Page 690 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 48 Drug Hypersensitivity 663

TAXANES HYPERSENSITIVITY
Taxus baccata Solvents and excipients
Taxane moiety
Paclitaxel Solvent
Docetaxel Cremophor EL
Cabazitaxel Polysorbate 80

IgG

C3a
C5a
IgE
Direct action

Mediators
LTC4
PGD2
Histamine
Tryptase
Mast cell/basophil
FiG 48.10 Taxanes: Plant origin, solvents, and excipients.

typically occur during the first or second lifetime exposure with For type I IgE- and non–IgE-mediated reactions, desensitiza-
such symptoms as throat tightness, flushing, hypotension, and tion is now the state-of-the-art management option in patients
dyspnea. However, some patients also report severe chest, back, who still require the offending drug as first-line therapy. Desen-
and/or pelvic pain. sitization has been successfully achieved for chemotherapy drugs,
IgE-mediated HSRs to taxane molecules have been reported, mAbs, antibiotics, and other medications in both adults and
leading to skin test evaluations for patients with taxane reactions. children. Although drug reactions are less common in children
When skin testing was performed in 145 patients with taxane- than in adults, perhaps because of fewer exposures, patients with
related HSRs, 103 (71%) had positive results. Thirty-six (22%) cystic fibrosis have an average 30% sensitization rate to antibiotics;
patients with negative skin test results eventually resumed regular they can be successfully desensitized with first-line antibiotics,
infusions. 53 even during lung transplantation. The mechanism of desensitiza-
tion for IgE-mediated reactions has been studied in vitro and
MANAGEMENT OF DRUG HYPERSENSITIVITY in rodents. Although antigen induces membrane changes leading
AND DESENSITIZATION to internalization of the antigen, IgE and FcεRI, when cells are
repeatedly exposed to increasing suboptimal drug concentrations,
Stopping a drug suspected of inducing a reaction has therapeutic this prevents these membrane events and blocks calcium entry
and diagnostic implications. If the symptoms are alleviated upon and the release of inflammatory mediators (Fig. 48.11). Other
cessation, it is likely, but not certain, that the drug was responsible mechanisms that may be relevant to human desensitization have
for the reaction. Although most type I symptoms are readily also been implicated (Fig. 48.12). Further research is needed to
reversible, death has occurred in patients on concomitant beta- better understand these.
blockers or ACE inhibitors when epinephrine did not reverse Application of the principles of desensitization has been
cardiovascular collapse. Patients with severe anaphylactic drug remarkably successful, and thousands of patients have been safely
reactions, as seen with chemotherapy and platins, may develop desensitized, including patients suffering severe anaphylactic
posttraumatic stress disorders. Severe reactions, such as DRESS, reactions. Indications for desensitization include type I IgE- and
SJS, and TEN, do not have specific therapies and require intensive non–IgE-mediated reactions. The risk/benefit ratio needs careful
and aggressive treatments, including steroids and/or immuno- consideration because desensitization can sometimes induce
globulin infusion at high doses, to accelerate the resolution of severe reactions. If there is a good alternative drug, desensitization
inflammatory events and facilitate recovery. Recurrence of these should not be attempted. Desensitization protocols generally
reactions upon inadvertent exposure can be lethal, and those involve diluting the drug up to 1/1000 of its normal concentration,
surviving can suffer life-debilitating consequences, such as followed by doubling doses at short intervals. A 12-step protocol
depression and increased suicides. Blindness, permanent hair for carboplatin desensitization is shown in Table 48.6. For patients
and nail loss, mucosal dryness, and fibrosis can dramatically with high risk, four bags and 16 steps may be used as shown in
decrease the quality of life in patients with SJS and TEN, and Table 48.7 for ofatumumab. For patients with local and systemic
patients with DRESS can have persistent hepatitis and/or reactions to subcutaneous injections, desensitization has been
eosinophilic cardiac complications. successfully achieved by the subcutaneous route.