Moderators: Dr. Dani Zander, Dr. David Hwang and Dr. Osamu Matsubara
Section 5 -
Pulmonary Manifestations of Potential Biowarfare Agents
David H. Walker
The opportunity to make the correct diagnosis of the index case of a bioterrorism event
quite probably could be that of a pathologist examining an autopsy or lung biopsy. Recognition of the
potential exposure of a large group of persons would enable early treatment in the prodromal stage or
even prophylaxis with greatly reduced morbidity and mortality. The goal of this presentation is to
prepare pathologists to identify the pulmonary lesions of anthrax, pneumonic plague, pneumonic tularemia,
glanders, typhus, Q fever, and brucellosis. The most likely means of dispersal of the microbial weapon
would be as an aerosol although ingestion of contaminated food or water is also possible. Pulmonary
involvement by some of these diseases is pneumonic (e.g., plague, tularemia, Q fever) with primary growth
of the inhaled bacteria in airspaces. Pulmonary involvement in some other diseases, however, follows
hematogenous spread to the lungs whether after initial inhalation, ingestion, or other means of
transmission (e.g., anthrax, secondary plague or tularemic pneumonia, glanders, typhus, brucellosis).
Infectious agents that have scarcely been considered as threats might be used (e.g., coccodioidomycosis,
histoplasmosis, or blastomycosis, which develop easily prepared spores, or tuberculosis, influenzavirus
A, or SARS-coronavirus, which are transmissible from person-to-person).
Inhalational anthrax provides a clear example of the challenge
and importance of a timely diagnosis. The incubation period is extremely variable (2-43 days), owing to
dose and variable delay in germination of inhaled spores. During the 3-4 days after onset, mild fever,
malaise, non-productive cough, and precordial discomfort resemble many other illnesses. Thereafter
sudden onset of dyspnea followed by cyanosis, stridor, rales, pleural effusions, and hypotensive shock,
the fulminant phase, leads to death 24 hours later despite contemporary intensive care. Diagnosis of the
index case, even at neuropsy, can alert physicians to provide early treatment and prophylaxis to other
Grossly there are usually massive hemorrhagic pleural effusions, hemorrhages in the
mediastinum, tracheobronchial lymph nodes, and tracheobronchial submucosa, gelatinous edema of the
mediastinum and parietal pleura, perihilar extension of mediastinal hemorrhages and edema into the lung,
and in half of the cases significant peripheral pulmonary hemorrhagic consolidations. Microscopically,
the gelatinous edema contains abundant fibrin, lymphatic vessels are frequently dilated and focally
obstructed by bacteria and inflammatory cells, and there is minimal accumulation of inflammatory cells in
the hemorrhages or edematous lesions. The peripheral hemorrhagic lesions contain only a small amount of
fibrin and few macrophages. They are likely caused by vasculitis and hematogenous spread of Bacillus anthracis to the lungs.
During the incubation period, anthrax spores are transported by alveolar macrophages to
mediastinal lymph nodes where they germinate, proliferate, secrete toxins, cause vasculitis and
hemorrhage, and spread into the blood. Anthrax causes respiratory failure mainly by compressive
atelectasis owing to pleural effusions with significant hematogenous hemorrhagic pneumonia in some
patients, but bronchopneumonia caused by primary germination and growth of B.
anthracis in the lungs does not occur.
After an incubation period of 1-3 days, patients who have inhaled Yersinia pestis from a bioweapon or aerosol generated by a coughing patient
develop high fever followed by chest pain, dyspnea, hemoptysis, and fulminant death. Chest radiographs
reveal multiple bilateral nodular consolidations that grossly represent nodules of necrosis and
hemorrhage that may be lobular, lobar or multilobar. Microscopic examination reveals necrotizing lobular
pneumonia with many 0.5-1 x 1-2 μm gram negative bacilli with bipolar safety pin appearance by gram,
methylene blue, Wayson and Wright-Giemsa stains. The alveoli also contain a protein-rich exudate, few
neutrophils, and no fibrin. There is also necrosis of alveolar walls and adjacent pleuritis.
After inhaling a low dose of Francisella tularensis, patients
develop fever, dry cough, and malaise. Bronchoscopy reveals focal-to-diffuse hemorrhagic erosions of the
bronchial mucosa. Chest radiographs demonstrate patchy, segmental, or subsegmental consolidation,
pleural effusions, hilar lymphadenopathy in 50%, and cavitation in 20% (best observed by CT examination).
At necropsy, gross examination shows bronchopneumonia, hilar lymphadenopathy, and pleural effusions.
Microscopically there is acute necrotizing hemorrhagic pneumonia. Alveoli contain edema, fibrin, a mixed
exudate with macrophages and necrotic neutrophils. Thrombosis of arteries and veins is associated with
infarction and cavitation. Lungs in late deaths are characterized by fibrosis, calcification, and/or
granulomatons inflammation. The draining lymph nodes contain sheets of bacteria, stellate abscesses with
geographic necrosis and later pallisading granulomas.
