Acute Glomerulonephritis Associated with Acute Q Fever: Case Report ...

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Acute Glomerulonephritis Associated with Acute Q Fever: Case Report and Review of the Renal Complications of Coxiella burnetii Infection Tony M. Korman, Denis W. Spelman, Greg J. Perry, and John P. Dowling

From the Departments of Microbiology and Infectious Diseases, Nephrology, and Pathology, Alfred Hospital, Inner and Eastern Health Care Network, Melbourne, Victoria, Australia

We report a case of acute glomerulonephritis associated with acute Q fever. An abattoir worker with a nonspecific febrile illness and pneumonia and abnormal liver function test results developed hematuria, proteinuria, and acute renal failure that resolved with appropriate antimicrobial therapy. Renal biopsy demonstrated diffuse proliferative and exudative glomerulonephritis. Serological tests confirmed recent infection with Coxiella burnetii, with a fourfold rise in the titer of phase II antibody, positive phase II IgM antibody, and negative phase I antibody. Other known causes of glomerulonephritis were excluded. Most reports of renal complications of C. burnetii infection describe glomerulonephritis associated with endocarditis due to chronic Q fever. Renal involvement in patients with acute C. burnetii infection has been rarely described. Glomerulonephritis should be recognized as a complication of acute C. burnetii infection and endocarditis due to chronic Q fever.

Q fever is a widely distributed zoonosis caused by Coxiella burnetii. Acute C. burnetii infection usually presents as a nonspecific febrile illness, atypical pneumonia, or hepatitis [1]. A variety of neurological syndromes associated with acute Q fever, including meningoencephalitis, have been reported [2]. Other reported complications of acute Q fever include hemolytic anemia, thyroiditis, pericarditis, myocarditis, mesenteric lymphadenopathy, pancreatitis, and epididymoorchitis [1]. The major form of chronic Q fever is endocarditis, while other manifestations include bone infection, chronic lung infection, and hepatitis [1]. Glomerulonephritis is a well-recognized complication of endocarditis due to chronic Q fever [3 – 12], but renal involvement in patients with acute C. burnetii infection has been rarely described [13, 14]. We report a case of acute glomerulonephritis associated with acute Q fever and review the literature regarding the renal complications of C. burnetii infection.

Case Report A 40-year-old previously well man presented with a 3-day history of fever, rigors, sweats, lethargy, myalgias, and macroscopic hematuria. He worked in an abattoir and had direct contact with meat carcasses; he had not been vaccinated against Q fever. In the previous month, three co-workers had developed Q fever. The hemoglobin level, total leukocyte count, and platelet count were normal, and examination of blood film showed

Received 30 June 1997; revised 3 September 1997. Reprints or correspondence: Dr. Tony M. Korman, Department of Microbiology, Monash University, Clayton, Victoria 3168 Australia. Clinical Infectious Diseases 1998;26:359–64 q 1998 by The University of Chicago. All rights reserved. 1058–4838/98/2602–0016$03.00

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40% neutrophils, 40% band forms, and toxic granulations. The serum urea level, creatinine level, electrolyte levels, and results of liver function tests (LFTs) were normal. The erythrocyte sedimentation rate (ESR) was 15 mm/h, and the C-reactive protein (CRP) level was 89 mg/L (normal value, õ10 mg/L). Urine microscopy revealed ú1 1 109 dysmorphic erythrocytes/L and no leukocytes. A routine urine culture for bacteria yielded no growth. Evaluation of a 24-hour urine collection revealed a creatinine clearance of 1 mL/s (normal range, 1.5 – 2.5 mL/s) and a total protein excretion of 0.77 g. Ultrasonography demonstrated that both kidneys were enlarged (length, 14 cm) without evidence of obstruction and that the liver and spleen were normal. Staphylococcus epidermidis was isolated from three of eight blood culture bottles, and therapy with flucloxacillin (1 g q6h iv) was commenced 2 days after presentation. The S. epidermidis isolates had differing colonial morphologies and antimicrobial susceptibilities, but all isolates were susceptible to flucloxacillin. The isolates were not available for further genotypic studies to investigate possible clonality of the organisms. There were no clinical signs of infective endocarditis, and no vegetations or valvular abnormalities were detected on a transthoracic echocardiogram. Percutaneous renal biopsy was performed 3 days after the initial presentation, and histopathologic examination revealed diffuse proliferative and exudative glomerulonephritis (figure 1). No segmental necrotizing lesions, subepithelial deposits, or membrane reduplication was seen. Immunohistochemical analysis demonstrated widespread light staining of the mesangium and arterioles with IgM antibody and faint staining of the mesangium with IgA and IgG antibodies. Staining for C3, C4, C1q, and fibrinogen was negative. Electron microscopy revealed leukocytic accumulation within the glomerular capillary loops, occasional mesangial deposits, widespread effacement of foot processes, and endothelial swelling.

