Case 4 -

Septicemic Plague Rebecca A. Irvine University of New Mexico Albuquerque, NM

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Clinical Summary A 54-year-old Caucasian, non-Hispanic woman from the East Mountains, near Albuquerque, New Mexico, was transferred to an Emergency Department from an Urgent Care Center. She had initially presented with a 5-day history of back and abdominal pain, sinus-headache type pain, "flu"-like symptoms and, most recently, bloody stool and emesis. At the Urgent Care center it had been noted that she was anuric with a WBC of 52K. She arrived at the E.D. unresponsive with agonal respirations and was promptly intubated. Despite continuous efforts at resuscitation, she was pronounced dead less than two hours after admission. There was no record of administration of broad-spectrum antimicrobials or obtaining a chest radiograph. An automated complete blood count could not be obtained. Manual reading showed a WBC of 31.7K, 67% PNMs and a platelet count of 45K. There was a pronounced left shift and toxic granulation was noted. Additionally, many bacteria were identified in antemortem blood specimens. Liver function testes were elevated and BUN & creatinine were 35 and 1.7 mg/dL, respectively. Lactic acid was greater than 12.0 mg/dL and quantitative D-DIMER was greater than 20.00. Her past medical history included a breast lumpectomy, lumbar spine surgery, appendectomy, tobacco use, past ethanolism (none for three years) and an allergy to penicillin. She had previously been in her usual state of health. There was no foreign travel, no transfusion history and family members were unaware of any contact with vectors. A complete autopsy was performed under the jurisdiction of the Medical Examiner approximately 11 hours after death. The decedent appeared acutely ill, without any identifiable external injuries. Grossly there was marked pulmonary congestion with a combined lung weight of 2,150 grams. The lungs were without focal or regional consolidation and while "wet", they were not "beefy" or airless. Frank blood was present throughout the upper gastrointestinal tract, without a focal source. There was no lymphadenopathy or recurrent mammary carcinoma. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Lung alveolar spaces with fibrin microthrombi and focal intra-alveolar bacteria overgrowing the septa. Case 4 - Figure 2 Occlusive fibrin thrombus in a pulmonary venule within which bacteria can be easily identified. Case 4 - Figure 3 Abundant intravascular bacteria are noted on multiple sections. Case 4 - Figure 4 Kidney with fibrin thrombi in capillary loops, overgrown with bacteria. Key Points: This entity may present with an aggressive clinical course and with great clinical diversity. Inflammatory change may be minimal. Due to public health and bioterrorism ramifications, a low index of suspicion should be maintained regardless of location. In the live patient, antimicrobials should be instituted promptly, before diagnosis can be confirmed. Diagnosis: Septicemic Plague Microscopically, abundant intravascular bacteria (Figure 3) were noted on multiple sections. The lungs (Figures 1-2) showed fibrin microthrombi and focal intra-alveolar bacteria overgrowing the septa. The kidney showed fibrin thrombi in the capillary loops (Figure 4), overgrown with bacteria. The liver showed early centrilobular necrosis. Viral cultures of the nasopharynx and both lungs were without growth. Fecal bacterial culture was without pathogens. Bacterial cultures of blood and both lungs grew Yesinia pestis. Home evaluation by an Epidemic Intelligence Service Officer from the CDC showed that the patient's dog and a trapped rock squirrel had evidence of past infection with Y. pestis. Discussion New Mexico is a marginalized state in terms of health care and it is not unusual to see the natural history of many infectious diseases, including those usually controllable by vaccination. Moreover, the climate, flora and fauna and elevation make it uniquely suited for such entities as Hantavirus and plague. Y. pestis was introduced to the US in 1900 and is currently detectable in many carnivorous mammals throughout the Western states. Over half of human infections originate in New Mexico. Residence-linked mapping of plague cases in New Mexico places 17.25% of the state at significant risk of plague exposure. The likelihood is related to elevation (increasing up to 2,300 meters above sea level) and by proximity to certain habitat types (juniper, pinon, Rocky Mountain pine). Seroprevalence in carnivore species where plague occurs ranges from 3% to 100%. The risk of both Hantavirus and plaque are predicted to increase during seasons of abundant rainfall. Plague is known to be present on every populated continent except Australia. The highest number of plaque cases since 1994 was reported by the CDC in 2006 in four states; New Mexico had more than half (7 cases, 2 fatal). Worldwide, an average of 1,700 cases has been reported annually during the last half-century. In the US, 390 cases were reported from 1947 to 1996. Although plague is relentlessly moving eastward, its occurrence in locations not known to harbor the enzootic infection (absent the possibility of travel post-infection) raises the possibility of artificial dissemination. Plague is a zoonotic infection caused by Y. pestis, an aerobic, non-motile, Gram negative bacillus (sometimes coccobacillus) most frequently inoculated through the bite of an infected flea or through an open sore during the handling of an infected animal. Most commonly, an infected pustule and lymphadenitis (bubo) herald the spread of bacteria. The organism is phagocytosed, but resists destruction. Septicemia and secondary pneumonia may ensue. Primary pneumonia may result from the inhalation of infected particles by a patient or animal with pneumonic plague. Inhalation of bacilli is believed to result in greater