Primary cutaneous aspergillosis (PCA) is a rare fungal infection that primarily affects individuals with impaired immunity. Extremely preterm infants (EPI) lack basic immune defenses such as a mature skin barrier. Additionally, invasive medical interventions place these neonates at a heightened risk for fungal skin infections. PCA presents with skin lesions such as pustules, ulcers, abscesses, bullae, erythematous plaques with white scales, or black eschars [1]. Untreated, it may progress to invasive neonatal aspergillosis, which carries a high mortality. Few case reports of PCA in EPI exist in the literature. Due to its rarity, early recognition is critical and may improve outcomes. A review of the literature from 1991 to 2023 identified 37 cases of neonatal PCA [1-6]. PCA is associated with death in neonates, with one study citing a mortality rate of 46% based on literature review of 41 reported cases [2]. Although the mortality rate was 100% in the cases documented in this report, the extent to which PCA infection ultimately contributed to eventual demise is unclear. Given likely underreported incidence, there is a need for further investigation of the pathophysiology of PCA in EPI, associated risk factors, treatment options, and potential prophylaxis [7]. This report contributes to the understanding of neonatal PCA by presenting the first known documented cluster of cases in Arizona and one of the largest case clusters in the United States. The case series examines the clinical presentation, diagnostic challenges, and treatment of PCA in four extremely preterm infants raising important questions about environmental exposures and the impact of fungal infections on EPI.

A male infant was born at 23 3/7 weeks gestation via precipitous vaginal delivery due to maternal vaginal bleeding and cervical changes, weighing 682g (1lb 8.1oz). At birth, he was diagnosed with secondary apnea, requiring positive pressure ventilation (PPV) for hypoxia. Initial management included mechanical ventilatory support, surfactant administration, and fluid resuscitation. On day of life (DOL) zero, he developed acute anemia, metabolic acidosis, and intraventricular hemorrhage (Grade 4 right, Grade 2-3 left) and also developed hypotension requiring vasoactive support with dopamine and epinephrine. By DOL one, he exhibited signs of dehydration requiring increased fluid resuscitation and was noted to have fragile-appearing skin with scattered ecchymosis. DOL two was significant for worsening skin breakdown, metabolic acidosis, severe neutropenia, leukopenia, and hypernatremia with increased insensible water losses. Thick, pink-tinged sputum required frequent endotracheal suctioning, and he was started on gentamicin for suspected sepsis. On DOL three, he developed multiple confluent violaceous patches some of which with central eschar and ulceration diffusely scattered across the lower abdomen, chest, left shoulder, and back (Figure 1). Blood cultures drawn on DOL two resulted positive within 12 hours for gram-negative rods, prompting initiation of ampicillin, cefepime, and gentamicin, along with discontinuation of fluconazole in favor of amphotericin B for suspected fungal involvement. Skin culture results later confirmed Aspergillus species. By DOL four, skin lesions remained unchanged in distribution and number, but the patient was noted to have increased extremity edema. Blood culture results identified Pantoea septica, an opportunistic neonatal pathogen, leading to the discontinuation of ampicillin while maintaining cefepime, gentamicin, and amphotericin B. Despite ongoing intensive management, the infant suffered clinical deterioration and was pronounced deceased on DOL four after four rounds of epinephrine and saline boluses. The infant had high-risk factors including extreme prematurity, respiratory distress and sepsis, all of which significantly contributed to their multifactorial clinical deterioration and demise.

Figure 1: Case 1 cutaneous findings that appeared on DOL 2.

A twin male preterm infant was born via emergency cesarean section at 22 0/7 weeks gestation weighing 470g (1lb 0.602). He was immediately transferred to the NICU requiring PPV via endotracheal tube (ET) on 100% FiO2. Curosurf was administered at seven minutes of life. On DOL one, the patient was started on prophylactic ampicillin, gentamicin, and fluconazole. On DOL two, the patient developed ventricular tachycardia in the setting of hyperkalemia. He was given a calcium gluconate bolus and insulin with subsequent arrhythmia resolution. The patient's condition continued to fluctuate along with treatment plans. On DOL eight, the infant developed a rash on the lower back, characterized by scattered circular plaques with peripheral crusting (Figure 2). Erosions were also noted on the back, which worsened by DOL nine with concern for fungal infection, prompting the addition of amphotericin B and cefepime to the treatment regimen. On DOL ten, a head ultrasound revealed new multifocal abnormalities concerning for a central nervous system (CNS) infection. That same day, the Aspergillus galactomannan test resulted positive. On DOL 11, a potassium hydroxide skin smear confirmed the presence of Aspergillus species. The patient passed away on DOL 11. Fungal blood cultures showed no growth over four weeks, making the initial Aspergillus galactomannan test the only positive blood test. The immediate cause of death was respiratory failure in the setting of pneumothorax secondary to extreme prematurity.

