Hemophagocytic 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 males and females diagnosed with this disease. In addition, there are two known X-linked forms of FHL, affecting only males.
HLH involves over-production and activation of normal infection-fighting cells called histiocytes and T cells. 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 hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from either both parents (autosomal recessive) or from the mother alone. 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.
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. Each full sibling of a child with FHL has a 25% chance of developing the disease, a 50% chance of carrying 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.
So-called “secondary HLH” is often diagnosed in older patients, and there is no family history of this disease. It may be associated with vaccinations, viral infections such as Epstein-Barr, cytomegalovirus (CMV), or herpes virus, and 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.
The first description of HLH was published in 1952, but it has only been in recent years that it has received more widespread attention. In 1985, physicians from around the world who were interested in studying the histiocytic disorders gathered in Philadelphia and formed the Histiocyte Society. Funds raised by the Histiocytosis Association, as well as national subgroups, have financed research that has led to significant breakthroughs in the diagnosis and treatment of HLH during the past 15 years. 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.
The symptoms of the primary and secondary forms of hemophagocytic lymphohistiocytosis (HLH) include:
Persistent fever, often high. Sometimes a microbial (often viral) cause is found, but this is common as a trigger of HLH/FHL.
Abnormal blood tests such as a) low red blood cells, b) low platelets, and c) low neutrophils.
Other blood abnormalities (liver dysfunction, elevated triglycerides, low sodium level, and low albumin level).
Skin rash, variable (30% of patients).
Enlarged lymph nodes.
Combined with evidence of immunologic dysfunction:
Decreased NK-cell function.
Increased T-cell activation as evidenced by increased sIL2ra (soluble IL-2 receptor alpha) in the blood.
Increased histiocyte activation as evidenced by increased ferritin.
CNS (central nervous system) involvement occurs in 50% of patients and may be present at the time of disease onset, or it can develop later.
A wide variety of symptoms of CNS disease include:
Low or abnormally increased muscle tone.
Difficulty with coordination.
Weakness of face/eye nerves.
Paralysis and coma (very rare).
On bone marrow examination, an abnormality in which histiocytes are “eating” other blood cells (also known as hemophagocytosis) can be detected. When prominent, this is a very useful diagnostic marker. Although the disease was named after this phenomenon, this symptom may be absent at onset or even throughout the course of the disease.
The Histiocyte Society has created diagnostic guidelines and recommendations concerning the treatment of HLH. The HLH-2004 research study, scheduled to conclude at the end of 2011, is to be used only at institutions with IRB (Institutional Review Board) approval and appropriate informal patient/family consent. The Histiocyte Society recommends the use of the HLH-94 treatment in conjunction with HLH-2004 diagnostic criteria as the standard of care until further analysis/publications recommend otherwise.
Adult-Onset Hemophagocytic Lymphohistiocytosis: A Rare Cause of Fevers and Multiorgan Failure in a Young Healthy Woman
INTRODUCTION:Hemophagocytic lymphohistiocytosis (HLH) is a rare disease marked by overactive histiocytes and lymphocytes and is associated with a high mortality(1). We present a case of HLH in an otherwise healthy young adult female who presented with recurrent fevers and multi-organ failure.
CASE PRESENTATION: A 20 year old previously healthy female presented to a community hospital with fevers to 105 F, body aches, and generalized weakness. The patient had a leukocytosis to 19.3 and a mild transaminitis. Chest radiography, blood, CSF and urine cultures were negative. Serologies and PCR studies for mycoplasma, syphilis, CMV, EBV, HSV, HIV and acetominophen level were negative. The patient was given broad spectrum antibiotics. She had persistent fevers and was transferred after one week to our institution. Multiple laboratory and imaging studies did not reveal an occult infection. The patient developed a worsening transaminitis with AST/ALT peaking at 8766/1115, a coagulopathy (INR of 1.9) and a lactic acidosis of 12.9. She was anemic at 6.5 and thrombocytopenic at 63. An abdominal MRI revealed splenomegaly. The patient developed cardiorespiratory failure requiring intubation and vasopressors. Ferritin was elevated at 28,000. The patient underwent a bone marrow biopsy which revealed hemophagocytosis. She was started on dexamethasone and etoposide. Over two weeks the patient’s liver failure and hypotension resolved and she was extubated.
