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Original article
The diagnosis of adult-onset haemophagocytic lymphohistiocytosis: lessons learned from a review of 29 cases of bone marrow haemophagocytosis in two large academic institutions
  1. Flavia G Rosado1,
  2. Elizabeth B Rinker2,
  3. W D Plummer3,
  4. William D Dupont3,
  5. Natalie M Spradlin4,
  6. Kaaren K Reichard5,
  7. Annette S Kim6
  1. 1Department of Pathology, West Virginia University, Morgantown, West Virginia, USA
  2. 2Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
  3. 3Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA
  4. 4Department of Hematology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  5. 5Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA
  6. 6Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Annette S Kim, Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Thorn 613A, Boston, MA 02115, USA; askim{at}bwh.harvard.edu

Abstract

Aims Haemophagocytic lymphohistiocytosis (HLH) is divided into paediatric (primary) and adult (secondary) types. While paediatric-HLH has been extensively characterised, similar studies in adults are limited. This study aims to evaluate the significance of the HLH diagnostic criteria as well as other clinical parameters in adults with bone marrow evidence of haemophagocytosis.

Methods We conducted a 10-year retrospective search of the pathology archives of two institutions for cases with bone marrow haemophagocytosis. We included those cases that fulfilled the currently established HLH diagnostic criteria. For the 29 cases that met inclusion criteria, we assessed clinical features, co-morbidities, therapy and clinical outcome. The effect of 19 clinical variables on mortality outcomes was assessed using logistic and hazard regression analyses.

Results Of cases for which an aetiology could be identified, infectious diseases were the most common association (14 of 19, 74%). Fever and elevated ferritin were the most frequently available criteria used to establish HLH. The overall mortality rate was 61% despite HLH-specific therapy, which had been initiated in 48% of the cases. The remaining cases were treated with supportive therapy and antibiotics. The most statistically significant marker of mortality was an elevated absolute neutrophil count (ANC), a feature not typical of HLH.

Conclusions Since elevated ANC correlates with poor outcomes in sepsis, and not HLH, we postulate that many of the patients fulfilling HLH diagnostic criteria in this study likely had sepsis/systemic inflammatory response syndrome rather than HLH. Our results highlight the need to define HLH diagnostic criteria specific to the adult population.

  • NEUTROPENIA
  • CLINICAL INFECTIOUS DISEASES
  • BONE MARROW
  • HEMATOPATHOLOGY

https://doi.org/10.1136/jclinpath-2015-203577

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    Introduction

    Haemophagocytic lymphohistiocytosis (HLH) is an uncommon syndrome characterised by the abrupt development of fever, splenomegaly and cytopenias with frequent concomitant involvement of various tissues by a lymphohistiocytic infiltrate and haemophagocytosis. HLH is caused by aberrant function of cytotoxic T/natural killer (NK) cells, which leads to an uncontrolled cytokine release pathologically and high mortality clinically.1

    HLH can be classified into primary and secondary forms. The primary (genetic) type of HLH encompasses those cases in which the T/NK cell dysfunction is caused by a specific genetic mutation and includes familial types of HLH (due to perforin gene mutations and other mutations involved in vesicle trafficking) and those associated with primary immunodeficiencies (eg, Chediak–Higashi, Griscelli syndrome, Hermansky–Pudlak and X-linked lymphoproliferative disease).1 In these cases, the catastrophic inflammatory response leads nearly uniformly to death unless HLH-specific therapy, which includes immunosuppressive chemotherapy and stem cell transplantation, is promptly initiated.2 The secondary (acquired or reactive) type of HLH, regardless of age, is defined by the lack of any known genetic defects. This type includes those that arise in patients with underlying autoimmune disorders, malignancies or infectious diseases.1 HLH has been reported in a wide age range. Primary types tend to manifest in early childhood, while secondary types are more frequently described in adults.3 ,4 Adult-onset HLH is a poorly understood entity that has been spotlighted only recently by several published series of cases.5–9 Diagnostic criteria developed by the Histiocyte Society2 (figure 1) have proven useful in identifying paediatric cases, but have been extensively criticised for their lack of specificity in critically ill adult patients, due to their overlap with criteria used to diagnose systemic inflammatory response syndrome (SIRS).10–12

    Figure 1
    Figure 1

    HLH diagnostic criteria. HLH, haemophagocytic lymphohistiocytosis; Hgb, haemoglobin; PLT, platelet count; ANC, absolute neutrophil count; WBC, white blood cell count; NK, natural killer; EBV, Epstein–Barr virus.

