Tularemia

Clinical Features

After an incubation period of 3-6 days (range 1-21 days; probably dose dependant), onset is usually acute. Tularemia typically appears in several forms, which can generally be categorized as either typhoidal or ulceroglandular. In humans, as few as 10 to 50 organisms will cause disease if inhaled or injected intradermally, whereas approximately 108 organisms are required with oral challenge.

Typhoidal tularemia (5-15 percent of naturally acquired cases) occurs mainly after inhalation of infectious aerosols but can occur after intradermal or gastrointestinal challenge. The disease manifests as a nonspecific syndrome consisting of abrupt onset of fever (38-40 degrees C), headache, malaise, myalgias, and prostration; but unlike most other forms of tularemia disease, it presents without lymphadenopathy. Occasionally patients will present with nausea, vomiting, diarrhea, or abdominal pain. Case fatality rates are approximately 35% in untreated, naturally acquired typhoidal cases. Survivors of untreated tularemia may have symptoms which persist for weeks or, less often, months, with progressive debilitation. Mortality is higher if pneumonia is also present; this is the form of disease most likely to be seen after an aerosol BW attack. Case fatality rates after a BW attack may be greater than the 1-3 percent seen with appropriately treated natural disease.

Ulceroglandular tularemia (75-85 percent of naturally acquired cases cases) is most often acquired through inoculation of the skin or mucous membranes with blood or tissue fluids of infected animals. It is characterized by usually sudden onset of fever (85%), chills (52%), headache (45%), cough (38%), and myalgias (31%), concurrent with the appearance of a painful papule at the site of inoculation. The papule progresses rapidly to pustule then painful ulcer, accompanied by development of painful regional lymphadenopathy. Cutaneous ulcers are generally 0.4-3.0 cm in diameter with heaped-up edges. Lymph nodes are 0.5 to 10 cm in diameter and usually tender. In 5-10 percent of cases there is focal lymphadenopathy without an obvious ulcer present. Enlarged nodes can become fluctuant and spontaneously drain even when the patient has been taking antibiotics, and, if untreated, can persist for months or even years.

In a minority of cases (1-2 percent) the site of primary inoculation is in the eye (oculoglandular disease); this occurs after inoculation of the conjunctivae by contaminated hands, by splattering of infected tissue fluids, or via infectious aerosols. Patients have unilateral, painful, purulent conjunctivitis with preauricular or cervical lymphadenopathy. Chemosis, periorbital edema, and small nodular granulomatous lesions or ulcerations of the conjunctiva are noted in some patients.

Pharyngitis can occur in up to 25 percent of all patients with tularemia. It usually presents as an acute exudative pharyngitis or tonsillitis, sometimes with ulceration and associated painful cervical lymphadenopathy. It may occur as a syndrome of isolated penicillin-unresponsive pharyngitis and mistaken for infectious mononucleosis or other viral pharyngitis.

Pulmonary involvement is present in 47-94 percent of all naturally occurring cases of disease. It may be severe and fulminant or mild and asymptomatic and can be associated with any form of tularemia (seen in 30 percent of ulceroglandular cases), but it is most common in typhoidal tularemia (up to 80 percent of cases). Pneumonitis is asymptomatic in up to 30 percent of cases but more commonly presents with non-productive cough and substernal chest pain and occasionally with pleuritic chest pain, dyspnea, purulent sputum, or hemoptysis. An atypical or interstitial perihilar process is common but fulminant lobar pneumonias, bronchiolitis, cavitary lesions, bronchopleural fistulas, and chronic, granulomatous processes have all been described. Hilar adenopathy is common and pleural effusions have been recorded in 15 percent of cases. Thirty percent of cases of tularemia pneumonia may be accompanied by pharyngitis. Like pneumonic plague, tularemia pneumonia can be primary after the inhalation of organisms or secondary after hematogenous spread from other sites. Untreated, mortality can approach 60 percent.

