Chikungunya

Clinical features

Pr Fabrice SIMON, MD, PhD

Department of Infectious Diseases and Tropical Medicine
LAVERAN Military Teaching Hospital - Marseille France

1
 Chikungunya, a double disease

Alphavirosis
Arboviral disease
Joint tropism
Epidemic
Acute primary infection
Due to Aedes expansion
Long-lasting rheumatic disorders
Visible, brutal
& High post-epidemic burden
Undermanaged

Coll. E. Javelle

2
 Chikungunya, first clinical descriptions

1954, Tanzania, the bending disease

Fever and intense pain in joints during acute stage

Commonly persisting for months

During 50 years, a benign infection in remote developing

countries of poor interest in public health
= NEGLECTED

Robinson MC. Trans R Soc Trop Med Hyg. 1955;49:28-32 Fourie & Morrison. S A Med J 1979;56:130-132
Brighton et al. S A Med J. 1983 Kennedy et al. J Rheumatol 1980;7:231-236 3
The lessons from the 2005-2006 outbreak in Indian Ocean

A perfect example of emergence

Not a negligible disease at all

- Brutality of the acute stage for most patients
- Wide clinical spectrum
- Unexpected complications and deaths during acute stage
- Long-lasting general and rheumatic disorders
- Lack of guidelines for clinical management, including persisting disorders
 Toward a better description of the clinical aspects
of chikungunya disease

1960 1980 2000 2017

4-10 millions
Less than one million cases in 50 years
of cases

PubMed
 The natural history of chikungunya disease

Acute
D1 to D21

60-80% spt

High viremia to D5-D7

Intense inflammation

Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 6

 The natural history of chikungunya disease

Acute Post-acute
D1 to D21 S4 to S12

70% spt

Inflammation and transient immune changes

Multifocal persistence of joint inflammation musculo-skeletal disorders

Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 7

 The natural history of chikungunya disease

Acute Post-acute Chronic

D1 to D21 S4 to S12 From M4 to

20-50% spt Up to
40-60% spt
after 2 years 6-8 years

Multifocal persistence of joint inflammation musculo-skeletal disorders +++

Rare evolution toward a chronic inflammatory rheumatism

Psycho-social consequences

Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 8

 Acute stage: frequently symptomatic

Differences between the outbreaks and the population studied

> 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 9
 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 10
 Multiple joint involvement

Bilateral, symmetrical, distal > 10 joints

Synovitis + periarticular edema +/- joint effusion
Less frequent in the elderly patients

Coll. F Simon

Coll. E. Javelle

Coll. E Javelle

Coll. F Simon
Simon et al. Medicine, 2007 Coll. F Simon
Godaert, pers. comm. 11
 Tendons involvement

Common, after one week

Mostly distal on thin distal joints

Coll. E. Javelle
Coll. E. Javelle

Simon et al. Medicine 2007 12

 Brutal multiple pain and disability

Outbreak in Comoros, 2005 (seroprevalence: 63%)

80% of CHIK-infected patients hospitalized/confined at home (mean: 6 days)

Queyriaux et al. Lancet Infect Dis. 2008;8:2-3

Sergon K et al. Am J Trop Med Hyg 2007; 76: 1189-1193.
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 Other common clinical manifestations

Reunion Island, 2006, 76 ambulatory CHIK patients, days 1, 7 and 25.

Frequent varied symptoms in many outpatients
cutaneous 50%, digestive 40%

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Thiberville et al. Plos NTD 2013
 Common skin manifestations
Maculo-papular exanthema Diffuse hyperemia

Coll. F Simon Coll. F. Simon

Facial oedema Distal subcutaneous oedema

Coll. F Simon

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 Atypical skin manifestations

Itching exanthema Bullous exanthema

Purpura

Coll E. Javelle
Coll. B. Lamey

Keratodermia Pseudochondritis

Coll. B. Lamey

Coll. F Simon

Coll. B. Lamey 16
 Other atypical benign manifestations

Lymphadenopathy

Minor bleedings

Coll. E Javelle
Parotitis (Guyana)

Ocular signs
Conjonctivitis, iridocyclitis, nodular episcleritis
Retinitis, optic neuritis

Mahendradas et al Ophthalmology 2008

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Epelboin et al Med et Mal Inf 2015
Common biological changes

CHIK+ CHIK-

18
Thiberville et al. Plos NTD 2013
Acute stage, high risk for clinical misdiagnosis

CHIKUNGUNYA FEVER
ZIKA
Acute polyarthritis
Red Tenosynovitis
eyes Distal
swelling

DENGUE
Rash Fever
FEVER
Myalgia MALARIA
Retro-orbital pain Bleedings Anemia
Transient arterial
hypotension Jaundice
Renal failure

Myalgia ADRS
Myocarditis
BACTERIAL
LEPTOSPIROSIS SEPSIS

Adapted from Simon et al, Schwartz, Infections in travelers, Ed 2009

Atypical hospitalized, complicated or severe cases

Reunion island, Outbreak 2005-2006

- Retro and prospective surveillance 2/3 of the population infected

On pregnancy

Atypical (hospital)

