- Email: [email protected]
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague
Human Pathology (2005) 36, 850 – 853
www.elsevier.com/locate/humpath
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague Jeannette Guarner MDa,*, Wun-Ju Shieh MD, PhDa, May Chu PhDb, David C. Perlman MDc, Jacob Kool MD, PhDb, Kenneth L. Gage PhDb, Paul Ettestad DCM, MSd, Sherif R. Zaki MD, PhDa a
Infectious Diseases Pathology Activity, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA b Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA c Beth Israel Medical Center, New York, NY 10003-3314, USA d Office of Epidemiology, New Mexico Department of Health, Santa Fe, NM 87502, USA Received 4 February 2005; accepted 19 May 2005
Keywords: Yersinia pestis; Limb ischemia; Immunohistochemistry
Summary In November 2002, a couple from New Mexico traveled to New York where both had fever and unilateral inguinal adenopathy. The husband was in septic shock when he sought medical care and was admitted to an intensive care unit, where he developed ischemic necrosis of his feet which later required bilateral amputation. Yersinia pestis was grown from his blood. Immunohistochemical assays using anti– Y pestis antibodies demonstrated multiple bacteria and granular antigens in and around vessels of the ischemic amputation tissues obtained 20 days after initiation of antibiotics; however, no evidence of Y pestis was present in viable tissues. Immunohistochemical evidence of Y pestis inside vessels of gangrenous feet in this patient underscores the importance of adequate excision of necrotic or partially necrotic tissues because antibiotics cannot be effectively delivered to necrotic and poorly perfused tissues. D 2005 Elsevier Inc. All rights reserved.
1. Introduction Limb ischemia requiring amputation usually occurs in patients with diabetes mellitus in whom atherosclerosis and infections by antibiotic-resistant organisms are frequent [1,2]. Limb amputations occasionally are necessary in patients with septic shock in whom soft-tissue and bone
T Corresponding author. E-mail address: [email protected] (J. Guarner). 0046-8177/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2005.05.016
necrosis occur because of hypoperfusion in a background of disseminated intravascular coagulation (DIC) [3,4]. In children, the most frequent infectious agent associated with amputations due to septic shock is meningococcemia, followed by Pseudomonas aeruginosa sepsis, varicella, and malaria [3-5]. In adults, limb amputations associated with shock have been described after Rocky Mountain spotted fever infections [5,6]. In November 2002, a couple from Santa Fe, NM, traveled to New York City, NY, where they developed fever and inguinal lymphadenopathy [7]. When the couple
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague sought medical attention in New York, a diagnosis of naturally acquired bubonic plague was considered and later confirmed because the Yersinia pestis isolated from the husband’s blood was genotypically indistinguishable from Y pestis isolated from fleas and a dead wood rat, obtained in and around the couple’s property in New Mexico during routine surveillance by the health department in July and November 2002 [7]. By the time the couple sought medical care, the husband was in septic shock and was admitted to an intensive care unit (ICU), where he developed ischemic necrosis of both feet leading to bilateral foot amputation 20 days after admission. This report describes the pathological and immunohistochemical (IHC) findings of Y pestis–induced limb gangrene and
851
shows the importance of studying pathological specimens during public health investigations.
2. Case report A 53-year-old diabetic man had fever, fatigue, and painful unilateral inguinal swelling 2 days before seeking medical care. On physical examination, he had diaphoresis, rigors, and lower-extremity cyanosis. His temperature was 40.28C, blood pressure was 78/50 mm Hg, and he had a tender left inguinal adenopathy with overlying edema. His white blood cell count was 24 700/lL (normal, 4300-10 800) and his platelet count was 72/lL (normal, 130 000-400 000). Blood
Fig. 1 Photomicrographs of tissue from amputated feet showing ischemic necrosis by Y pestis. Coagulative necrosis of tissues is demonstrated by loss of nuclei in the epidermis (A) and muscle (B). Basophilic rod-like structures (circled) can be observed inside blood vessels of muscle and probably represent Y pestis (B). Intact Y pestis and yersinial granular antigens can be observed in thrombi (C), ischemic dermis (D and E), and muscle (F) (A and B, hematoxylin and eosin stain; C-F, IHC assay with polyclonal anti–Y pestis F1 antibody; original magnifications 50 [A], 157.5 [B], and 250 [C-F]).
