C. Gregory Smith, MD, MPH, and Stanley I. Music, MD, DTPH (London)
Dr. Smith is Chair, NCMS Occupational and Environmental Health Committee, Adjunct Associate Professor, Dept. of Epidemiology, UNC School of Public Health, and medical epidemiologist in the NC Dept. of Health and Human Services/Occupational and Environmental Epidemiology Section (DHHS/OEES). Dr. Music is a medical epidemiologist retired from the US Centers for Disease Control and Prevention. He served as Section Chief of the DHHS/OEES from Nov. 1996-May 1998. He was instrumental in securing from the CDC approximately $1 million (recurring for the next 3-5 years) for research in NC on the potential adverse health effects associated with Pfiesteria.
Pfiesteria piscicida (Pp) and several other recently discovered one-celled microorganisms called dinoflagellates have been linked to flesh ulcers in fish and to fish kills ("lesioned fish kills") in eastern US coastal waters.1-3 Laboratory workers exposed to Pp toxins have developed transient, adverse neurocognitive effects, including memory disturbances, that have few, if any, residua. There are reports that individuals exposed to estuarine waters in Maryland in late summer and fall 1997, prior to and during lesioned fish kills, developed symptomatic neurocognitive deficits.4-8 In this article, we review studies done to define the risks of Pp toxin exposure and the efforts under way in North Carolina to further address this problem.
There have been numerous fish kills in North Carolina, including many attributed to Pp. Researchers here and in Florida have identified at least 3 distinct and potentially toxic estuarine dinoflagellates belonging to 3 different genera (Pfiesteria piscicida, Gyrodinium galatheanum, Crypto-peridiniopsis spp.) from affected Maryland waters.9 These dinoflagellates cannot be distinguished from one another without special preparation techniques, use of scanning electron microscopy, and evaluation by very well-trained eyes. The Pfiesteria look-alikes have been called Pfiesteria-like organisms (PLOs) and Pfiesteria-complex organisms (PCOs), but the terminology selected by the Centers for Disease Control and Prevention (CDC) is morphologically related organisms (MROs).10
P piscicida releases at least two different exotoxins (one water soluble and one lipid soluble.9 These toxins are reported to produce ulcerative lesions and neurologic effects in fish,2,3,11 but so far no field observation has conclusively demonstrated that ulcers are caused by Pp or MRO toxins. The lesions are chronic and are not induced at the time of acute fish kills. It is likely that an injury to fish epidermis (due to trauma, pathogens, parasites, or possibly sublethal exposure to dinoflagellate toxins) permits invasion by opportunistic bacterial and fungal pathogens. In fact, fungal invasion is so common that the term ulcerative mycosis has been used for these lesions.11
Despite much effort over the past 5 years, Pp toxins have not been chemically identified nor have standard animal bioassays provided any significant information on target organs or mechanism(s) of action. One problem is that the toxins appear to be unstable and degrade rapidly.3 In contrast, the endotoxins associated with red tides and other harmful algal blooms (HABs) that cause human illness primarily via consumption of contaminated shellfish and finfish are heat- and cold-stable.
In January 1998, a CDC-sponsored workgroup reviewed the 1997 findings from Maryland and other existing data. Because the reported adverse effects could not be attributed to a specific dinoflagellate or toxin, the workgroup suggested using the term "estuary-associated syndrome" until we learn more about these organisms and the toxins they produce. Various scientific panels and committees have concluded that there likely are differences in the geographic distribution and ecology of Pp and MROs, and that these species may produce many toxins.12 Differing toxins having different mechanisms of action will complicate exposure assessment, medical evaluation, and attribution of etiology of the potential adverse health effects of these organisms.
