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

Contents lists available at ScienceDirect

Transactions of the Royal Society ofTropical Medicine and Hygiene

journa l homepage: ht tp : / /www.e lsev ier .com/ locate / t rs tmh

eview

typical manifestations of chikungunya infection

enaka Rajapaksea,∗, Chathuraka Rodrigob, Anoja Rajapaksec

Department of Clinical Medicine, Faculty of Medicine, University of Colombo, 25 Kynsey Road, Colombo 08, Sri LankaUniversity Medical Unit, National Hospital, Colombo, Sri LankaNewark Hospital, Sherwood Forest NHS Trust, Newark, Nottinghamshire, UK

r t i c l e i n f o

rticle history:eceived 11 April 2009eceived in revised form 29 July 2009ccepted 30 July 2009vailable online 27 August 2009

eywords:

a b s t r a c t

Chikungunya fever is a viral infection transmitted to humans by the bite of infectedmosquitoes. Typical chikungunya virus (CHIKV) infection results in an acute febrile illnesscharacterized by severe joint pain and rash. Although chikungunya is generally not con-sidered life threatening, atypical clinical manifestations resulting in significant morbidityhave been documented, especially during epidemics. This review describes atypical mani-festations following CHIKV infection reported in the literature, categorized as neurological,cardiovascular, skin, ocular, renal and other manifestations. The importance of vertical

hikungunyatypical manifestationsncephalitisyocarditisortality

eview

transmission from an infected mother resulting in neonatal infection is also highlighted.CHIKV infection can result in severe illness needing intensive care, with significant mortal-ity. While there are many deaths reported which are directly attributable to CHIKV infection,background mortality is also increased during epidemics. In this context, considering CHIKVinfection a benign and non fatal illness has to be revisited.

yal Soc

© 2009 Ro

. Introduction

Chikungunya fever is a viral disease transmitted toumans by the bite of infected mosquitoes. The chikun-unya virus (CHIKV) is a member of the genus Alphavirus,n the family Togaviridae. CHIKV was first isolated from thelood of a febrile patient in Tanzania in 19531,2 and hasince been identified repeatedly in west, central and south-rn Africa and many parts of Asia; it has been cited as theause of numerous human epidemics in those areas sincehat time.3

CHIKV infection results in an acute debilitating febrile

llness, characterized by severe joint pain and rash3,4

Table 1). High fever may result, often accompanied byhills and rigors. The fever may subside and recur, show-ng a saddleback pattern similar to dengue. Arthralgia or

∗ Corresponding author. Tel.: +94 112 695300x134;ax: +94 112689188.

E-mail address: senaka.ucfm@gmail.com (S. Rajapakse).

035-9203/$ – see front matter © 2009 Royal Society of Tropical Medicine and Hoi:10.1016/j.trstmh.2009.07.031

iety of Tropical Medicine and Hygiene. Published by Elsevier Ltd.All rights reserved.

joint pain is often polyarticular and symmetrical involv-ing knees, elbows, ankles and small joints, and also sitesof previous injuries.5 The pain is most intense on wakingup in the morning. Chikungunya patients typically avoidmovement as much as possible–hence the derivation ofthe name from Makonde, the language of the ethnic groupMakonde in the southeastern part of Tanzania and northernMozambique, meaning ‘the illness of the bended walker’.1,2

Affected joints may swell without significant fluid accu-mulation. These symptoms may last from one week toseveral months and are accompanied by myalgia or mus-cle pain. The rash characteristically appears on the firstday of illness, but its onset may be delayed. It usuallyarises as a flush over the face and neck, which evolves toa maculopapular or macular form with pruritus. The othersymptoms include headache, photophobia, fatigue, nausea

and vomiting. Although, similar to dengue, mild haemor-rhagic phenomena such as a positive tourniquet test andpetichiae have been described with CHIKV infection, signif-icant haemorrhage is not a characteristic feature.6,7 Plasmaleakage resulting in shock which is characteristic of dengue

ygiene. Published by Elsevier Ltd. All rights reserved.

