Showing posts with label asthma. Show all posts
Showing posts with label asthma. Show all posts

Monday, August 8, 2016

Hutterite Dust versus Amish Dust





From previous posts, I consider asthma to be a good comparison illness with mental illnesses for a number of reasons.  The diagnosis is frequently unclear.  There are no specific diagnostic tests for asthma.  Attending even a state of the art clinic for asthma usually consists at some point of filling out a subjective checklist of symptoms and disability - including the frequency that a rescue inhaler is used.  The majority of asthmatics are symptomatic with wheezing.  The symptomatic state is often considered a sign of compliance with treatment measures, but the reality is that asthma is difficult to treat and there is a strong environmental component to treating it.  Depending on the physician, environmental engineering like air filters, dust removal, and avoidance of certain allergens is typically discussed but less often than in the past.  The mainstay of treatment is corticosteroid inhalers with long acting beta agonists where the corticosteroid inhaler alone is not enough.  Some authors have defined endophenotypes that may represent different disease mechanisms.  The overall prevalence of asthma has increased significantly suggesting an environmental component.

Additional epidemiology has shown that exposure to high microbial environments such as livestock exposure on traditional farms confers some protection in terms of the development of asthma.  The Amish are noted to have a decreased rate of asthma and allergic sensitization than non-farmers.  These factors led to a very interesting study in this week's New England Journal of Medicine.  In this study the authors elected to compare schoolchildren from both Amish and Hutterite families on a number of genetic and immunologic markers.  Sixty children were studied from both communities.  They were sex and age matched to within one year.  Half of the children were from an Amish community and half from a Hutterite community.  Both groups are from a similar European geography and on an SNP analysis of genetic association were strikingly similar in terms of comparison groups.  The main environmental variable was that the Amish farms were single family dairy farms and the Hutterite farms were communal mechanized farms.   Previous reports had determined that the Hutterite children had a higher prevalence of asthma (21.3% versus 5.2%) and allergic sensitization (33.3% versus 7.2%) than the Amish children.

Blood tests were done on the children to determine immune markers.  The Hutterite group had higher levels of IgE to common antigens.  The Hutterite children also had increased eosinophils, decreased neutrophils and about the same number of monocytes as the Amish children.  Blood samples were screened for 26 cytokines and 23 were found.  Median cytokine levels of each were higher in the Hutterite group even when the known asthmatics were excluded (there were no asthmatics in the Amish group).  Gene expression profiles were also generated for all of the subjects and pathway analysis was done with a standard informatics based approach.  From these analytics the authors concluded that the most significant module in both the Hutterite and Amish children contained 43 genes.  Eighteen of the genes resulting in overexpression of tumor necrosis factor (TNF) and and interferon regulatory factor 7 (IRF7) were present in the Amish children.  Both of these proteins are important in the innate response to microbial stimuli.  

The house dust experiment was conducted in a mouse model of asthma.  Dust extracts were administered intranasally over 4-5 weeks.  Hutterite dust produced airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage specimens from the mice but the Amish dust did not.  Mice deficient in MyD88 and Trif - proteins required for innate immunity signaling (5a) did not respond to the inhibitory effects of Amish dust extract on airway hyperresponsiveness or eosinophilia as further evidence that innate immunity is involved.                          

The authors and the accompanying editorial by Chatila (2) emphasize the importance of this study.  Amish dust is able to activate innate immunity by very specific mechanisms that led to its protective effects against allergic sensitization and allergic asthma. The authors cite the main deficiencies of the study as not looking at children younger than 6, limited dust sampling, and a sampling strategy of asthmatics that resulted in a higher numbers of Hutterite children with asthma.  The editorial suggests that the dose of dust to prevent or possible moderate asthma is not really determined.

This was a very elegant study that has the potential to create novel therapies for an illness that is currently not very well treated.  It highlights that fact that polygenic illnesses, especially those representing complex systems and complex interacting systems are difficult to characterize but with modern methods of analysis we are getting closer.  It was not too long ago that many of the molecules listed in the diagrams at the top of this page were not known to exist.  The best example I can think of is the leukotrienes that were collectively known as Slow Reacting Substance of Anaphylaxis or SRS-A. (4).  Cytokines were also unknown.  The fact that all asthmatics are not alike and that some authors believe that clear endophenotypes exist suggests that in the genes and proteins mentioned in this article significant variation should be expected.  If these findings are accurate, it also points out the importance of slight differences in the environment in the development of asthma.          


George Dawson, MD, DFAPA


References:


1: Michelle M. Stein, B.S., Cara L. Hrusch, Ph.D., Justyna Gozdz, B.A., Catherine Igartua, B.S., Vadim Pivniouk, Ph.D., Sean E. Murray, B.S., Julie G. Ledford, Ph.D., Mauricius Marques dos Santos, B.S., Rebecca L. Anderson, M.S., Nervana Metwali, Ph.D., Julia W. Neilson, Ph.D., Raina M. Maier, Ph.D., Jack A. Gilbert, Ph.D., Mark Holbreich, M.D., Peter S. Thorne, Ph.D., Fernando D. Martinez, M.D., Erika von Mutius, M.D., Donata Vercelli, M.D., Carole Ober, Ph.D., and Anne I. Sperling, Ph.D. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children N Engl J Med 2016; 375:411-421; August 4, 2016; DOI: 10.1056/NEJMoa1508749

2:   Talal A. Chatila, M.D., M.Sc. Innate Immunity in Asthma. N Engl J Med 2016; 375:477-479; August 4, 2016;  DOI: 10.1056/NEJMe1607438.

3:  Chapter 2:  Innate Immunity in Peter Parham.  The Immune System, Third Edition.  Garland Science, Taylor and Francis Group, LLC.  New York.  2009.  pp 31-70.

4:  Roitt I.  Essential Immunology, Third Edition.  Blackwell Scientific Publications, Oxford. 1977, p 157.

5:  Links to Kyoto Encyclopedia of Genes and Genomes (KEGG):

a) KEGG (MyD88-3 and trif):  Link
                
b) Toll like receptor signaling:  Link
                
c) NF- Kappa B signaling:  Link
                
d) Innate immunity:  Link
                
e) Adaptive immunity:  Link





Attribution:

Both graphics at the top of this page are from VisiScience.com and posted per their user agreement.




