Allergy/Immunology

The Rising Tide of Food Allergy

October 20, 2016

1280px-PeanutsBy Kristina Cieslak, MD

Peer Reviewed

Food allergies affect approximately 8% of children and 5% of adults, with a steadily increasing prevalence [1].  Risk factors for the development of food allergy are numerous and include genetics, sex, and ethnicity [1, 2]. Indeed, children with a parent or sibling with peanut allergy are seven times more likely to develop a peanut allergy of their own, and peanut allergy demonstrates a 64% concordance rate among monozygotic twins as compared to 7% among dizygotic twins [3, 4]. The influence of sex on allergy shifts with age, with a much higher rate of allergy seen in males during childhood and in females during adulthood, suggesting a possible hormonal impact on allergy development [5, 6].  Among ethnic groups, non-Hispanic black subjects demonstrate the highest prevalence of food allergy, though in the past ten years rates have increased most significantly among Hispanic children [7].

During an allergic food reaction, a deregulated immune system ramps up an inappropriate response to a small amount of a harmless ingested allergen.  Though not fully elucidated, a complex genetic-environmental interplay likely underlies this pathogenesis.  For example, breast-feeding and levels of vitamin D have both been purported to influence development of food allergy; however, these effects depend on the presence or absence of certain genetic variants and polymorphisms [8, 9]. Likewise, food allergy can both precede and result from alterations in the gut microbiome, the intricate and dynamic environment of thousands of microorganisms residing within the gastrointestinal tract.  Notably, mode of birth, diet, hygiene, and medication use can all affect the composition of this microbiome [10].

As the aforementioned genetic, sex, and ethnic risk factors remain static or are very slow to evolve on a population level, the question remains as to why food allergies appear to be on the rise.  One such theory centers on the hygiene hypothesis: reduced exposure to microbes during childhood results in defective immune system regulation and in the development of immune-mediated diseases including asthma, dermatitis, rhinitis, and food allergy later in life.  Large-scale societal changes that have reduced individual exposure to microbial antigens include improved sanitation, cleaner water and food sources, decreased prevalence of Helicobacter pylori infection, and decreased helminth infestation.  Consistent with this theory, rates of food allergy are highest in developed countries [11].  Furthermore, children raised on traditional farms, with heightened microbe exposure through contact with livestock and unprocessed milk, demonstrate a decreased incidence of allergic disease [12].  In this vein, probiotics, supplements that introduce potentially beneficial bacteria into the gut microbiome, are gaining traction as a potential therapy for allergic disease.  Forsberg et al recently demonstrated improved immune regulation with lowered allergen responsiveness among infants who received pre- and post-natal probiotic supplementation [13].

Antibiotics can also significantly alter the composition of the gut microbiome and may thus play a large role in food allergy development, especially given their current over-prescription [14].  An association between both maternal and child use of antibiotics has been found with cow’s milk allergy [14], and a large prospective birth cohort study found a positive relationship between antibiotic use and development of allergic disease [15]. Interestingly, administration of the gut bacteria class Clostridia, commonly found in the human gut, abolished peanut allergy in mice [16].  Though further testing and drug development are needed, this finding is an exciting development for potential allergy therapeutics, and also lends weight to the theory that antibiotic-mediated alteration of the gut microbiome has likely contributed to the allergy rise.

Additional evidence has demonstrated that trends in diet and environmental exposure may partially explain the increasing food allergy prevalence.  Lower levels of vitamin D, as a result of more time spent indoors, have been associated with the increased prevalence of asthma and allergy, with maternal intake of vitamin D during pregnancy shown to have a protective effect [17].  A western diet, low in fish and vegetables, along with a concurrent increase seen in childhood obesity, are also thought to contribute to allergy development, likely through a systemic inflammatory pathway [18].

Though not feasible to raise all children on farms, we may do well to heed the medical backlash against antibiotic overuse, encourage more outdoor play and exercise, and consider probiotic supplementation in the future.  It’s okay to get your hands a little dirty.

Dr. Kristina Cieslak is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Tania Elliot, MD, Instructor, Division of Infectious Diseases and Immunology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References 

  1. Sicherer SH, Sampson HA. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291-307; quiz 308. http://www.ncbi.nlm.nih.gov/pubmed/24388012

 

  1. Lack G. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012;129(5):1187-1197. http://www.ncbi.nlm.nih.gov/pubmed/22464642

 

  1. Hourihane JO, Dean TP, Warner JO. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ. 1996;313(7056):518-521. http://www.ncbi.nlm.nih.gov/pubmed/8789975

 

  1. Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol. 2000;106(1 Pt 1):53-56. http://www.ncbi.nlm.nih.gov/pubmed/10887305

 

  1. Emmett SE, Angus FJ, Fry JS, Lee PN. Perceived prevalence of peanut allergy in Great Britain and its association with other atopic conditions and with peanut allergy in other household members. Allergy. 1999;54(4):380-385. http://www.ncbi.nlm.nih.gov/pubmed/10371098

 

  1. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. 2003;112(6):1203-1207. http://www.ncbi.nlm.nih.gov/pubmed/14657884

 

  1. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549-1555. http://www.ncbi.nlm.nih.gov/pubmed/19917585

 

  1. Hong X, Wang G, Liu X, Kumar R, Tsai HJ, Arguelles L, et al. Gene polymorphisms, breast-feeding, and development of food sensitization in early childhood. J Allergy Clin Immunol. 2011;128(2):374-381 e372. http://www.ncbi.nlm.nih.gov/pubmed/21689850

 

  1. Liu X, Wang G, Hong X, Wang D, Tsai HJ, Zhang S, et al. Gene-vitamin D interactions on food sensitization: a prospective birth cohort study. Allergy. 2011;66(11):1442-1448. http://www.ncbi.nlm.nih.gov/pubmed/21819409

 

  1. Hormannsperger G, Clavel T, Haller D. Gut matters: microbe-host interactions in allergic diseases. J Allergy Clin Immunol. 2012;129(6):1452-1459. http://www.ncbi.nlm.nih.gov/pubmed/22322009

 

  1. Metcalfe DD, Sampson HA, Simon RA, Lack G. Food Allergy: Adverse Reactions to Foods and Food Additives. 5th ed. Chichester, West Sussex, England: John Wiley & Sons, Ltd.; 2014.

 

  1. von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol. 2010;10(12):861-868. http://www.ncbi.nlm.nih.gov/pubmed/21060319

 

  1. Forsberg A, Abrahamsson TR, Bjorksten B, Jenmalm MC. Pre- and post-natal Lactobacillus reuteri supplementation decreases allergen responsiveness in infancy. Clin Exp Allergy. 2013;43(4):434-442. http://www.ncbi.nlm.nih.gov/pubmed/23517039

 

  1. Metsala J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Mother’s and offspring’s use of antibiotics and infant allergy to cow’s milk. Epidemiology. 2013;24(2):303-309. http://www.ncbi.nlm.nih.gov/pubmed/23348066

 

  1. Wang JY, Liu LF, Chen CY, Huang YW, Hsiung CA, Tsai HJ. Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases. Int J Epidemiol. 2013;42(4):1087-1099. http://www.ncbi.nlm.nih.gov/pubmed/24062298

 

  1. Stefka AT, Feehley T, Tripathi P, Qiu J, McCoy K, Mazmanian SK, et al. Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci U S A. 2014;111(36):13145-13150. http://www.ncbi.nlm.nih.gov/pubmed/25157157

 

  1. Nwaru BI, Ahonen S, Kaila M, Erkkola M, Haapala AM, Kronberg-Kippila C, et al. Maternal diet during pregnancy and allergic sensitization in the offspring by 5 yrs of age: a prospective cohort study. Pediatr Allergy Immunol. 2010;21(1 Pt 1):29-37. http://www.ncbi.nlm.nih.gov/pubmed/20003068

 

  1. Visness CM, London SJ, Daniels JL, Kaufman JS, Yeatts KB, Siega-Riz AM, et al. Association of obesity with IgE levels and allergy symptoms in children and adolescents: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. 2009;123(5):1163-1169, 1169 e1161-1164. http://www.ncbi.nlm.nih.gov/pubmed/19230960

 

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.

Can we teach the immune system to fight cancer?

November 1, 2013

By Jenny Gartshteyn

Faculty Peer Reviewed

Since the start of vaccination – we’ve eradicated smallpox and polio, saved college kids from meningitis, averted flu epidemics, and decreased the incidence of HPV-related cervical cancer … but can we teach our immune systems to actively fight existing cancer?

Here’s the mechanism for an ideal anti-cancer vaccine:

With the growth and turnover of cancerous cells, cancer-specific tumor-associated antigens (TAAs) would be recognized and processed by professional antigen-presenting cells (APCs), such as dendritic cells and macrophages – which would present the antigens to T-cell receptors (TCR) via unique MHC:TCR binding sites. Intracellular antigens would be presented via the MHC class I molecules directly to cytotoxic CD8 cells, whereas extracellular antigens on cell-membranes would be presented via the MHC class II molecules to Cd4 helper cells. Despite this general rule, there also exists the possibility of cross-presentation by a minority of the dendritic cell subtypes – by which extracellular antigens can be presented to CD 8 cells via MHC-I (and vice versa). For example, as rapidly proliferating cancer cells undergo breakdown (autophagy), cell membrane components (that would normally be presented to CD4 cells via MHC-II) are engulfed by phagosomes and subsequently fused with and processed by liposomes – thereby allowing these extracellular cytoplasmic components to be presented to CD8 cells as well. Meanwhile, the cytotoxic CD8 response would be enhanced by the supporting CD4 helper response.

Here’s the reality:

Cancers are indeed “infiltrated with dendritic cells early in the course of disease – approximately 30% of node-negative early stage breast cancers have significant dendritic cell infiltration”. [1] Immune anti-tumor response may even be a prognostic indicator – for example, in ER-/HER2- breast cancer, each 10% increase in intratumor lymphocytic infiltration correlates with a 17% risk reduction of relapse and a 27% risk reduction of death [2]. The problem, however, is that the majority of tumor-associated antigens are actually over-expressed products of normal cellular genes. This means, that as a result of negative thymic selection early in T-cell development, only a mild-moderate affinity MHC:TCR binding occurs, and thus a less than ideal cytotoxic T-cell response. [3] Finally, most of the tumor-associated antigens are of intracellular protein origin and thus presented via the MHC Class I to CD8 T-cells only – resulting in a brief cytotoxic response with little CD4 enhancement/antibody response and only a moderate affinity CD-8 response [1]. To complicate matters further, while the Th1 Cd4 cells augment the CD8 and macrophage response via cytokines like IL-2 and TNF-alpha, the Th2 CD4 cells are less helpful, and may even be detrimental in cancer immunotherapy. Th2 CD4 cells produce IL4 cytokine (which functions as a regulator of B-cell expansion and therefore enhances cancer cell survival) as well as IL13, less well understood but known to correlate with metastatic tumor spread. [4] In the world of cancer vaccine, therefore, there is a focus on enhancing the CD8 and Th1 CD4 response while down-regulating the Th2 CD4 response – but more on this later.