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Figure 1. Renal biopsy specimen from a patient with acute Q fever that demonstrates diffuse proliferative and exudative glomerulonephritis. There is glomerular hypercellularity with endocapillary proliferation and moderate accumulation of mononuclear leukocytes in capillary loops (Silver-Masson stain; original magnification, 1 400).

Eight days after presentation (5 days after renal biopsy), acute renal failure developed. Laboratory studies disclosed the following values (normal ranges): serum sodium, 131 mmol/L (135 – 145 mmol/L); potassium, 4.4 mmol/L (3.5 – 5.0 mmol/L); chloride, 103 mmol/L (98 – 110 mmol/L); bicarbonate, 17 mmol/L (22 – 32 mmol/L); urea, 37.2 mmol/L (2.0 – 8.5 mmol/L); and creatinine, 0.88 mmol/L (0.07 – 0.13 mmol/L). The hemoglobin level and leukocyte count were normal; however, the platelet count was reduced to 82 1 109/L. The ESR was 60 mm/h, and the CRP level was 159 mg/L. LFTs disclosed the following abnormal values (normal values): bilirubin, 45 mmol/L (õ21 mmol/L); g-glutamyltransferase, 367 U/L (õ60 U/L); alkaline phosphatase, 253 U/L (õ110 U/L); alanine transaminase, 50 U/L (õ40 U/L) (the aspartate transaminase level was normal); and serum albumin, 19 g/L. The activated partial thromboplastin time was prolonged at 37 seconds (normal range, 25 – 35 seconds), and the international normalized ratio was 1.4. An enzyme-linked immunoassay (Medical Innovations Limited, Artamon, New South Wales, Australia) did not reveal IgG antibody to cardiolipin. Cold agglutinins were not detected. Levels of the serum complement components C3 and C4 were normal. Flucloxacillin therapy was ceased after 4 days, and a single dose of vancomycin (1 g iv) was administered. The patient was transferred to our institution for possible commencement of dialysis. He remained lethargic and had developed a nonproductive cough. Physical examination revealed a temperature of 387C and right basal chest crackles. No other significant abnormalities were detected; in particular, there was no splenomegaly. A chest roentgenogram revealed left perihilar consolidation, and a chest CT scan demonstrated lingular consolidation and small bilateral pleural effusions; an abdominal CT scan was unremarkable. Therapy with ceftriax-

