Approach
Clinical history and exam are the basis for determining which etiologic group the pustular rash belongs to. Diagnostic tests may also help differentiate the numerous causes of a pustular rash. For example, a positive bacterial, viral, or fungal culture would point to an infectious etiology. Eosinophils present in a skin biopsy might indicate a drug reaction.
History
History helps differentiate between the various etiologies causing pustular eruptions. Important components of the history include:
Time of onset and duration of rash
Onset within minutes
Fire ant bites result in immediate severe burning and itching at the sting sites. Localized hive develops at the sting site within 20 minutes, followed by a necrotic lesion, termed the sterile pustule, which lasts for several days.[32]
Onset with hours
In generalized pustular psoriasis (von Zumbusch type) there is a sudden eruption (within a few hours) of generalized sterile pustules.
Onset within days
Infantile scabies should be suspected in infants or children with generalized pruritus of recent onset.
Erythema toxicum neonatorum starts soon after birth and disappears spontaneously within a few weeks without sequelae.[30]
Congenital candidiasis is acquired in utero and presents at birth or within the first few days of life. In neonatal candidiasis, mucocutaneous Candida infection, acquired during or after delivery, develops after the first few days of life.[67]
Acute generalized exanthematous pustulosis (AGEP) may occur as a sudden eruption soon after, or within 1 to 2 weeks of, exposure to certain medications; rash lasting 6 to 31 days followed by desquamation.[68][69]
Onset within weeks
Drug rash with eosinophilia and systemic symptoms (DRESS) starts within 8 weeks after initiation of therapy.[46]
Corticosteroid-induced rosacea-like eruption/corticosteroid acne occurs weeks or months after initiation of corticosteroid therapy.[70]
In syphilis, secondary-stage lesions generally appear 2 to 12 weeks after initial appearance of primary lesions.[6]
In amicrobial pustulosis of the folds (APF), relapsing pustular lesions frequently have a chronic course with recalcitrant relapses. There is usually no relation between course of the cutaneous lesions and activity of associated autoimmune disorder.[41][71]
Neonatal cephalic pustulosis (neonatal acne) may be present at birth, but more frequently appears at 2 to 3 weeks of age and resolves spontaneously.
Systemic findings or constitutional changes associated with the onset or prior to the rash
In primary infection, HSV-1 mainly causes painful gingivostomatitis.[64]
Malaise, sore throat, headache, weight loss, low-grade fever, pruritus, and muscle aches may occur with secondary syphilis.[6]
In generalized pustular psoriasis (von Zumbusch type) pustules usually erupt in waves with recurrent bouts of fever, arthralgias, and myalgias.[50]
Behcet disease is characterized by oral aphthae and by at least 2 of the following: 1) genital aphthae, 2) synovitis, 3) posterior uveitis, 4) cutaneous pustular vasculitis, 5) meningoencephalitis, 6) recurrent genital ulcers, 7) uveitis in the absence of inflammatory bowel disease or collagen vascular disease.[23][Figure caption and citation for the preceding image starts]: Mouth and genital ulcers in Behcet diseaseFrom the collection of Dr Yusuf Yazici; used with permission [Citation ends].
Reactive arthritis classically includes the triad of conjunctivitis, urethritis, and arthritis in young male patients after gastrointestinal or urogenital infection; patients with reactive arthritis also manifest mucocutaneous symptoms: keratoderma blennorrhagicum, circinate balanitis, ulcerative vulvitis, nail changes, and oral lesions.[38]
In acne vulgaris, irregular menses, increased weight, diabetes, and/or hirsutism may point to androgen excess, resulting in acne lesions; congenital adrenal hyperplasia, PCOS, and other endocrine disorders with excess androgens may trigger development of acne vulgaris.[72][Figure caption and citation for the preceding image starts]: Nodulocystic acneUniversity of Michigan Department of Dermatology [Citation ends].
Drug history
Enquire about any new medications or treatment around the time that the rash began and response to any medications used to treat the rash.
