Q Fever: Consensus and Controversies. Path Update 2017 Dr Fiona Parsonson Melbourne Pathology

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1 Q Fever: Consensus and Controversies Path Update 2017 Dr Fiona Parsonson Melbourne Pathology

2 Coxiella burnetii Derrick described the first outbreak in Brisbane (1935), followed by isolation of the rickettsia by Burnet and Freeman Query fever First described in Australia in 1937 Worldwide (except NZ) zoonosis infecting a wide range of organisms from arthropods to humans Most commonly affecting cattle, sheep and goats Also other domestic animals, marsupials, marine mammals, reptiles, ticks and birds Birth products (up to 10 9 organisms/g in placenta) >> urine, faeces, milk Strict intracellular Gram negative bacteria Similar cell wall structure, not stainable by standard Gram technique (Gimenez better) CDC category B biological threat Eldin et al., CMR 2017; Harris et al., Epidemiol Infect 2013

4 Duron et al., PLOS Pathogens 2015

5 Cell biology Exists in different morphological forms, depending on the stage of its life cycle Large cell variants (LCV) Metabolically active, exponentially replicating, divide by binary fission inside a vacuole Small cell variants (SCV) Stationary, non-replicating form, occur when conditions are not favourable to growth Functionally spores

Omsland et al., PNAS 2012 TEM imaging (A), showing an initial inoculum with ultrastructural characteristics of SCV including small cell size (diameter: 0.188 ± 0.0044 μm) and condensed chromatin.

6 Omsland et al., PNAS 2012 TEM imaging (A), showing an initial inoculum with ultrastructural characteristics of SCV including small cell size (diameter: ± μm) and condensed chromatin. After 3 days incubation in ACCM, organisms exhibit LCV characteristics including increased cell size (diameter: ± μm) and dispersed chromatin. Mixed population after 6 days of incubation, with an overall reduction in cell size (diameter: ± μm).

Cell biology Virulent form = phase I First isolated from infected humans and animals When isolates are grown for an extended period in cell culture, the population gradually changes to the phase II

8 Cell biology Virulent form = phase I First isolated from infected humans and animals When isolates are grown for an extended period in cell culture, the population gradually changes to the phase II form (avirulent) Changes in the expression of genes, including outer membrane lipopolysaccharides Phase I cells have three unique sugars on the terminal end of cell wall LPS that are not present in phase II Key virulence factor Results in distinguishable immune responses van Schaik et al., Nature Reviews 2013; Eldin et al., CMR 2017

9 Epidemiology Transmission to humans: most commonly through inhalation of aerosolised bacteria spread in the environment by infected animals following delivery or abortion Role of ingestion is controversial (raw milk) Human-to-human transmission (anecdotal reports) Tick-borne? (not proven) Nosocomial infections (e.g. to obstetric staff following Caesarean); US cluster following injection of foetal sheep cells ( live cell therapy ) Epidemiology is highly variable and is dependent on the animal reservoir Sporadic, endemic or outbreak situations in different geographic areas Stevenson et al., BMJ Case Rep 2015; Harris et al., Epidemiol Infect 2012; Eldin et al., CMR 2017

Netherlands outbreak 2007-2010 Largest ever reported outbreak Epizooty from 2005, abortion rates of >60% on some goat farms >4,000 reported

10 Netherlands outbreak Largest ever reported outbreak Epizooty from 2005, abortion rates of >60% on some goat farms >4,000 reported human cases, and estimated 40,000 total cases Occurred in a population with previously low seroprevalence van der Hoek et al., Eurosurveillance 2010

11 Clinical presentation acute Q fever Up to 50% asymptomatic Acute, often undifferentiated, self-limiting febrile illness Usually lasts days Community acquired pneumonia 24% of cases of CAP in Cayenne in French Guiana, interstitial pattern Complications: endocarditis, hepatitis, fulminant disease Primary infection resolves in most patients without treatment, indicating the host immune response is adequate

12 Chronic Q fever Fever (65-100%) Night sweats Weight loss Fatigue, weakness Hepatosplenomegaly ~1-5% of acutely infected patients develop chronic disease Usually occurs 6-12 months after acute infection, but can occur at any time Cardiovascular involvement is the most common Other system involvement GIT?? CNS Bones and tendons Renal Skin Wegdem-Blans et al., J Infect 2010; Eldin et al., CMR 2017

Q fever endocarditis (QFE) Traditionally high mortality rate (>65%) Adequate treatment can reduce the mortality to <5% Predominantly aortic valve involved (>80%)

