Differential of chikungunya and dengue viruses: …...Zika Other alphavirus infections (e.g.,...

Differential of chikungunya and dengue viruses: Considerations for work-up

and management

J. Erin Staples, MD, PhDArboviral Diseases Branch

Centers for Disease Control and Prevention

National Center for Emerging and Zoonotic Infectious Diseases

Division of Vector-borne Diseases

Information to consider in development of differential diagnosis

� Factors to consider include:

� Age

� Clinical presentation (i.e., signs and symptoms)

� Travel history

� Exposure history (e.g., tick, mosquito, flood waters,

contact with animals, contact with sick persons)

� Medical history (e.g., underlying conditions,

vaccinations)

� Differential should be based on occurrence and

epidemiology of disease condition by location

Differential diagnosis for chikungunya

� Dengue � Rubella

� Leptospirosis � Measles

� Malaria � Adenovirus

� Rickettsia � Group A streptococcus

� Parvovirus � Post-infectious arthritis

� Enterovirus � Rheumatologic conditions

� Zika

� Other alphavirus infections (e.g., Mayaro, Ross River,

Barmah Forest, O’nyong-nyong, and Sindbis viruses)

Differential diagnosis for dengue

� Chikungunya � Zika

� Leptospirosis � Rubella

� Malaria � Measles

� Rickettsia � Adenovirus

� Parvovirus � Viral hepatitis

� Enterovirus � Influenza

� Melioidosis � Bacterial sepsis

� Typhoid fever � Meningococcemia

� West Nile � Group A streptococcus

� Other viral hemorrhagic fevers (e.g., Hantavirus,

CCHF, Arenaviruses, yellow fever)

Methodology for assessing differences in human

disease caused dengue and chikungunya viruses

� Selected papers where viruses were noted to be

affecting same population (not necessarily same

time)

� Compared clinical features to determine those that

were significantly different

Number of studies with significant symptoms and signs by disease

Symptom or sign

Arthralgia Cough

Myalgia Abdominal pain

Headache Diarrhea

Rash Pruritis

Vomiting Hemorrhage

Arthritis

Clinical symptoms of dengue versus chikungunya – Comparative studies (1)

Symptoms DengueN=54

ChikN=28

P value

Arthralgia 51% 71% 0.06

Myalgia 58% 82% 0.03

Headache 76% 75% 0.92

Cough 35% 15% 0.05

Skin Rash 6% 11% 0.41

Abdominal pain 25% 11% 0.15

Vomiting 43% 32% 0.35

Diarrhea 22% 18% 0.77

Arthritis 2% 0% 1.00

Reller ME et al. Chikungunya as a cause of acute febrile illness in Southern Sri Lanka. PLoSOne. 2013; 8:

e82259.

All ages

Hospitalized

and non-

hospitalized


Symptoms DengueN=53

ChikN=270

P value

Fever 93% 86% 0.16


Myalgia 71% 72% 0.96

Headache 86% 70% 0.01

Asthenia 79% 79% 0.72

Skin Rash 27% 41% 0.06

Pruiritis 20% 27% 0.26

Digestive signs 35% 32% 0.86

Hemorrhage 13% 2% 0.001

Nkoghe D et al. No clinical or biological difference between chikungunya and dengue fever during 2010 Gabonese outbreak. Inf Dis Rep. 2012;4: e5.

All ages

Hospitalized

and non-

hospitalized


Symptoms DengueN=116

ChikN=49

P value

Fever 100% 100% 1.00


Myalgia 95% 94% 0.81

Headache 94% 88% 0.18


Backbone pain 73% 65% 0.31

Watery diarrhea 48% 55% 0.43

Rash 30% 27% 0.64

Vomiting 25% 41% 0.04

Rezza G et al. Co-circulation of dengue and chikungunya viruses, Al Hudaydah, Yemen, 2012. EmergInfect Dis. 2014; 20: 1351.

All ages

Hospitalized



ChikN=131

P value

Fever 100% 100% 1.00


Myalgia 44% 31% 0.02

Headache 58% 41% 0.01


Skin Rash 18% 40% 0.001

Pruritis 12% 18% 0.2

Nausea/Vomiting 39% 21% 0.001

Taraphdar D et al. A comparative study of clinical features between monotypic and dual infection cases with

chikungunya virus and dengue virus in West Bengal, India. Am J Trop Med Hyg. 2012; 86: 720.

