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Tularemia: Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis
Last updated May 28, 2008
Agent
Pathogenesis
Epidemiology
—Reservoirs/Vectors/Modes of Transmission
—Naturally Occurring Tularemia in the United States
—Naturally Occurring Tularemia Worldwide
—Tularemia as a Biological Weapon
Clinical Syndromes
—Overview
—Glandular and Ulceroglandular Tularemia
—Pneumonic Tularemia
—Oculoglandular Tularemia
—Oropharyngeal Tularemia
—Typhoidal Tularemia
Pediatric Considerations
Differential Diagnosis
—Glandular Tularemia
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Ulceroglandular Tularemia
—Pneumonic Tularemia
—Oculoglandular Tularemia
—Oropharyngeal Tularemia
—Typhoidal Tularemia
Laboratory Diagnosis
—Specimen Collection and Transport
—Laboratory Biosafety and Biosecurity Information
—Laboratory Response Network (LRN)
—Standard Tests for Detection of F tularensis
—Additional Tests for Detection, Confirmation, and Characterization of F tularensis
Postexposure Prophylaxis for Tularemia
Treatment of Tularemia
Tularemia Vaccine
Infection Control
Issues Related to Autopsies and Burial
Public Health Reporting and Case Definitions
Images
References
Agent
Microbiologic Characteristics
Tularemia is caused by Francisella tularensis (formerly Pasteurella tularensis). Key microbiologic characteristics include the following (see References: CDC/ASM/APHL 2001: Basic protocols for level A laboratories for the presumptive identification of Francisella tularensis; Cross 2000; Sneath 1986; Wong 1999).
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Tiny, faintly staining, pleomorphic gram-negative rods (0.2-0.5 mcm x 0.7-1.0 mcm); smaller in patient samples than in culture; may be confused with Haemophilus species
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Difficult to see by light microscopy in blood, tissue samples, or other specimens that contain significant background material
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Nonsporulating, nonmotile
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Aerobic (obligatory)
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Requires cysteine (or cystine) for growth (although atypical strains that lack this requirement have been identified [see References: Bernard 1994])
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Grows on commercial blood culture media, but does not grow (or grows unreliably) on most other standard agar media
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Visible growth on appropriate media requires 2 to 4 days
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Weakly catalase-positive (although may be negative), oxidase-negative
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Thin lipid-rich capsule
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Distinctive cellular fatty-acid profile
Other characteristics of F tularensis include the following:
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Wild-type F tularensis strains generally are susceptible to aminoglycosides (streptomycin, gentamicin, kanamycin), tetracyclines, chloramphenicol, and fluoroquinolones.
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F tularensis strains generally are resistant to beta-lactam antibiotics, owing in part to beta-lactamase activity.
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Organisms can persist for long periods of time in water, mud, and decaying animal carcasses (ie, moist environments).
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Ingestion of F tularensis by environmental amebas may affect the bacterial ecology by:
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Increasing environmental resistance
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Increasing virulence (see References: Berdal 1996)
Subspecies
There are four subspecies of F tularensis. These subspecies can be differentiated by biochemical and molecular tests, and the current taxonomy is as follows (see References: Ellis 2002, Kugeler 2006, Morner 1993, Whipp 2003):
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F tularensis subsp tularensis (type A) (see References: Johansson 2004, Farlow 2005, Peterson 2006, Svensson 2004):
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Highly infectious, generally more virulent, and more genetically diverse than subsp holarctica
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Found primarily in North America
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Demonstrates citrulline ureidase activity
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Produces acid from glycerol fermentation
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Two distinct genetic clades have been identified. The geographic distribution of the two clades in human cases correlates with the distribution of arthropod vectors and rabbit hosts (see References: Farlow 2005):
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Clade 1 (aka subpopulation 1, A.I, type A-east) occurs primarily in the central United States, is associated with the distribution of Amblyomma americanum (the Lone Star tick) and Dermacentor variabilis (the American dog tick), and appears to have a high case-fatality rate.
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Clade 2 (aka subpopulation 2, A.II, type A-west) occurs primarily in the western United States, is associated with the distribution of Dermacentor andersoni (the Rocky Mountain wood tick) and Chrysops discalis (the deer fly), and has a low case-fatality rate.
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F tularensis subsp holarctica (type B): Less virulent than subsp tularensis, does not demonstrate citrulline-ureidase activity, and does not produce acid from glycerol fermentation; three biovars have been identified:
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Biovar I: erythromycin sensitive; primarily found in North America, Europe, Siberia, the Far East, and Kazakhstan
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Biovar II: erythromycin resistant; primarily found in Eurasia
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Biovar japonica: found in Japan
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F tularensis subsp mediasiatica: Found in the Central Asian republics of the former Soviet Union (virulence is similar to subsp holarctica); produces acid from glycerol and thus may be confused with subsp tularensis (see References: Whipp 2003)
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F tularensis subsp novicida: Considered to be of low virulence and generally causes illness only in immunocompromised hosts (see References: Titball 2003) (note: F tularensis and F novicida traditionally have been considered separate species; however, the current approach is to consider F novicida as a subspecies of F tularensis); produces acid from glycerol and thus may be confused with subsp tularensis [see References: Cross 2000, Hollis 1989, Sjostedt 2003, Titball 2003, Whipp 2003])
Genomic, Proteomic Studies
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Strains of both major clades (A.I and A.II) of F tularensis subsp tularensis have been fully sequenced (see References: Larsson 2005, Beckstrom-Sternberg 2007).
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Comparison of sequences from the A.I strain (Schu S4) and the A.II strain (WY96-3418) revealed extensive genomic variation between strains (rearrangements including insertion/deletions, translocations, inversions) but only one whole gene difference. The gene difference is a protein of unknown function (see References: Beckstrom-Sternberg 2007).
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Other investigators took two human clinical isolates (one of an A.I strain and one of an A.II strain) and used subtractive hybridization methods to compare the strains; 13 genomic regions of difference were found. The information was used to develop polymerase chain reaction (PCR) assays for discriminating between different species and for identifying A.I isolates (see References: Molins-Schneekloth 2008).
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More than 96% of the protein coding sequences of F tularensis have been sequenced, and the clones have been used to produce recombinant proteins for 72% of the genes (see References: Murthy 2007).
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A comparative proteome analysis of F tularensis subsp tularensis, F tularensis subsp holarctica, and F tularensis subsp novicida strains identified 27 F tularensis–specific spots, which may represent putative virulence factors (see References: Hubalek 2004). Comparative analysis of proteins from the highly virulent subsp tularensis strain SCHU S4 and three other strains of subsp holarctica may allow characterization of novel virulence factors (see References: Pavkova 2006).
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A study of genomic variable number tandem repeats (VNTR) suggests that F tularensis and F tularensis subsp holarctica display primarily clonal population structures, with little evidence of horizontal DNA transfer between subspecies (see References: Johansson 2004).
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Comparative genomic analyses of F tularensis subsp holarctica isolates from North America, France, and Spain identified a 1.59-kb genomic deletion specific to the French and Spanish isolates. Analyses suggested that these strains were recently introduced or had recently emerged by clonal expansion in France and the Iberian Peninsula (see References: Dempsey 2007).
