Jornadas de arbovirosis: dengue, chikungunya y Zika. Preparación y respuesta de los países del Cono Sur. Buenos Aires, Argentina, 4-5 noviembre 2015.

1. 1
Chikungunya diseaseChikungunya disease
Persisting stages: clinical features,
classification, case management
Pr Fabrice SIMON, MD, PhD
Department of Infectious Diseases and Tropical Medicine
LAVERAN Military Teaching Hospital - Marseille - France
simon-f@wanadoo.fr

2. 2
The natural history of chikungunya disease
• Three stages different in clinical features and treatment
Acute
D1 to D21
Post-acute
S4 to S12
Chronic
From M4 to …
High viremia to D5-D7
Intense inflammation
Multifocal persistence of joint inflammation  musculo-skeletal disorders
Rare evolution toward a real chronic inflammatory rheumatism
Psycho-social consequences of long-lasting rheumatic disorders
≈80% spt ≈70% spt ≈60% spt
20−50% spt
after 2 years
Up to
6-8 years
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

3. Post-acute stage
S4toS12

4. 4
Post-acute stage (S4-S12), clinical features
• Clinical persistence or relapse after transient improvement
• Common exacerbation at M2-M3
• Osteo-tendino-articular symptoms
• Polymorph and associated
• Initial sites +/- new sites with time
• General manifestations
• Vascular disorders
• Fatigue and depression
Simon F et coll. Medicine 2007;86: 123-37
Queyriaux B et col. Lancet Infect Dis 2008;8:2–3.
S4toS12

5. 5
Post-acute stage, miscellaneous rheumatic symptoms
• Persisting inflammatory arthralgias
• Distal, multiple, painful
• ± periarticular subcutaneous edema
• Tenosynovitis and tendonitis, bursitis
• Wrists, hands, ankles…
• Hypertrophic  tunnel syndromes
• Exacerbation of pain on previously injured/ill joints or bones
Simon F et coll. Medicine 2007
S4toS12
Typical locations
after 2 months

6. 6
Post-acute stage, persistent distal inflammatory arthralgias
S4toS12
Coll. F Simon
Coll. F Simon

7. 7
Post-acute stage, hypertrophic tenosynovitis
S4toS12
Coll. F Simon
Coll. F Simon
Coll. E. Javelle

8. 8
Post-acute stage, bursitis
S4toS12
Coll. F Simon
Coll. F Simon
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

9. 9Simon et al. Medicine 2007 Oliver et al PLoS NTD 2009
Post-acute stage, occasional peripheral vascular disorders
• Erythermalgia
• Raynaud’s syndrome
S4toS12
Coll. F Simon
Coll. F Simon

10. 10
Post-acute stage, general and psychic consequences
• Fatigue
• Totally incapacitated: 37,2%, important and very important: 47,3%,
rather or mildly important: 15,5%, absent: none.
• Impact on the mood
• Completely depressed: 4,6%, depressed: 35,5%, morally weakened :
47,4%, normal: 12,5%.
Queyriaux B et al. Lancet Infect Dis 2008
S4toS12

11. 11
Post-acute stage, principles of treatment
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
S4toS12

12. 12
Post-acute stage, clinical evaluation
• Physical examination
• Joints
• Pain, stiffness, edema, synovitis, effusion
• Number
 Tendons, bursae
S4toS12
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
 Clinical diagnosis for each site +++

13. 13
Specific clinical checking for post-CHIK “hot spots”
S4toS12
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

14. 14
Post-acute stage, pain evaluation
 Assessment of the pain with a visual scale
• Detection of a neuropathic component with DN4 questionnaire
S4toS12
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

15. 15
Post-acute stage, functional assessment
• Score RAPID3
S4toS12

16. 16
Post-acute stage, complementary evaluation
• Only few biological analyses before treatment
• Haemogram and C-reactive protein (mild elevation)
• Transaminases, creatininemia +/- uricemia
• No systematic imaging of the involved joints
• No bone erosion at that stage
• US-echography +++
- to distinguish synovitis and SC oedema, describe tendon lesions
S4toS12
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