The making of a cancer vaccine:

There are different approaches to tumor antigen delivery. Tumor antigens can be whole tumor cells (i.e: irradiated/lysed cancer cells from an autologous or allogenic source such as a previously resected tumor) or just parts of a cell (full length proteins). Alternatively, antigens can be specific peptides, which in turn can be loaded onto dendritic cells (DCs) in-vivo using chimeric proteins made of anti-DC receptor Ab; and subsequently re-infused into the patient. Finally, antigens can also be DNA or RNA strands that are transduced or transfected in a vector. For a more rigorous immune response to a vaccine, antigens can be combined with adjuvants, or boosters known to augment immune system activation (common examples include general immune stimulants like the BCG vaccine or non-specific bacterial products, as well as specific immune system activators such as the GCF stimulating factors). [5, 6]

Peptide vaccines are the most common, and one such example is the gp100 peptide from a melanoma antigen. In 2011, a phase 3 randomized control trial compared the standard treatment for advanced melanoma at the time, interleukin-2 (IL-2), with a vaccine (primed with gp-100 peptide) plus IL-2. [7] In the end, complete response was seen in 9% vs 1% (p-value 0.02) in the vaccine vs control group respectively. Although the benefit was minor, the interesting finding was that on immunologic analysis, anti-peptide reactivity developed in none of the 12 control patients as compared with 7 of the 37 tested patients in the experimental group. Why did only 7 of these 37 patients show the immunologic response?

Several factors play a role in inducing, and maintaining, an immunological response. First, a strong cytotoxic T-cell response must be induced. This is limited by self-immunity and the difficulty in identifying an effective antigen. Furthermore, even if good activation of cytotoxic CD8 T-cells is achieved – this activity may not be enough for a sustained long-term response without the support of helper/memory T-cells. Animal studies have shown that CD-8 activation via MHC-I presented antigens did induce a direct antitumor effect, however these same CD-8 cells were unable to support themselves in the absence of helper activity from CD4 T-h cells, which in turn are activated via the MHC-II antigens. [1] This brings us to the second point, that induction of a CD4 Th1 helper response is important in maintaining anti-tumor CD8 T-cell responsiveness. Third, regulatory T-cell response (such as the IL-4 and IL-13 producing Th2 cells) must be eliminated/suppressed. The failure of the gp-100 peptide to induce and maintain a good cytotoxic response may therefore stem from the failure to induce direct CD8 activation vs. failure to boost the cytotoxic response with a helper CD4 response vs. interference of response by regulatory cells/ctyotkines.

So, what do we have so far that works?

An alternative approach by Kantoff et al resulted in the first FDA approved anti-cancer vaccine known as Sipuleucel-T, approved for castration resistant, metastatic prostate cancer. [8] The vaccine consists of blood cells collected from individual patients (leukophoresis) and then fused with a protein called PA2024, which is a combination of a prostate antigen called prostatic acid phosphotase, and a granulocyte-macrophage-colony-stimulating factor and re-infused. The phase 3 trial involved 512 men with metastatic, castration resistant prostate cancer and showed a relative risk reduction for mortality of 22% (P=0.03). However, the validity of the trial was subsequently questioned. [9] Specifically, it was noted that patients aged >65y/o in the placebo arm had a higher than predicted mortality and that it was this age group that contributed to the significantly improved mortality in the vaccine arm of the trial; whereas patients <65y/o did not significantly benefit from the vaccine. It was therefore suggested that while leukophoresis removed the majority of mononuclear cells, only the control group received GM-CSF as part of the vaccine – and that the ultimate difference in mortality may be driven by an induced “immunodeficient” state in the control patients rather than a benefit from the vaccine itself. In support of this latter theory is the discomforting finding that at the end of the experiment, T-cell and B-cell reactivity against the original PA2024 antigen was only 28% and 27% respectively – suggesting a non-specific stimulating effect of GMCF with little selection for the original peptide antigen.

A similar concept of activating autologous immune cells against cancer is that of adoptive transfer of tumor-infiltrating lymphocytes (TIL). Simply put, autologous TILs are obtained from the patient’s tumor, expanded in vitro and subsequently re-infused into the patient after a course of lymphodepleting chemotherapy. In metastatic melanoma, response rates range from 40-50% with a small subpopulation of complete remission – although overall 3-year survival in those who do not achieve complete remision still remains low at 36%. [10, 11] An alternative to TIL therapy are the genetically engineered lymphocytes selected against a specific tumor antigen. Early phase I trials in metastatic colon ca and melanoma have shown clinical benefit, but have also raised concerns for significant side-effects when normal tissue is attacked. [12]

Approaching cancer immunotherapy from a different angle are attempts to eliminate the inhibitory T-cell checkpoints thereby allowing for a more potent, less regulated, cytotoxic t-cell response. Examples of such regulatory molecules are the CTLA-4 (cytotoxic t-lymphocyte associated antigen 4) and PD1 (programmed death 1) – both are inhibitory receptors expressed on T-cells and involved in downregulating T-cell activation. [13] In 2010, a monoclonal antibody blocking CTLA-4 (ipilimumab) was shown to improve survival by four months in patients with unresectable stage III or IV melanoma. [14]. More recently, in July 2013, two phase 1 clinical trials showed that monotherapy with anti- PD-1 receptor as well as combination therapy with anti-CTLA-4 and anti-PD-1 can induce an objective response in up to 50% of patients. [15, 16]

Summary:

The concept of giving our immune system a boost in the already innate ability to recognize and destroy cancer cells is ambitious and fraught with difficulty, but perhaps not impossible. Current ongoing research to improve current immune therapies ranges on the one hand, from molecular activation of immune cell receptors (e.g: CD40) mediating an overall pro-inflammatory response [17] to, on the other hand, using ionizing radiation to induce a pro-inflammatory cell injury response as a booster for antigen recognition and immune system activation [18]. So although we cannot yet use vaccines to eliminate cancer like we did smallpox and polio, we perhaps are – one step at a time- making advances in that direction.

Dr. Jenny Gartshteyn is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Sylvia Adams, Associate Professor, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons (A – normal cell division, B – cancer cell division; 1 – apoptosis; 2 – damaged cell. From the National Cancer Institute)

References:

1. Knutson, K.L. and M.L. Disis, Augmenting T helper cell immunity in cancer. Curr Drug Targets Immune Endocr Metabol Disord, 2005. 5(4): p. 365-71.  http://www.ncbi.nlm.nih.gov/pubmed/16375690

2. Loi, S., et al., Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol, 2013. 31(7): p. 860-7.  http://www.ncbi.nlm.nih.gov/pubmed/23341518

3. Durrant, L.G. and J.M. Ramage, Development of cancer vaccines to activate cytotoxic T lymphocytes. Expert Opin Biol Ther, 2005. 5(4): p. 555-63.  http://www.ncbi.nlm.nih.gov/pubmed/15934833

4. Hallett, M.A., K.T. Venmar, and B. Fingleton, Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13. Cancer Res, 2012. 72(24): p. 6338-43.  http://www.ncbi.nlm.nih.gov/pubmed/23222300

5. Renno, T., et al., What’s new in the field of cancer vaccines? Cell Mol Life Sci, 2003. 60(7): p. 1296-310.

6. Palucka, K., H. Ueno, and J. Banchereau, Recent developments in cancer vaccines. J Immunol, 2011. 186(3): p. 1325-31. http://www.ncbi.nlm.nih.gov/pubmed/21248270

7. Schwartzentruber, D.J., et al., gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med, 2011. 364(22): p. 2119-27.  http://www.ncbi.nlm.nih.gov/pubmed/21631324

8. Kantoff, P.W., et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med, 2010. 363(5): p. 411-22.  http://www.ncbi.nlm.nih.gov/pubmed/20818862

9. Huber, M.L., et al., Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst, 2012. 104(4): p. 273-9.  http://jnci.oxfordjournals.org/content/early/2012/01/09/jnci.djr514.full

10. Besser, M.J., et al., Adoptive Transfer of Tumor Infiltrating Lymphocytes in Metastatic Melanoma Patients: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies. Clin Cancer Res, 2013.

11. Rosenberg, S.A., et al., Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res, 2011. 17(13): p. 4550-7.  http://www.ncbi.nlm.nih.gov/pubmed/21498393

12. Park, T.S., S.A. Rosenberg, and R.A. Morgan, Treating cancer with genetically engineered T cells. Trends Biotechnol, 2011. 29(11): p. 550-7.  http://www.ncbi.nlm.nih.gov/pubmed/21663987

13. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012. 12(4): p. 252-64.  http://www.ncbi.nlm.nih.gov/pubmed/22437870

14. Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010. 363(8): p. 711-23.

15. Hamid, O., et al., Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med, 2013. 369(2): p. 134-44.

16. Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med, 2013. 369(2): p. 122-33.

17. Zhang, B., et al., The CD40/CD40L system: A new therapeutic target for disease. Immunol Lett, 2013. 153(1-2): p. 58-61.  http://scibite.com/site/library/2013_7/1/0/23892087.html

18. Formenti, S.C. and S. Demaria, Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst, 2013. 105(4): p. 256-65.

 

 

 

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.

 

 

 

Should Physicians Offer The HPV Vaccine To Men And Boys?

