A myriad of dermatoses resulting in vesicles, pustules, blisters, erosions, and ulcerations can present during the neonatal period. Some conditions, such as miliaria, are benign and self-limited. However, other entities can be life-threatening and severe, such as neonatal herpes simplex virus (HSV) infection or epidermolysis bullosa. Therefore, it is imperative to have an accurate and efficient approach for the prompt evaluation of these neonates. This article divides the vesiculopustular diseases in the neonate into three common categories: transient benign, infectious, and rare causes (see Sidebar 1, page 638) to provide a framework for the evaluation of these disorders.
The possibility of an infectious etiology must first be ruled out, as left untreated, these infections can have grave consequences. Before the discussion of the conditions within these categories, it is important to review pertinent bedside examinations that can be performed to help distinguish among the various disorders.
A skin scraping of vesiculopustules can be a helpful tool in navigating the differential diagnosis, based on predominant cell type found within the lesions. To perform a scraping, cleanse the area with an alcohol wipe and use a No. 15 scalpel blade to gently unroof the lesion. The contents can then be smeared onto a glass slide. Different stains or preparations of the contents that can be performed include Wright’s stain (Tzanck smear), Gram’s stain, mineral oil prep, and potassium hydroxide (KOH) wet prep. The contents should also be sent for bacterial, fungal, and viral culture/direct fluorescent antibody (DFA) testing.
A dermatology consultation and skin biopsy are imperative, especially when contemplating an uncommon cause or when the diagnosis is unclear. If only a few lesions are present, one must prioritize which examinations to perform. For example, if an infectious etiology is favored, specifically HSV, DFA testing, viral culture, and Tzanck smear are the pertinent tools needed to solidify the diagnosis. A summary of the examinations that can be performed on vesiculopustules is reviewed in Sidebar 2 (see page 642).
- Skin scraping
- Wright’s stain (Tzanck smear)
- Gram’s stain and bacterial culture
- Potassium hydroxide (KOH) wet preparation and fungal culture
- Mineral oil preparation
- Direct fluorescent antibody test and viral culture
- Skin biopsy
Methods for Examination of Vesiculopustules
Transient Benign Causes
Erythema Toxicum Neonatorum
Erythema toxicum neonatorum (ETN) is a common, benign, self-limited condition affecting neonates without racial or sexual predisposition. ETN has been reported to affect 50% to 70% of full-term infants. Several studies have confirmed that ETN is rare in low-birth weight (<2,500 g) and preterm infants.1 The etiology of ETN remains unknown; theories include allergic hypersensitivity reactions, environmental stimulation, and cutaneous immune reaction to undetectable microorganisms.2
The lesions of ETN are rarely present at birth (5%) and usually develop within 24 to 48 hours after birth, with 11% occurring before 24 hours of life and 25% occurring after 48 hours.3 Reports of onset as late as 2 weeks of life are reported; however, presentation this late is extremely rare.
Four distinct lesions are seen in varying combinations: wheals (hives), papules, pustules, and erythematous macules. There is a predilection for the torso, face, proximal extremities, and buttocks. The papules and pustules are usually 1 to 2 mm and are superimposed on wheals or erythematous macules, giving this eruption the characteristic “flea-bite” appearance. The palms and soles are virtually never involved.4 Mechanical irritation of the skin can often precipitate eruption of new lesions.5 The rash of ETN waxes and wanes, and individual lesions can last from 1 hour to 1 to 2 days before healing without sequelae. The eruption usually resolves entirely within 1 week.6
The diagnosis of ETN is generally clinically apparent. Supporting evidence for ETN includes peripheral blood eosinophilia, as well as numerous eosinophils seen on a Wright’s stained smear of a pustule. Skin biopsy is generally not warranted, unless it is an atypical presentation. No treatment is necessary and parental reassurance should be provided.
