CASE REPORT Rigour after treatment in a 55-year-old man

Patrick O’Byrne RN-EC PhD

he incidence of has increased, primarily among men who have sex with men. Syphilis presentation can be difficult to discern and might be missed, but should be suspected in persons who experience the classic Jarisch-Herxheimer reaction after treatment with b-lactam antibiotics. This case describes a 55-year-old male Tpatient with negative test results for HIV who presented to the clinic as a contact of a recent male sexual partner who was diagnosed with gonorrhea. This case suggests that ceftriaxone and azithromycin treatment of persons with unknown infectious syphilis infections might cause a classic posttreatment syphilis reaction (rigour that spontane- ously resolves). Patients should be informed to look for these Jarisch-Herxheimer reaction symptoms, and clinicians should assess for the symptoms of this reaction in patients who are at risk of syphilis.

Case Visit 1. A 55-year-old man presented to the sexually transmitted infection (STI) clinic after a recent casual male part- ner informed him he had been diagnosed with gonorrhea. The patient engaged in condomless receptive and penetra- tive oral and anal sex with this man. Table 1 provides a summary of the patient’s case. Review of systems: The patient was asymptomatic when he presented for care, but reported having had a painless genital lesion that was less than 1 cm2 approximately 4 to 6 weeks earlier; it resolved spontaneously after 7 to 10 days. The patient suspected the lesion was an “ingrown hair.” He denied rashes, hair loss, and mucous lesions. He denied current or recent rigour, fatigue, weight loss, , myalgia, arthralgia, headaches, and vision or hearing changes. Past medical history: The patient’s past medical history included insomnia, gastroesophageal reflux disease, and hypertension, for which he took trazodone, esomeprazole, and the telmisartan-amlodipine combination, respectively. He had been taking these drugs for longer than 12 months. He had started taking a fixed-dose combination of emtricitabine (200 mg) and tenofovir (300 mg) daily for HIV preexposure prophylaxis (PrEP) 5 months earlier.

Editor’s key points  The incidence of syphilis has increased, primarily among men who have sex with men. This article reviews the case of an asymptomatic 55-year-old man with negative test results for HIV who presented as a contact of a sexual partner with gonorrhea, experienced rigour after ceftriaxone and azithromycin administration, and was subsequently diagnosed with syphilis.

 Syphilis should be suspected in persons who experience the classic Jarisch-Herxheimer reaction (rigour that spontaneously resolves) after treatment with b-lactam antibiotics. The symptoms of Jarisch-Herxheimer reaction should be communicated to patients who are at risk of syphilis who receive treatment for gonorrhea with ceftriaxone and azithromycin. Patients should be instructed to return to the clinic for assessment if they experience these symptoms, and clinicians should consider providing empiric treatment while investigation results are pending.

 Clinicians should discuss HIV preexposure prophylaxis with patients diagnosed with syphilis, considering the elevated HIV seroconversion rates that frequently occur after this diagnosis. Points de repère du rédacteur  L’incidence de la syphilis a augmenté, surtout chez les hommes qui ont des relations sexuelles avec des hommes. Cet article passe en revue le cas d’un homme asymptomatique de 55 ans dont les résultats de dépistage du VIH étaient négatifs. Il avait consulté en raison d’un contact sexuel avec une personne atteinte de gonorrhée, et il a eu un frisson solennel à la suite de l’administration de ceftriaxone et d’azithromycine. Il a par la suite reçu un diagnostic de syphilis.

 Il y a lieu de suspecter la syphilis chez les personnes qui ont la réaction classique de Jarisch-Herxheimer (frisson solennel qui disparaît spontanément) après une thérapie aux antibiotiques β-lactame. Il faut expliquer les symptômes de la réaction de Jarisch-Herxheimer aux patients à risque de syphilis qui reçoivent un traitement pour la gonorrhée avec de la ceftriaxone et de l’azithromycine. Il faut aviser les patients qu’il faut revenir à la clinique pour une évaluation s’ils présentent de tels symptômes, et les cliniciens devraient envisager un traitement empirique en attendant les résultats de l’investigation.

 Les cliniciens devraient discuter de la prophylaxie préexposition au VIH avec les patients ayant reçu un diagnostic de syphilis, étant donné les taux élevés de séroconversion contre le VIH qui se produisent fréquemment après un tel diagnostic.

