# Presentation: 055992

## Bioterrorism Agents – PlagueLesson 3

- Differential Diagnosis

## Objectives

- List the diseases that should be considered in the differential diagnosis of plague
- Describe how to rule out other diseases when diagnosing plague

**Notes:**
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 

## 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

**Notes:**
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. 

## Bubonic Plague

- Disease Progression
- Septicemia
- Pneumonic Plague
- Meningitis (rare)
- Other Symptoms
- Restlessness, confusion, lack of coordination
- Intestinal discomfort
- Lymph nodes may suppurate second week

**Notes:**
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.  

## Bubonic PlagueDifferential Diagnosis

- Capnocytophaga canimorsus
- Cellulitis
- Lymphogranuloma venereum
- Non-specific infections

- Lymphogranuloma venereum

**Notes:**
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. 

## 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 |

*©* 2003 CIDRAP/IDSA

**Notes:**
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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## 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 10-30 days previously
  Suppuration, fistula tracts common
  Exquisite tenderness usually absent
  Although patients may appear ill (headache, fever, myalgias), systemic toxicity not present  |

*©* 2003 CIDRAP/IDSA

**Notes:**
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 10-30 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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## 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  |

*©* 2003 CIDRAP/IDSA

**Notes:**
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
  Adenitis occurs in the inguinal region 
  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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## 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)

**Notes:**
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. 

## 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

**Notes:**
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.

## Pneumonic Plague

## Primary Pneumonic PlagueOutbreak Diagnoses

- Presumptive; especially if associated
- Rule out other causes
- Severe pneumonia
- Rapidly progressive respiratory infection
- With or without sepsis

**Notes:**
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.

## Primary Pneumonic PlagueDifferential Diagnosis

- Inhalational anthrax
- Tularemia
- Community-acquired bacterial pneumonia
- Viral pneumonia
- Q fever

- Anthrax

**Notes:**
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 

## 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  |

*©* 2003 CIDRAP/IDSA

**Notes:**
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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## 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  |
| --- | --- |

*©* 2003 CIDRAP/IDSA

**Notes:**
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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## 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 |

*©* 2003 CIDRAP/IDSA

**Notes:**
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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## Septicemic Plague

- Incubation:  Most common as complication
- Symptoms
- Fever, chills, prostration
- Gastrointestinal
- Disease Progression
- Pupura
- DIC
- Amputation

- Pupura

**Notes:**
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.

## Septicemic PlagueDifferential Diagnosis

| Meningococcemia  | Evidence of meningitis |
| --- | --- |
| Septicemia caused by other gram-negative bacteria  | Underlying illness usually present  |

*©* 2003 CIDRAP/IDSA

**Notes:**
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, www.cidrap.umn.edu) and the Infectious Diseases Society of America (www.idsociety.org) with funding from the Centers for Disease Control and Prevention. ©2003 CIDRAP/IDSA.

## Review Questions

- Plague Lesson 3

## 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

**Notes:**
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.

## 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?

**Notes:**
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 102.3 F, and her pulse was rapid and thready. Liver not enlarged, no enlarged lymph nodes.
What diagnoses would you rule out with this patient?

## Plague Review QuestionLesson 3, Question 1

- What diagnoses would you rule out?
- Anthrax
- Tularemia
- Pneumonic Plague
- Bubonic Plague

**Notes:**
What diagnoses would you rule out?

A.  Anthrax
B.  Tularemia
C.  Pneumonic Plague
D.  Bubonic Plague

## Plague Review QuestionLesson 3, Question 1

- What diagnoses would you rule out?
- C.  Pneumonic Plague

**Notes:**
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.

## 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?

**Notes:**
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?

## Plague Review QuestionLesson 3, Question 2

- What illnesses would you include in differential?
- Tularemia
- Chancroid
- Cat-Scratch Fever
- Bubonic Plague

**Notes:**
What illnesses would you include in your differential diagnosis?

Tularemia
Chancroid
Cat-Scratch Fever
Bubonic Plague

## Plague Review QuestionLesson 3, Question 2

- What illnesses would you include in differential?
- D.  Bubonic Plague

**Notes:**
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.

## 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?

**Notes:**
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?

## 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

**Notes:**
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

## 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

**Notes:**
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.