Impetigo herpetiformis L40.1

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Dr. med. Jeton Luzha

All authors of this article

Last updated on: 23.10.2023

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Generalized pustular psoriasis of pregnancy; Impetigo herpetiformis Hebra-Kaposi; pustular psoriasis hypocalcaemica

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Kaposi, 1887

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Historical term for a rare, pregnancy-induced variant of pustular psoriasis generalisata. Clinically, there is a usually acute, generalized pustular clinical picture that is interpreted as the clinical manifestation of a previously latent, or de novo developing, pustular psoriasis generalisata in pregnancy.

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The etiology of impetigo herpetiformis (Ih) is not yet clear.

Genetics: According to some evidence, such as familial cases, genetic factors may influence the manifestation of impetigo herpetiformis. In impetigo herpetiformis, homozygous and heterozygous IL36RN mutations have been detected in Chinese and Japanese women (Sugiura K et al. (2015). The protein encoded by the IL36RN gene, IL-36 receptor antagonist IL-36Ra, is a member of the interleukin-1 cytokine family. This protein is found primarily in the skin, where it helps regulate inflammation, which is part of the body's early immune response. The IL36RN mutation is thought to have a significant etiopathogenetic role (e.g., in preventing potential risk to the mother and fetus) (Namazi N et al. 2018).

Hypocalcemia: Although it is difficult to always establish a causal relationship, other constellations may be associated with impetigo herpetiformis, such as hypocalcemia. Causative factors for hypocalcemia in impetigo herpetiformis include hypoparathyroidism, hypoalbuminemia, low vitamin D levels, and a decrease in ionized serum calcium concentration due to malabsorption (Namazi N et al 2018).

Medications: Furthermore, various medications also seem to be able to trigger impetigo herpetiformis. For example, an Ih developed at 34 weeks of gestation after a five-day course of N-butyl scopolammonium bromide. Ritodrine hydrochloride, a drug used to suppress premature uterine contractions, can also induce Ih, as can hydroxychloroquine (Guerriero C et al. 2008; Kuwabara Y ert al. 2011; Liu J et al. 2022).

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Pregnant women; age: 20-40 years; especially in the 2nd half of pregnancy. Recurrence is possible with each subsequent gravidity.

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Trunk, especially intertriginous area, also extremities. Mucous membrane: Mouth and upper respiratory tract.

Clinical features
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Acute onset with severe impairment of general condition, with marked feeling of illness, fever, chills, possibly diarrhea.

Initial bruising, exanthema with highly red, extensive erythema and plaques. After a few days, disseminated or grouped, 0.1-0.2 cm, white, non-follicular pustules develop on these areal lesions, which may later confluence to form larger "pus lakes."

Formation of anular formations is possible. Healing with formation of inwardly directed, collerette-like scaly seams.

Occurrence of erythroderma is possible.

Symptoms of hypocalcemia may develop (low serum calcium, tetany, Chvostek's sign).

This very rare pregnancy dermatosis is associated with the highest risk for the pregnant woman and fetus compared to the other pregnancy dermatoses.

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Dysproteinemia; leukocytosis; neutrophilia; iron deficiency with anemia; decreased serum calcium; decreased Vit D3 levels; markedly accelerated ESR; CRP is elevated.

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Differential diagnosis
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An important aspect of impetigo herpetiformis are the complications that can endanger the life of mother and child . A significant proportion of these complications are related to placental insufficiency and electrolyte imbalance, in addition to alterations in serum calcium.

Systemic symptoms such as nausea, vomiting, fever, chills, diarrhea, hypovolemic shock, seizures, and malaise, as well as laboratory findings such as leukocytosis, elevated ESR, hypocalcemia, hypoalbuminemia, and iron deficiency anemia may be associated with Ih.

In women diagnosed with impetigo herpetiformis at 32 weeks' gestation, gestational hypertension may exacerbate the condition.

In addition, impetigo herpetiformis has been associated with increased prenatal complications such as intrauterine growth restriction secondary to placental insufficiency, premature rupture of membranes, and even stillbirth. There is also a report of an infant born with central hypoventilation syndrome.

Recurrence has been described in up to nine pregnancies in one woman. This was also triggered by the use of oral contraceptives (combination of ethinyl estradiol and progesterone) in the same patient (Namazi N et al. 2018)....

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Cooperation with internists and, if necessary, gynecologists. In pregnancy, an interruptio or an early sectio should be considered due to high mortality of mother and child in case of pronounced symptoms.

External therapy
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Dehydrating measures. Application of ethanolic zinc oxide shaking mixture or dye brushes, e.g. with potassium permanganate (light pink) or methylrosanilinium chloride solution (gentian violet) to avoid secondary infections.

In addition, topical glucocorticoids such as 0.1% triamcinolone cream, 0.25% prednicarbate (e.g. Dermatop cream), 0.1% mometasone (e.g. Ecural fat cream) for improved healing of the skin as well as in case of highly inflammatory components.

Internal therapy
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There are few robust data on the treatment of impetigo herpetiformis. The main challenge is a possible critical condition of mother and child. Furthermore, the possible teratogenicity of the drugs used must be considered.

