characterized by a triad of rapidly progressive glomerulonephritis , hemoptysis and the presence of anti - glomerular basement membrane ( anti - gbm ) antibodies , goodpasture syndrome is a rare , life - threatening autoimmune disease .
the autoantibodies are targeted against the non - collagen domain 1 of the 3 chain of type iv collagen .
the 3 chain of type iv collagen is restricted to the basement membranes of the kidney , cochlear tissue , lung , bruch 's membrane of the retina and the testis .
the autoantibodies initiate destruction of the basement membranes of the kidney glomeruli , resulting in a focal necrotizing glomerulonephritis , which can be rapidly progressive and cause renal failure .
antoantibody - mediated damage of alveolar basement membranes leads to diffuse pulmonary hemorrhage , which if severe enough , can lead to respiratory failure . pulmonary symptoms often precede renal symptoms , and may occur weeks to months earlier .
the trigger for this autoantibody formation is unknown ; however , environmental factors are believed to unmask the usually hidden epitopes , eliciting autoantibody formation .
postulated environmental factors include viral infection , hydrocarbon solvent exposure and smoking [ 3 , 4 ] .
diffuse pulmonary hemorrhage in patients with anti - gbm autoantibodies is seen almost exclusively in active smokers .
additionally , this autoimmune disease is associated with certain human leukocyte antigen ( hla ) subtypes , such as hladrb1 * 1501 and * 1502 and hla - dr4 , has a slight male preponderance and is known to occur in two age peaks : the third decade and the fifth and sixth decades [ 5 , 6 ] . here
, we report an unusual case of a 40-year - old man with clinical evidence of goodpasture 's syndrome , a negative anti - gbm antibody serum result , eosinophilia and delta granule pool storage deficiency .
a 40-year - old caucasian man was admitted to the hospital complaining of a 3-week history of slight cough and increased shortness of breath on exertion and a 2-week history of occasional hemoptysis .
the patient 's medical history was scarce as he had not seen a doctor in over 20 years .
upon questioning , he reported a 33 pack - year history of smoking , a 27 -kg weight gain over the previous 5 years due to inactivity , no sexual contact or activity , no contact with sick people and no intravenous drug use in the past or present . besides being morbidly obese , he had no other known medical illnesses .
chest x - ray imaging revealed bilateral haziness , with extensive involvement of the right lung and the left lower lobe .
on physical examination , the patient was afebrile , and he had coarse breath sounds bilaterally with rare rhonci .
a complete blood count demonstrated a white blood count of 9.6  10 cells / l ( 4.411.3 
10 cells / l ) with 0.96  10 eosinophils / l ( 00.45  10 eosinophils / l ) .
he was put on nasal oxygen to improve oxygenation ; however , despite this intervention , blood gases worsened .
bronchoscopy was performed , which revealed diffuse airway bleeding ; however , an active bleeding site was not identified .
a significant amount of blood was seen in the patient 's mouth on intubation , and suctioning through a nasogastric tube yielded  200 ml of coffee ground contents. an extensive workup was done in an attempt to discern the etiology of his hemorrhagic lung disease .
tests included those for autoimmune diseases , acquired hemolytic anemias , microbial infection and coagulation disorders .
a cold agglutinin titer was reported positive ; however , a coomb 's test was negative .
rheumatoid factor and c - reactive protein levels were elevated at 23 u / l ( < 20 u / l ) and 44.67 mg / dl ( 03 mg / dl ) , respectively .
he tested negative for anti - neutrophil cytoplasmic antibodies ( ancas ) and anti - gbm antibodies .
one of two blood cultures revealed gram - positive cocci in clusters , later identified as oxacillin - resistant staphylococcus hominis .
the patient 's international normalized ratio remained slightly elevated at around 1.4 during his stay , with an unknown etiology .
blood was consequently sent for platelet electron microscopy study , which revealed platelets with an average of 2.79 delta granules per platelet ( 46 delta granules / platelet ) consistent with delta granule storage pool deficiency .
the patient 's condition continued to deteriorate during his 14-day hospital stay , with worsening anemia requiring receipt of multiple blood products , worsening oxygenation refractory to increased fraction of inspired oxygen ( fio2 ) , hypertension , hypernatremia , hypocalcemia , hypermagnesemia , blood urea nitrogen and creatinine reaching as high as 35 mmol / l ( 2.98.2 mmol / l ) and 230 mol / l ( 831
mol / l ) , respectively , indicating kidney failure , and alanine amino transferase ( alt or serum glutamic pyruvic transaminase ) and aspartate amino transferase ( ast or serum glutamic oxaloacetic transaminase ) of 371 u / l ( 436 u / l at 37c ) and 173 u / l ( 833 u / l at 37c ) , respectively , indicating liver failure .
