Review

The Emergence, Epidemiology, and Etiology of HaffDisease

PEI Pei, LI Xiao Yan, LU Shuang Shuang, LIU Zhe, WANG Rui#, LU Xuan Cheng#, and LU Kai#

Haff disease is a type of humanrhabdomyolysis characterized by the sudden onsetof unexplained muscular rigidity and an elevatedserum creatine kinase level within 24 h afterconsuming cooked aquatic products. Here, wereviewed a previous study on Haff disease andsummarized the clinical manifestations,epidemiological characteristics, and etiological datato confirm the incidence and global epidemiologyof the disease and identify the most commonseafood vectors. Future directions for Haff diseasestudy will include further prospective etiologicalstudies and the development of prevention andcontrol strategies.

Key words: Rhabdomyolysis; Seafood; Haffdisease; Crayfish; Epidemiology

Haff disease is a type of human rhabdomyolysischaracterized by the sudden onset of unexplainedmuscular rigidity and an elevated serum creatinekinase (CK) level within 24 h after consuming cookedfreshwater or seawater products[1]. Haff disease wasfirst identified in the summer and autumn of 1924near the Königsberger Haff shores along the Balticcoast[2-4]. The clinical manifestations of this diseasemainly involve the sudden onset of rhabdomyolysiswith severe muscle pain. In most patients, this isaccompanied with myoglobinuria, significantincreases in the serum levels of CK and myoglobin(Mb), and potential increases in the levels of othermuscle enzymes [e.g., lactate dehydrogenase,aspartate aminotransferase, alanineaminotransferase (ALT)]. Epidemiological studiesrevealed that patients with Haff disease hadconsumed cooked fish, including burbot (Lota lota)and pike (Esox spp.), or other aquatic productswithin 24 h prior to the onset of illness.

Similar outbreaks of Haff disease have occurredin many countries since its initial identification. Theidentified patients had consumed various types ofcooked fish or other aquatic products, includingburbot (L. lota), buffalo fish (Ictiobus cyprinellus),crayfish (Procambarus clarkii), freshwater pomfret

(Colossoma brachypomus), Cambaroides spp.,Atlantic salmon (Salmo salar), and boxfish(Ostraciontidae spp.). Increases in human standardsof living have led to the increasing availability of fishfor consumption and, consequently, increasingreports of Haff disease. However, the specific causeof Haff disease remains unclear. Chemical analysesof suspicious fish samples, blood samples, and urinesamples from cases for possible toxins, drugs, andhazardous elements produced negative results ortoxin levels below the toxicity thresholds. Currently,the following criteria are used to define cases of Haffdisease: (1) a history of consuming cooked aquaticproducts within 24 h prior to the onset of illness,(2) a markedly elevated (i.e., fivefold or greaterincrease over the normal levels) serum creatinephosphokinase level, and (3) a CK muscle/brain (CK-MB) fraction of < 5%[5].

Several studies regarding the clinicalmanifestations, epidemiological characteristics, andpathogenic factors of Haff disease have beenconducted since it was first reported in 1924. Thesestudies have laid a solid foundation to confirm thepathogenic and influencing factors of Haff disease, todetermine the means of preventing and controllingthe occurrence of this disease, and to supportfurther studies. This paper reviews the previousstudies of Haff disease that have been conductedworldwide while suggesting future researchdirections according to trends in the development ofrelated disciplines.The Epidemiology of Haff Disease　　 In the 9-yearperiod after the first report of Haff disease in 1924,more than 1,000 cases with similar symptoms werereported along the Haff shores during the summerand autumn seasons[1]. In the United States, mostpatients with Haff disease had consumed buffalo fish(I. cyprinellus) before the onset of illness[6-8]. In 2008,an outbreak of 27 cases of Haff disease was reportedin the Amazon region of Brazil, where the affectedpatients had consumed silver carp (Mylossoma spp.),black-finned colossoma (Colossoma macropomum),

doi: 10.3967/bes2019.096Chinese Center for Disease Control and Prevention, Beijing 102206, China

Biomed Environ Sci, 2019; 32(10): 769-778 769

or freshwater pompano (Piaractus brachypomus)[9].From June 2016 to April 2017, 67 cases of Haffdisease associated with the consumption of Olho-de-boi (Seriola spp.) or badejo (Mycteroperca spp.) werereported in Salvador, Brazil[10]. In Japan, 13 sporadiccases of Haff disease were reported between 1990and 2008, and all patients had a history ofconsuming boxfish (Ostraciontidae)[11-12]. These datademonstrate the particular epidemiologicalcharacteristics of Haff disease, including a dietaryhistory of cooked fish or other aquatic productswithin 24 h of the onset of illness and a location neara coastline, lake, or river.

In China, the number of cases of Haff disease hasincreased gradually since the initial report of 6confirmed cases associated with the consumption ofcrayfish in Beijing during August 2000[13]. In 2009, areported outbreak of 54 cases in Guangdong wasattributed to the consumption of freshwaterpomfret (C. brachypomus)[14]. However, mostChinese cases involved a dietary history of crayfish.Regarding the timing and location of Haff diseaseonset in China, cases have been reported during Julyand August of each year, which correlates stronglywith the crayfish consumption season[15-18]. Thispattern is also consistent with the observedconcentration of cases in areas with crayfishproduction and high-volume consumption, such asJiangsu, Anhui, and Hubei provinces[15]. Ma Shaoleiet al. performed a spatial autocorrelation analysis todetermine the incidence and spatial structure ofcrayfish-related rhabdomyolysis syndrome in Nanjingduring 2016. Notably, a global spatialautocorrelation of the high prevalent regionsrevealed that cases were concentrated mainly inurban areas adjacent to the Yangtze River[17]. Theliterature reviewed for this report included 1,118patients with age ranging from 4 to 97 years, ofwhich 484 (43.29%) were male. This finding wasconsistent with another study on the communalconsumption of crayfish, which found no statisticaldifference in the incidence of Haff disease betweenfemale and male subjects[19].Clinical Features　 　 As previously noted, Haffdisease is characterized mainly by the suddenidiopathic onset of rhabdomyolysis, which refers to avariety of pathological changes caused by hereditaryor acquired factors such as crush wounds, drugtoxicants, striated muscle cell damage, cellmembrane channels, and/or an abnormal energysupply. These conditions damage the cell membraneintegrity and expose the contents of cells, whichinclude enzymes such as Mb and CK, and toxic ionic

and small molecule substances. Accordingly,rhabdomyolysis is often accompanied with life-threatening metabolic disorders and acute renalfailure (ARF)[20-23]. The observed association of Haffdisease with a history of consuming freshwater orseawater foods within the previous 24 h excludesother potential etiologies of rhabdomyolysissyndrome such as excessive exercise, trauma,alcoholism, hereditary disease, drug use, infection,or metabolic abnormalities[24,25].