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A comparison of genomic sequences for a type A strain (Schu4) and a type B strain (OSU18) found that the most significant difference between the isolates studied was the amount of genomic rearrangement within the strains. The type A strain was highly rearranged compared with the type B strain and compared with the type B live vaccine strain (LVS). Numerous pseudogenes were present in the type A strain; these may contribute to pathogenicity (see References: Petrosino 2006).
Other Francisella species
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May be confused with F tularensis in clinical or environmental samples
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F philomiragia is the only other taxonomically defined species in the genus other than F tularensis. It is halophilic, rarely associated with human disease, and difficult to identify by conventional methods (see References: Ellis 2002, Friis-Moller 2004, Whipp 2003).
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Undefined Francisella-like bacteria appear to be common in the environment (see References: Barnes 2005).
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Pathogenesis
Virulence factors that contribute to pathogenesis of F tularensis have not been well defined and further studies are needed. The following points have been summarized in several recent studies and reviews (see References: Ellis 2002, Sjostedt 2003, Titball 2003):
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F tularensis is a facultative intracellular pathogen that multiplies predominantly within macrophages. The organisms initially enter macrophages through phagocytosis by a novel process of engulfment within asymmetric pseudopod loops and then disrupt the phagosomal membrane to gain direct access to the cytoplasm (see References: Clemens 2004). Adherence and uptake of F tularensis by macrophages is dependent on complement receptors and serum with intact complement factor C3; uptake also requires actin microfilaments (see References: Clemens 2005) as well as microtubules and other cytokeletal elements (see References: Lindemann 2007). Human macrophages appear to phagocytose more F tularensis organisms than monocytes. Complement receptor 3 (CR3), Fc gamma receptors and the mannose receptor on the cell surface, as well as surfactant protein A (SP-A) present in lung alveoli, apparently contribute to
this process (see References: Balagopal 2006). Infection of human monocytes by F tularensis Schu4 leads to IL-23 production, and its release may be relevant during immune responses in infection (see References: Butchar 2007).
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F tularensis virulence is determined in part by the ability of the organisms to replicate within macrophages. Bacteria are released from the macrophage following cell death by apoptosis. Organisms grown in macrophages have been shown to decrease stimulation of cytokine secretion and are more lethal to mice than organisms grown in broth (see References: Loegering 2006).
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A recent study using a murine model demonstrated high levels of F tularensis in the plasma of infected mice. On the basis of this finding, the authors suggest that F tularensis in the blood of infected hosts is taken up by and replicates within leukocytes and eventually escapes into the plasma, where it propagates a cycle of infection, escape, and reinfection (see References: Forestal 2007).
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Catalase, a bacterial enzyme that can detoxify bactericidal compounds such as H2O2 and ONOO-, may play a role in the differences observed between clinical strains of the pathogen (see References: Lindgren 2007).
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Intracellular survival requires altered expression of several genes.
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One recent study showed that acid phosphatases can affect intramacrophage survival of Francisella species (see References: Mohapatra 2007). A mutant strain with decreased acid phosphatase activity was found to be more susceptible to intracellular killing when compared with a wild type strain.
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In another study, inactivation of wbtA, a gene in the lipopolysaccharide O-antigen gene cluster, severely attenuated virulence in a mouse model (see References: Raynaud 2007). Additional experiments with strains containing mutated O antigen suggest that O antigen loss alters Francisella phenotype, abrogates virulence, and compromises induction of full protective immunity against F tularensis (see References: Li 2007). Mutant strains used in production of a vaccine reveal that Francisella possessing an inactivated wbtA-encoded dehydratase of the O antigen polysaccharide have a markedly attenuated virulence (see References: Sebastian 2007). Immunologically distinct O antigens serve as virulence determinants and protective antigens that differ between subspecies (see References: Thomas 2007).
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The capsule is necessary to protect against serum-mediated lysis but is not required for survival following phagocytosis. The capsule may be a necessary component of full virulence. Recent genome-wide analysis of 95 different genes in F tularensis identified a capsule gene responsible for virulence. Deletional mutation analysis of a capsule locus resembling the poly-gamma glutamate capsule biosynthesis locus of B anthracis revealed that the gene is essential for F tularensis virulence (see References: Su 2007).
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The lipopolysaccharide (LPS) does not exhibit the properties of a classic endotoxin and demonstrates low toxicity in vivo and in vitro, although LPS may have a role in macrophage growth. In human monocytic cells, F tularensis LPS has been shown to activate extracellular signal-regulated kinases and the production of pro-inflammatory proteins (see References: Duenas 2006).
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F tularensis subsp novicida mutants that lack LpxF, a selective phosphatase on the periplasmic surface of the inner membrane, were highly susceptible to polymyxin, a cationic antimicrobial peptide. LpxF likely represents a type of virulence factor that confers a distinct lipid A phenotype, preventing Francisella from activating host innate immune response and bactericidal actions of cationic peptides. Such lpxF mutants may be useful for immunizations against tularemia (see References: Wang 2007).
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The more virulent type A strains demonstrate citrulline ureidase activity; however, the role of this feature in virulence is not clear.
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The presence of type IV pili appears to be a virulence factor and may be particularly important for F tularensis infections that occur via the peripheral route. Direct repeat-mediated deletion of genes coding for type IV pili results in major virulence attenuation (see References: Forslund 2006).
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The type IV pili are involved in secretion of a number of proteins, including a protease referred to as PepO. PepO appears to increase production of endothelin and to increase vasoconstriction at the infection site; these factors may limit spread of the organisms.
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Pathogenic strains contain a mutation in pepO that abolishes its secretion. Mutational studies in mice suggest that loss of PepO protease may have contributed to the evolution of highly virulent Francisella strains (see References: Hager 2006).
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Recent studies of deletion mutants in complementation experiments have indicated that the tolC gene codes for a critical virulence factor of F tularensis in addition to playing a role in multidrug resistance (see References: Gil 2006).
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Transcriptional profiling of peripheral blood response during ulceroglandular tularemia provided a description of human gene subsets relevant to the pathogenesis of the disease and subsets that may serve as early diagnostic markers for infection. Researchers analyzed microarrays comprising 14,500 genes from seven affected individuals at five occasions during the first 2 weeks after the first hospital visit and convalescent samples 3 months afterward. They found that genes involved in generating innate and acquired immune responses were downregulated in the affected individuals, which presumably was caused by F tularensis (see References: Andersson 2006).
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Analyses with bacterial two-hybrid systems and biochemical assays have demonstrated that two proteins (MglA and SspA) associate with RNA polymerase to positively regulate virulence gene expression (see References: Charity 2007). Studies of MglA-regulated genes in in vivo competition experiments have led to the identification of five new Francisella virulence genes. Characterization of these genes may provide additional insight into pathogenesis of this organism (see References: Brotcke 2006). A newly constructed transposon mutant library of F tularensis subsp novicida, a low pathogenicity subspecies, may serve as a resource for detailed identification of virulence genes and other functional genes (see References: Gallagher 2007). A microarray-based negative selection screen used to identify Francisella genes that contribute to survival or growth in mice found 44 previously unidentified
genes necessary for Francisella virulence in vivo. These findings indicate that uncharacterized pathways may also cause disease (see References: Weiss 2007).
