Haemophagocytic Lymphohistiocytosis (HLH) is a rare disorder of the immune system primarily affecting young infants and children, although it can develop for the first time at any age. According to a large, population-based study published in Sweden, it was estimated to occur in 1.2 cases per million children, which corresponds to 1 in 50,000 births. However, this number must be considered minimal, as there are probably many patients today who are not diagnosed. For the autosomal-recessive forms of HLH (FHL), there is believed to be an equal number of male and female patients, but in addition, there are two known X-linked forms of FHL, affecting only males.
HLH involves over-production and activation of white blood cells called histiocytes and T cells, which normally combat infection. In contrast, often NK (natural killer) cell function is decreased. Decreased NK function is related to the consequence of genetic mutations which cause HLH. HLH is often referred to as either the “primary” form which is hereditary, or the “secondary” form associated with infections, viruses, autoimmune diseases, and malignancies (or cancers).
In the primary form, also known as Familial Haemophagocytic Lymphohistiocytosis (FHL or FHLH), defective genes are inherited from either both parents (autosomal recessive) or from the mother alone. In the latter case, the disease is called X-linked and only male children are affected. Since 1999, five genes have been identified which correspond with five subtypes of autosomal recessive HLH. The genes are PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A. PRF1 encodes the protein (or toxin) normally involved in “killing” or eliminating abnormal immune cells. The proteins encoded by the other four genes facilitate the delivery of perforin to the cells which are to be killed. XIAP/BIRC4 mutations can also be considered as a cause of familial HLH.
While great progress has been made through research in recent years to define these genes, there remains a considerable proportion of FHL patients with as yet unknown underlying gene defects.
Onset of disease occurs under the age of 1 year in an estimated 70% of cases. FHL is suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. In the autosomal recessive form of the disease, each full sibling of a child with FHL has a 25% chance of developing the disease, a 50% chance of carrying one copy of the defective gene (which is very rarely associated with any risk of disease), and a 25% chance of not being affected and not carrying the gene defect. In the X-linked form of the disease 50% of male children will carry the defective gene and may develop disease. Fifty % of female children also carry the defective gene and may transmit it to their children but do not develop disease because they inherit a normal copy of the gene from their father.
So-called “secondary HLH” is often diagnosed in older patients who have no family history of this disease. It may be associated with vaccinations, viral infections such as Epstein-Barr, cytomegalovirus (CMV) or other herpes viruses, as well as other underlying diseases, principally autoimmune disorders and cancers, as mentioned previously.
It is difficult to know whether a patient has primary or secondary HLH on the basis of symptoms, which may be very similar. Therefore, genetic testing is usually recommended in order to make the proper diagnosis, regardless of age.
As awareness and understanding of this disease have increased worldwide, the diagnosis and survival rates have improved significantly. However, HLH remains a rapidly progressive disease requiring effective immunosuppressive and anti-inflammatory therapy.
HLH also occurs in some closely related diseases. These include X-linked lymphoproliferative disease (XLP), which is due to mutations in the SH2D1A gene (XLP1) or XIAP / BIRC4 gene (XLP2), Griscelli syndrome type II, which is due to mutations in the Rab27a gene, and Chediak-Higashi syndrome, which is due to mutations in the LYST gene.
Why Do These Conditions Result in HLH?
The T cells and NK cells in patients with primary / familial HLH cannot kill virus-infected or other abnormal cells in the patient’s body like they normally would. T cells and NK cells normally do this by secreting signals into targeted abnormal cells.
The proteins made by the MUNC 13-4, STXBP2, STX11, Rab27a and LYST genes work like the machinery of a conveyor belt, and are responsible for the secretion of the signals out of T cells and NK cells. The PRF1 gene makes a protein called perforin. It works like a key, and allows the secreted death signals to enter inside a targeted abnormal cell, where the death signals can work.
SH2D1A is responsible for a more specialized mechanism, and also controls how the T cells themselves die. It is not yet entirely clear why XIAP / BIRC4 mutations cause HLH.
