Degree of immune suppression and risk of HIV-related Hodgkin lymphoma: time points matter

To the editor:

In a recent issue of Blood, Clifford and colleagues¹  reported interesting findings from the Swiss HIV Cohort Study pertaining to the debated relationship, in the setting of HIV infection, between occurrence of Hodgkin lymphoma (HL) and degree of immune suppression. In contrast to previous data from the United States,²  they found that HL risk did tend to increase with lowering CD4⁺ cell counts, with a statistically significant elevated risk related to a low CD4⁺/CD8⁺ ratio.¹  Lymphocytopenia due to sequestration of lymphocytes at the tumor site is common in immunocompetent people with HL^3,4  and data from Clifford and colleagues¹  provide, for the first time, evidence for a decline in the number of circulating CD4⁺ cells in the year preceding HL also in the setting of HIV infection. This observation makes timing of CD4⁺ cell counts with respect to HL diagnosis a key element to help elucidate the still controversial relationship between degree of immune suppression and HL. From this viewpoint, it should be noted that, in the US study, CD4⁺ cells were counted only once before HL and that only 27% of HL cases had a CD4⁺ cell count available in the 12 months preceding HL onset.²  This makes comparison of the findings of the 2 studies difficult.

In our opinion, the data provided by Clifford and colleagues¹  indicate that the meaning of CD4⁺ cell count should be interpreted with respect to the time period preceding HL diagnosis. According to this view, CD4⁺ cell count may convey different pathogenic implications for the occurrence of HL when measured at different time points before HL onset. Therefore, in HIV-infected persons, the number of circulating CD4⁺ T lymphocytes cannot be solely regarded as a surrogate marker of the level of immune competence or immune reconstitution after highly active antiretroviral therapy. In fact, due to the peculiar redistribution of CD4⁺ T cells that are diverted from periphery to the tumor sites since the early phases of HL pathogenesis,^3,4  the CD4⁺ T-cell count could also help identify HIV⁺ persons at high risk to develop HL. An attractive possibility to be investigated in prospective studies concerns, thus, the potential role of a persistent decline in CD4⁺ T-cell count as a marker predictive of an impending HL in HIV⁺ persons. The regular evaluation of CD4⁺ T-cell count currently performed in patients treated with highly active antiretroviral therapy makes this type of investigation feasible, while the concomitant evaluation of HIV viral load could help distinguish from progression of HIV disease. In addition, multiparametric evaluation of CD4⁺ T-cell attributes and their protective functions⁵  may help to further refine the predictive value of CD4⁺ T-cell counts.