Investigator Team's Response to [CDC's] MMWR Report that Includes Black Molds
In the last issue, two reports from the Centers for Disease Control's weekly newsletter, Morbidity and Mortality Weekly Report (MMWR), were reprinted. The second report questioned the conclusion of the investigator team that mold (including Stachybotrys) had played a major role in the lung bleeding of the eight babies in Cleveland.Members of the investigator team are listed at the end of this report. They published a rebuttal, which has been widely reprinted. It is reprinted here with permission from Ruth A. Etzel, M.D., Ph.D., Department of Environmental and Occupational Health, George Washington University School of Public Health and Health Services, Washington, DC. Views expressed here are those of the authors.
On March 10, 2000, through the office of Dr. Dixie Snider, the CDC in Atlanta released two reviews (internal and external) on studies of infant pulmonary hemorrhage in Cleveland associated with wet, poorly-maintained houses. The initial field studies (Montana et al., Etzel et al.) discussed had undergone previous peer review, first by several scientists during the CDC internal clearance process and then independently by the reviewers for the medical journals prior to publication. The March 10th MMWR (vol. 49 #9, p. 180) summarized the results of the subsequent reviews and included unrelated material about public concerns about buildings with black molds in the US, citing newspaper articles and opinion pieces in trade journals.The internal and external review reports summarized a great deal of thoughtful discussion by these two groups. However, neither review group included any member of the initial study team and neither review group visited Cleveland to see the buildings or talk to the families, community groups, Cuyahoga County Health Officials and building inspectors, nor the physicians at the Rainbow Babies & Children's Hospital. Although not reflected in the MMWR report, each of the investigators responded in-depth in writing to questions posed by the internal review group, and Dr. Dearborn and Terry Allan presented a detailed update to the external panel in Atlanta on Sept 15, 1999.Both the internal and external reviews acknowledged the hypothesis that massive exposure to Stachybotrys chartarum and other hydrophilic molds might well result in severe lung disease in infants. However, some important issues were evidently misunderstood by the review committees and by the drafter of the MMWR, Dr. Roy Baron.CDC has a long tradition of rapidly initiating epidemiologic investigations to promptly control disease outbreaks. The 1994 investigation of a cluster of cases of acute pulmonary hemorrhage in Cleveland was done in that tradition. Less than twelve hours elapsed between the time that Dr. Dorr Dearborn called the CDC about the cluster and the time that Dr. Ruth Etzel and Dr. Barbara Bowman arrived in Cleveland to begin the epidemiologic investigation. Despite the difficulties of undertaking a case-control study under these circumstances, the team designed and carried out a study that identified possible new avenues for prevention of infant pulmonary hemorrhage.Fortunately, we often do not need to understand causal mechanisms in their entirety to put prevention measures in place. Knowing even one small component may allow significant degrees of prevention. As every epidemiologist knows, John Snow took the handle off the pump on Broad Street and put an end to London's cholera outbreak. Abraham and David Lilienfeld, in Foundations of Epidemiology, relate that Snow's 1855 report "led to legislation mandating that all of the water companies in London filter their water by 1857, only two years after the report's publication. (It was not until 1883 that Robert Koch identified the cholera vibrio.)" (Foundations of Epidemiology, page 37)Among environmental epidemiologists, the precautionary principle is frequently used to inform public health decision making. The precautionary principle states:"We must act on facts, and on the most accurate interpretation of them, using the best scientific information. That does not mean we must sit back until we have 100% evidence about everything. Where the state of the health of the people is at stake, the risks can be so high and the costs of corrective action so great, that prevention is better than cure. We must analyze the possible benefits and costs of action and inaction. Where there are significant risks of damage to the public health, we should be prepared to take action to diminish those risks, even when the scientific knowledge is not conclusive, if the balance of likely costs and benefits justifies it." (Modified from a 1990 UK Department of Environment definition. In: Lancet 1998; 352:252.)In a 1990 paper published in the American Journal of Epidemiology, Drs. Rick Goodman, Jim Buehler and Jeff Koplan eloquently describe the importance of science and judgement in the epidemiologic field investigation. "In contrast to prospectively planned studies, which are based upon carefully developed and refined protocols, the investigative response to acute problems such as outbreaks must rely on data sources that are less readily controlled and that may literally change with each successive hour." (AJE, page 14)They go on to state (AJE, page 15), "In judging an epidemiologic field investigation, paramount consideration should be given to the quality of the science. However, this should not be the sole standard; rather, the full range