Hemophagocytic Lymphohistiocytosis (HLH)

The initial signs and symptoms of hemophagocytic lymphohistiocytosis (HLH) are described as nonspecific. This indicates that these signs and symptoms are similar to those of many other disorders or diseases and might be mistaken because they mimic other conditions. Nevertheless, the symptoms of HLH are more severe than those of other conditions.

The onset and severity can vary widely from person to person.

Common signs and symptoms of HLH

• Skin rash
• Persistent and prolonged high fever
• Generalized weakness
• Swollen liver, spleen, and lymph glands
• Jaundice
• Anemia
• Increased need for sleep
• Pale skin color
• Dyspnea (difficulty breathing)
• Bruising easily and frequently 
• Bleeding from the gums and nose 
• Signs of infection
• Headache
• Seizures
• Ataxia (wobbliness) or coordination problems
• Altered mental status
• Kidney impairment
• Cardiac problems
• Increased risk for certain types of cancer (leukemia, lymphoma)
• Irritability
• Abnormal muscle tone
• Neck stiffness
• Blindness or disturbance in vision
• Hypotension (extremely low blood pressure)
• Swelling due to fluid accumulation
• Paralysis and/or coma

HLH signs and symptoms often appear within the first months or years of life. However, in rare instances, affected individuals may not exhibit symptoms until late in childhood or even into adulthood. The condition usually leads to multi-organ involvement, necessitating prompt diagnosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing and potentially fatal hematologic disorder caused by ineffective and pathologic immune response system activation, which can mimic common emergency department presentations, such as:

• Sepsis
• Acute liver failure
• Disseminated intravascular coagulation
• Flu-like illnesses

Most people with HLH present after symptoms become severe, leading to life-threatening medical complications. Although the condition is rare, mortality rates are high, and diagnosing HLH is usually challenging.

HLH is an emergency condition, which needs early intervention.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder, and researchers are still learning about its causes. However, scientists believe that HLH is a disorder of the immune system, which has faulty DNA instructions for its roles and activities.

Currently, there are two types of HLH disorder, primary and acquired, with two different causes. Both of them have similar diseases mechanism in which the body's immune system attacks its healthy tissue and organs, causing severe systemic inflammatory syndrome that can be fatal. 

Depending on various causes, HLH can be divided into two types:

1. Primary or familial HLH (FHL)
   • Accounts for about 25 percent of cases.
   • It is called familial HLH because it can be passed to the next generation as a hereditary disorder. 
   • If both parents are genetic carriers of HLH, a child has a 25 percent risk of acquiring the disease, a 25 percent risk of not having the disease, and a 50 percent risk of being a carrier. Often, children with these genes are diagnosed at very young ages.
   • Defects in multiple genes, including PRF1, UNC13D, STXBP2, STX11, RAB27A, LYST, AP3B1, SH2D1A, and XIAP/BIRC4, cause primary HLH. 
   • Normally, all of these genes create proteins that govern immune cells. When these proteins are missing or do not function properly, immune system cells activate and expand uncontrollably, going beyond the point of battling genuine infections.
2. Acquired or secondary HLH
   •  Several conditions cause acquired HLH, which is more common in older children and adults. These conditions include:
     • Bacterial, fungal, or viral infections (Epstein-Barr virus, cytomegalovirus, or herpes)
     • A weak or diseased immune system
     • Cancer such as T-cell lymphoma or prostatic adenocarcinoma, hematological malignancies (such as leukemia)
     • Rheumatologic/autoimmune diseases such as those that attack the bone marrow
     • Diseases that occur due to suppression of the immune system owing to the use of immunosuppressive drugs
     • Pregnancy/HELLP syndrome (rare)

Risk factors for HLH

• HLH is most common in newborns and young children, but it can affect people of any age. 
• Men are at a slightly higher risk of this disease than women.
• Risk increases if someone in the family has HLH.
• Those who are prone to severe infections are at a higher risk of HLH.
• People who take medicines that suppress the immune system may develop HLH.

The specific cause of HLH is still being investigated. A postinfectious etiology is presumed but yet to be established. According to the suggested etiology, infection, cancer or the use of chemotherapeutic, or immunosuppressive medicines destroys the cellular genetic material, particularly in the bone marrow.

