Trans R Soc Trop Med Hyg 2014; 108: 183–184 doi:10.1093/trstmh/tru022
COMMENTARY
A country-wide field evaluation of rapid diagnostic test for meningococcal meningitis Suzanne Chanteau* P.O. Box 2290, 98703 Punaauia, Tahiti, French Polynesia *Corresponding author: Tel: +689 31 66 52; E-mail: [email protected]
We comment on a unique country-wide scale field evaluation of rapid diagnostic test (RDT) for meningococcal meningitis in Niger. The authors reported the good sensitivity and specificity of the test, and the reliability of results obtained in the field by non-specialized health staff. This finding allows us to consider RDT as a good candidate laboratory tool to be used for the case-based surveillance system, post introduction of the new conjugate A vaccine (MenAfriVac) in the African meningitis belt countries. In addition, RDT is also a potential point of care test to improve the management of meningitis patients. Keywords: Meningococcal meningitis, Rapid diagnostic test
Meningococcal disease is most prevalent in the sub-Saharan meningitis belt, an area of 22 countries that stretches from Senegal in the west to Ethiopia in the east, and has an at-risk population of about 430 million. The meningitis belt seems to be extending further south, touching regions that had been spared until now. The burden of the disease is considerable owing to intense recurring large-scale epidemics with annual incidence reaching 1000 cases per 100 000 population. During 1993– 2012, nearly 1 million suspected meningitis cases were reported, including an estimated 100 000 deaths; 80% of epidemics were caused by Neisseria meningitidis serogroup A.1 Niger is one of the most affected countries and together with Burkina Faso and Mali, it has benefited from the first introduction of mass immunization campaigns with the new meningococcal A conjugate vaccine, MenAfriVac (Serum Institute of India, Hadapsar, India). The article by Collard JM et al.2 reports on a large scale evaluation of previously developed rapid diagnostic tests (RDTs) for meningococcal meningitis.3–5 The duplex RDTs (serogroups A/C and Y/W) were prototypes produced in-house in the national reference laboratory (NRL) in Niamey (Niger).2 This was a unique country-wide scale study encompassing a network of 1419 trained health staff who realized RDT at primary care level and conveyed 10 265 cerebrospinal fluids (CSFs) to the NRL, where the RDTs were repeated and the conventional multiplex PCR performed.6 The study included 2095 CSFs with completed epidemiological, PCR and RDT data from both the field and the NRL. When evaluating a new diagnostic test, the choice of an appropriate reference standard is crucial for the legitimacy of the results. Sensitivity and specificity are usually determined with a reference gold standard test. However, the evaluation might be
particularly challenging if the gold standard assay itself is imperfect, which is sometimes the case. In the absence of a single reference test, combined results from two or three tests might then be used to produce a composite gold standard. For meningococcal meningitis, the culture is the usual gold standard test, but due to logistical constraints and its imperfection in the sub-Saharan context, it was not used by Collard JM et al.2 for their analysis. They used multiplex PCR as the first line gold standard test and CSF with discrepant results were later subjected to two other realtime PCR assays (RT-PCR), performed by an external reference laboratory. RT-PCR offers advantages of specificity (no contamination), sensitivity (better access to DNA matrix) and quantitative direct visualization of amplicons. Interestingly, two-thirds of the CSFs which were RDT positive but PCR negative, were found RT-PCR positive. Owing to the very strong concordance found between the RDT results from field staff and NRL, RDT may then be considered as an easy-to-use method. The overall sensitivity and specificity of RDT obtained at the NRL level, calculated using the combined PCRs as new gold standard, were 91.5 and 84.6%, respectively. These findings confirmed and strengthened the previous evaluation performed at a smaller scale and which focused on meningococcal A meningitis, using the old monoclonal antibody.3,4 Given the perspective of the changing epidemiological pattern of meningococcal meningitis in the African belt countries (reduction of the serogroup A in favor of the serogroup W), it would be very useful if the authors calculated specifically the sensitivity and specificity of RDT for the serogroup W. The introduction of MenAfriVac is a giant step towards achieving the elimination of epidemic meningitis as a public health problem in sub-Saharan Africa. Mass immunization campaigns aim to
# The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: [email protected].
183
Downloaded from http://trstmh.oxfordjournals.org/ at Michigan State University on February 24, 2015
Received 6 January 2014; revised 21 January 2014; accepted 22 January 2014
S. Chanteau
184
S. pneumonia, the second most frequent causal pathogen, in order to assist health staff.
Author’s contributions: SC has undertaken all the duties of authorship and is guarantor of the paper. Funding: None. Competing interests: None declared. Ethical approval: Not required.
