The present study clarified the characteristics of PML cases in Japan based on clinical data obtained through the laboratory testing for JCV DNA in CSF specimens. Mass screening of PML patients has not been feasible in Japan due to the lack of a suitable database for PML. The current strategy deals with a relatively small number of patients but has a distinct advantage in collecting precise real-time information for patients as well as specimens. The testing was constantly requested by the physicians via websites, despite the fact that there were at least 4 commercial laboratories providing similar assays during the study period according to our own survey. Thus, this internet-based approach is thought to be useful for sampling data for rare infectious diseases. In addition, as this diagnostic support system was conducted regardless of patient age, gender, underlying disease or medical history, precise information could be obtained not only from PML patients but also from CSF-JCV-negative individuals with similar conditions. These data are considered to be valuable for the examination of the overall background to PML in Japan.
A large number of PML patients had HIV infection / acquired immunodeficiency syndrome (AIDS) or hematologic disorders. Recent database analyses and other clinical studies in the USA have suggested that approximately 79–82% of PML patients are positive for HIV and 7.7–13% have hematological malignancies
[24, 26, 31]. In contrast, the proportion of HIV-related PML cases in Japan was approximately 33%, which is much lower than that in the USA. The difference in the ratios of HIV-related PML between these two countries must be interpreted based on the epidemiological status of HIV infection. According to the latest data from the Joint United Nations Programme on HIV/AIDS, World Health Organization
, the prevalence of HIV infection among adults in the USA (0.6%) is at least 6-fold higher than that in Japan (< 0.1%). Thus, it is reasonable to suppose that the relatively low proportion of HIV-related PML in Japan is associated the low prevalence of HIV infection. As a large proportion of HIV-infected individuals in Japan are male
, it is also reasonable that the sex ratio of HIV-related PML showed a predominance of males.
A notable finding of the present study is that hematologic disorders are a main risk factor for PML in Japan. Five of 19 patients in this group had received allogeneic HSCT, suggesting that this type of transplantation is an important risk factor of PML. In the other 14 PML cases, 11 individuals (patients 6–16) were administrated with chemotherapeutic and / or immunosuppressive agents for the treatment of hematologic malignancies. Thus, it is likely that these therapies are associated with the high incidence of PML cases in this category. The present study also demonstrates that the majority of PML patients with hematologic disorders are males. In contrast, the percentages of male patients with hematologic malignancies were similar to or slightly higher than those of females (leukemia, 59.1%; lymphoma, 52.9%; MM, 52.1%) according to the most recent statistics from the National Database for Cancer Incidence in Japan
. The reason for the male predominance among PML patients with hematologic disorders remains unknown. Further studies are needed on larger populations of PML patients to clarify the mechanism and significance of this sexual dimorphism. However, these data are thought to be beneficial for patients having similar underlying diseases.
In 50 subjects with autoimmune disorders, 3 SLE patients were diagnosed as having PML. These patients had been treated with immunosuppressive agents, such as tacrolimus, mesalazine, mycophenolate mofetil, prednisolone, and / or cyclophosphamide, but not with therapeutic antibodies. No PML cases were observed among individuals with other types of autoimmune disorders. In Japan, natalizumab and efalizumab are not currently approved for use, and rituximab is not licensed for the treatment of autoimmune disorders. Therefore, increased awareness may be needed about the potential for PML in accordance with the wide spread use of therapeutic monoclonal antibodies in this country. It was also shown that the occurrence of PML is uncommon in individuals receiving solid-organ transplantation. Among the total study population, only 10 subjects underwent kidney, liver, or heart transplantation, and PML developed in one liver-transplanted patient. As this patient had suffered from common variable immunodeficiency, the association between the transplantation and PML remains unclear. This situation can be explained by the limited number of patients, who underwent organ transplantation, especially from brain dead donors
. However, it is predicted that the risk of PML will increase in accordance with the revision of the transplantation law in 2010, which extends the availability of transplantation therapy