Clinical Syndromes

Clinical Syndromes

Overview

F tularensis infection can cause the following clinical syndromes (see References: Dennis 1998):

  • Glandular tularemia (10% to 25% of naturally occurring cases)
  • Ulceroglandular tularemia (45% to 85% 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 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 instituting 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). One study describes two cases of human infection with F tularensis that were initially diagnosed as herpes simplex or varicella zoster infection (see References: Byington 2008).

Clinical Features of Glandular and Ulceroglandular Tularemia

Feature

Characteristics

Incubation period

3-5 days (range, 1-14 days)

Presenting featuresa

—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; urticariab)
—Clinical features for 39 patients identified during outbreak of predominantly ulceroglandular tularemia associated with exposure to muskrats in Vermontc:
    ~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, 10,400/mm3)d; differential usually normal early in clinical course
—Elevated hepatic enzymes and bilirubin may occurd

Complications

—Suppuration of involved lymph nodes
—Secondary pneumonia (31% of patients with ulceroglandular disease in one case seriesdand 17% of patients with ulceroglandular or glandular disease in anothere)
—Involvement of other organs (via hematogenous spread)
—Sepsis syndrome
—Illness may be debilitating, with full recovery taking several months
—Lymphadenopathy may persist for monthse

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 eraf
—1.6% (2 of 123 patients with ulceroglandular or glandular tularemia) in case series of 165 treated cases occurring in Oklahoma 1979-1985g
—Fatalities usually associated with type A subspecies; type B subspecies less virulent

Abbreviations: WBC, white blood count.

aSee References: Cross 2000, Dennis 2001, Evans 1985, Penn 2010, Sanders 1968.
bSee References: Christenson 1984, Cross 2000, Dahlstrand 1971, Evans 1985.
cSee References: Young 1969.
dSee References: Evans 1985.
eSee References: Sanders 1968.
fSee References: Pullen 1945.
gSee References: Rhorbach 1991.


Clinical Features of Pneumonic Tularemiaa

Feature

Characteristics

Incubation period

3-5 days (range, 1-14 days)

Presenting featuresb

—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 exposurec:
    ~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 involvementd:
    ~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, 10,400/mm3)e; differential usually normal early in clinical course
—Elevated hepatic enzymes and bilirubin may occure
—Sputum Gram stain often not helpful in making diagnosis

Complications

—Lung abscesses or cavitary lesions
—Adult respiratory distress syndromef
—Fibrosis and calcifications in affected lung areas or pleura as illness resolves
—Granulomatous pleuritis (which may resemble tuberculosis)g
—Empyema with bronchopleural fistula
—Involvement of other organs through hematogenous spread
—Sepsis syndrome
—Meningitis
—Pericarditisd,e
—Illness may be debilitating, with full recovery taking several months; relapses have been reported with use of broad-spectrum antibioticsh

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 pneumoniae)
—Fatalities usually associated with type A subspecies; type B subspecies less virulent

Abbreviations: WBC, white blood count.

aPneumonic tularemia may result either from primary inhalational exposure or occur as a secondary process in other forms of tularemia. Similarly, inhalational exposure may cause primary pneumonic tularemia, oropharyngeal tularemia, or typhoidal tularemia without obvious pulmonary involvement. In the past, the term "typhoidal tularemia" was used to refer to infections caused by inhalational exposure, even if pneumonia was the primary manifestation. This has resulted in some confusion in the medical literature. Experts have suggested that the term "typhoidal tularemia" not be used in the context of inhalational exposure but rather be used only to describe cases of tularemia with constitutional symptoms or sepsis syndrome and no obvious anatomic focus of disease (see References: Dennis 2001, Syrjala 1986).
bSee References: Christenson 1984, Cross 2000, Dahlstrand 1971, Evans 1985, Fredricks 1996, Miller 1969, Roy 1989.
cSee References: Syrjala 1985.
dSee References: Rubin 1978.
eSee References: Evans 1985.
fSee References: Sunderrajan 1985.
gSee References: Schmid 1983: Granulomatous pleuritis caused by Francisella tularensis: possible confusion with tuberculous pleuritis.
hSee References: Overholt 1961.