Although numerous treatment suggestions for impetigo herpetiformis exist, there are no specific guidelines due to the rarity of the disease. They are mostly based on individual case reports. Fluid and electrolyte imbalances, especially hypovolemia, hypocalcemia, and low vitamin D levels, should be corrected promptly (Oumeish O et al 1982).

In the last decade, many patients have been treated with ciclosporin, corticosteroids, TNF-alpha inhibitors, interleukin (IL)-17 and IL-12/23 inhibitors, and granulocyte and monocyte adsorption apheresis. Single-case reports are available on these.

Granulocyte and monocyte adsorption apheresis may be an important option for patients with impetigo herpetiformis, as it is currently considered one of the therapeutic options with the fewest complications. Based on recent pathogenetic findings on the role of the IL-36 axis in psoriasis acuta generalisata and AGEP, biologic agents targeting the IL-36 pathway may also be an option in Ih (Seishima M et al. 2022). Furthermore, substitution of parathyroid hormone with dihydrotachysterol (eye drops 10) and calcium replacement according to blood levels (in tetany: 20 ml calcium solution 10%) should be sought. Caution. Digitized patients!

Therapeutic agents in detail:

Corticosteroids: Systemic corticosteroids (e.g. prednisolone), used in the past in the treatment of pustular psoriasis, are still the first-line drugs in I.h. Empfehelnswert is prednisolone in a dosage of 60-80 mg/day (e.g. Decortin H). The main problem of corticosteroid therapy in pregnancy is the increased incidence of cleft palate. However, because impetigo herpetiformis usually occurs late in the third trimester of pregnancy, corticosteroid therapy can be considered a safe choice. Local therapeutic use of mild to moderate corticosteroid externals should be considered.

Ciclosporin: Ciclosporin is a therapeutic option for patients who do not respond to corticosteroids. Ciclosporin is usually administered in combination with systemic corticosteroids (dosage of 2-7.5 mg/kg/day) (Patsatsi TD et al 2013). After starting treatment with ciclosporin, systemic corticosteroids can be phased out (Tintinger GR et al 2013).

Antibiotics: Ampicillin, macrolides, and clofazimine are among the antibiotics that have been shown to be effective in the treatment of impetigo herpetiformis.If this therapy is not sufficient, corticosteroids can be used in addition or as an alternative. Overall, cephalosporins are safe during pregnancy, and older cephalosporins are preferred (Tintinger GR et al 2013).

Biologics: Anti-TNF-α drugs such as infliximab and adalimumab are considered pregnancy category B drugs. Their use during pregnancy is not approved by the US Food and Drug Administration (FDA) (Chambers CD et al 2012). Also in the guideline of the European Academy of Dermatology and Venereology, the use of adalimumab or infliximab during pregnancy is not advocated (Namazi N et al. 2018).

A satisfactory outcome with ustekinumab in the case of "severe pustular psoriasis" during pregnancy has been reported (Andrulonis R et al 2012). Other positive casuitic communications exist from the humanized IL-17A monoclonal antibody secukinumab as well as brodalumab (IL-17RA antibody) (Chhabra G et al. 2019; Nakai Y et al. 2022).

Phototherapy: UVB is considered a safe option during pregnancy is recommended if there is insufficient response to corticosteroids. PUVA is also relatively safe (its administration has not resulted in an increase in the risk of congenital malformations or infant mortality), but may result in low birth weight in infants.

Retinoids: Although all systemic retinoids are contraindicated during pregnancy because of their teratogenic effects, they are used to treat impetigo herpetiformis after delivery (maternal consent required for appropriate contraception) (Bukhari A 2004).

Methotrexate: While the administration of methotrexate is not allowed during pregnancy, it has been used successfully to treat impetigo herpetiformis in the puerperium.

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Both mother and child are at risk; intensive medical monitoring of pregnancy. As a consequence of the mother's severe illness, miscarriages and premature births, even stillbirths, are possible. In most patients, there is a rapid regression of the disease after birth; recurrences are possible in subsequent pregnancies.

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Most pat. with impetigo herpetiformis have no personal or family history of psoriasis.

Case report(s)
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A 29-year-old woman became ill after 45 days of pregnancy with sudden onset of fever and extensive pustular exanthema. She had been taking medications, including hydroxychloroquine, before the onset of illness. The eruptions and systemic symptoms were treated with high-dose systemic steroids. However, on examination, the fetus was found to be dead. Dilation and curettage of the uterus were performed. At the last follow-up examination about 2 years later, she reported that she had delivered a healthy baby about 1 month earlier with pregnancy without complications(Liu J et al. 2022).

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  2. Andrulonis R et al (2012) Treatment of severe psoriasis with ustekinumab during pregnancy, Journal of Drugs in Dermatology (JDD) 11: 1240-1241, 2012.
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  5. Chang SE (2003) Impetigo herpetiformis followed by generalized pustular psoriasis: more evidence of the same disease entity. Int J Dermatol 42: 754-755
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Last updated on: 23.10.2023