In a reproductive‑age woman who develops fever and a pustular skin eruption a few days before her menstrual period, what are the likely diagnoses and how should it be evaluated and managed?

Premenstrual Fever and Pustules: Diagnosis and Management

Most Likely Diagnosis

The combination of fever and pustular eruption occurring cyclically before menstruation most strongly suggests autoimmune progesterone dermatitis (APD), though impetigo herpetiformis (pustular psoriasis of pregnancy) and acute generalized exanthematous pustulosis (AGEP) must be excluded. 1

Key Diagnostic Considerations

Autoimmune Progesterone Dermatitis

• APD presents with recurrent skin eruptions that correlate with peak progesterone levels in the luteal phase (7-10 days before menstruation), manifesting as pustules, urticaria, erythema multiforme-like lesions, or eczematous patches. 1
• The pathophysiology involves hypersensitivity to endogenous progesterone, with exacerbations occurring when progesterone peaks during the menstrual cycle. 1
• Fever may accompany severe flares, though it is less prominent than in impetigo herpetiformis. 1

Impetigo Herpetiformis (Pustular Psoriasis of Pregnancy)

• This rare pustular dermatosis typically occurs during pregnancy but can persist postpartum with menstrual exacerbations lasting years. 2
• One documented case showed monthly exacerbations during menstruation for 7 years postpartum, establishing that this condition can present with cyclical premenstrual flares. 2
• Clinical features include erythematous plaques studded with sterile pustules at the periphery, accompanied by high fever (>38°C), systemic symptoms (nausea, weakness), and potential complications including hypocalcemia. 3, 4
• The condition shares clinical and histological features with generalized pustular psoriasis but is triggered by hormonal changes. 2

Acute Generalized Exanthematous Pustulosis (AGEP)

• AGEP presents with widespread erythema and nonfollicular pustules, fever (>38°C), and leukocytosis, typically triggered by medications or foods. 5
• One case documented AGEP in a pregnant woman triggered by spoiled food, with fever and pustular eruption resolving after systemic corticosteroids. 5
• The key distinguishing feature is that AGEP is triggered by external exposures (drugs, foods) rather than hormonal cycles, making it less likely if symptoms recur predictably before each menstrual period. 5

Essential Diagnostic Workup

Immediate Clinical Assessment

• Document the precise timing of eruptions relative to the menstrual cycle—symptoms appearing 7-10 days before menses suggest progesterone-mediated disease, while onset during pregnancy or immediate postpartum suggests impetigo herpetiformis. 2, 1
• Examine for distribution pattern: APD can be localized or generalized; impetigo herpetiformis typically shows flexural involvement with peripheral pustule formation. 3, 4
• Assess for systemic toxicity: high fever (>38.3°C), rigors, and rapid deterioration indicate impetigo herpetiformis requiring urgent intervention. 3

Laboratory Investigations

• Obtain complete blood count (expect leukocytosis with neutrophilia in both impetigo herpetiformis and AGEP), comprehensive metabolic panel including calcium (hypocalcemia occurs in impetigo herpetiformis), and inflammatory markers (ESR, CRP). 3, 5
• Bacterial and fungal cultures of pustular contents should be sterile in all three conditions. 5
• Pregnancy test is mandatory in any reproductive-age woman with pustular eruption and fever. 3, 4

Skin Biopsy

• Histopathology shows subcorneal or intraepidermal pustules with neutrophils, spongiform pustules of Kogoj (in impetigo herpetiformis), and perivascular inflammatory infiltrate. 3, 5
• The presence of eosinophils in the infiltrate suggests AGEP rather than impetigo herpetiformis. 5

Hormonal Testing (for APD)

• Intradermal progesterone testing can confirm APD: inject 0.1 mL of aqueous progesterone (50 mg/mL) intradermally and observe for eczematous or urticarial reaction at 24-48 hours. 1
• This test should only be performed during the follicular phase (days 5-12 of cycle) when endogenous progesterone is low. 1

Management Algorithm

For Suspected Autoimmune Progesterone Dermatitis

• First-line treatment is combined oral contraceptives containing ethinyl estradiol with a progestin that has low androgenic activity, which suppresses ovulation and endogenous progesterone production. 1
• Systemic corticosteroids (prednisone 0.5-1 mg/kg/day) can be used for acute severe flares. 1
• Antihistamines provide symptomatic relief for urticarial components. 1

For Suspected Impetigo Herpetiformis

• Immediate treatment with systemic corticosteroids is mandatory: prednisolone 40-60 mg/day initially, with gradual taper based on clinical response. 3, 4
• If the patient is pregnant and deteriorating despite corticosteroids, delivery should be considered after 28 weeks gestation, as the condition may not resolve until pregnancy ends. 3
• Broad-spectrum antibiotics should be added if fever persists or secondary infection is suspected. 3
• Postpartum persistence requires continuation of corticosteroids; acitretin (0.5-1 mg/kg/day) can be added if lesions do not resolve, but this is contraindicated during pregnancy and breastfeeding. 3
• Monitor calcium levels and supplement if hypocalcemia develops. 3

For Suspected AGEP

• Identify and discontinue the triggering agent (medication or food exposure within 24-48 hours of eruption onset). 5
• Systemic corticosteroids (methylprednisolone in gradually reduced doses) accelerate resolution. 5
• Topical corticosteroids (fluocinonide 0.05% cream) and emollients provide symptomatic relief. 5
• AGEP is self-limited and resolves within 1-2 weeks after trigger removal, followed by desquamation. 5

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting biopsy results if the patient has high fever and systemic toxicity—start empiric corticosteroids immediately after obtaining cultures and biopsy. 3
• Do not attribute cyclical pustular eruptions to infection without considering hormonal triggers; bacterial cultures will be sterile in APD and impetigo herpetiformis. 5
• Do not prescribe acitretin or other retinoids to women of childbearing potential without confirming negative pregnancy test and ensuring reliable contraception, as these agents are highly teratogenic. 3
• Do not assume resolution of impetigo herpetiformis after delivery—postpartum persistence occurs and may require months of treatment. 3, 2
• Do not miss hypocalcemia in impetigo herpetiformis, as it can cause tetany and seizures; check calcium levels at presentation and monitor during treatment. 3

Monitoring and Follow-Up

• For APD, maintain a menstrual diary documenting eruption timing for at least 3 cycles to confirm the diagnosis and assess treatment response. 1
• For impetigo herpetiformis in pregnancy, perform serial ultrasounds and cardiotocography to monitor fetal well-being, as the condition carries risk of placental insufficiency and fetal complications. 4, 5
• After resolution, counsel patients with impetigo herpetiformis that recurrence in subsequent pregnancies is common and may occur earlier and more severely. 3