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Primary Care Corner with Geoffrey Modest MD: understated cervical cancer mortality and hpv in men

16 Feb, 17 | by EBM

By Dr. Geoffrey Modest

2 recent articles looked at US cervical cancer mortality and hpv infections in men.

  1. The New York Times reported a huge racial gap in cervical cancer deaths in the United States (see ). They referred to an article which calculated a much higher death rate from cervical cancer overall in the US than previously found, with an increased disparity between black and white women (see DOI: 10.1002/cncr.30507).


  • The age-standardized rate for cervical cancer death reported by the National Center for Health Statistics from 2000-2012 was 3.2/100K in white women and 5.7/100K in black women
  • However, these results were not corrected for the prevalence of hysterectomies, and given that hysterectomies are significantly more common in black women, the above statistics understated the cervical cancer death rates (since these cancers are essentially eliminated in people who’ve had hysterectomies for benign reasons, especially if the cervix is removed).


  • The overall prevalence of hysterectomies was 20% for women >20 years old, higher in black women for all ages between 45-69, peaking for both white and black women at ages 65-69, but this peak hysterectomy rate was 58% of black women vs 43% of white women [remarkably high numbers overall and shockingly so for older black women!!]
  • Correcting for the prevalence of hysterectomies, the mortality rate was 10.1/100K in black woman and 4.7/100K in white women.
  • Based on this, the disparity in mortality rates was underestimated by 44% over the published NCHS numbers.
  • The highest corrected rate was in black women > 85 years, with a death rate of 37/100K vs 11/100K for white women!!!
  • Using this corrected analysis, the rate of cervical cancer deaths in white women decreased at 0.8% per year, whereas for black women the annual decrease was 3.6%.


  • Each year more than 12,000 women in the US are diagnosed with cervical cancer and more than 4000 women die from it.
  • For the women in this study, the likelihood of a supracervical hysterectomy (i.e., leaving the cervix) was <2% (data from before 2004), though now is closer to 4-7.5%. So more individual data, even if available, would not have altered the results much
  • Cervical cancer is largely preventable through screening, and screening rates may be lower in poor and minority areas, although published results on this are equivocal. The data are clearer that black women tend to present with more advanced disease and may receive different treatments than white women, e.g. less surgery and more radiation for the same stage of cancer. For example, a recent large study of more than 15,000 patients with advanced cervical cancer found that more than half did not receive treatment considered to be standard of care, mostly those who were black and poor.
  • The corrected cervical cancer mortality rates in black American women is similar to those of many resource-poor countries in Latin America, Asia (excluding Japan), the Caribbean, and Africa (including sub-Saharan Africa). For white women, their corrected cervical mortality rates are similar to those of Europe, Australia, and Japan
  • The corrected mortality is significantly higher in black vs white women in all age groups, except those aged 20-29 and 35-39 (though increases pretty dramatically in women older than this)
  • Some of the methodologic weaknesses of the study include the potential for biases related to incomplete data and the merging of 2 unrelated databases with very different methodologies. The data on age-standardized death rates came from the National Center for Health Statistics (they also looked at the SEER database, which did not include every state and notably did not include Louisiana), whereas the data on hysterectomy prevalence came from the Behavioral Risk Factor Surveillance System survey, which is based on interviews.
  • It was quite striking to me when I was working in Chicago many many years ago that a very large number of my middle-aged to older black female patients had had hysterectomies when living in the Southern US, but were unaware they even had the surgery (many reported having had some surgery, but were never told that the doctors had done a hysterectomy). We were told that this was a not uncommon method of enforced birth control for black women…. So, since some were unaware they even had the surgery (and may be part of the older women now), the racial disparity may be even greater.

So, it is quite striking that black women in the United States have such a high death rate from cervical cancer. And, perhaps a real concern is that with the repeal of the Affordable Care Act, which does cover such screenings, there may be less access for many people for appropriate screenings. In addition, I am very concerned that the upcoming, likely attacks on Planned Parenthood and other clinics providing cervical cancer screening etc., will decrease access especially for poor women and women of color.

Relevant prior blogs: which reviews the American Society of Clinical Oncology guidelines presents data from a study in the Netherlands, suggesting that negative cervical HPV screening in women over age 40 supports a strategy of screening every 10 years which was a review of urinary screening for HPV, with my concern that clinicians will be doing far fewer pelvic exams (which certainly has its pluses, since these can be invasive and uncomfortable procedures for women), but with the caveat that I have seen several younger clinicians feeling less comfortable doing pelvic exams even when clinically indicated presents a study suggesting that we should do Pap smears in HIV patients, even post-hysterectomy


  1. Another article came out looking at the prevalence of genital HPV infections as well as vaccination rates in US adult men, from the National Health and Nutrition Examination Survey (NHANES) of 2013- 2014 (see doi:10.1001/jamaoncol.2016.6192).


