It's Wednesday morning at 10:15 AM.  And you're sitting in your allergy office with Mrs. X, a doctor's wife.  Frankly, you'd rather be somewhere else.  Anywhere-else.  In fact, very frankly, you'd like to be as far away from Mrs. X as humanly possible.  Because Mrs. X. isn't an atopic patient loaded with IgE.  And that means only one thing:  Trouble--trouble with a capital T. 

When Mrs. X. presented to your office yesterday, she complained of seasonal chronic sinus congestion in the spring and in the fall.  So you  tested her and found negative prick tests to all allergens, but just to "make sure" you had done some ID's to molds as well.  Fortunately, she had only a slight reaction which you told her was "insignificant"--you were secretly glad because you knew that injection immunotherapy doesn't do squat for mold allergy anyway.   You confidently told her that she "had no allergy", gave her the latest, greatest flavor-of-the-day nasal spray with the most colorful box you could find, and sent her on her way, reassuring her that all was well.  After all, you'd get reimbursed for the skin tests by her insurance company, and she got a free nasal spray sample out of it as well.  Life is good... Schazam!--Another case solved...

Then, unfortunately, she called you back early this morning, and that's when the problems began... after leaving your office she said later that evening she began to notice some  "strong reactions" at the sites of some of her former intradermal mold tests; they continued to grow overnight and now she feels miserable today after her prior testing the day before. In fact, she feels exactly like she feels during a bad day in the spring or fall mold seasons.  So she's now back in your office demanding an explanation as to what these events mean, and expects you to treat them.   

So now what?

Near as I can figure, you've got  3 choices on what you could do at this point: 

a:  you could let your p.a. see her and duck out the back door

b.  you could tell her that "we don't know what the "late phase cutaneous reaction" (LPCR) means" and ask her what she's got against using the latest & greatest nasal spray you gave her yesterday--and lay a heavy bill on her for good measure

c.  you could explain that her LPCR's mean she is a delayed reactor, explain the nature of her symptoms--that they correlate with the time course of the LPCR-- and treat her effectively with SLIT

If you scored "c" you're the sharpest tool in the shed.  Because SLIT works for LPCR's.  And I mean it really works... But to do SLIT on LPCR's you first have to get an idea of "how strong is strong?" for the LPCR.  You need to calibrate it, through doing three very basic things:

1.  Do repeat testing with serial IDT on the items she had LPCR to.   

2.  Observe at 12, 24, 48 hours.

3.  Start SLIT at the strongest IDT titration that is negative for LPCR.  That is, if she had positive LPCR's which swell at 24-48 hours on dilutions 2 & 3, and none at 4, then start SLIT at 4. 

Never "buildup" or give "high dose" SLIT treatment (like the European preseasonal rush protocols) to a patient with LPCR's and no immediate skin test positivity.  European preseasonal rush protocols work great for the atopic patient--I've done plenty of them--but they spell disaster for non-atopic patients with LPCR's.  When treating the LPCR, only go stronger on SLIT  if you repeat the testing first, and firmly establish that a higher dilution now causes no LPCR like it had previously done on earlier testing.  Only then can you could step up to the next higher dilution.  Remember:  this isn't IgE mediated sensitivity.  You don't need high dose treatment.  Low dose treatment at the threshold of the LPCR is enough. 

As mentioned earlier in this series, SCIT (not SLIT) for patients with immediate AND delayed reactions has been shown in 4 controlled trials to result in a reduction in delayed reactions.  SLIT does the same.  However, for patients with no immediate reactions, but a strong LPCR, SLIT is the way to go. You can successfully treat these patients. Over the years I've effectively treated LPCR's to dust, mold, and the occasional pollen that gives strong LPCR's but no immediate reactions--all with virtually no side effects and great clinical response.  Generally, over time, when repeat testing is done in a patient on SLIT, a reduction in LPCR's occurs, as evidenced by observing stronger IDT dilutions required to have any LPCR at all. 

And it works.  Believe me, dude, it works. 

I've been using variations of this approach for "problem" patients like Mrs. X for 25+ years, and I've found SLIT is the only thing that effectively addresses LPCR's to molds, dust, or pollens when there is a minimal immediate reaction or none at all, and the majority of the reaction is delayed.  And patients love it.  I love it because I no longer dread seeing Mrs. X.  And Mrs. X in turn thinks I  walk on water and sends all those atopics to me that I so lust after.  And life is good afterall... 