All ages

Hospitalized


Symptoms DengueN=16

ChikN=22

P value

Fever 100% 100% NS


Myalgia 50% 32% NS

Headache 69% 41% NS

Asthenia 81% 68% NS

Skin Rash 81% 73% NS

Pruritis 31% 48% NS

Hochedez P et al. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg. 2008; 78: 710.

Adult travelers

Non-

hospitalized



ChikN=53

P value

Fever 97% 96% 0.94


Myalgia 74% 32% 0.001

Headache 58% 23% 0.001

Cough 30% 19% 0.001

Skin Rash 28% 59% 0.001

Pruritis 4% 11% 0.11

Nausea/Vomiting 66% 21% 0.001

Diarrhea 40% 15% 0.002

Hemorrhage 13% 4% 0.08Mohd Zim MA et al. Chikungunya infection in Malaysia: comparison with dengue infection in adults and

predictors of persistent arthralgia. J Clin Virol. 2013; 56: 141.

Adults

Hospitalized

and non-

hospitalized


Symptoms DengueN=21

ChikN=23

P value

Fever 100% 100% 1.00


Myalgia 76% 70% 0.62

Headache 91% 61% 0.02

Cough 5% 17% 0.35

Skin Rash 33% 30% 0.84

Pruritis 14% 17% 1.00

Vomiting 62% 48% 0.35

Hemorrhage 24% 4% 0.09

Arthritis 0% 57% 0.001Kularatne SAM et al. Concurrent outbreaks of chikungunya and dengue fever in Kandy, Sri Lanka, 2006-

2007: a comparative analysis of clinical and laboratory features. Postgrad Med J. 2009; 85: 342.

Adults

Hospitalized


Symptoms DengueN=10

ChikN=32

P value

Arthralgia 44% 96% <0.05

Myalgia 88% 83% NS

Headache 44% 76% NS

Cough 30% 19% NS

Skin Rash 40% 88% <0.05

Abdominal pain 12% 22% NS

Vomiting 70% 19% <0.05

Diarrhea 40% 13% NS

Hemorrhage 40% 0% <0.05

Laoprasopwattana K et al. Differential diagnosis of chikungunya, dengue viral infection and other acute febrile

illnesses in children. Ped ID J. 2012; 31: 459.

Children

Hospitalized

and non-

hospitalized



ChikN=32

P value

Myalgia/arthralgia 12% 40% 0.01

Headache 45% 68% 0.04

Cough 22% 23% 0.80

Skin Rash 12% 59% 0.001

Vomiting 58% 59% 0.88

Diarrhea 6% 16% 0.15


Conjunctival injection 33% 56% 0.05

Nimmannitya S et al. Dengue and chikungunya virus infection in man in Thailand, 1962-1964: I. Observations on hospitalized patients with hemorrhagic fever. Am J Trop Med Hyg. 1969; 18: 954.

Children

Hospitalized

Number of studies with significant symptoms and signs by disease

Symptom or sign Dengue Chikungunya Neither (% Range)

Arthralgia (n=9) 5 (56%) 4 (44%) 40-100

Myalgia (n=9) 2 (22%) 2 (22%) 5 (56%)

Headache (n=9) 4 (44%) 1 (11%) 5 (56%) 44-98

Rash (n=9) 3 (33%) 6 (67%) 11-88

Vomiting (n=8) 3 (38%) 1 (13%) 3 (38%) 25-70

Cough (n=5) 2 (40%) 3 (60%) 5-35

Abd pain (n=5) 2 (40%) 3 (60%) 12-80

Diarrhea (n=5) 1 (20%) 4 (80%)

Pruritis (n=4) 4 (100%)

Hemorrhage (n=4) 2 (50%) 2 (50%) 13-40

Arthritis (n=2) 1 (50%) 1 (50%) 0-57

Summary of comparison of dengue versus chikungunya symptoms

� For all ages, no symptom consistently found to

be associated with chikungunya or dengue

� Chikungunya: Arthralgia and skin rash

� Dengue: Headache and hemorrhage

� For adults, proportions vary

� Chikungunya: Arthralgia, arthritis

� Dengue: GI symptoms

� For children, proportions vary

� Chikungunya: Arthralgia and skin rash

� Dengue: Hemorrhage

Laboratory findings of dengue versus chikungunya – Comparative studies (1)

