Summary
The human papilloma virus (HPV) causes 33,000 annual cancer cases of the cervix, vulva, vagina, penis, oral cavity, and anus. Advanced practice registered nurses (APRNs) need to use their unique relationships with patients to advocate for the HPV vaccine.
Original Article
The human papilloma vaccine: A time for NP leadership
By Robin L. Hardwicke PhD, RN, FNP-C, AACRN; Laura J. Benjamins MD, MPH; and Richard M. Grimes, PhD
Abstract: The human papilloma virus (HPV) causes 33,000 annual cancer cases of the cervix, vulva, vagina, penis, oral cavity, and anus. Advanced practice registered nurses (APRNs) need to use their unique relationships with patients to advocate for the HPV vaccine. The purpose of this article is to update APRNs on current knowledge regarding the HPV vaccine while providing appropriate information necessary for counseling patients and parents.
Over the last 20 years, there have been several meta-analyses and systematic reviews documenting that advanced practice registered nurses (APRNs) provide equivalent primary care when compared with primary care physicians. APRNs have also been recognized by patients as being better at educating and counseling with regard to health-related issues.1-3 In 2014, 205,000 APRNs were certified to practice in the United States. Approximately two-thirds of these were family, pediatric, or women’s health APRNs.4 This places a significant number of APRNs at the forefront of recommending, counseling, and ordering vaccinations.
The human papilloma virus (HPV) vaccine has the potential to prevent a significant number of cancer cases. The CDC reports that HPV types 16 and 18 are associated with approximately 12,000 cervical, 500 vaginal, 1,600 vulvar, and 400 penile cancer cases each year.5 The CDC also states that these HPV types also cause certain anal cancers, resulting in approximately 3,000 cases of HPV-associated anal cancers in women and 1,700 in men each year in the United States.6 As a result, the HPV vaccine is now approved for prevention of anal cancer.7 HPV is also linked to oropharyngeal cancer, a condition that occurs in 11,726 individuals annually (2,370 among females and 9,356 among males).5
Overall, the CDC states that oncogenic HPV types are associated with over 33,000 cases of cancer annually.5 Additionally, HPV has been found in squamous cell and nonsquamous cell skin cancers as well as in breast cancer tumors.8,9 A review of 20 studies from 19 different countries showed HPV in 0% to 68% of breast cancer tumors.10 It is not clear whether the presence of HPV is causative in skin or breast cancers, but it is intriguing that the virus is found so often in these tumors.
Preventative health maintenance, including routine vaccinations, has historically been well supported by healthcare providers (HCPs) and well received by the general public. The recommendation for hepatitis B vaccine is a prime example of public acceptance of a vaccine as a preventative measure for cancer. The hepatitis B virus is the causative agent in 50% to 60% of hepatocellular carcinoma cases.11
Since this vaccine was introduced, the incidence of hepatitis B declined from 373,000 in 1990 to 17,000 in 2010.12 Unfortunately, there has been significant opposition to the HPV vaccine. Systematic reviews of the literature have identified multiple concerns of HCPs regarding HPV vaccination: negative parental attitudes toward the vaccine; costs; a lack of knowledge regarding effectiveness; inadequate insurance coverage; reimbursement; a preference for immunizing older versus younger adolescents; and a preference to vaccinate girls rather than boys.12-14
Some clinicians may believe that it will be difficult to have patients return for second and third vaccine administrations. This concern can be alleviated, as a recent study showed that a single dose provides good protection, and two doses may be as effective as three doses.15 Although three doses is the ideal, there is evidence that even one or two doses will provide some protection.
Reviews have also identified parental concerns, including wanting more information before vaccinating children, the vaccine’s effect on sexual behavior, and a perception that there was a low risk of HPV infection, particularly among parents of boys. Irregular preventative care is another barrier discussed in the reviews.
