Chanthongthip, A

de Lamballerie, X

Dubot-Pérès, A

Newton, PN

Sengvilaipaseuth, O

Newton, Paul

Oxford University Research Archive

Is	Japanese	encephalitis	virus	the	aetiology	in	patients	with	anti-JEV	IgM	in	cerebrospinal	fluid?		Audrey	Dubot-Pérès1,2,3,	Onanong	Sengvilaipaseuth1,	Anisone	Chanthongthip1,	Paul	N	Newton1,3,	Xavier	de	Lamballerie2,4		1.	Lao-Oxford-Mahosot	Hospital-Wellcome	Trust	Research	Unit	(LOMWRU),	Microbiology	Laboratory,	Mahosot	Hospital,	Vientiane,	Laos.	2.	Aix	Marseille	Université,	IRD	French	Institute	of	Research	for	Development,	EHESP	French	School	of	Public	Health,	EPV	UMR_D	190	"Emergence	des	Pathologies	Virales",	13005	Marseille,	France.	3.	Centre	for	Tropical	Medicine	and	Global	Health,	Nuffield	Department	of	Clinical	Medicine,	University	of	Oxford,	Churchill	Hospital,	Oxford,	OX3	7FZ,	UK.	4.	IHU	Méditerranée	Infection,	APHM	Public	Hospitals	of	Marseille,	13005	Marseille,	France.		Acute	encephalitis	is	an	important	cause	of	death	and	morbidity	in	Asia,	especially	in	children.	Japanese	Encephalitis	virus	(JEV)	is	reported	as	the	most	commonly	identified	infectious	aetiology.	JEV	is	an	arbovirus	transmitted	between	Culex	mosquitoes,	pigs,	water	birds	and	humans.1	Tsai	and	colleagues	estimated	175,000	cases	(43,750	deaths)	due	to	JEV	in	1994.2	The	epidemiological	situation	remains	unclear	with	high	inequity	from	country	to	country	in	term	of	JEV	vaccination	and	reporting.3	The	recommended	diagnostic	methods	are	viral	isolation,	RT-PCR,	or	detection	of	anti-JEV	IgM	antibody	preferentially	in	CSF,	or	in	serum.4	However,	because	of	transient,	early	viraemia,	direct	detection	has	apparent	low	sensitivity.5	We	recruited,	between	2003	and	2011,	131	patients	admitted	with	acute	encephalitis	syndromes	(AES,	including	meningo-encephalitis	presentations,	107	patients)	or	pure	meningitis	syndromes	(24	patients)	at	Mahosot	Hospital,	Vientiane,	Lao	PDR,	who	fulfilled	the	WHO	criteria	for	biologically	confirmed	JEV.	Diagnosis	relied	on	direct	viral	detection	in	CSF	(5	patients,	4%)	and	detection	of	anti-JEV	IgM	(126	patients,	96%)	in	CSF	(71%)	or	just	sera	(25%)	(table	1).	In	patients	with	a	serological	diagnosis	of	JEV,	we	identified	alternative	aetiologies	in	15%,	using	direct	diagnosis	(i.e.	PCR	or	pathogen	isolation).	Many	of	the	pathogens	detected	have	been	associated	with	neurological	infections	and	constitute	convincing	aetiologies	that	alone	could	explain	the	patients’	clinical	presentation.	We	cannot	rule	out	that	this	series	includes	actual	dual	infections	since	JEV	may	share	exposure	risk	factors	with	other	pathogens.	However,	our	results	suggest	that	the	diagnosis	of	JEV	infection	by	serology	may	be	inaccurate	in	a	significant	proportion	of	patients.	If	this	hypothesis	is	correct,	the	Positive	Predictive	Value	of	anti-JEV	IgM	detection	would	appear	to	be	low;	lowest	in	patients	with	meningitis	and	when	IgM	is	detected	only	in	serum	(alternative	aetiologies	identified	in	12%	of	patients	with	AES;	29%	with	meningitis;	13%	with	CSF	anti-JEV	IgM;	21%	with	blood	anti-JEV	IgM	only).	Diagnosis	of	JEV	infection	by	IgM	detection	may	be	faulted	by	antigenic	cross-reaction	and	by	actual	secretion	of	anti-JEV	IgM	during	another	neurological	infection	in	patients	previously	immunised	against	JEV.		