Less known than melioidosis caused by Burkholderia
pseudomallei, glanders caused by B. mallei is a more severe biothreat
with all infections manifesting illness and 95% lethality. Melioidosis causes symptoms in only 0.1% of
infections, namely those with host factors such as renal disease. Glanders is a disease of equines that
was eradicated from the United States and Canada in the first half of the 20th century, but
Human glanders usually manifests as an acute disease with fever, headache, and myalgia
followed by septic death with a pustular rash in many patients who survive longer than two weeks.
Whether infection enters via percutaneous inoculation or inhalation, the lungs are involved by
hematogenous spread. In acute septic death 10-13 days after exposure, half of patients develop
interstitial pneumonia. In deaths 15-25 days after percutaneous inoculation, all patients develop
pulmonary lesions, usually military granulomas, often hemorrhagic suppurative pneumonia and obliterative
endarteritis. At 37-49 days, half of the patients manifest miliary granulomas, and the other half,
obliterative endarteritis. Inhalational transmission causes bronchial inflammation, and in deaths
occurring more than 100 days after exposure, there is severe lobular pneumonia.
The obliterative endarteritis that occurs in half of cases surviving longer than two weeks
resembles the pathology of septic emboli. The multiple pulmonary nodules are associated with waxy
central necrosis and a surrounding zone of hemorrhage. Microscopy reveals well formed granulomas and
vascular occlusion by fibrin with angiocentric inflammation. Infarction is a component of some of the
pulmonary and myocutaneous lesions.
The usual route of infection by Coxiella burnetii is via
inhalation of aerosol of spore-like bacteria. Although only 40% of infections are symptomatic, 4.4% of
patients are hospitalized with pneumonia. The stability of the agent, extremely low dose infectivity,
and acutely incapacitating illness in many patients led to its weaponization. There is abrupt onset of
chills, fever, fatigue, and headache with non-productive cough in a variable portion (4-90%) of cases.
Chest radiographs in patients with Q fever pneumonia may demonstrate segmental or subsegmental
consolidation, rounded opacity, atelectasis, pleural effusion, or hilar lymphadenopathy.
The major pulmonary target cells of C. burnetii are alveolar
macrophages, where the bacteria thrive in acidic phagolysosomes. Microscopy reveals
bronchioloalveolitis, interstitial and alveolar infiltrates of macrophages, lymphocytes, a few PMNs,
fibrin, and RBCs. The lesion resolves slowly and in the late stage has been characterized as a
Pulmonary Involvement in Vasculotropic Rickettsioses
Rickettsia prowazekii, R. rickettsii, R. typhi, and R. conorii are highly infectious by low dose aerosol, have extracellular forms
that with stable infectivity, and cause lifethreatening disease. Typhus and Rocky Mountain spotted fever
have case-fatality rates similar to category A agents. Their potential threat as agents of bioterror has
Rickettsioses acquired by aerosol are clinically indistinguishable from naturally
vector-borne infections. Patients present with fever, headache, and myalgia with rash appearing on day
3-5 or later. Cough occurs in a third or more of cases of epidemic typhus, Rocky Mountain spotted fever,
and murine typhus. The most severe cases manifest respiratory and neurologic involvement. Fatal disease
is frequently associated with adult respiratory distress syndrome.
There is extensive infection of endothelial cells of the pulmonary microcirculation by
rickettsiae, causing increased vascular permeability and non-cardiogenic pulmonary edema. At necropsy
the lungs are edematous and diffusely consolidated. Histopathologic lesions include interstitial
pneumonia and edema, alveolar edema fibrin, hemorrhages, and macrophages, diffuse alveolar damage often
with hyaline membranes, edema of the interlobular septa, and lymphohistocytic vasculitis.
Pulmonary Manifestations of Brucellosis
Pulmonary abnormalities occur infrequently in brucellosis. In a series of 1500 cases of
brucellosis, nine patients manifested fever and productive cough and six had rales. Chest radiographs
revealed patchy infiltrates or consolidation in five patients, pleural effusions in three, noncasesting
granulomas in one, and interstitial pneumonia in one.
Rhesus monkeys infected by inhalation of aerosol containing Brucella
melitensis developed little pulmonary pathology. Cultures containing 103 or more
bacteria were obtained in three of six animals. One animal showed mild multifocal interstitial pneumonia
containing lymphocytes, plasma cells, PMNs, and multinucleated grant cells, and another monkey had focal
pneumonia with alveolar, macrophages, eosinophils, few PMNs, and protein-rich edema. These lesions are
most likely the result of hematogenous spread of brucella to the lungs.
Immunohistochemical methods are available at the CDC to diagnose anthrax, plague,
tularemia, Q fever, brucellosis and Rocky Mountain spotted fever.
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