still , the patient developed progressive lung consolidation bilaterally , persistent hypoxia and recurrence of a significant output of  coffee ground material through his nasogastric tube . eventually , chest x - rays revealed bilateral  white out of the lungs and an accumulation of right pleural fluid .
a lung biopsy was considered at various points during his decline ; however , the patient was never well enough to undergo such a procedure . by the 14th day in the hospital
, the patient was oozing blood from multiple mucosal sites and areas of needle sticks , and the patient was deemed critically ill with a poor prognosis due to worsening kidney failure and anemia .
sections of the lungs revealed extensive intra - alveolar hemorrhage , edema , hemosiderin - laden macrophages , focal neutrophilic infiltration , wide - spread chronic inflammation and total disruption of the normal lung architecture ( figures 1 and 2 ) .
microscopic examination of the kidneys revealed extensive tubular cell nuclei dropout , consistent with acute tubular necrosis , which was caused by his persistent hypoxia secondary to his respiratory failure , and mesangial cell proliferation in the glomeruli , fibrin in the bowman spaces and occasional early crescent formation secondary to inflammatory destruction of the basement membranes in the renal glomeruli .
the most significant study involved immunofluorescence , which revealed focal faint linear immunoglobulin g ( igg ) deposits along the alveolar septa and strong extensive peripheral linear igg deposits in the capillary loops of the renal glomeruli ( figures 3 and 4 ) .
3.(a ) low - power photomicrograph of linear igg deposits in alveolar septa on immunofluorescence in a lung tissue section .
( b ) high - power photomicrograph of linear igg deposits in alveolar septa on immunofluorescence in a lung tissue section . 

4.photomicrograph of linear igg deposits along the gbm of a kidney tissue section shown via immunofluorescence .
( a ) low - power photomicrograph of linear igg deposits in alveolar septa on immunofluorescence in a lung tissue section .
( b ) high - power photomicrograph of linear igg deposits in alveolar septa on immunofluorescence in a lung tissue section .
photomicrograph of linear igg deposits along the gbm of a kidney tissue section shown via immunofluorescence .
goodpasture syndrome is a rare autoimmune disorder characterized by glomerulonephritis , hemoptysis and autoantibodies directed against a non - collagenous domain of the 3 chain of collagen type iv present in a few tissue basement membranes .
if not diagnosed and treated early , patients with goodpasture syndrome may develop respiratory and renal failure and die , or become dependent on dialysis if they survive .
many clinicians diagnose this syndrome with a variety of assays used to detect serum anti - gbm antibodies .
renal and lung tissue biopsies are also viewed as valuable in making the diagnosis , as the anti - gbm antibodies may be detected in these specimens by immunohistochemistry or immunofluorescence techniques .
a linear pattern of immunoglobulin along the basement membrane of renal glomerular capillaries and alveolar septa seen by immunofluorescence or immunohistochemistry is consistent with goodpasture syndrome .
the latter diagnostic tests are important in suspected clinical cases in which the serum anti - gbm antibody test is negative , as up to 15% of patients with goodpasture syndrome may have no detectable circulating antibodies .
this was the case in our patient , in which his repeated anti - gbm antibody tests came back negative ; however , the presence of these antibodies was confirmed by immunofluorescence in lung and renal tissue sections . further interesting findings in our patient , which to our knowledge have not been reported with any other case of goodpasture syndrome , were those of delta granule pool storage deficiency and eosinophilia .
there are at least a few cases of goodpasture syndrome to our knowledge that have been reported to occur in the context of negative anti - gbm serum results .
reported a case of a 55-year - old woman who presented with dyspnea and hemoptysis , bronchoscopy revealing diffuse alveolar hemorrhage , negative anti - gbm antibody by enzyme - linked immunosorbant assay , positive perinuclear anca at a dilution of 1:160 and glomerular crescents in renal biopsies under light microscopy .
immunofluorescence also demonstrated weak linear staining of the gbms with anti - complement 3 ( anti - c3 ) sera and strong linear staining with anti - igg sera .
another case of anti - gbm serum antibody - negative goodpasture syndrome reportedly occurred in a 44-year - old female with a 3 year history of recurrent hemoptysis and shortness of breath , yet clinically normal renal function .
initially , she had been treated for klebsiella pneumoniae after a positive sputum culture . on repeat presentation with hemoptysis during this period , her illness had been labeled as recurrent acute respiratory distress syndrome . on her fourth presentation with hemoptysis ,
other test results included a positive rheumatoid factor , autoantibodies , weakly positive anti - double stranded deoxyribonucleic acid negative cytoplasmic - anca and extensive ground glass appearance on a chest computed tomography scan .
