatic fever?

The Jones criteria are used to diagnose ARF and requires evidence of an antecedent Group A streptococcal infection as well as the presence of either two major criteria or one major criteria and two minor criteria. Evidence for antecedent streptococcal infection includes positive throat culture, positive rapid streptococcal antigen test, and elevated or dynamic ASO titers. Major criteria include carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. Minor criteria include arthralgia, fever, a prolonged PR interval, and elevated acute phase reactants (ESR/CRP).[2,3]

Alternatively, the proposed diagnostic criteria for PSRA includes the following clinical features: 1) an acute arthritis which is poorly responsive to salicylates or NSAIDs, 2) evidence of antecedant group A streptococcal infection and 3) a failure to fulfill the Jones Criteria for ARF.[4] There has been concern, however, that these suggested guidelines may lead to the over diagnosis of ARF and under diagnosis of PSRA as there are a large number of patients who meet the Jones Criteria with 1 major criterion and 2 minor criteria (e.g. arthritis, elevated ESR/CRP and fever) who may be better classified as having PSRA.[5] The absence of a diagnostic “gold standard” to differentiate between these two diseases necessitates that clinicians are forced to rely on criteria more easily delineated in written guidelines than with actual patients.

Case reports have better discerned the specific characteristics that help to distinguish PSRA from ARF. These finding include the observation that ARF is generally a disease of children, most commonly manifesting between 4-9 years of age, while PSRA follows a bimodal age distribution between the first and second decades and the third and fourth decades, respectively. This distinction also separates PSRA from reactive arthritis which has a single peak of distribution between 27-34 years of age. PSRA generally has a shorter latency to onset after streptococcal infection than ARF (within 2 weeks versus 2-3 weeks). The character of the arthritis in ARF is usually migratory and resolves within two weeks while in PSRA it is additive, symmetric, and averages at least two months in duration with reported cases of arthritis lasting as long as eight months. The involved joints, in order of frequency, include the knees, ankles, hips, wrists, shoulders and elbows.1 Finally, the response of ARF to aspirin and NSAIDs is rapid and impressive while in PSRA the benefit of NSAIDs is characteristically minimal.5 Case series from described the complete relief of symptoms after a short course of prednisone although this response has been variable in the literature.[6,7]

Both ARF and PSRA are autoimmune reactions. It appears that the M-protein of the offending streptococcal agent has homologous sequences to cardiac myosin and laminin and this molecular mimicry is believed to explain, in part, the cardiac manifestations of ARF through the induction of antibodies that recognize these sequences and subsequently induce an inflammatory response. On the other hand, antibodies against the M-protein have also been shown to react with joint cartilage and synovium—a finding that may suggest a unique mechanism the inflammatory reaction that occurs in PSRA.[5]

The decision of whether or not to initiate prophylactic antibiotics in patients with PSRA is an area of debate. In ARF, the standard of care for prophylaxis to prevent recurrence of heart disease is to give intramuscular penicillin G every 4 weeks. Prophylaxis should be continued for 10 years or until age 40 in patients with ARF and residual heart disease, for 10 years or until age 21 in a patient with ARF and carditis without residual heart disease and for 5 years or until age 21 in a patient with ARF without carditis.[8]

Alternatively, there is no evidence to support antibiotic prophylaxis in patients with PSRA.5,6 One large study on PSRA followed-up adult patients not receiving prophylaxis with transthoracic echocardiography for nine years and found no increased incidence of valvular heart disease compared to normal controls.9 There has been no randomized controlled trial evaluating the use of prophylactic antibiotics in patients with PSRA. Still, despite a lack of evidence, the American Heart Association recommends prophylaxis for up to one year followed by re-evaluation for valvular disease to make a decision for further prophylaxis.8 Some reassurance may be derived from the fact that the risk of cardiac involvement in PSRA appears to be almost non-existent in adults however there is a small risk of cardiac involvement in children. This may be attributable to the misclassification of ARF as PSRA rather than an intrinsic characteristic of the disease. Another explanation is that, similar to ARF in which cardiac risk is inversely correlated with age, this relationship may also extend to PSRA.[5]

In our patient, a transthoracic echocardiogram ruled out any cardiac manifestations of disease and prophylaxis was not initiated given the absence of supporting evidence in the literature. Overall, the long-term prognosis for the patient is excellent. Arthritis in PSRA lasts, on average, approximately two months and only about 19% will have any reccurence.10 Lastly, no literature currently exists on PSRA in pregnancy and, as far as we are able to determine, this is the first such reported case.