References 1 World Health Organization. Meningococcal disease in countries of the African meningitis belt, 2012- emerging needs and future perspective. Wkly Epidemiol Rec 2013;88:129–36. 2 Collard JM, Wang X, Mahamane AE et al. A five year fields assessment of rapid tests for meningococcal meningitis in Niger by using the combination of conventional and real-time PCR assays as a gold standard. Trans R Soc Trop Med Hyg 2014;108:6–12. 3 Chanteau S, Dartevelle S, Mahamane AE et al. New rapid diagnostic test for Neisseria meningitis serogroups A, C, W135 and Y. Plos Med 2006;3:1579–86. 4 Boisier P, Mahamane AE, Hamidou Amadou A et al. Field evaluation of rapid diagnostic tests for meningococcal meningitis in Niger. Trop Med Int Health 2009;14:1–7. 5 Terrade A, Collard JM, Nato F et al. Laboratory evaluation of a rapid diagnostic test for Neisseria meningitis serogroup A. Trans R Soc Trop Med Hyg 2013;107:460–1. 6 Chanteau S, Sidikou F, Djibo S et al. Scaling up of PCR-based surveillance of bacterial meningitis in the African meningitis belt: indisputable benefits of multiplex PCR assay in Niger. Trans R Soc Trop Med Hyg 2006;100:677–80. 7 Daugla D, Dami J, Gamougam K et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community trial. Lancet 2013;6736:61612–18. 8 PATH, WHO. Meningitis vaccine project. Program for Appropriate Technology in Health; World Health Organization; 2014. http:// www.meningvax.org/ [accessed 21 January 2014]. 9 Pai PN, Vadnais C, Denkinger C et al. Point of care testing for infectious diseases: diversity, complexity, and barriers in low end middle-income countries. Plos Med 2012;9;e1001306. 10 WHO. Laboratory Quality Management System: Handbook. Geneva: World Health Organization; 2012.
Downloaded from http://trstmh.oxfordjournals.org/ at Michigan State University on February 24, 2015
immediately reduce bacterial carriage and transmission, and thereby reduce disease-related morbidity and mortality.7 This vaccine is expected to stimulate long-lasting immunity and to produce herd immunity. The introduction of MenAfriVac began in 2010 and is planned to cover .300 million persons aged 1–29 years in 26 countries by 2016. An objective and reliable measurement of the impact of the vaccine is necessary and represents a new challenge for the next decade. The population based approach enhanced surveillance needs to be completed by casebased monitoring, including the identification of the causal pathogens. In 2012, the dramatic decrease of meningococcal A meningitis outbreaks and the change in the distribution of the causal pathogens (greater proportion of the serogroup W and of non-meningococcal pathogens such as Streptococcus pneumoniae) gave evidence of the immediate positive impact of MenAfriVac.1 The number of cases reported during the 2013 meningococcal season is the lowest recorded during the last 10 years.8 In addition to the monitoring of the impact of MenAfriVac, RDT could be used as a point of care (POC) testing to improve the management of meningitis patients in countries where laboratory infrastructures are poor or not existent. The rapid results allow the short initiation of appropriate therapy. The introduction of these assays in sub-Saharan Africa countries is dependent on access to fully validated commercial RDT at reasonable prices. However, the mere availability of tests does not automatically ensure their adoption or scale-up. It is important to understand the complex country specific barriers that could prevent the success of such a program.9 Factors that need to be taken into account to ensure the success of the program include the integration of POC in the national health system, a strong regulation for the supply of quality assured RDT, the identification of referral laboratories for qualified training and continuous quality assurance control, clear guidelines on how to include RDT in algorithms, and various incentives for reporting and notification of cases. A viable business model and the coordination of a national laboratory plan with a laboratory quality management system10 are prerequisites for the sustainability of meningococcal RDT as a POC test. Country-specific case-based surveillance strategies have been adopted in Niger, Burkina Faso and Mali and are being implemented in other countries. The multiplex PCR is the routinely used diagnostic method, with the constraint of transporting the CSF to reference laboratory level.6 Therefore, RDT may represent a realistic alternative tool to help implement the case-based surveillance strategy at the primary care level. These dipsticks are robust tests that can be stored at 258C and produce reliable results even when performed at high ambient temperature.3 In the near future, there is a need for the development of a dipstick for the serogroup X to complete the panel of RDTs, duplex RDT for N. meningitidis regardless of the serogroup involved and for
COMMENTARY
A country-wide field evaluation of rapid diagnostic test for meningococcal meningitis Suzanne Chanteau* P.O. Box 2290, 98703 Punaauia, Tahiti, French Polynesia *Corresponding author: Tel: +689 31 66 52; E-mail: [email protected]