  • NHANES collects information of representative cross-section samples of the US population.
  • 1868 men aged 18 to 59 were examined and DNA was extracted from self-collected penile swab specimens for HPV genotype.
  • Demographic and vaccination information was gathered by self-report.


  • The overall general HPV infection prevalence in males aged 18-59 was 45.2% (i.e., 34.8 million men). bimodal pattern, with peaks age 28-32 and another 58-59
  • The infection prevalence with at least one high risk HPV subtype by DNA testing was 25.1%
  • The overall prevalence of infection for subtypes covered by the HPV-9 valent vaccine was 15.1% (the 9-valent vaccine covers 90% of subtypes responsible for cervical cancer in women)
  • The specific very high-risk subtype prevalences: 4.3% for HPV-16 (3.3 million men), 1.7% for HPV-18 (1.3 million men)
  • In vaccine-eligible men, the prevalence of infection with at least one HPV strain targeted by the HPV-4 valent vaccine was 7.1% and by the HPV 9-valent vaccine was 15.4%
  • Among vaccine-eligible men, HPV vaccination coverage was 10.7% (i.e. more than 25 million vaccine-eligible men did not receive the vaccination)


  • HPV is the most commonly known sexually transmitted infection in the US. An estimated 79 million people in the US are infected with HPV, half of new infections occurring before age 24. There was a study about 10 years ago finding that 50% of women in their first year at college acquired HPV infection. In men, an estimated 160,000 are infected annually with low-risk HPV infections
  • In men, an estimated 9000 HPV-related cancers occur annually, responsible for 63% of penile cancers, 91% of anal cancers and 72% of oropharyngeal cancers (the oral HPV infection rates are around 10% for men and 4% for women). HPV can also cause recurrent respiratory papillomatosis
  • Men seem to clear HPV infection pretty quickly, with a study of 290 men finding that the 12-month risk of acquiring a new infection was 29%, with the median time to clearance being 5.9 months (Giuliano AR. J Infect Dis 2008; 198: 827). So, it seems likely that the point prevalence in the above study significantly understates the life-time acquisition rate for HPV, which is similar to that of women.
  • BUT, the major public health issue for men is that they can transmit this infection to women, potentially leading to cervical cancer, with a significant morbidity and mortality (as in first article above)
  • The CDC therefore published their recommendations for HPV vaccination: females aged 11 to 26; males aged 11 to 21, but from 21-26 being “recommended for persons with a risk factor (medical, occupational, lifestyle, or other indication”). Probably makes sense to support male vaccination till age 26, similar to the female recommendations

So, bottom line: these studies are very concerning, since on the one hand HPV infections are wide-spread and the number of unvaccinated men who are vaccine-eligible is staggering; on the other hand, cervical cancer death rates are quite high in the US and with a pretty dramatic black-white differential.

Primary Care Corner with Geoffrey Modest MD: 2-dose HPV vaccine for girls and boys

28 Nov, 16 | by EBM

By Dr. Geoffrey Modest

On 10/19/16, the CDC recommended that 9 to 14 year olds receive only 2 doses of the 9-valent HPV vaccine at least 6 months apart, instead of the prior recommendation for 3 doses. But those who started the series between ages of 15 through 26 continue to need 3 shots (see for the press release). Here is the article it was based on (see doi:10.1001/jama.2016.17615).


  • Open-label, non-inferiority study done in 52 ambulatory sites in 15 countries, with 5 cohorts:
    • Girls aged 9 to 14, getting 2 doses 6 months apart (n= 301)
    • Boys aged 9 to 14, getting 2 doses 6 months apart (n= 301)
    • Girls and boys aged 9 to 14 getting 2 doses 12 months apart (n= 301)
    • Girls age 9 to 14 getting 3 doses over 6 months, the current recommendation (n= 301)
    • Adolescent girls and young woman aged 16 to 26 getting 3 doses over 6 months, acting as the control group (n= 314)
  • Mean age 11, BMI 20, 60% white/17% Asian/10% black, 25% North America/20% Asian Pacific/30% Europe/15% Latin America/8% Africa
  • Eligible 9-14 yo’s had to be generally healthy and not sexually active prior to enrollment. Those in the control group (age 16-26) had to be generally healthy with 4 or fewer lifetime sexual partners. All of the intervention groups were seronegative for each subtype prior to the 1st dose of vaccination
  • The primary endpoint was the antibody response to each of the HPV types, assessed one month after the last dose of vaccine


  • More than 90% of participants in each cohort seroconverted to each HPV subtype
  • HPV antibody responses in girls and boys given the 2 doses were not inferior to the control group (p < 0.001 for each HPV type).
  • There was essentially no difference between boys’ and girls’ responses to the vaccine
  • There was also no difference between those receiving the 2nd dose after 6 months or after 12 months, though the antibody responses in those receiving the 2nddose after 12 months were someone higher than after 6 months
  • The antibody responses were roughly 2 to 3 times higher in the younger cohorts than the older control for each HPV type
  • Post hoc analysis assessing antibody response 6 months after the last dose of vaccine declined in all of the cohorts, but the antibody responses remained non-inferior in the 2-dose regimens
  • 22 participants had a serious adverse event, all not considered to be related to the vaccine. One person discontinued the study because of transient urticaria