- INTRODUCTION AND DEFINITIONS
- ASSOCIATED ILLNESSES
- Autoimmune disorders
- Other conditions
- Familial HLH
- HLH in adults
- - Underlying genetic defects
- Cytokine levels
- Natural killer cell and cytotoxic T cell activity
- - Perforin expression
- - Other abnormalities
- - Perforin (PRF1)
- - Munc 13-4 (UNC13D)
- - Syntaxin 11 (STX11)
- - Munc 18-2 (STXBP2)
- - XIAP (BIRC4)
- - Cytotoxic T-lymphocyte-associated antigen 4 and HLH
- - Associated genetic disorders
- CLINICAL AND PATHOLOGIC FINDINGS
- Initial presentation
- HLH simulating other conditions
- Pathologic findings
- Diagnostic criteria
- - Ferritin levels
- Specialized testing
- HLH-94 protocol
- - Long-term results
- - Hematopoietic cell transplantation
- Reduced-intensity transplantation
- HLH-2004 protocol
- - Use of cyclosporin
- Indications and general supportive care issues
- - Intravenous immunoglobulin
- Long-term follow-up
- Other treatment approaches
- MACROPHAGE ACTIVATION SYNDROME
- SUMMARY AND RECOMMENDATIONS
- When to suspect and diagnose HLH
- Differential diagnosis
- Treatment of HLH
INTRODUCTION AND DEFINITIONS
Hemophagocytic lymphohistiocytosis (HLH) is also known as autosomal recessive familial hemophagocytic lymphohistiocytosis (FHL), familial erythrophagocytic lymphohistiocytosis (FEL), and viral-associated hemophagocytic syndrome (VAHS). This aggressive and potentially life-threatening disease most often affects infants from birth to 18 months of age, but cases in older children and adults have been reported [1-5].
Use of the term “primary HLH” to denote the presence of an underlying genetic disorder and “secondary HLH” to denote presence of the HLH phenomenon occurring secondary to another condition (eg, viral illness, autoimmune disease, lymphoma) has caused a great deal of confusion among clinicians. This reflects the fact that in patients with inherited mutations predisposing to HLH, clinical symptoms are often triggered by viral infections.
- In pediatric patients, the same gene mutations can be present in both situations and there is no specific test with the ability to quickly define these two categories.
- In adult patients, genetic mutations are much less common, suggesting that most represent “secondary HLH.” (See ‘Underlying genetic defects’ below.)
With few exceptions, the clinical presentation and outcome are the same for both. A review has been written to help clinicians understand the many signs and symptoms of HLH besides the eight diagnostic criteria that can help with diagnosing this illness as well as the subtleties of its treatment .
HLH and a similar disorder, the macrophage activation syndrome (MAS), which occurs primarily in patients with juvenile idiopathic arthritis or systemic lupus erythematosus, will be discussed here .
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Learn how a rare disease known as histiocytosis and hemophagocytic lymphohistiocytosis can affect the lives of young children and their families. Then join the search for a cure.
Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantationDiscussion (source: http://bloodjournal.hematologylibrary.org/content/116/26/5824.full) click on the link above to read the full article.