mortality, and, although the ease of transmission is somewhat controversial, is the basis of concern about Y. pestis as an agent of bioterrorism. The plague bacillus may be a recently evolved clone of the enteric pathogen Yersinia pseudotuberculosis. Theoretically, neither bubonic nor septicemia plague spreads directly from person to person. The first [nonspecific] signs of pneumatic plague, similar to pneumonia, would be fever with cough and dyspnea and watery, possibly bloody (less commonly purulent) sputum. As in this case, gastrointestinal symptoms may later predominate. Cervical buboes are rare. Lung sections from a series of plague fatalities showed extreme variability in patterns, ranging from acute pneumonia, intra-alveolar edema and hemorrhage to unremarkable. The inflammatory reaction to the infection is frequently minimal, presumably due to proteins in the organism which block the host inflammatory response. In the case in question, the decedent had a classic picture of disseminated intravascular coagulation with superimposed abundant bacteria; no portal of infection was identified and the infection in this case is best described as septicemic. In contrast, buboes show effacement of nodal architecture with hemorrhage and necrosis. Figure 5 demonstrates lymph node histopathology from an 8-year-old boy who died of bubonic plague in New Mexico, and shows a neutrophilic infiltrate extending into perinodal soft tissue and local, acute vasculitis. Better preserved sections may show foamy macrophages and Giemsa-positive (or Wright's or Wayson positive-staining) intracellular rods. Diagnosis The standard method for diagnosing plague is bacterial culture, using blood, sputum or lymph node aspirate (the latter not without potential hazard during handling). Unfortunately, antibiotic susceptibility determination may extend from four to greater than 7 days, as growth in vitro is very slow. An enrichment protocol and flow cytometry may speed up the process. Direct fluorescent staining may be positive. Serologic tests for the F1 antigen of Y. pestis require acute- and convalescent-phase serum and a four-fold rise in specific antibody titer, and are therefore most useful for retrospective diagnosis. Polymerase Chain Reaction techniques have been used for diagnosis and surveillance. Immunohistochemical assays for use in formalin-fixed tissue are in use at the CDC. Directed vaccine candidates are being explored, although no known vaccine of proven efficacy currently exists. Treatment According to the World Health Organization, recognizing that plague is an international concern, the gold standard antimicrobials are tetracycline, chloramphenicol and streptomycin. Some resistance to streptomycin has been documented. Plague remains widely susceptible to several agents, the most efficient of which include third generation cephalosporins, aminogylcosides and fluoroquinolones. Doxycycline and imipenim have also been used with success. In individuals who have undergone excision of necrotic or partially necrotic tissue due to plague, intact organisms and granular antigens were identified in and around vessels in the resected tissue at 20 days after administration of antibiotics; this highlights the need for adequate excision of poorly perfused tissues with impaired antibiotic delivery. The key to successful treatment is recognition of the condition so that antimicrobial therapy can be promptly instituted along with indicated resuscitative interventions. Biosafety considerations Fortunately, Y. pestis is sensitive not only to multiple antimicrobials but also to sunlight and heating and does not survive long absent a host. The recommended biosafety level is 2 or 3 (the former representing working with culture material, the latter representing working with infected patients). In general, the biggest risk to autopsy personnel is the aerosolization of pathogens. Obviously, this should be avoided, and if pneumonic plague is suspected, negative-pressure environment examination of the lungs is ideal. N-95 masks, or equivalent, and splash protection are the mainstays of personal protection equipment (routine in our office). Equipment should be subjected to autoclaving or chemical decontamination. Selected references: CDC. MMWR Dispatch August 25, 2006 / 55(Dispatch);1-3 Guarner J, Wun-Ju Shieh et al. Immunohistochemical detection of Yersinia pestis in formalin-fixed, paraffin-embedded tissue. Am J Clin Pathol 2002; 117:205-9 Salkeld DJ, Stapp P. Seroprevalence rates and transmission of plague (Yesinia pestis) in mammalian carnivores. Vector Borne Zoonotic Dis 2006; 6:231-9 Eisen RJ, Reynolds PJ et al. Residence-linked human plague in New Mexico: a habitat-suitability model. Am J trop Med Hyg. 2007; 77:121-5 Eisen RJ, Enscore RE et al. Human plague in the southwestern United States, 1957-2004: spacial models of elevated risk of human exposure to Yersinia pestis. J Med Entomol. 2007; 44:530-7 Adjemian JZ, Foley P et al. Initiation and spread of traveling waves of plague, Yersinia pestis, in the western United States. Am J Trop Med Hyg. 2077 Feb; 76(2):365-75 Anyamba A, Chretien JP et al. Developing global climate anomalies suggest potential disease risks for 2006-2007. Int J Health Geog. 2006. 5:60 Guarner J, Shieh WJ et al. Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemia plague. Hum Pathol 2005; 36:850-3 Murphy BS, Wuff CR et al. Yersinia pestis YadC: a novel vaccine candidate against plague. Adv Exp Med Biol 2007; 603:400-14. Louie A, Denziel MR et al. Impact of resistance selection and mutant growth fitness on the relative efficacies of streptomycin and levofloxacin for plague therapy. Antimicrob Agents Chemother. 2007; 51:2661-7. CDC Biosafety in Microbiological and Biochemical Laboratories, 4th Ed. http://www.cdc.gov/OD/OHS/biosfty/bmbl4/bmbl4toc.htm Abstract from Inglesby TV, Dennis TV et al. Plague as a biologic weapon: medical and public health management. JAMA; 283:2290