March 23, 2012

By Kevin Burns

Faculty Peer Reviewed

On December 22, 2010, the US Food and Drug Administration (FDA) approved the quadrivalent human papillomavirus (HPV) vaccine (Gardasil; Merck, Whitehouse Station, New Jersey) for prevention of anal cancer and anal intraepithelial neoplasia (AIN) for males and females 9 to 26 years old.[1] HPV is the most common sexually transmitted infection in the United States and the high-risk subtypes 16 and 18 are linked to development of cervical, vaginal, vulvar, anal, penile, and oropharyngeal malignancies. The FDA-approved uses for Gardasil have followed the epidemiological evidence linking HPV infection to a growing number of cancers in both males and females. The FDA originally approved the quadrivalent HPV vaccine in 2006 for cervical cancer prevention in females aged 9 to 26 years. In 2008, the FDA approved its use for the prevention of vaginal and vulvar cancers in the same population.[2] In 2009, the FDA approved its use in males and females from 9 to 26 years old for prevention of anogenital warts.[3]

Human papilloma virus DNA can be detected in the cervical tissue of 27% of women, according to the National Health and Nutrition Examination Survey, but can be found in up to 45% of women 20-24 years of age.[4] In men, the prevalence varies depending on the site sampled, but ranges from 20 to 65%.[5] In a group of HIV-negative men who have sex with men (MSM), 48% were infected with HPV; the high-risk HPV types 16 and 18 (associated with malignancy) were found in 13.7% and 8.1% respectively, and the low-risk types 6 and 11 (associated with anogenital warts) were detected in 13.4% and 6.8%. The strains for which the quadrivalent HPV vaccine is targeted–6,11,16, and 18–are found in the anal canal of 25.2% of men and 11.2% at penile sites.[6] The highest risk population, HIV-positive MSM, have a 95% rate of anogenital HPV infection.[6] Risk factors for anal HPV infection in MSM include 3-6 lifetime male sexual partners, younger age, and smoking. Males with 2 or more male lifetime sexual partners have a 3-4 times increased risk of anal HPV infection.[6]

The high prevalence of anogenital HPV infection in men, specifically in MSM, has led to a connection with both benign and malignant lesions. The low-risk HPV types 6 and 11 account for 90% of condyloma acuminata (genital warts) and the majority of HPV disease burden in men.[5] Penile cancer is uncommon, occurring in 8 out of 1 million men per year, but HPV 16 and 18 cause 40% of the roughly 1500 US cases per year. The incidence of anal cancer, rare in the general population (1/100,000), is increased 37 times in HIV-positive men and up to 100 times in HIV-positive MSM.[5] HPV type 16 causes 66% of anal cancer and type 18 causes 5%.[7] For the general population, the risk of anal cancer in men caused by HPV is much lower than that for cervical cancer in women, but in HIV-positive MSM, the incidence of anal cancer exceeds that of cervical cancer prior to screening programs.[8] HIV-positive patients are at increased risk for anogenital malignancy because of immunosuppression leading to reduced clearance of HPV and increased oncogenesis in cells co-infected with HPV and HIV.[12] The quadrivalent HPV vaccine is safe and effective in HIV-1-infected men, displaying seroconversion rates of 98%, 99%, 100%, and 95% for HPV types 6,11,16, and 18, respectively.[7]

Implementing widespread vaccination programs is a societal economic decision, relying on the cost per quality-adjusted life-year gained (QALY) compared to other prevention programs. Currently, the HPV vaccine is only routinely offered to females aged 9 to 26 because several studies have shown the HPV vaccine to be cost-effective at preventing cervical cancer in this population. A study by Kim and Goldie of the Harvard School of Public Health concluded that the cost of vaccinating 12-year old girls to prevent cervical cancer was $43,600 per QALY gained but rose to $152,700 per QALY when including females up to age 26.[9 ] When including the disease burden from genital warts caused by HPV, the cost per QALY was only reduced to $133,600. In another model including 12-year-old boys in the HPV vaccination program, Kim and Goldie concluded that the cost per QALY from cervical cancer prevention was $290,290 compared with vaccinating girls only; when including all HPV-related diseases in both sexes, it cost $120,000 per QALY.[10] Kim and Goldie therefore concluded that it is not cost-effective to expand widespread vaccination to boys compared to girls alone.[10] In contrast to these findings, a study by Elbasha and Dasbach of Merck & Co, the manufacturer of Gardasil, proposed that expanding the HPV vaccine indication to boys would only cost $25,664 per QALY for all HPV-related outcomes compared to only girls.[11] This vastly different result comes from different modeling procedures; the Merck model included the estimated diminished quality of life in women living with cervical intraepithelial neoplasia and used a higher vaccine efficacy (and included a full-page discussion debating the findings of Kim and Goldie).[10,11]

When specifically focusing on the prevention of anal cancer and anogenital warts in the high-risk population of men who have sex with men, the vaccination cost per QALY was only $15,290 for males at 12 years of age without exposure to HPV and $37,830 per QALY for MSM aged 26 with prior HPV infection.[8] Compared with the cost of cervical cancer prevention in women ($43,600 to $152,700 per QALY), vaccinating MSM for the prevention of anal cancer appears even more cost-effective. With the reduced rate of HPV clearance in HIV-positive individuals, it is important for physicians to recommend that MSM, especially those who are HIV-positive, receive the HPV vaccine to prevent anogenital malignancy. Whether or not to offer the vaccine to other low-risk male populations is debated among public health officials and policymakers. It is a philosophical and ethical question whether to offer the HPV vaccine to these low-risk males, who will obtain little if any benefit from vaccination themselves, for the goal of preventing disease in their future sexual partners.

Commentary by Andrew B. Wallach, MD, FACP

Prevention–both primary (preventing disease from occurring at all) and secondary (detecting asymptomatic disease early and preventing progression)–remains the crux of primary care. Kevin Burns succinctly summarizes the clinical and economic data surrounding HPV vaccination of men and boys. Of note, on October 25, 2011, the Advisory Committee on Immunization Practices (ACIP) voted to expand the routine use of quadrivalent HPV vaccine (HPV4). The expanded recommendations for HPV4 vaccination include:

• Routine vaccination of adolescent boys 11-12 years of age,

• Catch-up vaccination of males 13-21 years of age,

• Permissive use of vaccine among males 9-10 and 22-26 years of age, and

• Routine vaccination of men ages 22-26 who have HIV infection or who have sex with men.

ACIP also updated the federal Vaccines for Children (VFC) Program resolution for HPV vaccine to allow routine use and catch-up vaccination with HPV4 for VFC-eligible boys 9-18 years of age. As a result, in New York State, boys 9-18 years of age who are VFC-eligible or who are enrolled in Child Health Plus may receive publicly-purchased HPV4 in their medical homes. Boys 9-18 years of age who are considered “underinsured” under the State’s expansion provision of the VFC program may also receive the HPV4 in their medical homes. And, under New York Insurance Law, private insurance plans that are regulated by New York State are now required to cover HPV4 for boys 9-18 years of age. As Benjamin Franklin once stated, “an ounce of prevention is worth a pound of cure.”

Kevin Burns is a 4th year medical student at NYU School of Medicine

Peer reviewed by Andrew Wallach, MD, Department of Medicine (GIM Div), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. U.S. Food and Drug Administration. Gardasil approved to prevent anal cancer. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm237941.htm.   Published December 22, 2010.  Accessed January 27, 2011.

2. U.S. Food and Drug Administration. FDA approves expanded uses for Gardasil to include preventing certain vulvar and vaginal cancers. http://www.fda.gov/newsevents/newsroom/pressannouncements/2008/ucm116945.htm.  Published September 12, 2008. Accessed January 27, 2011.

3. U.S. Food and Drug Administration. FDA approves new indication for Gardasil to prevent genital warts in men and boys. U.S. Food and Drug Administration. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm187003.htm.  Published October 16, 2009.  Accessed January 27, 2011.

4. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007:297(8):813-819. http://jama.ama-assn.org/content/297/8/813.full

5. Barroso LF 2nd, Wilkin T. Human papillomavirus vaccination in males: the state of the science. Curr Infect Dis Rep. 2011;13(2):175-181.

6. Goldstone S, Palefsky JM, Guiliano AR, et al. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. J Infect Dis. 2011:203(1):66–74. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086446/

7. Wilkin T, Lee J, Lensing S, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis. 2010:202(8):1246-1253.

8. Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis. 2010:10(12):845-852.

9. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med. 2008:359(8):821-832.

10. Kim JJ, Goldie SJ. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ. 2009:339:b3884.

11. Elbasha E, Dasbach E. Impact of vaccinating boys and men against HPV in the United States. Vaccine. 2010:28:6858-6867.

12.Vernon SD, Hart CE, Reeves WC, Icenogle JP. The HIV-1 tat protein enhances E2- dependent human papillomavirus 16 transcription. Virus Res. 1993;27(23):133-145.

Does the BCG Vaccine Really Work?

March 14, 2012

By Mitchell Kim

Faculty Peer Reviewed

Mycobacterium tuberculosis, an acid-fast bacillus, is the causative agent of tuberculosis (TB), an infection that causes significant morbidity and mortality worldwide. A highly contagious infection, TB is spread by aerosolized pulmonary droplet nuclei containing the infective organism. Most infections manifest as pulmonary disease, but TB is also known to cause meningitis, vertebral osteomyelitis, and other systemic diseases through hematogenous dissemination.[1] In 2009, there were an estimated 9.4 million incident and 14 million prevalent cases of TB worldwide, with a vast majority of cases occurring in developing countries of Asia and Africa. Approximately 1.7 million patients died of TB in 2009.[2]

TB has afflicted human civilization throughout known history, and may have killed more people than any other microbial agent. Hermann Koch first identified the bacillus in 1882, for which he was awarded the Nobel Prize in 1905. In 1921, Albert Calmette and Camille Guérin developed a live TB vaccine known as the bacille Calmette-Guérin (BCG) from an attenuated strain of Mycobacterium bovis.[3]

As the only TB vaccine, BCG has been in use since 1921,[4] and is now the most widely used vaccine worldwide,[5] with more than 3 billion total doses given. The BCG was initially administered as a live oral vaccine. This route of administration was stopped in 1930 following the Lübeck (Germany) disaster, in which 27% of 249 infants receiving the vaccine developed and died from TB. It was later discovered that the Lübeck vaccine was contaminated with virulent M tuberculosis. The intradermal route of administration was later found to be safe for mass vaccination, through studies conducted in the 1930s.[6] The World Health Organization currently recommends BCG vaccination for newborns in high-burden countries, although the protection against TB is thought to dissipate within 10-20 years.[7] The BCG vaccine is not used in the US, where TB control emphasizes treatment of latently infected individuals.[3]