852 cultures obtained before antibiotic treatment grew Y pestis, whereas those obtained after treatment showed no growth. Bronchoscopic secretions did not show evidence of Y pestis by using polymerase chain reaction. The patient was admitted to an ICU where he was treated for septic shock with vasopressors, activated protein C, and antibiotics (gentamicin, doxycycline, ciprofloxacin, and vancomycin). Twenty days after admission, the patient’s fever continued and his feet showed limb ischemia that required bilateral foot amputation. During his 6-week ICU stay, the patient required mechanical ventilation because of acute respiratory distress syndrome and hemodialysis because of acute renal failure. The patient eventually recovered and was discharged to a long-term care rehabilitation facility. Before the amputation, the feet looked pale and the tissues appeared nonviable; there were no areas of liquefaction or pus. Microscopically, widespread vascular thrombi were noted in the foot tissues, with consequent coagulative ischemia in the epidermis (Fig. 1A) and muscle (Fig. 1B); the tissue at the margins appeared viable. In nonviable tissue, basophilic rod-like structures were noted with hematoxylin and eosin stain (Fig. 1B), but gram-negative organisms were difficult to distinguish. Mixed gram-positive and gramnegative organisms were observed in the skin surface. Only formalin-fixed tissue was submitted to the Centers for Disease Control and Prevention (CDC) for examination precluding recovery of live bacteria. A previously described IHC assay for Y pestis was applied to ischemic and viable tissues [8]. Tissues were tested using a polyclonal anti-F1 Y pestis antibody (CDC, Fort Collins, Colo) and a monoclonal antibody against F1 of Y pestis (Naval Research Institute, Bethesda, Md). Negative controls included sequential slides incubated with normal rabbit serum or mouse ascitic fluid as primary antibody. In the ischemic tissues, multiple bacteria and granular antigens were observed. Intact bacteria were predominantly detected inside vessels, particularly if thrombi were present (Fig. 1C), whereas smallersized, granular staining antigens (corresponding to bacterial fragments) were more abundant and were seen in vessels and in the tissues surrounding these (Fig. 1D). The vessels containing the bacteria were mostly in the dermis (Fig. 1D and E) and in the muscle (Fig. 1C and F). No IHC evidence of Y pestis was found in the viable tissues.
3. Discussion We identified intact and fragmented Y pestis inside the vessels of an amputation specimen from a patient who had limb ischemia secondary to septic shock and DIC. This diabetic patient initially developed bubonic plague and then had septicemia, which seeded distal tissues with Y pestis; he presented to medical care in septic shock. In this patient, both hypoperfusion and diabetes contributed to ischemic necrosis of distal tissues. Hypoperfusion and concomitant DIC in septicemic plague may be important contributors to
J. Guarner et al. soft-tissue and bone necrosis, similar to the pathophysiology in patients with meningococcemia [3,4]. The presence of intact and fragmented Y pestis inside the blood vessels of ischemic tissues may also have contributed to hypoperfusion by releasing plasminogen activator and by forming local thrombi [9]. In addition, diabetes is an important risk factor for atherosclerosis and limb ischemia, and in diabetic patients, infections are frequent aggravating causes of morbidity [1,2]. Blood samples obtained from this patient after the administration of antibiotics were negative for Y pestis, implying that antibiotic treatment was rapidly effective in sterilizing circulating blood. However, Y pestis F1 antigens persisted in necrotic tissues for 20 days after antibiotic treatment. By promoting hypotension and DIC, Y pestis becomes trapped in hypoperfused tissues and can persist there by overcoming host defenses. In experiments, Y pestis has been shown to mount an impressive antiphagocytic activity via several proteins that dephosphorylate host cell adhesion molecules (YopH) and inactivate