Young adults who have not been immunized against HPV have similar concerns as those detailed above.17 These individuals are also concerned about the vaccine’s safety and whether it is necessary if they were not sexually active. Men were concerned that the HPV vaccine was not relevant for them.18 A study of young women from rural areas revealed that these women knew little about or were misinformed about cervical cancer, HPV, and the HPV vaccine. They also had environmental and personal barriers, such as transportation, child care, work, and school.19
The HPV vaccine
The HPV vaccine is available in three forms. A bivalent form protects against infection with HPV types 16 and 18, which are thought to cause 70% of cervical cancers as well as other genital cancers, anal cancer, and oropharyngeal cancer. The quadrivalent vaccine is also available, which prevents types 16 and 18 as well as types 6 and 11 (which cause genital warts, a condition that resulted in 353,000 provider visits in 2012).20,21 In early 2015, a new 9-valent vaccine was introduced that protects against HPV types 6 and 11 as well as oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58 that are thought to cause 90% of cervical cancers.22
These vaccines are given in three doses: an initial dose followed by two others at 2 months and 6 months later. This article focuses on the quadrivalent vaccine, as the safety and efficacy is more fully established. The recommendation for the HPV vaccine is that it should be administered to both boys and girls at ages 11 or 12 to ensure protection prior to their sexual debut; it can be given as young as age 9 years.
In addition, women through age 26 years and men through age 21 should be vaccinated if they have not been previously immunized. This age range is extended through age 26 for men who have sex with men.23 It is not necessary to confirm that a male patient has had sex with other men in order to receive the vaccine, and as a result, many insurers will cover the cost for males through age 26. However, as always, it best to check with the insurer to determine the extent of the coverage.
Patient/parent vaccine education
Most patients and parents trust their APRNs and follow their recommendations. How the provider approaches the HPV vaccine’s administration will likely affect its acceptance.24 Simply saying “Jamie is due for Tdap, Menactra, and HPV” is a different message than saying “Jamie is due for the Tdap and Menactra today. Do you want him/her to get the HPV vaccine as well?” Parents will pick up on the HCP’s anxiety if this vaccine is treated in a different manner than other immunizations.
When dealing with adult patients (ages 18 to 26), a similar approach can be used. Making the HPV vaccine part of a routine vaccine history will desensitize the issue and make it separate from sexual history taking. However, the vaccine should be strongly recommended in the event that there is evidence of sexual activity (for example, a sexually transmitted infection [STI]). If parents/patients want more information, the APRN can provide the following evidence-based information that can be used when parents or patients raise concerns.
HPV and sexual activity. A systematic review of literature identified multiple studies, indicating parental concerns that their children, particularly daughters, will be more likely to become sexually active if they receive the vaccine.25 The best evidence against this concern is a study conducted at a managed care organization that followed 493 HPV-immunized females and 905 unimmunized females for up to 3 years to see if the immunized females had higher rates of pregnancies or STIs; the researchers found no significant differences between the two groups.26
Many adolescents have sexual intercourse, but most are not developmentally prepared to think in a future-oriented fashion to forego sexual activity on the basis that they may get cancer years later. Because research findings suggest that the vaccine does not promote sexual activity, it is important to immunize and protect both those teens who already are sexually active and those who may become sexually active.
Vaccine effectiveness. It takes a while to appreciate the impact of a vaccine that prevents cancer 30 or 40 years after receiving it. However, there is current information that strongly suggests the possibility of the preventive effect of the HPV vaccine. Australia has aggressively advocated that girls and young women receive the vaccine and provides vaccination through its schools. As a result, over 75% of women age 14 to 17 years and 63% of those ages 18 to 26 years have received the vaccine.27
A study at the Melbourne Sexual Health Centre showed that there was a 92.6% decline in genital warts of patients under age 21 years and a 72.6% decline in those between 21 and 30 years of age within 4 years of the vaccine’s introduction in 2007. There was no decline in genital wart rates in women over 30 years of age. Interestingly, there was also an 81.8% decline in genital warts diagnosed in heterosexual men less than 21 years of age seen at the clinic, and a decline of 51.1% among 21- to 30-year-old heterosexual males. This happened even though males were not targeted for the vaccine until 2014.28 Clearly, the vaccine is effective against HPV 6 and 11.