Although widely used, the efficacy of the vaccine in preventing pulmonary TB is uncertain, with studies showing 0-80% protective benefit. A meta-analysis performed in 1994 showed that the BCG vaccine reduces the risk of pulmonary TB by 50% on average, with greater reduction in risk of disseminated TB and TB meningitis (78% and 64%, respectively).[8] It is currently accepted that the BCG vaccine provides protection against TB meningitis and disseminated TB in children, as well as leprosy in endemic areas such as Brazil, India, and Africa.[9]

There are several possible explanations for the variations in BCG vaccine efficacy found in different studies. Based on the observation that BCG vaccine trials showed more efficacy at higher latitudes than lower latitudes (P<0.00001), it is hypothesized that exposure to certain endemic mycobacteria, thought to be more common in lower latitudes, might provide natural immunity to the indigenous people, and the addition of BCG vaccine does not add much to this natural protection. The higher prevalence of skin reactivity to PPD-B (Mycobacterium avium-intracellulare antigen) in the lower latitudes supports this theory. However, there has been no conclusive link found between endemic Mycobacterium exposure and protection against TB. In addition, TB infection rates are highest in lower latitudes, where natural immunity should be the greatest;[5] this may indicate that other factors are at play. Other reasons why the observed efficacy of BCG vaccines may vary so widely is that they are produced at different sites around the world, with inconsistent quality control.[4] Also, the vaccine’s efficacy depends on the viability of the BCG organisms, which can be markedly altered by storage conditions.[10]

BCG is considered a safe vaccine,[4] with the main side effect being a localized reaction at the injection site with erythema and tenderness, followed by ulceration and scarring. This occurs almost invariably following correct intradermal administration. Overall, the rate of any adverse reaction has been reported to be between 0.1% and 19%[11] and serious adverse reactions such as osteitis, osteomyelitis, and disseminated BCG infection are rare [7] and estimated to occur less than once per 1 million doses given.[11] Disseminated BCG infection is a serious complication almost exclusively seen in immunized patients with underlying immunodeficiency, such as HIV infection or severe combined immunodeficiency. This complication carries a high mortality rate of 80-83%, and the incidence of fatality is estimated at 0.19-1.56 cases per 1 million vaccines given.[7]

Immunization with BCG vaccine increases the risk of a positive purified protein derivative tuberculin skin (PPD) test. This can complicate the interpretation of a PPD test, and may lead to unnecessary preventive treatment in people who do not truly have latent TB infection. However, it has been shown that a person’s age at time of BCG vaccination, as well as the years since vaccination, affects the risk of PPD positivity. Therefore, the US Preventive Services Task Force recommends PPD screening of high-risk patients, and that a >10 mm induration after PPD administration should not be attributed to the BCG vaccine. If a patient has a previous exposure to the BCG vaccine, the CDC recommends using the QuantiFERON-TB Gold test (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia), an interferon-gamma release assay, to detect TB exposure instead of the PPD. This test is specific for M tuberculosis proteins without cross-reactivity with BCG. The major drawback of the QFT-G test is that it is roughly 3 times more expensive than the PPD test.[12]

In summary, the BCG vaccine has been in use for 90 years to reduce the prevalence of TB infection. It is the most widely used vaccine worldwide, with 100 million doses administered every year.[7] Although the vaccine is compulsory in 64 countries and recommended in another 118, its use is uncommon in the US, where treatment of latent infection is the major form of TB control. The vaccine limits multiplication and systemic dissemination of TB [13] and decreases the morbidity and mortality of TB infection, but has no effect on its transmission [7] and has no use in the secondary prevention of TB.[13] The vaccine’s efficacy in preventing pulmonary TB is highly variable, but it is thought to be efficacious in preventing TB meningitis, disseminated TB, and leprosy. In order to make up for the BCG vaccine’s shortfalls in preventing pulmonary TB, substantial progress is being made in the field of TB vaccines. In 2010, 11 vaccine candidates were being evaluated in clinical trials, with 2 being evaluated for efficacy.[9] Future developments in the field of TB vaccine development may improve on the foundations built by the BCG vaccine in reducing the worldwide health burden of this ancient disease.

Mitchell Kim is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Holzman, MD, Professor Emeritus of Medicine and Environmental Medicine; Departments of Medicine (Infectious Disease and Immunology) and Environmental Medicine

Image courtesy of Wikimedia Commons

References

1. Raviglione MC, O’Brien RJ. Tuberculosis. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2008: 1006-1020.

2. World Health Organization. Global tuberculosis Control: WHO report 2010. http://www.who.int/tb/publications/global_report/en/.   Accessed September 11, 2011.

3. Daniel TM. The history of tuberculosis. Respir Med. 2006;100(11):1862-1870.

4. World Health Organization. Initiative for Vaccine Research: BCG–the current vaccine for tuberculosis. http://www.who.int/vaccine_research/diseases/tb/vaccine_development/bcg/en/.  Published 2011 .  Accessed September 11, 2011.

5. Fine PE. Variation in protection by BCG: implications of and for heterologous immunity. Lancet. 1995;346(8986):1339-1345.

6. Anderson P, Doherty TM. The success and failure of BCG–implications for a novel tuberculosis vaccine. Nat Rev Microbiol. 2005;3(8):656-662.

7. Rezai MS, Khotaei G, Mamishi S, Kheirkhah M, Parvaneh N. Disseminated Bacillus Calmette-Guérin infection after BCG vaccination. J Trop Pediatr. 2008; 54(6): 413-416.

8. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: Meta-analysis of the published literature. JAMA. 1994;271(9):698-702.

9. McShane H. Tuberculosis vaccines: beyond bacille Calmette-Guérin. Philos Trans R Soc Lond B Biol Sci. 2011;366(1579):2782-2789.

10. World Health Organization. Temperature sensitivity of vaccines. http://www.who.int/vaccines-documents/DocsPDF06/847.pdf. Published August, 2006. Accessed October 30, 2011.

11. Turnbull FM, McIntyre PB, Achat HM, et al. National study of adverse reactions after vaccination with bacille Calmette-Guérin. Clin Infect Dis. 2002;34(4):447-453.

12. Rowland K, Guthmann R, Jamieson B. Clinical inquiries. How should we manage a patient with a positive PPD and prior BCG vaccination? J Fam Pract. 2006;55(8):718-720.

13. Thayyil-Sudhan S, Kumar A, Singh M, Paul VK, Deorari AK. Safety and effectiveness of BCG vaccination in preterm babies. Arch Dis Child Fetal Neonatal Ed. 1999;81(1):F64-F66.

Understanding the Zoster Vaccine

July 13, 2011

By Michael Cohen

Faculty Peer Reviewed

The varicella-zoster virus (VZV) is well known to the majority of the population. In children, it strikes as varicella (chickenpox), characterized by pruritic, vesicular lesions in different stages of development dispersed over the body. A self-resolving and generally limited disease, this form of VZV infection is considered to be a nuisance more than a debilitating affliction, but rarely can have severe sequelae. In adults and the elderly VZV more commonly takes the form of zoster (shingles). This disease results from the eventual reactivation of latent VZV from the sensory neuron ganglia, where it remains dormant, and clinically manifests as a very painful, vesicular rash that follows a dermatomal distribution on the body. Unlike chickenpox, however, zoster has several severe sequelae, including postherpetic neuralgia,[1] or pain persisting for at least 3 months in the area of the skin eruption after resolution of the rash; herpes zoster ophthalmicus,[2] a crippling and sight-threatening condition; and Ramsay Hunt syndrome,[3] characterized by facial paralysis, ear pain, and auditory canal and auricular vesicles. Given the potential morbidity of VZV in adults, combined with the 32% lifetime risk of developing herpes zoster, the appropriate utilization of the herpes zoster vaccine is critically important.[4]

The Herpes Zoster Vaccine: How and Why it Works

Both the incidence of herpes zoster (HZ) and its complications increase with age. Seventy percent of cases occur in adults aged 50 years and older, and the debilitating sequelae of HZ develop more frequently in those aged 79 and older.[4] This is not surprising given that the incidence of HZ has shown to be directly correlated with one’s cell-mediated immunity (CMI).[5] As CMI against VZV declines below a certain threshold, whether due to normal aging or an immunocompromised state, the risk for VZV reactivation increases.[6] Conversely, maintaining high levels of CMI against VZV through re-exposure to the virus ultimately provides a defense against it.[7]

In the past, adults over 50 were frequently re-exposed to VZV by children with chickenpox, stimulating their CMI to stay above the crucial threshold.[8] It is hypothesized that the current widespread use of the chickenpox vaccine significantly reduces that avenue of exposure and allows one’s immunity to VZV to decrease slowly over time. This may potentially alter the natural course of HZ [9] and lead to a substantial increase in the number of HZ cases in adults in the years to come. It is estimated that in the adult population currently under 50 years of age, an additional 14.6 million cases of HZ (a 42% increase) [8] may develop over the next 50 years, resulting in substantial medical costs and morbidity.[10]

Administration of the live, attenuated zoster vaccine, also known as Zostavax, works by increasing CMI against VZV in immunocompetent adults, providing protection against the reactivation of VZV.[7, 11] The only major contraindication to the zoster vaccine is an immunocompromised state, as is true for all live, attenuated vaccines.[12]

Where We Stand

In 2006, Zostavax was approved by the Food and Drug Administration for use in individuals aged 60 and over. However, despite impressive evidence published in 2005 that the vaccine decreases the incidence of HZ by 51% and postherpetic neuralgia by 67% in immunocompetent adults over the age of 60,[11] and is extremely safe [13], vaccination rates remain abysmally low, documented at 2% in 2007 [14] and at 7% in 2008.[15] Some of the identified barriers to its use include lack of patient awareness, lack of physician recommendation, difficulty and expense related to storing the frozen vaccine, trouble with re-imbursement, and concern about the cost.[14, 16]

In March 2011, Zostavax was approved by the Food and Drug Administration for use in those aged 50 to 59 years old as well, a decision based on a multicenter study of 22,000 individuals aged 50 to 59 in which administration of the vaccine decreased the risk of herpes zoster by 70% over the course of one year.[17]

Conclusion

Administration of Zostavax to immunocompetent adults over the age of 50 has been proven to significantly reduce the incidence of HZ and its associated morbidities. It is important that physicians are aware of the beneficial effects of the zoster vaccine, the rationale for its use, and its few contraindications. It is hoped that the recent expansion of the age recommendations for the vaccine will increase patient and physician awareness of the vaccine’s efficacy, thus helping to increase the use of this powerful preventive tool.  Moreover, increasing education regarding the potential devastating complications of HZ and the substantial benefit derived from the low-risk vaccine needs to be the primary prevention strategy against the development of HZ disease.