Saturday, April 9, 2016

A Neanderthal - Further Confirmation And Much More On Personal DNA



I like the idea of getting my own DNA analyzed and studying the results.  In an earlier post, I described some results of an analysis through a National Geographic project, and the finding that 2.5% of my DNA was from Neanderthals.  The ability to sequence ancient DNA is a relatively new capability and in the few years that it has been done, it has yielded a number of significant findings.  The applicability to the field of psychiatry is limited at this time to 2 references (1,2).  An additional search on ancient DNA and psychiatry yields 4 additional references (4-6) looking at the early origins of mutation and how the associated disrupted regulatory mechanisms could lead to psychopathology.  One of the susceptibility markers for schizophrenia dates back to the last glacial maximum or 24,500 years BCE.  

After trying out the National Geographic site,  I decided to see if the 23andMe site had anything more to offer.  I pulled up their web site, paid the fee and they sent me a sampling kit.  Their sampling technology if different in that they use a tube of saliva as the sample rather than a scraping from the buccal mucosa.  They send you a number of e-mail updates and finally a notification that your DNA has been processed and the necessary reports have been generated.  There are 67 reports in all that focus on ancestry, carrier status, wellness, and traits.  Some reports are more useful than others.  For example it is interesting that a 4th digit on the hand longer than the second digit or a second toe longer than the great toe are inherited characteristics with certain probabilities.  Unless there are some additional health implications involved I don't really care about my longest toe or finger.  The data I am looking for is precisely the data that the FDA told 23andMe that it should not market in the first place.  That initial FDA warning looks at the testing that the company was offering.  In this document the abbreviation PGS is used for "Personal Genome Service":

"Some of the uses for which PGS is intended are particularly concerning, such as assessments for BRCA-related genetic risk and drug responses (e.g., warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) because of the potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these. For instance, if the BRCA-related risk assessment for breast or ovarian cancer reports a false positive, it could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions, while a false negative could result in a failure to recognize an actual risk that may exist......."

I am sure there are plenty of posts around the Internet on the regulatory aspects of DNA testing and what the FDA is doing to protect the American public.  23andMe does have consistent qualifying statements saying that none of the data is for medical purposes, only for research and education.  My interest is purely personal research and education.  What more can I learn about DNA, genetics, molecular biology and human diseases.  As noted in my original, what more can I learn about my ancestry and the fascinating subject of Paleogenetics and the associated big questions like why is Homo sapiens - the genus and species of all current human beings the only surviving Homo genus.  Why are all of the others extinct?  I also think that it is quite instructive to remind ourselves that as members of that species we all started out in East Africa and migrated all over the world.

Looking at the test results from the 23and Me analysis, there are four major categories and some are more useful than others.  Those categories include ancestry, traits,  carrier status, and wellness.  Since ancestry was the focus of the National Geographic experiment I took a look at that report first.  In terms of methodology the 23and Me technology looks at overlapping regions of DNA and homology with comparison regions of known ethnic groups.  I prepared the following table to look at the predictive value of the 23andMe approach compared with the National Geographic technique looking at the purported ancestries of my grandparents. (click on any graphic to enlarge)  


As noted in the above table, there is more coverage of ethnicities, using the 23andMe approach with  the best example being that it picks up Norwegian, Swedish, and Dutch markers that were not present in the NatGeo analysis.  There are a few problems that might not be obvious at first.  The test subject does complete information about ethnicities and populations of origin that may be incorporated into the algorithm that assigns probabilities of certain ancestry.  These questions reminded me of the clinical data required for quantitative electroencephalogram machines in the 1990s.  The algorithms were supposed to predict psychiatric diagnoses, but the clinical data that was required with every test, frequently interfered with what the machine was going to select.  I take a very dim view of what appear to be scientific decisions being made on the basis of added speculative data.   The ancestry interpretations also depend the level of confidence assigned to the analysis.  As an example, take a look at the following genealogy assessments - the top a conservative estimate and the bottom much more speculation.  Significant changes in the analysis occur just based on how speculative the analysis is.  All things considered, I am quite interested in the range of the analysis and all correlations at this point rather than precision, but is some cases precision is apparently available.         






All together there are 3 ancestry reports and the most interesting report for me was the Neanderthal analysis.  The test looks at 1,436 traits across the genome and generates a report based on a map of all 23 chromosomes and a table that takes a more detailed look several markers.

The traits report was significantly less interesting to me.  It answered the question about whether or not a genetic markers for a trait existed.  For example, the length of the second toe on the foot and the length of the fourth finger on the hand.  The testing predicts that I have a 96% chance of lighter skin and very little chance of freckling.  That is true.

Carrier status was similarly not very interesting.  There was a major focus on congenital illness rather than risk of chronic illness.  Some of the carrier states mentioned include: ARSACS, Agenesis of the Corpus Callosum With Peripheral neuropathy(ACCPN),  Autosomal Recessive Polycystic Kidney Disease (ARPKD) and 33 others.  My carrier status for these relatively rare conditions was negative.  That was really no surprise considering my age, family history, and the fact that most of these are illnesses of infancy or childhood.

The wellness section contained 6 reports and a few were moderately interesting.  Caffeine consumption is regulated by variants near the CYP1A2 and AHR genes and I have those variants.  The prevalence of these variants in various populations are also estimated and it seem that these variants are high.  I do tend to consume significant amounts of caffeine and it is hardly noticeable.  It seems like I am drinking decaffeinated beverages.  I have the rs73598374 variant in the ADA gene that is associated with deep sleep.  I do sleep for short periods of time, but my activity monitor suggests that my sleep may be deeper than people who sleep more hours.  I also have the rs3923809 variant in the BTBD9 gene that predicts more movement in sleep.  The R577X variant in the ACTN3 gene is present and that is associated with a greater portion of fast twitch muscle fibers or what the site refers to as sprinter/power muscle type.  The final two wellness traits were lactose intolerance and the alcohol flushing reaction.  I knew that I had neither trait prior to the genetic testing.

