Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96

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Tropical Medicine and Hygiene
journal homepage: http://www.elsevier.com/locate/trstmh

Review

Atypical manifestations of chikungunya infection

Senaka Rajapakse a,∗ , Chathuraka Rodrigo b , Anoja Rajapakse c
a
Department of Clinical Medicine, Faculty of Medicine, University of Colombo, 25 Kynsey Road, Colombo 08, Sri Lanka
b
University Medical Unit, National Hospital, Colombo, Sri Lanka
c
Newark Hospital, Sherwood Forest NHS Trust, Newark, Nottinghamshire, UK

a r t i c l e i n f o a b s t r a c t

Article history: Chikungunya fever is a viral infection transmitted to humans by the bite of infected
Received 11 April 2009 mosquitoes. Typical chikungunya virus (CHIKV) infection results in an acute febrile illness
Received in revised form 29 July 2009
characterized by severe joint pain and rash. Although chikungunya is generally not con-
Accepted 30 July 2009
sidered life threatening, atypical clinical manifestations resulting in significant morbidity
Available online 27 August 2009
have been documented, especially during epidemics. This review describes atypical mani-
festations following CHIKV infection reported in the literature, categorized as neurological,
Keywords:
cardiovascular, skin, ocular, renal and other manifestations. The importance of vertical
Chikungunya
Atypical manifestations transmission from an infected mother resulting in neonatal infection is also highlighted.
Encephalitis CHIKV infection can result in severe illness needing intensive care, with significant mortal-
Myocarditis ity. While there are many deaths reported which are directly attributable to CHIKV infection,
Mortality background mortality is also increased during epidemics. In this context, considering CHIKV
Review infection a benign and non fatal illness has to be revisited.
© 2009 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd.
All rights reserved.

1. Introduction joint pain is often polyarticular and symmetrical involv-

ing knees, elbows, ankles and small joints, and also sites
Chikungunya fever is a viral disease transmitted to of previous injuries.5 The pain is most intense on waking
humans by the bite of infected mosquitoes. The chikun- up in the morning. Chikungunya patients typically avoid
gunya virus (CHIKV) is a member of the genus Alphavirus, movement as much as possible–hence the derivation of
in the family Togaviridae. CHIKV was first isolated from the the name from Makonde, the language of the ethnic group
blood of a febrile patient in Tanzania in 19531,2 and has Makonde in the southeastern part of Tanzania and northern
since been identified repeatedly in west, central and south- Mozambique, meaning ‘the illness of the bended walker’.1,2
ern Africa and many parts of Asia; it has been cited as the Affected joints may swell without significant fluid accu-
cause of numerous human epidemics in those areas since mulation. These symptoms may last from one week to
that time.3 several months and are accompanied by myalgia or mus-
CHIKV infection results in an acute debilitating febrile cle pain. The rash characteristically appears on the first
illness, characterized by severe joint pain and rash3,4 day of illness, but its onset may be delayed. It usually
(Table 1). High fever may result, often accompanied by arises as a flush over the face and neck, which evolves to
chills and rigors. The fever may subside and recur, show- a maculopapular or macular form with pruritus. The other
ing a saddleback pattern similar to dengue. Arthralgia or symptoms include headache, photophobia, fatigue, nausea
and vomiting. Although, similar to dengue, mild haemor-
rhagic phenomena such as a positive tourniquet test and
∗ Corresponding author. Tel.: +94 112 695300x134;
petichiae have been described with CHIKV infection, signif-
fax: +94 112689188.
icant haemorrhage is not a characteristic feature.6,7 Plasma
E-mail address: senaka.ucfm@gmail.com (S. Rajapakse). leakage resulting in shock which is characteristic of dengue

0035-9203/$ – see front matter © 2009 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.trstmh.2009.07.031
90 S. Rajapakse et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96

