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Mina B, Dym JP, Kuepper F, et al. Fatal Inhalational Anthrax With Unknown Source of Exposure in a 61-Year-Old Woman in New York City. JAMA. 2002;287(7):858–862. doi:10.1001/jama.287.7.858
Author Affiliations: Section of Critical Care Medicine (Dr Mina), Department of Medicine (Drs Dym, Tso, Arrastia, Kaplounova, Faraj, Kwapniewski, Glick, and Fochios), Department of Radiology (Dr Krol), Section of Emergency Medicine (Dr Grosser), Section of Cardiology (Dr Remolina), Department of Pathology (Dr Vasovic), Section of Interventional Cardiology (Dr Moses), Microbiology Laboratory (Mr Robin), Section of Nephrology (Dr DeVita), and Section of Infectious Disease (Dr Tapper), Lenox Hill Hospital, New York, NY; and Charité of the Humboldt-University of Berlin, Germany (Mr Kuepper).
A 61-year-old woman who was a New York City hospital employee developed
fatal inhalational anthrax, but with an unknown source of anthrax exposure.
The patient presented with shortness of breath, malaise, and cough that had
developed 3 days prior to admission. Within hours of presentation, she developed
respiratory failure and septic shock and required mechanical ventilation and
vasopressor therapy. Spiral contrast–enhanced computed tomography of
the chest demonstrated large bilateral pleural effusions and hemorrhagic mediastinitis.
Blood cultures, as well as DNA amplification by polymerase chain reaction
of the blood, bronchial washings, and pleural fluid specimens, were positive
for Bacillus anthracis. The clinical course was complicated
by liver failure, renal failure, severe metabolic acidosis, disseminated intravascular
coagulopathy, and cardiac tamponade, and the patient died on the fourth hospital
day. The cause of death was inhalational anthrax. Despite epidemiologic investigation,
including environmental samples from the patient's residence and workplace,
no mechanism for anthrax exposure has been identified.
Anthrax is caused by the bacterium Bacillus anthracis and recently has been used as an agent of bioterrorism.1,2
The B anthracis spores lead to the disease by entering
the body cavity through skin contact, ingestion, or inhalation.3
Pulmonary anthrax is the most lethal form of the disease.4
Along with smallpox, tularemia, plague, and botulism, anthrax is now at the
forefront in the age of biological warfare.5-7
As of January 9, 2002, a total of 23 cases of anthrax have been reported
to the Centers for Disease Control and Prevention (CDC; Atlanta, Ga): 11 cases
were confirmed inhalational anthrax and 12 cases (7 confirmed and 5 suspected)
were cutaneous anthrax.8 An estimated 32 000
people were prescribed prophylactic antibiotic therapy between October 9 and
November 9, 2001.9 Anthrax spores have now
been found at government buildings, post offices, and media centers in Florida,
Washington, DC, New Jersey, and New York, NY. In this article, we report the
first case of inhalational anthrax in New York City, a 61-year-old hospital
employee who had none of the exposure risks previously described in this cluster
On October 28, 2001, a 61-year-old Vietnamese woman was brought into
the emergency department of Lenox Hill Hospital in New York City complaining
of weakness, chest heaviness, dyspnea, malaise, cough, and chills for the
preceding 3 days. On the day prior to admission, the cough was associated
with pink-tinged sputum. The patient previously had been in her usual state
of health and had worked until 2 days prior to admission. The patient denied
headache, neck pain, fever, sore throat, or skin rash. The patient had a medical
history of hypertension controlled with amlodipine and fosinopril. The patient
was a nonsmoker and denied alcohol use or recreational drug use. She had immigrated
to the United States from Vietnam 20 years earlier but had no recent travel.
She worked in the central supply room of a Manhattan hospital in a space shared
with a mail receiving and sorting room.
