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Sverdlovsk revisited: pulmonary pathology of inhalational anthrax versus anthraxlike Bacillus cereus pneumonia.

To the Editor.--The case report of rapidly progressive, fatal pneumonia caused by Bacillus cereus producing anthrax lethal toxin and edema toxin represents a landmark achievement in pathology. (1) The investigators' decisiveness and speed in applying a contemporary genome sequencing approach were remarkably effective in establishing a diagnosis and determining the absence of a public health emergency. The designation of the case as anthraxlike led me to compare it with the 41 documented cases in the 1979 Sverdlovsk (now Yekaterinburg), Russia, outbreak of inhalational anthrax associated with accidental release of Bacillus anthracis spores from a biologic weapons facility. (2)

Respiratory failure in inhalational anthrax is caused mainly by massive bilateral pleural effusions and compressive atelectasis and was the major cause of death in 39% (16 of 41) of the cases in Sverdlovsk, Russia. Indeed, the importance of draining these pleural effusions has received insufficient attention as a crucial, supportive therapeutic measure that increases the survival time for specific antimicrobial and antitoxin treatment to reverse the disease progression.

The pathogenesis of inhalational anthrax involves phagocytosis of B anthracis spores by pulmonary dendritic cells, transport of the spores within them to the tracheobronchial lymph nodes where the spores germinate, and replication of vegetative bacilli that secrete edema toxin and lethal toxin. (3) There, the toxins cause extensive tissue injury, hemorrhage, and extension of the process through the mediastinum, resulting in the characteristic radiographic mediastinal widening and chest pain. Invasion of the blood stream with hematogenous dissemination of the bacteria resulted in hemorrhagic meningitis as the major cause of death in 34% (14 of 41) of the Sverdlovsk cases.

The highly probable basis for the pulmonary parenchymal hemorrhages was multifocal vascular lesions. Anthrax vasculitis was identified as a key pathologic lesion in the Sverdlovsk casesand wascharacterized by fibrinoid necrosis of the vessel wall with mild neurotrophic and moderate macrophage infiltration. (2) Those lesions were also the apparent basis for hemorrhagic lesions in the meninges, gastrointestinal submucosa, and mediastinum. Another, less-critical pulmonary lesion was extension of the mediastinal hemorrhage and edema from the hilum of the lungs into the pulmonary parenchyma along the bronchovascular bundles.

Therecentcaseofpneumonia caused by B cereus producing anthrax toxins occurred in a welder, which has been reported previously in other cases in Texas and Louisiana. (4,5) The Sverdlovsk series of inhalational anthrax cases included patients who had arc welder's pulmonary hemosiderosis or silicosis. Cases with pneumoconiosis were more likely to have hemorrhagic pulmonary consolidation (75%, 6 of 8 patients) than were patients without pneumoconiosis (29%, 2 of 7 patients).

The Sverdlovsk autopsy series is particularly instructive for its indication of the pathogenesis, particularly hemorrhage from vasculitic lesions, and its indication of required supportive therapy, namely effective drainage of pleural effusions. The Sverdlovsk cases differed from the recent Texas case, which lacked the severe tracheobronchial and mediastinal hemorrhages and had abundant bacteria in the alveolar spaces, rather than predominantly in the pulmonary microcirculation.


Department of Pathology

University of Texas Medical Branch

Galveston, TX 77555-0609


(1.) Wright AM, Beres SB, Consamus EN, et al. Rapidly progressive, fatal, inhalation anthrax-like infection in a human: case report, pathogen genome sequencing, pathology, and coordinated response. Arch Pathol Lab Med. 2011; 135(11):1447-1459.

(2.) Grinberg LM, Abramova FA, Yampolskaya OV, Walker DH, Smith JH. Quantitative pathology of inhalational anthrax 1: quantitative microscopic findings. Mod Pathol. 2001; 14(5):482-495.

(3.) CleretA, Quesnel-Hellmann A, Vallon-Eberhard A, et al. Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route. J Immunol. 2007; 178(12):7994-8001.

(4.) Miller JM, Hair JG, Hebert M, Hebert L, Roberts Jr. FJ. Fulminating bacteremia and pneumonia due to Bacillus cereus. J Clin Microbiol. 1997; 35(2):504-507.

(5.) Avashia SB, Riggins WS, Lindley C, et al. Fatal pneumonia among metalworkers due to inhalation exposure to Bacillus cereus containing Bacillus anthracis toxin genes. Clin Inf Dis. 2007; 44(3):414-416.

doi: 10.5858/arpa.2011-0542-LE

In Reply.--We thank Dr Walker for his interest in, and comments about, our recent study. (1) The Sverdlovsk incident represented an unfortunate albeit useful opportunity to acquire extensive data about the pathologic findings of inhalation anthrax obtained at autopsy from 41 patients. (2-4) Epidemiologic investigation indicated that the outbreak occurred because of accidental aerosol release of at least 4 strains of Bacillus anthracis from a military base in southern Sverdlovsk, Russia, designated Compound 19. (2,5) The work by Grinberg et al (3) contains a unique and unusually rich compendium of pathologic findings. It emphasizes once again the critical importance of the autopsy in understanding human disease, especially for illnesses that are otherwise rare.

