By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Rituximab in HIV

Source: Bower M, et al. Brief communication: Rituximab in HIV-associated multicentric Castleman disease. Ann Int Med. 2007;147:836-839.

Castleman Disease, a rare lymphoproliferative disorder characterized by fever, lymphadenopathy, splenomegaly, high sedimentation rates, and polyclonal hypergammaglobulinemia, is being seen with increasing frequency in HIV-positive persons. Similar to Kaposi sarcoma, it is caused by the KS-associated herpes virus (also known as human herpes virus-8). Unlike KS, Castleman disease is associated with high levels of HHV-8 plasma viremia, which is a marker of disease activity.

Bower and colleagues treated 21 HIV+ patients with multicentric Castleman disease with rituximab at standard dosage (375 mg per M2) on a weekly basis for 4 weeks. The majority of the patients were male (86%), nearly half had a diagnosis of AIDS (42%), and 62% were receiving HAART. The median CD4 cell count at diagnosis was 300 cells/mL, and 43% had an undetectable plasma HIV RNA level. Half of the patients also had cutaneous KS. All but one patient had fever, 90% had splenomegaly, and 95% had high ESR; anemia, hypoalbuminemia, thrombocytopenia were frequently observed.

Twenty (95%) patients responded to treatment, with resolution of many systemic and clinical findings within one month, as well as radiographic improvement in two-thirds of the subjects. One patient developed progressive disease and died. Over a median follow-up of 12 months, the 2-year survival rate was 95% and the relapse-free survival rate was 92%. HHV-8 DNA viral load was measured in 11 patients before initiation of treatment, and was detectable in 9, with a median level of 700 copies/mL. Three months after treatment, 1 of 10 patients had detectable circulating plasma HHV-8 DNA. There was no apparent effect on CD4/CD8 cell counts or HIV RNA. Therapy was well tolerated, with no adverse effects, except that one-third of the patients developed progressive or reactivated KS.

Inflammatory markers (ESR, CRP) and globulin levels were reduced following completion of therapy, as were plasma cytokine levels (eg, IL-10) in the majority of patients. IL-10 has been especially linked to B-cell activation, and is produced by HHV-8-infected and HIV-Tat-induced cell lines. Many experts believe there is a close relationship between IL-10 production and Castleman disease, or at least that IL-10 may also be reflective of disease activity. Rituximab is a safe and effective treatment for HIV-associated Castleman disease, with no adverse effect on HIV disease progression, although patients with concurrent KS are at risk for reactivation of their cutaneous disease.

Heredity and Death from the Flu

Source: Albright FS, et al. Evidence for a heritable predisposition to death due to influenza. J Infect Dis. 2008;197:18-24.

Analysis of families with at least 3 generations of available data in the Utah Population Database over a period of 100 years (including geneologic data from the Church of Latter-Day Saints since the original pioneers) suggests a shared familial risk of mortality from influenza, beyond what would be predicted from shared exposure and environmental factors. Those individuals with a specific recorded cause of death and at least 3 generations of family data (including first and second cousins) (n = 388, 121 persons) were grouped by birth year, sex, and birthplace. Rates of mortality from influenza were determined for close primary genetic relationships (mother, daughter, sister) and all genetic relationships, and compared with matching controls.

Death attributable to influenza occurred in 4855 persons between 1904 and 2004. The relative risk of death from influenza was significantly increased for all first degree relatives (RR of death for siblings was 1.74 and for parents 1.37). Spouses of case subjects were also at higher risk of death, more than half of whom (59%) died within 3 weeks of the case subject; the remainder died over a period of 1 to 69 years. Second and third degree relatives of case subjects were also at significantly higher risk of death from influenza, and this relative risk held when data for case-relative pairs were compared with similarly matching control-pairs. While the bulk of the deaths occurred from 1918-1921, around the Influenza pandemic, only a minority of deaths in third degree relatives occurred within the same-time frame as case subjects; most were at least 1 year apart. Even when deaths during the 1918 pandemic were ignored, a familial predisposition for mortality from influenza was significant.

The close temporal association of mortality in the majority of spouses confirms a shared risk, such as virus strain or environmental factors. This makes sense, and no doubt contributes to some of the increased risk in close family members and, perhaps, even more distant relatives, who may have lived in close proximity to the case subject or who were exposed to the same strain of virus. But these data point to an added risk for family members, including second and third degree relatives, beyond that anticipated for the strain type, location, or environmental factors.

Genetic factors may play a contributing role in mortality from influenza. Similarly, observations of clusters of H5N1 infection reveal that many infections occurred within families, suggesting a predisposition to infection from avian influenza. For general practitioners, this data lends support to targeted vaccination of family members when one has the flu.

HealthDay Reporter, Jan. 14, 2008: Is Columbus to Blame for Syphilis?

Perhaps the Genovese, Portugese, or Spaniards will not be so quick to claim Christopher Columbus as their own, once they read this article in the January 15, 2008 issue of the Public Library of Science Neglected Tropical Diseases (I was not aware that syphilis was a neglected disease, at least not in San Francisco, until this article caught my eye).

The origins of classical sexually-transmitted syphilis, which is first believed to have appeared in Europe around 1495, just a few years after Columbus returned from the "New World," have long been debated. T. pallidum in South America causes yaws, is transmitted by close (but not necessarily) sexual contact, and results in chronic skin lesions with progression to adjacent bone and joints — an entirely different disease from syphilis. Whether environmental factors prompted this shift is not clear, but it has been surmised that a genetic shift in the organism occurred once Europeans acquired the infection.

In an attempt to piece together the evolutionary origins of syphilis, researchers examined 21 genetic regions of T. pallidum collected from 26 different locations throughout the world. Syphilis strains identified in Europe were the most recent to appear on the evolutionary scale, and were closely related to strains causing yaws in South America; however, the data pointed to an initial African origin for T. pallidum, which implies that syphilis was transported to the South America centuries earlier, where it evolved into yaws, and then later moved back across the ocean to Europe (read "Who gave pinta to the Santa Maria", by Robert Desowitz). Studies of skeletons lend further support to this theory.