- Email: [email protected]
Generalized Tetanus Despite Prior Vaccination and a Protective Level of Anti-Tetanus Antibodies
CASE REPORT
Generalized Tetanus Despite Prior Vaccination and a Protective Level of Anti-Tetanus Antibodies Daniel J. Livorsi, MD, Molly Eaton, MD and Jonathan Glass, MD
Abstract: Because of the success of widespread vaccination, tetanus rarely occurs in developed countries such as the United States. Vaccination, however, is not entirely protective even if patients develop an adequate antibody response. We discuss a case of generalized tetanus in an individual with both a history of prior vaccination and a measurable level of anti-tetanus antibodies at the time of presentation. We speculate that the patient’s preexisting antibodies may have moderated his course of illness. Key Indexing Terms: Generalized tetanus; Vaccination; Protective antibody. [Am J Med Sci 2010;339(2):200–201.]
B
ecause of successful immunization programs, tetanus has been nearly eradicated from developed countries. Sporadic cases, however, still occur: 19 cases were reported in the United States in 2008.1 Clinicians in developed countries are unfamiliar with tetanus, which could delay a diagnosis. Furthermore, some physicians may falsely believe that tetanus does not occur in a patient who has been vaccinated. A history of prior immunization should not dissuade a physician from making a diagnosis of tetanus. Even a protective level of anti-tetanus antibody cannot rule out the condition. Here, we describe a case of generalized tetanus that occurred in a patient who had been adequately vaccinated and whose serum demonstrated a protective level of anti-tetanus antibody.
CASE REPORT A 44-year-old man developed an itching sensation in his right calf 4 weeks before presentation. The itching sensation ascended to his right leg and began to involve his left leg as well. He later experienced muscle spasms in his right calf. These spasms were intensely painful, sudden in onset, and up to 10 minutes in duration. One week before presentation, these spasms started to occur more systemically, causing him to arch his back and hyperextend his neck. Even the slightest touch could provoke a spasm. He also developed trismus, dysphagia, and laryngospasms. One episode of jaw spasms resulted in a few broken teeth. He described a frequent, sudden need to urinate and diplopia in his left eye. He had had lost 20 pounds unintentionally since these symptoms began. The patient’s medical history was remarkable only for numerous shrapnel and gunshot wounds that he had endured during his years of military service. There was no family history of neuromuscular disease. He worked as a contractor and did a lot of repair work around his house. He had sustained
From the Departments of Infectious Disease (DJL, ME) and Neurology (JG), Emory University School of Medicine, Atlanta, Georgia. Submitted September 16, 2009; accepted in revised form September 18, 2009. Correspondence: Daniel J. Livorsi, MD, 108 Ponce de Leon Court, Decatur, GA 30030 (E-mail: [email protected]).
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many nail-related injuries over the past few years, including an accident 6 months ago when he drove a nail into his left ankle with a nail gun. He removed the nail with a crowbar and did not seek further medical care. He could not remember a more recent injury. On presentation, the patient had a temperature of 36°C, blood pressure 153/89 mm Hg, pulse 116 beats per minute, and 15 respirations per minute. The wound on his left ankle had healed. He had a left cranial nerve VI palsy, an exaggerated gag reflex, and a positive jaw jerk. He demonstrated normal strength and sensation in all limbs, but his muscle tone was increased. His patellar and ankle tendon reflexes were pathologically brisk. He exhibited bilateral Babinski signs. A complete blood count and a comprehensive metabolic panel, including his calcium level, were within normal limits. His creatinine kinase was elevated at 1446 units/L. Lumbar puncture revealed a protein level of 57 mg/dL in his cerebrospinal fluid, but there was no pleocytosis. Nerve conduction studies were normal except for the presence of afterpotentials following slow repetitive stimulation, suggesting peripheral nerve hyperexcitability. Needle electromyography studies were normal. The patient was diagnosed with generalized tetanus. He was admitted to the hospital and administered baclofen and benzodiazepines to control his muscle spasms. He was given 5000 units of the human tetanus immune globulin. Although there was no obvious wound site, he was also given a 7-day course of metronidazole. Supportive management was continued after discharge. At a 3-month follow-up visit, all of the above symptoms had resolved. Since the patient did give a history of tetanus vaccination 9 years prior, we checked his antibody level before administering the tetanus immunoglobulin. Using multianalyte fluorescent detection (ARUP Laboratories, Salt Lake City, UT),2 his level of tetanus antibody was found to be 2.78 IU/mL.