As	JEV	is	a	significant	public	health	burden	in	Asia,	this	observation	deserves	attention.	It	suggests	that	the	incidence	of	acute	neurological	infections	due	to	JEV	may	be	overestimated	and	that	detection	of	anti-JEV	IgM	in	such	patients	should	not	preclude	the	management	of	other	treatable	aetiologies,	in	particular	bacterial	infections.	Research	for	improvement	of	JEV	diagnosis	is	needed.		 		References			1	 Misra	UK,	Kalita	J.	Overview:	Japanese	encephalitis.	Prog	Neurobiol	2010;	91:108-20.		2	 Tsai	TF.	New	initiatives	for	the	control	of	Japanese	encephalitis	by	vaccination:	minutes	of	a	WHO/CVI	meeting,	Bangkok,	Thailand,	13–15	October	1998.	Vaccine	2000;	18:	1–25.		3	 Tarantola	A,	Goutard	F,	Newton	P,	et	al..	Estimating	the	Burden	of	Japanese	Encephalitis	Virus	and	Other	Encephalitides	in	Countries	of	the	Mekong	Region.	PLoS	Negl	Trop	Dis	2014;	8:	e2533.			4	 WHO.	Manual	for	the	Laboratory	Diagnosis	of	Japanese	Encephalitis	Virus	Infection.	March	2007.		5	 Feigin,	Cherry,	Demmler,	Kaplan	(eds.).	Textbook	of	pediatric	infectious	diseases	(5th	edition).	Saunders,	Philadelphia,	2004.			Conflicts	of	interest		All	authors	declare	no	conflict	of	interest.						Table	1.	Alternative	aetiologies	detected	in	JEV	patients	with	acute	encephalitis	or	meningitis	syndrome.			 Acute	Encephalitis	Syndrome*	(107	patients)	 Pure	Meningitis**	(24	patients)		 JEV	detection		in	CSF	(PCR	or	culture)	Anti-JEV	IgM	detection		in	CSF	Anti-JEV	IgM	detection		in	blood	only	Anti-JEV	IgM	detection		in	CSF	Anti-JEV	IgM	detection		in	blood	only	Number	of	patients	 5$	 77	 25	 16	 8		Number	of	patients	with	an	alternative	aetiology		(detection	in	CSF	by	culture	or	PCR)		List	of	pathogens	detected					0									5	(9%)			+	Leptospira	sp.	(1)	+	Mycobacterium	tuberculosis	(1)	+	Streptococcus	pneumoniae	(2)	+	Cryptococcus	neoformans	var	grubii	(1)			2	(1%)			+	Rickettsia	typhi	(1)	+	Streptococcus	pneumoniae	(1)		5	(31%)			+	Orientia	tsutsugamushi	(3)	+	Cryptococcus	neoformans	var	grubii	(1)	+	Cryptococcus	sp.	(1)		2	(25%)			+	Orientia	tsutsugamushi	(1)	+	Varicella	zoster	virus	(1)		Number	of	patients	with	an	alternative	aetiology	(detection	in	blood	by	culture	or	PCR)		List	of	pathogens	detected					0		2	(3%)				+	Rickettsia	typhi	(1)	+	Dengue	virus	(1)							3	(1%)				+	Burkholderia	pseudomallei	(2)	+	Orientia	tsutsugamushi	(1)		0		0		*	AES	patient	is	a	person	of	any	age,	at	any	time	of	year	with	acute	onset	of	fever	and	either	a	change	in	mental	status	and/or	new	onset	of	seizures	(excluding	simple	febrile	seizures,	defined	as	a	seizure	that	occurs	in	a	child	aged	6	months	to	less	than	6	years	old,	whose	only	finding	is	fever	and	a	single	generalized	convulsion	lasting	less	than	15	minutes,	and	who	recovers	consciousness	within	60	minutes	of	the	seizure).	**	Pure	meningitis	is	defined	as	a	sudden	onset	of	fever	with	neck	stiffness.		$	anti-JEV	IgM	was	detected	in	CSF	for	two	patients.			All	CSF	and	serum	samples	were	tested	using	the	Panbio	JEV/Dengue	IgM	Combo	ELISA	kit	(Alere),	WHO-recommended	test	for	JEV	diagnosis.		

How many patients with anti-JEV IgM in cerebrospinal fluid really have Japanese encephalitis?

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