lung biopsies showed linear deposition of igg in the alveolar capillary basement membranes using immunoperoxidase staining , and linear igg and c3 were seen along the renal capillary walls with immunofluorescence .
finally , a case of a 27-year - old male with goodpasture syndrome and undetectable anti - gbm circulating antibodies was reported by hellmann et al .
this patient , similar to our patient , developed dyspnea and hemoptysis , which eventually led to respiratory failure requiring intubation and mechanical ventilation . also like our patient , he was a heavy smoker and tested negative for ancas , anti - nuclear antibodies and a multitude of other autoantibodies .
his disease was confirmed on histological lung section by the presence of a faint but linear deposition of igg antibodies along the alveolar basement membranes .
several proposed mechanisms for why serum anti - gbm tests may be negative in some patients with goodpasture syndrome have been offered .
one proposed explanation is that the antibodies are of high affinity and are removed from the patient 's plasma by being bound to the kidney and alveolar basement membranes . on the contrary ,
the circulating serum antibodies may be of lower affinity than those that are tissue bound and thus are more easily washed away during the wash - out step of the assay .
finally , the assay 's renal tissue may have a different epitope than that present in the native kidney [ 1 , 7 ] . for
patients who present promptly with hemoptysis and subsequently receive steroid therapy early in the disease process , negative anti - gbm serum results along with only focal linear deposits in tissues may be due to steroid - induced immune suppression
. two unusual aspects of our patient 's case , unknown to us to have occurred concomitantly in other patients with goodpasture syndrome , include delta granule pool storage deficiency and eosinophilia .
delta granule pool storage deficiency is a heterogeneous disorder presenting with abnormalities in the second wave of platelet aggregation , a bleeding tendency and a decreased number of delta granules in platelets .
most commonly , patients experience mucocutaneous hemorrhage , excessive bleeding postoperatively and postpartum , epistaxis and easy bruising .
no evidence of parasites was found during the autopsy or in microscopic examination of tissues , nor ova or parasites detected in stool samples . also , no vasculitis was observed in tissue samples on histologic examination . in an article published in the cleveland clinic journal of medicine on diffuse alveolar hemorrhage ,
eosinophilia is said to be rare or mild in goodpasture syndrome ; however , the parameters of  mild are not defined .
still , it is possible that his eosinophilia was the result of an allergy developed from his reported unsanitary living conditions , which included an abundance of trash , dead mice and black mold .
the diffuse pulmonary hemorrhage associated with goodpasture syndrome occurs almost exclusively in active smokers , and is a postulated cause of unmasking the epitope which elicits the formation of the anti - gbm autoantibodies .
thus , his 33 pack - year smoking history put him at risk of developing this autoimmune disease , as well as increased his risk of diffuse pulmonary alveolar hemorrhage . additionally , his platelet disorder likely worsened his hemorrhagic lung condition by increasing his likelihood to bleed excessively .
finally , his negative anti - gbm antibody serum result and rapidly progressive condition prevented the ability to attain a lung or renal biopsy to establish the etiology of his disease , and thus , the correct treatment could not be determined .
this case demonstrates the difficulty in diagnosing goodpasture syndrome in an unusual patient in whom the anti - gbm antibody serum results are negative and a biopsy is unattainable , and the grave consequences in missing such a diagnosis .
 goodpasture syndrome is a rare , life - threatening autoimmune disease characterized by a triad of rapidly progressive glomerulonephritis , a hemorrhagic pulmonary condition and the presence of anti - glomerular basement membrane ( anti - gbm ) antibodies . 
 the antibodies initiate destruction of the kidney glomeruli , resulting in a focal necrotizing glomerulitis , which may progress rapidly to renal failure . 
 autoantibody - mediated damage of alveolar basement membranes leads to diffuse pulmonary hemorrhage , which in some cases may be severe enough to cause respiratory failure . 
 many clinicians use a variety of assays to detect serum anti - gbm antibodies ; however , these tests may be falsely negative in up to 15% of patients with goodpasture syndrome . here 
 , we report an unusual case of a 40-year - old man with clinical evidence of goodpasture syndrome , a negative anti - gbm antibody serum result , eosinophilia and delta granule pool storage deficiency . 
 after a 14-day hospital stay and extensive workup , as well as treatment with antibiotics , steroids and ventilator support for respiratory failure , the patient continued to deteriorate and entered multisystem organ failure . 
 the family decided to withdraw ventilator support , and the patient expired . 
 immunofluorescence testing for anti - gbm autoantibodies on lung and kidney tissues during an autopsy confirmed the diagnosis of goodpasture syndrome . 
Background
Case report
Discussion