DISCUSSION Clostridium tetani is a gram-positive, anaerobic bacillus. Its terminal spores are ubiquitous in nature and can cause clinical disease when they gain access to damaged human tissue. After inoculation, the spore transforms into a bacterium and produces tetanus toxin, or tetanospasmin. The toxin binds to peripheral nerve endings and migrates to the central nervous system. The toxin prevents the release of inhibitory neurotransmitters, which results in a sustained excitatory discharge that produces tonic muscle contractions and intermittent spasms. Toxin binding is irreversible, and clinical recovery requires the growth of new axonal nerve endings. Generalized tetanus is the most common form of disease. Our patient experienced some of its classic findings, including trismus, opisthotonus, and dysphagia. He also experienced laryngospasms. His weight loss may be a manifestation of
The American Journal of the Medical Sciences • Volume 339, Number 2, February 2010
Generalized Tetanus Despite Protective Antibodies
autonomic hyperactivity, a common complication of the disease. Because intubation was never needed, his overall clinical course can be classified as mild. There is no test to confirm or exclude the diagnosis of tetanus. Other alternate diagnoses to consider include druginduced dystonia, malignant neuroleptic syndrome, stiff man syndrome, and strychnine poisoning. None of these entities, however, were consistent with our patient’s clinical course. At the time of presentation, our patient had no visible portal of entry for C. tetani spores. It seems unlikely that our patient’s nail injury 5 months before the onset of symptoms was the source of his tetanus. The incubation period is normally ⬍21 days. In very rare situations, incubation periods up to 3 months have been reported.3 Like our patient, as many as 16% to 25% of tetanus cases have no source identified.4 – 6 In many of these cases, a recent injury may have been too trivial to be remembered. Our patient had sustained several puncture wounds in the past and only rarely sought medical care. Our patient’s anti-tetanus antibody was well above the historically defined protective level of 0.01 IU/mL.7 His elevated antibody level could reflect either prior vaccination or immunostimulation from active tetanus. Active infection with tetanus has been shown to produce a considerable—though perhaps nonspecific—antibody response.8 Because our patient had received a tetanus booster within the past 10 years, we suspect that at least a portion of his antibody level reflects prior vaccination. There are 8 other reports of generalized tetanus despite protective levels of antibody in previously vaccinated individuals.9 –16 Cases of neonatal tetanus despite protective antibody levels have also been reported.17,18 These reports used various techniques for measuring tetanus antibody, including mouse neutralization assays, hemagglutination assays, and enzyme-linked immunosorbent assays. Most had an antibody level ⱕ1 IU/mL, but at least 3 cases had antibody levels as high or higher than our patient.12,17,18 In some cases, the clinical course was felt to be milder because of elevated levels of anti-tetanus antibody.9,10 Our patient’s milder course may also have been related to his high level of antibody. Milder disease in vaccinated individuals has been reported elsewhere. A large series from World War II showed a shorter duration of illness in soldiers with nonfatal tetanus who had been previously vaccinated.3 In cases of neonatal tetanus, the fatality rate for babies born to vaccinated mothers was lower than that for babies born to nonvaccinated mothers.19 The definition of a “protective” level of anti-tetanus antibody has been largely extrapolated from animal studies. Guinea pigs injected with tetanus toxin were protected from death when their antibody level was at least 0.01 IU/mL.20 In this same animal study, however, 13% of the guinea pigs still developed nonfatal clinical disease despite antibody levels as high as 0.5 IU/mL. Instead of an absolute protective level of antibody, the real level of protection is probably dependent on the immune status of the host and the quantity of tetanus toxin produced. Perhaps any given serum level of antibody could be overwhelmed by a sufficiently large quantity of toxin. Other authors have speculated that there may be some antigenic variability between the tetanus toxin and the tetanus toxoid.9 Such a phenomenon could also explain why clinical tetanus can still develop in vaccinated individuals.