Diagnosis and Treatment
It is sometimes difficult to establish the diagnosis of Haemophagocytic Lymphohistiocytosis (HLH), and the combination of the physical symptoms and certain laboratory tests is required. (Note: The understanding of the pathology underlying HLH/FHL disease is evolving, and recommended “diagnostic” criteria are likely to be revised in the future.)
• Low or absent NK (natural killer) cell function.
• Prolonged fever.
• Blood cell abnormalities (low white cells, low red cells, low platelets).
• Enlarged spleen.
• Increased triglycerides (fat) or decreased fibrinogen (protein necessary for clotting) in the
• Increased ferritin (protein that stores iron) in the blood.
• Abnormal bone marrow test with evidence of Haemophagocytosis (ingestion of red or white cells by
histiocytes) but not malignancy or other cause.
• Abnormally high CD25 (also known as sIL2ra) in the blood indicating abnormally increased T-cell
Other symptoms may include:
• Enlarged liver/liver failure
• Enlarged lymph nodes
• Respiratory issues (coughing, respiratory distress)
• Altered mental functions
The test for low or absent natural killer cell (NK) function has been found useful in making a clinical diagnosis of HLH. This abnormality is found in many patients with FHL, as well as in many cases of secondary disease but rarely in the X-linked forms.
However, it is just one piece of information and should not be used to determine the diagnosis of HLH as primary or secondary. NK function cannot be determined before birth, and it may not be reliably studied until a child is at least 6 weeks of age. FHL is suspected if siblings have been diagnosed with HLH, if symptoms intensify during treatment for HLH, or if symptoms return after therapy has been stopped.
Since it is difficult to tell the difference between secondary HLH and FHL, any case of HLH should be considered for genetic testing to confirm the diagnosis. Since 1999, at least seven defective genes have been identified. Autosomal recessive: PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A. X-linked: SH2D1A, BIRC4.
There are some FHL patients (approximately 30%) with no identified gene defect, so normal genetic test results do not necessarily rule out the diagnosis of FHL. Genetic testing is usually done on blood, although other kinds of tissue samples can be used. Once the genetic cause is known, the parents can quickly be tested to confirm that they are carriers for that specific genetic type of FHL. Other siblings can also be easily tested, even before birth, once the genetic cause of the disorder in the family is known. Even in the event of death, salvaged tissue can be tested to determine if siblings are at risk.
In 1994, as a result of an international cooperative effort, the first treatment protocol for patients with HLH/FHL was designed. This included a combination of chemotherapy, immunotherapy and steroids, as well as antibiotics and antiviral drugs, followed by a stem-cell transplant in patients with persistent or recurring HLH or those with FHL. The HLH-2004 protocol was based on the HLH-94 protocol with minor changes such as cyclosporin, an immunosuppressant drug, being started at the onset of therapy rather than week #8. This protocol has been widely accepted internationally and is used in numerous countries on all continents but should still be considered experimental.
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.
FHL, however, when not treated, is usually rapidly fatal with an average historical survival of about 2 months. The treatment included in the HLH-2004 research protocol is intended to achieve stability of the disease symptoms so that a patient can then receive a stem-cell transplant, which is necessary for a cure.
In recent years, some transplant centers have adopted the use of reduced intensity conditioning (or “RIC”) to prepare for the stem cell transplant. This approach offers the possibility of better survival with stem cell transplant than the intensive chemotherapy protocols previously used.
As research continues, the outcome for patients with HLH/FHL has improved greatly in recent years. Approximately two-thirds of children with HLH who undergo transplantation can expect to be cured of their disease. However, there are a number of complications that can occur during the process of transplant, including severe inflammatory reactions, anemia, and graft-versus-host disease.
Long-term follow-up of survivors of transplants for HLH/FHL indicates that most return to a normal or near-normal quality of life. The results of transplantation are generally better when the procedure is performed at a major transplant center where the doctors are familiar with this disease. Early and accurate diagnosis is essential. However, there is still a high rate of death, indicating that education of the medical community regarding prompt diagnosis and management of the diseases is required.
Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.
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Haemophagocytic Syndromes (HLH)
These questions specifically relate to Haemophagocytic Syndromes (HLH).
1. What causes HLH?
HLH can either be acquired (secondary HLH) or inherited (FHL). Both forms of the disease can be triggered by infections, although it is not known why this happens. Secondary HLH may be triggered by vaccinations, viral infections such as Epstein-Barr, CMV (cytomegalovirus) or other herpes viruses, or other underlying diseases such as autoimmunity or cancer. In FHL, defective genes are inherited from one or both parents. Some other rare inherited immunodeficiencies may also be associated with HLH. The underlying immune defect and/or triggering events result in an abnormal immune response with activation of certain types of white blood cells (lymphocytes and macrophages) and the release of inflammatory proteins which then cause disease.
2. Is there a cure for HLH?
HLH patients with an underlying genetic defect can only be cured when the defective immune system is replaced by a healthy one which is what happens with a hematopoietic stem cell transplant. Secondary HLH cases can usually be cured by treating the underlying disease and sometimes additional immunosuppressive/immunomodulatory therapy.
3. What are the different therapies/treatments commonly used to treat HLH?
Some cases of secondary HLH can resolve spontaneously or after treatment of the underlying disease. Other cases are treated with a combination of chemotherapy (VP-16, methotrexate), immunotherapy (ATG, cyclosporin), and steroids. Any triggering infection has to be treated with appropriate antimicrobial drugs. Patients with persistent or recurring HLH or those with FHL additionally require a hematopoietic stem-cell transplant for recovery.
4. Why is routine newborn screening not available?
Although HLH may occur more frequently than some of the diseases routinely tested for, genetic testing for this disease is very complicated and very expensive.
5. How do I know if my child has primary HLH (inherited/FHL) or secondary HLH?
The clinical symptoms and laboratory findings do not differ in genetic or acquired HLH. Specific immunologic testing can raise the suspicion of genetic disease. In families with more than one affected child or in cases with disease reactivations there is a high probability of genetic disease. However, the identification of a genetic defect is necessary to prove it. Genetic testing is therefore recommended, regardless of age. Depending on the ethnic background up to 30% of patients with FHL have no identified gene defect, so negative test results do not necessarily rule out FHL.
6. How can I find out if my child’s siblings have HLH?
In autosomal recessive forms of the disease, each sibling of a child with FHL has a 25% chance of being affected. In related genetic disorders, including X-linked lymphoproliferative disease, each male child has a 50% chance of being affected. If a genetic defect is known in your family, genetic testing (before or after onset of symptoms) is available to identify siblings who may also be affected.
7. How can I find out if future children are at risk for developing HLH?
If a genetic defect has been identified in your family, prenatal diagnosis is possible by performing either amniocentesis or chorionic villus sampling (CVS) to test if the fetus is affected.
8. What is MAS (macrophage activation syndrome)?
Macrophage activation syndrome is a severe, life-threatening illness caused by the excessive production of types of white blood cells called T cells and macrophages. MAS has strong similarities with familial Haemophagocytic Lymphohistiocytosis (FHL) and virus-associated Haemophagocytic Lymphohistiocytosis (HLH). The exact relationship between MAS and HLH is yet to be determined, although some researchers believe that MAS is a secondary HLH disorder. The term is typically used for the HLH-like syndrome that can occur in patients with systemic onset juvenile arthritis.
9. What is reduced-intensity conditioning (RIC)?
Reduced-intensity conditioning is a less toxic pre-transplant therapy with the goal of suppressing the patient’s immune system enough so that it will accept donor stem cells while reducing the side effects of high dose chemotherapy The RIC may be used in some HLH patients, as well as some LCH patients with severe, resistant disease.
The answers to the following questions may be found in the Support Information.
How is it diagnosed?
How is it treated?
What are the clinical trials?
How do I cope with the diagnosis?