Signs DengueN=53

ChikN=270

P value

Mean ± SD Mean ± SD

Hemoglobin 11.9 ± 1.1 12.3 ± 1.7 0.49

Leukocytes 3390 ± 1517 5243 ± 1676 0.02

Lymphocytes 1401 ± 243 2228 ± 216 0.001

Platelets 226K ± 61 223K ± 82K 0.77

AST 18 ± 10 17 ± 11 0.38

ALT 50 ± 34 45 ± 35 0.58

Creatinine 88 ± 32 96 ± 32 0.14


All ages

Hospitalized

and non-

hospitalized


Signs DengueN=16

ChikN=22

P value

Anemia 0% 15% NS

Leukopenia 75% 40% 0.03

Lymphopenia 56% 90% 0.05

Neutropenia 81% 10% 0.001

Thrombocytopenia 88% 35% 0.002

Increased ALT 88% 65% NS

Increased CRP 77% 64% NS

Hochedez P et al. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg. 2008; 78: 710.

Adult travelers

Non-

hospitalized


Signs DengueN=113

ChikN=53

P value

Leukopenia 82% 28% 0.001

Thrombocytopenia 90% 28% 0.001

Increased AST 87% 37% 0.001

Mohd Zim MA et al. Chikungunya infection in Malaysia: comparison with dengue infection in adults and predictors of persistent arthralgia. J Clin Virol. 2013; 56: 141.

Adult

Hospitalized

and non-

hospitalized


Signs DengueN=21

ChikN=23

P value


Leukocytes 3600 ± 1010 4500 ± 1880 0.245

Platelets 75K ± 34K 117K ± 70 0.001

Adults

Hospitalized

Kularatne SAM et al. Concurrent outbreaks of chikungunya and dengue fever in Kandy, Sri Lanka, 2006-



Signs DengueN=10

ChikN=32

P value


Hematocrit (%) 40.3 ± 2.7 36.0 ± 6.0 NS

Leukocytes 3895 ± 1836 8295 ± 5194 <0.05

Platelets 127K ± 68K 259K ± 68K <0.05

Laoprasopwattana K et al. Differential diagnosis of chikungunya, dengue viral infection and other acute febrile illnesses in children. Ped ID J. 2012; 31: 459.

Children

Hospitalized

and non-

hospitalized

Summary of laboratory findings of dengue versus chikungunya

� Similar to symptoms, no laboratory finding was

consistently significant between studies

� Dengue is more likely to cause leukopenia,

neutropenia, and thrombocytopenia

� Chikungunya less likely to abnormal laboratory

findings than dengue

Clinical features of dengue versus chikungunya – Comparative studies (1)

Signs DengueN=21

ChikN=23

P value

Mean (Range) Mean (Range)

Fever duration (days) 5.1 (3-10) 4.0 (1-10) 0.08

Hospital stay (days) 3.6 (2-6) 2.9 (1-9) 0.16

Adults

Hospitalized

Kularatne SAM et al. Concurrent outbreaks of chikungunya and dengue fever in Kandy, Sri Lanka, 2006-



Signs DengueN=10

ChikN=32

P value


Days of illness when

seen by doctor2.6 ± 1.3 1.4 ± 0.9 <0.05

Fever duration

(days)4.2 ± 1.5 2.8 ± 2.0 NS

Children

Hospitalized

and non-

hospitalized

Laoprasopwattana K et al. Differential diagnosis of chikungunya, dengue viral infection and other acute febrile illnesses

in children. Ped ID J. 2012; 31: 459.


Signs DengueN=523

ChikN=32

P value

Median (Range) Median (Range)

Days of illness

when hospitalized4 (0-9) 1 (0-7) 0.01

N=241 N=32

Fever duration

(days)6 (2-8+) 4 (2-8+) 0.01

Children

Hospitalized

Nimmannitya S et al. Dengue and chikungunya virus infection in man in Thailand, 1962-1964: I. Observations on

hospitalized patients with hemorrhagic fever. Am J Trop Med Hyg. 1969; 18: 954.

