PRACTICE | CASES CPD

Fatal respiratory in a visitor to Canada

Scott Cholewa MA BHSc DPA, Fareen Karachiwalla MD MPH, Sarah E. Wilson MD MSc, Jeya Nadarajah MD MSc, Julianne V. Kus PhD MSc n Cite as: CMAJ 2021 January 4;193:E19-22. doi: 10.1503/cmaj.200707

69-year-old visitor to Canada from India presented to hospital with acute respiratory distress 48 hours after KEY POINTS arrival. The patient reported sore throat, hoarse voice • Although uncommon, cases of classic, toxin-producing andA dry cough, which had developed on departure from India respiratory diphtheria still occur in Canada and should be and progressed over 48 hours to , fever and included in the differential diagnosis for people with acute diaphoresis. The patient was otherwise healthy and had no ill respiratory illness who have recently arrived from a diphtheria- contacts, but was not up to date with routinely administered endemic country or are inadequately protected through immunization. vaccines. On review in a telemedicine clinic, the patient was advised to • Respiratory diphtheria is a medical emergency requiring administration of antitoxin and antimicrobial . present to the emergency department immediately, where they Local management of diphtheria cases involves were noted to have a slightly swollen neck, no palpable lymph • contact tracing and may require administration of postexposure nodes and no stridor. They reported a feeling of something stick- prophylaxis and immunization. ing in their throat, although obstruction was not noted. A neck • Toxigenic diphtheria is vaccine preventable. Those born in radiograph showed prominent prevertebral soft tissue swelling. Canada, newcomers to Canada and those planning to travel to A chest radiograph showed left lower lobe consolidation. We areas where diphtheria continues to circulate should ensure diagnosed possible , with concomitant bacterial pneu- their immunizations are up to date. monia, and as per local guidelines, gave the patient ceftriaxone and oseltamivir. We admitted the patient, and over the next 48 hours, they progressively deteriorated to hypoxemic respira- Although final confirmation that this was a diphtheria toxin– tory failure and acute respiratory distress syndrome, which was producing strain (via the modified Elek test) was still pend- ultimately fatal. ing, the National Microbiology Laboratory advised that the Results of the following tests were negative: blood samples majority of tox gene–positive isolates are toxin producers.1 for culture, nasopharyngeal swab for respiratory virus culture Given this, together with the patient’s clinical history and (adenovirus, influenza A and B, human metapneumovirus and epidemiologic information, we decided to initiate contact respiratory syncytial virus), and Legionella urine antigen. After tracing. Diphtheria toxin production was reported 6 days the patient died, the endotracheal sputum culture we sent at the after the positive PCR result. time of intubation was reported to show pure, light growth of Contact tracing was made possible through a collaboration “coryneform” bacteria. “Coryneform” or “diphtheroid” bacteria between local public health and the hospital’s preven- cultured from nonsterile sites are typically considered commen- tion and control department, with support provided by Public sal flora of little clinical significance. However, given it was a pure Health Ontario and the Public Health Agency of Canada. Four culture, we began further investigations. household members were identified, along with 7 health care Matrix-assisted laser desorption/ionization time-of-flight workers who may have been exposed to oropharyngeal secre- mass spectrometry (MALDI-TOF MS) identified the bacteria as tions in the absence of personal protective equipment. All con- Corynebacterium diphtheriae. As this microorganism is rarely tacts were advised of the exposure; assessed for any signs and encountered in most Canadian laboratories, we forwarded symptoms; swabbed with both a nasopharyngeal and throat the isolate to the provincial and national reference labora­ swab for bacterial specimens; given antimicrobial chemoprophy- tories for identification and toxin testing. The isolate was laxis (erythromycin); immunized, if they were not up to date with confirmed — by polymerase chain reaction (PCR) at the relevant vaccine; and excluded from school and health care set- National Microbiology Laboratory — to have the tox gene, tings until culture results were available. Secondary transmission which confers the ability to produce diphtheria toxin. was ruled out among all contacts.

