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 ~  Abstract
 ~ Introduction
 ~  Materials and Me...
 ~ Results
 ~ Discussion
 ~  References

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BRIEF COMMUNICATION
Year : 2017  |  Volume : 35  |  Issue : 2  |  Page : 286-289
 

Comparative analysis of syndromic case management and polymerase chain reaction based diagnostic assays for treatment of Neisseria gonorrhoeae, Chlamydia trachomatis and genital mycoplasmas in patients of genitourinary discharge


1 Department of Microbiology, AIIMS, New Delhi, India
2 Department of Dermatology and Venereology, AIIMS, New Delhi, India

Date of Web Publication5-Jul-2017

Correspondence Address:
Benu Dhawan
Department of Microbiology, AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_17_4

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 ~ Abstract 

To respond to the situation of high prevalence and need for effective treatment for sexually transmitted infections (STIs) in low-resource settings, syndromic diagnostic approach was recommended by the World Health Organization and was adopted by National AIDS Control Organization at the primary health centre level. A retrospective study was undertaken in symptomatic patients attending an STI clinic to validate the syndromic approach for genitourinary discharge syndrome. For aetiological diagnosis, culture and/or polymerase chain reaction was used. An infective aetiology could be established in only 20% (106 of 530) patients. The present data call for an early appraisal and review of the diagnostic policy by national authorities on syndromic case management.


Keywords: Chlamydia trachomatis, genital mycoplasmas, genitourinary discharge, polymerase chain reaction-based diagnosis, syndromic case management


How to cite this article:
Arif N, Sebastian S, Khanna N, Sood S, Dhawan B. Comparative analysis of syndromic case management and polymerase chain reaction based diagnostic assays for treatment of Neisseria gonorrhoeae, Chlamydia trachomatis and genital mycoplasmas in patients of genitourinary discharge. Indian J Med Microbiol 2017;35:286-9

How to cite this URL:
Arif N, Sebastian S, Khanna N, Sood S, Dhawan B. Comparative analysis of syndromic case management and polymerase chain reaction based diagnostic assays for treatment of Neisseria gonorrhoeae, Chlamydia trachomatis and genital mycoplasmas in patients of genitourinary discharge. Indian J Med Microbiol [serial online] 2017 [cited 2017 Sep 26];35:286-9. Available from: http://www.ijmm.org/text.asp?2017/35/2/286/209594



 ~ Introduction Top


Reproductive tract infections (RTI) including sexually transmitted infections (STIs) represent an important public health problem in developing countries. The World Health Organization (WHO) report states that 340 million new cases of STIs occur every year.[1] The National AIDS Control Organization (NACO), India estimates community-based prevalence of STIs to be 6% in sexually active adult population.[2]

The early diagnosis and treatment of STIs can prevent serious complications and long-term sequelae affecting reproductive health. STIs have been diagnosed using a number of ways, including laboratory diagnosis and syndromic diagnosis. Laboratory diagnosis though accurate is expensive and not feasible in many settings where adequate facilities are not available. To respond to the situation of high prevalence and need for effective treatment for STIs in low-resource settings, syndromic diagnostic approach was recommended by WHO and was adopted by NACO, India at the primary health centre level.[3] The approach was preferred as it was not only easy to implement but also cost-effective and feasible.

The syndromic approach relies on the identification of the aetiological organisms based on conglomeration of signs or symptoms that characterise a particular clinical condition. This often leads to overdiagnosis and overtreatment, with no consideration of asymptomatic populations.[4] Potential drug abuse is also a major concern with such an approach as is evident from rising minimum inhibitory concentrations of drugs used for treating the major STIs.[5]

As of now, syndromic approach is the only alternative in settings which have no laboratory infrastructure for diagnosis of STIs. However, there is no consensus of its effectiveness and impact on public health. To address this issue, this study was carried out among attendees of an STI clinic with the objective to validate the consistency of syndromic diagnosis with laboratory diagnosis of genitourinary discharge.