90 S. Rajapakse et al. / Transactions of the Royal Society of T

Table 1Criteria for diagnosis of chikungunya4

1. Clinical criteria: acute onset of fever >38.5 ◦C and severearthralgia/arthritis not explained by other medical conditions2. Epidemiological criteria: residing or having visited epidemicareas, having reported transmission within 15 days prior to theonset of symptoms3. Laboratory criteria: at least one of the following tests in theacute phase:• Virus isolation• Presence of viral RNA by RT-PCR• Presence of virus specific IgM antibodies in single serum sample

collected in acute or convalescent stage.• Four-fold rising of IgG titers in samples collected at least threeweeks apart

is not seen in chikungunya. Asymptomatic infection prob-ably occurs, but its prevalence is not known. In general,chikungunya is not considered life threatening, and in themajority spontaneous resolution occurs, although arthral-gia can remain for several years.8,9 During the epidemicin Reunion Island 57% of patients who developed chikun-gunya infection had persisting rheumatological symptoms15 months after diagnosis.8 Age over 45 years or a previoushistory of osteoarthritis or hypertension were risk factorsfor persistent joint symptoms, and the severity of pain atdisease onset was strongly associated with persistence.8

Commonly, clinicians consider chikungunya to be arelatively benign condition, the main troublesome mani-festations being rheumatological. However, many atypicalclinical manifestations resulting in significant morbidityand mortality have been documented in the literature. Thisreview describes these unusual manifestations. Increas-ing prevalence of the infection will result in these unusualmanifestations gaining greater clinical significance.

2. Methods

We searched MEDLINE using the search term ‘Chikun-gunya’, which returned 859 hits. Typical disease wasdefined as a febrile illness with arthralgia/arthritis, withlaboratory confirmation of CHIKV infection4 (Table 1).Non-specific symptoms such as nausea, vomiting, loss ofappetite and myalgia were considered expected symptomscommon to most viral infections. All other manifesta-tions specific to organ systems were considered ‘atypical’.By carefully searching through the abstracts we identi-fied published papers describing atypical manifestationsof chikungunya infection; these full papers were readthrough for data extraction. The epidemic of chikungunyain Reunion Island in 2006 provided considerable insightinto the clinical manifestations of the disease.10,11 Theseropositivity rate of the population during this epidemicwas high at 38.2% (approx. 785 000 inhabitants).12 Manyother case-series and case reports also provided valuableinformation on the atypical manifestations discussed here.

We categorized atypical manifestations based on the

systems affected (Table 2), as neurological, ocular, cardio-vascular, dermatological, renal and other miscellaneousmanifestations. We also examined instances of verticaltransmission, and reports of mortality arising from chikun-gunya infection. In the majority of papers reviewed, the

ropical Medicine and Hygiene 104 (2010) 89–96

diagnosis of chikungunya was confirmed by the presence ofat least one of the laboratory criteria listed in Table 1 (detec-tion of CHIKV IgM antibodies or CHIKV genomic productsin blood or other body fluids by RT-PCR) together withexclusion of other causes with reasonable certainty.

3. Results and Discussion

3.1. Neurological manifestations

A spectrum of neurological manifestations includingmeningoencephalitis, myelopathy and neuropathy havebeen reported following chikungunya infection. A ret-rospective study on atypical manifestations of CHIKVinfection during the epidemic on Reunion Island byEconomopoulou et al.10 describes 147 (24.1%) patients withneurological manifestations out of 610 patients with CHIKVinfection. The range of presentations included encephalitis(69, 11%), meningoencephalitis (15, 2%), epileptic seizures(12, 2%), Guillain-Barre syndrome (GBS) (4,1%), cerebellarsyndrome (3, < 1%) stroke (2, < 1%) and myelomeningoen-cephalitis (1, < 1%).