Red tides and other HABs have been documented since biblical times, and were known to North American and Caribbean Indians when Spanish explorers arrived here. Currently, 5 well-defined clinical illnesses (neurotoxic shellfish poisoning [NSP], paralytic shellfish poisoning [PSP], diarrheic shellfish poisoning [DSP], ciguatera fish poisoning [CFP], and amnesic shellfish poisoning [ASP]) are associated with specific toxins produced by dinoflagellates and diatoms. These illnesses13-15 result from consumption of contaminated shellfish (which accumulate the toxins via filterfeeding) or finfish (which accumulate toxins via bioaccumulation/bioconcentration). Eye, skin, and respiratory irritation have been attributed to toxins produced by the red tide dinoflagellate, Gymnodinium breve, and aerosolized by surf action.3,16
History documents the adverse health effects of HABs, and there is growing concern that such blooms are becoming more frequent and widespread. Why this should be so is not clear, but possible factors include climate change, nutrient loading of estuarine and marine waters, global transport of unprocessed seafood, and distribution of dinoflagellates around the world via the discharge of ballast or bilge waters from ships. Clinical illnesses due to specific dinoflagellates may occur anywhere ships release toxin-producing dinoflagellates into waters that are conducive to blooms. In addition, the rapid global transport of seafood harvested from waters where algal toxins are endemic increases the chances of human illness.17-20
In 1987, the Occupational and Environmental Epidemiology Section (OEES) of the NC Division of Epidemiology investigated a cluster of neurotoxic shellfish poisonings caused by a red tide that struck the North Carolina coast on Halloween. Shellfish beds were closed and the State Health Director issued a health advisory.21 It is likely that water currents transported the red tide from the Gulf of Mexico, through the Straits of Florida, to the Gulf Stream where an onshore eddy seeded North Carolinas coastal waters.22 That same year, state public health physicians encountered an unprecedented outbreak of ciguatera fish poisoning linked to fish caught off the North Carolina coast.23
Since May 1994, public health physicians in the OEES, in collaboration with other scientists and physicians, federal health and environmental agencies, and the private sector, have sought to determine whether Pfiesteria piscicida and MROs cause adverse human health effects and pose a significant risk to public healthand if so, what are the risk factors for illness? These efforts have included surveillance for evidence of human (as well as wildlife and pet) illness, surveillance of estuarine areas during fish kills, epidemiologic investigation, and independent medical review of "cases" of illness following exposure to estuarine waters (both in the presence and absence of lesioned fish kills), descriptive epidemiologic studies of individuals exposed to lesioned fish kills attributed to Pfiesteria,24 and analytic epidemiologic studies of occupationally exposed cohorts of watermen.25-26
The most recent inquiry involved rigorous medical evaluation (including neurocognitive testing) of 67 persons by a team of medical specialists from three North Carolina medical schools. It was designed and conducted under the guidance of an independent expert Task Force on Health Risk from Exposure to Fish Kill Waters, chaired by William Roper, dean of the UNC School of Public Health. The panels preliminary conclusion is that there is no evidence of severe, chronic, or widespread adverse health effects from exposures to fish kill waters in North Carolina. This independent review supports similar conclusions reached by the states public health physicians. Also, it is consonant with follow-up assessments of those reported to have suffered neurocognitive deficits from exposure to fish kill waters in Maryland. All deficits reportedly returned to normal within 6 months of exposure.27
Despite occasional misleading and inaccurate information presented in the lay press and on television, no physician practicing in North Carolina has yet reported a North Carolina "case" of human illness plausibly attributable to Pp or MROs. Virtually every suspect case has been attributed to other, more common and well-described causes. There have been no findings of any consequence, and no clusters of people reporting syndromic symptoms after exposure to estuarine waters or these organisms. In summary, a long series of surveillance and research efforts conducted by both state government and university sources has consistently come up empty.
Despite the reports from Maryland, no clusters of disease have been identified in any other state where Pp and MROs have been found, even when associated with lesioned fish kills. We have known about Pp for 7 years and suspected it of causing or contributing to many large fish kills during the past 10 years. Until recently, there have been virtually no formal warnings about or restrictions on entry or use of affected fish kill waters. Considering the thousands of human and animal exposures to estuarine waters during this period, one would think that physicians, veterinarians, or wildlife authorities would have noticed something unusual if these organisms produced clinically significant levels of biotoxins. The absence of clinically apparent illness is reassuring, but it is possible that subclinical illness may have occurred, but was not detected.
