Q:

1/7/2014
I would appreciate your opinion about this patient. He is a 40 year old physician with a 2 week history of recurrent (daily) episodes of throat and chest tightness accompanied by hoarseness and urticaria. One month ago at 2200 he felt his heart paused, chest tightness, shortness of breath (no coughing, wheezing, hoarseness or acid reflux) whilst sipping red wine. He felt "cold", but had no fever. The symptoms were intense for a few minutes and subsided over 1 hour. He cannot recall what he ate for dinner 5 hours before but may have had cheese and wine. A cardiology work-up (ECHO, Holter, ECG) were normal. Ten days later he was wine tasting and 15-30 minutes after about 10 sips of red and white wine and eating plain bread sticks, whilst in the car he noticed chest pressure, tightness in his trachea but no dyspnea. He drove for another 20 minutes to a restaurant where he had nasal congestion. He took 50 mg each of Benadryl and prednisone and 2 inhalations of albuterol. He had mild hoarseness and his pulse was 110. 911 was called and within 5-10 minutes his symptoms were improving (BP 130's/70's pulse 110 clear lungs O2 saturation mid 90's. Over 2 hours the symptoms resolved.

One day later, after eating breakfast he noticed throat tightness and pruritis but no hoarseness. The symptoms resolved 2 hours after taking Benadryl. Since then, he has had the gradual onset (over minutes) of throat tightness and hoarseness daily starting in the morning with improvement after 12.5-50 mg of Benadryl. On the day of his new patient visit the hoarseness persisted for several hours. Occasionally these symptoms recur between 3-4 p.m. and linger over 3-4 hours after taking Benadryl.

In early December he had dysphagia but after an EGD 5 days later it resolved. The EGD showed no eosinophils (3 biopsies of his esophagus and 1 of his antrum, done by a GI MD who is familiar with EoE) and no strictures or narrowing; however, the GI MD "dilated" his esophagus. He has no prior history of dysphagia.

In 2003 after eating crab he had urticaria and angioedema and got Benadryl and steroids in the ER. In 2004 he ate shrimp and go pruritis, flushing, urticaria and angioedema, which resolved < 24 hours after 1 dose each of Benadryl and prednisone. In 2008 he had chest pain (stess ECHO normal, EGD showed reflux). Since then,he started taking omeprazole and if he stops it, he has an acid taste and epigastric and chest burning. In 2011 he had episodic shortness of breath, hoarseness and throat tightness, once after lunch on rounds, other times after meals. In 2013 he ate white fish and developed nasal congestion, ocular pruritis, urticaria and angioedema; the symptoms resolved hours after Benadryl and prednisone. On 12/15/13 at a seafood restaurant, he did not eat (ate ham sandwich on white bread at home beforehand) but at the table had nasal congestion, itchy eyes, hives on his forehead, throat tightness and hoarseness 1-2 hours after arriving and he left the restaurant, took Benadryl and prednisone and the symptoms resolved minutes later.

He has had intermittent urticaria, especially in the spring and late fall since residency. He had childhood asthma. His nose is often congested (also when he has throat tightness).
Physical: mild dermatographism; decreased nasal patency (L); tender lower anterior neck (otherwise "normal). Spirometry: FEV1 88% FVC 72% FEF 25-75 138% PEFR 96% with no changes after bronchodilator.

Labs: tryptase 2; C3, C4 and C1 INH protein normal (no functional done); sIgE to all foods (including beef, turkey, pork, chicken, lamb, nuts, shrimp, and more (but not crab, yet) and alpha-gal negative; elevated sIgE to olive tree and alternaria. Crab sIgE will be done. Any ideas?

A:

Thank you for your inquiry.

The findings that your patient presents do not allow for a single, parsimonious diagnosis. They are quite heterogenous, and I do not think a single diagnosis could explain them all. In addition, it is my guess that many of the symptoms are unrelated. My guess also is that you will not find the etiology for these disparate episodes. The other notable issue about his history is that the characteristics of many of these episodes cannot be objectively confirmed. There are symptoms, but no "signs."

Having noted these generalizations, I will do my best to cite specific examples and make suggestions, but based upon the picture presented, it is unlikely that you will be able to make definitive diagnoses, and possibly not be able to offer your patient a satisfactory explanation for many of his symptoms.

As noted, the symptoms are so disparate that it is difficult to know where to start, but a good place would probably be his reactions to alcohol. We have had numerous entries on our "Ask the Expert" website related to "allergic-like" reactions to the ingestion of alcohol. They can have many different causes ranging from IgE-mediated reactions to the contents of alcohol including carbohydrate antigens and even hymenoptera contaminants within wine. In addition, they can be due to a deficiency in aldehyde dehydrogenase 2 which is far more common in Asians than it is in individuals of European descent, but does occur in the latter. There are entries that suggest possible tests that you might pursue including "prick to prick" test and oral challenge test with objective measurements such as pulmonary functions.