of limitations, pressures, and responsibilities imposed on the investigator must also be taken into account. The goal of the epidemiologist should be to maximize the scientific quality of the field investigation in the face of applicable limitations and competing interests."Thus, standards for an epidemiologic field investigation are that it: 1) address an important public health problem in the community, as defined by standard public health measures (e.g., attack rates, serious morbidity, or mortality) or community concern; 2) be timely; 3) examine resource needs early enough in the investigation and commit an appropriate amount of public resources; 4) use appropriate methods of descriptive and/or analytical epidemiology; 5) probe causality to the degree required to enable identification of the source and/or etiology of the problem; and 6) establish immediate control and long-term interventions." (AJE, page 15)
The investigator team has identified several problems with the MMWR characterization of the initial field studies, which include:
The MMWR indicated that mean Stachybotrysconcentrations were miscalculated.The mean S. chartarum concentrations were not miscalculated. Rather, the counts on all four agar plates were summed and then divided by four to obtain the mean count. CDC, in reanalyzing the data, summed only three plates for S. chartarum, and then divided by three to obtain the mean count. Our original method, using all the data available, is the more conservative method and actually resulted in a slightly decreased mean count.
The CDC is concerned about oversampling and potential investigator bias.Investigator bias is a consideration when the investigator is aware of which homes are case homes and which are control homes. The industrial hygienists were not told this information.
Possible unmeasured confounders.The MMWR states that the infant hemorrhage was possibly caused by unmeasured confounders, a potential problem in any epidemiologic study. The study team consulted a vast range of people all over the world trying to find possible causes for the exceptional circumstance they found themselves in; a 1000 fold increase in the number of idiopathic pulmonary hemosiderosis cases compared to historical norms. Every suggestion was pursued. Plans to continue the Cleveland case-control study prospectively and expand it nationally were submitted and reviewed by the CDC. The CDC elected not to pursue this work.
Assignment of an imputed data value.An imputed data value was used for one case since Stachybotrys was detected but "too few to count". The study mycologist reported that he detected one colony of S. atra on one plate of cellulose agar from this home (surface sample) and one colony of S. atraon one of the cellulose plates in the air filter cassette sample from the same home. Based on this, and in consultation with other study authors, he suggested that we should attempt to quantitate the number. One way to do this is to use the limit of detection divided by the square root of 2. This is a well-established method used by epidemiologists throughout the world; indeed it is normal practice when considering chemical exposures.
Sensitivity of the odds ratio and modeling for interactionage matching of controls.The MMWRis incorrect in stating that birth date should not be a source of confounding. Eight of the original ten cases in the initial field study were investigated retrospectively so it was important to have seasonal and weather comparisons across early infancy for the subjects and their homes. In addition, infants of different ages have quite different opportunities for exposure, depending on whether they are crawling, walking, putting things in their mouths, and eating a variety of foods. The study was designed with cases and controls matched on birth date (plus or minus two weeks).
The MMWR report states that "AIPH is not consistent with historical accounts of animal and human illnesses caused by S. chartarum." Indeed, the art of scientific discovery is to look at things in a new way and to see something that others may not have seen before. To imply that an observation cannot be true simply because it has not been previously reported in the literature is to take an ostrich-like approach to science.Historical accounts of illness in livestock or with occupational exposure only address adult animals and humans. It is well recognized that environmental exposures in early infancy can result in very different pathophysiology from that of adults. The study was limited to infants less than 12 months old; the mean age of cases has been 3 months (Dearborn et al.). Regardless, it is well established in the literature that hemorrhage is a consistent finding in trichothecene toxicosis and, in one study from Hungary (Andrassy et al.) nose bleeds were noted among adult workers exposed to aerosols of S. chartarumin contaminated hay.Subsequent experimentation by Finnish workers (Nikulin et al., 1996; Nikulin et al., 1997) in adult mice and by Dr. Dearborn's laboratory (Yike et al.) in infant rats has demonstrated that inhalation or tracheal instillation of Stachybotrys spores produces alveolar hemorrhage unless low-toxin or toxin-extracted spores are used. These studies further demonstrate histologically that the spores do reach the distal airways as expected from the aerodynamic size of ca. 5 microns (Sorenson et al.) The internal review group was aware of the Finnish studies and the external group heard a presentation of Dr. Dearborn's infant rat data.