Apart from the Neanderthal testing, the most interesting aspect of the this service is that ability to search your genome looking for points of interest.  I think that this will eventually be the most interesting aspect of these services as long as the users keep in mind that having a genotype, especially of a complex polygenic illness is a probability statement rather than a guarantee.  I am testing out two ways to do these searches.  The first strategy is based on protein analysis and I used a recent paper on bipolar disorder (I have a strong family history) to see if I could find any of these markers.  The original paper suggests that there are higher plasma concentrations of 6 proteins in bipolar disorder including GDF-15, HPX, HPN, MMP-7, RBP-4, and TTR.  A direct search yields a significant number of hits for HPX (5), HPN (14), and TTR (89) genes with specific information on markers, genomic position, possible variants and genotype.  In this case the original paper was a protein analysis and as far as I can tell there is no genetic analysis of the subgroup with higher levels of the identified proteins.  I have sent an e-mail to the lead author to see if I missed any papers on that issue.  An example of the data available searching on these proteins for the HPX protein is shown below:



The second option would be to search for known genotypes.  It is no secret from previous posts that I have asthma that was quiescent for most of my life that was reactivated about 3 years ago by a upper respiratory infection.  Asthma is an interesting disorder because the genetics are very complex just like psychiatric disorders.  For the critics who suggest that there are no tests of any sort for psychiatric disorders, these two sentences are from the latest chapter on the genetics of asthma from UpToDate (9) are instructive:

"Exploration of the genetics of asthma has also been hampered by the fact that there is no "gold standard" diagnostic test for asthma, and the clinical diagnosis is inconsistently applied.  To circumvent these issues, investigators have studied the distribution of asthma-related traits, including bronchial hyperresponsiveness and measures of atopy (eg, total serum IgE levels, skin test reactivity) in addition to the presence of an asthma diagnosis."

This same author reviews the genetic research on asthma to date and points out that prior to the retirement of the Genetic Association Database in 2014 there were over 500 genetic association studies on asthma that identified hundreds of candidate genes for asthma.  From those candidate gene studies, she gives the most replicated genes as filaggrin (FLG) - an epithelial barrier gene also important in atopic dermatitis,  ORMDL3 - a transmembrane protein, Beta-2 adrenergic receptor gene, and Interleukin-4 receptor gene.  Genome-wide association studies (GWAS) have supplanted candidate gene studies and over 50 GWAS have been done in asthma.  These studies have identified other candidate genes and generally shown that GWAS done in populations with European ancestry seem to have little applicability in more ethnically diverse populations.  ORMDL3 was identified in both types of studies so I searched for that in my own DNA and came up with the following:

            
In order to look at specific markers and asthma risk, I searched on one of the genotyped markers (rs8076131) in PubMed and came up with 7 papers on asthma susceptibility.  Searching more broadly on ORMDL3 showed 132 references that were less specific.

This ends my preliminary review on the availability of personal genomics for education and research purposes by individuals.  I hope to come up with more effective strategies to look at several additional disease phenotypes that I either personally possess or that were present in my first degree relatives.  For me, the paleogenetics and personal genome browsing were the most interesting aspects of this data.  For educational purposes, it highlights the difficulties of correlating genetics with disease phenotypes due in part to the fact that multiple genes and polygenes can produce the same phenotype and that makes the activity of specific genes difficult to determine in a DNA sample.



George Dawson, MD, DLFAPA

      



References:

1:  Srinivasan S, Bettella F, Mattingsdal M, Wang Y, Witoelar A, Schork AJ, Thompson WK, Zuber V; Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium, Winsvold BS, Zwart JA, Collier DA, Desikan RS, Melle I, Werge T, Dale AM, Djurovic S, Andreassen OA. Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biol Psychiatry. 2015 Oct 21. pii: S0006-3223(15)00855-0. doi: 10.1016/j.biopsych.2015.10.009. [Epub ahead of print] PubMed PMID: 26681495.

2:  Mariotti M, Smith TF, Sudmant PH, Goldberger G. Pseudogenization of testis-specific Lfg5 predates human/Neanderthal divergence. J Hum Genet. 2014 May;59(5):288-91. doi: 10.1038/jhg.2014.6. Epub 2014 Mar 6. PubMed PMID: 24599118.

3:  Sipahi L, Uddin M, Hou ZC, Aiello AE, Koenen KC, Galea S, Wildman DE. Ancient evolutionary origins of epigenetic regulation associated with posttraumatic stress disorder. Front Hum Neurosci. 2014 May 13;8:284. doi: 10.3389/fnhum.2014.00284. eCollection 2014. PubMed PMID: 24860472; PubMed Central PMCID: PMC4026723.

 4:  Zhang W, Tang J, Zhang AM, Peng MS, Xie HB, Tan L, Xu L, Zhang YP, Chen X, Yao YG. A matrilineal genetic legacy from the last glacial maximum confers susceptibility to schizophrenia in Han Chinese. J Genet Genomics. 2014 Jul 20;41(7):397-407. doi: 10.1016/j.jgg.2014.05.004. Epub 2014 Jun 2. PubMed PMID: 25064678. 

 5:  Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun. 2015 Mar 10;6:6404. doi: 10.1038/ncomms7404. PubMed PMID: 25752243; PubMed Central PMCID: PMC4355952. 

 6:  Toyota T, Yoshitsugu K, Ebihara M, Yamada K, Ohba H, Fukasawa M, Minabe Y, Nakamura K, Sekine Y, Takei N, Suzuki K, Itokawa M, Meerabux JM, Iwayama-Shigeno Y, Tomaru Y, Shimizu H, Hattori E, Mori N, Yoshikawa T. Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet. 2004 Mar 1;13(5):551-61. Epub 2004 Jan 6. PubMed PMID: 14709596.

7:  FDA Warning Letter to 23andMe

8:  Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. 2015 Dec 8;5:e689. doi: 10.1038/tp.2015.185. PubMed PMID: 26645624.

9:  Barnes KC.  Genetics of Asthma. In: UpToDate, Barnes PJ, Raby BA, Hollingsworth H (Ed), UpToDate, Waltham, MA. (Accessed on April 8, 2016)


Attributions:

All of the above graphics and tables with the sole exception the the ancestry table were generated with on site software at 23andMe based on my personal DNA sample.


Sunday, August 23, 2015

Evidence Based Urgent Care



I went in to urgent care today after battling an influenza-like illness that I got on a trip to Alaska, most likely in the flight home.  The symptoms are charted in the above graphic.  Without providing too much graphic detail on the symptoms, my concern was in whether or not I might have pneumonia and needed a chest x-ray.  Although I knew this was most likely not an influenza virus, the symptoms were fairly severe.  As an example, on last Saturday August 15, I had diffuse muscle pain that was so severe, I could barely move.  In the two days I took time off from work August 18 and 19, the muscle pain was restricted to chest wall muscles.  The cough had also become productive over the past 5 days.  I thought it was reasonable to get it checked out, especially against a backdrop of asthma and chronic asthma therapy.

