[Table of Contents]

Volume: 23S1 - January 1997

Canadian Contingency Plan for Viral Hemorrhagic Fevers and Other Related Diseases

MANAGEMENT OF THE PATIENT

There are five areas of concern: (1) patient isolation and protection of hospital staff; (2) laboratory tests and the collection of patient specimens; (3) laboratory processing of specimens; (4) performance of specific laboratory tests; (5) transportation of specimens for diagnostic tests; and (6) treatment of the patient.

1. Patient Isolation and Protection of Hospital Staff

a. Isolation precautions for patients incubating or in early-stage VHF

During the incubation period there is little risk from body fluids other than blood. However, decisions with regard to isolation and precaution techniques should be made in anticipation of the patient's condition worsening. Given the unpredictability of the disease and the potential for clinical infectivity to increase, it may be prudent to upgrade the isolation precautions as soon as feasible⁽¹⁹⁾ .

The patient should be admitted to a private room. While a room with negative air flow is not necessary at this stage, it may be necessary if the disease progresses; therefore, admitting the patient to a room with negative air flow at this stage may circumvent transfer later. An anteroom, stocked with supplies, with facilities for handwashing and an area for donning protective equipment is useful.

Gowns and gloves are recommended for all persons who enter the room. Fluid-resistant masks and goggles or other eye protection are recommended if there is any possibility of a blood splash, minor or major (e.g., blood splashes and aerolization of blood can occur when starting an IV, emptying a suction container, taking blood for laboratory analysis, or dropping a container containing blood). Extreme vigilance is required to prevent needle sticks or other sharp injuries. Parenteral exposure has been associated with a high risk of transmission, a short incubation period and severe disease. Eliminate sharp instruments wherever possible. If feasible, use a needleless intravenous system.

Patient care equipment (e.g., thermometers, blood pressure cuffs, stethoscopes, commodes, etc.) should be dedicated to the patient. Use disposable supplies whenever possible. Soiled linens, clothing and protective clothing should be deposited in water-soluble plastic laundry bags that are closed in the room where used. The laundry bags should then be inserted into a designated red laundry bag (or a bag of another recognized colour). Heavily soiled laundry should be taken directly to the laundry (not placed in laundry chutes or other storage area). Soiled linen must go directly to the washing machine, with laundry bags placed directly into the water. Gowns, gloves, and masks should be worn by laundry workers.

Caregivers and visitors should wash their hands with an antiseptic solution (e.g., chlorhexidine 2%, povidone-iodine 10%, and chlorhexidine 0.5% on alcohol) after any patient contact and after leaving the patient's room .

b. Isolation of patients in advanced or end-stage VHF

Virus can infect many organs including those critical for virus dissemination, such as salivary glands, kidneys, bladder, sweat glands, and lungs⁽¹⁹⁾ . Hemorrhage may be a prime feature of the clinical course with intense viremia as the disease progresses. The likelihood of staff exposure to blood or other body fluids and the opportunities for virus aerosolization increase with the deterioration of the patient's condition. Fluid-resistant gowns or coveralls, gloves, fluid-resistant masks that filter to 0.03 microns and fit securely, and face shields are highly recommended. A private room is necessary; negative air flow is also strongly recommended whenever possible.

Laboratory specimens should be disposed of in the routine manner for Level 4 pathogens. All laboratory specimens must be considered infectious and handled in a consistently safe manner from point of collection to disposal. Specimens should be carried by hand to the laboratory for testing. Limit testing to tests critical to the well being of the patient. All tests must be collected and performed in a way that prevents aerosol generation.

c. Disinfection of the environment

VHF viruses are lipid-enveloped RNA viruses and, as such, are inactivated by low-level disinfectants⁽¹⁹⁾. Low-level disinfectants will be effective for environmental cleaning. Products in this category include quaternary ammonium-based products, phenolic chlorine-based products, and iodophor formulations.

All body secretions, excretions, and fluids should be disinfected or inactivated prior to disposal (i.e., either by a chemical, autoclaving or sterilizing prior to flushing in municipal sewer systems).