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Table 1. Case summary TIME PATIENT’S HISTORY AND ASSESSMENTS, PLANS, AND RESULTS Past medical history • Gonorrhea (no other previous STIs) • Negative test results for HIV • Taking HIV PrEP • Insomnia • GERD • Hypertension Visit 1 Assessment • Presented to clinic as a gonorrhea contact • Reported a painless 1-cm2 penile lesion about 4-6 wk earlier that resolved without marking • Asymptomatic at time of visit • Unremarkable findings on examination Plan • Tested for and gonorrhea (urine sample, oral and rectal swabs), HIV, and syphilis • Treated empirically for gonorrhea Results • Rectal gonorrhea detected • Syphilis testing: CMIA result reactive, RPR titre 1:4, TPPA result reactive Visit 2 (8 d after visit 1) Assessment • Asymptomatic • Reported rigour about 2 h after empiric gonorrhea treatment at visit 1 Plan • Syphilis stage determined as early latent; treatment administered • Repeated syphilis serology Results • Syphilis testing: CMIA results reactive, RPR titre 1:8, TPPA results reactive Follow-up • Reported same rigour about 2 h after treatment CMIA—chemiluminescent microparticle immunoassay, GERD—gastroesophageal reflux disease, PrEP—preexposure prophylaxis, RPR—, STI—sexually transmitted infection, TPPA— pallidum passive particle agglutination assay.

The patient had similarly presented to the STI swabs and urine for gonorrhea and chlamydia testing, clinic 5 months previously as a contact of a gon- as well as blood for HIV and syphilis testing. As the orrhea case and was treated with 1 intramuscular patient was a contact of a gonorrhea case, this same dose of 250 mg of ceftriaxone (reconstituted with provider treated the patient in the clinic with 1 intra- 0.9 mL of 1% lidocaine) plus 1 oral dose of 1 g of muscular dose of 250 mg of ceftriaxone (reconstituted azithromycin.1,2 This treatment was administered with 0.9 mL of 1% lidocaine) plus 1 oral dose of 1 g at the clinic. He experienced no reaction after treat- of azithromycin.1,2 The patient remained in the clinic ment (both immediately after treatment and during after the injection without reaction. the following day): no nausea, no emesis, no diar- A fourth-generation antigen-antibody combination rhea, and no rigour. His test results at that time assay was used for HIV testing.3 Syphilis testing was were negative for gonorrhea and chlamydia (urine done using the reverse screening algorithm, starting nucleic acid amplification testing [NAAT], and pha- with a chemiluminescent microparticle immunoassay ryngeal and rectal cultures). He did not undergo (CMIA), followed by a rapid plasma reagin (RPR) test serology testing at the clinic, but had documented and a passive particle agglutina- negative HIV and syphilis test results from this time. tion assay (TPPA) for samples with positive screening On examination: The patient was afebrile and had results.4,5 Gonorrhea and chlamydia samples under- no perceptible rashes on his hands, feet, or trunk. His went NAAT.6-8 Of note, between the patient’s previous cervical nodes were not palpable or tender; he had no and current presentation for care, in Ontario, NAAT for oral lesions or erythema. He had no palpable inguinal extragenital samples was validated by the Public Health nodes or tenderness, and no lesions, erythema, or Ontario laboratory. This occurred owing to a greater tenderness of his penis or genital area; no urethral dis- than 2-fold increase in sensitivity of NAAT compared charge was present. He had no scrotal lesions or tes- with culture, and because the test swabs required were ticular tenderness. He had no external anal erythema, reduced from 2 swabs to 1. Moreover, extragenital test- lesions, or discharge. Anoscopy was not performed. ing is done with the same type of swab used for endo- Plan: The nurse practitioner who saw this patient cervical gonorrhea and chlamydia testing and is thus at his initial visit collected pharyngeal and rectal likely more readily available in many clinics.