I took my graphic along with me and showed it to the nurse and the physician.  I told her that I had bronchitis that was probably caused by a respiratory virus.  The nurse was overtly uninterested and at one point said that all she needed was a single symptom to write down and that symptom would be cough.  As she continued writing, she kept glancing at the graphic and taking additional notes.  I wanted to say: "Just scan it in and you can stop writing.  It contains almost all of the information that you need to know."  But I didn't.  I maintained standard medical office decorum.  As Seinfeld once said: "You go from the large waiting room to the smaller waiting room and wait again to see the doctor."  The nurse took all of my vitals including an oxygen saturation and stated matter-of-factly: "They're all normal."  My enthusiastic reply of "Good" was met with dead air.

The doctor walked in and I gave him a brief history.  He looked at my graphic and wrote down a few words.  He listened to all of my lung fields with a stethoscope and then listened to my heart sounds - both through my shirt.  The entire history and exam took about 5 - 10 minutes.  And then:

"You have bronchitis.  There is probably a lot of inflammation in there.  I am going to prescribe prednisone and an antibiotic.  Levaquin is a good one for this.."

At that point, I told him that I was already on two QTc interval prolonging drugs and that Levaquin might not be a good idea.

"OK then I will look up another antibiotic.  Doxycyline is one that should work.  Yes - there is no interaction between doxcycline and your medication.  Any other questions?"

I asked him about the issue of a chest x-ray.  I had three in the last two years and it seemed like the decision was a coin toss.

"I don't think so.  You have sounds all over your lungs and not in one place in particular.  If it doesn't get better I would do a chest x-ray.  Right now it is not going to change what I do."

I walked out with scripts for doxycycline 100 mg BID x 10 days and prednisone 40 mg QDAY x 5 days.  Entire length of the visit with the RN and MD about 15 minutes and I was the only patient in that clinic.

Of course all during this time, I was comparing the topology of this medical visit and medical care to the common uniformed criticisms of psychiatric care.  Just this morning and totally out of the blue somebody sent me a link to their letter in the British Medical Journal about the fact that 70% of clinical trials of paroxetine were unpublished.  He sent it in response to a post that I had made here some time ago, and apparently was unaware of the fact that I figured out that paroxetine was not a drug that I cared to prescribe by the time I had prescribed it to a second patient.  It should be obvious that unpublished clinical trials have been a significant problem in medicine for some time and that is nothing new in psychiatry.  Seems like the prevalent bias against psychiatry rearing its ugly head again.

How about the longstanding claim that psychiatric diagnoses are not valid because there is no "test" for them.  What was the "test" I got for bronchitis?  Of course there was none.  A diagnosis of bronchitis pretty much depends on the symptoms that I walked in with.  The same symptoms on the graphic that seemed to be shunned by the RN and casually interesting to the MD.  None of the measurements in the office had anything to do with bronchitis.  They were all essentially measures to look at whether or not I had any more significant disease - actually a more significant syndrome.  When I was an intern, we thought we had a more scientific way to analyze the problem.  We would obtain sputum samples and Gram stain the samples and culture them.  Once the integrity of the respiratory epithelium is disrupted there are all kinds of bacteria that colonize the area.  The sputum samples were not useful - either in terms of pathogenesis or guiding antibacterial therapy.  Thirty years later, antibacterial treatment of bronchitis is still empirical.  No specific pathogen is identified.  The thinking used to be that sputum indicated a bacterial infection, now we know it is just sloughed epithelium from the cytotoxic effect of viruses.  Empirical treatment of bronchitis is really no different than empirical treatment of any symptom defined mental illness.  Ignoring a couple hundred specific respiratory viruses is reminiscent of a hostile criticism of psychiatric nomenclature: "It is all one disease."  By comparison, acute bronchitis is also one disease.

Another interesting comparison is symptom severity.  I spend a lot of time discussing and documenting this with psychiatric disorders.  In the case of bronchitis, there was no particular interest in severity.  No questions about subjective experience, patterns of the cough, or sputum production.  You either have it or you don't.  Of course, I know that pattern recognition was in place and the physician was looking for signs of more significant illness like tachycardia, tachypnea, diaphoresis, and cyanosis.  But there were not any questions about functional capacity and how I was being affected (again more info in the graphic.)  Psychiatric diagnosis and treatment requires close attention to severity, impact on functional capacity and sleep, and whether the symptoms are in remission.

What about the "evidence basis" of the treatment?  A charitable interpretation of the e-mail about paroxetine would suggest that author was critical of the evidence basis for its use.  It is well known that over half of the drug studies from ClinicalTrials.gov are unpublished and that a significant number of the published trials omit details of interest (3) like side effects.  That same study looked at trials in 7 different medical specialties, none of them psychiatry.

It turns out that in clinical trials those adults with acute bronchitis treated with antibiotics are less likely to be rated as improved at follow up.  Some studies show a shorter duration of cough by 1/2 day but the trade off is a significant increase in antibiotic side effects with 19% of emergency department visits for adverse drug effects being due to antibiotics (1, 2).  A direct quote from UpToDate:

"Patients with known asthma may develop superimposed acute bronchitis.  It is common that such patients seek treatment and are inappropriately prescribed an antibiotic even though they usually have a viral illness."

The UpToDate review also looks at the associated issues of overprescription of antibiotics, the 20 year CDC initiative on antibiotic overprescribing that has essentially failed and the dire consequences of developing multiple antibiotic resistant bacterial strains.  My purpose here is not to imply anything about my treatment, but to illustrate that these practices are common and there is no equivalent amount of criticism similar to that targeted at psychiatric care.  In fact, if I wanted to take on the role of pseudopatient, I could walk in to any clinic or emergency department and walk out with the same prescriptions - even in the absence of acute bronchitis.  I could simply lie about the symptoms.  Nobody is going to ask me for a sputum sample, and 6/7 asthmatics have residual wheezing that can be picked up on a cursory exam.  Of course there would be public outcry.  I would be accused of lying to hard working physicians and wasting their time.  But that same poorly conceived idea is still cited as evidence against psychiatric diagnosis.

Unlike the unrealistic critics of psychiatry, my goal here is not to embarrass anyone, or illustrate that I am better than anyone.  But how is nonpublication of clinical trials of paroxetine (a drug that I have not prescribed in over 20 years) a problem with psychiatry?  Nonpublication of clinical trials is obviously a problem for everyone.  The poor quality of current clinical trials technology is a problem for everyone and unlike the Cochrane database, I don't see the point in the exhaustive documentation of predictable low quality results - at least not much of a point.