Personal protective equipment, including gloves, fluid-resistant masks with face shields, and fluid-resistant gowns, should be worn for cleaning up a spill of blood or other body fluid. (Protective booties and coveralls may be required if the spill is large). Remove excess blood or other body fluid with disposable towels. Discard the towels into a plastic-lined receptacle. After cleaning all the organic material from the surface, decontaminate the area with sodium hypochlorite (5% household bleach) or a low-level disinfectant. Leave the disinfectant in place for at least 10 minutes before rinsing.

d. Isolation of patient during convalescence

Virus may be excreted into the urine for weeks after recovery has begun. Disinfectant (e.g., household bleach) should be added to the toilet bowl prior to urinating or flushing for 6 weeks of convalescence or until patient has a negative culture for the virus. The average toilet contains 4 L of water in the toilet bowl prior to flushing. Place 50 to 100 cc of bleach in the toilet prior to urinating. Wait 5 minutes and then flush.

e. Postmortem

If the patient should die, handling of the body should be minimal. The corpse should be wrapped in a sealed leak-proof material, not embalmed, and then cremated or buried promptly in a sealed casket⁽¹⁹⁾ .

If an autopsy is necessary, the Provincial Coordinator should be consulted regarding appropriate precautions.

2. Laboratory Tests and the Collection of Patient Specimens

Upon presentation of a possible case of VHF, it is mandatory that the following tests be performed immediately:

• A thick and thin blood smear to look for malaria parasites - a second smear from a second specimen must be examined if the first does not reveal parasites;
• Two sets of blood cultures from separate venipunctures taken at least 30 minutes apart, with a total volume per set (two vials) of 20 to 30 cc;
• Unless there is an isolated automated system or the specimens have been inactivated (see below), manual white blood cell and differential counts, and either hemoglobin or hematocrit; and
• Urine culture, if urinalysis results suggest an infection.

The following five principles should be observed in the collection of all patient specimens.

1. Only specimens essential for diagnosis or monitoring should be obtained.

2. Specimens should be obtained by staff experienced in the required techniques. The same protective clothing as described for other hospital staff involved in the management of the patient should be worn by those obtaining and testing laboratory specimens.

3. Glass containers should be avoided whenever possible. Disposable sharp objects, such as scalpel blades, should be placed in puncture-proof containers immediately after use and later autoclaved before disposal or incineration.

4. Blood samples must be collected with extreme care to avoid self-inoculation. Universal Precautions should be strictly adhered to; needles must not be bent, broken, removed from disposable syringes, recapped or otherwise handled. After use, venipuncture equipment should be immediately placed in a rigid plastic container filled with disinfectant solution and autoclaved before disposal or incineration.

5. The entire outside surface of each specimen container should be wiped with disinfectant, and a label should be attached bearing the patient's name, hospital identification code, source of the specimen, date of collection, and the nature of the suspected infection. The specimens should then be double-bagged in secure, air-tight and water-tight bags, which have been similarly labelled. Bags containing specimens should be sponged with disinfectant before they are removed from the patient's room.

3. Laboratory Processing of Specimens

The laboratory receiving the specimen should be alerted to the potentially hazardous nature of the material being sent. Each laboratory should have prepared a contingency plan for these situations.

Laboratory staff dealing with specimens from patients with a suspected VHF must take, as a minimum, the same personal precautions as patient-care staff. Disposable gloves, fluid-resistant surgical masks, impermeable gowns, and protective eye wear should be worn. Depending on local conditions, the use of powered air-purifying respirators (PAPRs) and other respirators may be considered. Laboratory tests must be performed in biosafety cabinets. Blood cultures should be prepared in a closed system, if at all possible, and when not possible, all manipulations must occur in a tested and certified biosafety cabinet. Similar attention should be given to the cross matching of blood from patients with these diseases. Centrifuges must have sealed carriers or heads.

Every effort should be made to avoid creating an aerosol or splashing. Routine automated equipment should be used in the usual manner to prevent infections. The Office of Biosafety is available for consultation on biosafety practices and procedures.

Infectivity of serum may be reduced by heating with 0.3% beta-propriolactone for 30 minutes at 37^o C, heating serum samples for 60 minutes at 60^o C, or by treating the specimen with 2 megarads of gamma irradiation (with the specimen on ice to avoid overheating)^(20,21) . Serum separation should be done using sealed centrifuge cups or a sealed centrifuge head. Abundant supplies of disinfectant solutions should be readily available. Use of a PAPR may be appropriate when dealing with specimens that have not been decontaminated.

Recent U.S. recommendations⁽⁷⁾ state that serum used in laboratory tests should be pre-treated with polyethylene glycol p-tert-octylphenyl ether (Triton X^R -100); treatment with 10µL of 10% Triton X^R -100 per 1 mL of serum for 1 hour reduces the titre level of some of the VHFs viruses in serum, although 100% efficacy in inactivating these viruses should not be assumed.