Table 1 diagnosis of chikungunya was confirmed by the presence of

Criteria for diagnosis of chikungunya4
at least one of the laboratory criteria listed in Table 1 (detec-
1. Clinical criteria: acute onset of fever >38.5 ◦ C and severe tion of CHIKV IgM antibodies or CHIKV genomic products
arthralgia/arthritis not explained by other medical conditions in blood or other body fluids by RT-PCR) together with
2. Epidemiological criteria: residing or having visited epidemic exclusion of other causes with reasonable certainty.
areas, having reported transmission within 15 days prior to the
onset of symptoms
3. Laboratory criteria: at least one of the following tests in the 3. Results and Discussion
acute phase:
• Virus isolation 3.1. Neurological manifestations
• Presence of viral RNA by RT-PCR
• Presence of virus specific IgM antibodies in single serum sample
collected in acute or convalescent stage. A spectrum of neurological manifestations including
• Four-fold rising of IgG titers in samples collected at least three meningoencephalitis, myelopathy and neuropathy have
weeks apart been reported following chikungunya infection. A ret-
rospective study on atypical manifestations of CHIKV
infection during the epidemic on Reunion Island by
is not seen in chikungunya. Asymptomatic infection prob- Economopoulou et al.10 describes 147 (24.1%) patients with
ably occurs, but its prevalence is not known. In general, neurological manifestations out of 610 patients with CHIKV
chikungunya is not considered life threatening, and in the infection. The range of presentations included encephalitis
majority spontaneous resolution occurs, although arthral- (69, 11%), meningoencephalitis (15, 2%), epileptic seizures
gia can remain for several years.8,9 During the epidemic (12, 2%), Guillain-Barre syndrome (GBS) (4,1%), cerebellar
in Reunion Island 57% of patients who developed chikun- syndrome (3, < 1%) stroke (2, < 1%) and myelomeningoen-
gunya infection had persisting rheumatological symptoms cephalitis (1, < 1%).
15 months after diagnosis.8 Age over 45 years or a previous Tournebize et al.13 described 23 cases with neurological
history of osteoarthritis or hypertension were risk factors manifestations on Reunion Island. Disrupted behavior or
for persistent joint symptoms, and the severity of pain at altered mental status was common, seen in 95% of patients;
disease onset was strongly associated with persistence.8 other features such as headache (30%), seizure (26%), motor
Commonly, clinicians consider chikungunya to be a dysfunction (4%) and sensorial disorders (9%) were noted.
relatively benign condition, the main troublesome mani- Cerebrospinal fluid (CSF) findings were chiefly elevated
festations being rheumatological. However, many atypical CSF protein levels, normal glucose levels and pleocytosis.
clinical manifestations resulting in significant morbidity The diagnosis of CHIKV infection was confirmed by finding
and mortality have been documented in the literature. This either CHIKV specific IgM or RT-PCR in these patients. Elec-
review describes these unusual manifestations. Increas- troencephalography (EEG) changes were mostly of slow
ing prevalence of the infection will result in these unusual waves, with epileptiform activity seen in patients with fits.
manifestations gaining greater clinical significance. Neuroimaging was normal in these patients.
A case series of patients aged 12 to 84 years with
2. Methods chikungunya infection in Rajasthan, India by Rampal et al.14
reported neurological manifestations in as much as 33% (20
We searched MEDLINE using the search term ‘Chikun- out of 60). In this series, diagnosis of CHIKV infection was
gunya’, which returned 859 hits. Typical disease was based on a detailed clinical history and a positive IgM anti-
defined as a febrile illness with arthralgia/arthritis, with body test against the virus. Malaria, dengue and typhoid
laboratory confirmation of CHIKV infection4 (Table 1). were excluded by history and laboratory examinations. The
Non-specific symptoms such as nausea, vomiting, loss of onset of neurological manifestations was early, starting on
appetite and myalgia were considered expected symptoms the second or third day of illness. Of the 20 patients with
common to most viral infections. All other manifesta- neurological manifestations, 15 had encephalitis, three had
tions specific to organ systems were considered ‘atypical’. encephalomyelitis and two had optic neuritis. Symptomat-
By carefully searching through the abstracts we identi- ically, all 20 patients had altered sensorium with confusion
fied published papers describing atypical manifestations and delirium. Six patients had psychosis and another six
of chikungunya infection; these full papers were read had seizures, with normal EEG. The three patients with
through for data extraction. The epidemic of chikungunya myelitis had flaccid paraplegia. CSF examination was done
in Reunion Island in 2006 provided considerable insight in all 20 patients and 17 (85%) showed raised protein lev-
into the clinical manifestations of the disease.10,11 The els. Nine (45%) had total cell counts (mostly lymphocytes
seropositivity rate of the population during this epidemic and mononuclear cells) > 5/mm.3 No definite correlation
was high at 38.2% (approx. 785 000 inhabitants).12 Many was described between symptomatology and CSF findings.
other case-series and case reports also provided valuable All cases were treated symptomatically and 14 (70%) had
information on the atypical manifestations discussed here. improved within four to five days of illness and discharged.
We categorized atypical manifestations based on the There were six (30%) deaths in the series which is sig-
systems affected (Table 2), as neurological, ocular, cardio- nificantly high for a disease considered to be non-fatal.
vascular, dermatological, renal and other miscellaneous However, three of these patients were aged over 70 years
manifestations. We also examined instances of vertical and had multiple comorbidities, although it is unclear as
transmission, and reports of mortality arising from chikun- to whether the deaths were related to these or not. Hence
gunya infection. In the majority of papers reviewed, the the high mortality may have been an over-estimation, with
 S. Rajapakse et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96 91

