Vol. 15 •Issue 26 • Page 20
Outbreak: A Detective Story of Idiopathic Pulmonary Hemorrhage
Berton Roueche’s collection of 22 short stories in The Medical Detectives has intrigued me for years. In fact, his stories, based on 30 years of medical detective work from the 1940s through the 1970s, have spurred me to search the medical literature for interesting biomedical phenomena.
And I have found a cluster of such material in the form of a rare disorder known as idiopathic pulmonary hemosiderosis (IPH) /pulmonary hemorrhage. IPH occurs almost exclusively in children. In adult cases of diffuse alveolar hemorrhage (DAH), IPH is a rare causative factor. In two studies comprising 85 patients with DAH, only one patient had IPH.
Even though this is a rare disorder, in a five-year span between 1993 and 1998, physicians in Cleveland diagnosed IPH in 37 infants. This “outbreak” resulted in 12 deaths, including seven originally classified as sudden infant death syndrome. Thirty of the infants were African-American, and all lived in the same geographic area in eastern Cleveland. This cluster of IPH prompted an investigation by the Centers for Disease Control and Prevention.
For those unfamiliar with IPH, symptoms range from initial subtle nosebleeds and chest congestion to overt life-threatening hemorrhage. The most common etiology of IPH includes immune disorders like Goodpasture’s syndrome and systemic lupus erythematosus.
IMPACT ON CHILDREN
These are highly unlikely to occur in infants and have never been reported in children under 2 years of age. Because the clinical features of IPH overlap with those of other immune-related or immune-mediated DAH syndromes, negative renal and lung biopsy findings are required to substantiate the diagnosis.
An IPH diagnosis can be made only in individuals with recurrent episodes of DAH.
The natural history of the disorder is variable, but multiple episodes of DAH over many years is characteristic in adults.
An association of IPH in infants and young children with elevated IgG precipitins against cow milk proteins (Heiner’s syndrome) has been reported. And cardiac structural pathology giving increased pulmonary venous pressure is another cause.
Still, acute pulmonary hemorrhage in infants is probably more frequent than hemosiderosis and can arise from multiple causes (i.e., necrotizing pneumonia and trauma), but prolonged bleeding does not occur in these cases. Hemosiderosis is defined as alveolar and/or interstitial distribution of hemosiderin-laden macrophages.
Infants diagnosed with IPH usually present with respiratory distress requiring intensive care and ventilatory support. Many require blood transfusions and other supportive measures. Some of these patients may exhibit respiratory failure prior to any overt signs of hemorrhage that become apparent only during intubation. Steroidal therapy may be instituted, although the role of inflammation in these infants is not well established.
Bronchoscopy or bronchoalveolar lavage (BAL) should be performed more than three weeks after the initial bleeding episode to confirm hemosiderosis as opposed to isolated hemorrhage. The presence of large quantities of hemosiderin-laden macrophages helps to clinch the diagnosis of IPH.
CDC medical detectives launched an intense investigation after local and state health authorities speculated the raft of SIDS deaths might be related to pesticide exposure.
Here are some clues they studied:
• Four infants experienced clinical events associated with processes that usually do not result in respiratory failure, e.g., anesthesia induction for elective surgery, hypernatremic dehydration, water intoxication and febrile seizure.
• One infant suffered pulmonary hemorrhage associated with upper airway obstruction caused by automotive cervical trauma.
• One infant had a pulmonary hemorrhage while sleeping prone with her blanket impacted into her face.
Here are some more stats to throw into the mix: 11 percent had developmental delay and/or failure to thrive; 22 percent had seizures and other extrapulmonary manifestations; 19 percent had concomitant infections including Pneumocystis carinii pneumonia (PCP) and hemolysis with hemoglobinuria.
Twenty-two patients were available for subsequent bronchoscopy and presented with continued hemosiderosis, most for more than six months.
A sizable number of infants (39 percent) required additional therapy for reactive airways syndrome for three to six months following the IPH episode. According to Martinez, et. al., this is twice the incidence of respiratory illness with wheezing in normal infants.
Further epidemiological inquiry showed that in a 10-year period prior to 1993, there had been only three pediatric cases with this disorder at Rainbow Babies and Children’s Hospital, a referral center for all of northeastern Ohio. The Cleveland incidence revealed 1.5 cases of IPH per 1,000 live births, from 1993-1995.
As the investigation continued, the Cuyahoga County Coroner’s office conducted postmortem examinations of all infant medical cases between 1995-1999, prompted by the public health implications of the outbreak.
In this instance, the interface of the medical examiner/forensic pathologist and the public health and medical communities was vital during the epidemiological investigations and surveillance.
The scientific medical sleuths of the Cuyahoga County Coroner’s office discovered that seven infants, originally classified as SIDS deaths, had large amounts of pulmonary hemosiderin-laden macrophages. All but one of these infants had lived in the same Cleveland cluster area.
As the medical detectives from the CDC, the local and state health departments and the medical examiner’s office labored, they eliminated many possible causes for the frightening and fatal bleeding. They were concerned it could spread to other communities and fretted whether it was an endotoxin or some environmental contaminant.
