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Archive for June, 2014

Primary Care Corner with Geoffrey Modest MD: PCSK9 Inhibitor

25 Jun, 14 | by EBM

probably the most exciting new drug for lipids are the PCSK9 inhibitors. i have appended below a blog from march 2012 which discusses proposed mechanism of action of these inhibitors as well as an epidemiologic study showing that those with naturally occurring PCSK9 function loss had much lower LDL levels and many fewer  coronary events. this new multicenter, multi-country study is the longest RCT to look at evolocumab, a monoclonal antibody that inhibits PCSK9, to assess its safety and efficacy (see DOI: 10.1056/NEJMoa131622). 901 hyperlipidemic patients per ATPIII were put on several different meds/combos for 4-12 weeks, then randomization of those with CAD and LDL<100, or those without CAD but high risk if LDL<130 to either 420mg of evolocumab (subq injection) or placebo every 4 weeks.

–baseline characteristics: mean age 56, 47% male, 80% white, mean LDL 95-120,

results after 52 weeks, as compared to placebo group:

–baseline diet, evolocumab assoc with 55.7% reduction in LDL
–baseline atorvastatin 10mg, evolocumab assoc with 61.6% reduction in LDL
–baseline atorvastatin 80mg, evolocumab assoc with 56.8% reduction in LDL
–baseline atorvastatin 80mg + ezetimibe, evolocumab assoc with 48.5% reduction in LDL
–overall level of LDL was <70mg/dl in 82.3% of those on the evolocumab
–also significant reductions in apolipoprotein B (40%), non-HDL cholesterol (50%), lipoprotein (a) (25%), chol/HDL ratio (35%) and triglycerides (10%)
–and significant increases in HDL (5.4%), apo A-1 (3.0%). no change in CRP
–adverse effects: pretty minimal. without signif difference from placebo

so, really impressive numbers.  all in the right direction. BUT, a few little details.

–how does this translate into clinical events??  we know that ezetimibe lowers LDL a lot (20%), but to no avail. we know that CETP inhibitors (torcetrapib, dalcetrapib) dramatically increase HDL (50-100%) also to no avail. even with our relatively primitive (though improving) understanding of lipids, there are differences in LDLs (the big fluffy ones have 1/3 the coronary risk of the small dense ones — meaning for example that lowering LDL 20% but converting big ones to little ones may worsen the risk!) and HDLs (not just size, but those with apo c-III are pro-inflammatory and assoc with MORE cad. i myself have been led down the primrose path way too many times, thinking that homocysteine, vitamin E, hormone replacement, ezetimibe, CETP inhibitors, etc etc all played an important role…..  so, i really bring this new article up to show the impressive initial data but to warn about drawing any conclusions prior to real clinical data (eg ezetimibe was approved based on lipid changes, not clinical events).

–and, then there’s that pesky detail of cost

here is the prior blog from march 2012

2 interesting basic-science type articles on proprotein convertases: to my not-so-sophistocated understanding, these are proteins which, when cleaved and activated, affect cellular function and are often part of cellular homeostasis (like pro-insulin).  In any event, there is one (PCSK9, which is paraprotein covertase subtilisin/kexin 9, in case you were wondering), which degrades the hepatic LDL receptor and leads to increased levels of LDL (single point mutations which increase their activity are associated with very high LDLs as in familial autosomal dominant hyperlipidemia). (see N Engl J Med 2011;365:2507-18). Loss of function leads to significantly decreased LDLs, with one study showing 2.6% of black pts have this loss of function naturally, assoc with 88% dec in coronary risk, indep of other risk factors (see N Engl J Med 2006;354:1264-72).  Some animal studies with meds to decrease function assoc with >60% dec in LDL.  So, may be important in the future.



Primary Care Corner with Geoffrey Modest MD: Olive Oil and Atrial Fibrillation

24 Jun, 14 | by EBM

another article came out of the PREDIMED study (prevention with mediterranean diet study), where 6705 people without prevalent afib were randomly assigned to one of 3 diets: mediterranean diet supplemented with extra-virgin olive oil, mediterranean diet plus mixed nuts, or control group (low fat diet). in this post-hoc analysis they looked at the development of atrial fibrillation (see DOI: 10.1161/CIRCULATIONAHA.113.006921). [i posted blogs on 1/21/14 on primary CAD prevention and on diabetes prevention from this study — i appended excerpts below since they give details of diet]. the findings in the current study were:

–new cases of afib, after 4.7 years:

–med diet with supplemented extra-virgin olive oil: 72 cases, afib rate of 6.8 per 1000 person-years (and, there was a dose-response curve with higher olive oil consumption=less afib)
–med diet with supplemented mixed nuts: 82 cases, afib rate of 9.9 per 1000 person-years
–control diet: 92 new cases, afib rate of 10.1 per 1000 person-years

–so, HR of atrial fibrillation with extra-virgin olive oil vs control group was 0.62 (CI 0.45-0.85). non-significant diff between mixed nuts and control group (HR 0.89 with CI 0.65-1.20)

unclear why atrial fibrillation is decreased with olive oil. but, extra-virgin olive oil is known to have anti-inflammatory effects and reduces oxidative stress in patients with metabolic syndrome.  there is argument in the literature that these factors are important in the development of afib (higher CRP or IL-6 levels assoc with development of afib. same with markers of oxidative stress).

limitations of study above include that afib was not the primary endpoint of the study (CAD, stroke were), and spanish study with mostly older white people at high cardiovascular risk, limiting potential generalizability. overall, i think that extra-virgin olive oil has pretty profound protective vascular effects, but i would caution about extrapolating this result in a reductionist way. the olive oil was consumed in the context of an overall healthy diet (Mediterranean diet) and seemed to add benefit. assuming that frying chicken with breadcrumbs in extra-virgin olive oil and then sprinkling the potato chips with a little more may not have the same positive benefit…..



Primary Care Corner with Geoffrey Modest MD: FDA against aspirin for primary prevention

20 Jun, 14 | by EBM

FDA with consumer statement about aspirin for primary prevention of heart disease.  they comment:

Use of Aspirin for Primary Prevention of Heart Attack and Stroke

[05/02/2014] Cardiovascular disease, including heart disease and stroke, affects tens of millions of people in the United States.  Consumers and patients who do not suffer from cardiovascular disease sometimes consider taking aspirin to reduce the possibility of having a heart attack or stroke.  Reducing the possibility of having a first heart attack or stroke is called primary prevention.  The FDA has reviewed the available data and does not believe the evidence supports the general use of aspirin for primary prevention of a heart attack or stroke.  In fact, there are serious risks associated with the use of aspirin, including increased risk of bleeding in the stomach and brain, in situations where the benefit of aspirin for primary prevention has not been established.

The available evidence supports the use of aspirin for preventing another heart attack or stroke in patients who have cardiovascular disease or who have already had a heart attack or stroke. Reducing the risk of additional heart attacks or strokes is known as secondary prevention. In patients who have had a cardiovascular event, the known benefits of aspirin for secondary prevention outweigh the risk of bleeding.

FDA is committed to reviewing any data supporting new medicines and new uses to improve the health of the American public.

see full release at here.

This comment was in Physician’s First Watch by Larry Husten, noting that this was in response to FDA rejecting Bayer’s request for primary prevention indication:

Aspirin shouldn’t be marketed for primary prevention of heart attack or stroke, the FDA has announced. The statement follows the agency’s rejection on Friday of Bayer Healthcare’s decade-old petition requesting approval of a primary prevention indication.


i would just add that there may be other, nonvascular benefits from aspirin, esp in some cancer prevention. i have posted several blogs in the past 6 months showing aspirin is assoc with decreased cancer incidence and mortality overall, and some interesting data specifically on decreasing prostate, colon, breast, ovarian cancer and even prolonging life in patients with metastatic cancer (i can resend these if you want.  let me know). so, though the primary indication for aspirin, and the basis of the above FDA response, is around vascular disease (and i agree that the data for primary prevention is not good), there may be other important benefits (also one i sent out about dementia). most of this data is secondary analysis of RCTs, so is not completely statistically rigorous.


Primary Care Corner with Geoffrey Modest MD: Prophylactic Antibiotics in Kids with UTI and Vesicoureteral Reflux

18 Jun, 14 | by EBM

Vesicoureteral reflux is common in kids, is present in the third of children with febrile UTIs, and is associated with increased risk of renal scarring.  Studies have found mixed results on the efficacy of prophylactic antibiotics.  New England Journal with an article — a two-year randomized control trial in 607 children with vesicoureteral reflux diagnosed after a first or second febrile or symptomatic UTI, randomized to trimethoprim-sulfamethoxazole prophylaxis (3 mg trimethoprim, 15 mg sulfamethoxazole per kg of body weight) or placebo.  Primary outcome was preventing recurrent infections.  Secondary outcome was assessment of renal scarring, treatment failure (a composite of recurrences and scarring) and antimicrobial resistance (see DOI: 10.1056/NEJMoa1401811).  All urines were collected by catheterization or suprapubic aspiration.  Renal scanning was done at baseline and after 1 and 2 years.  Results:

–Average age 12 mo, 92% girls, 80% white, 40% with grade 2 and 40% with grade 3 reflux, 96% without any renal scarring at baseline
–Recurrent UTI in 39 of 302 children on prophylaxis versus 72 with 305 children on placebo (HR 0.50; CI 0.34-0.74).  8 children would need to be treated for 2 years to prevent one case of febrile or symptomatic UTI.
–In children whose index infection was febrile, prophylaxis even more effective (HR 0.41; CI 0.26-0.64)
–children with grade 3 or 4 reflux at baseline were at higher risk, with 22.9% versus 14.3% having a febrile or symptomatic recurrence
–Renal scarring did not differ between groups (11.9% with medication versus 10.2% with placebo)
–Voiding cystourethrography was performed at 2 years, was resolved in 51%, improved in 23%, unchanged in 18.5%, and worse in 7.2%.
–In 87 children with a first recurrence caused by Escherichia coli, proportion of isolates resistant to trimethoprim-sulfamethoxazole was 63% of prophylaxis group, and 19% in the placebo group

so, what does this all mean?   On the one hand, there clearly was benefit of prophylaxis to prevent symptomatic recurrence, and recurrent UTI could result in kids getting very sick quickly and needing to be hospitalized.  On the other hand, the fact that there was no significant increase in renal scarring without antibiotics is reassuring and the increase in antimicrobial resistance is concerning.  Some concerns with the study include the fact that only one antibiotic was used, and the fact that renal scarring was only assessed after 2 years, though the potential for renal scarring may extend beyond that time.  One option (from my secondary analysis of the data) might be to risk stratify patients: use prophylaxis if their first event was a febrile UTI and they have grade 3 or 4 reflux, or patients with multiple recurrent UTIs, or those with bladder or bowel dysfunction (who had a higher rate of recurrence in above study).  Another option, also not explored, is to give parents a prescription for full course antibiotics at home, with instructions to call the on-call primary care physician as soon as a child gets sick (allowing the option for very early treatment of an incipient infection).


Primary Care Corner with Geoffrey Modest MD: Antibiotics for Ulcerative Colitis??

17 Jun, 14 | by EBM

there has been ongoing speculation that there is a bacterial cause of ulcerative colitis (UC). Fusobacterium varium, in a prior study by the same researchers below, was found in actively inflamed colonic mucosa of patients with UC. (also, in mice, butyric acid, a byproduct of F. varium, causes UC-like lesions). so, this group devised an antibiotic cocktail active against F. varium (tid regimen of amoxacillin 500mg, tetracycline 500mg, and metronidazole 250mg for 2 weeks) and assessed its efficacy both in 30 patients with steroid-refractory and 64 patients with steroid-dependent active UC (see doi:10.1111/apt.12688).  primary endpoint was clinical response at 3 months after treatment completion. secondary endpoints were significant clinical and endoscopic score improvement at 12 months. results:

–Japanese multi-center non-randomized study. mean age 40. in steroid-dependent group, 45 males/19 females. pretty even in steroid-refractory group. extensive disease (70% of colon), mostly moderate severity. routine use of UC meds: sulfasalazine, 5-aminosalicylic acid, pred, azathioprine, 6-MP, mesalazine and/or probiotics — though <10% on azathiprine or mercaptorpurine. in steroid-dependent group, the steroid dose was tapered during the study — after week 8 by 5 mg/week until 20 mg dose. then decreased 2.5 mg/week til off.

–19 of 30 (63.3%) steroid-refractory and 47 of 64 (73.4%) of steroid-dependent had clinical resp in 2 weeks
–at 3 months, 60% of steroid-refractory and 56.3% of steroid-dependent achieved clinical remission
–at 12 months, 66.6% of steroid-refractory and 51.6% of steroid-dependent achieved clinical remission
–endoscopic activity scores paralleled the clinical activity scores
–in group with severe disease (16 pts), 80% with clinical response and 55% with clinical remission at 2 weeks, 3 and 12 months.
–in steroid-responsive group, 39 of 64 (60.9%) were able to stop steroids completely and remained in remission for 3 months
–the colectomy rate was 10% in steroid-refractory UC, less than reported rates with infliximab therapy

so, pretty impressive numbers. small study without control group, but cheap and easy treatment. also, Japanese study, so not sure the colonic microbiome is the same as here. but overall this study reminds me of a similar type study in the lancet around 20 years ago, finding that in a small number of patients with severe ITP and found to have H. pylori, H. pylori treatment led to dramatic remission of their ITP.  i happened to see someone around that time with ITP and severe ecchymoses, only marginally responsive to high dose prednisione, found to have H pylori antibody, treated for that and had a complete response within a month, and no recurrence since then….. so, these small research studies can be useful.


