Emerging Infectious Diseases
[Volume 6 No.2 / March - April 2000]
Dispatches
Haff Disease: From the Baltic Sea to the U.S. Shore
Udo Buchholz,* Eric Mouzin,* Robert Dickey, Ron
Moolenaar, Neil Sass, and Laurene Mascola*
*County of Los Angeles Department of Health Services, Los
Angeles, California, USA; Centers for Disease Control and
Prevention, Atlanta, Georgia, USA; Food and Drug
Administration, Dauphin Island, Alabama, USA; Food and Drug
Administration, Laurel, Maryland, USA
Haff disease, identified in Europe in 1924, is unexplained
rhabdomyolysis in a person who ate fish in the 24 hours before
onset of illness. We describe a series of six U.S. patients from
1997 and report new epidemiologic and etiologic aspects.
Although Haff disease is traditionally an epidemic foodborne
illness, these six cases occurred in two clusters and as one sporadic
case.
In the summer and fall of 1924, physicians near the Knigsberger
Haff shores along the Baltic coast recognized an outbreak of an
illness characterized by sudden, severe muscular rigidity (1-3). No
neurologic abnormalities, fever, splenomegaly, or hepatomegaly
were observed (1). Patients often had coffee-colored urine. The
clinical spectrum of disease varied, few patients died, and most
survivors recovered quickly. In the following 9 years, similar
outbreaks, affecting an estimated 1,000 persons, occurred
seasonally in the summer and fall along the coast of the "haff" (a
shallow lagoon). Recent ingestion of fish, usually cooked, was
common among those who became ill; species of fish included
burbot, eel, and pike. Seabirds and cats reportedly died after eating
fish in the wild. Because of the absence of fever and the fact that
fish had been cooked, known infectious causes were eliminated.
Several toxic etiologies were proposed but could not be confirmed.
Among these was arsenic poisoning (4), which is still cited in
modern medical dictionaries as the cause of Haff disease (5). From
1934 until 1984, other outbreaks resembling Haff disease were
described in Sweden and the Soviet Union (6-9). The first two
cases reported in the United States occurred in Texas in June 1984;
through 1996, only four more cases were reported: two from Los
Angeles, California, in 1985, and two from San Francisco,
California, in April 1986 (M. Tormey, pers. comm.). All patients
had eaten buffalo fish before onset of illness. Tests of the remains
of one of the fish meals suggested a neutral lipid as a causative
agent. Reports of six cases of Haff disease from California and
Missouri during a 5-month period (March-August) in 1997
prompted an investigation with the objectives of describing the
epidemiology and clinical characteristics of the 1997 U.S. cases of
Haff disease, tracing back implicated fish, and elucidating the
cause of Haff disease.
The Study
Based on the clinical description of the original cases from 1924 to
1933, we defined a case of Haff disease as illness in a person with
unexplained rhabdomyolysis who had eaten fish in the 24 hours
before onset of symptoms. The laboratory marker used to define
rhabdomyolysis was a fivefold or greater elevation in creatine
kinase (CK) levels, with a muscle/brain (MB) fraction <5% (10).
Cases were identified through county and state epidemiologists, as
well as the Food and Drug Administration (FDA) laboratories in
Bothell, Washington, and Dauphin Island, Alabama. We
interviewed all persons with cases reported to the Los Angeles
County Health Department or FDA. We reviewed medical records
for demographic information, medical history, course of illness,
and food exposures, including method of preparation and source of
food purchase. For the California cases (March 8- 9 and August 8),
we conducted active surveillance in city or community hospitals
near the case-patients' residence during the 5 days surrounding the
dates of onset. Surveillance included reviews of laboratory logs
(for cases with highly elevated CK but a low MB fraction) and
emergency room logs for all patients with a diagnosis of suspected
fish poisoning. 
Table. Symptoms of Haff disease cases, United States, 1997
State and local environmental management staff visited stores and
markets where fish was bought to trace the implicated fish lots. We
interviewed fish wholesalers regarding the number and location of
fishermen catching buffalo fish. Because fish eaten by the patients
originated from Louisiana and Missouri, we discussed with health
departments and environmental experts possible sources of fish
intoxication. Recovered leftovers and uncooked fish from the same
lot were tested for sodium channel-active biotoxins (e.g.,
ciguatoxin [the toxin of ciguatera] or saxitoxin [the toxin of
paralytic shellfish poisoning]), and cyanobacterial toxins (e.g.,
microcystin or nodularin, which are toxins of blue-green algae)
(11,12). Samples from the Bakersfield case were tested for
organophosphates, and other samples were tested for arsenic. To
characterize the physicochemical properties of the toxin, extract
from both cooked and uncooked fish was partitioned into water-
soluble, nonpolar lipid (hexane) and polar lipid (chloroform)
fractions. These fractions were then administered intraperitoneally
and orally to laboratory mice. Fractions causing toxicity to mice
were further analyzed for identification of the toxin.
