Idiopathic anaphylaxis, recalcitrant to therapy
Question:
4/2/2020
Can I have your thoughts on diagnosis and management of a male patient, 46 years old whom I suspect has mast cell activation disorder?
• Recurrent episodes of idiopathic anaphylaxis with evidence of considerably raised MC tryptase (~50-100 µg/l) and normal interval MCT (~5 µg/l). Episodes of flushing/abdominal cramps/diarrhoea since teens, some with collapse but diagnosed as anaphylaxis only 1.5 years ago. Frequency of episodes with severe hypotension increasing and currently presenting in an almost cyclical pattern with some prodromal symptoms (mainly lethargy, loss of appetite, sore throat and diarrhoea); requiring multiple IM doses of adrenaline 500µg. Remains having milder episodes with flushing/some urticaria and abdominal cramps/diarrhoea in between.
• Has reacted to amoxicillin (thought to be the culprit as he is a vet pharmacist) when challenged (1st dose of 16 mg) to exclude this as a culprit.
• No obvious other culprit found; negative sIgE to alpha-gal and ω5-gliadin, and unremarkable ISAC ImmunoCAP.
• Started on anti-mediator medication in Oct 2019 (fexofenadine 180 mg qds, ranitidine 150 mg bd, montelukast 10 mg od, ketotifen 1 mg bd, sodium cromoglicate 200 mg qds) with no change in frequency or severity of episodes; also trialled five days of prednisolone 40 mg once a day prior to suspected episodes (cycle and prodromal symptoms) with no effect.
• Bone marrow biopsy normal - normal morphology; no molecular changes noted (no evidence of mastocytosis, no mutations detected by high throughput sequencing).
• Started on omalizumab in Feb 2020 in addition to maintaining medication listed above. Within five to ten minutes of receiving 300 mg sc, developed widespread erythema, angioedema of the lower lip and hands, itchy palms and soles, cough and chest tightness, chest clear on auscultation and normal BP, HR and SpO2; MCT 20.7µg/l; no adrenaline given.
• Decision to give second omalizumab injection in March 2020 as no other treatment options available and felt benefits (had no anaphylaxis episodes since despite having the milder episodes described above) outweighed risks. Tolerated omalizumab with premedication with steroids and given in three graded doses.
Answer:
Thank you very much for your question. This is certainly a very difficult case, so I reached out to an anaphylaxis expert, Dr. Kevin Kelly. Please see his response below.
First some questions that might be helpful:
1. What is the occupation of the subject?
2. Are there occupational exposures that were considered?
3. How frequently is the anaphylaxis occurring?
4. Does the patient keep a diary of foods, spices, contacts (latex)?
5. Is the patient taking NSAIDS casually PRN?
Suggestions:
1. This is very difficult and the use of other biologics is not proven. One might consider using a lower dose of omalizumab for the first three months (150mg twice monthly). After three months if there is no more adverse reactions (and anaphylaxis is continuing at the same rate) then increase the dose. The use of omalizumab appears to have maximal effect after three months and is likely due to down regulation of IgE receptors on mast cells and possibly new mast cells with fewer receptors. Does this lead to stabilization of mast cells? Possibly with less anaphylaxis and possibly less severe individual episodes. As best I can tell, the adverse reactions to administration of omalizumab mostly occurred during the first few weeks to months of use.
2. I agree this does not appear to mastocytosis or MCAS but I would consider sharing this case with Mariana Castells, MD at Brigham and Women’s and Larry Schwartz MD PhD at VCU.
3. During the early years of the description of idiopathic anaphylaxis by Patterson’s group at Northwestern, the use of prolonged, high dose corticosteroid appeared to cause a remission of the disease. This was starting as high as 60 mg of prednisone for a minimum of two to four weeks and a slow taper over the next six months. As we all know, this risks significant side effects of steroids with the patient. The physician would need to weigh the risk and benefit with the patient. I included our paper on a case series of children with IA and another on adults.
4. The continued use of the complementing medications is possible not of value since no positive effect was observed.
5. In case of refractory episodes of anaphylaxis (which sounds like some of them are), the use of glucagon may be tried. Our paper for emergency room use of methylene blue infusion may be helpful if one of these episodes does not resolve with standard measures.
6. Leslie Grammar has a nice review in “up to date” that is more recent about diagnosis and treatment.
References:
1) Bauer CS, Vadas P, Kelly KJ. Methylene blue for the treatment of refractory anaphylaxis without hypotension. Am J Emerg Med. 2013;31(1):264.e3–264.e264005. doi:10.1016/j.ajem.2012.03.036
2) Ditto AM, Harris KE, Krasnick J, Miller MA, Patterson R. Idiopathic anaphylaxis: a series of 335 cases. Ann Allergy Asthma Immunol. 1996;77(4):285–291. doi:10.1016/S1081-1206(10)63322-4
3) Ditto AM, Krasnick J, Greenberger PA, Kelly KJ, McGrath K, Patterson R. Pediatric idiopathic anaphylaxis: experience with 22 patients. J Allergy Clin Immunol. 1997;100(3):320–326. doi:10.1016/s0091-6749(97)70244-6
Special thanks to Dr. Kelly for his detailed response.
Respectfully submitted
Jeffrey G Demain, MD, FAAAAI