Discussion
In this monocentric retrospective study, 13/237 (5.5%) patients with an
anaphylaxis event had a biphasic reaction. The mean time of onset for
the biphasic reaction was 8 hr. This observed prevalence, time of onset
and range are in line with the current literature (14, 15, 16, 17, 18).
However, our results differ from the literature in the distribution of
the severity grade according to the Ring and Messmer classification
(25), which is described in equal proportions for mild, moderate and
severe reactions (47).
Patients with biphasic and monophasic anaphylaxis did not differ in
clinical and allergological features, except for loss of consciousness
during anaphylaxis and asthma, both more frequent with biphasic than
monophasic anaphylaxis. Furthermore, basal tryptase levels were
significantly more elevated with biphasic than monophasic reactions.
That we found more loss of consciousness with biphasic than monophasic
reactions suggests a more severe reaction with the former. However, the
Ring and Messmer classification did not significantly differ between the
groups. The association between severe anaphylaxis and biphasic
reactions was recently investigated in a large cohort (42):
gastrointestinal, skin symptoms, respiratory arrest, cardiac symptoms,
and chronic urticaria were associated with the occurrence of biphasic
reaction. Such a difference with our results can be explained by the
limited number of biphasic patients in our study.
There are no reports of a link between asthma comorbidity and biphasic
anaphylaxis (48, 49), which could be explained by recruitment bias
because our hospital service also includes an asthma center. However,
none of the asthmatic patients with a biphasic reaction were followed by
fellow pulmonologists. Moreover, the proportion of asthmatic patients we
found is lower than in the literature (18.5% of 237 patients vs 22.5%
in a large anaphylaxis registry (3)).
Although asthma was more frequent with biphasic than monophasic
anaphylaxis, the former group exhibited no severe asthma, and
respiratory symptoms during anaphylaxis were similar in both groups.
Asthma is known to increase the severity of anaphylaxis (48, 50, 51),
and severe asthma is also associated with a predominance of mast cells
positive for tryptase and chymase in the airway submucosa and epithelium
(52). Furthermore, severe asthma was recently found associated with
elevated basal tryptase level (even independently of type 2
inflammation) (53). We cannot conclude a potential link with asthma
treatment because only two patients used inhaled corticosteroids in the
biphasic group.
In our study, basal tryptase level was higher with biphasic than
monophasic anaphylaxis. To our knowledge, this has never been reported.
A potential explanation could be the more frequent history of asthma in
the biphasic than monophasic group because basal tryptase level was
higher with biphasic than monophasic anaphylaxis for asthmatic patients.
Older age and renal failure increase tryptase levels and could be
confounding factors, so we examined the distribution of age between our
two groups and it was similar. Additionally, none of our biphasic
patients had renal failure. Kraft et al (42) found no significant
difference in mean basal tryptase level between monophasic (n = 4786)
and biphasic anaphylaxis (n = 237). However, the authors included
patients with systemic mastocytosis in their analysis, which could
perhaps mask a difference in basal tryptase level and explain the
discrepancy with our results. Other factors regulating the activation of
mast cells, such as the cytokine environmental network or genetic
regulation of tryptase production could be involved (54).
We found no significant difference in culprit allergens between
monophasic and biphasic anaphylaxis. The most common allergens in our
study were drugs and Hymenoptera venom, which agrees with the literature
on epidemiological prevalence for the cause of anaphylaxis in adults
(51, 55) and could explain the few patients with a food elicitor in our
study. In addition, the basal tryptase level in biphasic and monophasic
groups with an allergy to Hymenoptera venom was similar but was higher
in biphasic patients with drug allergy. This has not been reported
before and warrants confirmation in further studies.
The main strength of this study is the detailed information on patient
characteristics. Furthermore, symptoms and medical management of
biphasic phases were well documented. All patients with an anaphylaxis
reaction had documented basal tryptase level, allergy test results and a
complementary interview in our center.
The retrospective monocentric design of the study is its main
limitation. The lack of power due to a small number of participants with
biphasic reactions did not allow for applying a multivariate analysis of
risk factors.
In conclusion, we show for the first time that elevated basal tryptase
is linked to biphasic reactions. The role of basal tryptase level as a
risk factor for biphasic reaction requires further investigations.
Additionally, asthma and unconsciousness during the first phase of
anaphylaxis could be associated with a biphasic reaction. These findings
advocate for prolonged monitoring of these patients during their care.