Acute generalized exanthematous pustulosis is a rare but severe skin reaction, typically triggered by certain medications. It usually presents with sudden eruptions of sterile pustules on a red, swollen base. These pustules are non-infectious and usually accompanied by fever, elevated white blood cell counts (especially neutrophils), and sometimes mild organ involvement.

What is Acute Generalized Exanthematous Pustulosis?

AGEP is classified as a severe cutaneous adverse reaction (SCAR). The rash often begins within 1 to 5 days after drug exposure and rapidly spreads across the body, commonly affecting the face, armpits, groin, and trunk.

Though the condition is self-limiting and usually resolves within two weeks after the offending drug is stopped, hospitalization may be necessary in some cases due to systemic symptoms like high fever, dehydration, or organ stress. AGEP affects an estimated 1 to 5 individuals per million each year.¹

What causes Acute Generalized Exanthematous Pustulosis?

This skin condition is most frequently triggered by medications. Especially antibiotics of the class “β-lactams”. In rare cases, infections or environmental exposures can be the cause. Examples of drugs that have been linked with it include:²

Medication Type	Examples
Antibiotics	Amoxicillin Ampicillin Cephalosporins Ciprofloxacin Erythromycin Trimethoprim-sulfamethoxazole
Antifungals	Terbinafine Fluconazole
Antimalarials	Hydroxychloroquine Chloroquine
Antivirals	Oseltamivir Acyclovir
Calcium Channel Blockers	Diltiazem Nifedipine
Anti-epileptics	Carbamazepine Lamotrigine
NSAIDs	Ibuprofen Diclofenac Naproxen
Proton Pump Inhibitors	Omeprazole Lansoprazole
Psychotropic Drugs	Clozapine Olanzapine

Risk Factors of Acute Generalized Exanthematous Pustulosis

Medications are the cause behind this skin condition, but there are certain risk factors that can influence whether you will develop the condition or not. These include;

Age & Sex:

Acute generalized exanthematous pustulosis tends to affect adults aged 40 to 64 the most. It has a clear female predominance. Women represent up to 80% of reported cases, possibly due to hormonal aspects and differences in how women’s bodies process medications.

Medication Practices:

The risk of this skin condition grows when multiple drugs are being used, or if you’ve been hospitalized and exposed to various treatment protocols.

Genetic Factors:

Certain genetic predispositions increase the likelihood of this skin condition. If you have specific genetic markers like HLA-B51 or mutations in the IL36RN gene, your immune system might react more aggressively to medications and trigger a reaction like this condition.

Immune Dysfunction:

Those with a weak immune system or autoimmune conditions could be more susceptible to acute generalized exanthematous pustulosis. This is because your body might struggle to regulate its response to medications.

Geographic Variability:

In some regions, certain drugs are more commonly linked to acute generalized exanthematous pustulosis. For example, pristinamycin in France is a well-known trigger.³

Symptoms of Acute Generalized Exanthematous Pustulosis

The first symptoms come on within 24 to 48 hours after taking a medication. These include:

Rash with Pustules on Red Skin:

The skin rash in this skin condition is quite distinctive. It shows up as many small, non-infectious pustules (pinhead-sized pus bumps) on a background of red, swollen skin.
These pustules do not come from hair follicles, and they can number from a few to hundreds. The rash mainly affects larger folded areas like your armpits, groin, and creases. No bacteria are present, and it is sterile.

Red inflamed skin with small pustules — Acute generalized exanthematous pustulosis. Image credits: Wikimediamedia Medcoms under CC BY 1.0

You may also experience an intense itch called pruritus. Other skin phenomena like blisters and purpura may also be present.

Mucous Membrane Involvement:

Although the condition usually spares the mouth and other mucous membranes, about 20% of people may have mild involvement, such as redness or discomfort in the lips or inside the mouth. It usually affects just one area and isn’t erosive or deep.

Features other than Skin:

There are several clinical manifestations beyond skin, such as:

Swelling of the face
A high fever over 38°C/ 100.4
Malaise and feeling ill
But in some cases (about 17%), internal organs like the liver, kidneys, or lungs may be affected. The liver can show elevated enzymes, sometimes with fatty liver or liver swelling on ultrasound. Some may develop pleural effusions or fluid around the lungs.⁴

Pathology of Acute Generalized Exanthematous Pustulosis

This skin condition is specifically a Type IV hypersensitivity reaction. It is a delayed, T-cell-mediated immune reaction.

