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ID- Flu

Primary Care Corner with Geoffrey Modest MD: Dramatic Increase in Influenza Activity

14 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The CDC just published their influenza update, showing that it is now widespread in 43 states for the week ending 2/4/17 (see https://www.cdc.gov/flu/weekly/).

Details:

  • There are very high levels of flu activity in the South and Southeast, and most of New England (though not so much in MA, NH, VT)
  • 20 reported pediatric deaths so far, 5 in the last week
  • 21% of the samples sent to the lab have been positive for flu
  • 88% are influenza A, and of these 92% are subtype H3; and a subsample found it to be the same H3N2 strain which is covered by the vaccine
  • None of the samples tested showed resistance to neuraminidase inhibitors (e.g. oseltamivir, zanamivir or peramivir), though rare international cases have shown resistance to these meds, both to H1N1 and H3N2
  • Hospitalization rates from flu since October 2016 have been 24.3/100K. The vast majority in these have been in those >65yo (113.5/100K), and a review of 796 cases (11.7%) found that 95% had at least one reported underlying medical condition, mostly cardiac, respiratory, metabolic disorders (esp. diabetes), or neurologic disorders; with most common ones being asthma, chronic lung disease, and multiple sclerosis or muscular dystrophy

Commentary:

  • There are no data in this report at the apparent effectiveness of the current vaccine (i.e., were these cases of flu mostly in those not getting the vaccine??), though it is reassuring that that the match of vaccine subtypes did indeed reflect those of the current outbreak
  • One concern raised a few months ago was that there may be waning immunity after vaccination. The vaccine is available earlier than before, typically at the end of the summer, with instructions from the CDC and local health department to vaccinate people right away. But it seems that influenza outbreaks are occurring most often in the feb-april time-period. And, a study of the 2011/12 season showed that those immunized <3months before the flu outbreak had 53% vaccine effectiveness, whereas those immunized more than 3 months before had  only 12% effectiveness. (See Peabody RG. Euro Surveill. 2013 18(5):pii=20389)
  • It seems reasonable to continue giving the vaccine even now  in the midst of this outbreak, though there is about a 2 week period prior to its being effective. And to consider chemoprophylaxis, especially given the susceptibility of the current subtypes (see https://www.cdc.gov/mmwr/pdf/rr/rr6001.pdf for more info on chemoprophylaxis)

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 http://www.cdc.gov/media/releases/2016/s0622-laiv-flu.html ).

Results:

  • 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)

Commentary:

  • 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: Immunization Updates

8 Oct, 15 | by EBM

By Dr. Geoffrey Modest

So, on rare occasions, there is news which makes life easier for primary care (sort of like the convergence of a lunar eclipse and a super moon).

full-moon-914410_640

  1. The CDC’s Advisory Committee on Immunization Practices (ACIP) has actually simplified the pneumococcal vaccine schedule (see http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6434a4.htm?s_cid=mm6434a4_w ). I have sent out prior blogs detailing the confusing administration of PCV-13 (the 13-valent vaccine which has been given to kids for years) and PPSV-23 (the old 23-valent vaccine for adults) in immunocompetent adults >65yo, highlighting that the dose of PCV-13 should be at least one year after PPSV-23; though if PCV-13 is given first, then the PPSV-23 could be given 6-12 months later. So, the new recommendation is to wait >= 1 year in either of the  PPSV-23/PCV-13 sequences (note: there are no clinical data on the timing of the different vaccines, just immunogenicity studies which really do not even address these intervals directly, and one study finding more localized injection-site swelling if given at 2 month intervals vs 6 months apart). So, now, the common scenarios for an immunocompetent adult >65yo are:
  • If never got vaccine, give PCV-13 at age 65, then wait a year and give PPSV-23
  • If already given PPSV-23, then wait a year and give PCV-13 (no earlier than 65yo)
  • But, if got PPSV-23 younger than age 65 (smoker, asthma, chronic lung disease, etc. etc.), then give PCV-13 at age 65 (if at least one year after the PPSV-23), and then can get their regular post-65 PPSV-23 if at least 1 year after the PCV-13 and 5 years after their last PPSV-23.
  • If a dose of PPSV-23 is inadvertently given earlier than recommended, don’t repeat the dose.
  • Remember that 40% of invasive pneumococcal infections occurring in those >65yo are caused by serotypes unique to PPSV-23​​: i.e., we should generally make sure that those >65 yo get both vaccines

Got it? (It actually is a slight bit simpler….)