Brian Stierman is a fourth year medical student and NYU School of Medicine

Todd Cutler, MD, is a former Senior Chief Resident of NYU Langone Medical Center and is now an Assistant Professor of Medicine, NewYork-Presbyterian Hospital.

Peer reviewed by Peter Izmirly, MD, Division of Rheumatology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1) Mackie and Keat. Poststreptococcal reactive arthritis: what is it and how do we know? Rheumatology (Oxford) (2004) vol. 43 (8) pp. 949-54  http://rheumatology.oxfordjournals.org/content/44/1/136.2.full

2) Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. Guidelines for the diagnosis of rheumatic fever: Jones Criteria: 1992 update. JAMA. (1992) vol. 268 (15) pp. 2069-2073   http://www.ncbi.nlm.nih.gov/pubmed/1404745

3) Ferrieri and Jones Criteria Working Group. Proceedings of the Jones Criteria workshop. Circulation (2002) vol. 106 (19) pp. 2521-3

4) Ayoub EM and Ahmoud S. Update on the complications of group A streptococcal infections. Current Problems in Pediatrics. (1997) vol. (27) pp. 90-101  http://www.ncbi.nlm.nih.gov/pubmed/9099534?dopt=Abstract

5) van der Helm-van Mil. Acute rheumatic fever and poststreptococcal reactive arthritis reconsidered. Curr Opin Rheumatol (2010) vol. 22 (4) pp. 437-42   http://www.ncbi.nlm.nih.gov/pubmed/20150812

6) Aviles et al. Poststreptococcal reactive arthritis in adults: a case series. Mayo Clin Proc (2000) vol. 75 (2) pp. 144-7  http://www.torna.do/s/Poststreptococcal-reactive-arthritis-in-adults-a-case-series/

7) Logan and McKee. Poststreptococcal reactive arthritis. J Am Podiatr Med Assoc (2006) vol. 96 (4) pp. 362-6

8) Gerber MA, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis. Circulation. (2009) vol. (119) pp. 1541-1551  http://circ.ahajournals.org/content/119/11/1541.full

9) Van Bemmel et al. No increased risk of valvular heart disease in adult poststreptococcal reactive arthritis. Arthritis Rheum (2009) vol. 60 (4) pp. 987-993

10) Ahmoud S and Ayoub E. Poststreptococcal Reactive Arthritis. The Pediatric Infectious Disease Journal. (2001) vol. 20 (11) pp. 1081-1082

 

Promising New Hepatitis C Medications Raise Hopes, Questions

January 17, 2013

By Carl M. Gay, MD

Faculty Peer Reviewed

A healthy 61-year old man with a history of chronic genotype 1b hepatitis C virus infection of unknown duration arrives for his semiannual appointment in the Hepatology Clinic. The patient has previously been offered treatment with pegylated interferon and ribavirin, which he has declined on the basis of potential side effects and poor reported efficacy. He states that he has read that new treatment options for hepatitis C have recently become available…

Hepatitis C virus (HCV), first isolated in 1989, is a positive-stranded, enveloped RNA virus of the flaviviridae family.[1] A recent survey estimates the prevalence of Americans with antibodies to HCV to be over 4 million, including 3.2 million with evidence of HCV viral load, indicating chronic infection.[2] The majority of individuals with chronic HCV infection in the US are infected with genotype 1,[3] which has proven difficult to treat. Risk factors for the acquisition of HCV include intravenous drug use, high-risk sexual behavior, and blood transfusion prior to the advent of HCV screening in 1992, although many infected individuals have no risk factors for transmission.[4] While the incidence of acute HCV infection has decreased since its peak in the 1980s, estimates suggest that the prevalence of chronic HCV infection will not peak until 2015 [5] and that as few as 25-30% of chronic HCV cases are being diagnosed due to the asymptomatic nature of HCV infection in its early stages.[6]

