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Author: Stephen J. Klemawesch, MD

New Treatment for HAE (HANE)

New Treatment for HAE (HANE)

The New England Journal of Medicine recently published research done at the University of California on a new treatment for hereditary angioneurotic edema (HANE) also called hereditary angioedema (HAE). 

HANE or HAE is a rare genetic disorder that leads to unpredictable, disabling and occasionally fatal episodes of swelling.  The swelling can occur in any part(s) of the body.  It is caused by uncontrolled activity of the contact system components factor X11a and plasma Kallikrein which leads to excessive release of a bradykinin which in turn causes leaky blood vessels (vascular permeability) with the resultant swelling from the fluid that leaks out of the blood vessels. 

The most common form is due to reduced production or reduced functionality of a controller protein called C-1-esterase inhibitor.  But there are other forms including ones with normal C-1-inhibitor.

This latter group has been difficult to treat with most current therapies because they work by increasing production of function of C-1-inhibitor replace it directly or inhibit Kallikrein or block the bradykinin receptor.  The currently available therapies can be used either to treat/stop acute attacks or prophylactically.  In general, they work quite well but not 100%.  That is why improved therapies are being researched. 

The new drug being researched is donidalorsen which is an antisense oligonucleotide that selectively inhibits plasma prekallikrein production.  (Say what?)   Donidalorsen inhibits the production of plasma prekallikrein by means of ribonuclease (RNase) enzyme that degrades messenger RNA that would otherwise lead to prekallikrein production.  The idea is by moving a step earlier in the domino-like chain of events by reducing prekallikrein this will prevent kallikrein and eventually bradykinin. 

The UC researchers have conducted a small trial in 32 patients with a 90% reduction in attacks.  Moreover, the medication was not prone to causing side effects.  Larger trials are underway. 

EILO not EIEIO

EILO not EIEIO

EILO stands for exercise induced laryngeal obstruction and it is a newly understood reason for DOE (dyspnea on exertion) especially in children and adolescents.

Dyspnea (breathlessness) on exertion can occur for very diverse reasons including anemia, cardiovascular problems, neuro muscular problems and respiratory issues.  The most common respiratory cause for DOE is exercise induced bronchospasm (EIB) due to underlying asthma.  But asthma is an exhalation disease; that is, the main issue is getting air back out of the lungs.  EILO is an inhalation disease.  The larynx narrows with breathing in and causes stridor.  The narrowing doesn’t occur when the individual is at rest.  To complicate matters EILO can occur in asthmatics, so it’s important to understand the distinction. 

The University of Cincinnati Children’s Hospital has contributed significant understanding to EILO.  They feel it’s part of the spectrum of other laryngeal problems including irritable larynx syndrome and paradoxical laryngeal motion (also known as vocal cord dysfunction). 

Interestingly, using an asthma rescue inhaler prior to exercise does not prevent EILO (but it works like a charm for EIB).  What helps these patients most is retraining their laryngeal muscles via exercises prescribed by a speech pathologist.

Global Warming

Global Warming

The Journal of Allergy and Clinical Immunology had a recent article on global warming and the allergy epidemic.  Allergic diseases have reached epidemic proportions globally affecting 30% of the people on earth.  Just 20 years ago statistics in the US showed allergy affecting roughly 15 to 18% of Americans.  Despite new therapies allergic conditions are increasing in spectrum, frequency and severity. 

Since 1970 average temperatures have increased by 2 degrees Fahrenheit and green house gases have increased dramatically (primarily carbon dioxide and methane).  Thus, climate change has invoked allergic disease by a variety of mechanisms.  The changes in rainfall patterns, storms and winds affect pollination including the length and severity of pollen seasons.   Plants produce more pollen with higher levels of carbon dioxide.  Pollens are not only allergenic but carry lipid mediators that are proinflammatory. 

Flooding increases ambient mold levels.  More severe thunderstorms fractionate (split) pollens and make them more allergenic.  Wildfires and dust storms have both local and remote impacts.

Dear Dr. K;

Dear Dr. K;

As you know I’m overweight and I’m always reading about the health liabilities of fat.  But recently, I saw something about brown fat being good for health.  Can you elaborate?