© 2010 Lippincott Williams & Wilkins
Given the success of widespread tetanus vaccination, it would be premature to redefine the level of protective antibody. Nevertheless, the limitations of vaccination should be recognized. This case has illustrated that prior vaccination and protective antibody levels do not preclude tetanus. Physicians must instead rely on a patient’s clinical findings to confirm or refute the diagnosis. REFERENCES 1. Centers for Disease Control and Prevention. Notifiable disease/ deaths in selected cities weekly information. MMWR Morb Mortal Wkly Rep 2009;58:783. 2. Pickering JW, Martins TB, Schroder MC, et al. Comparison of a multiplex flow cytometric assay with enzyme-linked immunosorbent assay for quantitation of antibodies to tetanus, diphtheria, and Haemophilus influenzae type b. Clin Diag Lab Immunol 2002;9:872– 6. 3. Boyd JS. Tetanus in the African and European theatres of war. Lancet 1946;247:113–9. 4. Trujillo MJ, Castillo A, Espan˜a JV, et al. Tetanus in the adult: intensive care and management experience with 233 patients. Crit Care Med 1980;8:419 –23. 5. Edmondson RS, Flowers MW. Intensive care in tetanus: management, complications, and mortality in 100 cases. Br Med J 1979;1:1401– 4. 6. Patel JC, Mehta BC. Tetanus: study of 8,697 cases. Indian J Med Sci 1999;53:393– 401. 7. Scheibel I. The uses and results of active tetanus immunization. Bull World Health Organ 1955;13:381–94. 8. Yeni P, Carbon C, Tremolieres F, et al. Serum levels of antibody to toxoid during tetanus and after specific immunization of patients with tetanus. J Infect Dis 1982;145:278. 9. Berger SA, Cherubin CE, Nelson S, et al. Tetanus despite preexisting antitetanus antibody. JAMA 1978;240:769. 10. Passen EL, Andersen BR. Clinical tetanus despite a protective level of toxin-neutralizing antibody. JAMA 1986;255:1171–3. 11. Crone N, Reder AT. Severe tetanus in immunized patients with high anti-tetanus titers. Neurology 1992;42:761– 4. 12. Pryor T, Onarecker C, Coniglione T. Elevated antitoxin titers in a man with generalized tetanus. J Fam Pract 1997;44:299 –303. 13. Abrahamian FM, Pollack CV Jr, LoVecchio F, et al. Fatal tetanus in a drug abuser with “protective” antitetanus antibodies. J Emerg Med 2000;18:189 –93. 14. de La Chapelle A, Lavabre O, Pinsard M, et al. Tetanus in a renal transplant recipient exhibiting the presence of circulating antitetanus antibodies by ELISA. Biomed Pharmacother 2002;56:208 –10. 15. Beltran A, Go E, Haq M, et al. A case of clinical tetanus in a patient with protective antitetanus antibody level. South Med J 2007;100:83. 16. Goulon M, Girard O, Grosbuis S, et al. Antitetanus antibodies: assay before anatoxinotherapy in 64 tetanus patients. Nouv Presse Med 1972;1:3049 –50. 17. Maselle SY, Matre R, Mbise R, et al. Neonatal tetanus despite protective serum antitoxin concentration. FEMS Microbiol Immunol 1991;3:171–5. 18. de Moraes-Pinto MI, Oruamabo RS, Igbagiri FP, et al. Neonatal tetanus despite immunization and protective antitoxin antibody. J Infect Dis 1995;171:1076 –7. 19. Owa JA, Makinde OO. Neonatal tetanus in babies of women immunized with tetanus toxoid during pregnancy. Trop Doct 1990;20:156 –7. 20. Sneath P, Kerslake EG, Scruby F. Tetanus immunity: the resistance of guinea pigs to lethal spore doses induced by active and passive immunization. Am J Hyg 1937;25:464 –76.