I am also not about to attribute the differences in practice and clinical trials to the art of medicine.  This is a problem of analyzing huge amounts of data in biological systems.  There are widespread problems with clinical trial design in every area of medicine because they cannot analyze that data.  Contrary to being a "gold standard" there needs to be better stratification of heterogenous diseases whether that is depression or bronchitis.  We can only have more specific treatments when we have better characterized molecular pathology and the treatments to target that pathology.  That includes markers that would suggest which patients would respond to drug treatment and which would not.  There is a promising biomarker for bronchitis that should be treated with antibiotics right now, but it is not widely studied or widely available.

The highlights of this post have really not changed since I began pointing out that psychiatry is singled out for criticism by various people with various motivations.  Looking at the facts in this post should leave little doubt that this is merely a continuation in this trend of unrealistic and unfair criticism consistent with the dynamic I outlined in the past.

Some things just don't change.


George Dawson, MD, DFAPA



References:

1:  Thomas M. File.  Acute bronchitis in adults. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on August 23, 2015.)

2:  Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev. 2014 Mar 1;3:CD000245. doi: 10.1002/14651858.CD000245.pub3. Review. PubMed PMID: 24585130.

3: Riveros C, Dechartres A, Perrodeau E, Haneef R, Boutron I, Ravaud P. Timing and completeness of trial results posted at ClinicalTrials.gov and published in journals. PLoS Med. 2013 Dec;10(12):e1001566; discussion e1001566. doi: 10.1371/journal.pmed.1001566. Epub 2013 Dec 3. PubMed PMID: 24311990



Supplementary:

Graphic updated daily for the course of the illness:







This illness finally cleared at about Midnight on August 28, after 16 days.  The "common cold" typically lasts 2 - 3 weeks and is a significant cause of morbidity in this country.  I hope that I have also illustrated that it is also a problem in terms of treatment and a lack of real public health measures to reduce the spread of these viruses.

Wednesday, August 13, 2014

The Stanley Center Grant

 The details of this grant and some of the history of previous grants are given in this press release from the Broad Institute.  A few of the details include the fact that the Broad Institute has about 150 scientists working on the genetics of severe mental illnesses.  That focus includes detailing the genetic basis of these disorders, a more complete elaboration of the the pathways involved and developing molecules that can modify these pathways as a foundation for more effective medical treatment.   The focus of this group is on severe psychiatric disorders including schizophrenia, bipolar disorder, autism and attention deficit-hyperactivity disorder.  It was also the single largest donation for psychiatric research - ever.

Any search on research grants over the past decade will produce thousands of research articles that were funded by the Stanley Foundation.  The press release details the fact that grants from the Stanley Foundation have been incremental and that they are obviously monitored for progress by the grantees who are satisfied with the progress being made.  That has not stopped some critics from suggesting that the money is basically either wasted, that it could be better used for symptom control, or that it would be more useful for research in symptom control.  My goal here is to question some of these arguments about basic psychiatric research in much the same way that I question the arguments that usually attack psychiatric practice and clinical research.    My speculation is that the underlying premises in both cases are very similar.

The basic arguments about whether it is a good idea to fund basic science research as it applies to psychiatry range from speculation about whether or not it might be useful to the fact there are more urgent needs to funding on the clinical side.  Many of these arguments come down to the idea of symptom management versus a more scientific approach to the patient.  There are few areas in medicine that have a purely scientific approach to the patient at this time.   The more clearcut examples would be locating a lesion somewhere in the body, performing a biopsy and making tissue diagnosis.  That is an example of the highly regarded "test" to prove an illness that seems to be a popular idea about scientific medicine.  But in that case the science can run out at several levels.  The  diagnosis depends on correctly sampling the lesion and that can come down to the skill of the sampler.  It depends on the agreement of pathologists making the tissue diagnosis.  The tissue diagnosis may be irrelevant to the health of the patient if there are no treatments for the diagnosed illness.

In many cases in medicine, treatment depends on symptom recognition and monitoring.  In some cases  there are tests of basic anatomy or function.  A good example is asthma.  As I have previously posted here (see Myth 4), the majority of asthmatics have inadequate control of asthma and the approach to asthma is generally symptom control.  The current basic science of asthma depends on identifying genes and gene products that will allow for more specific treatment of the underlying pathophysiology and there are surprising similarities with mental illnesses.  For example, there is no single asthma gene.  The genetics of the various aspects of asthma pathophysiology including the degree to which it can be treated is assumed to be polygenic in the same manner as the genetics of severe psychiatric disorders.  The only difference being that a larger portion of the human genome is dedicated to brain proteins (personal correspondence with experts puts that figure as high as 25%).   Genome wide association studies of severe asthma can have as much difficulty identifying candidate genes that reach statistical significance.   Any thought experiment comparing the reference pathway for asthma to any number of similar pathways that are operative for brain plasticity, human consciousness and the variants we call mental illnesses will show that there are surprising few specific interventions for asthma signaling and that signaling occurring in the brain is even more complex.  The reason why we have impressive brain function is structural complexity at cellular, structural and biochemical pathway levels.   And yet the rhetoric of critics usually considers asthma as a disease to be more legitimate than psychiatric disorders and the lungs are apparently considered a more legitimate target for research funding than the brain.

What are the critics saying?  Allen Frances, MD DSM critic has decided that neuroscience research may be so complicated that the $650 million dollar grant may be a drop in the bucket in sorting out the basic science.  He suggests:

"But there is a cruel paradox when it comes to mental disorders. While we chase the receding holy grail of future basic science breakthrough, we are shamefully neglecting the needs of patients who are suffering right now. It is probably on average worse being a patient with severe mental illness in the US now than it was 150 years ago. It is certainly much worse being a patient with severe mental illness in the US as compared to most European countries."

My experience in psychiatry is clearly much different from Dr. Frances. Although I am probably at least a decade younger, I can remember a time when there was no treatment at all.  As a child I heard the stories of my great aunt working in a county sanatorium full of patients with tuberculosis and severe mental illnesses.  This was state-of-the-art treatment before the era of psychopharmacology.  Large numbers of institutionalized patients went there and many never left unless they had a mood disorder that suddenly remitted or they received electroconvulsive therapy.  Those leaving often ended up on county "poor farms" for the indigent.  Contrary to Dr. Frances observations that was about 50 years ago. Going back earlier than that I consider Shorter to be definitive.  In his text he describes what describes what it was like to have a psychotic disorder before the asylum era in many countries of the world and concludes:

"In a world without psychiatry, rather than being tolerated or indulged, the mentally ill were treated with a savage lack of feeling.  Before the advent of the therapeutic asylum,  there was no golden era, no idyllic refuge for those supposedly deviant from the values of capitalism.  To maintain otherwise is a fantasy."  (p4)     

Even when psychopharmacology became available to people in institutions it took a long time to make it to Main Street. In the small town of 10,000 people where I grew up, I witnessed a generation of people with autism, schizophrenia, post-traumatic stress disorder (from WWII and the Korean War) and bipolar disorder being treated with amitriptyline and benzodiazepines by primary care physicians. They may have been home from the state hospitals but with that treatment the outcomes were not much better.