17. 17
• Painkillers ++
• Acetaminophen and up to class 3; anti-neuropathic drug if test DN4+
• NSAIDs +++
• Full dose if not CI, prolonged liberation, switch if not sufficient; total:
2-12 weeks
• Oral corticosteroids: CAUTION
• For NSAID-refractory features only +++
• Low dose, total < 4 weeks, relay with NSAIDs
• See rheumatologist if dependency
• High risk for clinical intense relapse and side effects
S4toS12
Post-acute stage, drugs
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

18. 18
Post-acute stage, physical therapies +++
• To preserve articular amplitudes and muscle strength
• Activo-passive mobilisation and massages, ultrasounds
• Antalgic physiotherapy for refractory joints
• Arthritis, tenosynovitis  cryotherapy/orthese (night)
• Œdema  Scottich bath/pressotherapy/contention
• Tunnel syndrome infiltration (avoid surgery)
S4toS12
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

19. 19
Post-acute stage, start self-rehabilitation
• Soft sport activities
• Repetition of soft movements to reduce stiffness
S4toS12
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

20. Chronic stage
M4to…

21. 21
• Recovery: subjective criteria
• Persistence of the symptoms : pain, functional sequelae
• Degenerative disorders
• Tendon inflammation or synovitis: local or systemic process ?
• Notion of CHIK-attributed morbidity
• Difference with uninfected patients
What long-term outcome after a chikungunya infection ?
M4to…

22. 22
The post-CHIK persisting disorders in the literature
AREA (number of patients) YEAR OF
OUTBREAK
% TIME AFTER
CHIK ONSET
CHRONIC DISORDER REFERENCES
Reunion (106) 2005-2006 52% 17 months Chronic pains de Andrade DC et al. BMC Infect
Dis 2010
Reunion (88) 2005-2006 63,6% 18 months Persistent arthralgia (yes/no) Borgherini G et al. Clin Infect Dis
2008
Reunion (147) 2005-2006 57% 15 months Joint manifestations (NRS scale) Sissoko D et al. PLoS Negl Trop Dis
2009
India
Maharashtara (509)
2006 4,1%
1,6%
0,3%
12 months
24 months
12 months
Persistent rheumatic non-specific pain
Chronic inflammatory arthritis
Chopra A et al. Epidemiol Infect
2012
India
Karnataka Dakshina in
Kannada district (203)
Jan-august
2008
75%
31%
30%
46,3%
17%
13%
6%
1 month
1 month
1 month
10 months
10 months
10 months
10 months
Rheumatism
Swelling
Asthenia
Joint pain /swelling
ACR rheumatoid arthritis criteria
Asthenia
Neuritis
Manimunda SP et al. Trans R Soc
Trop Med Hyg 2010
India
Otoor village in Kerala (1396)
March-July
2007
55%
8,3%
15 months
15 months
Musculoskeletal pain
Chronic rheumatism (naïve to pain before
CHIK)
Mathew AJ et al. Int J Clin Pract
2011
Indian Ocean and South East
Asia (69)
Jan-Oct 2006 69%
13%
2 months
6 months
Persistent arthralgia Taubitz W et al. Clin Infect Dis 2007
Sri Lanka
Galagedara-Madige village in
Kandy District (513)
Oct 2006 45%
24%
8%
2,7%
14 days
7 months
12 months
36 months
Arthritic disability Kularatne SA et al. J Trop Med
2012
Italy (250) 2007 66,5% 12 months Myalgia, asthenia, arthralgia Moro ML et al. J Infect 2012
Japan (15 imported cases) 2005 6/15 Persistent arthralgia MizunoY et al. JInfect Chemother
Waning with time
Not to zero…
Wide clinical spectrum
Heterogeneity
of the methods
Lack of case-control studies

23. 23
Toward chronicity
Sissoko D et al. PLoS Negl Trop Dis. 2009.
Hoarau JJ et coll. J Immunol 2010
• Prevalence depending on the outbreak
• After 3 months : up to 80 to 93%
• After 15 months : up to 57%
• After 2,5 years : 47%
• Associated with non healing
• Intensity of the acute stage: pain, CRP, high viral load
• Age > 45 yo, pre-existing joint disorders
Moiton, M.P. et al. BEH thématique, 2008; 38-40
Sissoko D et al. PLoS Negl Trop Dis. 2009
Soumahoro M.K. et al. Rev Med Interne. 2008
Marimoutou C et al. Medicine 2012
M4to…

