II. Etiology and Pathophysiology
A. Primary vs. secondary disease
1. Children vs. adults
2. Forms of pulmonary hemosiderosis
B. Pathologic manifestations - hemosiderin laden macrophages
C. Immunologic mechanism
D. Stachybotrys atra association
III. Clinical Manifestations
C. Specific to different forms
A. Exclusionary diagnosis
B. Laboratory findings
C. Radiologic findings
D. Pulmonary function studies
F. Lung biopsy
C. Supportive care
D. Other treatments
VI. Prognosis and Mortality
A. Early diagnosis
B. Cleveland cases
At the conclusion of this article the practitioner should be able to:
1. Recognize the prevalence of this disease and it's different
2. Understand the pathology and etiology of pulmonary hemosiderosis.
3. Recognize the clinical manifestations of the disease and it's progression.
4. Recognize significance of laboratory and radiological testing results.
5. Understand the appropriate treatment protocols for this disease.
6. Recognize the prognosis and mortality of this disease.
7. Understand the newly recognized association with Stachybotrys atra and it's clinical significance.
is a rare condition that is known by a number of different names including
Celeen-Gellerstedt Syndrome, Goodpasteur's Disease, and Idiopathic Pulmonary
Hemosiderosis. The first pathologic description of this disease was by
Dr. Virchow in 1864. In 1918 Dr. Goodpasteur indicated an association
of pulmonary hemorrhage with glomerulonephritis thus leading to the naming
of this form of the disease after him. Dr. Celeen, in 1931, described
the clinical presentation of the disease, and, finally, in 1962, Dr. Heiner
proved that elimination of cow's milk from the diet could improve the symptoms
of many patients.
Pulmonary hemosiderosis is a rare and often fatal disease. Overall, in adults, males present with the disease twice as many times as females. The ratio of males to females is equal in children less than 10 years of age presenting with the idiopathic form of pulmonary hemosiderosis while males present with the disease more than females in adults. Adults with idiopathic pulmonary hemosiderosis usually present with less severity of symptoms as well. Males presenting with Goodpasteur's Syndrome present nine times more often then females.This disease usually occurs when the patient is in their mid-twenties.
Etiology and Pathophysiology
Pulmonary hemosiderosis can occur
as a primary disease or as a secondary complication of other diseases.
Commonly it presents as primary disease in children and secondary disease
in adult populations.The disease presents pathologically as a manifestation
of hemosiderin laden macrophage deposits in the lung. Hemosiderin is formed
by the breakdown of red blood cells and release of iron in heme. A second
possible pathology according to theorists is due to immunologic mechanisms
causing defects in the basement membrane of the pulmonary capillaries.
Epidemiologic and anecdotal data suggest that some cases may be related
to influenzal infections. Immunohistologic studies have indicated that
the majority of cases of Goodpasteur's syndrome involve a type II or cytotoxic
immune reaction within the lung and glomerulus of the kidney. There are
four types of primary pulmonary hemosiderosis: an idiopathic form,
a form associated with cow's milk hypersensitivity (Heiner syndrome), a
form occurring in association with myocarditis, and a form associated with
progressive glomerulonephritis (Goodpasteur's syndrome). Three types
of secondary pulmonary hemosiderosis are recognized: one occurs with mitral
stenosis and chronic left ventricular failure of any cause; one is associated
with collagen diseases; and on with hemorrhagic diseases.
The cause of idiopathic primary pulmonary hemosiderosis is unknown. Although the rarely reported familial incidence suggests a possible genetic basis for some cases, other explanations, such as an environmental toxin may also play a role. In one study, insecticides were suspected as a cause of pulmonary hemosiderosis. Children affected with cow's milk hypersensitivity (Heiner Syndrome) form of pulmonary hemosiderosis have the typical picture of idiopathic pulmonary hemosiderosis, unusually high serum titers of precipitins to multiple constituents of cow's milk, and positive intradermal skin tests to various cow's milk proteins.
Recently a pathologically significant cause of pulmonary hemosiderosis has been discovered through the association of Stachybotrys atra mold with the disease. Stachybotrys atra is a black, slimy mold found in the presence of water. This mold can appear in houses due to plumbing leaks, roof leaks, recent flooding or sewage backup. Stachybotrys atra is found on wood, ceiling tiles, wall paneling, unpainted plasterboard, cardboard boxes, cotton and newspapers. This particular mold does not grow on plastic, vinyl, concrete or ceramic surfaces. Hemorrhagic manifestations from Stachybotrys atra were first described from gastrointestinal hemorrhages of livestock due to ingestion of moldy feed. The pulmonary link between
idiopathic pulmonary hemosiderosis and Stachybotrys atra occurred from the notation of cases of the disease among infants in the Cleveland, Ohio area. It is theorized that mycotoxins produced by the mold inhibit normal lung growth among infants causing weakening of blood vessels in the lungs.
Clinical Manifestations and Diagnosis
Most of the clinical features are
related to blood in the alveoli and to the effects of chronic blood loss.