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one (1 g daily iv) and metronidazole (500 mg q8h iv) for bacterial pneumonia was commenced; in addition, doxycycline (100 mg b.i.d. orally) for empirical treatment of infections due to ‘‘atypical’’ pathogens (e.g., Chlamydia species and Mycoplasma pneumoniae), including zoonoses such as Q fever and leptospirosis, was administered. He became afebrile within 72 hours; however, a repeated chest roentgenogram showed new right lower lobe consolidation. Therapy with ceftriaxone and metronidazole was ceased, and treatment with imipenem/cilastatin (250 mg q12h iv) was administered for 3 days. His respiratory symptoms gradually abated, and his renal function gradually improved; dialysis was not required. Doxycycline therapy was continued for a total of 4 weeks. Two months later, he was well, and results of examination of a blood film, chest roentgenography, urinalysis, and LFTs; the CRP level; and his renal function had all returned to normal. Six months after the initial presentation, he remained well. Investigations for the etiology of the febrile illness, pneumonia, and glomerulonephritis were performed. Serum protein immunoelectrophoresis revealed no abnormalities, and the serum IgA level was normal. Antinuclear and antineutrophil cytoplasmic antibodies were not detected. Titers of antibodies to streptolysin O and streptococcal DNase B were normal. Antibodies to hepatitis B surface antigen, hepatitis C antigen, and HIV were not detected. No diagnostic rises in titers of antibodies to Brucella species, Chlamydia psittaci, locally prevalent Leptospira serovars, Legionella, and M. pneumoniae in acute- and convalescent-phase serum samples were detected by serological testing. Culture of urine specific for leptospires was negative. A CF test for C. burnetii demonstrated a titer of total phase II antibodies in an acute-phase serum sample of 1:20 and a titer of total phase II antibodies in a convalescent-phase serum sample taken 2 months after the initial presentation of ú1:2,560. Phase I antibodies were not detected. EIA revealed phase II IgM antibodies in both acute- and convalescent-phase serum samples. Discussion and Literature Review This is the second reported case of acute glomerulonephritis associated with acute Q fever that was confirmed by renal biopsy. An abattoir worker with a nonspecific febrile illness and pneumonia for whom results of LFTs were abnormal developed hematuria, proteinuria, and acute renal failure that resolved with appropriate antimicrobial therapy. Renal biopsy demonstrated diffuse proliferative and exudative glomerulonephritis; however, immunohistochemical analysis and electron microscopy did not reveal subepithelial deposits typical of post – streptococcal glomerulonephritis, and there was an insufficient level of IgA antibody in the mesangium to indicate IgA nephropathy. Serology was diagnostic for acute Q fever, with a fourfold rise in the titer of phase II antibody, positive phase II IgM antibody, and negative phase I antibody.

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Renal Complications of Q Fever

Investigations excluded other known infective causes of acute glomerulonephritis and renal failure. S. epidermidis was isolated from three of eight blood culture bottles; however, this organism was not considered to be clinically significant. Although genotyping could not be performed, differing phenotypes and antimicrobial susceptibility patterns suggested that more than one type was present, indicating probable contamination. There were no clinical or echocardiographic features of infective endocarditis. Flucloxacillin therapy has been associated with adverse renal effects; however, reports have described interstitial nephritis rather than a glomerular lesion. Flucloxacillin therapy was administered for only 1 day before the renal biopsy and 4 days before the onset of renal failure; it is unlikely to have contributed to the renal complication. Reviews of Q fever briefly mention renal dysfunction associated with endocarditis due to chronic Q fever and do not refer to renal complications of acute C. burnetii infection [1, 15]. The incidence of renal complications is unknown, since few case series of acute or chronic Q fever have systematically investigated renal abnormalities. Early reports suggested that microscopic hematuria may be uncommon [16, 17]. However, in three studies of endocarditis due to Q fever [8, 18, 19], hematuria was detected in 15 (36%) of 42 patients, although the glomerular origin was not documented. In an Australian series consisting almost exclusively of patients with acute Q fever [20], 67 (61%) of 109 had proteinuria, and 10 (13%) of 80 patients tested had sterile pyuria. Fourteen well-documented cases of renal complications of C. burnetii infection in the English-language literature, including the present case, are summarized in table 1 [3 – 14]; a case of endocarditis due to chronic Q fever that was associated with ‘‘focal glomerulonephritis’’ for which immunofluorescence was negative was not included, because further details were not provided [18]. In 11 cases, glomerulonephritis was associated with endocarditis due to chronic Q fever. In all but one case, positive titers of phase I antibody to C. burnetii were documented. C. burnetii was isolated or detected after death in cases 1 – 4 and was detected in epithelial cells in proximal tubules in case 2. Whittick [21] demonstrated rickettsial organisms in the tubular epithelium, glomeruli, and interstitium of the kidney in a fatal case of Q fever. Vacher-Coponat et al. [10] detected C. burnetii by immunoperoxidase staining of a renal tissue specimen in case 9. Previous investigators could not identify C. burnetii antigen at the glomerular level [5, 9]. Glomerular lesions were classified as focal and segmental proliferative in 3 cases, mesangiocapillary in 2, diffuse proliferative glomerulonephritis in 2, and ‘‘diffuse glomerulonephritis’’ in 1; in two early cases, ‘‘chronic lobular’’ lesions that would now be classified as mesangiocapillary glomerulonephritis were described. The biopsy results reported by Ferguson et al. [4] revealed a pattern suggestive of membranous nephropathy; however, no immunohistological study was reported. Results of immunofluorescence were variable, with granular deposits of IgM and C3 the most common finding.

