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

Key Summary Points Initiation of antibiotic or anthrax antiserum therapy during the prodromal phase of inhalational anthrax is associated with an improved short-term survival. Multidrug antibiotic regimens are associated with decreased mortality, especially when they are administered during the prodromal phase. Most surviving patients will probably require drainage of reaccumulating pleural effusions. Despite modern intensive care, fulminant-phase anthrax is rarely survivable. The 2001 anthrax attack demonstrated the vulnerability of the United States to anthrax bioterrorism. The mortality rate observed during the 2001 U.S. attack (45%) was considerably lower than that historically reported for inhalational anthrax (89% to 96%) (1, 2). This reduction generally is attributed to the rapid provision of antibiotics and supportive care in modern intensive care units (3). However, no comprehensive reviews of reports of inhalational anthrax cases (including those from 2001) that evaluate how patient factors and therapeutic interventions affect disease progression and mortality have been published. Before the introduction of antibiotics, anthrax infection was primarily treated with antiserum (4). Anthrax antiserum reportedly decreased mortality by 75% compared with no treatment (5-8), and its efficacy is supported by recent animal data (9). Later, effective antibiotics, such as penicillin and chloramphenicol, were added to anthrax treatment strategies (10, 11). Currently, combination antibiotic therapy with ciprofloxacin (or doxycycline), rifampin, and clindamycin is recommended on the basis of anecdotal evidence from the U.S. 2001 experience (1, 12, 13). Historically, the clinical course of untreated inhalational anthrax has been described as biphasic, with an initial benign prodromal latent phase, characterized by a nonspecific flu-like syndrome, followed by a severe fulminant acute phase, characterized by respiratory distress and shock that usually culminates in death (2, 14). The duration of the prodromal phase has been reported to range from 1 to 6 days (14, 15), whereas that of the fulminant phase has been described as less than 24 hours (14, 16). A 1957 study confirmed these estimates of disease progression but was based on only 6 patients (17). Because a report synthesizing the data from all reported cases of inhalational anthrax (including those from 2001) has not been published, we do not have accurate estimates of the time course associated with disease progression or a clear understanding of the extent to which patient characteristics and treatment factors affect disease progression and mortality. This information is important for developing appropriate treatment and prophylaxis protocols and for accurately simulating anthrax-related illness to inform planning efforts for bioterrorism preparedness. We systematically reviewed published cases of inhalational anthrax between 1900 and 2005 to evaluate the effects of patient factors (for example, age and sex) and therapeutic factors (for example, time to onset of treatment) on disease progression and mortality. Methods Literature Sources and Search Terms We searched MEDLINE to identify case reports of inhalational anthrax (January 1966 to June 2005) by using the Medical Subject Heading (MeSH) terms anthrax and case reports. Because many reports were published before 1966 (the earliest publication date referenced in MEDLINE), we performed additional comprehensive searches of retrieved bibliographies and the indexes of 14 selected journals from 1900 to 1966 (for example, New England Journal of Medicine, The Lancet, La Presse Mdicale, Deutsche Medizinische Wochenschrift, and La Semana Mdica) to obtain additional citations. We considered all case reports of inhalational anthrax to be potentially eligible for inclusion, regardless of language. Study Selection We considered a case report to be eligible for inclusion if its authors established a definitive diagnosis of inhalational anthrax. Appendix Table 1 presents the details of our inclusion criteria. We excluded articles that described cases presenting before 1900 because Bacillus anthracis was not identified as the causative agent of clinical inhalational anthrax until 1877 (18) and because the use of reliable microscopic (19) and culture examination techniques (20) to confirm the diagnosis were not developed until the late 19th century. Appendix Table 1. Inclusion Criteria Data Abstraction One author screened potentially relevant articles to determine whether they met inclusion criteria. Two authors independently abstracted data from each included English-language article and reviewed bibliographies for additional potentially relevant studies. One author abstracted data from nonEnglish-language articles. We resolved abstraction discrepancies by repeated review and discussion. If 2 or more studies presented the same data from 1 patient, we included these data only once in our