host cytoskeleton dynamics (YopP and YopJ) [10]. In addition, poor perfusion of antibiotics probably allowed for bacteria to persist in ischemic tissues. Although viability of bacteria cannot be established with the IHC assay, the persistence of Y pestis F1 indicates long-term stability of antigens that may have caused the continued fevers in our patient. Persistence of bacteria in gangrenous tissues after 5 to 7 weeks of treatment has been documented and, similar to our findings, underscores the importance of surgical excision of necrotic or partially necrotic tissues [5,6]. Septicemic plague can occur after either bubonic or pneumonic plague. In previous studies using IHC in human tissues, abundant intact Y pestis and bacterial fragments or granular antigens have been detected in blood vessels and the interstitium of organs, such as kidney and spleen [8]. In the feet of our patient, intact Y pestis was found primarily inside vessels with more abundant granular F1 antigen staining observed in vessels and in the tissue surrounding these vessels. The granular antigens observed with IHC assays represent intracellular and extracellular phagocytosed bacterial fragments present in areas of inflammation and necrotic debris. Granular antigens can be detected only by using IHC assays and have been identified even after antibiotic treatment in other bacterial infections, such as anthrax and leptospirosis [11-13]. These nonviable Y pestis bacterial fragments probably include a variety of bacterial substances, such as endotoxins. Y pestis endotoxin and shock-inducing inflammatory cytokines, such as tumor necrosis factor a and interferon c, contribute to the end stages of plague septic shock, which is similar to shock associated with other enterobacteriaceae [9,10]. During public health investigations, study of pathology specimens by using IHC has proven to be of great benefit. In the past, it has helped investigators discover new pathogens (Hantavirus in the United States), describe new manifestations of a well-known disease (cholecystitis due to
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague Leptospira), and confirm diagnosis in epidemiologically or clinically suspect cases (anthrax bioterorrist attack) [11-14]. The CDC advises that all clinicians, pathologists, and laboratorians be aware of the clinicopathologic features and the specimens required for diagnosis of diseases potentially caused by bioterrorism agents, including plague, so that public health measures are instituted to contain possible casualties [11,12,15]. In the case of plague, it is the pneumonic form that is most feared as a possible bioterrorism event, but as we learned from the anthrax bioterrorism attack of 2001, although the most feared form of anthrax is inhalational, cutaneous cases did occur and may be sentinel events [11,12]. Thus, being able to distinguish the different forms of plague (bubonic, primary pneumonic, septicemic, and secondary pneumonic) has important implications for public health and law enforcement investigations [8]. Travelers who acquire plague in an endemic area and become ill in a nonendemic location (peripatetic plague) frequently have fatal outcomes, misdiagnosis, and delays in treatment. The diagnosis of naturally acquired plague in the patient presented here and his spouse occurred promptly and excluded bioterrorism because a series of actions and collaborations ensued between public health and law enforcement agencies [7]. In summary, IHC assays can provide the diagnosis of plague in formalin-fixed tissues even after antibiotic treatment. Persistence of Y pestis and Y pestis antigens in ischemic tissues may contribute to disease morbidity and mortality through ongoing stimulation of cytokine cascades and may have therapeutic implications. Pathologists should be aware of the varied histopathologic manifestations of plague and the importance of obtaining adequate material for study.
References [1] Cruz CP, Eidt JF, Capps C, Kirtley L, Moursi MM. Major lower extremity amputations at a Veterans Affairs hospital. Am J Surg 2003; 186:449 - 54.