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In mice infected intranasally with the live vaccine strain of F tularensis subsp holarctica, tissue-specific interleukin (IL)-6, macrophage inflammatory protein 2, and monocyte chemotactic protein 1 were immune markers of mortality, while anti-LVS immunoglobulin M and IL-1-beta were associated with survival. Surviving mice had more prominent splenomegaly and normal-appearing lungs compared with moribund mice. Such results suggest that host immune factors can affect bacterial dissemination after respiratory infection (see References: Chiavolini 2008).
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Targeted gene disruption may discern virulence genes in F tularensis and the relative contributions of specific genes, including those within the F tularensis pathogenicity island. The technique has been optimized for F tularensis and employs mobile group II introns (targetrons). The method has been tested using three different subspecies (F tularensis subsp tularensis, holarctica, and novicida) and used to generate mutated strains for experiments (see References: Rodriguez 2008).
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Additional research has shown that the orphan response regulator pmrA is an important factor in controlling virulence in F tularensis subsp novicida, and a pmrA mutant strain is an effective vaccine against homologous challenge (see References: Mohapatra).
Pathologic features for the various clinical syndromes caused by F tularensis have been described and are briefly summarized below.
Pneumonic Tularemia
Organisms enter the lungs either through inhalation of infectious aerosols or through hematogenous spread. The infectious dose by the respiratory route is 10 to 50 organisms (see References: Franz 1997, Saslow 1961). Studies in a mouse model suggest that death following low-dose aerosol exposure is primarily due to systemic rather than pulmonary effects (see References: Conlan 2003). Among mice inoculated with Francisella intranasally, the organism became localized in the alveolus and replicated within alveolar type II (AT II) epithelial cells (see References: Hall 2007). Studies of cultured AT II cells demonstrate that they play a crucial role in the innate immune response to the organism (see References: Gentry 2007).
Once in the lungs, the organisms rapidly enter pulmonary macrophages (within minutes) and begin replicating. The explosive replicative capacity of F tularensis appears to be an important factor in virulence associated with pulmonary infection (see References: Malik 2006). An intense accumulation of inflammatory cells, particularly neutrophils and macrophages, can be seen at sites of bacterial replication. The influx of neutrophils appears to play more of a destructive than protective role in the host response.
The following features have been noted for pneumonic tularemia (see References: Lillie 1937, Stuart 1945, Syrjala 1986):
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Ulcerative bronchitis and bronchiolitis
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Hemorrhagic edema with a nonspecific inflammatory response consisting of lymphocytes, plasma cells, and eosinophils (early in the clinical course)
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Discrete nodules with acute suppurative necrosis of lung parenchyma
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Alveolar exudates involving mononuclear cells, fibrin, and red blood cells
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Nodular, segmental, or lobar consolidation
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Caseous or cavitary lesions (later in the clinical course)
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Granuloma formation (late in the clinical course)
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Pleural fibrinous, fibrinocellular, or fibrinocaseous exudation
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Hilar lymphadenopathy
Glandular and Ulceroglandular Tularemia
In both glandular and ulceroglandular tularemia, organisms enter the skin through the bite of infective arthropods, direct contact with infectious materials (such as contaminated carcasses), or percutaneous inoculation with a sharp object (such as a bone fragment from a contaminated carcass).
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Organisms can enter through inapparent breaks in the skin surface.
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The infectious dose for humans following percutaneous or inhalational inoculation is 10 to 50 organisms (see References: Cross 2000).
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In the ulceroglandular form, the organisms proliferate locally and cause a papule to develop at the site of inoculation within 3 to 5 days after initial exposure (see References: Cross 2000).
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The papule develops as a result of a localized inflammatory response that involves fibrin, neutrophils, macrophages, and T lymphocytes.
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The initial inflammatory nidus becomes necrotic and degenerates over the next several days, thereby forming a tender ulcerated lesion at the site of the papule.
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The ulcer is typically 2 to 4 cm in diameter and has an irregular and raised border.
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A dark scab (which may resemble the characteristic eschar of anthrax) may occur over the area of ulceration.
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Organisms spread from the site of inoculation to regional lymph nodes, where they cause necrotizing lymphadenitis surrounded by a neutrophilic and granulomatous inflammatory infiltrate (see References: CDC: Medical examiners, coroners, and biologic terrorism: A guidebook for surveillance and case management). Granulomas may develop in lymph nodes as the inflammatory process progresses; these may eventually coalesce to form abscesses. Follicular hyperplasia and inflammatory cell infiltrates involving predominantly granulocytes often are noted (see References: Sutinen 1986).
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Affected lymph nodes may become fluctuant, rupture, and sometimes create draining sinus tracts in the skin.
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Organisms may disseminate via hematogenous spread to involve multiple organs, and sepsis syndrome can occur.
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In glandular tularemia, regional lymph node involvement occurs, but ulceration at the site of inoculation is absent.
Oculoglandular Tularemia
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Organisms gain entry via the conjunctiva.
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Superficial necrosis and ulceration of the conjunctiva occur, often accompanied by lymphocytic infiltration. Papules also may be noted (see References: Lillie 1937).
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Granulomatous nodules may develop over time (see References: Lillie 1937).
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Organisms spread from the conjunctiva to the preauricular, submandibular, or cervical lymph nodes, where they cause focal necrosis and lesions similar to those noted with ulceroglandular tularemia.
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Infection most commonly is unilateral.
Oropharyngeal Tularemia
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Organisms enter the mucous membrane of the oropharynx following ingestion or inhalation of organisms.
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Exudative pharyngitis or tonsillitis usually occurs, and ulcers may develop.
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Organisms spread to the cervical lymph nodes where necrosis and suppuration may occur.
Typhoidal Tularemia
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Typhoidal tularemia involves a systemic illness without anatomic localization of infection.
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Organisms enter the bloodstream through breaks in the skin or through mucous membranes and may affect the lungs and reticuloendothelial organs (ie, lymph nodes, liver, spleen, bone marrow).
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Necrotic foci can occur in any involved organ, and caseating granulomas may develop.
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Sepsis may occur, leading to shock, organ system failure, adult respiratory distress syndrome, and disseminated intravascular coagulation.
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Epidemiology
Reservoirs/Vectors/Modes of Transmission
Reservoirs
Small and medium-sized mammals are the principal natural reservoirs for F tularensis. Examples include (see References: Dennis 1998, Gelman 1961, Hopla 1974):
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Lagomorphs (rabbits, hares) (predominantly North America, Europe, Japan)
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Aquatic rodents (beaver, muskrats, water voles)
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Field voles
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Water and wood rats
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Squirrels
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Lemmings (former Soviet Union, Sweden, Norway)
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Meadow and field mice (predominantly former Soviet Union)
Humans, other mammalian species (eg, cats, dogs, cattle, primates), and some species of birds, fish, and amphibians are incidental hosts.