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Test results: The patient had negative results for to mass release of lipoproteins from destroyed bacteria HIV, pharyngeal and urine gonorrhea and chlamydia, that induce rigour, myalgia, arthralgia, and headache.9 and rectal chlamydia. His rectal gonorrhea test result The Jarisch-Herxheimer reaction is not a hypersensitiv- was positive. For syphilis, the CMIA result was reac- ity, and the patient does not need to avoid . No tive, the RPR titre was 1:4, and the TPPA result was treatment is required, although antipyretics can allevi- reactive. The STI clinic nurses contacted the patient ate symptoms.2 Systemic corticosteroids can be used for and requested that he return to the clinic. severe reactions, but only with expert consultation.2 The postulation here is that this patient experienced Visit 2. On returning to the clinic 8 days after the first such a reaction after receiving treatment for gonor- visit, the patient was asymptomatic. To determine the rhea with a cephalosporin and macrolide. This is fitting, need for gonorrhea re-treatment, I inquired if he had had seeing as cephalosporins have a similar mechanism issues with treatment. He denied nausea, emesis, and of action to penicillin,10 and because these 2 medica- diarrhea, and he denied sexual contact with untreated tions can cure syphilis, although in higher doses and partners. He reported rigour about 2 hours after receiv- for a longer duration than what this patient received.1,2 ing gonorrhea treatment; rigour lasted less than 12 hours It is possible that such a reaction occurred here from and resolved spontaneously. He denied rashes, mucosal a subtherapeutic dose of these drugs. Supporting this irritation and pain, myalgia, and arthralgia. He denied assertion is that the patient had a similar reaction when experiencing such symptoms when he was treated treated with benzathine penicillin G. empirically for gonorrhea 5 months earlier. One similar case report exists. In this other case, the I repeated the syphilis bloodwork, determined the patient was an HIV-positive 32-year-old man who, simi- patient’s stage of infectious syphilis (early latent phase lar to this case, was diagnosed with rectal gonorrhea, was owing to no symptoms, a confirmed negative result 5 treated with ceftriaxone and azithromycin, and experi- months earlier, and no known contacts with any sexual enced rigour 6 hours later.11 The patient returned to the partners recently diagnosed with infectious syphilis). I clinic with a classic syphilis rash and received treatment for treated him with 1 intramuscular dose of 2.4 million syphilis. Serology results supported the syphilis diagnosis. units of benzathine penicillin G.1,2 He tolerated the injec- Another possible explanation for this patient’s symptoms tion well and had no reactions during the 15 minutes is HIV seroconversion,2 although this is unlikely based on he remained in the clinic. Interestingly, he reported a his use of HIV PrEP, which can prevent HIV transmission in similar Jarisch-Herxheimer–like reaction after this treat- more than 90% of those who take it.12 The patient’s symp- ment as well. Patients who receive more than 1 dose toms might also have been the result of an unrelated con- of antibiotics for syphilis typically only experience the comitant viral infection (eg, influenza), although the timing Jarisch-Herxheimer reaction with the first treatment; it is and duration of symptoms makes this unlikely. Likewise, possible that the second reaction occurred in this case drug-drug interactions are an unlikely cause of the patient’s because, in the first instance, the nurse practitioner had symptoms, as the only possible interaction is a category C not actually treated him for syphilis. Instead, the nurse interaction between azithromycin and trazodone (poten- practitioner had treated him for gonorrhea, and poten- tial corrected QT interval prolongation),13 and he had no tially induced this reaction with a dose of medication flulike reaction with concurrent use of these medications 5 that was appropriate for gonorrhea but subtherapeutic months previously. The patient’s reaction might also have for syphilis. It is thus possible that he experienced the been a Jarisch-Herxheimer reaction to a different spirochete, Jarisch-Herxheimer reaction twice. such as burgdorferi, which is prevalent locally.14 No Syphilis bloodwork from this second visit revealed testing was done to rule out , so this infection reactive CMIA results, an RPR titre of 1:8, and reactive is possible, although the patient did not have any related TPPA results, supporting the diagnosis of infectious symptoms including or neurologic find- syphilis. The change in syphilis titre might suggest the ings.15 As I work in an STI clinic, testing for Lyme disease is infection was primary (with a possible in an not available. Instead, I encouraged the patient to follow up undetected location such as the rectum); however, it with his family physician for further assessment. might also be normal laboratory variation in the mea- surement of a serofast state. Recommendations for practice This case highlights 3 points. The first is the need for clini- Discussion cians to include syphilis in the differential diagnosis of oral, It is possible this patient experienced a Jarisch-Herxheimer genital, and perianal lesions.1,2 This is particularly impor- reaction, which is common after treatment of spirochete tant owing to increasing rates of syphilis, primarily among infections (eg, syphilis, , pinta, Lyme disease).1,2,9 men who have sex with men.16,17 In such cases, it is ideal This reaction typically starts 2 hours after treatment and to consider (and provide) empiric treatment at the point resolves within 24 hours; it can occur during any stage of care, plus appropriate testing including serology and of syphilis.1,2,9 It is hypothesized that this reaction is due the consideration of direct fluorescent antibody (DFA) or