Additional data regarding the vaccine’s efficacy against the oncogenic types also comes from Australia. The rate of Pap tests with high-grade abnormalities declined by more than 50% in women under age 20 years and by about 25% in women between age 20 and 24 years between the introduction of the vaccine in 2007 and 2012. There was no decrease in abnormalities for women over age 30 years, the age group that was not targeted by the vaccine program.29 A similar reduction in abnormal Pap tests in young women was found in Denmark where the HPV vaccine has been widely used.30
A study of immunized, high-risk young women in the United States showed a 78% reduction in HPV types 6, 11, 16, and 18 when compared with historical controls.31 The National Health and Nutrition Examination Survey (NHANES) collected self-administered cervico-vaginal specimens from a random sample of households from 2003 to 2006 and again in 2009 to 2012. The presence of vaccine-preventable HPV among females ages 14 to 19 years decreased from 11.5% (2003 to 2006) to 4.3% (2009 to 2012) and from 18.5% to 12.1% among females ages 20 to 24 years; there were no significant declines in other age groups.32 Therefore, it seems clear that the vaccine is effective in reducing the likelihood of acquiring genital warts as well as the two oncogenic viruses that cause 70% of cervical cancers.
Age for immunization. Some parents do not wish to immunize their children prior to adolescence because they are not sexually active. In these cases, it is necessary to point out that the best time to immunize is before there is a likelihood of infection. Waiting until someone is sexually active before immunizing against HPV is similar to saying that one should not receive the measles, mumps, and rubella vaccine until after they have had measles.
Furthermore, HPV is an infection of skin and mucous membrane cells and is transmitted from skin to skin or from mucous membrane to mucous membrane. Therefore, transmission can occur during nonsexual events. Genital warts have been found in women who were found to have intact hymens.33 HPV has also been recovered from the fingertips of 30% of female college students in one study.34 As mentioned above, HPV-associated cancers are located at several sites other than the genitals.
Immunization of males. Both young men and parents of boys will raise the question, “Why should males be immunized when the vaccine prevents cervical cancer?” Parents and young men should be educated about the cancers that do not involve the cervix and the risk for males to acquire them. As described above, HPV can cause penile cancer, oral cancer, and anal cancer. Pointing out that a male’s HPV infection status puts the mother of their future children at risk for these cancers, and for cervical cancer, promotes thought-provoking consideration.
Vaccine safety. Concern of potential adverse events has been raised by both parents and by 18- to 26-year-old women for whom the vaccine is recommended. One study of 244 women between 18 and to 24 years old found that 22% were concerned about the vaccine’s safety.35 There is an extraordinary amount of information that attests to the safety of the vaccine. As of 2015, over 80,000,000 doses of the quadrivalent vaccine have been given.
No pattern of serious adverse reactions or causes of death has been attributed to the vaccine; however, like any vaccine, there will be some individuals who will experience pain, redness, or swelling in the arm where the injection is given. Other possible side effects may include fever, headache or feeling tired, nausea, and muscle or joint pain.14 The most common potentially harmful event is fainting. This was recorded in 3 out of 1,000 individuals receiving the HPV vaccine in clinical trials, which was equal to those who received placebo injections.36 Nonetheless, it is recommended that the injection be given while the recipient is seated and that they remain seated for 15 minutes afterward.
Vaccination of postadolescent women. Some 18- to 24-year-old women will question whether they should be immunized because they are not sexually active. As mentioned above, the ideal time to be vaccinated is before exposure. Women who are beginning to have sex are at significant risk of HPV infection. A study showed that 28.5% of women acquired HPV infection within 1 year of having sex with their first partner. If they were with that partner for 3 years, this risk approached 50%.37
However, it should also be pointed out that HPV has been recovered from the genitals of virgins and is regularly found in the oral cavity.38,39 The NHANES study collected oral swabs from a representative study of Americans and found that 5.6% of the individuals between the ages of 16 and 69 years were positive for HPV. Although the risk was higher for those who admitted to having oral sex, it was present in those who denied that behavior.40
Vaccine costs. Vaccination costs are a routine concern to both healthcare providers and those receiving the vaccine. The Patient Protection and Affordable Care Act requires that all insurers cover any vaccines that were recommended when the act was passed for individuals who are 0 through 18 years of age.41 At the time the act was passed, the HPV vaccine was only recommended for females; therefore, young males are not covered by this provision. However, some insurance companies will pay for male vaccines, and patients should contact these insurance companies to learn their coverage provisions.