Tables 1 and 2 summarize the existing reports ofHaff disease in the literature, including the serumlevels of CK and creatine kinase isoenzyme, whichare important for the diagnosis of Haff disease.Although most reported patients were dischargedafter hospitalization for symptomatic treatment, thetables describe the incidence of complications orother symptoms and related deaths. Additionalinformation about the affected subjects is alsopresented in both tables.

Haff disease is associated with varying degrees ofmuscle pain, which is concentrated mainly in theneck and shoulders or lower back[7,40], and this pain isusually the initial presenting sign[57]. Severe casesalso experience muscle tingling that is exacerbatedby activity[19,28]. In some cases, reddish-brown- orbrown-colored urine is observed, and symptomsmay be combined with limb or general weakness,chest discomfort, headache and dizziness, and/orgastrointestinal symptoms (e.g., nausea, vomiting,abdominal pain, and diarrhea)[16,26,28,30-32,34,36,39-

42,44,46,48,54,58]. Table 3 presents the distribution ofclinical manifestations in 641 cases reported in Chinathat met the above-stated criteria for Haff disease.

Regarding laboratory tests, elevated serum levelsof various kinases, including CK, CK isoenzyme,lactate dehydrogenase, and aspartateaminotransferase are observed in Haffdisease[7,15,16,19,26,28,30,31,37-41,44-46,48,58-60]. Of these, theincrease in CK is the most evident, with peak valuesas high as 39,164 U/L[47]. Additionally, a routineurinalysis may reveal blood or protein in theurine[7,19,30,32,34,38-40,44], with ARF in some cases[19]. Insome cases, routine blood testing revealed anincreased white blood cell count, elevatedneutrophil percentage, and hemoglobin and plateletlevels within the normal ranges[7,39,40]. Moreover,slightly elevated liver function markers (ALT) andnormal renal function were observed in somecases[39,40]. Cardiologic evaluations may reveal acardiac troponin T level of < 0.1 ng/mL and normalelectrocardiography findings[34,44]. Regarding musclefunction, electromyography may reveal myogenic

770 Biomed Environ Sci, 2019; 32(10): 769-778

Tabl

e 1.

Out

brea

ks o

f haf

f dise

ase

afte

r the

con

sum

ptio

n of

coo

ked

aqua

tic p

rodu

cts

Perio

dCo

untr

yCo

nsum

ed a

quat

icpr

oduc

tsSe

xAg

e (y

ears

)Sy

mpt

oms a

nd in

vest

igat

ion

findi

ngs

Refe

renc

e

1924

Köni

gsbe

rger

Haff

shor

esBu

rbot

, eel

, pik

e/

/Su

dden

, sev

ere

mus

cula

r rig

idity

and

cof

fee-

colo

red

urin

e. F

ew p

atie

nts

died

; sea

bird

s an

d ca

ts re

port

edly

died

aft

er c

onsu

min

g fis

h in

the

wild

.[1

,3,4

]

1942

.2–

1943

.4Sw

eden

, Lak

eYm

sen

Eel,

burb

ot, b

urbo

tliv

er, b

ream

M7F

4/

Inte

nse

pain

in th

e le

gs a

nd b

ack,

and

bla

ckish

-bro

wn-

colo

red

urin

e w

ithin

20

h af

ter m

eals.

Tw

o de

aths

: one

invo

lved

ure

mia

, and

the

othe

r ex

hibi

ted

sign

s of

sep

sis,

rena

l aff

ecta

tion,

and

mod

erat

e he

mat

uria

. Bot

hca

ses

had

fairl

y po

or h

ealth

due

to p

revi

ous

illne

sses

and

priv

atio

ns e

arlie

r in

the

year

. In

1941

, the

fish

in th

ela

ke d

ied,

as

did

mer

gans

ers

and

dive

rs th

at la

nded

on

the

lake

dur

ing

mig

ratio

n. C

ats

and

foxe

s in

the

shor

ear

ea d

ied

afte

r con

sum

ing

the

fish.

[2]

1984

.6/1

985/

1986

.4U

nite

d St

ates

Buffa

lo fi

sh6

/Te

sts o

f the

rem

ains

of a

fish

mea

l sug

gest

ed a

neu

tral

lipi

d as

the

caus

ativ

e ag

ent.

[1]

1997

.3U

nite

d St

ates

Buffa

lo fi

shF2

70, 7

3N

eck

pain

and

subs

eque

nt u

pper

lim

b st

iffne

ss, r

igid

ity, p

aral

ysis

, and

ext

rem

e se

nsiti

vity

eve

n to

ligh

t tou

ch8

h af

ter m

eals;

crea

tine

kina

se (C

K), 2

5,00

0 IU

/L; C

K m

uscl

e/br

ain

(CK-

MB)

frac

tion

at p

eak

valu

es, 2

.7%

and

0.5

%.

[6]

1997

.3U

nite

d St

ates

Buffa

lo fi

shM

133

Left

-sid

ed c

hest

pai

n th

at ra

diat

ed to

the

left

arm

8 h

aft

er m

eals;

CK,

4,1

40 IU

/L; C

K-M

B, 1

.4%

.[6

]

1997

.6U

nite

d St

ates

Buffa

lo fi

sh, c

arp

M1F

166

, 58

Gene

raliz

ed b

ody

ache

s and

mus

cle

stiff

ness

6 h

aft

er th

e m

eal;

CK, 1

7,70

0 IU

/L; C

K-M

B, 4

.8%

and

4.5

%.

[6]

1997

.8U

nite

d St

ates

Buffa

lo fi

shM

187

Stiff

ness

and

gen

eral

ized

mus

cle

tend

erne

ss 2

1 h

afte

r the

mea

l; CK

, 2,2

26 IU

/L; C

K-M

B, 2

.1%

.[8

]

2001

Uni

ted

Stat

esCr

awfis

h9

/M

yalg

ia (n

= 2

, 22.

2%),

ches

t pai

n (n

= 9

, 100

%),

naus

ea o

r vom

iting

(n =

9, 1

00%

), an

d br

own-

colo

red

urin

e(n

= 2

, 22.

2%);

CK, 6

,000

–8,6

70 IU

/L; C

K-M

B, <

5%

(100

%).

[8]

2001

.9U

nite

d St

ates

Salm

onM

1F1

61W

eakn

ess a

nd m

uscl

e ac

he; C

K, 2

85–4

11 U

/L.

