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Interim Guidelines for Smallpox Response and Management in Scotland in the Post-Eradication era

V Case definitions and laboratory investigation

35. The preliminary definitions given below may require revision by clinicians and public health personnel depending upon the scale of the outbreak.

37. Clinical case definition. An illness with acute onset of fever >38ºC, which is persistent, followed by a rash without other apparent cause characterised by vesicles or firm pustules at the same stage of development and with a predominantly centrifugal distribution.

39. The case definition in paragraph 35 describes the typical presentation of smallpox. The predictive value of this clinical case definition is likely to be low in the absence of circulating smallpox. Atypical presentations (haemorrhagic and malignant), and modified smallpox must also be considered.

41. Laboratory criteria for confirmation. Smallpox viruses are classified as Hazard Group 4 organisms and must be handled accordingly. Clinical samples from suspected cases must be handled with due regard to the likelihood that smallpox is present, and the appropriate procedures observed. Should it be necessary to conduct work other than in a Category 4 laboratory, a full risk assessment must be conducted.

43. The importance, and methods, of laboratory confirmation depend on the epidemiological situation:

• Electron microscopy (EM). In the initial cases or unrelated cases in a new geographical area, EM identification of orthopox virus in a patient with symptoms compatible with the clinical case definition indicates a probable case of smallpox - see paragraph 43. During an outbreak, in the presence of an epidemiological link to other confirmed cases, EM identification of orthopox virus may be regarded as confirmatory.

• Polymerase chain reaction (PCR) and viral isolation from culture (Category 4 laboratories only). Confirmation using these techniques is required for initial cases or unrelated cases in a new geographical area. They may also be of critical importance in distinguishing cases of variola and generalised vaccinia. Definitive diagnosis of smallpox will be based on the DNA sequence of PCR amplicons and the characteristics of viral isolates.

40. EM takes 2 hours and PCR takes 6 hours from receipt of specimens until results can be provided.

42. In a case with strongly suspicious clinical features and no other diagnosis, failure to detect any organism with EM or PCR does not exclude smallpox, and such cases may be regarded as probable.

44. If a large outbreak occurs, laboratory capacity will soon be overwhelmed. In this instance, priority for laboratory resources will include:

• Testing of clinical specimens from cases with unclear clinical presentations following expert assessment.

• Testing of clinical or environmental specimens that will provide information about a potential source of exposure to facilitate case detection and law enforcement activities.

In these circumstances, specimens will be triaged by local Infectious Disease Physicians, Virologists and Public Health Physicians, according to guidelines issued by the UK National, Scottish and Regional Smallpox Outbreak Control Centres (see section VII).

Case Classification

43. Suspected: a case of fever and rash consistent with the case definition (see paragraph 35), without laboratory confirmation or an epidemiological link to other cases. Initial cases of smallpox, or unrelated cases in a new geographical area are likely to present as suspected cases.

45. Probable: a case of fever and rash consistent with the case definition, plus:

• For initial cases of smallpox or unrelated cases in a new geographical area - EM identification of orthopox virus or a case with strongly suspicious clinical features and no other diagnosis.

• During an outbreak - an epidemiological link to a confirmed case.

45. Confirmed: a case of fever and rash consistent with the case definition, plus:

• For initial cases of smallpox or unrelated cases in a new geographical area - laboratory confirmation by PCR or viral isolation.

• During an outbreak - an epidemiological link to a confirmed case and EM identification of orthopox virus or a case with strongly suspicious clinical features and no other diagnosis.

46. Possible: acute onset of fever but no rash in a person with an epidemiological link to a confirmed case. The fever may be accompanied by prodromal symptoms such as prostration, severe headache or backache, rigors and generalised maculopapular rash. Control of an outbreak will depend on early identification and management of possible cases.

47. Table 2: summary of minimum criteria for case classification

    Classification	Fever *	Rash *	EM identification of orthopox	PCR positive for smallpox	Epidemiological link to another confirmed case of smallpox
    Suspected (Initial cases or during outbreak)	+	+	-	-	-
    Probable: Initial cases During outbreak	+	+	+/- #	-	-
    	+	+	-	-	+
    Confirmed: Initial cases During outbreak	+	+	+	+	-
    	+	+	+/- #	-	+
    Possible (During outbreak)	+	-	-	-	+

    * Fever and rash consistent with the case definition - see paragraph 35.

    # EM not required if the case has strongly suspicious clinical features with no other diagnosis.

48. The diagnosis of suspected or probable cases according to the clinical case definition requires assessment by a Smallpox Diagnostic Expert - see Sections VI.

49. Laboratory networks

50. The collection and transport of clinical specimens from suspected smallpox cases, including the equipment and procedures for taking specimens is described in Appendix 1.

52. Laboratory testing of clinical specimens from initial suspected cases will involve EM at the designated Category 3 laboratory in Scotland, the West of Scotland Regional Virus Laboratory (RVL) at Gartnavel General Hospital, Glasgow, followed by confirmation by PCR at a UK Reference Laboratory. These are the Central Public Health Laboratory (CPHL) and the Centre for Applied Microbiological Research (CAMR) (see Appendix 2).

54. Rapid real-time PCR tests for orthopox, varicella zoster and herpes simplex viruses are currently being evaluated, and it is planned that these could be made available to the RVL at Gartnavel General Hospital, Glasgow in the future.

56. Pre-exposure vaccination is required for staff who might be involved in handling clinical specimens from the initial suspected cases. At Alert Level 0 (see Section VI and Appendix 3), a small number of staff at the RVL at Gartnavel General Hospital, Glasgow and the UK Reference laboratories will be vaccinated (see Section VIII). In the event of an Alert Level 1, a larger number of laboratory staff will be vaccinated in case they are required to handle specimens.

58. It is possible that viral particles resembling smallpox may be identified on routine EM of vesicular fluid. In this event, the specimen should be sent immediately to a UK Reference laboratory according to the procedures described in Appendix 1. The virologist must also immediately inform the referring clinician who should arrange for a Smallpox Diagnostic Expert to assess the patient - see Section VI.

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