    SIRS is a clinical syndrome that, in combination with infection, defines sepsis. SIRS may be described by protean criteria of fever, tachycardia, tachypnoea and either leucocytosis or leucopenia (figure 2). However, since criteria for the diagnosis of HLH include fever and neutropenia and since these patients are quite ill, many patients with HLH will also demonstrate tachycardia and tachypnoea, thereby meeting criteria for SIRS. Since infection is a common cause for adult HLH, often these patients also meet criteria of sepsis as well. Thus, there is significant overlap between these two entities.

    Figure 2
    Figure 2

    (A) Diagnostic criteria for SIRS. (B) Clinical criteria for SIRS and HLH can overlap. SIRS, systemic inflammatory response syndrome; HLH, haemophagocytic lymphohistiocytosis; WBC, white blood cell count.

    The purpose of this study is to evaluate the clinical significance of the accepted HLH diagnostic criteria as well as other clinical parameters in the prognosis of HLH in adults. To accomplish this goal, we reviewed the laboratory findings and survival data of adult cases of bone marrow haemophagocytosis that fulfilled the currently accepted HLH diagnostic criteria. These results were contrasted with those reported in paediatric-HLH and in SIRS.

    Materials and methods

    Patient selection

    This study was approved by the Mayo Clinic Rochester and Vanderbilt University Medical Center Institutional Review Boards, and all patients provided authorisation to use their medical records for research purposes. All cases that had bone marrow haemophagocytosis in a 10-year period in adults >18 years of age and that fulfilled four additional required diagnostic criteria were included (figure 3). An electronic search of bone marrow biopsies using the key word ‘haemophagocytosis’ was conducted at the Mayo Clinic Rochester and at Vanderbilt University Medical Center, using the electronic applications for pathology reporting (laboratory information systems), CoPath and Triple G, respectively. An independently maintained list of clinical patients was also obtained from Vanderbilt University Medical Center. Available archival bone marrow material was reviewed to confirm the presence of significant haemophagocytosis, defined as the presence of exaggerated number of histiocytes containing intact nucleated cells within the cytoplasm (>1). The presence of intact cells defined the histiocyte activity as unusual and exaggerated, as histiocytes normally encountered in bone marrow specimens, even when numerous, contain debris rather than intact cells.13 ,14 Electronic medical records were obtained in order to identify cases that met diagnostic criteria for HLH, and to obtain other pertinent clinical, laboratory and outcomes data.

    Figure 3
    Figure 3

    Study design. Cases with documented bone marrow involvement were selected (n=59). Of those, 29 cases met diagnostic criteria for HLH (of which bone marrow histology involvement by HLH is one). A total of 18 clinical parameters and a treatment parameter were analysed and correlated with outcomes including a binary survival status as well as time to death for those that did not survive. HLH, haemophagocytic lymphohistiocytosis; Hgb, haemoglobin; PLT, platelet count; ANC, absolute neutrophil count; WBC, white blood cell count; NK, natural killer; EBV, Epstein–Barr virus.

    Statistical analysis

    All patients who died during the episode of diagnosed HLH did so within 90 days. Since time to death over this short interval is of limited clinical importance, we chose logistic regression as our primary analysis method with haemophagocytosis-related death as the outcome variable. The explanatory variables considered in these models are described in figure 3. Each variable was considered by itself and in combination with treatment (see figure 3). Categorical variables were fitted in these models with indicator covariates.15 The analogous proportional hazards regression analyses were also run to assess the effects of these explanatory variables on time-to-death. In these analyses, all patients were censored at 90 days even though continuous covariates were directly entered into these models. When significant, the associated assumption of a log-linear effect on mortal hazard was assessed with restricted cubic spline models.15 Survival differences between patients who did and did not receive HLH-specific chemotherapy were assessed by the log-rank test. The relationship between absolute neutrophil counts (ANCs) and the other explanatory variables was assessed by simple linear regressions.

