Benign skin disease with pustules in the newborn.

The neonatal period comprises the first four weeks of life. It is a period of adaptation where the skin often presents several changes: transient lesions, resulting from a physiological response, others as a consequence of transient diseases and some as markers of severe disorders. The presence of pustules in the skin of the newborn is always a reason for the family and for the assisting doctor to be worried, since the newborn is especially vulnerable to bacterial, viral or fungal infection. However, the majority of neonatal skin pustules is not infectious, comprising the benign neonatal pustulosis. Benign neonatal pustuloses are a group of clinical disease characterized by pustular eruptions in which a contagious agent is not responsible for its etiology. The most common ones are erythema toxicum neonatorum, the transient neonatal pustular melanosis and the benign cephalic pustulosis. These dermatoses are usually benign, asymptomatic and self-limited. It is important that the dermatologist and the neonatologist can identify benign and transient lesions, those caused by genodermatoses, and especially differentiate between neonates with systemic involvement from those with benign skin lesions, avoiding unnecessary diagnostic tests and worries.

INTRODUCTION

The neonatal period extends from birth to the first four weeks of life. [1] It is a time of adaptation where the newborn usually has various dermatological findings: temporary lesions, some as a result of a physiological response or transient diseases, and others as markers of serious diseases.[2-4] The presence of pustules or vesico-pustular lesion in newborns is always motive of concern to the family and to the attending physician, since at this age children are especially vulnerable to bacterial, viral or fungal infections.[5] Sometimes these lesions represent a diagnostic challenge because they may be due to a number of diseases with variable prognostics, so it is important to differentiate between benign and transient pustular eruptions from serious cases requiring hospitalization.[6]

Benign neonatal pustulosis (BNP) are a set of clinical conditions characterized by transient pustular rash on the newborn skin. These are thus designated because they are asymptomatic and self-limiting. They include sterile pustulosis, such as erythema toxicum neonatorum (ETN) and transient neonatal pustular melanosis (TNPM), in which no infectious agent can be implied in its etiology; and benign cephalic pustulosis (BCP) which, according to some authors, may be related to the presence of Malassezia. [5] Other benign dermatological findings that may present pustules during the neonatal period are: miliaria pustulosa; miliaria rubra (MR), which under occlusion areas may present vesicles with pustular appearance; infantile acropustulosis and eosinophilic folliculitis.

NEWBORN SKIN

Newborn (NB) skin is often characterized as delicate and fragile.[7] Functional differences between the newborn and adult skin may be attributed to differences in skin microstructure.[8] Besides being 40-60% thinner than adult skin, newborn skin has a higher transepidermal water loss and delay in sudoral response, believed to be due to the immaturity of the sympathetic system.[2] In neonatal period the skin plays an important role as a regulator of temperature and as a barrier against skin infections. The cutis of the newborn is also more likely to develop certain dermatoses such as irritant contact dermatitis, when compared with adult skin. [3,7]

The barrier function of human skin begins to develop in utero with the stratification of the epidermis during the first trimester of pregnancy, and it is believed to be complete by 34 weeks of gestation. [3,9] The formation of vernix caseosa in the third quarter contributes to the final stage of maturation of the epidermal barrier. [3] Despite the epidermal barrier function by baseline permeability being established at birth, increased risk of infections, dermatitis and percutaneous absorption of toxic agents can indicate an incomplete maturation in early neonatal period. [10]

NEONATAL SKIN PUSTULES

Dermatoses that can present pustules during the neonatal period can be divided into two major groups: infectious and non-infectious or sterile. [2] It is important that the neonatologist and the dermatologist know how to identify benign and transient lesions and, mainly, to differentiate newborns with systemic involvement from those in which the dermatosis is restricted to skin. [6,11]

Table 1 lists the major skin diseases in the neonatal period that presents pustules and its usual pathogens.

