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Infectious Diseases in Clinical Practice:
Special Articles: Clinical Pathological Conference

Clinical Pathological Conference

Ghanem, Khalil G. M.D.; Perez, John L. M.D.

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Abstract

This feature discloses the opinion of the discussant and the opinion of the audience by vote from the options that are listed in the differential diagnosis from the discussant. Comments are welcome (reprinted from The Johns Hokins University ID Website, http://www.hopkins-id.edu, with permission).

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AIDS Case 18: 26-Year-Old Woman with AIDS Presenting with an Acute Abdomen

History of present illness

A 26-year-old woman with AIDS, CD4 count of 26 cells/mm 3 , and viral load of 10,000 c/mL presented with excruciating abdominal pain. Her symptoms began approximately 4 weeks earlier with pain in the right upper quadrant associated with hiccoughs. The pain was exacerbated with deep inspiration and certain movements. She noted fevers and chills 2 days before admission. The abdominal pain progressed to the point that she was unable to walk or move. The patient denied nausea, vomiting, melena, hematochezia, diarrhea, or constipation. She also denied shortness of breath, cough, hemoptysis, weight loss, dysuria, hematuria, or vaginal discharge. In the 2 days before admission she had been unable to eat anything. Her last menstrual period was 3 weeks earlier and it had been normal.

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Past medical history

1. Cytomegalovirus (CMV) retinitis with a ganciclovir implant placed in the left eye 10 months earlier

2. Asthma

3. History of a positive syphilis serology with a negative cerebrospinal fluid analysis; treated with benzathine penicillin intramuscularly weekly ×3

4. Pelvic inflammatory disease (PID) treated 2 years earlier

5. Pneumocystis carinii pneumonia in 2000

6. Sickle cell trait

7. Chronic active hepatitis B

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Allergies

None

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Medications

* Stavudine, lamivudine, and efavirenz (started recently)

* Trimethoprim-sulfamethoxazole daily

* Azithromycin 1200 mg each week

* Ganciclovir 1 g orally three times daily

* Albuterol inhaler as needed

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Social history

The patient lives in a recovery house, and she last used intravenous drugs 2 months prior to admission. She smokes cigarettes and drinks alcohol occasionally. Her only sexual contact in the last 6 months has been her fiancé. She denies recent travel and has no pets.

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Physical examination

Temperature, 102.4°F; respiratory rate, 32 and shallow; pulse, 119 beats per minute; blood pressure, 85/60.

HEENT: Sclerae anicteric. The oropharynx was notable for thrush and poor dentition. Neck was supple and non-tender.

Chest: Clear to auscultation.

Cardiovascular: Regular tachycardia with a 2/6 systolic ejection murmur heard best at left lower sternal border.

Abdomen: Tense with guarding and rebound tenderness. Bowel sounds were audible but diminished.

Rectal examination: Stool was brown and hemoccult negative.

Pelvic examination: No external lesions. White discharge from the cervix. Cervical motion tenderness was difficult to assess caused by generalized abdominal pain.

Back: No costovertebral angle tenderness.

Extremities: No clubbing, cyanosis, or edema.

Skin: No lesions or rash.

Neurologic examination: Grossly intact.

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Differential diagnosis

1. Acute cholecystitis/cholangitis

2. Appendicitis

3. CMV colitis

4. PID/Fitz-Hugh-Curtis syndrome

5. Disseminated fungal/mycobacterial infection

6. Ischemic bowel

7. Clostridium difficile colitis

8. Intestinal lymphoma with perforation

9. Perforated peptic ulcer

10. Ectopic pregnancy

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Discussion

The patient is a 26-year-old woman with advanced AIDS who presents with signs and symptoms of a generalized peritonitis. The abdominal imaging studies point to two potential sources: the gallbladder and the appendix.