    Results

    Of 59 cases of bone marrow haemophagocytosis, none had all eight clinical and/or laboratorial data listed in figure 1 documented in their available medical records. However, a minimum of five positive criteria, including evidence of bone marrow haemophagocytosis, were obtained in the 29 cases of HLH included in this study, thereby fulfilling the criteria required for a diagnosis of HLH. Ages ranged from 19 to 85 (median 50) years, and the male to female ratio was 1.4:1. HLH (or rule out HLH) was listed as an indication for the bone marrow study in only 4 of 29 cases (14%) whereas cytopenias not otherwise ascribed to HLH were the indication in 66% of cases. Therefore, in the majority of cases, the bone marrow findings were the initial impetus to begin an HLH work-up. Among diagnostic criteria (table 1), ferritin (97% of all cases, 100% of cases where data were available) and fever (86% of all cases, 96% of cases where data were available) were the most frequently measured parameters used in making the clinical diagnosis of HLH. The single most common cytopenia identified was thrombocytopenia (platelet count <100  ×109/L found in 83% of all cases), and bilineal cytopenia was seen in 17 of 28 cases (59%). Conversely, NK cell function and soluble CD25 (IL-2 receptor) test results were available in only a minority of cases (three cases and six cases, respectively). Only one case of a 22-year-old male had genetic testing performed and was negative for the common genetic causes of HLH. To investigate if more stringent criteria for ferritin would be applicable, a threshold of >10 000 μg/L (22 470 pmol/L) was also examined. Of patients for whom ferritin levels were available, 18 of 28 cases (68%) had met these more stringent criteria for ferritin. Triglycerides and fibrinogen were less frequently abnormal (12 of 27 cases or 44% and 11 of 29 cases or 38%, respectively).

    View this table:
    Table 1

    Summary of clinical findings

    In 10 of 29 cases (34%) the underlying aetiology of the patient’s HLH was unclear (figure 4). Infectious diseases were the most frequent association (14 of 19 cases or 74%). The majority of these were acute Epstein–Barr virus (EBV) infection, histoplasmosis or bacterial infections (five cases of EBV, three of histoplasmosis, and three of bacterial of 14 infectious cases, a total of 79% of infections). In addition, two cases were associated with acute Cytomegalovirus (CMV) infection and one with infection by Mycobacterium kansasii. Lymphomas of T-cell lineage were the only identified malignancies, seen in 5 of 19 cases (26%).

    Figure 4
    Figure 4

    Distribution of infectious diseases seen in this series. EBV, Epstein–Barr virus.

    The overall mortality rate due to HLH was 61% (17 of 28 patients with long-term outcome data). All HLH-related deaths occurred within 90 days of the time of bone marrow identification of haemophagocytosis. All 28 patients had treatment data available for review. Of these, 13 patients (54%) received treatment according to the HLH-2004 protocol (corticosteroids, etoposide and ciclosporin A),2 while the remaining patients received antimicrobial therapy and other non-chemotherapy-based treatment options (supportive care). All patients who did not receive HLH-directed therapy had been diagnosed clinically as sepsis or SIRS based upon presentation and overall clinical history. Of the patients on the HLH-2004 protocol with follow-up data, seven patients (54%) died due to complications related to HLH (mean survival of 49 days, range 1–90 days). Conversely, 10 of 15 patients died while on supportive therapy (67%, mean survival 27 days, range 2–90 days). The differences in survival between patients on supportive therapy versus patients on HLH-2004 protocol were not statistically significant (p=0.21). The mean age of the HLH protocol group was 47 years, compared with 53 years of the supportive care group. There was no statistical difference between the two treatment groups across the 18 other parameters measured, with the exception of the number of cases with elevated soluble CD25 levels. Of the six cases that had testing for soluble CD25 levels, four were positive in the HLH-protocol group. However, all six cases that had the test results were from a single institution, and likely reflect the testing and treatment preferences of that institution.