Figure 2: Case 2 cutaneous findings that appeared on DOL 8.

A male neonate was delivered via spontaneous vaginal delivery at 22 4/7 gestation with a birth weight of 450g (15.9 oz). Due to extreme prematurity, the patient received PPV with 100% FiO2, Curosurf 1.5mL for surfactant replacement therapy, and dopamine for hypotension on DOL one. Given the presence of prolonged rupture of membranes (PROM) prior to delivery and high risk of infection due to extreme prematurity, prophylactic ampicillin and gentamicin were administered. On DOL two, fluconazole prophylaxis was initiated. On DOL three, Aquaphor was applied to the skin every six hours for skin barrier protection to lessen insensible water loss. On DOL four, the neonate developed extensive skin breakdown and bleeding that involved the lower extremities, chest, and axillae. Wound care included regular Mepilex Lite, Optifoam, and Bactroban application. The neonate's linens were replaced with a sterile blue towel nest. On DOL five, the infant was noted to have worsening ecchymosis, deep excoriations, and white crusted patches on the back that raised suspicion for fungal etiology (Figure 3). A galactomannan test returned positive suggesting an Aspergillus infection. Fungal cultures from the arterial line catheter exhibited no growth over four weeks. Fungal skin cultures were contaminated with bacterial overgrowth, preventing fungal species identification and confirmation of cutaneous fungal infection. Cultures were unable to be repeated as later that day the neonate developed a large right sided pneumothorax with near-total lung collapse leading to demise on DOL six.

Figure 3: Case 3 cutaneous findings that appeared on DOL 5.

A female neonate was delivered at 24 4/7 weeks due to advanced cervical dilation, progressing to preterm premature rupture of membranes (PPROM) and footling breech presentation. She was transferred via Air Ambulance to Phoenix. Maternal history included chorioamnionitis and Group B Streptococcus (GBS) positivity. On DOL zero, after umbilical arterial catheter (UAC) placement, leakage of serous fluid raised concerns for a patent urachus or peritoneal connection from an umbilical cord avulsion requiring surgical consultation and repair. On DOL eight, the patient was started on ampicillin and gentamicin after a wound culture from the back showed Staphylococcus haemolyticus resistant to cefazolin, clindamycin, and oxacillin, along with scant growth of Aspergillus species (Figure 4). By DOL nine, Aspergillus was confirmed, prompting pediatric infectious disease consultation. Blood and cerebrospinal fluid (CSF) cultures drawn on DOL ten were ultimately negative. The patient received 48 hours of empiric vancomycin and cefepime before starting a 14-day course of amphotericin B. Abdominal ultrasound imaging on DOL 11 was negative for microabscesses but mild volume overload was noted. On DOL 21, blood cultures were repeated due to worsening hypotension and feeding intolerance, and an additional two days of vancomycin and cefepime were given. By DOL 23, a renal ultrasound revealed high resistive indices in bilateral renal arteries, suggesting intrinsic renal pathology. Due to persistent hypotension and worsening renal function, liposomal amphotericin B was resumed on DOL 24. Despite antifungal therapy and supportive care, renal failure progressed and ultimately led to complications resulting in demise on DOL 24.

Figure 4: Case 4 cutaneous findings that appeared on DOL 5.