Summary of clinical features of dengue versus chikungunya

� In general, chikungunya patients will present to

medical care sooner than those with dengue

� Chikungunya patients also more likely to have

shorter duration of fever and hospitalization

� Findings were not significant in all studies

Summary of comparison of clinical presentation of chikungunya and dengue

� Although individuals symptoms and signs may

suggest chikungunya or dengue, no unique

clinical features to differentiate these diseases

� “The clinical and biological differences detected

in our analysis are not useful in the field. So, our

study confirms that the two diseases are

clinically similar and need for laboratory

confirmation for their recognition.”


Presentation of diseases or agents in differential diagnosis (1)

� Malaria – fever periodicity, altered consciousness;

mosquito exposure, travel/disease epidemiology

� Rickettsia – fever, myalgia, headache, abdominal

pain, eschar, maculopapular rash; tick exposure

� Zika virus infection – fever, rash, myalgia; travel/

disease epidemiology and vector exposure

� Alphaviral infections – fever, arthralgia/arthritis;

travel/disease epidemiology and vector exposure

� Leptospirosis – severe myalgia (calf muscles) with

conjunctival congestion; contaminated water


� Parvovirus – fever, runny nose, headache followed

by rash on face and body may have swollen joints,

slapped cheeks; sick contacts

� Enterovirus – fever, runny nose, cough, skin rash,

mouth blisters, myalgia, viral conjunctivitis;

seasonal epidemiology

� Adenovirus – respiratory illness (rhinitis, croup),

gastroenteritis, conjunctivitis; sick contacts

� Measles – acute viral respiratory illness with

cough, coryza, and conjunctivitis, Koplik spots;

sick contacts and vaccination status


� Rubella – rash starting on face and spreading to

the rest of body with low fevers (<39°C); sick

contacts and vaccination status

� Group A streptococcus – sore throat, rash;

seasonal epidemiology and sick contacts

� Post-infectious arthritis – arthritis of one or more,

typically larger joints; consider ASO titer

� Juvenile rheumatoid arthritis – abrupt onset of

fever and subsequent joint pain; check ESR


� West Nile disease – fever, myalgia, encephalitis or

meningitis; vector exposure

� Yellow fever – fever with jaundice or hemorrhage;

vector exposures, travel, vaccination status

� Viral hemorrhagic fevers – fever, nausea,

vomiting, hemorrhagic manifestations; rodent

exposure (Arenaviruses, Hantavirus),

tick/mosquito (RVF, CCHF)

� Melioidosis – fever, headache, anorexia, myalgia,

arthralgia; contaminated soil or surface water


� Meningococcemia – fever, nausea, vomiting, rash,

and confusion; sick contacts

� Typhoid fever – sustained fever, abdominal pain,

headache, anorexia, flat, rose-colored spots;

contaminated food, travel

� Influenza – fever, myalgia, headache, rhinitis,

cough; seasonal epidemiology

� Viral hepatitis (A/B/C/D/E) – fever, abdominal pain,

vomiting, jaundice; variable exposures

Clinical management (1)

� Assess hydration and hemodynamic status

� Refer/admit patients with delayed capillary refill,

narrow pulse pressure, hypotension, oliguria,

altered sensorium, or bleeding manifestations

� Evaluate for other serious conditions (e.g.,

dengue, malaria, and bacterial infections) and

treat or manage appropriately

� Obtain basic laboratory tests (e.g., complete blood

count, liver function tests, electrolytes)

� Evaluate for warning signs of dengue or malaria

Clinical management (2)

� Collect specimens for diagnostic testing

� Manage as dengue until dengue ruled out

� Proper clinical management of dengue reduces risk

of severe disease and death

� Aspirin and other NSAIDs can increase risk of

hemorrhage in patients with dengue

References for dengue and chikungunya (1)

� Caron M et al. Recent introduction and rapid dissemination of chikungunya virus and dengue virus serotype 2 associated with human and mosquito co-infections in Gabon, Central Africa. Clin Inf Dis. 2012; 55: e45.

� Chahar HS et al. Co-infections with chikungunya virus and dengue virus in Delhi, India. Emerg Inf Dis. 2009; 15: 1077.

� Ditsuwan T et al. Assessing the spreading patterns of dengue infection and chikungunya fever outbreaks in lower Southern Thailand using a geographic information system. Ann Epidemiol. 2011; 21: 253.