Blood smears (e.g., for malaria) are not infectious following fixation in solvents. Routine procedures can be used for automated analyzers; analyzers should be disinfected as recommended by the manufacturer or with a 500 parts per million solution of sodium hypochlorite (1:100 dilution of household bleach: 1/4 cup to 1 gallon water) after use.

Laboratory personnel accidentally exposed to potentially infected material through spills, splashes, injections, cuts or abrasions should immediately wash the infected part with soap or detergent, apply an antiseptic solution (e.g., chlorhexidine 2%, povidone-iodine 10%, and chlorhexidine 0.5% on alcohol) and notify the employee health office and the Infection Control Unit. Such individuals, as well as those with mucus membrane exposure to biologic fluids or unprotected inhalation of aerosolized material, should then be considered as high-risk contacts and placed under surveillance (see the section entitled "Identification, Surveillance and Management of Patient Contact").

Accidental spills of potentially contaminated material should be covered with absorbent paper towels, liberally covered with disinfectant and left to soak for 30 minutes before being wiped up. The area should be evacuated and secured. Following the removal of the initial material, the process should be repeated once again. Individuals attending to this task must wear protective attire. PAPRs or other respirators should be considered for those involved in the clean-up activity. Disposable gloves, impermeable gowns and protective eye wear, which must be removed immediately after completion of the process, should be placed in an autoclave bag and sterilized prior to disposal.

The United States Centers for Disease Control and Prevention (CDC) is evaluating the future of a mobile isolator that can be used as a portable laboratory to safely investigate cases of suspected or confirmed VHF. There is a similar unit in Canada. The U.S. facility is not currently available for use in Canada. The Canadian unit, while not routinely maintained in a state of immediate readiness, could be fully activated within a short time. Further information about the mobile laboratory in Canada can be obtained from the Federal Response Coordinator and/or the Office of Biosafety.

4. Performance of Specific Laboratory Tests

The need to do additional tests for the patient's welfare must be balanced against the possible danger to laboratory personnel. Only tests essential to patient care should be performed.

The diagnosis of VHF is confirmed by isolating the virus, by antigen detection by enzyme-linked immunosorbent assay (ELISA), viral genome detection by polymerase chain reaction (PCR), by demonstrating IgM antibody, or by demonstrating a fourfold rise in IgG antibody in serum. Antibody may not appear in the blood until the second week of illness. Virus is usually recovered from blood, although the Lassa virus may also be isolated from throat secretions or urine. Liver or spleen tissue collected after death may also be a rich source of virus. In hemorrhagic fever with renal syndrome, renal tissue should be obtained, and in cases of hantavirus pulmonary syndrome, lung tissue should be examined.

Designated laboratories for confirmatory diagnostic tests
Generally, it will be advisable to perform serology and attempt viral isolation. For VHF specimens which contain Level 4 agents such as Ebola and Marburg, viral isolation can only be performed at a Class 4 laboratory.

Serology on Level 4 VHF specimens may be performed at the following laboratory*:

Public Health Agency of Canada
National Microbiology Laboratory
National Laboratory for Zoonotic Diseases and Special Pathogens
1st Floor, Canadian Science Centre
1015 Arlington St
Winnipeg, Manitoba
R3E 3R2
Tel: (204) 789-6019
Cell: (204) 781-0549
Pager: (204) 932-2733
Attention: Heinz Feldmann

* This section is a modification from original plan.

It should be noted that not all VHFs are caused by Level 4 agents. Dengue hemorrhagic fever, for example, is caused by a virus that is Level 2 and hemorrhagic fever with renal syndrome or hantavirus pulmonary syndrome is caused by hantaviruses that are Level 3 agents. Specimens for these non-Level 4 agents can be adequately dealt with in Canada.

5. Transportation of Specimens for Diagnostic Tests

The shipment of patient specimens must be in compliance with the Transport of Dangerous Goods Regulations. This necessitates an Emergency Response Plan Number, which can only be obtained from Transport Canada (613-991-9396) following the submission of a written response plan. The advice and assistance of the provincial/territorial laboratory should be sought before any specimens are shipped and, preferably, all specimens referred for sending out for testing should be submitted through them. Shipment of specimens must be planned in coordination with the Federal Response Coordinator or the Director, Office of Biosafety, LCDC (Tel: 613-957-1779; Fax: 613-941-0596), and the laboratory to which specimens are being sent. The Emergency Response Plan Number and an emergency phone number must appear on the shipper's declaration form.