These four cases of neonatal primary cutaneous aspergillosis (PCA) highlight diagnostic and management challenges in extremely premature infants. The cases, identified in the NICU at Valleywise Health Medical Center in Phoenix, Arizona, underscore the vulnerability of this population due to immature immune defenses and frequent invasive procedures. The potential role of environmental factors, such as nearby construction and airborne fungal spores in the Arizona desert, raises concerns about exposure risks and the need for refined infection prevention efforts. Current literature suggests that nearby construction sites can be a source of fungal infections in hospitalized patients, supporting this as a possible source linked to each of the above reported cases given ongoing hospital reconstruction efforts during this cluster outbreak [8]. Additionally, current evidence supports a correlation between increased risk of fungal spore transmission during warmer months and in hot climates, again applicable to this case cluster in Arizona [8]. Ultimately, no definitive conclusion was made regarding infection source in these cases, highlighting the difficulty of identifying fungal contamination origins in healthcare settings. The extent to which underlying PCA infection contributed to the demise of each of these four neonates remains unclear. Despite appropriate antifungal prophylaxis with fluconazole and later with therapeutic amphotericin B after testing confirmation, the degree of successful infection treatment was undetermined due to subsequent demise attributed to complications of extreme prematurity soon after diagnosis. This underscores PCA as a potential contributor to the burden of disease in neonates at high risk for morbidity and mortality. The inability to pinpoint the exact source of exposure complicates prevention efforts, emphasizing the need for improved infection control measures in the NICU including enhanced air filtration, environmental monitoring, and targeted antifungal prophylaxis.

These cases also stress the importance of considering fungal infections in the differential diagnosis of neonatal skin lesions, particularly in endemic areas or when standard antimicrobial therapies fail. Emerging diagnostic tools like fungal PCR and antigen detection may facilitate earlier diagnosis and better outcomes. Multidisciplinary collaboration among neonatologists, infectious disease specialists, and dermatologists is crucial for timely recognition and management. Future research should focus on refining antifungal strategies, improving diagnostic methods, and conducting environmental risk assessments to reduce infection rates and improve neonatal outcomes.

The authors would like to acknowledge the NICU nursing staff, respiratory therapists, and infection prevention team at Valleywise Health Medical Center for their vigilance and dedication to patient care, which played a vital role in identifying and managing this clinical cluster.

Author Contributions

Merrill, T. Zoellner, and J. D. Blackwood conceptualized and drafted the initial manuscript and contributed equally as first authors.

Disclosure Statements

The authors have no financial relationships, conflicts of interest, or relevant disclosures related to the content of this manuscript. No funding was received for the preparation of this case series.

1. Amod FC, Coovadia YM, Pillay T, Ducasse G. Primary cutaneous aspergillosis in ventilated neonates. Pediatr Infect Dis J. 2000; 19: 482-483.
2. Gallais F, Denis J, Koobar O, Dillenseger L, Astruc D, Herbrecht R, et al. Simultaneous primary invasive cutaneous aspergillosis in two preterm twins: case report and review of the literature. BMC Infect Dis. 2017; 17: 535.
3. Frankenbusch K, Eifinger F, Kribs A, Rengelshausen J, Roth B. Severe primary cutaneous aspergillosis refractory to amphotericin and successful treatment with systemic voriconazole in two premature infants with extremely low birth weight. J Perinatol. 2006; 26: 511-514.
4. Frick MA, Boix H, Camba Longueira F, Martin-Gomez M, Rodrigo-Pendas J, Soler-Palacin P. Primary cutaneous aspergillosis in a preterm infant. Pediatr Infect Dis J. 2016; 35: 704-706.
5. Kimura H, Mitsuto I, Taguchi R, Anzawa K, Mochizuki T. Primary cutaneous aspergillosis caused by Aspergillus tamarii in a premature infant with extremely low birth weight: a case report with review. J Dermatol. 2018; 45: 622-625.
6. Mehler K, Cornely O, Seifert H, Zweigner J, Janssen S, Oberthuer A. Molds and more: rare fungal infections in preterm infants <24 weeks of gestation. Pediatr Infect Dis J. 2022; 41: 352-357.
7. Andresen J, Nygaard EA, Stordal K. Primary cutaneous aspergillosis (PCA): a case report. Acta Paediatr. 2005; 94: 761-762.
8. Pilmis B, Thepot-Seegers V, Angebault C, Weiss E, Alaabouche I, Bougnoux ME, et al. Could we predict airborne Aspergillus contamination during construction work?. Am J Infect Control. 2017; 45: 39-41.