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Archive for May, 2015

Primary Care Corner with Geoffrey Modest MD: Lung ultrasound to diagnose pneumonia?

27 May, 15 | by EBM

By: Dr. Geoffrey Modest
An Italian prospective study was just published looking at the merits of ultrasound in diagnosing pneumonia (see Am J Emerg Med 2015 May; 33:620.). Prior studies have found that chest xray (CXR) is not so sensitive, 43.5% in one study when compared to chest CT (which is considered the gold standard). details:

–275 patients with respiratory complaints (60% dyspnea, 25% cough, 10% purulent sputum, 15% pleuritic chest pain) and underwent chest CT. Mean age 71, 53.3% women.
–Chest CT was positive for pneumonia (PNA) in 87 patients, with “almost perfect” concordance between the readings of 2 radiologists.
–lung ultrasound (LUS), done within 3 hours of the CT, and was positive in 81 patients. 72 of them (88.9%) also had a positive chest CT

–the 9 false positives were: 3 lung cancer nodules, 3 cases of impaired ventilation not due to PNA, 3 cases of fibrotic bands
–the 15 false negatives were: 3 cases of posterior consolidations (the LUS was only performed on anterior-lateral chest), 5 cases of deep infection without contact with the pleura
–overall sensitivity was 82.8% (73.2-90%) and specificity was 95.5% (91.5-97.9%)
–interobserver variability: “almost perfect”
–in subgroup of patients with pleuritic chest pain: sensitivity was 91.7% and specificity was 97.4%
–in subgroup wihtout pleuritic chest pain: sensitivity was 81.3% and specificity was 95% (other studies found LUS less reliable with deep-seated infections)

–CXR was done in addition to LUS in 190 patients:

–sensitivity of LUS was 81.4% and of CXR was 64.3% (difference significant with p=0.036); specificities were similar (94.2% vs 90%)

–so, overall, LUS rules in consolidation well (+ likelihood ratio of 18.2), and is moderately good in ruling out consolidation ( – LR=0.18)

so, pretty inmpressive. This study confirms the relatively poor showing of CXR in diagnosing PNA, and found that LUS was really quite good, and the usual ultrasound concern of intra-observer variability was minimal. Although this needs to be validated in other settings, this study does hold out the promise of a noninvasive and nonradiation-associated evaluation of pneumonia.

Primary Care Corner with Geoffrey Modest MD: SGLT2 inhibitors for diabetes may cause ketoacidosis

27 May, 15 | by EBM

By: Dr. Geoffrey Modest 

The FDA just came out with a warning on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, including canagliflozin dapagliflozin, and empagliflozin (and the combo drugs including them) because of 20 cases of ketoacidosis. these drugs lead to increased urinary excretion of glucose, thereby lowering hemoglobin A1C. see here for the press release. findings of FDA:

 –from March 2013 to June 2014, there were 20 cases of ketoacidosis reported requiring emergency room visits, an unusual finding in type 2 diabetes. And there have been additional reports since June 2014.

–1/2 the cases did not have any typical DKA triggering factors, such as acute illness (urinary tract infection, urosepsis, gastroenteritis, influenza, trauma), reduced caloric or fluid intake, reduced insulin dose; also no factors associated with high anion-gap acidosis (hypovolemia, acute renal failure, hypoxemia, reduced oral intake, history of alcohol use)

–of note, the glucose levels in the patients were “only mildly elevated at less than 200 mg/dL in some reports, while patients with type 1 diabetes who have DKA typically have glucose levels greater than 250 mg/dL.”

