Hemophagocytic Lymphohistiocytosis: Would You Know It if You Saw It? - ASH Clinical News (2022)

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.

Diagnosing HLH

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

(Video) Hemophagocytic Lymphohistiocytosis (HLH)

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
  • hyperferritinemia
  • 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.

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.”

(Video) IDF Lunch & Learn: HLH (Hemophagocytic Lymphohistiocytosis)

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.”

(Video) Hemophagocytic Lymphohistiocytosis: A Rare Immune System Disorder

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].”

(Video) Severe Covid-19 and sHLH (secondary hemophagocytic lymphohistiocytosis),

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

(Video) Diagnosis Specific: Hemophagocytic Lymphohistiocytosis (HLH)


How do you know if you have HLH? ›

How is HLH diagnosed? Your healthcare provider bases a diagnosis of HLH on your symptoms, physical exam findings, and several lab tests. A prolonged fever is a commonly occurring symptom. An enlarged liver or spleen (located in the upper left side of the abdomen) are key physical findings.

What does hemophagocytic lymphohistiocytosis mean? ›

(HEE-moh-FA-goh-SIH-tik LIM-foh-HIS-tee-oh-sy-TOH-sis) A rare disorder in which histiocytes and lymphocytes (types of white blood cells) build up in organs including the skin, spleen, and liver, and destroy other blood cells.

Can HLH be misdiagnosed? ›

HLH is a difficult to diagnose early and can hide behind a maze of contradictory symptoms. This often results in misdiagnosis. The only curative therapy for primary HLH is bone marrow transplant, a high-risk procedure that isn't suitable for all patients.

Why does hemophagocytic lymphohistiocytosis occur? ›

It can be caused by some infections, cancer, and autoimmune diseases. If you have acquired HLH, your body's immune system does not work normally. Some white blood cells called histiocytes and lymphocytes attack your other blood cells. Abnormal blood cells then build up in your spleen and liver.

When do you suspect HLH? ›

HLH should be suspected in cases of an unexplained sudden onset of a systemic inflammatory response syndrome (SIRS), including fever, malaise, hepatosplenomegaly, jaundice, generalized lymphadenopathy, and cytopenias.

What are the chances of getting HLH? ›

HLH is a rare disease that affects about one in 50,000 births.

How many people survive HLH? ›

Adult (secondary) HLH has a poor prognosis, left untreated survival ranges from a few days to weeks owing to progressive organ failure with overall mortality ranging from 41%–75% [3].

What viruses can cause HLH? ›

Common pathogens reported to cause HLH include Epstein-Barr virus (EBV),3, 5 cytomegalovirus,6 human immunodeficiency virus (HIV),7, 8 hepatitis A virus,9, 10 bacteria,11 parasites,12 mycobacterium,13, 14, 15 and fungus.

Can HLH resolve itself? ›

Secondary HLH may resolve spontaneously or after treatment of the underlying disease, without the use of chemotherapy. Therefore treatment should be guided in part by the severity of the condition, as well as the cause of the disease.

How long can you have HLH? ›

Long-Term Outlook

Familial HLH is fatal without treatment, with median survival of about two to six months. Chemotherapy and/or immunotherapy temporarily control the disease, but symptoms inevitably return.

Can Covid cause HLH? ›

COVID-19-associated haemophagocytic lymphohistiocytosis (HLH) can present as a postacute COVID-19 syndrome, even after a pauci-symptomatic initial infection. The development of HLH after a SARS-CoV-2 infection is rare and represents an aberrant virus–host interaction.

What is Hemophagocytic activity? ›

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages.

Can a vaccine cause HLH? ›

Conclusion: COVID-19 vaccines may occasionally trigger HLH, and Anakinra may be an efficacious treatment option for this condition.

Is HLH a blood disorder? ›

Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome that can be fatal. This syndrome can sometimes occur in normal people with medical problems that can cause a strong activation of the immune system, such as infection or cancer. HLH in these settings is called Secondary HLH.

How many cases of HLH are there? ›

HLH is diagnosed in fewer than 1 out of every 50,000–100,000 children per year. The condition occurs equally often in boys and girls. Since HLH causes symptoms similar to many other disorders, doctors think that more children develop HLH than are recognized and reported.

Does HLH affect the kidneys? ›

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that causes severe systemic inflammation in a wide range of target organs including the kidney. The precise etiology of AKI in patients with HLH has not been adequately defined.

How common is HLH in adults? ›

Adult HLH is a rare and almost universally fatal disease entity without treatment with published median survival of 1.8–2.2 months. Its incidence is uncertain, as the diagnosis is difficult to make due to poor recognition, low index of suspicion, and lack of definitive diagnostic criteria.

How long do people with HLH live? ›

Long-Term Outlook

Familial HLH is fatal without treatment, with median survival of about two to six months. Chemotherapy and/or immunotherapy temporarily control the disease, but symptoms inevitably return.

How long is treatment for HLH? ›

In adults, we recommend an 8-week induction with etoposide (150 mg/m2) in patients with HLH but not MAS.

How many people have HLH? ›

It is estimated that primary HLH affects about 1 in every 50,000 births. Secondary (or acquired) HLH generally is diagnosed in older children and adults. Secondary HLH is not inherited, but rather thought to result from a temporary disturbance of the immune system.


1. Primary Haemophagocytic Lymphohistiocytosis: Overview and New Treatment Option
2. Diagnosis and management of Hemophagocytic lymphohistiocytosis (HLH)
(HMP Education)
3. Hemophagocytic Lymphohistiocytosis
(Internal Medicine)
4. Hemophagocytic Lymphohistiocytosis (HLH)
5. Hemophagocytic Lymphohistiocytosis: Advocacy Groups and Clinical Trials
6. Hemophagocytic lymphohistiocytosis HLH immune regulation and translation human immunology, Michael B

Top Articles

Latest Posts

Article information

Author: Nathanael Baumbach

Last Updated: 10/28/2022

Views: 5657

Rating: 4.4 / 5 (55 voted)

Reviews: 86% of readers found this page helpful

Author information

Name: Nathanael Baumbach

Birthday: 1998-12-02

Address: Apt. 829 751 Glover View, West Orlando, IN 22436

Phone: +901025288581

Job: Internal IT Coordinator

Hobby: Gunsmithing, Motor sports, Flying, Skiing, Hooping, Lego building, Ice skating

Introduction: My name is Nathanael Baumbach, I am a fantastic, nice, victorious, brave, healthy, cute, glorious person who loves writing and wants to share my knowledge and understanding with you.