Case presentation:
Patient X is the index case, previously healthy 18 months old female, the first child of healthy Saudi consanguineous parents, presented to our Emergency Department with a five-day history of high-grade fever, associated with diarrhea development lethargy, an anal lesion. Fever reached a Tmax of 39 Celcius and was partially responsive to antipyretics. Family History was positive for two childhood deaths at two years of age, with fever of unknown origin from the paternal side. One family member on the paternal side required intravenous immunoglobulin with an unknown cause—positive maternal family history of Behçet’s disease.
Physical Examination revealed a normal child with no findings apart from the presence of oral aphthous ulcers along buccal mucosa and an anal lesion, described to be 1cm x 1cm regular erythematous painless papule. The child underwent diagnostic workup and the initial investigations showed neutropenia and leukopenia, with white blood count (WBC) 4.58 10e9/L (reference range 4-11 10e9/L), ANC: 0.13 10e9/L, Hemoglobin: 10 g/dl, Platelet 154 10e9/L. Inflammatory markers showed increased CRP 148, ESR 120. Blood, urine, and cerebrospinal fluid cultures were negative.
Throughout her hospital stay, fever persisted at four hourly intervals reaching a T max of 40 Celsius for three months. Anal lesion progressed to enlarge and was complicated by cutaneous perianal fistula formation at 2’oclock and 9oclock position associated with exudative discharge. Exudative discharge grew Pseudomonas and Escherichia coli. Multiple Aphthous ulcers proceeded to develop in oral mucosa; oral scrapings showed growth of candida tropicalis. Diarrhea progressed to include hematochezia and blood clot passage requiring multiple blood transfusions.
The patient continued to be persistently neutropenic 0 - 0.35, leukopenic 0.22- 4.92, with thrombocytopenia development. Inflammatory markers remained elevated CRP 310 – ESR 120 ferritin 15141. The coagulation profile remained normal. Antinuclear antibodies (ANA) and anti-double-stranded DNA (anti-dsDNA) were negative. Immunoglobulin levels IgG 3.87 (2.9-10.7 g/L ), IgA 0.28 (0.40-1.20) and IgM 0.2 (0.3-1.5) remained unaffected along with post-vaccination titers. Oxidate burst test was resulted negative. Extensive workup for virology, fungemia, and mycobacterium all remained negative. C3 and C4 complement factors were within the normal range.
The perianal abscess was complicated by growth in size; and failure of formation of granulation tissue. Initially, stool for occult blood resulted positive, with the development of microcytic hypochromic anemia. Abscess depth progressed to involve vascular beddings resulting in hematochezia and fresh blood passage. Hemoglobin reached a low of 4mg/dl, requiring multiple blood transfusions and fresh frozen plasma (FFP). The Source of bleeding was not identified on a clinical basis. Mickell’s scan resulted in being negative as well as RBC technetium scan. Ultrasound was done, which was negative for intussusception and organomegaly. Endoscopy, and colonoscopic findings from the rectum to ascending colon were normal.
Intervention for neutropenia included methylprednisolone 10 mg/kg and intravenous immunoglobulin therapy with no response. A trial of Granulocyte colony-stimulating factor (GCSF) was initiated. She received a continuous infusion of GCSF 200 units for one month, with a lack of response. Furthermore, a trial of Human Leukocyte antigen typing was performed on both parents for future bone marrow transplant (BMT).
Bone Marrow Aspiration was performed, showing hypocellular bone marrow (50% cellularity), myeloid aplasia and extensive histiocytic proliferation with significant hemophagocytosis. Flow cytometry was performed on bone marrow aspirate showing severe lymphocytopenia (absolute including all lymphocyte subsets (B-,T-, NK-). The overall findings suggestive of primary or secondary immunodeficiency due to bone marrow suppression.
Blood passage was daily with the presence of clots; about 50 ml. At the time, fever continued, and tachycardia developed to reach a heart rate of 200 bpm. The patient was admitted under the care of the Pediatric Intensive Care Unit (PICU). Platelets declined to reach 1, despite multiple trials of platelets transfusion, as well as continuous infusion. After a multi-disciplinary meeting was conducted (involving general pediatrics, immunology, hematology-oncology, infectious diseases, gastroenterology, Rheumatology, Pediatric surgery, Pathology, PICU), it was agreed upon to initiate a trial of Anakinra 10 mg/kg interleukin (IL-1 receptor agonist); fever subsided for two days and resumed. A chimeric monoclonal antibody, infliximab, was given with no satisfactory outcome.
Whole Exome Sequencing demonstrated a homozygous pathogenic variant of the ADA2 gene suggesting VIAHS. Persistent massive peri rectal bleeding and tachycardia continued for a duration of two months. Cardiac ejection fraction was reduced; she was started on inotropic support and supportive management. She proceeded to develop acute kidney injury, liver injury with abdominal distention. Respiratory status declined secondary to abdominal compartment syndrome, and she was placed on maximum respiratory support. Despite all interventions, the patient arrested.