A 44-year-old Argentinean female with a 1-year history of arthritis and malaise was admitted to the hospital in April 2007 with fever, asthenia, and edema. The patient had previously suffered untreated high blood pressure and had been diagnosed with T. cruzi infection 20 years before admission.
Epidemiologically, the patient came from the Misiones province of northern Argentina, an endemic region for CD, and arrived in Spain 5 years before admittance. She never lived in a mud house, which is a risk factor for CD, but 25 years before admittance, she received a blood transfusion during her first delivery. In this case, the infection might have been caused by vector-borne transmission and/or by blood infected by T. cruzi that she received 25 years ago in a transfusion. Until April 2006, she remained asymptomatic, had not been followed-up for T. cruzi infection, and had never received specific treatment. The patient was admitted in our hospital from April 26 to May 5, 2007. At admission, abnormal laboratory values included leucopenia (3.5 × 109/L), low hemoglobin (83 g/L), and increased erythrocyte sedimentation rate (90 mm/hour), whereas C-reactive protein was normal (1 mg/dL). In addition, elevated urea (110 mg/dL), and creatinine (3.2 mg/dL) were detected. Urine analysis showed cloudy urine with proteinuria (2,165 mg/24 hours), a white cell count of 15–20 per high-power field (HPF), granular casts (1–2/HPF), and many erythrocytes. Autoantibody screening showed high titers of antinuclear antibodies (1:640) with a homogeneous pattern and antibodies against double-stranded DNA (dsDNA) up to 200 U/mL (normal range = 0.0–19.9). There were also low complement titers of C4 (< 0.07 g/L; normal range = 0.11–0.45), C3 (0.262 g/L; normal range = 0.820–1.870), and CH50 (2 U/mL; normal range = 34–71). Antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies, were negative.
Kidney biopsy showed diffuse lupus nephritis class IV-G (A) with an activity index of 10/24 and a chronicity index of 5/12. A diagnosis of SLE with active lupus nephritis was made, and treatment with three pulses of methylprednisolone (1 g/day for 3 days followed by prednisone at 1 mg/kg/day slowly tapered) was started on April 27, 2007. It was followed by monthly intravenous cyclophosphamide (IVC; 750 mg/m2
of body surface) for 6 months (from May to October 2007).
A control electrocardiogram (EKG) was normal, but echocardiography showed a concentric hypertrophy of the left ventricle, dilatation of the right atrium, mild tricuspid insufficiency, and mild pulmonary hypertension, probably caused by chronic hypertension.
Also at admission (April 2007), the patient was confirmed to be positive for T. cruzi
infection using two different serological enzyme-linked immunosorbent assay (ELISA) tests: ELISAr with a ratio of 8.3 (BioELISA Chagas, Biokit S.A., Lliçà d'Amunt, Barcelona, Spain with recombinant antigens) and ELISAc with a ratio of 153 (an in-house ELISA with whole T. cruzi
(). ELISA by Biokit was carried out following the instructions of the manufacturer. A cut-off was calculated by adding 0.300 to the mean absorbance of the negative control. The results are recorded as follows: positive, absorbance ratio sample/cut-off ≥ 1; negative, absorbance ratio sample/cut-off < 0.9; equivocal, absorbance ratio sample/cut-off ≥ 0.9 but < 1.0. For the ELISAc, the reaction was quantified as units (U) related to a positive serum, included in the plates, used as calibrator and arbitrarily set at 100 U. The cut-off was established at 20 U.
Serological and parasitological results for T. cruzi infection after treatment with benznidazole and posaconazole
In this context, after the initial immunosuppressive treatment, weekly clinical and parasitological (polymerase chain reaction [PCR] and thick blood film) follow-ups were made. In May 2007, a real-time PCR (RT-PCR)19
for T. cruzi
was positive (), which led to treatment with benznidazole of 5 mg/kg/day for 60 days starting simultaneously with the IVC treatment. The patient showed no clinical symptoms related to T. cruzi,
and no significant side effects related to benznidazole were detected.
After six monthly pulses of IVC, the patient's symptoms improved, and there was complete response of lupus nephritis (normalization of the plasma creatinine levels and disappearance of hematuria and proteinuria). Six months after the end of benznidazole treatment (February 2008) and before the next round of monthly IVC immunosuppressive treatment, a RT-PCR test for T. cruzi was carried out and was again found to be positive, although the calculated circulating parasite levels were 10–100 times lower than in the pre-benznidazole assay (). Because of the required maintenance of immunosuppressive treatment with azathioprine (100 mg/day orally), the risk of development of neurological or cardiac complications, and the failure of the benznidazole treatment, an off-label treatment with posaconazole (Noxafil oral suspension; Schering Plough Corporation, Kenilworth, NJ) was suggested on a compassionate basis with the agreement of the Spanish Ministry of Health. After informed consent by the patient, a 400 mg per 12 hour for 90 days posaconazole treatment was given, starting 45 days before the start of the new IVC treatment. Posaconazole was well-tolerated, and T. cruzi blood PCR was consistently negative throughout the follow-up interval that was 13 months after the start of posaconazole treatment (nine consecutive negative PCR tests); immunosuppressive treatment was maintained during this time (). After two additional quarterly pulses of IVC and then a switch to azathioprine (100 mg/day), the patient presented normal renal function and no SLE recurrence in January 2010. It should be noted that, despite consistently negative blood PCR tests after posaconazole treatment, the levels of anti-T. cruzi circulating antibodies detected by conventional serology remained essentially unchanged ().
Other drug therapies concomitant with posaconazole treatment included hydroxychloroquine (200 mg/day), enalapril (20 mg/day), atenolol (100 mg/day), omeprazole (20 mg/day), and atorvastatin (40 mg/day). Currently, 2 years after initial diagnosis, the patient continues with prednisone (2.5 mg/day), azathioprine (100 mg/day), hydroxychloroquine (200 mg/day), and calcium plus vitamin D.