Education & Training:

Surveillance of VPD Broadcast: Questions & Answers
Questions submitted during the Surveillance of Vaccine-Preventable Diseases broadcast of December 8, 2005

HPV

1. Is HPV a reportable disease? What methods will be used to evaluate HPV vaccine effectiveness?

   No, HPV is not reportable to the National Notifiable Diseases Surveillance System (NNDSS). Discussions and plans for post licensure surveillance and studies are underway to evaluate the roles of monitoring HPV infections, genital warts, and cervical cancer precursors to monitor effectiveness of HPV vaccine.

Influenza

1. When will Tamiflu be available to take along for those who travel in areas where there is avian influenza?

   As a result of increased demand for Tamiflu, Roche has decided to proactively manage the Tamiflu inventory. Their top priority is to ensure that the product will be available to patients who are diagnosed with influenza, as well as those in need of post-exposure treatment or prevention from seasonal influenza. Therefore, Roche has temporarily suspending shipment of Tamiflu until an increased incidence of seasonal flu is established, as tracked by FluStar.com. Roche will then distribute product to ensure that Tamiflu is available in the areas where flu emerges to meet the seasonal demand.

MMR

1. Since rubella and measles have been eradicated in the US, is it still necessary to test for immunity and vaccinate non-immune health care providers?

   Yes. When measles virus is introduced into a community, persons who work in healthcare facilities are at greater risk for acquiring measles than the general population (CDC. Measles, mumps and rubella – vaccine use and strategies for elimination of measles, rubella and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1998; 47 (No. RR-8):13 or
   www.cdc.gov/mmwr/PDF/rr/rr4708.pdf .
   Vaccination is still the best way to prevent rubella and measles in the US. Even though there is no sustained transmission of either measles or rubella in the US, there is always the risk of an imported case. This would occur if a traveler from a country where one or both of these diseases circulates visited the US while ill.

2. Which country in Latin America does not include rubella vaccine in their national program? Does Latin America use trivalent (MMR) or monovalent rubella vaccine?

   Haiti is the one country in Latin America that does not include rubella vaccine in their national program. This question was answered incorrectly on the air during the satellite broadcast: instead of the Dominican Republic, the correct answer is Haiti. Most countries use MR (measles and rubella) though a few use MMR.

3. When new hires are screened for rubella, how far back should they assess rubella vaccination history?
   
   Rubella vaccination should also be assessed back to childhood. Clinical diagnosis of rubella is unreliable and should not be considered in assessing immune status. Persons generally can be considered immune to rubella if they have documentation of vaccination with at least one dose of MMR or other live rubella-containing vaccine administered on or after their first birthday, have serologic evidence of rubella immunity, or were born before 1957 (except for women of childbearing age). Birth before 1957 is not acceptable evidence of immunity for women who might become pregnant. (Pink Book, p. 153 www.cdc.gov/vaccines/pubs/pinkbook/downloads/rubella.pdf
   www.cdc.gov/mmwr/PDF/rr/rr4708.pdf

Pertussis

1. In the CDC Surveillance Manual the clinical case definition is described as a cough for 2 wks, but I heard today that Dr Moran said 7days.

   The case definition in the Surveillance Manual gives the correct number of weeks of cough - two. When I mentioned one week of cough I was not speaking of the case definition, I was talking about when the diagnosis of pertussis should be suspected. Here is what I said: "The diagnosis of pertussis should be suspected in a person who develops a cough illness that lasts more than 7 days, or if the person has fits, or paroxysms of coughing."