How do I get the information I want?
How do I talk to my children about this?
How do we deal with the treatment?
What happens at the end of the treatment?
What resources are there for individuals or family support?
Where can I get financial support?
How do I find other patients?
Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.
Help ensure that we can continue to bring you this vital informational material, make a donation today
pubmed: haemophagocytic lymp...
NCBI: db=pubmed; Term=haemophagocytic lymphohistiocytosis
Hemophagocytic Lymphohistiocytosis: Management and Special Consideration in Human Immunodeficiency Virus Positive Patients with Immune Reconstitution Syndrome.
Cureus. 2019 Aug 16;11(8):e5402
Authors: Bindra BS, Garcia de de Jesus K, Cisneros O, Jorge VM, Kaur H
The human body is capable of reacting to multiple aggressors by developing an inflammatory response with the secretion of inflammatory cytokines. The worrisome clinical manifestations occur when this inflammatory response is disproportionate. Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe condition characterized by an overwhelming inflammatory response that may result in end-organ damage and might be fatal. Correspondingly, immune reconstitution inflammatory syndrome (IRIS) is another well-known disorder, seen commonly in human immunodeficiency virus (HIV)-infected patients after the commencement of highly active antiretroviral therapy (HAART). Both entities share a similar clinical presentation and a dismal prognosis. Due to widespread clinical manifestations and laboratory abnormalities, diagnosis is often missed at the time of presentation. There is little consensus on the treatment of secondary HLH, which is usually handled on a case-by-case basis. Rapid curbing of the widespread inflammatory response is the main goal of treatment. To the best of our knowledge, there is scarce literature available on the coexistence of HLH and IRIS; therefore, medical management in the co-occurrence of these two conditions needs to be further investigated.
PMID: 31620325 [PubMed]
Your Story - Gabby
Share your voice - Your story HLH
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Title: Our Mum Joan, her story - by the Family
Intro: We would like to share our story about our amazingly kind, polite, funny and oh so strong mum, who passed away peacefully surrounded by her 'chicks' (myself, my sister Diane and brother Andrew) in Barnsley District Hospital after a five week battle against this very cruel form of the disease - acquired Haemophagocytic Lymphohistiocytosis, (macrophage activation syndrome).
Mum first became ill on January 1st this year. She 'fell' on her way to the toilet in the early hours of new years day. She never drank more than a thimble full of alcohol, so we knew this was something serious. We were unable to reach her immediately and she was considered a 'long lay' and remained in hospital for a few weeks, before being transferred for rehabilitation. Her slow recovery was attributed to the 'long lay', as there was no obvious pathology…only non-specific raised serum ferritin and a slightly elevated liver marker identified on blood screening. Mum did return home to semi- independent living, but never returned to the level of health she had enjoyed before the 'fall'. In addition, mum lost her appetite and began having night sweats and had really no energy at all. Further visits by the GP led to further blood tests, which showed persistently elevated ferritin and also raised CA125, which led her down the route of ovarian cancer screening, but still no diagnosis. Mum 'fell' again on 15th May, but this time we got to her much sooner, following installation of a care button. She was on the floor, confused, as she had been on January 1st.
This was the true start of her decline. Ferritin was still high, and a couple of other non-specific markers were slightly raised, but nothing else. She soon became extremely unwell with suspected sepsis. Mum’s temperature spikes were becoming more and more frequent and difficult to control, but the underlying cause was still unknown. We were trying to remain positive, hoping that when we had a diagnosis, mum could get some treatment and would get better, but the doctors were baffled. Gradually, other blood markers manifested as abnormal, including the detection of antibodies to Epstein Barr Virus, and the decision was made to perform a bone marrow, following which mum was diagnosed with acquired HLH. By this time, she had become almost completely bed-bound. She was transferred to the haematology/chemotherapy ward and was initiated on high dose steroid therapy, while further tests were carried out to try to identify the underlying cause of the aHLH. After a small, initial response to steroids, mum had a further bone marrow, with trephine this time, and many more tests also followed. Unfortunately, the steroid response was inadequate and short-lived and mum deteriorated disturbingly quickly, with increasing loss of function and severity of blood parameters. On 18th June, we were given a diagnosis of aggressive lymphoma in her bone marrow. Mum died the following morning.