Tournebize et al.13 described 23 cases with neurologicalmanifestations on Reunion Island. Disrupted behavior oraltered mental status was common, seen in 95% of patients;other features such as headache (30%), seizure (26%), motordysfunction (4%) and sensorial disorders (9%) were noted.Cerebrospinal fluid (CSF) findings were chiefly elevatedCSF protein levels, normal glucose levels and pleocytosis.The diagnosis of CHIKV infection was confirmed by findingeither CHIKV specific IgM or RT-PCR in these patients. Elec-troencephalography (EEG) changes were mostly of slowwaves, with epileptiform activity seen in patients with fits.Neuroimaging was normal in these patients.

A case series of patients aged 12 to 84 years withchikungunya infection in Rajasthan, India by Rampal et al.14

reported neurological manifestations in as much as 33% (20out of 60). In this series, diagnosis of CHIKV infection wasbased on a detailed clinical history and a positive IgM anti-body test against the virus. Malaria, dengue and typhoidwere excluded by history and laboratory examinations. Theonset of neurological manifestations was early, starting onthe second or third day of illness. Of the 20 patients withneurological manifestations, 15 had encephalitis, three hadencephalomyelitis and two had optic neuritis. Symptomat-ically, all 20 patients had altered sensorium with confusionand delirium. Six patients had psychosis and another sixhad seizures, with normal EEG. The three patients withmyelitis had flaccid paraplegia. CSF examination was donein all 20 patients and 17 (85%) showed raised protein lev-els. Nine (45%) had total cell counts (mostly lymphocytesand mononuclear cells) > 5/mm.3 No definite correlationwas described between symptomatology and CSF findings.All cases were treated symptomatically and 14 (70%) hadimproved within four to five days of illness and discharged.There were six (30%) deaths in the series which is sig-

nificantly high for a disease considered to be non-fatal.However, three of these patients were aged over 70 yearsand had multiple comorbidities, although it is unclear asto whether the deaths were related to these or not. Hencethe 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 2Summary of reported atypical manifestations of chikungunya infection with references

System Manifestations References

Neurological Encephalopathy/encephalitis/meningoencephalitis

Lewthwaite et al.(2009),19 Economopoulou etal.(2008),10 Robin et al.(2008),18 Musthafa etal. (2008),22 Lemant et al.(2008),20 Rampal etal.(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 etal.(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 Mahendradaset 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 etal.(2007),24 Murthy et al.(2007)26

Neonatal infection with vertical transmission Ante-partum foetal deaths,meningoencephalitis, disseminated

tion

Gerardin et al.(2008),33 Lenglet et al. (2006),34

Robillard et al. (2006)35

ry failuypoadr

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intravascular coagulaOther possible associations Pneumonia, respirato

pancreatitis, SIADH, h

eath occurring not primarily due to chikungunya infec-ion. Out of the six deaths, only one patient, aged 45 years,ad an abnormal CT scan which showed cerebral haem-rrhages and cerebral oedema, which were attributed toesult from chikungunya in the absence of other identifi-ble causes. Of the two remaining patients, one, aged 65ears, had altered sensorium, psychosis and incontinence,ith mild reduction in motor power. She initially improved

nd was discharged, was readmitted eight days later witharaplegia, subsequently left against medical advice andied at home five days later. Details regarding the cause ofeath of the sixth patient are not available.

Lebrun et al.15 reported two cases of GBS possibly asso-iated with CHIKV infection during the Reunion Islandpidemic. Both patients were positive for IgM antibodiesgainst chikungunya but had a negative result in RT-PCRor CHIKV genomic products in both serum and CSF. CSFrotein levels were high though cell counts were normal.hese two patients deteriorated rapidly needing intubationnd mechanical ventilation but recovered completely fol-

owing the administration of intravenous immunoglobulinor five days. Authors attribute the failure to detect genomicroducts of the virus by PCR to the short period of viraemia.he onset of GBS was observed between days 7-14 afterhe onset of initial symptoms (fever and rash).15 Wielanek

re, hepatitis,enalism

Economopoulou et al.(2008),10 Lemant etal.(2008)20

et al.16 describes another three patients with GBS duringthe same epidemic. (GBS confirmed by nerve conductiontests and clinical picture; CHIKV infection confirmed withpositive IgM antibodies in serum; and other pathologiesincluding HIV, C. jejuni, cytomegalovirus, M. pneumoniae,Epstein-Barr virus, dengue virus and Chlamydia pneumo-niae excluded with serological tests). One patient presentedwithin three days of fever and the other two after one andtwo weeks respectively. Interestingly, the incidence of GBSsyndrome in Reunion Island increased in 2006 (3.3/100000) compared to 2005 (2.7/100 000) and returned to base-line in 2007 (2.87/100 000).17

