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cryoglobulinemia ( cg ) occurs when the serum contains cryoglobulins , either single or mixed immunoglobulins , which precipitate at low temperatures .
this can result in an immune - complex mediated , small - to - medium vasculitis that most commonly affects the kidneys and the skin .
ie also has the ability to manifest clinically through immune - mediated phenomena and thus can cause overlapping symptoms , namely positive rheumatoid factor ( rf ) and glomerulonephritis ( gn ) .
a 42-year - old man with known history of ivdu and hcv infection presented with complaints of bilateral lower extremity edema , rash , increasing abdominal girth , diffuse abdominal pain , and generalized fatigue .
his lower extremity edema had been present for 6 months and he had been evaluated for it on 2 previous occasions with negative lower extremity ultrasound examinations and had taken a 30-day course of furosemide with some improvement ; all other symptoms were new to this presentation .
initial laboratory values were significant for creatinine 1.7  mg / dl ( reference range 0.81.4  mg / dl ) , elevated white blood cell count of 18 , 000/mcl ( 450011,000/mcl ) and hiv screening test that was non - reactive .
a percutaneous kidney biopsy was subsequently performed revealing igm dominant mesangioproliferative gn with features suggestive of cg ( fig . 1 , fig . 2 , fig . 3 , fig .
4 ) , likely related to chronic infection including chronic hepatitis c or chronic bacterial infection .
the patient was treated with corticosteroid therapy for presumed mixed cg , however on hospital day 3 his renal function continued to deteriorate and the patient was transferred to our tertiary care center for further evaluation for possible rituximab and/or plasmapheresis therapy . upon arrival ,
the patient s physical exam was notable for anasarca , a grade 2 diastolic murmur and several painless , small , erythematous macules on bilateral lower extremities , not extending to the soles of his feet .
initial laboratory results were significant for creatinine 3  mg / dl ( 0.81.4  mg / dl ) , total protein 8.4  g / dl ( 6.38.2  g / dl ) , albumin 2.4  g / dl ( 3.45.0  g / dl ) , hemoglobin 8  g / dl ( 13.517.5  g / dl ) , white blood cell count 35,000/mcl ( 450011,000/mcl ) and urinalysis with 30  mg / dl of protein ; platelet count and the remainder of the comprehensive metabolic panel were within normal limits .
other pertinent laboratory studies revealed low c3 and c4 complement levels ( c3 level 88252  mg / dl , c4 88206  mg / dl ) , negative rf , and negative cryoglobulins .
blood and urine cultures obtained prior to transfer both grew enterococcus faecalis , leading the care team to ascribe the bacteremia to a urinary source and the patient was started on daptomycin and ceftriaxone ( due to a previous adverse reaction to ampicillin ) .
repeat blood cultures were again positive for e. faecalis . due to the persistent bacteremia and the patient s high - risk behavior ,
a transthoracic echocardiogram ( tte ) demonstrated severe aortic insufficiency , severe left atrial enlargement , and thickening of the mitral valve leaflets with trace regurgitation .
subsequent transesophagealechocardiogram confirmed these results and revealed mitral and aortic valve vegetations ( fig . 5 , fig . 6 ,
the antibiotic regimen was changed to vancomycin and gentamicin , with subsequent improvement in abdominal pain , lower extremity edema , and renal function ( creatinine 1.8  mg / dl ( 0.81.4  mg / dl ) ) .
the cardiothoracic surgery team evaluated the patient and recommended valve replacement following completion of the antibiotic course and scheduled the patient for a clinic visit in six weeks .
the delay was due to concern for continued ivdu after the procedure and subsequent reinfection .
the patient was discharged to a skilled nursing facility to receive a total six - week course of antibiotics for infective endocarditis .
he recovered and returned home without issues , but failed to follow up with his clinic appointment for primary care or for surgical evaluation.fig .
the glomerular basement membranes are unremarkable without spikes , holes , splitting , or corrugation.fig .
2immunofluorescence.on a scale of 03 + , there is 2 + diffuse global granular mesangial with very segmental capillary loop staining for igm ( leh ) and 12 + c3 staining ( right ) in a similar pattern.fig .
2fig . 3kappa and lambda immunofluorescence.on a scale of 03 + , there is equal 12 + diffuse segmental to global granular mesangial staining for kappa and lambda.fig .
4electron microscopy.there are scattered mesangial immune complex deposits ( leh ) with vague annular substructure ( right).fig .
the glomerular basement membranes are unremarkable without spikes , holes , splitting , or corrugation . on a scale of 03 + ,
there is 2 + diffuse global granular mesangial with very segmental capillary loop staining for igm ( leh ) and 12 + c3 staining ( right ) in a similar pattern .
there is equal 12 + diffuse segmental to global granular mesangial staining for kappa and lambda .
there are scattered mesangial immune complex deposits ( leh ) with vague annular substructure ( right ) .
type i is defined by the presence of a monoclonal immunoglobulin ( ig ) , predominantly resulting from hematologic diagnoses such as waldenstrom s macroglobulinemia , chronic lymphocytic leukemia , and multiple myeloma .
type ii is a mixture of polyclonal ig and monoclonal ig , predominantly resulting from infection such as hcv or human immunodeficiency virus ( hiv ) .
type iii consists solely of polyclonal ig , often associated with autoimmune disorders such as henoch - schonlein purpura , systemic lupus erythematosus , sjogren syndrome , connective tissue disease , sarcoidosis and others , but also has been described as resulting from hcv infection .
