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.

Influenza — 2007/2008

Source: MMWR June 29, 2007, www.cdc.gov

Guidelines for this year's influenza season are now available, with important recommendations to hospitals and clinics. The 2007/2008 trivalent vaccine contains A/Solomon Islands/ 3/2006 (H1N1-like), A/Wisconsin/ 67/2005 (H3N2-like), and B/Malaysia/ 2506/2004-like antigens. The A/Solomon Islands component, which a recent antigenic variant of the former A/Caledonia, is a new addition to the vaccine, while the other 2 antigens remain unchanged. While H1 viruses were more common during the peak season in February 2007, H3 viruses were more frequently identified later in the season in March through May. A few Influenza B viruses were also identified.

Vaccine coverage still falls below 50% for children, health care personnel, pregnant women, and adults with risk factors for influenza complications.

The target groups for vaccination have not changed. But the ACIP is re-emphasizing the following:

  • Administration of 2 doses of vaccine to all children aged 6 months to 8 years;
  • If children received only one dose in previous years, they should receive 2 doses this year. If they received two doses last year, then one dose this year is sufficient);
  • Any one who requests vaccine should receive it; in other words, any one wishing to reduce their risk of influenza, even if they do not fall into a risk category, is a candidate for vaccination;

In addition, the ACIP strongly recommends:

  • Health care facilities should offer immunization clinics throughout the flu season;
  • Health care facilities should consider the level of vaccination among health care workers a patient safety quality measure.
  • Health care facilities should implement policies such that health care workers refusing vaccination shall sign a declination.

Drug-induced Agranulocytosis

Source: Andersohn F et al. Systematic Review: Agranulocytosis induced by non-chemotherapy drugs. Ann Intern Med 2007;146:657-665.

One of my long-standing HIV-infected patients returned to clinic last week with a surprising laboratory test result: he had acutely developed neutropenia with a white blood count of 2.3 with 13% granulocytes (absolute neutrophil count, ~0.3 x 109 cells/L). A quick review of his drug list included wellbutrin and amitrypfiline (he was not receiving antiretrovirals), revealed only one new addition to his regimen: terbenafine. Further investigation revealed another surprising finding: terbenafine has been rarely associated with agranulocytosis. He had received this agent in the past for 3 months with no difficulty.

Agranulocytosis (neutropenia < 0.5 x 109 cells/L) from antimicrobials, or from other drugs in patients receiving antimicrobials, is an infrequent but critical finding, often requiring Infectious Disease consultation. Antimicrobials are frequently suspect, chief among them penicillins and some cephalosporins, although there is limited evidence to support causality for many agents. For example, in observational studies, trimethoprim-sulfamethoxazole is included in the top 5 single agents associated with an increased risk for acute agranulocytosis, although based on case reports, these authors found only level 2 evidence to support an association with this agent.

These authors conducted a systematic review of 980 reported cases of non-chemotherapy drug-induced agranulocytosis since 1966, including the likely agents, the duration of drug exposure, the duration of neutropenia, and mortality. A total of 125 agents were definitely or probably related to acute agranulocytosis. Based on reported cases, 36 drugs had level 1 evidence and 89 drugs had level 2 evidence they were responsible for causing the acute agranulocytosis. More than half the cases were definitely or probably due to 11 of the agents (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine).

The median duration of treatment was a little as 2 days for dipyrone to 60 days for levamisole, and was longer than one month for three-fourths of the suspect agents. The time between presentation and normalization of neutrophil count ranged from 4 to 24 days. Six percent of cases were fatal, although patients who received Gm-CSF or G-CSF had a 5% fatality rate, and the case fatality rate decreased after 1990 once these drugs were available. Patients with a nadir neutrophil counts <0.1 x 109 cells/L had a significantly higher rates of infection (59% vs 39%), sepsis (20% vs 6%), and mortality (10% vs 3%) than those with higher nadir counts. Fortunately, the median duration of neutropenia was fairly short for most agents, including beta-lactam agents (ranging from 4 to 8 days).

It behooves each of us to be able to identify antimicrobial and non-antimicrobial agents with potential for causing neutropenia. In this review, terbenafine was associated with 5 reported cases of acute agranulocytosis, and was listed as having only level 2 evidence for causality. Improved reporting of cases and suspect agents would greatly enhance our databank.

