Management of Pustules and Vesicles in Afebrile Infants ≤60 Days Evaluated by Dermatology

In this multicenter, retrospective cohort study, we reviewed data obtained from the electronic medical records (EMR) of patients ages 60 days or younger who received a pediatric dermatology consultation at 1 of 6 academic pediatric centers across the United States (Medical University of South Carolina Children’s Health, Nationwide Children’s Hospital, NewYork-Presbyterian Morgan Stanley Children’s Hospital, Texas Children’s Hospital, University of California San Francisco Benioff Children’s Hospitals, University of Florida Health) between September 1, 2013 and August 31, 2019. Institutional review board approval was obtained at each participating institution. Informed consent was waived as only deidentified data were collected. EMR reviewed include dermatology consultation notes and available clinical photos.

Of the 879 infants ≤60 days examined by a dermatologist in this multicenter, retrospective chart review, 183 afebrile infants had skin lesions documented as pustules, vesicles, and/or bullae on manual review of medical records (Fig 1). Infants were excluded from the analysis if fever (defined as temperature ≥38.0°C) was recorded on presentation or by guardian report. Pertinent EMR data were entered into a secure Research Data Capture database hosted by Texas Children’s Hospital.

Race and ethnicity were aggregated from EMR, which reflected the self-reported data obtained during standard clinical intake procedures. Patients were categorized as white, black, Hispanic/Latino, Asian or Pacific Islander, other, or unknown. Patients were also categorized by pregnancy length as classified as preterm (<37 weeks gestational age [GA]), full-term (37 weeks ≤ GA <42 weeks), and post-term (≥42 weeks GA). The patients for whom EMR records did not contain pregnancy length classification was categorized as unknown. The pregnancy lengths of 6 children were not included in the records and were, therefore, excluded in the GA analysis. Lesion morphology and distribution, as well as final diagnosis, were recorded from the dermatology consult and follow-up notes.

SBI was defined as bacteremia, urinary tract infection, or meningitis. HSV was classified as skin, eye, and mouth (SEM) if surface swabs of skin, conjunctivae, mouth, or nasopharynx were positive on HSV polymerase chain reaction (PCR), direct immunofluorescence assay (DFA), or viral culture. Disseminated HSV was defined as positive HSV PCR, DFA, or viral culture in the presence of hepatitis or other end-organ damage, other than isolated central nervous system (CNS) manifestations. CNS HSV disease was defined as a positive cerebrospinal fluid (CSF) PCR or viral culture in the absence of other end-organ damage.¹² It was assumed that if the patient did not return to the participating institution after discharge, they did not subsequently develop an SBI, HSV infection, or other disseminated infection.

Categorical variables are reported as counts and percentages. Continuous variables are reported as means with SDs. Statistical significance was determined by using the Fisher’s exact test and a critical α of 0.05. Statistical analysis was performed with Stata (Stata Corp., College Station, TX, USA).

Among the afebrile infants ≤60 days with pustules, vesicles, and/or bullae (n = 183), 73% (134 of 183) of patients were born full-term, 23% (43 of 183) were preterm, and 3% (6 of 183) had unknown pregnancy length classifications. Table 1 outlines the demographic features of patients by gestational age (GA) classification. Of the 183 infants, 124 (67.8%) infants presented with pustules, 57 (31.1%) with vesicles, and 19 (10.4%) with bullae. Eighteen (9.8%) infants presented with both pustules and vesicles. Lesions most commonly occurred on the head (113 patients or 61.7%). Eighty-three (45.3%) patients had lesions on the trunk, 80 (43.7%) on the extremities, 47 (25.7%) in the diaper area, and 22 (12.0%) on skin folds. Ninety-five subjects (51.9%) had more than 1 affected site.

Seventy infants were evaluated by dermatology in the NICU, 40 in the ED, 22 in the newborn nursery, and 51 in other inpatient units. Of the 40 evaluated in the ED, 21 (52.5%) were admitted. The mean age of infants admitted from the ED was 15.1 days (SD 10.9), whereas the mean of infants who were not admitted was 20.8 days old (SD 13.4). Nine of the 40 admitted infants (22.5%) were ultimately diagnosed with skin-limited infection. Seven (18.5%) were diagnosed with Staphylococcus infection, of which 1 was found with coinfection with Streptococcus pyogenes. Two (5%) were diagnosed with HSV SEM disease.