114 Canadian Family Physician | Le Médecin de famille canadien } Vol 65: FEBRUARY | FÉVRIER 2019 CASE REPORT polymerase chain reaction (PCR) testing of syphilitic as a contact of a gonorrhea case, experienced rigour after lesions.1,2 Specifically, DFA and PCR testing involve speci- ceftriaxone and azithromycin administration, and was sub- men collection from a potential syphilitic lesion, whether sequently diagnosed with syphilis. This case supports a pre- a chancre, condyloma latum, or mucous patch. When vious case report of a similar situation,11 and highlights that results are positive, DFA and PCR confirm the presence of clinicians should inform patients about Jarisch-Herxheimer syphilis organisms. Of note, DFA and PCR testing of syphi- reaction symptoms and consider these symptoms as indica- lis lesions can detect primary infection before the develop- tors of syphilis in otherwise asymptomatic patients. Finally, ment of systemic markers that can be detected in serology. clinicians should discuss HIV PrEP with patients diagnosed Second, the symptoms of Jarisch-Herxheimer reaction with syphilis, considering the elevated HIV seroconversion should be communicated to patients who are at risk of rates that occur after this diagnosis. This helps ensure com- syphilis who receive treatment for gonorrhea with ceftriax- prehensive sexual health service provision. one and azithromycin. This involves explicitly listing these Dr O’Byrne is Associate Professor in the School of Nursing at the University of Ottawa symptoms to patients at the time of treatment as part of in Ontario and a nurse practitioner at the Sexual Health Clinic in Ottawa. reviewing posttreatment precautions (eg, reviewing the Competing interests None declared symptoms of anaphylaxis, recommending avoiding sexual Correspondence activity until no longer infectious, recommending avoiding Dr Patrick O’Byrne; e-mail [email protected] sexual contact with untreated partners). Patients should be References 1. Centers for Disease Control and Prevention. 2015 Sexually transmitted diseases treatment instructed to return to the clinic for assessment if they expe- guidelines. Atlanta, GA: Centers for Disease Control and Prevention; 2015. Available from: rience Jarisch-Herxheimer–like symptoms, and clinicians www.cdc.gov/std/tg2015/default.htm. Accessed 2018 Sep 13. 2. Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections. Ottawa, should consider providing empiric treatment while inves- ON: Government of Canada; 2018. Available from: www.canada.ca/en/public-health/services/ infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/sexually- tigations are pending for patients with these symptoms. transmitted-infections.html. Accessed 2018 Sep 13. 11 3. Public Health Ontario. HIV—diagnostic serology. Toronto, ON: Ontario Agency for Health Protection This approach aligns with the previous case report, in and Promotion; 2016. Available from: www.publichealthontario.ca/en/ServicesAndTools/ which the clinicians aptly suspected and empirically treated LaboratoryServices/Pages/HIV_Diagnostic_Serology.aspx. Accessed 2018 Sep 13. 4. Public Health Ontario. Syphilis—serology. Toronto, ON: Ontario Agency for Health Protection and syphilis based on the patient’s risk factors for syphilis plus Promotion; 2017. Available from: www.publichealthontario.ca/en/ServicesAndTools/ LaboratoryServices/Pages/Syphilis_Screen_Serology.aspx. Accessed 2018 Sep 13. a Jarisch-Herxheimer–like reaction after receiving ceftriax- 5. Public Health Ontario. Syphilis (Treponema pallidum) serologic testing update—changes to one and azithromycin treatment for gonorrhea. Similarly, screening test and algorithm. Toronto, ON: Ontario Agency for Health Protection and Promotion; 2017. Available from: www.publichealthontario.ca/en/eRepository/LAB_SD_057_Syphilis_ clinicians who examine patients who were recently treated Treponema_pallidum_serology_testing.pdf. Accessed 2018 Sep 13. 