Gallstones or biliary sludge are the common components of acute cholecystitis or ascending cholangitis in the general population. In AIDS patients, CMV, Cryptosporidium parvum, and microsporidia are associated with a distinctive cholangiopathy. The patient’s normal bilirubin, alkaline phosphatase, amylase, and lipase argue against this diagnosis. Appendicitis also remains a diagnostic possibility.

Colitis should be prominent in the differential diagnosis of an AIDS patient presenting with peritoneal signs and symptoms. CMV or C. difficile may cause an aggressive colitis in this clinical setting. A computed tomographic scan will typically show diffuse thickening of the colon in either form of colitis, which was not present in this case. Ischemic bowel is also a consideration. Whereas atherosclerosis is an unlikely underlying cause of ischemic colitis in a young patient, endocarditis with embolism might produce such a scenario in an injection drug user. Other potential causes of her acute abdomen include perforation of bowel, either caused by CMV, another infectious process, or malignancy. However, perforation is unlikely in the absence of free air on abdominal imaging.

Lactic acidosis caused by nucleoside analogue toxicity should be considered in a patient taking this class of drugs (particularly stavudine), who presents with tachypnea, abdominal pain, and elevated transaminases. However, our patient’s normal lactate level is inconsistent with this diagnosis.

The patient is sexually active with a history of multiple sexually transmitted diseases. Therefore, one is bound to consider ectopic pregnancy and PID in the differential diagnosis. The former can be ruled out with a negative serum pregnancy test. The Fitz-Hugh-Curtis syndrome, an infectious peri-hepatitis associated with PID, would be quite consistent with this patient’s clinical presentation and imaging studies.

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Discussant’s vote

Fitz-Hugh-Curtis syndrome

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Audience’s vote

Fitz-Hugh-Curtis syndrome

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Diagnostic procedure

Because of the severity of the patient’s pain and her worsening clinical status, she was taken emergently for an exploratory laparoscopy. Her gallbladder was normal in appearance. Her appendix was also normal. There were “violin string” adhesions noted between the anterior edge of the liver and the anterior abdominal wall. Her fallopian tubes were covered with an inflammatory exudate (Fig. 4). There was no evidence of a tubo-ovarian abscess (TOA). An ovarian cyst was noted (Fig. 5), but it was not infected. A diagnosis of Fitz-Hugh-Curtis syndrome was made. Cervical and intraoperative cultures remained negative, although the patient had received antimicrobial therapy.

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Clinical course

The patient was treated with intravenous clindamycin and gentamicin. She improved and was discharged home on the ninth hospital day to complete an oral course of antibiotics. Notably, her fiancé, who is also human immunodeficiency virus (HIV)-infected, was treated for gonorrhea while the patient was hospitalized.

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Comment

Six to twenty-two percent of women in the United States who are diagnosed with PID also have HIV. Several retrospective studies have been conducted looking at the interaction between the two diseases; however, the lack of standard diagnostic criteria, clinical criteria, and microbiologic criteria clouded the interpretation of their results.

A prospective study by Irwin et al. [1] compared PID in 44 HIV-infected women and 163 non-HIV-infected women. Both groups presented with similar signs and symptoms, but HIV-infected women were more likely to have an adnexal mass on sonography (46% versus 27%). In the study, HIV-infected women had unusual features on endometrial histology, with a plasma cell endometritis, suggesting that HIV may impair the acute inflammatory response to bacterial endometritis. Microbiology in the two groups did not differ significantly. Sixteen percent of HIV-infected women versus 3.7% of non-infected women had invasive procedures to diagnose or treat PID.

Among populations of presumed HIV-seronegative women, clinical criteria alone had 46%–74% positive predictive value in diagnosing PID. A laparoscopic study in Kenya in women who presented with PID was recently published [2] . Of 133 women who had laparoscopically proven salpingitis, 39% were HIV positive. TOA were found in 30% of HIV-positive patients compared with 15% of HIV-negative patients. Fifty-five percent of HIV-infected women with a CD4 percentage <14 had a TOA compared with 28% of those with a CD4 percentage >14. A lower proportion of HIVinfected women with salpingitis had gonococcal or chlamydial infection and a higher proportion had anaerobic infections. Length of hospital stay was prolonged in HIV-infected women with a CD4 percentage <14. However, the response to antimicrobial therapy and drainage of TOA was similar regardless of HIV status.