On physical examination, the patient had a respiratory rate of 38/min
and was in respiratory distress. Blood pressure was 128/60 mm Hg, pulse was
86/min, and temperature was 97°F (36°C). Head examination results
were normal without scleral icterus or oral thrush. The neck was supple with
no bruits or jugular venous distension, and the trachea was midline. There
was no evidence of cervical or axillary adenopathy. Chest examination revealed
inspiratory rales and decreased breath sounds bilaterally. Heart examination
revealed regular rate and rhythm, with normal S1 and S2
and no S3, S4, or murmurs. The abdomen was soft, nontender,
and nondistended, and no organomegaly was evident. There were no neurological
deficits. No skin lesions were detected.
The initial portable view of the chest obtained shortly after presentation
demonstrated marked widening of the superior mediastinum, with moderate bilateral
pleural effusions, fluid in the minor fissure, and bilateral perihilar infiltrates
(Figure 1A). An electrocardiogram
showed sinus tachycardia at a rate of 101/min without any signs of myocardial
ischemia. Arterial blood gas values obtained while the patient was receiving
supplemental oxygen (100% nonrebreather face mask) were: pH, 7.41; partial
pressure of carbon dioxide, 40 mm Hg; partial pressure of oxygen, 122 mm Hg;
and oxygen saturation, 99%. Laboratory values on hospital admission are shown
in Table 1. A bedside echocardiogram
showed normal left ventricular function and wall motion, slight aortic regurgitation,
a small pericardial effusion, and an aneurysm of the ascending aorta. Blood
cultures were drawn and were submitted in aerobic and anaerobic culture bottles
(BioMerieux, Raleigh-Durham, NC). The patient was initially treated presumptively
for congestive heart failure with 20 mg of intravenous furosemide. Empirical
intravenous levofloxacin, 500 mg/d, was administered for community-acquired
pneumonia and the possibility of inhalational anthrax.
The patient was admitted to the medical intensive care unit. Her respiratory
and hemodynamic status deteriorated rapidly, and she was immediately intubated
because of tachypnea, respiratory distress, and oxygen desaturation. Frothy
pink secretions were suctioned from the endotracheal tube. Pulmonary artery
catheterization revealed right atrial pressure of 4 mm Hg (reference range,
0-6 mm Hg), right ventricular pressure of 17/5 mm Hg (reference range, 20-30/0-5
mm Hg), and pulmonary artery pressure of 20/10 mm Hg (reference range, 20-30/5-15
mm Hg), but pulmonary artery wedge pressures could not be measured. After
unsuccessful crystalloid resuscitation, vasopressor therapy (norepinephrine,
phenylephrine, and, later, vasopressin) was initiated. The differential diagnosis
included dissecting ascending aortic aneurysm with leakage, severe community-acquired
pneumonia, vasculitis (Wegener granulomatosis), and inhalational anthrax.
Rifampin, 300 mg intravenously every 8 hours, and clindamycin, 800 mg every
8 hours, were added to the antibiotic regimen, and the levofloxacin dosage
was increased to 500 mg every 12 hours.
Repeat chest radiograph revealed progressive widening of the mediastinum,
and the tip of the pulmonary artery catheter was positioned in the main pulmonary
artery trunk. Spiral computed tomography of the chest demonstrated large bilateral
pleural effusions, a small amount of blood layering in the dependent portion
of the right pleural space, and a large amount of edema and hemorrhage in
the soft tissues surrounding the trachea, bronchi, and hilar regions bilaterally,
with complete infiltration of the mediastinal fat planes, bronchial mucosal
thickening, encasement and compression of the hilar vessels (Figure 2A). An intact 4.2-cm aneurysm of the ascending aorta was
incidentally noted. Delayed images at 20 minutes demonstrated multiple confluent
ringlike areas of enhancement with hypodense centers compatible with hemorrhagic
lymph node necrosis involving the subcarinal, paratracheal, subaortic, and
azygoesophageal recess nodes (Figure 2B).
A high-density pericardial effusion, suggesting hemorrhage, was also present.