From March through August 1997, two clusters of Haff disease
cases occurred in Los Angeles, California, and St. Louis, Missouri
(13); one isolated case occurred in Bakersfield, California. The Los
Angeles cluster consisted of two sisters who lived together and a
third patient who was admitted to the same hospital during the
same weekend. The St. Louis cluster was a married couple. The
four meals, all eaten at home, contained buffalo fish. Six (75%) of
the eight persons who ate buffalo fish became ill. All patients were
>30 years of age (33 to 87 years); five were Ukrainian immigrants,
and one was African American. Three of the six patients were
taking medications, including aspirin, codeine, and simvastatin,
that could have exacerbated rhabdomyolysis. Two persons who
vomited shortly after the meal had either milder symptoms or
lower laboratory values. The median incubation time to onset of
symptoms after fish ingestion was 8 hours (6 to 21 hours). All
patients were hospitalized, none died, and the median hospital stay
was 3 days. Clinically, five of six patients had rapid onset of
generalized muscular pain and rigidity, so severe that in one case
ventilation was required (Table). In one patient who had chest pain
only, the diagnosis of Haff disease was made through the exclusion
of other causes of chest pain and the epidemiologic link with two
other case-patients who had eaten buffalo fish purchased from the
same market. The predominant laboratory abnormalities were
elevated CK and myoglobin. Other muscle enzymes, such as
glutamate oxalate transaminase, glutamate pyruvate transaminase,
and lactate dehydrogenase, were also elevated. The CK was
elevated to a mean of 12,700 IU/L (normal is usually <300 IU/L)
(Figure). At the peak of the CK, the MB fraction was <5% in all
cases. The mean maximum myoglobin level, tested in three
patients, was 6,997 IU/L (upper limit of normal 100 IU/L).
Treatment consisted of intravenous fluids, in addition to mannitol
or bicarbonate. Several of the patients had variable sequelae,
including weakness and fatigue, for several months after the acute
stage. Active surveillance has identified no further cases. Buffalo
fish (Ictiobus cyprinellus) is a bottom-feeding freshwater fish
similar to carp. The fish was fried (four cases) or cooked for 3.5
hours as "gefilte fish" (two cases). Fish were purchased locally
either in a supermarket (California) or alive from a fish tank at a
market (Missouri). Fish lots were caught by approximately 25
commercial fishermen from rivers in Louisiana (three incidents) or
five fishermen in rivers and lakes near St. Louis, Missouri (one
incident). No specific bodies of water could be identified as the
origin of implicated fish. No fish or unusual animal die-off was
noted in the areas where buffalo fish were caught.
Figure. Creatine kinase elevation after the onset of symptoms in a
patient with Haff disease, California, 1997.
Tests of the fish for toxins were either negative or below toxicity
thresholds. The fact that the eaten fish was thoroughly cooked
suggests that the presumed toxin is heat-stable. Mice fed hexane-
soluble products extracted from cooked fish had behavioral
changes consistent with muscle impairment; bladders contained
red-brown urine.
Conclusions
Historically, Haff disease has been identified during seasonal
outbreaks in Europe. This report documents that it may also occur
sporadically or in small clusters. Ten of the 12 U.S. cases of Haff
disease reported since 1984 occurred during March through August
(M. Tormey, pers. comm.). All patients had eaten buffalo fish
before becoming ill; 8 of the 12 patients were California residents,
although the buffalo fish was caught in Louisiana or Missouri
waters.
Most reported cases or outbreaks of Haff disease have been
associated with freshwater fish, unlike most other seafood-related
illnesses (e.g., ciguatera, scombroid fish poisoning, or paralytic
shellfish poisoning), which are associated with saltwater fish (14).
The clinical symptoms of Haff disease also differ from those of any
other fish-related toxic or bacterial illness. Symptoms of
rhabdomyolysis predominate and neurologic features are absent, in
contrast to ciguatera or the various forms of shellfish poisoning
(14). Because of the spectrum of symptoms, the potential for
misdiagnosis is considerable. Furthermore, an increasing number
of health-conscious persons prefer diets that include fish. In 1998,
more than 4 billion pounds of fish, both domestic and imported,
were eaten in the United States (website of National Oceanic and
Atmospheric Administration: www.nmfs.org) Unusual smell or
taste does not help identify toxic fish, and normal cooking methods
cannot detoxify a fish capable of causing Haff disease. Because
Haff disease may occur not only in epidemics but also in small
clusters or sporadically, fish consumption should be included in the
history of patients with unexplained rhabdomyolysis.
Acknowledgments
We thank Steve Musser, Martin Robl, James Ahlrep, and Richard
Honkanen for laboratory support; Doug Dodson, Diane Rackers,
Louise McFarland, Al Medina, Michael Tormey, and S.B. Werner
for their advice and help; Piotr Kramarz for his translation of
Russian articles; and the staff of the Kern County Health
Department, particularly Drs. Dulan, Talbot, and Steve Terrell-
Perica, for their cooperation and tireless support in the
investigation.
Dr. Buchholz, who was with the Centers for Disease Control and
Prevention, at the time of this study, is a medical epidemiologist
with the Los Angeles County Department of Health Services. His
interests include foodborne disease epidemiology, outbreak
investigations, and surveillance for listeriosis and influenza.
Address for correspondence: Udo Buchholz, Los Angeles County
Department of Health Services, Acute Communicable Disease
Control, 313 N. Figueroa St., Room 212, Los Angeles, CA 90012,
USA; fax: 213-482-4856; e-mail: ubuchholz@dhs.co.la.ca.us.
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Emerging Infectious Diseases
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Centers for Disease Control and Prevention
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