Clinical Features of Oculoglandular Tularemia

Feature

Characteristics

Incubation period

3-5 days (range, 1-14 days)

Presenting featuresa

—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) b
—Constitutional symptoms (fever, chills, malaise, anorexia)
—History of minor eye trauma, swimming in potentially contaminated water (possibly a risk factor)b, 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 helpfulb

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 erac
—Fatalities rare with appropriate antibiotic therapy

aSee References: Cross 2000, Guerrant 1976, Halperin 1985, Penn 2010.
bSee References: Halperin 1985.
cSee References: Pullen 1945.


Clinical Features of Oropharyngeal Tularemia

Feature

Characteristics

Incubation period

3-5 days (range, 1-14 days)

Presenting featuresa

—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, in which 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 patientsb:
    ~Erythema (50%)
    ~Petechiae or hemorrhage (25%)
    ~Exudate (17%)
    ~Ulcers (8%)

—The most common symptoms among 145 patients in Turkeyc:

    ~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/hrc

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

Abbreviation: ESR, erythrocyte sedimentation rate.

aSee References: Luotonen 1986, Tunga 2007, Tyson 1976.
bSee References: Evans 1985.
cSee References: Meric 2008.


Clinical Features of Typhoidal Tularemiaa

Feature

Characteristics

Incubation period

3-5 days (range, 1-14 days)

Presenting featuresb

—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, 10,400/mm3); differential usually normalc
—Elevated hepatic enzymes and bilirubin may occurc
—Microscopic pyuria may occurc

Complications

—Secondary pneumonia (83% of patients with typhoidal disease in one case seriesc and 50% in anotherd)
—Involvement of other organs via hematogenous spread (eg, meningitis,e hepatitis and jaundice,f splenic rupture, encephalitis, pericarditis,c peritonitis, osteomyelitis)
—Sepsis syndrome
—Rhabdomyolysisg
—Renal failured
—Illness may be debilitating, with full recovery taking several months; relapses have been reported with use of broad-spectrum antibioticsh

Case-fatality rate

—50% in one series of 14 patients with typhoidal tularemia among case series of 225 patients reported from pre-antibiotic erai
—6.6% (2 of 30 patients with typhoidal tularemia) in case series of 165 treated cases occurring in Oklahoma 1979-1985 j
—Fatalities usually associated with type A subspecies; type B subspecies less virulent

aIn the past, the term "typhoidal tularemia" was used to refer to infections caused by inhalational exposure, even if pneumonia was the primary manifestation. This has resulted in some confusion in the medical literature. Experts have suggested that the term "typhoidal tularemia" not be used in the context of inhalational exposure but rather be used only to describe cases of tularemia with constitutional symptoms or sepsis syndrome and no obvious anatomic focus of disease (see References: Dennis 2001, Syrjala 1986).
bSee References: Christenson 1984, Cross 2000, Dahlstrand 1971, Dennis 2001, Evans 1985, Penn 2010, Sanders 1968.
cSee References: Evans 1985.
dSee References: Sanders 1968.
eSee References: Lovell 1986, Stuart 1945.
fSee References: Ortego 1986.
gSee References: Klotz 1987, Penn 1987.
hSee References: Overholt 1961.
iSee References: Pullen 1945.
jSee References: Rohrbach 1991.

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.

Comparison Between Cases of Tularemia in Children and Adults, Arkansas 1983

Type of Disease or Symptoms

Percentage of Children
(n = 28)

Percentage of Adults
(n = 43)

Type of Disease

Glandular

Ulceroglandular
Pneumonic
Oculoglandular

Oropharyngeal
Typhoidal
Unclassified

25

45
14
2

4
2
6

12

51
18


12
11

Symptoms

Lymphadenopathy
Fever
Ulcer/papule
Pharyngitis
Myalgias/arthralgias
Nausea/vomiting
Hepatosplenomegaly

Headache
Cough

Chills
Diarrhea
Conjunctivitis

96
87
45
43
39
35
35

9
9


4
4

65
21a
51

2
19

5
5

5
5

aAlthough this percentage was reported for fever among adults in this series of patients, fever generally is a hallmark finding for tularemia.

Adapted from Jacobs 1985 (see References).

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