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75

A24-year-old man presentedwith severe anemia (hemoglo-bin 62 g/L). He had a 1-month history of dry cough, chest painthat was intermittent and pleuritic, andprogressive breathlessness on exer-tion. The patient reported having occa-sional chills and night sweats. He de-nied weight loss or hemoptysis. Aradiograph of his chest taken 2 weeksbefore presentation had shown pul-monary infiltrates in the lower regionsof both lungs (Figure 1A). He had sub-sequently completed a 10-day courseof moxifloxacin. The patient was asmoker. He also reported that, 2 to 3years before, he had engaged in manyepisodes of unprotected sex with amale partner who was discovered tohave multiple other sexual partnersduring the same period.

On examination, the patient waspale and had tachycardia. We found nocyanosis or clubbing. His oxygen satu-ration was 96% by pulse oximetrywhile breathing ambient air. His lungswere clear to auscultation. Laboratorytests showed a hemoglobin concentra-tion of 62 g/L (mean corpuscular vol-ume 82 fL) and a reticulocyte count of84 × 109/L. The ferritin level (86 μg/L)and the serum creatinine level (108

μmol/L) were within normal limits. Hisleukocyte count differential was alsonormal. His lactate dehydrogenaselevel, total bilirubin level, internationalnormalized ratio and partial thrombo-plastin time were within normal limits.A chest radiograph showed a decreasein the pulmonary infiltrates on the rightside and an increase on the left side(Figure 1B).

What is the next most appropri-ate diagnostic test or procedure?

a. Computed tomography scan of thechest

b. Urinalysisc. HIV testd. Bronchoscopy with bronchoalveolar

lavagee. Further testing for hemolysis, in-

cluding testing for cold agglutinins

All of these investigations might beconsidered appropriate at this point. Inour patient’s case, the tests that led tothe actual diagnosis were (b) and (d).

After being given a blood transfu-sion, the patient felt well and was dis-charged. We arranged for close follow-up on an outpatient basis to assess hissymptoms, HIV status and hemoglobin

level. We administered a course ofazithromycin for a presumptive diagno-sis of mycoplasma pneumonia, possi-bly associated with hemolytic anemiadue to cold agglutinins or anemia sec-ondary to HIV infection. The HIV testresult was reported 1 week later andwas negative.

The patient presented again 6 weekslater with the same symptoms. This timehis hemoglobin level was 73 g/L, hisserum creatinine was 118 μmol/L, and aurinalysis showed proteinuria (3+) andmicroscopic hematuria (5+). No castswere present. A chest radiographshowed worsening of the pulmonary in-filtrates on both sides (Figure 2).

What is your diagnosis?

a. Pneumocystis jiroveci infectionb. Löffler syndromec. Goodpasture syndromed. Churg–Strauss syndromee. Cryptogenic organizing pneumonia

Migratory pulmonary infiltrates

What is your call?

DO

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See page 76 for the diagnosis.

Figure 1: Chest radiographs taken (A) 2 weeks before evaluation showing pulmonaryinfiltrates in the lower regions of both lungs, and (B) during evaluation showing im-provement in pulmonary infiltrates on the right side and worsening of infiltrates onthe left side.

Figure 2: Chest radiograph taken 6weeks after initial evaluation showingnew pulmonary infiltrates in the rightmid-lung zone and worsening infil-trates in the lower lung zones on bothsides.

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CMAJ • JANUARY 6, 2009 • 180(1)76

Discussion

The diagnosis is (c) Goodpasture syn-drome. The presence of risk factors forHIV infection led us to focus initiallyon infectious causes. After HIV infec-tion was ruled out, we discovered sig-nificant microscopic hematuria whichraised the possibility of a pulmonary–renal syndrome. Bronchoscopy withbronchoalveolar lavage showed diffusealveolar hemorrhage. Tests for antinu-clear antibodies and antineutrophil cyto-plasmic autoantibodies were negative.However, the titre of antiglomerularbasement membrane antibodies was el-evated at 1:40. Renal biopsy showed le-sions that were segmental and necrotiz-ing with cellular crescents (Figure 3A).Linear staining of glomerular basementmembranes was strongly positive forIgG (Figure 3B). Both the lesions andthe linear staining features are diagnos-tic of Goodpasture syndrome.

The patient was administered pred-nisone and cyclophosphamide and under-went a series of 9 plasma-exchange treat-ments. Test results for antiglomerularbasement membrane antibodies werenegative after 3 months of therapy. After6 months of follow-up, the patient had nosymptoms and his serum creatinine levelhad decreased to within normal limits.