Bilateral chest tubes were inserted and each drained more than 1 L of
serosanguinous fluid. Pleural fluid analysis produced the following values:
glucose, 147 mg/dL (8.2 mmol/L); total protein, 4.2 g/dL; lactic dehydrogenase,
1264 U/L; white blood cell count, 3.0 × 103/µL; and
red blood cell count, 0.073 × 106/µL. At the time of
admission to the intensive care unit, the patient had an Acute Physiology
and Chronic Health Evaluation III score of 143, with predicted intensive care
unit and hospital mortality of 80% and 89%, respectively.
On the second hospital day, fiberoptic bronchoscopy revealed severe
hemorrhagic tracheobronchitis with oozing of bloody fluid from the mucosal
surfaces and easy sloughing of the mucosa. The patient developed worsening
hepatic function with increasing aminotransferases, nonoliguric renal failure
with creatinine level increasing to 1.9 mg/dL (168 µmol/L), lactic acidosis
(lactate, 75 mg/dL), leukocytosis (23.9 × 103/µL),
and disseminated intravascular coagulopathy (Table 1). A continuous infusion of furosemide was initiated and
multiple blood products were transfused. Blood cultures obtained on admission
became positive for large gram-positive bacilli after 20 hours of incubation
(Figure 1B). Smears of the broth
were Gram stained and revealed gram-positive rods in extremely long chains.
Examination of a wet preparation of the blood culture broth demonstrated that
the organism was nonmotile. Blood, pleural fluid, and bronchial wash specimens
were sent for DNA amplification by polymerase chain reaction (PCR). A repeat
echocardiogram confirmed a slight increase in the amount of pericardial fluid.
On the third hospital day, phenylephrine was tapered off and the norepinephrine
dose was decreased by 50%. The patient's respiratory status deteriorated,
with worsening oxygenation and ventilation. The blood culture isolate was
confirmed as B anthracis by gamma phage lysis and
direct fluorescent antibody testing against capsular and cell wall antigens
at the New York City Department of Health and the CDC. Blood, pleural fluid,
and bronchial washings were also positive by PCR for B anthracis at the same laboratories. Levofloxacin was discontinued and ciprofloxacin,
400 mg every 12 hours, was initiated. Repeat echocardiogram confirmed an increase
in the size of the pericardial effusion and mild-to-moderate right atrial
and ventricular collapse during early diastole. Cardiac index was 2.6 L/(min/m2) (reference range, 2.4-4.0 L/[min/m2]), systemic vascular
resistance was 1131 (dynes · s · m2)/cm5
(reference range, 900-1400 [dynes · s · m2]/cm5), and a pulmonary capillary wedge pressure was 13 mm Hg (reference
range, 6-12 mm Hg), with no evidence of equalization of pressures. A follow-up
echocardiogram 5 hours later documented further increase in the pericardial
fluid with evidence of collapse of the right atrium and ventricle.
The patient's respiratory status deteriorated further, and blood gas
analysis revealed a pH of 7.49, a partial pressure of carbon dioxide of 37
mm Hg, a partial pressure of oxygen of 59 mm Hg, and an oxygen saturation
of 92% with pressure-control ventilation, with pressure control of 20 cm H2O, 100% oxygen, and positive end-expiratory pressure of 5 cm H2O. Because of her deteriorating hemodynamic status and inability to
maintain adequate oxygenation, a bedside echocardiographically guided pericardiocentesis
was attempted unsuccessfully by the interventional cardiology service. The
patient decompensated further, with worsening oxygenation and refractory hypotension
with vasopressors, and she became bradycardic and pulseless. Cardiopulmonary
resuscitation was unsuccessful and the patient died on the fourth hospital
day. Repeat blood cultures from the second and fourth hospital days were negative
for any pathogens.
An autopsy performed at the office of the chief medical examiner of
the city of New York confirmed marked hemorrhagic mediastinitis. The hilar
and peribronchial lymph nodes were enlarged, necrotic, and replaced by hematoma.
Touch prep revealed few scattered gram-positive bacilli. There was a large
hemorrhagic pericardial effusion and extensive pulmonary edema. There was
no meningitis, bronchopneumonia, splenomegaly, or mesenteric lymphadenopathy.