Infectious perihepatitis, or the Fitz-Hugh-Curtis syndrome, is thought to occur in 1% to 10% of patients with PID. Some estimates are as high as 15%–30%. The syndrome was initially described in 1848 by a Danish surgeon, who called it “colica scrotorum.” The classic presentation is composed of two phases—acute and chronic. The acute phase is characterized by the sudden onset of excruciating, sharp pain at the right lower rib margin. The pain, which may be referred to the right shoulder or inner arm, is pleuritic, exacerbated by coughing, and may cause nausea or hiccoughs. Chills, fevers, and night sweats frequently accompany the other symptoms. At laparotomy, “violin string” adhesions may be observed between the anterior surface of the liver and the abdominal wall. Microscopic examination of the liver reveals inflammation of the capsule, but not the parenchyma. The chronic phase is characterized by either the persistence of right upper quadrant discomfort or the disappearance of all the symptoms. The initial view that this entity was only caused by the gonococcus and only occurred in women has been recently modified. It is now evident that C. trachomatis and anaerobic bacteria frequently play a role in this entity, and that Fitz-Hugh-Curtis syndrome also occurs in men [3] .

References

Irwin KL, et al. Influence of human immunodeficiency virus infection on pelvic inflammatory disease. Obstet Gynecol 2000;95:525–34. View Full Text | PubMed | CrossRef Cited Here... |

Cohen CR, et al. Effect of human immunodeficiency virus type 1 infection upon acute salpingitis: a laparoscopic study. J Infect Dis 1998;178:1352–8. View Full Text | PubMed | CrossRef Cited Here... |

Lopez-Zeno JA, et al. The Fitz-Hugh-Curtis syndrome revisited: changing perspectives after half a century. J Reprod Med 1985;30:567–82. PubMed Cited Here... |

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ID Case 23: Rapidly Progressive Pneumonia in a Patient with an Unusual Occupation

History of present illness

A 39-year-old, previously healthy man was transferred for evaluation of pneumonia complicated by rapid respiratory failure. The patient worked as a biological weapons expert for the military. According to his wife, much of his work is classified, and she was not aware of the details of specific projects. The patient had recently been deployed on a mission to a northern European country. He developed a fever and a cough on the flight back to the United States. His symptoms progressed to include myalgias, arthralgias, a headache, and dyspnea over the next day. He was hospitalized and quickly developed respiratory failure requiring mechanical ventilation. Notably, the patient’s friend, who had been traveling with him, also had an acute febrile illness that began on the flight home. His friend had not reported to work. The patient was transferred to our hospital for further evaluation. Attempts to contact his supervisor overnight had failed.

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Past medical history

None

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Vaccination history

Unknown

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Allergies

No known allergies

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Medications (on transfer)

* Ampicillin/sulbactam

* Cefazolin

* Doxycycline

* Erythromycin

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Social history

The patient is married; there are no known sexual exposures outside of his marriage. There is no history of smoking or illicit drugs. The patient drinks alcohol occasionally.

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Family history

Non-contributory

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Physical examination

Intubated male, sedated in respiratory and contact isolation. Temperature, 38.2°C; blood pressure, 108/51; pulse, 103 beats per minute; respiratory rate, 24/min.