Pityrosporum folliculitis incidence can be associated with either immunosuppressive or chemotherapy treatment.[73]
Pustular drug rash secondary to epidermal growth factor receptor (EGFR) inhibitors (cetuximab, erlotinib, gefitinib) may appear between 1 to 3 weeks after onset of EGFR inhibitor treatment for colorectal or non-small cell lung cancer.[43]
Acute generalized exanthematous pustulosis (AGEP) may occur, often in female patients, after exposure to antimicrobials (commonly aminopenicillins and macrolides), diltiazem, sulfonamides, terbinafine, quinolones, acetaminophen, progesterone preparations, or mercury.[68][69]
In generalized pustular psoriasis (von Zumbusch type) there may be a history of drug administration with coal tar, iodides and minocycline, or corticosteroid withdrawal.[50]
In candidal infection and disseminated candidiasis, risk factors include treatment with broad-spectrum antibiotics and corticosteroid treatment.[12][Figure caption and citation for the preceding image starts]: Infant presenting with rash formerly known as moniliasis, now called candidiasis, caused by Candida sppPublic Health Image Library, CDC [Citation ends].
In perioral dermatitis, overhydration of skin caused by frequent use of occlusive moisturizing emollients leads to irritation and impairment of skin barrier function; abuse of topical corticosteroids can be another triggering factor in some cases.[74]
Drug rash with eosinophilia and systemic symptoms (DRESS) starts within 8 weeks after initiation of therapy.[46] Medication history may include carbamazepine, phenytoin, phenobarbital, zonisamide, mexiletine, dapsone, sulfasalazine and allopurinol, sulfonamides, allopurinol, gold salts, dapsone and minocycline.
Gram-negative folliculitis should be considered in acne patients without significant improvement of acne lesions after 3 to 6 months of treatment with oral tetracyclines.[5]
Folliculitis is a rare manifestation of herpes virus infection, and should be considered in patients with folliculitis refractory to antibiotic or antifungal treatment.[75]
Past medical history
Psoriasis may be associated with pustular psoriasis.[55]
Inflammatory bowel disease may be associated with pyoderma gangrenosum.
Immunosuppression can be associated with eosinophilic folliculitis (Ofuji syndrome/disease), folliculitis caused by herpes virus candidal infection, and disseminated candidiasis.
In generalized pustular psoriasis (von Zumbusch type) there may be a history of impetigo herpetiformis in prior pregnancy or a history of trigger factors such as infections (e.g., URTI), pregnancy, hypocalcemia, and hypoparathyroidism.[50]
In pustulosis palmaris et plantaris (PPP), focal infection, such as tooth infection or tonsillitis, is a well-known exacerbating factor.[76]
Amicrobial pustulosis of the folds (APF) occurs typically in association with an autoimmune or connective tissue disease, including SLE, scleroderma overlap syndrome, discoid lupus erythematosus, sicca syndrome, celiac disease, idiopathic thrombocytopenia, or myasthenia gravis.[41][71]
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease), eosinophilic folliculitis (Ofuji syndrome/disease), infantile acropustulosis (IA), acrodermatitis continua, pustulosis palmaris et plantaris (PPP), Behcet disease, and amicrobial pustulosis of the folds are recurrent conditions.
Family members with similar signs and symptoms or any sick contacts
In infantile scabies history of itching in other family members should be sought and may help diagnosis.[16][Figure caption and citation for the preceding image starts]: Scabies: characteristic linear burrows in skinFrom the collection of Dr Laura Ferris; used with permission [Citation ends].
In generalized pustular psoriasis (von Zumbusch type) there may be a family history of psoriasis.
Occupational history (e.g., contact with animals or fomites)
In cases of dermatophytosis tinea barbae, farm workers are most often affected because the usual cause is a zoophilic organism.[77][Figure caption and citation for the preceding image starts]: Tinea barbae. Note the pustules in the follicles, redness, and scalingDepartment of Dermatology Medical University of South Carolina; used with permission [Citation ends].
