clinical features and complications...• neonatal infection within the first week of life –...
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Chikungunya Clinical features and complications
Prof Fabrice SIMON, MD, PhD
Department of Infectious Diseases and Tropical Medicine
LAVERAN Military Teaching Hospital - Marseille - France
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Conflict of interest
• Collaboration with Valneva on a vaccine candidate
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Chikungunya, two diseases in one
• Arthropod-borne virus
- Transmitted by Aedes spp. mosquitoes
• Alphavirus
- 3 lineages
- Strong arthrotropism
• Biphasic disease
- Fever & arthralgia at acute stage
- Chronic rheumatic and general disorders
Long-term burden in public heath
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The natural history of chikungunya disease: three stages
Acute
D1 to D14
High viremia to D5-D7
Intense inflammation
60-80% spt
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
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Acute stage: frequently symptomatic
• > 70% of symptomatic cases in Comoros archipelago, Reunion
and India, 2005-2006
• 82% asymptomatic in Philippines, 2014
• 58.3% asymptomatic children in Managua, Nicaragua; 2014
• 15,7% of asymptomatic blood donors in French West Indies
Josseran L et coll. Emerg Infect Dis 2006:12:1994-5
Kumar et al., 2011, Sergon et al. 2007, Sissoko et al., 2008
Yoon et al 2015, ; Kuan et al. 2016
Leparc-Goffart, personal comunication
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Acute stage: common features
• Fever (90-96%) : high, 2-4 days
• Multiple arthralgia +/- arthritides (95-100%) : the CHIK signature
Brutal disability in daily life
• +/- other non severe manifestations
• Spontaneous mild to complete improvement after 10-12 days,
or not…
Borgherini G et coll. Clin Infect Dis 2007;44:1401-7 Hochedez et al. Eurosurveillance 2007, 12: 1
Simon F et coll. Medicine 2007;86: 123-37 Josseran L et coll. Emerg Infect Dis 2006:12:1994-5
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• Bilateral, symmetrical, distal > 10 joints
• Synovitis + periarticular edema + tendonitis +/- joint effusion
• Less frequent in the elderly patients
Simon et al. Medicine, 2007
Godaert, JAGS 2018 7
Multiple joint involvement
Coll. F Simon
Coll. F Simon Coll. F Simon
Coll. E. Javelle
Coll. E Javelle
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Other common clinical manifestations
Thiberville et al. Plos NTD 2013
Reunion Island, 2006, 76 ambulatory CHIK patients, days 1, 7 and 25. Frequent varied symptoms outpatients
cutaneous 50%, digestive 40%
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Facial oedema
Common skin manifestations
Coll. F Simon
Maculo-papular exanthema
Coll. F Simon Coll. F. Simon
Distal subcutaneous oedema
Diffuse hyperemia
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Brutal multiple pain and disability
Queyriaux et al. Lancet Infect Dis. 2008;8:2-3
Sergon K et al. Am J Trop Med Hyg 2007; 76: 1189-1193.
• Outbreak in Comoros, 2005 (seroprevalence: 63%)
80% of CHIK-infected patients hospitalized/confined at home (mean: 6 days)
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Atypical hospitalized, complicated or severe cases
11 Economopoulou et al Epidemiol. Infect. 2008
0 100 200 300 400 500 600 700
CHIKV-related-deaths
Severe (hospital)
Atypical (hospital)
On pregnancy
• Reunion island, Outbreak 2005-2006 - About one third of the population infected
- “Rare” complications
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Mother-to-child transmission
• Per-partum viremia (7 days before - 2 days after delivery)
- 50% vertical transmission
- No protection by caesarian section protection
• Neonatal infection within the first week of life – Lethargy, fever, poor feeding, edema, erythrodermia followed by skin peeling
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Robin et al Eur J Pediatr 2010
Fritel X et al. Emerg Infect Dis. 2010
Gérardin et al PloS Med 2008; PLoS Negl Trop Dis 2014