 ~ Materials and Methods Top


A tertiary care centre-based, retrospective study was undertaken in symptomatic patients attending an STI clinic in north India between August 2015 and October 2016. All sexually active men with urethral discharge (UD) syndrome and women with endocervical discharge of age group 15–58 years were included in the study. Samples consisted of urethral/endocervical swabs and or first voided urine (FVU) for detection of  Neisseria More Details gonorrhoeae, Chlamydia trachomatis and genital mycoplasmas and. Rectal swabs were also received from patients as and when indicated. The study participants were not identified on the basis of their sexual practices or high-risk behaviour. All samples were processed on the day of collection.

Samples were processed for N. gonorrhoeae, C. trachomatis and genital mycoplasmas. Culture for N. gonorrhoeae was done on modified Thayer-Martin medium containing vancomycin, colistin, nystatin, trimethoprim inhibitors and chocolate agar (Columbia agar base plus sheep blood). The isolates were confirmed positive by oxidase superoxol test and rapid carbohydrate utilisation test.[6] For detection of genital mycoplasmas, swabs were transported in 2 ml of pleuropneumonia-like organisms medium broth (Difco, USA) containing urea for Ureaplasma spp. and arginine for Mycoplasma hominis. DNA was extracted using QIAamp Mini Kit (QIAGEN, Hilden, Germany) according to the manufacturer's instructions. The extracted DNA was stored at −20°C till further use for polymerase chain reaction (PCR) assays.

A multiplex PCR targeting the urease gene of Ureaplasma spp. and 16Sr DNA of M. hominis was performed.[7] In addition, a PCR was also performed to detect Mycoplasma genitalium by targeting the 140 kDa adhesion gene using primers MgPa-1 and MgPa-3.[8] To detect C. trachomatis infection, a DNA PCR was performed targeting the cryptic plasmid using primers KL-1 and KL-2 and confirmed by a second PCR targeting the ompA gene.[9],[10]


 ~ Results Top


A total of 558 samples were collected from 530 patients during the study. These included 218 endocervical swabs, 2 rectal swabs from women with rectal discharge, 200 urethral swabs and 117 FVU samples from men with UD syndrome and 21 rectal swabs from men with rectal discharge.

Infections due to N. gonorrhoeae, C. trachomatis, Ureaplasma spp. and Mycoplasma hominis were detected in 3% (16), 8% (46), 5.6% (30) and 2.6% (14) patients, respectively. None of the patients were positive for Mycoplasma genitalium. Of the 23 rectal swabs received, 7 (30.43%) tested positive for C. trachomatis. Coinfections were observed in 13 (2%) patients, the most common coinfection being C. trachomatis and Ureaplasma spp. in 7 of the 13 patients. Thus, an aetiological diagnosis could be established in 20% (106 of 530) patients only, the remaining, 80% patients were treated without any laboratory confirmed aetiological diagnosis.


 ~ Discussion Top


The WHO endorses the syndromic case management protocol for STIs/RTIs.[11] As STIs are an important risk factor for HIV, NACO has also incorporated syndromic management of STIs/RTIs in the NACP/RCH programs.[3] Under this approach, STIs/RTIs are classified into easily identifiable syndromes, and the treatment is provided depending on common organisms causing the syndrome. The drugs included in kit-1(Grey) for UD, cervicitis discharge, anorectal discharge (ARD) are azithromycin (1 g) and cefixime (400 mg). The patients enrolled in this study were patients with urethral, endocervical or ARD who were constitutively treated on the basis of clinical diagnosis and syndromic case management as suggested by NACO.

This study highlights a wide variation between syndromic-based diagnosis and laboratory-based aetiological diagnosis in symptomatic patients with genitourinary discharge. Previous studies have reported a low specificity and positive predictive value of Syndromic Case Management (SCM).[12],[13] Many of the previous studies reported from India did not use molecular methods for validation.[12],[14] Non-availability of nucleic acid-based tests like PCR, as mentioned above, could also have resulted in the lower detection of C. trachomatis and genital mycoplasmas these agents by laboratory methods used in other Indian studies.[12],[14] Ray et al.(2009) compared the level of agreement of clinical diagnosis to history-based diagnosis with increased sensitivity (80.5%) but low specificity (48.6%).[12] In the present study, syndromic approach for urogenital discharge was over predictive of the presence of N. gonorrhoea, C. trachomatis and genital mycoplasmas. Of the 530 patients with urogenital discharge, an aetiological diagnosis of N. gonorrhoeae, C. trachomatis and or genital mycoplasmas was made in 20% patients only, resulting in overtreatment of 80% patients with cefixime and azithromycin. This underscores the importance for establishing aetiology-based treatment of STI Syndromes. If etiology is established with the use of standard diagnostic modalities, overtreatment can be done away with. In view of this, we recommend a revision in the guidelines for syndromic approach and its validation.