There were no hemorrhagic lesions of the liver or kidney. The cause of death
was inhalational anthrax and the manner of death was homicide (oral communication,
James Gill, MD, New York City Medical Examiner Office, January 14, 2002).
For the patient presented herein, there were no obvious links to any
of the settings previously associated with either naturally occurring or bioterrorism-associated
anthrax. Inhalational anthrax was considered in this patient from the time
of admission because of the widespread publicity surrounding previous cutaneous
anthrax cases in New York City and the alerts issued to the medical community
by the New York City Department of Health. Despite early institution of antibiotics,
the disease progressed rapidly, resulting in multiple organ failure and large
pericardial effusion precipitating hemodynamic instability.
The clinical presentation of inhalational anthrax in this patient was
typical. Several days of a nonspecific prodrome of malaise, generalized weakness,
chills, and occasional chest pain preceded complete respiratory failure, septic
shock, a large pleural effusion, and multiple organ dysfunction. Hemorrhagic
mediastinitis and hemorrhagic pericardial effusion may have contributed to
respiratory failure. Death occurred 7 days after the onset of symptoms, similar
to that reported by Dixon et al.4
The anthrax bacillus is a gram-positive, aerobic, spore-forming microorganism.
Aerosolized anthrax spores can be trapped in the upper airways, although spores
of 2 to 3 µm can pass through the bronchi to the alveoli. The spores
are engulfed by macrophages, which carry them to the peribronchial and mediastinal
lymph nodes, where they germinate and replicate into vegetative bacilli. This
leads to hemorrhagic lymphadenitis and the enlarged mediastinum that is observed
on radiographic images.4,7 Mediastinal
hemorrhage with high-density adenopathy in an acutely ill patient with no
history of trauma should raise concern for inhalational anthrax infection.
Inhalational anthrax is not considered a true pneumonia, and death results
from septicemia, toxemia, or pulmonary complications and usually occurs within
36 hours.4 As of November 7, 2001, 5 of the
11 patients with inhalational anthrax associated with bioterrorism in the
United States have died. The 6 survivors were treated in the prodromal phase
of the disease; none of the patients who required intubation or who became
hemodynamically unstable have survived.10 Early
suspicion and initiation of antibiotic therapy while awaiting culture results
may improve the prognosis.1
The initial diagnosis of anthrax is usually made by positive cultures
of blood, cerebrospinal fluid, or skin lesion (vesicular fluid or eschar).3 Rapid identification of the growing organism can be
made by direct fluorescent antibody testing and gamma phage lysis. DNA amplification
from body fluids by PCR may help in early diagnosis of the disease. Antibody
testing by enzyme-linked immunosorbent assay may yield positive results in
convalescent serum specimens.4 Currently, such
tests are available only in local and state public health laboratories or
at the CDC.
To date, 7 cases of cutaneous anthrax and 1 case of inhalational anthrax
have been reported in New York City. All of the cutaneous cases occurred among
employees or persons directly associated with the media; 2 were NBC employees,
1 was a CBS employee, 3 were from the New York Post,
and 1 was the infant of an ABC employee. Environmental samples from these
media companies' buildings were positive for anthrax spores.
The patient presented in this case report differed from other reported
cases of inhalational anthrax in that no clear risk for exposure has yet been
determined. Extensive environmental samples from the patient's residence and
workplace were negative for B anthracis by PCR and
conventional bacterial cultures. Nasal cultures taken from personal contacts
and coworkers in the same workplace environment were also negative for B anthracis. Environmental samples from surfaces and an
air filtration system from the subway route that the patient rode daily were
also negative for anthrax (New York City Department of Health and CDC).8,11-13
It has been postulated that infection from a cross-contaminated envelope
may have been the source of anthrax transmission in this patient.8 However, it is unclear why she is the only patient
in New York City to date who has developed inhalational anthrax. Nonetheless,
even patients without obvious sources of possible anthrax exposure may be
at risk for bioterrorism-associated diseases. Heightened public health and
health care facility surveillance efforts, increased awareness by the public,
and health care professional education are needed to ensure that the unusual
clinical presentations of such rare infections do not go unrecognized.