Infectious Diseases: January 15, 2005

Influenza, Pneumonia, and Other Respiratory Infections

Hoft DF, Belshe RB. The genetic archaeology of influenza. N Engl J Med. 2004;351:2550-2551. This is a report in the "Clinical Implications of Basic Research" section of The New England Journal of Medicine in which the study authors summarize the implications of a recent report by Kobasa and coworkers,^[1] showing that the hemagglutinin antigen of the 1918-1919 strain of influenza ("Spanish flu") is an important determinant of virulence. The study used reverse genetics to synthesize the hemagglutinin and neuraminidase genes from the 1918-1919 influenza strain. In the mouse model, wild-type influenza strains cause infection limited to the bronchioli, but strains containing the hemagglutinin antigen from the 1918-1919 strain caused widespread pulmonary infection with massive increases in inflammatory cytokines, resulting in severe hemorrhage that resembled the pathologic found in human infections in the 1918-1919 pandemic. The report also indicated that persons born after 1920 lack an antibody against this hemagglutinin. Important messages from this report include the following:

The identification of this virulence motif could be used to detect the emergence of new virulent strains of influenza. The identification of this antigen could lead to vaccines that would be protective. The pathophysiological events show massive inflammation induced by chemokine and cytokine responses that indicate that immune response is largely responsible for the pathological events. Of interest is the observation that the highest death rates in the 1918-1919 pandemic were associated with young and middle-aged adults. By contrast, most deaths in influenza epidemics in the current era are restricted to the elderly or even the "elderly, elderly." The pathogenic mechanism described would explain this profound difference. The demonstration of a persistent antibody to the hemagglutinin from the 1918-1919 strain in persons born before 1920 indicates that influenza-specific memory can persist for 80 years.

Tweed SA, Skowronski DM, David ST, et al. Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis. 2004;10:2196. There was an outbreak of avian influenza on a farm in British Columbia, Canada, that began on February 6, 2004 and resulted in a modest increase in deaths among chickens, initially in 1 barn, but then to a much wider area. The result was the requirement of the Canadian Food Inspection Agency to cull all chickens in the region, a total of 19 million birds. The implicated strain was avian influenza A (H7N2). This report concerns the risk of human infection associated with this outbreak that included approximately 2000 poultry farm workers and 650 federal workers who assisted the outbreak management. Those involved in culling used N95 masks, gloves, goggles, biosafety suits, and footwear; prophylactic oseltamivir was given for the duration of exposure plus 7 days. Infection was defined by the typical symptoms of conjunctivitis and influenza-like symptoms among federal workers, farm workers, and their household contacts. Cases were confirmed by respiratory specimens showing the H7 subtype of influenza by polymerase chain reaction (PCR) or culture. There were 2 confirmed cases, both with conjunctival contact due to inadequate eyewear. Neither were taking oseltamivir prophylaxis. Both had conjunctivitis; both were treated with oseltamivir; and both had complete resolution. There was no serologic response to influenza A H7. The study authors conclude that these are the first reported cases of human infection with avian influenza A (H7N3).

Comment: This form of avian influenza must be distinguished from the H5N1 strain reported from Vietnam and Thailand. The H7N3 strain reported appears to be quite similar to the A (H7N7) strain reported from The Netherlands, which was associated with conjunctivitis and a relatively mild influenza-like illness.^[2] The study authors warn that the reduced virulence of this strain does not detract from its pandemic potential.

Garbino J, Gerbase MW, Wunderli W, et al. Lower respiratory viral illnesses: improved diagnosis by molecular methods and clinical impact. Am J Respir Crit Care Med. 2004;170:1197-1203. This report from Geneva, Switzerland, summarizes a retrospective analysis of the yield of respiratory viruses and atypical bacteria in bronchoaveolar lavage (BAL) specimens. There were 2 groups: Group 1 (n = 117) had BAL specimens obtained from patients with clinical evidence of a respiratory infection, whereas group 2 (n = 31) had BAL specimens for other indications. The major diagnostic test was reverse transcription (RT)-PCR, which was used to detect 11 different viruses and the 3 atypical bacteria. The results showed positive results in 39 (33%) of the 117 specimens from patients in group 1 and 2 (6%) from the 31 specimens from group 2. The major reason for BAL was suspected pulmonary infection in patients with immunosuppressive therapy (58%) and organ transplantation recipients (51%). The major viral pathogens recovered were rhinovirus and respiratory syncytial virus (RSV). The only atypical bacterium found was Mycobacterium pneumoniae in 6 cases. These results are summarized in Table 1 .

The study authors conclude that respiratory viruses are frequent causes of morbidity, especially in lung transplant recipients. The relevance of this observation is the potential role of pleconaril or protease inhibitors, which may be developed for a role in these infections.

Comment: The accompanying editorial by Steven Greenberg^[3] notes that RT-PCR has identified respiratory viruses at a rate of 3- to 4-fold higher than conventional cell culture and standard serology. As with prior studies, a group at particular risk is lung transplant recipients; these viruses are also important in asthma and exacerbations of chronic obstructive pulmonary disease. They account for about half of all hospitalized patients with acute exacerbation of chronic bronchitis.^[4] He also notes that the only vaccine available for these agents is the influenza vaccine, and the only approved antivirals are for influenza and ribavirin for RSV.

