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Systematic Review: A Century of Inhalational Anthrax Cases from 1900 to 2005

Jon-Erik C. Holty, MD, MS; Dena M. Bravata, MD, MS; Hau Liu, MD, MPH, MBA; Richard A. Olshen, PhD; Kathryn M. McDonald, MM; and Douglas K. Owens, MD, MS
[+] Article, Author, and Disclosure Information

From the Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Center for Primary Care and Outcomes Research, Stanford University, Stanford, California; and Stanford University–University of California, San Francisco, Evidence-based Practice Center, Stanford, California.

Acknowledgments: The authors thank Corinna Haberland, MD, MS; Veronika Sharp, MD; Pavel Strnad, MD; Kelvin Tan, MS; Suzana Tulac, PhD; and Irina Worthey for their assistance in translating non–English-language articles. The authors also thank Ingram Olkin, PhD, for statistical assistance; Nathaniel Hupert, MD, MPH, for comments on the manuscript; and Rebecca Kim and Emilee Wilhelm for retrieving articles.

Grant Support: This work was performed by the Stanford University–University of California, San Francisco, Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract no. 290-02-0017). This project was also supported in part by the U.S. Department of Veterans Affairs. Dr. Olshen was supported in part by National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering grant 2-R01-EB-002784-30.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Jon-Erik C. Holty, MD, MS, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, 300 Pasteur Drive, H3143, Stanford, CA 94305-5236.

Current Author Addresses: Dr. Holty: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, 300 Pasteur Drive, H3143, Stanford, CA 94305-5236.

Drs. Bravata and Liu and Ms. McDonald: Center for Primary Care and Outcomes Research, Stanford University, 117 Encina Commons, Stanford, CA 94305-6019.

Dr. Olshen: Department of Health Research and Policy, Stanford University, T138C Redwood Building, Stanford, CA 94305-5405.

Dr. Owens: Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue (111A), Palo Alto, CA 94304.

Ann Intern Med. 2006;144(4):270-280. doi:10.7326/0003-4819-144-4-200602210-00009
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Background: Mortality from inhalational anthrax during the 2001 U.S. attack was substantially lower than that reported historically.

Purpose: To systematically review all published inhalational anthrax case reports to evaluate the predictors of disease progression and mortality.

Data Sources: MEDLINE (1966–2005), 14 selected journal indexes (1900–1966), and bibliographies of all retrieved articles.

Study Selection: Case reports (in any language) between 1900 and 2005 that met predefined criteria.

Data Extraction: Two authors (1 author for non–English-language reports) independently abstracted patient data.

Data Synthesis: The authors found 106 reports of 82 cases of inhalational anthrax. Mortality was statistically significantly lower for patients receiving antibiotics or anthrax antiserum during the prodromal phase of disease, multidrug antibiotic regimens, or pleural fluid drainage. Patients in the 2001 U.S. attack were less likely to die than historical anthrax case-patients (45% vs. 92%; P < 0.001) and were more likely to receive antibiotics during the prodromal phase (64% vs. 13%; P < 0.001), multidrug regimens (91% vs. 50%; P = 0.027), or pleural fluid drainage (73% vs. 11%; P < 0.001). Patients who progressed to the fulminant phase had a mortality rate of 97% (regardless of the treatment they received), and all patients with anthrax meningoencephalitis died.

Limitations: This was a retrospective case review of previously published heterogeneous reports.

Conclusions: Despite advances in supportive care, fulminant-phase inhalational anthrax is usually fatal. Initiation of antibiotic or anthrax antiserum therapy during the prodromal phase is associated with markedly improved survival, although other aspects of care, differences in clinical circumstances, or unreported factors may contribute to this observed reduction in mortality. Efforts to improve early diagnosis and timely initiation of appropriate antibiotics are critical to reducing mortality.


Grahic Jump Location
Appendix Figure 1. This figure shows point and range time estimates (minimum and maximum) from symptom onset until antibiotic or antiserum therapy initiation for those who lived and those who died. US = United States.
Time duration from symptom onset to antibiotic initiation.
Grahic Jump Location
Grahic Jump Location
Appendix Figure 2. The maximum likelihood estimate of untreated (i.e., no antibiotics or antiserum), prodromal to fulminant-phase disease progression is shown by using a Weibull ( ) or log-normal ( ) distribution. Panels C and D show the probability of progression from prodromal to fulminant phase after symptom onset if no antibiotics or anthrax antiserum are given by using the Weibull or log-normal distribution, respectively.
Weibull and log-normal maximum likelihood estimates of untreated prodromal stage duration.panel Apanel B
Grahic Jump Location
Grahic Jump Location
Figure 2.
Predicted mortality rate on the basis of time of antibiotic initiation.circlesquare

This graph predicts mortality rate as a function between symptom onset and antibiotic initiation. On day 4 after symptom onset (where 51% of patients are predicted to have progressed to the fulminant phase), the mortality rate was estimated at 58%: ([{0.012 × 4} + 0.1] × 0.49) + (1.0 × 0.51). See text for details. This curve closely matches the observed mortality during the 2001 U.S. attack. The median time from symptom onset to antibiotic treatment for U.S. 2001 cases was 4.7 days. The U.S. 2001 patients who received antibiotics in less than 4.7 days (median, 3.3 days) had an observed mortality rate of 40% ( ; predicted mortality rate, 45%). Antibiotic treatment initiation of 4.7 days or more (median, 4.9 days) during the U.S. 2001 attack resulted in an observed mortality rate of 75% ( ; predicted mortality rate, 74%). This graph assumes that multidrug regimens, pleural fluid drainage, and intensive care support are provided, as observed during the 2001 U.S. attack.

Grahic Jump Location




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