Symptoms are those of recurrent or chronic pulmonary disease and include
cough, hemoptysis, dyspnea, wheezing, and occasional cyanosis associated
with fatigue and pallor. The cough may be productive of blood sputum or
vomiting of large quantities of blood may occur. During acute attacks,
which usually last 2-4 days, the patient may become febrile. In later
stages the patient will hematuria, proteinuria, urinary casts, hypertension,
hepatosplenomegaly (approximately 25% of cases) and clubbing of the extremities.
Lymphadenopathy may be present in younger patients. These additional
manifestations occur at differing levels dependent upon a number of factors
including the type of pulmonary hemosiderosis that may be present.
The usual clinical features of fever, tachycardia, tachypnea, leukocytosis, respiratory distress, and abnormal radiographic findings may suggest bacterial pneumonia, and only prolonged follow-up will reveal the correct diagnosis. In some cases the early manifestations of illness are related to chronic iron deficiency anemia, which is often refractory to therapy, and the characteristic pulmonary symptoms do not appear until much later. Paradoxically, the patient may have severe pulmonary manifestations without radiologic abnormalities or the radiologic picture may be abnormal before pulmonary symptoms have occurred.
Certain manifestations of the disease are specific to the different forms of the disease while other manifestations are more difficult to determine the type of hemosiderosis present. Some patients have varying degrees of inflammation of the myocardium associated with pulmonary hemosiderosis, and, if significant myocardial disease is present when pulmonary symptoms are first noted, it may be impossible to determine whether the hemosiderosis is a primary or secondary phenomenon. The clinical picture does not differ from that of the idiopathic disease except that the heart may be enlarged and there may be electrocardiographic signs compatible with myocarditis. In Goodpasteur's Syndrome the presentation of the disease, initially, may be similar to idiopathic pulmonary hemosiderosis with hemoptysis and iron deficiency anemia but careful investigation will usually reveal a glomerulonephritis. Patients most often have progressive renal disease with hypertension and eventual renal failure and death. In patients with cow milk sensitivity the patient may present with recurrent otitis media, chronic rhinitis, vomiting and diarrhea. For secondary pulmonary hemosiderosis there are many associative manifestations. Heart disease producing a chronic increase in pulmonary capillary pressure, such as mitral stenosis, can lead to intrapulmonary hemorrhage and secondary hemosiderosis. Collagen vascular diseases may present clinical manifestations of pulmonary hemosiderosis. Occasionally, the vascular changes of polyarteritis are initially limited to the lungs. Other diseases, such as rheumatoid arthritis, may also produce pulmonary hemosiderosis as an effect of generalized diffuse vasculitis. A few patients with anaphylactic purpura or thrombocytopenic purpura have similarly had hemosiderosis secondary to intrapulmonary hemorrhage.
Diagnosis of pulmonary hemosiderosis is frequently one of exclusion. After elimination of all other causes of the pulmonary hemorrhage the diagnosis of hemosiderosis becomes the diagnosis of work-up. Laboratory findings usually are significant for anemia, reticulocytosis, an increased sedimentation rate, and guiac positive stools. The anemia is typically microcytic and hypochromic; serum iron concentrations are low, and there may be elevations in bilirubin, urobilinogen, and reticulocyte counts. Hemosiderin can usually be demonstrated in macrophages in smears of sputum or material obtained from tracheal or gastric aspirates. Eosinophilia is present in approximately 20% of patients and 90% of patients with Goodpasteur's Syndrome have anti-basement membrane antibodies. Radiologically the patient will present with pulmonary infiltrates in a "bat-wing" presentation. Radiologic changes range from minimal infiltrates
resembling pneumonia to massive pulmonary involvement with secondary atelectasis, emphysema, and hilar lymphadenopathy. These findings are presumed to be the result of episodes of pulmonary hemorrhage. Reticular densities may evolve as well; these believe to be caused by incorporation of blood pigment within the interstitium. The findings may suggest tuberculosis or pulmonary edema, and significant changes may be seen from day to day. The patients in later stages of the disease will also have evidence of cor pulmonale. Eighteen percent of patients diagnosed with Goodpasteur's Syndrome will have a normal chest x-ray.
Pulmonary function studies performed on patients with pulmonary hemosiderosis generally indicate poor compliance and airway obstruction. Bronchoscopy washings will show the presence of hemosiderin laden macrophages. A definitive diagnosis is usually obtained through open lung biopsy. This procedure establishes the diagnosis by histologic demonstration of intra-alveolar hemorrhage, large numbers of hemosiderin laden macrophages, alveolar epithelial hyperplasia, interstitial fibrosis, and sclerosis of small vessels. Biopsy samples may also show destruction of the elastic fibers in the lung, and basement membrane damage. The open technique is favored over needle aspiration because needle aspiration is often associated with hemorrhage.