–median time to development of DKA was 2 weeks after initiation of drug therapy with SGLT2 inhibitor, but the spread was great (range 1 to 175 days) [and may be much greater as we are more alert to this association and discover more cases]

–the FDA with continue to monitor these drugs to see if there needs to be changes in labeling.

so, as I’ve mentioned before, I am really reluctant to use these new-fangled drugs. In part because they are new and untested long-term (and this is a case in point). In part because none of them have looked at the important clinical endpoints (death, heart disease, microvascular complications, etc) but only at the effect on the surrogate marker of hemoglobin A1C. And, in part, because of the hassle of getting prior approvals from insurance companies to use these new and expensive meds. The other take-home message for us is to be alert to the possibility of DKA even in patients with blood sugar <200 mg/dL…​

Primary Care Corner with Geoffrey Modest MD: Vitamin d and falls in the elderly???

27 May, 15 | by EBM

By: Dr. Geoffrey Modest

A recent article, which got some general press, looked at the utility of exercise and/or vitamin D in fall prevention in older women (see JAMA Intern Med. 2015;175(5):703-711). The backdrop here is that falls are common in the elderly, and 20% lead to injury requiring medical attention. A systematic review and meta-analysis documented the benefit of vitamin D (see J Clin Endocrinol Metab, October 2011, 96(10):2997–3006), finding that in 26 studies with 46K people (majority elderly women), vitamin D was associated with 14% decreased risk of falls (47% in those vitamin D deficient, 10% in those not deficient, and both statistically significant), and this was especially true in patients who had calcium co-administered with the vitamin D. The US Preventive Services Task Force (USPSTF) in 2012 “recommends exercise or physical therapy and vitamin D supplementation to prevent falls in community-dwelling adults aged 65 years or older who are at increased risk for falls”, a grade B recommendation.


(LeBlanc & Chou, 2015)

Details of the new study:

–2-year double-blind, placebo controlled vitamin D and open exercise trial, with 409 home-dwelling women 70-80 years old in Finland who had at least 1 fall in previous year, did not use vitamin D supplements, and could exercise.
–median age 74, BMI 28, 25(OH) vit D level 27 ng/ml, PTH 5 pg/ml, MMSE 28, 45% with hypertension, 20% cardiovasc disease, 10% diabetes, 25-30% osteoarthritis, <5% depression
–4 groups: placebo without exercise, vitamin D 800 IU/d without exercise, placebo with exercise, and vitamin D 800 IU/d with exercise. exercise was group training 2x/week for first 12 months, then 1x/week, with alternating exercise classes (balance challenging, weight bearing, strengthening, agility, and functional exercises) and gym exercises (weight machines, free weights). Also there was a home-training program for 5-15 minutes on all the other days.
–primary outcome: monthly reported falls. secondary outcome: injurious falls, and the number of fallers and injured fallers
–results: in units of falls/100-person-years

–placebo without exercise: 118.2, but secondary outcome of injurious fall rate: 13.2
–vitamin D without exercise: 132.1, but secondary outcome of injurious fall rate: 12.9
–placebo and exercise: 120.7, but secondary outcome of injurious fall rate: 6.5
–placebo and vitamin D: 113.1, but secondary outcome of injurious fall rate: 5.0
–hazard ratios for injured fallers were significantly lower among exercisers, both with (HR 0.38) and without vitamin D (HR 0.47)
–vitamin D groups did maintain femoral neck bone mineral density and increased trabecular density slightly, vs small losses in the non-vitamin D groups
–exercise improved muscle strength and balance, and vitamin D added nothing to that
–adherence: 98.1% with pills and those on vitamin D had 25(OH) D levels increasing to 37.0 ng/ml at 24 months;72.8% for training sessions; 66.1% with home exercises
–adverse effects: no severe effects/injuries from training program, though 22 in training program and 1 not in program saw MD for musculoskeletal concerns.
their conclusions:
–rate of injurious falls and injured fallers more than halved with strength and balance training
–neither exercise nor vitamin D affected the rate of falls
–exercise improved physical functioning

So, this study raises several issues. Overall this was a group of quite healthy and quite fit women (both their baseline Short Physical Performance Battery and Mini Mential Status Exam were very close to the highest scores possible). But the devil is in the details. Despite headlines like “neither vitamin D nor exercise affects overall fall rates in older women” in Journal Watch, and their comment that “these results weaken speculation that vitamin D supplementation alone can prevent falls”, this trial was done in women who were not vitamin D deficient: the Endocrine Society in the US defines vitamin D deficiency as <20 ng/ml, and suggests maintenance vitamin D dosages of 1500-2000 IU/day in those who had been deficient– see doi: 10.1210/jc.2011-0385. The meta-analysis above cited has diagrams showing the difference in fall prevention in people who are vs are not vitamin D deficient, though I will append at the bottom a more recent analysis done by the editorialists (see JAMA Intern Med. 2015;175(5):712-713).