Certain cells proliferate as a result of DNA damage. These phagocytes cause HLH by triggering a hyperinflammatory response and attacking the body's other blood cells. A genetic abnormality associated with FHL should be tested out in children. HLH in adults should initiate screening for underlying cancer.

Secondary hemophagocytic lymphohistiocytosis (HLH) can arise spontaneously or in the context of familial HLH. It is hypothesized to be connected to immunological activation caused by viral infections, such as:

• Epstein-Barr virus (EBV)
• Human herpes simplex virus (HSV) and some other human herpes viruses
• Influenza virus
• COVID-19 virus 
• Coxsackievirus B
• Cytomegalovirus (CMV) 
• Respiratory syncytial virus
• Rotavirus
• Adenovirus infections

The most common viruses that trigger HLH are EBV, CMV, and HSV. In people with HIV, HLH has been linked to the start of “highly active antiretroviral therapy.” EBV-associated HLH may appear in the same way as T-cell lymphoma. In newborns, HLH associated with human HSV, coxsackievirus B, and echovirus should be considered.

There have been reports that COVID-19 can cause hemophagocytic lymphohistiocytosis (HLH) as a result of a cytokine storm. Cytokine storm syndrome is a group of medical diseases in which the immune system creates an abnormally large number of inflammatory signals. Cytokine storm symptoms can range from mild (flu-like) to severe and possibly fatal, resulting in organ failure and death.

Cytokine storm is more common in people with specific genetic disorders. This is true for individuals who have familial HLH. People with HLH are prone to experiencing cytokine storms in response to infections such as COVID-19. 

HLH disorder in people who have had COVID-19 is usually rare. Immune dysregulation following the COVID-19 infection may be the primary cause of HLH in such people.

Although more people are managing to survive severe COVID-19 infections, there is still a lack of statistics on the outcomes beyond initial hospitalization. There is a significant risk of HLH two weeks after COVID-19 recovery. Early detection of HLH symptoms following COVID-19 recovery should result in timely treatment. HLH may be an unreported cause of mortality in post-acute COVID-19 syndrome.

Ticks are capable of transmitting bacterial, viral, and parasitic diseases. In the study of tick-borne diseases, epidemiology plays a critical role. Tick bites from both nymphs and adults can transfer infections that may rarely trigger hemophagocytic lymphohistiocytosis (HLH); this is true for those who have risk factors for HLH. Tick-borne HLH is linked with significant mortality and morbidity. This emphasizes the need for understanding the diagnostic criteria for HLH.

Hemophagocytic lymphohistiocytosis (HLH) can be diagnosed through a combination of symptoms and blood tests. The following tests can be used to diagnose HLH:

• Physical exam to check for fever and enlarged spleen, lymph nodes, or liver
• Blood work may include complete blood count, ferritin, triglycerides, fibrinogen, liver enzymes, and clotting studies
• Special tests to evaluate immune system function
• Biopsy, usually of bone marrow, may be needed, but doctors may recommend a biopsy of other tissue to rule out other conditions

It is challenging to diagnose HLH due to its nonspecific presentation. A blood smear is a very useful tool in diagnosing HLH. A bone marrow biopsy can confirm an HLH diagnosis by showing evidence of bone marrow destruction by macrophages.

Early treatment should be instituted because hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition. To stop the disease from spreading and help the body regain its vital functions, the underlying cause should be identified, and medication should be given for the cause.

The goal of the treatment should be to reduce the hyperactivity of the immune system. Limiting immune system activity slows the body's response to HLH. In addition, it's crucial to prevent and treat infections during the treatment phase.

