Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder in which histiocytes and lymphocytes create a hyperinflammatory response that damages multiple organs.1 People with HLH can present with fever, enlarged liver or spleen, cytopenias, and neurologic abnormalities. If a clinician does not know what to look for, they may see a patient with HLH and not realize it.
- Prevalence (U.S.): Unknown, most often affects infants and young children
- Number of FDA-approved treatments: 1 (emapalumab)
- Social media hashtag: #HLH
- Resources: Immune Deficiency Foundation (IDF)
The IDF is dedicated to improving the diagnosis, treatment, and quality of life of people affected by primary immunodeficiency, such as HLH, through supporting advocacy, education, and research.
Recognized since the 1950s, the disorder can be either familial or sporadic, the latter being associated with environmental triggers such as infection, malignancy, or rheumatologic disorders, according to Kenneth L. McClain, MD, PhD, director of the histiocytosis program at Texas Children’s Cancer and Hematology Centers.
“HLH is a devilishly hard syndrome to diagnose and it is devilishly hard to treat,” Dr. McClain said, owing to the diversity in its presentation and its association with a variety of triggers. The challenges in diagnosing HLH means that it can often go undiagnosed, making it difficult – if not impossible – to estimate its true prevalence. The best estimate of the incidence of familial HLH comes from Sweden, he noted, where infants who are diagnosed with HLH undergo sequencing to identify associated genetic mutations and are included in a national registry. A 2015 analysis placed the estimated incidence of primary HLH at 1.5 cases per million live births.2
“At Texas Children’s, where we have a big interest in HLH, we surveyed our patient population and found that about one of every 3,000 children admitted to our hospital had HLH,” Dr. McClain said.
The syndrome was previously described as primary or familial HLH (indicated by inheritance of gene mutations resulting in cytotoxic lymphocyte dysfunction) or secondary or acquired HLH. Recently, Dr. McClain and colleagues from the North American Consortium for Histiocytosis (NACHO) published a paper calling for a distinction between “HLH disease” and “HLH disease mimics” based on “specific etiologic associations, not the ambiguous dichotomy of ‘primary’ and ‘secondary.’”3 They also called for specific categorization of HLH subtypes, including rheumatologic HLH, malignancy-associated HLH, HLH with immune compromise, iatrogenic HLH, and “other” HLH, based on an improved understanding of the syndrome’s pathophysiology.
HLH is a disease of hyperimmunity, explained Michael B. Jordan, MD, of the division of immunobiology at Cincinnati Children’s Hospital Medical Center.
“Unlike autoimmune diseases, which have self-reactivity, HLH is a result of immune activation,” he said. “We call it ‘hyperimmunity’ because in HLH, T-cell activation basically revs up in an uncontrolled fashion that is very toxic.”
In addition, multiple genetic models have demonstrated that interferon-gamma is a key mediator of disease development and is thought to be the likely connector between activated T cells and activation of macrophages.3
According to Dr. Jordan, the diagnostic workup for HLH is often prompted when a patient presents with fever and cytopenias. Much of the established diagnostic criteria is based on expert opinion rather than evidence-based guidelines.
The criteria for an HLH diagnosis was established based on the five inclusion criteria of the HLH-94 study, a prospective international study conducted by the Histiocyte Society in 1994 that evaluated outcomes with etoposide, corticosteroids, and cyclosporine in pediatric patients. These included:
- clinical criteria (fever, splenomegaly)
- laboratory criteria (cytopenias: hemoglobin <90 g/L, platelets <100×109/L, neutrophils <1.0×109/L, and hypertriglyceridemia or hypofibrinogenemia)
- histopathologic criteria (hemophagocytosis in bone marrow or spleen or lymph nodes with no evidence of malignancy)4
Those were updated with three additional criteria for the HLH-2004 study:
- low/absent natural killer cell activity
- high-soluble interleukin-2-receptor levels5
The clinical diagnosis of HLH in both children and adults relies on the criteria laid out in the HLH-94 and HLH-2004 studies. While pediatric patients must meet five of the eight criteria laid out in the HLH trials, natural killer cell activity is not useful in adults, said Nancy Berliner, MD, chief of the division of hematology at Brigham and Women’s Hospital and professor at Harvard Medical School. Therefore, adults must fulfill five of seven criteria.