13 Q fever endocarditis (QFE) Traditionally high mortality rate (>65%) Adequate treatment can reduce the mortality to <5% Predominantly aortic valve involved (>80%) Increased risk in patients with underlying valvular disease, including bicuspid aortic valves or prosthetic valves Chieng et al, Heart Lung and Circulation, 2016

14 Q fever in pregnancy As pregnancy develops, latent viable C. burnetii begins to replicate in the placenta and foetus, leading to infection and foetal death Impact depends on virulence of the circulating strain France, Spain high impact Germany, Denmark, Netherlands lower impact Can be included in the TORCH agents under Other Eldin et al., CMR 2017

15 Laboratory diagnosis Detection of C. burnetii DNA by qpcr in blood, heart valve or tissue specimens Can detect DNA prior to seroconversion in primary infection Targets: IS1111 (16-23s RNA, sod, com1, ompa) Culture Only recently able to be cultured in anexic media; research technique Shell vial cell culture is still the most common technique used Histopathological analysis of tissue E.g. cardiac valve: significant fibrosis and calcifications, slight inflammation and vascularisation, small or absent vegetations Fibrin-ring granuloma "doughnut" Immunohistochemical staining using mouse anti-c. burnetii mab

16 Laboratory diagnosis Sensitivity of C. burnetii culture from cardiac valves: 73.3% (11/15), 88.9% (8/9) from two studies Sensitivity of C. burnetii culture in blood specimens: 40.0% (6/15), 52.9% (9/17) Comparable differences for DNA detection by PCR in blood and tissue: sensitivity of 22.9% in blood, 100% from cardiac valves Sensitivity of histological staining on valve tissue: 55.5% (5/9) and 66.7% (10/15) Lepidi et al., J Infect Dis 2003; Brouqui et al., Am J Med 1994

17 Laboratory diagnosis serology First line diagnostic technique Antibody to phase II antigen - predominant during acute infection Detectable 7-15 days after primary infection, declines over 3-6 months Four-fold rise in titer in sera taken 3-6 weeks apart (acute and convalescent) indicates acute Q fever Residual antibody may persist for life Early treatment does not affect the phase II response

18 Laboratory diagnosis serology Antibody to phase I antigen associated with persistent or chronic infection, Caused by persisting antigenic stimulation Traditional paradigm is that a titer of 1:800 is diagnostic of QFE The higher the titer, the higher the PPV: 37% at1:800, 75% at 1:6400 Cases of chronic Q fever with lower titer phase I antibody have been reported Discussions about the optimal cut-off values and suggestions of the incorporation of clinical characteristics in the diagnosis of chronic Q fever have emerged

19 Munster et al., BCM Women s 2010 PCR

20 Serological techniques Indirect fluorescent antibody tests (IFAT) Reference method, able to distinguish between acute, past and chronic infection Allows detection of phase I and phase II IgG and IgM Higher sensitivity for phase II IgM compared to ELISA; however no significant difference in the diagnosis of acute Q fever Improved sensitivity for the detection of phase I IgG at low titers Validated to use for monitoring of phase I IgG following treatment Better for determining immunity following vaccination longer time to decline in levels ELISA Commonly used due to simplicity, less subjective interpretation (easier inter-laboratory correlation) 2-stage techniques EIA screening followed by IFAT for negative samples CF More rarely used, lower sensitivity for both IgG and IgM Wegdam-Blans et al., Clin Vaccine Immunol 2012

22 Diagnosis imaging Chieng et al, Heart Lung and Circulation 2016 Chieng et al., Heart Lung and Circulation, 2016

) based on retrospective studies of patients with chronic infection ECHO findings can be non-specific or absent,

23 Diagnosis The Controversy Variety of diagnostic methods used until recently; Combination of the Duke criteria, Q fever phase I IgG titer of 1:800, imaging and microbiology Cut off of 1:800 first suggested in 1994 (DuPont et al.) based on retrospective studies of patients with chronic infection ECHO findings can be non-specific or absent, particularly early in disease Low sensitivity of culture/pcr on blood requiring tissue/invasive sampling Andrade et al., BCMJ 2008

24 Diagnosis Expert opinion Raoult et al. Chronic Q fever Endocarditis was associated with high levels of IgG phase I antibodies, with titers of 800, and defined by a spontaneous progression longer than 6 months Modification of the Duke criteria, with the inclusion of the Q fever serological cutoff as a major criterion, improving the diagnosis of C. burnetii endocarditis Revaluation of the PPV of this cutoff: proposed a new serological IgG phase I cutoff at 1:1,600 Differentiation of C. burnetii vascular graft, joint, and bone infections However, the reanalysis of the literature by a different team, [lead to] a corpus of controversial hypotheses Raoult et al., Medicine, 2000; Raoult, J Infect 2012

