Pfiesteria complex organisms and human illness. (Review Article).

ABSTRACT

Background. Pfiesteria piscicida and look-alike dinoflagellates are collectively known as Pfiesteria complex organisms (PCOs). The purposes of this paper are to evaluate the threat that PCOs pose to human health and to clarify some common misconceptions concerning these organisms.

Methods. References about P piscicida and PGOs were identified and reviewed using MEDLINE, Sea Grant databases, and other sources obtained from various Internet sites.

Results. Researchers exposed to aerosols of water containing P piscicida in a laboratory setting exhibited a variety of symptoms, including reversible cognitive impairment and loss of short-term memory. This led to multiple biologic, animal model, and epidemiologic studies that are reviewed and discussed.

Conclusions. Exposure to P piscicida and possibly other PCOs can cause human illness. Until further isolation and purification of toxins from PCOs allows for development of tests to detect these toxins, predicting and documenting toxic PCO fish kills as well as potential PCO-related illness will be difficult.

**********

PFIESTERIA PISCICIDA and Pfiesteria complex organisms (PCOs) have received extensive media coverage, particularly in mid-Atlantic and coastal states of the Southeast. Such reports are frequently inaccurate or grossly sensationalized. Pfiesteria piscicida, dubbed the "cell from hell" by the New York Times, has been called "a twin-tailed microscopic monster that eats blood," "fish AIDS," and "as menacing as the Ebola virus--only closer to home." The hysteria generated by a largely unscientific media reporting such misinformation to a scientifically illiterate public has had an impact on many industries and has even become a political issue. Patients exposed to these reports are increasingly likely to turn to their physicians for advice about the hazards of these organisms. The purpose of this article is to provide the clinician with a review of what is currently known about Pfiesteria, PCOs, and human health.

THE ORGANISM(S)

Pfiesteria piscicida is a protist in the division Dinoflagellata (also called Dinoflagellida). Dinoflagellates are single-celled eukaryotic microorganisms (therefore not a bacterium or a virus) found in fresh and salt waters. Pfesteria piscicida and at least 10 other organisms that look similar when examined under the light microscope are known collectively as either PCOs or morphologically related organisms (MROs). Pfiesteria piscicida, first shown to kill fish in a laboratory setting in 1988, (1) has been associated with fish kills mainly in estuarine waters of North Carolina. (2) Pfiesteria complex organisms have been recovered in waters from the Delaware Bay to the Gulf of Mexico and have also been implicated in fish kills occurring in Maryland, Virginia, and possibly Florida. (3)

Although it is a single-celled organism, P piscicida has a complex life cycle with at least 24 morphologically different life forms. (4-7) A nontoxic amoeboid form is shown in Figure 1. Although incapable of producing chlorophyll, Pfiesteria can grow photosynthetically by utilizing the chloroplasts of ingested phytoplankton. (5-7) Hence, it deserves its reputation as being both animal-like and plant-like.

The presence of finfish (especially menhaden, Brevoortia tyrannus) or their excreta can trigger a transformation from a quiescent cyst form found in sediments to a free-swimming flagellate vegetative cell. The toxic vegetative cells are thought to produce two exotoxins: a water-soluble neurotoxin that rapidly kills fish and a lipid-soluble toxin that initiates epidermal necrosis in fish. (5-9) Soon after feeding on tissue debris of fish caused by release of these exotoxins, the organism encysts and returns to the sediment. (2) A typical "punched out lesion" observed on moribund and dead fish during PCO-related fish kills is shown in Figure 2. The etiology of these ulcerative lesions is still controversial, since some believe that they are caused by fungal organisms (eg, Aphanomyces), (10) a concept that is not new. (11) It is possible that the Pfiesteria toxin might induce initial epidermal necrolysis, allowing for opportunistic infection by other microbes.