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A recent serologic survey of 91 cats in Connecticut and New York found that 12% had antibody to F tularensis (see References: Magnarelli 2007).
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An outbreak of tularemia in commercially distributed prairie dogs was recognized in the United States in 2002 (see References: CDC: Outbreak of tularemia among commercially distributed prairie dogs, 2002; Petersen 2004). Serologic testing of potentially exposed persons demonstrated that one person (an animal handler) had a positive F tularensis titer of 1:128 on initial testing that subsequently declined to 1:32 on follow-up testing at 4 and 6 months, suggesting prairie dog–to-human transmission (see References: Avashia 2004).
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A recent outbreak in a colony of semi–free living common marmosets in Gottingen, Germany, represented the first isolates found in Germany in 45 years. The area had several geographic and ecological characteristics known to favor long-term presence of F tularensis. Multiple factors could be responsible and include persistence of the pathogen in remote areas, continuous reintroduction from Eastern European countries after the fall of the Iron Curtain, or introduction through bird migration (see References: Splettstoesser 2007).
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Outbreaks also have occurred in nonhuman primates housed outdoors. In a German primate facility, 18 of 35 cynomolgus monkeys (Macaca fasicularis) contracted tularemia within a 2-year period; six of the animals died (see References: Matz-Rensing 2007).
Information from studies conducted on Martha's Vineyard suggest that F tularensis can persist in the environment and that persons can acquire infection by engaging in activities that lead to aerosolization (such as lawn mowing, weed-whacking, and using a power blower) (see References: Feldman 2001, Feldman 2003). A recent analysis of sera from a variety of mammals on Martha’s Vineyard found that skunks and raccoons were frequently seroreactive (49% of skunks tested and 52% of raccoons), whereas white-footed mice, cottontail rabbits, deer, rats, and dogs were much more likely to be seronegative (see References: Berrada 2006).
During the fall and winter of 2003, F tularensis was identified on several filters from a biodetection air-monitoring system in Houston, Texas (see References: CIDRAP News 2003). An investigation conducted at that time supported contamination of the filters by naturally occurring F tularensis organisms, although the environmental reservoir was not definitively identified. As with the studies on Martha's Vineyard, these findings support persistence of F tularensis in the environment over time.
F tularensis appears to survive within Acanthamoeba (a relatively ubiquitous protozoa), suggesting that these organisms may serve as a reservoir for F tularensis. Survival within Acanthamoeba may provide a mechanism for F tularensis to persist in the environment (see References: Abd 2003).
Vectors
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A number of different arthropod vectors that transmit F tularensis have been identified (see References: Dennis 1998, Hopla 1974).
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Primary vectors are ticks (United States, former Soviet Union, and Japan), mosquitoes (former Soviet Union, Scandinavia, and the Baltic region), and biting flies (United States [particularly Utah, Nevada, and California] and former Soviet Union). Examples of specific species include:
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Ticks: A americanum (Lone Star tick), D andersoni (Rocky Mountain wood tick), D variabilis (American dog tick), Ixodes scapularis, Ixodes pacificus, and Ixodes dentatus
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Mosquitoes: Aedes cinereus and Aedes excrucians
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Biting flies: C discalis (deer fly), Chrysops aestuans, Chrysops relictus, and Chrysozona pluvialis
Modes of transmission
The average incubation period is 3 to 5 days. F tularensis can be transmitted to humans via various mechanisms:
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Bites by infected arthropods (see References: Klock 1973, Markowitz 1985)
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Handling of infectious animal tissues or fluids (see References: Young 1969)
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Ingestion of contaminated food or water (see References: Greco 1987, Mignani 1988, Reintjes 2002); murine models have confirmed that F tularensis is an effective oral pathogen and may pose a hazard, particularly to immunocompromised individuals if ingested in contaminated food or water (see References: KuoLee 2007: Mouse model of oral infection)
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Possibly direct contact with contaminated soil or water
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Inhalation of infectious aerosols, including dust from contaminated hay (see References: Dahlstrand 1971) and aerosols generated by lawn mowing and brush cutting (see References: Feldman 2001, Feldman 2003)
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Exposure in the laboratory setting (eg, inhalation of infectious aerosols, handling cultures or other infectious materials, accidental percutaneous exposure) (see References: Overholt 1961, Pike 1976)
Person-to-person transmission has not been documented.
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Naturally Occurring Tularemia in the United States
Historical perspective
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Colloquial terms for human illness associated with F tularensis include "rabbit fever," "deerfly fever," and "lemming fever."
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Most US cases in recent years have been associated with bites from infected arthropods, although rabbits, hares, and other small mammals continue to be major sources of exposure for cases in the southeastern United States (see References: Dennis 1998).
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During the 1930s, 2,000 or more cases were reported annually. Since that time, reported case numbers have gradually declined.
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During the 1990s, the mean number of cases reported each year was 124 (although this number likely does not reflect actual incidence since many cases either are not reported or are not accurately diagnosed) (see References: CDC: Tularemia—United States, 1990-2000). States with the highest number of reported cases during these years included Arkansas, Missouri, Oklahoma, Kansas, South Dakota, and Montana. Martha's Vineyard also had a high number of identified cases. Reported incidence rates were higher in males than in females, with the highest rates reported for children 5 to 9 years old and persons 75 to 84 years of age.
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Traditionally most cases have occurred in rural or semirural environments; cases rarely occur in urban settings.
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In the United States, cases occur most commonly between May and August, although cases can occur during any time of year (see References: CDC 2002).
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Data from a study of cases in the United States from 1964 through 2004 indicate that type A and type B infections differ in terms of affected populations, anatomic site of isolation, and geographic distribution. Molecular subtyping and pulsed-field gel electrophoresis defined two subpopulations of type A organisms (type A-east, type A-west) that differ in geographic distribution, disease outcome, and transmission (see References: Staples 2006).
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Type A-west infections were less severe than either type B or type-A east infections. The case fatality rate for type A-east was 14%, for type B was 7%, and for Type A-west was 0%.
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Type A-west infections occurred predominantly in the arid regions of the southwestern United States.
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Type B infections clustered along major waterways, including the upper Mississippi River, and areas with high rainfall, such as the Pacific Northwest.
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Type A-east infections occurred in Arkansas, Missouri, Oklahoma, and along the Atlantic Coast east of the Appalachians.
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Climate change may affect future distribution of tularemia: Modeling studies suggest that, as the climate warms, the southern border of tularemia distributions in the United States will shift northward about 600 km. This could mean a reduced incidence in the south central United States (eg, Louisiana, Mississippi) and a greater incidence in north central states (eg, Michigan to North Dakota) (see References: Nakazawa 2007).
Outbreaks
Outbreaks of tularemia occasionally have been recognized in the United States; examples include the following.