Table 2
Summary of reported atypical manifestations of chikungunya infection with references

System Manifestations References

Neurological Encephalopathy/encephalitis/ Lewthwaite et al.(2009),19 Economopoulou et

meningoencephalitis al.(2008),10 Robin et al.(2008),18 Musthafa et
al. (2008),22 Lemant et al.(2008),20 Rampal et
al.(2007)14
Seizures Lewthwaite et al. (2009),19 Robin et al.
(2008),18 Economopoulou et al.(2008),10
Rampal et al. (2007)14
Neuropathy Economopoulou et al.(2008),10 Lemant et
al.(2008)20
Guillain-Barre syndrome Wielanek et al.(2009),16 Lebrun et al.(2009),15
Lemant et al.(2008)20
Cerebellar syndrome Economopoulou et al.(2008)10
Cardiovascular Myocarditis/pericarditis Simon et al.(2008),28 Economopoulou et al.
(2008),10 Lemant et al.(2008)20
Heart failure Economopoulou et al.(2008)10
Arrhythmias Economopoulou et al.(2008 10
Unstable blood pressure Economopoulou et al.(2008)10
Ischaemic heart disease/myocardial infarction Economopoulou et al.(2008)10
Renal Nephritis Solanki et al.(2007)30
Acute renal failure Economopoulou et al.(2008),10 Mahendradas
et al.(2007),24 Sissoko et al.(2006)29
Skin Maculopapular eruption Inamadar et al.(2008)31
Pigmentation Inamadar et al.(2008)31
Penoscrotal ulcers Mishra and Rajawat(2008)32
Bullous dermatosis Economopoulou et al.(2008)10
Ocular Optic neuritis Mahesh et al. (2008),27 Mittal et al.(2007),23
Lalitha et al.(2007)25
Iridocyclitis Mahendradas et al.(2007),24 Lalitha et al.
(2007)25
Episcleritis Mahendradas et al.(2007)24
Retinitis Mahesh et al.(2008),27 Mahendradas et
al.(2007),24 Murthy et al.(2007)26
Neonatal infection with vertical transmission Ante-partum foetal deaths, Gerardin et al.(2008),33 Lenglet et al. (2006),34
meningoencephalitis, disseminated Robillard et al. (2006)35
intravascular coagulation
Other possible associations Pneumonia, respiratory failure, hepatitis, Economopoulou et al.(2008),10 Lemant et
pancreatitis, SIADH, hypoadrenalism al.(2008)20

