1. Bioterrorism Agents – Plague Lesson 3
Differential Diagnosis

2. Objectives
List the diseases that should be considered in the differential diagnosis of plague
Describe how to rule out other diseases when diagnosing plague
In this lesson we will cover the differential diagnosis of plague so that you can differentiate the onset of plague symptoms from other similar diseases. At the end of this lesson you should be able to:
List the diseases that should be considered in the differential diagnosis of plague
Describe how to rule out other diseases when diagnosing plague

3. Bubonic Plague Incubation: 2 to 6 days Symptoms Chills, high fever
Swollen and painful lymph nodes in groin, thigh, underarm and/or neck
Buboes at site of inoculation
Lymph nodes not hot, skin smooth and red
Rapid pulse
Hypotension
Bubonic Plague
Incubation Period- 2-6 days.
Symptoms-
Bubonic plague usually begins abruptly with chills followed by a high fever and swollen, painful lymph nodes in the groin, thigh, underarm (axilla), and/or neck. The lymphadenopathy of primary bubonic plague usually presents unilaterally.
No more than 24 hours after initial symptom onset, patients develop buboes, which are grossly enlarged, extremely tender lymph nodes draining at the respective site of inoculation. The lymph nodes may be so tender that the patient may avoid moving that area.
The affected lymph nodes usually do not feel hot, although the skin appears smooth and reddened.
The site where the patient was bitten by infected fleas can sometimes develop small skin lesions, often appearing to be either water-filled blisters or thick coagulated crusts.
The patient may experience a rapid pulse and hypotension.

4. Bubonic Plague Disease Progression Other Symptoms Septicemia
Pneumonic Plague
Meningitis (rare)
Other Symptoms
Restlessness, confusion, lack of coordination
Intestinal discomfort
Lymph nodes may suppurate second week
Progression of Disease-
If bubonic plague is not treated, the bacteria can spread through the bloodstream causing septicemia or it can infect the lungs, causing a secondary case of pneumonic plague. Rarely, it can progress to meningitis.
Individuals with bubonic plague may experience prostration, restlessness, confusion, delirium, and a lack of coordination.
Some patients may experience intestinal discomfort like nausea, vomiting, diarrhea, and/or abdominal pain.
The lymph nodes may begin to suppurate during the second week.

5. Bubonic Plague Differential Diagnosis
Capnocytophaga canimorsus
Cellulitis
Lymphogranuloma venereum
Non-specific infections
Diseases to Consider - Acute lymphadenitis associated with bubonic plague must be differentiated from other causes. You should note that the bubo is exquisitely tender, whereas that is not generally the case with these other diseases. Also, with plague, a rapid onset of fever accompanies the lymph node swelling.
Other causes can be:
Appendicitis - abdominal mesenteric nodes become painful from infective flea bites to the trunk.
Capnocytophaga canimorsus - from animal bites or scratches.
Cellulitis - They produce localizing lymphadenopathy.
Lymphogranuloma Venereum
Non-specific Infections - May produce localized, unilateral lymphadenopathy.
Lymphogranuloma venereum

6. Bubonic Plague Differential Diagnosis
Streptococcal or staphylococcal adenitis (Staphylococcal aureus, Staphylococcal pyogenes)
Purulent/ inflamed lesion often distal to nodes
Involved nodes more likely to be fluctuant
Ascending lymphangitis or cellulitis may be present
Tularemia
(Francisella tularensis)
Ulcer or pustule distal to nodes
Rarely as fulminant as in plague
Systemic toxicity uncommon
Cat scratch disease
(B. henselae)
History of cat contact/scratch
Indolent clinical course
Primary lesion at site of scratch
No systemic toxicity
Streptococcal or staphylococcal adenitis (Staphylococcal aureus, Staphylococcal pyogenes)
Purulent or inflamed lesion often noted distal to involved nodes (i.e., pustule, infected traumatic lesion)
Involved nodes more likely to be fluctuant
Associated ascending lymphangitis or cellulitis may be present (generally not seen with plague)
Tularemia (Francisella tularensis)
Ulcer or pustule often present distal to involved nodes
Clinical course rarely as fulminant as in plague
Systemic toxicity uncommon
Cat scratch disease (B. 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)
Systemic toxicity not present
Please note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