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Generalized Tetanus Despite Prior Vaccination and a Protective Level of Anti-Tetanus Antibodies Daniel J. Livorsi, MD, Molly Eaton, MD and Jonathan Glass, MD
Abstract: Because of the success of widespread vaccination, tetanus rarely occurs in developed countries such as the United States. Vaccination, however, is not entirely protective even if patients develop an adequate antibody response. We discuss a case of generalized tetanus in an individual with both a history of prior vaccination and a measurable level of anti-tetanus antibodies at the time of presentation. We speculate that the patient’s preexisting antibodies may have moderated his course of illness. Key Indexing Terms: Generalized tetanus; Vaccination; Protective antibody. [Am J Med Sci 2010;339(2):200–201.]
B
ecause of successful immunization programs, tetanus has been nearly eradicated from developed countries. Sporadic cases, however, still occur: 19 cases were reported in the United States in 2008.1 Clinicians in developed countries are unfamiliar with tetanus, which could delay a diagnosis. Furthermore, some physicians may falsely believe that tetanus does not occur in a patient who has been vaccinated. A history of prior immunization should not dissuade a physician from making a diagnosis of tetanus. Even a protective level of anti-tetanus antibody cannot rule out the condition. Here, we describe a case of generalized tetanus that occurred in a patient who had been adequately vaccinated and whose serum demonstrated a protective level of anti-tetanus antibody.
CASE REPORT A 44-year-old man developed an itching sensation in his right calf 4 weeks before presentation. The itching sensation ascended to his right leg and began to involve his left leg as well. He later experienced muscle spasms in his right calf. These spasms were intensely painful, sudden in onset, and up to 10 minutes in duration. One week before presentation, these spasms started to occur more systemically, causing him to arch his back and hyperextend his neck. Even the slightest touch could provoke a spasm. He also developed trismus, dysphagia, and laryngospasms. One episode of jaw spasms resulted in a few broken teeth. He described a frequent, sudden need to urinate and diplopia in his left eye. He had had lost 20 pounds unintentionally since these symptoms began. The patient’s medical history was remarkable only for numerous shrapnel and gunshot wounds that he had endured during his years of military service. There was no family history of neuromuscular disease. He worked as a contractor and did a lot of repair work around his house. He had sustained
From the Departments of Infectious Disease (DJL, ME) and Neurology (JG), Emory University School of Medicine, Atlanta, Georgia. Submitted September 16, 2009; accepted in revised form September 18, 2009. Correspondence: Daniel J. Livorsi, MD, 108 Ponce de Leon Court, Decatur, GA 30030 (E-mail: [email protected]).
200
many nail-related injuries over the past few years, including an accident 6 months ago when he drove a nail into his left ankle with a nail gun. He removed the nail with a crowbar and did not seek further medical care. He could not remember a more recent injury. On presentation, the patient had a temperature of 36°C, blood pressure 153/89 mm Hg, pulse 116 beats per minute, and 15 respirations per minute. The wound on his left ankle had healed. He had a left cranial nerve VI palsy, an exaggerated gag reflex, and a positive jaw jerk. He demonstrated normal strength and sensation in all limbs, but his muscle tone was increased. His patellar and ankle tendon reflexes were pathologically brisk. He exhibited bilateral Babinski signs. A complete blood count and a comprehensive metabolic panel, including his calcium level, were within normal limits. His creatinine kinase was elevated at 1446 units/L. Lumbar puncture revealed a protein level of 57 mg/dL in his cerebrospinal fluid, but there was no pleocytosis. Nerve conduction studies were normal except for the presence of afterpotentials following slow repetitive stimulation, suggesting peripheral nerve hyperexcitability. Needle electromyography studies were normal. The patient was diagnosed with generalized tetanus. He was admitted to the hospital and administered baclofen and benzodiazepines to control his muscle spasms. He was given 5000 units of the human tetanus immune globulin. Although there was no obvious wound site, he was also given a 7-day course of metronidazole. Supportive management was continued after discharge. At a 3-month follow-up visit, all of the above symptoms had resolved. Since the patient did give a history of tetanus vaccination 9 years prior, we checked his antibody level before administering the tetanus immunoglobulin. Using multianalyte fluorescent detection (ARUP Laboratories, Salt Lake City, UT),2 his level of tetanus antibody was found to be 2.78 IU/mL.
