Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of extreme inflammation occurring in association with genetic defects involving the granule-dependent cytotoxic pathway of CD8+ T cells or NK cells and/or a wide variety of triggers including infections, malignancies, and rheumatologic disorders. Because of its relative rarity and the nonspecific nature of the individual clinical and laboratory abnormalities comprising the characteristic Bpattern^of HLH, the diagnosis can be elusive. Furthermore, some of the laboratory tests included in the diagnostic criteria are time-consuming or not widely available, and since many of these patients are critically ill, HLH must be considered early on so that the diagnosis can be established and potentially life-saving treatment initiated. Since the diagnosis of HLH is truly a clinicopathologic correlation, in this article, we as a team of pediatric clinical and laboratory physicians will use exemplary cases from our own institution with a variety of clinical presentations to illustrate the many Bfaces^of HLH; deconstruct the diagnosis; point out some of the challenges, limitations, pearls and pitfalls; and make it easier to understand the pathophysiology in context. However, while we may see relatively more cases working in a tertiary care children's hospital, HLH is a disease of both children and adults. Illustrative cases Case 1The patient was a previously healthy black 4-month-old girl transferred from an outside hospital. Two weeks prior, she had developed low-grade fever and a rash which was initially attributed to a viral exanthem, but because of worsening fever (to 40°C), she presented to the emergency department (ED), was found to have a platelet count of 70×10 3 /mL, admitted for further evaluation including a full septic work-up, and started on empiric antibiotics. Her white blood cell count, hemoglobin, and platelet count all progressively declined (with a nadir absolute neutrophil count of 0.2×10 3 /mL, hemoglobin dropping to 6.6 g/dL, and 21×10 3 /mL platelets) and she developed mild hepatosplenomegaly which was confirmed by abdominal ultrasonography, prompting bone marrow examination which showed no evidence of leukemia, neuroblastoma, or hemophagocytosis. Although initially her ferritin was 17 ng/dL, at the outside hospital it ultimately reached the 500 s, while fibrinogen decreased to <100 mg/ dL. Steroids were begun as treatment for HLH shortly after transfer to our institution and while an infectious etiology was not uncovered, additional testing revealed a ferritin of 4873 ng/mL, sCD25 level of 34,826 U/mL (age-specific reference range: 334-3026), absent NK cell function, and compound heterozygosity for two previously described mutations in PRF1 that are associated with familial HLH. Her initial cerebrospinal fluid (CSF) showed a minimally elevated protein without pleocytosis which normalized within 2 weeks of therapy and never exhibited neurologic symptoms. Three

Hemofagocitinė limfohistiocitozė: literatūros apžvalga

“…Esant kalcio jonams, perforinas patenka į ląstelės taikinio membraną (ją perforuoja), polimerizuojasi ir membranoje susiformuoja poros, kurių dėka ląstelė ima irti dėl osmotinės lizės (8,10,13). Galiausiai, į pakitusios ląs-telės citoplazmą per poras prasiskverbęs granzimas B per kaspazių kaskadą inicijuoja jos apoptozę (1,3,5,8,10,13). Suirus patogeninei ląstelei nutraukiama antigeninė stimuliacija ir užbaigiamas imuninis atsakas.…”

“…Tad HLH diferencijavimas nuo kitų karščiavimą sukeliančių patologijų yra rimtas iš-šūkis. HLH metu stebimas febrilus karščiavimas (>38,5 °C), užtrukęs nuo 4 iki 41 dienos ir pasitaikantis apie 91-97 % pacientų (5,8,9). Užsitęsęs febrilus karščiavimas kartu esant kitiems pakitimams -citopenijai, žymiai padidėjusiai feritino (>3 000 ng/ml) ar sCD25 koncentracijai kraujyje (>2 400 U/ml) -tai HLH įtarimą pavirtinantys kriterijai) (9).…”

“…Feritinas >500 ng/ml* 8. Padidėjęs tirpaus IL-2 receptoriaus (sCD25) kiekis (>2 400 U/ml) * Kelių autorių straipniuose nurodoma, kad feritino kiekis >3 000 ng/ml yra dažnas HLH požymis, o jo padidė-jimas >10 000 ng/ml -labai jautrus ir specifinis HLH rodmuo (1,5,9). trakto infiltraciją limfocitais ar makrofagais (8).…”

“…Kepenų funkcijos sutrikimas lemia hipoalbunimemiją ir skysčių rentenciją (ascitą, periferines edemas, poliserozitą). Naujagimiams gali pasireikšti kepenų nepakankamumo klinika ir hydrops fetalis (5,8). Dėl HLH būdingos hipofibrinogenemijos ir kepenų funkcijos sutrikimo dažnai vystosi koagulopatija: maždaug 95 % pacientų, kuriems vystosi kraujavimo klinika, būdinga diseminuota intravazalinė koagulopatija (DIK).…”

“…Be trombocitopenijos taip pat galima trombocitų disfunkcija. Todėl HLH metu yra didelė ūminio nukraujavimo rizika (5,8).…”