Idiopathic Anaphylaxis With Elevated Tryptase: When to Biopsy the Marrow
A woman's worst anaphylactic episode had no hives at all — just sudden unconsciousness. Her tryptase alone wouldn't justify a marrow biopsy. A validated risk score built for exactly her pattern says something different.
P.N., a 54-year-old woman, has had three anaphylactic episodes in the past two years — two clearly triggered by wasp stings while gardening, one with no trigger she or her doctors have ever identified. What has stayed with her allergist longer than the sting history is a detail from her worst episode: she went from feeling fine to unconscious in under ten minutes, with no hives, no flushing, nothing on her skin at all to signal what was happening internally, a pattern strikingly different from the itchy, visibly alarming reactions people generally picture when they hear the word anaphylaxis. A baseline tryptase, drawn weeks later while she felt entirely well, came back at 13.8 ng/mL — mildly above the general reference range, though below the 20 nanogram threshold some clinicians treat as their own personal trigger for a bone marrow biopsy. She gardens most weekends, has no other chronic medical conditions, and until her allergist raised it directly, had never connected her fainting spell to an allergic mechanism at all — she had assumed, and told the ambulance crew at the time, that she must have simply overheated.
The REMA score, developed by the Spanish Network on Mastocytosis specifically to predict which adults presenting with anaphylaxis are likely to have an underlying clonal mast cell disorder, weighs two of the features her case has heavily and two of them against her. Syncope carries the single largest weight in the instrument, and a reaction free of urticaria or angioedema adds to it; but the score subtracts a point for female sex, and it subtracts another for a baseline tryptase under 15, which is where her 13.8 sits. Run against her actual history, those four variables net out at exactly 2 — the cutoff at or above which the validation cohort found a meaningfully elevated probability of an underlying clonal disorder. She clears the threshold on her syncope and her missing hives alone, with her tryptase and her sex both pulling the other way, which is precisely the number nobody would have reached from that 13.8 read on its own.
At the bedside
I'd biopsy her now. Her tryptase alone, 13.8, wouldn't get me there — but the REMA score isn't just her tryptase, and the feature that actually stands out in her history, a severe reaction with no urticaria or angioedema at all, is one of the specific findings that score was built to catch. Skin-symptom-free anaphylaxis is a recognized signal for underlying clonal mast cell disease independent of where the raw tryptase number sits.
I'd want to be more careful about how far we generalize that score before committing her to a bone marrow biopsy. REMA was derived and validated mostly in patients with venom-triggered reactions, and its own original cohort found male sex independently predictive — she's being scored by a tool built on a population that doesn't fully resemble her own presentation. A mildly elevated tryptase also isn't only explained by clonal disease; hereditary alpha-tryptasemia produces exactly this kind of modest, chronic elevation without any bone marrow abnormality at all. And note what that does to the score — nothing. At 13.8 her tryptase is already scoring against her, and only a value above 25 would have added points, so HaT can't be inflating this number. That's the problem. Her score is being carried entirely by the syncope and the absent hives, and those are exactly the features the REMA has been shown not to discriminate well between clonal disease and an HaT genotype. The score can't tell those two apart in her.
I'm not saying her risk is zero. I'm saying we haven't actually ruled out the simpler explanation yet.
That's the right correction, and it's resolvable before either of you has to act on an assumption. Tryptase genotyping is cheap and noninvasive, and it addresses the blind spot just described rather than the arithmetic — not whether HaT inflated her number, but whether an HaT genotype is the non-clonal explanation for a presentation her score cannot distinguish from clonal disease. Send it first. If it's negative, her score stands as a genuine signal and I'd support proceeding to biopsy without further delay. I'd add the one caveat that cuts against my own sequencing: a positive HaT result doesn't exclude clonal disease, since the two co-occur, so a positive can't be treated as an all-clear either.
Agreed: hereditary alpha-tryptasemia genetic testing sent first; bone marrow biopsy planned contingent on that result, proceeding promptly if HaT is negative given her REMA score and the urticaria-free severity of her worst episode.
Not agreed, and left open rather than smoothed over:
The hematologist wants biopsy pursued regardless, given the syncope pattern alone.
The allergist thinks a positive result should meaningfully lower the threshold for stopping the workup there.