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Electron microscopy findings reported in three cases included epithelial cell foot process fusion, mesangial deposits, and subendothelial deposits. Antimicrobial therapy included tetracycline compounds in nine cases and ciprofloxacin in one case; however, renal function improved only in three cases. Five patients died, two patients had persistent renal dysfunction, and the outcome was not reported in one case. As other investigators have noted [7, 9], one patient (case 3) was also positive for antibodies to hepatitis B surface antigen, and the etiology of glomerulonephritis in this case is uncertain. Apart from the present case, there are only two other reported cases of renal complications associated with acute Q fever. Morovic et al. [13] described a case (no. 12) of acute renal failure in a man from a region of endemicity for Q fever who had a febrile illness, pneumonia, and a skin rash. Therapy with oral b-lactam antibiotics was administered for 5 days with little improvement. Phase I antibodies were negative, and indirect immunofluorescence and ELISA revealed titers of phase II antibody that were ‘‘diagnostic’’ for acute Q fever. There were no pre- or postrenal causes of renal failure, and infection with other organisms that may affect the kidney were excluded, although b-lactam antibiotics are a possible alternative cause of acute renal failure. Proteinuria and hematuria were present; however, renal biopsy was not performed to confirm suspected glomerulonephritis. Acute renal failure resolved spontaneously, and dialysis was not required. Tolosa-Vilella et al. [14] reported a case (no. 13) of acute Q fever complicated by glomerulonephritis and acute renal dysfunction. The serum creatinine level was elevated to 1.9 mg/dL, and urinalysis revealed hematuria and proteinuria. Renal biopsy demonstrated mesangioproliferative glomerulonephritis, and immunofluorescence results were negative; electron microscopy was not reported. Titers of phase I antibody were negative, and there was a diagnostic rise in titers of phase II antibody; IgG antibodies to cardiolipin and lupus anticoagulant were detected in acute-phase serum samples and were negative 3 months later. Therapy with amoxicillin/clavulanate was administered empirically for 6 days without clinical improvement. Renal function progressively improved, although hematuria and proteinuria persisted after almost 2 years. These investigators mentioned other cases of acute renal failure associated with acute Q fever that were reported in the non-English literature, including two cases with proteinuria in which renal biopsies were not performed. C. burnetii is an intracellular pathogen that lives in an acidic vacuole in eukaryotic cells [1]. The pathogenesis of Q fever, in particular acute infection, is little understood, because of the self-limiting nature of the illness and low mortality rates [15]. Examination of biopsy specimens obtained during acute C. burnetii infection shows a major inflammatory response but few organisms [1]. The pathogenesis of glomerulonephritis in patients with chronic Q fever has been attributed to immune complex deposition [8], a mechanism consistent with granular deposits demonstrated by immunofluorescence of renal biopsy specimens.

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Table 1. Details of reported cases of renal complictions of Coxiella burnetii infection.

