Smallpox laboratories

Clinicians should not order smallpox laboratory testing for moderate or low-risk patients. Given that the global prevalence of smallpox is zero, the positive predictive value of a positive laboratory test for smallpox is extremely low, especially in patients who do not meet the case definition. Testing only high-risk patients for smallpox reduces the likelihood of false positive lab results with their attendant serious consequences. 

CDC Case Definition An illness with acute onset of fever >101°F followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without other apparent cause. Clinically consistent cases are those presentations of smallpox that do not meet this classical clinical case definition (1) hemorrhagic type, (2) flat type, and (3) variola sine eruptione. Laboratory criteria for diagnosis is (1) polymerase chain reaction (PCR) identification of variola DNA in a clinical specimen, or (2) isolation of smallpox (variola) virus from a clinical specimen (Level D laboratory only confirmed by variola PCR). 

The last naturally acquired case of smallpox occurred in 1977. The last cases of smallpox, from laboratory exposure, occurred in 1978. In the United States, routine vaccination against smallpox ended in 1972. Since the vaccine is no longer recommended, the vaccine is not available. The CDC maintains an emergency supply of vaccine that can be released if necessary, since post-exposure vaccination is effective. 

Although smallpox disease has been eradicated, two countries still keep smallpox virus (variola) stocks. Two laboratories hold stocks of smallpox virus (variola). These are the WHO Collaborating Centres in Atlanta, USA and Koltsovo, Russian Federation. 

In addition to the stock of smallpox vaccine in the US, an additional 50-100 million doses are estimated to exist worldwide. Many countries still hold smallpox vaccine (vaccinia) stocks. WHO recommends that countries that still have stocks of smallpox vaccine (vaccinia) maintain these stocks. This recommendation has been made for two reasons. Firstly, small amounts of vaccine are still needed to vaccinate laboratory personnel handling vaccinia virus and other members of this virus family. Some of these viruses are found in nature and cause illness among animals, and some are used in research to make new, safer vaccines against a variety of infectious diseases. Secondly, smallpox vaccine, vaccinia, will also be needed in case of a deliberate or accidental release of smallpox virus, variola. 

How many people would have to get smallpox before it is considered an outbreak One suspected case of smallpox is considered a public health emergency. Smallpox surveillance in the United States includes detecting a suspected case or cases, making a definitive diagnosis with rapid laboratory confirmation at CDC, and preventing further smallpox transmission. A suspected smallpox case should be reported immediately by telephone to state or local health officials. They should immediately obtain advice regarding isolation of the patient or patients, and on laboratory specimen collection. State or local health officials should notify CDC immediately at (404) 639-2184 or (404) 639-0385 if a suspected case of smallpox is reported. 

If a vaccinated or unvaccinated contact experiences a fever >101° F (38° C) during the 17-day period after his or her last exposure to a smallpox patient, the contact should be isolated immediately to prevent contact with nonvaccinated or nonimmune persons until smallpox can be ruled out by clinical or laboratory examination. 

When a laboratory is unable to identify an organism in a clinical specimen, it should be sent to a laboratory where the agent can be characterized, such as the state public health laboratory or, in some large metropolitan areas, the local health department laboratory. Any clinical specimens suspected to contain variola (smallpox) should be reported to local and state health authorities and then transported to CDC. All variola diagnostics should be conducted at CDC laboratories. Clinical laboratories should report any clusters or findings that could indicate intentional release of a biologic agent to their state and local health departments. 

Since the terrorist attack on New York s World Trade Center, discussions about the global exchange of disease have often focused on bioterrorism. In response to a possible bioterrorist release of smallpox, the U.S. government has stockpiled vaccine and implemented a largely unsuccessful program to vaccinate first responders (Gursky and Parikh 2005). Yet, if smallpox reappears, it will likely do so from the laboratories in the world s most scientifically developed nations. When it comes to infectious diseases, each part of the world threatens and is a threat to its neighbors. 

Laboratory diagnosis of smallpox is essential and specimens should be obtained by people vaccinated against... 

