Distinct from mastocytosis and simple allergy and characterized by constitutive mast cell (MC) activation and aberrant MC reactivity with little to no excessive MC accumulation, MC activation syndrome (MCAS) presents as acute-on-chronic multisystem polymorbidity of generally inflammatory ± allergic theme and may be epidemically prevalent (PLoS ONE 2013;8(9):e76241). Occasional patients (pts) suffer nearly continuous anaphylactoid and/or dysautonomic states poorly controlled by intermittently dosed epinephrine (epi), antihistamines, steroids, etc. Many medications (meds) have helped MCAS pts, but there are not yet any biomarkers predictive of effective therapy. Pts often try many meds, but med trials in pts suffering very frequent flares are impractical in that a flaring soon after dosing of a new med cannot be distinguished from "baseline" flaring from yet-uncontrolled disease vs. flaring in specific reaction to the new med. Thus, med trials in severe MCAS often are prematurely terminated for safety. Some modicum of stability is required to pursue med trials in such pts. Diphenhydramine (DPH) is a well tolerated histamine H1 receptor blocker which can quickly suppress MC activation and is used to treat allergic reactions and anaphylaxis. However, its half-life is as short as 1 hr (www.drugbank.ca/drugs/DB01075). Severely afflicted MCAS pts often need many DPH treatments each day (preferably intravenously (IV) for fastest onset of action); cumulative daily dosing often is 10-fold or more greater than the common single dosage of 25-50 mg. Intermittently dosed, though, its initially therapeutic serum level rapidly declines to subtherapeutic and the pt seesaws into yet another flare. The safety of continuous DPH infusion (CDI) was established in trials of the "BAD" regimen (DPH (Benadryl), lorazepam (Ativan), and dexamethasone) in refractory chemotherapy-induced emesis in adult and pediatric pts (Bone Marrow Transplant 1999;24:561; Pediatr Blood Cancer 2007;48:330). Reviewed here are several cases of life-threatening MCAS stabilized with CDI.
Methods: Ten pts were treated (age range 18-49; 9 women). All were disabled from virtually continuous anaphylactoid and/or severely dysautonomic (e.g., pseudoepileptic, hypotensive, etc.) flaring despite multiple treatments daily including subcutaneous epi, DPH (25-100 mg doses by IV, intramuscular, and/or oral routes), H2 blockers, etc. Median total daily DPH dose before CDI was 600 mg (range 600-800 mg = 25-33 mg/hr). CDI was initiated in all at 5 mg/hr (≤20% of total daily DPH dose). With each flare, rescue DPH 25-50 mg IV was given and CDI was increased 1-2 mg/hr.
Results: All 10 pts were already hospitalized for virtually continuous anaphylaxis; 2 had been continuously in intensive care units (ICUs) for 12 days and 8 weeks. Nine pts (including both ICU pts) ceased flaring once CDI reached 10-12 mg/hr (240-288 mg/d, <50% of prior total daily DPH consumption). Rates <10 mg/hr were uniformly ineffective. One pt reached 17 mg/hr without responding and treatment was stopped. Responders ceased flaring 12-24h, and were discharged 18-48h, after initiation of CDI. With indwelling lines and portable pumps, responders could continue CDI and demand-dose bolus DPH to address further flares. Two responders continued after discharge to suffer a flare every ~1-2 days, but increase of CDI to 13-14.5 mg/hr (312-348 mg/d) reduced flares to once every 1-4 weeks. With follow-up ranging 0.5-21 months (median 13), responders report continuing flares at greatly reduced rates ranging ~1-4/month (and much less severe), each time readily controllable with 10-25 mg of bolus DPH. No tolerance or other evidence of waning DPH effect was seen. No early or late toxicity has been identified. Eight responders pursued trials of other meds which generally proved well-tolerated, but no responder has gained sufficient improvement with other meds to permit weaning off CDI.
Conclusions: In this small retrospective series of MCAS pts suffering almost continuous anaphylactoid/dysautonomic flares, CDI at 10-14.5 mg/hr appeared effective in most pts at dramatically reducing flare rates and appeared safely sustainable at stable dosing for at least 21 months. Stabilization has enabled successful trials of other helpful meds, but no pt has yet successfully stopped CDI. More research is needed to better understand MCAS pathobiology and identify better treatments.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.