24. 24Simon F, personal data
Neck
Shoulders
Elbows
Wrists
Hands
Back
Hips
Knees
Ankles
Heels
Feet
54,1%
46,2 %
31,3 %
71,0 %
82,1 %
28,0 %
14,1 %
51,3 %
70,9 %
29,6 %
68,7 %
757 military policemen,
Reunion Island, 2006
6 months after onset
672 answerers
M: 95%,
mean age : 40 yo
126 CHIK+
86% chronic arthralgia
Chronic arthralgias - M6
M4to…

25. 25
• Inflammatory
• Pain & morning stiffness
• Improved with motion (32%)
• Fluctuations
relapses 65 %
continue 27 %
continue, then relapsing 4 %
continue with increase
due to relapses
4 %
Profile of chronic pain
Simon F, personal data
Chronic arthralgias – M6 (2)
M4to…

26. 26
Shoulders
Elbows
Wrists
Hands
Back
Hips
Knees
Ankles
Feet
88,5 %
88,2 %
85,1 %
80,8 %
95,5 %
40,0 %
83,9 %
65,1%
76,9 %
Chronic joint stiffness – M6
Simon F, personal datac
M4to…

27. 27
CHIK+not healed
CHIK+ healed
CHIK-
Rheumatic overmorbidity… even after recovery !
Marimoutou C et al. Medicine 2012
M4to…

28. 28
Chronic impact on the mood – M24
Fatigue CHIK+
Depression CHIK+
Fatigue CHIK-
Depression CHIK-
Marimoutou C et al. Medicine 2012
M4to…

29. 29
Chronic stage, up to 6 years…
>once/month 2008 2012
CHIK+ CHIK+ CHIK-
Pain 83 70 35
Stiffness 82 53 18
Swelling 50 20 2
>once/month 2008 2012
CHIK+ CHIK+ CHIK-
Fatigue 17 60 32
Headache 14 42 29
Depression 4 21 6
Rheumatic symptoms Other symptoms
Marimoutou C et al. BMC Musc Dis 2015
French gendarmes cohort
Reunion exposure, 2006
Follow-up 2008-2012 period
M4to…

30. 30
Chronic stage, up to 6 years…
>once/month 2008 2012
CHIK+ CHIK+ CHIK-
Pain 83 70 35
Stiffness 82 53 18
Swelling 50 20 2
>once/month 2008 2012
CHIK+ CHIK+ CHIK-
Fatigue 17 60 32
Headache 14 42 29
Depression 4 21 6
Rheumatic symptoms Other symptoms
Marimoutou C et al. BMC Musc Dis 2015
French gendarmes cohort
Reunion exposure, 2006
Follow-up 2008-2012 period
>
>
>>
>
>
>
M4to…

31. 31
Chronic stage, clinical features and classification
• Same spectrum than at post-acute stage
• Persistence of miscellaneous rheumatic disorders
• Anxio-depressive reaction, fatigue
• Impaired quality of life
• Musculoskeletal disorders: 95 % of the chronic patients
• Favored by absence of efficient anti-inflammatory treatment
and by joints’ overuse
• Post-CHIK chronic inflammatory rheumatism (CIR): 1-5%
Essakjjee et al. Postgrad Med 2013 Rosario V et al. 2015
M4to…

32. 32
• No synovitis 
• Improvement of the distal tenosynovitis
• Palmar and plantar fasciitis +++
• New tendonitis on more proximal joints
• Achille’s tendons, elbows
• Shoulders, hips, knees
• Contracture in axial muscles
Simon F et coll. Medicine 2007 and personal data
The most frequent situation, multiple tendon disorders
Coll. F Simon
M4to…
Typical locations
after 6 months

33. 33
Frequent MSD, multiple tendon disorders
Coll. F Simon
Coll. F Simon
M4to…
Coll. F Simon
Coll. F Simon
Palmar
nodular
fasciitis

34. 34
• Common normality on X-rays of joints for most patients
• Mild changes in biological tests for most patients
• Mild inflammatory syndrome
• Rare rheumatoid factor, including anti-CCP antibodies
• No antinuclear factors
• +/- long persistence of anti-CHIKV IgM
Simon F et coll. Medicine 2007
Chronic stage, mild biological & radiological changes
M4to…