853
[2] Grimble SA, Magee TR, Galland RB. Methicillin resistant Staphylococcus aureus in patients undergoing major amputation. Eur J Vasc Endovasc Surg 2001;22:215 - 8. [3] Palacios J, Serafim Z, Leal MJ. Mutilations due to medical disorders in children. Pediatr Surg Int 2003;1:91 - 5. [4] Cremer R, Leclerc F, Jude B, Sadik A, Leteurtre S, Fourier C, et al. Are there specific haemostatic abnormalities in children surviving septic shock with purpura and having skin necrosis or limb ischaemia that need skin grafts or limb amputations? Eur J Pediatr 1999;158: 127 - 32. [5] Kirkland KB, Marcom PK, Sexton DJ, Dumler JS, Walker DH. Rocky Mountain spotted fever complicated by gangrene: report of six cases and review. Clin Infect Dis 1993;16:629 - 34. [6] Hove MG, Walker DH. Persistence of rickettsiae in the partially viable gangrenous margins of amputated extremities 5 to 7 weeks after onset of Rocky Mountain spotted fever. Arch Pathol Lab Med 1995;119: 429 - 31. [7] CDC. Imported plague—New York City, 2002. MMWR Morb Mortal Wkly Rep 2003;52:725 - 8. [8] Guarner J, Shieh WJ, Greer PW, Gabastou JM, Chu M, Hayes E, et al. Immunohistochemical detection of Yersinia pestis in formalin-fixed, paraffin-embedded tissue. Am J Clin Pathol 2002;117:205 - 9. [9] McGovern TW, Friedlander AM. Plague. In: Sidell FR, Takafuji ET, Franz DR, editors. Textbook of military medicine: medical aspects of chemical and biological warfare. Part 1: warefare, weaponry, and the casualty. Washington (DC)7 Office of the Surgeon General at TMM publications, Borden Institute, Walter Reed Army Medical Center; 1997. p. 479 - 502. [10] Cornelis GR. Molecular and cell biology aspects of plague. Proc Natl Acad Sci U S A 2000;97:8778 - 83. [11] Guarner J, Jernigan JA, Shieh WJ, Tatti K, Flannagan LM, Stephens DS, et al. Pathology and pathogenesis of bioterrorism-related inhalational anthrax. Am J Pathol 2003;163:701 - 9. [12] Shieh WJ, Guarner J, Paddock C, Greer P, Tatti K, Fischer M, et al. The critical role of pathology in the investigation of bioterrorismrelated cutaneous anthrax. Am J Pathol 2003;163:1901 - 10. [13] Guarner J, Shieh WJ, Morgan J, Bragg SL, Bajani MD, Tappero JW, et al. Leptospirosis mimicking acute cholecystitis among athletes participating in a triathlon. Hum Pathol 2001;32:750 - 2. [14] Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, et al. Hantavirus pulmonary syndrome, pathogenesis of an emerging infectious disease. Am J Pathol 1995;146:552 - 79. [15] Nolte KD, Hanzlick RL, Payne DC, Kroger AT, Oliver WR, Baker AM, et al. Medical examiners, coroners, and biologic terrorism: a guidebook for surveillance and case management. MMWR Recomm Rep 2004;53(Rr-8):1 - 36.
www.elsevier.com/locate/humpath
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague Jeannette Guarner MDa,*, Wun-Ju Shieh MD, PhDa, May Chu PhDb, David C. Perlman MDc, Jacob Kool MD, PhDb, Kenneth L. Gage PhDb, Paul Ettestad DCM, MSd, Sherif R. Zaki MD, PhDa a
Infectious Diseases Pathology Activity, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA b Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA c Beth Israel Medical Center, New York, NY 10003-3314, USA d Office of Epidemiology, New Mexico Department of Health, Santa Fe, NM 87502, USA Received 4 February 2005; accepted 19 May 2005
Keywords: Yersinia pestis; Limb ischemia; Immunohistochemistry
Summary In November 2002, a couple from New Mexico traveled to New York where both had fever and unilateral inguinal adenopathy. The husband was in septic shock when he sought medical care and was admitted to an intensive care unit, where he developed ischemic necrosis of his feet which later required bilateral amputation. Yersinia pestis was grown from his blood. Immunohistochemical assays using anti– Y pestis antibodies demonstrated multiple bacteria and granular antigens in and around vessels of the ischemic amputation tissues obtained 20 days after initiation of antibiotics; however, no evidence of Y pestis was present in viable tissues. Immunohistochemical evidence of Y pestis inside vessels of gangrenous feet in this patient underscores the importance of adequate excision of necrotic or partially necrotic tissues because antibiotics cannot be effectively delivered to necrotic and poorly perfused tissues. D 2005 Elsevier Inc. All rights reserved.