Eyes: Anicteric, no injection, no evidence of conjunctivitis, pupils pinpoint

Nose: Mucous membranes were intact

Neck: No lymphadenopathy or rigidity, no jugular venous distention

Lungs: Course breath sounds, no dullness to percussion, no egophony, no wheezes, rhonchi

Heart: Tachycardic, without murmurs, rubs, or gallops

Abdomen: Soft, non-tender, non-distended without enlargement of the liver or spleen

Extremities: No clubbing, cyanosis, or edema

Skin: Erythematous, blanching rash on the neck. No petechiae, purpura, eschars, ulcers, vesicles, or ecchymoses

Genitourinary examination: Normal

Rectal: Brown stool, heme negative

Urinalysis: Hazy, 10–15 RBC, 2–3 WBC, + bilirubin

Chest roentgenogram: Diffuse bilateral infiltrates consistent with adult respiratory distress syndrome

Chest computed tomogram: Diffuse bilateral infiltrates consistent with pulmonary edema or adult respiratory distress syndrome

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Differential diagnosis

Pulmonary anthrax

Legionnaire’s disease

Pneumonic plague (Yersinia pestis)

Tularemia

Streptococcus pneumoniae

Staphylococcus aureus

Neisseria meningitidis

Gram-negative bacilli

Toxic shock syndrome secondary to group A streptococcus

Rocky Mountain spotted fever

Hantavirus

Influenza

Smallpox

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Discussion

This is a completely healthy man who developed a devastating febrile illness soon after a trip to Northern Europe. He had acute respiratory failure, anemia, thrombocytopenia, and an elevated bilirubin. There was neither renal involvement nor evidence of a hemolytic/microangiopathic process, thus excluding the hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. The patient’s history of being a biological weapons expert and going on a recent “mission” raise the question of whether his illness could be a manifestation of a terrorist attack. Inhaled anthrax can lead to sepsis with adult respiratory distress syndrome and rapid death. However, the classic presentation is of hemorrhagic mediastinitis, with mediastinal widening on chest radiograph. The course of pulmonary anthrax is so rapid that the patient is typically moribund before pulmonary infiltrates develop. Pneumonic plague is another disease that has been manipulated for military use and should be considered in this patient. The absence of lymphadenopathy and hemoptysis make plague less likely, but do not rule it out. Many of the patient’s initial flu-like symptoms are typical of pneumonic tularemia. In this disease, there may be a progression to the respiratory distress syndrome, but typically the course is not as rapid as seen in this case. The possibility of exposure to any of the three agents of biological warfare is notably decreased by the lack of additional cases.

N. meningitidis should be considered and covered with appropriate therapy in any previously healthy individual with a rapidly progressing febrile illness. In this patient, there are no clinical signs of meningitis, purpura, or adrenal failure, which may be seen with overwhelming meningococcal sepsis. The pneumococcus is the most common cause of community acquired pneumonia and may cause severe illness. However, the pace of illness in this young man seems too rapid for S. pneumoniae. Legionella pneumophila can also cause acute respiratory failure and should be covered empirically in any patient being admitted to the intensive care unit with pneumonia. His age is strongly against the diagnosis. The blanching, erythematous rash on his neck is suggestive of a group A streptococcus infection and early toxic shock syndrome. S. aureus can also cause a rapidly progressive pneumonia, most classically after a bout of influenza. Lastly, influenza and hantavirus (Sin Nombre virus) should also be considered as potential etiologies, although the epidemiology was against both.

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Discussant’s vote

Tularemia

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Audience’s vote

Tularemia

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Diagnostic procedure/clinical course

Blood cultures yielded group A streptococcus. The patient was treated initially with cefepime and azithromycin in the intensive care unit. He rapidly improved over 5 days, was extubated, and sent to a regular hospital bed. After culture results, his antibiotic therapy was converted to penicillin.

After admission, additional background information about the patient became available. He is a biological weapons expert who works in a military lab. He manages polymerase chain reaction studies on plates collected from machines called portal shields. These devices are large air samplers that detect pathogens that may be used as biological weapons. They are deployed in areas where troops are located. The patient’s lab screens these samples and attempts to quickly identify potential pathogens or toxins and relay the information back to the field commander. The patient’s supervisors did not believe that he had been exposed to biological weapons. His recent trip to Northern Europe was for a conference on biological weapons. He has been immunized against anthrax, meningococcus, and hepatitis A and B. His friend, who also became ill on the trip home, had a mild febrile illness, which was treated with amoxicillin/clavulanate, with an uneventful recovery.