Primary Care Corner with Geoffrey Modest MD: Stroke Secondary Prevention Guidelines

13 Jun, 14 | by EBM

update on 2011 guidelines on stroke prevention in patients with prior stroke or TIA (see DOI: 10.1161/STR.0000000000000024)

background: stroke still very prevalent. 700K adults with ischemic stroke/yr in the US. addl 240K with TIA (with residual high risk of subsequent stroke, 3-4%/yr, similar to having had initial ischemic stroke. rate is lower than before because of widespread use of antiplatelet drugs, treatment for hypertension, afib, hyperlipidemia, arterial obstruction).

changes from 2011 (there are lots of them, and these are just the changes):


–initiate therapy if systolic >140, or diastolic >90. no clear evidence that one class of drug is superior [though prior studies in previous posts have found increased stroke in meds with higher bp variability, with amlodipine having the least]. uncertain benefit if initial blood pressure lower than that
–goal bp is 140/90. “might be reasonable goal” of systolic 130, if lacunar stroke
–if pt has stroke/TIA with history of htn, then resume BP meds after the first few days.


–intensive statin therapy if LDL >100 if presumed atherosclerotic stroke, even without other evidence of atherosclerotic disease. less strong recommendation if LDL <100
–still focus on lifestyle interventions

–glucose disorders

 –screen all pts with stroke/TIA for diabetes. A1C likely to be most accurate in period after acute event.


 –screen with BMI. wt loss is clearly beneficial to improve cardiovasc risk factors, though data on stroke prevention are lacking [several studies have found that BMI is less predictive than waist circumference or other measures of abdominal obesity, as noted in prior blogs]

–physical inactivity

–3-4 sessions/week of moderate to vigorous aerobic activity (at least breaking a sweat or noticeably increased heart rate), lasting 40 minutes. consider enrollment in program for this


 –nutrition assessment, counseling if appropriate, not give vitamin supplements, reduce sodium to <2.4 g/d, consider Mediterranean-type diet over low-fat diet

–sleep apnea

–consider sleep study (high prevalence of sleep apnea in those with stroke/TIA — on order of 50-75%!!, and 70-80% of them undiagnosed. clinical history (sleepiness and BMI) not accurate enough; CPAP improves outcomes in most studies). Note that they and the Am Acad of Sleep Med suggest routine polysomnography in patients with ischemic stroke/TIA

–extracranial carotid disease

 –in pts with carotid stenosis (>70% obstruction by noninvasive test, >50% with invasive) and anticipated peri-op complication rate of <6%:
–consider carotid endarterectomy if <70 yo
–consider carotid angioplasty with stent if younger
–not recommend routine duplex ultrasound for routine followup after procedure

–intracranial atherosclerosis

 –in general if ischemic stroke/TIA with 50-99% stenosis of major intracranial artery, use aspirin 325 mg/d
–if recent stroke/TIA (within past 30 days) and severe stenosis (70-99%) of major intracranial artery, consider adding clopidogrel 75 to aspirin 325 for 90 days

–for pts with intracranial artery stenosis of 50-99%,

–data insufficient regarding usefulness of clopidogrel alone, combo aspirin/dipyridamole, cilostazol alone (insufficient data)
–maintain systolic bp <140 and use high-intensity statin
–not recommend stenting in general. use of Wingspan or other stents is considered investigational, even if progressive symptoms, severe stenosis (70-99%), and already taking aspirin plus clopidogrel

–atrial fibrillation

–pts with stroke/TIA and no known cause, consider 30-day ambulatory monitoring within 6 months of event
–vitamin K antagonists, apixaban, dabigatran (apixaban higher level of evidence) are all okay as initial therapy for nonvalvular AF, either paroxysmal or permanent. rivaroxaban is reasonable, though lower level of evidence. should be started within 14 days of onset of symptoms
–adding on antiplatelet therapy not indicated, unless clinically apparent CAD, esp if acute coronary syndrome or stent
–for patients unable to take anticoagulants, use aspirin alone [though see excerpt from recent afib guidelines below, which downplay aspirin]. addition of clopidogrel “might be reasonable”

