Ask the Expert : Phillip Lieberman, MD Repeated Episodes of Anaphylaxis with Normal Serum Tryptase but Elevated Levels of Urinary Prostaglandin D2 Phillip Lieberman, MD For more Ask the Expert questions and answer, visit www.aaaai.org/ask-the-expert.aspx.
Question: For 3 years, my 54-year-old male patient has had 4-week episodes of urticaria at night during sleep in bed, separated by 4- to 6-week asymptomatic periods. Urticaria responds to diphenhydramine. Between March and August 2012 there were 3 very different episodes. Each happened when he was asleep at night. He awakens with a “stomach ache” and rectal urgency, His palms itch, then his scalp, groin, and buttocks itch. He feels hot but does not sweat. Urticaria with or without angioedema of the lips and face follows. He has a bowel movement, then becomes orthostatic and loses consciousness. By the time paramedics arrive he is already improving. If he takes diphenhydramine early in the process and lies flat, he is spared the syncope. He is a creature of habit. There have no changes in his home or at his workplace. He does not have a snack before bed. He has never been atopic. His only medications are amlodipine, benazepril, and metoprolol for hypertension; Pravachol for dyslipidemia; and a baby aspirin. These medications have been the same for years. He occasionally takes ibuprofen for low back pain, but never has done so on a day he has one of these episodes. He feels very well overall and has no constitutional symptoms of illness. His vital signs are heart rate of 88, blood pressure of 134/90 mm Hg, respirations of 22, temperature of 98.8 F, height of 70 inches, and weight of 215 pounds. Darier’s sign* was negative. There is no redness of his bulbar or palpebral conjunctivae. His nasal mucosa is slightly pale pink, but there is no turbinate edema or abnormal mucus. There is no lymphadenopathy, hepatosplenomegaly, or thyromegaly. The heart and lung examinations are unremarkable. There are no cutaneous stigmata of atopy or urticaria pigmentosa. The rest of the physical examination is normal. Laboratory results are as follows. Baseline study results are all normal, namely serum serotonin, catecholamines, substance P, vasointestinal polypeptide, pancreastatin, plus 24-hour urine for 5-hydroxyindoleacetic acid. The plasminogen activator inhibitor
*
Darier’s sign: a burning or itching sensation induced by stroking skin lesions in cases of urticaria pigmentosa. The area may become raised and red. (Source: Mosby’s Medical Dictionary, 8th edition. Ó 2009, Elsevier.) Available online April 22, 2013. Cite this article as: Lieberman P. Repeated episodes of anaphylaxis with normal serum tryptase but elevated levels of urinary prostaglandin D2. J Allergy Clin Immunol: In Practice 2013;1:539-40. http://dx.doi.org/10.1016/j.jaip.2013.03.008. J Allergy Clin Immunol: In Practice 2013;1:539-40. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.03.008
antigen and the T-cell subsets by flow cytometry were drawn but are not available. I asked the patient to talk to his cardiologist about getting off his b-blocker and to take no nonsteroidal anti-inflammatory agent other than his baby aspirin. In the subsequent 4 months he had only one episode which was very mild. He had flushing and felt hot, but had none of the other symptoms. He took hydroxyzine and ranitidine and went to the emergency department as I instructed him to do, and had acute studies done. This is where it gets weird. Serum tryptase was 10.4 (5000 ng/L. It was sent by Mayo to InterScience Institute, where the supervisor ordered it repeated with the same results. Normal values were obtained for 24-hour urinary n-methyl histamine, metanephrines, normetanephrine, norepinephrine, epinephrine, and dopamine. My question is this: if this is a mast cell disorder, how could there be such a discrepancy between the 24-hour urinary PGD2 and the serum tryptase immediately after a mild episode? Is there another source for PGD2 other than mast cells? Should this patient have a bone marrow aspirate and biopsy now or should we wait a number of months for another episode and look for acute laboratory data again? After all, he has been having urticaria for 4 years and it is 10 months since he had his first anaphylactoid episode. Thank you for taking my case report.