DISCUSSION Clostridium tetani is a gram-positive, anaerobic bacillus. Its terminal spores are ubiquitous in nature and can cause clinical disease when they gain access to damaged human tissue. After inoculation, the spore transforms into a bacterium and produces tetanus toxin, or tetanospasmin. The toxin binds to peripheral nerve endings and migrates to the central nervous system. The toxin prevents the release of inhibitory neurotransmitters, which results in a sustained excitatory discharge that produces tonic muscle contractions and intermittent spasms. Toxin binding is irreversible, and clinical recovery requires the growth of new axonal nerve endings. Generalized tetanus is the most common form of disease. Our patient experienced some of its classic findings, including trismus, opisthotonus, and dysphagia. He also experienced laryngospasms. His weight loss may be a manifestation of
The American Journal of the Medical Sciences • Volume 339, Number 2, February 2010
Generalized Tetanus Despite Protective Antibodies
autonomic hyperactivity, a common complication of the disease. Because intubation was never needed, his overall clinical course can be classified as mild. There is no test to confirm or exclude the diagnosis of tetanus. Other alternate diagnoses to consider include druginduced dystonia, malignant neuroleptic syndrome, stiff man syndrome, and strychnine poisoning. None of these entities, however, were consistent with our patient’s clinical course. At the time of presentation, our patient had no visible portal of entry for C. tetani spores. It seems unlikely that our patient’s nail injury 5 months before the onset of symptoms was the source of his tetanus. The incubation period is normally ⬍21 days. In very rare situations, incubation periods up to 3 months have been reported.3 Like our patient, as many as 16% to 25% of tetanus cases have no source identified.4 – 6 In many of these cases, a recent injury may have been too trivial to be remembered. Our patient had sustained several puncture wounds in the past and only rarely sought medical care. Our patient’s anti-tetanus antibody was well above the historically defined protective level of 0.01 IU/mL.7 His elevated antibody level could reflect either prior vaccination or immunostimulation from active tetanus. Active infection with tetanus has been shown to produce a considerable—though perhaps nonspecific—antibody response.8 Because our patient had received a tetanus booster within the past 10 years, we suspect that at least a portion of his antibody level reflects prior vaccination. There are 8 other reports of generalized tetanus despite protective levels of antibody in previously vaccinated individuals.9 –16 Cases of neonatal tetanus despite protective antibody levels have also been reported.17,18 These reports used various techniques for measuring tetanus antibody, including mouse neutralization assays, hemagglutination assays, and enzyme-linked immunosorbent assays. Most had an antibody level ⱕ1 IU/mL, but at least 3 cases had antibody levels as high or higher than our patient.12,17,18 In some cases, the clinical course was felt to be milder because of elevated levels of anti-tetanus antibody.9,10 Our patient’s milder course may also have been related to his high level of antibody. Milder disease in vaccinated individuals has been reported elsewhere. A large series from World War II showed a shorter duration of illness in soldiers with nonfatal tetanus who had been previously vaccinated.3 In cases of neonatal tetanus, the fatality rate for babies born to vaccinated mothers was lower than that for babies born to nonvaccinated mothers.19 The definition of a “protective” level of anti-tetanus antibody has been largely extrapolated from animal studies. Guinea pigs injected with tetanus toxin were protected from death when their antibody level was at least 0.01 IU/mL.20 In this same animal study, however, 13% of the guinea pigs still developed nonfatal clinical disease despite antibody levels as high as 0.5 IU/mL. Instead of an absolute protective level of antibody, the real level of protection is probably dependent on the immune status of the host and the quantity of tetanus toxin produced. Perhaps any given serum level of antibody could be overwhelmed by a sufficiently large quantity of toxin. Other authors have speculated that there may be some antigenic variability between the tetanus toxin and the tetanus toxoid.9 Such a phenomenon could also explain why clinical tetanus can still develop in vaccinated individuals.