HCV is the most common cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in the US.[7] While many patients with chronic HCV infection will never experience any serious complications, data show that roughly one-third of patients with untreated chronic HCV will progress to cirrhosis within 20 years.[7,8] Identifying this third of chronic HCV patients has proven difficult, however, because of poor correlation between quantification of HCV viral load and clinical outcomes.[8] Because of this, treatment may be initiated at any point in the natural history of HCV infection, although liver fibrosis is the best indication to initiate antiviral therapy to prevent progression. Thus, patients with chronic HCV infection should be regularly surveyed for abnormalities in liver biomarkers and with ultrasound to determine whether a liver biopsy to assess for fibrosis is indicated.[9]

Treatment of chronic HCV infection with interferon-alpha predates the identification of HCV itself,[10] but sustained responses were below 10% following a 6-month course.[11] Improvements to this treatment regimen came in 2 forms: the addition of the antiviral compound ribavirin, which more than doubled the sustained response rate,[12] and the covalent modification of interferon with polyethylene glycol (peg), which vastly improved the half-life of the molecule.[13] However, pegylated interferon + ribavirin “double therapy” yielded a sustained virologic response, defined as undetectable HCV viral load 24 weeks following cessation of therapy, in only ~40% of patients infected with HCV genotype 1.[14]

While the difficulty in generating models to study HCV infection has made analyses difficult, it is widely believed that exogenous interferon reduces HCV indirectly, by activating cell-surface interferon receptors and inducing JAK/STAT signaling. This subsequently alters transcription and translation of genes associated with inflammation and protein degradation to induce an “antiviral” state.[15,16] Several mechanisms have been proposed for the synergistic effect of ribavirin when paired with interferon therapy. Ribavirin is a guanosine analog and, as such, may be phosphorylated and subsequently incorporated into nascent RNA chains, causing early termination.[16,17] Other proposed mechanisms include ribavirin-dependent induction of catastrophic viral mutations, depletion of GTP required for RNA synthesis, and synergistic influence on the induction of interferon-dependent genes.[17,18] As a result of these indirect mechanisms of double therapy, there are considerable side effects associated with treatment, including cytopenias, fatigue, depression, pruritus, and anorexia.[19] Furthermore, for genotype 1, this therapy is continued for 48 weeks and includes weekly subcutaneous injections of interferon.[19] The poor efficacy and side effect profile paired with the length and mode of treatment administration underscore the need for direct therapies.

Recent advances in both in vitro and in vivo models of HCV infection have identified numerous candidates for drug targeting within the HCV proteome.[20] The function of the nonstructural 3 (NS3) serine proteases is twofold. They are responsible for both the cleavage of the HCV polyprotein and for inhibition of innate immune signaling within hepatocytes via cleavage and inactivation of interferon-beta promoter stimulator 1.[20] These NS3 molecules have been specifically targeted by 2 recently FDA-approved medications, telaprevir (Incivek, Vertex Pharmaceuticals, Boston, MA) and boceprevir (Victrelis, Merck, Whitehouse Station, NJ). Several recent clinical trials have highlighted the significant improvement in the efficacy of HCV treatment with “triple therapy” including an NS3 protease inhibitor in conjunction with peg-interferon and ribavirin.