We comment on a unique country-wide scale field evaluation of rapid diagnostic test (RDT) for meningococcal meningitis in Niger. The authors reported the good sensitivity and specificity of the test, and the reliability of results obtained in the field by non-specialized health staff. This finding allows us to consider RDT as a good candidate laboratory tool to be used for the case-based surveillance system, post introduction of the new conjugate A vaccine (MenAfriVac) in the African meningitis belt countries. In addition, RDT is also a potential point of care test to improve the management of meningitis patients. Keywords: Meningococcal meningitis, Rapid diagnostic test
Meningococcal disease is most prevalent in the sub-Saharan meningitis belt, an area of 22 countries that stretches from Senegal in the west to Ethiopia in the east, and has an at-risk population of about 430 million. The meningitis belt seems to be extending further south, touching regions that had been spared until now. The burden of the disease is considerable owing to intense recurring large-scale epidemics with annual incidence reaching 1000 cases per 100 000 population. During 1993– 2012, nearly 1 million suspected meningitis cases were reported, including an estimated 100 000 deaths; 80% of epidemics were caused by Neisseria meningitidis serogroup A.1 Niger is one of the most affected countries and together with Burkina Faso and Mali, it has benefited from the first introduction of mass immunization campaigns with the new meningococcal A conjugate vaccine, MenAfriVac (Serum Institute of India, Hadapsar, India). The article by Collard JM et al.2 reports on a large scale evaluation of previously developed rapid diagnostic tests (RDTs) for meningococcal meningitis.3–5 The duplex RDTs (serogroups A/C and Y/W) were prototypes produced in-house in the national reference laboratory (NRL) in Niamey (Niger).2 This was a unique country-wide scale study encompassing a network of 1419 trained health staff who realized RDT at primary care level and conveyed 10 265 cerebrospinal fluids (CSFs) to the NRL, where the RDTs were repeated and the conventional multiplex PCR performed.6 The study included 2095 CSFs with completed epidemiological, PCR and RDT data from both the field and the NRL. When evaluating a new diagnostic test, the choice of an appropriate reference standard is crucial for the legitimacy of the results. Sensitivity and specificity are usually determined with a reference gold standard test. However, the evaluation might be
particularly challenging if the gold standard assay itself is imperfect, which is sometimes the case. In the absence of a single reference test, combined results from two or three tests might then be used to produce a composite gold standard. For meningococcal meningitis, the culture is the usual gold standard test, but due to logistical constraints and its imperfection in the sub-Saharan context, it was not used by Collard JM et al.2 for their analysis. They used multiplex PCR as the first line gold standard test and CSF with discrepant results were later subjected to two other realtime PCR assays (RT-PCR), performed by an external reference laboratory. RT-PCR offers advantages of specificity (no contamination), sensitivity (better access to DNA matrix) and quantitative direct visualization of amplicons. Interestingly, two-thirds of the CSFs which were RDT positive but PCR negative, were found RT-PCR positive. Owing to the very strong concordance found between the RDT results from field staff and NRL, RDT may then be considered as an easy-to-use method. The overall sensitivity and specificity of RDT obtained at the NRL level, calculated using the combined PCRs as new gold standard, were 91.5 and 84.6%, respectively. These findings confirmed and strengthened the previous evaluation performed at a smaller scale and which focused on meningococcal A meningitis, using the old monoclonal antibody.3,4 Given the perspective of the changing epidemiological pattern of meningococcal meningitis in the African belt countries (reduction of the serogroup A in favor of the serogroup W), it would be very useful if the authors calculated specifically the sensitivity and specificity of RDT for the serogroup W. The introduction of MenAfriVac is a giant step towards achieving the elimination of epidemic meningitis as a public health problem in sub-Saharan Africa. Mass immunization campaigns aim to
# The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: [email protected].
183
Downloaded from http://trstmh.oxfordjournals.org/ at Michigan State University on February 24, 2015
Received 6 January 2014; revised 21 January 2014; accepted 22 January 2014
S. Chanteau
184
S. pneumonia, the second most frequent causal pathogen, in order to assist health staff.
Author’s contributions: SC has undertaken all the duties of authorship and is guarantor of the paper. Funding: None. Competing interests: None declared. Ethical approval: Not required.