But, for immunocompromised people (asplenia, HIV, nephrotic syndrome, chronic renal failure, congenital immunodeficiency, cancers, organ transplant), the interval for all patients above age 2 is PCV-13 followed by PPSV-23 after 8 weeks. If they got PPSV-23 first, they should wait 8 weeks for PCV-13 until they are 18yo, thereafter wait 1 year.

  1. So far, not a lot of influenza activity in the US (through 9/5/15), but the good news: all of the virus samples collected so far in the US and other countries have been “antigenically and/or genetically characterized as being similar to the influenza vaccine viruses recommended for inclusion in the 2015-2016 Northern Hemisphere vaccine” (see http://1.usa.gov/1VGKSHe). I.e., it seems like a good match. Which is, by the way, really different from last year, where there was really low vaccine effectiveness against the predominant influenza A (H3N2) virus, and the laboratory data showed a poor antigenic/genetic match.  We’ll see…..  But at least it looks good so far.

By the way, the breakdown for the first 1698 cases of influenza so far in the US is 54% influenza A (of which 5% were pH1N1, 93% H3N2), 46% influenza B. There have been a handful of variant viruses but of the H3N2 and H1N1 strains. All of the tested viruses were susceptible to neuraminidase inhibitors, but adamantanes (e.g. amanadine) does not work/lots of resistance.​

 

Primary Care Corner with Geoffrey Modest MD: Oseltamivir for Influenza

27 Aug, 15 | by EBM

By Dr. Geoffrey Modest

As we approach flu season again, there was another article looking at the effectiveness of oseltamivir (see DOI: 10.1093/infdis/jiv058​). This was an observational community-based study in Hong Kong from 2008-2013.

Background:

Details:

  • This was an observational study of 582 patients with laboratory-confirmed influenza (121 children<5yo, 250 were >18yo– I’m not sure of the real numbers since what they stated in the text differed from the table). Baseline characteristics were similar, though more of the treated ones had myalgias and fewer got antipyretics. 223 were treated with oseltamivir (185 with influenza A and 38 with influenza B), and 359 did not get antivirals (258 with influenza A and 101 with B)

Results:

  • For those who took oseltamivir within 24 hours of onset of symptoms, the median duration of “all self-reported symptoms” until complete resolution of symptoms was reduced by 56%, including resolution of fever and respiratory symptoms (all with p<0.01). There was no significant oseltamivireffect if the onset of symptoms was >24 hours previously. On reviewing the graphs of symptom reduction, there was a 10% difference after 1 day, 20% after 2 days and 35% after 3 days (i.e., the decrease in symptoms happened pretty quickly). Symptoms were only assessed once a day.
  • Those on oseltamivir had no significant decreases in either viral shedding or in transmission of influenza to household contacts, independent of duration of symptoms in the index patient.

So, these results differed a bit from the BMJ meta-analysis from 4 months ago which really found minimal efficacy (e.g., decrease in time to first alleviation of symptoms from 7 days to 6.3 days). Of note, in the current study, there was no change in viral shedding or household transmission, and its effects were limited to those initiating meds within 24 hours of the onset of symptoms. This was an observational study and is therefore not conclusive​ (we know that those getting meds were a little different than those who did not, and, most importantly, was there a placebo effect??).  But, the CDC still recommends oseltamivir (see http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm ), especially in higher risk individuals (<2yo, >64yo, those with chronic medical conditions, pregnant women, those with BMI>40, those in chronic care facilities), given as soon as possible after onset of symptoms, but especially if symptoms  <48 hours (can be longer with severe symptoms or hospitalization). Bottom line for me: I continue to be underwhelmed by these meds, given the minimal efficacy in the large meta-analysis and high rate of adverse effects. And, of course, the effectiveness of these drugs in the future will be affected by neuraminidase inhibitor resistance, which has played a role in the past.

