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Physician Information

November 19, 2001

Physician Guidelines for Evaluation of Possible Anthrax Disease


Specimen Form

Contents:

  1. Clinical presentation of anthrax
  2. Case Definitions for cutaneous and inhalational anthrax
  3. Diagnostic tests for cutaneous and inhalational anthrax
  4. Diagnostic workup for evaluating patients with possible cutaneous and inhalational anthrax
  5. Reporting of possible anthrax cases to the New Jersey Department of Health and Senior Services (NJDHSS)
  6. Instructions for submitting and handling specimens for diagnostic testing to the New Jersey Department of Health and Senior Services (NJDHSS)
  7. Antibiotic prophylaxis for anthrax exposure: general recommendations and recommendations for New Jersey residents
  8. Recommendations for the treatment of confirmed cases of anthrax

New Jersey state regulations require that all physicians or other health care providers immediately notify the local health or state health department if they suspect a patient has cutaneous or inhalational anthrax

New Jersey Department of Health and Senior Services:
8am to 8pm: 609-538-6030 or 609-588-7500
8pm-8am: 609-392-2020

A. Clinical Presentation of Anthrax

1. Cutaneous Anthrax
Cutaneous Disease usually begins as a small papule, which enlarges and progresses to a vesicle or bulla in 1-2 days. The vesicles may become hemorrhagic, with satellite vesicles. The lesion then ulcerates and forms a black eschar (necrotic ulcer) in 3 to 7 days. The lesion is usually painless and the tissue surrounding the skin lesion is often erythematous, and may have varying degrees of edema (brawny, gelatinous, non-pitting edema). Patients may have fever, malaise, headache and regional lymphadenopathy. The case fatality rate for cutaneous anthrax is 20% without and < 1% with antibiotic treatment. Cutaneous anthrax is not easily transmissible from person to person, although there is a very low risk of infection if there is direct contact with the drainage from an open sore. The incubation period is usually from 1-7 days, but may range up to 15 days.

2. Inhalational Anthrax
Inhalational anthrax is the most lethal form of anthrax, and symptoms can progress quickly to respiratory failure or shock. It classically presents with a brief prodrome resembling a viral respiratory illness followed by development of hypoxia and dyspnea, with radiographic evidence of mediastinal widening. However, in some recent cases of inhalational anthrax, patients have presented with acute onset of fever, dry cough, and hilar or mediastinal adenopathy and lung infiltrates or pleural effusions. In recent cases, the pleural effusion has been bloody. Signs and symptoms of meningitis are seen in approximately 50% of patients.

The incubation period of inhalational anthrax among humans is unclear, but it is reported to most often range between 1 and 7 days, and on rare occasion can extend out to 60 days post exposure. Case-fatality rate estimates for inhalational anthrax are based on incomplete information regarding exposed populations and infected populations in the few case series and studies that have been published. In these instances the case-fatality rate was high (~85%). Early treatment appears to be effective in preventing severe illness and death. In the recent cases, early initiation of treatment was associated with a 60% survival rate.

NJDHSS requests that all providers seeing patients with a non-specific, febrile, flu-like illness obtain a thorough employment history, including whether the patient is a postal worker or handles mail, and ask about any exposure to suspicious letters or powders in the preceding week. Persons at increased risk of anthrax include:

Postal workers, especially if they work or spend time in (a) a mail distribution center where automated sorting machines are operating or (b) in a New Jersey postal facility.

Employees of media corporations or other high-profile companies/institutions (e.g., government organizations), especially if they routinely handle mail.

Anyone reporting a potential high-risk exposure to contaminated powder in the week prior to illness onset (e.g., aerosolization of powder when opening or handling a letter deemed to be a credible threat; criteria for a credible threat include an envelope containing powder that is either (a) addressed to a high-profile person or corporation and/or (b) if the letter contains a written threat).

Healthcare providers who see patients in one of these high risk groups presenting with a recent onset (i.e. within the preceding 7 days) of a non-specific febrile, flu-like illness should consider the possibility of early inhalational anthrax infection.