Dr. Berliner estimated that at least 50% of cases of HLH in adults are associated with malignancy, typically lymphoid malignancy. Other triggers include infection (commonly Epstein-Barr virus) or autoimmune disease.
A molecular diagnosis of HLH is also possible, defined as the presence of pathologic mutations in PRF1, UNC13D, STXBP2, Rab27a, STX11, SH2D1A, or XIAP. These diagnoses occur almost entirely in children.
“Until about 20 years ago, no one even knew that HLH occurred in adults,” Dr. Berliner noted. “One of the likely reasons that it took so long to recognize HLH in adults is that many patients who are in septic shock will fulfill many of these criteria, or at least come close.”
Most of the criteria are non-specific, she added. “There really is no gold standard to tell you that a patient has HLH.”
Dr. McClain said that many of the criteria established by the HLH-94 and HLH-2004 studies are outdated and do not include new clinical and laboratory features that have been found to be much more important. He and other members of NACHO have established an algorithm for the diagnostic workup of HLH in newly presenting patients that includes markers of immune activation (sCD25, granzyme B expression, CXCL9) and genetic testing (multigene panel or whole exome) to establish risk of HLH recurrence.3
Ensuring Prompt Treatment
Patients who experience flares associated with HLH are, in effect, having an inflammatory storm, Dr. Jordan explained. The goal of treatment, therefore, is to halt any underlying trigger and control the overactive immune system.
The current standard of care for HLH (etoposide and corticosteroids) was established by the HLH-94 study. This study looked at children ages 15 or younger who fulfilled diagnostic criteria of HLH and had no prior treatment with chemotherapy or cyclosporine. HLH-2004 confirmed that patients with HLH could be rescued with a combination of etoposide and dexamethasone.
“Etoposide is good at killing activated T cells,” Dr. Jordan said, but Dr. McClain noted that the use of steroids in this setting can be tricky.
“The high-dose steroids have to be tapered down gradually and, as we decrease the dose, we often end up releasing control of the immune system,” Dr. McClain explained. “Sometimes, we are forced to put patients back on steroids while we consider alternative treatments.”
In 2018, the U.S. Food and Drug Administration (FDA) approved the monoclonal antibody emapalumab, which binds and neutralizes interferon-gamma, for adult and pediatric patients with recurrent or refractory HLH.6 This approval was based on a single-arm study in 27 children who received emapalumab with background dexamethasone. The overall response rate was 65%.7 The investigators also noted that emapalumab was not associated with any organ toxicity, though 10 patients developed severe infections during treatment.
However, Dr. McClain noted that emapalumab is not equally effective for all patients. In adults, Dr. Berliner added, its use is even a bit controversial.
“In the trial used to support its approval, the drug was never given to anyone over the age of 12,” Dr. Berliner noted. “The result is that there has only been scattershot use of emapalumab in adults.”
In fact, the European Medicines Agency recommended against marketing authorization for emapalumab for pediatric patients in 2020.8 The agency wrote that “the results of the study were not considered sufficient to conclude that [emapalumab] was effective in treatment of primary HLH.” Because patients received other medicine and symptoms varied over time, “it was not possible to conclude that the response seen in some patients was due to the effect of [emapalumab],” the agency continued. “Furthermore, the effect of emapalumab could not be sufficiently supported by available data on how the medicine works, and the role of interferon gamma in how primary HLH develops is not fully understood.”
Other therapies are being explored for HLH, including JAK inhibitors. Animal studies of the JAK1/2 inhibitor ruxolitinib showed significant decreases in clinical and laboratory manifestations of HLH, with improved survival in mice infected with lymphocytic choriomeningitis virus.9
There are no published clinical trials of JAK inhibition in HLH, but case reports in children and adults have shown that HLH can be successfully treated with ruxolitinib, Dr. Berliner said.
There are also ongoing trials in France looking at the anti-CD52 monoclonal antibody alemtuzumab for refractory HLH, Dr. Jordan added. Still, all of these treatments are acting as a bridge to transplantation because “if a patient has a cytotoxic deficiency, they will keep developing episodes of hyperinflammation,” he explained. “Immune suppression is necessary to control these episodes and it is too risky for someone to stay in that state indefinitely.”