    Patient outcomes were compared with each of the 18 clinical and laboratory findings listed in figure 3, both individually and segregated by treatment, considered either as continuous numerical values (where appropriate) or as dichotomous variables (ie, fulfilled diagnostic criteria or did not). Outcomes were defined either dichotomously as death due to haemophagocytic disease, or recovery from HLH (even if the patient subsequently expired from non-HLH-unrelated causes). None of the 18 variables listed in figure 3 correlated with death from haemophagocytic disease. In order to account for time to death in our analyses we also ran proportional hazards regression analyses on these same variables. Again, none of the variables were significant, with the exception of the ANC. Contrary to the expectation of cytopenias in HLH, neutropenia was not associated with an earlier death. Rather, high ANCs were associated with increased risk of death (HR=1.24, p=0.010). Figure 5 shows the hazard rate ratio as a function of ANC in comparison to a reference value of 2.68×109/L (the mean value for all study subjects). This model assumes a log-linear relationship between ANC values and the mortal hazard rate ratio. Although the power was low, there was no evidence that this log-linear assumption was false (p=0.40). Accordingly, ANC showed a positive correlation with the overall white blood cell count (p<0.005).

    Figure 5
    Figure 5

    Graph of mortal hazard rate ratio as a function of absolute neutrophil count (ANC). The reference ANC value is set equal to 2.68 K/μL (or ×109/L), the mean ANC value in this study. Mortal hazard increased with increasing ANCs.

    Discussion

    It has been previously reported that HLH is likely underdiagnosed, since the symptoms are protean and specific tests are more esoteric and are not performed without a high degree of suspicion.1 In fact, the diagnosis of HLH could be established in only 29 of the 59 cases (49%) in which bone marrow haemophagocytosis was reported. Many of the excluded cases may have been HLH, but HLH could not be confirmed because the relevant diagnostic tests had not been ordered. For instance, only a few cases had tests to assess NK/T-cell dysfunction, including three cases with NK-cell function measured by 51-Cr release assay and six cases with soluble CD25 levels. In only one of the cases was genetic testing for common mutations in primary HLH requested. Thus, in the other cases the possibility of a concurrent genetic mutation cannot be excluded, although this testing may be lower yield in the adult population where late manifestation of a primary cause for HLH becomes less likely with age. However, the potential to identify a genetic lesion as the driver for HLH must be weighed against the cost of a test with low prior probability, especially for family counselling purposes or for research purposes to help elucidate underlying mechanisms in this poorly understood syndrome.

    The most common criteria that allowed the diagnosis of HLH to be made were ferritin levels and presence of fever, followed by bicytopenia. It should be noted that inclusion criteria for this study involved one of the diagnostic criteria, positive bone marrow haemophagocytosis, as this criterion was used to search for possible HLH cases in our databases. However, it is well known that the histological identification of haemophagocytosis is not required to make the diagnosis of HLH. The design of the study, mandated by practical database search considerations, is therefore admittedly limited by selection bias, as HLH cases that do not have marrow haemophagocytosis were not included. Evidence of bone marrow haemophagocytosis has been identified previously as a marker of HLH with poor specificity but moderate sensitivity (60% and 83%, respectively, by one report).13 ,14 Thus, our pragmatic practice of using bone marrow haemophagocytosis as the initial selection criterion, while imperfect, should have captured the majority of HLH cases. Our final inclusion list, only 49% of the initial list, is similar to the reported specificity rate.