35. 35
• Not pre-existing before acute CHIK infection
• Confirmation of the recent CHIK infection
• Subsequent evolution > 3months after acute stage  ++
• No other aetiology found
• Fitting the criteria of the classical CIR definitions ++
- Presence of synovitis, not arthralgia only
Rare post-CHIK chronic inflammatory rheumatisms
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
M4to…

36. 36Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
International criteria for CIR
M4to…

37. 37
• Rheumatoid arthritis RA (ACR 2010 criteria)
• 1/3 with anti-CCP; 60 % with bone erosions; initial corticoresistance
• Peripheral spondyloarthritis SA (ASAS 2011 criteria)
• Pseudo-psoriatic, multiple synovitis, enthesal inflammation (heels…)
• Unclassified polyarthritis (non RA-SA chronic polyarthritis)
• Poor response to anti-inflammatory drugs
• Possible evolution to RA or SA
Bouquillard E, Combe F, Joint Bone Spine 2009 Malvy D et coll., BMC Infect Dis 2009 Ribera A et coll., Med Trop 2012
Three post-CHIK chronic inflammatory rheumatisms (CIR)
M4to…

38. 38
Coll. E Javelle
Coll. E Javelle
Coll. E Javelle
Coll. F Simon
Coll. F Simon
Coll. F Simon
Coll E. Javelle
Post-CHIK
rheumatoid arthritis
Post-CHIK
spondyloarthritis
Bouquillard E, Combe F, Joint Bone Spine 2009 Malvy D et coll., BMC Infect Dis 2009
Ribera A et coll., Med Trop 2012 Foissac M. et al. Emerg Infect Dis 2015
M4to…

39. 39
Chronic stage, two categories of patients
≈ 5%
≈ 95%
Musculoskeletal disorders
No synovitis
Chronic inflammatory rheumatisms
Presence of synovitis
Localized
Mono- or oligo-articular involvement
Other local complications
Diffuse
Distal polyarthralgia with SC oedema
Diffuse polyalgia, fatigue
Rheumatoid arthritis ++
Spondyloarthritis
Unclassified polyarthritis
(diagnostic after exclusion RA/SA/other)
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
M4to…

40. 40
Chronic stage, clinical assessment
• The same systematic screening as for the post-acute stage
• In-depth assessment for social impact of the post-CHIK status
• Private life, work…
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
M4to…

41. 41
Chronic stage, biological assessment
Confirmation of
chikungunya
Level of
inflammation
and
dysimmunity
Pre-treatment
checking
Underlying
disease?
Serology CHIK
(IgG)
Haemogram
(sedimentation
rate)
C-reactive protein
Anti-CCP2,
Rheumatoid factors
Anti-nuclear AB
C3 C4 CH50
HLA B27 if
suspected SA
Ionogram
Creatinin
Transaminases
Glycemia
HbA1C if diabetes
± urine stick
+/- uricemia
HIV/HBV/HCV
TSH, CPK
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
M4to…

42. 42
M4to…
Chronic stage, imaging according to clinical feature
• Systematic screening recommended by guidelines for RA and SA
• X-ray of any symptomatic joint
• Echography for involved joint or tendon
- Confirmation of synovitis, stdy of tendon change
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

43. 43
Chronic stage, diagnosis algorithm
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
M4to…

44. 44
Chronic stage, treatment
• For all patients +++
• Painkillers, physiotherapy, local treatment, psycho-social support,
prolonged follow-up + specific treatment
• Non-RIC MSD
• Non inflammatory features: NSAIDs for weeks, local treatments
• Polyarthralgia with periarticular oedema: NSAIDs, short corticotherapy
(2nd
line), local treatments
• Aspecific diffuse pain: other cause ? Specialists’ advices required
• Post-CHIK CIR = CIR
• Follow the guidelines ++ ! Early start, adequate drug and dose
• No prolonged corticotherapy; special place for methotrexate
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
M4to…
Four RCT:
Poor quality
Inconclusive