[9]

1990

–200

8Ja

pan

Boxf

ish13

/Se

vere

mus

cle

pain

and

bla

ck-c

olor

ed u

rine.

[26]

2007

.8Ja

pan

Cow

fish

M1

40M

yalg

ia, n

ause

a, c

hest

pre

ssur

e, a

nd d

yspn

ea; p

eak

CK, 1

8291

0 IU

/L. C

ardi

opul

mon

ary

arre

st a

nd a

cute

rena

lfa

ilure

dev

elop

ed a

fter

59

h, a

nd h

emod

iafil

trat

ion

was

per

form

ed. O

n ho

spita

l day

16,

the

patie

nt d

ied

ofca

rdia

c ar

rest

cau

sed

by h

yper

kale

mia

, whi

ch w

as p

roba

bly

indu

ced

by m

yocy

toly

sis.

[11]

2008

.6–9

Braz

ilSi

lver

dol

lar,

blac

k-fin

ned

colo

ssom

aM

15F1

213

-80

Mya

lgia

(n =

27,

100

%),

che

st p

ain

(n =

19,

70.

4%),

nec

k pa

in (n

= 1

7, 6

2.9%

), m

uscu

lar

stiff

ness

(n =

13, 4

8.1%

), pa

in u

pon

light

touc

h (n

= 1

2, 4

4.4%

), w

eakn

ess

(n =

11,

40.

7%),

naus

ea (n

= 1

1, 4

0.7%

), m

uscl

eco

ntra

ctur

e (n

= 1

0, 3

7%),

dark

-col

ored

urin

e (n

= 9

, 33.

3%),

vom

iting

(n =

9, 3

3.3%

), m

alai

se (n

= 8

, 29.

6%),

and

diar

rhea

(n =

4, 1

4.8%

); CK

, 2,7

95 U

/L (r

ange

, 1,4

44–3

6,89

6 U

/L).

In 2

pat

ient

s, m

yogl

obin

leve

ls ex

ceed

ed70

0 U

/L.

[9]

2011

Braz

ilM

ylos

som

adu

riven

tre

M1

48Su

dden

, pr

ogre

ssiv

e, d

iffus

e, a

nd la

ncin

g ab

dom

inal

pai

n a

ccom

pani

ed b

y tw

o e

piso

des

of v

omit

ing,

prog

ress

ive

poly

mya

lgia

(pre

dom

inan

tly in

the

low

er li

mbs

), as

then

ia, a

nd p

rogr

essi

vely

dis

ablin

g m

uscu

lar

wea

knes

s with

in 2

h; c

reat

ine

phos

phok

inas

e (C

PK),

4,45

6U/L

.[1

2]

2014

Uni

ted

Stat

esBu

ffalo

fish

F134

Back

pai

n ra

diat

ing

to th

e ch

est,

into

the

neck

, and

into

bot

h bu

ttoc

ks; p

eak

CK, 3

0,54

9 IU

/L.

[7]

2013

Uni

ted

Stat

esBu

ffalo

fish

M1

48Su

dden

-ons

et d

iffus

e m

yalg

ia, e

spec

ially

in th

e le

gs, c

hest

, and

bac

k as

soci

ated

with

mild

dia

phor

esis

and

dark

brow

n-co

lore

d ur

ine.

Urin

alys

is w

as p

ositi

ve w

ith 4

+ he

mog

lobi

n; C

PK, 1

6,19

2IU

/L; s

erum

myo

glob

in, >

4,00

0 ng

/mL.

His

mot

her h

ad p

revi

ously

con

sum

ed b

uffa

lo fi

sh.

[27]

2014

.12

Uni

ted

Stat

esGr

ass c

arp

F254

Body

pai

n an

d w

eakn

ess

with

in 4

h, a

ssoc

iate

d w

ith 3

epi

sode

s of

non

-bili

ous

and

non-

bloo

dy v

omiti

ng th

epr

evio

us n

ight

; CK,

19,

124

UL.

[28]

2016

.6–

2017

.4Br

azil

Olh

o-de

-boi

, bad

ejo

6743

(17–

75)

Case

s re

port

ed fr

om D

ecem

ber 1

, 201

6, to

Janu

ary

31, 2

017.

M9F

6. P

atie

nts

man

ifest

ed n

eck/

trap

eziu

m p

ain

(n =

14,

93.

3%),

arm

pai

n (n

= 1

4, 9

3.3%

), th

igh

or le

g pa

in (n

= 1

3, 8

6.7%

), ba

ck p

ain

(n =

10,

66.

7%),

dark

-co

lore

d ur

ine

(n =

8, 5

3.3%

), th

orac

ic p

ain

(n =

2, 1

3.3%

), a

bdom

inal

pai

n (n

= 2

, 13.

3%),

thro

at p

ain

(n =

1, 6

.7%

), m

uscl

e w

eakn

ess

(n =

6, 4

0%),

and

rash

(n =

4, 2

6.7%

); C

K, 7

43–1

0575

5 U

/L; C

K-M

B, 1

.9%

–6.3

%.

Thirt

een

patie

nts w

ere

hosp

italiz

ed; 2

cas

es o

f acu

te k

idne

y in

jury

and

0 d

eath

.

[10]

Characteristics of haff disease 771

Tabl

e 2.

Out

brea

ks o

f haf

f dise

ase

afte

r the

con

sum

ptio

n of

coo

ked

aqua

tic p

rodu

cts i

n Ch

ina

Perio

dCi

tyCo

nsum

ed a

quat

icpr

oduc

tsSe

xAg

e (y

ears

)Sy

mpt

oms a

nd in

vest

igat

ion

findi

ngs

Refe

renc

es

2000

.8Be

ijing

Cray

fish

M1

42Se

vere

mya

lgia

with

wea

knes

s 7

h af

ter e

atin

g 50

0 g

of c

rayf

ish;

CK,

10,

150

U/L

. Mild

sym

ptom

s in

ano

ther

youn

g m

ale

patie

nt.

[29]

2000

.8Be

ijing

Cray

fish

M1

40M

oder

ate

mya

lgia

with

wea

knes

s aft

er 7

h; C

K, 2

,000

U/L

.[2

9]

2000

.8Be

ijing

Cray

fish

F138

Mod

erat

e m

yalg

ia w

ith w

eakn

ess

12 h

aft

er e

atin

g 50

0 g

of c

rayf

ish;

CK,

376

U/L

. Sym

ptom

s im

prov

ed b

utre

laps

ed 4

day

s la

ter a

t an

8-h

time

poin

t aft

er c

onsu

min

g le

ftov

er c

rayf

ish. H

er c

hild

(M/8

) had

mild

mya

lgia

and

naus

ea.