7. Bubonic Plague Differential Diagnosis
Mycobacterial infection, including scrofula (Mycobacterium tuberculosis and other Mycobacterium species)
Adenitis occurs in cervical region
Usually painless
Indolent clinical course
More likely to occur in immunocompromised patients
Lymphogranuloma venereum
(Chlamydia trachomatis)
Adenitis occurs in the inguinal region
Sexual exposure days previously
Suppuration, fistula tracts common
Exquisite tenderness usually absent
Although patients may appear ill (headache, fever, myalgias), systemic toxicity not present
Mycobacterial infection, including scrofula (Mycobacterium tuberculosis and other Mycobacterium species)
With scrofula, adenitis occurs in cervical region
Usually painless
Indolent clinical course
Infections with species other than M. tuberculosis more likely to occur in immunocompromised patients
Lymphogranuloma venereum (Chlamydia trachomatis)
Adenitis occurs in the inguinal region
History of sexual exposure days previously
Suppuration, fistula tracts common
Although LGV buboes may be somewhat tender, exquisite tenderness usually absent
Although patients may appear ill (headache, fever, myalgias), systemic toxicity not present
TPlease note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

8. Bubonic Plague Differential Diagnosis
Chancroid
(Hemophilus ducreyi)
Adenitis occurs in inguinal region
Ulcerative lesion present
Systemic symptoms uncommon; toxicity does not occur
Primary genital herpes
Genital area
Adenitis occurs in the inguinal region
Severe systemic toxicity not present
Primary or secondary syphilis
(Treponema pallidum)
Enlarged lymph nodes in inguinal region
Lymph nodes generally painless
Chancre may be noted
Strangulated inguinal hernias
Evidence of bowel involvement
Chancroid (Hemophilus ducreyi)
Adenitis occurs in the inguinal region
Ulcerative lesion present
Systemic symptoms uncommon; toxicity does not occur
Primary genital herpes
Herpes lesions present in genital area
Although patients may be ill (fever, headache), severe systemic toxicity not present
Primary or secondary syphilis (Treponema pallidum)
Enlarged lymph nodes in the inguinal region
Lymph nodes generally painless
Chancre may be noted with primary syphilis
Strangulated inguinal hernias
Evidence of bowel involvement
Please note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

9. Pneumonic Plague Incubation: 2 to 4 days (Range: 1-6 days) Symptoms
Fever, chills, malaise, myalgias
Productive cough, watery mucoid
Chest pain, dyspnea
Hemoptysis
Gastrointestinal
Cervical Bubo (rare)
Primary Pneumonic Plague
Incubation Period- 2-4 days with range of 1-6 days.
Symptoms-
Acute onset of fever, chills, malaise, and myalgias associated with progressive lethargy.
A productive cough of copious watery mucoid sputum that may be bloody. Associated chest pain and increasing dyspnea. Hemoptysis is a classic sign that should suggest plague in the appropriate clinical context, but sputum may be watery or purulent.
Gastrointestinal symptoms may be prominent with pneumonic plague; these include nausea, vomiting, diarrhea, and abdominal pain.
A cervical bubo is infrequently present.

10. Pneumonic Plague Rapidly progressive
Respiratory failure within 2 to 4 days
Chest X-Rays – bilateral patchy infiltrates
Shock, hypotension, multi-organ failure
Treat within 24 hours or almost universally fatal
Primary Pneumonic Plague
Progression of Disease
Pneumonic plague is rapidly progressive. Patients experience increasing dyspnea, stridor, and cyanosis. Rapidly progressive respiratory failure and sepsis within 2 to 4 days of onset of illness is typical of pneumonic plague.
Chest x-rays can be variable but frequently show bilateral patchy infiltrates or consolidation.
Shock, including hypotension and multi-organ failure, may also occur. Without early detection and treatment within 24 hours of symptom onset, pneumonic plague is almost universally fatal.