2. How long will the PCR remain to be positive in the treated and the non-treated case?

   Regarding the length of time a PCR might remain positive after treatment, you might want to refer to "Detection of Bordetella pertussis by polymerase chain reaction and culture in the nasopharynx of erythromycin-treated infants with pertussis" published by Edelman K, Nikkari S, Ruuskanen O, He Q, Viljanen M, Mertsola J. in the Pediatric Infectious Diseases Journal in 1996 Jan;15:54-7. Here is the abstract:
   
   BACKGROUND: Pertussis is a highly contagious respiratory disease and the most serious effects occur in young infants. Recently it has been shown that rapid and highly specific PCR can be a useful diagnostic tool for detection of pertussis infection. To our knowledge there are no previous studies concerning the disappearance of Bordetella pertussis DNA from the nasopharynx during antimicrobial treatment. METHODS: We studied prospectively how rapidly live B. pertussis organisms and DNA of these bacteria disappear from the nasopharynx during erythromycin therapy in unvaccinated infants. Eighty-five nasopharyngeal swabs obtained from nine erythromycin-treated infants with pertussis on consecutive days during hospitalization were tested by PCR and culture. The PCR products were further analyzed by Southern hybridization. RESULTS: On the fourth day of treatment 56% of the samples were positive by culture and 89% by PCR, whereas after 7 days the rates were 0 and 56%, respectively. In seven of nine patients PCR remained positive for 1 to 7 days longer than culture. The follow-up study also showed the semiquantitative nature of the PCR assay. The intensity of the PCR products in agarose gel usually weakened with time during erythromycin therapy. CONCLUSIONS: The results of this study show that PCR assay can achieve the specific diagnosis of pertussis infection in a large proportion of infants even when antimicrobial treatment has killed the organisms and culture is no longer positive. This is just a study of unvaccinated infants but clearly the DNA can be found days after the bacteria have been killed.
   
   As for the length of time after cough onset that PCR remains positive in vaccinated persons, you might be interested in "Diagnosing Pertussis: The Role of Polymerase Chain Reaction" published by Ellen Bamberger MD, Nitza Lahat PhD, Vladimir Gershtein PhD, Rosa Gershtein PhD, Daniel Benilevi MD, Sara Shapiro PhD, Imad Kassis MD, Lisa Rubin MPH, MD and Isaac Srugo MD in the Israel Medical Association Journal 2005;7:351–354. The analysis is a bit complicated but they report that "Cough duration was also a statistically significant clinical marker of infection in the pre-vaccinated group (OR 0.52, P < 0.05), indicating that for each additional week of cough duration the likelihood of infection declines by over 50%. A decomposition analysis indicated that sensitivity is greatest with cough duration of 1 week or less (41.3% with a positive PCR), declining as duration increases and eventually leveling out at 13.04% with a positive PCR at 2–3 weeks." I would say that in most cases it is probably no longer worth testing by PCR more than 2-3 weeks after cough onset.

3. Please comment on current prophylaxis recommendations for contacts to pertussis cases.

   You can access recommendations for pertussis outbreaks at www.cdc.gov/vaccines/pubs/pertussis-guide/guide.htm
   For specific antibiotic regimens, see www.cdc.gov/mmwr/preview/mmwrhtml/rr5414a1.htm

4. We’ve has a recent influx of pertussis reports with practitioner recommending post exposure prophylaxis based on pertussis serological testing. What information can be used to give practitioner the best testing recommendations?
   
   Pertussis culture is considered the gold standard lab test, but the organism is difficult to culture and many laboratories no longer have personnel with sufficient expertise in the process. Culture is affected by specimen collection, transport, and isolation techniques. Isolation rates are highest in the first 3—4 weeks of illness (catarrhal and early paroxysmal stages). Cultures are less likely to be positive in immunized individuals, later in illness, and in individuals who have received antibiotics. Cultures are variably positive (30-50%) and often give results too late for clinical usefulness. Since adolescents and adults have often been coughing for several weeks before they go to the doctor, it is often too late. Success of culture declines after 2 weeks of cough illness, antibiotic treatment, and vaccination. Cultures can be negative with even one dose of antibiotic.
   