  • The 9-valent HPV vaccine provides protection against 7 high-risk HPV types responsible for 90% of cervical cancers or other anogenital cancers, as well as 2 other types responsible for 90% of genital warts.
  • The WHO in 2014 changed their recommendations for girls aged 9 to 14 from a 3 dose to a 2 dose schedule (at 0 and 6 months).
  • Other studies have suggested that a longer interval between the 1st and 2nd dose is more immunogenic, and that a 2nd dose earlier than 5 months after the 1st dose seems to be less effective; i.e. the second dose should not be before 6 months, and is more immunogenic at least in the short-term if given after 12 months as in the above study, or perhaps even later (the CDC press release only states that the second dose should be at least 6 months later)
  • Other studies of also found that coadministration of the 9-valent HPV vaccine with diphtheria, tetanus, pertussis, polio, and meningococcal vaccines can be done at the same visit.
  • This study did not have clear clinical outcomes, though it seems to me that antibody response is a reasonable surrogate marker for clinical protection. A prior blog (see , or see Joura EA. N Engl J Med 2015; 372: 711) dealt with the initial recommendations for the 9-valent vaccine, showing that not only was this vaccine immunogenic, it was also quite safe, and provided 7% efficacy in preventing >= CIN2 lesions. — And HPV vaccine is not only quite expensive, it is also very painful and requires more medical visits to do 3 vs 2 injections.
  • It should be noted that there are no data showing what the minimum clinically-effective protective titer is for HPV vaccination
  • The investigators will be following antibody persistence and the duration of protection over time.
  • This study was designed to look at a younger cohort because of their increased HPV-vaccine immunogenicity, as documented in other studies (and confirmed in this study). It certainly seems reasonable that a subsequent study should look at the effectiveness of 2-dose regimens for those older than 14 and those who have been more sexually active/have evidence of prior infection by some of the HPV types.

Primary Care Corner with Geoffrey Modest MD: Meningococcal vaccine in HIV-positive patients

15 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There are 2 potentially very serious bacterial infections, both with functional vaccines available but not previously recommended, that seem to be more common in HIV infected patients: HIB (haemophilus influenzae type B) and meningococcus. The Advisory Committee on Immunization Practices, ACIP,  just came out with recommendations to immunize HIV-positive patients against meningococcus.


  1. For the HIB infection: I had been immunizing all HIV patients with HIB vaccine until a few years ago, based on a case-control study about 20 years ago showing a higher prevalence of invasive HIB infections in HIV positive patients. Though the data on efficacy were lacking, it seemed to me that the potential benefit far outweighed the very low risk of this tried-and-true vaccine. The current feeling, from my reading, is that while HIV may be a risk factor for invasive HIB infections, the incidence of HIB infections overall has plummeted due to the aggressive HIB immunizations of children, dramatically decreasing the HIB reservoir and shifting the serotype of prevalent H flu infections dramatically away from typable to nontypables. So, it does seems unnecessary to immunize. But, it still may still be reasonable to vaccinate those patients who come from and return to countries without universal pediatric HIB immunization.
  1. Meningococcal vaccine: I also began immunizing my HIV patients with meningococcal conjugate vaccine several years ago, after the outbreak of meningococcal disease in HIV-positive people in New York, though I stopped a couple years ago because of strong and persistent statements by the CDC not to do so. The new recommendations, however, are that all HIV-infected persons be immunized pretty aggressively (see ).
  • Those < 2 years old should get MenACWY-CRM (Menveo) at 2, 4, 6, and 12-15 months, or get MenACWY-D (Menactra) at ages 9-23 months and then 12 weeks later (with the caveats that this last one be given: only if >4 weeks after finishing the pneumococcal conjugate vaccine and either before or concomitantly with DTaP — see below)
  • Those > 2 years old and not previously vaccinated should get a 2-dose primary series of the conjugate vaccine (either of the above), 8-12 weeks apart
  • Those who had most recent vaccine dose < age 7 years should get a booster 3 years later, then every 5 years thereafter
  • Those who had most recent vaccine dose > age 7 years should get a booster 5 years later, and every 5 years throughout life.
  • The immunogenicity study (comparing a single vs a series of 2 vaccines in patients with CD4 percent>15%) noted serious adverse events in 2.2-6.5% six weeks post-vaccination, the number of adverse events being inversely related to CD4 percent, and only one of the serious adverse events (ocular pain) felt to be related to MenACWY-D. A study in kids aged 2-10 found 5% had a serious adverse event, but none felt to be attributable to the vaccine
  • Overall, from a lifetime perspective, vaccination was calculated to lead to the prevention of approx 122 cases of meningococcal disease and 23 deaths, and 385 quality-adjusted life years (QALY) could be saved, with mean cost of $732,000 per QALY if the primary series of vaccines and lifelong boosters every 5 years were given.