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Comment

This patient was ultimately determined to have a severe community-acquired pneumonia caused by group A streptococcus, with elements of the toxic shock syndrome. The drama of his patient’s presentation was augmented considerably by his occupation, and concern that his illness was caused by an agent of biological warfare. The scant historical information that was available in the first 12 hours of his illness compounded anxieties. In this section, I will review concerns that have been raised in the past few years about biological weapons and terrorism.

There are several infectious agents that may be suitable as biological weapons. Ideal pathogens or toxins should be easy to grow and manufacture, survive aerosolization, have a high case fatality rate, and have the potential for secondary spread. The organisms or toxins that have been considered for military or terrorist purposes include Bacillus anthracis, variola, Yersinia pestis, botulinum toxin, Francisella tularensis, and a number of agents that cause viral hemorrhagic fever [1–4] . In recent years, we have become aware of the extensive biological weapons’ program of the former Soviet Union and the accidental release of anthrax at Sverdlovsk. Additionally, 8000 L of anthrax spore suspension and botulinum toxin were loaded onto SCUD missiles by Iraq during the Iraq-Iran war. The religious cult that was responsible for the sarin nerve gas attack in Japan in 1995 had tried and failed to release anthrax and botulinum toxin eight times previously. Given the escalation of conflict throughout the world over the past few months, it is worth briefly reviewing the two most dreaded potential biological weapons: anthrax and smallpox.

B. anthracis is an aerobic, gram-positive, spore-forming, nonmotile rod. The spores can easily be aerosolized and will germinate in a suitable host. The three clinical manifestations of naturally acquired anthrax are gastrointestinal, cutaneous, and inhalational. Wool sorters and individuals who work with animal hides are at particular risk for anthrax. In the gut, the spores germinate in the upper or lower gastrointestinal track and cause ulceration, regional lymphadenopathy, edema, and sepsis. When the cecum and terminal ileum are involved, patients develop vomiting, malaise, and bloody diarrhea that progresses to an acute abdomen and shock. Cutaneous anthrax occurs after inoculation of the spores into the skin. Symptoms may occur as late as 12 days after infection. The skin lesion begins as a pruritic papule that enlarges within 1–2 days into a round, regular ulcer surrounded by vesicles. Subsequently, a black, necrotic central eschar develops with associated edema. After 1–2 weeks, the lesion dries and falls off. Antibiotics do not affect the development of the eschar but decrease mortality from secondary sepsis substantially.

Inhalational anthrax is the most feared form of disease: the case fatality rate is 80% to 100%. Only 2500–55,000 spores are needed to kill 50% of persons exposed. As an aerosol, anthrax spores are odorless and colorless. Disease can occur as late as 60 days after exposure. The spores are inhaled, ingested by pulmonary macrophages, and are transported to the mediastinal lymph nodes. Once the spores germinate, they cause disease rapidly. In the first phase of the illness, only nonspecific signs are present: fever, dyspnea, cough, headache, vomiting, chills, weakness, abdominal pain, and chest pain. After a few hours or days there is an abrupt development of high fever, dyspnea, diaphoresis, shock, massive lymphadenopathy, and expansion of the mediastinum, which produces a characteristic appearance on chest roentgenogram. Up to half of patients develop hemorrhagic meningitis. Death occurs within hours. The lung pathology does not show a pneumonia, but hemorrhagic thoracic lymphadenitis and hemorrhagic mediastinitis. Focal necrotizing hemorrhagic lesions can be seen in the lungs. B. anthracis grows well in cultures from blood or skin lesions, but can also be visualized in biopsy specimens and peripheral blood smears. A problem with the unsuspected case is the tendency of most labs to discard blood cultures as “Bacillus sp.—probable contaminant” without speciation. The simultaneous appearance of multiple cases of a severe flu-like illness, characterized by a fulminant course, a widened mediastinum on chest roentgenogram, or gram-positive rods in a blood smear or culture, is suggestive of a military attack with anthrax.