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Martha's Vineyard, 2000: Fifteen cases of tularemia were reported; 11 patients had primary pneumonic disease and one patient died (see References: Feldman 2001). Illness was caused by F tularensis, type A. Patients were more likely than controls to have used a lawn mower or brush cutters in the 2 weeks before illness onset.
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South Dakota, 1984: Twenty cases of glandular tularemia were reported in children and young adults on Crow Creek Indian reservations in the state (see References: Markowitz 1985). Illness was mild (fever, headache, and lymphadenopathy) and was presumably caused by F tularensis, type B. A similar outbreak occurred in 1979 on the Crow Indian Reservation in Montana, where 12 cases were identified (see References: Schmid 1983: Clinically mild tularemia associated with tick-borne Francisella tularensis).
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Utah, 1971: Thirty-nine cases of tularemia were reported; most patients contracted illness from the bite of an infected deerfly (see References: Klock 1973). Clinical features included cutaneous ulcers at the site of a bite, lymphadenopathy, fever, chronic malaise, and weakness; all patients recovered. Strain type was not reported.
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Vermont, 1968: Forty-seven cases of tularemia were diagnosed in persons who had handled muskrats in the 4 weeks before illness onset (see References: Young 1969). No fatalities were reported, but 14 patients had a severe prostrating illness that lasted an average of 10 days. Strain type was not reported.
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Naturally Occurring Tularemia Worldwide
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Outside the United States, the incidence of disease is highest in Scandinavian countries and Russia (see References: Dennis 1998).
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Tularemia is endemic in neoarctic and paleoarctic regions between the latitudes of 30° and 71° N (ie, North America, Europe, states of the Russian Federation, China, and Japan [see References: Dennis 1998]).
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European outbreaks have been reported (see References: Christenson 1984, Dahlstrand 1971, Eliasson 2002, Greco 1987, Perez-Castrillon 2001, Reintjes 2002, Syrjala 1985).
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Sweden periodically has years of heavy tularemia activity. In 2003, 698 cases were reported, with a peak in August (300 cases) and September (164 cases). Other years of heavy activity include 1967, 1970, 1981, and 2000 (see References: Payne 2005). A large outbreak (90 cases) occurred in central Sweden in 2006 (see References: Wik 2006).
-
An ongoing outbreak of tularemia in Bulgaria (1997 into 2005) may be the result of changes in agricultural practices made in that country during the 1990s. These changes affected the way in which the arable soil was plowed, leaving rodent holes intact. As a result, the population of rodents increased substantially, allowing expansion of the rodent reservoir (see References: Kantardjiev 2006).
-
New technologies in agricultural production, development of economic activities in rural areas, gardening, and leisure activities in Slovakia may have contributed to the rise in cases in western regions of that country since the early 1990s (see References: Gurycova 2006).
-
A point source outbreak of tularemia involving 15 patients occurred in France in 2004 (see References: Siret 2006). Twelve patients presented with pulmonary tularemia and three with typhoidal tularemia. An epidemiologic investigation found that all of the patients had been at a renovated mill on the evening of August 4, 2004. Investigators postulated that the cases may have been exposed to contaminated dust particles suspended in the air while firewood was carried through the ground floor of the building or by contaminated particles present in dog fur (a dog with the group tested positive for previous contact with F tularensis).
-
Outbreaks occurred in three provinces in northwestern Turkey in February 2004 and again in February 2005 (61 cases) after a 60 year hiatus. Epidemiologic and environmental findings suggested that contaminated water or food was the cause (see References: Celebi 2006, Gurcan 2006). Comparison of outbreaks in 2000 and 2005 suggest that both were waterborne, although the outbreaks had too few cases to determine definitively whether the characteristics of tularemia outbreaks in the region were changing (see References: Ozdemir 2007).
-
An outbreak in the Castilla y Leon region of Spain resulted in more than 500 cases of tularemia in the fall of 2007. The outbreak is thought to have arisen from unusual climatic and environmental circumstances. About half of the cases were from inhalation, the remainder from direct inoculation (see References: Martin 2007).
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Tularemia as a Biological Weapon
The following information supports the use of F tularensis as a potential biological weapon (see References: Christopher 1997; Dennis 2001; CDC: Tularemia Fact Sheet; WHO: Health aspects of chemical and biological weapons).
-
During World War II, the Japanese conducted research on F tularensis as a biological weapon.
-
During the 1950s and 1960s, the United States developed weapons that could deliver aerosolized F tularensis organisms. The United States government stockpiled weaponized tularemia until stockpiles were destroyed in 1973.
-
The former Soviet Union also weaponized F tularensis; the Soviet program included development of antibiotic- and vaccine-resistant strains.
-
In 1969, the World Health Organization estimated that an aerosol dispersal of 50 kg of virulent F tularensis over a metropolitan area with 5 million inhabitants in a developed country would result in 250,000 illnesses, including 19,000 deaths
The most likely form of intentional release for F tularensis organisms would be via infectious aerosols. An aerosol release would be expected to cause the following clinical syndromes:
-
Many of the patients would present with primary pneumonic tularemia; however, some would present with a nonspecific febrile illness of varying severity (ie, typhoidal tularemia).
-
Cases of oculoglandular tularemia could occur from eye contamination.
-
Cases of glandular or ulceroglandular disease could occur through exposure of broken skin to infectious aerosol.
-
Cases of oropharyngeal disease also could occur through inhalation of organisms.
An outbreak of tularemia caused by a bioterrorist attack would be expected to have the following features:
-
The incubation period generally correlates with the virulence of the infecting strain; in a bioterrorist attack, a highly virulent strain with a relatively short incubation period likely would be used. Illness onsets would generally occur 3 to 5 days after the initial release but could occur as soon as 1 day and up to 14 days later.
-
Illness would probably occur in an urban area and not in rural regions (where naturally occurring tularemia would be more prevalent).
-
Patients would not have risk factors for tularemia exposure (eg, outdoor field work, recent outdoor recreational activity, agricultural exposures, exposure to tissues of potentially infected animals).
In the event of a bioterrorist attack, use of F tularensis strains with enhanced virulence or antimicrobial resistance is of concern; therefore, past experience may not be a valuable predictor of disease severity under such circumstances.
Some animals might serve as sentinels of certain bioterrorism agents, including Bacillus anthracis and Yersinia pestis. While animals are not likely to provide early warning for a bioterrorist event cause by F tularensis, a recent review indicates that animals (such as prairie dogs, other rodents, raccoons, skunks, and cats) could serve as markers for ongoing exposure risk following a tularemia bioterrorist event or could propagate or maintain an epidemic (see References: Rabinowitz 2006).
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Clinical Syndromes
Overview
F tularensis infection can cause the following clinical syndromes (see References: Dennis 1998):
-
Ulceroglandular tularemia (45% to 85% of naturally occurring cases)
-
Glandular tularemia (10% to 25% of naturally occurring cases)
-
Pneumonic tularemia (<5% of naturally occurring cases, although outbreaks following inhalational exposure have been reported; secondary pneumonia [often associated with the typhoidal form] occurs relatively frequently and results from hematogenous spread to the lungs)
-
Oculoglandular tularemia (<5%)
-
Oropharyngeal tularemia (<5%)
-
Typhoidal tularemia (<5%; although in outbreaks caused by aerosol exposure, this percentage may be much higher)
Tularemia can range from a mild infection to a severe life-threatening illness.