death occurring not primarily due to chikungunya infec- et al.16 describes another three patients with GBS during
tion. Out of the six deaths, only one patient, aged 45 years, the same epidemic. (GBS confirmed by nerve conduction
had an abnormal CT scan which showed cerebral haem- tests and clinical picture; CHIKV infection confirmed with
orrhages and cerebral oedema, which were attributed to positive IgM antibodies in serum; and other pathologies
result from chikungunya in the absence of other identifi- including HIV, C. jejuni, cytomegalovirus, M. pneumoniae,
able causes. Of the two remaining patients, one, aged 65 Epstein-Barr virus, dengue virus and Chlamydia pneumo-
years, had altered sensorium, psychosis and incontinence, niae excluded with serological tests). One patient presented
with mild reduction in motor power. She initially improved within three days of fever and the other two after one and
and was discharged, was readmitted eight days later with two weeks respectively. Interestingly, the incidence of GBS
paraplegia, subsequently left against medical advice and syndrome in Reunion Island increased in 2006 (3.3/100
died at home five days later. Details regarding the cause of 000) compared to 2005 (2.7/100 000) and returned to base-
death of the sixth patient are not available. line in 2007 (2.87/100 000).17
Lebrun et al.15 reported two cases of GBS possibly asso- Neurological manifestations in paediatric practice are
ciated with CHIKV infection during the Reunion Island also of interest. Robin et al.18 describes a case series of
epidemic. Both patients were positive for IgM antibodies 30 (24.6%) children (out of 122 confirmed cases of chikun-
against chikungunya but had a negative result in RT-PCR gunya) with neurological involvement during the epidemic
for CHIKV genomic products in both serum and CSF. CSF in Reunion Island. The spectrum of manifestations was sim-
protein levels were high though cell counts were normal. ilar to adults. Twelve had encephalitis (defined as reduced
These two patients deteriorated rapidly needing intubation level of consciousness plus either CSF pleocytosis, seizures
and mechanical ventilation but recovered completely fol- or focal neurological signs), four had acute encephalopa-
lowing the administration of intravenous immunoglobulin thy (reduced level of consciousness only) and another four
for five days. Authors attribute the failure to detect genomic had meningeal syndrome. Ten patients had seizures dur-
products of the virus by PCR to the short period of viraemia. ing the febrile episode. Whether seizures were due to
The onset of GBS was observed between days 7-14 after chikungunya or whether they were febrile seizures is not
the onset of initial symptoms (fever and rash).15 Wielanek clear. EEG was non specific in these patients. Infection was
92 S. Rajapakse et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96

