An opinionated take on NEJM highlights for August 2016: cleanliness is not next to healthiness, testing before thinking, a long slog for precision medicine


There is such a thing as too much hygiene

The prevalence of asthma in children has increased dramatically over the last few decades. Observational studies have shown that children in “dirty” environments such as farms seem to be relatively protected from asthma.  A theory is that the lack of exposure to microbes leads to higher sensitivity to allergens, but this causality has been hard to show. Amish and Hutterite farm communities are genetically similar, but Amish rely on animals instead of machinery, and Amish children have much lower incidence of asthma. In a fascinating study comparing Amish and Hutterite, it is shown that there are profound differences between the two groups in the following (1) the microbial flora collected from house dust and bedding (2) the baseline immune cellular signature in the blood of those children (3) the response of mouse models for asthma exposed to house dust (Amish dust is protective against mouse asthma, Hutterite dust is not).  The upshot is that the importance of the microbiome goes well beyond the gut – and considering the burden of pediatric asthma, there might be an opportunity to manipulate this with a lot a value.   Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children; Innate Immunity in Asthma (free access)


Medical wild goose chases are expensive and maybe common

An instructive clinical case presentation of a man with a high blood calcium level and renal failure. It is a picture highly suggestive of the milk alkali syndrome (which it turned out to be), but somehow the treating team became focused on the possibility of a malignancy. To quote the discussant:  “The diagnosis of the milk alkali syndrome can be made with relatively few tests, and one of the notable features of this case was the overutilization of laboratory testing. For this patient, 117 laboratory tests were ordered and 360 results were reported over the course of two visits to the outpatient clinic and a 3-day hospital stay.”  In the current paradigm under which physicians look at the clinical picture and develop a list of potential diagnoses (known as “the differential”) in their head over a few minutes, neglecting a relevant diagnostic path will happen (rarely with talented physicians, more often with those who are less so). Usually, this is self-correcting because once a line of investigation is exhausted, it prompts consideration of alternatives, but as this case shows, it can be very expensive. Clearly, there is an opportunity for intelligent systems leveraging the EHR to suggest prioritized differentials in support of clinical decision making.  Case 24-2016 — A 66-Year-Old Man with Malaise, Weakness, and Hypercalcemia (subscription access)


Who should get post-op chemotherapy in breast cancer? 

Whether or not to treat with adjuvant chemotherapy after complete resection of non-metastatic breast cancer to prevent a recurrence is a tricky question. Chemotherapy does reduce the recurrence rate, but that rate is only 10%-20% at 5 years to begin with, so for more than 80% of the patients, it’s an unpleasant intervention fraught with side effects with no benefit. Attempts have been made to design genetic/gene expression tests to discriminate between patients who would benefit or not. One of them, Mammaprint, was studied in a trial whereby patients who had discordant clinical risk and genetic risk (i.e. low/high, and high/low) were randomized to adjuvant chemotherapy or none. The idea was that one might see a benefit to treat patients with low clinical risk and high genetic test risk (who would otherwise not be treated), and avoid chemotherapy in patients with high clinical risk and low genetic test risk without negative impact. The results were underwhelming: no difference in chemotherapy vs. none for those with low clinical risk and high genetic test risk, and a slight worsening of outcomes without chemotherapy for those with high clinical risk and low genetic test risk. But even more discouraging is that it took 6000 patients and 6 years to get the answer.  Considering the promise of personalized medicine revolves around myriads of possible gene signatures, it is clear that different approaches are needed or we will never get there. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer; Increasing Precision in Adjuvant Therapy for Breast Cancer (subscription access);Uncertainty in the Era of Precision Medicine (free access)


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.