–MI and thrombus

–use of vitamin K antagonists (INR 2-3) if ischemic stroke/TIA in setting of acute anterior MI with thrombus or without thrombus but with anterior apical dyskinesis, for 3 months. can also use low molecular wt heparin (LMWH), dabigatran, rivaroxaban or apixiaban for 3 months if intolerant of vit K antag


–use vit K antag  for at least 3 months if left atrial or ventric thrombus, or if dilated cardiomyopathy (LVEF<35%), or restrictive cardiomyop. can use dabigatran, rivaroxaban or apixiaban for at least 3 months if intolerant of vit K antag

–valvular heart disease

–new guideline is to consider adding aspirin to adequate vit K antag if rheumatic mitral valve disease and still get ischemic stroke/TIA

–prosthetic heart valve

–new guideline if mechanical mitral valve and history of ischemic stroke/TIA before insertion of valve: goal INR 2.5-3.5

–antiplatelet therapy

–consider combo of aspirin and clopidogrel within 24 hours of ischemic stroke/TIA and continue for 90 days
–adding antiplatelet therapy to vit K antag unclear in patients with stroke/TIA along with atrial fib and CAD. (unstable angina and stents are should get the combo)

–aortic arch atheroma

–use antiplatelet and statin therapy. anticoagulation unclear, surgery not recommended


–if PFO and venous source of embolism, anti-coagulation (or IVC filter if contraindicated). not do PFO closure if no clear venous source, but consider if there is a venous source (eg DVT)

–hypercoagulation assessment

–unknown utility to screen (though screening for homocysteine is not indicated). but if hypercoag state found, can consider anticoagulation, or antiplatelet if that is contraindicated
–anti-phospholipid screen — not do routinely if other reason for ischemic stroke/TIA identified (eg atherosclerosis, afib, carotid disease). use antiplatelet therapy if anti-phospholipid antiody found


–if condition outside of pregnancy indicating need for anticoagulation, use LMWH bid or subq unfractionated heparin (UFH) throughout pregnancy, though can substitute vit K antag from 13th week til close to delivery
–if low-risk situation and antiplatelet therapy would be considered outside of pregnancy, either use UFH or LMWH or no treatmemnt (but not antiplatelet therapy) in first trimester


–in situation where anticoag necessary outside of pregnancy, use warfarin, UFH or LMWH. if antiplatelet therapy would have been used, use low-dose aspirin

so, nothing too striking. largely incorporates other guidelines. pretty convincing argument to consider sleep studies more routinely, given the evidence.


Primary Care Corner with Geoffrey Modest MD: Physical Activity Decreases Knee Arthritis Disability

11 Jun, 14 | by EBM

bmj article found that there was a relationship between greater physical activity and reduced risk of disability in adults with either known DJD or at high risk (see doi: 10.1136/bmj.g2472). prospective multisite cohort study of 1680 community dwelling adults aged >49yo with known knee DJD (symptoms in at least one knee with osteophyte and pain, aching or stiffness on most days for at least one month in the prior 12 months) or risk factors for developing DJD (knee symptoms in the prior 12 months, overwt, knee injury causing difficulty walking for at least one week, fam hx of total knee replacemetn for DJD, Heberden’s nodes and age 70-79). primary outcome of development of disability (defined as difficulty in carrying out activities essential to independent living) at 2 year followup in those free of baseline disability. also followed a cohort of 1814 adults to assess disability progression as a secondary outcome (this group was free of severe baseline disability in basic activities of daily life). this study assessed the intensity of physical activity (moderate-vigorous vs light intensity), using an accelerometer for 7 consecutive days (which measures the weighted sum of accelerations over one minute, weighted by the magnitude of acceleration) to verify. the patients were stratified into quartiles of either light or moderate-vigorous activity. results:

 –149 cases of new disability identified,
–these 149 people averaged 302 minutes/day of non-sedentary activity, 284 minutes being light intensity activities (ie, not a lot of moderate-vigorous activity)
–primary outcome: light intensity activity had strong inverse relation with development of disability for men, women, and adults with or without baseline knee DJD. similar strong inverse relation with moderate-vigorous exercise, but of note the benefit of light intensity activity was independent of doing more vigorous activity
–as an example of the protection: average person in 2nd quartile of light activity (mean 255 min/d) had 43% decrease in age-adjusted hazard for developing disability (vs patient in quartile with least time, at 192 min/d). and, average person in 2nd quartile of mod-vigorous activity (18 min/d) had 53% reduced risk of developing disability as those in lowest quartile (12 min/d).
–secondary outcome: greatest disability progression in those who spent the least time in light or moderate-vigorous activity