Transient Neonatal Pustular Melanosis
Transient neonatal pustular melanosis (TNPM) is a common, benign, self-limited condition that affects approximately 5% of full-term black and 0.6% of white infants with equal frequencies among male and female neonates. The etiology of TNPM is unknown. The relationship between this disorder and ETN has been debated because over-lapping clinical and histologic features can be seen.7 The lesions of TNPM are most commonly seen on the forehead, neck, back, under the chin, and behind the ears. In contrast to ETN, the lesions of TNPM are invariably present at birth and can affect all parts of the body, including the palms and soles.
TNPM progresses through three stages: superficial vesiculopustules ranging from 1 to 10 mm (most often 2 to 3 mm) with mild or no underlying erythema. These vesiculopustules then rupture, resulting in hyperpigmented macules with a collarette of scale, followed by residual hyperpigmented macules that can persist for months before resolving (see Figure 1, page 636).8 At times, the vesiculopustular stage is unnoticed because these lesions are very superficial and can easily be wiped away after delivery or bathing. All stages of the lesions can be present at birth.
Figure 1. Transient Neonatal Pustular Melanosis. Figures 1–6, Figures 8–11, and Figures 13–16 Courtesy Richard Antaya, MD.
The diagnosis of TNPM can usually be made clinically based on the characteristic morphology and location of lesions. Helpful clues to differentiate TNPM from ETN include presence of lesions at birth, involvement of palms and soles, absence of underlying erythema, presence of hyperpigmentation, and findings on Wright’s stain. Usually a Wright’s stain of a pustule in TNPM demonstrates a predominance of neutrophils with occasional eosinophils. Importantly, a Gram’s stain demonstrates an absence of organisms, ruling out a bacterial etiology. No intervention is warranted except parental reassurance.
Miliaria (prickly heat) is a common benign condition affecting up to 15% of newborns due to obstruction of eccrine sweat glands. Miliaria can be exacerbated by warm and humid environments, either ambient temperatures or iatrogenic in nature (ie, radiant warmers) or with excessive bundling. Miliaria is seen in two forms in neonates with the morphology dictated by the level of obstruction of the eccrine gland and duct within the skin. Miliaria crystallina is due to obstruction within or under the most superficial (corneal) layer of the epidermis resulting in superficial vesicles (see Figure 2, page 636). In contrast, miliaria rubra results from obstruction deeper in the epidermis producing a more inflammatory response of erythematous papules and pustules.9 Lesions of miliaria have a predilection for areas of skin that are occluded, including the forehead, cheeks, and torso. Miliaria neonatorum is self-limited and is best prevented by environmental controls and cool, light clothing.
Figure 2. Miliaria Crystallina.
Neonatal Cephalic Pustulosis
Neonatal cephalic pustulosis (previously called neonatal acne) is seen in 20% of newborns and presents in the first 2 to 3 weeks of life. It is characterized by inflammatory pustules and papules concentrated on the forehead, cheeks, chin, neck, and upper chest and back (see Figure 3, page 636). Unlike acne vulgaris, there are no true comedones (white heads or black heads). Malassezia (Pityrosporum) species, which have been cultured from the pustules in neonates with this disorder, may be pathogenic in this condition, or merely an innocent bystander and part of the normal flora.10,11 Neonatal cephalic pustulosis usually self-remits within weeks but can be treated with a topical targeted against Malassezia yeast forms, such as 2% ketoconazole cream. This disorder should be differentiated from infantile acne, with later onset at 3 to 6 months of age. Infantile acne is clinically more similar to acne vulgaris, with a comedonal component and a less transient course.
Figure 3. Neonatal Cephalic Pustulosis.
Several infectious diseases result in vesiculopustules or bullae in the neonate. These include, but are not limited to, infections or infestations with Staphylococcus aureus, group B streptococcus, listeria, scabies, candidiasis, Treponema pallidum, and HSV. Rapid and accurate diagnosis of these conditions are necessary for prompt therapeutic intervention to reduce morbidity and mortality.