There has been much discussion of seafood-borne risks from Pp and MROs, but there are few appropriate studies. The absence of outbreaks of seafood-borne illness during or after major lesioned fish kills in North Carolina, Virginia, and Maryland is reassuring. The observed instability of Pp toxins (compared to those that cause shellfish and fish poisoning) and limited data showing that neurocognitive deficits do not follow consumption of seafood8 suggest that there is no significant public health risk from consumption of normal-appearing finfish and crabs harvested from waters containing Pp and MROs. Definitive answers to these questions await identification and characterization of Pfiesteria biotoxins.
A number of erroneous reports have attributed rashes and other skin lesions to Pp and MROs. Some have even included pictures of human skin ulcers juxtaposed to fish ulcers.28-29 Thorough evaluation of reported cases by OEES medical epidemiologists, as well as by dermatologists in both North Carolina and Maryland, has attributed most cases to bacteria and other microbes common to estuarine waters and known to cause rashes, boils, ulcers, and other skin problems. Sometimes skin lesions were caused by chronic irritation and trauma associated with fishing and crabbing and from occupational sun and water exposure; still others were unrelated to water exposure.
Burning or stinging of the skin after water contact was reported by 9 of 13 patients in Maryland who had direct contact with putatively "toxic" estuarine water. A few demonstrated red, edematous papules on the trunk or extremities. Skin biopsies from 6 patients showed variable and nonspecific inflammation suggesting "reactive erythema," allergic, toxic, or eczematous reactions.30 Clinicians need to know that dinoflagellates are not known to invade human skin or colonize wounds, and that no known lesions or histopathologic findings are pathognomonic for Pp and MROs.
Patients with possible Pp/MRO exposure and unexplained skin findings should be referred to a dermatologist. Photographs and biopsies of lesions are recommended when clinically indicated.30 Despite the present lack of significant dermatologic findings, one of the toxins produced by Pp is the suspected cause of dermonecrotic effects in fish, and the contention that Pp causes irritation, paresthesia, and other dermatologic problems in humans is not implausible. We need further study to validate or invalidate these claims.
Neurologic Symptoms/Neurocognitive Deficits
Culture of Pp (stimulated to produce toxin) in improperly ventilated laboratories has led to neurologic symptoms and neurocognitive impairment (as well as skin rashes and a host of nonspecific complaints) among some scientists and laboratory workers.31 The nature and intensity of exposure under these conditions is only poorly understood and partially documented, and the route of exposure (inhalation of aerosols, or absorption from skin or mucous membranes) remains unclear. In addition to case reports of laboratory exposures, some animal evidence supports Pp toxins as a cause of neurocognitive impairment. Rats injected with water taken from aquaria containing toxic Pp demonstrated significant learning impairment (compared to controls), which persisted up to 10 weeks after injection. At necropsy, no gross or histopathological abnormalities were noted in the major potential target organs of exposed rats.32
In August 1997, a multispecialty medical team from the University of Maryland and Johns Hopkins University examined 13 persons who had been exposed to estuarine waters containing toxic Pp and MROs. Other than minor dermatologic findings (see above), physical examination was unremarkable and all ancillary laboratory evaluations (blood counts, blood chemistries, liver and renal function profiles, immune system profiles, pulmonary function tests, etc.) were unremarkable. Routine mental status examination was normal, but subjective and objective difficulties with learning and memory were associated with exposure to affected waters.4-7
The Maryland investigation had serious design problems that hamper meaningful interpretation (the examiners were not blinded; there were no contemporaneous controls; "case" detection depended almost exclusively on neuropsychological tests), but the effort was undertaken in good faith by talented scientific and medical professionals who, like their counterparts elsewhere, have been constrained by the lack of a specific biomarker for exposure to Pp. We are not entirely sure what organisms the Maryland people were exposed to, but they include at least one look-alike dinoflagellate of a different genus, Cryptoperidiniopsis. This dinoflagellate was present in the affected Maryland waters and has been associated with major recent lesioned fish kills in Florida. The best we can say is that a possible new disease entity (estuary-associated syndrome) exists, but its conclusive definition awaits identification of the putative biotoxins and development of true, objective measures for exposure and disease.
