Case Report
Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis Theo Gülen, Hans Hägglund, Sven-Erik Dahlén, Birgitta Sander, Barbro Dahlén, Gunnar Nilsson Lancet 2014; 383: 1608 Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge (T Gülen MD, B Dahlén MD), Department of Hematology, Karolinska University Hospital Huddinge (H Hägglund MD), National Institute of Environmental Medicine, Karolinska Institutet (S-E Dahlén MD), Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge (B Sander MD), Clinical Immunology and Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (G Nilsson PhD) Correspondence to: Dr Gunnar Nilsson, Clinical Immunology and Allergy, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden [email protected]
In May, 2008, a 41-year-old man was referred to our allergy clinic with recurrent spells of severe flushing, malaise, nausea, palpitations and dizziness, with no known trigger. Since the first attack in April, 1988, he had consulted several doctors, undergoing extensive medical assessment, which excluded metabolic, cardiovascular, psychological, and neurological disease. From the outset the patient had recorded 97 attacks and classified them according to severity (figure). Most incidents were mild, but he was taken to the emergency room needing epinephrine or corticosteroids six times, was occasionally unconscious, with faecal incontinence, and was admitted to intensive care twice. The patient described an episode as “Everything begins with a vague feeling of nausea, followed rapidly by an increase in heart rate. My pulse can become as high as 150 beats per min”. Initial symptoms often lasted 10 min, and were followed by tingling of the tongue, sweating, and flushing of the face and the trunk. Occasionally he had severe vomiting, and on some occasions a low body temperature (35·7°C) was recorded on examination in hospital. The duration of symptoms varied, with a severe attack lasting more than 30 min. Afterwards he often had severe headache, chills, persistent nausea, and swelling of the mouth and tongue, lasting for several hours. Seizures were never reported. Our initial investigations revealed no allergy, but he had raised baseline serum tryptase of 160 ng/mL (reference ≤11·4 ng/mL), increased urinary concentrations of 11β-PGF2α (127 ng/mmol creatinine; reference ≤35 ng/mmol creatinine) and leukotriene E4 (131 ng/mmol creatine; reference ≤70 ng/mmol creatine), supporting an Morning Daytime Evening
10
Night No data
No action Medical care Emergency care
Severity
8
6
4
2
0 1985
1990
1995
2000 Year
2005
2010
Figure: Distribution and severity of symptomatic episodes, 1988–2013 Reaction severity was graded on a scale of 1–10, with grade 1 being increased heart rate, grade 2 including tingling of the tongue, sweating, and flushing, grade 3 meaning blurry vision and having to lie down, and grade 4 substantial nausea. Grade 5 corresponds to severe nausea and presyncope, and grade 6 includes vomiting. Grades 7–9 are decreasing levels of consciousness, and at grade 10 the patient is unconscious. Based on a figure drawn by the patient.
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underlying mast-cell-activation disease. Bone marrow biopsy showed numerous mast cell aggregates, spindleshaped mast cells, an aberrant mast cell phenotype expressing CD2/CD25, and KIT D816V mutation. Based on these findings, we diagnosed systemic mastocytosis.1,2 Since June, 2009, the patient has been taking prophylactic desloratadine (15 mg daily), ranitidine (300 mg daily), and montelukast (20 mg daily). At follow-up in February, 2014, he reported 56 months without a severe reaction (figure), and 39 months without any attacks at all. He now carries an epinephrine syringe at all times. Mastocytosis is characterised by the accumulation, activation, and proliferation of mast cells in various organs.1,2 Symptoms are typically episodic and associated with the release of mast cell mediators. One of the most common presentations is anaphylactic symptoms that recur in a self-limiting and stereotypical fashion.3 Consequently, many patients with mastocytosis are initially admitted for anaphylaxis. The differential diagnosis of spells is challenging, and this case exemplifies a common problem in patients with mastocytosis. Despite the rarity of this condition, general practitioners and emergency physicians should be aware of systemic mastocytosis as a possible cause of recurrent, indeterminate spells and anaphylaxis. Although spells in mastocytosis are due to mast cell mediators,4 current prophylactic treatment usually consists of antihistamine alone,5 leaving other potent mediators unopposed. It is worth noting that in this case combined histamine and leukotriene-receptor antagonism has so far prevented the recurrence of severe reactions. Contributors TG, BD, and HH assessed and managed the patient; S-ED and BS contributed to the clinical diagnosis. All authors wrote the manuscript. Written consent to publish was obtained. Acknowledgments We thank the patient and his wife for collecting the data, and Ingrid Delin and Johan Bood for mediator measurement. The study was supported by unconditional grants from the Centre for Allergy Research, Karolinska Institutet, the Swedish Research Council, and Stockholm County Council. References 1 Horny HP, Metcalfe DD, Bennett JM, et al. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2008: 54–63. 2 Butterfield JH. Systemic mastocytosis: clinical manifestations and differential diagnosis. Immunol Allergy Clin North Am 2006; 26: 487–513. 3 Young WF Jr, Maddox DE. Spells: in search of a cause. Mayo Clin Proc 1995; 70: 757–65. 4 Roberts LJ 2nd, Sweetman BJ, Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med 1980; 303: 1400–04. 5 Tolar J, Tope WD, Neglia JP. Leukotriene-receptor inhibition for the treatment of systemic mastocytosis. N Engl J Med 2004; 350: 735–36.