Response: Thank you for your inquiry. I will start this response with a direct answer to the most important clinical question that you asked. Yes, in my opinion, you do need to do a bone marrow biopsy (rather than aspirate) on your patient. Having said this, I will expand on this point and present the rationale for this opinion as well as look at other salient points brought up by your patient’s presentation. Several issues of importance are illustrated in this patient’s presentation. These are the differential diagnosis, the nocturnal predisposition for the episodes, the medications the patient was taking, and the disjunction between the mediators that were measured. We will discuss each of these. 1. The differential diagnosis of an anaphylactic episode and the distinction between anaphylaxis and those conditions that mimic an anaphylactic episode are illustrated by your workup that included not only an assay of mast cell mediators but also a search for markers of other conditions. It is of note that you 539
540
ASK THE EXPERT
measured serotonin, catecholamines, 5-hydroxyindoleacetic acid, pancreastatin, and neuropeptides. The presentation that included abdominal symptoms certainly merited obtaining this workup. It calls attention to the fact that the differential in your case includes vasointestinal polypeptide-secreting tumors (pancreastatin, neuropeptides), carcinoid syndrome (serotonin, 5-hydroxyindoleacetic acid), and paradoxical pheochromocytoma (catecholamines). I might mention, parenthetically, that I see no rationale for the measurement of plasminogen activator inhibitor antigen or T-cell subsets. 2. It is also of interest that the episodes in your patient have all been nocturnal. I would therefore mention, parenthetically, that nocturnal episodes suggest the presence of IgE antigalactose-alpha-1,3-galactose (alpha-gal). Because your patient has no history consistent with this in terms of mammalian meat ingestion, I do not believe that this diagnosis is likely, but wanted to mention it for the sake of completeness and for the readers of this response. I do not know if you reside in an area endemic for the Lone Star tick (Amblyomma americanum), but, if you do, ordering a serum-specific IgE to alpha-gal would be something to consider even though, as noted, the history does not suggest this other than for the fact these episodes have been nocturnal. 3. You appropriately addressed the issue of the b-adrenergic blocking agent, and I also suggest that the angiotensinconverting enzyme inhibitor be discontinued if possible. The reason for this is that your patient experienced a hypotensive reaction, and part of the endogenous compensatory response to hypotension in anaphylaxis is generated through the activity of angiotensin II. In addition, angiotensin-converting enzyme inhibitors also prevent the degradation of kinins, and kinins can play a role in the pathogenesis of anaphylactic episodes. Although the role of angiotensin enzyme inhibitors as a risk factor for anaphylaxis has only been demonstrated conclusively in reactions to hymenoptera stings,1 in my opinion, the same principles would apply in a patient exhibiting idiopathic episodes of anaphylaxis. 4. Last but not least, I would like to address the discrepancy between the prostaglandin D2 levels and the serum tryptase which you highlighted in your inquiry. There are multiple cellular sources of prostaglandins. For example, eosinophils can be a source of this molecule.2 Nonetheless, mast cells are the major source of prostaglandin D2, and mast cell activation can be monitored in vivo by measuring prostaglandin D2 and its metabolites.3 The question then becomes, does a selective elevation of prostaglandin D2 (as compared with other mediators) have clinical import. The concept that there can be a disjunction in levels of mast cell mediators during an episode of anaphylaxis is not new. The
J ALLERGY CLIN IMMUNOL: IN PRACTICE SEPTEMBER/OCTOBER 2013
measurement of mediators during events has documented variations on numerous occasions.4-6 For example, Lin et al4 found that 42 of 97 patients who experienced anaphylaxis had elevations in histamine, whereas only 20 experienced elevations in tryptase. In addition, patients with elevated histamine were more likely to have urticaria, more extensive erythema, abnormal abdominal findings, and wheezing. Vadas et al5 demonstrated that platelet-activating factor correlated better with the manifestations of anaphylaxis than did other mediators. In addition, Stone and colleagues6 found that IL-2, IL-6, IL-10, TNF-receptor 1, mast cell tryptase, and histamine were all elevated in patients with severe reactions. However, those studies were designed to look at the sensitivity and specificity of these mediators in anaphylactic episodes in general and not identify a specific cause of these anaphylactic events. However, elevations of prostaglandin D2 and its metabolites may play a role in identifying mastocytosis per se as the cause of such episodes.7 This can of course be of clinical importance because such patients have been shown to respond to aspirin therapy, but not to antihistamine treatment.7 This observation is one of the salient reasons I suggested that a bone marrow biopsy be done. Because of the elevation in prostaglandin D2, mastocytosis or a mast cell-activating disorder is a strong diagnostic consideration, and the only definitive way to make a diagnosis would be a bone marrow biopsy. Thank you again for your inquiry, and we hope this response is helpful to you. REFERENCES 1. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase—study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009;124:1047-54. 2. Luna-Gomes T, Magalhães KG, Mesquita-Santos FP, Bakker-Abreu I, Samico RF, Molinaro R, et al. Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation. J Immunol 2011;187: 6518-26. 3. Ono E, Taniguchi M, Mital H, Fukutomil Y, Higashil N, Miyazaki E, et al. Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis. Clin Exp Allergy 2009;39:72-80. 4. Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department-based study. J Allergy Clin Immunol 2000;106(1 Pt 1):65-71. 5. Vadas P, Perelman B, Liss G. Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. J Allergy Clin Immunol 2013;131:144-9. 6. Stone SF, Cotterell C, Isbister GK, Holdgate A, Brown SG. Emergency Department Anaphylaxis Investigators. Elevated serum cytokines during human anaphylaxis: Identification of potential mediators of acute allergic reactions. J Allergy Clin Immunol 2009;124:786-92. 7. Butterfield JH, Weiler CR. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol 2008;147:338-43.
