Legionellosis. Legionnaires Disease Pontiac fever Rare non pneumonic infections 10/04/2015. Nonmotile replicative phase inside amoebae

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1 Legionellosis Legionnaires Disease Pontiac fever Rare non pneumonic infections Planktonic flagellated virulent transmissive Nonmotile replicative phase inside amoebae 1

2 Biofilm in plumbing system 2

3 Clin Micro Rev 2015;28: Environment Human Host 3

4 NEJM N Engl J Med 1977; 297: Broad Street Broad Street 1977; 297: Community acquired and nosocomial Mostly sporadic and occasionally outbreaks Often severe and life threatening Risk factors males, smoking, older age, chronic cardiovascular or respiratory disease, diabetes, alcohol misuse, cancer and immunosuppression Incubation: 2-10 days Mortality: 8-12% (15-35% for nosocomial) 4

The Lancet Infectious Diseases 2009; 9:512-519 Legionnaires Disease is not an atypical pneumonia The atypical organisms, so called

pneumoniae, Legionella species, and respiratory viruses.

5 The Lancet Infectious Diseases 2009; 9: Legionnaires Disease is not an atypical pneumonia The atypical organisms, so called because they are not detectable on Gram stain or cultivatable on standard bacteriologic media, include M. pneumoniae, C. pneumoniae, Legionella species, and respiratory viruses. Clinical Presentation of LD Clinical and radiologic features are indistinguishable from other CAPs (i.e the features are not atypical) Clinical scoring systems are unreliable There are no distinguishing biomarkers 5

New Zealand 2013 : Incidence 35 / million per year Lancet Infectious Diseases 2013: 14;1011-1021 Legionella Noifications by Year 1991-2015* 500 ACT NSW NT QLD SA TAS VIC WA Rate Melbourne Aquarium

6 New Zealand 2013 : Incidence 35 / million per year Lancet Infectious Diseases 2013: 14; Legionella Noifications by Year * 500 ACT NSW NT QLD SA TAS VIC WA Rate Melbourne Aquarium (n=125) Cooling towers MJA 2004; 180: No. of cases Rate per million population 6

Legionella NNDS System, 2011 50.5% Lp/Ll 0 > = = < < > < 48.

7 Legionella NNDS System, % Lp/Ll 0 > = = < < > < 48.6% CDI 2013; 37: E380 Notified cases Australia 2011 Communicable Diseases Intelligence 2013; 37; No4 E313 7

8 Communicable Diseases Intelligence 2013; 37; No4 E313 Prevalence of LD among patients with pneumonia Adults with CAP worldwide Typically 1-10%, mean ~5 % Australia -ACAPS -3.4% (CID 2008;46: ) Adults with CAP Christchurch NZ during spring/ summer ~ 19% Children with CAP Very uncommon 8

Legionnaires Disease is more than just about outbreaks and cooling towers 1981; 94: 739-740 Isolation of L.

Results from a Legionella longbeachae case-control study in SA Epi & Inf 2007; 135:34-39 Legionellosis

average) In Christchurch it is the most commonly identified cause of pneumonia for about half the year Has a

9 Legionnaires Disease is more than just about outbreaks and cooling towers 1981; 94: Isolation of L.longbeachae sg1 from potting mixes. T W Steele et al AEM 1990; 56:49-53 Does using potting mix make you sick? Results from a Legionella longbeachae case-control study in SA Epi & Inf 2007; 135:34-39 Legionellosis Notification Rates - NZ One third to one half of cases come from Canterbury ( incidence > 3 times the national average) In Christchurch it is the most commonly identified cause of pneumonia for about half the year Has a seasonal peak in activity in spring/summer more predictable than influenza ~ 85% of cases are due to Legionella longbeachae 9

positive specimens Association between Ct and culture positivity Correlation - bacterial load

10 22 to 92 cases (x4) 1 in 20 positive 1 in 9 positive peak season (Nov Jan) Mostly L.longbeachae Distribution of cycle threshold (Ct) values for polymerase chain reaction positive specimens Association between Ct and culture positivity Correlation - bacterial load and disease severity Ct values lower for ICU admissions; non survival Decreased with increasing CURB-65 score 10

11 PCR is the diagnostic method of choice for Legionnaires Disease J. Clin. Microbiol. 2013;51: Antigen Detection Antibody Detection PCR 11

or heat Specifically requested Fewer than 50% produce sputum Rejection criteria should