Of the 183 patients, lesions were attributed to infectious etiologies in 71 (38.8%) infants and noninfectious etiologies in 122 (66.6%). Nine infants (4.9%) were given multiple diagnoses. Detail of final diagnoses is included in Table 2. Blood cultures were obtained in 105 (57.3%) infants, urine cultures in 71 (38.8%) infants, lumbar puncture in 61 (33.3%) infants. One hundred twenty-seven (69.4%) infants were evaluated for HSV using viral skin culture, DFA, and/or PCR. Ninety-seven (53.0%) went on to receive intravenous antibiotics, 81 (44.3%) received intravenous acyclovir, 12 (6.5%) received oral antibiotics, and 81 (44.3%) received topical antibiotics. Of the 99 patients who received systemic antibiotics, 46 (46.5%) had unremarkable infectious workups. The remaining 53 had infections; 3 received systemic antibiotics for treatment of unrelated urinary tract infections (UTI). See Table 3 for a summary of work-up and outcomes.

There were no positive cerebrospinal fluid nor pathogenic blood cultures in this cohort. Three blood cultures (2.8%, n = 104) grew coagulase-negative Staphylococcus and were considered contaminants. Of 6 positive urine cultures, 3 grew contaminants (specifically, the vaginal flora Gardnerella vaginalis), 1 resulted in confirmed UTI (growing the uropathogen Proteus mirabillis), and 2 resulted in uncertain diagnosis (potential contaminants, but not enough data to confirm). Among the patients with positive urine cultures, the only patient with a positive lesional skin culture grew methicillin-sensitive Staphylococcus aureus, which was not concordant with the urine culture.

Of the 127 newborns evaluated for HSV, 9 infants (7.1%) were diagnosed with HSV. Seven cases (5.5%) had SEM disease, and 2 (1.6%) had disseminated HSV. All cases of SEM were in full-term infants; both cases of disseminated HSV occurred in preterm infants. Of these cases of neonatal HSV infection, 1 infant presented with coalesced vesicles (11.1%), 1 (11.1%) infant presented with vesicles, and 3 (33.3%) infants presented with both pustules and vesicles. Four (44.4%) infants presented with pustules without vesicles or bullae reported; in these infants, pustules were accompanied by punched-out and/or grouped erosions.

Angioinvasive fungal infection was diagnosed in 5 (2.7%) infants, all of whom were born less than 28 weeks GA, with mean gestational age 24.5 weeks. Pustules were seen in all 5 infants, 2 (40.0%) had erosions, 2 (40.0%) had plaques, 2 (40.0%) had crusting, 1 (20.0%) had an eschar, and 1 (20.0%) had patches. None of the affected infants had vesicles or bullae. Lesions were present on the trunk in 80% (4 of 5) of the cases.

Preterm infants born earlier than 32 weeks GA had greater rates of life-threatening infections (P < .01) when compared with those born after 32 weeks GA. Of the 9 infants born earlier than 28 weeks GA, 8 (88.9%) were diagnosed with an infection. Seven of the 8 infections (87.5%) were considered potentially life threatening: 5 angioinvasive fungal infections, 1 congenital cutaneous candidiasis, and 1 disseminated HSV infection. Seven of the 14 life-threatening infections detected in this study were in full-term infants; in these full-term infants, SEM was the only life-threatening infection diagnosed.

There are no published practice recommendations guiding the evaluation of afebrile infants ≤60 days with pustular or vesicular eruptions. This study highlights that pustules or vesicles in an afebrile infant are common, comprising 21% of all pediatric dermatology consults in infants from this cohort. Many afebrile infants with pustules or vesicles had extensive diagnostic testing and empirical treatment. Despite administration of systemic antibiotics in over half of the cohort, no SBI was detected that could be attributed to a skin source. None of the afebrile infants in our study were found to have invasive bacterial infection (IBIs), defined as bacteremia or meningitis. The evidence for risk of IBIs in the setting of neonatal skin and soft tissue infections (SSTIs) has not been well established in the literature. After pooling the outcome data from 5 relevant studies on the subset of infants with uncomplicated SSTIs (n = 1056),^13–17 there were no afebrile infants with an SSTI that were found to have a concomitant SBI. In other words, previous data suggest that the risk of concurrent IBIs in an afebrile infant with an SSTI is very low.^13–17 Despite this, 33% of infants underwent lumbar puncture, 57% underwent blood culture, and 53% received intravenous antibiotics and more than half of afebrile infants ≤60 days evaluated in the ED were admitted. The most frequently ordered test was a catheterized urine culture, ordered for 78% of infants, yet there were no UTIs detected with evidence of a skin source.