What is Under Way
Normally, the "discovery" of a new disease of public health importance leads to an organized surveillance for the disease. Usually this means making the disease reportable and asking physicians and laboratories to report confirmed, suspected, or possible cases to the state health agency. This is not yet possible for Pp and MROs.
In 1997, Congress appropriated $7 million to evaluate the public health aspects of Pfiesteria. A multistate cooperative agreement under the auspices of the CDC took effect earlier this year and is expected to continue for several years. North Carolina has benefited from this, and from special state funds made available to the OEES. The NC component of a standardized multistate surveillance effort33 will begin this summer.
A planned prospective cohort study involving several states will enroll up to 200 North Carolina fishermen and crabbers who work in estuaries where Pp and MROs live, and compare them to matched controls (fishermen who work in ocean waters presumably free of significant numbers of these organisms). This study will resolve the difficulties associated with earlier retrospective studies by having baseline clinical and neuropsychological data before exposure to estuarine waters and by having the study participants serve as their own internal controls. Extensive efforts will be made to obtain water samples to assess exposure to organisms and their toxins. The current lack of quick assays for the toxins is being addressed vigorously by federal and university research teams and will be incorporated into the study should they become available.34 The North Carolina research will be conducted by a consortium of the UNC-CH, Duke, and ECU medical schools and the UNC School of Public Health. Studies will include comprehensive medical evaluations with neuropsychological testing. If successful, by next summer we may know better whether there are adverse human health effects from exposure to these dinoflagellates in the natural environment.
Personal Protective Equipment
Until the risk of exposure to Pp and MROs is better defined, North Carolina public health officials recommend that risky waters (those containing HABs and fish kills) be avoided by all except state employees collecting water and fish samples. The OEES has developed a prevention-oriented protocol for workers that includes the use of personal protective equipment (PPE) to minimize exposure to putative toxins. The work protocol is designed to minimize the very real risk of heat stress and heat stroke while using respirators and protective clothing in hot weather. Work personnel will be educated and trained in risk prevention. The PPE protocol has been reviewed by a subcommittee of the NCMS Occupational and Environmental Health Committee, which includes occupational medicine physicians from Duke and ECU, and has been submitted to the Pfiesteria Task Force for review.
A toll-free hotline (888/823-6915) is available for questions about the location of current fish kills, to provide information for anyone who may have been exposed or affected, and to serve as an elementary surveillance mechanism for possible HAB-related illness. The OEES is providing communications upgrades to county health departments, so that the latest information will be just a local phone call away for citizens and health care providers alike. There are plans for a Pfiesteria home page on the World Wide Web. Special web access for clinicians providing updates and diagnostic information and assistance will be included. OEES public health staff will continue to attend and present CME sessions and updates at various scientific and medical meetings, including those sponsored by local medical societies, as well as state and federal health agencies.
Although HABs are but one cause for fish kills, the state currently posts advisory notices regarding all fish kills, and continues to warn people to avoid them, as common sense would dictate. In addition, a protocol for closing and reopening rivers and other coastal waters affected by HABs has been developed and can be implemented at the discretion of the State Health Director. A central point of contact for all Pfiesteria and HAB issues is Kathleen Buckheit, MPH, RN, COHN-S. Ms. Buckheit is an occupational health nurse and the newly installed head of the OEESs Harmful Algal Blooms Program. Her number is 919/715-6422.
The authors express their appreciation to Drs. William Burke, Woodhall Stopford, and Patricia Tester for their review of this paper.
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©1998 North Carolina Medical Society
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