Because clusters of disease have not been reported in other flood-prone areas of the country, we cannot conclude that they did not occur. Absence of evidence is not evidence of absence. There is no national surveillance for AIPH, and physicians who have tried to report cases to CDC in 1998 and 1999 were told that CDC was no longer collecting this information. Furthermore, it is not correct that a dominant fungus in the original Cleveland homes, Stachybotrys chartarum, always occurs in flooded buildings. It is more common in buildings with chronic water intrusion problems.
It is untrue that clusters of acute idiopathic pulmonary hemorrhage in infants have not occurred in other regions of the country. The literature includes a cluster in Michigan (reported in 1996 in Chest) and one in Wisconsin (reported by pediatric pulmonologists from the Medical College of Wisconsin in a poster at the annual meeting of the American Thoracic Society in 1997) although there was no characterization of the homes involved. Several case reports of toxigenic fungi exposures related to pulmonary hemorrhage have appeared recently, coming from Texas, Kansas, and Missouri (see references). The Texas case was actually a seven year old boy with IPH from whom lung washings grew Stachybotrys.
The manuscript describing CDC's epidemiologic investigation of the cases of acute pulmonary hemorrhage in Chicago is not yet completed. A draft of the analysis shows that Stachybotrys atra was detected in a higher proportion of control homes than in case homes. However, Trichoderma, another water-loving fungus that, like Stachybotrys, can produce trichothecenes, was found in a higher proportion of case homes than control homes. The significance of this finding is not clear.
Case identification and subsequent experience in Northeast Ohio.Cases of pulmonary hemorrhage in infants have continued to occur in the Cleveland area. For public health reasons, some of these cases have been defined as "unexplained" pulmonary hemorrhage in infants and have included cases diagnosed on the basis of extensive hemosiderosis at post mortem. However, we have applied a more stringent case definition to include only infants that we have cared for at Rainbow Babies & Children's Hospital. This latter group is referred to as "idiopathic" pulmonary hemorrhage in infants (IPHI) because we have reached this diagnosis of exclusion by ruling out known causes (e.g. necrotizing pneumonia, congenital heart defects, trauma, etc). This is the same case definition used in the initial study. We have now cared for 30 cases of IPHI including the original 10 cases. All but one of these patients had acute, overt PH; five have died. Twenty-four of the 28 homes investigated were found to contain Stachybotrys and one had Trichoderma, i.e. 89% of these IPHI infants came from home environments containing documented toxigenic fungi. Similarly, 85% of these homes had a history of water damage and 85% of the infants were exposed to environmental tobacco smoke in their homes. Thus, subsequent experience substantiates the initial field study conclusions; it was presented to the external panel.Investigator Team
Ruth A. Etzel, M.D., Ph.D.*Director, Div. of Epidemiology & Risk AssessmentOffice of Public Health and ScienceU.S. Department of AgricultureWashington, D.C.Dorr G. Dearborn, Ph.D., M.D.Associate Professor, Pediatrics and BiochemistryDepartment of Pediatrics, Pulmonary DivisionRainbow Babies & Childrens HospitalCase Western Reserve University, School of MedicineCleveland, OhioTerry M. Allan, M.P.H.Director of Community HealthCuyahoga County Board of HealthCleveland, OhioTimothy E. Horgan, M.P.H.Health CommissionerCuyahoga County Board of HealthCleveland, OhioW. G. Sorenson, Ph.D.Senior Scientist (retired)National Institute of Occupational Safety and HealthMorgantown, VABruce B. Jarvis, Ph.D.Professor & ChairmanDepartment of Chemistry and BiochemistryUniversity of MarylandCollege Park, MarylandJ. David Miller, Ph.D.ProfessorDepartment of ChemistryCarleton UniversityOttawa, ON