© 2021 Joule Inc. or its licensors CMAJ | JANUARY 4, 2021 | VOLUME 193 | ISSUE 1 E19 PRACTICE E20 per 100 000 population ( 0.03 cases from about100casesper100 000populationin1924to Nationally, theincidenceoftoxigenicdiphtheriahasdeclined immunization programsthatwereintroducedinthe1920s. Diphtheria isuncommoninCanada,owingtothesuccessof Epidemiology ness, andtopromotevaccinationacrossthelifespan. recently arrivingfromendemicareaswithacuterespiratoryill- clinicians toconsider this diagnosis,particularlyinpeople present in Canada. This case serves as an important reminder to gencies — such as toxin-producing, respiratory diphtheria — to opportunities foruncommonmedicalandpublichealthemer- Increased globaltravelandgrowingvaccinehesitancypresent Discussion diphtheria occurredin1995. and inOntario,thelastreportedcaseoftoxigenicrespiratory most recent fatalcase inaCanadian resident occurred in2010, (e.g., hospitals, community clinics) Health care Sector Box 1:Roles andresponsibilities for toxigenic diphtheriafollow-up (e.g., local, provincial, national) Public health Microbiology Laboratory)Microbiology reference laboratory, National Laboratory (e.g.,front-line, provincial 3 n Roles andresponsibilities • • • • • • • • • • • • = 10 cases) in 2017. • • • • Provincial publichealth(e.g.,MinistryofHealth,PublicHealthOntario): • • • • • Local publichealth: Support follow-upofanyhealthcareworkersidentifiedasclosecontactswhorequirecontactmanagement Support assessingclosecontacts(viacollectionofnasopharyngealandthroatswabs) Institute appropriateinfectionpreventionandcontrolmeasures Report promptlytolocalpublichealth Provide promptdiagnosisandtreatment All levels:Provideadviceregardingtesting, turnaroundtimes,interpretation • National MicrobiologyLaboratory: • • Provincial referencemicrobiologylaboratories: • Front-line laboratories: • • National publichealth(e.g.,PublicHealthAgencyofCanada): CMAJ Coordinate notificationtoPublicHealthAgencyofCanada,asneeded Conduct provincialdiseasesurveillance Provide adviceorconsultationtolocalpublichealth Coordinate accesstodiphtheriaantitoxin Lead communitymessaging,ifrequired Lead communitycontactmanagement Support collectionofswabsandimmunizationcontacts Conduct localsurveillance Begin contactmanagementimmediately diphtheria toxin gene; iftoxPCRispositive,performamodified Elektesttodefinitivelyshowthattheisolateproduces Perform Process primarysamplestoculturespecifically forC.diphtheriaewhensuspected(e.g.,contactsofacase) National MicrobiologyLaboratory Confirm identification,andifdeterminedtobeCorynebacteriumdiphtheriae , submitisolateto Process primaryspecimensandprovidepreliminaryidentification Liaise withothernationalgovernmentsforcontacttracinginhomecountry, asneeded Conduct nationalsurveillanceactivities | JANUARY 4, 2021 -gene polymerase chain reaction testing (PCR) to determine if isolate possesses the toxin tox-gene polymerasechainreactiontesting (PCR)todetermineifisolatepossessesthetoxin 2 The | VOLUME 193 opathy andmyocarditis. culosis). rarely, byothertoxigenicspecies(C.ulceransandC.pseudotuber- strains ofthegram-positivebacteriaC.diphtheriaeor,more ducing ornot.Respiratorydiphtheriaiscausedbytoxigenic (e.g., cutaneousversusrespiratory)andwhetheritistoxinpro- types. Itisclassified according to bothanatomicsiteofinfection Diphtheria isadiseasewithrangeofclinicalmanifestationsand Clinical presentationandacutemanagement genic isdeterminedbythepresenceoftox sic respiratorydiphtheriais5%–10%. a “bullneck.” lymph nodes,anteriorneckandsubmandibulararea,resembling tonsils andsignificantswellingoftheuvula,tonsils,cervical respiratory diphtheria include a greyish-white membrane on the and acuterespiratorydistress. cervical lymphnodes,progressingtoupperairwayobstruction typically includefever,,hoarsevoiceandenlarged Complications oftoxindisseminationincludeperipheralneur 4 Initialsymptomsofpharyngealortonsillardiphtheria 5 | ISSUE 1 6 Theestimatedcasefatalityrateofclas- 4 Twoclassicsignsoftoxigenic 5 Whetherastrainistoxi- gene, ascertained gene, ascertained ­ PRACTICE ​ :​ 18 In ; E21 /2019​ 11,12 2018 associ- 301. Avail-