The anthrax vaccine requires six doses to complete the series; however, adequate protection is thought to occur after two doses. The availability of this vaccine is limited to military personnel. In the setting of a contained casualty setting, intravenous ciprofloxacin is recommended by the Working Group of Civilian Biodefense. Therapy may be converted to an oral preparation when the patient has stabilized, but must be continued for 60 days because of the danger of delayed spore germination. Ciprofloxacin is recommended for children and pregnant women in this setting, because the risk of death from inhalational anthrax far exceeds the risk of toxicity of the drugs. Penicillin and doxycycline are alternatives but should only be used when the susceptibilities are known. If intravenous therapy is not feasible because of a large-scale attack, then oral ciprofloxacin, doxycycline, or amoxicillin may be used. Respiratory isolation is not required, and the risk of secondary spread is negligible.

Smallpox is caused by a DNA virus of the genus Orthopoxvirus. There have been no human cases since 1978. There are two strains, variola minor and major. Vaccination in the United States was stopped in 1972, and currently no more than 20% of the population is immune. Variola major causes an illness with a mortality rate of 30%. There is no treatment, and in an aerosol form, the virus can survive for 24 hours or more and is highly infectious: a few virions may be sufficient to cause infection. Unlike anthrax, secondary spread is of paramount concern with smallpox. For every case of smallpox, it is estimated that at least 10 secondary cases will result.

Infection is caused by virus implantation in the upper airways. After migration to lymph nodes, patients become viremic on day 3 or 4. A secondary viremia develops at around day 8, but the incubation may range from 7 to 17 days. Symptoms include high fever, malaise, prostration, headache, backache, and toxemia. A maculopapular rash appears initially on the mucosa of the mouth, pharynx, face, and forearms, and subsequently spreads to the trunk and legs. It then becomes vesicular, and eventually forms tense pustules. All of the cutaneous lesions are in the same phase of development, unlike chickenpox in which lesions are in different phases of development at presentation. The rash begins to resolve on the eighth or ninth day. The patient is contagious via droplet nuclei or fomites when the rash is present. There are two other forms of the disease worth mentioning. In the hemorrhagic form, severe toxemia and a dusky erythematous rash develop and evolve into petechiae and frank hemorrhage into the skin and mucous membranes. Death ensues in about 30%, usually on the fifth or sixth day after the onset of rash. In the malignant form, toxemia is followed by soft, flat, velvety, and confluent lesions, which never become pustules. If the patient survives, large amounts of dermis may slough, leaving the tell-tale pitted scars.

There is no treatment for smallpox except supportive care, but the administration of vaccine in the first 4 days of exposure may prevent or significantly ameliorate subsequent illness. This is thought to be particularly effective in those with prior vaccinations due to amnestic responses. However, vaccine supplies are limited and in the advent of an attack, it may not be possible to vaccinate all exposed. Vaccinia immune globulin is also available in extremely limited supply and is recommend in those who experience vaccine reactions or for the immunocompromised. All suspected infected individuals should be put into very strict respiratory and contact isolation.

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Selected Readings

1. Inglesby T, Grossman R, O’Toole T. A plague on your city: observations from topoff. Clin Infect Dis 2001; 32:436–45.

2. O’Toole T, Inglesby TV. Facing the biological weapons threat. Lancet 2000; 356:1128–9.

3. Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Eitzen E, Jahrling PB, Hauer J, Layton M, McDade J, Osterholm MT, O’Toole T, Parker G, Perl T, Russell PK, Tonat K. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999; 281:2127–37.

4. Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Hauer J, McDade J, Osterholm MT, O’Toole T, Parker G, Perl TM, Russell PK, Tonat K. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999; 281:1735–45.

© 2001 Lippincott Williams & Wilkins, Inc.