In orf, there may be a history of contact with lesions on animals (usually sheep or goats) or contaminated fomites.[10]
Environmental exposure
History of exposure to contaminated water in hot tubs, swimming pools, saunas, and hydrotherapy pools that are underchlorinated may suggest folliculitis caused by Pseudomonas.[78]
Pityrosporum folliculitis is more prevalent in hot and humid climates.[73]
Miliaria rubra ("prickly heat") presents in overheated and febrile infants[33] and less commonly in adults.[35][Figure caption and citation for the preceding image starts]: Miliaria rubraFrom the collection of Brian L. Swick; used with permission [Citation ends].
Herpes simplex virus reactivation can be triggered by UV light exposure.
Clinical exam
A thorough clinical exam is essential in finding the etiology for the pustular rash. Important considerations for the physical exam include:
Size
Folliculitis typically presents with multiple small papules and pustules on an erythematous base.[Figure caption and citation for the preceding image starts]: Superficial folliculitis with prominent erythematous papules and pustulesFrom the collection of Dr Professor Baden; used with permission [Citation ends].
In folliculitis due to Pseudomonas, 2- to 10-mm follicular papules, vesicles, and pustules, which may be crusted, are mostly seen in areas of the body that have been immersed in the contaminated water.[78]
In bullous impetigo, blisters are usually less than 3 cm in diameter.[2][Figure caption and citation for the preceding image starts]: Neonate with bullous impetigoFrom the collection of Michael Freeman; used with permission [Citation ends].
In generalized pustular psoriasis (von Zumbusch type), pustules are 2 to 3 mm in diameter usually on an erythematous base; pustules may coalesce into larger lakes of pus.
In transient neonatal pustular melanosis, superficial, 2- to 10-mm vesiculopustules without inflammation are present at or near birth.
In secondary syphilis, lesions are typically reddish brown and 3 to 10 mm in size.[Figure caption and citation for the preceding image starts]: Secondary syphilitic lesions on the facePublic Health Image Library, CDC [Citation ends].
In infantile scabies, the pathognomonic scabies burrow is an elevated white and serpiginous tract 0.3 to 0.5 mm by 10 mm long.[Figure caption and citation for the preceding image starts]: Scabies: characteristic linear burrows in skinFrom the collection of Dr Laura Ferris; used with permission [Citation ends].
In perioral dermatitis, erythematous papules or papulopustules are usually not larger than 2 mm.
In milia rubra, 1- to 3-mm erythematous, nonfollicular-based papules and papulopustules appear due to heat.[Figure caption and citation for the preceding image starts]: Miliaria rubraFrom the collection of Brian L. Swick; used with permission [Citation ends].
Location and distribution
Impetigo and folliculitis caused by Staphylococcus aureus more commonly occur in areas of traumatised skin.
Folliculitis will usually occur on a hair-bearing site.[Figure caption and citation for the preceding image starts]: Superficial folliculitis with prominent erythematous papules and pustulesFrom the collection of Dr Professor Baden; used with permission [Citation ends].
Tinea barbae involves skin and coarse hairs of the beard and mustache area.[15][Figure caption and citation for the preceding image starts]: Tinea barbae. Note the pustules in the follicles, redness, and scalingDepartment of Dermatology Medical University of South Carolina; used with permission [Citation ends].
In pseudofolliculitis barbae, papules and pustules appear most commonly in the beard distribution; anterior neckline, mandibular areas, cheeks, and chin are the most common sites. There is a history of shaving or tweezing the affected area.[26]
Tinea cruris occurs in the groin area.
Tinea corporis presents on the trunk, extremities, or face.[79][Figure caption and citation for the preceding image starts]: Tinea corporis of the axilla. Central clearing with an active border of inflammation noted. Satellite lesion is presentDepartment of Dermatology Medical University of South Carolina; used with permission [Citation ends].
Tinea pedis presents with fungal maceration, and fissuring of the soles of the feet.[Figure caption and citation for the preceding image starts]: Tinea pedis. Intense inflammation produces hyperpigmentation and vesicle formation. Vesiculobullous form of tinea pedisDepartment of Dermatology Medical University of South Carolina; used with permission [Citation ends].