Yes, I can, or at least I’ll give it my best shot.  Adipose tissue (fat) is an underappreciated and misunderstood vital organ in the human body.  It consists of two types of fat:  white adipose tissue (WAT) and brown adipose tissue (BAT).  In lean adults WAT accounts for 30 to 40% of total body mass in women and 15 to 25% of total body mass in men.  While BAT accounts for roughly 1% of total body mass. 

You are correct about the negative implications of too much WAT but it’s the “too much” which is the operant concept.  The Goldilocks scenario of “just right” pertains to WAT.  Believe it or not children born with congenital absences of fat have multiple severe health consequences and shorter lives.  We all need the right amount of WAT.  It subserves four main functions: thermal insulation, mechanical protection, storage of readily available fuel energy and hormonal function.  Successful pregnancy requires the last two functions.

The problem with obesity is that the individual WAT cells expand from 30 to 100 µm in size. As they do so the swelling compromises blood delivery of oxygen to these cells which causes the cells to set off “fire alarm alerts” through a variety of mechanisms:  altering the expression (function) of more than 1,000 genes, triggering insulin resistance (type II diabetes), releasing a spectrum of inflammation causing chemicals, impairing normal immune function (hence increased risk with COVID), and leading to deposition of triglycerides inside blood vessels and in the liver (leading to vascular disease and fatty liver). 

BAT on the other hand, reduces inflammation in the body.  It also improves insulin sensitivity, thus preventing diabetes.  BAT generates heat (thermogenesis) when we are chilled and in doing so burns calories.  BAT helps improve bone density.  BAT releases a healthy hormone called adiponectin.  Most centenarians (people aged 100 plus) have high levels of adiponectin.  Regular exercise increases our stores of BAT even if the exercise does not lead to weight loss. 

Microglia and COVID

Microglia and COVID

The last issue of this newsletter had an article about COVID brain studies in the UK.  A recent article in Science adds to these preliminary findings.  Neuroscientists in this country have noticed that the neurologic symptoms seen in many COVID patients (fatigue, brain fog, trouble remembering and headache) are very similar to those seen in other viral infections and with disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and even with chemotherapy. 

In addition to similar symptoms, the brains in all these cases show changes in the microglia.  Microglia are the supporting and nurturing cells for the neuronal cells that allow us to think and act.  It seems that immune activation of these cells in response to COVID infection causes the microglia to go into hyper drive and interfere with normal neuronal function. 

Spinal taps done on patients with “COVID brain” show higher levels of immune activating proteins than normal patients.  One of these proteins is CCL11, which is also found in the spinal fluid of patients with dementia. 

Drug Resistance is a Prolific Killer

Drug Resistance is a Prolific Killer

Bacterial infections that don’t respond to antibiotics are becoming a major cause of death around the world.  The British Medical Journal Lancet recently reported 1.3 million deaths globally due to antibiotic resistant infections.  This translates to 16.4 deaths per 100,000 people.  This is twice as many people than those who died from malaria (the fifth leading cause of death worldwide).  

The bacteria that are the mischief makers include E. coli, Staph aureus, Clostridium difficile, Klebsiella spp, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus faecium and Enterobacteriaceae. 

The two main causes of the problem are bacteria’s innate ability to mutate to drug resistant forms and overuse of antibiotics.  The overuse phenomenon is in both people and animals.  The industrial nature of food production utilizes antibiotics in the food for chickens, turkeys, cows, pigs and cattle with the subsequent transfer to humans via their diet.  The other overuse is in medical treatment of people.  It is estimated that at least 2/3 of antibiotics prescribed for humans are not needed as the illness is viral in nature, not bacterial.  Also, even in true bacterial infections such as pneumonia and urinary infections the length of antibiotic prescriptions is greater than necessary to resolve the infection.  In this regard a recently published research study by John’s Hopkins University found a similar clinical cure rate in children with community acquired pneumonia with a five-day antibiotic regimen versus a standard ten-day regimen.  Multiple research studies have found similar results in uncomplicated urinary tract infections.   