3. References

A detailed description of anthrax can be found in the following recent publications:

B. Case Definitions for Cutaneous and Inhalational Anthrax

1. Cutaneous Anthrax
A potential case of cutaneous anthrax is defined as:

Onset of illness after September 18, 2001 and one of the following:

1) A highly suspicious lesion, including:
     a) ulcerative lesion with surrounding erythema, edema or vesicles;
             AND/OR
     b) a blackened eschar forming 3 to 7 days after onset of the skin lesion

OR

2) An ulcerative or necrotic lesion AND
     a) a history of possible exposure to anthrax, including being a postal worker
            OR
     b) laboratory evidence suggestive of B. anthracis infection, such as:
          i) gram stain showing positive bacilli from a skin lesion, sterile fluid, or tissue;
          ii) culture showing encapsulated non-motile, non-hemolytic bacilli from any body fluid or site.


2. Inhalational Anthrax
A potential case of inhalational anthrax is defined as the acute onset of illness after September 18, 2001 with:

1) Fever, cough, and an abnormal chest X-ray in an individual with no prior history of chronic pulmonary disease. Radiographic findings particularly suggestive of anthrax include mediastinal widening and bilateral effusions.

OR

2) Fever and respiratory failure or severe respiratory distress not clearly attributable to a previously diagnosed chronic illness such as COPD, asthma, or CHF

OR

3) Sepsis of unknown etiology.

C. Diagnostic Tests for Cutaneous and Inhalational Anthrax

Gram stain: B. anthracis is a gram-positive rod and may be seen on gram stain of body fluids and tissue.

Culture: B. anthracis is easily grown on blood agar medium, and most clinical laboratories are capable of making a presumptive identification of B. anthracis. Specimens that are presumptive positive for B. anthracis should be sent to the reference laboratory at NJDHSS for confirmation.

Polymerase Chain Reaction (PCR): PCR can detect the presence of the organism in blood, other body fluids (e.g., CSF and pleural fluid) and tissue. PCR may be positive even if the organism is no longer viable. PCR is available only at CDC.

Immunohistochemical (IHC) staining of tissue: IHC can detect the presence of B. anthracis in tissue and certain body fluids (e.g., pleural fluid), as well as in paraffin-embedded specimens (i..e, tissue or cellblocks). IHC may be positive even if the organism is no longer viable. IHC is available only from CDC

Serology: A serologic test for the antibody to B. anthracis protective antigen is under development at CDC and should be considered a research tool at this time. The utility of serology for the diagnosis of anthrax is not known, and routine serologic testing is not indicated. In certain circumstances serology may be indicated, provided it is done in conjunction with other diagnostic tests. This should be discussed with the NDJHSS on a case-by-case basis.

The utility of serologic testing for the diagnosis of anthrax is not known;
routine serologic testing should NOT be done

Nasal swabs: Nasal swab cultures should not be used to diagnose anthrax or to evaluate whether an individual person had been exposed. Nasal swab cultures may be useful in epidemiologic investigations to determine whether a population has been exposed to B. anthracis. The presence of B. anthracis from a nasal swab culture cannot be determined by gram stain or colony characteristics alone and requires confirmation by qualified laboratories.

Nasal swab cultures should not be used to diagnose anthrax
or evaluate whether an individual person has been exposed to anthrax

D. Diagnostic Workup for Evaluating Patients with Possible Cutaneous and Inhalational Anthrax (www.cdc.gov/mmwr/preview/mmwrhtml/mm5043a1.htm)

1. Cutaneous Anthrax
The workup of a patient with suspected cutaneous anthrax should include, but not necessarily be limited to:

1. Gram stain and culture of the lesion
2. Biopsy of the lesion for histopathology, IHC, PCR - biopsies should be taken at the junction of the central area of ulcer/eschar and the surrounding erythematous skin.
3. If patient is febrile or in hospital, whole blood for PCR
4. If patient is febrile or in hospital, consider blood cultures

In addition to tests for anthrax, the workup of any patient with possible anthrax should include tests to evaluate for other etiologies of the cutaneous lesions (i.e. herpes) if indicated. Patients should be treated presumptively with antibiotics pending diagnostic test results (www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm).

When working up a case of possible cutaneous anthrax, physicians
should also consider other diagnoses and test and treat accordingly

2. Inhalational Anthrax
The workup of a patient with suspected inhalational anthrax will depend on the clinical nature of the illness. Components of the workup may include:

Testing in hospital
1. Blood culture
2. If meningeal signs are present: CSF gram stain, culture, and cell count
3. If pleural fluid is present: gram stain and culture of pleural fluid (in hospital laboratory)
4. Chest X-ray and/or chest CT to assess for mediastinal and hilar adenopathy: classic findings include a widened mediastinum and, in recent cases pleural effusions. However, any abnormal chest x-ray should prompt consideration of inhalational anthrax. A chest CT scan may be more sensitive than chest x-ray to assess for mediastinal adenopathy.