  • The risk of meningococcal infection in HIV patients, from data from the US, UK, and South Africa, is 5-13x that of non-HIV infected, with prevalence of 3.6-6.6 per 100,000, and with a case-fatality rate that is a bit mixed: those with HIV in South Africa had about twice the meningococcal case fatality rate (20% vs 11%), though this was not found in New York or the UK.
  • The risk of meningococcal disease is higher in those with high viral loads or low CD4 counts, though the immunogenicity of the vaccine is about 50% lower in those with lower CD4 counts (i.e., better to wait until the CD4 increases in those with uncontrolled infections, though unclear exactly what the cut-point here is from the studies. The one study the MMWR quoted used the CD4 cutpoint of 200 from a New York study, finding a 5.3-fold increased risk with CD4<200). Similar risk in men and women.
  • The majority of meningococcal infections in HIV-infected people are of serogroups A,C,W, and Y. One issue is that the largest database, the passive National Notifiable Diseases Surveillance System, does not include HIV status. The Active Bacterial Core surveillance (ABCs), a smaller database from 10 sites and representing 14% of the US population, does include HIV status. Based on these somewhat limited data, there were 62 cases of meningococcal disease in HIV-infected patients from 1995-2015, 13% were serogroup B and 10% were of unknown serotypes; 92% of cases were in people aged 20-59 years old
  • They do note that the only licensed vaccine for those >55 years old is the meningococcal polysaccharide vaccine; they still recommend the MenACWY conjugate vaccine, based on limited data.
  • The recommendations for infants 2-23 months are complex: they recommend the MenACWY-CRM and not the MenACWY-D because of potential immune interference with the PCV conjugate vaccine with the latter, as well as potential interference of DTaP with MenACWY-D if the MenACWY-D was given 30 days after the DTaP, but not if the 2 are given simultaneously or if the MenACWY-D is given first
  • Ndata on efficacy or adverse events if meningococcal vaccine given during pregnancy or lactation
  • So, the bottom line for me: I do plan to restart giving HIB vaccine to HIV-infected patients who are going back and forth to countries without routine HIB vaccination for kids (not CDC recommended, but makes sense to me). in addition, i will adopt the meningococcal conjugate vaccine according to the ACIP schedule above, including the booster immunization every 5 years, though i will wait until the CD4 increases to a level of >15% or until it plateaus at its highest CD4 percent (using the CD4 percent, as in the studies they quoted: there was no mention of the absolute CD4 count). I will also wait until the viral load is suppressed, since the limited data found a better response if the viral load was lower, in one of the studies if <400. The CDC does not mention anything about meningococcal serogroup B vaccination, but i would consider using the meningococcal B vaccine if there were a local outbreak of serogroup B infections (though my literature search revealed nothing on the immunogenicity or efficacy of that vaccine in HIV-positive patients).

Primary Care Corner with Geoffrey Modest MD: Flu Nasal Spray Ineffective

5 Jul, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent CDC evaluation of the effectiveness of the live attenuated flu vaccine (LAIV), finding essentially no protective effect last year (see ).


  • In May, the CDC found preliminary data of vaccine effectiveness for those 2-17 yo:
    • LAIV: 3% (CI: -49 to 37%), so no significant effect!!
    • Inactivated influenza vaccine (IIV): 63% (52-72) effective
  • Bottom line: “CDC’s Advisory Committee on Immunization Practices (ACIP) today voted that live attenuated influenza vaccine (LAIV), also known as the “nasal spray” flu vaccine, should not be used during the 2016-2017 flu season”
  • The annual flu vaccine for anyone >6 months old should be one of the shots: the inactivated influenza vaccine (IIV) or recombinant influenza vaccine (RIV)


  • There has been a pretty consistently poor showing for LAIV over the past few years: the prior 2 seasons found significantly decreased effectiveness as well. and before then, even when there was pretty much similar effectiveness of LAIV and IIV in kids, there were diminishing effectiveness in adults >30 yo (on my review of the age-based effectiveness published by the CDC)
  • These results were pretty surprising, since
    • LAIV is a live virus, and is associated with higher antibody responses, and some suggestion of more efficacy than IIV with influenza virus genetic drift
    • The flu virus attacks through the nasal mucosa, and the local IgA response to the live vaccine should increase its protection over the injected killed vaccine
    • Earlier studies found at least equal and some superior efficacy of LAIV: 80% in 2012
    • There was even early speculation that it could be given less often (perhaps every 2 years, given the increased immunogenicity)
    • As a result of the above logic, I have been preferentially using LAIV in kids, when appropriate, though not in those >30 yo
  • So, I am really not sure why there is less effectiveness for the live vaccine over the past several years. But the data speak volumes, given their consistency…. and we should not use this vaccine on anyone in the upcoming year or in the future, barring documented improvements in technology/efficacy.

