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.

CDC Flu Update

CDC New Conference, February 8, 2008.

In a news conference February 8, 2008, officials from the CDC announced that preliminary data suggest there is a mismatch between circulating influenza virus in the United States this winter and this year's influenza vaccine. Curtis Allen and Joe Bresee, the Branch Chiefs for epidemiology, CDC Influenza Division, told reporters that 93% of circulating Influenza B virus, and up to 21% of circulating Influenza A virus, may not match the current vaccine. Thus far, 197 Influenza isolates have been characterized, including 53 Influenza A/H3N2, 101 Influenza A/H1N1, and 43 Influenza B virus. Forty of the 43 Influenza B virus cases (93%) are from a lineage distinct from the B/Malaysia-like component of the 2007-2008 vaccine, so the vaccine will provide no cross protection for Influenza B. The circulating Influenza A/H3N2 virus is predominately A/Brisbane/10/2007, which is anti-genically similar to the current A/Wisconsin component in this year's vaccine, so there should be some cross-protection provided by this year's vaccine.

The flu season started out slowly this year, but cases have begun to escalate fairly rapidly the last few weeks. Officials urged people to continue to receive this year's vaccine, despite the apparent mismatch of 2 of the 3 components, as it still provides good protection for the predominant circulating Influenza A strain, as well as some likely cross protection for the less common Influenza A strain.

Physicians are reminded to be on the alert for MRSA superinfection in patients with the flu; last year, 15 of 73 influenza-related deaths (21%) were the result of MRSA infection.

The 5th Human Malaria

Source: Cox-Singh J, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008;46:165-171.

Following the deaths of four previously healthy individuals in Malaysia, from what was initially believed to be Plasmodium malariae between 2004-2005, and an outbreak of symptomatic malaria secondary to Plasmodium knowlesi in a northwestern state of Borneo, Cox-Singh and colleagues set about to determine the incidence of P. knowlesi infection in humans from the Malaysia peninsula and Malay Bornea.

P. knowlesi is believed to be an "Old World" infection, predominately infecting certain primate species, although it is permissive to humans under certain environmental circumstances. The potential for human-to-human transmission exists, and gametocytes have been observed in human blood specimens. A limitation to more widespread human infection with this plasmodium species is its mosquito vector, Anopheles latus, which has a limited habitat in forested areas in parts of Borneo and the South Pacific. Human infection due to P. knowlesi has been identified in persons from China, Thailand, and Burma (although, as data suggest, the identification of this organism by microscopy may be frequently mistaken, as P. knowlesi morphologically resembles P. malariae). Unlike P. malariae, which takes a relatively benign course in humans, with low grade parasitemia, P. knowlesi multiplies rapidly and quickly leads to high level parasitemia, similar to P. falciparum.

Cox-Singh et al examined 960 blood spots collected and archived from unselected patients hospitalized with malaria throughout Malaysia between 2001-2006. DNA was extracted, and nested PCR speciation assays were compared with the results of microscopy. Routine microscopy had identified P. vivax in 45% of the these patients, P. malariae in 33%, P. falciparum in 23%, and P. ovale in 0.2%. In contrast, nested PCR demonstrated that 266 of the 960 (28%) subjects in Sarawak hospitals, 41 of 49 (84%) of cases in Sabah district, and all 5 cases from Pahang, Peninsular Malaysia were infected with P. knowlesi. In Sarawak, Malay Borneo, 5.5% of the cases were due to mixed infection with P. knowlesi and other plasmodium species. Only 4 cases were PCR+ for P. malariae. Of the 312 cases initially identified by microscopy as P. malariae in Sarawak, 228 were PCR+ for P. knowlesi; most of the rest were due to P. falciparum or P. vivax, suggesting that microscopic identification of these organisms is frequently flawed.

The four fatal cases presented with parasite loads ranging from 75,000 to 765,000/ml, with significant thrombocytopenia and hepatorenal dysfunction. The patients died within 2 hrs to 13 days of presentation. Only P. knowlesi DNA was detected from their blood samples.