Treatment options for HLH

• Medical treatments
  • Corticosteroids, such as dexamethasone, are used to fight against inflammation.
  • Immunotherapeutic medicines are used to strengthen the immune system of the affected individual.
  • If HLH is secondary to some infections, such as bacterial, viral, or fungal, respective antibiotics are used (such as cyclosporine).
  • Intravenous polyvalent immunoglobulins have also been used in some trials.
  • Intravenous antimicrobial therapy is used to treat underlying infections.
  • Blood transfusion and oxygen therapy may be recommended for those who are very sick.
  • FDA recently approved a gamma-blocking antibody medication Gamifant® (emapalumab) for treating primary HLH in newborns and adults.
• Chemo drugs
  • Shown to be effective according to various research studies. All these medications are currently in trials:
    • Etoposide
    • Cyclophosphamide
    • Doxorubicin
    • Vincristine
    • Prednisone
• Autologous stem cell transplant 
  • In some cases, stem cell therapy has been used to treat HLH, and the results have been promising. 
  • In this therapy, stem cells are extracted from a healthy person and transplanted into the bone marrow of the person with HLH. 
  • A series of diagnostic tests are performed before therapy to assess the person’s physical health and to determine if they can withstand the transplantation process. 
  • The person is then given chemotherapy, which kills the defective bone marrow cells, making room for new cells to be transplanted. This is known as “conditioning.” 
  • Donor stem cells from a healthy, compatible donor are transplanted into the bone marrow of the person with HLH after successful conditioning. The person is then kept under constant medical supervision.
• Clinical trials
  • If medications, stem cell therapy, or condition management are not successful, healthcare providers may consider clinical trials. 
  • These come with high risk and many possible side effects, which your doctor will discuss with you to help you decide on your health.
• Prevention of HLH
  • Because the causes are beyond our control, there is no way to prevent HLH from occurring, but here are some ways you can reduce the risk of HLH:
    • Eating a well-balanced diet 
    • Exercising regularly
    • Avoiding contact with people who are infected with a virus
    • Wearing protective gear to prevent injuries
    • Properly cleaning and caring for any injuries to prevent infections
    • Managing any underlying conditions
    • Genetic testing before planning a family

People who are successfully treated should keep up with doctor appointments and lead a healthy lifestyle.

There isn't a specific drug that can cure hemophagocytic lymphohistiocytosis (HLH). With timely intervention and accurate treatments and therapy, some people showed extremely positive results. All the medications are presently on a trial basis, which may or may not work depending on the severity of the condition. In certain cases, stem cell or bone marrow transplantation can result in a cure.

HLH therapy, including stem cell transplant, has transformed the treatment and has the potential to result in long-term survival and cure. Children who have received a stem cell transplant have a 66 percent five-year survival rate. Infections, particularly fungal infections, are a leading cause of mortality in HLH children after transplant. Another significant limitation is that this approach can only treat the familial type of HLH. This procedure is not 100 percent effective; instead, the rate of successful transplants is as low as 40 percent.

People with HLH who are cured by stem cell transplants may need lifelong medications, a healthy diet, and lifestyle modification to avoid infections and stay healthy.

As survival rates in people with hemophagocytic lymphohistiocytosis (HLH) have improved significantly, it has become increasingly important to thoroughly assess long-term complications of HLH, the most important of which are neurological symptoms. Unfortunately, significant motor and cognitive deficits may occur in people with HLH.

Early detection and treatment of central nervous system (CNS) diseases may prevent irreversible CNS injury and are essential to improving long-term outcomes. However, outcomes after treatment are unknown because trials have primarily focused on survival rates and causes of HLH.

If left untreated, hemophagocytic lymphohistiocytosis (HLH) is almost always fatal. Because HLH progresses rapidly and can be fatal, it is crucial to recognize the condition and begin treatment as soon as possible.

An early review of familial HLH showed a one-month survival rate from the onset of symptoms and a one-year survival rate of five percent from diagnosis. Despite early detection and adequate treatment, HLH has a 50 percent initial mortality rate, with 90 percent dying within the first eight weeks of treatment due to uncontrolled disease. Adult HLH is a rare and almost universally fatal disease without treatment, with a published median survival of 1.8 to 2.2 months. These rates are largely influenced by the underlying pathology. A poor prognosis is associated with delayed diagnosis and multi-organ involvement.

Long-term follow-up of HLH/familial HLH transplant survivors shows that the majority return to a normal or near-normal quality of life. Transplantation outcomes are often better when conducted at a prominent transplant facility where the experts have in-depth knowledge about this condition. However, there is still a significant fatality rate, indicating that the medical community needs to be educated on disease identification and management.

Recent research studies have added to our understanding of HLH pathophysiology, leading to new treatment possibilities; however, considerable effort has to be made to raise awareness and enhance the efficacy of the HLH treatment regimen.