   Due to perceived increased sensitivity and faster reporting, DNA amplification [e.g., polymerase chain reaction (PCR)], many laboratories have abandoned culture and started pertussis testing by PCR. No FDA-licensed product is available and there are no nationally recognized standardized protocols, reagents, or reporting formats for pertussis PCR testing. Specificity can be poor with high rates of false positives in some laboratories. Exclusive reliance on non-standardized PCR tests resulted in overdiagnosis in several recent large outbreaks. Overdiagnosis had important public health consequences including unnecessary treatment of PCR false-positive individuals and inappropriate chemoprophylaxis of contacts, with adverse events from unwarranted antibiotic therapy in both. PCR is also affected by specimen collection. A poorly taken NP swab will likely be negative in both culture and PCR. PCR is less affected by prior antibiotic therapy, but this is a relative thing and PCR will be negative--it just takes a little longer (and that time depends on the initial bacterial load, the person's immune status, and the antibiotic treatment). Previous vaccination results in some degree of immunity, which results in a lower bacterial load, which can ultimately affect the PCR test. Specificity can be a problem with PCR---there are lots of reasons for false positive PCR tests.
   
   Serologic testing could be useful in adults and adolescents. However, there is no FDA licensed serology test. The current serologic tests were developed for use in vaccine trials and thus measure antibody response to vaccine antigens. So a positive serology simply means that the person has been exposed to pertussis (by infection or by vaccination). There are several papers that have looked at establishing a high cut-off value above which is suggestive of recent infection (within the last 2 years). However, the assays that are available commercially do not differentiate infection from vaccination. They simply show that the person has no detectable antibody to pertussis or has detectable antibody. These commercial assays cannot be used to determine whether this reflects recent infection, past infection, or past vaccination. CDC is working with the FDA to develop a serologic assay with a cut-off that is suggestive of recent infection. Of course, any assay with such a cut-off will misclassify a certain percentage of individuals incorrectly (both ways). The MA DOH does have a serology test that can be used in people >11 years old (to eliminate some of the problems from recent vaccination). They validated this assay with culture and established a cut-off level that is 63% sensitive and 99% specific. The CDC/FDA assay will be somewhat similar to the MA assay. We are looking to develop a serologic assay that can be used by the state health departments. We are also working with other investigators to look at other serologic assays that would use pertussis antigens not found in the vaccine. Obviously that is going to take a longer amount of time to get such an assay to the point where it could be used in the diagnostic lab.

Polio

1. If a child received 4 doses of IPV, all 4 weeks or more apart, the last dose coming at 28 months (of age?), does the child need a dose after 4 years of age?

   Yes, a dose should be administered on or after the 4th birthday to boost antibody titers to high levels for long-lasting protection. An extra dose before 4 years of age does not eliminate the need for the 4-6 year old dose.
   "All children should receive four doses of IPV at ages 2, 4, and 6-18 months and 4-6 years. The first and second doses of IPV are necessary to induce a primary immune response, and the third and fourth doses ensure 'boosting' of antibody titers to high levels.. . . All children who have received three doses of IPV before age 4 years should receive a fourth dose before or at school entry. The fourth dose is not needed if the third dose is administered on or after the fourth birthday." (CDC. MMWR Recommendation & Report on "Poliomyelitis Prevention in the United States: Updated Recommendations of the Advisory Committee on Immunization Practices," published May 19, 2000.)

   The preferred interval between the second and third doses of IPV is 2-8 months. However, if accelerated protection is needed, the minimum interval between doses of IPV is 4 weeks. Children who receive three doses of IPV before the fourth birthday should receive a fourth dose before or at school entry. (CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, Hamborsky J, Wolfe S, eds. 8th ed. Washington DC: Public Health Foundation, 2004. p. 95). Pink Book: www.cdc.gov/vaccines/pubs/pinkbook/downloads/polio-508.pdf

Varicella

1. Given the many cases of varicella we still see and hear about, won’t individual case-reporting of varicella take up a lot of time and resources for local health departments?

