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.

California Influenza Strain Given the Boot

ProMED-mail March 3, 2006; promed@promedmail.org

The California Influenza Strain (A/California/07/2004 [H3N2]), first isolated in our own backyard in Santa Clara County, included in the 2005-2006 trivalent influenza vaccine, has been given the boot! Instead, the United States Advisory Committee on Immunization Practices has chosen a Wisconsin strain of Influenza A (A/Wisconsin/67/2005 [H3N2]) for next year’s vaccine. Although many virus strains found circulating this year were related to A/California, there was an increasing prevalence of infections due to strains related to A/Wisconsin.

In addition, the Influenza B Shanghai strain is being replaced by a Malaysian strain of Influenza B (B/Malyasia/2506/2004), which is antigenically equivalent to an Ohio strain found in the United States. The third component of the vaccine will remain A/Caledonia/20/99 [H1N1]. Experts caution that the inclusion of 2 new strains of virus may create problems with vaccine production this year, as manufacturers have to create whole new batches of virus, with a bit less predictability in production. In the past 3 years, only one new strain of virus was introduced into vaccine production.

Global flu activity remains low this year, compared with recent years, with only scattered hot spots of greater flu activity in Europe.

HBV, DNA, and Hepatocellular Carcinoma

Chen CJ, et al. Risk of Hepatocellular Carcinoma Across a Biological Gradient of Serum Hepatitis B Virus DNA Level. JAMA. 2006;295:65-73.

More than 350 million people in the world are infected with HBV, many of whom were perinatally infected or infected at a young age. These individuals are at significant risk for hepatitic cirrhosis, liver failure, and hepatocellular carcinoma. Earlier studies have confirmed that risk factors for developing hepatocellular carcinoma include male gender, older age, duration of infection, cigarette smoking, alcohol consumption, elevated transaminases, cirrhosis, and evidence of HBe antigen.

Now, Chen and colleagues have found a statistically significant relationship between higher levels of circulating HBV DNA and the development of hepatocellular carcinoma. Beginning in 1991, nearly 24,000 individuals in Taiwan agrees to participate in a prospective national cancer screening program. A total of 3563 individuals, aged 30-65 years, who were seropositive for Hepatitis Bs Ag and seronegative for HCV were included in this study. Of these, 15% were seropositive for HBe antigen, 6% had elevated serum ALT levels, and only 2% had cirrhosis at entry to study. About one-fourth had undetectable levels of plasma HBV DNA < 300 copies/mL, 32% less than 10,000 copies, and 17% had > 1 million copies.

During a mean follow-up of 11.4 years, there were 164 cases of hepatocellular carcinoma and 346 deaths. After adjusting for other risk factors, higher levels of HBV DNA were associated with a higher incidence of hepatocellular carcinoma, in a dose-response relationship. The cumulative incidence of hepatocellular carcinoma ranged from 1.3% in patients with undetectable levels of HBV DNA to 14.9% for those with > 1 million copies (P < .001). This relationship was strongest in those who were HBe Ag seronegative with normal liver function studies at entry to study.

Persistently high levels of circulating HBV DNA throughout the study were also associated with a greater risk of hepatocellular carcinoma. While fluctuations in HBV DNA occurred throughout the study, in part from intercurrent treatment, some patients spontaneously became HBe antigen seronegative. Follow-up serum samples collected a mean of 10 years later found that 42% of those who were initially HBe antigen seropositive were seronegative at the last sample available for testing. This group was less likely to have higher HBV viral loads > 100,000 than who remained positive for HBe Ag (55% vs 95%). Those with sustained high-level viremia and persistence of HBe Ag remained at the greatest risk for hepatocellular carcinoma. Nonetheless, even in those with loss of HBe antigen over time, sustained high-level viremia remained a strong predictor of hepatocellular carcinoma risk.

Based on the consistency of the dose-response relationship between HBV DNA levels and hepatocellular risk, Chen et al advocate for regular monitoring of HBV DNA levels, even in those patients previously perceived to be at lower risk (HBe Ag seronegative, normal liver function studies and no evidence of cirrhosis). This data suggests the importance of close follow-up, routine radiographic screening and screening of alpha fetoprotein levels, and antiviral treatment, even in those patients who are HBe antigen seronegative with HBV DNA levels > 10,000.

