Correspondence

An Outbreak of Primary Pneumonic Tularemia

N Engl J Med 2002; 346:1027-1029March 28, 2002

Article

To the Editor:

We disagree with Feldman et al. and Hornick (Nov. 29 issue)1,2 about establishing a diagnosis of primary pneumonic tularemia on the basis of clinical symptoms and a single high titer of anti–Francisella tularensis antibody alone, even during an outbreak of tularemia. A single high titer may reflect a previous infection with F. tularensis, either symptomatic or asymptomatic. High titers of both IgG and IgM antibodies, determined by agglutination assay or enzyme-linked immunosorbent assay, can persist for more than 10 years.3 Asymptomatic infection is not uncommon.4 Unlike the ulceroglandular form of tularemia, the pneumonic form has no clinical characteristics to distinguish it from pneumonia of other causes. Therefore, before F. tularensis is considered the cause of a pneumonic infection in a patient with a single high titer of antibody, other causes should be ruled out. Furthermore, contrary to what is stated in the editorial, a positive titer after one week of illness is more likely to denote a previous infection than a present infection, since antibodies often develop late in the course of tularemia.3

During a recent outbreak in Sweden, 26 patients with tularemia were seen in our department. All nine patients with paired serum samples initially had negative titers by agglutination assay, and six of those samples had been obtained more than a week after the onset of illness (on days 8, 10, 10, 10, 12, and 18).

Kristoffer Strålin, M.D.
Henrik Eliasson, M.D.
Erik Bäck, M.D., Ph.D.
Örebro University Hospital, 70185 Örebro, Sweden
kristoffer.stralin@orebroll.se

4 References

1. 1

   Feldman KA, Enscore RE, Lathrop SL, et al. An outbreak of primary pneumonic tularemia on Martha's Vineyard. N Engl J Med 2001;345:1601-1606
   Full Text | Web of Science | Medline

2. 2

   Hornick R. Tularemia revisited. N Engl J Med 2001;345:1637-1639
   Full Text | Web of Science | Medline

3. 3

   Tarnvik A. Nature of protective immunity to Francisella tularensis. Rev Infect Dis 1989;11:440-451
   CrossRef | Medline

4. 4

   Dahlstrand S, Ringertz O, Zetterberg B. Airborne tularemia in Sweden. Scand J Infect Dis 1971;3:7-16
   Medline

To the Editor:

In his editorial, Hornick suggests that fluoroquinolones be considered in the treatment of tularemia, although only a few patients have been reported to have been cured with these drugs. In an outbreak in 1997 and 1998, ciprofloxacin was used in 66 patients, with better results than with the usual therapeutic regimens. It was used as a second-line treatment after the failure of other treatments in 34 patients, 30 of whom were cured.1 Fluoroquinolones should probably be considered first-line treatment because they are effective, have fewer side effects than other drugs, and are easy to administer.

José-Luis Pérez-Castrillón, M.D.
Pablo Bachiller-Luque, M.D.
Francisco-Javier Mena-Martín, M.D.
University Hospital Río Hortega, 47010 Valladolid, Spain
castrv@terra.es

1 References

1. 1

   Perez-Castrillon JL, Bachiller-Luque P, Martin-Luquero M, Mena-Martin FJ, Herreros V. Tularemia epidemic in northwestern Spain: clinical description and therapeutic response. Clin Infect Dis 2001;33:573-576
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Strålin et al., in that a fourfold or greater change in the titer of anti–F. tularensis antibody is necessary to confirm a diagnosis of tularemia serologically. We also concur that in patients with suspected pneumonic tularemia, other causes of community-acquired pneumonia and atypical pneumonia must be considered. In our epidemiologic investigation, we used clinical findings supported by elevated serologic titers to identify cases; paired serum samples were sought for this purpose but not always obtained.

Of the 11 patients with primary pneumonic tularemia in the 2000 outbreak, 7 had at least a fourfold rise in the serum titer of anti–F. tularensis antibody, and 1 had a positive culture for F. tularensis. The three additional patients meeting our case definition of pneumonic tularemia had single titers of 1:1280, 1:256, and 1:128. Both patients with the more easily distinguished ulceroglandular form had single titers of 1:1024. Of the two patients with a typhoidal presentation, one (in whom the first sample was collected two months after the onset of illness) had a titer that decreased by a factor of eight; the other had a threefold increase, but it was not possible to obtain an additional serum sample.