Neurological manifestations in paediatric practice arealso of interest. Robin et al.18 describes a case series of30 (24.6%) children (out of 122 confirmed cases of chikun-gunya) with neurological involvement during the epidemicin Reunion Island. The spectrum of manifestations was sim-ilar to adults. Twelve had encephalitis (defined as reducedlevel of consciousness plus either CSF pleocytosis, seizuresor focal neurological signs), four had acute encephalopa-

thy (reduced level of consciousness only) and another fourhad meningeal syndrome. Ten patients had seizures dur-ing the febrile episode. Whether seizures were due tochikungunya or whether they were febrile seizures is notclear. EEG was non specific in these patients. Infection was

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confirmed by either detecting IgM antibodies in serum, orviral genomic products by RT-PCR in serum or CSF. Twentythree (76.6%) patients had CSF analyzed; CSF was withinnormal limits in the majority. Magnetic Resonance Imaging(MRI) was performed in 14 (46.6%) patients and five (35.7%)were abnormal. Two (6.7%) patients died in the series withone having circulatory collapse with massive haemorrhageand the other having cerebral oedema.9

In a study from India, Lewthwaite et al.19 describesdetecting chikungunya viral genomic products in eight(14%) children out of 58 presenting with CNS symp-toms. All eight patients had malaria excluded by parasitetesting; dengue and Japanese encephalitis excluded bynegative serology and CSF testing. Symptoms includedaltered mental status (7, 87%), seizures (6, 75%), apha-sia (3, 37%) and meningism (3, 37%). Six (75%) patientsrecovered fully while 2 (25%) had persisting cognitiveimpairment.

Lemant et al.20 in a case series of 33 patients withconfirmed CHIKV infection reported 14 (42%) cases ofencephalopathy and one (3%) case of GBS. Singh et al.21

described another case series during an epidemic inAndaman and Nicobar islands, where 10 cases of acute flac-cid paralysis were reported after a CHIKV-like infection21.In four of those patients, CHIKV IgM antibody test was pos-itive.

Mustafa et al.22 reports a case of acute diffuseencephalomyelitis (ADEM) in a 45 year old Indian maleduring a chikungunya epidemic in Kerala, India. The patientpresented with rapid onset quadriplegia and slurred speechin the second week following a febrile illness. The clinicalpicture was typical of chikungunya and serology (IgM) waspositive. MRI showed multiple white matter lesions in sub-cortical, periventricular and gangliocapsular regions. Thepatient improved after being treated with IV methylpred-nisolone.

Overall, CHIKV infection can result in a wide vari-ety of neurological conditions (Table 2), and neurologicalmanifestations can occur in up to one third of patients.Encephalitis appears to be the most common manifes-tation, its incidence ranging from 11 to 18%. Certainly,difficulties may arise as in determining whether CHIKVinfection is the definite cause of the neurological mani-festations, especially during epidemics and in areas wherethe prevalence of the disease is high. The possibility of co-infection with other infections which can either directlyor indirectly result in neurological manifestations is a pos-sible confounding factor in all of these case series. Inmany of the studies, the reported degree to which inves-tigations were performed to exclude other infections wasvariable. Economopolou et al.10 do not mention investiga-tions done to exclude other causes. Rampal et al.14 excludedmalaria, typhoid and dengue. Robin et al.18 excluded bac-terial CNS by negative culture, and Herpes infection bynegative serology in a third of patients. Lewthwaite etal.19 excluded malaria, typhoid and Japanese encephalitis

by laboratory testing. The identification of CHIKV infec-tion in CNS samples in the study by Tournebize et al.13

suggests strongly that the manifestations were due tochikungunya. In the case of the reported occurrences ofGBS,15,16 CHIKV antibodies were detected in serum and

ropical Medicine and Hygiene 104 (2010) 89–96

CSF, though genomic products were not detected, andserology for other recognized causes of GBS were nega-tive.