The only cruel paradox that I find quite offensive is the blatant discrimination of governments at all levels and their business proxies against anyone in this country with an addiction or a mental illness.  I don't understand all of the bluster about a diagnostic manual that clearly has not made a whit of difference since it was released or endless debates about conflict of interest that apply to a handful of physicians when this massive injustice exists and when clinical psychiatrists have to deal with it every day and many times a day.   I don't know who "we" refers to in the post, but I can say without a doubt that the technology and know-how is there to alleviate a significant degree of suffering for people with chronic and severe psychiatric disorders right now and at a very reasonable cost.  That cost will not be the few hundred dollars that it takes to see someone in 4 - 15 minute "med check" clinic visits a year and provide them with (now generic) medications.  No -  one year of care will cost about the same amount as a middle-aged person presenting to the emergency department with chest pain.  The reason why care for people with chronic severe mental illness is better in other countries is that there are no financial incentives in those countries for corporations to make money by denying care for the treatment of mental illness and addiction.  That is the cruel paradox in this country, not neuroscience research occurring at the expense of clinical care.  If a billion dollars was directed to clinical care in this country - my guess is that half of it would end up in the hands of the insurance industry rather than providing medical care.

The image of the "receding holy grail" of a future basic science breakthrough is certainly admirable rhetoric, but it is just that.   We have spent too much time rearranging the deck chairs of DSM technology.  Is there any informed person out there who thinks that it makes sense to keep rearranging diagnostic criteria, while clinicians basically focus on the same handful of disorders?  Is there any informed clinician out there who doesn't see the basic disorders as heterogenous conditions mapped onto unique conscious states?  With those basic premises there are just a couple of possible outcomes.   Continue pretending like the past two decades that everyone with these heterogeneous disorders can be treated the same way with a specific medication or type of psychotherapy.  The alternative is to look for specific subtypes based on more than clinical criteria that will produce better treatments with fewer side effects and better outcomes.  And since when is basic science research done in hopes of a clinical breakthrough?  Basic science research is hypothesis testing in the service of more science.  Science as the process that it is.  Any criticism that initially critiques terminology based psychiatry and suggests that it is a vehicle for the expansion of the pharmaceutical industry while suggesting that research funds should be directed at symptom control based on those crude definitions and research is internally inconsistent and defies logic.

I unequivocally applaud the past and current efforts of the Stanley Foundation.  At a time when mental health research and clinical services are subjected to intensive rationing efforts, it is inspiring when a private foundation comes forward in the face of all of those biases and makes an statement about how important this area of science is.  It is one thing to talk about stigma and quite another to come out and treat basic neuroscience and the associated disorders as seriously as any other major health problem.  Hopefully it will inspire others to provide grants for funding research and the development of clinical neuroscience programs that can be applied and taught to psychiatrists during residency training.



George Dawson, MD, DFAPA


1: Reardon S. Gene-hunt gain for mental health. Nature. 2014 Jul 22;511(7510): 393. doi: 10.1038/511393a. PubMed PMID: 25056042.

2:  Adam D.  Cause is not everything in mental illness.  Nature.  2014 Jul 30; 511(7511): 509

3:  Shorter E,  A History of Psychiatry.  John Wiley & Sons.  New York, 1997.



Friday, February 7, 2014

Medical Knowledge Goes A Long Way - Or Does it?

"Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality." - Frontiers in Microbiology October 1, 2013.

For starters this is a lengthy and somewhat obsessive look at a personal episode of illness and the implications it has for some of the common threads on this blog ( overidealization of general medicine, dislike of psychiatry, inaccurate comparisons of psychiatry to the rest of medicine, wild criticism of psychiatry, etc.).  So if you are not into that - this would be a good place to stop and move on...........

I have been off work 9 out of the past 10 days with an upper respiratory infection leading to an exacerbation of asthma.  At least that is one theory.  I first noticed it when I stepped off my ergometer trainer about 2 weeks ago and noticed that I did not seem to be able to take a deep breath and I was wheezing mildly.  I saw an Internist the next day who did a history and examination and got a chest x-ray and an electrocardiogram - both of which were normal.  She decided to double the dose of a corticosteroid inhaler that I was using and told me to increase double the dose of the albuterol inhaler I was using.  She said she would not add oral prednisone at this point.  When I got home I realized that my corticosteroid inhaler was empty and I needed a new one.  The office was contacted and sent a prescription for the previous dose rather than the new dose.  When I called and asked them to read the documentation, the note mentioned an even higher dose that was not possible with the inhaler I was using.  The inhaler cost $187 for one month so I figured it was easier just to start using it rather than wait for them to sort of all of the communication problems, especially because the physician was not available for another several days and I was still wheezing.

Two days passed and my breathing seemed slightly better so I went into work.  By mid afternoon the inability to take in a deep breath came back and I went to an Urgent Care clinic through my health plan right after work.   The new doctor repeated the history, physical, and chest x-ray (again negative).  He prescribed a more intensive course of therapy with a 12 day prednisone taper starting at 60 mg/day and a nebulizer machine with ampules of 2.5 mg albuterol.  He told me to keep taking both inhalers and add both of these.  When I got home I took the prednisone and assembled and used the nebulizer.

I will digress to say that I am a firm believer in the absolute need to control blood pressure and pulse.  I measure my blood pressure and pulse four times a day or more depending on the circumstances.  White coat hypertension probably happens but how many people know what their blood pressure is once they get back home?  I know from personal experience that a hostile work environment can drive both your pulse and blood pressure through the roof not just for days but for weeks to months.  The only time I am comfortable being hypertensive is when I am exercising because it it physiological, I have been monitored doing it by sports physiologists and they were happy with it, and I know there is a compensatory post exercise response that controls BP and pulse in the long run.  I take what most physicians agree is a homeopathic amount of antihypertensive but my BP is never greater than the CDC recommended cut off blood pressure of 120/80.  It is usually 10 points less.   That belief comes from seeing many people over the years who had decades of untreated hypertension that either they or their physician seemed to attribute to something else.  Psychiatrists are occasionally in the situation of treating patients with extremely high  blood pressures like greater than 200 systolic and 120 diastolic who refuse treatment.  They are usually being seen by psychiatrists because of the need to get a court order for them to be treated and that often takes several weeks, putting the patient at risk all the while.  I have seen the full spectrum of blood pressure related problems and there is only one logical conclusion that blood pressure needs to be well controlled.