this was an observational study. concern is always that of reverse causation (eg, unmeasured baseline disability which decreased the likelihood a person would exercise and itself increased likelihood of defined disability later). to minimize this possibility, they did start with patients who were free of disability at baseline and controlled for baseline gait speed as well as potential confounders of chronic medial conditions, socioeconomic factors, obesity, depression, pain. (turns out that depression and pain were independently assoc with developing disability).  this study adds to prior studies (including RCTs) also finding that exercise reduces disability. these results, perhaps not so surprising, reinforce that even light physical activity appears to protect against disability. similar to small amounts of weight loss (5% range) is associated with pretty striking effects on insulin sensitivity and diabetes control.  bottom line, i think, is that we as medical providers can advocate for small incremental changes with patients, and that these are actually very helpful — patients do not need to run marathons or revert to their ideal body weight to get significant benefit of lifestyle changes.


Primary Care Corner with Geoffrey Modest MD: Food Diversity in Young Kids and Subsequent Allergy

10 Jun, 14 | by EBM

as perhaps a complementary article to the blog last week on soluble fiber, changes in the microbiome, and asthma, this article also came out finding that increased variety of foods introduced in the first year of life led to decreased asthma, food allergy and food sensitization, as well as several biological markers of allergy (see this was a birth cohort study of 856 children from rural Europe with parents reporting monthly food diaries during the first year of life (which should decrease likelihood of reverse causality). they also assessed environmental factors and the development of allergic diseases up til the kids were 6 years old. results:

–51.5% of kids grew up on farms, 53.6% had at least one allergic parent (note: this may affect generalizability of results) –dose-response effect: each additional food item introduced into the diet was associated with 26% decreased likelihood of developing asthma, with similar effect on food allergy and food sensitization. –this inverse relation between increased complementary foods and asthma did not change after if parents avoided food because of presumed allergy. the relation between numbers of foods and allergies was independent of whether the kids grew up on farms or had allergic parent(s) –in terms of specific foods, strong negative association with milk products (eg yogurt and butter) or with in the first year of life and subsequent allergies –also increased expression of marker for regulatory Tcells in those on diverse diets –this same research group previously reported similar findings with atopic dermatitis

one link with the last study is that the infant gut develops its microbiome early which may be affected by different foods ingested. studies have found an inverse relation between bacterial diversity of the gut microbiota in the first month of life and later development of eczema. prior pediatric feeding guidelines have recommended food allergy avoidance/delayed introduction of foods to prevent allergic diseases, but no clear benefit has been evident and there has been a clear increase in allergic diseases — hence newer guidelines have changed (eg, see doi: 10.1097/MPG.0b013e3181615cf2, or see below). as in the previous blog on asthma and the microbiome, the current study again challenges our model of health and disease. had we been “protecting” our kids too much by overly regulating/constraining what they eat? (perhaps similar to the studies finding that kids in “cleaner environments” at an early age are more allergic later on).  have the recommendations by various societies (pediatrics, nutrition), which seem to be based on logic (better to have kids in clean surroundings, or old guidelines to avoid potentially allergy-inducing foods…) been myopic/ looking only short-term? we have certainly been through a prolonged strong recommendation by the am heart assn and various nutrition societies that low fat/high carb diets were good for the heart (and perhaps the resulting dramatic increase in obesity/diabetes)… the issue, as always, is to develop our models of disease with our best understanding of physiology, etc, but then to continually test and challenge them. here is prior blog on nutrition recs for kids: There were recent recommendations from the American Academy of of Allergy, Asthma, and Immunology regarding the primary prevention of allergic disease in infants through nutritional interventions (see doi: 10.1016/j.jaip.2012.09.003).  These recommendations were specifically for prevention of allergy and not for kids who already have allergic disorders.  In brief, through their literature review which is current as of August 2012, they suggest the following:

— maternal avoidance during pregnancy of essential foods such as milk and eggs is not recommended.  The data are mixed and inconclusive for peanut ingestion during pregnancy and the subsequent development of peanut allergy in children, so no recommendation is made. (Given the severity of peanut allergy and data suggesting that maternal ingestion of peanuts more than a few times a week may be associated with peanut sensitization in infants, it still might be prudent to minimize peanut ingestion to less than twice a week.  My suggestion.)

— maternal avoidance of highly allergenic foods during lactation is not recommended at this time.