Titer* of antibody to C. burnetii Case no. [reference(s)]

Age (y)/sex

Q fever: acute or chronic/ complication(s)

Phase I

Phase II

1 [3]

48/M

Chronic/endocarditis

1:64

1:256

2 [4]

48/M


1:3,200 to 1:6,400

1:3,200 to 1:6,400

3 [5]

58/M


1:640

1:640‡

4 [6, 7]

40/F


1:5,120

1:10, 240, IgM not detected

5 [8] 6 [9]

63/M 33/M

Chronic/endocarditis Chronic/endocarditis

1:128 1:512

NR 1:4,096

7 [9]

38/M


NR

1:4,096

8 [9]

37/F


1:4,096

1:2,048

9 [10]

69/M


Initial: IgG, 1:51,200; IgA, 1:1,600; IgM, 1:1,600; posttreatment: IgG, 1:6,400; IgA, 1:100; IgM, 1:25

Initial: IgG, 1:51,200; IgA, 1:1,600; IgM, 1:1,600; posttreatment: IgG, 1:12,800; IgA, 1:100; IgM, 1:50

10 [11]

28/F


Initial: 1:5,120; 3 mo later: 1:5, 120§

11 [12]

41/F

Chronic/endocarditis, mixed cryoglobulinemia

Initial: ú1:4,096; 8 mo later: ú1:4,096

ú1:4,096x

12 [13]

32/M

Acute/pneumonia, skin rash

Negative

Positive

13 [14]

31/M

Acute/hepatitis

õ1:32

Acute phase: 1:160; convalescent phase: 1:10,240#

14 [PR]

40/M

Acute/pneumonia, hepatitis

õ1:10

Acute phase: 1:20; convalescent phase: ú1:2,560, IgM detected

NOTE. IF Å immunofluorescence; ND Å not done; NR Å not reported; PR Å present report. * CF test except indirect IF for cases 9 – 11. Method not stated for cases 6 – 8. † Rickettsia-like organisms detected in epithelial cells in proximal tubules. ‡ Also positive for antibody to hepatitis B surface antigen. § Antibodies not specified as phase I or phase II. x Serum cryoglobulin levels elevated. # Antibodies to phospholipids detected.

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Table 1. (Continued ) Renal biopsy finding Classification of glomerulonephritis: histopathology

Electron microscopy

IF

Antimicrobial therapy

Outcome

‘‘Chronic lobular (Ellis type II)’’

NR

NR

Penicillin, tetracycline

‘‘Chronic lobular’’: generalized diffuse basement membrane thickening, endothelial cell proliferation†

NR

NR

Penicillin, tetracycline

Mesangiocapillary: endothelial and mesangial cell proliferation, glomerulosclerosis

IgG, IgA, and C3 granular pattern

Co-trimoxazole

Mesangiocapillary: diffuse mesangial and capillary loop thickening

IgM, C3

Mesangial deposits, epithelial cell foot process fusion NR

‘‘Diffuse glomerulonephritis’’ Focal and segmental proliferative: increased mesangial matrix

NR NR

NR Doxycycline, lincomycin

NR

Streptomycin, penicillin, doxycycline

Death

NR

Co-trimoxazole, doxycycline

Renal function improved

Focal and segmental proliferative: mesangial proliferation, deposits within double contours of basement membrane Diffuse proliferative: increased mesangial cells, capillary loop leukocytes

NR IgM and C3 granular deposits IgM and C3 granular deposits IgM, C3, C4, and C1q granular deposits IgG, IgM, C1q, and C3 diffuse deposits IgM and C3 granular deposits

NR

Chloroquine, doxycycline


Tetracycline, lincomycin

ND

ND

Foot process fusion, subendothelial deposits ND

Ciprofloxacin

Clinical condition improved, persistent hematuria Renal function improved

ND

ND

ND

b-Lactam agents


Mesangioproliferative, focal and segmental: mesangial hypercellularity Diffuse proliferative and exudative: endocapillary proliferation, capillary loop leukocytes

Negative

NR

Amoxicillin/clavulanate


IgM, IgA, IgG

Mesangial deposits, foot process effacement, endothelial swelling

Flucloxacillin, vancomycin, ceftriaxone, metronidazole, doxycycline, imipenem/cilastin


Focal and segmental proliferative: increased mesangial matrix Diffuse proliferative

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Tetracycline, lincomycin

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Death; postmortem: C. burnetii isolated Death; postmortem: C. burnetii isolated from aortic valve, liver, and kidney Death; postmortem: C. burnetii isolated Death; postmortem: C. burnetii detected NR Persistent renal dysfunction