In addition, the HPV vaccine is covered for both males and females by the Vaccines for Children Program, which provides vaccines at no cost to children up to age 18 years who are uninsured, underinsured, or have Medicaid or Children’s Health Insurance Plan. APRNs should make certain that their practice participates in this program so that their patients are eligible. And, even if they cannot obtain funding for immunizing young males, the Australian data show that if young women are immunized, young heterosexual men will be far less likely to acquire HPV infections.
Discussion
From a medical and public health perspective, it is surprising that a vaccine that prevents cancer is not as widely adopted in the United States as has been in other countries. A potential explanation for this is that clinicians have not been advocates for the vaccine. A nationwide survey of 776 family practitioners (47%) and pediatricians (53%) showed that 27% of the physicians reported they do not strongly endorse the HPV vaccine or routinely recommend it for 11- to 12-year-old girls (26%) or boys (39%). Most of these physicians (59%) use a risk-based approach to recommending the HPV vaccine. The quality of HPV immunization recommendations was lower among physicians who were uncomfortable talking about the HPV vaccine or who believed parents did not value it.
Pediatricians (54%) were more likely to follow recommendations for HPV immunizations than family physicians (37%).23 While this means that pediatricians outperformed family physicians, it also means that nearly half of pediatricians surveyed were not advocates of the HPV vaccine. A more recent study showed some improvement in recommending the HPV vaccine. A survey of pediatricians (n = 364) and family practitioners (n = 218) showed that 60% of pediatricians and 59% of family practitioners strongly recommend the HPV vaccine for 11- to 12-year-old girls, whereas 52% of pediatricians and 41% of family practitioners strongly recommend the vaccine for 11- to 12-year-old boys.43
Again, it is useful to point out that 40% of pediatricians and family practitioners do not follow the vaccine recommendations for girls and half or more do not follow them for boys. APRNs have also been found to not follow vaccine recommendations. A survey of 575 primary care providers whose practices included adolescents (47% family medicine physicians, 20% pediatricians, and 33% APRNs) found that only 76% of these clinicians said that they recommend the vaccine more than 75% of the time to their 11- to 12-year-old female patients, and less than half were likely to recommend it for a boys of that age.
Pediatricians were slightly more likely to recommend it for their female patients than family practitioners or APRNs. However, there was a much larger difference in recommending the vaccine for boys between pediatricians (67% of the time), family practitioners (42%), and APRNs (41%).44 The importance of provider recommendations was illustrated in a study of 18- to 26-year-old women in which the women demonstrated they were three times more likely to take the HPV vaccine if their physician strongly recommended it as opposed to having a lukewarm recommendation.45
Given the effectiveness of the vaccine to prevent cancer and genital warts, providers should now be more proactive in using the vaccine. Providers should no longer let the ear of offending parents/patients hinder the vaccine from reaching its full potential. Although more research needs to be done to determine the most effective counseling messages, there are suggested topics to cover based on the clinical experiences of the authors (see Counseling patients and parents).
Knowing that patients see APRNs as better educators and counselors as compared with their physician counterparts, APRNs should take leadership in advocating for, counseling about, and administering the HPV vaccine. It is particularly important that this occur, as the number of APRNs is now approaching the number of primary care physicians and will soon represent the majority of primary health providers in the United States.4 Therefore, APRNs will be a powerful force in reducing future cancers and to significantly reduce the 353,000 visits for genital warts that occur annually.
REFERENCES
1. Brown SA, Grimes DE. A meta-analysis of nurse practitioners and nurse midwives in primary care. Nurs Res. 1995;44(6), 332-339.
2. Martínez-González NA, Djalali S, Tandjung R, et al. Substitution of physicians by nurses in primary care: a systematic review and meta-analysis. BMC Health Serv Res. 2014;14:214.
3. Charlton CR, Dearing KS, Berry JA, Johnson MJ. Nurse practitioners' communication styles and their impact on patient outcomes: an integrated literature review. J Am Acad Nurse Pract. 2008;20(7):382-388.