Question: For 3 years, my 54-year-old male patient has had 4-week episodes of urticaria at night during sleep in bed, separated by 4- to 6-week asymptomatic periods. Urticaria responds to diphenhydramine. Between March and August 2012 there were 3 very different episodes. Each happened when he was asleep at night. He awakens with a “stomach ache” and rectal urgency, His palms itch, then his scalp, groin, and buttocks itch. He feels hot but does not sweat. Urticaria with or without angioedema of the lips and face follows. He has a bowel movement, then becomes orthostatic and loses consciousness. By the time paramedics arrive he is already improving. If he takes diphenhydramine early in the process and lies flat, he is spared the syncope. He is a creature of habit. There have no changes in his home or at his workplace. He does not have a snack before bed. He has never been atopic. His only medications are amlodipine, benazepril, and metoprolol for hypertension; Pravachol for dyslipidemia; and a baby aspirin. These medications have been the same for years. He occasionally takes ibuprofen for low back pain, but never has done so on a day he has one of these episodes. He feels very well overall and has no constitutional symptoms of illness. His vital signs are heart rate of 88, blood pressure of 134/90 mm Hg, respirations of 22, temperature of 98.8 F, height of 70 inches, and weight of 215 pounds. Darier’s sign* was negative. There is no redness of his bulbar or palpebral conjunctivae. His nasal mucosa is slightly pale pink, but there is no turbinate edema or abnormal mucus. There is no lymphadenopathy, hepatosplenomegaly, or thyromegaly. The heart and lung examinations are unremarkable. There are no cutaneous stigmata of atopy or urticaria pigmentosa. The rest of the physical examination is normal. Laboratory results are as follows. Baseline study results are all normal, namely serum serotonin, catecholamines, substance P, vasointestinal polypeptide, pancreastatin, plus 24-hour urine for 5-hydroxyindoleacetic acid. The plasminogen activator inhibitor
*
Darier’s sign: a burning or itching sensation induced by stroking skin lesions in cases of urticaria pigmentosa. The area may become raised and red. (Source: Mosby’s Medical Dictionary, 8th edition. Ó 2009, Elsevier.) Available online April 22, 2013. Cite this article as: Lieberman P. Repeated episodes of anaphylaxis with normal serum tryptase but elevated levels of urinary prostaglandin D2. J Allergy Clin Immunol: In Practice 2013;1:539-40. http://dx.doi.org/10.1016/j.jaip.2013.03.008. J Allergy Clin Immunol: In Practice 2013;1:539-40. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.03.008
antigen and the T-cell subsets by flow cytometry were drawn but are not available. I asked the patient to talk to his cardiologist about getting off his b-blocker and to take no nonsteroidal anti-inflammatory agent other than his baby aspirin. In the subsequent 4 months he had only one episode which was very mild. He had flushing and felt hot, but had none of the other symptoms. He took hydroxyzine and ranitidine and went to the emergency department as I instructed him to do, and had acute studies done. This is where it gets weird. Serum tryptase was 10.4 (5000 ng/L. It was sent by Mayo to InterScience Institute, where the supervisor ordered it repeated with the same results. Normal values were obtained for 24-hour urinary n-methyl histamine, metanephrines, normetanephrine, norepinephrine, epinephrine, and dopamine. My question is this: if this is a mast cell disorder, how could there be such a discrepancy between the 24-hour urinary PGD2 and the serum tryptase immediately after a mild episode? Is there another source for PGD2 other than mast cells? Should this patient have a bone marrow aspirate and biopsy now or should we wait a number of months for another episode and look for acute laboratory data again? After all, he has been having urticaria for 4 years and it is 10 months since he had his first anaphylactoid episode. Thank you for taking my case report.
