Pulmonary Hemosiderosis
Outline
I. Introduction
A.
Names
B.
History
C.
Prevalence
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
A.
General
B.
Progressive
C.
Specific to different forms
IV. Diagnosis
A.
Exclusionary diagnosis
B.
Laboratory findings
C.
Radiologic findings
D.
Pulmonary function studies
E.
Bronchoscopy
F.
Lung biopsy
V. Treatment
A.
Immunosuppression
B.
Chelation
C.
Supportive care
D.
Other treatments
VI. Prognosis and Mortality
VII. Conclusion
A.
Early diagnosis
B.
Cleveland cases
1. recognition
2. prevention
3. surveillance
Goals
At the conclusion
of this article the practitioner should be able to:
1. Recognize the prevalence of this disease and it's different
forms.
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.
Introduction
Pulmonary hemosiderosis
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.
Conclusion
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.