Severe (hospital)

CHIKV-related-deaths

0 100 200 300 400 500 600 700

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Economopoulou et al Epidemiol. Infect. 2008 20
Atypical hospitalized, complicated or severe cases

> 600 CHIK-infected pregnant women

Vertical transmission - 44 neonatal severe infections
224 atypical cases younger than 16 years

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Economopoulou et al Epidemiol. Infect. 2008 21
 Mother-to-child transmission

Antepartum viremia
No overmorbidity
10% infants with IgG cleared progressively

Per-partum viremia (7days before-2days after delivery)

50% vertical transmission
without caesarian section protection

Vigilance in preterm pregnant women

Delivery as late as possible after the mother
CHIK onset

Grardin et al PloS Med 2008; PLoS Negl Trop Dis 2014

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 Neonatal chikungunya

Symptomatic within the first week of life

Lethargy, fever, poor feeding, edema, erythrodermia followed by skin peeling

Robin et al Eur J Pediatr 2010

Fritel X et al. Emerg Infect Dis. 2010
Grardin et al PloS Med 2008; PLoS Negl Trop Dis 2014
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 Neonatal chikungunya

50% with severe infection

High letality rate
50% encephalitis with 50% permanent disabilities and altered
intellectual quotient
Hemorrhagic fever
Bullous skin lesions
Multivisceral deficiency

Grardin et al PloS Med 2008

Grardin et al PLoS Negl Trop Dis 2014
Robin et al Eur J Pediatr 2010
Fritel X et al. Emerg Infect Dis. 2010 24
Atypical hospitalized, complicated or severe cases

610 atypical adult cases:

222 severe (36%),
84 (14%) ICU, 65 deaths (10%)

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Economopoulou et al Epidemiol. Infect. 2008 25
 The harmful partners of CHIKV +++++

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

Co-infections +
Dengue, malaria, leptospirosis, bacterial sepsis
Economopoulou et al Epidemiol. Infect. 2008 26
Rajapakse et al Trans R Soc Trop Med Hyg 2010
 Complications due to CHIKV plus cofactors

NEUROLOGIC Stroke , epilepsy

Frequent
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 Main contribution

Thrombosis, of cofactors
pulmonary embolism, cardiac failure, asthma or chronic
obstructive pulmonary disorder
and underlying decompensated,
conditions to bacterial
pneumonia
chikungunya severity
CUTANEOUS Toxic epidermal necrolysis (NSAIDs)

SEVERE SEPSIS, Co-infections: dengue, malaria, leptospirosis, urinary tract infection,

SHOCK bacteremia

HEMORRHAGIC Dengue coinfection, NSAIDs , aspirin

ENDOCRIN Diabetes decompensation

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 Complications with a direct role of CHIKV

NEUROLOGIC
D
Meningoencephalitis++
Rare
E
1,4-3/1,000 case Guillain Barre syndrome
C
Seizure, confusion
R
HEPATIC E Acute (fulminant) hepatitis
A
CARDIAC S Myocarditis
I
N
SEVERE SEPSIS Aggressive clinical course, rapid haemodynamic deterioration,
G
SHOCK multisystem failure without documented coinfection or antibiotic efficacy
I
CUTANEOUS Bullous dermatosis, epidermolysis (newborns, adults, lupus)
N
C
RENAL I Nephritis (interstitial)
D
HEMORRHAGIC E Newborns (vasculitis?)
N
ENDOCRINE C Inappropriate hypersecretion of antidiuretic syndrome
E hypoadrenalism

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 Three newly described complications
Bullous epidermolysis and Sepsis Acute vascular purpura
multivisceral failure on And septic shock distal necrosis
systemic lupus

Atypical & severe

High letality
Coll. E Javelle

Hyperleucocytosis
Renal failure

Coll. E Javelle
No other infection

Torres et al IDCases 2 2015

Hoen et al.
Coll. E Javelle
Emerg Infect Dis 2016 Torres et al IDCases 2 2015
Polomat et al Rev Med Intern 2014
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 Chikungunya-associated mortality

Excess deaths observed in Reunion, India (Ahmedabad)

- Underestimation in Brazil

Case fatality rate close to that of seasonal flu

From 0.3-1/1,000 in Reunion Island, 2006 and Martinique, 2014
Chikungunya mortality
Risk factors for chikungunya-associated severity and/or fatality
- Age 60 years, higher if 85 years
- Hypertension, underlying cardiac disorders
- Use of NSAIDs
- Alcohol abuse
- Systemic lupus
Tandale et al JCV 2009
Rajapakse et al Trans R Soc Trop Med Hyg 2010
Josseran et al EID 2006
Economopoulou et al Epidemiol. Infect. 2008
Mavalankar et al. Emerg Infec dis 2008
Gazre et al Ranimation 2011
Renault et al Am J Trop Med Hyg 2007 & EID 2008 30
Pamplona de Ges Cavalcanti 2017
INVS CIRE ARS Martinique
Management of CHIK-suspected patients

Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 31

 Treatment during the acute stage
Only one RCT

negative
No efficient antiviral drug

Painkillers +++
Acetaminophen +++, switch to class 2 if necessary (caution to toxicity)
No NSAIDs before D10 (DENGUE = DANGER) & no corticosteroids
Relative rest +/- antalgic physiotherapy

Rehydration ++ & control of of underlying conditions

Specific management for complicated/atypical cases or

susceptible patients (elderly, neonates, pregnant women)

Abdelnabi et al Antiviral Research 2015 Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 32
 Post-acute stage (S4-S12): clinical features

Clinical persistence or relapse after transient improvement

Common exacerbation at M2-M3

General manifestations
Fatigue and depressive reaction

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;8:23. 33
 Frequent disability in daily life

Chikungunya, the bending disease

Typical locations
after 2 months
 Toward chronicity

Prevalence depending on the outbreak

After 3 months : up to 80 to 93%

After 2,5 years : about 50%
General and rheumatic overmorbidity up to 6 years
Moiton, M.P. et al. BEH thmatique, 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

Associated with non healing

Intensity of the acute stage: pain, CRP, high viral load
Age > 45 yo, pre-existing joint disorders

Sissoko D et al. PLoS Negl Trop Dis. 2009.

Hoarau JJ et coll. J Immunol 2010
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 Chronic arthralgias and stiffness- M6

757 military policemen,

Reunion Island, 2006

6 months after onset

672 answerers
M: 95%, mean age : 40 yo
126 CHIK+

86% chronic arthralgia

Simon F, personal data 36
Rheumatic overmorbidity after 2 years even after recovery !

CHIK+not healed

CHIK+ healed

CHIK-

Marimoutou C et al. Medicine 2012 37

 Chronic stage, up to 6 years

Rheumatic symptoms Other symptoms

>once/month 2008 2012 >once/month 2008 2012

CHIK+ CHIK+ CHIK- CHIK+ CHIK+ CHIK-

Pain 83 70 35 Fatigue 17 60 32

Stiffness 82 53 18
Headache 14 42 29

Swelling 50 20 2 Depression 4 21 6

French gendarmes cohort

+ Increased medical consumption
Reunion exposure, 2006
Follow-up 2008-2012 period
+ Impaired QoL 39
Marimoutou C et al. BMC Musc Dis 2015
 Two categories of persisting rheumatic disorders

Musculoskeletal disorders Chronic inflammatory

No synovitis rheumatisms
Presence of synovitis

Localized +++ Rheumatoid arthritis ++

Multifocal ++ Unclassified polyarthritis +

Diffuse + Spondyloarthritis

> 99% < 1%

Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 40

Multiple mechanical disorders: THE MOST FREQUENT

NO SYNOVITIS
98-99% of the chronic patients
Pain, stiffness, tendonitis, bursitis, muscle contractures,
deconditioning
Typical locations
after 6 months

Coll. F Simon
Coll. F Simon

Coll. F Simon

Coll. F Simon
Simon F et coll. Medicine 2007 and personal data 41
Post-CHIK chronic inflammatory rheumatisms: RARE (<1%)

PRESENCE OF SYNOVITIS, not arthralgia only

Subsequent evolution > 3 months after acute stage
Fitting the criteria of the classical CIR definitions
Rheumatoid arthritis+++, undifferentiated polyarthritis, exacerbation of
spondyloarthritis, RS3PE

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 42
 Persisting symptoms, major role for primary care

Physical assessment
+/- biological testings Partial Improvement
+/- imaging Healing

General
Musculo-skeletal
Practitioners disorders
Painkillers, NSAID
Uncontrolled symptoms after 6-8
and physiotherapy weeks of standard treatment
during 6-8 weeks Complex situation
If refractory, test Diagnosis uncertainty
systemic steroids

Experts in post-CHIK disease

Multidisciplinary team
Rheumatologists and other specialists
Chronic inflammatory rheumatisms
 The real burden of a CHIK outbreak in a population

All patients having been infected

Cumulated
number
of cases

Months Years

epidemic period post-epidemic period

End of the outbreak

 The real burden of a CHIK outbreak in a population

All patients having been infected

Cumulated
number
of cases

Asymptomatic infection,
recovered patients
without sequelae
or active pain

Symptomatic patients
with musculoskeletal disorders
(without polyarthritis)

Symptomatic patients with chronic inflammatory rheumatisms

Months Years

epidemic period post-epidemic period

End of the outbreak

 Chikungunyma, a double challenge

Arboviral disease Alphaviral disease

Control the spread Manage the patients
Avoid new infections
Acute infection
Aedes and
and persisting symptoms+++
viremic patients

http://www.paho.org/
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 08/08/2017
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 Pr Fabrice SIMON

Service de pathologie infectieuse et tropicale

Hpital dinstruction des armes LAVERAN
Bd LAVERAN
13013 Marseille - France

+ 33 4 91 61 72 48

simon-f@wanadoo.fr
fabrice2.simon@intradef.gouv.fr
chikungunya.laveran.marseille@gmail.com

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