Unusual Manifestations of Acute Q Fever

Autoimmune Hemolytic Anemia and Tubulointerstitial Nephritis

Serdal Korkmaz; Nazif Elaldi; Mansur Kayatas; Mehmet Sencan; Esin Yildiz


Ann Clin Microbiol Antimicrob. 2012;11(14) 

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Pneumonia and hepatitis are frequently seen in acute Q fever and there are two additional manifestations in our patient: TIN with acute renal dysfunction and Coombs' positive AIHA. Glomerulonephritis, attributed to immune-complex deposition and a well-recognized feature of chronic form of Q fever, is described less frequently in acute form.[4] Since a small number of cases have reviewed systematically, the incidence of renal complication in Q fever is unknown. In a recent retrospective study performed in 54 acute Q fever patients have demonstrated 33% of patients having renal failure.[5] Acute TIN is an important cause of acute renal failure, and often associated with use of drugs and various infections. Those most commonly implicated are antibiotics (penicillins, cephalosporins, sulfonamides and rifampicin) and non-steroidal anti-inflammatory drugs although cases of TIN have been linked to many medications.[6] Clarithromycin has also been reported previously as an aetiological factor in TIN.[7] Despite using two aetiologic agents (ampicillin and clarithromycin) in the patient for developing TIN, we believe that it has occurred due to Q fever. Firstly, the patient had a history of using any medications before referring to the hospital and he received those antibiotics only for a day before rising blood BUN and creatinine levels. These are unlikely to have contributed to the renal complication. Secondly, extremely lower hemoglobin concentration, a higher bilirubin level and a positive direct Coombs' test on admittance suggesting strongly autoimmune events. The other mechanism for renal involvement by an infection agent is via direct parenchyma infiltration or a systemic inflammatory response against the bacteria. Rickettsial organisms in the tubular epithelium glomeruli and interstitium of the kidney in a fatal case of Q fever have been demonstrated.[8]

Apart from the present case, there are only a few case reports concerning renal complications associated with acute Q fever in the literature in English. A case of acute renal failure in a male patient with acute Q fever who had a febrile illness, pneumonia, and a skin rash was described.[9] The authors reported that there were proteinuria and hematuria in the patient but renal biopsy was not done to confirm suspected glomerulonephritis. They stated that renal failure improved in the patient without dialysis treatment. Korman et al. [10] also reported a male case of acute diffuse proliferative and exudative glomerulonephritis, resolving spontenously, associated with acute Q fever. Antiphospholipid antibodies may also accompanied with acute renal failure in Q fever. Tolosa-Vilella et al. [11] described a case of acute Q fever with mesangioproliferative glomerulonephritis and immunglobulin (Ig) G antibodies to cardiolipin and lupus anticoagulant in acute-phase serum samples. A recent case report has noticed a female patient with postinfectious glomerulonephritis associated with acute form of the disease.[12] Sometimes renal failure in Q fever may not to be related with acute glomerulonephritis or TIN as in our case. A case of acute Q fever associated by extreme rhabdomyolysis and consecutive acute renal failure treated with continuous venovenous hemodiafiltration was presented.[13]

Interaction of C. burnetii with the host's immune system is complex and still poorly understood. Immune control of C. burnetii is T-cell dependent but does not lead to C. burnetii eradication. The organism is able to grow and multiply within phagolysosomes.[14] The expression of antigens specific to C. burnetii in the membranes of infected host cells [15] supports the hypothesis that infected cells are detected by the immune system and lysed by antibody-dependent cellular cytotoxicity by monocytes and other effector cells. Specific immunoglobulins are secreted following infections. IgG is mainly directed against phase II antigen, whereas IgM is directed against both phase I and II cells.[16] Chronic infections are believed to be a result of immunological reactions and/or defects.[14,16] During chronic Q fever, the immune response is ineffective and may also be harmful, causing leucocytoclastic vasculitis and glomerulonephritis.[16] A variety of autoantibodies have been described in Q fever, including antismooth muscle and antimitochondrial antibodies, ANA, rheumatoid factor, and cold agglutinins.[17] All of these autoantibodies were negative in our case.

Seroconversion to C. burnetii develops usually 7–15 days after onset of clinical symptoms, and antibodies against phase I and phase II appear in the blood. The presence of both an anti-phase II IgG titer of ≥1:200 and IgM titer of ≥1:50 is 100% predictive of acute Q fever. However, such results are observed only in 10% of patients during the second week following the onset of symptoms.[18] A clinical and laboratory study which was performed in 22 patients with acute Q fever showed that fifth day serum samples had a sensitivity of 80% in the diagnosis of acute Q fever and sixth to eleventh day serum samples had a sensitivity of 83% by the IFA technique.[19] However, cross-reactivity with other infectious agents such as ChlamydiaBartonella and Legionella species has been observed especially in chronic Q fever.[20–22] Two hundred and eleven serum samples of acute and chronic Q fever by the IFA test revealed that four serum samples (1.9%) had antibodies against both C. burnetii and Legionella pneumophila.[20] More than 50% of patients with chronic Q fever had sera containing cross-reacting antibodies to Bartonella henselae or Bartonella quintana.[21] It has been proposed that a differential diagnosis among the infections is easily established when quantitative antibody titers against both anti-phase I and anti-phase II C. burnetii antigens are determined.[18] Because of its protean manifestations, leptospirosis mimics many other infectious diseases including Q fever with pneumonia and it must also be differentiated from Q fever.[23]

Various mechanisms are responsible for hemolytic anemia in the course of an infection including direct invasion of red blood cell by the pathogen, toxin production, mechanical effects and immune-mediated hemolysis. Immune mechanisms can also be divided into autoimmune, antigen-antibody complexes and polyagglutination reactions.[24] The patient was anemic on admittance and totally 18 units of erythrocyte suspension were administered during the hospitalization period. The negativity of cold agglutinins, positivity of direct and indirect Coombs' tests and a higher reticulocyte count suggested strongly that AIHA occurred due to autoimmune events needing steroid therapy. Warm and cold agglutinins can occur during the infectious and non-infectious events and the most of AIHAs are caused by warm antibodies, whereas cold antibodies are less commonly detected. The direct Coombs' test is the first step in diagnosing of AIHA, and the distinction of warm and cold agglutinins can help in the differential diagnosis of the cause of AIHA. In warm antibody AIHA, standard first line therapy is corticosteroids with or without high dose of immunoglobulin, whereas splenectomy is considered second-line therapy. Patients with cold agglutinins are refractory to steroids and splenectomy.[25] Since the warm and cold agglutinin tests were not available in our institution, these agglutinins could not be identified in the patient for the explaining of the cause of AIHA. Because responded well to the corticosteroid therapy, we think the cause of AIHA is warm agglutinins.

Despite the recommended therapy regimen for Q fever is doxycycline, clarithromycin is a reasonable treatment for acute Q fever.[26] The corticosteroid therapy had two useful effects on our patient. First, it eliminated the autoimmune hemolytic process and therefore, the patient did not need any blood transfusions Second, being useful for inflammatory events, it relieved the renal dysfunction which caused by acute TIN. Additionally, hemodialysis program contributed to control of uremic symptoms in the patient.


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