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Neonatal chikungunya
• 50% with severe infection
– High lethality rate
– Hemorrhagic fever
– Bullous skin lesions
– Multivisceral deficiency
– 50% encephalitis with 50% permanent disabilities
and altered intellectual quotient in survivors
13
Gérardin et al PloS Med 2008
Gérardin et al PLoS Negl Trop Dis 2014
Robin et al Eur J Pediatr 2010
Fritel X et al. Emerg Infect Dis. 2010
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The harmful partners of CHIKV in adults
• Underlying diseases ++++
– Chronic organ failure (heart, kidney, lung) decompensation
– Auto-immune disorders (systemic lupus)
– And/or overwhelming CHIKV infection
• Decubitus complications (elderly)++
– Thrombosis, deconditioning, ulcers
• Iatrogenic +++ – Drug misuse and overuse
– Hepatic, cutaneous or renal toxicity, diabetes under steroids
• Co-infections + – Dengue, malaria, leptospirosis, bacterial sepsis
14 Economopoulou et al Epidemiol. Infect. 2008
Rajapakse et al Trans R Soc Trop Med Hyg 2010
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Complications due to CHIKV plus cofactors
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NEUROLOGIC Stroke , epilepsy
RENAL Rhabdomyolysis, dehydration, exacerbation of preexisting chronic
renal failure, NSAIDs
HEPATIC Alcohol, chronic viral hepatitis, cirrhosis, acetaminophen
CARDIAC Exacerbation of preexisting cardiopathy, myocardial infarction,
arythmia
RESPIRATORY Thrombosis, pulmonary embolism, cardiac failure, asthma or chronic
obstructive pulmonary disorder decompensated, bacterial
pneumonia
CUTANEOUS Toxic epidermal necrolysis (NSAIDs)
SEVERE SEPSIS,
SHOCK
Co-infections: dengue, malaria, leptospirosis, urinary tract infection,
bacteremia
HEMORRHAGIC Dengue coinfection, NSAIDs , aspirin
ENDOCRIN Diabetes decompensation
Frequent
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NEUROLOGIC
1,4-3/1,000 cases
Meningoencephalitis++
Guillain Barre syndrome
Seizure, confusion
HEPATIC Acute (fulminant) hepatitis
CARDIAC Myocarditis
SEVERE SEPSIS
SHOCK
Aggressive clinical course, rapid haemodynamic deterioration,
multisystem failure without documented coinfection or antibiotic efficacy
CUTANEOUS Bullous dermatosis, epidermolysis (newborns, adults, lupus)
RENAL Nephritis (interstitial)
HEMORRHAGIC
Newborns (vasculitis?)
ENDOCRINE Inappropriate hypersecretion of antidiuretic syndrome
hypoadrenalism
D
E
C
R
E
A
S
I
N
G
I
N
C
I
D
E
N
C
E
Rare
Complications with a direct role of CHIKV
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Chikungunya mortality
• Excess deaths observed in Reunion, India (Ahmedabad)
- Underestimation assumed in Brazil
• Case fatality rate close to that of seasonal flu
– From 0.3-1/1,000 in Reunion Island, 2006 and Martinique, 2014
– Sometimes higher (Brazil, Colombia) drug misuse?
• Risk factors for chikungunya-associated severity and/or fatality
- Age ≥ 60 years, higher if ≥ 85 years; peripartum period
- Hypertension, underlying cardiac disorders, diabetes
- Use of NSAIDs, alcohol abuse
- Systemic lupus
Josseran et al EID 2006
Mavalankar et al. Emerg Infec dis 2008
Renault et al Am J Trop Med Hyg 2007 & EID 2008
INVS CIRE ARS Martinique 17
Tandale et al JCV 2009
Rajapakse et al Trans R Soc Trop Med Hyg 2010
Economopoulou et al Epidemiol. Infect. 2008
Gaüzère et al Réanimation 2011
Pamplona de Góes Cavalcanti 2017
Chikungunya-associated mortality
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The natural history of chikungunya disease: three stages
Acute
D1 to D14
Post-acute
W4 to W12
Inflammation and transient immune changes
Multifocal persistence of joint inflammation musculo-skeletal disorders
70% spt
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
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Post-acute stage (S4-S12): clinical features
• Clinical persistence or relapse after transient improvement
- Common exacerbation at M2-M3
• Fatigue and sadness
• Osteo-tendino-articular symptoms +++
-Polymorph and associated
-Initial sites +/- new sites with time
Simon F et coll. Medicine 2007;86: 123-37
Queyriaux B et col. Lancet Infect Dis 2008;8:2–3.