Primary Care Corner with Geoffrey Modest MD: Flu Vaccine Recommendations 2015-6

17 Aug, 15 | by EBM

By Dr. Geoffrey Modest

MMWR just published the influenza vaccine recommendations for 2015-16 (See​ ). In brief:

  • As per usual, vaccine is recommended for all >6 months old who do not have contraindications, and should be offered starting in October, before flu cases start. They also recommend vaccinating early even if the ideal vaccine preparation is not available, in order to avoid missed opportunities [eg, for the elderly, I would wait for the high-dose vaccine only if it will be available prior to the onset of flu season and it is clear that the patient will get the vaccine].
  • Children 6 months til 8 years still need 2 doses (second dose >4 weeks later) if they have not had prior flu vaccines (at least 2 doses before 7/1/15). Unlike last year, there is no special consideration of influenza A (H1N1).4092914530_b23270543a_o
  • The vaccine this year will contain A/California/7/2009 (H1N1), A/Switzerland/9715293/2013 (H3N2), and B/Phuket/3073/2013 (Yamagata lineage). The influenza A H3N2 and influenza B components are new this year. There will also be a quadrivalent vaccine, which includes these three plus B/Brisbane/60/2008 (Victoria lineage), as was included in the quadrivalent vaccine the last 2 years [CDC does not prefer either the trivalent or quadrivalent vaccine at this time, though this could change after the flu season begins.]
  • The live-attenuated vaccine (LAIV), previously recommended as the preferred vaccine in kids aged 2-8, is no longer recommended over the inactivated vaccine injection, since there have been inconsistent findings more recently about the LAIV efficacy (in fact the LAIV4 vaccine in 2013-14 had poor efficacy against the predominant H1N1 flu virus that year). As before, LAIV can be used from age 2-49 yo unless there are contraindications, such as: children 2-4 yo who have asthma or wheezing episode in the last 12 months; LAIV is listed as a precaution in older kids and adults with asthma who “may be at increased risk for wheezing after administration of LAIV” and in those with chronic lung, heart, renal, liver, neuro, heme or metabolic disorders (ie, safety of LAIV is not clearly established in those with these underlying medical conditions) — I would add here that I do have a couple of older kids/adolescents who are quite large, very unwilling to have an injection, and pose a risk to themselves and the injectors, and I have given LAIV, with parental consent, in these cases even if there is mild asthma (ie, protection from flu, I felt, trumped the potential of some increased risk of wheezing). LAIV should still not be given to those with documented egg allergy (not enough data),  those taking aspirin, or those immunocompromised or taking care of severely immunosuppressed persons (or should avoid contact with them for at least 7 days after LAIV, given the theoretical risk of transmission).
  • For those with egg allergy, best to use an egg-free preparation (only indicated in those at least 18 yo), though they note that “severe allergic reactions to egg-based influenza vaccines are unlikely” based on a study of 4172 egg-allergic patients who had no episodes of anaphylaxis after the regular vaccine, though the VAERS (Vaccine Adverse Event Reporting System) does have a few reported cases. Small studies (up to 282 kids aged 2-17, of which 115 had anaphylaxis to eggs in the past) reported no cases of severe allergic reaction to LAIV. Given that these are small studies, they recommend using inactivated vaccine if the recombinant non-egg produced vaccine is not available, and that it should be given by a “physician with experience in the recognition and management of severe allergic conditions”

Primary Care Corner with Geoffrey Modest MD: Pertussis vaccine in adolescents and only transient immunity

21 May, 15 | by EBM

By: Dr. Geoffrey Modest

Here is a new analysis of Tdap vaccine effectiveness (VE) in the 2012 pertussis outbreak in Washington State (see DOI: 10.1542/peds.2014-3358). In a case-control study of adolescents born between 1993-2000, they correlated cases of pertussis in patients who had Tdap vaccination vs controls, matched by primary provider clinic and birth year. Those born between 1993-97 had a mix of whole-cell (DTP) and acellular (Tdap) vaccines, whereas those born from 1998-2000 had only the acellular Tdap vaccines. The 2012 pertussis outbreak in Washington State included nearly 5000 reported cases, with an unexpectedly high incidence in 13-14 year olds despite the high Tdap vaccination rate of 86%.


–In those receiving only acellular vaccine (450 cases, 1246 controls), overall VE was 63.9% (50-74%), with

–VE in those receiving the last Tdap within 12 months was 73% (60-82%)

–VE in those receiving the last Tdap from 12-23 months was 54.9% (32.4-70.0%)

–VE in those receiving the last Tdap from 24-47 months was 34.2% (-0.03-58%)

–no difference if look at confirmed (B pertussis isolated) vs clinically-diagnosed cases

–In the older group receiving a mixture of DTP and Tdap vaccines (386 cases, 1076 controls), overall VE was 51.5% (26.1%-68.1%), with 77% having received their last Tdap at least 3 years before the outbreak (as an older cohort, they received their 11-12 yo booster longer before the epidemic). So, the authors stratified the patients by either having had the Dtap less than or more than 4 years before the outbreak and found essentially the same VE’s (51.5% and 52.2% respectively for <48 months and >48 months). Given the differences in times from the last vaccination, the authors were unable to compare directly the findings between those who received the mixed vaccines vs those with only Tdap.