[29]

2000

.8Be

ijing

Cray

fish

F136

Seve

re m

yalg

ia w

ith w

eakn

ess

7 h

afte

r eat

ing

500

g of

cra

yfis

h. S

ympt

oms

impr

oved

6 h

late

r. A

ped

iatr

icpa

tient

dev

elop

ed m

ild w

eakn

ess.

[29]

2000

.8Be

ijing

Cray

fish

F140

Mod

erat

e m

yalg

ia w

ith w

eakn

ess 1

5 h

afte

r eat

ing

400

g of

cra

yfish

; CK,

6,0

00 U

/L.

[29]

2000

.8Be

ijing

Cray

fish

F136

Mya

lgia

and

wea

knes

s 7 h

aft

er e

atin

g 20

pie

ces o

f cra

yfish

. Sym

ptom

s im

prov

ed 1

2 h

late

r.[2

9]

2009

.1Li

anzh

ou,

Guan

gdon

gPo

mfr

etM

36F1

843

(4–7

4)

Sym

ptom

ons

et 7

h (r

ange

, 10

min

–41.

5 h)

aft

er e

atin

g 50

–70

g of

pom

fret

, inc

ludi

ng w

eakn

ess (

n =

45, 8

3%),

mya

lgia

(n =

41,

76%

), na

usea

(n =

34,

63%

), ab

dom

inal

pai

n (n

= 3

4, 6

3%),

dry

mou

th (n

= 2

5, 4

6%),

vom

iting

(n =

25,

46%

), an

d di

zzin

ess

(n =

18,

33%

), di

arrh

ea (n

= 1

8, 3

3%),

and

head

ache

(n =

12,

22%

); se

verit

y/se

rum

CPK,

11,

696U

/L.

[14]

2010

.8N

anjin

g, Ji

angs

uCr

ayfis

hM

9F14

36 (2

0–79

)

Sym

ptom

ons

et, i

nclu

ding

mya

lgia

(n =

23,

100

%),

brow

n-co

lore

d ur

ine

(n =

9, 3

9.1%

), nu

mbn

ess

of th

e lim

bs(n

= 4

, 17.

4%),

nau

sea

(n =

4, 1

7.4%

), w

eakn

ess

(n =

3, 1

3%),

vom

iting

(n =

3, 1

3%),

che

st ti

ghtn

ess

(n =

3, 1

3%),

abdo

min

al p

ain

(n =

3, 1

3%),

ches

t pai

n (n

= 2

, 8.7

%),

and

diar

rhea

(n =

2, 8

.7%

), 4.

8 h

(ran

ge, 3

–12

h)af

ter e

atin

g; C

K, 4

,655

U/L

.

[30]

2010

.7–8

Nan

jing,

Jian

gsu

Cray

fish

M4F

728

(9–3

8)Sy

mpt

om o

nset

, inc

ludi

ng m

yalg

ia (n

= 1

1, 1

00%

), w

eakn

ess

(n =

9, 8

1.8%

), b

row

n-co

lore

d ur

ine

(n =

7, 6

3.6%

), na

usea

(n =

5, 4

5.5%

), vo

miti

ng (n

= 2

, 18.

2%),

and

hoar

se v

oice

(9.1

%) 3

–9 h

aft

er e

atin

g 10

pie

ces

of c

rayf

ish; C

K, 2

,013

–18,

520

(7,9

52.2

) U/L

.[3

1]

2010

.7–9

Nan

jing,

Jian

gsu

Cray

fish

M1

38M

yalg

ia w

ith b

row

n-co

lore

d ur

ine

6 h

afte

r ea

ting;

CK,

3,6

00 U

/L. H

is w

ife a

nd d

augh

ter

deve

lope

d si

mila

rsy

mpt

oms.

[32]

2010

.7–9

Nan

jing,

Jian

gsu

Cray

fish

F121

Mya

lgia

with

bro

wn-

colo

red

urin

e 1

h af

ter

eatin

g; C

K, 2

,176

U/L

. One

of t

he 7

peo

ple

who

ate

with

the

refe

rent

pat

ient

dev

elop

ed si

mila

r sym

ptom

s.[3

2]

2010

Shiji

azhu

ang,

Hebe

iCr

ayfis

hM

126

Mya

lgia

with

wea

knes

s; C

K, 2

7,17

4 U

/L. P

atho

logi

cal a

naly

sis

of th

e le

ft b

icep

s br

achi

i mus

cle

reve

aled

rhab

dom

yoly

sis.

[33]

2012

.8N

anjin

g, Ji

angs

uCr

ayfis

hM

144

Mya

lgia

, che

st ti

ghtn

ess,

and

shor

tnes

s of

bre

ath

5 h

afte

r eat

ing

10 p

iece

s of

cra

yfish

; CK,

1,6

00 U

/L; C

K-M

B,92

6 U

/L.

[34]

2012

.8N

anjin

g, Ji

angs

uCr

ayfis

hM

131

Mya

lgia

, che

st ti

ghtn

ess,

and

shor

tnes

s of

bre

ath

7 h

afte

r eat

ing

10 p

iece

s of

cra

yfish

; CK,

1,0

56 U

/L; C

K-M

B,13

5 U

/L. A

seco

nd p

erso

n w

ho a

te 4

–5 p

iece

s of c

rayf

ish d

id n

ot d

evel

op sy

mpt

oms.

[34]

2012

.8Ya

ngzh

ou,

Jiang

suCr

ayfis

hM

1F2

30–3

7M

yalg

ia a

nd v

omiti

ng 7

–8 h

aft

er e

atin

g 20

–40

piec

es o

f cra

yfish

; CK,

350

–5,4

72 U

/L. T

hree

add

ition

al p

eopl

edi

d no

t dev

elop

sym

ptom

s.[1

5-16

]

2012

.8Ya

ngzh

ou,

Jiang

suCr

ayfis

hM

138

Mya

lgia

7 h

aft

er e

atin

g 30

pie

ces o

f cra

yfish

; CK,

3,4

70 U

/L. F

our o

ther

peo

ple

did

not d

evel

op sy

mpt

oms.

[15-

16]

2013

.8Hu

ai’a

n, Ji

angs

uCr

ayfis

hM

118

Mya

lgia

6 h

aft

er e

atin

g 30

pie

ces o

f cra

yfish

; CK,

622

U/L

; CK-

MB,

73.

1 U

/L.