The PROVE 1 randomized, controlled clinical trial found that while double therapy for 48 weeks achieved a sustained virologic response in only 41% of all patients with previously untreated genotype 1 chronic HCV, those who underwent triple therapy with telaprevir for the initial 12 weeks, followed by 36 weeks of double therapy, had a sustained virologic response in 67%, which was significantly greater.[21] The PROVE 2 trial subsequently showed that a similar sustained virologic response of 69% (vs 46% for 48 weeks of double therapy alone) can be obtained in genotype 1-infected patients with only 12 additional weeks of double therapy following 12 weeks of triple therapy with telaprevir.[22] The ADVANCE trial has shown that the treatment can be further simplified by response-guided therapy, in which an extended rapid virologic response (ie, undetectable HCV viral load between 4 and 12 weeks of triple therapy with telaprevir) can be used as an indication for cessation of therapy after only 12 additional weeks of pegylated interferon-ribavirin double therapy.[23] These patients had similar sustained virologic responses (75% vs 44% for 48 weeks of double therapy alone) to the PROVE 1 and PROVE 2 trials, which included 36 weeks of double therapy following telaprevir.[23] The SPRINT-1 trial found similarly promising results for boceprevir with the caveat that a 4-week lead-in of double therapy is required prior to 44 weeks of triple therapy with boceprevir in order to achieve the best results of 75% (vs 38% for 48 weeks of double therapy alone).[24] The SPRINT-2 trial additionally showed that response-guided therapy, similar to that utilized in the ADVANCE trial for telaprevir, can be used with boceprevir, again with a 4-week lead-in of double therapy alone.[25] While these results all apply to patients with chronic HCV genotype 1 infection who were previously untreated, like the patient in the initial case, additional randomized, controlled clinical trials have showed promising results for triple therapy for those patients who have previously failed double therapy.[26,27]

Thus, the current treatment guidelines for a patient like the one in the case above would be telaprevir 750 mg by mouth 3 times daily with peg-interferon and ribavirin for 12 weeks, with viral load assays between 4 and 12 weeks of treatment.[28] Depending on the virologic response at these time points, double therapy would follow for either an additional 12 or 36 weeks.[28] A 4-week lead-in of double therapy followed by either 24 or 44 weeks of boceprevir-based triple therapy, depending on virologic response between 8 and 24 weeks of therapy, would be an FDA-approved, albeit more complicated, alternative.[28]

While the prospect of a curative 24-week regimen for genotype 1 HCV infection is certainly exciting, even the most generous predictions of sustained virologic response suggest that 20% of patients will fail to respond to the new regimens. Furthermore, there are considerable side effects associated with telaprevir and boceprevir, including anemia and rash; triple therapy combines the potential side effects of 3 agents. Initial data have, however, highlighted the fact that relapse is common in patients who receive NS3 protease inhibitors without double therapy.[22] Thus, the precautions associated with double therapy and the indications for its initiation continue to be pertinent for the addition of these new agents. For patients like the one in this case, without any clinical signs of decompensated cirrhosis, the decision of whether to treat his HCV infection remains challenging.

Carl Gay, MD is a former medical student at NYU School of Medicine

Peer reviewed by Natalie Levy, MD, Department of Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244(4902):359-362.  http://www.ncbi.nlm.nih.gov/pubmed/11983439

2. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-714.

3. Alter MJ, Kurszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341(8):556-562. http://archive.is/MVA0

4. Wang CC, Krantz E, Klarquist J, et al. Acute hepatitis C in a contemporary US cohort: modes of acquisition and factors influencing viral clearance. J Infect Dis. 2007;196(10):1474-1482.

5. Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31(3):777-782.

6. Management of hepatitis C. NIH Consens Statement. 1997;15(3):1-41. http://consensus.nih.gov/1997/1997HepatitisC105html.htm

7. Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004; 24(Suppl 2):S3-S8.

8. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825-832.

9. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology. 2008;134(6):1670-1681.

10. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315(25):1575-1578.

11. Di Bisceglie AM, Hoofnagle JH. Optimal therapy of hepatitis C. Hepatology. 2002;36(5 Suppl 1): S121-S127.

12. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis. 1999;19(Suppl 1):S57-S65.

13. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343(23):1666-1672.

14. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-982.  http://www.nejm.org/doi/full/10.1056/NEJMoa020047

15. Zhu H, Zhao H, Collins CD, et al. Gene expression associated with interferon alfa antiviral activity in an HCV replicon cell line. Hepatology. 2003;37(5):1180-1188.  http://www.ncbi.nlm.nih.gov/pubmed/12717400

16. de Veer MJ, Holko M, Frevel M, et al. Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69(6):912-920.  http://www.jleukbio.org/content/69/6/912.full.pdf

17. Maag D, Castro C, Hong Z, Cameron CE. Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem. 2001;276(49):46094-46098.

18. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436(7053):967-972.

19. Ward RP, Kugelmas M. Using pegylated interferon and ribavirin to treat patients with chronic hepatitis C. Am Fam Physician. 2005;72(4):655-662.  http://www.aafp.org/afp/2005/0815/p655.html

20. Boonstra A, van der Laan LJ, Vanwolleghem T, Janssen HL. Experimental models for hepatitis C viral infection. Hepatology. 2009;50(5):1646-1655.

21. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827-1838.

22. Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839-1850.

23. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-2416.

24. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomized, multicentre phase 2 trial. Lancet. 2010;276(9742):705-716.

25. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-1206.  http://www.ncbi.nlm.nih.gov/pubmed/21449783

26. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417-2428.

27. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207-1217.

28. Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med. 2011;364(25):2429-2438.  http://www.nejm.org/doi/full/10.1056/NEJMcp1006613

Morgellons: Real Disease or Delusion Turned Internet Meme?

October 3, 2012

By Robert Mazgaj

Faculty Peer Reviewed

Morgellons disease is an “unexplained dermopathy” characterized by fibers emerging from skin lesions, and associated with various cutaneous sensations.[1] Inspired by a curious medical condition reported by a 17th century English physician, Morgellons was actually named in 2002 by Mary Leitao, a layperson, to describe the mysterious set of symptoms reportedly suffered by her then 2-year-old son.[2,3] Leitao then launched the not-for-profit Morgellons Research Foundation (MRF) along with a (no longer active) website, www.morgellons.org.[3] MRF successfully petitioned members of Congress as well as the public to convince the Centers for Disease Control (CDC) to perform an epidemiologic study of Morgellons disease. In January 2012, the CDC published their findings from this investigation on the peer-reviewed online journal PLoS ONE.[1]

The CDC study enrolled members of Kaiser Permanent of Northern California (KPNC), a managed care consortium of about 3.2 million members.[1] For the purposes of the study, the CDC defined a case-patient as any patient who received care at KPNC between July 1, 2006 and June 30, 2008 and reported fibers or similar forms of solid material such as “threads, specks, dots, fuzzballs and granules” and at least one of the following:

1. A skin lesion such as a rash, wound, ulcer or nodule.

2. A disturbing skin symptom such as pruritus, feeling that something is crawling on top of or under the skin, or stinging, biting, or a pins and needles sensation.

The CDC identified a total of 115 case-patients, yielding a prevalence of 3.65 per 100,000 enrollees. These case-patients were mostly female (77%) and white (77%) and had a median age of approximately 55 years. More than half of all case-patients admitted to additional symptoms including fatigue of at least 6 months duration and musculoskeletal complaints. More than half of all case-patients also rated their general health status as fair or poor on a web-based survey. The case-patients reported using a variety of over-the-counter, prescription, and alternative therapies to relieve their dermatologic complaints, but no treatment was reported to be regularly effective.

Of the 115 identified case-patients, 41 received comprehensive evaluations, including clinical examinations by both internists and dermatologists; histopathologic, immunohistochemical, molecular, and chemical analysis of skin biopsies; molecular and spectral analysis of collected fibers and other material; neurocognitive and neuropsychiatric testing; extensive blood tests; chest radiographs; urinalysis and culture; and drug testing of collected hair samples. These clinical evaluations yielded the following results:

1. Skin lesions were most consistent with “arthropod bites or chronic excoriations.”

2. No parasites or mycobacteria were found in skin biopsies.

3. Collected fibers and other materials were mostly of textile origin.

4. Fifty-nine percent of case-patients had cognitive deficits.

5. Fifty percent tested positive for drugs, including amphetamines, barbiturates, benzodiazepines, opiates, cannabinoids, and propoxyphene.