Determining who should undergo transplantation is also controversial, Dr. Berliner said, aside from adults with lymphoma-associated HLH. Anyone with active HLH cannot receive a transplant, but otherwise, she is fairly aggressive with recommending transplant.
“Usually, we transplant anyone who has had an episode of HLH that was associated with multiorgan failure, but whose disease has gone into remission,” Dr. Berliner said. “That is highly variable though, and depends on how comfortable the transplant service is with transplanting these patients.”
Increasing Incidence or Increasing Recognition?
Due to its overlapping presentation with other inflammatory syndromes and the possibility of missed diagnoses, determining the exact incidence of HLH is nearly impossible. However, experts agreed that the reported incidence is definitely increasing. For example, in the Swedish national registry, incidence of primary HLH increased from 1.2 cases per million in 2006 to 1.5 cases per million in 2011.2
Whether this growing number reflects an actual increase in cases or simply a greater awareness of the syndrome is unclear.
“Genetic deficiencies are at the heart of this syndrome, but there are many other patients who meet the criteria,” Dr. Jordan said. “These are the patients who appear to be increasingly recognized, and many of those are adults.”
Dr. Berliner agreed. “When I saw my first [adult] patient with HLH, there were close to zero references about HLH in PubMed when I looked it up. Now there are hundreds.”
This increased recognition is happening outside of hematology, too. Many patients with HLH will show up to the hospital when they are critically ill and initially be treated by an intensivist in the intensive care unit, explained Dr. Jordan, or by infectious disease specialists who are often consulted in cases of prolonged unexplained fevers. Other patients may present with liver failure and see someone on the gastrointestinal service first and, in rare cases, individuals may present with neurologic involvement and see a neurologist first.
However, he noted, most patients present with cytopenias and end up in the care of a hematologist fairly quickly.
From there, a patient’s management may be shared among other specialists depending on the category of the disease, Dr. Berliner said. For example, if a patient has a malignancy-associated HLH, a hematologist/oncologist will be involved, while a patient with HLH caused by infection will likely be comanaged with an infectious disease specialist. Those with macrophage activation syndrome may be comanaged with rheumatologists, she said.
Dr. Berliner said she believes the increased awareness around HLH may be only part of the reason that clinicians are seeing more patients with the syndrome. “The world is also changing,” she said. “We have many more biologic and immunosuppressive drugs, and many new organisms. It is not clear whether or not some of these factors are contributing to a possible increase [in patients experiencing immune dysregulation].”
In fact, the question of whether there is increased incidence or increased recognition is one she poses at the beginning of her lectures on HLH.
“I suspect the answer may be ‘both,’” she said. “These patients are very sick and it is hard for me to imagine that everybody escaped notice for all those years because the findings tend to be nonspecific. On the other hand, it is possible that HLH was just diagnosed as other things.”
In the age of COVID-19, it is possible that even more cases of HLH are going unrecognized. The cytokine release syndrome, or cytokine storm, associated with COVID-19 looks much like HLH, Dr. Berliner explained. “I don’t think patients with COVID-19 [and the associated cytokine storm] truly have HLH, but they certainly might fulfill a lot of the criteria for it,” she said. “That is just another one of the reasons HLH is so difficult to diagnose.” —By Leah Lawrence
- Genetic and Rare Diseases Information Center. Familial hemophagocytic lymphohistiocytosis. Accessed March 24, 2021. https://rarediseases.info.nih.gov/diseases/6589/familial-hemophagocytic-lymphohistiocytosis.
- Meeths M, Horne A, Sabel M, et al. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer. 2015;62(2):346-352.
- Jordan MB, Allen CE, Greenberg J, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019;66(11):e27929.
- Henter J-I, Arico M, Egeler RM, et al. HLH-94: A treatment protocol for hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 1997;28(5):342-347.
- Henter J-I, Horne A, Arico M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.
- FDA news release. FDA approves emapalumab for hemophagocytic lymphohistiocytosis. Accessed March 18, 2021. https://www.fda.gov/drugs/fda-approves-emapalumab-hemophagocytic-lymphohistiocytosis.
- Locatelli F, Jordan MB, Cesaro S, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-1822.
- European Medicines Agency. Gamifant. Accessed March 18, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/gamifant.
- Das R, Guan P, Sprague L, et al. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood. 2016;127(13):1666-1675.