Phenotype Switching From Delayed Cutaneous Reactions to Immediate Anaphylaxis Upon Rechallenge With Paclitaxel

To the Editor,

Paclitaxel is a well-established cause of immediate hypersensitivity reactions (HSRs), which are traditionally attributed to non-immunoglobulin E (IgE)-mediated mast cell activation related to the Cremophor EL vehicle.¹ In contrast, delayed cutaneous HSRs occurring several days after paclitaxel administration are considered type IV reactions mediated by T cells.² Here, we describe a clinically important hypersensitivity phenotype in which delayed maculopapular eruptions accompanied by fever preceded severe immediate anaphylaxis upon paclitaxel rechallenge.

We report 5 patients (mean age 43 ± 8.3 years) with breast, ovarian, cervical, or unknown primary cancer who developed delayed maculopapular rashes with fever 6–8 days after their first exposure to paclitaxel. The timing and clinical characteristics of these delayed reactions are consistent with previously reported delayed paclitaxel HSRs.³,⁴ These symptoms improved with supportive care or systemic corticosteroids. However, all patients experienced acute immediate reactions, including anaphylaxis, during subsequent paclitaxel administration. These reactions occurred within minutes of re-exposure and were characterized by respiratory compromise, urticaria (n = 2), and severe facial erythema (n = 1), with hypotension occurring in three cases (Table). In all cases, paclitaxel was the only agent administered at the time of anaphylaxis, supporting drug causality.

Table. Clinical characteristics and outcomes of paclitaxel-induced delayed-to-immediate hypersensitivity reaction phenotype.

Feature/case		Case 1	Case 2	Case 3	Case 4	Case 5
Patient information
	Age/sex	48/M	41/F	42/F	53/F	31/F
	Underlying cancer	Metastatic carcinoma of unknown primary	Cervical cancer	Breast cancer	Ovarian cancer	Breast cancer
	Total IgE (IU/mL)	N/A	43.4	3,011	336	220
	Prior history of allergic diseases	None	None	None	Allergic rhinitis	None
	Concomitant chemotherapy	Carboplatin	Pembrolizumab, cisplatin	Pembrolizumab, carboplatin	Carboplatin	Pembrolizumab, carboplatin
Initial delayed reactions (cycle 1)
	Paclitaxel dose (1st infusion) & brand name	Total 360 mg, 175 mg/m2, Taxol®	Total 280 mg, 175 mg/m2, Padexol®	Total 130 mg, 80 mg/m2, Taxol®	Total 280 mg, 175 mg/m2, Genexol®	Total 130 mg, 80 mg/m2, Padexol®
	Onset (days post-infusion)	8 days	8 days	8 days	6 days	8 days
	Key symptoms	Diffuse erythematous pruritic rash (Supplementary Fig. S1A), fever, dyspnea, oral swelling	Widespread erythematous maculopapular rash (Supplementary Fig. S1B), erythema of the oral mucosa, fever	Diffuse rash (Supplementary Fig. S1D), lip swelling, fever, general weakness	Widespread maculopapular rash (Supplementary Fig. S1F), chills, fever	Diffuse pruritic rash (Supplementary Fig. S1H), fever, chills, sore throat
	Peak temperature	37.9℃	40.8℃	38.6℃	38.2℃	39℃
	Lab findings	WBCs: 4,800/uL, eosinophils: 2.9%, AST/ALT: 108/225 IU/L, CRP: 3.55 mg/dL	WBCs: 4,500/uL, eosinophils: 1.8%, AST/ALT: 281/263 IU/L, CRP: 6.25 mg/dL (initial), CRP: 21.47 (peak, 2 days later)	WBCs: 10,100/μL, eosinophils: 0.7%, CRP: 32.24 mg/dL, AST/ALT: 27/57 IU/L (initial), AST/ALT: 99/134 IU/L (peak, 4 days later)	WBCs: 2,000/uL, eosinophils: 8.4%, CRP: 3.35 mg/dL, AST/ALT: 16/20 IU/L	WBCs: 14,900/uL, eosinophils: 0.7%, CRP: 1.04 mg/dL, AST/ALT: 34/42 IU/L (initial), AST/ALT: 67/118 IU/L (peak, 2 days later)
Subsequent immediate anaphylaxis (upon rechallenge)
	Status of co-administered drugs	Carboplatin withheld	Pembrolizumab omitted	Paclitaxel administered as a single agent on the rechallenge day	Carboplatin withheld	Paclitaxel administered as a single agent on the rechallenge day
			Cisplatin withheld
	Paclitaxel dose (2nd infusion)	Total 280 mg, 140 mg/m2, Taxol®	Total 220 mg, 135 mg/m2, Taxol®	Total 130 mg, 80 mg/m2, Taxol®	Total 280 mg, 175 mg/m2, Genexol®	Total 140 mg, 80 mg/m2, Padexol®
	Onset time (infused volume)	8 min (20.8 cc)	15 min (15.7 cc)	40 min (7.1 cc of 10-fold-diluted desensitization solution)	27 min (25.7 cc)	6 min
	Key symptoms	Hypotension, dyspnea, unresponsiveness, pulseless electrical activity	Chest tightness, dyspnea, diaphoresis, hypotension, hypoxia, wheezing, urticaria	Flushing, urticaria, pruritus, nausea, diarrhea, chest tightness, dyspnea	Diaphoresis, chest tightness, dizziness, hypotension, hypoxia	Facial and neck flushing, severe nausea, burning sensation in throat/esophagus, emesis, dyspnea, desaturation (SpO2 91%)
	Tryptase (acute event/baseline, ug/L)	109.0/N/A	N/A	(1st) 1.4/< 1.0	N/A	N/A
				(2nd) < 1.0/< 1.0
	Interleukin-6 (acute event/baseline, pg/mL)	N/A	N/A	(1st) 5.6/7.0	N/A	N/A
				(2nd) 1.5/7.0
	Anaphylaxis outcome	Post-cardiac arrest care, intubation, vasopressors, continuous renal replacement therapy, discharged after weeks of rehabilitation	Emergency department transfer, inpatient observation, desensitization planned	Desensitization terminated	Emergency department transfer, inpatient observation, desensitization planned	Desensitization planned
Desensitization attempts
	Protocol	N/A	4-bag, 16-step	(1st) 3-bag, 12-step; (2nd) 4-bag, 16-step	(1st) 3-bag, 12-step; (2nd–3rd) 4-bag, 16-step; (4th–5th) 3-bag, 12-step	(1st–5th) 4-bag, 16-step
	Breakthrough reactions (step; symptoms)	N/A	Steps 7, 8, 10, 12, 15, 16; recurrent hives (Supplementary Fig. S1C), nausea, facial flushing, hypotension, fever	(1st) Steps 7, 8, 9; flushing, urticaria, nausea, diarrhea, chest tightness; (2nd) Steps 9, 12, 14; urticaria (Supplementary Fig. S1E), cough, chest tightness, abdominal pain, tenesmus	(1st) Steps 9, 11, 12; facial erythema, urticaria (Supplementary Fig. S1G); (2nd) Step 10; mild urticaria; (3rd–5th) No breakthrough reactions	(1st) Steps 10, 11, 16; facial flushing, pruritus, delayed rash (Supplementary Fig. S1I); (2nd–3rd) No breakthrough reactions; (4th) Steps 4, 16; spreading erythema on the lower extremities, pruritus; (5th) Steps 6, 16; erythematous patches spreading to the extremities, pruritus
	Final paclitaxel status	All taxanes were contraindicated	No further paclitaxel	No further paclitaxel	Completed planned chemotherapy	Completed planned chemotherapy