Any nondifferential misclassification, in which the case status of study participants is misclassified independently of their exposure status, results in bias toward the null. If the three patients with pneumonic tularemia who had single titers are reclassified as controls, the odds ratio associated with use of a lawn mower or brush cutter in the two weeks before illness is 13.1 (95 percent confidence interval, 1.5 to 612.1), as compared with the reported odds ratio of 9.2 (95 percent confidence interval, 1.6 to 68.0).

Our experiences with microagglutination titers agree with those of others. The patient with pneumonic tularemia who died in the summer of 2000 was seronegative 11 days after the onset of illness; tularemia was confirmed by isolation of F. tularensis. In 2001 we detected antibody in serum specimens from three patients from the 1978 outbreak on Martha's Vineyard1 (two with titers of 1:128 and one with a titer of 1:256); a fourth patient from the 1978 outbreak was seronegative.

Katherine A. Feldman, D.V.M., M.P.H.
David T. Dennis, M.D., M.P.H.
Edward B. Hayes, M.D.
Centers for Disease Control and Prevention, Fort Collins, CO 80522
kfeldman@cdc.gov

1 References

1. 1

   Teutsch SM, Martone WJ, Brink EW, et al. Pneumonic tularemia on Martha's Vineyard. N Engl J Med 1979;301:826-828
   Full Text | Web of Science | Medline

Author/Editor Response

The editorialist replies:

To the Editor: Strålin et al. question my statements regarding the elements used in diagnosing pneumonitis caused by F. tularensis. This form of tularemia is rare in the United States. Most patients are infected with the virulent type A organisms and are usually quite ill; appropriate, prompt administration of an antibiotic will prevent death and reduce the severity of illness. Making a diagnosis in these patients is difficult; in the editorial I cite a report of a fatal case that was not identified as tularemia disease.1 Obviously, culture of sputum, gastric, and throat specimens is the ideal method of making a diagnosis. This is a risk for laboratory workers unless they are notified about the possibility of F. tularensis in the specimens. Because it is a rare infection, few physicians request a culture for the organisms. Therefore, serologic studies are obtained, frequently after the patient has been ill for a week. If a serum sample is screened for antibodies to F. tularensis and the patient has a titer of 1:160, it would be prudent to treat the patient with an antibiotic known to be effective in the treatment of tularemia. The classic fourfold rise in antibody titer would confirm the diagnosis, even if no culture had been obtained.

Strålin and colleagues are correct in noting that few patients have a titer of 1:160 at one week. However, in an outbreak involving type A organisms, that titer would be considered diagnostic of tularemia, because few serologic surveys have been performed in areas where infection with the type A strain is endemic and in persons who have no history of tularemia. Patients who have had type A pneumonitis do have persistent agglutinating-antibody titers for several years and should be immune to reinfection, if they are immunocompetent.

Pérez-Castrillón et al. have reported the use of fluoroquinolones in the treatment of patients with tularemia. I was aware of their report and should have acknowledged their work. In their study, the less virulent form of F. tularensis was the causative microbe. Presumably, disease caused by type A organisms will be as responsive as the less virulent form. However, only a few patients with type A disease have been successfully treated.

Richard Hornick, M.D.
Orlando Regional Healthcare, Orlando, FL 32806
dickh@orhs.org

1 References

1. 1

   Tularemia -- Oklahoma, 2000. MMWR Morb Mortal Wkly Rep 2001;50:704-706
   Medline

Citing Articles (2)

Citing Articles

1. 1

   Henrik Eliasson, Tina Broman, Mats Forsman, Erik Bäck. (2006) Tularemia: Current Epidemiology and Disease Management. Infectious Disease Clinics of North America 20:2, 289-311
   CrossRef

2. 2

   Henrik Eliasson, Anders Sjöstedt, Erik Bäck. (2005) Clinical use of a diagnostic PCR for Francisella tularensis in patients with suspected ulceroglandular tularaemia. Scandinavian Journal of Infectious Diseases 37:11-12, 833-837
   CrossRef