–There was  more protection with the Tdap brand Boostrix than Adacel, though the confidence intervals overlapped

See blog from a few months ago for a more detailed critique of the acellular pertussis component, though I did append it below. I also included below a couple of graphs from the CDC, the first showing the increase in pertussis since the first few years of the 2000 decade, and the second with the age distribution of cases

CDC graph(CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance System)

So, a few additional comments:

–the graphs below clearly show the dramatic increase in cases in those <1 yo, reinforcing the recommendation that pregnant women receive the Tdap vaccine during pregnancy, and the waning immunity noted above supports the recommendation that this be repeated for each pregnancy.

–the increase noted in the graph below in 7-10 year olds, a cohort that received only the acellular Tdap vaccine, also reinforces the attenuated protection, as found in this study

–the actual utility of Tdap vaccination in post-adolescence is pretty unclear. Seems like there is, at best, pretty transient protection (older people have been part of the outbreaks). all of this begs for a new pertussis vaccine with improved immunogenicity and longer duration of protection (the lower incidence of pertussis found on those adolescents receiving a mixture of DTP and Tdap vaccines suggest longer-lasting VE, even though the last DTP was many years before.)

Primary Care Corner with Geoffrey Modest MD: Measles and immunosuppression

21 May, 15 | by EBM

By: Dr. Geoffrey Modest 

Of late, it seems that I have been mostly trashing immunization, specifically the pertussis component of Tdap. so, I thought I should highlight a really interesting (to me) article from the journal Science on the mysteries of the remarkably successful measles vaccine (see doi: 10.1126/science.aaa3662). Here is a brief review of the article.

–mass measles vaccination in the past reduced childhood mortality by 30-50% in resource-poor countries and up to 90% in the most impoverished countries. This benefit could not be explained simply by preventing measles infection alone.

–measles virus (MV) infection is associated with profound immunosuppression, and recent data challenge the prior notion that this is a transient phenomenon:

    –data (mostly animal) suggest that measles infection leads to a loss in immune memory cells, and that this is prevented by vaccination

–in macaques, measles infection leads to systemic depletion of lymphocytes and reduced innate immune cell proliferation. MV leads to replacement of “the previous memory cell repertoire with measles virus-specific lymphocytes, resulting in ‘immune amnesia’ to non-measles pathogens”. Recovery of these memory cells requires restimulation by the appropriate antigens

–in the current study, they looked at 4 sets of data from resource-rich countries with adequate data on the pre- and post-measles vaccination period (England, Wales, US, Denmark) to test the hypothesis that MV infection leads to immune amnesia, findings:

–there was a significant correspondence between measles disease incidence and mortality overall

–there was significant reduction in nonmeasles infectious disease mortality associated with the introduction of the measles vaccine (vaccination programs occurred at different times in the different countries, 20 years later in Denmark)

–the data from England and Wales suggested that the duration of MV-immunomodulation lasted 28 months on average. In the US data it was 31 months, and 30 months in Denmark

–this time lag was consistent for age groups 1-4 yo and 5-9 yo.

–the increase in mortality was consistent for different diseases (pneumonia, dysentery/diarrhea) and different organisms (bacteria –eg strep, pneumococcus, typhoid, meningococcus — as well as fungal and viral pathogens), though not so for septicemia and rubella, which seemed to have shorter periods of immunologic amnesia (3 months and 12 months, respectively). This suggests a pretty global immune amnesia.

–looking at pertussis, which is not associated with immunosuppression,  vaccination did not influence non-pertussis mortality in England and Wales

–one interesting corollary of the above finding is that MV infection could diminish the herd immunity effect (ie, population immunity) from other infections (ie, not only increase the susceptibility of an individual infected with MV to a non-measles infection, but also of a non-measles infection being more likely to spread throughout the population, even to those who did not get MV but are susceptible to other infections). Or to put that more concretely, if you need 80% immunity in a community to prevent the spreading of infectious disease XXX, and the level is 90% in that community, a measles outbreak may bring that immunity level down to 50-60%, making the whole community more susceptible to the spread of infection XXX.

So, again, the above data challenge the usual (simplistic) understanding about vaccination — its effects are not simply increasing immunity to its targeted specific microbial species, but that any immunologic manipulation may have collateral effects on the functioning of the immune system overall (sort of like medication effects — the adverse effects found are just collateral effects on other cells in the body, and are above and beyond the desired targeted effects). What are the implications of this?