This is the first direct comparison demonstrating a significant survival advantage for patients undergoing RIC-HCT compared with MAC-HCT for definitive cure of HLH, which supports the initial observation of good outcomes of RIC-HCT for HLH reported by Cooper et al.16,17 We have observed that RIC eliminates the early mortality (< 180 days) that is often observed in patients with HLH undergoing MAC HCT,21 and RIC significantly improves survival, with a 3-year survival rate of 92%. As in a previous cohort of HLH patients treated with RIC-HCT,17 we observed no cases of hepatic veno-occlusive disease, which can occur in 5%-30% of patients with HLH undergoing MAC HCT,8–10 and there were no cases of fatal pneumonitis/acute respiratory distress syndrome or fatal hyperinflammatory syndromes. Notably, we observed no differences in infectious complications between the MAC and RIC groups. This is in agreement with a previous study, which also found no differences in infectious complications between alemtuzumab and ATG-containing regimens in pediatric patients.22
We observed a high incidence of mixed chimerism among the RIC patients reported here (65%) compared with the MAC group (18%). Mixed chimerism often occurs in patients with HLH undergoing allogeneic HCT, and has been reported in 10%-50% of HLH patients who are long-term survivors of MAC regimens,8–10 and 29% of HLH patients receiving a RIC regimen similar to the one reported here (Cooper et al).17
There are several possible explanations for the increased incidence of mixed chimerism observed in our cohort compared with the cohort of HLH patients previously reported who received RIC. All patients treated with RIC-HCT at our center received steroids as part of their GVHD prophylaxis whereas the HLH patients undergoing RIC-HCT reported by Cooper et al17 received only cyclosporine for GVHD prophylaxis. Although the addition of steroids to GVHD prophylaxis may contribute to the increased incidence of mixed chimerism observed in our cohort, this is likely less significant given that mixed chimerism has been reported in 63% of 120 adult patients with a variety of malignancies receiving alemtuzumab as part of preparative regimens containing fludarabine/melphalan, fludarabine/busulfan, or clofarabine/melphalan, who received only tacrolimus for GVHD prophylaxis.23 In addition, mixed donor chimerism including the T-cell compartment has been reported in half of adult patients with acute myeloid leukemia and myelodysplastic syndromes after allogeneic HCT after alemtuzumab, fludarabine, and busulfan using only cyclosporine for GVHD prophylaxis.24
Another possible explanation is that the patients reported by Cooper et al received 1 mg/kg total alemtuzumab, which is less than the average alemtuzumab dose given to our patients, 2.1 mg/kg. Although we did not observe a direct effect of alemtuzumab dose on the incidence of mixed chimerism, we did observe that mixed chimerism is particularly common among patients treated with the proximal alemtuzumab schedule (79%). This suggests that the timing of alemtuzumab administration affects the incidence of mixed chimerism, likely because of higher systemic levels of alemtuzumab at the time of graft infusion and resultant increased graft lymphocyte/T-cell depletion. Younger age was also associated with the development of mixed chimerism. It is possible that there could be differences in the pharmacokinetics of alemtuzumab in the youngest patients who may result in higher levels of alemtuzumab at the time of graft administration.
No primary graft-associated acute GVHD was observed in patients receiving proximal alemtuzumab, with the exception of 1 patient who developed GVHD only after abrupt cessation of GVHD prophylaxis because of rapidly waning donor chimerism. This again suggests more effective lymphocyte/T-cell depletion of the graft with proximal alemtuzumab administration. A previous study noted no occurrence of GVHD among patients receiving alemtuzumab compared with ATG-containing regimens,22 and mixed chimerism has also been shown to be associated with decreased risk of GVHD in other studies.23,24
Despite the development and persistence of mixed chimerism in the RIC group, RIC-HCT was successful in 96% of patients, who remain free of HLH. Similar to a previous report,9 we observed a relapse of HLH in a RIC patient as whole blood donor chimerism decreased to below 10%, and this patient subsequently received a second successful HCT after MAC. The majority of all other patients with mixed donor chimerism received intervention with early wean from GVHD prophylaxis and/or were given DLI to stabilize or increase donor chimerism in an active effort to maintain whole blood donor chimerism above 20%.
The greatest benefit of RIC-HCT is the significantly improved patient survival. The 3-year probability of survival more than doubles with RIC in our series, increasing from 43% for patients undergoing MAC-HCT to 92% for patients undergoing RIC-HCT. The survival that we observed with MAC is similar to that reported by Baker et al in 1997,12 but lower than the survival observed in more recent reports. This may be because our center is a tertiary referral center, and it has been our experience that patients with straightforward clinical courses often undergo HCT at other US institutions, whereas patients with difficult or recalcitrant disease are often referred. However, even with comparison to the highest reported survival rate among HLH patients undergoing MAC-HCT, 64%,8the survival that we have observed here is still significantly improved in comparison.