Numbers in parentheses (e.g., 1st, 2nd) refer to the order of rapid drug desensitization attempts.

M, male; F, female; IgE, immunoglobulin E; N/A, not available; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; SpO2, peripheral capillary oxygen saturation.

A striking and consistent feature of the initial delayed reactions was the presence of fever, suggesting systemic immune activation rather than isolated cutaneous involvement. This clinical sequence suggests that delayed type IV reactions and immediate anaphylaxis, while traditionally classified as mechanistically distinct,² are not necessarily independent phenomena. Instead, our observations support the concept of phenotype switching, in which an initial delayed HSR may predispose patients to subsequent immediate, potentially life-threatening reactions upon rechallenge. An association between delayed and immediate HSRs to paclitaxel has been suggested in prior observational studies.³,⁴ Moreover, a fatal case of paclitaxel-induced anaphylaxis preceded by a delayed HSR has been reported, underscoring the potential severity of this pattern.⁵

Notably, all four patients who underwent rapid drug desensitization experienced recurrent breakthrough reactions (BTRs), which occurred in 8 of 13 total desensitization cycles (61.5%). These BTRs often occurred at early or low-dose steps despite intensified premedication. This unusually high rate of BTRs contrasts with previously reported outcomes of taxane desensitization, in which BTRs occurred in a minority of patients.⁶,⁷ These findings suggest that the delayed-to-immediate phenotype may represent a high-risk endophenotype characterized by persistent immune activation. Clinical manifestations of delayed cutaneous reactions and immediate hypersensitivity during rechallenge or desensitization are shown in the Supplementary Fig. S1.

The precise immunologic mechanisms underlying this phenotype remain unclear. While immediate paclitaxel reactions have long been considered predominantly non-IgE-mediated,¹ IgE-mediated mechanisms have been demonstrated in a subset of patients with taxane hypersensitivity, even during early treatment cycles.¹,⁷ Alternatively, immune activation associated with the T-cell–mediated delayed reaction may lower the threshold for mast cell activation upon re-exposure.

Delayed maculopapular eruptions accompanied by fever after paclitaxel administration should not be dismissed as minor adverse events. Rather, they may serve as a sentinel warning for immediate anaphylaxis upon re-exposure. Patients exhibiting this pattern warrant prompt allergy referral, careful risk stratification, and cautious consideration of rechallenge strategies, including modified desensitization protocols or alternative therapies.

SUPPLEMENTARY MATERIAL

Supplementary Fig. S1

Clinical manifestations of delayed and acute hypersensitivity reactions to paclitaxel. (A) Delayed cutaneous eruption after the first paclitaxel administration in Case 1. (B) Delayed maculopapular eruption on the lower extremities following initial paclitaxel administration in Case 2. (C) Acute generalized urticaria during desensitization in Case 2. (D) Delayed maculopapular rash after the first paclitaxel administration in Case 3. (E) Acute urticaria with erythema and flushing on the face and neck during paclitaxel desensitization in Case 3. (F) Widespread rash on the trunk following initial paclitaxel exposure in Case 4. (G) Acute urticarial eruption during paclitaxel desensitization in Case 4. (H) Delayed pruritic maculopapular rash following the first paclitaxel administration in Case 5. (I) Recurrent delayed rash on day 3 after paclitaxel desensitization in Case 5.