12 Culture Culture Sensitivity 10-80% Buffered charcoal yeast extract (BCYE) + α ketoglutarate + cysteine ± antibiotics Slower to grow plates held 7 days Pretreat acid or heat Specifically requested Fewer than 50% produce sputum Rejection criteria should not be applied often non purulent Legionella - does not activate the alarm of blood cultures systems 12

No. Year Sex/ Age Hosp Site Host Organism LUA Serology Outcome 1 2005 M/62.1 C Sputum CAP:Psoriatic arthritis, mtx 2 2009 M/62.2 F BAL CAP:SLE pred, mycophenylate L.pneumophila nd L.

13 No. Year Sex/ Age Hosp Site Host Organism LUA Serology Outcome M/62.1 C Sputum CAP:Psoriatic arthritis, mtx M/62.2 F BAL CAP:SLE pred, mycophenylate L.pneumophila nd L. longbeachae nd neg (single sample) neg (2 days apart) Deceased Deceased CAP: CLL neg (no SC M/58.8 A BW/BAL L. longbeachae nd Survived immunosuppressed over 6m) CAP: Lung abscess; F/80.8 E Lung L. longbeachae nd Ll: 4096 Survived smoker HAP: refractory M/73.7 B BAL myelodysplasia;aml L.pneumophila POS neg (single Deceased sample) SC Ll M/73.9 D BAL CAP: Dalby L. longbeachae NEG Deceased (8d) neg (no SC F/46.1 B BW/Sputum HAP: Relapsed AML L.pneumophila POS Survived + over 8w) M/66.9 B Pleural F/Sputum M/80.3 C Wrist Culture Positives SNP * HAP: Cardiac amyloid L.pneumophila POS neg Deceased RA, mtx; multiple sc nodules L.sainthelensi nd nd Survived M/55.6 A Sputum HAP/CAP?: Supraglottic SCC; Crohns azothioprine L.pneumophila POS neg Survived M/66.4 A BW HAP: CLL L.pneumophila nd neg (no SC over 8w) Survived + Legionella Urinary Antigen 13

days of illness Quick - < 4 hours Useful in those who do not produce sputum Immunosuppressed patients can

14 Legionella Urinary Antigen Only detects L.pneumophila serogroup 1 Sensitivity: 70-80% Specificity: approaching 100% May be negative during first 1-3 days of illness Quick - < 4 hours Useful in those who do not produce sputum Immunosuppressed patients can excrete Ag for > 60 days (>300d) MJA 2007;187:36-39 Legionella Urinary Antigen EIA Binax Now sg1 Biorad IVD Research ICT Binax Now sg1 Oxoid Xpect PCR Life River FIA Quidel Corporation 14

15 Legionella Urinary Antigen No. of Tests LUA negative 1 3 LUA positive 11/2261 tests positive (0.5%) 7 patients positive Peaked in 2013 Wesley Outbreak No. Year Legionella Urinary Antigen Sex/ Age Hosp Host Site Culture LUA PCR Serol Outco me F/47.8 A F/39.9 C M/73.7 B M/66.9 B CAP: Crohns Humira CAP: Psoriatic arthritis on immunosuppres sion HAP: refractory myelodysplasia; AML HAP: Cardiac amyloid * LUA pos 2 months later ND ND POS ND Neg Survived ND ND POS ND SC: 2048 Survived BAL L.pneumophila POS ND Neg Deceased Pl Fluid, Sputum L.pneumophila POS ND Neg Deceased F/46.1* B HAP: Relapsed AML Sputum L.pneumophila POS ND Neg Survived M/61.9 D CAP: Unknown ND Negative POS POS SC: 512 Survived M/55.6 C HAP/CAP?: Supraglottic SCC; Crohns azothioprine Sputum L.pneumophila POS ND Neg Survived 15

16 Serology Indirect immunofluoresence (IFA) Subjective Low titre positives Cut-off for significance 20-30% don t seroconvert Seroconversion 2-10 weeks Cross reactivity especially pooled antigen Absorption of sera with E.coli O13:K92:H4 Range of antigens L. pneumophila sg1; sg1 14; sg1 6; sg7 14 L.longbeachae sg1 sg2; L.bozemanni; L.micdadei Wilkinson HW JCM 1979;10(5):685-9 Serology * L.pneumophila sg1 IFA tests; patients Serology ALL SNP : Legionella pneumophilia sg1 Titre Total % Total < total