Pfiesteria piscicida has been shown to be tolerant of salinities ranging from 0 to 35 parts per thousand (ppt) (from fresh to sea water, respectively) and a broad range of water temperatures. (4) However, the rare toxic forms are most prevalent at salinities around 15 ppt and temperatures [greater than or equal to]26[degrees]C. (4) Blooms of PCOs have also been reported to be stimulated by excess nutrients such as phosphorus and nitrogen. (4) Because these factors also stimulate growth of their algal prey species, such water conditions may indirectly increase the risk of toxic outbreaks of PCOs simply by increasing the total PCO loads. (4,12,13) Hence "Pfiesteria season" occurs during the late summer months, particularly in nutrient-enriched estuarine waters. However, Pfiesteria has been identified in fresh water aquaculture facilities, as well as in the open Atlantic. (2,4)

PCO-RELATED ILLNESS

The first evidence that PCOs might cause human illness was provided by case studies of three researchers who were apparently intoxicated while working in a closed laboratory setting by chronic exposure to PCO-laden aquarium water containing high concentrations of organisms. (4) All three workers had asthenia, skin lesions, emotional lability, and memory dysfunction. Other symptoms included spatial disorientation, impaired reading and concentration, paraesthesias, myalgias, arthralgias, headache, nausea, abdominal pain, vomiting (but not diarrhea), hyperhidrosis, conjunctivitis, and dyspnea. Vital signs and results of routine neurologic examinations were essentially normal. Resolution of the most striking symptom, severe loss of short-term memory, required 1 or more weeks after cessation of exposure. Consistent with the cognitive deficits experienced by these people, rats injected with aquarium water containing toxic forms of P piscicida, but not rats receiving uninfested aquanum water, exhibited reversible l earning deficits that persisted up to 10 weeks. (14,15) No hematologic or histopathologic abnormalities were found in the exposed rats.

Despite the occurrence of multiple PCO-related fish kills in North Carolina waters, (2) to date no definite case of human illness attributable to environmental exposure to PCO-laden water has been reported by any physician practicing in North Carolina. (16) This suggests that environmental or recreational exposure to PCOs might pose little threat to human health. Such a contention is supported by the finding that the health of 254 crabbers who work PCO-endemic regions of the estuarine Pamlico and Neuse Rivers of North Carolina is similar to that of 114 crabbers who fish in the Albemarle Sound, a North Carolina sound that has never had a documented PCO-related fish kill. (17) However, as noted by the authors, crabbers are skilled at avoiding waters experiencing fish kills, and hence there might have been little or no differences in exposure to PCO exotoxins between the two groups. (17) This important retrospective study is being extended to a prospective cohort study in which efforts to gauge exposure to PCOs are made. (16)

Fish kills associated with toxic PCOs were documented in Maryland waters for the first time in August and September 1997. (18) Before these fish kills, watermen began noticing increasing numbers of fish with lesions, and a group of persons who were exposed to affected fish began to complain of fatigue, skin irritation, and memory loss. These complaints prompted the Maryland Department of Health and Mental Hygiene to convene a team of health experts to look for a possible link between environmental exposure to PCOs and human health. (19,20) The team found evidence of neuropsychologic deficits and illness in a group of 13 fishermen who worked estuarine waters but not in a group of 8 oceanside watermen. (21) A toll-free hotline, in operation from August 30 to September 14, 1997, and referrals to the medical team identified 53 persons thought to be ill because of exposure to toxic PCOs. Premorbid conditions were subsequently found to account for illness in 5 of these cases, leaving a total of 48 persons with pos sible PCO-related illness. (21)

In September 1997, the CDC organized a workshop of public health experts from 8 southeastern states and a number of federal agencies to delineate a public health response to PCOs. (22) An important outcome of that meeting was a consensus on "a combined set of environmental conditions and clinical signs and symptoms that together may represent adverse consequences of exposure to these organisms". (19) To meet the criteria for diagnosis by this tentative working definition of PCO-related illness, which was initially termed "estuary-associated syndrome" (EAS), a patient must have been exposed to estuarine waters containing PCO organisms or fish with lesions "consistent with PCO toxicity" and display certain clinical signs and symptoms such as (1) memory loss, or (2) confusion, or (3) acute skin burning on direct contact with water, or (4) any 3 of 6 other complaints (Table 1).

