Cerebrospinal fluid (CSF) protein and glucose examinations are usually performed in chemical pathology departments on autoanalysers. Tuberculosis (TB) is a group 3 biological agent under Directive 2000/54/EC of the European Parliament but in the biochemistry laboratory, no extra precautions are taken in its analysis in possible TB cases. The issue of laboratory practice and safety in the biochemical analyses of CSF specimens, when tuberculosis infection is in question is addressed in the context of ambiguity in the implementation of current national and international health and safety regulations. Additional protective measures for laboratory staff during the analysis of CSF TB samples should force a change in current laboratory practice and become a regulatory issue under ISO 15189. Annual Mantoux skin test or an interferon-? release assay for TB should be mandatory for relevant staff. This manuscript addresses the issue of biochemistry laboratory practice and safety in the biochemical analyses of CSF specimens when tuberculosis infection is in question in the context of the ambiguity of statutory health and safety regulations

Christopher O’Hagan

William P. Tormey

Biochemia Medica

English

PubMed

HRČAK - Portal of Croatian Scientific and Professional Journals

©Copyright by Croatian Society of Medical Biochemistry and Laboratory Medicine. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.http://dx .doi .org/10 .11613/BM .2015 .035 Biochemia Medica 2015;25(3):359–62   359ReviewCerebrospinal fluid protein and glucose examinations and tuberculosis: Will laboratory safety regulations force a change of practice? William P. Tormey*1,2,3, Christopher O’Hagan11Department of Chemical Pathology, Beaumont Hospital, Dublin, Ireland2Athlone Institute of Technology, Athlone, Ireland3Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland*Corresponding author: billtormey@gmail.comAbstractCerebrospinal fluid (CSF) protein and glucose examinations are usually performed in chemical pathology departments on autoanalysers. Tuberculo-sis (TB) is a group 3 biological agent under Directive 2000/54/EC of the European Parliament but in the biochemistry laboratory, no extra precautions are taken in its analysis in possible TB cases. The issue of laboratory practice and safety in the biochemical analyses of CSF specimens, when tubercu-losis infection is in question is addressed in the context of ambiguity in the implementation of current national and international health and safety regulations. Additional protective measures for laboratory staff during the analysis of CSF TB samples should force a change in current laboratory practice and become a regulatory issue under ISO 15189. Annual Mantoux skin test or an interferon-γ release assay for TB should be mandatory for relevant staff. This manuscript addresses the issue of biochemistry laboratory practice and safety in the biochemical analyses of CSF specimens when tuberculosis infection is in question in the context of the ambiguity of statutory health and safety regulations.Key words: glucose; proteins; cerebrospinal fluid; tuberculosis; safety; accreditationReceived: July 15, 2015 Accepted: July 23, 2015IntroductionCerebrospinal fluid (CSF) protein and glucose ex-aminations in confirmed and possible cases of tu-berculosis (TB) are carried out in the chemical pa-thology laboratory. CSF protein is normally de-rived from plasma and protein levels are < 1% of plasma levels (1). CSF glucose is normally about 60% of plasma levels. The normal CSF/plasma glu-cose ratio varies from 0.3 to 0.9 with variation in CSF glucose in response to changes in blood glu-cose reflecting a lag phase in CSF/blood equilibri-um time. During the recovery phase in the treat-ment of meningitis, CSF glucose normalizes before protein levels and cell counts. Patients with chron-ic tuberculous meningitis have abnormal CSF with lymphocytic pleocytosis, decreased glucose and increased protein (2). In routine practice, CSF bio-chemical analyses in meningitis may include lac-tate, C-reactive protein, adenosine deaminase and lactate dehydrogenase.  This manuscript addresses the issue of biochemis-try laboratory practice and safety in the biochemi-cal analyses of CSF specimens when tuberculosis infection is in question in the context of the ambi-guity of statutory health and safety regulations. The Health and Safety Authority in Ireland has for-mally challenged the safety of current laboratory practice in the biochemical analysis of CSF sam-ples where group 3 biological agents are con-cerned and the issue has implications across the European Union. A “group 3 biological agent” may cause severe human disease and represents a seri-ous hazard to employees thus presenting a risk of spreading to the community, although there is usually effective prophylaxis or treatment availa-Biochemia Medica 2015;25(3):359–62  http://dx .doi .org/10 .11613/BM .2015 .035 360Tormey WP, O’Hagan C. CSF chemistry analysis, tuberculosis and safetyble. By contrast, a group 1 biological agent is un-likely to cause disease to employees and a group 2 agent can cause disease to employees although it is unlikely to spread to the community and there is usually effective prophylaxis or treatment available. Tuberculosis, laboratory health and safety and regulationTuberculosis is a group 3 biological agent as listed in Code of Practice for the Safety, Health and Wel-fare at Work (Biological Agent) Regulations 2013 in Ireland. These Regulations transpose Directive 2000/54/EC of the European