confirmed by either detecting IgM antibodies in serum, or CSF, though genomic products were not detected, and
viral genomic products by RT-PCR in serum or CSF. Twenty serology for other recognized causes of GBS were nega-
three (76.6%) patients had CSF analyzed; CSF was within tive.
normal limits in the majority. Magnetic Resonance Imaging Nonetheless, current evidence suggests that it is impor-
(MRI) was performed in 14 (46.6%) patients and five (35.7%) tant to consider CHIKV infection as the cause in patients
were abnormal. Two (6.7%) patients died in the series with presenting with neurological manifestations together with
one having circulatory collapse with massive haemorrhage features of CHIKV infection (fever and arthritis), or during
and the other having cerebral oedema.9 epidemics. Diagnosis is largely clinical, together with lab-
In a study from India, Lewthwaite et al.19 describes oratory confirmation of recent CHIKV infection (Table 1).
detecting chikungunya viral genomic products in eight EEG changes appear to be non-specific and unhelpful in
(14%) children out of 58 presenting with CNS symp- diagnosis, from the limited evidence available; further
toms. All eight patients had malaria excluded by parasite studies are clearly required. CSF findings appear to be sim-
testing; dengue and Japanese encephalitis excluded by ilar to those seen in viral encephalitis/meningitis: elevated
negative serology and CSF testing. Symptoms included proteins, normal glucose and pleocytosis.14,15,18 Detection
altered mental status (7, 87%), seizures (6, 75%), apha- of CHIKV IgM or viral genomic products by RT-PCR in
sia (3, 37%) and meningism (3, 37%). Six (75%) patients CSF may be of value in patients with CNS manifestations,
recovered fully while 2 (25%) had persisting cognitive although this needs further study. Little is known about the
impairment. value of neuroimaging, although haemorrhages,14 white
Lemant et al.20 in a case series of 33 patients with matter changes22 and ring-enhancing lesions14 have been
confirmed CHIKV infection reported 14 (42%) cases of described.
encephalopathy and one (3%) case of GBS. Singh et al.21
described another case series during an epidemic in 3.2. Ocular manifestations
Andaman and Nicobar islands, where 10 cases of acute flac-
cid paralysis were reported after a CHIKV-like infection21 . Ocular manifestations are another recognized compli-
In four of those patients, CHIKV IgM antibody test was pos- cation of CHIKV infection (Table 2). Mittal et al.23 describes
itive. a case series of 14 patients (19 eyes) with confirmed
Mustafa et al.22 reports a case of acute diffuse CHIKV infection (serology for CHIKV IgM antibodies pos-
encephalomyelitis (ADEM) in a 45 year old Indian male itive with other common infective causes excluded) and
during a chikungunya epidemic in Kerala, India. The patient optic neuritis. Eight (42%) eyes had papillitis, four (21%)
presented with rapid onset quadriplegia and slurred speech had retrobulbar neuritis, another four (21%) had optic tract
in the second week following a febrile illness. The clinical involvement and three (16%) had neuroretinitis. Symp-
picture was typical of chikungunya and serology (IgM) was tomatology included blurred vision, reduced visual acuity,
positive. MRI showed multiple white matter lesions in sub- field defects and reduced colour vision. Three (21%) of these
cortical, periventricular and gangliocapsular regions. The patients had other CNS manifestations namely bilateral
patient improved after being treated with IV methylpred- ophthalmoplegia with hemiparesis, sensory neuronal deaf-
nisolone. ness of acute onset and unilateral facial nerve palsy. All
Overall, CHIKV infection can result in a wide vari- patients were treated with corticosteroids. Complete or
ety of neurological conditions (Table 2), and neurological partial improvement of vision was reported in 10 (71%)
manifestations can occur in up to one third of patients. patients with good response to steroids if given early
Encephalitis appears to be the most common manifes- in course of illness. The exact mechanism of neuritis is
tation, its incidence ranging from 11 to 18%. Certainly, unknown, but five (36%) patients had symptoms with acute
difficulties may arise as in determining whether CHIKV illness while the onset was delayed in the rest. The possi-
infection is the definite cause of the neurological mani- bility of direct viral induced damage as well as immune
festations, especially during epidemics and in areas where mediated damage has been suggested.23 Retrobulbar optic
the prevalence of the disease is high. The possibility of co- neuritis leading to permanent blindness has also been
infection with other infections which can either directly described.14
or indirectly result in neurological manifestations is a pos- In another case series from Bangalore, India, Mahen-
sible confounding factor in all of these case series. In dradas et al.24 describe a different spectrum of ocular
many of the studies, the reported degree to which inves- manifestations in nine patients with a positive serology for
tigations were performed to exclude other infections was CHIKV (supported by the typical clinical picture of infec-
variable. Economopolou et al.10 do not mention investiga- tion). Five (55%) had iridocyclitis, three (33%) had retinitis
tions done to exclude other causes. Rampal et al.14 excluded and one patient had nodular episcleritis. The onset of ocu-
malaria, typhoid and dengue. Robin et al.18 excluded bac- lar manifestations lagged 4–12 weeks behind the acute
terial CNS by negative culture, and Herpes infection by illness (fever and rash). Patients were empirically treated
negative serology in a third of patients. Lewthwaite et with acyclovir and prednisolone. All patients made a com-
al.19 excluded malaria, typhoid and Japanese encephalitis plete recovery. Lalitha et al.25 described the occurrence
by laboratory testing. The identification of CHIKV infec- of granulomatous and nongranulomatous anterior uveitis,
tion in CNS samples in the study by Tournebize et al.13 optic neuritis, retrobulbar neuritis and dendritic lesions in
suggests strongly that the manifestations were due to a descriptive study of 37 patients with serologically con-
chikungunya. In the case of the reported occurrences of firmed CHIKV infection. Good clinical recovery of vision
GBS,15,16 CHIKV antibodies were detected in serum and was seen in the majority.
 S. Rajapakse et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96 93

