Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis

Abstract

Background The standard diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include hyperferritinemia to >500 ng/mL. This ferritin threshold is based on pediatric data, and evidence for its application among adults with secondary HLH is lacking. Objective and Methods We conducted a retrospective study assessing the relationship between extreme hyperferritinemia and adult secondary HLH at our institution. All adult inpatients seen over a 10‐year period, with serum ferritin >5000 ng/mL, were included. Results Among 1055 patients with serum ferritin >5000 ng/mL, there were 69 cases of HLH (HLH prevalence of 6.5%). Mean ferritin among HLH patients was 70 398 ng/mL (SD 122 908), median 40 019 ng/mL (IQR 16 051‐68 326). The prevalence of HLH only reached 50% as serum ferritin approached 90 000 ng/mL. A variety of conditions were contributory to hyperferritinemia, most commonly bacterial sepsis (33%), hematologic malignancy (29%), renal failure (24%), and liver injury (18%). The optimal cutoff ferritin for diagnosis of HLH was 16 000 ng/mL (sensitivity 79.4%, specificity 79.2%, PPV 20.9%, and NPV 98.2%). Conclusions The threshold ferritin levels used in diagnostic criteria for adult secondary HLH are too low to be clinically relevant, and efforts should be undertaken to revise them upward. Similar reappraisals should be taken of the other criteria used to diagnose adult HLH.

Ferritin index is a strong prognostic marker in adult hemophagocytic lymphohistiocytosis

“…In terms of diagnosis, a prospective cohort study confirmed that HLH‐2004 criteria may be a beneficial instrument for early diagnosis of adult HLH 16 . However, studies have also shown that hyperferritinemia is not specific for adult or paediatric HLH and the value ferritin levels used in diagnostic criteria for adult HLH are too low to be clinically relevant 17,18 . In terms of the prognosis of the disease, investigations have been made to explore the relationship between ferritin and survival in patients with HLH, 19,20 Lin et al discovered that compared with a paediatric patient with ferritin decrease < 50%, a paediatric patient with a higher ferritin decrease (>95%) has an increased chance of survivour (17‐fold) 14 .…”

Cytomegalovirus pneumonitis-induced secondary hemophagocytic lymphohistiocytosis and SIADH in an immunocompetent elderly male literature review

“…At the time of 2004 criteria set up, serum ferritin > 500 ng/mL had a sensitivity of 84 % with no documented specificity [ 7 ]. In adults, ferritin levels ≥ 3000 μg/L are not predictive of HLH, whereas, in the pediatric population levels ≥ 10,000 μg/L are 90 % sensitive and 96 % specific [ 7 ]. In adults, there is no established upper limit for ferritin that is specific for HLH [ 7 , 8 ].…”

“…In adults, ferritin levels ≥ 3000 μg/L are not predictive of HLH, whereas, in the pediatric population levels ≥ 10,000 μg/L are 90 % sensitive and 96 % specific [ 7 ]. In adults, there is no established upper limit for ferritin that is specific for HLH [ 7 , 8 ]. In a recent retrospective study in 2019, they reviewed 1055 adult patients with serum ferritin > 5000 ng/mL for HLH.…”

“…The ideal ferritin breakpoint for HLH diagnosis was 16,000 ng/mL (sensitivity 79.4 %, specificity 79.2 %, positive predictive value (PPV) 20.9 %, and negative predictive value (NPV) 98.2 %). They concluded that baseline ferritin levels utilized in the diagnostic criteria are too small for clinical relevance and propose revising them to a higher value [ 7 ]. They recommend revisiting ferritin and other criteria used in diagnosing adult HLH.…”

“…They recommend revisiting ferritin and other criteria used in diagnosing adult HLH. Normal serum ferritin level < 500 ng/mL essentially rules out secondary HLH giving it a high negative predictive value [ 7 ].…”