Evidence Based Practice Infectious Mononuclosis Biology Essay

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Infectious mononucleosis is a lifelong clinical disease, primarily associated with the Epstein-Barr virus. In the USA, there is an estimated 500 cases per 100,000 individuals diagnosed each year(1,2). Common symptoms include sore throat, fatigue, fever and lymphadenopathy. Although rarely fatal, IM can lead to other serious complications including splenic rupture and breathing difficulties(2).

In the haematology laboratory at Victoria Hospital in Fife, the current practice for IM diagnosis is to perform a full blood count (FBC) and blood film (BF) followed by a monospot (heterophile antigen test). Over recent months, it has been noticed that the number of requests for monospots has risen although the number of positive results remains low.

Due to laboratory financial constraints and the possible introduction of vetting criteria for monospot testing, an audit(Appendix A) was performed to determine the number of monospots performed in one month, along with the clinical details and results. Findings showed that only 10 of the 99 requests had a positive monospot test. In addition, it was highlighted that 70% of the requests did not have any of the typical FBC and BF findings associated with IM, such as lymphocytosis and the presence of atypical lymphocytes respectively. Although the audit showed that a large percentage of monospot tests are requested for the inappropriate reasons, for example as part of a malaise screen with no other significant symptoms, the negative findings may be associated with the limitations of the monospot rather than due to being requested unnecessarily.

The vetting criteria will include the FBC and BF findings and depending upon the results, the monospot test may not be performed (Figure 1). However, monospots, as well as FBC and BF's, may give false negative results in a quarter of cases with early disease (1st week of symptoms)(3) and in the majority of children less than 4 years old. Additionally, 10-20% of IM infected adults fail to produce IM heterophile antibodies, which would also lead to a negative monospot test(Appendix B). These cases are referred to as heterophile negative EBV induced IM. Furthermore, monospot tests are unable to distinguish between primary disease, reactivated IM and persistent antibody presence, as heterophile antibodies can persist for many years at low levels, along with a normal FBC and BF(1,2,4). It is also worth noting that other serious conditions including human immunodeficiency, cytomegalovirus, infection with Toxoplasma gondii and some malignancies may present with symptoms of IM and produce positive monospots (false positive)(3, Appendix B)

Therefore, it is worth considering using other IM diagnostic methods such as EBV serological studies, including viral capsid antigen (VCA) tests (EBV Anti-VCA IgM and IgG-antibodies) and IgG-antibodies to EBV nuclear antigen 1 (EBNA-1), for an definite diagnosis of IM, along with the phase of disease(1,3,4) (Table 1).

Figure 1 - Potential Vetting Criteria for IM Testing and Diagnosis (adapted from 3)

* It is assumed that a monospot test would give a non-specific result

Table 1 - EBV Serological Tests and their Association with IM (adapted from 2)

EBV Serological Test

Association with IM

EBV Anti-VCA IgM-antibodies

Detected in early disease, disappearing within 4-8 weeks. Diagnostic of primary infection.

EBV Anti-VCA IgG-antibodies

Detected in early disease and remain in system for life. Diagnostic of primary and chronic infection.

IgG-antibodies to EBNA-1

Detected several weeks after presenting symptoms. Diagnostic of past infection.

Question

Population: Individuals with suspected EBV induced IM

Intervention: EBV serological studies

Comparison: Monospot

Outcome : Valid replacement test (improved sensitivity and specificity by

establishing presence of infection and stage of disease at diagnosis)

Do EBV serological studies provide a valid replacement for the monospot test and improve sensitivity and specificity of diagnosis in patients with suspected EBV induced IM?

Search Strategy

Potential words / phrases to use for search:

Infectious mononucleosis

Epstein-Barr virus

Monospot

Heterophile antigen test

EBV serology

Antibod* (antibody, antibodies)

Viral capsid antigen test (VCA)

EBV nuclear antigen 1 (EBNA-1)

Compared

Diagnosis

The search strategy began by working through each database, using the search terms deemed most important, before narrowing them down (where required) using filters or changing search words. Table 2 demonstrates the order of resources used and search terms.