Bottom line: this study really does not add much overall. Giving vitamin D to healthy, fit 74 year old women (even though they did fall in the year prior to the study), who already have sufficient vitamin D levels — it is not so surprising that the added 800 IU didn’t do much. The exercise component does show value (as in other studies), though in this study it was not in falls overall but in injurious falls. So, I still would either check vitamin D levels/treat if low in elderly women, or just treat with vitamin D if the latitude and general assessment is that vitamin D deficiency is really common; I would also make sure that there is sufficient calcium in the diet or through supplements. And, of course, I would encourage balance and strengthening exercises.

Primary Care Corner with Geoffrey Modest MD: Celiac disease and neuropathy

22 May, 15 | by EBM

By: Dr. Geoffrey Modest 

Peripheral neuropathy has been associated with celiac disease in past studies, typically based in referral centers. The current population-based study in Sweden looked more systematically at the association (see doi:10.1001/jamaneurol.2015.0475​). As background, celiac disease is pretty common, with prevalence of about 1%, and peripheral neuropathy is present in 2-7% of the population. Details of the study:

–Data collected on small intestine biopsies performed at Sweden’s 28 pathology departments from 1969-2008

–They compared the risk of neuropathy in 28,232 patients with celiac disease vs 139,473 age- and sex-matched controls (median age at diagnosis of 29: 42% were 0-19 yo, 18% 20-39, 22% 40-59, 18% >60; 62% female; comorbidity of type 1 diabetes in 3.2 vs 0.4% in controls, alcohol use in 2.7 vs 2.6%). Patients had confirmed celiac disease (CD), with villous atrophy, Marsh 3

–CD was associated with a 2.5-fold (2.1-3.0, p<0.001) increased risk of later neuropathy (0.7% vs 0.3% in controls, absolute risk of 64/100K vs 15/100K)

–CD also associated with increased risk of

–chronic inflammatory demyelinating neuropathy: 2.8-fold (1.6-5.1, p<0.001)

–autonomic neuropathy: 4.2-fold (1.4-12.3, p=0.009)

–mononeuritis multiplex: 7.6-fold (1.8-32.4, p=0.006)

–but not with acute inflammatory demyelinating polyneuropathy: 0.8-fold (0.3-2.1, p=0.68)

–No difference in neuropathy by sex, or age. Overall risk decreased minimally from 2.5 fold to 2.3-fold (1.9-2.7) after controlling for educational level, SES, type 1 or 2 diabetes, autoimmune thyroid disease, rheumatologic diseases, pernicious anemia, vitamin deficiencies, and alcoholic disorders.

–Association with neuropathy was pretty consistent in group with <1 yr of followup vs 1-5 yr, vs >5 yr

–There was a positive association between any neuropathy and CD, even when the diagnosis of neuropathy preceded the diagnosis of CD with an odds ratio of  1.8; 1.4-2.2, p<0.001

So, seems like we really should add an evaluation for CD as part of our neuropathy workup. In small studies, it seems that the association of CD with neuropathy is not necessarily associated with CD-related vitamin deficiencies (one study of 18 patients with confirmed CD and neuropathy found that they all had normal vitamin B12 levels). My sense, given the pretty low absolute association as noted above in Sweden, is that screening questions about GI symptoms seem appropriate. It might also be reasonable to perform serologic studies for CD, since there are some data suggesting that a gluten-free diet may either prevent or ameliorate the neuropathy (this is not very robust data), and on the other hand there are data suggesting that there are many people with “asymptomatic” CD who actually do feel better on a gluten-free diet, they might have significant malabsorption issues that should be detected/addressed, and (data not so robust) asymptomatic patients may still be at higher risk of lymphoma or autoimmune diseases which decreases with a gluten-free diet.