Bilateral retinitis has been described following CHIKV pain, she presented with chest pain and ECG showed ST
infection.24,26,27 Murthy et al.26 describe a patient with segment elevation in anteroseptal leads. Troponin I levels
bilateral retinitis in whom deterioration of vision started were elevated and a transthoracic echocardiogram demon-
three weeks after febrile illness. Serology was positive for strated a mild pericardial effusion. Intracardiac MRI done
CHIKV IgM antibodies at presentation, but later serum and at acute stage showed a subepicardial delayed enhance-
aqueous humor were positive for herpes simplex virus ment in apical and apicolateral walls of the left ventricle
(HSV) genomic products as well. The patient was treated and the lateral wall of the right ventricle. These changes
with a cocktail of antiviral drugs including IV acyclovir remained one year after treatment. She responded to
and later intravitreal gancyclovir, together with corticos- high dose aspirin with resolving of clinical symptoms and
teroids. Though the progression of lesions stopped, further ECG changes. CHIKV infection was confirmed by serology
improvement of vision was not observed. The two patients and other infective causes for myocarditis were excluded
with dendritic lesions reported by Lalitha et al.25 were by appropriate tests. The persistence of cardiac muscle
not investigated for possible HSV infection, but were also changes detected on MRI suggests that CHIKV might pre-
treated with acyclovir, with some response. While the den- dispose to dilated cardiomyopathy later in life. Myocarditis
dritic lesions seen could well be due to CHIKV, whether without heart failure may be missed as symptoms are
CHIKV infection predisposes to HSV is not known, and masked by diffuse myalgia and arthralgia.
needs further study. Mahesh et al.27 describe a 48 year old
female developing bilateral neuroretinitis two weeks after 3.4. Renal manifestations
a serology proven CHIKV infection. She was treated with
steroids and two months later visual acuity had gradually The retrospective analysis by Economopoulou et al.10
improved. The delayed onset of ocular manifestations in reveals 120 (20%) cases of pre-renal failure out of 610
these patients suggest a delayed immune response to infec- patients with atypical manifestations during acute infec-
tion. While in most instances recovery of vision to normal tion. Around one third of the patients with pre-renal
occurs, CHIKV infection can result in blindness, especially if failure had pre-existing renal disease, mostly chronic kid-
associated with optic neuritis or neuroretinitis. Estimates ney disease. One patient in the case series described by
of the incidence of ocular manifestations could not be made Mahendradas et al.24 with regard to ocular manifestations
from the available studies, as the reported case series were also developed acute renal failure during the systemic ill-
from tertiary referral centres. ness, likely to be pre renal azotemia which responded
to hydration. Another two cases of acute renal failure
3.3. Cardiovascular manifestations were reported during an epidemic in Mayotte, Comoros
Archipelago.29
Though myocarditis is cited as a possible complication Other renal manifestations of CHIKV infection were not
of CHIKV infection, confirmed cases in the literature are reported until a case report published in 2007 by Solanki
rare. Several cases were reported in the 1970s together et al.30 They described a 16 year old male patient with
with the epidemic in Reunion Island. In the retrospec- nephritic syndrome during a CHIKV epidemic in Delhi.
tive data analysis of the Reunion Island epidemic by His serum was positive for CHIKV genomic products, and
Economopoulou et al.,10 84 (13%) cases had heart fail- symptoms included facial and ankle oedema, abdominal
ure during acute infection though 50 (59%) of them had pain, gross haematuria and a maculopapular rash. There
underlying heart disease. Similarly there were 44 (7%) was no past history of renal disease. Investigations for an
cases of arrhythmias but 16 (36%) of them had an under- alternative aetiology were negative. The patient made a full
lying cardiac or a systemic cause predisposing to such an recovery with conservative management.
event. There were 35 (6%) cases of myocarditis or pericardi-
tis retrospectively associated with CHIKV infection. Four 3.5. Skin manifestations
(<1%) patients had a myocardial infarction during acute
infection but two (<1%) of them had a previous history The most commonly documented dermatological man-
of coronary artery disease. It is difficult, from this study, ifestation in a ‘typical’ CHIKV infection is a maculopapular
to determine the actual incidence or pattern of cardiac rash starting over the face and neck area and spreading
involvement attributable to chikungunya infection, since out.2 Inamada et al.,31 from a study in India, reported that
many patients had underlying heart disease. Whether the pigmentary changes were the commonest skin manifes-
effects of chikungunya on the heart are more likely to tation, seen in 42%, followed by maculopapular eruption
symptomatically manifest in patients with underlying car- (33%) and intertriginous aphthous-like ulcers (21.37%).
diac disease, or whether patients with underlying heart Generalized vesiculobullous eruptions (2.75%) were rarely
disease are more likely to develop cardiac involvement seen, and were found only in infants. Economopoulou et
cannot be determined from available evidence, and fur- al.10 reported bullous dermatosis with concurrent CHIKV
ther studies are needed. Similarly, other causes of cardiac infection. Mishra and Rajawat32 reported a series of 16
involvement (other viral causes of myocarditis, leptospiro- males with penoscrotal ulceration during an outbreak in
sis and coronary artery disease) were not adequately central India in 2008. However a diagnosis of CHIKV infec-
excluded in the study. tion was made only on clinical grounds in this series
Simon et al.28 report one case of myopericarditis in a 21 without any serological confirmation. Ulcers were noted
year old woman with a travel history in Reunion Island dur- to develop between days 13–35 of illness and varied from
ing the epidemic in 2006. After three days of fever with joint one to three in number. They were punched out deep ulcers
94 S. Rajapakse et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96