–the reverse could be true: vaccination could conceivably cause profound alterations of the immune system or other systemic effects which undercut the protection from the vaccine. Examples might include the earlier rotavirus vaccine, associated with documented increased risk of intusseseption in kids; and even the measles vaccine, which is associated with enough immunosuppression itself that you need to wait 4-6 weeks afterwards to get reliable results from a PPD test. So, it is important to look at even more than vaccine-specific clinical benefits but at a much larger picture (such as the overall mortality effects noted in the measles study above)

–there may not be much of a correlation between a robust antibody response and clinical disease protection. For example the recent dengue vaccine achieved robust immunologic response from all 4 serotypes included in the vaccine, but there was no significant clinical protection in those with serotype 2 infection.

–and, yet again, this measles article brings up the importance of our always challenging and modifying our understanding of physiologic processes.

Primary Care Corner with Geoffrey Modest MD: MMR vaccination and autism, again

2 May, 15 | by EBM

By: Dr. Geoffrey Modest 

Yet another study on the relationship (or lack ​thereof) between MMR vaccination and autism. I bring this up since this is a large study but includes kids at higher risk of autism (see JAMA. 2015;313(15):1534-1540). This is a retrospective cohort study from a large health insurer (Optum) database, using claims data (the insurer is mostly in the south and Midwest of the US, though does have people in all regions. 75% white, 9% Hispanic, 3.5% black and 3.5% Asian).



–95,727 kids who had older siblings. Autism spectrum disorder (ASD) was defined as 2 claims with a diagnosis of autistic disorder or pervasive developmental disorder, including Asperger. All kids were continuously enrolled in the health plan from birth to age 5 during 2001-2012.
–944 (1.04%) were diagnosed with ASD. 1929 had an older sibling with ASD, of which 134 (6.9%) were diagnosed with ASD, vs 860 (0.9%) of those without an older sib having ASD
–MMR vaccination rates were 84% (n= 78,564) at 2 years of age and 92% (86,063) at 5 years in those without an affected older sib, and 73% (n=1409) at 2 years and 86% (n=1660) at 5 years in those with an older sib with ASD
–for children with an older sib with ASD: at age 2, the adjusted relative risk of ASD for 1 dose of MMR vs no vaccine was 0.76 (0.49-1.18); at age 5 the RR for 2 doses of MMR vs no vaccine was 0.56 (0.31-1.01)  — ie, a trend to lower likelihood!!
–for children with no older sib with ASD: at age 2, the adjusted relative risk of ASD for 1 dose of MMR vs no vaccine was 0.91 (0.67-1.20); at age 5 the RR for 2 doses of MMR vs no vaccine was 1.12 (0.78-1.59)
–risk was adjusted for birth year, sex, region, race/ethnicity, maternal/paternal highest education level, mother’s and father’s age at birth of index infant, Childhood Chronic Condition score, seizure, allergies, preterm birth

So, bottom line: another study not finding a link between MMR and ASD, even in kids at higher risk of ASD because of family history (older sib with diagnosis of ASD). Not a great study, since based on insurance claims, but seems to me quite likely that ASD would have been coded as a diagnosis, especially with the concern about the linkage with MMR. Although the insured are a select population (eg working), the prevalence of ASD reported as 1.04% is in line with the nationally-reported 1.5%, and the % of younger sibs developing ASD who have an affected older sib (6.9%) is also within the range of published estimates of 6.4-24.7%. I am actually impressed in this study that 86% of 5 year olds with an affected sib actually got 2 MMR vaccines, given the hype in the popular press!! and, maybe MMR vaccination is even protective, given the trend noted above.

Primary Care Corner with Geoffrey Modest MD: HPV vaccine recommendation update

1 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

The Advisory Committee on Immunization Practices of the CDC  just updated their HPV vaccination recommendations to include a 9-valent vaccine (see here​). There are now 3 approved vaccines: Cervarix, a bivalent one against strains 16,18; Gardisil, a 4-valent one against 6,11,16,18; and now Gardisil-9, against 6,11,16,18,31,33,45,52,58. the 4-valent (4vHPV) and 9-valent (9vHPV) ones are licensed for use in men and women.


–Background: in the US 64% of invasive HPV-associated cancers are attributable to strains 16 or 18, and 10% are attributable to the new strains covered in 9vHPV.

–Phase III study comparing 9vHPV with 4vHPV​ in 14K females 16-26 yo found 96.7% efficacy to prevent >=CIN2 caused by the covered strains of 31,33,45,52,58 (there were very few caused by 6,11,16,18, but immunogencity against these strains was not inferior to that of 4vHPV)


–Seroconversion rates against all nine strains was >99%

–Safety profiles of 9vHPV and 4vHPV​ were similar, most adverse events were injection site-related (pain, swelling, erythema), though these local reactions were more common with 9vHPV (40.3% vs 29.1%). Males have fewer injection-site reactions than females.

–Recommendations: routinely begin at age 11-12, but can start at age 9. Vaccine also recommended for females aged 13-26, males 13-21. Males 22-26 may be vaccinated when MSM or immunocompromised (including HIV).