For very recent flu vaccine recommendations by the CDC, see http://blogs.bmj.com/ebm/2015/08/17/primary-care-corner-with-geoffrey-modest-md-flu-vaccine-recommendations-2015-6/ .​

 

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 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6430a3.htm​ ). 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: Flu vaccine coverage this year

11 Dec, 14 | by EBM

By: Dr. Geoffrey Modest 

The CDC sent out a health alert based on initial evaluations of influenza types in the US, noting a significant mismatch with those covered by the vaccine (see here).  They note:

091103-N-2562S-004–Influenza A (H3N2) is so far the most frequently reported influenza virus found (though influenza is still pretty uncommon, they have found influenza A (H3N2) in almost all states). So far, 91% of 1228 positive samples have been influenza A.

–In the past, influenza A (H3N2) ​has been associated with higher overall and age-specific hospitalization rates and mortality (esp in the old, young and those with chronic medical conditions)

–Only 48% of the influenza A (H3N2) analyzed so far are antigenically similar to the influenza A (H3N2) vaccine component, with 52% showing antigenic drift (only 85 samples tested). Of note, the vaccine-types chosen each year are set the prior February, too late to change the vaccine now.

–This type of antigenic drift is associated with decreased vaccine effectiveness. Though there may be some cross-protection. also, no evident antigenic drift for influenza A (H1N1) or influenza B

–So, this finding still reinforces the importance of the vaccine even in its reduced-effectiveness state, given the annual influenza mortality of 3,000-49,000 people in the US over the past 30 years, but especially the importance of the neuraminidase inhibitors — oseltamivir (Tamiflu) and zanamivir (Relenza) — both for treating the flu (shorter duration of symptoms, reduced risk of complications, reduced risk of death in hospitalized patients), and for prevention in high risk situations. And these drugs should be given as soon as possible after symptoms begin, preferably within 48 hours. All viruses tested so far are susceptible to these drugs.

–I would add, from previous years, that when influenzal illnesses first begin in a community, it is useful to do lab test for flu (though don’t wait for results before treating with neuraminidase inhibitors). But when influenza is established in a community, the likelihood of someone with typical symptoms having influenza is so high that it is not useful or necessary to do lab tests (ie, the post-test probability doesn’t change much when the pre-test probability is high, based on symptoms and prevalence of of influenza in the community). just treat them.

I would add to the above that this blog post of 2 Cochrane reviews of neuraminidase inhibitors finding that

–There was significant drug company malfeasance in releasing the raw data

–Osteltamivir has better evidence of efficacy than zanamivir

–The benefits are not very dramatic (decreased symptoms of 16.7 hours, with no difference in hospital admissions, pneumonia or any serious complications)

​–There were significant adverse events (nausea, vomiting, increased QTc, psych effects, headaches)

Reviewing the studies themselves show a remarkable diversity of outcomes with neuraminidase inhibitors, with some showing significant reductions in pneumonia and mortality and others not. so, it is really hard for us mere mortals to be sure…. My practice has been to use only osteltamivir (not zanamivir), only when studies show minimal resistance (as appears to be the case so far this year), and especially in more symptomatic people (high fever) or significant medical comorbidities.​

Primary Care Corner with Geoffrey Modest MD: Neuraminidase Inhibs for Flu– Lack of Significant Efficacy

6 May, 14 | by EBM

BMJ came out with 2 articles from the Cochrane group on neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) (see here for oseltamivir and here for zanamivir). these papers are updated systematic reviews, and for oseltamivir (per the editorialist) “is the culmination of a four and a half year battle for access to the raw data from industry funded trials of oseltamivir, a drug on which the world has spent billions of dollars”, and reflects very different results than that presented to regulators, policy makers, the public etc by the drug makers. brief summaries:

oseltamivir: 83 RCTs on adults and kids. results:

–treatment studies:

–time to first alleviation of symptoms: decreased 16.7 hours (from 7 days to 6.3 days). no effect on kids with asthma, but healthy kids decreased symptoms by 29 hours
–no diff in admissions to hospital for adult. sparse data on kids.
–no diff in pneumonia, bronchitis, otitis media, sinusitis or any serious complication
–but increased nausea (number needed to harm NNTH 28) and vomiting (NNTH 22) with oseltamivir in adults and and vomiting in kids (NNTH 19). also inc QTc (NNTH 25)
–prophylaxis trials, oseltamivir dec symptomatic flu in pts by 55% and households by 13.6%, but no effect on asymptomatic flu and no evidence of dec transmission. in prophylaxis trials, inc risk of psych adverse events (NNTH 94), with dose response curve. increased headaches (NNTH 32), renal events — esp dec creat clearance (NNTH 150) and nausea (NNTH 25)
–authors note: “in a primary or secondary prophylaxis indication the postulated central effect of oseltamivir is confined to suppressing symptoms, because infection, according to Roche (the manufaturer) is not prevented”.

zanamirir:  54 RCTs in kids and adults.

–treatment studies:

–zanamivir reduced time to first alleviation of sx by 0.60 days (from 6.6 to 6.0 days, 14.4 hours) in adults. not significant in kids.
–no diff in pneumonia (investigator-reported or by CXR) in adults. also nonsignificant effect in kids
–no diff in otitis media or sinusitis in adults and kids, small effect in bronchitis only in adults (1.8%)

–prophylaxis studies:
–no diff in asymptomatic flu cases in individuals or households. only 2 small studies found effect in symptomatic flu in adults by 14.8%.
–no signif adverse events

so, what does this all mean?  of note the WHO has oseltamivir on their list of “essential drugs”. but neither of these drugs have significant effects on preventing or treating major complications of flu. the CDC also fully embraced these drugs (without having full transparent access to data) as did the am acad of pediatrics, making claims that starting these drugs early prevent serious complications. in these studies, it is unclear if using zanamivir, for example, actually reduces symptoms more than taking symptom relief meds.  the data from these studies are pretty compelling (and quite striking, since these drugs have been around for 15 years!): the benefits of these drugs are pretty minimal, the cost is high, the incidence of adverse effects (with oseltamivir) is high, and the imperative to use them comes from the lack of transparency and withholding info by big pharma.

geoff

Primary Care Corner with Geoffrey Modest MD: Influenza 2013

23 Oct, 13 | by EBM

see below. mmwr on influenza control. i felt proud to know that one of the influenza strains covered by the vaccine is from massachusetts.  we finally made it.

you can click on the link to read the whole article. just a couple of changes:

–Boston added!

–several new formulations, including quadrivalent, egg-free (for ages 18-49 only).  we only have the trivalent at the health center at this point

there was info a couple of years ago suggesting deceasing efficacy of the live attenuated vaccine (LAIV) vs inactivated as people reach the ripe old age of around 35-40. (i don’t have that reference). not mentioned in   mmwr. there was an article comparing vaccines (see DOI:10.1111/j.1750-2659.2010.00183.x) which suggested that the live vaccine may be more effective as a priming vaccine and the TIV more effective in boosting pre-existing immunity.  which could explain the age difference (if it is real). i personally stopped using the LAIV in patients over late 30’s because of the data from a few years ago, but since not mentioned in MMWR, probably it is okay to use it.

 

geoff

 

From: Centers for Disease Control & Prevention [mailto:cdc@service.govdelivery.com]
Sent: Thursday, September 19, 2013 12:19 PM
To: Modest, Geoffrey A.,M.D.
Subject: MMWR Vol. 62 / No. RR-7

 

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Recommendations and Reports
Volume 62, No. RR-7
September 20, 2013

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Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization
Practices
United States,
2013
2014

This report updates the 2012 recommendations by CDC’s Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccines for the prevention and control of seasonal influenza. Routine annual influenza vaccination is recommended for all persons aged ≥6 months. For the 2013–14 influenza season, it is expected that trivalent live attenuated influenza vaccine (LAIV3) will be replaced by a quadrivalent LAIV formulation (LAIV4). Inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Vaccine virus strains included in the 2013–14 U.S. trivalent influenza vaccines will be an A/California/7/2009 (H1N1)–like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012–like virus. Quadrivalent vaccines will include an additional influenza B virus strain, a B/Brisbane/60/2008–like virus, intended to ensure that both influenza B virus antigenic lineages (Victoria and Yamagata) are included in the vaccine. This information is intended for vaccination providers, immunization program personnel, and public
health personnel.

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Department of Health and Human Services
Centers for Disease Control and Prevention

 


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