Nonetheless, current evidence suggests that it is impor-tant to consider CHIKV infection as the cause in patientspresenting with neurological manifestations together withfeatures of CHIKV infection (fever and arthritis), or duringepidemics. Diagnosis is largely clinical, together with lab-oratory confirmation of recent CHIKV infection (Table 1).EEG changes appear to be non-specific and unhelpful indiagnosis, from the limited evidence available; furtherstudies are clearly required. CSF findings appear to be sim-ilar to those seen in viral encephalitis/meningitis: elevatedproteins, normal glucose and pleocytosis.14,15,18 Detectionof CHIKV IgM or viral genomic products by RT-PCR inCSF may be of value in patients with CNS manifestations,although this needs further study. Little is known about thevalue of neuroimaging, although haemorrhages,14 whitematter changes22 and ring-enhancing lesions14 have beendescribed.

3.2. Ocular manifestations

Ocular manifestations are another recognized compli-cation of CHIKV infection (Table 2). Mittal et al.23 describesa case series of 14 patients (19 eyes) with confirmedCHIKV infection (serology for CHIKV IgM antibodies pos-itive with other common infective causes excluded) andoptic neuritis. Eight (42%) eyes had papillitis, four (21%)had retrobulbar neuritis, another four (21%) had optic tractinvolvement and three (16%) had neuroretinitis. Symp-tomatology included blurred vision, reduced visual acuity,field defects and reduced colour vision. Three (21%) of thesepatients had other CNS manifestations namely bilateralophthalmoplegia with hemiparesis, sensory neuronal deaf-ness of acute onset and unilateral facial nerve palsy. Allpatients were treated with corticosteroids. Complete orpartial improvement of vision was reported in 10 (71%)patients with good response to steroids if given earlyin course of illness. The exact mechanism of neuritis isunknown, but five (36%) patients had symptoms with acuteillness while the onset was delayed in the rest. The possi-bility of direct viral induced damage as well as immunemediated damage has been suggested.23 Retrobulbar opticneuritis leading to permanent blindness has also beendescribed.14

In another case series from Bangalore, India, Mahen-dradas et al.24 describe a different spectrum of ocularmanifestations in nine patients with a positive serology forCHIKV (supported by the typical clinical picture of infec-tion). Five (55%) had iridocyclitis, three (33%) had retinitisand one patient had nodular episcleritis. The onset of ocu-lar manifestations lagged 4–12 weeks behind the acuteillness (fever and rash). Patients were empirically treatedwith acyclovir and prednisolone. All patients made a com-plete recovery. Lalitha et al.25 described the occurrence

of granulomatous and nongranulomatous anterior uveitis,optic neuritis, retrobulbar neuritis and dendritic lesions ina descriptive study of 37 patients with serologically con-firmed CHIKV infection. Good clinical recovery of visionwas seen in the majority.

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Bilateral retinitis has been described following CHIKVnfection.24,26,27 Murthy et al.26 describe a patient withilateral retinitis in whom deterioration of vision startedhree weeks after febrile illness. Serology was positive forHIKV IgM antibodies at presentation, but later serum andqueous humor were positive for herpes simplex virusHSV) genomic products as well. The patient was treatedith a cocktail of antiviral drugs including IV acyclovir

nd later intravitreal gancyclovir, together with corticos-eroids. Though the progression of lesions stopped, furthermprovement of vision was not observed. The two patients

