Correspondence

Self-Administration of Salmonella Endotoxin

N Engl J Med 1993; 329:1426-1427November 4, 1993

Article

To the Editor:

The report (May 20 issue)1 of a middle-aged laboratory worker who self-administered a large dose of endotoxin, leading to the development of the septic shock syndrome, raises questions about the patient's subsequent care. The case report makes no mention of whether a psychiatric consultation was obtained before the patient was discharged or whether outpatient psychiatric care was arranged. In this patient, possible suicidal intent should be considered.

People with autogenic illnesses often work, as this patient apparently did, in medical or laboratory surroundings. In a series of 32 cases of factitious fever and self-induced infection,2 the patients included 9 nurses, medical technicians, a graduate student in microbiology, a Navy corpsman, and a pharmacist. Ten of the 32 patients had a borderline personality disorder; the other 22 had a heterogeneous spectrum of psychiatric diagnoses. A few, like the patient described in the article by Taveira da Silva et al.,1 had organic illnesses. Was this the patient's first and only instance of self-induced disease, or was autogenic illness a recurrent, longstanding problem?

Robert Stern, M.D., Ph.D.
Yale University School of Medicine, New Haven, CT 06510

2 References

1. 1

   Taveira da Silva AM, Kaulbach HC, Chuidian FS, Lambert DR, Suffredini AF, Danner RL. Shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. N Engl J Med 1993;328:1457-1460
   Full Text | Web of Science | Medline

2. 2

   Aduan RP, Fauci AS, Dale DC, Herzberg JH, Wolff SM. Factitious fever and self-induced infection -- a report of 32 cases and review of the literature. Ann Intern Med 1979;90:230-242
   Web of Science | Medline

To the Editor:

I suggest that the observations of Taveira da Silva et al. cast further doubt on the role of endotoxin in the sepsis syndrome1.

The patient's elevated pulmonary-capillary wedge pressure 12 hours after the endotoxin injection and the rapid therapeutic response, with a decrease in heart rate following the administration of furosemide after 44 hours, suggest that the pulmonary edema was more likely a consequence of the positive fluid balance of 15 liters than of a capillary leak.

The metabolic and coagulation abnormalities were surprisingly mild given the 1-mg dose of endotoxin administered and the levels of tumor necrosis factor (and endotoxin) that were measured. If each Escherichia coli cell is assumed to contain a total of 10^-14 g of endotoxin,2 the dose of endotoxin administered was equivalent to the total contained in 10¹¹ bacterial cells. This is 10 times the 100 percent lethal dose (10¹⁰ cells) of live E. coli bacteria in baboons3 -- a dose at which the mean time to death is eight hours.

I disagree with the conclusion that the successful outcome may have been due to the limited nature of the insult. The standard of care for neurosyphilis in the prepenicillin era4 was the infusion of endotoxin over a period of several days, with dose escalations reaching a level equal to that self-administered by the patient. After a period of adaptation, patients with neurosyphilis were said to tolerate the infusions so well that the treating physicians would administer viable malarial parasites as a second-line agent to produce fever.

James C. Hurley, M.B., B.S., Ph.D., F.R.A.C.P.
Children's Hospital and Medical Center, Seattle, WA 98105

4 References

1. 1

   Hurley JC. Reappraisal of the role of endotoxin in the sepsis syndrome. Lancet 1993;341:1133-1135
   CrossRef | Web of Science | Medline

2. 2

   Neidhardt FC. Chemical composition of Escherichia coli. In: Neidhardt FC, Ingraham JL, Low KB, Magasanik B, Schaechter M, Umbarger HE, eds. Escherichia coli and Salmonella typhimurium: cellular and molecular biology. Vol. 1. Washington, D.C.: American Society for Microbiology, 1987:3-6.
   