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The natural history of chikungunya disease: three stages
Acute
D1 to D14
Post-acute
W3 to W12
Chronic
From M4 to …
Multifocal persistence of joint inflammation musculo-skeletal disorders +++
Rare evolution toward a chronic inflammatory rheumatism
Psycho-social consequences
40-60% spt 20-50% spt after 2 years
Up to 6-8 years
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
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Simon F, personal data
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 and stiffness- M6
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CHIK+not healed
CHIK+ healed
CHIK-
Rheumatic overmorbidity after 2 years… even after recovery !
Marimoutou C et al. Medicine 2012
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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
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Chronic stage, up to 6 years…
Marimoutou C et al. ISHEID 2014, Marseille
CHIK+
CHIK-
2012
2012
2008
2008
French gendarmes cohort
Reunion exposure, 2006
Follow-up 2008-2012 period
• Long impaired quality of life
• And increased medical consumption
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Van Aalst et al. Trav Med Infect Dis 2017
Prevalence of post-CHIK rheumatic disorders in adults
Different
methods
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Two types of post-CHIK rheumatisms
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• Majority of the patients
- Especially among those older than 30 years
• Mixed mechanisms
- Initial articular inflammation: not treated
- Pre-existing joint lesions
- Prolonged overuse
- Muscle deconditionning
• Degenerative cascade
• Multiple and evolutive
Simon F et coll. Medicine 2007 and personal data
Mechanical musculoskeletal disorders: VERY FREQUENT
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• NO SYNOVITIS +++
- Interest of US echography when doubt
• Miscellaneous features
- Tendonitis, tenosynovitis, bursitis
- Plantar and palmar fasciitis
- Enthesitis
- Distal subcutaneous oedema
- Muscle contractures
Mainly mechanical abarticular disorders
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Tenosynovitis, tendonitis
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Post-CHIK neglected stiffness in many patients
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Evolution of MSD with time
E Javelle, CHU Martinique
F Simon, collection personnelle
Pers. data, HIA Laveran, Marseille
Coll. F Simon F Simon, collection personnelle
• Incomplete improvement, then « relapse »
• Centripetal evolution
• For years
1-3 mois 4-6 mois 7-12 mois 13-18 mois
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• Higher incidence of tunnel syndromes per and post-epidemic
• Pathogenesis
‒ Intense inflammatory tenosynovitis +/- direct neuropathy
Tunnel post-CHIK syndromes
Puccioni-Sohler et al. IJID 2016 Kularatne et al. J Trop Med 2012
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• PRESENCE OF SYNOVITIS, not arthralgia only
• Subsequent evolution > 3 months after acute stage
• Fitting the criteria of the classical CIR definitions
• Rheumatoid arthritis RA
• Exacerbation of peripheral spondyloarthritis SA
• Rarely, other forms
• RS3PE, unclassified polyarthritis (non RA-SA chronic polyarthritis)
Post-CHIK chronic inflammatory rheumatisms: RARE (<2%)
Coll. E Javelle
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
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Post-CHIK chronic inflammatory rheumatisms (CIR)
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Stiffness
Pain
Handicap
in daily life
Stop of physical
activities
Deconditioning
Stiffening Rapid weight change
Mainly gain.
Depression
Limitation in social
life
Chikungunya
Self-depreciation
The post-CHIK vicious circle
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The post-chikungunya
clinical constellation
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Months Years
End of the outbreak
epidemic period post-epidemic period … …
All patients having been infected
The high impact of a CHIK outbreak on public health
Cumulated
number
of cases
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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
Suffering
Handicap Money
The high impact of a CHIK outbreak on public health
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Experience-based treatment
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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 high impact of a CHIK outbreak on public health
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Months Years
End of the outbreak
epidemic period post-epidemic period … …
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
Early adequate treatment could reduce the burden
For « all »,
Optimal Treatment
For CIR,
specific treatment Cumulated
number
of cases
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TAKE HOME MESSAGES
• Mostly symptomatic for adults
• Acute stage
• Typical features: frequent incapacitation
• Rare complications neonates, patients with underlying diseases
• Long-term general and rheumatic disorders for many patients
• Most patients with cumulative chronic MSD
• Some patients with CIR
• Common impact on mental health, daily life and budget
• The largest cause of the CHIKV-related burden
Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015
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This lecture results from the multidisciplinary experience
of the French Military Medical Services
in collaboration with:
the University Hospitals of Reunion, Martinique and Marseille,
GPs from Guadeloupe
and the expert group for the French guidelines.
m