Fever has been previously reported to be commonly absent among infants with HSV infection.¹⁸ HSV incidence was <1% in a large cohort of hospitalized febrile infants (n = 26 533).¹⁸ In contrast, 7.1% (9 of 127) of afebrile infants ≤60 days with pustules and/or vesicles evaluated for HSV in this study were diagnosed with HSV infection. The diagnostic sensitivity and specificity of vesicular rash has been reported to be as high as 85.7% and 88.2%, respectively, for identifying neonatal HSV infection.¹⁹ Skin lesions are reported to be present in over 80% of infants with SEM disease, 65.9% of infants with CNS disease, and a 35.9% of infants with disseminated disease.¹ 

The expected morphology of skin lesions in neonatal HSV is “grouped vesicles on an erythematous base.”^2,4 There is a paucity of published data detailing skin findings of neonatal HSV. In existing studies of neonatal HSV,^18–23 3 of 9 articles described the presence of vesicles without pustules, 2 described pustules and vesicles, 2 contained only nonspecific descriptors, such as “rash” or “skin lesions,” and 2 had no description of cutaneous findings. In our cohort (n = 9), pustules were a common morphology in infants diagnosed with HSV and were more common than vesicles (75% and 50%, respectively). In these cases, pustules were either accompanied by vesicles or accompanied by punched-out or grouped erosions (1 of 3 and 2 of 3, respectively). Thus, the presence of pustules when accompanied by other morphologies suggestive of HSV (co-occurrence of vesicles, grouped lesions or suspicious erosions) warrants evaluation for HSV.

The mean age of infants with HSV infection was 15 days (range: 0–51 days; interquartile range: 9–19 days). This finding is consistent with previous study data that shows that frequency of HSV infection is highest in the second week of life and declines substantially in the second month.^18,21 Of the 3 subtypes of neonatal HSV, the disseminated form carries the highest mortality rate, with a relative risk for death 33 times greater than other HSV subtypes combined.²⁴ A retrospective study at a tertiary children’s hospital found the mortality rate of disseminated HSV to be 45% despite antiviral therapy.²³ Although the total number of neonatal HSV cases in this cohort was small, disseminated disease appeared to correlate with prematurity; SEM was diagnosed in 7 full-term infants and disseminated HSV was diagnosed in 2 premature infants. Thus, although full-term infants comprised the majority of the HSV infections in this cohort (7 out of 9), it is worth noting that the 2 preterm infants affected by both had disseminated forms of the infection, associated with much higher mortality. The prognosis of HSV infection in preterm infants has been previously understudied and warrants further consideration.²⁴ 

Eschar and ulceration are concerning skin findings in immunocompromised patients²⁵ and may indicate the presence of angioinvasive fungal diseases, such as mucormycosis. These infections may be heralded by vesicles and pustules.²⁶ Of the 5 cases of angioinvasive fungal infections in our cohort, all occurred in extremely preterm infants and 45% (5 of 11) of extremely preterm infants with pustules were diagnosed with angioinvasive fungal disease.

Our study had several limitations. First, although 6 academic institutions collected data across a 6-year period, the data are limited by the sample size and rare incidence of serious infections. Second, it is worth noting that study subjects likely had atypical or severe presentations of pustules and/or vesicles or complicated clinical histories that warranted pediatric dermatology consultation. As these presentations received subspecialty consultation in the tertiary care setting, the rate of infectious disease may be overrepresented. Third, these findings may not be generalizable to outpatient primary care, as subjects were restricted to infants who received a dermatology consult with precise morphologic assessment of their skin lesions. Finally, the retrospective nature of this study limited data collection; thus, elements of the history (eg, GA) were unavailable for some patients. Despite the retrospective nature of the study, missing a subsequent presentation of a fulminant infection was considered unlikely as each patient was previously evaluated in a tertiary care setting.