[15]

2013

.6Sh

angh

aiCr

ayfis

hM

166

Mya

lgia

, wea

knes

s, m

uscl

e rig

idity

, olig

uria

, bro

wn-

colo

red

urin

e, a

nd s

hort

ness

of b

reat

h 12

h a

fter

eat

ing;

CK, 1

,600

U/L

; CK-

MB,

926

U/L

. The

pat

ient

was

dia

gnos

ed w

ith H

aff d

isea

se c

ompl

icat

ed b

y m

ultip

le o

rgan

failu

re. H

is co

nditi

on d

eter

iora

ted

desp

ite su

ppor

tive

and

sym

ptom

atic

trea

tmen

ts, a

nd h

e ul

timat

ely

died

.[3

5]

772 Biomed Environ Sci, 2019; 32(10): 769-778

Cont

inue

dPe

riod

City

Cons

umed

aqu

atic

prod

ucts

Sex

Age

(yea

rs)

Sym

ptom

s and

inve

stig

atio

n fin

ding

sRe

fere

nces

2014

.7W

uhu,

Anh

uiCr

ayfis

hM

141

Mya

lgia

, wea

knes

s, a

nd b

row

n-co

lore

d ur

ine

12 h

aft

er e

atin

g 1

kg o

f cra

yfish

; CK,

3,5

99 U

/L; C

K-M

B, 1

79 U

/L.

[36]

2014

.8W

uhu,

Anh

uiCr

ayfis

hM

143

Mya

lgia

11

h af

ter e

atin

g 0.

5 kg

of c

rayf

ish; C

K, 1

,187

U/L

; CK-

MB,

52

U/L

.[3

6]

2014

.8N

anjin

g, Ji

angs

uCr

ayfis

hM

1F1

32–3

3M

yalg

ia 8

–13

h af

ter c

onsu

min

g 10

–20

piec

es o

f cra

yfish

; CK,

500

–3,6

85 U

/L; C

K-M

B, 6

4–11

4 U

/L.

[15]

2015

.10–

201

6.9

Shan

ghai

Cray

fish

M35

F18

52 (1

6–97

)M

yalg

ia, d

iarr

hea,

or v

omiti

ng (n

= 1

eac

h); C

K, 3

,561

U/L

; CK-

MB,

187

U/L

.[3

7]

2015

.5Ya

nche

ng,

Jiang

suCr

ayfis

hM

162

Abdo

min

al p

ain,

vom

iting

, ave

rsio

n to

col

d, a

nd p

urpu

ra 4

–5 h

aft

er e

atin

g 10

pie

ces o

f cra

yfish

; CK,

901

.4 U

/L;

CK-M

B, 2

9.1

U/L

. The

pat

ient

dev

elop

ed sy

mpt

oms

of m

ultip

le o

rgan

failu

re a

nd w

as d

ischa

rged

aft

er re

scue

in th

e in

tens

ive

care

uni

t.[3

8]

2016

.7–8

Nan

jing,

Jian

gsu

Cray

fish

M72

F12

538

(17–

67)

Sym

ptom

ons

et w

ithin

2.5

–12

h, in

clud

ing

mya

lgia

(n

= 19

7, 1

00%

), br

own-

colo

red

urin

e (

n =

90, 4

5.7

%),

wea

knes

s (n

= 4

7, 2

3.8%

), na

usea

(n =

30,

15.

2%),

ches

t tig

htne

ss (n

= 2

5, 1

2.7%

), vo

miti

ng (n

= 2

0, 1

0.2%

),ch

est p

ain

(n =

19,

9.6

%),

num

bnes

s of t

he li

mbs

(n =

18,

9.1

%),

abdo

min

al p

ain

(n =

16,

8.1

%),

and

diar

rhea

(n=

15, 7

.6%

); CK

, 4,6

57±2

,178

U/L

; CK-

MB,

3,1

35±1

,547

U/L

.

[39]

2016

.7–8

Wuh

u, A

nhui

Cray

fish

M37

F712

–70

Mya

lgia

(n =

107

, 100

%),

brow

n-co

lore

d ur

ine

(n =

65,

60.

75%

), nu

mbn

ess o

f the

lim

bs (n

= 4

8, 4

4.86

%),

ches

ttig

htne

ss (n

= 4

2, 3

9.25

%),

naus

ea a

nd v

omiti

ng (n

= 8

, 7.4

8%),

diar

rhea

(n =

4, 3

.74%

), an

d ab

dom

inal

pai

n (n

= 3,

2.8

%);

CPK,

5,0

24 U

/L.

[40]

2016

.7–9

Guan

gdon

gCr

ayfis

hM

18F3

011

–59

Sym

ptom

ons

et, i

nclu

ding

mya

lgia

(n =

45,

93.

8%),

wea

knes

s (n

= 2

3, 4

7.9%

), sh

ortn

ess

of b

reat

h (n

= 1

9,39

.6%

), an

d ch

est t

ight

ness

(n =

19,

39.

6%),

7 h

(ran

ge, 1

–19

h) a

fter

eat

ing

20 (r

ange

, 2–6

0) p

iece

s of c

rayf

ish;

CK, 6

7–36

,164

U/L

; CK-

MB

exce

edin

g th

e no

rmal

lim

its in

26

case

s, C

K ex

ceed

ing

the

norm

al li

mits

in 2

0 ca

ses.

[41]

2016

.7–1

0W

uhu,

Anh

uiCr

ayfis

hM

31F7

138

Sym

ptom

ons

et, i

nclu

ding

mya

lgia

(n =

102

), w

eakn

ess

(n =

86,

84.

3%),

che

st ti

ghtn

ess

(n =

42,

41.

2%),

abdo

min

al p

ain

and

diar

rhea

(n =

19,

18.

63%

), na

usea

and

vom

iting

(n =

16,

15.

7%),

and

brow

n-co

lore

d ur

ine

(n =

2),

5.42

h a

fter

eat

ing

11.6

7±6.

19 p

iece

s of c

rayf

ish; C

K, 4

,479

.52

U/L

; CK-

MB,

172

.56

U/L

.[4

2]

2016

.7–8

Nan

jing,

Jian

gsu

Cray

fish

M28

F38

36 (1

8–76

)Sy

mpt

om o

nset

, inc

ludi

ng m

yalg

ia (n

= 6

6, 1

00%

) and

bro

wn-

colo

red

urin

e (n

= 1

9, 2

8.8%

), w

ithin

5.5

h(r

ange

, 1–2

4 h)

; CK,

327

1 IU

/L (r

ange

, 223

–163

,200

IU/L

); CK

-MB,

78.