Goodpasture syndrome is rare, af-fecting fewer than 1 person permillion.1 Autoantibodies directedagainst the glomerular basement mem-brane are produced in response to anunknown stimulus and cause glomeru-lonephritis. In about 60% of cases, theyalso cause pulmonary hemorrhage bytargeting antigens in the alveolar base-ment membrane. Cigarette smoking in-creases the risk of pulmonary involve-ment.2 The lungs are affected morefrequently in younger adults.

Patients with the pulmonary mani-festations of Goodpasture syndrome present with dyspnea and cough.3

Hemoptysis occurs less frequently. Pul-monary infiltrates are frequently migra-tory, and iron deficiency anemia mayoccur.

The term “migratory” is used to de-scribe recurrent pulmonary infiltratesthat appear and resolve over a short pe-

riod (days to weeks), with new infiltratesdeveloping elsewhere in the lungs. Theinfiltrates thus appear to move or “mi-grate” through the lungs over time.

Pulmonary function testing in pa-tients with Goodpasture syndromeshows an elevated diffusing capacityfor carbon monoxide. The lung is morelikely to be affected if there is an-tecedent parenchymal injury caused byfactors such as infection or, more fre-quently, cigarette smoking. Constitu-tional symptoms of fatigue, weight lossand fever are rare and often suggest analternate cause such as vasculitis.

A diagnosis of Goodpasture syn-drome is based on the findings of testsfor antiglomerular basement membraneantibodies and from a renal biopsy. Thebiopsy will show linear IgG depositsalong the glomerular basement mem-brane, which are pathognomonic forthe disorder (Figure 3B). Treatmentconsists of high-dose prednisone andcyclophosphamide therapy in combina-tion with plasmapheresis. However,limited evidence is available to supportthis treatment.4 Long-term outcomesfor Goodpasture syndrome depend onthe initial degree of renal impairmentand the severity of histologic findings.

Three learning points arise from thiscase. First, pulmonary hemorrhage isan important cause of severe anemiaand should be considered in the differ-ential diagnosis. An absence of hemop-tysis does not rule out significant pul-monary hemorrhage.

Second, relatively small rises in serumcreatinine levels can imply a significant

loss of renal function. Our patient’sserum creatinine level was elevated onlyminimally; his pulmonary symptomswere much more prominent. Therefore,we did not initially consider the possibil-ity of a pulmonary–renal syndrome. Ourexample highlights the importance of rec-ognizing the relatively poor sensitivity ofserum creatinine levels for detecting earlyreductions in glomerular filtration rate inacute kidney injury. Serum creatinine lev-els change little when the glomerular fil-tration rate is reduced from 120 mL/minto 90 mL/min. But it rises significantlywith a reduction in the glomerular filtra-tion rate from 90 mL/min to 60 mL/min.Therefore, clinicians should consider di-rectly assessing the glomerular filtrationrate by measuring creatinine clearancewhen any uncertainty exists about the sig-nificance of the serum creatinine value.

Third, urinalysis should be includedin any assessment because it is fast, in-expensive and often informative. Wewould have been more likely to con-sider a pulmonary–renal syndrome inour patient’s case had we been aware ofthe microscopic hematuria.

In short, pulmonary hemorrhageshould be considered in any patientpresenting with recurrent pulmonaryinfiltrates, particularly if there is unex-plained anemia.

Diagnostic testing

Considerations when selecting a diag-nostic test include not only the relevanceof the result to the clinician’s ability torule in or out important diagnostic hy-

Figure 3: (A) A renal biopsy specimen stained with silver methenamine showing prolif-erating epithelial cells in a crescent form within the glomerulus (arrow), the character-istic morphology of rapidly progressive glomerulonephritis. (B) Immunofluorescentstain for IgG showing linear staining of the glomerular basement membrane, a sign ofantiglomerular basement membrane antibodies.

What is your call?

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CMAJ • JANUARY 6, 2009 • 180(1) 77

potheses (i.e., probable or life-threaten-ing conditions) and the expense of thetest, but also the ease and speed withwhich the test may be performed. AnHIV test was certainly indicated in thiscase, but the results would not have beenimmediately available for use. A periph-eral blood film would have been helpfulin narrowing the differential diagnosis ifthe patient’s anemia was thought to berelated to hemolysis. However, themarkers of hemolysis were otherwise re-assuring. Urinalysis is an inexpensive,easy and rapid test that allows a clinicianto assess the possibility of a pulmonary–renal syndrome when evaluating a pa-tient with unexplained pulmonary infil-trates. Therefore, it is the next best test.

Computed tomography scanning andbronchoscopy are more expensive pro-cedures that should be considered atsome point to aid in diagnosis but willnot narrow the differential diagnosis asefficiently.