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: Cancer screening rates

13 May, 15 | by EBM

By: Dr. Geoffrey Modest 

MMWR just published the 2013 National Health Interview Survey (NHIS) on cancer screening rates, with targets established by Healthy People 2020 using the US Preventive Services Task Force guidelines (see here).


Overall, there was not much improvement from 2010 to 2013 in breast, cervical or colorectal cancer (CRC) screening, and cervical cancer screening rates even declined. NHIS is an annual survey of a nationally representative sample of the civilian US population, with surveys of randomly selected adults. In 2013 had a 61.2% response rate.


–Mammography in women aged 50-74: 72.6%, below the target of 81.1%. no significant change from 2010. On more detailed review:

–lower in women aged 50-64 than 65-74

–lower among Hispanics
–lower among those with less education or income

lowest in those without primary care (29.7%) or insurance (38.5%)

–Pap tests: 80.7% of women aged 21-65 had an appropriately recent pap test, below the target of 93.0%, below the 2008 baseline of 84.5%, and declined 5.5% from 2000 to 2013. On more detailed review:

–lower for Asians, Hispanics, foreign-born, and women aged 51-65

–lower in those with less education or income

lowest in those without primary care (62.1%) or insurance (62.0%)

–CRC screening: 58.2% of those aged 50-75 had CRC screening, below the target of 70.5%, but above the 2008 baseline of 52.1%. Use increased dramatically from 2000 to 2013 by 24.6 percentage points, though did not increase from 2010 to 2013. On more detailed review:

–lower among Asians and all Hispanic subgroups except Puerto Ricans

–lower among those aged 50-64 (52.8%) than 65-75 (69.4%)

–lower in those with less education or income

lowest in those without primary care (17.8%) or insurance (23.5%)

So, a few points.

–No real progress since 2010 (not much change in mammography or CRC testing, decline in paps)

–There were dramatically decreased rates of screening (35-40 percentage points less)  in uninsured and those without primary care. This underscores perhaps the most glaring deficiency/disparity of our current health care system: we do not have an inclusive coherent system of care (as exists in the rest of industrialized and many less-industrialized countries) which not only is socially reprehensible, but ironically is a lot more expensive (it turns out, for example, that treating the undetected cancers later is quite expensive…)

–One concern I have brought up before is that the recommendation for decreased pap smear screening in  2012, with screening every 5 years in those >30yo and normal results, may reinforce both a more casual attitude to screening and less provider experience/comfort with doing pelvic exams even when important diagnostically (and in my role as an educator, that is my observation — even women with lower abdominal pain are not routinely getting pelvics).  For more blogs on screening, see here.​

–One should bear in mind that the above data are as reported by the patient.  in fact, the actual screening rates may be quite different. for example, I have seen several women who state that they had a pap smear when in fact they have had only a pelvic exam in the emergency room

–Another real concern is that we are apparently not doing any better overall despite the increasing use of electronic medical records (EMRs) and reminder systems, since one of the obvious changes to improve screening would be increased reminders to patients and providers. Perhaps those of us using EMRs are a bit inured of these reminders, as nurses and others in ICUs are of alarms. This observation may undercut one of the strongest arguments for EMRs — that they would improve routine screening through incorporated reminder systems…

Primary Care Corner with Geoffrey Modest MD: Mammography screening, again, from another perspective

12 May, 15 | by EBM

By: Dr. Geoffrey Modest

This editorial is from Eric Topol, and raises concerns about the utility of mammography screening . one issue not addressed by him is primary prevention of breast cancer by decreasing environmental exposure to carcinogens: there are thousands of new chemicals developed in the US each year; historically many of them have estrogenic effects (which may not be the only way that breast cancer is stimulated); they seem to make their way into our air, water, and food supply; and essentially none of them have any significant safety checks prior to being mass-produced and released.