These data conclusively demonstrate that P. knowlesi is not only responsible for human cases of malaria in Malay Borneo but is quite common, and may result in life threatening disease. Treatment of these cases should be prompt and aggressive, similar to that for P. falciparum.

More on XDR-TB: Did DOT do it?

Source: Pillay M, Sturm AW. Evolution of the extensively drug-resistant F15/LAM4/KZN strain of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa. Clin Infect Dis. 2007;45:1409-1414.

Experts estimate that fewer than 5% of MDR-TB isolates around the world are actually recognized, due to a dirth of laboratory capability and surveillance in many poorer countries. Few programs have the capacity to do even basic smears and cultures, let alone susceptibility testing to first line agents; testing to second line agents is limited to a handful of specialized laboratories, and testing for certain agents is difficult and non-standardized (capreomycin). As a result, experts are concerned that many cases of MDR- and XDR-TB are being missed, with the potential for public health disaster. Already more than 400 cases if XDR-TB have been recognized in South Africa, which are overwhelming health facilities caring for patients with TB. Attempts to contain the spread of this infection by forcibly isolating patients with drug-resistant disease failed miserably last year, when patients escaped a locked facility to return home to their families. It is suspected that many other XDR-TB cases remain undetected; other patients with HIV infection may die too quickly for their infection to be recognized.

A recent effort to screen for drug-resistant isolates in Botswana identified 100 cases of multidrug-resistant disease, and two cases of XDR-TB.

Because KwaZulu-Natal has been considered "ground zero" for many of the identified cases of XDR-TB, Pillay and Sturm examined resistance patterns of isolates from this area from 1994 to 2005. The majority of XDR-TB cases appear to be due to single strain of M. tuberculosis (F15/LAM4/KZN). This strain was detected as early as 1994, when it was responsible for a number of cases of MDR-TB. Over the years, resistance to additional agents was identified, and Pillay and Sturm tracked the evolution of resistance in this strain, with the step-wise occurrence of resistant to seven different drugs, beginning with isoniazid-ethambutol and isoniazid-rifampin-resistant strains, to the sequential addition of resistance to ethambutol, streptomycin, ethionamide, thiacetazone, capreomycin, kanamycin/amikacin, and finally fluoroquinolones. The first XDR-TB strain was recognized in 2001 in South Africa.

Sadly, Pillay and Sturm believe that the creation of this super-bug coincides with the initiation of directly-observed, therapy-based and directly-observed, therapy-plus-based programs in this part of the country. This strategy, though well-meaning, was intended to prevent the spread of drug-susceptible strains, as well as limit the occurrence of drug-resistant strains by ensuring adherence to therapy. It was hoped that those few patients who were non-compliant, or who did not complete their 6-month treatment course, would have insufficient exposure to drug to promote resistance. However, this strategy did not include drug susceptibility testing for second line agents; for strains exhibiting resistance to first line agents, patients were treated with empiric alternate agents, such as ethambutol and cycloserine, combined with pyrazinamide or kanamycin. As a result, patients were unwittingly treated with only one or two active agents.

Thus, MDR-resistant strains already present at low levels in 1994, began showing evidence of further resistance to ethambutol and ethionamide in 1997, kanamycin in 1999, and fluoroquinolones in 2000. Re-treatment strategies with the empiric addition of streptomycin to the standard 4-drug regimen in patients who had interrupted their therapy further cemented the evolution of resistance to the predominant XDR strain today, but also probably explains a divergence in XDR isolates now in circulation.

This evolution of drug resistance occurred at the same time more persons were infected with HIV, resulting in a greater number of susceptible and contagious individuals. There is also some data that the F15/LAM4/KZN strain may be more transmissible than other strains.

Not only does this report reinforce the idea of evolutionary imperative, but reinforces the dire public health need for laboratory support, trained personnel, and a better treatment plan in the global fight against drug-resistant TB. Given the eventuality that more of these isolates will make their way to the United States, if you suspect MDR or XDR-TB in persons from southern African or the former Soviet Republics, contact your local public health department. Newer molecular technologies, such as the Deakon PCR for INH/rifampin resistance, are available for use, and can quickly provide information direct from sputum specimens well before the results of culture are available.