In acrodermatitis continua, lesions begin on 1 digit, but other digits may become involved during the chronic course of the disease.
Pustular drug rash secondary to epidermal growth factor receptor (EGFR) inhibitors (cetuximab, erlotinib, gefitinib) commonly affects the face (nose, cheeks, nasolabial folds, chin, forehead), areas of the upper chest and/or back.[43]
Acute generalized exanthematous pustulosis (AGEP) is localized mainly to main folds (neck, axillae, groins).[68]
Transient neonatal pustular melanosis occurs predominantly on the forehead, back, posterior neck, and shins.[33]
Pustulosis palmaris et plantaris (PPP) is characterized by multiple pustules and erythematous plaques on palms and soles.[76]
In gram-negative folliculitis, lesions are limited to the face. Lesions consist of superficial small pustules located in the nasolabial line and on the upper lip and chin, associated with inflammatory papulopustular lesions of the cheeks and perioral region, or deeply sited and painful nodules of the cheeks.[80]
In secondary syphilis, painless coin-like macular lesions appear on the flank, shoulders, arms, chest, back, hands, and soles of the feet; lesions are typically reddish brown and 3 to 10 mm in size; variations of secondary syphilis skin eruptions may include pustules;[Figure caption and citation for the preceding image starts]: Secondary syphilitic lesions on the facePublic Health Image Library, CDC [Citation ends].
other associated lesions include patchy (moth-eaten) alopecia, genital lesions (condylomata lata), superficial mucosal erosions (mucus patches).[6]In perioral dermatitis, although perioral is the most frequent location, periocular areas, nasolabial folds, and glabella may also be affected.[40]
Neonatal cephalic pustulosis (neonatal acne) is characterized by small, inflammatory, erythematous papules and pustules found on the cheeks, forehead, and scalp.[33]
In ulcerative or typical pyoderma gangrenosum, the lower extremity is the most common site of involvement.
In amicrobial pustulosis of the folds (APF), the lesions predominate in the cutaneous folds, the scalp, the genital area, and the external auditory canal.[41]
Erosive pustular dermatosis occurs on actinically damaged scalp skin.
Pattern of the pustules (e.g., are the pustules grouped, intact, associated with surrounding erythema, diffuse versus localized, or in a dermatomal distribution?)
In herpes simplex virus, initial lesions appear as erythematous papules that turn into grouped vesicles and pustules eventuating into crusts.[81]
In acne vulgaris, papules and pustules are associated with comedones.[Figure caption and citation for the preceding image starts]: Nodulocystic acneUniversity of Michigan Department of Dermatology [Citation ends].
In infantile scabies, classical eruption of scabies presents as pruritic papules, vesicles, pustules, and linear burrows.[Figure caption and citation for the preceding image starts]: Scabies: characteristic linear burrows in skinFrom the collection of Dr Laura Ferris; used with permission [Citation ends].
In amicrobial pustulosis of the folds (APF), cutaneous eruption consists of small follicular and nonfollicular sterile pustules, coalescing into erosive plaques.[41]
Other clinical considerations are as follows:
Does the patient have fever?
Fever may be found in acute generalized exanthematous pustulosis (AGEP), pustular psoriasis, and cellulitis.
Are there other associated skin findings?
Erosions, ulcerations, and sinus tracts may be found in pyoderma gangrenosum.
Pitting of nails can be seen in pustular psoriasis.
Are there other systemic signs?.
In generalized pustular psoriasis (von Zumbusch type), synovitis can be found in patients with related psoriatic arthritis.
Oral and genital ulcers may be present in Behcet disease.[23][Figure caption and citation for the preceding image starts]: Mouth and genital ulcers in Behcet diseaseFrom the collection of Dr Yusuf Yazici; used with permission [Citation ends].
Patients with reactive arthritis may have conjunctivitis and mucocutaneous symptoms: keratoderma blennorrhagicum, circinate balanitis, ulcerative vulvitis, nail changes, and oral lesions.[38][Figure caption and citation for the preceding image starts]: Pustules in a patient with reactive arthritisPublic Health Image Library, CDC [Citation ends].