Isolation and Quarantine for TB: What Rights Do You Have?

Source: Parmet WE. Legal power and legal rights - isolation and quarantine in the case of drug-resistant tuberculosis. N Engl J Med 2007;357(5);433-435.

The recent case of the atlanta attorney with active pulmonary tuberculosis who re-entered the United States against the "recommendation" of the CDC (assisted by an incredibly naive border guard) raised all kinds of questions in the press and among laypersons about the legal authority of the states and the federal government to isolate or quarantine individuals. Heretofore many individuals were unaware of this authority, which some found imperative and reassuring, and others saw as a part of an emerging threat to civil liberties. Mr. Andrew Speaker's case struck at the heart of American society: when does the common good of the public outweigh the rights of the individual?

This interesting article highlights some of the history and issues regarding that authority, which I learned is not unfettered and subject to judicial oversight. Firstly, there is a difference between isolation of an individual who is known to be contagious, and quarantine of goods or individuals who may have been exposed to a contagious disease. While we isolate individuals with TB, patients potentially exposed to SARS, for example, are quarantined. Both may be done on a voluntary basis or, if necessary, forcibly. Both the states and federal government have the authority to compel either action, although generally the federal government's role is limited to goods or individuals entering the country or crossing state lines (as in Mr. Andrew Speaker's case).

Importantly, retained individuals have a right to a court review of their detention's legality. While the courts generally give deference to state authority in the isolation of patients with tuberculosis, the courts have stipulated a number of conditions, including that such individuals retain the right to counsel and to a hearing by an independent decision maker. Constitutional guarantees of equal protection and due process are protected. For example, in New York, 90% of patients isolated for tuberculosis in the 1990s were non-white and 60% were homeless, raising concerns that isolation practices were being unfairly applied — although those may the very groups most affected by MTb. However, the potential for discrimination reinforces the need for judicial oversight, at least to ensure public trust.

Some courts have held that the government must provide "clear and convincing" evidence of public health risk. Unfortunately, what has not been clarified is the duration of detention before a hearing is required, what probability of risk justifies isolation, how infectious a person must be to justify isolation, and what procedures are considered "legal" if mass quarantine is required (e.g., for avian influenza or SARS).

In addition, some courts have specified that the government is responsible for providing the least restrictive alternative for preventing a public health risk. Because states have argued that a failure to comply with directly observed therapy was the basis for forcible detection, the courts left open the possibility that compulsory isolation may not be constitutional in states that do not provide directly observed therapy. In Mr. Speaker's case, when contacted by the CDC in Italy and asked to voluntarily report to authorities in Rome, what was the obligation of the Federal Government to provide him safe passage home in order to consider him non-compliant? During the SARS outbreak in Toronto, the government largely relied on voluntary quarantine, but provided social support and compensation for quarantined persons, making voluntary quarantine more feasible.

Since 9-11, newer federal regulations, which are still being reviewed, have clarified and expanded the government's authority for compulsory detention for isolation or quarantine. This entails short-term detention of individuals for up to 3 business days without access to legal representation or a court hearing. Individuals subject to non-provisional quarantine would still retain the right to a hearing but no attorney would be provided and there would not be an independent decision maker. Furthermore, the CDC would be able to isolate individuals without first having to demonstrate a significant public health risk or provide a least restrictive alternative.

While this may make sense in certain circumstance, where insufficient data exists or is not yet available but a threat is believed by authorities to be considerable and legitimate, it nonetheless makes civil libertarians quite nervous. Without the necessary teeth to exercize their authority, how can we expect public health officials to respond when needed? e.g., try taking 100 people on a plane from Taiwan, landing in San Jose, to the closest hospital for evaluation, and eventual quarantine, because 2 people on board might have SARS (which, in reality, took months to confirm). How about when the appropriate laboratory tests don't even exist? I suspect that (at least) the U.S. public is unprepared for a disaster, naive to the complexities of infectious disease outbreaks (learned best from the movie "Outbreak" — just give me the antisera), and presume the government will oversee their safety without impinging on their individual rights.