Staphylococcus aureus Infection
S. aureus infections can produce vesiculopustules or bullae in the neonate via two methods: direct infection of the skin and exotoxin production. Onset of lesions is usually after 48 hours and within the first few weeks of life. Direct infection of the skin results in staphylococcal pyoderma, which manifests as vesicles, pustules, erythematous papules, folliculitis, cellulitis, and/or honey-colored crusted areas. When large, flaccid bullae are present (bullous impetigo, see Figure 4, page 637), it is due to local exotoxin production.12 The predominant strain of S. aureus resulting in bullous impetigo possesses phage group II type 71, which produces an exfoliative toxin that cleaves the skin at the level of the superficial epidermis. Thus, large flaccid bullae are formed that easily rupture and leave a distinct collarette of scale around a moist, erythematous erosion and after drying, a light brown varnish-like crust. The lesions of Staph infection concentrate in the periumbilical area, neck folds, and diaper area but can occur anywhere on the body.
Figure 4. Bullous Impetigo.
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS) is precipitated by an extracutaneous infection with the same strains of S. aureus as those causing bullous impetigo. In SSSS, unlike bullous impetigo, there is systemic liberation of the exotoxin that results in lesions. The organism may reside in the nasopharynx or conjunctivae, or be secondary to omphalitis or other soft tissue infection. There are two phases of the eruption. The first phase is marked by erythema or erythematous sandpaper-like papules with accentuation in the folds and periorifically.
The infant usually exhibits signs suggestive of a systemic infection. The skin is exquisitely tender and a key sign is that affected infants do not want to be held. During the second phase, the skin develops flaccid blisters and desquamation, leaving moist erosions with crusting. The skin heaps up and wrinkles when tangential force is applied to it (Darier’s sign). Periorbital, perinasal, perioral, and intertriginous areas are usually affected earlier and to a greater extent than other locations. Periorifical skin often develops characteristic radial crusting and fissuring. Because of large areas of skin barrier disruption, there is a high risk of secondary infection, fluid and electrolyte disturbances, temperature instability. There is a 4% mortality rate in affected neonates.
Diagnosis can be established via Gram’s stain of a pustule or blister, which exhibit Gram-positive cocci in clusters along with neutrophils and confirmed with bacterial culture in bullous impetigo. Gram’s stain and culture are negative in SSSS. A search for a pyogenic infection should be performed for suspected cases of SSSS. If there is a clinical concern for toxic epidermal necrolysis (TEN), skin from a blister roof can be snipped (or skin biopsy performed) and sent for pathological examination. Blister roofs from SSSS only exhibit a granular layer and stratum corneum, whereas those from TEN reveal a complete necrotic epidermis. For SSSS, patients frequently require narcotics for pain control, correction of fluid and electrolytes, and meticulous wound care.
Scabies is a cutaneous infestation caused by the mite Sarcoptes scabiei. To manifest scabies, one must be sensitized first to the mite; therefore, it cannot present in the neonatal period before 3 to 4 weeks of age, as this amount of time is required to develop hypersensitivity. The infant may not be bothered by the infestation or may develop irritability and poor feeding. It presents as a pruritic, generalized eruption and may include the face, scalp, diaper area, palms, and soles.13 Eczematized crusted vesicles and pustules are seen along with nodules and burrows (see Figure 5, page 637). Diagnosis can be confirmed with a mineral oil scraping of the skin that can demonstrate feces, ova, or a mite (see Figure 5, page 637). Treatment of choice for infants is topical 5% permethrin cream applied over the entire cutaneous surface, including the head and neck. Permethrin cream is left on overnight, washed off in the morning, and this treatment cycle is repeated in 7 days. Concurrent treatment of all close contacts and environmental controls are required to prevent reinfestation. Thus far, there have been no reported cases of permethrin-induced neurotoxicity.
Figure 5 A–B. A. Scabies with Burrows in an Adult Patient. B. Scabies Mite (larva) Seen from Oil Preparation of Skin Scraping.