1 ng

/mL

(ran

ge. 3

.7–1

,676

ng/

mL)

.[4

3]

2016

.6–8

Ma’

ansh

an,

Anhu

iCr

ayfis

hM

28F6

242

(11–

84)

Sym

ptom

ons

et, i

nclu

ding

mya

lgia

(n =

90,

100

%),

wea

knes

s (n

= 6

2, 6

8.89

%),

brow

n-co

lore

d ur

ine

(n =

11,

12.2

2%),

ches

t pai

n (n

= 6

, 6.6

7%),

naus

ea (n

= 5

, 5.5

6%),

abdo

min

al p

ain

(n =

2, 2

.22%

), an

d sh

ortn

ess

ofbr

eath

(n =

1, 1

.11%

), w

ithin

1–1

5 h;

CK,

624

9.36

U/L

; CK-

MB,

383

.99

ng/L

.[4

4]

2016

.7W

uhu,

Anh

uiCr

ayfis

hM

7F33

/M

yalg

ia 4

0, b

row

n-co

lore

d ur

ine

1.[4

5]

2016

.8W

uhan

, Hub

eiCr

ayfis

hM

138

Mya

lgia

, wea

knes

s, n

ause

a, a

nd v

omiti

ng 1

1 h

afte

r eat

ing

500

g of

cra

yfish

; CK,

6,4

40 U

/L.

[46]

2016

.8W

uhan

, Hub

eiCr

ayfis

hF1

37M

yalg

ia, w

eakn

ess,

nau

sea,

and

vom

iting

6 h

aft

er e

atin

g 50

0 g

of c

rayf

ish; C

K, 1

,057

U/L

.[4

6]

unkn

own

Baod

ing,

Heb

eiCr

ayfis

hF1

43W

eakn

ess a

fter

20

h; C

K, 3

9,16

4 U

/L; C

K-M

B, 6

46 U

/L.

[47]

unkn

own

Baod

ing,

Heb

eiCr

ayfis

hM

127

Abdo

min

al p

ain,

nau

sea,

and

vom

iting

with

in 1

5 h;

CK,

24,

356

U/L

; CK-

MB,

421

U/L

.[4

7]

unkn

own

Baod

ing,

Heb

eiCr

ayfis

hF1

36M

yalg

ia a

nd w

eakn

ess w

ithin

6 h

; CK,

20,

110

U/L

; CK-

MB,

1,0

16 U

/L.

[47]

2016

.7–8

Nan

jing,

Jian

gsu

Cray

fish

M35

F49

39 (1

5–89

)O

nset

of s

ympt

oms,

incl

udin

g m

yalg

ia (n

= 8

4, 1

00%

), b

row

n-co

lore

d ur

ine

(n =

52,

61.

2%),

sho

rtne

ss o

fbr

eath

(n =

42,

50%

), na

usea

(n =

21,

25%

), vo

miti

ng (n

= 1

6, 1

9%),

wea

knes

s (n

= 13

, 15.

5%),

and

num

bnes

s of

the

limbs

(n =

12,

14.

3%),

with

in 7

.86

h; C

K, 6

,105

.49

U/L

.[4

8]

Characteristics of haff disease 773

damage[31], while a pathological analysis of thepainful muscle may reveal rhabdomyolysis[33].

Despite the above findings, the prognosis of Haffdisease is good. With supportive treatment,including rest, intravenous fluid hydration, andbicarbonate infusion, the symptoms resolve, and thelevels of muscle enzymes return to normal.However, a few serious cases may develop renal andother organ failures. In 2015, one case ofrhabdomyolysis syndrome in Yancheng, Jiangsu, wasattributed to the consumption of crayfish. Thepatient subsequently developed septic shock,multiple organ dysfunction syndrome, and acuterenal failure. Although he became critically ill, hewas discharged after treatment in the intensive careunit (ICU)[38]. Furthermore, a 31-year-old man inNanjing was diagnosed with Haff disease afterconsuming cooked crayfish. After a 5-hour period ofhospitalization, the patient developed an acute lunginjury. He was treated with intravenous fluidhydration and bicarbonate infusion and wasdischarged after 9 days. It remains unknownwhether the lung was the direct target of the toxin inthat case[56].

Haff disease is rarely associated with mortality.In 2013, one male patient in Shanghai developedmuscle pain, fatigue, muscle rigidity, oliguria, brown-colored urine, and shortness of breath 12 h after

Cont

inue

dPe

riod

City

Cons

umed

aqu

atic

prod

ucts

Sex

Age

(yea

rs)

Sym

ptom

s and

inve

stig

atio

n fin

ding

sRe

fere

nces

2016

.7–1

0N

anjin

g, Ji

angs

uCr

ayfis

hM

50F2

834

Mya

lgia

, wea

knes

s, c

hest

tigh

tnes

s, a

nd b

row

n-co

lore

d ur

ine

with

in 6

–24

h; C

K, 8

,976

±2,3

54 U

/L.

[49]

2016

.8Sh

enzh

en,

Guan

gdon

gCr

ayfis

hM

1F 3

22–4

1M

yalg

ia (n

= 4

) and

nau

sea

(n =

1) w

ithin

4–6

h; C

K, 1

452–

1553

4 IU

/L; C

K-M

B, 1

.3–4

.8%

.[5

0, 5

1]

2016

.8Ho

ng K

ong

Cray

fish

F155

Mya

lgia

with

in 4

h.

[52]

2016

.9Ho

ng K

ong

Cray

fish

F130

Mya

lgia

with

in 5

h. T

wo

othe

r peo

ple

did

not d

evel

op sy

mpt

oms.

[52]

2016

.8He

fei,

Anhu

iCr

ayfis

hF1

25M

yalg

ia a

nd n

ause

a 5.

5 h

afte

r eat

ing

30 p

iece

s of c

rayf

ish; C

K-M

B, 3

7.7

ng/m

L.[5

3]

2016

.6–7

Nan

jing,

Jian

gsu

Cray

fish

M14

F34

38 ±

11

Mya

lgia

, wea

knes

s, n

ause

a an

d vo

miti

ng, a

bdom

inal

pai

n, d

iarr

hea,

and

che

st ti

ghtn

ess w

ithin

2–2

4 h.