Table 1

Neonatal dermatoses that occur with pustules

Neonatal dermatoses that occur with pustules
Infectious causes
a) Bacterial:
	– Bullous impetigo (Staphylococcus aureus)
	– Folliculitis (Staphylococcus aureus, Streptococcus, negative Gram bacteria)
	– Ecthyma (Staphylococcus aureus)
	– Ecthyma gangrenosum (Pseudomona aeruginosa)
	– Congenital syphilis (Treponema pallidum)
b) Viral
	– Neonatal herpes simplex (herpes simplex virus)
	– Congenital herpes (intrauterine infection by herpes
	simplex virus)
	– Neonatal varicella (varicella zoster virus)
	– Cytomegalic inclusion disease (Cytomegalovirus)
	– Congenital Epstein-Barr virus syndrome (Ep-
	stein-Barr virus)
c) Fungal
	– Congenital candidiasis (Candida albicans, C. glabrata)
	– Neonatal candidiasis (Candida albicans, C.parapsilosis)
	– Pityrosporum folliculitis (Malassezia sp.)
d) Parasites
	– Scabies (Sarcoptes scabiei)
Non-infectious causes
a) Miliaria pustulosa or profunda
b) Transient benign neonatal pustules
	-Erythema toxicum neonatorum (ETN)
	-Transient neonatal pustular melanosis (TNPM)
c) Infantile acropustulosis
d) Benign cephalic pustulosis (BCP) including neonatal acne
f) Pigmentary incontinence
g) Neonatal Langerhans cell histiocytosis
h) Transient myeloproliferative disease in patients with Down syndrome
i) Eosinophilic pustular folliculitis in childhood
j) Eosinophilic papular-pustular rash of Hyper IgE syndrome
k) Eeosinophilic pustulosis
l) Neonatal Behcet's disease
m) Neonatal pustular psoriasis

In most cases, BNP are transient, and caused by environmental factors, or occur as a physiological skin response.[6] Diagnosis of BNP is clinical, but in atypical cases it may be necessary to use methods of investigation with complementary tests, preferably non-invasive, and that are useful in differentiating benign and transient pustules from serious cases requiring hospitalization.

Facing the newborn with pustules, maternal diseases should be discarded, such as vulvovaginal candidiasis, genital herpes, syphilis and scabies. Dermatological examination of the newborn should evaluate the distribution and morphology of lesions, the time when the skin lesions appeared and how they evolved. It is important to discard the signs of systemic disease in newborns as fever or hepatosplenomegaly. Realization of the direct examination of the lesion scraping and staining by Gram method can identify the presence of Gram positive bacteria such as Staphylococcus and Streptococcus, and less frequently, Gram negative; moreover, it helps to identify the cellular composition of the inflammatory infiltrate when present. [12] Direct examination of scales clarified with potassium hydroxide allows identifying fungal elements, which is useful for the detection of dermatophytosis and other infections caused by Malassezia or Candida spp. The cytodiagnosis of Tzank informs about the presence of multinucleated cells and inclusion bodies suggestive of herpes infection. Direct examination of lesion scraping can identify mites such as Sarcoptes scabiei. These procedures are generally sufficient to identify an infectious process; in the case of persistent doubt, syphilis serology, culture of pustules’ contents or skin biopsy should be performed. [5]

BENIGN SKIN PUSTULOSES IN NEONATAL PERIOD

The main lesions described as typical of the neonatal period include erythema toxicum neonatorum (ETN), transient neonatal pustular melanosis (TNPM) and benign cephalic pustulosis (BCP). These are a benign, self-limited, asymptomatic skin diseases that occur in the first days of life. In rare cases, miliaria rubra can present pustules, mainly in the areas of friction, or even progress to miliaria pustulosa in the skin of the newborn.

Erythema toxicum neonatorum:

Erythema toxicum neonatorum (ETN) is considered an inflammatory reaction of the skin and is also called allergic neonatal erythema or neonatal erythema. [13] It is characterized by erythematous papules and sterile pustules surrounded by an erythematous halo measuring approximately 1 to 2 cm affecting the trunk, the extremities and face of the NB (Figures 1 and 2). Lesions usually appear on the second day of life and regress in 5 to 14 days, but atypical setting may have a later onset. [14-16]

Figure 1

Erythema toxic neonatorum. A: ETN lesions on the trunk and limbs of a full-term newborn. B: Detail of the lesion: pustule surrounded by an erythematous halo of appoximatelly 2 cm on the thigh side. C: Pustules affecting the back of the upper limbs D: Involvement of the face

Figure 2

Erythema toxicum neonatorum (ETN). A and B: Lesion characteristic of ETN: pustule surrounded by an erythematous halo. C and D: ETN pustulosis

ETN occurs in about 16% of NB. [17] In a multicenter study with 2878 newborns, performed in a capital in the Southern region of Brazil, ETN was observed in 21% of the NB. [18]