with surrounding skin thickening and healthy granulation Overall it is reasonable to assume that if a mother has
tissue at base. Biopsy from one patient showed a perivas- viraemia at the time of delivery there is a high chance of
cular mononuclear cell infiltrate (which has been reported transmission of disease to baby. Neonatal disease as a result
elsewhere as a consistent finding in CHIKV induced skin of such vertical transmission can be severe, with neuro-
manifestations31 ). Bacterial cultures were negative. They logical or haematological manifestations and permanent
were treated with oral erythromycin and prednisolone, and disability.
the ulcers healed with scarring. The authors maintain that
it is unlikely that these ulcers were due to a drug reac- 3.7. Other manifestations
tion, and cite similar unpublished reports in India. In none
of the reports were attempts made to identify the CHIKV Data from the epidemic on Reunion Island describes
virus from the skin lesions. several other serious conditions associated with CHIKV
infection.10,20 These include pneumonia, respiratory fail-
3.6. Neonatal infection and mother to child transmission ure, hepatic insufficiency, hepatitis, pancreatitis, rhab-
domyolysis and multiple organ failure. There were a few
The Reunion Island based studies during its epidemic cases of endocrinological abnormalities reported during
have given an insight to this aspect of the disease. A large acute illness as well. These include syndrome of inappropri-
scale multidisciplinary prospective study in 2005–2006 ate hypersecretion of antidiuretic syndrome (SIADH) and
by Gerardin et al.33 studied 7504 pregnant women in hypoadrenalism. Major haemorrhage is uncommon follow-
Reunion Island. As confirmed by clinical history and a pos- ing CHIKV infection,7 and a shock syndrome similar to
itive IgM serology/RT-PCR, 678 (9%) women were infected dengue has not been described. Robin et al.18 suggest that
with CHIKV during the antepartum period and another 61 CHIKV may induce a vasculitis. In this series, CT and MRI
(0.8%) during the intrapartum (± two days of delivery) or scans of some patients with CNS manifestations showed
prepartum (day seven to day three before delivery) peri- cerebral haemorrhages. One child in this series died with
ods. Thirty-nine (0.5%) women had intrapartum viraemia massive bleeding manifestations and circulatory collapse.
and 22 (0.3%) had prepartum viraemia. Evidence is not conclusive, however, and further studies
There were three (0.44%) cases of early antepartum are needed.
foetal deaths (APFD) occurring before 22 weeks of ges-
tation directly attributable to CHIKV infection. The three 3.8. Deaths due to chikungunya
women were viraemic as confirmed by RT-PCR two weeks
prior to miscarriage, and amniocentesis was positive for Prior to the outbreak in Reunion Island in 2005–2006,
CHIKV RT-PCR. However, there were no APFD deaths chikungunya was not considered to be a fatal illness. Dur-
directly attributable to CHIKV after 22 weeks. All the ing that epidemic there were many reports of severe illness
babies born to women infected during the antepartum and deaths attributed to chikungunya infection and its
period had no detectable CHIKV IgM at birth. Seventy complications;20 mortality rates are variable, but have
(10.3%) infants had maternal IgG antibodies which cleared been reported as high as 48%.20 A study on crude death rates
progressively. on Reunion during the outbreak supports these findings