Any positive cultures for suspicious Bacillus species should be
sent immediately to the NJDHSS for confirmation

Special tests - The tests listed below are only available from CDC. All specimens sent to CDC must be sent through the NJDHSS.
5. Whole Blood for PCR
6. Body fluid (e.g., CSF, pleural fluid) for PCR
7. Tissue specimens for PCR and IHC
8. Serum for serology, if indicated

In addition to tests for anthrax, the workup of any patient with possible inhalational anthrax should include tests to evaluate for other etiologies of the cutaneous lesions (i.e. herpes) if indicated. Patients should be treated presumptively with antibiotics pending diagnostic test results (www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm).

In the workup of a case of possible inhalational anthrax, physicians should
also consider other diagnoses and test and treat accordingly

E. Reporting of Possible Anthrax Cases to New Jersey Department of Health and Senior Services (NJDHSS)

Since late October 2001, NJDHSS has been actively tracking potential cases of anthrax through ongoing and regular communication with a network of hospitals in New Jersey, as well as Delaware and parts of Pennsylvania. In addition, any New Jersey health care worker treating a patient with suspected or confirmed anthrax should report the case immediately to NJDHSS (609-538-6030 or 609-588-7500).

F. Instructions for Submitting and Handling Specimens for Diagnostic Testing to New Jersey Department of Health and Senior Services (NJDHSS)

Specimens will not be accepted for testing by NJDHSS or CDC until a clinician
has reported and discussed the case with NJDHSS (609-538-6030 or 609-588-7500).

1. Culture and gram stain
Culture and gram stain of skin lesion and skin biopsy should be sent to the hospital laboratory. If suspicious Bacillus species are identified, contact NJDHSS immediately.

1. Synthetic (non-cotton) swab with non-wooden stick for culture and gram stain of material swabbed from the exudates or the most actively inflamed area of the eschar.
2. Sterile punch biopsy specimen should be sent in sterile saline for culture.

2. Tissue for IHC and PCR
Two biopsies should be sent:

1. One biopsy specimen submerged in formalin, kept at room temperature, for immunohistochemical staining. Paraffin-embedded specimens are acceptable as well.

2. One biopsy specimen in a sterile screw top tube, frozen at -70 degrees C or placed on dry ice for PCR. If dry ice is unavailable, refrigerate and ship on regular ice.

If only one biopsy is obtained, it should be placed in formalin and sent for immunohistochemical staining.

3. Whole blood for PCR
If a patient with a suspicious case of cutaneous anthrax is febrile or hospitalized, blood should be sent for PCR.

1. Whole blood should be collected in a red top tube.
2. Ship the tube refrigerated or at room temperature. Do not freeze specimen.

4. Serology
The utility of serology for the diagnosis of anthrax is not known and routine serologic testing is not indicated. In certain circumstances serologic testing may be done, provided it is done in conjunction with other diagnostic tests. This should be discussed with the NJDHSS on a case-by-case basis.

1. Acute serum (ideally collected within 5 days of illness onset)
     - Collect ~5 ml of whole blood in a serum separator tube
     - Refrigerate or keep at room temperature
     - Spin down as soon as possible
     - Separate serum into a 5 ml serum separator tube and refrigerate
2. Convalescent serum (collected 14-21 days after acute sera collected)
     - Collect ~5 ml of whole blood in a serum separator tube
     - Refrigerate or keep at room temperature
     - Spin down as soon as possible
     - Separate serum into a 5 ml serum separator tube and refrigerate

A "New Jersey Specimen Form" must be included with all samples submissions
(See Appendix I)

G. Antibiotic Prophylaxis for Anthrax Exposure: General Recommendations and Recommendations for New Jersey Residents

1. General recommendations
Antibiotic prophylaxis (post exposure prophylaxis [PEP]) is used to only prevent inhalation anthrax in the event of a known exposure to aerosolized spores of B. anthracis. The utility of PEP in preventing cutaneous anthrax after a known exposure is not known. Doxycycline is the drug of choice for post-exposure prophylaxis, unless there is a medical contraindication (see table below). Alternative drugs include ciprofloxacin and amoxicillin. All individuals taking post-exposure prophylaxis should take the full 60 days of medication. CDC guidelines for antimicrobial prophylaxis for anthrax exposure have been published in the MMWR: Update: Investigation of Anthrax Associated with Intentional Exposure and Interim Public Health Guidelines: October 2001. MMWR. October 19, 2001:50(41);889-893.
(http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5041a1.htm).