Among the 48 persons identified in Maryland as possibly having PCO-related illness, 32 met the CDC guidelines. Of these 32, 25 had neuropsychologic testing, with 11 scoring below the 10th percentile on the Rey Auditory Verbal Learning Test (RAVLT). The RAYLT is a standardized test for assessing learning and memory. (23) Of the 16 persons not meeting CDC guidelines, 9 had neuropsychologic testing, with 2 of these 9 scoring below the 10th percentile on the RAVLT. All 18 unexposed controls were tested, and all had normal RAVLT scores. (21) Among a group of 22 persons with signs of learning/memory impairment (low RAVLT scores) after exposure to PCO-laden water, there were complaints of problems with forgetfulness (90%), prospective memory (60%), concentration (54%), and "information overload" (25%). Because 75% of such patients will pass routine mental status examinations such as the Mini-Mental State Examination, a detailed clinical symptoms interview is critical for determining whether a patient should be refe rred for a standard neuropsychologic evaluation. (24) No symptoms of depression or hostility were detected by a Profile of Mood States depression scale, but compared with controls, PCO-exposed individuals were more likely to "feel shaky, on edge, uneasy, nervous, confused, bewildered, or uncertain." (24)

Persons with abnormal RAVLT scores also experienced more symptoms than individuals with normal scores. Hence, although not pathognomonic for this illness, poor performance on neuropsychologic tests such as the RAVLT may have high positive predictive value, while the CDC criteria may be most useful for ruling out PCO-related disease (high negative predictive value). (21)

In one Maryland study, 7 of 13 persons thought to have PCO-related illness showed a variety of dermatologic problems that arose in temporal association with PCO exposure. (25) Although a few of these lesions were of unknown etiology, the consulting dermatologists found that the majority were the result of common diagnosable dermatoses and other skin lesions and were unrelated to PCO exposure. The few cases that were nondiagnostic (erythematous papules and patches) were of a mild nature. Biopsies of these undiagnosed skin lesions both in this study and by another physician in Pocomoke City, Md, (26,27) exhibited either nonspecific chronic inflammatory responses or an infiltrate containing eosinophils (probably indicating an allergic origin). Hence, despite the similarity in appearance between PCO-associated lesions on fish and certain lesions on humans (as is frequently noted in the popular press), the authors concluded that a majority of rashes or other skin lesions in PCO-exposed individuals are probably no t due to PCO exposure. (25) However, an intense cutaneous burning sensation, which was relieved spontaneously within 12 hours or immediately by washing with tap water, experienced by 9 of these persons upon direct contact with PCO-laden water is significant and could be a symptom of PCO exposure. (25) At our referral medical center in eastern North Carolina, we have not yet seen any patients with cutaneous symptoms, skin lesions or rashes that we could attribute to PCOs despite looking for evidence for many years.

In the Maryland study, fishing and catching or handling fish with lesions were activities most strongly associated with illness meeting the CDC criteria for EAS and low RAVLT scores. The odds of having illness associated with handling affected fish were reduced by the use of gloves. The risk of illness, as determined by the CDC's criteria for EAS, was elevated by boating, but the risk of low RAVLT scores was not.

In contrast to illness caused by other toxic phytoplankton (Table 2) (28-30) PCO-related illness is most likely not associated with consumption of finfish, crabs, or shellfish. (8,21) We speculate that these organisms may not concentrate the exotoxin(s), or possibly the toxins may be short-lived and/or destroyed in the human gut. Although the sample size precluded accurate risk estimates, swimming surprisingly did not appear to increase the risk of PCO-related illness in the Maryland study. (21)

The CDC criteria for EAS were based either on the observation of fish with "lesions consistent with PCO toxicity" or the detection of PCOs (perhaps nontoxic) in the water column. Because of the controversy about the etiology of "consistent" lesions on fish, because of the a number of morphologically similar organisms (using light microscope identification techniques), and because the presence of Pfiesteria piscicda may not indicate the presence of actual toxin, the CDC established new criteria in 1999 for what is now termed "possible estuary-associated syndrome" (PEAS) (Table 3). (31) In a 6-state (Delaware, Florida, Maryland, North Carolina, South Carolina, and Virginia) passive surveillance study for PEAS from June 1, 1998, through December 31, 1999, no cases have been identified that have met these PEAS criteria. (32)