Diagnosis Consensus guidelines Dutch Q fever consensus group (2012) aimed to summarize the available knowledge on clinical presentation, microbiological diagnosis, and imaging techniques for the

25 Diagnosis Consensus guidelines Dutch Q fever consensus group (2012) aimed to summarize the available knowledge on clinical presentation, microbiological diagnosis, and imaging techniques for the diagnosis of chronic Q fever and to provide a basis for uniformity in the work-up of patients suspected of having this infection The validity of using a cut off phase I titer called into question High phase I with other cardiovascular risk factors can pose a therapeutic dilemma High false positive rate using a cut off of 1:800, however the effect on the NPV of increasing the cut off to 1:1600 not well evaluated Conversely, chronic Q fever cannot be excluded if the phase I titer is <1:800 Inter-laboratory concordance in interpretation of IFA titer can be as low as 35% Committing patient to prolonged and intensive antibiotic therapy for 18 months minimum Wegdam-Blans et al., J Infect 2012

26 Dutch consensus guideline on chronic Q fever diagnosis Proven Q fever Probable Q fever Possible Q fever 1. Positive C. burnetii PCR in blood or tissue OR 2. IFA 1:1024 for C. burnetii phase I IgG AND definite endocarditis according to the modified Duke criteria OR proven large vessel or prosthetic infection by imaging studies (18FDG-PET, CT, MRI or abdominal doppler ultrasound) IFA 1:1024 for C. burnetii phase I IgG AND one or more of following criteria: - Valvulopathy not meeting the major criteria of the modified Duke criteria - Known aneurysm and/or vascular or cardiac valve prosthesis without signs of infection by imaging studies - Suspected osteomyelitis or hepatitis as manifestation of chronic Q fever - Pregnancy - Symptoms and signs of chronic infection, such as fever, weight loss, night sweats, hepatosplenomegaly, persistent raised ESR and CRP - Granulomatous tissue inflammation, proven by histological examination - Immunocompromised state IFA 1:1024 for C. burnetii phase I IgG without manifestations meeting the criteria for proven or probable chronic Q fever

27 Raoult, J Infect 2012 Expert response

Response Isolated serological criteria for diagnosis are simplistic Mixing different entities under a generic term neglects the natural history and determinants of disease Prevention strategies and

28 Response Isolated serological criteria for diagnosis are simplistic Mixing different entities under a generic term neglects the natural history and determinants of disease Prevention strategies and prognosis for chronic Q fever infection depend on the definition and understanding of the natural history of the disease The large number of chronic Q fever cases recorded following the Netherlands outbreak (250 persons to date) may reflect the failure of the Dutch strategy to preventively and systematically detect and treat people at risk, specifically those with predisposing cardiovascular risk factors. Raoult, J Infect 2012; Eldin et al., CMR 2017

29 Raoult, J Infect 2012

30 Kampschreur et al., Emerg Infect Dis 2013

33 Treatment Challenging All drugs are bacteriostatic in action Acidic phagosome environment inhibits antibiotic activity Antibiotic susceptibility testing not routine Doxycycline remains the most effective drug MIC <2 mg/l Addition of hydroxychloroquine as a alkylating agent can restore bacteriocidal action of doxy: shorter duration of treatment and lower risk of relapse Sulfamethoxazole-trimethoprim Fluoroquinolones

34 Doxycycline 200mg BD for 2 weeks Bactrim plus folic acid in pregnancy Patients who did not receive antibiotics for acute Q fever had an increased risk for developing chronic Q fever Prophylaxis in high risk cardiovascular patients Recommended by Raoult et el. Eldin et al., CMR 2017

35 Treatment chronic Q fever Prolonged therapy with doxycycline plus hydroxychloroquine 18 months recommended for native valve endocarditis 24 months for prosthetic valve Longer?? Monitoring every 3 months Valve surgery may be required Vascular disease surgery associated with better outcomes Other foci??

36 Treatment chronic fatigue syndrome No definite strategy recommended to date Randomised control trials underway in the Netherlands Cognitive behaviour therapy Doxycycline

37 Summary Acute Q fever Prophylaxis Echocardiography +/- further investigations after acute Q fever Chronic Q fever Guidelines Dutch more simple, probably more sensitive at the loss of specificity, correlated treatment guidelines Raoult et al. increased specificity, more difficult to clarify relationship to treatment More to come Treatment

38 The End

Q FEVER Australian and global perspectives including the recent Netherlands outbreak

Q FEVER Australian and global perspectives including the recent Netherlands outbreak Coxiella burnetii, the causative bacterium for Q Fever is ubiquitous. Thought to be present in every land mass with