analyses. We abstracted 4 types of data from each included article: year of disease onset, patient information (that is, age, sex, and nationality), symptom and disease progression information (for example, time of onset of symptoms, fulminant phase, and recovery or death and whether the patient developed meningitis), and treatment information (for example, time and disease stage of the initiation of appropriate treatment and hospitalization). We based our criteria for determining whether a patient had progressed from the prodromal phase to the fulminant phase on distinguishing clinical features of five 2001 (3, 21, 22) and five 1957 (17) cases of fulminant inhalational anthrax. The fulminant phase is described historically as a severe symptomatic disease characterized by abrupt respiratory distress (for example, dyspnea, stridor, and cyanosis) and shock. Meningoencephalitis has been reported to occur in up to 50% of cases of fulminant inhalational anthrax (23). We considered any patient who had marked cyanosis with respiratory failure, who needed mechanical ventilation, who had meningoencephalitis, or who died as having been in the fulminant phase of disease. We used the reported time of an acute change in symptoms or deteriorating clinical picture to estimate when a confirmed fulminant case had progressed from the prodromal phase. We considered therapy for inhalational anthrax to be appropriate if either an antibiotic to which anthrax is susceptible was given (by oral, intramuscular, or intravenous routes) (24-27) or anthrax antiserum therapy was initiated. We classified patients who received antibiotics that are resistant to strains of B. anthracis (<70% susceptibility) as having received no antibiotics. If treatment with antibiotics or antiserum was given, we assumed that the treatment was appropriately dosed and administered. Statistical Analyses We used univariate analyses with SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina), to summarize the key patient and treatment characteristics. We compared categorical variables with the Fisher exact test and continuous variables with a 2-tailed WilcoxonMannWhitney test. For single comparisons, we considered a P value less than 0.05 to be statistically significant. When comparing U.S. 2001 with pre-2001 cases (or comparing patients who lived with those who died), we applied a Bonferroni correction to account for multiple comparisons (we considered P< 0.025 to be statistically significant: 0.05/2 = 0.025). We computed correlations for pairs of predictors available for each case at the beginning of the course of disease. Adjustments for Censored Data Infectious disease data are subject to incomplete observations of event times (that is, to censoring), particularly in the presence of therapeutic interventions. This can lead to invalid estimation of relevant event time distributions. For example, patients with longer prodromal stage durations are more likely to receive antibiotics than patients with shorter prodromal stage durations, and they may be, therefore, less likely to progress to fulminant stage or death. To account for censoring of our time data, we used maximum likelihood estimates by using both Weibull and log-normal distributions (28). The Appendix provides a detailed description of these analyses. Evaluating Predictors of Disease Progression and Mortality We used a multivariate Cox proportional hazards model to evaluate the prognostic effects of the following features on survival: providing antibiotics or antiserum (a time-dependent covariate in 3 categories: none, single-drug regimen, or multidrug regimen); the stage during which treatment with antibiotics or antiserum was initiated (prodromal stage vs. fulminant stage or no therapy); age (continuous variable); sex; if therapy was given, whether patients received a multidrug regimen (for example, 2 appropriate antibiotics or combination antibioticanthrax antiserum therapy); the use of pleural fluid drainage (a time-dependent covariate); development of anthrax meningoencephalitis (a time-dependent covariate); and whether the case was from the 2001 U.S. attack. We assessed each variable by stepwise backward regression using a P value cutoff of 0.100 or less. We excluded 8 adult patients for whom age was not reported. Although we did not perform extensive goodness-of-fit tests of our models, we did at least fit models in which we entered time not only linearly but also quadratically. Improvement in fit, as judged by conventional Wald and other tests, did not result, nor did including quadratic time variables further explain the data. To estimate mortality as a function of duration from symptom onset to antibiotic initiation, we first calculated a disease progression curve describing the time from symptom onset to fulminant phase among untreated patients by using the Weibull maximum likelihood estimates from the 71 cases for which time estimates were known. We then assigned a mortality rate to patients who had treatmen