Table taken from: Update: Investigation of Anthrax Associated with Intentional Exposure and Interim Public Health Guidelines: October 2001. MMWR. October 19, 2001:50(41);889-893.

2. Specific recommendations for New Jersey
As of November 15, 2001 NJDSS post exposure prophylaxis is recommended only for employees and business visitors in the Hamilton (Route 130) Mail Processing Facility from September 18 through October 18, 2001.

All samples taken from the public parts of the building have tested negative for B. anthracis, thus antibiotic prophylaxis is not recommended for visitors to the public areas of the mail facility.

In certain postal facilities post-exposure prophylaxis was started before the extent of the exposure was known. Subsequent investigations found that persons who work in these facilities were not at risk of inhalational anthrax and continued post-exposure prophylaxis is not indicated. These post offices included: West Trenton, Princeton, Bellmawr, as well as post offices that receive mail from the Hamilton Processing Plant.


Persons who work in the Hamilton (Route 130) Mail Processing Facility from September 18 through October 18, 2001 should take 60 days of antibiotic prophylaxis

Persons who work in West Trenton, Princeton, and Bellmawr facilities,
as well as those who work in post offices that receive mail from Hamilton
should STOP taking medication, if they have not already done so.

H. Recommendations for the Treatment of Confirmed Cases of Anthrax
The following treatment guidelines have been adapted from CDC recommendations: Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Exposure Management and Antimicrobial Therapy. MMWR. October 2001 October 26, 2001: 50(42);909-919. (www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm)

1. Inhalational anthrax (Table 1)
Because of the mortality associated with inhalational anthrax, two or more antimicrobial agents predicted to be effective are recommended. However, controlled studies to support a multiple drug approach are not available. Other agents with in vitro activity suggested for use in conjunction with ciprofloxacin or doxycycline include rifampin, vancomycin, imipenem, chloramphenicol, penicillin and ampicillin, clindamycin, and clarithromycin; but other than for penicillin, limited or no data exist regarding the use of these agents in the treatment of inhalational B. anthracis infection. Cephalosorins and trimethoprim-sulfamethoxazole should not be used for therapy. Regimens being used to treat patients associated with the recent event include ciprofloxacin, rifampin, and vancomycin; and ciprofloxacin, rifampin, and clindamycin.

Analysis of the 10 cases of inhalational anthrax occurring as part of the present outbreak indicate that survival has been associated with earlier initiation of antibiotic therapy.

Toxin-mediated morbidity is a major complication of systemic anthrax. Corticosteroids have been suggested as adjunct therapy for inhalational anthrax associated with extensive edema, respiratory compromise, and meningitis.



Table taken from: Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Exposure Management and Antimicrobial Therapy. MMWR. October 2001 October 26, 2001: 50(42);909-919. (www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm)

2. Cutaneous anthrax (Table 2)
For cutaneous anthrax, ciprofloxacin and doxycycline also are first-line therapy. As for inhalational disease, intravenous therapy with a multidrug regimen is recommended for cutaneous anthrax with signs of systemic involvement, for extensive edema, or for lesions on the head and neck. In cutaneous anthrax, antimicrobial treatment may render lesions culture negative in 24 hours, although progression to eschar formation still occurs. Some experts recommend that corticosteroids be considered for extensive edema or swelling of the head and neck region associated with cutaneous anthrax. Cutaneous anthrax is typically treated for 7-10 days; however, in this bioterrorism attack, the risk for simultaneous aerosol exposure appears to be high. Although infection may produce an effective immune response, a potential for reactivation of latent infection may exist. Therefore, persons with cutaneous anthrax associated with this attack should be treated for 60 days.



Table taken from: Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Exposure Management and Antimicrobial Therapy. MMWR. October 2001 October 26, 2001: 50(42);909-919. (www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm)

For more information on antimicrobial regimens for anthrax prophylaxis see
General information: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm
Pregnant women: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5043a5.htm

Appendix I: New Jersey Specimen Form




 
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