Drug Exposure & Immune Recognition:

When a person takes a triggering medication, the drug or its metabolites may bind to proteins in the body. These new complexes are recognized as foreign by T-cells, especially CD4+ and CD8+ T lymphocytes.

These T-cells are “primed” to see the drug as harmful. Once re-exposed to the drug, even in small amounts, the immune system is rapidly activated.

T-Cell Activation & Immune Response:

Once activated, the T-cells proliferate and release cytokines, chemical messengers that drive inflammation. Key cytokines involved include:

IIL-8, which strongly attracts neutrophils to the skin
GM-CSF, which promotes white blood cell survival and function
IFN-γ and TNF-α increase the intensity of the immune response, causing damage to skin cells

Neutrophil Recruitment & Pustule Formation:

Following the cytokine release, large numbers of neutrophils are drawn to the outer layers of the skin. These neutrophils accumulate in the upper epidermis and cause:

Formation of tiny bacteria-free pustules filled with neutrophils.
The skin becomes red, swollen, and studded with these pinhead-sized pustules.
Unlike typical allergic rashes, acute generalized exanthematous pustulosis shows a very rapid onset and massive neutrophilic response, not just itching or redness.

In addition to neutrophils, eosinophils (often involved in allergies) and cytotoxic T-cells may contribute. These can:

Trigger apoptosis (cell death) in skin cells (keratinocytes).
Contribute to mild vasculitis (inflammation of small blood vessels).
This results in collateral tissue damage and further swelling.

Resolution Mechanism:

Once the drug is discontinued, the immune system gradually “stands down.”

The cytokine signals stop, and neutrophils reduce
Pustules dry up. Skin starts to peel and heal, typically over 1 to 2 weeks.
No long-term scarring occurs, though severe cases may involve organs.
In some rare cases, re-exposure to the same drug can trigger the reaction again, often more severely.⁵

What is seen in Acute Generalized Exanthematous Pustulosis histology?

Doctors can view your skin samples and observe certain changes in your skin’s histology if you have this skin condition, such as:

Spongiform pustules that are located just below the stratum corneum and within the epidermis, filled with neutrophils
Papillary dermal edema from inflamed blood vessels
Perivascular infiltrates composed of neutrophils, mixed with eosinophils and lymphocytes
Exocytosis of inflammatory cells from the dermis into the epidermis
Focal necrosis of keratinocytes
Mild vasculitis⁶

How is Acute Generalized Exanthematous Pustulosis diagnosed?

Diagnosis of acute generalized exanthematous pustulosis is largely clinical. The EuroSCAR scoring system is often used to confirm this skin condition.

History & Physical Exam:

Doctors will ask you about any drugs you’ve just started prior to the development of the rash, as well as other medical history that can raise suspicion of this condition. The exam will include inspection of your skin with the naked eye as well as under a dermatoscope.

Investigations:

The doctor will request several blood tests to look for signs of inflammation or infection.

A CBC checks your white blood cells. In acute generalized exanthematous pustulosis, the white blood cell count is usually high, especially a type called neutrophils. Sometimes, another type of white blood cell called eosinophils is also increased.
Inflammatory markers such as CRP and ESR may be higher than normal, showing that the body is reacting to something.
Liver/ kidney function tests are done to make sure that your internal organs are working well and not affected by the reaction or by any medicines.
Serum electrolytes are tested to check for any imbalances, especially if you have fever, dehydration, or peeling skin.
A skin biopsy is one of the most important tests for diagnosing this skin condition. The biopsy also helps rule out other diseases, such as pustular psoriasis or drug reactions like Stevens-Johnson’s syndrome.
If needed, fluid from the pustules may be collected and sent for a pus culture to check for infection. In this skin condition, no bacteria grow in the culture. This helps confirm that the pustules are due to inflammation rather than an infection.
Patch testing is not done during the acute phase, but can be done later after recovery. It helps identify the exact drug that caused the reaction, especially if you were taking multiple medications. A small amount of the suspected drug is applied to your skin to check for a delayed allergic reaction.

EuroSCAR Scoring System:

Doctors use a special scoring system called EuroSCAR to help figure out if you have acute generalized exanthematous pustulosis using different clinical features. Each part gives points, and the total score tells the doctor how likely it is that you have the condition.

