Sex: M
Vaccine: BCG
Symptoms: C-reactive protein increased, CSF culture negative, Chemokine increased, Culture wound positive, Deficiency of the interleukin-1 receptor antagonist
Clinical narrative: Immune Reconstitution Inflammatory Syndrome associated with disseminated infection derived from prior BCG vaccination; Immune Reconstitution Inflammatory Syndrome associated with disseminated infection derived from prior BCG vaccination; Literature Report. This literature marketed report has been received from the authors of a published literature article, titled as stated above and refers to a 5-year-old male patient.  The patient's medical history was not reported. The patient's concurrent conditions included dominant IFN-?R1 deficiency. Concomitant therapies were not reported.   On an unknown date, the patient started therapy with BCG (BCG VACCINE USP), administered by percutaneous route (lot # and expiration date were not reported) for the treatment of prevention of Tuberculosis. A 5-year-old boy with autosomal dominant IFN-?R1 deficiency (frameshift mutation c819_822 del TAAT) and disseminated mycobacterial infection was referred to institution for evaluation and treatment. He had received BCG vaccination at birth and presented at 2 years of age with recurrent fevers, night sweats, failure to thrive, and a rapidly progressive right upper eyelid mass extending into the orbital space and causing significant right eye proptosis. He was treated for presumptive tuberculosis for positive acid-fast bacilli (AFB) stain and culture, without treatment response, and had progression of disease with ongoing fevers, recurrent pustular skin lesions, and worsening protein calorie malnutrition, ultimately leading to the diagnosis of IFN-?R1 deficiency. He was referred to institution for management and initiation of adjuvant IFN-? therapy. Initial evaluation revealed a febrile, irritable child with large open wounds involving the entire calvarium, severe right eye proptosis exposing the entire globe and periorbital soft tissues along with associated ophthalmoplegia and loss of vision. On an unknown date, magnetic resonance imaging (MRI) of the brain and orbits with contrast demonstrated a heterogeneously enhancing, irregularly shaped mass centered around the lesser and greater wings of the right sphenoid bone involving the right pterygoid fossa, extending into the orbit, compromising the optic nerve and intracranially, invading the anterior cranial fossa and suprasellar cistern. The intracranial component of the mass had surrounding vasogenic edema and marked mass effect. There was also irregular moth-eaten destruction of the calvarium and the frontal, parietal, and temporal bones extending circumferentially with epidural thickening mainly at the convexities. On an unknown date, biopsies of the cranium revealed acute on chronic osteomyelitis with soft tissue involvement and numerous AFB. Foamy macrophages and neutrophils were seen without classic granuloma formation. On an unknown date, cerebrospinal fluid cultures were negative for bacteria, mycobacterial, fungal, and viral pathogens. On an unknown date, wound culture revealed M. tuberculosis complex, which on genetic testing  was speciated as Mycobacterium bovis BCG strain, consistent with disseminated infection derived from prior BCG vaccination. The antimycobacterial treatment was modified to isoniazid, rifampin, ethambutol, moxifloxacin, clofazimine, and linezolid, and IFN- ? (titrated up to 1.4 mcg/kg/dose) three times per week with good treatment response. After 16 months of therapy, he had resolution of constitutional symptoms and improved nutritional status with markedly decreased burden of disease. On an unknown date, MR imaging showed decreased size of the intracranial enhancing component and healing of skull lesions and associated epidural involvement. However, a complete cure for the infection was not achieved.  The patient underwent haploidentical bone marrow transplantation from his mother for correction of the underlying immunodeficiency and ultimate cure of the BCG infection. He received a reduced toxicity, busulfan-based (total exposure 48 mg*h/L) myeloablative conditioning with low-dose total body  irradiation (TBI) (200 cGy) without serotherapy. Graft-versus host disease (GVHD) prophylaxis was accomplished with posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. IFN-? was discontinued prior to the conditioning while antimycobacterial drugs (isoniazid, ethambutol, clofazimine, and moxifloxacin) were continued. Linezolid was stopped prior to the transplant cell infusion. He was also empirically started on eltrombopag, with the intention of facilitating engraftment. Viral and antifungal prophylaxis were added. Neutrophil and platelet engraftment occurred on Days +17 and +24, respectively  The patient's post-HCT course (Days +60 to +150) was complicated by intermittent low-grade fevers and multiple erythematous nodules arising from the forehead and calvarium draining purulent and necrotic material. During this period, the patient's head circumference gradually increased by 6 cm. On an unknown date, MRI of the brain showed multiple subgaleal complex solid and cystic rim-enhancing lesions, in association with small defects of the outer skull tables involving the right temporalis muscle and bifrontal scalp. The patient remained neurologically intact. The diagnosis of Immune Reconstitution Inflammatory Syndrome  (IRIS) was made based upon worsening clinical symptoms and radiological imaging alongside repetitive negative microbiological investigations and correction of the patient's underlying immune defect as evidenced by full (> 98%) donor chimerism in whole blood. Functional studies demonstrated normal monocyte STAT 1 phosphorylation and strong polyfunctional cytokine responses to TB antigens by flow cytometry. Inflammatory biomarkers were measured serially with findings of increased C-reactive protein (CRP), ferritin, and IL2SR indicating T cell activation . CXCL9 was also measured at Days +111 and +173 with elevated values of 207 and 521 pg/mL (reference range = 121 pg/mL) consistent with downstream IFN-? signaling. The patient was managed with supportive care, and symptoms of IRIS began to resolve by Day +150 with a resolution of fevers followed by a gradual decrease in head circumference to baseline.  On Day+190, the patient developed a sudden increase in transaminases without cholestasis. His antimycobacterial regimen was discontinued. Liver biopsy revealed mild duct injury and periportal inflammatory infiltrates consistent with GVHD and rare  non-necrotizing poorly formed granulomas with negative AFB Fite and ZiehlNeelsen stains suspicious of resolving mycobacterial IRIS. The patient was treated for GVHD with tacrolimus and prednisolone (2 mg/kg/day), which were later transitioned to ruxolitinib 2.5 mg twice daily. All immunosuppression was discontinued after 10 months of therapy. He is now approximately 4 years post-HCT and has been doing well off antimicrobials and immunosuppressive medications.   At the reporting time, the patient was recovering from IRIS and disseminated BCG infection. The action taken with suspect therapy was reported as not applicable.   The authors considered the events to be related to suspect therapy.   Upon internal review, the events IRIS and disseminated BCG infection were determined to be medically significant. Patient was hospitalized for both events, as he was admitted to the institution. A copy of the published article is attached as further documentation of the patient's experience.