Despite media reports to the contrary in the popular press, no current evidence suggests that PCOs invade human tissue or enter the bloodstream. Since the symptoms of PCO-related PEAS are believed to be toxin mediated, there is no need for specialized cultures or antibiotics to treat suspected illness, other than those routine ones indicated by clinical signs/symptoms of other suspected illnesses. Use of cholestyramine to treat PEAS has been reported (26,27) but must be viewed as anecdotal.

CONCLUSIONS

Exposure to some PCOs may cause human illness in the right setting. It is not known why environmental exposure to PCOs in Maryland waters, but not in North Carolina waters, has led to illness. Water samples from the Pocomoke River of Maryland, where PCO-related fish kills occurred in 1997, contained a new genus termed Cryptoperidiniopsoid, (33) previously dubbed "Saint John's microbe" (Fig 3). This PCO has also been identified in North Carolina and Florida. Other PCOs are currently being identified and classified. Since these PCOs represent different species and in some cases genera, it is likely that the various PCOs differ in the types and amounts of toxins produced and, indeed, some may be nontoxic. If true, then the constellation of PCOs in the environment might dictate the variety of toxins present, the nature of the clinical syndrome, and the risk of environmental exposure. Until more is known about the nature and diversity of toxins produced, it seems reasonable to refer to all illness fulfilling the criteria in Table 3 as PEAS.

It is not surprising that PCOs could cause illness, since about 4% of dinoflagellates are known to cause human illness. In fact, many of the signs and symptoms of PCO-related illness are similar to those caused by ingestion of endotoxins produced by well-known toxic dinoflagellates and diatoms (Table 2). However, unlike ciguatera fish poisoning, paralytic shellfish poisoning, and amnesic shellfish poisoning, no one has been known to die of PCO exposure. While it is too early to definitively rule Out the possibility of long-term sequelae associated with PCO exposure, based on today's evidence it seems reasonable to reassure patients who have PEAS that their symptoms will likely resolve spontaneously over the course of 3 to 6 months at most. (20) This should help ease a patient's shaky, uneasy, nervous, edgy moods, which might possibly be reactions to a memory deficit. (24) Strategies for managing memory and concentration problems (19) may help the patient function better during this period and further relieve uneasy feelings.

Obviously, offering such reassurance requires an accurate diagnosis, and currently diagnosing PCO-related illness is largely a matter of ruling out other causes. If a patient is suspected of having a cognitive PCO-related illness, a neurologist and neuropsychologist should be consulted. The battery of tests administered should include "measures of complex learning and memory, divided attention, psychomotor speed and dexterity." (20,24)

Pfiesteria complex organisms have never been recovered from fish lesions and hence should not be considered infectious agents. Exposure to filter-sterilized exotoxins of P piscicida is sufficient to kill fish and initiate formation of lesions on fish. (2) Crude preparations of P piscicida exotoxin(s) have potent cytotoxic activity, with a median lethal concentration ([LC.sub.50]) of <1 x [10.sup.16] g/mL for mouse neuroblastoma cells. This is 100,000 times more potent than tetrodotoxin ([LC.sub.50] of 1 x [10.sup.-11] g/mL). (9) Although it has not yet been proven, human illness could result from skin contact and/or breathing aerosols of water that contain soluble exotoxin(s). Currently, it appears that ingestion of seafood does not pose a risk. (8,21) However, until the toxins are purified to homogeneity and markers for detecting them are developed, little can be said about what constitutes an exposure sufficient to cause illness.