17 Serology * L.longbeachae IFA tests; patients Serology ALL SNP : Legionella longbeacheae Titre Total % Total < total Nucleic Acid Detection (e.g. PCR) Detects Legionella DNA High sensitivity and specificity Faster TAT than culture Detects all species and serogroups Costs and technical expertise no longer a barrier for some laboratories Commercial NAATs now available e.g AusDiagnostics 17

Any Sputum will do Sputum - preferred sample for PCR testing Quality measures do not apply Induced sputums should be collected from patients who cannot expectorate Collecting induced sputum increases

18 Any Sputum will do Sputum - preferred sample for PCR testing Quality measures do not apply Induced sputums should be collected from patients who cannot expectorate Collecting induced sputum increases case detection by about 36% Eur Respir J 2014; 43: Which patients with pneumonia should be tested for Legionnaires Disease? British Thoracic Society LUA; Legionella culture all patients with high severity pneumonia Other patients with specific risk factors All patients with CAP during outbreaks NICE (National Institute for Health and Care Excellence LUA moderate-or high severity CAP IDSA Guidelines LUA, Culture if LUA positive severe CAP; ICU admission, failure of outpatient antibiotic treatment, active alcohol abuse, travel within the past 2 weeks, pleural effusion 18

National Legionnaires Disease Case Finding (LegiNZ) 1 Year study To

treatment protocols Canterbury Approach Sputum samples tested for

pneumonia Clinical information: pneumonia consolidation CAP

19 National Legionnaires Disease Case Finding (LegiNZ) 1 Year study To better understand national epidemiology To inform regional testing and treatment protocols Canterbury Approach Sputum samples tested for Legionella by PCR if there is any indication that the patient has pneumonia Clinical information: pneumonia consolidation CAP Immunocompromised LUA has been ordered PCR specifically requested Chief Health Officers Report 19

20 Not in cooling towers Wesley Outbreak Present in water in patient rooms - shower head & basins P of 85 (17.6%) of hospital water outlets cultured L. pneumophila serotype 1 on initial survey P P Bartley PB et al Science Translational Medicine (submitted) Wesley Response No new admissions Alternative hygiene measures (bottled water, no showering) Scalding of the WDS - 60 C 10 minutes Disinfection of WDS - alkaline detergent (ph = 10.0) containing 10 mg/l free chlorine In-line chlorinator systems Intensive monitoring - L. pneumophila in water specimens 20

21 Reference strains and non related isolates 2013 outbreak patient 2013 outbreak patient 2011 patient 2013 hot water isolate Point Prevalence Study Public and Private Hospitals and RACF s 21

22 CID Advance Access March 18, 2015 No safe level of legionella colonisation sites that could serve as a trigger point 30% previously suggested Wesley 17.6% at time of outbreak 22

23 Travel associated LD pdf Travel associated LD sociated_legionnaires_disease_2007.pdf 23

diagnostic method of choice Non pneumophila disease:underdiagnosed An ideal approach is

24 Travel Associated LD Key messages Ubiquitous environmental organism Not an atypical pneumonia LD is more than just outbreaks, cooling towers and potable water PCR is the diagnostic method of choice Non pneumophila disease:underdiagnosed An ideal approach is to respond to local epidemiology - however we need to first define the local epidemiology 24

Acknowledgements Prof David Murdoch Christchurch Australasian Society for Infectious Diseases (ASID) 2015 typing Monoclonal antibody methods restriction endonuclease analysis

25 Acknowledgements Prof David Murdoch Christchurch Australasian Society for Infectious Diseases (ASID) 2015 typing Monoclonal antibody methods restriction endonuclease analysis (REA) ribotyping, amplified fragment length polymorphism (AFLP), pulsed field gel electrophoresis (PFGE), restriction fragment length polymorphism (RFLP), arbitrarily primed PCR 7 25

26 Wesley Outbreak Not in cooling towers Present in patients water - shower head & basin in patient s room 26

Current and Emerging Legionella Diagnostics

Current and Emerging Legionella Diagnostics Nicole Wolter Centre for Respiratory Diseases and Meningitis (CRDM) National Institute for Communicable Diseases nicolew@nicd.ac.za 7 th FIDSSA Conference, Cape