ith dendritic lesions reported by Lalitha et al.25 wereot investigated for possible HSV infection, but were alsoreated with acyclovir, with some response. While the den-ritic lesions seen could well be due to CHIKV, whetherHIKV infection predisposes to HSV is not known, andeeds further study. Mahesh et al.27 describe a 48 year old

emale developing bilateral neuroretinitis two weeks afterserology proven CHIKV infection. She was treated with

teroids and two months later visual acuity had graduallymproved. The delayed onset of ocular manifestations inhese patients suggest a delayed immune response to infec-ion. While in most instances recovery of vision to normalccurs, CHIKV infection can result in blindness, especially ifssociated with optic neuritis or neuroretinitis. Estimatesf the incidence of ocular manifestations could not be maderom the available studies, as the reported case series wererom tertiary referral centres.

.3. Cardiovascular manifestations

Though myocarditis is cited as a possible complicationf CHIKV infection, confirmed cases in the literature areare. Several cases were reported in the 1970s togetherith the epidemic in Reunion Island. In the retrospec-

ive data analysis of the Reunion Island epidemic byconomopoulou et al.,10 84 (13%) cases had heart fail-re during acute infection though 50 (59%) of them hadnderlying heart disease. Similarly there were 44 (7%)ases of arrhythmias but 16 (36%) of them had an under-ying cardiac or a systemic cause predisposing to such anvent. There were 35 (6%) cases of myocarditis or pericardi-is retrospectively associated with CHIKV infection. Four<1%) patients had a myocardial infarction during acutenfection but two (<1%) of them had a previous historyf coronary artery disease. It is difficult, from this study,o determine the actual incidence or pattern of cardiacnvolvement attributable to chikungunya infection, since

any patients had underlying heart disease. Whether theffects of chikungunya on the heart are more likely toymptomatically manifest in patients with underlying car-iac disease, or whether patients with underlying heartisease are more likely to develop cardiac involvementannot be determined from available evidence, and fur-her studies are needed. Similarly, other causes of cardiacnvolvement (other viral causes of myocarditis, leptospiro-

is and coronary artery disease) were not adequatelyxcluded in the study.

Simon et al.28 report one case of myopericarditis in a 21ear old woman with a travel history in Reunion Island dur-ng the epidemic in 2006. After three days of fever with joint

ropical Medicine and Hygiene 104 (2010) 89–96 93

pain, she presented with chest pain and ECG showed STsegment elevation in anteroseptal leads. Troponin I levelswere elevated and a transthoracic echocardiogram demon-strated a mild pericardial effusion. Intracardiac MRI doneat acute stage showed a subepicardial delayed enhance-ment in apical and apicolateral walls of the left ventricleand the lateral wall of the right ventricle. These changesremained one year after treatment. She responded tohigh dose aspirin with resolving of clinical symptoms andECG changes. CHIKV infection was confirmed by serologyand other infective causes for myocarditis were excludedby appropriate tests. The persistence of cardiac musclechanges detected on MRI suggests that CHIKV might pre-dispose to dilated cardiomyopathy later in life. Myocarditiswithout heart failure may be missed as symptoms aremasked by diffuse myalgia and arthralgia.

3.4. Renal manifestations

The retrospective analysis by Economopoulou et al.10

reveals 120 (20%) cases of pre-renal failure out of 610patients with atypical manifestations during acute infec-tion. Around one third of the patients with pre-renalfailure had pre-existing renal disease, mostly chronic kid-ney disease. One patient in the case series described byMahendradas et al.24 with regard to ocular manifestationsalso developed acute renal failure during the systemic ill-ness, likely to be pre renal azotemia which respondedto hydration. Another two cases of acute renal failurewere reported during an epidemic in Mayotte, ComorosArchipelago.29

Other renal manifestations of CHIKV infection were notreported until a case report published in 2007 by Solankiet al.30 They described a 16 year old male patient withnephritic syndrome during a CHIKV epidemic in Delhi.His serum was positive for CHIKV genomic products, andsymptoms included facial and ankle oedema, abdominalpain, gross haematuria and a maculopapular rash. Therewas no past history of renal disease. Investigations for analternative aetiology were negative. The patient made a fullrecovery with conservative management.