As noted, it is advisable to perform serology tests and attempt viral isolation. The essential specimens to be submitted for virus isolation are a sample of venous blood, a mid-stream ("clean-catch") specimen of urine, and a throat swab. If postmortem specimens are available, samples from serum, liver, spleen, lung, and kidney should be sent for culture. The following procedures should be followed:

1. Ten mL of venous whole blood should be collected and submitted as is (i.e., clotted and not separated).

2. Mid-stream urine specimens should be collected by clean catch. Five mL of urine should be put in a plastic screw-cap container with one of the following: rabbit serum albumin diluted to a final concentration of 25%, human serum albumin diluted to a 1% concentration, or bovine serum albumin at a final concentration of 10%. The sample should be buffered.

3. Throat swabs should be placed in plastic screw-cap containers in 1 mL of sterile, phosphate-buffered neutral saline containing 25% rabbit serum, 1% human serum albumin, or 10% bovine serum albumin.

4. Tissue samples for analysis should be placed in plastic screw-cap containers, stored at -70° C until ready for shipment, and then shipped packed in dry ice.

All specimens should be packaged using approved Transport Canada packaging; the most convenient commercially available package is the Saf-T-Pak, catalogue number STP 100, obtained from Saf-T-Pak, Inc., 10450 Mayfield Road, Edmonton, Alberta, T5P 4P4; Telephone (403-486-0211); Fax (403-486-0235). Other commercially available packagings may be obtained from Environmental Packaging Systems Ltd. (902-461-1300). The sender should obtain and forward, by telephone or fax, the waybill number and anticipated time of arrival to facilitate tracing of the package, if required.

When serology alone is to be performed in Canada, only adherence to the following procedure is required.

1. The Saf-T-Pak comes with all necessary labels and instructions for proper packaging.

2. After applying the hazard label to the box, one prints above it "Infectious substances affecting humans UN 2814."

3. Then one completes the "To" and "From" on the top of the box. The "Shipper's declaration for dangerous goods", supplied with the Saf-T-Pak, should be completed.

4. A carrier waybill is supplied by the courrier company. On it one writes, "Dangerous goods as per attached shipper's declaration."

When viral isolation is to be attempted, the package must be placed on dry ice. Therefore, in addition to the above, the Saf-T-Pak is placed in a styrofoam cooler and surrounded with dry ice. On the outside of the cooler, one must affix all the labels and markings that are also on the inner box (e.g., the Saf-T-Pak). In addition, the following markings relevant to the dry ice must be affixed: "Dry ice, UN 1845", the net weight of the dry ice (e.g., 1500 g), and a Class 9 hazard label. The shipper's declaration should be completed.

Specimens for either serology or viral isolation sent to the CDC require an import permit from the American government. These permits must be obtained by telephoning the Office of Biosafety, CDC (404-639-3235). The Office of Biosafety may then fax an import permit to the shipper. As noted above, any shipment of material to the U.S. should be coordinated with the involved provincial laboratory and LCDC.]

6. Treatment of the Patient

The supportive care of critically ill VHF patients is the same as that provided to other critically ill patients. Consultation with infectious disease specialists and infection control officials is recommended.

The anti-viral drug ribavirin should be used intravenously to treat all confirmed cases of Lassa VHF. Ribavirin has some effect against the virus that causes Congo-Crimean VHF; its use in patients with confirmed Congo-Crimean VHF should be considered. In addition,there is some evidence to suggest that ribavirin may have some effect against the American hemorrhagic fever viruses such as Junin. Ribavirin does not appear to be indicated for filoviruses (i.e., Marburg and Ebola VHFs). If a non-filovirus VHF is strongly suspected, treatment with ribavirin may begin while confirmation of the diagnosis is pending.

The dose and route of administration are as follows: ribavirin 30 mg/kg loading dose intravenously (IV), then 16 mg/kg IV every 6 hours for 4 days, and then 8 mg/kg IV every 8 hours for 6 days (total treatment time 10 days). Ribavirin for parenteral use is not a licensed preparation in Canada. To obtain this agent as an emergency drug, request authorization from the Emergency Drug Release Program, Bureau of Pharmaceutical Assessment, Drugs Directorate, (613-941-2108) during regular business hours (0830-1630 EST) and (613-941-3061) after hours. Authorized supplies of ribavirin will be supplied by the National Defence Medical Centre, Ottawa.

Careful fluid management of patients is important to minimize the risks of pulmonary congestion and edema. Central pressure monitoring may be a useful aid in the medical management of these patients but there are serious issues related to the associated risks to medical staff that require consideration.

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