Compared to antepartum infection, pre- and intra- by showing 260 excess deaths between January and April
partum infections carried a significant morbidity in terms 2006.36 The study by Economopoulou et al.10 reported that
of vertical transmission. Vertical transmission was defined 65 patients with atypical manifestations died, giving a mor-
as CHIKV infection developing within the first week of life tality rate of 10.6%. Commonly observed immediate causes
of a neonate in the absence of risk of mosquito bites. Of the of death in these patients were heart failure, multiple
neonates born to 61 women having viraemia at the time of organ failure, hepatitis, encephalitis/meningoencephalitis,
delivery, 19 (31%) fulfilled criteria for vertical transmission. bullous dermatoses and myocarditis/pericarditis. Age over
All of these women had intrapartum symptoms rather than 85 years and alcohol abuse have been associated with
pre-partum symptoms. Hence the rate of vertical transmis- increased mortality.
sion stood at 49% (19/39) with caesarian section offering Some deaths occurring during an epidemic may go
no protection against transmission. Infected neonates unnoticed as health professionals may not attribute them
showed symptoms of fever and poor feeding. Clinical to CHIKV. In India a possible 1.39 million cases of CHIKV
signs included rubella or roseola like exanthema, petechiae were estimated in 2006, but no deaths attributed to CHIKV
and distal joint oedema. Ten (53%) neonates had severe were reported. However a mortality analysis was car-
infection with nine (47%) having encephalopathy and ried out in Ahmedabad which reported 60 777 suspected
one (5%) having haemorrhagic fever (four (44%) patients cases of chikungunya in an epidemic between August and
had laboratory evidence of DIC). Four (44%) children November 2006.37 Comparison of mortality data for the
with encephalopathy had permanent disabilities in later same months in previous years has shown an excess of
follow up. 2944 deaths during this period.
In another study of the same island, a vertical trans-
mission rate of 48% (16/33) was reported for women with 4. Conclusion
intrapartum viraemia.34 A similar study involving 84 preg-
nant patients demonstrated vertical transmission in 10 Until recently chikungunya was considered to be a
(12%) cases.35 In this series four (40%) neonates had menin- benign illness. Numerous case-series and case reports
goencephalitis and three (30%) had DIC. have since challenged the ‘benign’ nature of the illness.
 S. Rajapakse et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 89–96 95

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all the duties of authorship, i.e. data retrieval and analysis, 21. Singh SS, Manimunda SP, Sugunan AP, Sahina, Vijayachari P. Four
and drafting and revising the manuscript. SR is guarantor cases of acute flaccid paralysis associated with chikungunya virus
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gunya fever. J Assoc Physicians India 2008;56:473.
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Funding: None. Optic neuritis associated with chikungunya virus infection in South
India. Arch Ophthalmol 2007;125:1381–6.
24. Mahendradas P, Ranganna SK, Shetty R, Balu R, Narayana KM, Babu
Conflicts of interest: None declared. RB, et al. Ocular manifestations associated with chikungunya. Oph-
thalmology 2008;115:287–91.
25. Lalitha P, Rathinam S, Banushree K, Maheshkumar S, Vijayakumar
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