 So far, I've talked about the LPCR (late-phase cutaneous reaction, a.k.a. "delayed skin test") and to briefly summarize what I started in part I, the "conventional wisdom" on the LPCR is:  1.  We know the LPCR is a real phenomenon, but we don't know what it really means clinically 2.  The LPCR is not an "allergic response (in the IgE mediated sense of the term).   And because most allergists suffer from a lack of curiosity (and subsequent inattention to the patient's clinical history), they largely ignore the LPCR in the clinical setting.  And that's a shame.  Before I go any further, I'm going to wax a bit philosophical on you at this time, and give a quotation from Hindu Prince Gautama Siddharta, the founder of Buddhism, 563-483 B.C:

 “Do not believe in anything simply because you have heard it. Do not believe in anything simply because it is spoken and rumored by many. Do not believe in anything simply because it is found written in your religious books. Do not believe in anything merely on the authority of your teachers and elders. Do not believe in traditions because they have been handed down for many generations. But after observation and analysis, when you find that anything agrees with reason and is conducive to the good and benefit of one and all, then accept it and live up to it.”

Nowhere is this quote more appropriate than when we look at the LPCR...especially the part of the quote stating "do not believe in traditions because they have been handed down for many generations", but we should always use "observation and analysis" to come to the Truth.  Facing the truth sometimes requires change...

And allergists like change the way dinosaurs liked meteors. 

And please understand that what I'm going to tell you in my entry below, do not believe at face value...just as I have asked you not to believe the "conventional wisdom" at face value.  In short, check it out yourself, by your own careful observations of your patients. Be observant.  And be curious! 

Pearl #1:  When a patient has LPCR; their symptoms will follow the course of the LPCR. 

You like Tuesdays?  For me  they are one of the most interesting  work-days of the week.  Here's  why:  because when I see a patient has LPCR's on their testing, and they flare 24-48 hours later, it stands to reason that their symptoms will flare 24-48 hours later.  And I have a whole bunch of people who basically "hang out" at their desk job Monday thru Friday, and then on the weekend--often Sunday--they finally get down to "real work"--you know, sweeping out the root cellar or the garage, working on the compost pile, mowing the lawn, cleaning out the old leaves from the gutters, etc. etc. etc.  And you know what?  Often they have no reaction--for a while.  Then they have a rough nite sleeping Sunday, feel terrible Monday morning, get typically worse throughout the day, and end up talking to me on Tuesday.  So when you see a strong LPCR to any allergen, always query the patient about symptoms 12-48 hours after such an exposure in the future.  When the patient with a LPCR to dust sweeps the garage out, his most important symptoms will be 24-48 hours later, and he/she will have symptoms that you and your patient will likely miss unless you're observant and curious!  The same idea applies to the mold sensitive patient who tends their garden or mows their lawn--how do they feel 12-24 hours later?  48 hours later?  This idea is the single most important "pearl" I have learned from my patients regarding the LPCR.  

Pearl #2:  Symptoms in the patient with LPCR typically tend to be more systemic in nature than immediate skin test patients.  Of course, since this is a non-IgE mediated reaction, if you just "ask for" IgE symptoms like ocular itching, sneezing, etc. you usually won't see them.  Instead, if you query patients, you'll find they will complain of nasal/sinus congestion, progressive fatigue and flu-like symptoms, and sometimes headaches and neurological symptoms hours after an inciting exposure.  

Pearl #3:  Molds are the most characteristic inhalant to trigger LPCR's although they can occur from virtually any inhalant antigen.Virtually any inhalant can cause LPCR's but in our midwest location, I have seen that time and again that mold antigens are the overwhelming culprits.  I see alot of people with seasonal sinus congestion and seasonal malaise and aching in the spring and fall, and their immediate skin test reactions are disappointing.  But their LPCRs typically are NOT disappointing at all--especially to molds.  However, exceptions do occur.  For example, I can recall recently a  patient of mine with seasonal sinus congestion triggering migraine headaches each spring,  who ended up having extremely strong delayed reactions to tree pollens.  In fact, after we did IDT on her and she had no immediate reaction the day of testing, 12 hours later severe sinus congestion and eventual migraine ensuded; in retrospect these were likely precipitated by our prior skin tests.

