Table 4.

Natural course of pneumonic tularemia in human and cynomolgus macaque.

Disease symptoms and signs Humana		Cynomolgus macaqueb
Time course of disease	Approximately 2 weeks from onset of symptoms to death, with a range of 10–25 days	Typically 2–7 days from onset of fever to death
Body temperature	Fever can develop after a few days of illness (i.e., after 2–3 days after inhalation of a high dose of F. tularensis Schu S4)	Fever in 100% of cases (typically starting on Day 2–3 post-exposure)
F. tularensis detected	Positive in blood but not in all cases, positive in pharyngeal washings, sputum specimens, and gastric aspirates	Positive in blood but not in all cases, positive in lung, liver, spleen, and lymph nodes
Heart rate	Usually elevated but it can be slower than would be expected in the presence of high fever (pulse – temperature deficit)	Elevated (typically starting on Day 2 or 3 post-exposure)
Respiration rate	No change initially. Fulminant disease can rapidly progress to pneumonia and respiratory failure	Elevated (typically starting on Day 2 or 3 post-exposure)
Lung pathology	Pleural exudates, adhesions, and focal modular lesions can be found. Lobular pneumonia often involving all lobes is observed with areas of coagulation and caseous necrosis and sometimes cavitation. Microscopically, the exudate is composed of mononuclear cells with few lymphocytes, erythrocytes, epithelial cells, and plasma cells. The alveolar spaces are filled with exudate and sometimes fibrin. The alveolar septa are congested and may be necrotic. Blood vessels may show mononuclear infiltration, necrosis, and thrombosis. The perivascular lymphatics may be distended with a cellular or caseous exudate	Adhesions and discoloration of the lungs; fluid in the thoracic and abdominal cavities; necrotizing inflammation with variable amounts of hemorrhage and edema. The lesions were most consistent with a subacute necrotizing and suppurative bronchopneumonia with the most extensive lesions seen associated with larger airways and pulmonary arterioles and arteries. Abundant macrophages were present within neutrophilic or necrotic foci in the alveoli of lungs or surrounding liquefied necrotic centers forming caseating granulomas
Other findings	No specific clinical laboratory findings stand out. White blood count may reveal leukocytosis but not as elevated as would be expected for invasive bacterial disease. Increased CRP levels	Moderate leukocytosis on Day 2–3 followed by a drop after 48 h. Increase in CRP levels starting on Day 3

^aData from publications describing pneumonic tularemia in humans (Permar and Maclachlan, 1931; Blackford and Casey, 1941; Stuart and Pullen, 1945; McCrumb, 1961; Overholt et al., 1961; Saslaw et al., 1961; Hornick and Eigelsbach, 1966; Sawyer et al., 1966; Beisel, 1967; Beisel et al., 1967; Provenza et al., 1986; Syrjala, 1986; Penn and Kinasewitz, 1987; Tarnvik et al., 1989; Hoel et al., 1991; Scofield et al., 1992; Sjostedt et al., 1997; Dennis et al., 2001; Feldman et al., 2001; Haristoy et al., 2003; Lamps et al., 2004; Tarnvik and Chu, 2007; Penn, 2009; Fritzsch and Splettstoesser, 2010; Thomas and Schaffner, 2010; Egan et al., 2011; Weber et al., 2012; Johansson et al., 2014).

^bReference is made to the disease signs in animals exposed to 300–3,000 cfu Schu S4 in natural history studies described in this manuscript.