-
Before antibiotic therapy was available, the overall case-fatality rate was approximately 7%, although rates as high as 50% were seen with pneumonia and other forms of severe infection (see References: Dennis 2001, Pullen 1945).
-
Currently, case-fatality rates are low (approximately 2%) (see References: Evans 1985).
-
Most patients respond rapidly to appropriate antibiotic therapy, with fever and generalized symptoms improving in 24 to 48 hours.
-
Type A tularemia is more severe than type B, which is generally a mild illness.
-
One study identified the following factors as associated with a poor outcome (ie, death, relapse, prolonged recovery) (see References: Penn 1987):
-
Underlying comorbidity (eg, alcoholism, diabetes)
-
Delay in seeking medical care
-
Delay in institution of appropriate antibiotic therapy
Clinical features for the major syndromes caused by F tularensis are outlined in the tables below. Initial signs and symptoms can be relatively nondescript and the diagnosis may be missed (see References: Dembek 2003).
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|
Feature
|
Characteristics
|
|
Incubation period
|
3-5 days (range, 1-14 days)
|
|
Presenting features*
|
—Local painful cutaneous lesion at site of inoculation (papule that ulcerates within a few days) in ulceroglandular form; no cutaneous lesion in glandular form
—Tender regional lymphadenopathy
—Fever
—Constitutional symptoms (chills, malaise, myalgias, arthralgias, headache, anorexia)
—Other skin lesions may be noted (erythema nodosum; erythema multiforme–like exanthem on hands, arms, or legs; maculopapular rash, acneiform lesions, urticaria†)
—Clinical features for 39 patients identified during outbreak of predominantly ulceroglandular tularemia associated with exposure to muskrats in Vermont‡:
~Fever (97%)
~Cutaneous ulcers (74%)
~Axillary adenopathy (67%)
~Chills (59%)
~Myalgias (56%)
~Malaise (51%)
~Diaphoresis (28%)
~Epitrochlear adenopathy (25%)
~Nausea and vomiting (8%)
~Pleuritic chest pain (5%)
~Cough (5%)
~Preauricular adenopathy (2%)
|
|
Laboratory features
|
—In one series of 88 patients with tularemia, admission WBCs ranged from 5,000 to 22,000/mm3 (median, 10,400mm3)§; differential usually normal early in clinical course
—Elevated hepatic enzymes and bilirubin may occur§
|
|
Complications
|
—Suppuration of involved lymph nodes
—Secondary pneumonia (31% of patients with ulceroglandular disease in one case series§ and 17% of patients with ulceroglandular or glandular disease in another**)
—Involvement of other organs (via hematogenous spread)
—Sepsis syndrome
—Illness may be debilitating, with full recovery taking several months
—Lymphadenopathy may persist for months**
|
|
Case-fatality rate
|
—4.4% of 181 patients with ulceroglandular tularemia and 4.3% of 23 patients with glandular tularemia among case series of 225 patients reported from pre-antibiotic era††
—1.6% (2 of 123 patients with ulceroglandular or glandular tularemia) in case series of 165 treated cases occurring in Oklahoma 1979-1885‡‡
—Fatalities usually associated with type A subspecies; type B subspecies less virulent
|
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|
Feature
|
Characteristics
|
|
Incubation period
|
3-5 days (range, 1-14 days)
|
|
Presenting features†
|
—Patients often present with community-acquired atypical pneumonia nonresponsive to conventional antibiotic therapy
—Predominant symptoms include abrupt onset of fever, nonproductive cough, myalgias (particularly low back)
—Nausea, vomiting, diarrhea may occur
—Illness may be rapidly progressive and severe or may be indolent with progressive weakness and weight loss over several weeks to months
—Skin lesions may be noted (erythema nodosum; erythema multiforme–like exanthem on hands, arms, or legs; maculopapular rash; acneiform lesions; urticaria)
—Presenting features for 53 Finnish patients with inhalational exposure‡:
~Fever (100%)
~Headache, myalgias, arthralgias ("most")
~Dry cough (45%)
~Retrosternal discomfort, pleural pain, or dyspnea (45%)
~Sore throat (23%)
~Hemoptysis (2%)
|
|
Laboratory features
|
—Radiographic findings for 50 tularemia patients with pleuropulmonary involvement§:
~Patchy subsegmental air space opacities (74%; unilateral in 54% overall)
~Hilar adenopathy (32%)
~Pleural effusion (30%; unilateral in 20% overall)
~Lobar or segmental opacities (18%; all unilateral)
~Cavitation (16%)
~Oval opacities (8%)
~Cardiomegaly with pulmonary edema pattern (6%; caused by pericarditis in one case)
~Apical infiltrate (4%)
~Empyema and bronchopleural fistula (4%)
~Mediastinal mass (2%; caused by hilar adenopathy)
~Miliary pattern (2%)
—In one series of 88 patients with tularemia, admission WBCs ranged from 5,000 to 22,000/mm3 (median, 10,400mm3)**; differential usually normal early in clinical course
—Elevated
hepatic enzymes and bilirubin may occur**
—Sputum Gram stain often not helpful in making diagnosis
|
|
Complications
|
—Lung abscesses or cavitary lesions
—Adult respiratory distress syndrome††
—Fibrosis and calcifications in affected lung areas or pleura as illness resolves
—Granulomatous pleuritis (which may resemble tuberculosis)‡‡
—Empyema with bronchopleural fistula
—Involvement of other organs through hematogenous spread
—Sepsis syndrome
—Meningitis
—Pericarditis§**
—Illness may be debilitating, with full recovery taking several months; relapses have been reported with use of broad-spectrum antibiotics§§
|
|
Case-fatality rate
|
—Fatalities rare with appropriate antibiotic therapy (reported as 2.3% in one case series of 88 patients with tularemia, about half of whom had pulmonary involvement; both deaths occurred in patients with pneumonia**)
—Fatalities usually associated with type A subspecies; type B subspecies less virulent