Getting Not-Ready-To-Quit Smokers to Quit

Getting Not-Ready-To-Quit Smokers to Quit

JAMA (Journal of American Medical Association) just published research on this quit smoking project.  After years of decline in the number of smokers in the US, sadly there is a major upsurge among American youth.  Currently 14% of adults use tobacco (cigarettes or E. cigarettes) while 24% of teens do.  The prevailing thought among psychologists has been that until a smoker is ready to quit the likelihood of motivating them or helping them is nil.  The JAMA article reflects research into a new approach called brief abstinence games.  Basically, the researchers asked smokers to “take a break”.  As a control group they used non-inhalation nicotine in the form of nicotine lozenges. 

The researchers were pleasantly surprised that taking a break for a very brief time (a day or so) over a period of time led to 18% of the smokers quitting.  This study was done in adults, not teens.  So, the next project will be aimed at this younger population.  

Alpha-gal Revisited

Alpha-gal Revisited

Several years ago, this newsletter discussed a new form of anaphylaxis due to tick bites.  The syndrome is peculiar in several ways.  Most importantly the anaphylaxis is delayed from the exposure by several hours.  Also, it occurs after eating mammalian meat such as beef and pork. 

Alpha-gal is a glycoprotein that is found in mammalian meats.  The patient becomes sensitized to the alpha-gal from a tick bite because the ticks secrete alpha-gal in their saliva when they bite humans.  In order to diagnose the condition, the patient needs to be tested for alpha-gal.  They do not show a positive response to the standard allergy tests for beef, pork, etc. 

The new twist is that certain round worms, such as Ascaris lumbricoides also contain alpha-gal and infestation with these worms can lead to the same syndrome. 

Clusterin

Clusterin

Another molecule (Clusterin) has been discovered that protects the brain from inflammation and is generated by exercise.  Several years ago, neuroscientists discovered irisin as a protection for brain inflammation that is produced by exercise.

The current concept regarding dementia is that it occurs due to chronic inflammation in the brain with resultant scar tissue (amyloid plaque).  In this regard scientists have studied patients with early dementia and have found an improvement in cognitive function via a daily exercise routine.   The exercise leads to increased production of both irisin and Clusterin.

Dear Dr. K;

Dear Dr. K;

Thank you for keeping an open dialogue with me about Covid vaccines.  As you know, I opted against vaccination.  However, over Christmas I caught Covid, but luckily it was a mild flu like illness.  So, I guess I should be OK from here on out. 

I’m glad your illness was mild, but I’m a little hesitant about predicting how things will play out in the future.  First of all, just as vaccination doesn’t provide iron-clad protection so too natural immunity via infection is not 100% effective in preventing re-infection.  Therefore, with the extended nature of the pandemic, following Covid avoidance precautions still makes sense. 

Another concern I have is the frequency of post-Covid sequelae especially neurologic ones.  By now, the general public is well aware of Covid illness’ predilection to impact the sense of taste/smell.  As it turns out, this is just the tip of the proverbial iceberg.  At this point in the pandemic, it seems that roughly 70% of infected individuals suffer some sort of extended neurological issue.  For many it’s the smell/taste scenario and for others protracted headaches.  Of much graver concern is research done by Oxford University on 45,000 people in the UK which showed loss of brain mass as measured by CT scanning.  The loss was primarily in the frontal and temporal lobes which subserve the senses of taste and smell but also cognition. 

In this regard, the Oxford scientists conducted performance tests on some of the Covid patients and found they were slower in processing information than non-infected counterparts.  Also, there was no correlation between the severity of the illness (hospitalized verses non-hospitalized) and the loss of brain matter. 

These facts set up a comparison with Alzheimer’s disease where a common symptom is loss of sense of smell along with frontal/temporal lobes pathology.  In fact, some neuro scientists posit that Alzheimer’s disease is caused by chronic inflammation in genetically susceptible individuals to a prior viral infection.  What isn’t known is the potential for brain mass recovery in these individuals.  Neuroplasticity allows marked recovery of the brain from many insults.  Perhaps this will still be true with “Covid brain”.  But for now, I think it’s still best to not catch the illness.