Ecthyma gangrenosum due to Pseudomonas aeruginosa sepsis as initial manifestation of X-linked agammaglobulinemia: a case report

X-linked agammaglobulinemia (XLA) is a rare inheritable disease characterized by primary immunodeficiency and caused by monogenic mutations in the Bruton tyrosine kinase (BTK) gene [1, 2]. The mutations prevent precursor B cells in the bone marrow from forming mature, circulating B-lymphocytes, which results in clinically undetectable levels of all immunoglobulin isotypes. In human subjects with immunodeficiency, XLA has been associated with opportunistic infection by the gram-negative bacterium Pseudomonas aeruginosa [3]. Ecthyma gangrenosum is a cutaneous lesion caused by P. aeruginosa that requires prompt diagnosis and treatment [4]. Here, we report the case of a 20-month-old boy with XLA and ecthyma gangrenosum caused by P. aeruginosa as the initial presenting feature. Sanger sequencing revealed a new hemizygous variant of the X-linked BTK gene (c.262G > T in exon 4).

A 20-month-old boy presented to our institution on April 11, 2018 with a 4-day history of fever reaching 39.5^oC, vomiting, and diarrhea. The parents noted asymmetrical skin lesions on the patient’s limbs one day prior to admission. He was previously healthy, and had no known history of drug allergies, recent travel, or family history of immunodeficiency. The patient had received age-appropriate live attenuated vaccines and showed no symptoms of discomfort.

On admission, physical examination showed the patient had met typical developmental milestones. He was lethargic and febrile (39.1^oC); pulse rate was 155/min, respiratory rate was 56/min, and blood pressure was normal. The patient had a bulging anterior fontanelle, pupils were equal and reactive, and there was no abnormality in limb strength. Apparent subcostal retraction was observed. Arterial oxygen saturation (SaO₂) was 100%. Fine inspiratory rales were present on auscultation. Multiple purple necrotic lesions were visible on the abdomen and the right leg (Fig. 1). Laboratory tests (Table 1) revealed low peripheral white blood cell count 0.26 × 10⁹/L (normal reference values: 4–10 × 10⁹/L) with neutropenia (neutrophils, 0.05 × 10⁹/L; normal reference values: 1.8–6.3 × 10⁹/L ), eosinophils 0.01 × 10⁹/L (normal reference values: 0.02–0.52 × 10⁹/L), lymphocytes 0.16 × 10⁹/L (normal reference values: 1.1–3.2 × 10⁹/L), monocytes 0.04 × 10⁹/L (normal reference values: 0.1–0.6 × 10⁹/L), and elevations in C-reactive protein (CRP, 86 mg/dL; normal reference value: <8.0 ) and procalcitonin (49.04 ng/mL; normal reference value: <2.0).