I am also a student of respiratory viruses and a veteran of two different avian influenza task forces.  The task force experience left me quite pessimistic about our ability to fight off any actual pandemic for a reason that is quite striking - the denial that there is an airborne route of infection.  Everyone on the task force was focused on hand washing and controlling fomites and there was very little focus on what was needed to contain airborne infections, probably because we learned that capacity would be overwhelmed on the first day of the pandemic.  At that point we are basically in a slightly better position than we were in the influenza epidemic of 1918.  At one point they showed us a couple of plastic covered pallets of Tamiflu in a government warehouse somewhere.  I stopped attending when they started to talk about where the dead bodies would be stored.

But my interest is also in the area of common everyday respiratory viruses.  When you are working in a hospital with 1970s era ventilation systems (contain the air to save heat) you witness the staff around you and yourself and the patients get ill in mini-epidemics 3 - 4 times a year.  All with the same symptoms of varying severity.  Some will end up on antibiotics and some will end up on Medrol dose packs or both.  It happens whether you wash your hands or not.  At some point I started to e-mail the Minnesota Department of Health and inquire about the respiratory surveillance of flu and flu like illness.  At some point they got tired of my email and put it all online.  The bottom panels show (with a lag time) the likely viral culprits based on various identification methods.  Rhinovirus and adenovirus are among the usual suspects.  Reading my copy of Gorbach, Bartlett and Blacklow confirms the syndromes.These are the kinds of trends I would see every year.  I consulted with a top expert in airborne viruses in building.  He had done the first studies to confirm that viruses can be sampled in the airflow of buildings and that they are typically airborne viruses.  For two years, I studied the airflow and filtering characteristics of buildings and how older ventilation systems might be modifiable to reduce the risk of respiratory infect by airborne viruses.  I looked at the specific air flow characteristics of the building I worked in.  I surveyed the employees on each unit showing a high clustering of upper respiratory infections and and flu like illnesses.   During that entire time I got numerous respiratory infections with no exacerbations of asthma, but according to the following graphic - it was just a matter of time (click to enlarge):

            

After the initial nebulizer treatment my systolic and diastolic blood pressure was up about 30% and I was feeling somewhat agitated and anxious.  I had only had one nebulizer treatment in my life and it was about 20 years ago.  I looked at the doses and found the inhaler contained 180 mcg of albuterol compared to the 2.5 mg in the nebulizer with greater bioavailability.  In other words the nebulizer delivered 14 times the dose and I was told to use it up to 6 times a day.  I slept about 2 hours that night.

The next day I ran a drug interaction search on my revised list of medications and several potential drug interactions were noted - a couple of them significant.  I logged into my health plan and sent my personal Internist a note with several question on the interactions with drugs and my existing medical morbidities.  He called me up concerned that I might have the flu, but I had just seen him and been referred for an extensive immunology evaluation for the flu shot and got it.  I told him about my experience with the nebulizer and he chuckled:  "In the ER they might give you this very 1 - 2 hours but of course you are hooked up to a monitor and they are checking your blood every hour."  At this point I have not had a single blood test.  He suggested that I try a new inhaler - levalbuterol and the equivalent nebulizers.  They were supposed to have fewer side effects.  I spaced the treatments out exactly 8 hours and five minutes after the third treatment my heart rate shot up to 140 beats per minute and a blood pressure of 147/103.  I took some medication that I knew would bring it down in about 45 minutes, but also prepared to call 911 if it continued to climb.  Gradually over the course of 30 minutes my blood pressure and pulse recovered.

So what can be concluded by my latest foray into the healthcare system?

1.  Medical knowledge may not lead to any improvements.  As far as I can tell nobody is very receptive to the idea that respiratory viruses exist and that while hand washing is helpful it will not necessarily protect you against some of the worst viruses.  The unreceptive parties occur at all administrative levels and seem content with watching employees get recurrent viral infections and use their paid time off.  Is that a form of cost shifting?

2.  Syndromal diagnoses are alive and well in medicine and not just psychiatry.  I have talked with 4 physicians during this week long bout of illness and none of them have a clear diagnosis other than an exacerbation of asthma.  The asthma we are talking about is not a specific type or subtype that may have implications for treatment - but the good old heterogeneous type.  As heterogeneous as just about every known psychiatric diagnosis.  The first physician thought the likely cause was dry winter air.  By the time I had seen the second physician I had some additional symptoms to suggest a URI.  Only my personal physician seemed concerned that I may have influenza and called me back a second day to make sure that I had not developed a fever.  I had vital signs determined, peak flow meters, oxygen saturations, 2 chest x-rays and an electrocardiogram.  None of the tests was a biological test for asthma or whether there was an underlying infectious agent.  None of the tests were positive or could quantitate my illness.  Recall that a typical argument rolled out about psychiatric diagnoses is that there is no specific test and that they are all syndromes.  I learned that clinics in my health care system no longer do the rapid test for influenza because it is not considered to be accurate.  In all cases I was being treated based on a syndrome and nothing else.

3.  Could a more specific diagnosis be worthwhile?  Most certainly since there is some evidence that rhinovirus is a common cause of asthma exacerbations and may also be a cause for asthma in childhood.  There is also evidence that rhinovirus can replicate its RNA in the lower respiratory tract for up to 16 days post infection.  It was only recently discovered that rhinovirus inhabits the lower respiratory tract and can replicate there.  The biological test that was done for influenza is no longer used because it was inaccurate, would that be useful to know?  I have a previous post here about asthma endophenotypes.  Is there an endophenotype for rhinovirus induced asthma?  Is it caused by epigenetic mechanisms?  These are all parallel questions that psychiatric researchers are working on right now with most major psychiatric disorders.