* The views expressed here are those of the author and do not necessarily reflect those of the Department of Agriculture.References
American Academy of Pediatrics Committee on Environmental Health. "Toxic effects of indoor molds." (1998) Pediatrics101:712-714.Andrassy, K; Horvath, I; Lakos, T; and Toke, Z. "Mass incidence of mycotoxicoses in Hajdu-Bihar county." (1979) Mykosen 23:130-133.Dearborn, DG; Yike, I; Sorenson, WG; Miller, MJ; and Etzel, RA. "Overview of investigations into pulmonary hemorrhage among infants in Cleveland, Ohio." (1999) Environmental Health Perspectives, Vol.107, Suppl.3, 495-499.Etzel, RA; Montana, E; Sorenson, WG; Kullman, GJ; Allan, TM; and Dearborn, DG. "Acute Pulmonary Hemorrhage in Infants Associated with Exposure to Stachybotrys atra and Other Fungi." (1998) Arch Pediatr Adolesc Med 152:757-762.Goodman, RA; Buehler, JW; and Koplan, JP. "The epidemiologic field investigation: science and judgement in public health practice." (1990) Am J Epidemiol 132:9-16.Horton, R. "The precautionary principle." London: UK Department of Environment (1990) In: Lancet 1998; 352:252.Lilienfeld, AM, and Lilienfeld, DE. Foundations of Epidemiology (Second Edition). New York: Oxford University Press: 1980, p. 37.Montana, E; Etzel, RA; Allan, T; Horgan, TE; and Dearborn, DG. "Environmental risk factors associated with pediatric idiopathic pulmonary hemorrhage/hemosiderosis in a Cleveland community." Pediatrics, 99:1, 1997. (http://www.pediatrics.org/cgi/content/full/99/1/e5)Nikulin, M; Reijula, K; Jarvis, BB; and Hintikka, E-L. "Experimental lung mycotoxicosis in mice induced by Stachybotrys atra." (1996) Int J Exp Path, 77:213-218.Nikulin, M; Reijula, K; Jarvis, BB; Veijalainen, P; and Hintikka, E-L. "Effects of intranasal exposure to spores of Stachybotrys atra in mice." (1997) Fundamental and Applied Toxicology, 35:182-188.Pappas, MD; Sarnaik, AP; Meert, KL; Hasan, RA; and Lieh-Lai, MW. "Idiopathic pulmonary hemorrhage in infancy: clinical features and management with high-frequency ventilation." (1996) Chest; 110:553-555.Snow, J. "On the mode of communication of cholera." (1936) In: Snow on Cholera. New York: The Commonwealth Fund, pp.1-175.Sorenson, WG; Frazer, DG; Jarvis, BB; Simpson, J.; and Robinson, VA. "Trichothecene mycotoxins in aerosolized conidia of Stachybotrys atra." (1987) Appl Envir Microbiol, 53:1370-1375.Yike, I; Miller, MJ; and Dearborn, DG. "Animal model of Stachybotrys chartarum induced hemorrhage in the developing lung," Am Thoracic Soc, 1999 International Conference, Abst, p. 274.
Elidemir, O; Colasurdo, GN; Rossman, SN; and Fan, LL. "Isolation of Stachybotrys from the lung of a child with pulmonary hemosiderosis." (1999) Pediatrics, 104:964-966.Flappan, SM; Portnoy, J; Jones, P; and Barnes, C. "Infant pulmonary hemorrhage in a suburban home with water damage and mold (Stachybotrys atra)." (1999) Environmental Health Perspectives, 107:927-930.Novotny, WE, and Dixit, A. "Pulmonary hemorrhage in an infant following two weeks of fungal exposure." (2000) Arch Pediatr Adolesc Med, 154:271-275, 2000.Tripi, PA; Modlin, S; Sorenson, WG; and Dearborn, DG. "Acute pulmonary hemorrhage in an infant during induction of general anesthesia." (2000) Paediatric Anesthesia, 10:92-94.Vesper, SJ; Dearborn, DG; Yike, I; Allan, T; Sobolewski, J; Hinkley, SF; Jarvis, BB; and Haugland, RA. "Evaluation of Stachybotrys chartarum in idiopathic pulmonary hemorrhage case house before, during, and after remediation." (2000) J. Urban Health: Bulletin of the New York Academy of Medicine, vol 77:66-85.
Find out more http://www.moldreporter.org/investigator-teams-response-to-cdcs-mmwr-report/
