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Acute generalized exanthematouspustulosis-like, folliculitic drug

reaction pattern caused by celecoxibJanthorn Pakdeethai,* Sue-Ann Ho,* Derrick Aw* &Kong Bing Tan†Departments of *Medicine and †Pathology, National University Hospital,Singapore

ABSTRACT: An extensive range of diseases or reactions can cause pustular eruptions of the skin.Drug-provoked cutaneous eruptions includes acute generalized exanthematous pustulosis (AGEP) andacneiform eruption. We report a 50-year-old man who developed fever and a sudden eruption ofwidespread pustules 12 days after ingestion of celecoxib prescribed for a prolapsed intervertebral disc.AGEP was diagnosed based on the typical history, characteristic features, and laboratory findings.However, histopathological findings were consistent with folliculitic drug reaction pattern withoutfeatures of AGEP. We present, the first known reported case of folliculitic drug reaction pattern causedby celecoxib.

KEYWORDS: acneiform eruption, acute generalized exanthematous pustulosis, celecoxib,cyclooxygenase type 2 inhibitors, folliculitis, pustular eruption

Drug-induced folliculitis is a rare subtype ofadverse drug reaction (ADR), characterized byacneiform eruptions, primarily affecting nonacnearea, such as arms and legs. We describe a caseof amicrobial folliculitis caused by celecoxib(Celebrex; Pfizer Pharmaceuticals LLC., Caguas,Puerto Rico), a cyclooxygenase (COX)-2 inhibi-tor. The patient was treated with corticosteroidpulse therapy. Skin lesions healed without scarring.

Case report

A 50-year-old Malay man with a recent diagnosisof prolapsed intervertebral disc, presented to theEmergency Department with fever of 39.5°C and asudden eruption of widespread nonpruritic, non-tender rash which had started 2 days earlier. Theskin rash was initially limited to the buttock butrapidly spread to the entire skin, that is to say, theback, chest, face, neck, and upper and lower limbs.A day after the onset of the rash, he developed sorethroat and pain in the mouth. He was recently diag-nosed with prolapsed intervertebral disc and hadbeen taking celecoxib 200 mg twice a day for 12days prior to presentation. There was no personalor family history of skin disease, such as psoriasis.

Dermatologic examination revealed numerousstrikingly pinpoint pustules sitting on diffuse,

Address correspondence and reprint requests to: JanthornPakdeethai, MBBS, MRCP(UK), MMed (Int Med), Dip (FamilyPractice Dermatology), Dip (Family Medicine), Department ofMedicine, National University Hospital, Singapore 119074 oremail: janthorn_pakdeethai@nuhs.edu.sg

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erythematous, and edematous patches andplaques (FIG. 1), predominantly on the back, chest,and face. In addition, there were targetoid purpuricmacules on the trunk and proximal limbs, as wellas pustules in the buccal mucosa. The conjunctivaewere injected, but there was no involvement of theexternal genitalia.

Laboratory tests revealed leukocytosis with awhite cell count of 26.8 ¥ 109/L (reference range (RR)3.26–9.28 ¥ 109/L), of which 94.8% (25.4 ¥ 109/L, RR1.41–6.83 ¥ 109/L) were neutrophils. Absolute esosi-nophil count was normal (0.23 ¥ 109/L, RR 0.00–0.72¥ 109/L). C-reactive protein level was elevated(326 mg/L, RR 0–10). Renal and liver function testswere unremarkable. Aerobic and anaerobic bacte-rial cultures of the patient’s peripheral blood, urine,and pustules were negative.

On the basis of the medical history, clinicalpicture, and investigations, a clinical diagnosis ofacute generalized exanthematous pustulosis(AGEP) was made. Systemic corticosteroid andempirical antistaphylococcal antibiotic werepromptly instituted. The suspected culprit drug(celecoxib) was immediately withdrawn.