Michael Cohen is a 4th year medical student at NYU School of Medicine.

Reviewed by Elisabeth J. Cohen, MD, Professor, Department of Ophthalmology, NYU Langone Medical Center

Image courtesy of Wikimedia commons

References

  1. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67(2-3):241-251.
  2. Pavan-Langston D. Herpes zoster ophthalmicus. Neurology. 1995;45(12 Suppl 8):S50-51.
  3. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001;71(2):149–154.
  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. Hope-Simpson R. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med. 1965;58:9-20.
  6. Oxman MN. Immunization to reduce the frequency and severity of herpes zoster and its complications. Neurology. 1995;45(12 Suppl 8):S41-46.
  7. Weinberg A, Zhang JH, Oxman MN, et al. Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine. J Infect Dis. 2009;200(7):1068–1077.
  8. Schuette MC, Hethcote HW. Modeling the effects of varicella vaccination programs on the incidence of chickenpox and shingles. Bull Math Biol. 1999;61(6):1031-1064.
  9. Reynolds MA, Chaves SS, Harpaz R, Lopez AS, Seward JF. The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J Infect Dis. 2008;197 Suppl 2:S224-227.
  10. Goldman GS. Cost benefit analysis of universal varicella vaccination in the U.S. taking into account the closely related herpes-zoster epidemiology. Vaccine. 2005;23(25):3349-3355.
  11. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Engl J Med. 2005;352(22):2271-2284.
  12. Harpaz R, Ortega-Sanchez IR, Seward JF. Advisory Committee on Immunization Practices (AICP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008; 57(RR-5):1-30. Accessed at http://www.cdc.gov/mmwr/PDF/rr/rr5705.pdf 11 April 2011.
  13. Simberkoff MS, Arbeit RD, Johnson GR, et al. Safety of herpes zoster vaccine in the shingles prevention study. Ann Intern Med. 2010;152(9):545-554.
  14. Lu PJ, Euler GL, Jumaan AO, Harpaz R. Herpes zoster vaccination among adults aged 60 years or older in the United States, 2007: uptake of the first new vaccine to target seniors. Vaccine. 2009;27(6):882-7.
  15. Schiller JS, Euler GL. Vaccination coverage estimates from the National Health Interview Survey: United States, 2008. Atlanta: Centers for Disease Control and Prevention; 2009 at http://www.cdc.gov/nchs/data/hestat/vaccine_coverage/vaccine_coverage.pdf Accessed 10 April 2011.
  16. Hurley LP, Lindley MC, Harpaz R, et al. Barriers to the use of herpes zoster vaccine. Ann Intern Med. 2010;152(9):555-560.
  17. Food and Drug Administration Web site. http://http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm248390.htm Accessed 11 April 2011. (referencing clinical trial NCT00534248).

The Resurgence of Pertussis: Is Lack of Adult Vaccination to Blame?

February 23, 2011

By Ijeoma Ejigiri, Class of 2011

Faculty Peer Reviewed

Whooping cough. 100 day cough.  Pertussis.  These are the various names for the disease caused by the bacterium Bordetella pertussis.  This small gram-negative coccobacillus, transmitted via respiratory droplets, is responsible for causing coughing paroxysms followed by a long inspiratory gasp, during which the characteristic high-pitched “whoop” occurs.[1]  These coughing paroxysms can last for ten weeks or longer, hence the moniker “100 day cough.”   The paroxysmal phase is usually preceded by a prodromal illness that is typically indistinguishable from a viral upper respiratory infection.  While pertussis typically affects infants, adolescents and adults are susceptible as well.  Adults may not exhibit some of the typical manifestations of the disease, presumably due to partial immunity from previous infection or immunization.   In fact, the disease is often misdiagnosed as acute bronchitis or remains undiagnosed.[2]

During the 20th century pertussis was a major cause of morbidity and mortality among infants and children.  From 1922 to 1948, pertussis was the leading cause of death due to an infectious disease among American children younger than 14.[3]  With the advent of the whole-cell pertussis vaccine, the rates of pertussis infection dropped to an all-time low in 1976, with only 1010 reported cases.[4]  Currently, children in the United States are vaccinated with a combination vaccine, diphtheria-tetanus-acellular pertussis (DTaP).  Whole cell pertussis vaccines are not currently used in the United States, but are still used in other countries.  Adolescents and adults should receive a booster vaccine with the combination of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).[5]

The incidence of pertussis changes in a cyclical fashion, with spikes occurring approximately every 5 years.[4]  Recently there has been a dramatic resurgence of pertussis in the United States.  Pertussis infection rates have been steadily rising since the 1980s.  In California during 2010 there were a total of 8383 reported cases of pertussis, the most since 1947.[6]  Outbreaks were also reported in Pennsylvania, New York, South Carolina, and Michigan.[7]

The cause of the resurgence of pertussis is thought to be multifactorial.  One hypothesis is that decreased rates of childhood vaccination are playing a role in this epidemic. There has been a growing anti-vaccine movement due to the concern of autism and other diseases associated with vaccine administration.  A study performed by the National Committee on Quality Assurance reported that DTaP vaccination rates dropped from 87.2% in 2008 to 85.4% in 2009.[8].  The San Francisco school systems are reporting remarkably low immunization rates due to parent concerns about vaccination.[7]

Adolescents and adults are important reservoirs of the bacteria.  Some have suggested that the majority of pertussis cases are occurring in adolescents and adults.   The Centers for Disease Control and Prevention (CDC) reported that pertussis infection rates in adolescents and adults rose from 19.8% in 1989 to 28% in 1994.[9]  These infection rates are likely underestimates, given that pertussis is often misdiagnosed in adolescents and adults, who often present atypically.[4]  Treatment is often delayed or inappropriate treatment is initiated. Adolescents and adults serve as a source of infection of pertussis for other household contacts, including small children.  In a recent study conducted in Sydney, Australia, during a pertussis outbreak in 2009, household contacts such as parents and siblings were identified as sources of infection for 60% of infants.[10]  Several other studies have identified parents, grandparents, adolescents, and even healthcare workers as significant sources of transmission to infants.[11]

This begs the question of why pertussis cases are rising among adult populations.  As mentioned above, the Tdap booster vaccine is recommended for adolescents and adults, and the immunity provided by this booster lasts approximately 10 to 12 years.  However, if adults do not obtain their booster vaccination as scheduled, waning immunity puts them at increased risk for pertussis infection. Cost and lack of access to healthcare are two reasons why adults are not receiving their vaccinations as scheduled. The elderly population is particularly susceptible to pertussis infection due to waning immunity; however, Medicare often does not reimburse for vaccination of adults against whooping cough, leaving this particularly vulnerable population to pay for the cost of vaccination out of pocket.[7]  Lack of awareness of the need of vaccinations among adults is also an issue. There is a perception that vaccinations are reserved for children.  In a recent survey of 1000 adults conducted by the National Foundation for Infectious Diseases, 40% of respondents said “they had vaccines as a child so they do not need them again” and 18% of respondents said “vaccines are not necessary for adults.”[12]

Clearly there is a need for better education about the importance of vaccination for adults, both for whooping cough and the other vaccine-preventable diseases.  According to the Department of Health and Human Services, 95% of the 50 000 Americans who die each year from vaccine-preventable diseases are adults.[13]  There are several efforts in place to help raise awareness of pertussis and encourage adult vaccination.  The vaccine maker, Sanofi-Aventis, is sponsoring public-service announcements on pertussis.  Also, the CDC has issued alerts on pertussis and provides many resources for health care professionals, parents, and patients desiring more information.[14]  Health care professionals at all levels should make concerted efforts to increase adult awareness of the need for vaccinations.

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

Peer reviewed by Vinh Pham, MD,  Assistant Professor of Medicine (Infectious Disease and Immunology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Hewlett E. Bordetella species. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed.  Philadelphia, PA: Churchill Livingstone;  2000:2701.

2. Hewlett EL, Edwards KM. Clinical practice. Pertussis–not just for kids. N Engl J Med. 2005;352(12):1215-1222.

3. Long SS. Pertussis. In: Nelson WE, ed. Textbook of Pediatrics. Philadelphia, PA: Saunders; 1996:779-784.

4. Black S. Epidemiology of pertussis. Pediatr Infect Dis J. 1997;16(4 Suppl):S85-89.

5. American Academy of Pediatrics. Pertussis. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds.  Red Book: 2009 Report of the Committee on Infectious Diseases, 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:504.

6. Centers for Disease Control and Prevention (CDC).  Pertussis outbreaks. http://www.cdc.gov/pertussis/outbreaks.html.  Accessed February 14, 2011.

7. Roehr B. Whooping cough outbreak hits several US states. BMJ. 2010;341:c4627.

8. National Committee for Quality Assurance.  The State of Health Care Quality. Reform, The Quality Agenda and Resource Use. 2010.  http://www.ncqa.org/Portals/0/State%20of%20Health%20Care/2010/SOHC%202010%20-%20Full.pdf. Accessed October 21, 2010.

9. Centers for Disease Control. Reported vaccine-preventable diseases: United States, 1993, and the Childhood Immunization Initiative. MMWR. 1994;43(04):57-60.

10. Jardine A, Conaty SJ, Lowbridge C, Staff M, Vally H. Who gives pertussis to infants? Source of infection for laboratory confirmed cases less than 12 months of age during an epidemic, Sydney, 2009. Commun Dis Intell. 2010;34(2):116-121.

11. Schellekens J, von König CH, Gardner P. Pertussis sources of infection and routes of transmission in the vaccination era. Pediatr Infect Dis J.  2005;24(5 Suppl):S19-24.

12. National Foundation for Infectious Diseases. American adults’ awareness about immunization. CARAVAN® omnibus surveys, conducted October 25–28, 2007, by Opinion Research Corporation. http://www.nfid.org/pdf/publications/adultimmcta.pdf. Accessed October 21, 2010.

13. Department of Health and Human Services. Centers for Medicare & Medicaid Services. Adult immunization overview. http://www.cms.hhs.gov/AdultImmunizations. Accessed June 24, 2008.

