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Last Updated

06 Nov 2002

Source: Barakat LA et al. Fatal inhalational Anthrax in a 94-year-old Connecticut woman. JAMA 287(7), 863-868, 2002 (Feb. 20, 2002).

On November 16, 2001, a 94-year-old woman from Oxford, Conn, with fever, fatigue, myalgias, dry cough, and shortness of breath of approximately 3 days' duration was evaluated at her local hospital. During the preceding 2 months, following the death of a close friend, she had experienced depressive symptoms, including decreased appetite and increased general fatigue. On the day before admission, family members noted that she was confused. There was no recent history of headache, chills, sweats, sore throat, rhinorrhea, hemoptysis, chest pain, abdominal pain, nausea, vomiting, or diarrhea. She had chronic obstructive pulmonary disease. She had a 22-pack-year smoking history but had not smoked in 30 years. She also had hypertension and chronic renal insufficiency. Her medications included montelukast, irbesartan, loratadine, alprazolam, inhaled salmeterol xinafoate/fluticasone propionate, and azelastine nasal spray. Her only nonprescription medication was a multivitamin tablet, and she rarely drank alcohol. Her diet was unremarkable. The patient had lived alone since the death of her husband 22 years earlier. She had previously worked as a legal secretary. She had no recent travel and had no pets. Additional history obtained following admission revealed that she did not remember opening any mail containing powder.

On admission, the patient's vital signs were a temperature of 102.3░F (39.1░C), blood pressure of 106/50 mm Hg with no orthostatic changes, pulse of 119/min, and respiratory rate of 18/min. Oxygen saturation was 93% while breathing room air. She was alert and oriented, there were no signs of meningeal irritation, and the remainder of the physical examination, including skin, was unremarkable.

Laboratory findings included a total white blood cell count of 8.1 x 103/ÁL (78% neutrophils, 15% lymphocytes, and 7% monocytes) and normal hematocrit and platelet counts. Serum urea nitrogen level was 39 mg/dL (13.9 mmol/L), serum creatinine level was 1.3 mg/dL (115 Ámol/L), and serum electrolyte levels were within normal ranges, except for a sodium level of 134 mEq/L. Serum chemistry levels were normal except for an aspartate aminotransferase of 45 U/L. Urinalysis showed 3 to 5 white blood cells per high-power field and moderate bacteria. Posterior-anterior and lateral chest radiographs were initially interpreted as having no evidence of pulmonary infiltrates, widened mediastinum, or pleural effusion (Figure 1A).

Figure 1A. Admission chest radiograph.
Admission posterior-anterior chest radiograph shows possible left hilar enlargement (white arrowhead) and blunting of the left costophrenic angle (black arrowhead), possibly due to a small left pleural effusion.

However, later comparison with films obtained 3 years previously suggested possible interval enlargement of the left hilum and a possible small left pleural effusion. Computed tomography of the chest was not performed.

Blood and urine cultures were obtained, and the patient was admitted to the hospital with a diagnosis of viral syndrome and dehydration. Initial treatment included intravenous hydration and observation. Antibiotic therapy was not initiated on the day of admission.

Figure 1B. Gram stain of blood culture.
Gram stain of blood culture isolate showing gram-positive rods in chains (original magnification x 100).

On the morning of November 17, the patient was febrile but clinically stable. Using a colorimetric detection system (BacT/Alert, Organon Technica Corp, Durham, NC), growth of gram-positive bacilli in chains was detected in all 4 blood culture bottles after 14 hours of incubation (Figure 1B). The urine culture grew more than 100 000 colony-forming units/mL of Escherichia coli that were susceptible to ampicillin. Approximately 24 hours after presentation, the patient received a single 2-g dose of ceftazidime, and vancomycin, 1 g/d intravenously, was begun. Oral ciprofloxacin, 500 mg every 12 hours, and ampicillin/sulbactam, 3 g intravenously every 6 hours, were added. Blood cultures obtained 3 hours after initiation of antibiotics were sterile.

Figure 2A. Portable Chest Radiographs.
Portable chest radiograph shows bilateral lower lung consolidation, left greater than right, and hazy opacity on the left chest suggestive of pleural effusion.

On November 18, the patient developed respiratory distress. Her white blood cell count was 13.3 x 103/ÁL (80% neutrophils, 11% lymphocytes, and 9% monocytes) and her oxygen saturation decreased to 90% while receiving 2 L/min of oxygen via nasal cannula. A chest radiograph showed clear evidence of a left pleural effusion (Figure 2A). Intravenous vancomycin and oral ciprofloxacin were continued, ampicillin/sulbactam was discontinued, and intravenous erythromycin (500 mg every 6 hours) was initiated in the early hours of November 19.