[54]

2016

.7–8

Nan

jing,

Jian

gsu

Cray

fish

M9F

3238

Mya

lgia

, wea

knes

s, a

nd e

leva

ted

CK w

ithin

24

h.[5

5]

Unk

now

nN

anjin

g, Ji

angs

uCr

ayfis

hM

131

Ches

t, ba

ck, a

nd s

houl

der p

ain,

who

le-b

ody

num

bnes

s, a

nd n

ause

a an

d vo

miti

ng 6

h a

fter

the

mea

l; CK

, 371

(rang

e, 2

0–1,

74U

/L);

CK-M

B, 3

3 (r

ange

, 1–18

U/L

). In

trav

enou

s flu

id h

ydra

tion

and

bica

rbon

ate

infu

sion

5 h

late

r.

Diff

use

mya

lgia

acc

ompa

nied

with

che

st ti

ghtn

ess,

rapi

d an

d sh

allo

w re

spir

atio

n, a

nd a

few

bila

tera

lpu

lmon

ary

crac

kles

. Com

pute

d to

mog

raph

y le

d to

a d

iagn

osis

of H

aff d

iseas

e co

mpl

icat

ed b

y ac

ute

lung

inju

ry.

It re

mai

ns u

nkno

wn

whe

ther

the

lung

was

the

dire

ct ta

rget

of t

he to

xin.

[56]

Table 3. Clinical manifestations of confirmed casesin China

Clinical manifestation Number Percent（%）

Myalgia 632 98.60

Brown-colored urine 257 40.09

Weakness 184 28.71

Nausea 105 16.38

Vomiting 87 13.57

Chest tightness 72 11.23

Shortness of breath 44 6.86

Diarrhea 39 6.08

Chest pain 32 4.99

Numbness 31 4.84

Dry mouth 26 4.06

Abdominal pain 24 3.74

Headache 12 1.87

Voice hoarseness 1 0.16

Aversion to cold 1 0.16

Purpura 1 0.16

774 Biomed Environ Sci, 2019; 32(10): 769-778

consuming crayfish. A laboratory examinationrevealed a CK level of 358.6 U/L. Following amisdiagnosis of lumbar disc herniation, he wasadmitted to the hospital with multiple organ failurebut died after receiving treatment in the ICU[35].Generally, an early and accurate diagnosis andprovision of active therapy to prevent complicationsare key factors required to improve patientoutcomes.Causes of Haff Disease　 　 Three categories offactors are known to cause rhabdomyolysis[20,61,62]:physical factors, nonphysical factors, and geneticfactors. Physical factors include squeezing andtrauma, exercise and excess muscle activity, statusepilepticus, electric shock, high fever, andheatstroke. Nonphysical factors include drugs, suchas statins, poisons, bacterial (e.g., Legionella) andviral infections (influenza A, B), and electrolyteimbalances (e.g., hypokalemia, hypophosphatemia,hyponatremia, and hypocalcemia). Genetic factorsinclude autoimmune diseases (e.g., polymyositis anddermatomyositis), endocrinological and geneticmetabolic diseases (e.g., diabetes), and factors thatcan cause rhabdomyolysis.

Studies of the risk factors of Haff disease havebeen conducted consistently since the discovery ofthe disease. Descriptive epidemiological studies havesuggested an etiology associated closely with theconsumption of cooked seawater or freshwaterfoods. Furthermore, analytical epidemiologicalstudies (e.g., case-control and cohort studies) andchemical analyses of collected biological sampleshave been conducted to determine the risk factorsfor Haff disease in cooked aquatic products, and atoxicity test has been developed to establish ananimal model of Haff disease. One unmatched case-control study conducted in Nanjing in August 2010involved the administration of a telephone/face-to-face questionnaire survey on food consumption in20 patients with rhabdomyolysis syndrome and in 25patients who had shared food with the patients.Subsequently, the subjects’ dietary histories, diseasestatuses, background diseases, alcohol consumptionduring the suspected crayfish meals, physicaltraining habits, and allergic histories wereinvestigated, and an association was found betweenthe consumption of > 10 pieces of crayfish and anincreased risk of disease[63]. In 2009, Huang Qionget al. conducted a retrospective cohort study on anoutbreak of Haff disease caused by freshwaterpomfret in Guangdong Province. Of the 3,857 Jiubeiresidents, 159 people had consumed pomfrets, and

50 members of this subgroup became ill. A dose-response relationship between fish consumption andelevated serum levels of muscle enzymes (CK, CK-MB, aspartate aminotransferase) were observed.Residents who did not eat fish were unaffected[14].Although these studies demonstrate a closeassociation between the consumption of cookedaquatic products and the occurrence of Haff disease,the specific etiological factors require furtherinvestigation.

Previous studies have screened food samplesand biological samples from patients for drugs andtoxicants known to cause rhabdomyolysis syndrome.In one study by Buchholz et al., recovered leftoversand uncooked buffalo fish from the same lot weretested for active sodium channel biotoxins [e.g.,ciguatoxin (the toxin of ciguatera) or saxitoxin (thetoxin associated with paralytic shellfish poisoning)],cyanobacterial toxins (e.g., the blue-green algaltoxins microcystin or nodularin), organophosphates,and arsenic. However, the tests produced negativeresults or values below the toxicity thresholds[1].Huang Qiong et al. tested fish, water, and soilsamples for microcystins, toxins (including scorpiontoxin, chelating base, histamine, ractopamine, F-, CL-,NO3-, NO2-, and SO4

2-), and 26 heavy metals (Be, Na,Mg, Al, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se,Mo, Ag, Cd, Sn, Sb, Ba, Tl, Pb, Th, and U) usingchemical analysis techniques and methods such asliquid chromatography-mass spectrometry (MS), ionchromatography, gas chromatography-MS,inductively coupled plasma-MS, and atomic forcespectroscopy. Similarly, the results were eithernegative or below the toxicity thresholds[14]. In acytotoxicity and hemolysis analysis of palytoxins,Chen Xiaofeng et al. revealed that methanol/watergills, intestines, and glands extracts from crayfishwere not inhibited effectively by ouabain, indicatingthat the rhabdomyolysis-inducing toxin was not anallergen or palytoxin[64]. According to Chen Yan et al.,a chemical analysis of crayfish samples purchasedfrom a market and of blood and urine samples from2 cases did not reveal any possible toxins, drugs, andhazardous elements among at least 200 screenedcompounds with known relevance torhabdomyolysis (e.g., macrolides, sulfonamides,polyether antibiotics, β-agonists, organophosphoruspesticides, aniline, phenylamine, m-nitroaniline andp-nitroaniline, arsenic, cadmium, and other heavymetals)[63]. He Ying[65] found that althoughcyanobacteria, equisetum, and heavy metals inducedincreases in the serum CK level in the Institute ofCancer Research (ICR) mice, the related changes in

Characteristics of haff disease 775

enzyme activities were insufficient to induce Haffdisease and did not cause symptoms ofrhabdomyolysis in the ICR mice. No substancescurrently known to cause rhabdomyolysis weredetected in samples of aquatic products consumedby patients with Haff disease or in the urine andblood samples of these patients.