Cutaneous infections due to Candida can be divided into congenitally and neonatally acquired disease.14 Congenital candidiasis is relatively rare and due to intrauterine infection. It usually presents at birth but may manifest during the first week of life. Risk factors for congenital candidiasis, include preterm delivery, uterine foreign body (eg, retained IUD or cervical cerclage) and maternal-vaginal candidiasis.15
Congenital candidiasis can have a range of findings, including diffuse erythema, erythematous papules, vesiculopustules, or fine scaling. In most cases, there is a fine papular rash, followed by the development of pustules and, finally, desquamation.16 Lesions are present on the face, chest, back, and extremities, including the palms and soles, with noted sparing of the diaper area and oral mucosa (see Figure 6, page 638).
In contrast, neonatal candidiasis is acquired during delivery or postnatally and presents after 7 days. Neonatal candidiasis, characterized by mucocutaneous lesions, manifests as oral thrush and beefy pink-red patches with satellite papules and pustules in the diaper and intertriginous areas (see Figure 7, page 638). In both cases, diagnosis can be made with a skin scraping and potassium hydroxide (KOH) wet preparation, which show illustrate pseudohyphae and spores (see Figure 8, page 639). The majority of infants with congenital candidiasis do not have systemic infection; however, preterm and very-low birth weight (<1,500 g) infants are at risk for disseminated disease and require parenteral antifungal agents. Otherwise, well infants not in the aforementioned categories can be treated with topical antifungal agents, such as ketoconazole. Similarly, topical antifungals used safely for the treatment of immunocompetent infants with neonatal candidiasis. Low-birth weight and preterm infants should be monitored closely for systemic dissemination, with blood, urine, and CSF cultures obtained if signs of systemic infection present.
Figure 7. Congenital Candidiasis in a 9-Day-Old Term Infant. A Septic Work up Was Completed when Pustules Developed at 2 Days of Life. Fungal Culture of Pustules Rapidly Grew Candida Albicans, and the Infant Responded to Topical Ketoconazole Without Sequelae. courtesy of Mary Wu Chang, MD.
Figure 8. Neonatal Candidiasis (Candidal Diaper Dermatitis).
Although congenital syphilis is rare, recent reports note that after declining for 14 years, the rate of congenital syphilis in the United States increased by 23%, from 8.2 cases per 100,000 live births in 2005 to 10.1 during 2008.17 It is also alarming that 60% of neonates with congenital syphilis are asymptomatic at birth. Vesicles, pustules, erosions and ulcerations have been reported but are rare. Hemorrhagic vesicles or bulla on the palms and soles are pathognomonic (see Figure 9, page 639) but is an exceedingly uncommon finding.18
Figure 9. Pseudohyphae and Spores on KOH Prep Confirm Candidiasis.
Most times, infants have mucosal lesions of condylomata, rhinitis, and mucous patches and cutaneous findings of macules or papules or a papulosquamous eruption (see Figure 10, page 640). In these infants, signs of systemic involvement are seen, such as anemia, jaundice, and hepatosplenomegaly. The transplacental transfer of maternal antibodies complicates the diagnosis of congenital syphilis. Recent guidelines from the Centers for Disease Control and Prevention (CDC) guidelines state that all infants born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on infant serum to avoid a false-positive result.19 Infants with proven or highly probable disease should be treated with a 10-day course of IV or IM penicillin G.
Figure 10. Congenital Syphilis with Hemorrhagic Bullae of the Feet.
Neonatal Herpes Simplex Virus Infection
Neonatal HSV infection occurs in 1 of every 3,200 live births, with 70% of cases being caused by HSV-2. The neonate’s risk of acquiring HSV is related to the stage of maternal infection.20 Primary infections portend a high rate of transmission of 30% to 60%, whereas recurrent infections carry only a 1% to 5% risk. Neonatal HSV infection can result in great morbidity and mortality.