4.  Cost shifting to the patient is paramount from several sources.  I purchased 3 - $200 inhalers in 3 days that were not covered by my insurer.  The first one was an error because it would have covered 2 weeks of treatment and it did not match the documentation in the original note.  In all three cases the pharmacists warned me about the high cost of the inhaler, but when I asked them if there was a generic substitution they said there was none.  The current albuterol inhaler also has no generic apparently because it is the only environmentally friendly one.  That is the difference between a $50 copay and a $4 copay.  There is also an angle from the perspective of ethical purism and pharmaceutical manufacturers.  Is this a case to be made for samples?  Should a patient try a sample of the inhaler in their doctor's office to make  sure they can tolerate it and know the price before going to the pharmacy?  That way there would be an assurance that the patient could tolerate and afford a very expensive medication.  I currently have $400 of inhalers that will be used twice and are otherwise worthless to me.  The other scenario that is difficult to contemplate is a person being forced to drive away from the pharmacy without a medication due to the surprise cost or copay.

5.  There was minimal discussion of side effects and contingencies but scripting was noted.  Scripting is a public relations initiative where health care personnel are trained to ask questions that the patient may be asked about in a satisfaction survey.  For example at the end of the visit the physician says: "Do you have any additional questions for me today?"  A week later you get a survey to rate the physician on whether or not he asked that question.  In the meantime no warnings about prednisone or what to do if I got hypertension or tachycardia from the albuterol.  I was told that I might expect some palpitations and that might be expected because "there was more medicine in there than from the inhaler".  The levoalbuterol was supposed to solve the problem but it resulted in significant tachycardia and I later learned it was pulled from a hospital formulary because it did not "work as advertised".  That is the optical isomer did not protect against side effects like tachycardia.

6.  Pattern matching is implicit and probably carries the day.  I have previously written about the importance of pattern matching in medical diagnosis and it was probably a significant factor in all of my physician encounters.  They looked at me and could tell I was not acutely ill - I did not need to go to a hospital.  There are various ways of phrasing it but that conclusion was uniform.  The pattern matching also probably drives a lot of the questions that flowed from the patterns of asthma exacerbation in their previous patient encounters.

7.  Complex medical diagnoses are a process.  On this blog I have pointed out why a checklist screening is generally an inadequate approach.  There is probably no better example than logging in to your health care system's triage software and realizing that your problem is not listed among the choices.  In this case information changed over time from asthma due cold air to asthma due to a viral exacerbation.  The treatment was also significantly and expensively changed along the way.

8.  Asthma and related conditions are a huge public health problem.  The prevalence of asthma is about 10% in developing countries and it accounts for 1 of every 250 deaths worldwide.  Only 1 in 7 people with asthma have it well controlled.  Public health interventions seem like a last resort.  Trying to get people interested in the true nature of airborne viruses and how to prevent these cyclical infections is practically impossible as far as I can tell.  I have corresponded with the head of the Cochrane Collaboration section on Physical interventions to interrupt or reduce the spread of respiratory viruses who cautioned me that no one knows how URIs spread or how many of the interventions work!  Even World Health Organization (WHO) initiatives seems to leave out the all important aspect of building design and airflow.  There seems to be a distinct medical bias when it comes to respiratory infections.  The only potentially useful and very cost effective public health interventions that I may have availed myself of are the pneumococcal vaccine polyvalent (Pneumovax) vaccine and the influenza vaccine.

A related issue is how much epigenetics comes into play, specifically epigenetic modifications that occur to environmental exposure of let's say - rhinovirus.  Is it possible that exposure to rhinovirus causes more long term health problems for kids than exposure to cigarette smoke?  If that is even possible, why aren't we doing more about it?

9. The elegant hypothetical molecular mechanisms of disease don't translate well to clinical medicine in the case of asthma any more than they do with mental illnesses.  Skeptics and critics of psychiatry (most of whom seem to know nothing about molecular biology) frequently use this rhetoric without understanding how little these mechanisms apply in other major diseases.  Cytokine signalling alone has been described as "having such staggering complexity that the long term behavior of system is essentially unpredictable."  Brain complexity is far greater.  The use of prednisone to shut down inflammation is more of a shotgun approach to shutting down inflammation rather than anything to do with disease specificity.  Given the fact that endophenotypes are not actually diagnosed at this point and viral infections often are associated with acute onset of asthma, it would seem that there is not a lot of diagnostic specificity beside the syndromes.  There is also the question of the time course of improvement.  People have ideas about how quickly medication prescribed by a psychiatrist should take to work.  Very few of those ideas are accurate.  On the other hand here I am on day 16 of treatment for asthma and I am still ill.  Aren't real treatments that are based on elegant biological mechanisms supposed to work faster than that?

In the end I am reminded that psychiatry is no different than the rest of medicine that deals with complex heterogenous conditions.  Diagnoses are imprecise, there is a focus on patterns, there are very few pathognomonic or gold standard tests, and the management of side effects of medications is as important as treating the underlying problem - at least in non acute situations.  Information transfer between the patient and physician is imperfect and nobody seems to be working on ways to optimize it.  If anything the critical time domain is being restricted by businesses and governments.  Those same businesses and governments seem completely disinterested in non medical approaches to reducing disease burden like building design.  There are plenty of false positives and the best assurance you can get is from a single physician who knows you the best.  Despite all of the medical care I have received these past two weeks, I think about all of the decisions I had to make on my own and ask myself: "How do people with no medical training decide what to do in this situation and how do they know what information is relevant?"

It must be mind boggling.

Despite all of the technology and medical knowledge a lot of the information transfer still comes down to what happens between the patient and the doctor.  There has to be enough time for that  to happen.  It has to be meaningful and the patient should know what to do if problems occur.

That is true for doctors of all specialties.

George Dawson, MD, DFAPA

Supplementary Information 1:  The supplementary material here is a graphical primer on allergic asthma and how exacerbations of asthma may occur.  Rather than an airborne allergen a respiratory virus triggers the cascade of events that leads to the flare up (top figure).  That fact is still only recently being elucidated.  For example, rhinovirus is a common initiator and it has only recently been demonstrated that rhinovirus replicates in the lower respiratory tract and that rhinovirus RNA can be present for as long as 16 days.  As indicated by the tables that follow, cytokine signalling in asthma is complex.  The authors show here it may involve up to 22 separate cytokines.  Corticosteroids like prednisone and prednisolone inhibit gene expression via transcription factor NFκB to decrease the activity of cytokines.  They also reduce the activity of nitric oxide, prostaglandins, leukotrienes, and adhesion molecules by similar effects on on synthesis and decrease lymphocyte activity.

























Supplementary Information 2:  I have a post available that looks at the early addition of prednisone, but there is a lot of additional information.  The following table is the actual course of treatment that I received from four different physicians (color coded) over the course of two weeks.  It is posted here for discussion purposes only and should not in any way be construed as medical advice.  The disclaimer for this blog applies in that nothing here is for the purpose of medical treatment or advice.