References 1 World Health Organization. Meningococcal disease in countries of the African meningitis belt, 2012- emerging needs and future perspective. Wkly Epidemiol Rec 2013;88:129–36. 2 Collard JM, Wang X, Mahamane AE et al. A five year fields assessment of rapid tests for meningococcal meningitis in Niger by using the combination of conventional and real-time PCR assays as a gold standard. Trans R Soc Trop Med Hyg 2014;108:6–12. 3 Chanteau S, Dartevelle S, Mahamane AE et al. New rapid diagnostic test for Neisseria meningitis serogroups A, C, W135 and Y. Plos Med 2006;3:1579–86. 4 Boisier P, Mahamane AE, Hamidou Amadou A et al. Field evaluation of rapid diagnostic tests for meningococcal meningitis in Niger. Trop Med Int Health 2009;14:1–7. 5 Terrade A, Collard JM, Nato F et al. Laboratory evaluation of a rapid diagnostic test for Neisseria meningitis serogroup A. Trans R Soc Trop Med Hyg 2013;107:460–1. 6 Chanteau S, Sidikou F, Djibo S et al. Scaling up of PCR-based surveillance of bacterial meningitis in the African meningitis belt: indisputable benefits of multiplex PCR assay in Niger. Trans R Soc Trop Med Hyg 2006;100:677–80. 7 Daugla D, Dami J, Gamougam K et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community trial. Lancet 2013;6736:61612–18. 8 PATH, WHO. Meningitis vaccine project. Program for Appropriate Technology in Health; World Health Organization; 2014. http:// www.meningvax.org/ [accessed 21 January 2014]. 9 Pai PN, Vadnais C, Denkinger C et al. Point of care testing for infectious diseases: diversity, complexity, and barriers in low end middle-income countries. Plos Med 2012;9;e1001306. 10 WHO. Laboratory Quality Management System: Handbook. Geneva: World Health Organization; 2012.
Downloaded from http://trstmh.oxfordjournals.org/ at Michigan State University on February 24, 2015
immediately reduce bacterial carriage and transmission, and thereby reduce disease-related morbidity and mortality.7 This vaccine is expected to stimulate long-lasting immunity and to produce herd immunity. The introduction of MenAfriVac began in 2010 and is planned to cover .300 million persons aged 1–29 years in 26 countries by 2016. An objective and reliable measurement of the impact of the vaccine is necessary and represents a new challenge for the next decade. The population based approach enhanced surveillance needs to be completed by casebased monitoring, including the identification of the causal pathogens. In 2012, the dramatic decrease of meningococcal A meningitis outbreaks and the change in the distribution of the causal pathogens (greater proportion of the serogroup W and of non-meningococcal pathogens such as Streptococcus pneumoniae) gave evidence of the immediate positive impact of MenAfriVac.1 The number of cases reported during the 2013 meningococcal season is the lowest recorded during the last 10 years.8 In addition to the monitoring of the impact of MenAfriVac, RDT could be used as a point of care (POC) testing to improve the management of meningitis patients in countries where laboratory infrastructures are poor or not existent. The rapid results allow the short initiation of appropriate therapy. The introduction of these assays in sub-Saharan Africa countries is dependent on access to fully validated commercial RDT at reasonable prices. However, the mere availability of tests does not automatically ensure their adoption or scale-up. It is important to understand the complex country specific barriers that could prevent the success of such a program.9 Factors that need to be taken into account to ensure the success of the program include the integration of POC in the national health system, a strong regulation for the supply of quality assured RDT, the identification of referral laboratories for qualified training and continuous quality assurance control, clear guidelines on how to include RDT in algorithms, and various incentives for reporting and notification of cases. A viable business model and the coordination of a national laboratory plan with a laboratory quality management system10 are prerequisites for the sustainability of meningococcal RDT as a POC test. Country-specific case-based surveillance strategies have been adopted in Niger, Burkina Faso and Mali and are being implemented in other countries. The multiplex PCR is the routinely used diagnostic method, with the constraint of transporting the CSF to reference laboratory level.6 Therefore, RDT may represent a realistic alternative tool to help implement the case-based surveillance strategy at the primary care level. These dipsticks are robust tests that can be stored at 258C and produce reliable results even when performed at high ambient temperature.3 In the near future, there is a need for the development of a dipstick for the serogroup X to complete the panel of RDTs, duplex RDT for N. meningitidis regardless of the serogroup involved and for