Jackson ML, Neuzil KM, Thompson WW, et al. The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis. 2004;39:1642-1650. This report involves patients from the Group Health Cooperative in Seattle, Washington. The goal was to assess the burden of community-acquired pneumonia (CAP) in 46,237 persons ≥ 65 years old enrolled in this health maintenance organization (HMO) from 1998 through 2001. The analysis determined the rate of pneumonia with standard definitions and analyzed several variables in their database. During the study period, there were over 122,000 person-years of observation. There were approximately 2400 hospitalizations for CAP and 3100 outpatient encounters for presumptive pneumonia. Charts were available for 97% and the diagnosis was confirmed in 60% to 70%. The rate was dependent to a large extent on age: It was 18.2 cases per 1000 person-years for enrollees who were 65-69 years old and 52.3 cases per 1000 person-years for those over 85 years. In total, approximately 60% of all pneumonia cases were managed on an outpatient basis. Risk factors associated with CAP are shown in Table 2 .

The study authors conclude that there are approximately 915,900 cases of CAP among persons over the age of 65 in the United States, and that approximately 5% of persons over 85 years have a new episode of CAP each year.

Panpanich R, Lerttrakarnnon P, Laopaiboon M. Azithromycin for acute lower respiratory tract infections. Cochrane Database Syst Rev. 2004;(4):CD001954. This is an updated Cochrane Review to determine the relative effectiveness of azithromycin compared with amoxicillin or amoxicillin-clavulanic acid in the treatment of lower respiratory tract infections. The review included 14 trials with 2521 patients. The pooled analysis showed no significant difference between the 2 groups (relative risk [RR] = .96) in terms of the rate of failure at day 10-14 and no difference in the rates of microbial pathogen eradication (RR = .98). However, there was a reduction in adverse events associated with azithromycin treatment (RR = .75). The study authors conclude that "there is unclear evidence that azithromycin is superior to amoxicillin or amoxicillin/clavulanate in treating lower respiratory tract infections."

Lee GM, Lett S, Schauer S, et al; Massachusetts Pertussis Study Group. Societal costs and morbidity of pertussis in adolescents and adults. Clin Infect Dis. 2004;39:1572-1580. This is a report from the "Massachusetts Pertussis Study Group" that analyzed the medical costs of pertussis detected through the enhanced pertussis surveillance system of the Massachusetts Department of Public Health for the 3-year period of 1998-2000. For this analysis, a confirmed case of pertussis was defined as a person with (1) an acute cough illness with a positive culture for Bordetella pertussis or (2) a cough lasting at least 2 weeks with at least 1 of the following symptoms: paroxysm, whoop, or post-tussive vomiting plus laboratory confirmation by serology or PCR. The analysis included 1679 adolescents and 936 adults. The method of establishing the diagnosis in these cases was by culture in 15%, serologic analysis in 83%, and epidemiologic linkage in 2%. The following observations seem important:

Massachusetts has 2% of the entire population but 23% of reported cases of pertussis during this period. This indicates the level of underreporting. Interviews were conducted in a subset of pertussis patients. At the time of interview (41 and 48 days after the onset of cough for adolescents and adults, respectively), 79% of adolescents and 83% of adults were still coughing. At about 100 days, 38% of adolescents and 61% of adults were still coughing. The numbers of patients requiring hospitalization were 13 of 1679 (.8%) of adolescents and 27 of 936 (3%) of adults. The mean medical cost for adolescents was $242 and for adults was $326; nonmedical costs based on interviews averaged $447 for adults and $155 for adolescents.

The study authors conclude that there are significant morbidity and costs associated with pertussis, and the major morbidity and costs were related to the prolonged duration of the cough.

Comment: The editorial comment on the prior 2 reviews was from Colin Marchant^[5] in the commentary entitled "The 100-Day Cough: The Time for Prevention Has Arrived." It is noted that 2 populations remain largely unprotected from pertussis despite routine use of whole-cell pertussis vaccines that were introduced for routine use in the 1950s: infants in the first 6 months of life who have not received the first of 3 doses of acellular vaccine and adults and adolescents whose immunity has decreased. He emphasizes the extraordinary duration of symptoms associated with pertussis on the basis of the preceding report, in which one third of adolescents and one half of adults had a persistent cough lasting 100 days. This was frequently associated with difficulties sleeping, weight loss, and lost time from work and school. The potential benefit of universal immunization would be based in part on the opportunity to prevent this prolonged illness and to indirectly protect infants. In the latter case, it is noted that routine use of pneumococcal conjugate vaccine in infants has reduced the frequency of invasive pneumococcal disease in adults.^[6] The goal here would be to protect infants by immunization of adults because the mother is the usual source of disease in infants.^[7]

Medscape Infectious Diseases. 2005;7(1) © 2005  Medscape

Cite this: Infectious Diseases: January 15, 2005 - Medscape - Jan 27, 2005.