11 296- 45: 2019; BMC Infect Dis However, in this spe- this in However, 3,8 Increase in detection of corynebacterium Can Commun Dis Rep et al. , T - are defined as house Close contacts Recent case reports have documented documented have case reports Recent Burdz 8 Severe diphtheria with neurologic and myocardial Severe diphtheria with neurologic and myocardial In a case report of respiratory diphtheria, diphtheria, In a case report of respiratory . AL, J 11,12 ISSUE 1 ISSUE Tham | Pacheco , (accessed 2019 https://diseases.canada.ca/notifiable/charts?c=pl (accessed 2019 S DL, editor. Control of communicable diseases manual. 20th ed. Washington KA, www.canada.ca/content/dam/phac-aspc/documents/services/reports http://health.gov.on.ca/en/pro/programs/publichealth/oph_standards/ report. case a patient: Swedish a in involvement diphtheriae in Canada: 2006–2019. able: 359. Skogmar Bernard -publications/canada-communicable-disease-report-ccdr/monthly-issue​ -45/issue-11-november-7-2019/ccdrv45i11a04-eng.pdf (accessed 2019 Dec. 14). Reported cases from 1924 to 2018 in Canada — notifiable diseases on-line [data file]. Ottawa: Public Health Agency of Canada; modified 2020 Aug. 11. Available: Dec. 15). Infectious diseases protocol — Appendix A: Disease-specific chapters. Chapter: Diphtheria. Toronto: Ministry of Health and Long-Term Care; 2019:1-13. Avail- able: docs/diphtheria_chapter.pdf (accessed 2019 Dec. 15). Heymann (DC): American Public Health Association; 2014. Diphtheria: for health professionals. Ottawa: Public Health Agency of Canada; modified 2018 June 21. Available: www.canada.ca/en/public-health/services/ immunization/vaccine-preventable-diseases/diphtheria/health-professionals. html (accessed 2019 Dec. 7). Lastly, we considered how to manage close contacts Lastly, we considered This fatal case is a reminder that diphtheria, endemic in many endemic that diphtheria, reminder is a fatal case This

. . . patients presenting with respiratory distress, clinicians should clinicians should patients presenting with respiratory distress, recent among particularly diphtheria, of diagnosis the consider Immunization sta- travellers or immigrants from endemic areas. should be assessed to tus of newcomers and frequent travellers of increasing vaccine ensure individuals are up to date. In a time presentations of long- hesitancy and extensive global movement, be ignored. forgotten diseases such as diphtheria cannot secondary transmission of cutaneous and respiratory toxigenic toxigenic and respiratory transmission of cutaneous secondary swabbing detected through to close contacts, C. diphtheriae before chemoprophylaxis. contact had close face-to-face persons who have hold members, workers and health care such as intimate contact to a case secretions from the case, following exposed to oropharyngeal - contact management for invasive menin the same principles as gococcal disease. References 1 2. 3. 4 5. 6 cific case, the patient sat beside their spouse in the window spouse in the window cific case, the patient sat beside their additional no yielded this so side, other the on one no with seat, the case to India via contacts. We sent formal notification about other close contacts the Public Health Agency of Canada. No were identified in India. any time in Canada. parts of the world, can present itself at described countries have nonendemic case reports from Recent diphtheria among both toxigenic respiratory and cutaneous and refugees. returning travellers, visitors, immigrants further transmission. further subsequent transmission from an asymptomatic carrier was from an asymptomatic carrier was subsequent transmission contact follow-up activities. identified after additional - flight to Canada. Both meningococ ated with the international - are associated with droplet transmis cal disease and diphtheria guidance in this area, we followed the sion. With limited for cases of invasive meningococcal approach taken in Canada have travelled by air, which is to ensure disease in people who either side of the case contact tracing for passengers sitting on hours. 8 than more lasting rides plane on VOLUME 193 VOLUME |