Differential diagnosis: Pneumocystisjiroveci infection is a common oppor-tunistic pulmonary infection in patientswith poorly controlled HIV infection(Table 1). It typically presents with an in-sidious onset of dyspnea, dry cough andconstitutional symptoms associated withbilateral pulmonary infiltrates. In our pa-tient’s case, the absence of risk factorsfor immunocompromise (e.g., long-termcorticosteroid therapy or use of other im-

munosuppressive medications) and thenegative HIV test result ruled out thepossibility of P. jiroveci infection.

Löffler syndrome consists of transientmigratory pulmonary infiltrates that areassociated with peripheral eosinophilia.It originates in the transpulmonary pas-sage of helminth larvae, most notably as-cariasis. Our patient was an unlikely can-didate for this diagnosis given theabsence of peripheral eosinophilia and alack of risk factors for parasitic infection.

Patients with the pulmonary mani-festations of Churg–Strauss syndromeclassically present with severe, refrac-tory asthma-like symptoms. The ab-sence of typical clinical features or peripheral eosinophilia, together withthe negative test result for antineu-trophil cytoplasmic autoantibodies,ruled out this diagnosis.

Cryptogenic organizing pneumoniais an inflammatory disorder of thesmall airways, alveolar ducts and alve-oli that frequently mimics community-acquired pneumonia in its presentation.It is a diagnosis of exclusion. The pul-monary hemorrhage that we found onbronchoalveolar lavage confirmed analternate diagnosis of diffuse alveolarhemorrhage.

Ewan C. Goligher MDDepartment of MedicineAllan S. Detsky MD PhDDepartment of Medicine andDepartment of Health PolicyManagement and Evaluation

University of TorontoToronto, Ont.

REFERENCES1. Bolton WK. Goodpasture’s syndrome. Kidney Int

1996;50:1753-66.2. Donaghy M, Rees AJ. Cigarette smoking and lung

hemorrhage in glomerulonephritis caused by au-toantibodies to glomerular basement membrane.Lancet 1983;2:1390-2.

3. Ball JA, Young KR Jr. Pulmonary manifestationsof Goodpasture’s syndrome, antiglomerular base-ment membrane disease and related disorders.Clin Chest Med 1998;19:777-91.

4. Levy JB, Turner AN, Rees AJ, et al. Long-termoutcome of anti-glomerular basement membraneantibody disease treated with plasma exchange andimmunosuppression. Ann Intern Med 2001;134:1033-42.

This article has been peer reviewed.

Competing interests: None declared.

Table 1: Differential diagnosis of Goodpasture syndrome

Condition Characteristics

Pneumocystis jiroveci infection

Occurs in immunocompromised patients. Patients may present with subacute onset of cough, dyspnea, hypoxemia and bilateral pulmonary infiltrates in a “bat wing” distribution. Often associated with an elevated serum lactate dehydrogenase level. Diagnosis is based on microscopic examination of samples of bronchoalveolar lavage fluid.

Goodpasture syndrome

Pulmonary–renal syndrome characterized by rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. Pulmonary symptoms accompanied by acute renal failure or hematuria (gross or microscopic) should raise clinical suspicion. Patients are typically younger adults and frequently report a history of cigarette smoking.

Löffler syndrome

The transpulmonary passage of helminth larvae produces a prototypical syndrome of transient pulmonary infiltrates and peripheral blood eosinophilia. Ascaris lumbricoides infection is the most common cause worldwide; hookworms and Strongyloides stercoralis may also produce the syndrome. Patients frequently complain of an irritating, nonproductive cough and burning substernal discomfort aggravated by coughing or deep breathing. Sometimes dyspnea, wheezing and blood-tinged sputum occur.

Churg–Strauss syndrome

Small-vessel vasculitis mediated by antineutrophil cytoplasmic autoantibodies that is associated with peripheral eosinophilia. It causes a clinical syndrome affecting the skin, joints, heart and peripheral nerves. It is also a well-described cause of pulmonary–renal syndrome. Patients with pulmonary disease classically present with severe, refractory asthma-like symptoms. Pulmonary hemorrhage is unusual.

Cryptogenic organizing pneumonia

Idiopathic inflammatory process of the small airways and alveoli. By definition, it is the pathologic equivalent of bronchiolitis obliterans with organizing pneumonia (BOOP), which occurs in the setting of underlying infectious or immune disorders. Clinical presentation frequently mimics that of community-acquired pneumonia. Pulmonary infiltrates are frequently migratory and usually occur bilaterally in peripheral lung zones. Diagnosis relies on characteristic histopathologic changes in a lung biopsy sample in the absence of any known secondary causes.

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