A score of 0 or less means it’s almost definitely not acute generalized exanthematous pustulosis.
A score of 1 to 4 means it might be acute generalized exanthematous pustulosis, but we can’t say for sure.
A score of 5 to 7 means it’s probably acute generalized exanthematous pustulosis.
A score of 8 to 12 means it’s almost definitely acute generalized exanthematous pustulosis.

Method of Scoring

Your doctor carefully examines your skin, reviews test results, and looks at biopsy samples. Points are awarded or taken away based on the details below:

Pustules on the skin

No pustules, or hard to tell: 0
A few, not very typical ones: +1
Many pustules that match AGEP: +2

Redness of the skin

No redness or can’t say: 0
Some redness but unclear: +1
Bright, widespread redness: +1

How the rash spreads

Spread is unclear or can’t be traced: 0
Started on the face or skin folds and spread fast to arms, legs, or chest: +2

Skin peeling after the rash

No peeling, or hard to say: 0
Skin peeled after rash went down: +1

Mouth or eye involvement

If your mouth or eyes are affected: −2
If not affected: 0

When the rash appeared

If it started more than 10 days after taking the suspected drug: −2
If it started within 10 days: 0

How long did the rash last

More than 15 days: −4
Got better within 15 days: 0

Fever

If you had a fever of 38°C or higher: +1
If you didn’t have a fever or it was lower: 0

White blood cell count

WBC count above 7,000: +1
Normal or low WBC: 0

What the Skin Biopsy Shows

The biopsy helps a lot with diagnosis. If it clearly shows a different condition, your doctor will subtract 10 points. If the biopsy doesn’t help or wasn’t done, it’s counted as 0 points.

But if the biopsy matches AGEP, here’s how it adds up:

Neutrophils (a type of white cell) pushing into the upper layers of the skin: +1
Small pustules with swelling in the top skin layers: +2
Special “spongy-looking” pustules with swelling (called spongiform pustules): +3⁷

Treatment for Acute Generalized Exanthematous Pustulosis

Managing this skin condition mostly comes down to stopping the medicine that caused it and giving your body the support it needs to recover.

Stop the Triggering Medicine:

The first and most important step is to identify and stop the medicine that caused your body to react. Most cases are triggered by antibiotics, and the rash often improves within a few days after stopping the drug.

Symptomatic Relief:

To make you more comfortable while your skin heals, doctors may use:

Moisturizers to soothe dry, peeling skin
Topical corticosteroids to reduce redness and inflammation
Oral antihistamines to help with itching
Pain relievers (like paracetamol) to manage fever and discomfort
In more severe cases, your doctor might prescribe oral or intravenous steroids (like prednisone) to manage the immune response and speed up recovery during the acute stage.

Supportive Hospital Care:

applying moisturizer to the irritated skin - Acute Generalized Exanthematous Pustulosis — Moisturizing creams reduce itching associated with acute exanthematous pustulosis

This skin condition can be intense, especially in the early phase. Many patients need short-term hospital care for:

Fluid and electrolyte replacement, especially if there’s fever, peeling skin, or dehydration.
Close monitoring of symptoms and any complications.⁸

Can Acute Generalized Exanthematous Pustulosis come back?

Recurrence of this skin condition is rare but possible if the patient is re-exposed to the drug. So, avoid the medicine that caused it. Make sure it’s noted in your medical record. Let all your healthcare providers know to prevent accidental re-exposure.

Acute Generalized Exanthematous Pustulosis vs Pustular Psoriasis

Acute generalized exanthematous pustulosis is an acute drug reaction that resolves quickly after stopping the medication. Meanwhile, pustular psoriasis is a chronic autoimmune disease with recurrent flares. The pustules of this skin condition are small, sterile, and short-lived, whereas pustular psoriasis features larger, longer-lasting pustules. Fever is more common in acute generalized exanthematous pustulosis.⁹

Conclusion

This skin condition is a type of hypersensitivity type IV reaction to certain medications. It results in the formation of pustules on your body immediately after you’re exposed to the trigger. Treatment requires stopping the causative agent immediately and providing supportive care. Acute generalized exanthematous pustulosis recurrences happen when you keep taking the causative agent.

Refrences

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Szatkowski, J., & Schwartz, R. A. (2015). Acute generalized exanthematous pustulosis (AGEP): A review and update. Journal of the American Academy of Dermatology, 73(5), 843–848. https://doi.org/10.1016/j.jaad.2015.07.017
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Acute Generalized Exanthematous Pustulosis: Causes & Treatment

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