Many causes of fish kills are unrelated to PCOs, including low dissolved oxygen, presence of hydrogen sulfide, blue-green algae, and other toxic and pathogenic microorganisms. Regardless of the cause, all persons should avoid skiing, swimming, fishing, and other forms of exposure to waters in which a fish kill is occurring. If exposed to waters in which a PCO bloom is suspected, thorough washing with soap and clean water is recommended. Because bleach kills even resistant forms of P piscicida, (2) washing with dilute bleach (10 has been advocated by some; however, since PCOs are not infectious organisms the utility of this is questionable. Fish with lesions, fish displaying unusual behavior, or fish caught in the midst of a fish kill should not be consumed. If fish with lesions must be handled, rubber gloves should be worn as a precaution. Fish kills should be reported to the appropriate environmental or natural resource agency in your state. All persons should comply with closures and health advisories poste d by the state. Any illness thought to result from PCO exposure should be reported to county or state health authorities, since funds have been allocated for a large coordinated interstate study of PEAS. Current hotlines for reporting fish kills and health problems possibly related to PCOs are listed in Table 4, as well as Internet addresses for selected web sites that post information concerning PCO issues. These sites were selected because they are updated regularly, include references and/or extensive bibliographies, have exceptional educational value, or are extensively linked to other resources.

The Pfiesteria/PCO studies that are currently under way are looking into whether these organisms pose any significant health risk to populations along our coast. It is still controversial whether these health risks have been exaggerated, as has been suggested, (34) or whether there is significant health risk in the outdoors environment along our coast. It must be remembered through this controversy that scientists working in a closed laboratory setting were made temporarily ill from working with this organism. In addition, all agree that avoidance of waters containing dead or dying fish is prudent.

In conclusion, Pfiesteria/PCO toxins have not yet been identified, isolated, and purified in sufficient quantities to allow development of diagnostic methods. In this regard, proof that PEAS is a true syndrome due to PCOs is currently lacking. Because there are no pathognomonic signs or symptoms for the "syndrome" and biologic markers are currently unavailable, diagnosis is completely subjective and a matter of excluding other diagnoses. (35) In suspected cases, referral to the PEAS study program in your state would seem most logical.

TABLE 1

Initial (1997) Centers for Disease Control and Prevention Criteria (22)
for Adverse Consequences of Exposure to Pfiesteria Complex Organisms
(PCOs)


Exposure to estuarian water characterized by any of the following:

     Fish with lesions consistent with P piseicida or PCO toxicity
      ([greater than or equal to]20% of a sample of [greater than or
      equal to]50 fish of a single species having lesions), or
     Fish kill involving fish with lesions consistent with P piscidia
      or PCO toxicity, or
     Fish kill involving fish without lesions, if P piscicida or PCOs
      are present and no other explanation for fish kill can be found.

and

Any of the following signs and symptoms

     Memory loss or
     Confusion or
     Acute skin burning on direct contact with water or
     Three or more of the following:
      Headaches
      Skin rash
      Eye irritation
      Upper respiratory tract irritation
      Muscle cramps
      Gastrointestinal complaints
      Nausea/vomiting
TABLE 2

Human Illness Associated With Marine Phytoplankton (28-30)

Condition              Distribution               Toxin(s)

Ciguatera fish         Pantropical                Ciguatoxin and 5 other
 poisoning                                        toxins; finfish
                                                  concentrate and
                                                  remain toxic 2 years;
                                                  50,000 cases/year



Paralytic shellfish    Subarctic to tropic        Saxitoxin (blocks Na+
 poisoning             (primarily American        channels) and [greater
                       Samoa, Calif. Wash,        than or equal to]21
                       New England)               others. Finfish
                                                  concentrate shellfish
                                                  concentrate, marine
                                                  mammal deaths

Neurologie/neurotoxic  Caribbean,                 [greater than or equal
 shellfish poisoning   Gulf of Mexico             to] brevetoxins,
                                                  shellfish concentrate
                                                  most common in Gulf
                                                  States; marine mammal
                                                  deaths

Amnesic shellfish      Canada/NE US,              Domnoic acid
 poisoning             Wash, Ore, Calif           Shellfish concentrate
                                                  (especially mussels);
                                                  finfish concentrate