6. All chest radiographs were normal.

Based on these results, the authors of the study concluded that, although Morgellons is associated with a significant reduction in quality of life, no causative medical condition or infectious agent was found in the case-patients. They likened this “unexplained dermopathy” to delusional infestation, a well-characterized psychiatric disorder responsive to antipsychotics.

One of the most intriguing facts gleaned from the study was that more than 75% of case-patients reported onset of their symptoms after 2002, the year in which Mary Leitao launched MRF and its website.[1] This finding begs the question of whether the Internet helped spread a delusion to individuals with pre-existing psychiatric morbidities. In fact, even before the CDC study’s results were released, several articles suggesting this very possibility were published. Although these suspicions may never be proven, they raise the provocative issue of the considerable influence of Internet memes on beliefs in modern society.[2] The term meme, first coined by the British evolutionary biologist Richard Dawkins in his 1976 book The Selfish Gene,[3] refers to an idea or concept that is essentially the cultural analogue of a gene. That is, a meme can be spread from generation to generation, change due to imperfect copying, and be selected for or against within a given culture. Examples of memes include musical pieces, religious beliefs and one-liners from movies.

A study published in Psychosomatics offered an explanation of how a meme such as Morgellons disease came to be rapidly accepted by a relatively large online community.[4] First, simply being able to attach a specific label to one’s own perceptual abnormalities provides significant, albeit temporary, relief of anxiety. Second, interacting with others supposedly suffering from the same ailment breaks one’s social isolation and provides a sense of legitimization and comfort.[4] This confers on the Morgellons meme a significant advantage in the marketplace of ideas that is the Internet over the competing meme of delusional parasitosis, a much more stigmatizing label. Thus, we see that the psychological appeal of an idea, and not necessarily its validity, can be more valuable to its success as an Internet meme. Finally, it becomes apparent that the conventional definition of a delusion as a fixed, false belief not held by one’s culture may be challenged by the rise of the Internet as an unprecedented platform for the exchange and acceptance of memes, and quite possibly, delusions as well [5].

By Robert Mazgaj, 2nd year medical student at NYU School of Medicine

Peer reviewed by Mitchell Charap, MD, Medicine (GIM Div), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Pearson ML, Selby JV, Katz KA, et al. Clinical, epidemiologic, histopathologic and molecular features of an unexplained dermopathy. PLoS ONE. 2012;7(1):e29908. Published January 25, 2012. Accessed January 27, 2012. http://www.plosone.org/article/citationList.action?articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.0029908

[2] Lustig A, Mackay S, Strauss J. Morgellons disease as Internet meme. Psychosomatics. 2009;50(1):90. http://www.ncbi.nlm.nih.gov/pubmed/19213978?dopt=Abstract

[3] Dawkins R. The Selfish Gene. Oxford, England: Oxford University Press; 1976.

[4] Freudenreich O, Kontos N, Tranulis C, Cather C. Morgellons disease, or antipsychotic-responsive delusional parasitosis, in an HIV patient: beliefs in the age of the Internet. Psychosomatics. 2010;51(6):453-457. http://www.ncbi.nlm.nih.gov/pubmed/21051675

[5] Vila-Rodriguez F, Macewan BG. Delusional parasitosis facilitated by web-based dissemination. Am J Psychiatry. 2008;165(12):1612. http://www.ncbi.nlm.nih.gov/pubmed/19047336

Vancomycin Resistance in Staphylococcus Aureus: A Dangerous Dent in Our Armamentarium?