Pearl #4:  When you see a patient in your practice "for a second opinion" who has had failed attempts at prior immunotherapy because of delayed reactions at their injection sites and trouble building up their dose, pay particular attention to the LPCRs that occur, and strongly consider SLIT as an alternative (more about this in part III).  As a consulting allergist, I often see patients for a "secocnd opinion" who have seen another allergist and had one or more failed courses of immunotherapy.  They haven't been able to build up their immunotherapy adequately, and one of the biggest causes is LPCR's.  As you'll see in my next journal entry, SLIT works slick for this problem, with a few caveats which I'll give later. 

Pearl #5:  If a patient has LPCRs to inhalants--such as molds, dust, or other antigens, they are "delayed reactors" and this will be their modus operandi for other allergens, such as foods.  Another big reason why patients aren't well after a course of immunotherapy is often a hidden food sensitivity, which in these types of patients is often of delayed-onset type, just like their inhalant sensitivities. 

Pearl #6:  If a patient has LPCRs to inhalants, the former sites of skin testing may exhibit a curious phenomenon of "memory", whereby a subsequent exposure to the offending allergen can cause inflammation and itching at the prior skin test site.  I have seen patients who had delayed reactions to molds, and sometimes dust, who on subsequent heavy exposure to their allergen will have pruritis and even some redness occur at prior skin test sites, even months after testing has occured.  Ingestion of food yeast can trigger itching at sites of prior skin tests to molds, and excessive regrowth of Candida in the body after antibiotics can trigger itching and redness at the site of a former Candida skin test.

As I have already mentioned, probably the greatest "pearl" I can give you with this journal entry is to not always accept at "face value" the "conventional wisdom" handed down to us but in your work with allergy patients, be curious, be observant, and analyze.  The rewards are great!

Allergists like to read skin tests.  And we think we're pretty good at it.  And we are--for the first few minutes...But there's a catch:  after reading the initial test response at about 15 minutes, we think the job is over.  And premature judgement is sometimes worse than no judgement at all.  And it doesn't matter whether we're the President and we stride across an aircraft carrier and announce "Mission Accomplished" to the world , or whether we allergists stride across the room and announce "Mission Accomplished" to our patients after the initial prick test reading, in reality the job isn't done.  In fact, we're in a big mess.  I'm reminded of the joke:  What does the allergist like to watch on TV?  Answer:  Anything at all--but only for the first 15-20 minutes...

In truth, after we're done watching "Prime Time" (the first few minutes of the prick test) we "turn off the TV".  And that's a shame, because The Late Show is just beginning.  And, in my opinion, it's a far more interesting show than anything running on "Prime Time".  It stars (none other than) The Delayed Skin Test Response, otherwise known as the Late-Phase Cutaneous Reaction (LPCR for short).  I've been watching this "late show" now for 27 years (30 if you include my fellowship), and it never ceases to intrigue, surprise, and confound me.  David Letterman couldn't do it better.  I said it before, and I'll say it again:  As allergists, we should be following the skin test to extinction.  This series will be based around the following 3 areas: 

•  Part I:  Histopathology, Immunology & characteristics of the LPCR
• Part II:  Diagnostic pearls for the LPCR:  clinical correlations
• Part III: Treatment pearls for the LPCR

But first, before beginning, in the spirit of The Late Show, I've got a "Top Ten" list for you.  So, Here goes:  The Top Ten Reasons to Recognize and Treat the LPCR:

Reason #10:  It can explain puzzling reactions to traditional "build-up" immunotherapy that sometimes occur in patients

Reason #9:   It can help explain many puzzling aspects of your patients history that otherwise couldn't be explained

Reason #8:   It can explain--and help you relieve-- alot of debilitating symptoms your patients have

Reason #7:   LPCR's occur in lots of patients.  I mean lots.

Reason #6:   There is an effective treatment for LPCR's in patients:  SLIT

Reason #5:   Looking for and treating LPCR's will make you look smart to your patients 

Reason #4:   If you can help these patients, they'll bring in more patients to your office for treatment--often the "bread-and-butter" atopics that your heart lusts after (a la Jimmy Carter) 

Reason #3:  If you understand the implications of the LPCR, you won't have to read this stupid list anymore.