Until recently, smallpox vaccine was approved by the U.S. Food and Drug Administration for use only in persons in special-risk categories, including laboratory... 

In 1980, the US Public Health Service first recommended the use of Vaccinia (smallpox) vaccine to protect laboratory workers occupationally exposed to orthopoxviruses. In 1991, the Centers for Disease Control, Atlanta, Georgia, published recommendations on Vaccinia vaccine. From 1983 to 1991, 4649 doses of smallpox vaccine were administered, of which 57% were given in 1989-91. The proportion of primary vaccinations increased from 4% in 1983-88 to 14% in 1989-91. Of vaccinees 93% reported no signs or symptoms after vaccination. Reported adverse reactions were mild lymphadenopathy, fever or chills, and tenderness at the site of vaccination. No severe adverse effects were reported. However, one vaccinee reported a spontaneous abortion 5 months after primary vaccination (16). 

A 26-year-old laboratory worker, who had been vaccinated against smallpox in childhood, developed a pustule and erythema on his left thumb 3 days after an accidental needle-stick while working with Vaccinia virus. Further pustules occurred on the fourth and fifth fingers of the same hand, accompanied by a large... 

Other guidelines exist, are more specific (e.g., for influenza, smallpox vaccines), or cover specific topics (e.g., adjuvants). Brennan and Dougan2 and Dempster and Howarth3 present a list of the most relevant guidelines. Also of note is the fact that guidelines may differ between countries for example, Japan considers a DNA/plasmid vaccine a gene therapy product. All pivotal studies should be conducted in compliance with Good Laboratory Practice (GLP).18... 

The origins of antiviral therapies can be traced to the early 1950s, when sulfonamide antibiotics were tested for activity against poxviruses using mice infected with vaccinia (1). A decade of work at the Wellcome laboratories culminated in the development of methisazone, which was introduced in 1960 for the prophylaxis of smallpox (see Scheme 1). Notable success in the smallpox epidemic in Madras in 1963 demonstrated the value of this compound, but vaccines introduced soon after led to eradication of the disease and made the compound redundant. However, the principle that chemotherapy was effective for treating antiviral diseases had been demonstrated. 

A survey conducted 20 years ago and based on a total of 3921 cases showed 59% of laboratory-acquired infections had occurred in research laboratories (1). The majority of infections were of laboratory personnel but, in some cases, staff working outside the laboratory were also affected. Other events have emphasized the need for effective biosafety measures. These include two escapes of smallpox virus from laboratories that resulted in members of the public becoming fatally infected the emergence of new viral diseases with high case-fatality rates and the recognition that laboratory-based investigations would need to be made on viruses for which no prophylactic or therapeutic measures were available. Table 1 lists some viruses that have been identified as causal agents of laboratory-acquired infections (2-4). 

Three years after smallpox eradication, in 1980, the World Health Organization (WHO) recommended that aU countries cease smallpox vaccination. In addition, WHO recommended that all laboratories destroy stocks of the virus or transfer them to either of two WHO reference laboratories, the Institute of Virus Preparations in Moscow, Russia, or the Centers for Disease Control and Prevention (CDC) in the United States. However, there may have been stocks of virus elsewhere (26,27). Although the WHO Advisory Committee on Variola Virus research recommend eradication of aU smallpox stocks by June 30,2002, the WHO Health Assembly has delayed this each year because of concerns that stocks of virus are needed for continued study (28). 

Instead, the diagnostic priority for laboratory testing in moderate risk patients is to rule out chickenpox, the disease most commonly confused with smallpox. Therefore, moderate risk patients require rapid diagnostic testing for varicella zoster virus (VZV) (25). 

The recommendations state that hospitals should vaccinate enough staff in each category to ensure continuity of care (32). Health care workers performing the vaccinations should first receive the vaccine to minimize the consequences of inadvertent inoculation. Laboratory workers are not included in the recommendations because the quantity of smallpox virus likely to be present in clinical specimens is low. 

These are anthrax, smallpox, plague, botulism, tularemia, viral hemorrhagic fevers and ricin. They can disseminate and present a high risk on public health. Most of them require Level 4 Biosafety laboratories. 

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