The Dubbo Infection Outcomes Study

Transcription

1 The Dubbo Infection Outcomes Study Determinants of protracted illness after acute infection

2 Dubbo Infection Outcomes Study Three parallel cohorts Epstein-Barr virus: - infectious mononucleosis - established model of post-infection fatigue (PIFS) - natural persistence of the organism via latency Ross River virus: - mosquito-borne seasonal infection - rash and arthritis - linked to a prolonged musculo-skeletal pain syndrome Q fever: - zoonotic infection caused by Coxiella burnetii - severe acute illness with hepatitis and pneumonia - rare long-lasting chronic, localised infections

3 Dubbo Infection Outcomes Study Onset of symptoms Attend general practice Diagnostic laboratory tests EBV, RRV, QF IgM Contact by research team and enrolment Not enroled Limited data collection Self-report cohort Questionnaires Follow-up Main cohort Interviews Serological confirmation Follow-up

4 Dubbo Infection Outcomes Study - main cohort GP visit Acute EBV, RRV, Q fever infection Enrolment 2-3 weeks 4-6 weeks Interviews, self-report questionnaires, blood sampling Self-report questionnaires, blood sampling Self-report questionnaires, blood sampling 3 months Self-report questionnaires, blood sampling Cases Matched controls 6 months Physician/psychiatrist review, lab. Ix Recovered PIFS cohort Recovered control cohort 12 months Self-report questionnaires, blood sampling

5 Characteristics of the cohort (n=254) EBV RRV QF Unconf. Sample size (n) Age (mean; yrs) Sex (% female) Education (%<10 yrs) Employed (%) Student (%)

6 Natural history of symptoms in acute EBV Confirmed EBV (n=68) Percentage (%) with symptom Fatigue Sore Throat Tender Glands Fever Anorexia Sleep disturbance Headaches Malaise * Weeks Post Onset

7 Natural history of symptoms in acute QF Confirmed QF (n=45) Fever Fatigue Malaise Headaches Chills Sweating Arthraglia Anorexia * Weeks post onset

8 Natural history of symptoms in acute RRV Confirmed RRV (n=60) Percentage (%) with symptom Fatigue Arthralgia Myalgia Headaches Malaise Sleep disturbance Rash Sweats * Weeks Post Onset

9 Dubbo Infection Outcomes Study Conclusions - outcomes data Prolonged illness is common after EBV, RRV, Q fever Fatigue, musculo-skeletal skeletal pain are features

10 Dubbo Infection Outcomes Study Hypothesis testing Case-control series - cases: six months of more of disabling illness - controls: matched by age, sex, pathogen; prompt recovery Longitudinally collected samples and data: - psychological factors - microbiological factors - immunological factors - genetic factors

11 EBV case-control control series Persistence of anti-vca IgM Cumulative % subjects positive <3 w eeks 3<6 w eeks 6<9 w eeks 9<12 w eeks 3<6 months 6<9 months 9<12 months >12 months controls cases Time post onset of symptoms

12 EBV case-control control series Leucocyte subsets and their activation CD8+DR+ % of CD3+CD8+ cells HLA-DR > >12 wk wk wk wk mo mo mo mo wk wk wk wk mo mo mo mo Controls Cases Time post onset of symptoms

13 EBV case-control control series EBV cellular viral load Mean log 10 copies/10 6 PBMC <3 weeks 3<6 weeks 6<9 weeks 9<12 weeks 3-6 months 6-9 months 9-12 months >12 months cases controls Time post onset of symptoms

14 Dubbo Infection Outcomes Study Pathogenesis: case-control control series No evidence for abnormal persistence of organism No significant difference in the immune response Psychological disorder not a risk factor

15 Dubbo Infection Outcomes Study Avidity studies Serological diagnosis of primary infection based on a single IgM antibody result is unreliable IgG IgG avidity for antigen matures in primary immune responses Relevance to EBV and RRV diagnoses

16 The Dubbo Infection Outcomes Study Serological responses EBV Proportion (%) of the group positive % of the group positive Weeks post onset of symptoms 28 VCA IgM VCA IgG EBNA IgM EBNA IgG

17 Dubbo Infection Outcomes Study Avidity studies - EBV 28 subjects with clinical diagnosis of glandular fever and consistently positive IgM anti-vca or IgG seroconversion 35 subjects with pre-existing existing IgG anti-vca and confirmed hepatitis A, HIV or CMV infection EBV EBV IgG anti-vca, IgM anti-vca EBV EBV IgG anti-vca avidity (8M urea)

18 The Dubbo Infection Outcomes Study Serological responses (IgG VCA avidity) Number (%) of group with positive serology Sample size (n) VCA EBNA IgG IgM IgG IgM Mean IgG VCA avidity (SD) Hepatitis A (100) 12 (80) 15 (100) 12 (80) 95 (5.7) HIV (100) 5 (36) 14 (100) 10 (71) 98 (2.8) CMV 6 6 (100) 1 (16) 6 (100) 6 (100) 96 (3.2) Combined (100) 18 (51) 35 (100) 28 (80) 96.3 (4.4)

19 The Dubbo Infection Outcomes Study Serological responses (IgG VCA avidity) EBV Percentage avidity Avidity EBV CMV HIV Hepatitis A Weeks post onset of symptoms Number of samples from EBV cases tested: n =

20 Dubbo Infection Outcomes Study Avidity studies - EBV IgM IgM anti-vca: - sensitivity 100% - specificity 49% (14 of 35 false positives) IgM IgM anti-vca + low avidity IgG anti-vca: - sensitivity 93% - specificity 97%

21 Dubbo Infection Outcomes Study Dubbo Infection Avidity studies - RRV 89 subjects with clinical RRV infection and RRV IgM 88 subjects with confirmed EBV or QF infection and IgG anti-rrv

22 The Dubbo Infection Outcomes Study Serological responses (IgG RRV avidity) RRV 100 Percentage avidity RRV non RRV Weeks post onset of symptoms Weeks post onset of symptoms

23 Dubbo Infection Outcomes Study Avidity studies - RRV IgM IgM anti-rrv: - sensitivity 100% - specificity 78% (19 of 88 sera false positive) IgM IgM anti-rrv + low avidity IgG anti-rrv: - sensitivity 92% - specificity 100%

24 Research team Dubbo Study Maree Wilkinson, Sue Newham, Valma Cahill (Dubbo - field & laboratory) Justine Diver (UNSW - admin) Ian Hickie,, Tracey Davenport (USyd - Psych) Barb Cameron (UNSW - Immunology) Ute Vollmer-Conna (UNSW - Psycho-immunology) Collaborators: Rajiv Khanna, Mandvi Bharadwaj (QIMR - EBV) Barrie Marmion, Ray Harris (IMVS - QF) Heather Dunckley,, Andrew Geczy (ARCBS - Genetics) Bill Reeves, Suzanne Vernon, Toni Whistler, (CDC - Gene expression) Peter Robertson, Ross Whybin, Bill Rawlinson (SEALS - avidity studies)