ETN is most commonly observed in male newborns. [13,18] It also tends to be more prevalent in fullterm compared with preterm newborns; in NB who are born during the spring months; in NB with good health - characterized by the Apgar score in the first minute of life greater than 8, and in the children born of mothers with no gestational risk factors. [18,19]

ETN was reported by some authors as being more frequent in newborns delivered by cesarean, while other authors affirm that it is more common in vaginal delivery, and a study conducted in the Southern region of Brazil observed no difference between types of delivery. [13,18,20,21] It was also described as being more prevalent in children of multiparous mothers by some authors and with no difference between the type of delivery by others. [18,21]

There are cases of ETN predominantly pustular, but they are uncommon. In such cases there is a tendency to use some synonyms, such as transient neonatal pustulosis, pustular ETN and atypical ETN (Figure 2). [22,23]

The cytological examination of pustule reveals the presence of numerous eosinophils. Histopathological changes include subcorneal pustule; dense inflammatory infiltrate mainly near the hair follicles, comprising numerous dendritic cells, eosinophils, neutrophils and macrophages. High expression of E-selectin molecule was demonstrated, as well as pro-inflammatory cytokines IL-1α and IL-1β, IL-8 chemokine and eotaxin. [24,25]

Although the etiology of ETN is still considered unknown, some studies have shown activation of the immune response in the lesions, suggesting that this setting may correspond to an inflammatory reaction of the skin to microbial colonization occured at birth.[17,26,27] It was also shown the activation of the immune system through the identification of inflammatory mediators aquaporin-1 (AQP1), aquaporin-3 (AQP3), psoriasin and nitric oxide synthase (NOS) by immunohistochemistry in ETN lesions. [28]

Among the children with allergy manifestation during the first two years, 84.2% had ETN or low skin pH at birth, and atopic dermatitis was diagnosed in 85.7% of the NB who presented the pustulosis. [29] The description of ETN in siblings raises the possibility that common environmental and genetic factors may also influence its development. [23]

Transient neonatal pustular melanosis:

Transient neonatal pustular melanosis (TNPM) is characterized by flaccid and superficial pustules, which disrupt easily forming a collarette of scales, and thus progressing to residual hyperpigmented macules of residual character (Figures 3 and 4). 30 All areas of the body can be affected, including palms, soles and genitalia. Lesions are usually present at birth. (Figure 3)

Figure 3

Transient neonatal pustular melanosis. Hyperchromic macules present at birth

Figure 4

Transient neonatal pustular melanosis (TNPM). Presence of pustules, hyperchromic macules and scaling in newborn with 24 hours of life

TNPM is more prevalent in African-American NB, occurring in about 5% of black NB and in only 0.2% of whites. [31] A study conducted in maternity hospitals in Porto Alegre showed a prevalence of 3.4%. [18]

TNPM affects both sexes with the same frequency. [6,18] Cytological examination of the pustules show polymorphonuclear neutrophils. So far the etiological mechanisms of TNPM are not clear. It is likely that TNPM corresponds to a variance of ETN, as there are described cases in which the same NB presents clinical and histological findings of ETN and TNPM, and other cases in which clinical findings are characteristic of TNPM, but the histology shows findings characteristic of ETN.[5,14] In addition, it is often difficult to establish a clear distinction between the two diseases, which has raised the idea that the same unknown trigger factor would cause initially different settings when it affects the skin of the fetus (TNPM) or of the NB (ETN). Because of the difficulty in differentiating the clinical and histopathological limit of both diseases, Ferrandiz et al proposed the term sterile transient neonatal pustulosis to unify ETN and TNPM. [5]

Benign cephalic pustulosis:

Benign cephalic pustulosis (BCP) was described in 1991 by Aractingi. It is a relatively common benign disease with prevalence estimated between 10% and 66% in the neonatal period, and it presents a benign and self-limited course. [5,12,32] This dermatosis is characterized by multiple inflammatory papules and pustules on the face and scalp that usually begin between 5 days and 3 weeks of age (Figure 5 and 6). [2] The direct examination of smear of pustule, clarified with potassium hydroxide, can show mycotic elements and culture can show Malassezia synpodialis, and less frequently M. furfur or M. globosa. [12] A study conducted in Turkey with 104 newborns showed that colonization by Malassezia increases significantly with days of life of the NB with BCP (5% in the first week, 30% between the second and fourth week of life). However, this correlation between neonatal cephalic pustulosis and colonization by Malassezia is not well established.[33]

Figure 5

Benign cephalic pustulosis. Erythematous papules and pustules on the face of a newborn with three weeks of life