11. Pneumonic Plague

12. Primary Pneumonic Plague Outbreak Diagnoses
Presumptive; especially if associated
Rule out other causes
Severe pneumonia
Rapidly progressive respiratory infection
With or without sepsis
Primary Pneumonic Plague
Confirmation of Disease-
Once an outbreak of pneumonic plague occurs, a presumptive diagnosis can be made for anyone presenting with symptoms of pneumonia, if there is a history of exposure to the following:
the source,
suspected source of the outbreak, or
another confirmed case of pneumonic plague.
Even during a confirmed outbreak, other causes of severe pneumonia or rapidly progressive respiratory infection with or without sepsis should still be considered in the differential diagnosis.

13. Primary Pneumonic Plague Differential Diagnosis
Inhalational anthrax
Tularemia
Community-acquired bacterial pneumonia
Viral pneumonia
Q fever
Primary Pneumonic Plague
Diseases to Consider -The acute onset of fever, cough, and dyspnea associated with pneumonic plague must be differentiated from other causes of severe respiratory infection such as:
Inhalational anthrax
Tularemia
Community-acquired bacterial pneumonia
Viral pneumonia
Q fever
Anthrax

14. Primary Pneumonic Plague Differential Diagnosis
Inhalational anthrax
(Bacillus anthracis)
Widened mediastinum and pleural effusions
Not true pneumonia
Minimal sputum production
Hemoptysis uncommon
Tularemia
(Francisella tularensis)
Not as rapid or fulminant as in pneumonic plague
Inhalational anthrax (Bacillus anthracis)
Widened mediastinum and pleural effusions seen on CXR or chest CT
Not true pneumonia; minimal sputum production
Hemoptysis uncommon (if present, suggests diagnosis of plague)
Tularemia (Francisella tularensis)
Clinical course not as rapid or fulminant as in pneumonic plague
Please note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

15. Primary Pneumonic Plague Differential Diagnosis
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 (e.g., Staphyloccocus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis)
Rarely as fulminant
Usually occur in persons with underlying pulmonary or other disease or in the elderly
Bird exposure with psittacosis
Gram stain may be useful
Community outbreaks not as explosive as pneumonic plague outbreak
S. pneumoniae usually institutional
Community outbreaks of Legionnaires' disease often involve exposure to cooling systems
Community-acquired bacterial pneumonia Rarely as fulminant as pneumonic plague
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 the elderly
Bird exposure with psittacosis
Gram stain of sputum may be useful
Community outbreaks caused by other etiologic agents not likely to be as explosive as pneumonic plague outbreak
Outbreaks of S. pneumoniae usually institutional
Community outbreaks of Legionnaires' disease often involve exposure to cooling systems
Please note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

16. Primary Pneumonic Plague Differential Diagnosis
Viral pneumonia
Influenza
Hantavirus
RSV
CMV
Influenza generally seasonal
History of recent cruise ship travel or travel to tropics
Exposure to excrement of mice with Hantavirus
RSV usually occurs in children
CMV usually occurs in immunocompromised patients
Q fever
(Coxiella burnetii)
Exposure to infected parturient cats, cattle, sheep, goats
Severe pneumonia not prominent
Viral pneumonias like 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 or 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
Q fever (Coxiella burnetii)
Exposure to infected parturient cats, cattle, sheep, goats
Severe pneumonia not prominent feature
Please note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

17. Septicemic Plague Incubation: Most common as complication Symptoms
Fever, chills, prostration
Gastrointestinal
Disease Progression
Pupura
DIC
Amputation
Septicemic Plague - The endotoxemia and systemic inflammatory response syndrome associated with septicemic plague must be differentiated from any bacterial or viral invasion of the body that can cause septicemic shock.
Incubation Period- Occurs when plague bacteria multiply in the blood. Septicemic plague is more common than primary pneumonic plague and is usually associated with hunters skinning infected animals.
Symptoms- Acute onset of fever, chills, prostration, abdominal pain, nausea, and vomiting.
Progression of Disease- Pupura and disseminated intravascular coagulation (DIC) are quite common with plague sepsis. Eventual amputation of fingers, toes, or feet is not uncommon.
Pupura