September 13, 2012

By Bryan Stierman

Faculty Peer Reviewed

Staphylococcus aureus, first discovered in the 1880s, is one of the most widespread human pathogens. It is also a commensal organism, with about 20% of the population permanently colonized and 60% of the population intermittently colonized.[1] There is a wide variety of potential diseases that may develop when S aureus further invades the body, necessitating the use of antibiotics. Since the introduction of antibiotics into clinical practice, S aureus has developed unique ways to combat them. The evolution of S aureus resistance begins with the introduction of penicillin into clinical use in the mid 1940s, when it was routinely used for the successful treatment of S aureus. By the early 1950s, penicillin resistance had already developed and quickly became widespread.[2] Vancomycin, a compound first discovered from the organism Streptomyces orientalis on the island of Borneo, was approved for use in humans in 1958 but quickly fell by the wayside with the development of penicillinase-resistant methicillin in 1961. Methicillin-resistant S aureus (MRSA) developed rapidly, with the first strains isolated in less than a year and the first evidence of failed treatment in humans in 1968.[2,3] As MRSA strains became increasingly common, attention once again shifted to vancomycin, which saw a dramatic increase in use beginning in the early 1980s as it became the standard of care for MRSA.[4] Given the history of rapid development of methicillin resistance to S aureus, many feared the development of further resistance, and justifiably so, as vancomycin resistance has since been reported, beginning in 1997.[3]

Vancomycin-intermediate S aureus (VISA) is defined by the minimum inhibitory concentration (MIC) of 4-8 micrograms/milliliter in susceptibility testing.[5] Vancomycin-resistant S aureus (VRSA) is defined by any MIC higher than this. While these definitions make distinctions based on MIC alone, the mechanisms of resistance differ between the organisms in each resistance category.

The first vancomycin-resistant S aureus discovered was VISA, first identified in Japan in 1997.[3] The exact mechanism of resistance among VISA is not clear, but is thought to occur through an accumulation of various mutations that result in changes to the cell wall. One cell wall change that appears to be a universal characteristic is thickening.[6][7] Increased thickness of the cell wall is related to poor cross-linking, which leads to an excess of precursors with D-Ala-D-Ala termini, the peptidoglycan targets of vancomycin. These termini are able to bind the drug and prevent its diffusion to sites of synthesis at the inner aspect of the cell wall.[6,8] Interestingly, resistance appears to require a greater utilization of cell resources than normal MRSA strains, which leads to a slower doubling time. Indeed, in a vancomycin-free environment, vancomycin-susceptible MRSA strains are selected for. Thus, the very mechanisms that protect these bacteria also decrease their ability to transmit from person to person.[7] However, there exists a subtype of VISA known as heterogeneous vancomycin-intermediate S aureus (hVISA) in which a small number of cells in any given colony maintain a more resistant phenotype while the vast majority do not. This allows for the overall population of cells to grow more rapidly and infect more readily while still maintaining a subset of resistant cells that are capable of surviving in the setting of vancomycin use. It is thought that up to 20% of MRSA isolates in some areas may display the hVISA phenotype.[9] Currently, recognition of hVISA suffers from a lack of standardized testing.[7] Simple MIC susceptibility tests are not adequate, and population analysis profiles or other nonstandardized methods must be used. These tests are available in some clinical microbiology labs by special request.

More recently, the first strain found to be fully resistant to vancomycin (vancomycin-resistant S aureus or VRSA) was isolated. The first clinical case of VRSA was reported in 2002 in a woman from southeast Michigan with multiple recurrent diabetic foot ulcers. This woman was noted to be co-infected with vancomycin-resistant Enterococcus faecalis (VRE) and MRSA. Subsequent cultures later revealed the development of a vancomycin-resistant strain of S aureus, which was found to have an identical VanA transposon sequence to the previously isolated E faecalis. Despite resistance to vancomycin, multiple other susceptibilities were reported for this organism and the patient was treated successfully.[10] The proposed mechanism for the development of VRSA from MRSA involves VanA transposon transmission from VRE. It is likely that this occurred by means of conjugation between MRSA and VRE, followed by transposition of the VanA element to the MRSA chromosome. VanA confers resistance as a result of d-Ala-d-Lac peptidoglycan precursors that vancomycin can’t bind to.[6] As of September 2011, there were 12 total reported cases of VRSA in the United States, none of which resulted from person-to-person transmission.[11,12]