— they recommend exclusive breast-feeding for at least 4 months and up to 6 months of age,which may possibly reduce the subsequent development of atopic dermatitis in kids younger than the age of two years and to reduce early-onset wheezing before age 4 years, as well as to reduce the incidence of cow’s milk allergy but not food allergy in general for the first two years of life. the data are however not conclusive

— for infants that have increased risk of allergic disease (eg lots of fam members with allergic diseases, though this definition varies considerably from one study to another) and cannot be exclusively breast fed for the first 4 to 6 months of life, hydrolyzed formula appears to offer advantages to prevent allergic disease and cow’s milk allergy.  An extensive casein or whey hydrolysate formula may be slightly more beneficial than the partial whey hydrolysate formula. There does not seem to be any advantage to soy based formulas.

— as I mentioned in my e-mail on celiac disease, there has been a major rethinking of introduction of complementary foods in infants.  The gist of these studies, which are observational, is that delayed introduction of  cereal grains, cow’s milk, eggs, and even peanut butter may lead to more allergic problems.  The report details these observational studies, which are quite impressive, and notes that there need to be interventional studies done.  But they do state that the studies support the general notion that highly allergenic foods may be introduced earlier in the diet as complementary foods.  They do note that it is important to start solid foods by 6 months of age to support growth, though different societies very a bit on this recommendation. (see DOI: 10.1053/j.gastro.2013.04.051, which suggested more specifically that gluten-containing foods be added after 6 months of age in small quantities at first and while breastfeeding at the same time)

— guidelines on food introduction have basically not changed, with the introduction of a single ingredient foods between 4 to 6 months of age at a rate not faster than one new food every 3 to 5 days.  Complementary foods are typically rice or oat cereal, yellow/orange vegetables, fruits, green vegetables, and then age-appropriate staged foods with meats.  They do not recommend delaying the introduction of acidic fruits, though they can cause localized perioral reactions on contact with the skin.  These do not usually result in systemic reactions and therefore should not be delayed.  Highly allergenic food should not be the first complementary food introduced, however once a few typical complementary foods are tolerated, highly allergenic foods may be introduced.  Whole cow’s milk as the infant’s main drink or other cow’s milk-based products such as cheese and yogurt are safe before the age 1, but should be minimized because of increased solute load and low iron content.

— children who have one underlying food allergy are at risk for other food allergies.  Referral to an allergist is recommended.  Children with siblings with peanut allergy have a 7% risk of peanut allergy themselves.  They feel that these children can have peanuts at home, in the form of peanut butter to avoid choking. they suggested the first introduction to peanuts be at home as opposed to in daycare.  Parents should be told that the initial reaction to such foods as peanuts typically happen after the initial ingestion but that fatal reactions have not been reported on a first exposure.


Primary Care Corner with Geoffrey Modest MD: You Are What You Eat

6 Jun, 14 | by EBM

an article and editorial in Nature Medicine looked at dietary soluble fiber, changes in the gut flora (microbiome) and allergic airway disease. there have been articles suggesting that increased dietary fiber (esp soluble fiber) is linked to decreased risk of inflammatory diseases, esp in the gut. there are also some data finding associations between the higher incidence of asthma in those eating western diets and lower incidence on mediterranean diets. one potential explanation has been that gut microbes convert dietary fiber into short-chain fatty acids (SCFAs), which decrease inflammatory pathways in macrophages and dendritic cells, promote development of regulator T cells and maintain intestinal epithelial health.  for a detailed overview, see doi:10.1038/nm.3472.

in the current study (see doi:10.1038/nm.3444), researchers show how intake of high amounts of dietary fiber regulates the immune system in the lungs, decreasing the effect of  T helper type 2 cells allergy mediators, leading to lower allergic airway inflammation. (ie, dietary changes lead to immunologic changes in the lung). they had 2 different approaches to see if high soluble fiber diet could modulate airway inflammation. first, they fed mice a regular fiber diet vs low fiber diet, then exposed them to house dust mites, finding that the mice on the low fiber diet had elevated airway eosinophils, interleukins 4,5,13,and 17A, total IgE, dust mite specific IgG antibodies, mucous production and airway hyperreactivity. in a complementary experiment, they increased the fiber content of the food, with one group of mice fed high soluble fiber (30% pectin) and the control group given bulking fiber (30% cellulose). [in mice and men (humans….) pectin (but not cellulose) is fermented into SCFAs.] the high soluble fiber diet led to lower levels of allergic inflammation, decreased IgE, eosinophils and the above interleukins, and improved airway resistance. they also looked at the bacterial diversity of the GI tract, finding that it was increased in the high soluble fiber diet and decreased by the low-fiber diet — supporting the relationship between diet, changes in the microbiome, and changes in physiology leading to differences in allergic response (presumably mediated through SCFAs).  for example clostridial species IV and XIAa, major producers of SCFAs, disappeared from mice on the low-fiber diet. there were also changes in the microbiome in the lung, though less impressive than in the gut. mice on the low-soluble fiber diet were then injected with propionate (an SCFA whose level was decreased in the low-fiber group), finding significantly reduced allergic inflammation and improved airway resistance.

