Secondary hemophagocytic lymphohistiocytosis (sHLH) is a severe syndrome resulting from an overactive and uncontrolled immune response. It is not a form of cancer, but a hyperinflammatory condition triggered by other medical problems that send the body’s defense systems into overdrive. This immune activation leads to the proliferation of immune cells called lymphocytes and macrophages. These cells release a flood of inflammatory proteins, creating a “cytokine storm” that can cause widespread tissue and organ damage.
Underlying Triggers of Secondary HLH
The hyperinflammatory state of sHLH is set in motion by a medical condition that provokes a strong, unrelenting immune reaction. Infections are a common cause, with the Epstein-Barr virus (EBV), the virus responsible for mononucleosis, being a frequent trigger. Other viruses like cytomegalovirus (CMV), as well as various bacteria and fungi, can also initiate the syndrome.
Malignancies are another major category of triggers. Cancers of the blood and lymphatic system, such as lymphomas and leukemias, are often implicated. In these situations, the cancer acts as the persistent stimulus that drives the immune system into a state of harmful overactivation. The resulting HLH can sometimes be the first sign of an undiagnosed malignancy.
A third group of triggers includes autoimmune and rheumatic diseases. Conditions where the immune system attacks the body’s own tissues, such as systemic lupus erythematosus and rheumatoid arthritis, can lead to sHLH. In these instances, the chronic inflammation of the autoimmune disorder escalates into the systemic inflammation of HLH. Less commonly, certain medications or complications after an organ or stem cell transplant can also serve as triggers.
Recognizable Signs and Symptoms
The clinical presentation of sHLH is characterized by intense and persistent symptoms that signal a widespread inflammatory crisis. A high, unremitting fever is one of the most common signs, which often does not respond to standard antibiotic or antiviral medications. This fever is a direct result of the high levels of inflammatory cytokines circulating throughout the body.
Many patients develop an enlarged liver and spleen, a condition known as hepatosplenomegaly. This occurs as overactive immune cells accumulate in these organs, causing them to swell and lead to abdominal pain. Another frequent finding is cytopenias, meaning dangerously low levels of blood cells. This can manifest as anemia, increased susceptibility to infections, and easy bruising or bleeding from a deficit of platelets.
A skin rash is another potential symptom. The systemic inflammation can also affect the central nervous system, leading to neurological symptoms. These can include seizures, unexplained irritability, confusion, or a decreased level of consciousness, indicating that the inflammation has reached the brain.
The Diagnostic Process
Confirming a diagnosis of sHLH is a complex process, as there is no single definitive test. Physicians rely on a combination of clinical signs and a panel of specific laboratory tests. The process involves using formal criteria, such as the HLH-2004 guidelines, which require a patient to exhibit a specific number of defined abnormalities.
Blood tests are used to look for a characteristic pattern of results that paint a picture of severe, systemic inflammation. Important markers include:
- Extremely high levels of ferritin, a protein that stores iron
- Elevated triglycerides, a type of fat in the blood
- Low levels of fibrinogen, a protein necessary for blood clotting
- A high concentration of soluble CD25, a molecule indicating widespread T-cell activation
Specialized tests are used to assess immune system function. One such test measures the activity of Natural Killer (NK) cells, a type of immune cell important for controlling immune responses. In many cases of HLH, the function of these NK cells is significantly reduced or absent.
A bone marrow biopsy is another common diagnostic procedure. A small sample of bone marrow is examined to look for evidence of hemophagocytosis—the phenomenon where activated macrophages engulf other blood cells. While the presence of hemophagocytosis is a strong indicator, its absence does not rule out HLH, making the combination of all findings necessary for an accurate diagnosis.
Treatment Approaches
Treatment for sHLH is intensive and operates on two main fronts: controlling the life-threatening hyperinflammation and addressing the underlying trigger. The first goal is to calm the cytokine storm and suppress the overactive immune system. This is achieved with high-dose corticosteroids, such as dexamethasone, which have powerful anti-inflammatory effects.
In many cases, corticosteroids alone are not sufficient to quell the severe inflammation. Chemotherapy agents, most commonly etoposide, are often used in combination with steroids. Etoposide works by inhibiting the proliferation of the overactive immune cells driving the disease. Other immunosuppressive drugs, like cyclosporine, may also be incorporated into the regimen.
The second goal is to treat the specific trigger. If an infection like EBV is identified, antiviral medications are administered. If the HLH is driven by a malignancy, chemotherapy targeted at the specific cancer is initiated. For autoimmune-related HLH, treatments are focused on managing the underlying rheumatic disease. Newer biologic therapies that block specific cytokines are also emerging as options in managing the hyperinflammation.
Prognosis and Recovery Factors
The outcome for patients with sHLH is highly variable and depends on several interconnected factors. A patient’s age and overall health at the time of diagnosis play a significant role in their ability to tolerate the aggressive treatments required.
A primary factor in the prognosis is the underlying trigger and how effectively it can be treated. HLH triggered by a manageable infection may have a better outlook than HLH from an advanced malignancy. The severity of the HLH when treatment begins is another consideration, as patients with multi-organ failure face a more challenging course.
The speed of diagnosis and treatment is also a major determinant of the outcome. Prompt intervention to suppress the cytokine storm and treat the trigger can prevent irreversible organ damage. Following successful treatment, ongoing follow-up care is necessary to monitor for relapse, as the condition can recur if the trigger is not fully resolved.