David S. Stephens

Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax

During October and November 2001, public health authorities investigated 11 patients with inhalational anthrax related to a bioterrorism attack in the United States. Formalin-fixed samples from 8 patients were available for pathological and immunohistochemical (IHC) study using monoclonal antibodies against the Bacillus anthracis cell wall and capsule. Prominent serosanguinous pleural effusions and hemorrhagic mediastinitis were found in 5 patients who died. Pulmonary infiltrates seen on chest radiographs corresponded to intraalveolar edema and hyaline membranes. IHC assays demonstrated abundant intra- and extracellular bacilli, bacillary fragments, and granular antigen-staining in mediastinal lymph nodes, surrounding soft tissues, and pleura. IHC staining in lung, liver, spleen, and intestine was present primarily inside blood vessels and sinusoids. Grams staining of tissues was not consistently positive. In 3 surviving patients, IHC of pleural samples demonstrated abundant granular antigen-staining and rare bacilli while transbronchial biopsies showed granular antigen-staining in interstitial cells. In surviving patients, bacilli were not observed with grams stains. Pathological and IHC studies of patients who died of bioterrorism-related inhalational anthrax confirmed the route of infection. IHC was indispensable for diagnosis of surviving anthrax cases. The presence of B. anthracis antigens in the pleurae could explain the prominent and persistent hemorrhagic pleural effusions.

Genetic Basis for Nongroupable Neisseria meningitidis

Nongroupable Neisseria meningitidis may constitute one-third or more of meningococcal isolates recovered from the nasopharynx of human carriers. The genetic basis for nongroupability was determined in isolates obtained from a population-based study in which 60 (30.9%) of 194 meningococcal isolates from asymptomatic carriers were not groupable. Forty-two percent of nongroupable isolates were related to serogroup Y ET-508/ST-23 clonal complex strains, the most common groupable carrier isolate from the study population. Nongroupable isolates were all rapidly killed by 10% normal human serum. The capsule loci of 6 of the ET-508/ST-23 complex strains and of 25 other genetically diverse nongroupable meningococci were studied in detail. Serogroup A or novel capsule biosynthesis genes were not found. Nongroupable isolates were genetically serogroup Y, B, or C isolates that did not express capsule but were related to groupable isolates found in the population (class I); capsule deficient because of insertion element-associated deletions of capsule biosynthesis genes (class II); or isolates that lacked all capsule genes and formed a distinct genetic cluster not associated with meningococcal disease (class III).

Pathogenesis and diagnosis of human meningococcal disease using immunohistochemical and PCR assays.

Neisseria meningitidis remains the leading cause of fatal sepsis. Cultures may not be available in fulminant fatal cases. An immunohistochemical assay for N meningitidis was applied to formalin-fixed samples from 14 patients with meningococcal disease. Histopathologic findings in 12 fatal cases included interstitial pneumonitis, hemorrhagic adrenal glands, myocarditis, meningitis, and thrombi in the glomeruli and choroid plexus. Meningeal inflammation was observed in 6 patients. Skin biopsies of 2 surviving patients showed leukocytoclastic vasculitis and cellulitis. By using immunohistochemical analysis, meningococci and granular meningococcal antigens were observed inside monocytes, neutrophils, and endothelial cells or extracellularly. By using real-time polymerase chain reaction (PCR) on formalin-fixed tissue samples, meningococcal serogroup determination was possible in 11 of 14 cases (8 serogroup C, 2 Y, and 1 B). Diagnosis and serogrouping of N meningitidis can be performed using immunohistochemical analysis and PCR on formalin-fixed tissue samples. Immunohistochemical analysis determined the distribution of meningococci and meningococcal antigens in tissue samples, allowing better insights into N meningitidis pathogenesis.

Assessing the Risk of Laboratory-Acquired Meningococcal Disease

ABSTRACT Neisseria meningitidis is infrequently reported as a laboratory-acquired infection. Prompted by two cases in the United States in 2000, we assessed this risk among laboratorians. We identified cases of meningococcal disease that were possibly acquired or suspected of being acquired in a laboratory by placing an information request on e-mail discussion groups of infectious disease, microbiology, and infection control professional organizations. A probable case of laboratory-acquired meningococcal disease was defined as illness meeting the case definition for meningococcal disease in a laboratorian who had occupational exposure to an N. meningitidis isolate of the same serogroup within 14 days of illness onset. Sixteen cases of probable laboratory-acquired meningococcal disease occurring worldwide between 1985 and 2001 were identified, including six U.S. cases between 1996 and 2000. Nine cases (56%) were serogroup B; seven (44%) were serogroup C. Eight cases (50%) were fatal. All cases occurred among clinical microbiologists. In 15 cases (94%), isolate manipulation was performed without respiratory protection. We estimated that an average of three microbiologists are exposed to the 3,000 meningococcal isolates seen in U.S. laboratories yearly and calculated an attack rate of 13/100,000 microbiologists between 1996 and 2001, compared to 0.2/100,000 among U.S. adults in general. The rate and case/fatality ratio of meningococcal disease among microbiologists are higher than those in the general U.S. population. Specific risk factors for laboratory-acquired infection are likely associated with exposure to droplets or aerosols containing N. meningitidis. Prevention should focus on the implementation of class II biological safety cabinets or additional respiratory protection during manipulation of suspected meningococcal isolates.

Economics of an Adolescent Meningococcal Conjugate Vaccination Catch-up Campaign in the United States

BACKGROUNDnIn June 2005, the Advisory Committee on Immunization Practices recommended the newly licensed quadrivalent meningococcal conjugate vaccine for routine use among all US children aged 11 years. A 1-time catch-up vaccination campaign for children and adolescents aged 11-17 years, followed by routine annual immunization of each child aged 11 years, could generate immediate herd immunity benefits. The objective of our study was to analyze the cost-effectiveness of a catch-up vaccination campaign with quadrivalent meningococcal conjugate vaccine for children and adolescents aged 11-17 years.nnnMETHODSnWe built a probabilistic model of disease burden and economic impacts for a 10-year period with and without a program of adolescent catch-up meningococcal vaccination, followed by 9 years of routine immunization of children aged 11 years. We used US age- and serogroup-specific surveillance data on incidence and mortality. Assumptions related to the impact of herd immunity were drawn from experience with routine meningococcal vaccination in the United Kingdom. We estimated costs per case, deaths prevented, life-years saved, and quality-adjusted life-years saved.nnnRESULTSnWith herd immunity, the catch-up and routine vaccination program for adolescents would prevent 8251 cases of meningococcal disease in a 10-year period (a 48% decrease). Excluding program costs, this catch-up and routine vaccination program would save US

Management of anthrax meningitis

551 million in direct costs and

Molecular epidemiology of sporadic (endemic) serogroup C meningococcal disease

920 million in indirect costs, including costs associated with permanent disability and premature death. At

Common Variable Hypogammaglobulinemia Complicated by an Unusual T-Suppressor/Cytotoxic Cell Lymphoma

83 per vaccinee, the catch-up vaccination would cost society approximately

The changing epidemiology of meningococcal disease in the United States

223,000 per case averted, approximately

Invasion associated genes from neisseria meningitidis serogroup b

2.6 million per death prevented, approximately