On November 19, review of the preliminary microbiologic analysis of the blood isolate raised suspicion for anthrax; therefore, the Connecticut Department of Public Health was notified about the positive blood culture results, and assistance in ruling out B anthracis was requested. The patient's condition deteriorated with worsening hypoxemia and renal function (serum urea nitrogen and serum creatinine levels of 43 mg/dL [15.4 mmol/L] and 2.6 mg/dL [230 Ámol/L], respectively). Her white blood cell count was 25.0 x 103/ÁL (83% segmented neutrophils, 8% band forms, and 8% lymphocytes). Chest radiograph showed progression of the left pleural effusion. A left thoracentesis yielded 800 mL of serosanguinous fluid, with 4224 red blood cells, 1463 white blood cells, a pH of 7.12, lactate dehydrogenase level of 611 U/L, glucose level of 259 mg/dL (14.4 mmol/L), and protein level of 3.4 g/dL. No organisms were seen on the Gram stain of the pleural fluid, and bacterial culture of the fluid did not grow, but subsequent testing at the Centers for Disease Control and Prevention showed that the B anthracis-specific polymerase chain reaction (PCR) assay was positive. The patient required endotracheal intubation and mechanical ventilation. In addition to vancomycin, clindamycin, 900 mg intravenously every 6 hours, was begun, erythromycin was discontinued, and the route of ciprofloxacin administration was changed from oral to intravenous. Methylprednisolone, 40 mg intravenously every 8 hours, was initiated.

On November 20, the isolate was identified as B anthracis by the Connecticut state laboratory, with confirmation at the Centers for Disease Control and Prevention the following day. Confirmatory testing of the isolate included gamma phage lysis and detection of capsule and cell-wall antigens by direct fluorescent antibody assays. In addition, PCR showed that the isolates contained B anthracis-specific DNA. The isolates were susceptible to ciprofloxacin, tetracycline, penicillin, and a number of other antibiotics. The antibiotic susceptibilities were identical to the isolates obtained from other patients during this bioterrorism-related anthrax outbreak. Subsequent multiple-locus variable-number tandem repeat analysis revealed that the isolate was also genetically indistinguishable compared with the other strains from cases of bioterrorism-related anthrax.

Figure 2B. Portable Chest Radiographs.
Supine portable chest radiograph demonstrates extensive consolidation in both lower lungs and bilateral hazy opacities suggesting pleural effusion.

Between November 19 and 21, the patient remained febrile with a maximum temperature of 101.5░F (38.6░C). She developed hypotension requiring treatment with vasopressors and required high levels of supplemental oxygen (80% fraction of inspired oxygen) to maintain adequate oxygenation. Chest radiographs revealed progressive consolidation and a new right pleural effusion (Figure 2B). A chest tube was placed in the left pleural space. Total white blood cell count increased to 43.6 x 103/ÁL (83% segmented neutrophils, 12% lymphocytes, and 5% monocytes) and serum creatinine level increased to 3.7 mg/dL (327 Ámol/L). Hematocrit, platelet count, liver enzymes, and coagulation profile remained normal, with the exception of an aspartate aminotransferase level of 61 U/L. The patient's condition continued to deteriorate, and she died on November 21.

Figure 3A. Mediastinal Lymph Nodes.
Photomicrograph of a postmortem mediastinal lymph node shows hemorrhage, necrosis, and nodular collections of immunoblasts (hematoxylin-eosin stain, original magnification x25).

The case was reported to the state medical examiner. An autopsy was performed 8 hours after death. More than 1 L of serosanguinous fluid was present in the right pleural cavity, and the right lung had areas of patchy consolidation. A chest tube was noted within the left pleural space. There was no evidence of a primary cutaneous lesion. The mediastinal lymph nodes were enlarged and hemorrhagic. The central nervous system was unremarkable, and, except for small, granular, and cystic kidneys, the abdominal organs were grossly normal. Microscopic examination demonstrated extensive necrosis and hemorrhage of mediastinal lymph nodes (Figure 3A), intra-alveolar and interstitial edema with focal hemorrhage and fibrin deposition in the lungs, and splenic necrosis. There was no histopathologic evidence of pneumonia.

Immunohistochemical staining using B anthracis capsule and cell-wall monoclonal antibodies showed abundant bacilli and granular staining in the mediastinal lymph nodes (Figure 3B), cellular fraction of the pleural effusion, visceral and parietal pleura, and pulmonary interstitium. No pathologic or immunopathologic evidence of B anthracis was identified in the abdominal organs or central nervous system using tissue Gram stains or immunohistochemical stains.

Figure 3B. Mediastinal Lymph Nodes.
Photomicrograph of an immunohistochemical assay of a mediastinal lymph node shows Bacillus anthracis bacilli (arrows), numerous red staining polymorphic particles, and red-purple dust. The polymorphic particles and red-purple dust represent bacterial fragments and antigens that are being processed by inflammatory cells. The fragments and antigens that seem more compact, as if they were staining the cytoplasm of cells, are considered intracellular while those that appear single or as red-purple dust are mostly extracellular (immunohistochemical assay with a mouse monoclonal anti-B anthracis cell wall antibody and detection with alkaline phosphatase and naphthol fast red, original magnification x 100).

Postmortem blood; pleural fluid; and spleen, lung, liver, and mediastinal lymph node tissue specimens were inoculated onto bacteriologic media for culture and tested for B anthracisľspecific DNA using PCR. Growth of B anthracis was detected only from the mediastinal lymph node; all other postmortem specimens were sterile. The mediastinal lymph node tissue was also the only postmortem specimen from which B anthracis DNA was detected by PCR assay. The cause of death was certified as inhalational anthrax.

Serial serum samples obtained on November 16, 17, 18, and 19 were tested for IgG antibody to the protective antigen component of the anthrax toxins by enzyme-linked immunosorbent assay; all samples were nonreactive.


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