Ecthyma gangrenosum due to P. aeruginosa sepsis was suspected. Intravenous ceftazidime (50 mg/kg, twice a day) was initiated. Four hours after admission, the patient experienced a seizure that was controlled by phenobarbital (5 mg/kg, iv). Two hours later, SaO₂ decreased to 86%. The patient was transferred to the pediatric intensive care unit (ICU) for mechanical ventilation. One hour after ICU admission, blood pressure was 50/30 mmHg and heart rate was 185/min. The patient received fluid resuscitation and inotropic support. Urine output was < 0.5 mL/kg/h during the 12 hours following ICU admission, and plasma albumin was 19 g/L (normal reference values: 37–52 g/L). Capillary leakage syndrome was considered. Colloids, including albumin, were given intravenously and continuous renal replacement therapy was initiated, but high fever persisted with repeated seizures. Blood, skin lesion, and stool culture samples taken on admission and returned on Day 3 of admission showed P. aeruginosa was found in all specimens and was sensitive to meropenem and levofloxacin but resistant to ceftazidime and pieracillin. Ceftazidime was replaced with meropenem (40 mg/kg, q8h) and levofloxacin (5 mg/kg, q12h). On Day 6 of admission, white blood cell count recovered to 4.1 × 10⁹/L and CRP was 27 mg/dL, but enterococcus was found in the cerebrospinal fluid. Meropenem and levofloxacin were replaced with vancomycin (15 mg/kg, q6h) combined with meropenem (40 mg/kg, q8h). On Day 8 of admission, the patient’s body temperature returned to normal. On Day 9 of admission, a cranial computed tomography (CT) scan showed diffuse brain edema (Fig. 2a). Cerebrospinal fluid (CSF) examination revealed protein 5.68 g/L, glucose 2.62 mmol/L (blood glucose, 7.0 mmol /L), total cell numbers 1273*10^6/L, nucleated cells 1238*10^6/L, multinucleated cells 74%, and mononuclear cells 26%. Purulent meningitis was considered, and ceftazidime treatment was continued. Intravenous mannitol (5 ml/kg body weight, q4h) and oxcarbazepine (5 mg/kg body weight, q12h) were given to control intracranial edema and seizures. Over the subsequent three days, the dose of oxcarbazepine was gradually increased to a maximum of 20 mg/kg body weight. The patient was taken off the ventilator. On Day 11 of admission, the patient experienced fever and diarrhea, and P. aeruginosa was resistant to meropenem but sensitive to levofloxacin; therefore, meropenem was replaced with levofloxacin. On Day 13 of admission, the patient was transferred back to the general ward; his state of consciousness was evaluated as a light coma. On Day 15 of admission, the patient’s body temperature returned to normal, and his diarrhea was greatly alleviated.

An immune panel was ordered (Table 1), which showed: plasma IgG 4.94 g/L (normal reference: 2.86–16.8 g/L), IgA 0.068 g/L (normal reference: 0.19–1.75 g/L), and IgM 0.185 g/L (normal reference: 0.43–1.63 g/L). The percentage of T lymphocytes (CD3⁺) was 96.48% (normal reference: 39%-73%) and B-cells (CD3⁻CD19⁺) were absent (0.1%, normal reference: 7%-41%) in peripheral blood. Second generation sequencing of immune-related genes was performed to screen possible mutations; subsequently, Sanger sequencing was applied to verify possible mutations. A hemizygous mutation (c.262G > T) in exon 4 of the X-linked BTK gene was found (Fig. 3, upper panel). The patient was diagnosed with XLA, and the mother was identified as a carrier (Fig. 3, bottom panel).

On Day 25 of admission, the patient was moderately comatose, spontaneous movements were reduced, and his response to stimulus or pain was poor. Cranial magnetic resonance imaging (MRI) showed severe hydrocephalus, which was managed by Ommaya reservoir implantation (Fig. 2b-c). On Day 70 of admission, repeat cranial MRI showed no significant increase in hydrocephalus, and CSF examination was normal; therefore, a ventriculoperitoneal shunt was inserted (Fig. 2d-e). On Day 29 of admission, the patient’s left elbow became swollen and movement was restricted. X-ray showed soft tissue swelling around the elbow (Fig. 4A). Pyogenic osteomyelitis was considered, and antibiotics (levofloxacin and vancomycin) were continued. On Day 47 of admission, MRI showed bone destruction in the left elbow joint and adjacent soft tissue swelling (Fig. 4B), supporting the diagnosis of pyogenic osteomyelitis. The left elbow remained swollen, but some movement was restored. Repeat culture of blood, stool, and CSF specimens revealed negative results. Considering the condition of the patient, antibiotics were changed to intravenous piperacillin-tazobactam (4:1, 50 mg/kg, q8h) for 3 weeks.

On Day 129 of admission, repeat MRI indicated that hydrocephalus was stable, and the child was discharged from hospital. Monthly intravenous immunoglobulin was prescribed. At the last follow-up on February 10, 2020, the patient remained bed-ridden in a semi-conscious state, with limited responses to stimuli, increased muscle tone, and a normal swallowing reflex.