1. Introduction Limb ischemia requiring amputation usually occurs in patients with diabetes mellitus in whom atherosclerosis and infections by antibiotic-resistant organisms are frequent [1,2]. Limb amputations occasionally are necessary in patients with septic shock in whom soft-tissue and bone
T Corresponding author. E-mail address: [email protected] (J. Guarner). 0046-8177/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2005.05.016
necrosis occur because of hypoperfusion in a background of disseminated intravascular coagulation (DIC) [3,4]. In children, the most frequent infectious agent associated with amputations due to septic shock is meningococcemia, followed by Pseudomonas aeruginosa sepsis, varicella, and malaria [3-5]. In adults, limb amputations associated with shock have been described after Rocky Mountain spotted fever infections [5,6]. In November 2002, a couple from Santa Fe, NM, traveled to New York City, NY, where they developed fever and inguinal lymphadenopathy [7]. When the couple
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague sought medical attention in New York, a diagnosis of naturally acquired bubonic plague was considered and later confirmed because the Yersinia pestis isolated from the husband’s blood was genotypically indistinguishable from Y pestis isolated from fleas and a dead wood rat, obtained in and around the couple’s property in New Mexico during routine surveillance by the health department in July and November 2002 [7]. By the time the couple sought medical care, the husband was in septic shock and was admitted to an intensive care unit (ICU), where he developed ischemic necrosis of both feet leading to bilateral foot amputation 20 days after admission. This report describes the pathological and immunohistochemical (IHC) findings of Y pestis–induced limb gangrene and
851
shows the importance of studying pathological specimens during public health investigations.
2. Case report A 53-year-old diabetic man had fever, fatigue, and painful unilateral inguinal swelling 2 days before seeking medical care. On physical examination, he had diaphoresis, rigors, and lower-extremity cyanosis. His temperature was 40.28C, blood pressure was 78/50 mm Hg, and he had a tender left inguinal adenopathy with overlying edema. His white blood cell count was 24 700/lL (normal, 4300-10 800) and his platelet count was 72/lL (normal, 130 000-400 000). Blood
Fig. 1 Photomicrographs of tissue from amputated feet showing ischemic necrosis by Y pestis. Coagulative necrosis of tissues is demonstrated by loss of nuclei in the epidermis (A) and muscle (B). Basophilic rod-like structures (circled) can be observed inside blood vessels of muscle and probably represent Y pestis (B). Intact Y pestis and yersinial granular antigens can be observed in thrombi (C), ischemic dermis (D and E), and muscle (F) (A and B, hematoxylin and eosin stain; C-F, IHC assay with polyclonal anti–Y pestis F1 antibody; original magnifications 50 [A], 157.5 [B], and 250 [C-F]).
852 cultures obtained before antibiotic treatment grew Y pestis, whereas those obtained after treatment showed no growth. Bronchoscopic secretions did not show evidence of Y pestis by using polymerase chain reaction. The patient was admitted to an ICU where he was treated for septic shock with vasopressors, activated protein C, and antibiotics (gentamicin, doxycycline, ciprofloxacin, and vancomycin). Twenty days after admission, the patient’s fever continued and his feet showed limb ischemia that required bilateral foot amputation. During his 6-week ICU stay, the patient required mechanical ventilation because of acute respiratory distress syndrome and hemodialysis because of acute renal failure. The patient eventually recovered and was discharged to a long-term care rehabilitation facility. Before the amputation, the feet looked pale and the tissues appeared nonviable; there were no areas of liquefaction or pus. Microscopically, widespread vascular thrombi were noted in the foot tissues, with consequent coagulative ischemia in the epidermis (Fig. 1A) and muscle (Fig. 1B); the tissue at the margins appeared viable. In nonviable tissue, basophilic rod-like structures were noted with hematoxylin and eosin stain (Fig. 1B), but gram-negative organisms were difficult to distinguish. Mixed gram-positive and gramnegative organisms were observed in the skin surface. Only formalin-fixed tissue was submitted to the Centers for Disease Control and Prevention (CDC) for examination precluding recovery of live bacteria. A previously described IHC assay for Y pestis was applied to ischemic and viable tissues [8]. Tissues were tested using a polyclonal anti-F1 Y pestis antibody (CDC, Fort Collins, Colo) and a monoclonal antibody against F1 of Y pestis (Naval Research Institute, Bethesda, Md). Negative controls included sequential slides incubated with normal rabbit serum or mouse ascitic fluid as primary antibody. In the ischemic tissues, multiple bacteria and granular antigens were observed. Intact bacteria were predominantly detected inside vessels, particularly if thrombi were present (Fig. 1C), whereas smallersized, granular staining antigens (corresponding to bacterial fragments) were more abundant and were seen in vessels and in the tissues surrounding these (Fig. 1D). The vessels containing the bacteria were mostly in the dermis (Fig. 1D and E) and in the muscle (Fig. 1C and F). No IHC evidence of Y pestis was found in the viable tissues.