6. Public Health Ontario. /Neisseria gonorrhoeae (CT/GC)—nucleic acid with these medications should also explicitly inquire about amplification testing (NAAT)—urine. Toronto, ON: Ontario Agency for Health Protection and Promotion; 2018. Available from: www.publichealthontario.ca/en/ServicesAndTools/ Jarisch-Herxheimer reaction symptoms, and not assume LaboratoryServices/Pages/Chlamydia_trachomatis_NAAT_Urine.aspx. Accessed 2018 Sep 13. that patients would necessarily report such symptoms with- 7. Public Health Ontario. Chlamydia trachomatis and Neisseria gonorrhoeae—sensitivity and speci- ficity of the Hologic Aptima Combo 2 assay. Toronto, ON: Ontario Agency for Health Protection and out explicit inquiry. Although the patient in this case volun- Promotion; 2018. Available from: www.publichealthontario.ca/en/eRepository/LAB_SD_005_ Chlamydia_and_gonorrhoeae_sensitivity_specificity_GenProbe.pdf. Accessed 2018 Sep 13. teered this information without being precisely asked about 8. Public Health Ontario. Chlamydia trachomatis and Neisseria gonorrhoeae—implementation of nucleic the symptoms of this reaction, he only provided this infor- acid amplification testing (NAAT) for rectal and pharyngeal sites. Toronto, ON: Ontario Agency for Health Protection and Promotion; 2018. Available from: www.publichealthontario.ca/en/eRepository/ mation once I inquired if he had experienced any symptoms LAB_SD_128_CT_GC_NAAT_Rectal_Pharyngeal_Implementation.pdf. Accessed 2018 Sep 13. 9. Singh AE, Romanowski B. Syphilis: review with emphasis on clinical, epidemiologic, and some after his gonorrhea treatment. This highlights the need for biologic features. Clin Microbiol Rev 1999;12(2):187-209. 10. Petri WA Jr. , cephalosporins, and other b-lactam antibiotics. In: Brunton LL, Chabner clinicians to positively review these symptoms. BA, Knollman BC, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. Third, although less applicable to this case because 12th ed. New York, NY: McGraw-Hill; 2011. p. 1477-504. 11. Chan DJ, Michelmore HM, Gold J. A diagnosis unmasked by an unusual reaction to ceftriaxone the patient was already taking HIV PrEP, syphilis is an therapy for gonorrhoeal infection. Med J Aust 2003;178(8):404-5. 12. Tan DHS, Hull MW, Yoong D, Tremblay C, O’Byrne P, Thomas R, et al. Canadian guideline established risk factor for HIV acquisition, meaning that on HIV pre-exposure prophylaxis and nonoccupational postexposure prophylaxis. CMAJ a syphilis diagnosis should signal clinicians to ensure 2017;189(47):E1448-58. Erratum in: CMAJ 2018;190(25):E782. 13. Lexicomp Online [database]. Interactions. Hudson, OH: Wolters Kluwer Clinical Drug Information. HIV testing is performed and, if test results are negative 14. Ottawa Public Health. Lyme disease. Ottawa, ON: Ottawa Public Health. Available from: www.ottawa publichealth.ca/en/professionals-and-partners/hcp-lyme-disease.aspx. Accessed 2018 Sep 13. for HIV, to consider HIV PrEP. In the existing PrEP stud- 15. Wright WF, Riedel DJ, Talwani R, Gilliam BL. Diagnosis and management of Lyme disease. Am 18 Fam Physician 2012;85(11):1086-93. ies, seroconversion rates within 12 months of syphilis 16. Centers for Disease Control and Prevention. 2016 Sexually transmitted diseases surveillance. diagnosis ranged between 1 in 20 and 1 in 30 persons.19,20 Syphilis. Atlanta, GA: Centers for Disease Control and Prevention; 2017. Available from: www.cdc. gov/std/stats16/syphilis.htm. Accessed 2018 Sep 13. Data from Vancouver, BC, also found elevated HIV inci- 17. Choudhri Y, Miller J, Sandhu J, Leon A, Aho J. Infectious and congenital syphilis in Canada, 2010- 2015. Can Commun Dis Rep 2018;44(2):43-8. dence after syphilis diagnosis (3.6 per 100 person-years), 18. Peterman TA, Newman DR, Maddox L, Schmitt K, Shiver S. High risk for HIV following syphilis which increased to 17 per 100 person-years for patients diagnosis among men in Florida, 2000-2011. Public Health Rep 2014;129(2):164-9. 19. Pathela P, Braunstein SL, Blank S, Shepard C, Schillinger JA. The high risk of an HIV diagnosis with concurrent gonorrhea and syphilis diagnoses.21 Thus, following a diagnosis of syphilis: a population-level analysis of New York City men. Clin Infect Dis 2015;61(2):281-7. Epub 2015 Apr 13. nearly 1 in 5 such persons would acquire HIV within 12 20. Solomon MM, Mayer KH, Glidden DV, Liu AY, McMahan VM, Guanira JV, et al. Syphilis predicts HIV incidence among men and transgender women who have sex with men in a preexposure months of this presentation, highlighting the importance prophylaxis trial. Clin Infect Dis 2014;59(7):1020-6. Epub 2014 Jun 13. of PrEP for such patients. Recent Canadian guidelines12 21. Hull M, Edward J, Kelley J; on behalf of The Network. PEP/PrEP update—a BC case study [webi- nar]. Toronto, ON: CATIE; 2017. Available from: www.catie.ca/sites/default/files/pep-prep-bc- detail how to provide this intervention. casestudy-03272017.pdf. Accessed 2019 Jan 6.

Conclusion This article has been peer reviewed. This article reviews the case of an asymptomatic 55-year- Cet article a fait l’objet d’une révision par des pairs. old man with negative test results for HIV who presented Can Fam Physician 2019;65:112-5

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