3.5. Skin manifestations

The most commonly documented dermatological man-ifestation in a ‘typical’ CHIKV infection is a maculopapularrash starting over the face and neck area and spreadingout.2 Inamada et al.,31 from a study in India, reported thatpigmentary changes were the commonest skin manifes-tation, seen in 42%, followed by maculopapular eruption(33%) and intertriginous aphthous-like ulcers (21.37%).Generalized vesiculobullous eruptions (2.75%) were rarelyseen, and were found only in infants. Economopoulou etal.10 reported bullous dermatosis with concurrent CHIKVinfection. Mishra and Rajawat32 reported a series of 16males with penoscrotal ulceration during an outbreak in

central India in 2008. However a diagnosis of CHIKV infec-tion was made only on clinical grounds in this serieswithout any serological confirmation. Ulcers were notedto develop between days 13–35 of illness and varied fromone to three in number. They were punched out deep ulcers

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with surrounding skin thickening and healthy granulationtissue at base. Biopsy from one patient showed a perivas-cular mononuclear cell infiltrate (which has been reportedelsewhere as a consistent finding in CHIKV induced skinmanifestations31). Bacterial cultures were negative. Theywere treated with oral erythromycin and prednisolone, andthe ulcers healed with scarring. The authors maintain thatit is unlikely that these ulcers were due to a drug reac-tion, and cite similar unpublished reports in India. In noneof the reports were attempts made to identify the CHIKVvirus from the skin lesions.

3.6. Neonatal infection and mother to child transmission

The Reunion Island based studies during its epidemichave given an insight to this aspect of the disease. A largescale multidisciplinary prospective study in 2005–2006by Gerardin et al.33 studied 7504 pregnant women inReunion Island. As confirmed by clinical history and a pos-itive IgM serology/RT-PCR, 678 (9%) women were infectedwith CHIKV during the antepartum period and another 61(0.8%) during the intrapartum (± two days of delivery) orprepartum (day seven to day three before delivery) peri-ods. Thirty-nine (0.5%) women had intrapartum viraemiaand 22 (0.3%) had prepartum viraemia.

There were three (0.44%) cases of early antepartumfoetal deaths (APFD) occurring before 22 weeks of ges-tation directly attributable to CHIKV infection. The threewomen were viraemic as confirmed by RT-PCR two weeksprior to miscarriage, and amniocentesis was positive forCHIKV RT-PCR. However, there were no APFD deathsdirectly attributable to CHIKV after 22 weeks. All thebabies born to women infected during the antepartumperiod had no detectable CHIKV IgM at birth. Seventy(10.3%) infants had maternal IgG antibodies which clearedprogressively.

Compared to antepartum infection, pre- and intra-partum infections carried a significant morbidity in termsof vertical transmission. Vertical transmission was definedas CHIKV infection developing within the first week of lifeof a neonate in the absence of risk of mosquito bites. Of theneonates born to 61 women having viraemia at the time ofdelivery, 19 (31%) fulfilled criteria for vertical transmission.All of these women had intrapartum symptoms rather thanpre-partum symptoms. Hence the rate of vertical transmis-sion stood at 49% (19/39) with caesarian section offeringno protection against transmission. Infected neonatesshowed symptoms of fever and poor feeding. Clinicalsigns included rubella or roseola like exanthema, petechiaeand distal joint oedema. Ten (53%) neonates had severeinfection with nine (47%) having encephalopathy andone (5%) having haemorrhagic fever (four (44%) patientshad laboratory evidence of DIC). Four (44%) childrenwith encephalopathy had permanent disabilities in laterfollow up.

In another study of the same island, a vertical trans-

mission rate of 48% (16/33) was reported for women withintrapartum viraemia.34 A similar study involving 84 preg-nant patients demonstrated vertical transmission in 10(12%) cases.35 In this series four (40%) neonates had menin-goencephalitis and three (30%) had DIC.

ropical Medicine and Hygiene 104 (2010) 89–96

Overall it is reasonable to assume that if a mother hasviraemia at the time of delivery there is a high chance oftransmission of disease to baby. Neonatal disease as a resultof such vertical transmission can be severe, with neuro-logical or haematological manifestations and permanentdisability.