www.thelancet.com Vol 383 May 3, 2014
Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis Theo Gülen, Hans Hägglund, Sven-Erik Dahlén, Birgitta Sander, Barbro Dahlén, Gunnar Nilsson Lancet 2014; 383: 1608 Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge (T Gülen MD, B Dahlén MD), Department of Hematology, Karolinska University Hospital Huddinge (H Hägglund MD), National Institute of Environmental Medicine, Karolinska Institutet (S-E Dahlén MD), Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge (B Sander MD), Clinical Immunology and Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (G Nilsson PhD) Correspondence to: Dr Gunnar Nilsson, Clinical Immunology and Allergy, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden [email protected]
In May, 2008, a 41-year-old man was referred to our allergy clinic with recurrent spells of severe flushing, malaise, nausea, palpitations and dizziness, with no known trigger. Since the first attack in April, 1988, he had consulted several doctors, undergoing extensive medical assessment, which excluded metabolic, cardiovascular, psychological, and neurological disease. From the outset the patient had recorded 97 attacks and classified them according to severity (figure). Most incidents were mild, but he was taken to the emergency room needing epinephrine or corticosteroids six times, was occasionally unconscious, with faecal incontinence, and was admitted to intensive care twice. The patient described an episode as “Everything begins with a vague feeling of nausea, followed rapidly by an increase in heart rate. My pulse can become as high as 150 beats per min”. Initial symptoms often lasted 10 min, and were followed by tingling of the tongue, sweating, and flushing of the face and the trunk. Occasionally he had severe vomiting, and on some occasions a low body temperature (35·7°C) was recorded on examination in hospital. The duration of symptoms varied, with a severe attack lasting more than 30 min. Afterwards he often had severe headache, chills, persistent nausea, and swelling of the mouth and tongue, lasting for several hours. Seizures were never reported. Our initial investigations revealed no allergy, but he had raised baseline serum tryptase of 160 ng/mL (reference ≤11·4 ng/mL), increased urinary concentrations of 11β-PGF2α (127 ng/mmol creatinine; reference ≤35 ng/mmol creatinine) and leukotriene E4 (131 ng/mmol creatine; reference ≤70 ng/mmol creatine), supporting an Morning Daytime Evening
10
Night No data
No action Medical care Emergency care
Severity
8
6
4
2
0 1985
1990
1995
2000 Year
2005
2010
Figure: Distribution and severity of symptomatic episodes, 1988–2013 Reaction severity was graded on a scale of 1–10, with grade 1 being increased heart rate, grade 2 including tingling of the tongue, sweating, and flushing, grade 3 meaning blurry vision and having to lie down, and grade 4 substantial nausea. Grade 5 corresponds to severe nausea and presyncope, and grade 6 includes vomiting. Grades 7–9 are decreasing levels of consciousness, and at grade 10 the patient is unconscious. Based on a figure drawn by the patient.
1608
underlying mast-cell-activation disease. Bone marrow biopsy showed numerous mast cell aggregates, spindleshaped mast cells, an aberrant mast cell phenotype expressing CD2/CD25, and KIT D816V mutation. Based on these findings, we diagnosed systemic mastocytosis.1,2 Since June, 2009, the patient has been taking prophylactic desloratadine (15 mg daily), ranitidine (300 mg daily), and montelukast (20 mg daily). At follow-up in February, 2014, he reported 56 months without a severe reaction (figure), and 39 months without any attacks at all. He now carries an epinephrine syringe at all times. Mastocytosis is characterised by the accumulation, activation, and proliferation of mast cells in various organs.1,2 Symptoms are typically episodic and associated with the release of mast cell mediators. One of the most common presentations is anaphylactic symptoms that recur in a self-limiting and stereotypical fashion.3 Consequently, many patients with mastocytosis are initially admitted for anaphylaxis. The differential diagnosis of spells is challenging, and this case exemplifies a common problem in patients with mastocytosis. Despite the rarity of this condition, general practitioners and emergency physicians should be aware of systemic mastocytosis as a possible cause of recurrent, indeterminate spells and anaphylaxis. Although spells in mastocytosis are due to mast cell mediators,4 current prophylactic treatment usually consists of antihistamine alone,5 leaving other potent mediators unopposed. It is worth noting that in this case combined histamine and leukotriene-receptor antagonism has so far prevented the recurrence of severe reactions. Contributors TG, BD, and HH assessed and managed the patient; S-ED and BS contributed to the clinical diagnosis. All authors wrote the manuscript. Written consent to publish was obtained. Acknowledgments We thank the patient and his wife for collecting the data, and Ingrid Delin and Johan Bood for mediator measurement. The study was supported by unconditional grants from the Centre for Allergy Research, Karolinska Institutet, the Swedish Research Council, and Stockholm County Council. References 1 Horny HP, Metcalfe DD, Bennett JM, et al. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2008: 54–63. 2 Butterfield JH. Systemic mastocytosis: clinical manifestations and differential diagnosis. Immunol Allergy Clin North Am 2006; 26: 487–513. 3 Young WF Jr, Maddox DE. Spells: in search of a cause. Mayo Clin Proc 1995; 70: 757–65. 4 Roberts LJ 2nd, Sweetman BJ, Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med 1980; 303: 1400–04. 5 Tolar J, Tope WD, Neglia JP. Leukotriene-receptor inhibition for the treatment of systemic mastocytosis. N Engl J Med 2004; 350: 735–36.
www.thelancet.com Vol 383 May 3, 2014