|
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|
Feature
|
Characteristics
|
|
Incubation period
|
3-5 days (range, 1-14 days)
|
|
Presenting features*
|
—Multiple painful yellow conjunctival nodules
—Conjunctival ulcers
—Chemosis
—Periorbital and facial edema around affected eye
—Extremely tender regional adenopathy involving preauricular, submandibular, or cervical lymph nodes; edema around affected nodes may be present
—Patients may present with Parinaud's syndrome (unilateral granulomatous conjunctivitis and enlarged preauricular lymph nodes)†
—Constitutional symptoms (fever, chills, malaise, anorexia)
—History of minor eye trauma, swimming in potentially contaminated water (possibly a risk factor)†, or tick exposure may be present with naturally acquired infection
|
|
Laboratory features
|
—Generally unremarkable
—Gram stain of conjunctival scrapings may demonstrate organisms, although Gram stain often not helpful†
|
|
Complications
|
—Suppuration of affected lymph nodes
—Sepsis syndrome
—Involvement of other organs (through hematogenous spread)
|
|
Case-fatality rate
|
—1 (14.3%) of 7 patients with oculoglandular tularemia among case series of 225 patients reported from pre-antibiotic era‡
—Fatalities rare with appropriate antibiotic therapy
|
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|
Feature
|
Characteristics
|
|
Incubation period
|
3-5 days (range, 1-14 days)
|
|
Presenting features*
|
—Fever
—Constitutional symptoms (chills, malaise, myalgias, arthralgias)
—Exudative pharyngitis or tonsillitis
—Ulcerations of pharynx, tonsils, soft palate
—Stomatitis (less common)
—May see pharyngeal membrane suggestive of diphtheria (membrane associated with tularemia does not bleed if removed, unlike diphtheria where removal of membrane reveals bleeding submucosa)
—Cervical or retropharyngeal adenopathy (cervical nodes tender to palpation)
—Concomitant pneumonia often present
—Patients may present with dental abscesses
—Findings in 12 patients with pharyngeal involvement in case series of 88 patients†:
~Erythema (50%)
~Petechiae or hemorrhage (25%)
~Exudate (17%)
~Ulcers (8%)
—The most common symptoms among 145 patients in Turkey‡:
~Swelling of the neck (92%)
~Sore throat (92%)
~Fever (90%)
|
|
Laboratory features
|
—Generally unremarkable, although leukocytosis may be present
—Among patients in Turkey, ESR was elevated in all, and 79% had an ESR exceeding 55 mm/hr‡
|
|
Complications
|
—Sepsis syndrome
—Suppuration of involved lymph nodes
—Involvement of other organs (via hematogenous spread)
—Illness may be debilitating, with full recovery taking several months
|
|
Case-fatality rate
|
—Fatalities rare with appropriate antibiotic therapy
—Fatalities usually associated with type A subspecies; type B subspecies less virulent
|
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|
Feature
|
Characteristics
|
|
Incubation period
|
3-5 days (range, 1-14 days)
|
|
Presenting features†
|
—Fever
—Constitutional symptoms (chills, malaise, weakness, myalgias, arthralgias)
—Prostration
—Dehydration
—Gastrointestinal symptoms (watery, nonbloody diarrhea; vomiting; abdominal pain)
—Skin lesions may be noted (erythema nodosum; erythema multiforme–like exanthem on hands, arms, or legs; maculopapular rash; acneiform lesions; urticaria)
|
|
Laboratory features
|
—In one series of 88 patients with tularemia, admission WBCs ranged from 5,000 to 22,000/mm3 (median, 10,400mm3; differential usually normal)‡
—Elevated hepatic enzymes and bilirubin may occur‡
—Microscopic pyuria may occur‡
|
|
Complications
|
—Secondary pneumonia (83% of patients with typhoidal disease in one case series‡ and 50% in another§)
—Involvement of other organs via hematogenous spread (eg, meningitis,** hepatitis and jaundice,†† splenic rupture, encephalitis, pericarditis,‡ peritonitis, osteomyelitis)
—Sepsis syndrome
—Rhabdomyolysis‡‡
—Renal failure§
—Illness may be debilitating, with full recovery taking several months, relapses have been reported with use of broad-spectrum antibiotics§§
|
|
Case-fatality rate
|
—50% in one series of 14 patients with typhoidal tularemia among case series of 225 patients reported from pre-antibiotic era***
—6.6% (2 of 30 patients with typhoidal tularemia) in case series of 165 treated cases occurring in Oklahoma 1979-1885†††
—Fatalities usually associated with type A subspecies; type B subspecies less virulent
|
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Pediatric Considerations
In general, clinical manifestations of tularemia are similar in children and adults. One report from Arkansas compared type of illness and clinical symptoms between children and adults with naturally occurring tularemia identified in 1983; findings are noted in the following table.
|
Type of Disease or Symptoms
|
Percentage of Children
(N =28)
|
Percentage of Adults
(N = 43)
|
|
Type of Disease
|
|
Ulceroglandular
Glandular
Pneumonic
Oropharyngeal
Oculoglandular
Typhoidal
Unclassified
|
45
25
14
4
2
2
6
|
51
12
18
—
—
12
11
|
|
Symptoms
|
|
Lymphadenopathy
Fever
Ulcer/papule
Pharyngitis
Myalgias/arthralgias
Nausea/vomiting
Headache
Cough
Diarrhea
Conjunctivitis
|
96
87
45
43
39
35
9
9
4
4
|
65
21*
51
—
2
19
5
5
5
—
|
According to the American Academy of Pediatrics (AAP), streptomycin is the treatment of choice for children, with gentamicin being an effective alternative (see References: AAP 2000). Other therapies cited by the AAP include tetracycline and chloramphenicol, although relapse rates are higher with these agents.
Ciprofloxacin has recently been shown to be an effective therapy for tularemia in children (see References: Johansson 2000: Ciprofloxacin for treatment of tularemia in children; Johansson 2002).
See the section on Treatment of Tularemia for specific drug regimens.