The next issue that you could take a look at is his "present illness" which is described as a "two week history of recurrent (daily) episodes of throat and chest tightness accompanied by hoarseness and urticaria." In my opinion, of prime importance in regards to dealing with these episodes is to observe the patient during an event. I think it is important for you to be able to see him with the urticaria and, at that time, also obtain objective confirmation of his chest symptoms if possible (at least do an inspiratory/expiratory flow volume loop). In addition, it would also be nice if he could be seen by an otolaryngologist at that time for a laryngoscopy. In my experience, patients with vocal cord dysfunction abnormalities can present with very similar symptoms, and flushing which can be confused with urticaria. If you cannot see him personally during these episodes then it would be important for him to obtain a good photo of his skin lesions (preferably with a quality camera rather than a phone camera). Personal visualization would be superior, and the addition of the pulmonary functions and/or visualization of his vocal cords would be preferred. If not, at least a confirmation of the cutaneous lesions is indicated.

I do not believe you will find the cause of these acute events, but if you do not find physical confirmation (signs as well as symptoms), a somatoform reaction would have to be strongly considered. If urticaria does occur, I think that you have already worked him up adequately as far as skin testing is concerned, so it is doubtful you will find a cause. But if he is indeed having urticaria, obtaining a tryptase during the event may be helpful (although doubtful). If you cannot see him in time, then a 24-hour urinary histamine might be of value. If either is elevated, then you could consider, although mastocytosis is highly unlikely, an 816V mutation analysis.

I mentioned earlier that a visit to an otolaryngologist during an episode would be of value, but if he cannot be seen at the time of an event, I would still suggest a visit to an otolaryngologist skilled in the interpretation of vocal cord dysfunction syndrome. Since wine seems to be one of the triggers, a provocative challenge with wine while under observation (direct laryngoscopy) can be highly useful in discerning the pathophysiology underlying the hoarseness and throat tightness.

We have also had postings regarding these types of challenges on our website, and for your convenience, I have copied one such posting below.

If none of these suggestions are helpful, and it is not unlikely that this will occur, you might complete your workup looking for other causes that could produce the type of symptoms you have described. These would include a search for VIPomas by assaying substance P, neurokinin A, pancreastatin, et cetera; and, for the sake of completeness, a urinary 5-hydroxyendolycetic acid.

Even with an extension of your workup, it is not unlikely, as mentioned above, that you will be unable to find explanations for these events, and I certainly do not think you will find a single condition to explain all that you have described.

Of all the things mentioned above, I think it is most important for you to try and obtain objective confirmation of these manifestations by direct observation during an event, and even consider challenge if you are not able to personally see him during an episode. Very helpful in this regard, as noted, would be simultaneous direct laryngoscopy as well as pulmonary functions.

Thank you again for your inquiry and we hope this response is helpful to you.

Diagnosis of vocal cord dysfunction syndrome
Question:
For patients that you suspect may have at least a component of vocal cord dysfunction (VCD), and assuming you do not do rhinolaryngoscopy in your office, do you first refer to ENT or do you refer to Speech Therapy first? From my understanding, VCD can be difficult to definitively diagnose unless the vocal cords are visualized to be moving abnormally while the patient is having symptoms; frequently the vocal cords when visualized appear to move normally when patient is not having symptoms.

Additionally, VCD can co-exist in patients with asthma and if an asthma patient is not well controlled despite medications, it is recommended to consider VCD. And, based on my understanding, just because an ENT evaluation is done and the vocal cords appear to be moving normally at the time of exam, unless patient is having symptoms, this evaluation does not rule out VCD. So, if you have suspicion of VCD and you do not do rhinolaryngoscopy in your office, is it a reasonable approach to first refer to Speech Therapy for teaching of breathing exercises which may be helpful? Thanks for your input!

Answer:
Thank you for your recent inquiry.

First, you are correct in that:

Vocal cord dysfunction syndrome (VCD) cannot be diagnosed definitively without visualizing the vocal cords.

A normal vocal cord examination can exist when the patient is in an asymptomatic phase.

VCD can coexist with asthma.

Having said that, I call your attention to respiratory irritant challenges to assist in the diagnosis. I have copied below two abstracts which describe this procedure. And, although you are correct in that a definitive diagnosis requires direct visualization of the vocal cords during a symptomatic period, one might consider these challenges in-office to get evidence of vocal cord dysfunction syndrome by measuring inspiratory/expiratory flow volume loops pre- and post-challenge.

The classical vocal cord dysfunction syndrome would be characterized by a relatively normal post-challenge expiratory flow volume loop with truncation of the inspiratory flow volume loop. If clinical suspicion is very high, such a challenge, coupled with a classic history would, with relative accuracy, confirm the diagnosis.