Accordingly, researchers conducted animalexperiments and established a mouse model ofrhabdomyolysis to determine the substances incooked aquatic products that cause Haff disease.Buchholz et al. separated the extracts of buffalo fishsamples into water-soluble, nonpolar lipid and polarlipid fractions, which were administeredintraperitoneally and orally to laboratory mice. Mice-fed hexane-soluble products exhibited behavioralchanges consistent with muscle impairment and red-brown-colored urine in the bladders[1]. Huang Qionget al. found that samples of freshwater pomfret fromthe same reservoir could induce muscle damage inmice[14]. Moreover, some batches of crayfish inducedrhabdomyolysis syndrome in some mice in a dose-dependent manner[41].

Some Chinese scholars have speculated thatrhabdomyolysis syndrome may be related to anallergic reaction. Accordingly, LIN Jiang Weiconducted a series of studies of crayfish poisoningbut ultimately did not detect an association betweensea anemone toxin and allergic reactions. Moreover,Huang Qiong et al.[41] observed that crayfish liver andpancreas could induce a decrease in the serum totalimmunoglobulin G antibody level, suggesting a weakor nonexistent association between rhabdomyolysisand allergy.

Professor Adgren suggested that themanifestations of Haff disease were consistent witha disease known as Chastek paralysis, which was firstobserved on silver fox farms in the United States.Subsequently, Ender and Helgebostad demonstratedthat Chastek paralysis could be induced by a dietdeficient in vitamin B1. Interestingly, Green andEvans reported that certain types of fish, particularlycarp, contain a substance that inactivates vitaminB1. Moreover, foxes with Chastek disease recoveredrapidly when treated with high doses of vitaminB1[2]. However, the potential association betweenHaff disease and vitamin B1 deficiency has not beenstudied further.

In summary, the etiology of Haff disease remainsunknown. Further study is required to determinewhether cooked aquatic products contain anunknown heat-stable, tissue-specific, and non-neurotoxic pathological factors or whether the

consumption of cooked aquatic foods activatesparticular signaling pathways that inducerhabdomyolysis.

The literature demonstrates an evident globalincrease in the number of reports of Haff diseasesince its first report in 1924. A review of thisliterature demonstrated that the existing researchwas based mostly on case reports from hospitals.Accordingly, the current body of knowledge facesseveral shortcomings. First, since the main clinicalmanifestation of Haff disease is muscle pain, manypotential cases with mild symptoms may not havebeen detected. Second, researchers have useddifferent approaches to verify their hypothesesregarding the etiology of Haff disease, andaccordingly, the study was not conductedsystematically. Different researchers may not haveconsidered the relevant case conditions andcontributing factors because of limitations specific totheir scenarios. Researchers may also haveinsufficient data on the health risks associated withdisease-causing food cultures and ecologicalenvironment factors. For example, in a study of Haffdisease in Beijing in 2000, the researcher lackedtrace data about the Cambaroides spp. consumed bythe subjects and did not collect food or biologicalsamples for further studies of the causative factors.Third, few studies have explored rhabdomyolysis inexperimental animals, such as mice, and suchresearch remains in the initial exploration stage. Todate, all experimental materials have been sampledfrom patients’ leftovers and from reservoirs wherethe aquatic foods were caught. Any previously drawnconclusions will require further validation becausethe epidemiological hypothesis and directions ofanimal experiments remain unclear. Therefore,future studies of the health hazards, epidemiologicalcharacteristics, and influencing factors related toHaff disease and new animal models are required.This research can be approached through thefollowing aspects:

(1) The epidemiological characteristics andinfluencing factors, including the collection andclassification of previous cases of Haff disease.Researchers could construct a Haff disease casemonitoring system and perform retrospectiveinvestigations in high-incidence provinces.Epidemiological investigations should use standardquestionnaires to collect case information, andbiological, food, and environmental samples shouldbe collected. Descriptive epidemiological studies toclarify the health hazards and epidemiologicalcharacteristics of the disease should be developed

776 Biomed Environ Sci, 2019; 32(10): 769-778

systematically, and case-control and cohort studiesshould be conducted to determine the influencingfactors.

(2) Research on the health risk factors associatedwith the culture, transportation, sales, and ecologicalenvironments of disease-causing aquatic foods (e.g.,crayfish, burbot, buffalo fish). In China, Haff diseaseis mainly caused by the consumption of crayfish, andecological studies should investigate the reservoirsand wild fishing areas of these organisms. Riskfactors associated with breeding, transportation, andsales practices should be explored for possiblehealth risk factors.

(3) Establishment of an animal model ofrhabdomyolysis syndrome and animal test study. Ananimal model of rhabdomyolysis syndrome shouldbe established using experimental animals ofdifferent species and germ lines. Pilot experimentsbased on epidemiological studies should beconducted in these animal models to verify thehypotheses of epidemiological investigations and toscreen positive samples.

In conclusion, Haff disease, an idiopathic form ofrhabdomyolysis syndrome associated with theconsumption of freshwater marine products, hasimportant impacts on human health, socioeconomicdevelopment, and stability. Haff disease can easilyinduce a social panic, given the acute incidence andpotential severity and its association with theconsumption of cooked aquatic foods. Anunderstanding of the influencing and pathologicalfactors associated with Haff disease wouldcontribute significantly to preventing the occurrenceof disease and would positively influence healthydietary choices and the formulation of relevantindustrial standards.Author Contributions　 　 Conceived and designed the manuscript, LU Xuan Cheng, WANG Rui, and PEIPei; searched and read the papers, PEI Pei, LUShuang Shuang, LI Xiao Yan, and LIU Zhe; wrote themanuscript, PEI Pei; critically revised the manuscript,LU Xuan Cheng and WANG Rui; and provided thefinal approval of the manuscript to be published, LUKai, LU Xuan Cheng, and WANG Rui.Competing Interests　　None of the authors havecompeting interests to declare.

#Correspondence should be addressed to WANG Rui,PhD, Tel: 86-13520153670, E-mail: wangrui@chinacdc.cn;LU Xuan Cheng, PhD, Tel: 86-137180700001, E-mail:luxc@chinacdc.cn; LU Kai, PhD, Tel: 86-15210365022,E-mail: lukai@chinacdc.cn

Biographical note of the first author: PEI Pei, female,born in 1995, bachelor's degree, majoring in public health.

Received: February 22, 2019;Accepted: August 22, 2019

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