3.7. Other manifestations

Data from the epidemic on Reunion Island describesseveral other serious conditions associated with CHIKVinfection.10,20 These include pneumonia, respiratory fail-ure, hepatic insufficiency, hepatitis, pancreatitis, rhab-domyolysis and multiple organ failure. There were a fewcases of endocrinological abnormalities reported duringacute illness as well. These include syndrome of inappropri-ate hypersecretion of antidiuretic syndrome (SIADH) andhypoadrenalism. Major haemorrhage is uncommon follow-ing CHIKV infection,7 and a shock syndrome similar todengue has not been described. Robin et al.18 suggest thatCHIKV may induce a vasculitis. In this series, CT and MRIscans of some patients with CNS manifestations showedcerebral haemorrhages. One child in this series died withmassive bleeding manifestations and circulatory collapse.Evidence is not conclusive, however, and further studiesare needed.

3.8. Deaths due to chikungunya

Prior to the outbreak in Reunion Island in 2005–2006,chikungunya was not considered to be a fatal illness. Dur-ing that epidemic there were many reports of severe illnessand deaths attributed to chikungunya infection and itscomplications;20 mortality rates are variable, but havebeen reported as high as 48%.20 A study on crude death rateson Reunion during the outbreak supports these findingsby showing 260 excess deaths between January and April2006.36 The study by Economopoulou et al.10 reported that65 patients with atypical manifestations died, giving a mor-tality rate of 10.6%. Commonly observed immediate causesof death in these patients were heart failure, multipleorgan failure, hepatitis, encephalitis/meningoencephalitis,bullous dermatoses and myocarditis/pericarditis. Age over85 years and alcohol abuse have been associated withincreased mortality.

Some deaths occurring during an epidemic may gounnoticed as health professionals may not attribute themto CHIKV. In India a possible 1.39 million cases of CHIKVwere estimated in 2006, but no deaths attributed to CHIKVwere reported. However a mortality analysis was car-ried out in Ahmedabad which reported 60 777 suspectedcases of chikungunya in an epidemic between August andNovember 2006.37 Comparison of mortality data for thesame months in previous years has shown an excess of2944 deaths during this period.

4. Conclusion

Until recently chikungunya was considered to be abenign illness. Numerous case-series and case reportshave since challenged the ‘benign’ nature of the illness.

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typical presentations and complications of chikungunyaever include neurological, cardiac, renal, skin and ocular

anifestations that can have serious consequences for theatient.

Pre-existing co-morbidity appears to increase the like-ihood of most of these complications.10 The incidence oftypical manifestations appears to be higher in patientsged 65 years and over, with patients over 40 years of ageore likely to develop severe disease.10 Whether atypicalanifestations are due to an unusual host response to the

irus, or due to mutant variants of CHIKV is yet unknown.ntrapartum viraemia in mothers increases the risk of ver-ical transmission that may result in severe infection ineonates. Morbidity from these complications is likely to beignificant especially at times of epidemics when infectionpreads rapidly. CHIKV infection can result in serious illnessequiring intensive care, and can cause death.20 Further-ore, mortality analysis during times of epidemics have

hown that an excess number of deaths have occurred dur-ng such periods, though not directly attributed to illness.linicians and epidemiologists should be alert to the wideange of clinical manifestations that can occur followingHIKV infection; early detection of these complications byhe treating clinicians will doubtless improve outcome andeduce mortality in severe cases. CHIKV infection should noonger be considered a disease with a benign course.

uthors’ contributions: SR, CR and AR have undertakenll the duties of authorship, i.e. data retrieval and analysis,nd drafting and revising the manuscript. SR is guarantorf the paper.

unding: None.

onflicts of interest: None declared.

thical approval: Not required.

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