Diagnostic tests
Diagnostic tests are not always necessary. It is possible to make a confident clinical diagnosis of conditions such as perioral dermatitis, miliaria rubra ("prickly heat"), acne vulgaris, pustular rosacea, corticosteroid-induced rosacea-like eruption and corticosteroid acne.
Further diagnostic tests are selected depending on the likely differential diagnosis and may include microbiological tests, blood tests and skin biopsy.
Microbiological tests
Gram stain is indicated in suspected bacterial and fungal infections. It may be ordered to exclude infection in some inflammatory conditions, e.g., erythema toxicum neonatorum and neonatal cephalic pustulosis.
Skin culture for bacteria is indicated if a bacterial infection is suspected.
Potassium hydroxide (KOH) smears demonstrate hyphae and spores in fungal infection. They are indicated if a yeast or fungal infection is suspected and provide a rapid diagnosis of a fungal cause.
In candidal infection and disseminated candidiasis, serologic 1,3 beta-glucan assay can be done for further confirmation.
Skin culture for fungi is indicated if a fungal or yeast infection is suspected.
Tzanck smear can be done if herpes simplex virus is suspected. Further testing for confirmation of herpes simplex virus includes direct immunofluorescence study and DNA analysis via PCR. Skin culture for herpes viruses may be indicated in some immunosuppressed patients.
VDRL and RPR are indicated for initial testing if clinical features of secondary syphilis are present, with further confirmation with darkfield microscopy: direct visualization of organism, FTA-ABS test, microhemagglutination assay for Treponema pallidum, or histology of skin biopsy.
Microscopic mineral preparation for the presence of Sarcoptes scabiei mites, eggs, or feces (scybala) should be done if features of infantile scabies are present.
Blood tests
Comprehensive metabolic panel and CBC may be abnormal if there are systemic symptoms associated with the patient's disease. These tests may be necessary prior to, or during systemic treatment. CBC may show changes consistent with an infectious etiology for the pustular rash.
A metabolic panel is indicated in cases of acute generalized exanthematous pustulosis (AGEP) and generalized pustular psoriasis (von Zumbusch type) to evaluate for hypocalcemia.
ESR will be elevated in generalized pustular psoriasis (von Zumbusch type).
In cases of acne vulgaris, the diagnosis is usually clinical; however, further tests to evaluate the underlying cause should be considered in female patients and include free testosterone and dehydroepiandrosterone sulfate to evaluate for PCOS or an androgen-secreting tumor. LH may be elevated in PCOS. FSH may be elevated in primary ovarian failure.
Additional testing after CBC and skin biopsy in drug rash with eosinophilia and systemic symptoms (DRESS) should include liver function tests, serum creatinine level and TSH.
Skin biopsy
Skin biopsy for routine histology and special staining should be done if the clinician narrows down the differential diagnosis, but is not absolutely sure of the diagnosis based on history and clinical exam of the patient. Special stains can help determine if the pustular rash is due to an infectious cause.
Other investigations
After skin biopsy, further testing includes serum protein electrophoresis and immunofluorescence in subcorneal pustular dermatosis (Sneddon-Wilkinson disease).
Skin testing, ELISA, or RAST will confirm fire ant hypersensitivity in suspected fire ant bites.
Rechallenge with the suspected drug, patch testing, interferon-gamma release assay, or in vitro testing with a macrophage migration inhibition factor test or mast cell degranulation test, are confirmatory tests for AGEP.
Plain x-ray of the involved joints, joint aspiration, and skin biopsy are indicated in reactive arthritis.
Additional testing after CBC and skin biopsy in drug rash with eosinophilia and systemic symptoms (DRESS) should include urinalysis and chest x-ray.
In typical and atypical pyoderma gangrenosum, the following tests should be done to evaluate the underlying cause: hepatitis profile, serum and/or urine protein electrophoresis, peripheral blood smear, bone marrow aspiration for evidence of hematologic malignancies, and investigations to exclude associated inflammatory bowel disease such as ulcerative colitis.
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