In the diagnosis of afebrile infants with pustules and/or vesicles, noninfectious etiologies were diagnosed two-thirds of the time and infection one-third of the time. The majority of the infections (80.3%, 59 of 71) were superficial. Life-threatening forms of infection were overall uncommon and included neonatal HSV (found in both full-term and preterm populations) and angioinvasive fungal infections (found exclusively in extremely preterm infants). There were no cases of invasive bacterial infections. A practice algorithm (Fig 2) is proposed to assist in the evaluation and management of well-appearing, afebrile full-term infants ages 60 days or younger that present with fluid-filled lesions.

Based on the results of this multicenter retrospective study, in the context of previously reported data,^13–17 an SBI workup may be unnecessary in well-appearing, full-term infants who present with vesicles or pustules in the absence of fever. Empirical parenteral antibiotics are not recommended as there is little evidence to support the development of SBI from skin lesions in the absence of other clinical signs of infection.^13–17 

There was an appreciable risk of HSV infection among afebrile infants with pustules and/or vesicles. Skin exams of HSV infections were always notable for vesicles or erosions, suggesting that the presence of these lesions may be used as a screening tool in the approach of a well-appearing infant with vesiculopustular eruption. In certain inpatient and ED settings, HSV PCR is a relatively rapid and reliable test that can help determine whether to pursue lumbar puncture and/or admission in an infant with clinically suspicious skin findings. Outpatient settings may be limited by the speed of HSV PCR testing, in which case, referral for elevated level of care in the ED or inpatient setting may be required. In infants with medium to high risk of HSV, empiric antiviral therapy can be initiated while awaiting skin HSV PCR results. If lumbar puncture is delayed, HSV in the CSF will remain detectable for 5 to 7 days even after initiation of acyclovir therapy.²⁷ Additional high-risk symptoms include poor feeding, lethargy, temperature instability, elevated hepatic enzymes, CSF pleocytosis, respiratory distress, thrombocytopenia, and seizures.^19,20 

In the absence of HSV risk factors, full-term, well-appearing, afebrile infants with isolated pustules (without punched out or grouped erosions or vesicles present) may be managed as an outpatient with close follow up. Rather than an SBI workup, surface swabs (HSV or varicella PCR, bacterial and fungal cultures) may be used as initial diagnostic testing to exclude HSV and confirm suspicion of common benign infectious etiologies, such as staphylococcal pustulosis and cutaneous candidiasis. Surface bacterial and fungal cultures were helpful in determining the diagnosis in most full-term infants (bacterial cultures were diagnostic 33.0% [35 of 106] of the time and fungal cultures were diagnostic in 25.6% [22 of 86]) and should be considered in the evaluation of infants presenting with pustules and/or vesicles. Several noninfectious etiologies of pustules, bullae, or vesicles may require additional workup and management. Persistent or worsening lesions, lesions accompanied by systemic symptoms, large bullae, and/or sloughing lesions are particularly worrisome. When infections are excluded, pediatric dermatology consultation should be considered for workup of other etiologies, such as neonatal lupus, epidermolytic ichthyosis, or epidermolysis bullosa. In preterm infants, especially <32 weeks, additional testing (eg, blood culture, liver enzymes, coagulation panel) are warranted since these infants are a high-risk group for developing invasive infections. When extremely preterm infants present with fluid-filled lesions, a full infectious work-up, including evaluation for superficial and disseminated bacterial, viral and fungal infections, and dermatology consultation, are recommended. Angioinvasive fungal infections, which are rare in full-term infants, should be high on the differential diagnosis in this vulnerable population. Fungal cultures, and potentially early initiation of antifungal therapy, are recommended in the setting of pustules in extremely preterm infants.

Full-term, well-appearing, afebrile infants ≤60 days of age presenting with pustules or vesicles may not require full SBI work-up, although larger studies are needed. HSV testing is recommended in all infants with vesicles, grouped pustules, or pustules accompanied by punched out or grouped erosions. Preterm infants should be assessed for disseminated fungal infection and HSV in the setting of fluid-filled skin lesions.

We thank Neha Kinariwalla, MD, Department of Dermatology, Brown University and Margaret Scollan, MD, Department of Dermatology, Columbia University for their administrative assistance in acquiring institutional review board approval of the manuscript.

CNS

central nervous system

ED

emergency department

EMR

electronic medical record

GA

gestational age

HSV

herpes simplex virus

IBI

invasive bacterial infection

SBI

serious bacterial infection

SEM

skin eye mouth

SSTI

skin and soft tissue infection

UTI

urinary tract infection