Histopathological findings of a lesional punchbiopsy with hematoxylin–eosin stain showed mildvacuolar interface changes at the basal epidermiswith superficial perivascular infiltrate of lympho-cytes and neutrophils. A hair follicle showed acuteinflammation and epithelial disruption (FIG. 2).Special stains, gram stains, and periodic acid Schiffwere negative for bacteria and fungi. No features ofAGEP were noted.

The rash stopped progressing from the fourthday of the eruption onset, and the patient becameafebrile from the fifth eruptive day. He was dis-charged after 5 days of hospitalization. Upon

review in the outpatient clinic 2 weeks later, theeruption had completely resolved with postinflam-matory hyperpigmentation.

Discussion

AGEP, a not uncommon cutaneous drug reactionpattern, was diagnosed based on the rash charac-teristics. Nevertheless, there was no histologic evi-dence of subcorneal or intraepidermal pustule,one out of the five main criteria for diagnosis ofAGEP as proposed by Sidoroff et al. (1). Our litera-ture research returned 3 case reports of AGEP withcollections of neutrophils around hair folliclesresembling folliculitis (2). However, other charac-teristic histologic features of AGEP present in thesecases (neutrophilic spongiosis, edematous papil-lary dermis, and necrotic keratinocytes) are absentin our case.

On the other hand, drug-induced folliculitis,also known as acneiform eruption, is rare. A widearray of medications are known to be associatedwith this type of ADR, for example, corticosteroids,in particular dexamethasone (3), hormones, suchas those contained in the oral contraceptive pills(4), calcineurin-inhibitor (5), aromatic anticonvul-sants, such as phenytoin (6), and antibiotics, suchas isoniazid (7). Halogenated aromatic compoundsmay cause chloracne (8), and exogenous factors,such as radiation, have also been implicated. Psy-chotropic medication, such as lithium (9), and,fairly recently, epidermal growth factor receptorinhibitors, such as cetuximab (10), are well-knowncauses of folliculitic reaction pattern, of whichmany cases display folliculitis with an infiltrate ofneutrophils rather than true acne. Standard acne

FIG. 1. Photomicograph shows acute-on-chronic inflamma-tory infiltrate within and around a hair follicle, causing itsdisruption (H and E, original magnification ¥60).

FIG. 2. Pustules on diffuse, erythematous, and edematouspatches and plagues.

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treatments can be employed without discontinu-ing the essential medications.

This case demonstrates an AGEP-like eruptionwith histolopathological features consistent withfolliculitis, both being differential diagnoses of apustular drug eruption, and highlights the fact thatdiscrimination of various causes of pustular rashis challenging, and close clinicopathological cor-relation is needed to establish and document newfindings, especially with the advent of medicaltherapy. To the best of our knowledge, this is thefirst reported case of celecoxib-induced folliculiticADR.

References

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2. Lin J-H, Sheu H-M, Lee JY. Acute generalized exanthema-tous pustulosis with erythema multiforme-like lesions. EurJ Dermatol 2002: 12 (5): 475–478.

3. Fung MA, Berger TG. A prospective study of acute-onsetsteroid acne associated with administration of intravenouscorticosteroids. Dermatology 2000: 200: 43–44.

4. Ilse JR, Greenberg HL, Bennett DD. Levonorgestrel-releasing intrauterine system and new-onset acne. Cutis2008: 82: 158.

5. Bakos L, Bakos RM. Focal acne during topical tacrolimustherapy for vitiligo. Arch Dermatol 2007: 143: 1223–1224.

6. Scheinfeld N. Impact of phenytoin therapy on the skin andskin disease. Expert Opin Drug Saf 2004: 3: 655–665.

7. Cohen LK, George W, Smith R. Isoniazid-induced acne andpellagra. Occurrence in slow inactivators of isoniazid. ArchDermatol 1974: 109: 377–381.

8. Tindall JP. Chloracne and chloracnegens. J Am Acad Der-matol 1985: 13: 539–558.

9. Kanzaki T. Acneiform eruption induced by lithium carbon-ate. J Dermatol 1991: 18: 481–483.

10. Duvic M. EGFR inhibitor-associated acneiform folliculitis:assessment and management. Am J Clin Dermatol 2008: 9:285–294.

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