45. 45
Chronic stage, treatment for post-CHIK CIR
Post-CHIK RA(1)
French guidelines (SFR 2014)
Methotrexate (MTX): early in first-line
Alternative with other DMARDs (leflunomide, sulfasalazine)
Biological agents if poor response to the 1rst
line and
unfavourable progonsis
Follow-up with DAS 28 score
Post-CHIK SA(2)
French guidelines (SFR 2014)
NSAIDs in first line
Methotrexate or sulfasalazine in 2nd
line if peripheral synovitis
Biological agents if poor response or side effects to the
NSAIDs or DMARDs
Post-CHIK UP(3)
NSAIDs in first line
Corticotherapy in 2nd
line
Methotrexate in 3rd
line or to spare steroids;
alternative: hydroxychloroquine (not validated here)
1 : Gaujoux-Viala C, Joint Bone Spine 2014;81(4):287-97. ; 2 : Wendling D, et al. Joint Bone Spine 2014;81(1):6 14. ;‑
3: Ribéra A, et al. Méd Trop 2012;72 Spec No:83 5.‑
M4to…

46. 46
ResolutiveResolutive
Possibly destructive
if delayed treatment
Possibly destructive
if delayed treatment
Local inflammatory
post-infectious
→ MSD
Local inflammatory
post-infectious
→ MSD
Systemic
auto-inflammatory
→ CIR
Systemic
auto-inflammatory
→ CIR
Painkillers
DMARDs
Spare tendons & muscles
Painkillers
DMARDs
Spare tendons & muscles
Painkillers
Anti-inflammatory drugs
Spare tendons & muscles
Painkillers
Anti-inflammatory drugs
Spare tendons & muscles
Chronic stage, the two opposite outcomes
GP
Physiotherapist
Rheumatologist
GP
Physiotherapist
M4to…

47. Months Years
End of the outbreak
 epidemic period   post-epidemic period … … 
Cumulated
number
of cases
All patients having been infected
Symptomatic patients
with musculoskeletal disorders
(without polyarthritis)
Symptomatic patients with chronic inflammatory rheumatisms
Asymptomatic infection,
recovered patients
without sequelae
or active pain
The natural post-epidemic outcome in a population
Adapted from Simon F et al. N Engl J Med June 2015 (in press)
CHIK as an alphaviral outbreak
= a check

48. Months Years
End of the outbreak
 epidemic period   post-epidemic period … … 
Cumulated
number
of cases
All patients having been infected
Symptomatic patients
with musculoskeletal disorders
(without polyarthritis)
Symptomatic patients with chronic inflammatory rheumatisms
Asymptomatic infection,
recovered patients
without sequelae
or active pain
What we recommend…
Adapted from Simon F et al. N Engl J Med June 2015 (in press)
For CIR,
early
DMARD
For « all »,
prompt
optimal
treatment

49. Months Years
End of the outbreak
 epidemic period   post-epidemic period … … 
Cumulated
number
of cases
All patients having been infected
Symptomatic patients
with musculoskeletal disorders
(without polyarthritis)
Symptomatic patients with chronic inflammatory rheumatisms
Asymptomatic infection,
recovered patients
without sequelae
or active pain
What we hope!
For CIR,
early
DMARD
Adapted from Simon F et al. N Engl J Med June 2015 (in press)
For « all »,
prompt
optimal
treatment

50. 50
TAKE HOME MESSAGES ON PERSISTING SYMPTOMS
• CHIKUNGUNYA IS NOT DENGUE (BIS)
• Post-infective status harder and longer than dengue
• Specific case management ++++
– Early clinical assessment (hot spots)
– Post-CHIK kit treatment: painkillers, NSAIDs, physiotherapy
– Detection of refractory cases : do not miss CIR
– Need for a specific network with a step-by-step strategy for patients with
post-CHIK rheumatic disorders
D0toD21
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015

51. For more information, contact
simon-f@wanadoo.fr
fabrice2.simon@intradef.gouv.fr
OPEN ACCESS ONLINE
English & French
(coming next:Spanish version from PAHO)

52. 52
This lecture results from the multidisciplinary experience
of the French Army Health Service
in collaboration with the University Hospitals
in Reunion and Martinique islands, and in Marseille,
and the expert group for the French guidelines
Special thanks to all my CHIK colleagues,
especially to Dr JAVELLE, MARIMOUTOU and DEMOUX
 Version 04/11/2015 