Figure 6

Benign cephalic pustulosis (BCP). Erythematous papules and pustules on the face

Miliaria:

Miliaria is a common condition in newborns and is more observed during the summer months, febrile periods or in NB with excess clothing.[2] The most common is miliaria crystalline (MC), which is characterized by small vesicles over healthy skin, especially face, neck and trunk (Figures 7 and 8). Miliaria rubra (MR) is caused by obstruction of eccrine sweat gland duct, slightly deeper than MC, with sweat retention in the epidermis. MR is characterized by numerous erythematous papules or grouped pruritic papular vesicles, and when they are in areas under occlusion they can have a pustular aspect (Figure 8). [11] Rarely MR can progress to deep miliaria or miliaria pustulosa (MP), caused by a deeper obstruction of the eccrine gland duct and characterized by the presence of pustules (Figure 8). [32] MR lesions usually begin after the second week of life and predominate in the trunk and in intertriginous areas where occlusion by clothing is accentuated. In hot environments lesions on the scalp, face and neck may appear.[5] It is the only pustular eruption of NB where most cells observed in cytology are lymphocytes.[5] A recent analytical study of pustular eruptions in newborns showed that Staphylococcus aureus was isolated in 29.4% of cases of MP. [6] Diagnosis of miliaria is clinical. Lesions may resolve without intervention, but there is a proven benefit in lowering the environment temperature, thus reducing the NB transpiration.[32]

Figure 7

Miliaria crystallina. Microvesicles affecting the forehead of a newborn

Figure 8

Miliaria. A: Miliaria crystallina: microvesicles in the neck and chest of a newborn. B and D: Miliaria pustulosa: pustules on the axillary region of a newborn. C: Miliaria rubra: erythematous papules on the trunk of an newborn

UNUSUAL CAUSES OF NEONATAL PUSTULOSIS

The differential diagnosis of neonatal benign pustulosis (NBP) is performed with the infantile acropustulosis (IA), eosinophilic pustular folliculitis (EPF) and scabies, which are dermatosis that present as pruritic vesicopustules, most common in infants, but that have been reported in the neonatal period.[5]

Infantile acropustulosis:

Infantile acropustulosis (IA) is characterized by the recurrent appearance of very pruritic vesicopustules, with palmar and plantar predominance, but that can affect the back of the hands, feet, ankles, wrists and scalp.[5] It usually appears between the first 2 and 12 months of life, with eruptions that last between 7 to 14 days, interspersed with periods of a few weeks of remission, and it is rare in the neonatal period. The cytological examination of the lesions shows predominance of neutrophils and histopathological examination demonstrates the presence of intraepidermal pustules with polymorphonuclear neutrophils and eosinophils. Scabies is its main differential diagnosis.[34]

Eosinophilic pustular folliculitis:

Eosinophilic pustular folliculitis (EPF) usually affects infants between 5 and 10 months of life.[35] It is characterized by polymorphous eruption with very pruritic vesicopustules that coalesce forming exudative and crusted plates located mainly on the scalp and less often on the face and extremities.[5] Eruptions are intermittent, lasting from one to four weeks, self-limited, disappearing in several months to a few years. Microscopy shows infiltrates with eosinophils and neutrophils of perifollicular distribution on the scalp, and perivascular distribution on the skin. Blood count shows leukocytosis and eosinophilia in 70% of cases. [32]

Scabies

Scabies is an infectious disease that occurs when the parasite Sarcoptes scabei invades the stratum corneum. It can affect the newborn if contamination occurs soon after birth. The clinical pattern of scabies in NB is different from that observed in infants, older children and adults. In the newborn, vesicles are a frequent finding and there is a tendency to form pustules on the initial course of the infestation.[11] Irritability, poor eating and little weight gain are also characteristic.

CONCLUSION

Pustulous settings are common in newborns and can be related to infections or benign skin diseases. It is important that the benign pustulosis of the neonatal period, such as erythema toxicum neonatorum, transient neonatal pustular melanosis, benign cephalic pustulosis and miliaria are recognized from the clinical setting, in order to avoid unnecessary procedures.

Answer key
Psoriasis: new comorbidities 2016;91(1):08-16.
1. C	6. B	11. C	16. A
2. B	7. B	12. B	17. A
3. C	8. D	13. D	18. A
4. D	9. A	14. C	19. D
5. A	10. C	15. B	20. D

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