Parliament. Contain-ment restrictions are required by the regulations. Regulation 3 (1) states: ..”these Regulations and any relevant code of practice, apply to activities in a place of work where existing or potential, whether deliber-ate or incidental, exposure to a biological agent has occurred or may occur” (3).Schedule 2 of the Safety Health and Welfare (Bio-logical Agents) regulations lists the measures for prevention and risk reduction. There is a require-ment to design work processes and engineering control measures to avoid or minimize the risk of the release of a biological agent into the place of work. Hygiene measures must be used to prevent or reduce accidental transfer or release of a biolog-ical agent from the place of work. Collective and individual protective measures must be used where exposure cannot be avoided by other means. A further requirement is unclear and states that “the testing, where necessary and technically possible, for the presence, outside the primary physi-cal confinement, of a biological agent used at work” (4). In the context of TB, the requirements seem to require special suited protection, a negative air pressure safety cabinet and a separate area for TB biochemical testing. Are these requirements current practice in general hospital laboratories? From enquiries in Ireland and the UK, the answer appears to be No!Conventional practiceThere are no special precautions with regard to bi-ochemistry sample analysis and infectivity listed or referred to in Henry’s textbook with regard to cases where TB is a differential in the diagnosis (1). The TB reference laboratory in Ireland does not recommend any particular laboratory precautions such as negative pressure fume cupboards and full masks and gowns. Neither do the Canadian, UK or Indian or United States Guidelines (5-8). Lack of evidence of laboratory staff infectionIn a survey of laboratory staff in the UK, two cases of TB were reported in a biochemistry department within 18,310 person years of exposure. Details were not provided (9). While there is a theoretic risk, it must be witheringly small. In contrast, the risk to nurses even in short contact with an infec-tious patient is real. In 2012, there were 364 cases of tuberculosis reported in Ireland of which 3 (0.8%) were TB meningitis. The literature on laboratory associated infections reveals 5,346 such infections between 1930 and 2000. These cases appear to refer to microbiology processes overwhelmingly. Historic data from the United States in the period from 1930 to 1950 found a total of 775 cases of laboratory-acquired infections of which 153 were TB. World data from 1950 to 1963 revealed 191 cases of which 21 were TB. In a literature survey covering 1979–2004, there were 1,141 laboratory acquired infections of which 199 were Mycobacterium tuberculosis (10). Data from England and Wales found that laboratory workers showed a 5.4 times increased risk of ac-quiring TB compared to the general population with the highest risk ratio 7.5 among technical staff.Surveillance precautionsThe US Morbidity and Mortality Weekly Report is-sued guidelines on the prevention of transmission of TB in healthcare settings in 2005. Laboratory workers should be screened for TB if they share airspace with an infected person or if they partici-pate in suspected or confirmed TB specimen pro-cessing. As a surveillance precaution, all health care workers should have baseline TB screening http://dx .doi .org/10 .11613/BM .2015 .035 Biochemia Medica 2015;25(3):359–62   361Tormey WP, O’Hagan C. CSF chemistry analysis, tuberculosis and safetyon job commencement using a two-step tubercu-lin skin test or a single whole blood gamma inter-feron assay. Annual clinical appraisals should then be carried out. Medical scientists may need respir-atory protection depending on the type of ventila-tion in use in the laboratory and the likelihood of aerosolization of viable TB as a result of a labora-tory procedure (11). Codes of practiceIn the US, Biosafety in Microbiological and Bio-medical Laboratories (BMBL) has become the code of practice for biosafety (12). No reference is made to processing CSF specimens in a biochemistry au-toanalyser but any maneuver that produces an aerosol heightens the infection risk. The require-ment for tuberculosis is that “all aerosol-generating activities must be conducted in a biological safety cabinet”. Biosafety Level 2 (BSL-2) practices and procedures seems the safest protocol to adopt but in practice, how will this be applied to biochemical analyses of CSF samples? The availability of simple, easy to use, point-of-care testing devices allow the routine use of biological safety cabinets for CSF glucose analysis but low levels of protein are be-yond the device sensitivities. In England, TB is in hazard Group 3 and must be processed in a microbiological safety cabinet un-der full containment level 3 conditions. Does this happen with biochemical analyses in English or Irish hospitals? No!A detailed public health report from Belgium in 2006, described common laboratory methodolo-gies involved in TB analysis but biochemical auto-analysers did not feature (13). Current analytical practiceThe Beckman Coulter AU 5400 autoanalyser (Bath, UK) is used for estimation of CSF glucose and pro-tein in this institution. Aerosol micro-droplets are possible in the process of autopipetting a speci-men aliquot into the cuvette and also at the rea-gent mixing stage. All infectious blood specimens involving HIV, HepB, HepC and unknown are treat-ed in a similar manner. It is impossible to eliminate all risk from infectious pathogens. Accreditation challenge and improved safety monitoringISO 15189 accreditation inspectors have not fo-cused or commented on this issue to date. Will the precautionary principle be applied with CSF glu-cose and protein analysis being performed in neg-ative pressure cabinets with staff in space suits us-ing specially designated equipment or will com-mon sense prevail and current practice continue?  