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Differential Diagnosis
|
Condition*†
|
Distinguishing Features
|
|
Bubonic plague (Yersinia pestis)
|
—Clinical course often fulminant
—Systemic toxicity common
|
|
Cat-scratch disease (Bartonella henselae)
|
—History of contact with cats; usually history of cat-scratch
—Indolent clinical course; progresses over weeks
—Primary lesion at site of scratch often present (small papule, vesicle)
|
|
Mycobacterial infection, including scrofula (Mycobacterium tuberculosis and other Mycobacterium species)
|
—With scrofula, adenitis occurs in cervical region
—Lymph nodes generally painless and nontender
—Infections with species other than M tuberculosis more likely to occur in immunocompromised patients
|
|
Sporotrichosis (Sporothrix schenckii)
|
—Lymph nodes generally painless and nontender
—Systemic symptoms absent
—Painless papulonodular cutaneous lesion usually present distal to involved lymph nodes; secondary cutaneous lesions may occur along lymphatic channels
—Patients often have history of contact with soil, plants, or plant products (eg, sphagnum moss, thorned plants such as rose bushes)
|
|
Streptococcal or staphylococcal adenitis (Staphylococcus aureus, Streptococcus pyogenes)
|
—Site of initiating infection often present distal to involved nodes (ie, pustule, infected traumatic lesion)
—Involved nodes more likely to be fluctuant
|
|
Chancroid (Haemophilus ducreyi)
|
—Adenitis occurs in inguinal region only
—Ulcerative lesion present
—History of sexual exposure or activity
|
|
Lymphogranuloma venereum (Chlamydia trachomatis)
|
—Adenitis occurs in inguinal region only
—History of sexual exposure 10-30 days previously
—Suppuration, fistula tracts common
—Although lymph nodes may be somewhat tender, exquisite tenderness usually absent
—History of sexual exposure or activity
|
|
Primary genital herpes
|
—Herpes lesions in genital area
—Adenitis in inguinal region only
—History of sexual exposure or activity
|
|
Secondary syphilis (Treponema pallidum)
|
—Enlarged lymph nodes in inguinal region only
—Lymph nodes generally painless and nontender
—History of sexual exposure or activity
|
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|
Condition
|
Distinguishing Features
|
|
Anthrax (Bacillus anthracis)
|
—Painless ulcer that develops into black eschar over several days
—Extensive non-pitting edema around lesion may occur
|
|
Orf (orf virus, a parapox virus)
|
—Occurs in farm workers
—Characterized by pustule that progresses to weeping nodule
—Regional adenitis may occur, but not common
|
|
Pasteurella infections (Pasteurella multocida)
|
—History of dog or cat exposure (animal bite or licking of open wound)
—Regional lymphadenopathy occurs in 30%-40% of cases
|
|
Primary syphilis (Treponema pallidum)
|
—Characterized by painless ulcer (chancre) in genital area
—Lymph nodes generally painless and nontender
|
|
Rat-bite fever (Spirillum minus)*
|
—Infection caused by S minus occurs in Asia
—Maculopapular rash over palms, soles, and extremities 2-4 days after onset of fever
|
|
Rickettsialpox (Rickettsia akari)
|
—Initial presentation involves painless papule which forms black eschar
—Generalized maculopapular rash appears 2-3 days later
—Regional lymphadenopathy usually present but nontender
|
|
Scrub typhus (Orientia tsutsugamushi; formerly Rickettsia tsutsugamushi)
|
—Zoonotic infection from chigger bites
—Occurs in endemic areas (Asia and Western Pacific)
—Often associated with a generalized maculopapular rash
|
|
Staphylococcal or streptococcal cellulitis (S aureus, S pyogenes)
|
—May be history of trauma or preexisting lesion at site of infection
|
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|
Condition*†
|
Distinguishing Features
|
|
Community-acquired bacterial pneumonia
—Mycoplasmal pneumonia (Mycoplasma pneumoniae)
—Pneumonia caused by Chlamydia pneumoniae
—Legionnaires' disease (Legionella pneumophila or other Legionella species)
—Psittacosis (Chlamydia psittaci)
—Other bacterial agents (eg, Staphyloccocus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis)
|
—Legionellosis and many other bacterial agents (S aureus, S pneumoniae, H influenzae, K pneumoniae, M catarrhalis) usually occur in persons with underlying pulmonary or other disease or in elderly
—Bird exposure with psittacosis
—Community outbreaks caused by other etiologic agents less likely to suggest point-source outbreak (as would be seen with intentional release of F tularensis)
—Outbreaks of S pneumoniae usually institutional
—Community outbreaks of Legionnaires' disease often involve exposure to cooling towers
—Gram stain of sputum may be useful in distinguishing agents
|
|
Inhalational anthrax (Bacillus anthracis)
|
—Widened mediastinum and pleural effusions seen on CXR or chest CT
—Not true pneumonia; minimal sputum production
—Severe and rapidly progressive course; often fulminant and fatal
|
|
Pneumonic plague (Yersinia pestis)
|
—Hemoptysis commonly occurs
—Consolidation often noted on CXR early in clinical course (radiographic evidence of pneumonia in patients with tularemia generally not as pronounced early in clinical course)
—Severe and rapidly progressive course; often fulminant and fatal
|
|
Q fever (Coxiella burnetii)
|
—Exposure to infected parturient cats, cattle, sheep, goats
—May be difficult to distinguish clinically from pneumonic tularemia
|
|
Tuberculosis (Mycobacterium tuberculosis)
|
—More common among elderly or among persons who have lived in tuberculosis-endemic countries (ie, developing world, countries of former Soviet Union)
|
|
Viral pneumonia
—Influenza
—Hantavirus
—RSV
—CMV
|
—Influenza generally seasonal (October-March in United States) or involves history of recent cruise ship travel or travel to tropics
—Exposure to excrement (urine and feces) of mice with Hantavirus
—RSV usually occurs in children (although may be cause of pneumonia in elderly); tends to be seasonal (winter/spring)
—CMV usually occurs in immunocompromised patients
|
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|
Condition*†
|
Distinguishing Features
|
|
Adenoviral infection (adenovirus)
|
—Generally not associated with regional lymphadenopathy
—Systemic symptoms absent
—Commonly hemorrhagic
|
|
Cat-scratch disease (Bartonella henselae)
|
—Watery discharge, granulomatous conjunctival nodule, chemosis
—Lymph nodes nontender
—Mild systemic toxicity may be present but usually less severe than that seen with tularemia
|
|
Coccidioidomycosis (Coccidioides immitis)
|
—Granulomatous conjunctival nodule with small areas of necrosis
—Lymph nodes may be tender and some systemic toxicity may be present
|
|
Herpes infection (herpes simplex virus)
|
—Causes characteristic dendritic keratitis in addition to conjunctivitis
|
|
Pyogenic bacterial infections
|
—Mild cases not associated with regional lymphadenopathy
—Systemic symptoms usually absent
|
|
Sporotrichosis (Sporothrix schenckii)
|
—Firm chancre in skin of eyelid, yellow conjunctival nodules, subcutaneous nodules along lymphatics
—Lymph nodes nontender
—Systemic symptoms absent
|
|
Syphilis (Treponema pallidum)
|
—Conjunctival ulcer with indurated margin and gray base
—Lymph nodes nontender
—Systemic symptoms absent
|
|
Tuberculosis (Mycobacterium tuberculosis)
|
—Small conjunctival ulcer embedded in nodule
—Lymph nodes nontender
—Systemic symptoms generally absent
|
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|
Condition*
|
Distinguishing Features
|
|
Streptococcal pharyngitis (Streptococcus pyogenes)
|
—Responds to penicillin therapy
|
|
Infectious mononucleosis (Epstein-Barr virus)
|
—Most common in young adults
—Splenomegaly commonly occurs
|
|
Adenoviral infection (adenovirus)
|
—Occurs mostly in children and young adults
—Often associated with rhinorrhea
|
|
Diphtheria (Corynebacterium diphtheriae)
|
—Primarily occurs in nonimmune children under 15 yr of age
—Removal of pharyngeal membrane often causes bleeding of submucosa (unlike tularemia)
|
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|
Condition
|
Distinguishing Features
|
|
Typhoidal tularemia without sepsis*
|
|
Brucellosis (Brucella abortus and other Brucella species)
|
—Usually history of contact with tissues, blood, aborted fetuses of infected animals (cattle, swine, goats, sheep)
—Occupational disease
|
|
Disseminated mycobacterial or fungal infection
|
—Underlying illness usually present
|
|
Endocarditis
|
—Features of endocarditis (eg, cardiac murmur, embolic phenomenon) often present
—Risk factors may be present (underlying cardiac abnormality, prosthetic valve, injecting drug use)
|
|
Leptospirosis (Leptospira interrogans)
|
—History of exposure to infected animals or to water or soil contaminated with urine from infected animals
—Characteristic features (in addition to acute onset of febrile illness) include conjunctival suffusion, s | | | |