Table 2 - Search Strategies for identifying the relevant literature

Resource (database)

Search Terms **

Filters Applied

Total Number of Hits

Irrelevant Hits

Relevant Hits

Bandolier

Infectious mononucleosis

None

1

1

0

Epstein-Barr virus

None

1

1

0

BestBETs

Infectious mononucleosis

None

0

0

0

Epstein-Barr virus

None

0

0

0

Trip

Infectious mononucleosis

None

1389

N/A

N/A

Infectious mononucleosis and monospot

None

40

N/A

N/A

Infectious mononucleosis and monospot and EBV serology

None

16

N/A

N/A

Infectious mononucleosis and monospot and EBV serology

Evidence based synopses

1

0

1

NHS Evidence

Infectious mononucleosis

None

201

N/A

N/A

Infectious mononucleosis and monospot

None

0

0

0

Infectious mononucleosis and diagnosis

None

146

N/A

N/A

Infectious mononucleosis and diagnosis

Diagnosis

35

N/A

N/A

Infectious mononucleosis and diagnosis and EBV serology

Diagnosis

3

3

0

Infectious mononucleosis and diagnosis and EBV serology

Removed "diagnosis" filter

9

0

1

Epstein-Barr virus and diagnosis and EBV serology

None

13

13

0

Cochrane

Infectious mononucleosis

None

3

3

0

Epstein-Barr virus

None

1

1

0

Infectious mononucleosis and diagnosis

None

7

5

2

PubMed

Infectious mononucleosis

None

7888

N/A

N/A

Infectious mononucleosis and EBV serology

None

965

N/A

N/A

Infectious mononucleosis and EBV serology and comparison

None

31

N/A

N/A

Infectious mononucleosis and EBV serology and heterophile

None

85

N/A

N/A

Infectious mononucleosis and EBV serology and heterophile

Humans

81

N/A

N/A

Infectious mononucleosis and EBV serology and heterophile and diagnosis

Humans

69

N/A

N/A

Infectious mononucleosis and EBV serology and heterophile and diagnosis and comparison

Humans

4

3

1

Infectious mononucleosis and EBV serology and monospot

Humans

14

11

3

EBNA-1 and viral capsid antibody and heterophile

Humans

7

4

3

Antibod* and infectious mononucleosis

N/A

2144

N/A

N/A

Antibod* and infectious mononucleosis and diagnosis

N/A

1475

N/A

N/A

Antibod* and infectious mononucleosis and diagnosis

Humans

1395

N/A

N/A

Antibod* and infectious mononucleosis and diagnosis

Humans and 5 years

72

N/A

N/A

Antibod* and infectious mononucleosis and diagnosis and compared

Humans and 5 years

16

15

1

** Search terms have been entered into table in order they were input into each database. N/A = not applicable (used in irrelevant/relevant column when search hit is too high)

Results of Search

Author

Date and Country

Title of Paper

Source of Evidence

Lattimore K A

2001, USA

Accurate diagnosis of EBV mono with rapid heterophile latex agglutination depends on the test used

Trip - University of Michigan Department of Pediatrics. Evidence -based pediatrics website

Health protection agency (Standards unit, Microbiology services divison)

2012, UK

UK standards for microbiology investigations. Epstein-Barr virus serology

NHS Evidence - Virology (V26, 4)

Andersson A, Vetter V, Kreutzer L and Bauer G

1994

Avidities of IgG directed against viral capsid antigen or early antigen: useful markers for significant Epstein-Barr virus serology

Cochrane - Journal of medical virology

Tamaro G, Donato M, Princi T and Parco S

2009, Italy

Correlation between the immunological condition and the results of immunoenzymatic tests in diagnosing infectious mononucleosis

Cochrane - Acta bio-medica : Atenei Parmensis

Siennicka J and Trzcińska A

2007, Poland

Laboratory diagnosis of Epstein-Barr virus infection

PubMed - Med Dosw Mikrobiol

Vouloumanou E K, Rafailidis P I and Falagas M E

2012, Greece

Current diagnosis and management of infectious mononucleosis

PubMed - Current Opinion Hematololgy

Papesch M and Watkins R

2001, UK

Epstein-Barr virus infectious mononucleosis

PubMed - Clinical Otolaryngology and Allied Sciences

Sević S

1997, Croatia

Serologic diagnosis of acute infectious mononucleosis

PubMed - med Pregl

Klutts J S, Ford B A, Perez N R and Gronowski A M

2009, USA

Evidence-based approach for interpretation of Epstein-Barr virus serological patterns

PubMed - Journal of Clinical Microbiology

De Paschale M, Agrappi C, Manco M T, Mirri P, Viganò E F and Clerici P

2009, Italy

Seroepidemiology of EBV and interpretation of the "isolated VCA IgG" pattern

PubMed - Journal of Medical Virology

Nystad T W and Myrmel H

2007, Norway

Prevalence of primary versus reactivated Epstein-Barr virus infection in patients with VCA IgG-, VCA IgM- and EBNA-1-antibodies and suspected infectious mononucleosis

PubMed - Journal of Clinical Virology

Llor C, Hernández M, Hernández S, Martínez T and Gómez F F

2012, Spain

Validity of a point-of-care based on heterophile antibody detection for the diagnosis of infectious mononucleosis in primary care.