Reason #2:  You'll want to tune into the Late Show LCPR rather than just watching the Prime Time Prick (test, that is!) 

Reason #1:  You'll be smarter than David Letterman. 

Now if that list  doesn't put some propellant into that "demo inhaler" on your desk, I don't know what will.  But before we get "to the good clinical stuff", let me review some basics about the LPCR which we all should be familiar with.  Please yawn now and get it overwith, because here it comes:

• When you look under the hood, you'll see the LPCR is really a mixed cellular infiltrate with edema, and sometimes fibrin deposition.  There is no vascular damage, IgG, IgA, or IgM deposition.  Nor is their evidence of complement activation.  A variety of cells, including macrophages, eosinophils, tryptase positive mast cells, and neutrophils can be found. 
• The LPCR is in part mediated by antigen-specific MHC restricted T-cells.  T cells are present in the inflammatory LPCR infiltrate, and the LPCR is thought to be partially dependent on them.
• Documented agents stimulating immunologic activation of the mast cells that have induced the LPCR include: molds, pollens, danders, mites, and enzymes, some drugs, anti-IgE antibodies, and possibly some foods
• There are at least 4 randomized, controlled clinical trials of immunotherapy in patients with immediate skin test reactivity & LPCR's who had reduction in LPCR's and symptoms with immunotherapy.  However, to my knowledge, there have been no clinical trials of immunotherapy on patients with no immediate skin test reactivity and only LPCR's--and as you'll see later, this is where SLIT excels.  Like gangbusters. 

   

  Stop yawning now.  As I've mentioned above, I've been observing LPCR's in my allergy patients for a long time; I've been observing these LPCR's while employing IDT (or SET) testing--not prick testing--in my practice, and my observations are thus within this context.  (Why I prefer IDT over standard prick testing is a subject worthy of a separate entry in itself, but we'll let that pass for the moment).  Anyway, although I've never seen it directly proposed, It seems that there are two distinctly different type of LPCR's I have seen in practice: 

Type 1:  A LPCR following a skin test that is positive for immediate reactivity.  These are the reactions that occur after a patient typically has an initial strong response to something such as ragweed or dust.  They have a strong immediate AND delayed reaction.  In general, these LPCR's occur fairly early, typically within a few hours of initial application, and swell alot during the next 6-12 hours, when they should be read when the response plateaus, and are usually gone in 24-48 hours.  They don't usually blister or ulcerate, and leave no residual mark  at the site.  

Type II:  A LPCR following a skin test that is negative for immediate reactivity.  These occur in the patient who has "disappointing" skin tests.  You know, the farmer who swears he has sinus problems in the spring and fall, and his initial 10 minute reading shows virtually nothing.  Typically, these LPCR's have a later onset--typically 12-24 hours after application, peak at 24-48 hours, and can linger for days, and in extreme cases can blister and even leave a persistent mark where they were applied.  These are the Energizer-Bunny reactions--they just keep going and going and going... Molds, in particular, are classic to give this response.  These reactions should be read at 24 and at 48 hours after application.   These can be particularly nasty.

I can almost hear you asking at this point:  "So we see some patients exhibit a LPCR--so what?; we don't know what the LPCR really means".  Well, Jerome, you don't know what it means because you're not looking.  I've been looking for 30 years, and the next part of this series will talk about what a patient with LPCR "looks like" from a clinical perspective.  What the LPCR really means from the patient's point of view.  So stay tuned.  The plot thickens.  Speaking of which, in view of the time course of the LPCR maybe I should have named this series "24 hours" instead of "The Late Show"--or is that title for a series already taken? 

I love movies...any movie.  But the movies I love the most are from what I call "The Golden Age of Movies"...You see, way back before the digital "light and sound shows" of today, there were...Actors.   When Bogie walked into Rick's Cafe with his white tux and cigarette, he didn't need any sissy digitized backdrop to jazz things up or to compensate for any lack of acting on his part.  The movie and the power behind the movie was:  himself. Pure and simple. No Pixar.  No computers. 

And it was magic.