A major strength of our study compared to previous studies is that it is the first study from India to determine the aetiological role of C. trachomatis genital mycoplasmas in urogenital discharge syndrome using NAATs. Ryan and Holmes (1995) recommend the use of PCR as gold standards to assess SCM of genital infections from time to time.[15] NAATs are considered to be the standard for diagnosis though they are not available in all settings of a developing country. Whenever available, testing should be done to establish the aetiology before instituting any treatment. Syndromic approach is based on subjective judgement which may lead to misdiagnosis and mistreatment. This itself contributes to more ecowaste than implementing sophisticated diagnostic modalities. In our study, low aetiological diagnosis as compared to syndromic diagnosis could be attributed to physiological discharge and self-medications. However, since PCR-based diagnostic assays were used for testing of all the samples, the likelihood of missed diagnosis seems unlikely.

Our results emphasise that SCM is imprecise and results in treatment errors. In circumstances where treatment modality varies, as in case of rectal infections, syndromic approach may not be sufficient. Recent analyses have suggested a potential advantage of doxycycline compared to azithromycin as single-dose azithromycin may not lead to sustained drug concentrations capable of curing the extragenital infection. Thus, for rectal C. trachomatis infections, response to treatment is better with doxycycline and not azithromycin as suggested by SCM as per NACO guidelines.[16]

M. hominis is another aetiological agent which is not being adequately treated by SCM protocol of urogenital discharge since it is intrinsically resistant to azithromycin. Genitourinary infections with M. hominis require treatment with doxycycline. Unnecessary treatment in some patients and inadequate treatment in others will only add to the ever increasing burden of resistance. As evidenced by our previous study, intermediate level resistance to azithromycin and doxycycline was noted in 4% and 8% of isolates, respectively.[17] In view of changing antimicrobial susceptibility patterns, algorithms need to be regularly updated, appropriate for a given setting based on local aetiological and antimicrobial susceptibility data.

To conclude, in resource-poor countries which lack trained personnel and laboratory facilities, SCM remains a rational approach to STD care. However, its successful implementation requires regular evaluation of its algorithm. It should cover variables related to the aetiological agents for a given syndrome using highly sensitive and specific diagnostic techniques like NAATs and monitoring of antimicrobial susceptibility patterns at regular intervals. No single algorithm is appropriate for different settings. Hence, decision to adopt an algorithm should be setting specific considering the variation in STD epidemiology. The present data call for an early appraisal and review of the diagnostic policy by national authorities, and the introduction and/or strengthening of laboratory facilities, especially at the peripheral level. Tertiary care centres can periodically assess the burden of STIs in the community and also monitor antimicrobial resistance patterns using laboratory tests to determine strategies. This may avoid misuse of antibiotics and prevent the development of antimicrobial resistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 ~ References Top

1.
World Health Organization. Sexually Transmitted Infections: WHO/HIV_AIDS. Geneva: WHO; February, 2004. Available from: http://www.who.int/hiv/pub/sti/pub6/en/. [Last accessed on 2016 Dec 20].  Back to cited text no. 1
    
2.
National AIDS Control Organization. Operational Guidelines for Programme Managers and Service Providers for Strengthening STI/RTI Services. New Delhi, India: Ministry of Health and Family Welfare, Government of India; 2012. Available from: http://www.naco.gov.in/documents/operational-guidelines. [Last accessed on 2016 Dec 20].  Back to cited text no. 2
    
3.
National AIDS Control Organization. Ministry of Health and Family Welfare, Government of India. National Guidelines on Prevention, Management and Control of Reproductive Tract Infections Including Sexually Transmitted Infections. New Delhi, India: 2010. Available from: http://www.naco.gov.in/documents/operational-guidelines. [Last accessed on 2016 Dec 20].  Back to cited text no. 3
    