18. Septicemic Plague Differential Diagnosis
Meningococcemia
Evidence of meningitis
Septicemia caused by other gram-negative bacteria
Underlying illness usually present
Meningococcemia
More likely to have evidence of meningitis (but not always present)
Septicemia caused by other gram-negative bacteria
Underlying illness usually present
Please note: The following listing is not comprehensive, but represents the most commonly considered diagnoses when ruling out plague.
This material was developed through a collaborative effort of CIDRAP (Center for Infectious Disease Research and Policy, and the Infectious Diseases Society of America ( with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.
© 2003 CIDRAP/IDSA

19. Review Questions
Plague Lesson 3

20. Plague Review Question Lesson 3, Question 1
36yo, F, Chicago, IL
Housekeeper
No hx of travel, animal exposure
Symptoms
Severe abdominal pain
Productive cough
Shortness of breath
Lesson Self-Assessment- Mrs. Smith
1) Patient –36-year-old, female, Chicago, Illinois
Occupation - Housekeeper at large hotel
Travel – None
Animal Exposure – One healthy cat. No exposure to ill animals
Symptoms - Early yesterday, onset of malaise, body aches, chills, headache and GI symptoms, to include nausea, vomiting and diarrhea.
Today - Awoke with worsening symptoms: severe abdominal pain, productive cough, and shortness of breath.

21. Plague Review Question Lesson 3, Question 1
Exam Findings
Productive cough, thick, bloody sputum
Bilateral rales
Little-to-no air movement lower left lung field
Chest X-Ray – bilateral infiltrates
CSF – Cloudy
Temperature – 102.3F
Pulse rapid and thready
Liver not enlarged, no enlarged lymph nodes
What diagnoses would you rule out?
Examination Findings – Patient cough producing thick, bloody sputum. Bilateral rales, little-to-no air movement in the left lower lung field, and dullness on percussion over the lower half of her left lung. Chest radiograph showed bilateral infiltrates with consolidation in the left lung field. CSF obtained via the LP was cloudy in appearance. Her temperature was F, and her pulse was rapid and thready. Liver not enlarged, no enlarged lymph nodes.
What diagnoses would you rule out with this patient?

22. Plague Review Question Lesson 3, Question 1
What diagnoses would you rule out?
Anthrax
Tularemia
Pneumonic Plague
Bubonic Plague
What diagnoses would you rule out?
A. Anthrax
B. Tularemia
C. Pneumonic Plague
D. Bubonic Plague

23. Plague Review Question Lesson 3, Question 1
What diagnoses would you rule out?
C. Pneumonic Plague
The symptomology and rapid progression of disease is strongly suggestive of pneumonic plague. Further laboratory testing should be pursued to help confirm or rule out this disease.
Inhalational anthrax does not present as a true pneumonia and does not produce sputum. Also, evidence of widening of the mediastinum would begin to show by this stage and the lymph nodes would be enlarged.
While tularemia and pneumonic plague share many of the same symptoms, the clinical course for tularemia is not as rapid. Mrs. Smith’s quick progression to pneumonia tends to suggest this is not tularemia.
While it is possible for patients with Bubonic Plague to progress rapidly to Pneumonic Plague, one would expect to find a bubo on examination.

24. Plague Review Question Lesson 3, Question 2
32yo, M, Philadelphia, PA
Computer Programmer
No hx travel, Healthy dog
Symptoms
Headache, chills, fever x 2 days
Vomiting x 1 day
Orange-sized swelling, left inguinal
Delirious
What illnesses would you include in differential?
2) Patient - 32-year-old male, Philadelphia, Pennsylvania
Occupation – Computer Programmer
Travel – None outside the state in the past year
Animal Exposure – One healthy dog, no other exposure to ill animals
Symptoms - Admitted to Downtown Hospital in Philadelphia, Pennsylvania because of a two-day history of headaches, chills and fever. The day before admission, he began vomiting. Today, an orange-sized swelling in the left inguinal was noted and the patient was delirious.
What illnesses would you include in your differential diagnosis?