Our case (1) of rapidly progressive, fatal pneumonia caused by a strain of Bacillus cereus containing genes encoding anthrax toxin and other virulence factors has many similarities to those reported in the Sverdlovsk series. The letter by Dr Walker (based on the findings reported by Grinberg et al (3)) describes anthrax toxins causing extensive tissue injury and hemorrhage of the mediastinum resulting in the characteristic radiographic mediastinal widening. We note that our patient lacked the characteristic mediastinal "gelatinous edema" described by Grinberg et al (3) but did have a serosanguinous pericardial effusion (150 mL) that caused mild mediastinal widening grossly. In addition, the patient had substernal chest pain on admission. However, to our knowledge, mediastinal widening was not noted to be a significant finding at the time of radiographic studies.

The tracheobronchial tree in our case had diffuse and severe hemorrhage with extensive necrosis and sloughing of the respiratory epithelium, as well as fibrin deposition admixed with focal inflammatory infiltrates. These findings also are similar to some of the cases reported in the Sverdlovsk series. (3) The patient was intubated for 4 days before autopsy; thus, some of these changes may be related to intubation, particularly the sloughing of the epithelium. However, we believe the hemorrhage is a true finding, given the patient's initial presentation of massive hemoptysis.

Hemorrhagic meningitis was described in 51% (21 of 41) of the Sverdlovsk cases. (4) Our patient had diffuse cerebral edema, focal subarachnoid hemorrhage, and diffuse vascular congestion, but no inflammation or microorganisms were seen.

The development of massive pleural effusions is a significant finding in patients with anthrax and is potentially treatable. Our patient quickly developed respiratory failure shortly after arrival at the outside hospital and was intubated emergently. He developed a left pneumothorax and large, right pleural effusion for which chest tubes were placed and drainage ensued. However, despite proper chest tube positioning, a large amount of serosanguinous pleural fluid remained in the pleural cavities (right, 500 mL; left, 100 mL) at autopsy.

Our case had abundant gram-positive bacteria within the pleura, as described in previous anthrax cases. Although no organisms were seen in the microcirculation, given the patient's positive blood culture results from multiple samples, we believe that bacilli were also likely present in the microvasculature but simply not seen in the sections examined. The rapid administration of antibiotics on admission and throughout his 4-day hospital stay likely decreased the bacterial burden, which may explain the paucity of bacteria. As Dr Walker correctly notes, our case differs from the Sverdlovsk cases in the sense that our patient also had numerous organisms in the alveolar spaces. However, Grinberg et al (3) also describe several cases with bacilli involvement of alveolar spaces, particularly in the hilar region, which was theorized to be direct extension from high organism burden in the hilar lymph nodes and the mediastinum. Early radiologic findings in our case included a perihilar nodular infiltrate of the left lung and consolidation in the right lung. These findings are in keeping with the idea of direct spread from the hilum, with the right lung having more severe and advanced involvement, which is also consistent with our findings at autopsy. Similar to previously described anthrax cases, our case had very little inflammatory cell infiltrate, much less than would be expected given the number of organisms present. Presence of B cereus in the alveolar spaces has previously been described in cases of immunocompromised patients who develop B cereus pneumonia. In that regard, our investigation did not find our patient to be significantly immunocompromised.

Thus, our case had many clinical, histologic, and molecular similarities to classically described anthrax cases, leading us to conclude that anthraxlike is an accurate and suitable descriptor. That said, the 2 diseases are not identical. Finally, although the bacterial strain from our case had genes encoding the 3 proteins comprising anthrax toxin, we only formally tested for production of one of those proteins (protective antigen) by immunohistochemistry. We are grateful for the author's interest in our publication and for drawing attention to the superb work by Grinberg et al. (3)




Department of Pathology and Genomic Medicine

The Methodist Hospital System

Houston, TX 77030


(1.) Wright AM, Beres SB, Consamus EN, et al. Rapidly progressive, fatal, inhalation anthrax-like infection in a human. Arch Pathol Lab Med. 2011; 135(11):1447-1459.

(2.) Meselson M, Guillemin J, Hugh-Jackson M, et al. The Sverdlovsk anthrax outbreak of 1979. Science. 1994; 266(5188):1202-1208.

(3.) Grinberg LM, Abramova FA, Yampolskaya OV, Walker DH, Smith JH. Quantitative pathology of inhalational anthrax I: quantitative microscopic findings. Mod Pathol. 2001; 14(5):482-495.

(4.) Abramova FA, Grinberg LM, Yampolskaya OV, Walker DH. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci U S A. 1993; 90(6):2291-2294.

(5.) Jackson PJ, Hugh-Jones ME, Adair DM, et al. PCR analysis of tissue samples from the 1979 Sverdlovsk anthrax victims: the presence of multiple Bacillus anthracis strains in different victims. Proc Natl Acad Sci USA. 1998; 95(3):1224-1229.

doi: 10.5858/arpa.2011-0568-LE
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Title Annotation:Letters to the Editor
Author:Walker, David
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Mar 1, 2012
Previous Article:Introduction to continuing special series.
Next Article:Erratum.

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