In 349 out of 556 patients, ferritin was measured in combination with transferrin (62.8%); 171 patients had more than one ferritin measurement (30.8%). Among all included patients, two patients were diagnosed with MAS and therefore treated. In one further patient who died, aHLH was suspected but not treated. Another deceased patient had histiocytosis X in his history.
Twenty-three patients fulfilled at least four HLH-2004 criteria. Eleven patients scored at least 80% in the HScore. These patients were reviewed by the aHLH expert team and aHLH was retrospectively diagnosed in nine patients of whom four patients had died (44.4%; Table 3). In two of these patients, MAS was diagnosed and treated (one patient was treated shortly before death with a significant delay of 9 weeks after admission, the other patient survived). Hence, 7 out of 9 cases remained undiagnosed during ICU treatment (77.8%). Furthermore, aHLH was not confirmed retrospectively in the patient who was suspected for aHLH but left untreated. The deceased patient with histiocytosis X in his history was not scored as aHLH. Three additional deceased patients scored positive with 5 out of 8 HLH-2004 criteria or had an HScore of at least 90%, but were reviewed as being unlikely to have suffered from aHLH. These patients are listed in Suppl. Table 3, http://links.lww.com/SHK/A665. Overall, ICU patients with measured ferritin and hyperferritinemia showed an aHLH rate of 3.7%, which rises up to 5.6% when only deceased patients are considered. Mortality in this selected cohort was 44.4%.
Adult HLH is a rare life-threatening hyperinflammatory syndrome due to uncontrolled immune regulation causing MODS with fatal outcome (19). Little is known about its epidemiology in ICUs, though an increasing number of case reports and series were published during the last decade (9, 28–31). Barba et al. (29) and Buyse at al. (30) reported 71 and 56 ICU patients, respectively, suffering from aHLH with mortality rates of 68% and 52%. All of these patients were admitted due to acute multiple organ failure. A recent study of Halacli et al. (32) investigated HLH-2004 criteria in 10 patients suffering from severe sepsis and septic shock. All had at least 5 out of 8 positive criteria but only one was correctly diagnosed and treated. This study exluded patients with malignancies, which constitute a major proportion of adult patients with aHLH as shown by us and others (33, 34). As malignant disorders and anticancer treatment predispose patients to develop aHLH, excluding those patients ignores a significant risk population.
A very valuable, easily available and cost-effective marker in the clinical context is serum ferritin. Eighty-four percent sensitivity was calculated for the 500 μg/L cutoff in the pediatric HLH-1994 trial (6). This trial included children with the age up to 18 years and may therefore not be representative for adult patients with HLH. Pediatricians have revisited their databases by thorough calculations and improved sensitivity/specificity by providing a threshold of more than 10,000 μg/L in children (37). The use of ferritin as a highly predictive laboratory test for aHLH recently was challenged by retrospective large-scale analysis of hospital databases screened for hyperferritinemic all-age patients (38, 39). Schram et al. and Sackett et al. pointed out that ferritin as high as more than 10,000 μg/L is a poor predictive biomarker in the context of multiple pathophysiologic conditions causing a hyperferritinemic state (liver damage, hemolytic conditions, hemodialysis, hemosiderosis in transfusion dependent patients, malignancy, infections, and others). However, hyperferritinemia in the clinical context of progressive fever, cytopenia, and splenomegaly is highly valuable in particular in ICUs, where sepsis is the major overlapping clinical condition (40). In accordance to previous case series in ICUs (31, 41), ferritin ranged between 3,102 and 107,470 μg/L in our study. Saeed et al. (42) found a ferritin of 3,951 μg/L in ICUs with 88% sensitivity and 82% specificity, whereas a cutoff value of 3,095 μg/L was at 100% sensitivity and 82.6% specificity in our case series. In analogy to ferritin in aHLH, procalcitonin is a widely used biomarker to identify bacterial infections in critically ill sepsis patients. Yet, procalcitonin can be upregulated in cancer and other cytokine storm disorders without bacterial blood stream infections, leaving us with the notion of a large metaanalysis that test results “must be interpreted carefully in the context of medical history, physical examination, and microbiological assessment” (43). This, in our opinion, is a core message for improving diagnostic vigilance in ICUs: 1. Focus on medical history: Almost half of our aHLH patients had a previously diagnosed hematologic malignancy. Two additional patients had autoimmune/inflammatory conditions, and only a third of the patients developed aHLH without a known immune affection. 2. Repeatedly focus on physical examination and follow-up diagnostic procedures: As overt inflammation obscures histopathology, malignant lymphoma may remain undetected and may require repeated follow-up invasive diagnostic procedures (liver, skin, lymph node, spleen, liquor) guided by sequential imaging procedures including positron emission tomography (PET) (44, 45). Adult HLH is not a disease by itself, but rather an inflammatory tip of an iceberg of an underlying disorder. It is enriched in patients with acquired or induced immunosuppression (46, 47). In summary, it cannot be overemphasized to assess ferritin in every patient with unexplained cytopenia, organomegaly, or fever refractory to antibiotics, and to include ferritin to the sepsis work-up.
Bone marrow diagnostics are needed as part of the HLH-2004 criteria to search for hemophagocytosis. Yet, hemophagocytosis may only be detectable in 60% to 80% of patients with HLH despite its name-giving role (1). To perform, a bone marrow biopsy is not only mandatory in the search for hemophagocytosis, but also required as part of a thorough lymphoma and infectious disease (tuberculosis, leishmaniasis) work-up. In contrast, functional NK cell diagnostics, which are part of the HLH-2004 criteria, are usually dispensable, as most patients enter ICUs deeply cytopenic, and may be pretreated with lymphocyte depleting steroids. Fardet et al. also excluded measurement of NK cell function from the diagnostic panel (Suppl. Table 2, http://links.lww.com/SHK/A665) (16). Tests are time consuming and costly and should never cause delayed treatment due to pending test results (20).
It is important to reflect on patient age in our and many other patient series of aHLH: age in this series ranges from 20 to 65 years, median age in the German aHLH registry is about 50 years (17–80) (34). Hence, elderly patients should not be withheld from aHLH work-up.
It is of note that a recently published subgroup analysis of a large randomized controlled multicenter trial that tested interleukin-1 receptor blockade via Anakinra in sepsis demonstrated potential use of Anakinra in patients with aHLH symptoms, i.e., hepatobiliary dysfunction and disseminated intravascular coagulation (52). Although Anakinra failed to demonstrate beneficial effects in the entire sepsis cohort, this subgroup analysis shed further light on potentially undetected aHLH patients in ICUs.
Our study has some obvious limitations: first, this is a retrospective chart review analysis. It depends on patchy data documentation in particular with regard to HLH-2004 diagnostic criteria. Second, aHLH diagnosis from charts only has the limitation of being devoid of the full clinical picture. Third, due to the time lapsing between start of symptoms and sampling for ferritin measurement, it is probable that patients with hyperferritinemia were lost. Nonetheless, our data bare comparison with the available literature and provide evidence that undetected aHLH patients do not receive appropriate treatment with subsequent fatal outcome.
The authors thank Victoria Windmann and Anna Heptner for their help with the manuscript. Preliminary data of this manuscript were presented at DIVI 2016, Hamburg as an e-poster, and at Sepsis Update 2017, Weimar as a poster.
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