The improved survival may be a result of the “reduced intensity” of fludarabine and melphalan compared with traditional MAC regimens, or it is also possible that survival is improved simply because of the inclusion of alemtuzumab in the regimen. Alemtuzumab is efficient at depleting T cells and also CD52-expressing antigen-presenting cells, which may effectively treat any residual/smoldering HLH at the time of transplantation. Parenthetically, we have observed a beneficial effect of alemtuzumab for treatment of refractory HLH (unpublished data). The fatal periengraftment hyperinflammatory syndromes that have been observed in patients with HLH may also be prevented by alemtuzumab via efficient depletion of both host and donor antigen-presenting and effector cells.
Given the significantly improved survival of patients with HLH undergoing RIC-HCT, we recommend that all patients with HLH receive RIC regimens if a suitable bone marrow or peripheral blood stem cell source is identified. Choice of preparative regimen when a cord blood graft is the only option should be carefully considered, as the lack of any ready source of DLI is a concern given the high percentage of mixed chimerism observed with RIC. It appears that whole blood donor chimerism above 10%-20% does indeed protect against HLH, as the only patient to relapse HLH did so only after donor chimerism fell to less than 10%. Frequent monitoring of chimerism studies is essential, and centers should be prepared to stabilize donor chimerism with early withdrawal of GVHD prophylaxis or administration of DLI if needed. Future studies to more closely measure donor chimerism within the myeloid and lymphoid compartments, and specifically within the lymphocyte subsets, are needed to determine which cell populations are most critical for protection against HLH.
Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation.
Recent experience suggests that reduced-intensity conditioning (RIC) regimens can improve the outcomes of patients with hemophagocytic lymphohistiocytosis (HLH) undergoing allogeneic hematopoietic cell transplantation (HCT). However, studies directly comparing RIC to myeloablative conditioning (MAC) regimens are lacking. Forty patients with HLH underwent allogeneic HCT between 2003-2009 at Cincinnati Children’s Hospital. Fourteen patients received MAC consisting of busulfan, cyclophosphamide, and anti-thymocyte globulin +/- etoposide. Twenty-six patients received RIC consisting of fludarabine, melphalan, and alemtuzumab. All patients engrafted. Acute GVHD grades II-III occurred in 14% of MAC patients and 8% of RIC patients (p=0.3171). Post-transplant mixed donor/recipient chimerism developed in 18% of MAC patients and 65% of RIC patients (p=0.0110). The majority of patients with mixed chimerism received intervention with reduction of immune suppression +/- donor lymphocyte infusion (DLI) or stem cell boost which stabilized or increased donor contribution to hematopoiesis and prevented relapse of HLH in all but 1 patient. Grade II-III GVHD occurred in 5/14 RIC patients following DLI. The overall estimated 3-year-survival post-HCT was 43% (confidence interval (CI) = +/-26%) for MAC patients and 92% (CI = +/-11%) for RIC patients (p=0.0001). We conclude that RIC significantly improves the outcome of patients with HLH undergoing allogeneic HCT.
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States;
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20855862
- DOI: http://dx.doi.org/10.1182/blood-2010-04-282392
Preparative treatment of transplant recipient with various conditioning regimens including radiation, immune sera, chemotherapy, and/or immunosuppressive agents, prior to transplantation. Transplantation conditioning is very common before bone marrow transplantation.
Reflex closure of the eyelid occurring as a result of classical conditioning.
Physical Conditioning, Animal
Physical conditioning of domestic, laboratory, and zoo animals. Includes exercising of animals.
The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host.
Methods to determine in patients the nature of a disease or disorder at its early stage of progression. Generally, early diagnosis improves PROGNOSIS and TREATMENT OUTCOME.