14. Centers for Disease Control. Pertussis (whooping cough) vaccination. http://www.cdc.gov/vaccines/vpd-vac/pertussis/default.htm.

A Vaccine Against Nicotine—New Hope or Mere Hype?

February 18, 2011

By Carolan Hass, Class of 2012

Faculty Peer Reviewed

Cigarettes remain an anathema to many physicians.  Like so many unhealthy behaviors over which a clinician has little control, it can be frustrating to deal with a habit that can do so much harm to a patient, but which may be deeply entrenched in his daily life.  Although the percentage of current cigarette-smoking US adults has steadily decreased from 34.1% in 1978 to 19.8% in 2007 [1] there remains vast room for improvement.  A fifty-percent reduction in US smokers could save the country $96 billion a year.[2]  It is exciting that a new pharmacological agent will soon be available to help patients overcome what is possibly the most addictive drug on the planet.

Three companies are currently working on nicotine vaccines: Nabi Biopharmaceuticals in the US, Cytos AG in Switzerland, and Celtic Pharma in the UK.[3]  The American product NicVAX® will most likely be the soonest approved in the US and is the focus here.

The basic design of the vaccine depends on the production of an antibody response that generates immune complexes of nicotine-anti-nicotine immunoglobulin G so large that they cannot cross the blood-brain barrier.  The smoker has diminished stimulation of nicotinic receptors in the brain and decreased pleasure in response to smoking.[3]  The proof of concept was first demonstrated in animal studies.[4]  In one study, rats that had been vaccinated were compared with non-vaccinated controls.[5]  The groups were administered large doses of nicotine, then a final radio-labeled dose of nicotine.  Blood and brain levels of nicotine were compared in the two groups, with brain levels significantly reduced in the vaccinated group compared to the naïve group and serum concentrations of nicotine higher in the vaccinated group.

In a double-blinded phase II clinical trial for Nabi’s nicotine conjugate vaccine (NicVAX®), four serial vaccinations at doses of 0 (placebo), 50 µg, 100 µg and 200 µg were given to smokers who had no intent to quit.[6]  The outcomes were safety and immunogenicity.    Safety was assessed via physical examination, vital signs, electrocardiogram, blood and urine tests, recorded adverse events, and questionnaires on allergic reactions.  The trial indicated that nicotine vaccine is safe and well tolerated.  Antibody levels were assessed with ELISA and found to reach levels of >30 µg/mL in the 200 µg group.  This level had been demonstrated in independent studies to substantially change nicotine distribution in rats.[4]  The study recruitment size was small (n=68); however, in this trial there was no indication of compensatory smoking or increased nicotine withdrawal as measured by subjects’ self-reported daily smoking and cravings, carbon monoxide blood levels, and urinary nicotine metabolite levels.

In Phase IIb clinical trials, the study design was altered so that some groups received an increased dose of vaccine and more shots were administered.[7]  The trial was also double-blinded and placebo-controlled.  301 participants enrolled, all of whom smoked at least 15 cigarettes per day, with an average consumption of 24 cigarettes per day at enrollment.  At 6 months, the primary endpoint–continuous carbon-monoxide-confirmed abstinence from weeks 19-26–was found to be significantly higher only in the participants with the highest antibody responses to the vaccine (the top 30%).  24.6% in this group were abstinent compared to 12% in the placebo group (p=.024).  At 12 months, the subjects treated with the “optimal dose” of nicotine conjugate vaccine–five injections of 400 µg–had a 16% quit rate and remained abstinent versus 6% of the placebo group (p=.038).  The 400 µg group was the only group that had a statistically significant difference from the placebo group in 12-month sustained abstinence.

Double-blinded, placebo-controlled Phase III trials are currently underway with a primary outcome of smoking abstinence rate at 12 months.[7]  The results are expected in 2011 and 2012.  Participants must be current smokers who smoke at least 10 cigarettes per day and will receive 6 shots over 6 months.  Each trial is enrolling approximately 1000 participants.

While current evidence and statements from Nabi and other groups look promising, physicians must look keenly into the results of the phase III trials currently underway to see if the vaccines are truly effective, especially since the prior trials have had lower enrollment numbers. Le Houezec published a thoughtful commentary in Clinical Pharmacology and Therapeutics in 2005.[8]  While maintaining an optimistic tone, he judiciously pointed out factors that physicians will have to keep in mind, should the vaccine become available.  To summarize: 1) Patients have variable responses to vaccinations and some may need regular boosters.  2) Physicians should continue to monitor both studies and their patients using nicotine vaccine therapy for evidence of compensatory smoking: he notes that production of IgG in response to vaccination is capped at no more than 0.1-0.2 g/L and that this amount of IgG could be overcome by the amount of nicotine in ten cigarettes.  3) Patients should begin cessation at an appropriate time after vaccination, as antibody response may take months.  4) The vaccine would be best for smokers wishing to quit, ex-smokers wishing to avoid relapse, and adolescents hoping not to start.  The Phase III trials should be able to address some of these issues, particularly points 2 and 3. Other issues on the table will be cost and the availability of blood tests to see if patients are producing adequate antibody.  Nabi has created its own ELISA test to detect nicotine antibody, which will enter into the cost of the vaccine.[6]  Finally, the six injections being administered in the phase III trials require a burdensome time commitment. The cost-benefit ratio in terms of time, money, and success rates will undoubtedly affect the practicality of the vaccine.

If NicVAX® proves to be relatively inexpensive and safe and if Nabi can come up with a way to distribute it in fewer than six doses, it could become a mainstream element of tobacco cessation therapy.  It could potentially be applied to cessation of other tobacco products.  Based on current evidence and the willingness of the National Institute on Drug Abuse to grant Nabi millions of dollars to conduct these trials, the future looks promising.

Alas, the nicotine vaccine shall by no means act as a “magic pill.”  Patient education and participation remain crucial to success in smoking cessation.  Nevertheless, it may be a beneficial tool for physicians to help willing patients succeed in quitting.

Carolan Hass is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Ellie Grossman, MD, Assistant Professor of Medicine, Dir Bellevue,  Stop Smoking Program

Image courtesy of Wikimedia Commons

References:

1. National Center for Health Statistics.  Health, United States, 2009: With Special Feature on Medical Technology. Hyattsville, MD. 2010.   Cigarette smoking among high school students and adults, United States, 1965-2007; Figure 6, p. 24. http://www.cdc.gov/tobacco/data_statistics/tables/trends/cig_smoking/index.htm Accessed July 26, 2010.

2. CDC. Smoking-attributed mortality, years of potential life lost, and productivity losses–United States, 2000-2004.  MMWR. 2008;57(45):1226-1228.  http://www.cdc.gov/tobacco/data_statistics/mmwrs/byyear/2008/mm5745a3/highlights.htm Accessed July 26, 2010.

3. Cerny EH, Cerny T. Vaccines against nicotine.  Hum Vaccin. 2009;5(4);200-205.

4. Pentel PR, Malin D, Ennifar S, et al. A nicotine conjugate vaccine reduces nicotine redistribution to brain and attenuates its behavioral and cardiovascular effects in rats.  Pharmacol Biochem Behav. 2000;65(1):191-198.

5. Cerny EH, Lévy R, Mauel J, et al. Preclinical development of a vaccine “against smoking.” Onkologie. 2002; 25(5):406–11.

6. Hatsukami DK, Rennard S, Jorenby D, et al.  Safety and immunogenicity of a nicotine conjugate vaccine in current smokers.  Clin Pharmacol Ther. 2005:78(5);456-467.

7. Clinical Trials. NicVAX (Nicotine Conjugate Vaccine). Nabi Biopharmaceuticals website.  http://www.nabi.com/pipeline/clinicaltrials.php#3 Accessed July 27, 2010.

8. Le Houezec J.  Why a nicotine vaccine? Clin Pharmacol Ther. 2005; 78(5):453-455.

Which Thyroid Antibody Assays Should be Checked in Patients with Thyroid Disease?

April 14, 2010

thyroidMichael Chu MD

Faculty peer reviewed

Case:

A 44-year old female presented to the emergency room with complaints of a lower extremity rash and swelling.  The patient had been in her usual state of health when she presented to her primary care physician with complaints of palpitations, weight loss and insomnia.  Lab tests were performed and she was given a diagnosis of hyperthyroidism.  She was started on propranolol and methimazole, which the patient took intermittently due to intolerance of side effects, which she perceived as the rash and swelling. 

INTRO

Graves’ disease is characterized by the presence of hyperthyroidism, goiter, and sometimes ophthalmopathy and dermopathy.  It is a condition believed to belong to a spectrum of diseases termed autoimmune thyroid diseases, of which Hashimoto’s thyroiditis, postpartum thyroiditis, silent thyroiditis, and atrophic autoimmune thyroiditis belong.  The primary event in autoimmune thyroid diseases is likely T-cell mediated and many of the tissue consequences in both Graves’ and Hashimoto’s disease are caused by specific sub-sets of lymphocytes, lymphokines, as well as antibodies.  The T-cell factors induce the B-cells to produce antibodies: Thyroid Stimulating Immunoglobulins in Graves’ and anti-Thyroglobulin,  anti-thyroid peroxidase, and anti-thyroid symporter in all autoimmune thyroid disorders, as well as TSH-blocking antibodies.  The TSH-blocking antibodies interfere with the ability of native TSH and TSI to up-regulate the TSH receptor.  The net thyroid functional effect is the sum of the trophic and inhibitory factors, anti-enzyme effects, and destructive T-Cell phenomenoa .    For example, in Graves’ disease activation of the thyroid stimulating hormone receptor causes increased production of thyroid hormone leading to hyperthyroidism1, and in Hashimoto’s thyroiditis, anti- anti-thyroid peroxidase antibodies block organification of iodine and may lead to reduced T-4/T-3 levels.  The major thyroid related antigens that are known to have antibodies made against them are the TSH receptor, thyroglobulin, thyroid peroxidase, and the sodium/iodine symporter.2 

In pregnant women, an important issue relates to the immunoglobulins crossing the placenta, which could cause transient neonatal (or fetal) hyper- or hypothyroidism.

Here we will discuss the clinical use of thyroid antibody assays in patients with thyroid diseases.