So, I agree with Topol that mammography is a terrible test in many ways, and in particular that it prevents so few breast cancer deaths in the current setting where breast cancer is the second leading cause of cancer deaths in women (in 2013 total of 273K women died of cancer, 72K from lung and 39K from breast).  I did post about the new USPSTF recommendations recently, and this and other breast cancer screening blogs can be found here. Topol brings up the intriguing suggestion that maybe we can risk-stratify women, such that low risk women (esp low genetic risk) might not get screening mammograms at all, where the likelihood of a false positive is very high, along with the attendant issues of anxiety, medicalization, followup testing, invasive biopsies, more potentially cancer-causing xrays, and even unnecessary toxic chemo/radiotherapy. and mammograms could be used for more targeted higher risk women. needless to say, this would need to be tested…


Primary Care Corner with Geoffrey Modest MD: Vitamin D and atopic dermatitis in kids

12 May, 15 | by EBM

By: Dr. Geoffrey Modest

Atopic dermatitis (AD) is pretty common in kids (up to 25%), typically occurring early on (45% of cases begin within first 6 months of life, 60% within first year), and 70% remit spontaneously by adolescence. In those with AD there are significant immunologic changes (increase in Th2 cells and decrease in Th1 cells in their skin, though there are differences in these T-cell subsets in the acute AD phase, with Th2 cells and their associated cytokines of IL-4, IL-5, IL-13 predominating, but in the chronic phase the Th1 cells and their associated IFN-g, IL-5,IL-12 predominate. Vitamin D receptors are all over the body, including in the skin and in the immune system, and a small RCT in AD patients randomized to vitamin D 1,600 IU/d found clinical improvement after 60 days. The current study looked further into the immunologic changes and clinical effects of vitamin D supplementation in AD patients (see Arch Allergy Immunol 2015;166:91–96​).



–39 children with chronic AD (mean age 4, 38% with family history of asthma, 87% family history of allergies, 33% of the kids had asthma and 33% had rhinitis; 8% had mild AD/46% moderate and 46% severe; 90% with total IgE increased and 23% had documented food allergy, 21% for inhalants only; 38% tested positive for dust mite allergen and 44% for eggs. overall skin test positivity was present in 79%). These AD patients were compared with 20 nonallergic healthy controls.​

— baseline cytokine (IL-2, IL-4, IL-6, IFN-g, TNF-a) and vitamin D levels were assessed, along with SCORAD (an AD clinical scoring system) index.

–then the patients were treated with vitamin D (1,000 IU/day) for 3 months.

–Families of AD patients were asked not to use topical steroids (6 did use them sporadically) or oral steroids (none used)


–all cytokines except TNF-a were elevated in the AD kids
–baseline vitamin D levels in the AD and control patients were similar (23 ng/ml in AD group and 20 ng/ml in controls)

–after vitamin D supplementation, the vit D levels increased from 23 ng/ml to 29 ng/ml

–the altered cytokines  (IL-2, IL-4, IL-6, IFN-g) were all statistically significantly and dramatically reduced after the vitamin D supplementation, and were within the range of the normal kids

–the SCORAD index decreased from 46.13 +/- 15.68 to 22.57 +/- 15.28, p<0.001) — a SCORAD index of 25-50 reflects moderate AD

In terms of the role of helper T cell subsets, in brief Th1 cells are moere involved in immunity to intracellular pathogens and in autoimmunity; Th2 more with defense against parasites and with atopic diseases. the balance of Th1/Th2 may be important in terms of disease progression. People with higher ratios and HIV infection have slower disease progression. The most significant initial cytokine associated with Th1 is IL-12, and also IFN-g. Th2 is most strongly associated with IL-4.