Although there have been no major outbreaks of VRSA, the past cases present a serious concern for future strains with increased infectivity. VISA and, more specifically, hVISA already seem to be present within a large number of MRSA isolates. Keeping this threat in check will require a multidisciplinary approach from public health officials, pharmaceutical companies, and individual practitioners. On the horizon, new antibiotics including lipoglycopeptides such as dalbavancin, oritavancin, telavancin, and new cephalosporins such as ceftaroline and ceftobiprole show promise against resistant strains of S aureus.[9,12] Additionally, studies involving combination therapy to prevent further selection for mutants in cases of serious S aureus infections may be warranted. The CDC provides a testing algorithm for clinical laboratories in the diagnosis and reporting of VRSA.[5] However, techniques that improve and standardize the methods for recognizing hVISA are needed. Healthcare providers can best help prevent this emerging threat by rigorously adhering to infection control guidelines, including proper isolation techniques, use of antibiotics as indicated by best clinical practice, and a continued vigilance against both MRSA and VRSA.

Brian Stierman is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Bo Shopsin, MD, Medicine (Infectious Disease), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev. 1997;10(3): 505-520. http://cmr.asm.org/content/10/3/505.long

2. National Institute of Allergy and Infectious Diseases. Methicillin-resistant Staphylococcus aureus history. http://www.niaid.nih.gov/topics/antimicrobialResistance/Examples/mrsa/pages/history.aspx Updated March 4 2008. Accessed December 20, 2011.

3. Labelle A, Kollef MH. Emergence of methicillin-resistant Staphylococcus aureus. PCCSU. http://www.chestnet.org/accp/pccsu/emergence-methicillin-resistant-staphylococcus-aureus Published November 3, 2008.  Accessed December 20, 2011.

4. Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42(S1):S5-S12. http://cid.oxfordjournals.org/content/42/Supplement_1/S5.long

5. Centers for Disease Control and Prevention. CDC reminds clinical laboratories and healthcare infection preventionists of their role in the search and containment of vancomycin-resistant Staphylococcus aureus (VRSA). http://www.health.ri.gov/materialbyothers/201005CDCAdvisoryVRSA.pdf Updated May 2010. Accessed December 20, 2011.

6. Périchon B, Courvalin P. VanA-type vancomycin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2009;53(11):4580-4587. http://aac.asm.org/content/53/11/4580.full

7. Cui L, Ma X, Sato K, et al. Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J Clin Microbiol. 2003; 41(1):5-14. http://jcm.asm.org/content/41/1/5.full

8. Fridkin SK. Vancomycin-intermediate and resistant Staphylococcus aureus: what the infectious disease specialist needs to know. Clin Infect Dis. 2001;32(1):108-115. http://cid.oxfordjournals.org/content/32/1/108.full

9. Howden BP, Davies JK, Johnson PDR, Stinear TP, Grayson ML. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev. 2010; 23(1):99-139. http://cmr.asm.org/content/23/1/99.full

10. Chang S, Sievert DM, Hageman JC, et al. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med. 2003;348(14):1342-1347. http://www.nejm.org/doi/full/10.1056/NEJMoa025025

11. Hayakawa K, Marchaim D, Vidaillac C, et al. Prevalence of vancomycin-resistant Enterococcus faecalis in the region with the highest prevalence of vancomycin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol. 2011;32(9):922-924. http://www.jstor.org/stable/10.1086/661599

12. Zhanel GG, Rossnagel E, Nichol K, et al. Ceftaroline pharmacodynamic activity versus community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus, heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus using an in vitro model. J Antimicrob Chemother. 2011;66(6):1301-1305. http://jac.oxfordjournals.org/content/66/6/1301.full