For me, this has been particularly tough to accept, as I am a clinical scientist working in a specialist haematological malignancy diagnostic unit, and my specialty is aggressive lymphoma. Knowing there was something quite wrong with mum, but not being able to make the diagnosis in time to save her was extremely difficult to accept. Acquired HLH is extremely rare, with most doctors seeing only a handful of cases in a career. It is difficult to diagnose, and more often than not, once the diagnosis is made, there is no way back, no chance of cure. Earlier, more accurate screening and diagnosis and increased awareness of the potential diagnosis are essential to reduce deaths from this cruel disease in the future. There is limited government funding for rare diseases, and therefore the only way this can improve is if research is funded by charitable donations.
RIP Joan Crosland 13/10/1941-19/6/2019
Title: My Mum Anita, her story - by Barry Skinner
Intro: In mid-August 2018, my mum, Anita (71), fell ill following a trip to London.
She initially had an upset stomach and high temperature. My mum's GP assumed a virus and asked her to go home, rest and it should pass in a few days. Anita continued to feel more unwell, several more visits to the GP all resulted in her being told it was just a virus that needed to run its course. About 10 days after starting to feel unwell Anita was admitted to a respiratory ward at Royal Bolton hospital in a very poorly state with breathing difficulties. The doctors suspected pneumonia and placed her on high dose antibiotics. After 4 days and no response to the antibiotics, Anita started to have large spikes in her temperature (swinging fever as the doctors called it). Every 8 hours her temperature would spike and she needed IV paracetamol to bring it under control. The temperature spikes started to get closer together, so close in fact she had to try and ride them out because sufficient time had not passed for her to have more paracetamol.
None of the treatment was working and my mum was very sick and had been in hospital for 10 days now. A bone marrow biopsy was taken, and they put her on steroids. The steroids gave her instant respite, her temperature spikes stopped and as a family we were able to spend a little bit of quality time with her. 3 days later the bone marrow results came back which indicated HLH.
We had never heard of it, but the doctors gave us the awful news that it would take our mum very quickly. Anita was too old for a bone marrow transplant and too poorly for Chemotherapy, she died on the 21st September 2018, 9 days after the HLH diagnosis and about 5 weeks after falling ill.
This condition is so rare that doctors are not able to diagnose it quickly I hope that by providing more information the awareness increases and doctors are able to diagnose sooner so that more patients have a better chance to beat this devastating disease.
Title: Vanessa's HLH Story - by Annette & Terry Powell
Intro: In October 2016 our daughter Vanessa, aged 42, had a slight cough...
After a few weeks, it got worse. She went to her GP who said it was a virus. Some five weeks later the cough still persisted and she went back to the GP who prescribed antibiotics. Vanessa completed the course but was still feeling poorly, and we were concerned about her health as she had always been a healthy person. Just after Christmas Vanessa had an emergency appointment and was then admitted to the Royal Glamorgan Hospital at Llantrisant. After numerous tests she was transferred to University Hospital of Wales, Cardiff, and underwent further tests. After 2 weeks which, by this time Vanessa was extremely ill, HLH was diagnosed. Once this was established treatment began and by the end of January she had made a remarkable recovery. She was sent home on January 31st, 2017 with a medication pack and then had to attend the UHW day-centre on a weekly basis to complete Chemotherapy, which ended on March 10th last. On March 13th Vanessa had a slight cough and temperature and contacted the UHW day-centre, and went back to the day-centre and her antibiotics were changed and she came home.
By Wednesday March 15th despite the antibiotics, Vanessa’s temperature had risen to a critical point and she was re-admitted to the UHW Haematology Ward and then into intensive care. A new type of Chemotherapy drug was introduced but sadly was unsuccessful. Finally, although every effort was made by the medical team to control and eliminate HLH, it was so aggressive that eventually her organs collapsed and she was placed on a life support machine.