� Halstead SB et al. Dengue and chikungunya virus infection in man in Thailand, 1962-1964. II. Observations on disease in outpatients. Am J Trop Med Hyg. 1969; 18: 972.

� Hertz JT et al. Chikungunya and dengue fever among hospitalized febrile patients in Northern Tanzania. Am J Trop Med Hyg. 2012; 86: 171.

� Hochedez P et al. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg. 2008; 78: 710.


� Kularatne SAM et al. Concurrent outbreaks of chikungunya and dengue fever in Kandy, Sri Lanka, 2006-2007: a comparative analysis of clinical and laboratory features. Postgrad Med J. 2009; 85: 342.

� Laoprasopwattana K et al. Differential diagnosis of chikungunya, dengue viral infection and other acute febrile illnesses in children. Ped ID J. 2012; 31: 459.

� Lee VJ et al. Simple clinical and laboratory predictors of chikungunya versus dengue infections in adults. PLoS Negl Trop Dis. 2012; 6: e1786.

� Leroy EM et al. Concurrent chikungunya and dengue virus infections during simultaneous outbreaks, Gabon, 2007. Emerg Inf Dis. 2009; 15: 591.

� Mohd Zim MA et al. Chikungunya infection in Malaysia: comparison with dengue infection in adults and predictors of persistent arthralgia. J Clin Virol. 2013; 56: 141.

� Myers RM et al. Concurrent isolation from patient of two arboviruses, chikungunya and dengue Type 2. Science. 1967; 157: 1307.

� Nakgoi K et al. Dengue, Japanese encephalitis and chikungunya virus antibody prevalence among captive monkey (Macaca nemestrina) colonies of northern Thailand. Am J Primatol. 2014; 76: 97.

References for dengue and chikungunya (3)� Neeraja M et al. The clinical, serological and molecular diagnosis of emerging

dengue infection at a tertiary care institute in Southern India. J Clin Diag Res. 2013; 7: 457.

� Nimmannitya S et al. Dengue and chikungunya virus infection in man in Thailand, 1962-1964: I. Observations on hospitalized patients with hemorrhagic fever. Am J Trop Med Hyg. 1969; 18: 954.

� Nimmannitya S et al. Comparative clinical and laboratory findings in confirmed dengue and chikungunya infections. WHO Bull. 1969.

� Nkoghe D et al. No clinical or biological difference between chikungunya and dengue fever during 2010 Gabonese outbreak. Inf Dis Rep. 2012;4: e5.

� Omarjee R et al. Importance of case definition to monitor ongoing outbreak of chikunugnya virus on a background of actively circulating dengue virus, St. Martin, December 2013 to 2014. Eurosurveill. 2012; 19: pii=20753.

� Potiwat R et al. Competitive suppression between chikungunya and dengue virus in Aedes albopictus c6/36 cell line. Southeast Asian J Trop Med Pub Health. 2011; 42: 1388.

� Ratsitorahina M et al. Outbreak of dengue and chikungunya fever, Toamasina, Madagascar, 2006. Emerg Inf Dis. 2008; 14: 1135.


� Reller ME et al. Chikungunya as a cause of acute febrile illness in Southern Sri Lanka. PLoSOne. 2013; 8: e82259.

� Rezza G et al. Co-circulation of dengue and chikungunya viruses, Al Hudaydah, Yemen, 2012. Emerg Infect Dis. 2014; 20: 1351.

� Rohani A et al. Refractoriness of Aedes aegypti (Linnaeus) to dual infection with dengue and chikungunya virus. Southeast Asian J Trop Med Pub Health. 2009; 40: 443.

� Singh P et al. The first dominant co-circulation of both dengue and chikungunya viruses during the post-monsoon period of 2010 in Delhi, India. Epidemiol Infect. 2012; 140: 1337.

� Taraphdar D et al. A comparative study of clinical features between monotypic and dual infection cases with chikungunya virus and dengue virus in West Bengal, India. Am J Trop Med Hyg. 2012; 86: 720.

� Vazeille M et al. Orally co-infected Aedes albopictus from La Reunion Island, Indian Ocean, can deliver both dengue and chikungunya infectious particles in their saliva. PLoS Negl Trop Dis. 2010. 4: e706.

Differential of chikungunya and dengue viruses: …...Zika Other alphavirus infections (e.g.,...

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