THYROID STIMULATING HORMONE RECEPTOR ANTIBODY

Antibodies to the Thyroid Stimulating Hormone (TSH) receptor have been found in both Graves’ and Hashimoto’s disease patients, however the stimulating variety of antibodies is specific to Graves’ disease.  TSH receptor antibody assays have been reported to have a specificity of 99.6% with a sensitivity of 98.8% for Graves’ disease.3   TSH receptor antibodies have been used in various roles such as for diagnosis, as a marker of severity and as an aid for choice of treatment for Graves’ disease, however they are not commonly tested for in North America, mostly due to regional differences in practice and cost-effectiveness.4 

THYROID STIMULATING ANTIBODY

Thyroid Stimulating antibody assays measure the ability of IgG to bind to TSH receptor on cells and stimulate adenylate cyclase production.  They are also referred to as thyroid-stimulating immunoglobulin (TSI) assays.  Thyroid stimulating immunoglobulins (TSI) have been detected in 77.8% to 92% of Graves’ patients.5-6   In clinical practice, TSI is not necessary to diagnose Graves’ disease, however it may be used to predict relapse or remission after treatment of Graves’ disease with radioiodine7 or methimazole8, as persistent elevation of TSI correlates with disease activity and remission is normally accompanied by a decrease in activity.

 NOMENCLATURE

Of note, the nomenclature for TSH receptor-antibody assays are known to be inconsistent and confusing.9  Assays that measure binding of TSH to solubilized receptor are referred to as TRAb (thyroid receptor antibody), TBII (TSH-binding inhibitor immunoglobulin), or LATS (long-acting thyroid stimulator).  Assays that measure the ability of IgG to bind to TSH receptor on cells and stimulate adenylate cyclase production are referred to as TSI (thyroid-stimulating immunoglobulin) assays.  LATS was the first anti-TSH assay, is a heterophile antibody, reacting with mouse, not human thyroid, and is of historical interest only.

ANTI- THYROGLOBULIN and ANTI-THYROID PEROXIDASE ANTIBODIES

Thyroglobulin (Tg) is a large glycoprotein that is synthesized by follicular cells in the thyroid gland and secreted into the lumen of the thyroid follicle.  Thyroid peroxidase (TPO) is a key enzyme in the production of thyroid hormone.  TPO catalyzes the iodination of tyrosine residues in thyroglobulin to form monoiodotyrosine that goes on to form diiodotyrosine and ultimately thyroxine.  Antibodies to Tg (anti-Tg) and TPO (anti-TPO) are present in both Hashimoto’s and Graves’ disease patients.

The American Thyroid Association (ATA) guideline statement on treatment of patients with hypothyroidism recommends testing for either anti-TPO or anti-Tg antibodies when autoimmune thyroiditis is suspected as the underlying cause of hypothyroidism and that the anti-TPO antibody test is the more sensitive and specific of the two tests.10 

In patients with subclinical hypothyroidism, painless thyroiditis or postpartum thyroiditis, the presence of anti-TPO antibodies may help predict progression to permanent hypothyroidism.  In patients with subclinical hypothyroidism and positive anti-thyroid antibodies, the ATA states that treatment of hypothyroidism is probably advisable because of the high likelihood of progression to overt hypothyroidism.10  If treatment is deferred, at least yearly evaluation for clinical or biochemical evidence of hypothyroidism is recommended.

In Hashimoto’s patients, anti-TPO and anti-Tg abs have respective prevalence rates of 90-100% and 80-90%.   In Graves’ patients, anti-TPO and anti-Tg abs have respective prevalence rates of 50-70% and 50-80%.11 These antibodies are not specific to these particular diseases. 

CONCLUSIONS

In summary, patients with primary hypothyroidism, anti-TPO and anti-Tg antibodies may be obtained to support the diagnosis of autoimmune thyroiditis, with the former test shown to help predict progression of sub-clinical hypothyroidism to overt hypothyroidism.  In patients with primary hyperthyroidism, a TSI assay may be obtained to support the diagnosis of Graves’ disease and may be followed as a measure of disease activity.  Anti-TPO and anti-Tg antibodies may be present in Graves’ disease patients as an epiphenomenon, but are not causative, in contrast to TSI, which is responsible for the excessive production of T-4/T-3.  In addition,  the TSI, anti-TPO, and TSH blocking antibodies are helpful in predicting the development of transient neonatal Graves’ disease or hypothyroidism in pregnant women with Graves’ disease or Hashimoto’s thyroiditis. 

RESOLUTION OF CASE

The patient was thought to have a drug rash induced by methimazole, which was stopped.  The thyroid stimulating hormone level was 0.004 mIU/mL (normal: 0.35-4.8 mIU/mL), the free T4 level was 3.42 ng/dL (normal: 0.9-1.9 ng/dL).  Thyroglobulin antibodies and Thyroid Peroxidase antibodies were elevated.  A 24-hour radioiodine uptake measurement was elevated and a scan of the thyroid revealed diffuse elevated activity in the thyroid consistent with a diagnosis of Graves’ disease.  The patient subsequently underwent radioiodine treatment of the thyroid gland.

Dr. Chu is a 3rd year resident in internal medicine at NYU Medical Center.

A PRACTICAL OVERVIEW OF THE IMMUNE THYROID DIATHESIS

Commentary by Manfred Blum MD, Professor, NYU Division of Endocrinology

Dr. Michael Chu has presented a classic instance of an allergic reaction to methimazole in a woman with thyrotoxic Graves’ disease and excellently reviewed the pathophysiology of the various thyroid antibodies.  Let me briefly review the etiology, diagnosis and management of patients with the immune thyroid diathesis.

Immune thyroid disease (ITD) is responsible for the vast majority of hypo- and hyperthyroidism in the North America and for a much of euthyroid, thyroid enlargement.  Worldwide, only iodine-deficiency accounts for more thyroid pathology.

ITD is not one disorder.  Rather, there is a spectrum of clinical disorders that occur in a familial setting, most often among women, and frequently associated with other immune-mediated non-thyroid diseases.  The disorders are not fixed and may wax and wane in intensity or evolve from one clinical expression to another, for instance from hyperthyroidism to hypothyroidism.  ITD may be expressed solely in the thyroid, like goiter, have systemic secondary consequences, like myxedema, or primarily affect several organ systems, like Graves’ disease.  The manifestations of ITD are influenced by co-morbidities, past events, environmental factors, and notably local T-lymphocyte phenomena and several immunoglobulins that have unique specificities and impact on thyroid function.  TSI binds to and stimulates the TSH receptor to enhance thyroid hormone levels, anti-TPO antibody interferes with the function of the thyroid peroxidase enzyme to reduce thyroxine production, TSH-blocking antibody impedes TSH and TSI activity at the TSH receptor, also reducing hormone levels, but anti-thyroglobulin antibodies have no known hormonal consequences.  All of the antibodies cross the placenta and affect the fetal and neonatal thyroid for the duration of maternal 7S immunoglobulins in the neonatal circulation.  There are no easily available assessments of the T-lymphocyte factors and their pathophysiology is a subject of ongoing investigation.

The presence of anti-thyroid antibodies in the serum is a label signifying that autoimmune disease is operative and that other illness of this type may be present in the patient or family. The assays offer essential specific diagnostic information about etiology but no insight into thyroid function. The latter requires measurement of TSH.

The following table offers guidelines to common clinical use of anti-thyroid serologic tests.

 

GUIDELINES TO THE USE OF ANTI-THYROID SEROLOGIC TESTS

 

Clinical Condition

Why Do Tests

ATPO

ATg

TSI

CONSIDER Next StepS

Goiter Assess for AITD

X

X

 

If ITD (+), consider presence of other AIDs

Check TSH

Dominant Nodule in Goiter
  • Assess for Hashimoto’s
  • Knowledge helps cytological interpretation of a nodule

X

X

 

If (+) consider other AIDs

If (+) check TSH

  • If TSH is low do RAI Scan
  • If TSH is normal do FNB and Alert Ultrasonographer & Cytologist to diagnosis
Thyrotoxicosis

 

 

Assess for ITD etiology

If positive

 

 

 

If negative

X

X

X

If (+) consider other AIDs

If (+) Graves’

  • Check RAIU To R/O silent thyroiditis
  • Treat as appropriate

 

If (-) R/O TNG or TAN & Rx

Euthyroid Exophthalmos Assess for ITD

If positive

 

 

If negative

X

X

X

 

If (+) Graves’ eye disease & Monitor for hyperthyroidism

If (+) consider other AIDs

If (-) R/O local lesion

Hypothyroidism with high TSH Assess for ITD etiology

X

X

 

If (+) Hashimoto’s & Rx with T-4

If (+) consider other AIs

If (-) R/O other etiology

Hypothyroidism with low TSH  

 

 

 

Evaluate Pituitary
Family history of AI disorders Assess for sub-clinical ITD

X

X

 

If (+) check TSH & thyroid size

If (-) Observe thyroid

Routine Screening No

 

 

 

 

ITD = immune thyroid diseases, AIDs = autoimmune diseases, ATPO = Antithyroid peroxidase antibodies, ATg = Antithyroglobulin antibodies,  TSI = Thyroid stimulating immunoglobulin,  FNB fine needle biopsy of thyroid nodule, Rx = treat

 References

1Adams DD, Fastier FN, Howie JB et al. Stimulation of the human thyroid by infusions of plasma containing LATS protector. J Clin Endocrinol Metab 1974; 39:826.

 2Hadj-Kacem H, Rebuffat S, Mnif-Feki M, Belguith-Maalej S, Ayadi H, Peraldi-Roux S.  Autoimmune thyroid diseases: genetic susceptibility of thyroid-specific genes and thyroid autoantigens contributions.  International Journal of Immunogenetics. 36(2):85-96, 2009 Apr.

 3Costagliola S, Morgenthaler NG, Hoermann R, Badenhoop K, Struck J, Freitag D, Poertl S, Weglohner W, Hollidt JM, Quadbeck B, Dumont JE, Schumm-Draeger PM, Bergmann A, Mann K, Vassart G, Usadel KH.  Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease.  J Clin Endocrinol Metab 1999 Jan;84(1):90-7.

 4Orgiazzi J.  Anti-TSH receptor antibodies in clinical practice.  Endocrinol Metab Clin North Am. 2000 Jun;29(2):339-55, vii.

 5Macchia E, Concetti R, Borgoni F, Cetani F, Fenzi GF, Pinchera A.  Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness.  Autoimmunity. 1989;3(2):103-12.

 6Takasu N, Oshiro C, Akamine H, Komiya I, Nagata A, Sato Y, Yoshimura H, Ito K.  Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Graves’ patients and in 686 normal subjects.  Journal of Endocrinological Investigation. 20(8):452-61, 1997 Sep.