1 icians C. diph- 7 provides 8 JANUARY 4, 2021 JANUARY | CMAJ 9,10 e isolates are relatively infrequent in Can- infrequent diphtheriae isolates are relatively C. Although all close contacts were asymptomatic, con- 3 ia in marginalized populations in both Canada and else- In our case, the timelines associated with culture identifica- and toxigenicity after a full incubation period (10 d) had theriae and toxigenicity after a full incubation period (10 d) had passed. tion and subsequent confirmation of toxigenicity presented tion and subsequent confirmation of toxigenicity presented public health challenges. The clinical and local public health of presence the confirming results the received teams tact management activities were carried out because of the pos- sibility of an asymptomatic carrier state, a possible source of

In Canada, the public health management of toxigenic diphtheria In Canada, the public health management a coordin­ and requires transmission further prevent critical to is ­ ated response (Box 1), including facilitation of access to diph and contact follow-up theria antitoxin, contact identification and nasopharyngeal status, immunization of assessment (i.e., - transmis secondary of evidence early out rule to swabs throat are positive, follow- sion and chemoprophylaxis). If initial swabs the cessation of anti­ up cultures taken at least 24 hours after ring of contact microbial therapy are required, and an expanded health public Although considered. be to need may identification required only for toxi- management of close contacts is typically local public health genic diphtheria, it is not uncommon for of C. diphtheriae authorities to receive reports of identification Follow-up This results are available. culture several days before toxigenicity public health actions challenges the timeliness of implementing in the event toxigenicity is confirmed. One UK guideline Although clinical microbiology laboratories, ada, changes in front-line - MALDI-TOF MS, may help to increase iden including adoption of - This is summarized in a 2019 publica tification of these isolates. 1200% increase in referrals to the National tion that described a for toxin testing between 2006 and 2019 Microbiology Laboratory (from 8 per yr to about 180 per yr). Most isolates were taken from 8% were toxigenic. cutaneous, not respiratory, sites, and only can access diphtheria antitoxin by contacting public health contacting public health antitoxin by can access diphtheria this coordinates Health of Ministry the Ontario, In departments. supply of diphtheria antitoxin. function, with a centralized Diagnosis by using PCR and, if positive, confirmation that diphtheria toxin is diphtheria that confirmation if positive, PCR and, by using respiratory Toxigenic test. Elek modified the using expressed, anti- requiring both diphtheria is a medical emergency diphtheria laboratory for waiting without therapy, antimicrobial and toxin of management and monitoring Careful airway confirmation. clin­ is essential. Canadian neurologic function ­cardiac and Despite increased microbiological detection, classic respiratory respiratory classic detection, microbiological increased Despite in Canada. toxigenic diphtheria remains uncommon more specific guidance on contact tracing before toxigenicity more specific guidance on contact tracing before toxigenicity the of severity clinical the on depending available, are results index case, epidemiologic risk factors that increase the likeli- hood of toxigenicity (for example, travel) and the estimated time to definitive laboratory results. Nontoxigenic diphtheria is not reportable in Canada and typically does not require contact follow-up, although clusters of nontoxigenic cutaneous diph­ ther­ where are well described. PRACTICE E22 9 8. 7. . lished and agreed to be accountable for all aspects of the work. lished andagreedtobeaccountableforallaspectsofthework. tant intellectual content, gave final approval of the version to be pub drafting the manuscript. All of the authors revised it critically forimpor- the conceptionanddesignofwork.Allauthorscontributedto Contributors: ScottCholewaandFareenKarachiwallacontributedto (Wilson), Toronto,Ont. University, Kingston,Ont.;InstituteforClinicalEvaluativeStudies, ment ofFamilyMedicine,SchoolMedicine(Karachiwalla),Queen’s of Toronto;PublicHealthOntario(Wilson,Kus),Toronto,Ont.;Depart- Department ofLaboratoryMedicineandPathobiology(Kus),University Health (Karachiwalla,Wilson),andFacultyofMedicine(Nadarajah), Municipality ofYork,Newmarket,Ont.;DallaLanaSchoolPublic Affiliations: PublicHealthBranch(Cholewa,Karachiwalla),Regional The authorshaveobtainedconsentfromthepatient’snextofkin. This articlehasbeenpeerreviewed. Competing interests:Nonedeclared. Lowe _Guidelines_Final.pdf (accessed2019Dec.15). government/uploads/system/uploads/attachment_data/file/774753/Diphtheria Health England;2015:1-47.Available:https://assets.publishing.service.gov.uk/ of diphtheria(inEnglandandWales):2015guidelines.London(UK):Public Diphtheria GuidelinesWorkingGroup.Publichealthcontrolandmanagement -professionals.pdf (accessed2019Dec.15). ca/en/pro/publications/disease/pdf/2015-05-22-diphtheria-guide-health-care​ Ministry ofHealthandLong-TermCare;2015.Available:www.health.gov.on. Diphtheria guideforhealthcareprofessionals.Toronto:PublicHealthDivision, 2011; lation ofVancouver,BritishColumbia,Canada:a10-yearreview. 49: CF, 2664- Bernard 6 . KA, Romney MG. Cutaneous diphtheriaintheurbanpoorpopu- CMAJ | JANUARY 4, 2021 J ClinMicrobiol - ​