Treatment, Prognosis and Mortality
Medical management of pulmonary
hemosiderosis usually involves the administration of oral and intravenous
steroids and cytotoxic agents as immunosuppressants. Common medications
used for this purpose include methylprednisolone, hydrocortisone, azathioprine,
cyclophosphamide and chlorambucil. Corticosteroids are commonly administered
intravenously at a dosage of one milligram per kilogram per each
twenty four hours. Iron chelation has been shown to be of some use as well
with administration of deferoxamine. Supportive care is given to the patient
with oxygen administration for periods of hypoxemia and intubation and
mechanical ventilation if the patient develops respiratory failure. Blood
transfusions are indicated for severe anemia. Other treatment consists
of plasmaphoresis and plasma exchange for basement membrane antibody (IgG)
removal. In severe cases splenectomy has also been used in the treatment
of pulmonary hemosiderosis for its immunosuppressive effect.
In patients with hypersensitivity to cow's mild (Heiner Syndrome), symptoms improve when cow's milk is removed from the diet and return with its reintroduction. Some patients fail to improve at all on a milk-free diet, and others without multiple serum precipitins have improved. Some of these patients with high titers of milk precipitins and pulmonary hemosiderosis develop cor pulmonale secondary to hypertrophied nasopharyngeal lymphoid tissue. These patients should also have a tonsilloadenoidectomy. In general, patients with hemosiderosis and precipitins to cow's milk have a better prognosis than do those with other forms of the disease, and they may eventually lose their sensitivity to milk.
Although recurrent attacks make prognosis of hemosiderosis unclear it is associated with a significantly high mortality rate. The poorest prognosis is seen in patients with Goodpasteur's Syndrome due to the associated renal failure. Patients with Goodpasteur's Syndrome usually succumb to the disease within six to twelve months of diagnosis. In idiopathic pulmonary hemosiderosis average lifespan after diagnosis is approximately two and one half years with actual life span ranges between one and five years. In all forms of the disease there is a significant decrease in prognosis shown with the severity of the first episode of hemorrhage.
Early diagnosis and treatment
of pulmonary hemosiderosis has a significant effect on the lifespan and
debility of patients. The form taken by the disease and understanding
of the different forms is also necessary for improved prognosis and decreased
mortality. This is especially true with the newly recognized form of the
disease due to Stachybotrys atra mycotoxin inhalation. Infants who
present with pulmonary hemosiderosis due to this mold show significant
improvement and decreased risk of mortality once the mold is identified
and removed from the environment.
In the Cleveland, Ohio cases of the disease ten infants were hospitalized due to pulmonary hemosiderosis of unknown etiology. Of these ten infants, five re-hemorrhaged after discharge from the hospital and return to their homes. One infant died as a result of the hemorrhaging. A number of events occurred due to recognition of the disease and it's association with the Stachybotrys atra mold. The Centers for Disease Control began a surveillance project nationwide and discovered that Cleveland was not the only city affected by this form of pulmonary hemosiderosis. Thirty-two cases were noted in Ohio and more than 47 cases were noted nationally. A case control study is now being conducted by Rainbow Babies and Children's Hospital (University Hospital) in Cleveland in association with the Cuyahoga County Board of Health, Cleveland Department of Public Health and Centers for Disease Control to investigate the association of this mold to pulmonary hemosiderosis. The Cuyahoga County Coroner also investigated infant deaths in the time period surrounding the first presentation of this illness and noted that some cases of reported Sudden Infant Death Syndrome (SIDS) may have been due to pulmonary hemosiderosis as evidenced by extensive hemosiderin laden macrophages in the lung tissue on autopsy. The Coroner also indicated that there may be a higher prevalence for the disease as associated with Stachybotrys atra in the black population. Recommendations by the Centers for Disease Control in regards to this form of pulmonary hemosiderosis include the cleaning and removal of items after significant water damage or flooding. There recommendations are for the use of diluted chlorine bleach solution (1 cup bleach to 1 gallon water) to disinfect the water laden areas. They also state that dish soap can be added to the bleach to cut dirt and oil. The bleach solution should be left on surfaces for 15minutes and then thoroughly rinsed and dried. Persons who perform the cleaning procedure are recommended to wear masks. The Centers for Disease Control also recommends that if large areas of water damage are present within a home or building that commercial cleaning services be employed in the cleanup of the areas prone to development of the Stachybotrys atra mold. The Centers for Disease Control also recommends that carpeting, paper, cardboard and cellulose materials be discarded to further eradicate areas for mold growth. No further episodes of pulmonary hemosiderosis have been noted in the infants who were originally exposed to the mold and incurred pulmonary hemorrhage. This indicates the importance of recognizing the effect of this mold on infant lungs and immediate investigation of the environment of infants presenting with pulmonary hemosiderosis.
Because of difficulties in pinpointing a specific cause of pulmonary hemosiderosis it remains a very difficult disease to identify. It is the absence of diagnostic features combined with the clinical picture that constitute the diagnostic criteria for these disorders. For any patient presenting to the acute care facility with hemoptysis or hematemesis this disease should be placed into the list of differential diagnoses and can be investigated after all other causes of these two clinical manifestations are ruled out.
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