© 2010 Lippincott Williams & Wilkins
Given the success of widespread tetanus vaccination, it would be premature to redefine the level of protective antibody. Nevertheless, the limitations of vaccination should be recognized. This case has illustrated that prior vaccination and protective antibody levels do not preclude tetanus. Physicians must instead rely on a patient’s clinical findings to confirm or refute the diagnosis. REFERENCES 1. Centers for Disease Control and Prevention. Notifiable disease/ deaths in selected cities weekly information. MMWR Morb Mortal Wkly Rep 2009;58:783. 2. Pickering JW, Martins TB, Schroder MC, et al. Comparison of a multiplex flow cytometric assay with enzyme-linked immunosorbent assay for quantitation of antibodies to tetanus, diphtheria, and Haemophilus influenzae type b. Clin Diag Lab Immunol 2002;9:872– 6. 3. Boyd JS. Tetanus in the African and European theatres of war. Lancet 1946;247:113–9. 4. Trujillo MJ, Castillo A, Espan˜a JV, et al. Tetanus in the adult: intensive care and management experience with 233 patients. Crit Care Med 1980;8:419 –23. 5. Edmondson RS, Flowers MW. Intensive care in tetanus: management, complications, and mortality in 100 cases. Br Med J 1979;1:1401– 4. 6. Patel JC, Mehta BC. Tetanus: study of 8,697 cases. Indian J Med Sci 1999;53:393– 401. 7. Scheibel I. The uses and results of active tetanus immunization. Bull World Health Organ 1955;13:381–94. 8. Yeni P, Carbon C, Tremolieres F, et al. Serum levels of antibody to toxoid during tetanus and after specific immunization of patients with tetanus. J Infect Dis 1982;145:278. 9. Berger SA, Cherubin CE, Nelson S, et al. Tetanus despite preexisting antitetanus antibody. JAMA 1978;240:769. 10. Passen EL, Andersen BR. Clinical tetanus despite a protective level of toxin-neutralizing antibody. JAMA 1986;255:1171–3. 11. Crone N, Reder AT. Severe tetanus in immunized patients with high anti-tetanus titers. Neurology 1992;42:761– 4. 12. Pryor T, Onarecker C, Coniglione T. Elevated antitoxin titers in a man with generalized tetanus. J Fam Pract 1997;44:299 –303. 13. Abrahamian FM, Pollack CV Jr, LoVecchio F, et al. Fatal tetanus in a drug abuser with “protective” antitetanus antibodies. J Emerg Med 2000;18:189 –93. 14. de La Chapelle A, Lavabre O, Pinsard M, et al. Tetanus in a renal transplant recipient exhibiting the presence of circulating antitetanus antibodies by ELISA. Biomed Pharmacother 2002;56:208 –10. 15. Beltran A, Go E, Haq M, et al. A case of clinical tetanus in a patient with protective antitetanus antibody level. South Med J 2007;100:83. 16. Goulon M, Girard O, Grosbuis S, et al. Antitetanus antibodies: assay before anatoxinotherapy in 64 tetanus patients. Nouv Presse Med 1972;1:3049 –50. 17. Maselle SY, Matre R, Mbise R, et al. Neonatal tetanus despite protective serum antitoxin concentration. FEMS Microbiol Immunol 1991;3:171–5. 18. de Moraes-Pinto MI, Oruamabo RS, Igbagiri FP, et al. Neonatal tetanus despite immunization and protective antitoxin antibody. J Infect Dis 1995;171:1076 –7. 19. Owa JA, Makinde OO. Neonatal tetanus in babies of women immunized with tetanus toxoid during pregnancy. Trop Doct 1990;20:156 –7. 20. Sneath P, Kerslake EG, Scruby F. Tetanus immunity: the resistance of guinea pigs to lethal spore doses induced by active and passive immunization. Am J Hyg 1937;25:464 –76.
201