| VOLUME 193 Correspondence to:ScottCholewa,[email protected] tre, PublicHealthOntarioandtheNationalMicrobiologyLaboratory. ogy Laboratory;andlaboratorystaffatHamiltonHealthSciencesCen- Hamilton HealthSciencesCentre;KathrynBernard,NationalMicrobiol- Candace Wong,YorkRegionPublicHealth;Dr.DeborahYamamura, tina Cuillerier,ThomasLo,AndreaMain,MarjolynPritchardand the followingindividuals:Dr.MichelleMurti,PublicHealthOntario;Mar- Acknowledgements: Theauthorsacknowledgethecontributionsof tions aremade.See:https://creativecommons.org/licenses/by-nc-nd/4.0/ mercial (i.e.,researchoreducationaluse),andnomodificationsadapta- provided thattheoriginalpublicationisproperlycited,usenoncom- licence, whichpermitsuse,distributionandreproductioninanymedium, with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) Content licence: This is anOpenAccessarticle distributed inaccordance up wasfromexistingorganizationaloperatingbudgets. Funding: Fundingforthiscaseinvestigationandpublichealthfollow- 11. 10. 12. Edwards genic infection,German,2016–2017.EmergInfectDis2018;24:1239-45. Dangel Jané United Kingdom,2017.EuroSurveill2018;23:1700681. diphtheriae byafullyimmunisedresidentreturningfromvisittoWestAfrica, interval, Catalonia,Spain,2015.EuroSurveill2018;23:17-00183. contact tracingresultsandconsiderationsfollowinga30-yeardisease-free M , A, Vidal D, Berger Kent | ISSUE 1 MJ, A, D, Camps Konrad Lester N C, R, , et al. et al. et al. Transmission oftoxigenicCorynebacterium A caseofrespiratorytoxigenicdiphtheria: Geographically diverseclustersofnontoxi-