To the Editors: We report the case of a 21-year-old female who developed a serious bacterial infection while receiving the anti-interleukin-6 (IL-6) receptor monoclonal antibody tocilizumab and in whom the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) responses were blunted by her immunosuppressive therapy. Serum procalcitonin (PCT), however, remained a useful marker of the acute infection and her subsequent clinical improvement, suggesting an important role for PCT in the diagnosis of serious infection in patients receiving tocilizumab. A 21-year-old female with juvenile idiopathic arthritis and chronic abdominal pain presented to the emergency department with fever, abdominal pain, vomiting and diarrhea 1 day after her biweekly infusion of tocilizumab. Physical examination was unrevealing, and routine laboratory testing showed a white blood cell count of 8300/mm3 with 70% neutrophils, CRP <0.5 mg/dL (normal <1.0 mg/dL) and an ESR of 3 mm/hr, and she was discharged. She returned 1 day later with worsened abdominal pain and was hospitalized. Abdominal computed tomography and pelvic inflammatory disease testing were negative. On hospital day 2, acute otitis media was noted, and she developed a generalized erythrodermal rash with bullous sloughing consistent clinically and on subsequent biopsy with staphylococcal scalded-skin syndrome associated with the acute otitis media. She was treated with ampicillin-sulbactam and slowly improved. She was discharged completely recovered after 8 days of hospitalization on oral amoxicillin-clavulanic acid. Blood testing throughout showed persistently low ESR and CRP (Table 1). Given the suspected inhibition of these markers by tocilizumab, a serum procalcitonin test was ordered on hospital day 5 and retrospectively performed on 3 prior frozen serum samples, including 1 taken at the time of her initial Emergency Department presentation. The initial PCT of 15.96 ng/mL (normal 0.0–0.5 ng/mL) was highly suggestive of bacterial infection, and subsequent values showed a clear trend toward normalization, reaching 0.54 ng/mL by day 5 after exposure to antistaphylococcal therapy.TABLE 1: Laboratory and Temperature Values During Hospital CourseProcalcitonin, a 116 amino acid peptide precursor to calcitonin, is transcribed by the calcitonin-related polypeptide alpha gene on chromosome 11. In the setting of bacterial infection, PCT is released in large quantities in to the circulation from a wide range of differentiated parenchymal tissues, particularly fat cells.1 PCT release is driven in vivo primarily by the proinflammatory cytokines tumor necrosis factor-α and IL-1ß.2 IL-6 is a critical mediator of inflammation and plays a central role in the induction of acute phase reactants in the liver, including CRP and fibrinogen, the primary driver of elevated ESR. Other cytokines, notably IL-1 and tumor necrosis factor-α, which can also elevate CRP and ESR, appear to do so through stimulation of IL-6.3 Although IL-6 can stimulate PCT release in vitro, in vivo it is not essential and elevation of IL-6 can occur without a rise in PCT, as demonstrated in a study of 360 febrile children with proven viral infections.4,5 Little published information exists demonstrating the effects of biological immunosuppressant agents on the PCT compared with other acute phase reactants. Tocilizumab is a mouse derived, humanized monoclonal antibody directed against the IL-6 receptor. Given the central role of IL-6 in CRP and ESR elevation, and the distinct alternate pathways of procalcitonin release, an IL-6 inhibitor should blunt the response to CRP and ESR while allowing PCT to elevate in response to severe bacterial infection, as was demonstrated in this case. In patients undergoing therapy with IL-6 receptor inhibitors, PCT may be the preferred surrogate marker of bacterial infection. James T. Gaensbauer, MD, MScPH Craig A. Press, MD, PhD Department of Pediatrics Section on Infectious Diseases J. Roger Hollister, MD Department of Pediatrics Section of Allergy, Immunology and Rheumatology University of Colorado School of Medicine Aurora, CO Edwin J. Asturias, MD Department of Pediatrics Section on Infectious Diseases University of Colorado School of Medicine Aurora, CO Center for Global Health Colorado School of Public Health Aurora, CO
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May 23, 2023
Sarah Walker + 4
Open Access