   Yes, it definitely can, and it can take up a lot of time for the people who will report the cases to the health department as well. There are two key ways to decrease the impact of implementing case-based varicella surveillance. First, instead of collecting all of the data on the varicella worksheet, jurisdictions that are beginning surveillance programs may initially report three key variables on each reported case: age, varicella vaccination history, and severity of disease. These data will allow the states and CDC to assess the impact of vaccination on disease reduction in specific age groups and possible shifts in varicella incidence to older persons as well as appropriate targeting of vaccination programs by age; evaluate the proportion of all cases that are vaccinated (or have breakthrough disease), and better understand vaccine effectiveness; and assess severity of remaining disease, and how vaccination may alter severity. As it becomes more feasible, states should consider incorporating additional variables into surveillance, for example, data on source patients, and laboratory information on cases. Another way to decrease the resources needed for varicella surveillance is that instead of implementing state-wide surveillance, the state may choose to implement sentinel-site surveillance. Sentinel-site surveillance allows the state to choose either representative reporting sites throughout the state, or select counties within the state, or some combination. Sites can then be monitored across time so that the state can assess trends. (Letter sent to all state and territorial Immunization Program Managers from CDC, September 2004)

2. A 4 year old female had chickenpox vaccine at 12 months of age and now has a breakthrough rash with 15 maculopapulovesicular lesions and 3 vesicular lesions after exposure to wild type virus. What is your recommendation for her 11 ½ month-old sibling who was exposed to her rash in the last 2 days but experienced a fever of 102°F last evening.

   Although the fever could be unrelated to varicella, if both the 11½ month-old and the 4 year old children were exposed to the same case at the same time, then the 11½ month-old may also have wild type varicella virus from that exposure. The incubation period for varicella is at least 10 days, so it is unlikely that the infant would have a rash from exposure to the 4 year-old if the 4 year-old child began having rash one day before the 11½ month-old developed fever. The parents should continue to monitor the child and consult a physician as needed. Meanwhile, both children should be isolated and kept away from other susceptible persons.

3. Is information related to shingles (incidence of disease and/or death) included in the varicella data? Have there been any studies to look at the changes in the incidence of shingles since the recommendation for varicella immunization was implemented? Is shingles reportable?

   The varicella data referred to in the presentation includes only acute varicella cases. Yes, there have been several post licensure studies that have looked at the effect of varicella vaccine on zoster; however, there is not a clear conclusion on the overall impact of varicella on zoster incidence. Some studies seem to indicate that zoster incidence is unchanged, and others seem to show a gradual increase over time. The problem with each of these studies is that there are little data that show the incidence of zoster prior to licensure of the vaccine, so there are limited baseline data from which to measure or compare current trends. Herpes zoster rates among persons (children) who received varicella vaccine are lower than the herpes zoster rates in children who were not vaccinated but had varicella. This is also true among children with immune compromising conditions, such as leukemia.

   Additional References:
   Jumaan AO, Jackson LA, Bohlke K, Galil K, Seward JF. Incidence of herpes zoster, before and after varicella-vaccination – associated decreases in the incidence of varicella, 1992-2002. J Infect Dis 2005;191:1999-2001

   Yih WK, Brooks DR, Lett SM, Jumaan AO, Zhang Z, Clements KM, Seward JF. The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage. BMC Public Health 2005;5:68
   
   A new herpes zoster vaccine (ZOSTAVAX) may be available by 2006 to prevent herpes zoster and its main complication, post herpetic neuralgia (PHN). (Oman MN, Levin MJ, Johnson GR, Schmader KE, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271-84).

   Herpes Zoster is not currently a nationally notifiable disease reportable through NNDSS. There has been some discussion with the Council of State and Territorial Epidemiologists (CSTE) since 1995 about making it reportable.

4. When new-hires are screened for varicella, how far back should vaccination status be assessed?
   
   Vaccination and disease history for varicella should be assessed back to childhood since most vaccines and vaccine-preventable diseases occur in childhood. If there is a question on whether a person had varicella or the vaccination, that person can either have serologic testing for immunity, or receive the 2-dose vaccination series. (Pink Book, 2004 p.158)

   

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