4. American Association of Nurse Practitioners. NP Fact Sheet. 2018. www.aanp.org/all-about-nps/np-fact-sheet.
5. Centers for Disease Control and Prevention. Human papillomavirus-associated cancers – United States, 2004-2008. Morb Mortal Wkly Rep. 2012;61(15):258-261.
6. Centers for Disease Control and Prevention. HPV-associated anal cancer rates by race and ethnicity. 2017. www.cdc.gov/cancer/hpv/statistics/anal.
7. Food and Drug Administration. Gardasil. 2018. https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM094042.
8. Arron ST, Jennings L, Nindl I, et al. Viral oncogenesis and its role in nonmelanoma skin cancer. Brit J derm. 2011;164(6):1201-1213.
9. Dubina M, Goldenberg G. Viral-associated nonmelanoma skin cancers: a review. Am J Dermatopathol. 2009;31(6):561-573.
10. Amarante MK, Watanabe MA. The possible involvement of virus in breast cancer. J Cancer Res Clin Oncol. 2009;135(3):329-337.
11. Wong CH, Goh KL. Chronic hepatitis B infection and liver cancer. Biomed Imaging Interv J. 2006;2(3):e7.
12. Centers for Disease Control and Prevention. Historical reported cases and estimates of viral hepatitis.
2017. www.cdc.gov/hepatitis/Statistics/IncidenceArchive.htm.
13. Holman DM, Benard V, Roland KB, Watson M, Liddon N, Stokley S. Barriers to human papillomavirus vaccination among US adolescents: a systematic review of the literature. JAMA Pediatr.2014;168(1):76-82.
14. Ferrer HB, Trotter C, Hickman M, Audrey S. Barriers and facilitators to HPV vaccination of young women in high-income countries: a qualitative systematic review and evidence synthesis. BMC Public Health. 2014;14:700.
15. Downs LS Jr, Scarinci I, Einstein MH, Collins Y, Flowers L. Overcoming the barriers to HPV vaccination in high-risk populations in the US. Gynecol Oncol. 2010;117(3):486-490.
16. Kreimer AR, Struyf F, Del Rosario-Raymundo MR et al. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA trials. Lancet Oncol. 2015;16(7):775-778.
17. Price RA, Tiro JA, Saraiya M, Meissner H, Breen N. Use of Human papillomavirus vaccine among young adult women in the United States: an analysis of the 2008 National Health Interview Survey. Cancer. 2011;117(24):5560–5568.
18. Newman PA, Logie CH, Doukas N, Asakura K. HPV vaccine acceptability among men: a systematic review and meta-analysis. Sex Transm Infect. 2013;89(7):568-574.
19. Mills LA, Head KJ, Vanderpool RC. HPV vaccination among young adult women: a perspective from Appalachian Kentucky. Prev Chronic Dis. 2013;10:E17.
20. Centers for Disease Control and Prevention. Frequently asked questions about HPV vaccine safety. 2018. www.cdc.gov/vaccinesafety/vaccines/hpv/hpv-safety-faqs.html.
21. Centers for Disease control and Prevention. Table 45. Selected STDs and complications – initial visits to physicians’ offices, National Disease and Therapeutic Index, United States, 1966-2012. 2014. www.cdc.gov/std/stats12/tables/45.htm.
22. Food and Drug Administration. Gardasil 9. 2018. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm426445.htm.
23. Center for Disease Control and Prevention. Human papillomavirus vaccination. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep. 2014;63(5):1-30.
24. Gilkey MB, Malo TL, Shah PD, Hall ME, Brewer NT. Quality of physician communication about human papillomavirus vaccine: findings from a national survey. Cancer Epidemiol Biomarkers Prev. 2015;24(11):1673-1679.
25. Trim K, Nagji N, Elit L, Roy K. Parental knowledge, attitudes, and behaviours towards human papillomavirus vaccination for their children: a systematic review from 2001 to 2011. Obstet Gynecol Int. 2012:921236.