However, after consultation with the medical team and a heart-breaking family meeting, it was decided to turn off the machine and let Vanessa die in peace and with dignity, and she passed away at UHW at 12.10 pm on Saturday March 25th, 2017.
For us it was the hardest decision we, as a family had to make, but feel it is the correct one. Our lovely daughter Vanessa is now at rest and nothing can hurt her anymore.
Title: Young Person HLH – Our prefect daughter by Nicola Jackson
Intro: Our perfect 20-year-old daughter was taken ill just before Christmas 2015…
We took her to our local GP, she had swollen glands and was just unwell, she had no sign of infection and so they sent us to the local Ear Nose & Throat outpatients to have it checked out.
Chelsea was diagnosed Glandular Fever, her white blood cell count was quite low, but they were not too concerned, 3 days later Chelsea’s throat was very sore, so we took her to the Emergency Doctors and they diagnosed Tonsillitis. Chelsea was prescribed a 10-day course of strong antibiotics.
After a few days the antibiotics did not seem to be working and Chelsea did not appear to be getting any better, she was struggling to speak and swallow. We took her to the Accident & Emergency and she was immediately admitted, her temperature was really high and she was subsequently transferred to the ENT ward for intravenous antibiotics.
After two days the Doctors said that she had been tested for CMV infection and that her liver and spleen were swollen, Chelsea was placed on antiviral medication and moved to another ward.
Over the next few days her breathing worsened and Chelsea was moved to Intensive Care. Her bloods were all over the place and her body was struggling to cope. Chelsea was placed into an Induced Coma and placed on a kidney machine due to the amount of acids in her blood.
A bone marrow test was taken and this is when the HLH was mentioned, Chelsea would be started on chemotherapy and steroids the next day. A biopsy was also taken on Chelsea’s neck.
We had a telephone call on Sunday 17th January 2016 to say that Chelsea’s organs were failing and that there was no brain function at all, it was just the machines that were keeping her alive.
The family had to make the agonising decision to let our beautiful girl pass on with all of her family around her.
We as a family, hope that we can help raise awareness of this condition in order that it can be investigated and tested for sooner to enable earlier diagnosis, timing is crucial in the treatment of this devastating disease.
Title: Young Person HLH – My Beautiful Daughter by Anne Goldring…
Intro: Anne Goldring shares the devastating story of the loss of her daughter Jo to HLH…
My beautiful 16-year-old daughter Jo took ill at the end of May 2015. She started with just a fever, no other symptoms at all. The fever started spiking to 39 degrees with no change for about two days despite having paracetamol cool baths etc. nothing would bring her temperature down.
After two days we went to a local GP who did a urine sample and said she had a kidney infection gave antibiotics and said carry on with paracetamol.
After 3more days of this treatment she was no better and was transferred to our local hospital. She was taken for an MRI scan and was given multiple antibiotics by IV along with several other medications.
After 3 days she was discharged after having a test which showed glandular fever.
We returned home only for her to deteriorate even more so. After another trip to the local doctor we returned again to our local hospital. She was literally pumped full of more antibiotics paracetamol and was given enough IV protein, put on a strict fluid intake as her kidneys were failing but still they had no idea what they were treating her for.
After five days she had got so bad they had to transfer her to St. Thomas in London. Where she was admitted to intensive care.
The specialists told me that they had never seen such a sick child. By this time, she had fluid around her heart, kidney failure and was very very sick. She was attached to tubes 24 hours a day. She had been there 4 days when they decided that she needed to be on a 24-hour kidney dialysis machine as she had a high amount of ammonia in her blood.
At this point she was kept under complete sedation. From that day they finally found a specialist who took a bone marrow sample and Jo was diagnosed with HLH, by this time it was too late.
For another 4 days we had to watch her deteriorating it was the worst time of our life and I would do anything to make sure no one else suffers like we have.