3. Discussion We identified intact and fragmented Y pestis inside the vessels of an amputation specimen from a patient who had limb ischemia secondary to septic shock and DIC. This diabetic patient initially developed bubonic plague and then had septicemia, which seeded distal tissues with Y pestis; he presented to medical care in septic shock. In this patient, both hypoperfusion and diabetes contributed to ischemic necrosis of distal tissues. Hypoperfusion and concomitant DIC in septicemic plague may be important contributors to
J. Guarner et al. soft-tissue and bone necrosis, similar to the pathophysiology in patients with meningococcemia [3,4]. The presence of intact and fragmented Y pestis inside the blood vessels of ischemic tissues may also have contributed to hypoperfusion by releasing plasminogen activator and by forming local thrombi [9]. In addition, diabetes is an important risk factor for atherosclerosis and limb ischemia, and in diabetic patients, infections are frequent aggravating causes of morbidity [1,2]. Blood samples obtained from this patient after the administration of antibiotics were negative for Y pestis, implying that antibiotic treatment was rapidly effective in sterilizing circulating blood. However, Y pestis F1 antigens persisted in necrotic tissues for 20 days after antibiotic treatment. By promoting hypotension and DIC, Y pestis becomes trapped in hypoperfused tissues and can persist there by overcoming host defenses. In experiments, Y pestis has been shown to mount an impressive antiphagocytic activity via several proteins that dephosphorylate host cell adhesion molecules (YopH) and inactivate host cytoskeleton dynamics (YopP and YopJ) [10]. In addition, poor perfusion of antibiotics probably allowed for bacteria to persist in ischemic tissues. Although viability of bacteria cannot be established with the IHC assay, the persistence of Y pestis F1 indicates long-term stability of antigens that may have caused the continued fevers in our patient. Persistence of bacteria in gangrenous tissues after 5 to 7 weeks of treatment has been documented and, similar to our findings, underscores the importance of surgical excision of necrotic or partially necrotic tissues [5,6]. Septicemic plague can occur after either bubonic or pneumonic plague. In previous studies using IHC in human tissues, abundant intact Y pestis and bacterial fragments or granular antigens have been detected in blood vessels and the interstitium of organs, such as kidney and spleen [8]. In the feet of our patient, intact Y pestis was found primarily inside vessels with more abundant granular F1 antigen staining observed in vessels and in the tissue surrounding these vessels. The granular antigens observed with IHC assays represent intracellular and extracellular phagocytosed bacterial fragments present in areas of inflammation and necrotic debris. Granular antigens can be detected only by using IHC assays and have been identified even after antibiotic treatment in other bacterial infections, such as anthrax and leptospirosis [11-13]. These nonviable Y pestis bacterial fragments probably include a variety of bacterial substances, such as endotoxins. Y pestis endotoxin and shock-inducing inflammatory cytokines, such as tumor necrosis factor a and interferon c, contribute to the end stages of plague septic shock, which is similar to shock associated with other enterobacteriaceae [9,10]. During public health investigations, study of pathology specimens by using IHC has proven to be of great benefit. In the past, it has helped investigators discover new pathogens (Hantavirus in the United States), describe new manifestations of a well-known disease (cholecystitis due to
Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague Leptospira), and confirm diagnosis in epidemiologically or clinically suspect cases (anthrax bioterorrist attack) [11-14]. The CDC advises that all clinicians, pathologists, and laboratorians be aware of the clinicopathologic features and the specimens required for diagnosis of diseases potentially caused by bioterrorism agents, including plague, so that public health measures are instituted to contain possible casualties [11,12,15]. In the case of plague, it is the pneumonic form that is most feared as a possible bioterrorism event, but as we learned from the anthrax bioterrorism attack of 2001, although the most feared form of anthrax is inhalational, cutaneous cases did occur and may be sentinel events [11,12]. Thus, being able to distinguish the different forms of plague (bubonic, primary pneumonic, septicemic, and secondary pneumonic) has important implications for public health and law enforcement investigations [8]. Travelers who acquire plague in an endemic area and become ill in a nonendemic location (peripatetic plague) frequently have fatal outcomes, misdiagnosis, and delays in treatment. The diagnosis of naturally acquired plague in the patient presented here and his spouse occurred promptly and excluded bioterrorism because a series of actions and collaborations ensued between public health and law enforcement agencies [7]. In summary, IHC assays can provide the diagnosis of plague in formalin-fixed tissues even after antibiotic treatment. Persistence of Y pestis and Y pestis antigens in ischemic tissues may contribute to disease morbidity and mortality through ongoing stimulation of cytokine cascades and may have therapeutic implications. Pathologists should be aware of the varied histopathologic manifestations of plague and the importance of obtaining adequate material for study.