Diarrheal shellfish    Europe, Canada,Japan, New  Okadaic acid
 poisoning             Zealand, South America;
                       organisms seen in US
                       waters

Condition              Organism(s)

Ciguatera fish         Cambierdiscus toxicus
 poisoning             and others






Paralytic shellfish    Gonyaulax tamarensis,
 poisoning             Alexandrium spp.
                       Organism encysts





Neurologie/neurotoxic  Gymnnodinium breve,
 shellfish poisoning   "Red tide organism"





Amnesic shellfish      Pseudonilzchia pungens
 poisoning             (a diatom) and other spp



Diarrheal shellfish    Dinophysis
 poisoning



Condition              Symptoms                   Route

Ciguatera fish         Diarrhea, nausea/          Ingestion, toxin
 poisoning             vomiting, abdominal        passed up food chain
                       pain, pain/weakness
                       lower extremities,
                       paresthesias, temperature
                       reversal, "aching teeth,"
                       coma/death (rare)

Paralytic shellfish    Paresthesias (mouth/       Ingestion
 poisoning             extremities), diarrhea,
                       nausea/vomiting,
                       abdominal pain, ataxia
                       (rare), respiratory
                       arrest (rare), death
                       (rare)

Neurologie/neurotoxic  Diarrhea, nausea/          Ingestion/
 shellfish poisoning   vomiting, ataxia/vertigo,  inhalation
                       paresthesias, temperature
                       reversal, asthma-like
                       respiratory distress


Amnesic shellfish      Gastroenteritis, memory    Ingestion
 poisoning             deficits/amnesia,
                       confusion, death (4%)


Diarrheal shellfish    Nausea/vomiting,           Ingestion
 poisoning             diarrhea abdominal
                       pain


Condition              Onset       Duration

Ciguatera fish         1 hr-2      Weeks to
 poisoning             days        months






Paralytic shellfish    Minutes to  2-3 days
 poisoning             hours






Neurologie/neurotoxic  Minutes to  Days
 shellfish poisoning   hours       (self-
                                   limiting)




Amnesic shellfish      Minutes to  Chronic
 poisoning             hours       residual



Diarrheal shellfish    Minutes to  Days
 poisoning             hours       (self-
                                   limiting)
TABLE 3

Current (1999) Centers for Disease Control and Prevention Criteria (31)
for Adverse Consequences of Exposure to PCOs: Possible
Estuary-Associated Syndrome (PEAS)


Persons are considered to have PEAS if:

   They report symptoms developing within 2 weeks after exposure
to estuarine water:

   They report memory loss or confusion of any duration and/or
three or more selected symptoms (ie, headache, skin rash at
the site of water contract, sensation of burning skin, eye
irriation, upper respiratory tract irritation, music cramps,
and gastrointestinal symptoms) that--with the exception of
skin rash at the site of water contact and sensation of
burning skin--persist for [greater than or equal to]2
weeks; and

    A health-care provider cannot identify another cause for
the symptoms.
TABLE 4

Selected Pfiesteria-Related Web Sites and Hotline Numbers


Useful web sites:

Environmental Protection Agency
(http://www.epa.gov/owow/estuaries/pfiesteria/)

Centers for Disease Control and Prevention
(http://www.cdc.gov/nceh/programs/ehserv/EHSA/hottopics/
Pfiesteria%20piscicida.htm)

University of Maryland
(http://www.mdsg.umd.edu/fish-health/pfiesteria/)

North Carolina State University
(http://www.pfiesteria.org/)

State of North Carolina
(http://www.schs.state.nc.us/epi/hab/facts.cfm)

State of Virginia
(http://www.vdh.state.va.us/epi/pfiestef.htm)

ECOHAB: Florida project
(http://www.fmri.usf.edu/ecohab/fhab.htm)

State Fish Kill/Pfiesteria Hotlines:

Maryland          (1-888-584-3110)
Virginia          (1-888-238-6154)
North Carolina J  (1-888-823-6915)
Florida           (1-888-232-8635)
Delaware          (1-800-523-3336)
South Carolina    (1-888-481-0125)