PubMed - European Journal of General Practice

Reflection

I researched various databases, looking for relevant literature to help answer my question on whether EBV serological studies are a valid replacement for the monospot test. I found my question to be both relevant to my workplace and specific enough to obtain enough literature to help come to a generalised conclusion.

I prepared before beginning my search by doing background reading around my question which gave me a good insight to the general areas I need to concentrate on, however, as I had no previous experience of this type of database searching, I found it quite difficult to know which key words to use. I wrote a list of relevant words in order of importance to help keep me on the right track.

In the beginning, I found this task quite daunting as my searches produced "hits" with either an extremely high number (7000 in PubMed) or a very low number (0 in BestBETs) and I found it difficult to know when to apply filters, add additional search terms or use wildcards.

I performed quite a lot of individual searches, only changing one word or filter at a time to make it easier for myself since it was a new experience. Also, on this occasion, I did not use any Boolean operators and I subsequently realised that I could have saved myself some search time initially by searching for "infectious mononucleosis" OR "Epstein-Barr virus" instead of searching for these terms individually. This practice will change in the future as I feel more confident in my abilities to perform database searches as well as feeling more confident using wildcards, which I did towards the end of my searches (e.g. antibod*). I also found that using some basic filters such as 'humans' and publication date (e.g. 'last 5 years') at the beginning may also save me some search time right at the beginning.

When performing this type of database search in the future, I think I will start with the database I found to be most useful, which was PubMed. I found it produced the most relevant papers and I found it quite easy to use. I have significantly developed my knowledge and skills in this area and my ability to search databases will be used during the rest of my MSc and in my current practice in the laboratory when required.

References

Vouloumanou E K, Rafilidis P I and Falagas M E. Current diagnosis and management of infectious mononucleosis. Myeloid Biology. 2012;1:14-20

Luzuriaga K and Sullivan J L. Infectious mononucleosis. The New England Journal of Medicine. 2010; 362(21):1993-2000

Hurt C and Tammaro D. Diagnostic evaluation of monocucleosis-like illness. The Americal Journal of Medicine. 2007;120(10):911,e1-911.e8

Nystad T W and Myrmel H. Prevalence of primary versus reactivated Epstein-Barr virus infection with VCA IgG-, VCA IgM- and EBNA-1-antibodies and suspected infectious mononucleosis. Journal of Clinical Virology. 2007;38:292-297

Appendix A

Horizontal Audit of IM Screening Tests Sept 2012

Total Tests = 99, age range 3 months - 77 years, most requests as expected in the teens - twenties. 96 were GP requests, only three IM screening requests were added by BMS staff, all having lymphocytosis. All were reported on the same day the request was received by the lab.

Total Positives = 10 (10.1%), all except one of the positives had typical IM features, lymphocytosis and reactive lymphocytes in the film. The single positive without IM features had a normal FBC and blood film and no legible clinical details.

Total Negative =89 (89.9%)

Clinical Details both groups (red = IM slide positive)

FBC Results for the negative group.

The Diagnosis of IM is characterised by pharyngitis, lymphadenopathy and malaise. This diagnosis is supported by typical FBC results (lymphocytosis and atypicals in the film). The FBC has a sensitivity of 75% and specificity of 92% for the diagnosis of IM. The IM slide test for the heterophil antibody has a reported sensitivity of approximately 85% and specificity of 94%. (review by Luzuriaga and Sulivan, Infectious Monomucleosis NEJM, 2010, 263 21, pages 1993-2000.).

More that 70% of FAL requests fail to meet any of the above diagnostic or laboratory criteria. In some cases it appears as though the IM slide test is use as part of a 'Tired/Malaise' screening process. This is supported as 9 of the IM slide test requests also had a Ferritin request.

Using our current test cards it costs approximately £1.00 per test, if we introduced even the most basic level of request control i.e. normal FBC without Lymphocytosis, Atypicals in the film)

Brian H Little BMS 2

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