How to treat hemophagocytic syndrome caused by Epstein-Barr virus infection?

Author: Wang Zhao, Chief Physician, Beijing Friendship Hospital, Capital Medical University

Reviewer: Zhang Yu, researcher at Chinese Center for Disease Control and Prevention

Hemophagocytic syndrome is divided into two categories: primary and secondary. Among the secondary causes, the most common is infection, among which viral infection is the most common. Among viral infections, the most important is Epstein-Barr virus-related hemophagocytic syndrome.

In our country, currently more than half of the hemophagocytic syndromes are Epstein-Barr virus-related hemophagocytic syndromes.

Of course, EBV-associated hemophagocytic syndrome is not the same as EBV-positive hemophagocytic syndrome.

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First, Epstein-Barr virus positivity can be a trigger for primary hemophagocytic syndrome. Because of a gene defect, the disease may not necessarily occur. It will only be induced when there is infection, stress, or taking some drugs; and Epstein-Barr virus can be a very good trigger for primary hemophagocytic syndrome. Therefore, if a patient has hemophagocytic syndrome and is Epstein-Barr virus positive, especially in children, pay attention to whether it is primary hemophagocytic syndrome. There was a 52-year-old patient with hemophagocytic syndrome who was Epstein-Barr virus positive. Later investigation found that he had a homozygous pathogenic gene change, so he had primary hemophagocytic syndrome. Therefore, if Epstein-Barr virus is positive, the possibility of primary hemophagocytic syndrome must be ruled out first.

Second, tumors must be ruled out. Many tumors, especially lymphomas, are often accompanied by Epstein-Barr virus positivity. The most classic of these tumors is called NK/T cell lymphoma, and most patients have positive peripheral blood Epstein-Barr virus. However, although these patients are Epstein-Barr virus positive and meet the diagnosis of hemophagocytic syndrome, further examination shows that they are NK/T cell lymphomas. We do not call this type of patient Epstein-Barr virus-associated hemophagocytic syndrome, but call it lymphoma-associated hemophagocytic syndrome. Epstein-Barr virus is just a concomitant manifestation of the tumor.

Third, some people have underlying rheumatic and immune diseases. If they are infected or the Epstein-Barr virus is reactivated during the treatment process, it may induce hemophagocytic syndrome. This condition is generally not called Epstein-Barr virus-associated hemophagocytic syndrome, but is more often called rheumatic and immune disease-associated hemophagocytic syndrome.

Therefore, only when the EB virus is positive and combined with hemophagocytic syndrome, and the above factors are excluded, can it be called EB virus-associated hemophagocytic syndrome.

For the treatment of EB virus-associated hemophagocytic syndrome, we first need to identify whether the EB virus infects B lymphocytes, T lymphocytes, or NK cells.

If the infected cells are B lymphocytes, anti-CD20 monoclonal antibodies can generally be used. CD20 is mainly expressed on B cells. Anti-CD20 monoclonal antibodies can be used to eliminate B cells. When B cells are eliminated, the EB virus loses its "support" and disappears naturally. Therefore, eliminating the EB virus by eliminating B cells can achieve very good results. When the EB virus is gone, the hemophagocytic syndrome will also be cured.

If it is a T cell or NK cell infection, it is generally treated with a combination of cytotoxic drugs, hormones and immunosuppressants. This treatment can often only control symptoms and is prone to relapse.

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Many patients, especially adults, need allogeneic hematopoietic stem cell transplantation. However, for children, if the hemophagocytic syndrome is well controlled and only the EB virus does not turn negative, it can be observed to see whether his immune function can eliminate the T cells and NK cells infected by the EB virus.

Why? Because children's immune function is not perfect. As they grow and develop, their immune systems gradually mature and they may be able to eliminate the virus, so there is no need for transplantation. However, adults' immune systems are already very mature. If they have immune deficiencies, whether congenital or acquired, they cannot recover on their own, so the virus infection will persist and continue to occur until death.

Therefore, for children and adults, the treatment paths and treatment methods are different. Of course, different treatment strategies must be adopted based on examination and classification.

For example, children with Epstein-Barr virus-related hemophagocytic syndrome also need transplantation if they have recurrent attacks, because without transplantation, the child will be at risk of death. In addition, if the examination finds a genetic defect and it is primary hemophagocytic syndrome, transplantation is also necessary.

There is another situation, what if B cells, T cells, NK cells are all infected, or two or more cell lines are infected? This treatment mode is generally treated according to the T cell and NK cell infection mode, which means that anti-CD20 monoclonal antibodies are not recommended because anti-CD20 monoclonal antibodies can only eliminate B cells.

There is a disease called chronic active Epstein-Barr virus disease, which is often accompanied by hemophagocytic syndrome during the progression of the disease. In patients with chronic active Epstein-Barr virus disease combined with hemophagocytic syndrome, the Epstein-Barr virus infects T cells, NK cells, or multiple lineage lymphocytes. The treatment at this time is often allogeneic hematopoietic stem cell transplantation, and there is almost no other treatment option.