–Injection intervals: the same for all 3 vaccines: minimal interval of 1-2 months between 1st and 2nd dose, then 3 months minimum between 2nd and 3rd dose but maintain 6 months between 1st and 3rd dose.  No data on the immunogenicity of <3 doses of vaccine (this should be studied, given the cost and adverse reactions to this vaccine. I have seen studies in the past looking at 2 doses of the earlier vaccines showing reasonable immunogenicity)

–Not recommended in pregnancy, but no need to get a pregnancy test to give the vaccine and no intervention needed if given during pregnancy (though the CDC would like to track these patients, and it is reassuring that there were no pregnancy-related issues with the prior 2 vaccines, including 4vHPV​ which is made basically the same way)

So, seems reasonable. Lots of details are remaining, such as what to do if there is a long interval between the vaccines (is there any time delay where one has to restart the process?). Or what to do if the patient has already started one of the previous vaccine regimens, though in any case the CDC recommends completing the series, since all of them get the big villains (strains 16,18). But given the lack of immunogenicity studies with fewer than 3 doses of 9vHPV, it is hard to say that there is any utility of switching midstream to 9vHPV​ — ie, there would only be 1 or 2 doses covering the new strains and is this clinically efficacious? Also, the new vaccine is applicable only to those never vaccinated (ie, don’t give the new vaccine if the patient has had either of the 2 other approved ones).

Primary Care Corner with Geoffrey Modest MD: Pertussis vaccine — not quite up to snuff

19 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

I’ve commented in a few blogs about the resurgence of pertussis, despite immunizing adults with the Tdap. I thought it might be useful to elaborate — there have been a few insights into what seems to be happening.

–In the bad old days, pertussis infection was pretty rampant in the US

–With the development of the whole inactivated  pertussis vaccine in the 1940s, the number of cases plummeted from 157/100K to 1/100K in 1973.

–There have been gradual increases in pertussis since 1982, attributed to the fact that immunity from pertussis is not life-long, as for example, it is with measles. In 2012 there were 42,000 cases in the US. Some of this is undoubtedly ascertainment bias: for example, a study of adolescents/adults with prolonged cough actually looked at it and found that 13-20% had b. Pertussis infection (see Clin Microbiol Rev 2005; 18: 326). Also, newer studies are using PCR and finding much more b. pertussis overall than previously.

–Because of adverse effects (esp high fevers, with about 1 in 330 kids getting temperatures > 105 deg, and about 1/2 getting temps >100.4 —  by the way, these were treatable with acetaminophen, and we used to suggest giving the kid acetaminophen prior to the vaccine, which used to prevent many of the complications), an acellular vaccine was developed in the 1990s based on pieces of the b. pertussis bacterium, renaming the old DPT as DTaP, and was used exclusively in kids (the “a” was for acellular).

–However, it became clear that the immunogenicity of the acellular pertussis component was not as strong as the older inactivated pertussis vaccine (see, for example, NEJM 2012; 367: 785). A California study looked at kids who received their fifth/final dose of DTaP from 2006-2011, a time-span which included the large pertussis outbreak in 2010. They looked at 277 kids who developed pertussis (PCR positive) vs 3318 PCR-negative controls and determined when they received their last DTaP vaccine, finding that those who developed PCR-positive pertussis were more likely to receive their DTaP earlier, with an odds of acquiring pertussis increasing 42% per year (see NEJM 2012; 367: 1012).

–As pertussis infections became more common, the CDC  recommended adults be vaccinated with the acellular vaccine (Tdap) once, though we are now experiencing pertussis outbreaks in adults within a few years after this vaccine was administered (making the suggestion of one vaccine in one’s adult life a tad suspect).

–Infant baboons were infected with b. pertussis bacteria at age 7 months, with 2 groups having been vaccinated before (with either acellular or whole-cell pertussis vaccines at ages 2, 4,and 6 months), a group naive to infection and unvaccinated, and another group who had prior infection. Results: colonization of the nasopharynx was no different in those who were unvaccinated and naive to infection and those immunized with the acellular vaccine (there was a gradual decrease in colonization after 14 days, cleared by 30 days). There was dramatically less colonization in those given whole-cell vaccine (almost all cleared by 14 days). And there was no colonization in those previously infected. Those with nasopharyngeal colonization after acellular vaccine were able to transmit pertussis infection to naive animals.

Also, they found that the actual immunologic T-cell response of those given the whole-cell vaccine was the same as seen in baboons who had natural infection, whereas the acellular vaccine produced a significantly different immunologic response (see doi/10.1073/pnas.1314688110).

–So, let’s see: we have a serious infection which does not create life-long immunity, an old vaccine that really worked well but had too many adverse effects, a new vaccine which not only does not elicit the same immunologic response as the natural infection but seems to work only transiently and probably does not do much to affect colonization or potential transmission….. About time to develop a more effective pertussis vaccine????

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