Disappearance of Rheumatic Fever in the United States?

Shulman ST, et al. Temporal Changes in Streptococcal M Protein Types and the Near-Disappearance of Acute Rheumatic Fever in the United States. Clin Infect Dis. 2006;42:441-447.

In the past year, I have seen 2 young Asian-Indian women, both in their late 20s and with small children, with acute rheumatic fever and polyarthritis. One gave a history of acute rheumatic fever (ARF) at age 11 in India, treated with prophylactic procaine penicillin injections for 5 years. One gave a history of an ARF-like illness at age 7 in India, never diagnosed as such at the time. Both had evidence of pre-existing rheumatic heart disease on echocardiogram. Both were evaluated by a number of different physicians for "fever of unknown origin" (one for about one month, and one for 4 days in hospital) before a diagnosis of ARF was made.

These 2 cases are probably the first and only cases of ARF I’ve seen in 18 years as an Infectious Disease physician. None of the other physicians involved in the care of these young women recalled ever having seen a case. It is interesting that both were essentially imported cases, although they had obviously been re-infected here in the United States.

Others have also observed the near-disappearance of ARF in the United States over the past ~30-40 years, postulating that better access to medical care, more rapid and effective diagnostic techniques and treatment of acute streptococcal pharyngitis, and less crowded living conditions may play a role. In addition, recent data suggests a diminished prevalence of M types of Group A streptococcus (GAS), which have higher toxin and M protein content, larger capsules (increased mucoidity), and are believed to be more rheumatogenic.

Shulman and colleagues examined the prevalence of rheumatogenic and non-rheumatogenic GAS types over the past ~40 years. While almost half (49.7%) of the 468 isolates collected from children with acute pharyngitis in 1961-1968 were rheumatogenic types, only 10.6% of 450 isolates obtained from children in Chicago and about 18% of 3969 isolates collected nationwide from 2000-2004 were rheumatogenic. During this interval, there was a virtual disappearance of enm strains, which encode for the M protein. At the same time, there was an increase in those strains believed to be non-rheumatogenic, which accounted for about 5% of cases of pharyngitis in earlier years, but about 28% of cases in 2000-2004.

Interestingly, the prevalence of M1 strains did not significantly change over time. This heterogeneous group of GAS are generally considered more likely to cause invasive disease, glomerulonephritis and acute renal failure, and toxic shock. This serotype was the most common M type found in Shulman’s data in the 1960s and in the 2000s, and includes rheumatogenic strains. However, data suggests there may be genotypic shift occurring in these strains, with more of the current M1 strains producing an M protein different from classical, older rheumatogenic M1 strains.

This data is especially timely, with the recent completion of 2 Phase 1 trails of GAS vaccines. These 6-valent and 26-valent vaccines are based on M proteins, appear to be immunogenic and, unlike earlier attempts at vaccine development, do not appear to cross-react with human tissue proteins. About 90% of the recognized rheumatogenic types are included in the 26-valent vaccine, making it potentially an ideal candidate for clinical trails in developing countries endemic for ARF. However, vaccine development is still hampered by differing strain prevalences in different countries.

Hepatitis A in Travelers

Mutsch M, et al. Hepatitis A Virus Infections in Travelers, 1988-2004. Clin Infect Dis. 2006;42:490-497.

Mutsch and colleagues tracked cases of Hepatitis A in Switzerland from 1988 to 2004, observing a significant reduction in cases of HAV infection over time, most likely from effective HAV vaccination of travelers. And yet, travel remains the biggest single risk for HAV infection. Recent travel accounted for nearly half (42%) of all HAV infections; 82% of these reported visiting friends or relatives. Risk factors for HAV infection with a travel history included younger age, foreign nationality, and exposure to a sick contact or contaminated food. The incidence of HAV infection in visitors to specific countries, in descending order, was Turkey, Kenya, India, Egypt, Brazil and Mexico. Mutsch and colleagues concluded that unvaccinated children of foreign born immigrants returning with their kids to visit friends and family in their country of birth are at the greatest risk for HAV infection. Special attention is required to reach these parents, who may perceive that the risk of travel to their home country is low, for pre-travel advice and appropriate vaccination of their non-immune children.