risk factors include : age greater than 60 years old , male gender , history of ivdu , poor dentition , structural heart disease , intracardiac or intravascular access devices , chronic hemodialysis , diabetes mellitus , and hiv infection .
duke criteria comprise a collection of major and minor criteria to establish a diagnosis of ie ( outlined in table 1 ) .
some clinical findings of ie overlap with cg including arthralgias , abdominal pain , petechiae , renal dysfunction , positive rf , elevated esr and crp . while c4 levels are typically low in both processes , reflecting ongoing consumption by immune complexes , c3 is also low in ie but is generally unaffected or only mildly diminished in cg .table 1endocarditis diagnostic criteria  modified duke criteria.table 1major criteriapositive blood culturestypical pathogens from at least two separate cultures ( staphylococcus aureus , streptococcus bovis or viridans , hacek * organisms , enterococcus)evidence of endocardial involvement by echocardiographyendocardial vegetation , perivalvular abscess , new partial dehiscence of prosthetics valve , new valvular regurgitationcoxiella burnetti blood culturesingle positive culture or anti - phase 1 igg antibody titer > 1:800minor criteriapredispositionheart condition , intravenous drug use , indwelling catheters , poor dentition , diabetes mellitus , hemodialysisfevergreater than or equal to thirty - eight degrees celsiusmicrobiologic evidencepositive blood culture not meeting major criteriavascular phenomenaseptic arterial or pulmonary emboli , mycotic aneurysms , intracranial or conjunctival hemorrhages , janeway lesionsimmune phenomenarheumatoid factor , glomerulonephritis , osler s nodes , roth s spotshighly probable : 2 major or 1 major and 3 minor or 5 minor criteria.possible : 1 major and 1 minor or 3 minor.*haemophilus , aggregatibacter , cardiobacterium , eikenella , kingella .
highly probable : 2 major or 1 major and 3 minor or 5 minor criteria .
in cg , the renal disease is most commonly attributed to immune complex deposition , but may be a result of thrombotic disease .
microscopy of kidney tissue samples most often yields results consistent with mesangioproliferative gn with hypercellularity from an influx of inflammatory cells , immune deposition , and thickening of glomerular elements . in ie , renal disease is thought to be sequela of vascular occlusion by microthrombi that lead to local immune - mediated vasculitis . .
as with cg , a membranoproliferative - pattern gn with igg and c3 deposition is the traditional pattern of injury for ie .
however , a recent study of clinical specimens demonstrated that ie presented most commonly with crescentic gn , followed by diffuse proliferation , and finally mesangial proliferation without endocapillary proliferation or crescent formation , the latter of which was seen in this case . confounding this case if the presence of dominant igm staining in addition to c3 .
thus , no definitive etiology could be identified by renal biopsy alone in this case .
early recognition of ie is important as it is reported that in - hospital mortality is 1823% and 6-month mortality is 2227% .
however , in one case series , ie was unrecognized in almost 1/5 of cases at the time of nephrology consult .
if a patient is clinically stable , treatment can wait until blood culture results are available and targeted therapy can be delivered .
when patients are acutely ill , empiric treatment should be given after two or three sets of blood cultures are drawn and vancomycin is an appropriate choice for most patients .
a cardiac surgery consultation is recommended for cases where complications arise or are suspected such as infection of prosthetic valves , heart block , systemic emboli , or new moderate to severe heart failure .
assessment of response is based on clinical observation ; fever should resolve between 37  days , and repeat cultures should demonstrate clearance of bacteremia .
duration of therapy can vary based on organism , but is typically six weeks starting with the first day of negative blood cultures .
this case highlights the similarity in risk factors , clinical findings , and renal complications of ie and mixed cg .
it also provides an opportunity for reflection on the use of heuristics and how bias can affect diagnosis and treatment .
healthcare providers must maintain a broad differential and continue to re - evaluate the patient as additional information arises . due to hcv infection and acute kidney injury , it was reasonable to suspect cg in this patient .
kidney biopsy results added support for this diagnosis , but mesangioproliferative gn is not specific for cg and chronic infection can yield similar results .
in addition , it is very common to see a urinary tract infection ( uti ) in hospitalized patients .
when blood cultures returned positive , they were believed to be from a urinary source , however ivdu should significantly elevate the suspicion for endocarditis . anchoring to the original admit diagnoses , uti and cg , led to the belief that two distinct processes were occurring .
however in this particular case , occam s razor appears to prevail and all findings could be attributed to ie .
this research did not receive any specific grant from funding agencies in the public , commercial , or not - for - profit sectors .
this case of infective endocarditis masquerading as mixed cryoglobulinemia in a man with a history of intravenous drug use ( ivdu ) and hepatitis c virus ( hcv ) highlights the importance of maintaining a broad differential and continually re - evaluating the working diagnosis as new information presents itself . 
 the patient presented to an outside hospital and was treated for presumptive mixed cryoglobulinemia with corticosteroid therapy . 
 when the patient did not improve , he was transferred to a tertiary care center for possible rituximab and/or plasmapheresis . 
 further investigation revealed enterococcus bacteremia with subsequent workup consistent with infective endocarditis ( ie ) . 
 this case highlights a diagnostic dilemma and demonstrates the importance of a thorough evaluation as it pertains to overlapping features of ie and mixed cryoglobulinemia .