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Tetracycline compounds, especially doxycycline, are recommended as treatment of acute Q fever [22]. In the report by Tolosa-Vilella et al. [14], the improvement in renal function was not attributed to treatment with b-lactam antibiotics. In the present case, acute renal failure resolved with appropriate antimicrobial therapy. Long-term treatment with combinations of doxycyline and fluoroquinolones is recommended for chronic Q fever [22]. The disappointing results of treatment of glomerulonephritis associated with endocarditis due to chronic Q fever reflect the poor prognosis of those cases, which are often diagnosed late in the course of the illness. Prevention of Q fever involves vaccination and avoidance of contact with infected animals. Vaccines against phase I organisms provide effective immunity [23, 24] and should be administered to at-risk populations such as abattoir workers, veterinarians, and dairy farmers [1]. C. burnetii infection should be considered in the differential diagnosis of acute glomerulonephritis and renal failure, particularly in patients with accompanying pneumonia or in high-risk individuals such as abattoir workers.

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7. Uff JS, Evans DJ. Mesangiocapillary glomerulonephritis associated with Q fever endocarditis. Histopathology 1977; 1:463 – 72. 8. Turck WPG, Howitt G, Turnberg LA, et al. Chronic Q fever. Q J Med 1976; 178:193 – 217. 9. Perez-Fontan M, Huarte E, Tellez A, Rodriguez-Carmona A, Picazo ML, Martinez-Ara J. Glomerular nephropathy associated with chronic Q fever. Am J Kidney Dis 1988; 11:298 – 306. 10. Vacher-Coponat H, Dussol B, Raoult D, Casanova P, Berland Y. Proliferative glomerulonephritis revealing Q fever. Am J Nephrol 1996; 16: 159 – 61. 11. Rosman MS, Lubbe WF, Hayden M, Basson N, Uys CJ. Q fever endocarditis: a report of 2 cases. S Afr Med J 1978; 53:296 – 300. 12. Enzenauer RJ, Arend WP, Emlen JW. Mixed cryoglobulinemia associated with chronic Q fever. J Rheumatol 1991; 18:76 – 8. 13. Morovic M, Dzelalija B, Novakovic S, Stankovic S, Dujella J. Acute renal failure as the main complication of acute infection with Coxiella burnetii [letter]. Nephron 1993; 64:335. 14. Tolosa-Vilella C, RodrıB guez-Jornet A, Font-Rocabanyera J, AndreuNavarro X. Mesangioproliferative glomerulonephritis and antibodies to phospholipids in a patient with acute Q fever: case report. Clin Infect Dis 1995; 21:196 – 8. 15. Reimer LG. Q fever. Clin Microbiol Rev 1993; 6:193 – 8. 16. Grist NR. Q fever endocarditis. Am Heart J 1968; 75:846. 17. Robson AO, Shimmin CDGL. Chronic Q fever: clinical aspects of a patient with endocarditis. BMJ 1959; 2:980. 18. Tobin MJ, Cahill N, Gearty G, et al. Q fever endocarditis. Am J Med 1982; 72:396 – 400. 19. Wilson HG, Neilson GH, Galea EG, Stafford G, O’Brien MF. Q fever endocarditis in Queensland. Circulation 1976; 53:680 – 4. 20. Spelman DW. Q fever: a study of 111 consecutive cases. Med J Aust 1982; 1:547 – 53. 21. Whittick JW. Necropsy findings in a case of Q fever in Britain. BMJ 1950; 1:979. 22. Raoult D. Treatment of Q fever. Antimicrob Agents Chemother 1993; 37: 1733 – 6. 23. Marmion BP, Ormsbee RA, Kyrkou M, et al. Vaccine prophylaxis of abattoir-associated Q fever: eight years experience in Australian abattoirs. Epidemiol Infect 1990; 104:275 – 87. 24. Ackland JR, Worswick DA, Marmion BP. Vaccine prophylaxis of Q fever. A follow-up study of the efficacy of Q-Vax (CSL) 1985-1990. Med J Aust 1994; 160:704 – 8.

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