Three patterns of neonatal HSV are seen: mucocutaneous localized disease, disseminated disease, and CNS disease in the absence of visceral involvement.21 Cutaneous findings can be present in all three forms of the disease but are present in only 30% of all cases at the onset of symptoms. Congenital infection results in a preterm, low-birth weight infant with microcephaly, chorioretinitis, and cutaneous findings of vesicles, pustules, widespread erosions, scars, and areas with absence of skin. Prognosis is grave for these infants.22 Neonatal HSV infection presents on average at 5 days, with grouped or single vesicles and pustules on erythematous bases found on any area of the body, but can concentrate on the presenting part (see Figure 11, page 640). Crusted papules and erosions can also occur. Other mucocutaneous findings include poorly healing scalp monitoring electrode sites, oral ulcers, and keratoconjunctivitis.
Figure 11. Congenital Syphilis with Copper-Colored Macules.
Skin scraping from the base of an unroofed lesion for Wright’s stain (Tzanck preparation) should be performed. In cases of HSV infection, ballooned or multinucleated giant epithelial cells representing virally infected keratinocytes are seen (see Figure 12, see page 641). DFA testing is a rapid means to differentiate HSV-1 and HSV-2 infections. The presence of HSV should be confirmed with viral cultures because false-positive DFA can be seen in non-infectious disorders, typically with eosinophil-rich infiltrates, such as in ETN.
Figure 12. Cutaneous Herpes Simplex Virus in a Term Infant. The Infant Responded Well to Systemic Acyclovir Without Sequelae. Courtesy of Mary Wu Chang, MD.
Comprehensive evaluation of infants with suspected or confirmed HSV infection should be performed, even for infants with presumed localized cutaneous, ocular, or mucous membrane disease. This must include HSV DNA PCR of the blood and CSF because the risk of untreated CNS and disseminated disease is great.23
Parenteral acyclovir is the requisite treatment for all neonates with HSV infection, including those with localized mucocutaneous disease. Acyclovir should be administered for 14 days for infants with cutaneous, ocular, or mucous membrane disease and for 21 days for CNS or disseminated disease.23 Approximately 50% of surviving infants experience cutaneous recurrences, and the utility of chronic suppressive acyclovir therapy remains controversial.24
Eosinophilic Pustular Folliculitis of Infancy
Eosinophilic pustular folliculitis presents at birth to a few months of life with pruritic, grouped, 1 mm to 2 mm follicularly based papules, pustules, and crusts. The lesions are most commonly seen on the scalp and face, and at times on the trunk, hands, and feet. These lesions are very pruritic, last days to weeks, and, over months to years, recur in subsequent crops.25 There is no associated systemic illness, but peripheral blood eosinophilia can occur.26 Eosinophilic pustular folliculitis of infancy is not associated with HIV infection, in contrast to the adult form. A Wright’s stain of a pustule will reveal numerous eosinophils (see Figure 13, page 643). As this disorder is self-limited, treatment is geared toward symptomatic relief with potent topical corticosteroids and/or oral antihistamines.
Figure 13. Virally Infected Keratinocytes Forming a Multinucleated Giant Cell on Tzanck Prep.
Infantile acropustulosis (acropustulosis of infancy) can be seen rarely in the neonatal period as recurrent crops of pruritic acral papules, vesicles, and pustules (see Figure 14).27 This condition occurs in all races and is often noted in infants adopted from other countries.28 Etiology is unknown, but one study noted one-third of infants had previous scabies infestation (“postscabetic infantile acropustulosis”). The lesions are most often localized to the palms and soles, with the scalp, face, and trunk being variably affected. The lesions last 7 to 14 days and often recur in crops at approximately 3 to 4 weeks. The recurrences become less severe and less frequent with time, and eventual spontaneous remission usually occurs within 2 to 3 years. Early in the course of the condition, a Wright’s stain of a nascent pustule may reveal eosinophils, whereas later, neutrophils may be seen. Infantile acropustulosis appears clinically similar to scabies infestation, and active scabies infection must be ruled out. Symptoms can be controlled with potent topical corticosteroids along with oral antihistamines. Oral dapsone can be effective and is reserved for refractory cases.