Although there was no formal control in this study, they did find that those kids who did not adhere to the vitamin D supplementation or did not have much of a bump in their vitamin D levels did not have a significant change in their SCORAD index or cytokine levels. So, given the data that vitamin D may well be important in immune function in general and the results in this and the other study cited above, it certainly seems reasonable to me to check vitamin D levels and supplement in kids with atopic dermatitis.

Primary Care Corner with Geoffrey Modest MD: Melatonin and delirium prevention

11 May, 15 | by EBM

By: Dr. Geoffrey Modest

There have been a few articles looking at melatonin and one of its derivatives to decrease the development of delirium in hospitalized patients (thanks to my brother Andrew for bringing this to my attention). Delirium, from many studies, is common (30% of those hospitalized who are over 65 yo, 40% in those in ICU, and is often underdiagnosed). One article looked at ramelteon, a melatonin agonist with high affinity for the MT1 and MT2 receptors (more potent than melatonin by 6-fold and 3-fold, respectively, so that comparing 8mg of ramelteon has, for example, a 16- and 8-fold increased potency vs 3mg of melatonin) — see JAMA Psychiatry. 2014;71(4):397-403).

Details of this study:

 –67 patients (mean age 78, 40% male, with most admitted with either stroke, infection, or fracture) from 4 university hospitals and 1 general hospital in Japan.

–24 patients in ICUs and 43 on hospital wards were randomly assigned to ramelteon 8mg/d vs placebo nightly for 7 nights


-ramelteon was associated with a lower risk of delirium (1 vs 11 patients: 3% vs 32%, p=0.003) with RR 0.09 (0.01-0.69). the effect was evident within 2-3 days of admission

–controlling for risk factors (age, diagnosis of dementia, admission diagnosis of infection), ramelteon still significantly associated with decreased delirium risk [P=0.01, odds ratio 0.07 (0.008-0.54)]

–there were no differences in any of the sleep parameters in those on ramelteon (difficulty falling asleep, staying asleep, early awakening, sleep quality or duration), though more in the placebo group did get hydroxyzine, which has weak anticholinergic effects, for sleep (though, controlling for the use of hydroxyzine, there still was a significant benefit of ramelteon on delirium). so, it does not seem that sleep deprivation had a significant role in the occurrence of delirium

–subgroup analysis showed ramelteon’s benefits were even in those without prior history of delirium. (too few patients in sample with history of delirium to see any difference)

–adverse events potentially attributable to drug: zero  — though other studies on ramelteon have shown slight increases in somnolence (5% vs 3%), dizziness (5% vs 3%) and fatigue (4% vs 2%)

This was a pretty benign intervention in a small number of patients but with pretty dramatic outcome, especially since the only other medications showing any benefit in some studies are antipsychotics that have lots of adverse effects. Trials of cholinesterase inhibitors (eg donepezil) mostly produce just adverse effects. other studies on ramelteon confirm its benefit in sleep-promotion in the elderly, at both the 4 and 8mg dosages (likely related to restoring the otherwise decreasing endogenous melatonin levels with aging). Other small RCTs have found some benefit of melatonin at doses of 3mg, 5mg, and 10mg in restoring circadian rhythms in ICU patients and decreasing delirium in medical  or elective surgical patients. The main issues with this ramelteon study is the small sample size, some differences in those with baseline dementia (24% in the placebo group and 15% in those on ramelteon), and lack of breakdown of which patients were in the ICU vs the wards (though there was no difference in the APACHE scores, Charlson comorbidity index, or performance status of the randomized patients)

Bottom line:

–there seems to be some utility of melatonin or derivatives (ramelteon) in restoring circadian rhythm, sleep and preventing delirium in hospitalized patients

–the big issue to me with melatonin is that it is a “supplement”, not subject to the FDA regulation, and there have been dramatic differences found in the actual amount of melatonin in the advertised doses.

–the average wholesale price of ramelteon (which is not available as a generic) is  $333 for 30 pills and requires a prior approval from medicaid ….  so, will stick with melatonin for now.

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