3. 3

   Wessels BC, Wells MT, Gaffin SL, Brock-Utne JG, Gathiram P, Hinshaw LB. Plasma endotoxin concentration in healthy primates and during E. coli-induced shock. Crit Care Med 1988;16:601-605
   CrossRef | Web of Science | Medline

4. 4

   Heyman A. The treatment of neurosyphilis by continuous infusion of typhoid vaccine. Venereal Disease Information 1945;51-7.
   

Author/Editor Response

The authors reply:

To the Editor: In response to Dr. Stern we wish to point out that details not germane to the effects of endotoxin were omitted from the case report at the patient's request. This was the patient's only instance of self-induced illness, and the patient did receive appropriate inpatient and outpatient care.

We disagree with Dr. Hurley's statement that this case casts “further doubt on the role of endotoxin in the sepsis syndrome.” Our patient had all the clinical manifestations of septic shock, confirming that endotoxin alone can initiate these events. The positive fluid balance of 15 liters was part of the resuscitation effort. Fluid loading to increase the pulmonary-capillary wedge pressure to 12 to 18 mm Hg and to optimize ventricular performance is standard in the treatment of septic shock1. The fluid requirement is in itself an indication of increased vascular permeability. Furthermore, as the shock syndrome resolves, the need for a small dose of furosemide after fluid resuscitation is not unusual.

Data on infusions of live bacteria in other species should not be extrapolated to this case. The toxicity of different preparations of endotoxin can vary widely. In addition, the median lethal doses of different bacterial strains can vary by several logs. We agree, however, that factors other than endotoxin may cause or affect the development of septic shock. Endotoxemia is not a necessary component of septic shock,2 and even in gram-negative infections, bacterial products other than endotoxin may be important contributors to toxicity3. Furthermore, it is not yet clear that therapies directed at endotoxemia itself will be of benefit in septic shock4. Once this syndrome has developed, neutralization of circulating endotoxin may not be useful, because tachyphylaxis to endotoxin (tolerance) may develop or ongoing toxicity may be due to tissue- or cell-associated endotoxin.

The treatment we used is not analogous to the treatment of neurosyphilis. That therapy employed killed bacteria preparations (not purified endotoxin), prolonged infusions (not bolus injections), and the gradual acclimation (over a period of several days) of the patients to material containing endotoxin. Tolerance to repeat challenges of endotoxin has been well described5. Dr. Hurley implies that our patient survived because endotoxin is safe in the dose administered. The patient presented to the hospital with a blood pressure of 42/20 mm Hg and required norepinephrine infusion for two days. It seems reasonable to conclude that without medical intervention, death was imminent.

Angelo M. Taveira da Silva, M.D., Ph.D.
Georgetown University Hospital, Washington, DC 20007

Anthony F. Suffredini, M.D.
Robert L. Danner, M.D.
National Institutes of Health, Bethesda, MD 20892

5 References

1. 1

   Root RK, Jacobs R. Septicemia and septic shock. In: Wilson JD, Braunwald E, Isselbacher KJ, et al., eds. Harrison's principles of internal medicine. 12th ed. Vol. 1. New York: McGraw-Hill, 1991:502-7.
   

2. 2

   Danner RL, Natanson C, Elin RJ, et al. Pseudomonas aeruginosa compared with Escherichia coli produces less endotoxemia but more cardiovascular dysfunction and mortality in a canine model of septic shock. Chest 1990;98:1480-1487
   CrossRef | Web of Science | Medline

3. 3

   Natanson C, Danner RL, Elin RJ, et al. Role of endotoxemia in cardiovascular dysfunction and mortality: Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J Clin Invest 1989;83:243-251
   CrossRef | Web of Science | Medline

4. 4

   Corriveau CC, Danner RL. Endotoxin as a therapeutic target in septic shock. Infect Agents Dis 1993;2:35-43
   Medline

5. 5

   Greisman SE, Hornick RB, Wagner HN Jr, Woodward WE, Woodward TE. The role of endotoxin during typhoid fever and tularemia in man. IV. The integrity of the endotoxin tolerance mechanisms during infection. J Clin Invest 1969;48:613-629
   CrossRef | Web of Science | Medline