 7Wortsman J, McConnachie P, Tahara K, Kohn LD. Thyrotropin receptor epitopes recognized by Graves’ autoantibodies developing under immunosuppressive therapy. J Clin Endocrinol Metab. 1998; 83(7):2302-2308.

 8Chiovato L, Fiore E, Vitti P, et al. Outcome of thyroid function in Graves’ patients treated with radioiodine: Role of thyroid-stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage. J Clin Endocrinol Metab. 1998; 83:40-46.

 9Lab facets: Thyroid Stimulating Immunoglobulins (TSI).  https://www.labcorp.com/pdf/TSI_Thyroid_Stimulating_Immunoglobulin_LabFacets_1442.pdf.  Accessed 7/13/09.

 10Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism.  American Thyroid Association.  1995.  http://www.thyroid.org/professionals/index.html.

 11Davies T.  Pathogenesis of Hashimoto’s Thyroiditis (chronic autoimmune thyroiditis).  Uptodate.com.  Accessed 7/15/09.

Wheal and Flare: Chronic Urticaria Revisited

September 9, 2009

hivesErin Ducharme MD

Faculty peer reviewed by Rardi Feigenbaum MD

Urticaria is a common cutaneous disorder characterized by transient edematous plaques resulting from acute dermal edema and surrounding erythema. Roughly 20% of the general population will manifest urticaria at some point in their lives, qualifying it as a condition caregivers should be able to recognize and treat. When the unsightly wheal and flare reaction combined with periods of intense pruritis persists for greater than six weeks without an identifiable causative agent, the condition is referred to as chronic idiopathic urticaria (CIU).

While the majority of CU is categorized as idiopathic, in roughly one third to one half of patients autoimmunity appears to drive the disease process. Of patients with autoimmune chronic urticaria, more than half have functional autoantibodies against the high-affinity IgE receptor FcεR1 located on skin mast cells. Another 10% are found to have circulating anti-IgE IgG. A significant fraction of patients with autoimmune urticaria also have antithyroglobulin and/or antimicrosomal antibody, with or without abnormal thyroid function.

Although controversial, some authors suggest that the etiology of disease for a portion of CIU patients is a pseudoallergy to food ingredients. The concept of pseudoallergic reactions was introduced in 1983 to describe responses to a food or chemical that mimicked the signs and symptoms of an allergic reaction but without isolation of specific IgE antibodies against the offending agent. Implicated agents include preservatives, sweeteners, artificial food dyes, aromatic volatile compounds in tomatoes, herbs, wine, salicylic acid, orange oil, alcohol, high dietary fat. Various studies report remission rates due to elimination diets ranging between 31% and 100%, including ‘full’ and ‘partial’ responders, however, as a long-term treatment plan these strict diets are often difficult to adhere to. Elimination diets can occasionally be useful in diagnosis (i.e. symptoms resolve when a particular food is avoided and reoccur when the food is reintroduced), but more often than not a causative agent is not identified. A pilot study published this fall in Clinical and Experimental Allergy outlines a stepwise reintroduction diet for patient’s who have demonstrated complete remission during an elimination diet as a means to identifying individual problem foods.

Chronic urticaria can be frustrating to treat as some patients may not improve or may require years of medication for symptom control. Though often overlooked as a trivial condition, the physical, functional and psychosocial consequences of chronic urticaria can be debilitating. In fact, one study found that the degree of disability and lowered quality of life experienced by those with CIU rivals that of older patients with ischemic heart disease. Not only does CIU negatively impact health and quality of life but it also imparts a significant financial burden on individuals as well as society. In addition to direct costs of medication, one study calculated 25 to 30% lost productivity at work, school, or in daily activities among CIU sufferers.

The newer second generation H1 antihistamines are replacing their older counterparts as first-line therapy for symptomatic urticaria. These agents are either non-sedating or at least less sedating than first generation H1 blockers with an overall favorable safety profile. Included in this group are loratadine, desloratadine, fexofenadine, and cetirizine.

Levocetirizine is among the newest in this class and after several years on the European market was approved in May 2007 for use in the United States in the treatment of symptoms associated with seasonal perennial allergic rhinitis and for uncomplicated skin manifestations of CIU. The clinical efficacy of levocetirizine for the treatment of CIU in adults has been established in three large multicenter, well controlled trials, though notably these are trials of drug vs. placebo.

The use of antihistamines in CIU makes sense because histamine is largely responsible for the urticarial triad of wheals, erythema, and pruritis. Interestingly, however, disease activity has been linked to a variety of other pro-inflammatory molecules and an increasing body of evidence suggests that newer antihistamine agents also modulate these disease-driving processes. Increased levels of cellular adhesion molecules (CAMs) have been demonstrated in physical and chronic idiopathic urticarias suggesting a role for these transmembrane protein receptors in disease pathogenesis. CAMs are thought to control recruitment, migration, and activation of inflammatory cells in sites of inflammation. In a recent study, CAM levels (specifically ELAM-1 and P-selectin) decreased with use of a second generation antihistamine, paralleling clinical improvement in patients with chronic urticaria. Second generation antihistamines have also demonstrated efficacy in inhibiting cytokine release from mast cells and basophils in vitro, suggesting another anti-inflammatory mechanism of action for this drug class.

Some patients will exhibit intolerance or resistance to antihistamines and alternative therapies are available including leukotriene modifiers, dapsone, sulfasalazine, or hydroxychloroquine. Evidence supporting efficacy of most of these treatments, however, is currently limited to anecdotal accounts. In refractory cases it would be prudent to refer patients to an allergist or dermatologist before initiating second-line therapy.

With the addition of a safe and effective new pharmaceutical, the discovery of other disease-driving mechanisms and thus new targets for therapy, and the development of a method for identifying urticaria-inducing food which takes into account personal tastes and eating habits, urticaria-sufferers have cause to stop scratching and smiling again.

Commentary by Rardi Feigenbaum, MD, Clinical Assistant Professor, NYU Department of Medicine

This post brings up some important points regarding urticaria:
–Urticaria (with or without angioedema) is common. It is one of the most common diagnoses seen by allergists.
–Urticaria can be a very frustrating condition for the patient. Its seemingly random onset and waxing and waning nature and overlap of symptoms with many allergic (IgE mediated) syndromes convinces most patients there is a hidden allergen which is causing the condition. However, over the years, studies have consistently refuted this theory and a “cause” is rarely in Chronic Idiopathic Urticaria (CIU.)
–I think that most allergists would consider the “pseudoallergy” food theory of urticaria to be very, very controversial, although “never say never…”
–Most patients can be controlled with the right combination of meds.

References
1. Adelsberg BR.  Sedation and performance issues in the treatment of allergic conditions. Arch Intern Med. 1997; 157:494-500.

2. Gaillard AW, Gruisen A, de Jong R.  The influence of antihistamines on human performance. Eur J Clin Pharmacol. 1988;35:249-253.

 3. Grant JA, Riethuisen JM, Moulaert B, DeVos C.  A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol. 2002;88:190-197.

4. Kay GG, Quig ME.  Impact of sedating antihistamines on safety and productivity. Allergy Asthma Proc. 2001;22:281-283.

5. Kłos K, Kruszewski J, Kruszewski R, Sułek K.  The effect of 5-days of cetirizine, desloratadine, fexofenadine 120 and 180 mg, levocetirizine, loratadine treatment on the histamine-induced skin reaction and skin blood flow–a randomized, double-blind, placebo controlled trial. Pol Merkur Lekarski. 2006;21:449-453.

6. Molimard M, Diquet B, Benedetti MS.  Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans. Fundam Clin Pharmacol. 2004;18:399-411.

7. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW.  The impact of chronic urticaria on quality of life. Br J Dermatol. 1997;136:197-201.

8. Tong LJ, Balakrishnan G, Kochan JP, Kinét JP, Kaplan AP. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. Apr 1997;99(4):461-5.

9. Witek TJ Jr, Canestrari DA, Miller RD, Yang JY, Riker DK.   Characterization of daytime sleepiness and psychomotor performance following H1 receptor antagonists. Ann Allergy Asthma Immunol. 1995;74:419-426.

 

 

Mystery Quiz- The Answer

March 10, 2009

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is allergic bronchopulmonary aspergillosis (ABPA). The CXR shows right upper lobe opacities, two of which appear round (Image 3, arrow) and another tubular (Image 3, arrowhead), and a left upper lobe opacity which has the characteristics of subsegmental atelectasis (Image 3, double arrows). The CT scan, performed ten days after the CXR, shows central bronchiectasis of the RUL (Image 4, arrows); tubular branching shadows (Image 6, arrow) as well as ring shadows (Image 5 and 6, arrowhead) all of which represent ectatic airways filled with mucoid material. A left upper lobe ectatic airway with thickening of the bronchial wall is also present (Image 7, arrow). The left upper lobe subsegmental atelectasis seen on the initial CXR was not visible on the CT image, indicating clearing of mucoid impaction.

ABPA is seen in a small percentage of patients with asthma and represents a complex hypersensitivity reaction to aspergillus antigens colonizing the airways. The diagnosis is established when multiple clinical findings are present. These include frequently refractory asthma, eosinophilia, serum IgE reactive to aspergillus antigen, and very elevated total serum IgE levels (>1000 IU). Characteristic imaging shows central bronchiectasis and mucoid impaction (“finger in glove” shadows, Image 6, arrow) that result in subsegmental atelectasis, often in an upper lobe distribution. The atelectasis can appear migratory as one area clears and another becomes impacted. In addition to patients with asthma, ABPA is associated with cystic fibrosis in a small percentage of cases. Treatment consists of high dose glucocorticoids followed by a slow taper. Serum IgE levels decline but typically do not normalize and recurrences of disease are associated with increasing serum IgE levels. There is some evidence that the addition of itraconazole to glucocorticoids may be helpful. The addition of the antifungal agent may decrease the burden of aspergillus colonization and lead to less hypersensitivity. Left untreated, ABPA may progress to irreversible fibrosis.

Our patient was initially treated as an asthma exacerbation due to pneumonia. However, this initial diagnosis gave way to a final diagnosis of ABPA when the serum IgE level returned at 1365 IU (reference range 0-158), serum IgE specific for Aspergillus fumigatus was elevated and the CT imaging showed characteristic findings.

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