Here is a blog on the microbiome and heart disease, from 4/8/2013:

Article in NY times today (see here) seems that presumptive coronary heart disease culprit of carnitine (in red meat, same Latin route at “carnivore”) may be only partially correct. Published in Nature Medicine (see doi:10.1038/nm.3145). Turns out to (maybe) be more complex:

–in regular meat eaters, eating a sirloin leads to an increase in TMAO (trimethylamine-N-oxide), which in lab studies leads to accumulation of cholesterol in macrophages and and also seems to decrease the ability to excrete excess cholesterol (for excruciating detail, see the paper itself), with some previous data that blood TMAO is assoc with CAD, both in humans and mice
–in vegan who had a similar meal of sirloin (presumably with a significant bribe), no increase in TMAO.
–larger group of vegetarians given carnitine pill had no inc in TMAO.
–so, speculation that it was intestinal bacteria responsible (precursor TMA known to be produced by intestinal bacteria), and that the intestinal flora are different in vegetarians than meat-eaters — mouse studies show that increasing L-carnitine ingestion leads to changes in intestinal bacteria.  beef has highest level of carnitine. Lesser amounts in fish, chicken, and dairy. Also in high-energy drinks for body-builders
–meat-eaters pretreated with antibiotics to sterilize colon did no have TMAO in their blood
–further analysis of 2600 pts, controlling for traditional risk factors, found that TMAO and not carnitine assoc with CAD

bottom line from these studies: you are what you eat — diet leads to changes in the gut flora which leads to remote (and local) changes in the organism (mice and humans) and increased disease states. the concern, of course, is that there are lots of things we medical providers do which result in microbiomic changes (eg, antibiotics, colon preps for colonoscopy, suggesting certain diets such as the Adkins diet high in protein and low in fiber — all done with the perhaps overly simplistic understanding that antibiotics are necessary (which is often not true), colonoscopy is important for colonic polyp/cancer detection (overall true, though the newer genetic tests not requiring a colon prep are pretty intriguing), and the Adkins diet is good for lowering blood sugar and weight (also true, but there may be longer term adverse effects which were not even on the radar screen when this diet was in its hayday).



Primary Care Corner with Geoffrey Modest MD: Educational Program to Decrease Benzo Use in Elderly

4 Jun, 14 | by EBM

one of the “choosing wisely” items of the american geriatric society is to avoid the use of benzodiazepines in people over 65 yo because of the associated increased risk of falls and hip fractures. of note, benzos comprise 20-25% of “inappropriate” scripts for elderly, with prevalence of use at 5-32% in community-dwelling elders. a study was done of direct-to-consumer advertising to see if that could decrease benzo usage in community-dwelling people >65yo on chronic benzos (see doi:10.1001/jamainternmed.2014.949). in this study community pharmacies were randomly assigned to either intervention or control, with approx 150 patients aged 65-95 yo in each group. patients in the active arm of the trial got an 8-page booklet with a self-assessment component about benzo use, presentation of evidence of benzo harm, drug interactions, peer champion stories to augment self-efficacy, suggestions for alternative therapies for insomnia or anxiety, and specifics for stepwise taper. the patients were then urged to discuss this with their MD or pharmacist. they then measured benzo usage 6 months later. results:

 –indication for chronic benzos: 60% for insomnia and 48% for anxiety, mean duration 10 years and average daily dose = 1.3mg equivalents of lorazepam
–86% of participants completed the 6-month follow-up
–of those in the intervention group, 62% initiated conversation about benzo cessation with their medical provider and/or pharmacist
–at 6 months, 27% in the intervention group and 5% in control group had discontinued the benzos, a highly significant difference, with NNT of 4.  dose reduction in an additional 11%
–no interaction effect in subgroup analysis for age>80, sex, duration of use, indication for use, dose, prior attempts to taper, concomitant polypharmacy (>10 drugs/d)

 so, pretty remarkable changes through direct patient education and empowerment. 27% of patients on reasonably high doses of benzos for 10 years were able to completely taper off benzos and additional 11% to cut back!! runs counter to the complacent attitude that “my patient is doing fine. stable. sleeping better. why change anything since he/she is having no problems/falls. and besides, he/she probably is addicted and will go through potentially traumatic withdrawal…..”


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