References [1] Cruz CP, Eidt JF, Capps C, Kirtley L, Moursi MM. Major lower extremity amputations at a Veterans Affairs hospital. Am J Surg 2003; 186:449 - 54.
853
[2] Grimble SA, Magee TR, Galland RB. Methicillin resistant Staphylococcus aureus in patients undergoing major amputation. Eur J Vasc Endovasc Surg 2001;22:215 - 8. [3] Palacios J, Serafim Z, Leal MJ. Mutilations due to medical disorders in children. Pediatr Surg Int 2003;1:91 - 5. [4] Cremer R, Leclerc F, Jude B, Sadik A, Leteurtre S, Fourier C, et al. Are there specific haemostatic abnormalities in children surviving septic shock with purpura and having skin necrosis or limb ischaemia that need skin grafts or limb amputations? Eur J Pediatr 1999;158: 127 - 32. [5] Kirkland KB, Marcom PK, Sexton DJ, Dumler JS, Walker DH. Rocky Mountain spotted fever complicated by gangrene: report of six cases and review. Clin Infect Dis 1993;16:629 - 34. [6] Hove MG, Walker DH. Persistence of rickettsiae in the partially viable gangrenous margins of amputated extremities 5 to 7 weeks after onset of Rocky Mountain spotted fever. Arch Pathol Lab Med 1995;119: 429 - 31. [7] CDC. Imported plague—New York City, 2002. MMWR Morb Mortal Wkly Rep 2003;52:725 - 8. [8] Guarner J, Shieh WJ, Greer PW, Gabastou JM, Chu M, Hayes E, et al. Immunohistochemical detection of Yersinia pestis in formalin-fixed, paraffin-embedded tissue. Am J Clin Pathol 2002;117:205 - 9. [9] McGovern TW, Friedlander AM. Plague. In: Sidell FR, Takafuji ET, Franz DR, editors. Textbook of military medicine: medical aspects of chemical and biological warfare. Part 1: warefare, weaponry, and the casualty. Washington (DC)7 Office of the Surgeon General at TMM publications, Borden Institute, Walter Reed Army Medical Center; 1997. p. 479 - 502. [10] Cornelis GR. Molecular and cell biology aspects of plague. Proc Natl Acad Sci U S A 2000;97:8778 - 83. [11] Guarner J, Jernigan JA, Shieh WJ, Tatti K, Flannagan LM, Stephens DS, et al. Pathology and pathogenesis of bioterrorism-related inhalational anthrax. Am J Pathol 2003;163:701 - 9. [12] Shieh WJ, Guarner J, Paddock C, Greer P, Tatti K, Fischer M, et al. The critical role of pathology in the investigation of bioterrorismrelated cutaneous anthrax. Am J Pathol 2003;163:1901 - 10. [13] Guarner J, Shieh WJ, Morgan J, Bragg SL, Bajani MD, Tappero JW, et al. Leptospirosis mimicking acute cholecystitis among athletes participating in a triathlon. Hum Pathol 2001;32:750 - 2. [14] Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, et al. Hantavirus pulmonary syndrome, pathogenesis of an emerging infectious disease. Am J Pathol 1995;146:552 - 79. [15] Nolte KD, Hanzlick RL, Payne DC, Kroger AT, Oliver WR, Baker AM, et al. Medical examiners, coroners, and biologic terrorism: a guidebook for surveillance and case management. MMWR Recomm Rep 2004;53(Rr-8):1 - 36.