    Our study shows that infectious diseases are frequently seen in adult cases that fulfil HLH diagnostic criteria (48% of all cases and 74% of cases where a trigger was identified). These included acute EBV infections, histoplasmosis and bacterial infections. This result is similar to those seen in prior reports of HLH, regardless of age.1 ,16 ,17

    In our series, we did not observe a survival difference between those patients treated with HLH-specific chemotherapy protocol compared with those who received supportive therapy alone (54% mortality, mean survival 49 days, compared with 67% mortality, mean survival 27 days, respectively, log rank p value=0.21). Our results contrast with those observed in cohorts of paediatric cases, in which mortality decreases from 95% (median survival of 2 months) without HLH protocol therapy to 45% with HLH protocol.18 ,19

    A survival rate of 33% with the use of supportive therapy alone (including antimicrobial therapy) seen in this series of adult cases is therefore in marked contrast to studies of paediatric HLH. To explain this unexpected outcome data, we raise the possibility that those patients who survive with supportive therapy are in fact patients suffering an inflammatory disorder on the spectrum of SIRS rather than HLH (figure 2B).10 ,20 ,21 This is supported by the fact that the only statistically significant parameter that associated with increased risk of death was an elevated ANC, which is known to occur in SIRS and severe sepsis (figure 2).22–24 Typical HLH, on the other hand, is associated with persistent or progressive neutropenia, rather than neutrophilia, and a neutrophilic spike would not be expected in untreated HLH.1 ,2 It should be noted, however, that the neutrophil counts used in this study were single time point snapshots of this dynamic clinical parameter (concurrent with the bone marrow biopsy). The poor specificity of the finding of bone marrow haemophagocytosis for the diagnosis of HLH further supports this theory, since this histological criterion for HLH can be seen in other circumstances that fail to fulfil criteria for HLH.13 ,14 This lack of specificity raises the possibility that many cases that do also happen to fulfil criteria for HLH may in reality demonstrate haemophagocytosis for other reasons, such as SIRS and/or sepsis.

    The clinical and laboratory features of HLH are known to overlap significantly with those of SIRS.10 In fact, all of the HLH diagnostic criteria, except for the genetic abnormalities, can also be seen in SIRS, including elevated ferritin levels.5 Increasing the threshold of ferritin to 10 000 μg/L (22 470 pmol/L) has been previously suggested as a way to increase specificity of ferritin level in the diagnosis of HLH.25 However, in this study, no change in mortality was seen when limiting the analysis to only those cases with a ferritin level of >10 000 μg/L, therefore suggesting no added specificity to the clinical diagnosis of HLH when using higher ferritin cut-off values. Although patients with higher ferritin did have a lower ANC on average than patients with ferritin <10 000 μg/L, this finding was not statistically significant.

    In conclusion, meaningful issues emerge from this retrospective study of adult-onset HLH. It is clear that there should be broader use of appropriate diagnostic testing in cases with a high clinical or pathological suspicion of HLH, including an increased use of NK/T cell function studies. In addition, the unexpectedly high rate of recovery in patients treated with supportive care only and association of elevated ANCs with mortality raise concern for lack of specificity of currently established diagnostic criteria and clinical overlap with SIRS. In addition, the lack of improved survival with HLH-directed therapy compared with supportive care only highlights the need for improved strategies to define and treat syndromes on the spectrum between HLH and SIRS.

    Take home messages

    • The most common identifiable cause of adult haemophagocytic lymphohistiocytosis (HLH) is infection.

    • The mortality of adult HLH is significantly different from that in the paediatric population.

    • An elevated absolute neutrophil count is associated with increased risk of death in adult HLH.

    • In some cases, adult HLH and sepsis/systemic inflammatory response syndrome may represent a spectrum of the same infectious process.

    Acknowledgments

    The authors would like to thank Sid Lathrop for her assistance with data collection and Dr Alison Woodworth for helpful discussions on SIRS.

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    Supplementary materials

    • Abstract in Portuguese

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Handling editor Mary Frances McMullin

    • Contributors FGR, EBR and NMS provided the data. ASK, KKR, WDP and WDD analysed the data. FGR and ASK wrote the manuscript. All authors edited and approved the final version.

    • Competing interests None declared.

    • Ethics approval IRBs of both Vanderbilt University Medical Center and Mayo Clinic Rochester.

    • Provenance and peer review Not commissioned; externally peer reviewed.