25. Plague Review Question Lesson 3, Question 2
What illnesses would you include in differential?
Tularemia
Chancroid
Cat-Scratch Fever
Bubonic Plague
What illnesses would you include in your differential diagnosis?
Tularemia
Chancroid
Cat-Scratch Fever
Bubonic Plague

26. Plague Review Question Lesson 3, Question 2
What illnesses would you include in differential?
D. Bubonic Plague
The best answer is D. Bubonic Plague
Because of the rapid progression of symptoms and presence of the bubo, this patient is highly suspicious for bubonic plague, despite the lack of exposure.
While there is usually extensive lymph node involvement with tularemia, there is usually an ulcer or pustule present distal to the involved nodes and the patient is usually not septic.
With chancroid, adenitis does occur in the inguinal region. However, with chancroid there is an ulcerative lesion present, systemic symptoms are uncommon and toxicity does not occur
With cat-scratch fever, there is a history of contact with cats and evidence of a cat scratch. In addition, it usually takes weeks for the disease to progress and systemic toxicity is not present.

27. Plague Review Question Lesson 3, Question 3
56yo, M, Miami, Florida
Salesman
Hx of Travel to New Mexico last week
No hx of animal exposure
Symptoms
Malaise, myalgia, chills, headache, GI sxs x 3 days
Worsening sx’s, severe abdominal, productive cough, shortness of breath x 1 day
Today – Pupura, DIC, hypotension
How would you relate it to plague?
Patient – Previously healthy 56-year-old, male, Miami, Florida
Occupation – Salesman at local department store
Travel – Camping trip to New Mexico last week
Animal Exposure – No pets or exposure to ill animals
Symptoms – Three days ago, onset of malaise, body aches, chills, headache and GI symptoms, to include nausea, vomiting and diarrhea. Yesterday, awoke with worsening symptoms: severe abdominal pain, productive cough, and shortness of breath. Admitted to hospital today with purpura, disseminated intravascular coagulation (DIC), and hypotension.
While it’s clear that this is septicemia, how would you relate it to plague?

28. Plague Review Question Lesson 3, Question 3
How would you relate it to plague?
Presence of gram-positive bacteria
Hx of travel to plague endemic area
Rapid progression of disease
B and C
While you know this is septicemia, how would you relate it to plague?
A. The presence of gram-positive bacteria in sputum specimens
B. A history of travel to plague endemic area and/or exposure to ill animals
The rapid progression of disease
Both B and C

29. Plague Review Question Lesson 3, Question 3
How would you relate it to plague?
Both B and C
Hx of travel to plague endemic area
Rapid progression of disease
The best answer is D, both B and C.
Combining his recent exposure to a plague-endemic area with the rapid progression of disease is an important clue that points to plague, in this case. However, if he had not had the history of travel, the rapid progression of disease is concerning. Laboratory testing should be pursued as quickly as possible.
The appearance of gram-positive rods should prompt you to seek causes other than plague. The plague bacteria are actually gram-negative rods, having a “safety pin” appearance. This, combined with chest x-ray results, can help to increase your suspicion to start patients on the appropriate antibiotic regimen for plague, after consultation with your health department.
History of travel is an excellent indicator if the patient has had travel to plague-endemic areas. However, if the patient has no history of travel, you should still maintain plague as a possibility if no other causes are found; especially given the rapid progression of the disease. The rapid progression of the disease is also an excellent indicator, given the patient’s previously healthy state. This, coupled with his history of recent travel to a plague-endemic area, is an important clue to consider plague as the cause. Laboratory testing should be pursued as quickly as possible.