And a long time ago, I contend we had a similar Golden Age:  Of Allergy.  Am I just being maudlin?  Think about it.  There was a time when allergists diagnostically didn't have serum IgE levels or other immunological parameters to measure and follow; to "fall back on" when seeing a patient.  They only had their 4 senses, and a skin test.  They would listen to their patient, observe, and draw their own conclusions, not preconceived by the "tyranny" of IgE (i.e, "it's not IgE mediated, so who cares?").  If a patient ached after eating a food, they recorded it.  If a patient had vaginitis symptoms after an exposure, they recorded it.  If a patient had headaches after  ingesting a food, they recorded it.  It was in this spirit of observation that Albert Rowe's textbook on food allergy was born.  Likewise Arthur F. Coca's textbook "Familial Nonreaginic Food Allergy".  And Rinkel, Randolph, and Zeller's work "Food Allergy".  The list goes on and on.  These are seminal examples of the Clinician At Work.  And just like we can learn alot about how to make great movies NOW, when we watch the Old Masters at work in classic flicks, so we as modern allergists can take a cue from the Old Masters when it comes to broadening our horizons in the present day allergy field.  As I've said before in prior entries, the discovery of IgE was the best thing--and the worst thing--for the field of allergy....for when we got IgE... we ceased being curious...

  In the Golden Age, the allergist also didn't have effective "asthma controller" medications for their patient population.  Perhaps this made immunotherapy much more attractive than it is today--it was, so to speak, "the only show in town".  We certainly had a number allergists actively trying to optimize immunotherapy treatment  at that time--Herbert Rinkel, French Hansel, and others were very active in this area....Our mantra at the time was not "Asthma Controller Medication" because we didn't have effective controller medication at the time--immunotherapy was the only performer on stage....

Now, am I suggesting that the "old days" of allergy were better than what the modern allergist has to offer?  No, of course not.  But I am suggesting that we can learn from early clinicians, who were unencumbered by the "knowledge" we now have about immunological mechanisms, and take away a valuable lesson:  focus on the patient and their reactions to the environment, even if it is non-IgE mediated.  ... Which brings me to the topic of my next miniseries, "The Late Show", which will begin shortly... 

"The Late Show" stars "The delayed skin test reaction", which, like Rodney Dangerfield, "just gets no respect" by the allergy community at large.  Yet, this is not a new phenomenon:   it was first described by Walker & Adkinson in 1917.  They described "hot, very red, slightly elevated reactions..resembling a mild infection, but sterile...(which) disappear over the next two days..."  And over the next 90 years, have we made any progress in this area?  Take a look at what a standard allergy textbook says about the matter...

"Late phase reactions are often not recorded because their exact significance is unknown..."

       --Allergy, Principles & Practice, 5th Edition

         Elliott Middleton, Ed
 

Here is an official statement by the ACAAI concerning delayed skin test reactions:

Delayed reactions can occur several hours after skin testing, sometimes causing swollen, reddened bumps at the spot where the testing was done. The delayed reaction usually disappears 24 to 48 hours later, but should be reported to the physician. However, when there has been no immediate reaction, delayed reactions do not signify the presence of allergy. (my emphasis)

As clinicians, we should follow the skin text to extinction.  Not become bored with it after ten minutes of observation.  Where is our sense of curiosity?  What an incredible cop-out to say it "doesn't signify the presence of allergy".    Well, what DOES it signify, Gaylord?  "Shouldn't we be listening to the patient, recording their delayed skin test reactions, and trying to make sense of this mystery without preconceived notions--in short, trying to emulate the Old Masters  in "The Golden Age" of allergy?  As the late Keith Eaton MD explained, in writing about the delayed skin test, he concluded:

"there must be a strong presumption that such reproducible and marked bodily reactions are not going to be without biological significance, which is probably associated with a disease state..."

"But you're not talking about an immediate skin test reaction", I can almost hear you say, "so it isn't a concern".  Well, you know how I feel about lack of interest? To quote another figure from the Golden Age of Movies,

Frankly, My Dear, I don't give a damn..." 

As I've mentioned before in a prior journal entry, one of the hallmarks of a superior allergist is simply being curious about what we can't easily explain.  And our sense of curiosity is unfortunately as empty as a cannister of albuterol in the hands of a status asthmaticus patient...but no more...for grab your popcorn, because we're going to "The Late Show"--and confront the mystery behind the delayed allergy reaction. Stay tuned...I promise this show is a good one...and in the meantime, as one of my favorite actors was fond of saying, "Here's looking at you, kid..."