And why, they asked, was it all found in the same geographic area of the city?
The investigators isolated two common ingredients: poverty and poor indoor air quality.
Although the medical investigators initially suspected toxic exposure from something like a pesticide, a detailed analysis of all the data pointed to poor indoor air quality marked by toxigenic fungi (molds) and environmental tobacco smoke.
The infants’ homes had a high prevalence of water damage and a high quantity of airborne S. chartarum and toxigenic fungus that thrives on water-damaged surfaces such as wood and gypsum board.
S. chartarum, (a.k.a. S. atra) requires water-soaked cellulose for growth and is found in indoor environments with water damage from flooding or leaks. Other toxigenic fungi were prevalent in the residences, including Aspergillus, Clado.sporium and Penicillium.
Multivariate matched analysis implicated exposure to environmental tobacco smoke as a risk factor in the presence of S. chartarum.
The study found infants with IPH were more likely than controls to live in homes with toxigenic S. chartarum and other fungi in the indoor air. S. chartarum produces potent metabolites profoundly toxic to humans and animals. These metabolites include satratoxin G and H and roridin, the most potent compounds of a larger group of substances known as trichothecenes.
Other trichothecenes such as deoxynivalenol and T-2 have been extensively studied, especially by the Department of Defense, because of their implied use as biochemical warfare agents in Afghanistan by Russian forces in the 1980s in a form that was termed “yellow rain.”
Other toxins produced by S. chartarum include phenyl spirodrimanes, inhibitors of complement activation, especially C 5; cyclosporin, an immune suppressant targeting T-lymphocytes; and stachybocins, a newly recognized class of mycotoxins that are endothelium receptor antagonists.
Although S. chartarum spores are not known to germinate in the lung, nor is there a yeast form of this fungus, inhalation produces a mycotoxicosis. When S. chartarum spores dry out, they are readily aerosolized and their size (4.0-6.0 x 7.9- 12 mu) and ellipsoid shape allow inhalation by stream passage out to the distal airways.
Concern about S. chartarum and other indoor molds surfaced in the mid-1980s. Documentation from Canada and the U.S. in both residential and non-industrial settings suggests that chronic indoor air exposures are associated with a multiple array of symptoms ranging from simple irritations to chronic and debilitating symptoms.
Environmentally mediated immune dysfunction has also been associated with exposures to S. chartarum. It is also known, via animal studies utilizing five-week old adult mice, that after inhalation of fungal spores, trichothecenes tend to kill macrophages ingesting the spores.
Thurman, et. al., showed in their research that the pulmonary inflammation seen in animal models in some acute and sub-acute studies is in contrast to previous studies with aerosolized solutions of trichothecenes. The latter produced no respiratory tract inflammation; rather, cell necrosis and lysis were seen in spleen, thymus and intestines.
The pathogenesis of IPH in young infants in the Cleveland cluster appeared to arise from inhalation of S. chartarum spores containing trichothecene compounds which are potent protein synthesis inhibitors, notably satratoxins G and H, or roridin. The rapidly growing lungs of young infants appear to be especially vulnerable to the toxic metabolite of toxigenic molds. Protein synthesis of type IV collagen and other basement membrane constituents would be particularly sensitive to inhibition. This can lead to focal areas of capillary fragility.
The synergistic effects of environmental tobacco smoke exposures could contribute to overall pathogenesis of IPH by inducing pulmonary vasoconstriction, thus increasing the vasculature pressures and biophysical stres.ses on already fragile capillary structures.
The stachybocins may contribute directly to the hemorrhage by antagonizing the vasoactive properties of endothelin-1, a paracrine hormone released by endothelial cells in response to hypoxia.
In conclusion and to summarize, an intense epidemiologic investigation of pulmonary hemorrhage in infants revealed an association with exposure to S. chartarum and other airborne toxigenic fungi (molds). Exposure to environmental tobacco smoke appears to have acted as a co-factor in the presence of S. chartarum.
The pathophysiologic concepts seem to follow in a logical progression stemming from the clinical profiles and the biochemical mechanisms of mycotoxins.
Clearly, infants should be excluded from indoor environments found to contain toxigenic fungi and environmental tobacco smoke. Substandard housing with conditions of chronic water incursion must be avoided and reported to appropriate authorities (i.e., housing inspectors, public health department, etc.) and any flooding should be cleaned up quickly and adequately prior to reoccupancy.
This cluster case study will, hopefully, serve to increase awareness among all health professionals on the impact of social and physical environments on human health and the importance of environmental exposure assessments.
For list of references and a full version of the article, see this article on our Web site at www. Respiratory-care-sleep-medicine.advanceweb.com.
Frank Rando, an Arizona practitioner, is an environmental health scientist-hazardous materials specialist with experience in disaster management, public health and EMS special operations. He is a recognized authority on bio-chemical and radiological defense and hazardous materials toxicology. You can contact him at [email protected].