References

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(2.) Burkholder JM, Noga EJ, Hobbs CH, et al: New "phantom" dinoflagellate is the causative agent of major estuarine fish kills. Nature 1992; 358:407-410

(3.) Kaiser J: Meeting briefs: new clues for two toxicological mysteries. Science 1997;276:201

(4.) Glasgow HB, Burkholder JM, Schmechel DE, et al: Insidious effects of a toxic estuarine dinofiagellate on fish survival and human health. J Toxicol Environ Health 1995; 46:501-522

(5.) Burkholder JM: The lurking perils of Pfiesteria. SciAm 1999; 281:4249

(6.) Burkholder JM, Glasgow HB Jr: Trophic controls on stage transformations of a toxic ambush-predator dinoflagellate. J Eultaryol Microbrol 1997; 44:200-205

(7.) Burkholder JM, Glasgow HB Jr: Pfiesteria piscicida and other Pfiesteria-like dinoflagellates: behavior impacts and environmental controls. Limnology and Oceanography 1997; 42:10521075

(8.) McClellan-Green PD, Jaykus LA, Green DP: Consumer health risk due to incidental exposure of fish to Pfiesteria piscicida. final report. North Carolina Sea Grant College Program, 1998. Report No. UNC-SG-98-02, pp 107-131

(9.) McClellan-Green PD, Noga E, Baden D, et al: Cytotoxicity of a putative toxin from Pfiesteria piscicida dinofiagellate. Fundam Appl Toxicol 1997; 36:276

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(11.) Noga EJ, Dykstra MK, Levine JF: Fish diseases in the Albermarle-Pamlico Estuary. Water Resources Research Institute of the University of North Carolina, Raleigh, NC. Report No. 238, 1989

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(13.) University of Maryland Center for Environmental Science. The Cambridge Consensus: Forum on land-based pollution and toxic dinoflagellates in Chesapeake Bay. Available at http://www.mdsg.umd.edu/fish-health/Pfiesteria/cambridge.html. Assessed October 16,1997

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(15.) Levin ED, Simon BB, Schmechel DE, et al: Pftesteria toxin and learning performance. Neuroloxical Teratol 1999; 21:215-221

(16.) Smith CG, Music SI: Pfiesteria in North Carolina: the medical inquiry continues. NC Med J 1998; 59:216-220

(17.) Griffith D, Borre K, Schecter A, et al: An exploratory study of potential human health effects of deteriorating water quality among North Carolina crabbers. Final report. North Carolina Sea Grant College Program, 1998. Report No. UNC-SG-98-02, pp 2-87

(18.) Kane As, Oldach D, Reimschuessel R: Fish lesions in the Chesapeake Bay: Pfiesteria-like dinoflagellates and other etiologies. Md Med J 1998; 47:106-112

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(20.) Grattan LM, Oldach D, Perl TM, et al: Learning and memory difficulties after environmental exposure to waterways containing toxin-producing Pfiesteria or Pfiesteria-like dinoflagellates. Lancet 1998; 352:532-539

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RELATED ARTICLE: KEY POINTS

* Exposure to Pfiesteria piscicida and Pfiesteria complex organisms (PCOs) may cause human illness in the right setting.

* Toxin(s) produced by P piscicida and possibly from other PCOs have not been isolated in sufficient quantities for study, and biomarkers for them are currently unavailable.

* Diagnosis of possible estuary-associated syndrome (PEAS) is largely subjective at present.

* Pfiesteria piscicida is not infectious, and there is no current evidence that it enters the food chain.

* A large well-funded coordinated study of PEAS in six southeastern states is under way, and physicians should consider referring suspected patients to responsible state health agencies.

From the Division of Dermatology, Brody School of Medicine at East Carolina University, Greenville, NC.

Supported in part by the Summer Research Scholars Program and the Office of Generalist Programs of East Carolina University School of Medicine (Dr. Collier).

Reprint requests to William A. Burke, MD, 600 Moye Blvd, 3E113 Brody Bldg, Greenville, NC 27858-4354.