It is possible that additional preventive measures for biochemical analyses of TB specimens will be-come the norm because health and safety regula-tions specify more stringent precautions than are currently in widespread practice. Where suitably sensitive point-of-care devices for relevant bio-chemical analytes become available, these can be used in the negative air pressure biological safety cabinets in the microbiology departments which would divert the issue away from biochemistry technologists. Concluding recommendation for staffStaff involved in testing of TB specimens in clinical chemistry laboratories as well as those in microbi-ology laboratories should have baseline screening for TB on job commencement and follow-up an-nual clinical appraisals. Annual Mantoux skin test or an interferon-γ release assay should be done to check for conversion. Those with positive results should have a chest X-ray and appropriate treat-ment. These annual staff tests are not done in Clin-ical Chemistry departments at present. Potential conflict of interestNone declared.Biochemia Medica 2015;25(3):359–62  http://dx .doi .org/10 .11613/BM .2015 .035 362Tormey WP, O’Hagan C. CSF chemistry analysis, tuberculosis and safetyReferences 1 . Karcher S . McPherson RA . Cerebrospinal, synovial, sero-us body fluids, and alternative specimens . In . Henry’s cli-nical diagnosis and management by laboratory methods . 22ed . McPherson RA, Pincus MR Eds . Elsevier Saunders Phi-ladelphia . 2011; Ch 29, 480-506 . 2 . Patel VB, Burger I, Connolly C . Temporal evolution of cere-brospinal fluid following initiation of treatment for tuber-culous meningitis . S Afr Med J 2008;98:610-3 .  3 . Safety, health and welfare at work (Biological agents) Re-gulations 2013 . SI number 572 of 2013 . Stationary Offi-ce, Government Publications . Dublin . Available at: http://www .hsa .ie/eng/Legislation/New_Legislation/Biologi-cal%20Agents%20Regulations%202013 .pdf . Accessed April 27, 2015 . 4 . Safety Health and Welfare (Biological Agents) Regulations 2013 . Schedule 2 . Irish Statute Book . Available at: http://www .irishstatutebook .ie/2013/en/si/0572 .html . Accessed April 27, 2015 . 5 . Canadian Tuberculosis Standards . Public Health Agency of Canada . The Lung Association . Canadian Thoracic Society . 7th Edition . 2014 . Available at: http://tbevidence .org/wp-content/uploads/2014/04/Canadian_TB_Standards_7th-edition_English .pdf . Accessed December 1st, 2014 . 6 . NICE Clinical Guideline 117 . Developed by the national collaborating centre for chronic conditions and the cen-tre for clinical practice at NICE . Tuberculosis: Clinical di-agnosis and management of tuberculosis, and mea-sures for its prevention and control . March . 2011 . Availa-ble at: http://www .nice .org .uk/guidance/cg117/chapter/1-guidance#diagnosis . Accessed April 26, 2015 . 7 . World Health Organisation . Standards for TB care in India . Central TB Division . Ministry of Health and Family Welfa-re, Government of India and World Health Organisation . New Delhi 110 011 . 2014 . Available at: http://tbevidence .org/wp-content/uploads/2014/04/STCI-2014 .pdf . Accessed April 26, 2015 . 8 . Shinnick TM, Iademarco MF, Ridderhof JC . National plan for reliable tuberculosis laboratory services using a systems approach . Centres for Disease Control and Prevention . Home, MMWR, 2005 . Available at:m http://www .cdc .gov/mmwr/preview/mmwrhtml/rr5406a1 .htm . Accessed De-cember 2nd, 2014 . 9 . Grist NR, Emslie JAN . Association of clinical pathologi-sts’ surverys of infection in British clinical laboratori-es, 1970-1989 . J Clin Pathol 1994;47:391-4 . http://dx .doi .org/10 .1136/jcp .47 .5 .391 .10 . Harding AL, Byers K . Epidemiology of Laboratory-acquired Infections” . In Fleming DO, Hunt DL, eds Biological Safety, Principles and Practices,4th ed . 2006 . Washington, DC:ASM Press . 11 . Centres for Disease Control and Prevention . Guidelines for preventing the transmission of mycobacterium tuberculo-sis in health-care settings 2005 . MMWR 2005;54 (No . RR-17):3-4 .12 . Mycobacterium tuberculosis complex . Biosafety in micro-biological and biomedical laboratories . 5th Edition . US De-partment of Health and Public Services . Public Health Ser-vice, Centres for Disease Control and Prevention, National Institutes of Health . Atlanta, Georgia, USA . HHS Publicati-on No . (CDC) 21-1112 .2009 . 145-147 . Available at: http://www .cdc .gov/biosafety/publications/bmbl5/BMBL .pdf . Accessed April 26, 2015 .13 . Scientific Institute of Public Health . Division of Biosafety and Biotechnology . 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Cerebrospinal fluid protein and glucose examinations and tuberculosis: Will laboratory safety regulations force a change of practice?

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Christopher O'Hagan

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Cerebrospinal fluid protein and glucose examinations and tuberculosis: Will laboratory safety regulations force a change of practice?

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