26. Bednarczyk RA, Davis R, Ault K, Orenstein W, Omer SB. Sexual activity-related outcomes after human papillomavirus vaccination of 11- to 12-year-olds. Pediatrics. 2012;130:798-805.
27. National HPV Vaccination Program Register. HPV vaccination coverage by dose 2016. 2018. www.hpvregister.org.au/research/coverage-data/HPV-vaccination-coverage-by-dose-2016.
28. Read TR, Hocking JS, Chen MY, Donovan B, Bradshaw CS, Fairley CK. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex Transm Infect. 2011;87(7):544-547.
29. Victorian Cervical Cytology Registry. Statistical report 2015. 2018. www.vccr.org/data-research/statistical-reports/annual-statistical-reports.
30. Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papilloma vaccine on cervical neoplasia--nationwide follow-up of young Danish women. J Natl Cancer Inst. 2014;106(3):djt460.
31. Cummings T, Zimet GD, Brown D, et al. Reduction of HPV infections through vaccination among at-risk urban adolescents. Vaccine. 2012;30:5496-5499.
32. Markowitz LE, Liu G, Hariri S, Steinau M, Dunne EF, Unger ER. Prevalence of HPV after introduction of the vaccination program in the United States. Pediatrics. 2016;137(3):e20151968.
33. Shew ML,Weaver B, Tu W, Tong Y, Fortenberry JD, Brown DR. High frequency of human papillomavirus detection in the vagina before first vaginal intercourse among females enrolled in a longitudinal cohort study. J Infect Dis. 2013;207(6):1012-1015.
34. Winer RL, Hughes JP, Feng Q, et al. Detection of genital HPV types in fingertip samples from newly sexually active female university students. Cancer Epidemiol Biomarkers Prev. 2010;19:1682.
35. Caskey R, Lindau ST, Alexander GC. Knowledge and early adoption of the HPV vaccine among girls and young women: results of a national survey. J Adolesc Health. 2009;45:453.
36. Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine. Pediatr Infect Dis J. 2009;29:95-101.
37. Winer RL, Feng Q, Hughes JP, et al. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis. 2008;197:279-282.
38. Frega A, Cenci M, Stentella P, et al. Human papillomavirus in virgins and behaviour at risk. Cancer Lett. 2003;194(1):21-24.
39. Shew M, Weaver B, Tu W, et al. High frequency of human papillomavirus detection in the vagina before first vaginal intercourse among females enrolled in a longitudinal cohort study. J Infect Dis. 2013;207:1012-1015.
40. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693-703.
41. .Department of Health and Human Services. The Affordable Care Act and Immunization. 2017. www.hhs.gov/healthcare/facts-and-features/fact-sheets/aca-andimmunization.
index.html.
42. Centers for Disease Control and Prevention. VFC Program. 2017. www.cdc.gov/features/vfcprogram.
43. Allison MA, Hurley LP, Markowitz L, et al. Primary care physicians’ perspectives about HPV vaccine. Pediatrics. 2016;137(2):e20152488.
44. McRee AL, Gilkey MB, Dempsey AF. HPV vaccine hesitancy: findings from a statewide survey of healthcare providers. J Pediatr Health Care. 2014;28(6):541-549.
45. Rosenthal SL, Weiss TW, Zimet GD, Ma L, Good MB, Vichnin MD. Predictors of HPV vaccine uptake among women aged 19-26: importance of a physician’s recommendation. Vaccine. 2011;29(5):890-895.
Robin L. Hardwicke is a professor of internal medicine and obstetrics/gynecology and reproductive medicine at the University of Texas Medical School at Houston, Houston Tex.
Laura J. Benjamins is an associate professor at the Department of Pediatrics, Division of Adolescent Medicine Center for Clinical Research and Evidence Based Medicine, the University of Texas Health Science Center at Houston, Houston Tex.
Richard M. Grimes is an adjunct professor at the Department of Internal Medicine, McGovern Medical School, University of Texas, Houston Health Science Center at Houston, Houston, Tex.
This manuscript was funded in part by the Baylor–UT Houston Center for AIDS Research Core Support Grant number AI36211 from the National Institute of Allergy and Infectious Diseases.