Figure 14. Eosinophils on Wright’s Stain from a Pustule from an Infant with Eosinophilic Pustular Folliculitis.
Epidermolysis bullosa (EB) encompasses a heterogeneous group of hereditary disorders due to mutations affecting structural proteins and is characterized by the formation of blisters following minimal trauma or friction. EB affects 1 in 17,000 live births worldwide.29
EB can be divided into four groups, based upon the level in the skin at which the blister forms. EB simplex involves separation within the epidermis. Junctional EB has separation between the epidermis and the dermis. The separation in dystrophic EB is below the lamina densa of the basement membrane zone (upper dermis).30 The fourth subtype is the very rare Kindler syndrome, in which blister formation occurs at various levels within the skin.31 Further subtypes are based on mode of inheritance, localized versus generalized disease, underlying genetic abnormalities, and associated findings.
EB simplex is the most common form of EB, accounting for approximately 90% of cases. Again, in this form of EB, the blister is formed within the epidermis. EB simplex presents with vesicles, bullae, and erosions at birth, which occurs at sites of trauma. One common type has a predilection for the palms and soles. The blisters are flaccid, heal without scarring, and decrease in frequency with age.32 The most severe form of EB simplex is the Dowling-Meara subtype, which results in widespread herpetiform (grouped) blister formation.33 These neonates have a higher mortality rate secondary to sepsis.
Junctional EB is the least common form, accounting for fewer than 1% of cases. Vesicles, bullae, and erosions that heal with atrophic scars characterize this type of EB. The mucous membranes, principally oral, respiratory, ocular, and gastrointestinal, are affected. Prominent nail dystrophy is also seen along with dental hypoplasia (a later finding).34 Dystrophic EB can result in localized and generalized blister formation and heals with dystrophic scars. The most severe and life threatening forms of EB are recessive dystrophic EB and the Herlitz form of junctional EB.
Kindler syndrome is caused by deficiency of kindlin-1 protein, whose normal function is to stabilize the dermoepidermal junction.35 Kindler syndrome results in generalized blistering in the neonatal period that heal with atrophic scars. Other associated findings include thickening of the palms and soles, nail dystrophy, and urethral strictures.36
The diagnosis of EB should be suspected in neonates with increased skin fragility and in cases of widespread vesicles or bullae (see Figure 15, page 643). Diagnosis is based on skin biopsy with electron microscopy, immunofluorescence mapping, and mutation analysis. There is no cure for EB; however, skin-directed therapy should be geared toward prevention of trauma and infection. The pertinent skin care for infants with suspected epidermolysis bullosa is reviewed in Sidebar 3 (see page 643).
Figure 15. Infantile Acropustulosis of the Foot
- Remove infant from incubator immediately.
- Keep ambient temperature as cool as possible.
- Dress infant in soft, well-fitting clothes, with feet covered.
- Infant should be clothed; friction of limbs against limbs will induce more blister formation.
- Put clothes on inside out and avoid pressure by seams.
- Keep bed linens straight, without folds, and make sure infant does not touch side of bed.
- Place no plastic armbands, security anklets, or pacifiers on the infant.
- Reduce handling of infant to a minimum.
- Anyone handling infant cannot be wearing zippers, buttons, bracelets, watches, or rings, or have long fingernails.
- Spread fingers wide when picking infant up.
- To cleanse infant, dab gently, do not scrub.
- Gently unroof or pop all blisters and cover with nonadherent dressings (Telfa, Mepilex, etc.).
- Place no tape or adhesive on the skin.
- Cushion arm with gauze before inflating cuff for blood pressure measurements.
- No per-rectum medications or thermometers should be used.
Skin Care for Infants with Epidermolysis Bullosa