Response: Thank you for your inquiry. I will start this response with a direct answer to the most important clinical question that you asked. Yes, in my opinion, you do need to do a bone marrow biopsy (rather than aspirate) on your patient. Having said this, I will expand on this point and present the rationale for this opinion as well as look at other salient points brought up by your patient’s presentation. Several issues of importance are illustrated in this patient’s presentation. These are the differential diagnosis, the nocturnal predisposition for the episodes, the medications the patient was taking, and the disjunction between the mediators that were measured. We will discuss each of these. 1. The differential diagnosis of an anaphylactic episode and the distinction between anaphylaxis and those conditions that mimic an anaphylactic episode are illustrated by your workup that included not only an assay of mast cell mediators but also a search for markers of other conditions. It is of note that you 539
540
ASK THE EXPERT
measured serotonin, catecholamines, 5-hydroxyindoleacetic acid, pancreastatin, and neuropeptides. The presentation that included abdominal symptoms certainly merited obtaining this workup. It calls attention to the fact that the differential in your case includes vasointestinal polypeptide-secreting tumors (pancreastatin, neuropeptides), carcinoid syndrome (serotonin, 5-hydroxyindoleacetic acid), and paradoxical pheochromocytoma (catecholamines). I might mention, parenthetically, that I see no rationale for the measurement of plasminogen activator inhibitor antigen or T-cell subsets. 2. It is also of interest that the episodes in your patient have all been nocturnal. I would therefore mention, parenthetically, that nocturnal episodes suggest the presence of IgE antigalactose-alpha-1,3-galactose (alpha-gal). Because your patient has no history consistent with this in terms of mammalian meat ingestion, I do not believe that this diagnosis is likely, but wanted to mention it for the sake of completeness and for the readers of this response. I do not know if you reside in an area endemic for the Lone Star tick (Amblyomma americanum), but, if you do, ordering a serum-specific IgE to alpha-gal would be something to consider even though, as noted, the history does not suggest this other than for the fact these episodes have been nocturnal. 3. You appropriately addressed the issue of the b-adrenergic blocking agent, and I also suggest that the angiotensinconverting enzyme inhibitor be discontinued if possible. The reason for this is that your patient experienced a hypotensive reaction, and part of the endogenous compensatory response to hypotension in anaphylaxis is generated through the activity of angiotensin II. In addition, angiotensin-converting enzyme inhibitors also prevent the degradation of kinins, and kinins can play a role in the pathogenesis of anaphylactic episodes. Although the role of angiotensin enzyme inhibitors as a risk factor for anaphylaxis has only been demonstrated conclusively in reactions to hymenoptera stings,1 in my opinion, the same principles would apply in a patient exhibiting idiopathic episodes of anaphylaxis. 4. Last but not least, I would like to address the discrepancy between the prostaglandin D2 levels and the serum tryptase which you highlighted in your inquiry. There are multiple cellular sources of prostaglandins. For example, eosinophils can be a source of this molecule.2 Nonetheless, mast cells are the major source of prostaglandin D2, and mast cell activation can be monitored in vivo by measuring prostaglandin D2 and its metabolites.3 The question then becomes, does a selective elevation of prostaglandin D2 (as compared with other mediators) have clinical import. The concept that there can be a disjunction in levels of mast cell mediators during an episode of anaphylaxis is not new. The
J ALLERGY CLIN IMMUNOL: IN PRACTICE SEPTEMBER/OCTOBER 2013
measurement of mediators during events has documented variations on numerous occasions.4-6 For example, Lin et al4 found that 42 of 97 patients who experienced anaphylaxis had elevations in histamine, whereas only 20 experienced elevations in tryptase. In addition, patients with elevated histamine were more likely to have urticaria, more extensive erythema, abnormal abdominal findings, and wheezing. Vadas et al5 demonstrated that platelet-activating factor correlated better with the manifestations of anaphylaxis than did other mediators. In addition, Stone and colleagues6 found that IL-2, IL-6, IL-10, TNF-receptor 1, mast cell tryptase, and histamine were all elevated in patients with severe reactions. However, those studies were designed to look at the sensitivity and specificity of these mediators in anaphylactic episodes in general and not identify a specific cause of these anaphylactic events. However, elevations of prostaglandin D2 and its metabolites may play a role in identifying mastocytosis per se as the cause of such episodes.7 This can of course be of clinical importance because such patients have been shown to respond to aspirin therapy, but not to antihistamine treatment.7 This observation is one of the salient reasons I suggested that a bone marrow biopsy be done. Because of the elevation in prostaglandin D2, mastocytosis or a mast cell-activating disorder is a strong diagnostic consideration, and the only definitive way to make a diagnosis would be a bone marrow biopsy. Thank you again for your inquiry, and we hope this response is helpful to you. REFERENCES 1. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase—study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009;124:1047-54. 2. Luna-Gomes T, Magalhães KG, Mesquita-Santos FP, Bakker-Abreu I, Samico RF, Molinaro R, et al. Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation. J Immunol 2011;187: 6518-26. 3. Ono E, Taniguchi M, Mital H, Fukutomil Y, Higashil N, Miyazaki E, et al. Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis. Clin Exp Allergy 2009;39:72-80. 4. Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department-based study. J Allergy Clin Immunol 2000;106(1 Pt 1):65-71. 5. Vadas P, Perelman B, Liss G. Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. J Allergy Clin Immunol 2013;131:144-9. 6. Stone SF, Cotterell C, Isbister GK, Holdgate A, Brown SG. Emergency Department Anaphylaxis Investigators. Elevated serum cytokines during human anaphylaxis: Identification of potential mediators of acute allergic reactions. J Allergy Clin Immunol 2009;124:786-92. 7. Butterfield JH, Weiler CR. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol 2008;147:338-43.