4.
Nessa K, Waris SA, Alam A, Huq M, Nahar S, Chawdhury FA, et al. Sexually transmitted infections among brothel-based sex workers in bangladesh: High prevalence of asymptomatic infection. Sex Transm Dis 2005;32:13-9.  Back to cited text no. 4
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5.
Díaz L, Cabrera LE, Fernández T, Ibáñez I, Torres Y, Obregón Y, et al. Frequency and antimicrobial sensitivity of Ureaplasma urealyticum and Mycoplasma hominis in patients with vaginal discharge. MEDICC Rev 2013;15:45-7.  Back to cited text no. 5
    
6.
World Health Organization. Laboratory Diagnosis of Gonorrhoea. WHO Regional Publication, South-East Asia Series No. 33. Geneva: WHO; 1999. Available from: http://www.w3.whosea.org/book33. [Last accessed on 2016 Dec 20].  Back to cited text no. 6
    
7.
Stellrecht KA, Woron AM, Mishrik NG, Venezia RA. Comparison of multiplex PCR assay with culture for detection of genital mycoplasmas. J Clin Microbiol 2004;42:1528-33.  Back to cited text no. 7
    
8.
Jensen JS, Uldum SA, Søndergård-Andersen J, Vuust J, Lind K. Polymerase chain reaction for detection of Mycoplasma genitalium in clinical samples. J Clin Microbiol 1991;29:46-50.  Back to cited text no. 8
    
9.
Mahony J, Chong S, Jang D, Luinstra K, Faught M, Dalby D, et al. Urine specimens from pregnant and nonpregnant women inhibitory to amplification of Chlamydia trachomatis nucleic acid by PCR, ligase chain reaction, and transcription-mediated amplification: Identification of urinary substances associated with inhibition and removal of inhibitory activity. J Clin Microbiol 1998;36:3122-6.  Back to cited text no. 9
    
10.
Gao X, Chen XS, Yin YP, Zhong MY, Shi MQ, Wei WH, et al. Distribution study of Chlamydia trachomatis serovars among high-risk women in China performed using PCR-restriction fragment length polymorphism genotyping. J Clin Microbiol 2007;45:1185-9.  Back to cited text no. 10
    
11.
World Health Organization. Guidelines for the Management of Sexually Transmitted Infections. Geneva: WHO Press; 2001. Available from: http://www.who.int/hiv/topics/vct/sw_toolkit/guidelines_management_sti.pdf. [Last accessed on 2016 Dec 20].  Back to cited text no. 11
    
12.
Ray K, Muralidhar S, Bala M, Kumari M, Salhan S, Gupta SM, et al. Comparative study of syndromic and etiological diagnosis of reproductive tract infections/sexually transmitted infections in women in Delhi. Int J Infect Dis 2009;13:e352-9.  Back to cited text no. 12
    
13.
Hawkes S, Morison L, Foster S, Gausia K, Chakraborty J, Peeling RW, et al. Reproductive-tract infections in women in low-income, low-prevalence situations: Assessment of syndromic management in Matlab, Bangladesh. Lancet 1999;354:1776-81.  Back to cited text no. 13
    
14.
Sonkar SC, Wasnik K, Kumar A, Mittal P, Saluja D. Comparative analysis of syndromic and PCR-based diagnostic assay reveals misdiagnosis/overtreatment for trichomoniasis based on subjective judgment in symptomatic patients. Infect Dis Poverty 2016;5:42.  Back to cited text no. 14
    
15.
Ryan CA, Holmes KK. Editorial: How should clinical algorithms be used for syndromic management of cervical and vaginal infections? Clin Infect Dis 1995;21:1456-8.  Back to cited text no. 15
    
16.
Kong FY, Tabrizi SN, Fairley CK, Vodstrcil LA, Huston WM, Chen M, et al. The efficacy of azithromycin and doxycycline for the treatment of rectal chlamydia infection: A systematic review and meta-analysis. J Antimicrob Chemother 2015;70:1290-7.  Back to cited text no. 16
    
17.
Saigal K, Dhawan B, Rawre J, Khanna N, Chaudhry R. Genital Mycoplasma and Chlamydia trachomatis infections in patients with genital tract infections attending a tertiary care hospital of North India. Indian J Pathol Microbiol 2016;59:194-6.  Back to cited text no. 17
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