The answer as to whether or not an otolaryngologist referral or a direct referral to a speech therapist would be the suggested "next step" is highly dependent on your own local situation. In our area we have a speech therapist who specializes in this disorder and does direct vocal cord visualization (as would an otolaryngologist). Obviously, we would strongly consider a first referral to this particular speech therapist.

Thus, I cannot answer this question definitively for you, as it would depend on your local situation. In some areas, provocative challenges are performed by otolaryngologists, and in other areas, not. I would think your referral would depend upon your own relationship with the local otolaryngologists and/or speech therapists, and their relative interest in this subject.

Finally, I would not consider speech therapy per se until which time a diagnosis has been confirmed. It is a tedious form of therapy which does not work in every instance, but can be quite helpful in some patients where the diagnosis has been firmly established.

Thus, in direct answer to your last question, I would make an attempt to solidify the diagnosis, at least with an in-office provocative challenge if appropriate, followed by pulmonary function testing or direct visualization of the vocal cords during an episode if this can be arranged before I committed a patient to long-term speech therapy.

Thank you again for your inquiry and we hope this response is helpful to you.

Ann Allergy Asthma Immunol. 1995 Jul;75(1):25-8.
Direct laryngoscopy with provocation: a useful method to distinguish acute laryngeal edema from nonorganic disease.
Ditto AM, Grammer LC, Kern RC.
Source
Department of Medicine, Northwestern University Medical School, Chicago, Illinois, USA.
Abstract
Background: Acute laryngeal edema is a manifestation of anaphylaxis, is frequently sudden in onset and requires immediate treatment to prevent further airway compromise. Nonorganic disease such as globus hystericus may present with symptoms similar to acute laryngeal edema. Distinguishing life-threatening acute laryngeal edema from non-life-threatening disease may be difficult.
Objective: We present a patient in which direct laryngoscopy was used to distinguish acute laryngeal edema from nonorganic disease.
Methods: A case report of a woman who had presented to numerous emergency rooms with symptoms of cough, sensation of throat closing, and hoarseness when exposed to odors such as nail polish remover and musk cologne. She was treated repeatedly with subcutaneous epinephrine, oral diphenhydramine and intravenous methylprednisolone. Her history was not classic for IgE-mediated anaphylaxis and we challenged her with nail polish remover while visualizing her vocal cords with direct laryngoscopy.
Results: Upon challenge with an offending agent, her symptoms were again suggestive of life-threatening laryngeal edema. Direct laryngoscopy, however, revealed no objective evidence of airway obstruction.
Conclusion: Direct laryngoscopy with provocation is useful in distinguishing acute laryngeal edema from nonorganic disease.

62 Diagnosis of Vocal Cord Dysfunction by Irritant Challenges K. A. Pacheco, E. Chenworth, F. B. Blager; National Jewish Health, Denver, CO.
Rationale: Vocal cord dysfunction (VCD) may be confused with asthma, and is difficult to diagnose. We developed challenge protocols to 3 common respiratory irritants to specifically diagnose vocal cord dysfunction.
Methods: Challenges to ammonia, cigarette smoke, and perfume were developed in a Challenge Chamber. Concentrations of ammonia, particulates, and CO were measured below the OSHA PEL to ensure patient safety. Length of exposure was 10 - 20 minutes; vital signs, symptoms, and spirometry were monitored before and after. VCD was diagnosed based on direct laryngoscopy performed immediately following each challenge.
Results: 91 patients in whom VCD was suspected were referred for irritant challenges from 01/04 to 04/10, of whom 84 had complete data. VCD was diagnosed in 63 subjects (75%). Subjects did not differ by age, BMI, smoking status, methacholine reactivity, atopic status, pre and post vital signs, spirometry, or inspiratory loops, but more women were diagnosed with VCD than men (80% vs. 53%, p50.048). Subjects ultimately diagnosed with VCD had higher rates of baseline hoarseness/throat irritation (30% vs. 10%, p50.08), and end of challenge throat tightness (48% vs. 15%, p50.006), hoarseness (54% vs. 30%, p50.06), and runny nose (19% vs. 5%, p50.09). Subjects with VCD completed slightly shorter challenges (13.2 vs. 14.8 min) and were more likely to undergo ammonia challenges than those without VCD, but the differences were not statistically significant.
Conclusions: Irritant challenges are useful to diagnose VCD in patients in whom the diagnosis is suspected. In addition to laryngoscopy, baseline hoarseness and end of challenge throat tightness distinguished the groups.
J ALLERGY CLIN IMMUNOL FEBRUARY 2011.

Sincerely,
Phil Lieberman, M.D.

 

AAAAI - American Academy of Allergy Asthma & Immunology