Disseminated rhodococcus equi infection in HIV infection despite highly active antiretroviral therapy

In April 2002 a 49 year-old HIV-infected woman was admitted to hospital for persistent fever above 38°C and cough (Table 1). She had started HAART with didanosine, lamivudine and indinavir in October 2001,when her CD4+ cells count was 118/μL, and 2 months later had developed brain and brain stem vasculitis-like contrast-enhancing, white matter lesions, consistent with immune reconstitution central nervous system (CNS) manifestations, for which she did not receive any treatment.

At the time of admission in April, CD4+ cell count was 123/μL and HIV-RNA was undetectable. Chest X-ray showed a nodular opacity in the left upper lobe and R. equi was cultured in blood and sputum, leading to a diagnosis of R.equi pneumonia. Intravenous treatment with vancomycin, imipenem, ceftriaxone and ciprofloxacin was started, along with oral prednisone (75 mg qd for 8 days, then tapered in 20 days) for a concomitant, likely HIV-related, severe thrombocytopenia. In May 2002, the patient presented with generalized seizures. Brain magnetic resonance imaging (MRI) confirmed the presence of the known vasculitis-like lesions, still contrast enhancing, but also showed an extracranial abscess, which was surgically removed and from which R. equi was cultured. Intravenous antibiotic treatment was continued for a total of 8 weeks, then the patient received oral ciprofloxacin and chlarithromycin for the following 15 weeks. In July 2002 patient's respiratory symptoms resolved, CD4+ cells count was 161/μL and HIV RNA 10,800 c/ml (patient had discontinued therapy in May because of diarrhoea and resumed same HAART in June), chest X-ray and CT scan showed complete regression of the lung nodules. Because of new onset of cognitive symptoms, and persistence of the contrast-enhancing vasculitis-like brain lesions, oral prednisone was started at 1 mg/Kg and gradually tapered for a total of five months.

In December 2002, about 20 weeks after interruption of anti-rhodococcal treatment, patient developed anisocoria, right hemiparesis, hypoaesthesia, hypopallaesthesia, and dysmetria. At MRI, the known white matter lesions were still present but no longer contrast enhancing (Figure 1a), however, the exam showed two new contrast-enhancing nodular lesions, surrounded by oedema (Figure 1b, c). Cerebrospinal fluid (CSF) examination was unremarkable, no bacteria, mycobacteria and fungi were cultured, cryptococcal antigen and Epstein-Barr virus DNA were undetectable. Antitoxoplasmic treatment was given empirically for 3 weeks, without improvement of clinical conditions, and followed by enlargement of the nodular lesions at MRI (Figure 1d-f). In the suspect of brain rhodococcosis, intravenous treatment with ciprofloxacin, vancomycin and ceftriaxone was given for 3 weeks, together with oral prednisone, followed by resolution of focal symptoms and improvement of MRI lesions. During the following years, severe neurological impairment with gait impairment persisted, the patient developed progressive dementia and was admitted to a long-term medical facility. Follow-up brain MRIs documented the disappearance of the abscesses, persistence of the vasculitis-like lesions and development of cerebral atrophy. Patient changed HAART for toxicity many times, and her immunovirological situation remained stable. She did not develop rhodococcosis relapses or other opportunistic complications, but died in December 2010 for ischemic cardiac events.

A 45 year old, HIV-infected woman, with a history of breast carcinoma successfully treated with quadrantectomy and local radiotherapy, presented in May 2005 with low-grade fever (below 38°C), cough and dyspnea (Table 2). She was off HAART since 2000, her CD4+ cells count was 133/μl and HIV RNA 40,700 c/ml. She was on cotrimoxazole as primary P. jiroveci pneumonia prophylaxis. Chest X-ray and CT scan showed a 5 cm pulmonary nodule in the upper right pulmonary lobe (Figure 2a, b). R. equi was isolated from expectorate and, based on the results of antibiogram, patient received 2 weeks of intravenous rifampicin, levofloxacin and azythromicin, followed by 8 weeks of oral levofloxacin and azythromicin. HAART with lamivudine, tenofovir and efavirenz was also started. Respiratory symptoms resolved with progressive reduction of the pulmonary lesions. In August, CD4+ cells count was 60/μl and HIV RNA was undetectable (<50 c/ml). During the following years, patient adherence to HAART remained poor until she stopped treatment in 2008. Her CD4+ cells count always remained below 200/μl, nevertheless, she neither experience respiratory diseases nor any other HIV-related manifestations.

In the summer of 2009, 4 years after R. equi pneumonia, patient reported a weight loss of 10 Kg in 3 months and low-grade fever, and noticed a subcutaneous, non painful nodule in the right thigh. CD4+ cells count was 90/μL and HIV RNA 78,650 c/mL. An MRI of the tight lesion was highly suggestive for a neoplastic lesion, with necrosis and inflammation (Figure 2c, d), which prompted a diagnostic work-up for tumor identification and staging. A CT scan showed multiple abdominal enlarged lymph nodes, and a 18-fluodeoxyglucose (FDG) PET/CT scan showed increased metabolic activity of the thigh lesion, colon and spleen (Figure 2e). However, a needle biopsy of the thigh nodule demonstrated a non necrotic granuloma, from which R.equi was cultured. A colonoscopy showed a polipoid, stenotic lesion, which histologically disclosed a picture of malakoplakia, with the presence of microorganisms with morphology and staining features consistent with R.equi. Based on the antibiogram, azythromicin, levofloxacin and ryfampicin was started in September 2009. HAART with tenofovir, emtricitabine and atazanavir was introduced 1 month later, with rifampicin replaced by rifabutin, followed by prompt virological response, but no significant CD4+ cells increase.

During the following weeks, patient's conditions continued to worsen, with further weight loss, fever persistently above 38°C, and onset of dyspnea, ascites and diarrhoea. An abdominal MRI showed a 4 cm wide lesion of colon and a 3 cm wide lesion in perisplenic peritoneum; abdominal, celiac, para-hepatic and para-aortic enlarged lymph nodes of 1-2 cm of diameter, peritoneal and pleural effusion, while a chest high resolution CT scan showed multiple lung consolidations. In November, antibiotic treatment was switched to imipenem and amikacin, whilw HAART was modified with atazanavir replaced by darunavir/ritonavir, followed by significant clinical improvement and reduction of both dimension and metabolic activity of the thigh lesion and abdominal lymph nodes, as documented by conventional CT and 18-FDG PET/CT scans. After 3 weeks, treatment was replaced by oral levofloxacin and azythromicin. Remarkably, a new gastric hypercaptation was noted at 18-FDG PET/CT scan. In January 2010, the patient received extracorporeal lithotripsy for nephrolithiasis, possibly consequent to granulomatosis-associated hypercalciuria. At this time there was no longer evidence of the thigh lesion.

In February 2010, after 10 weeks of anti-rhodococcal oral therapy, patient self-suspended antibiotic and antiretroviral therapy for severe gastralgia. An esophago-gastro-duodenoscopy (EGDS) showed esophageal candidiasis and the presence of a large stomach ulceration, which was histologically proved to be a large B cell diffuse lymphoma. CD4+ cells count was 62/μL and HIV-RNA undetectable (<50 c/mL). Patient started proton pump inhibitors and fluconazole.

In March 2010 the patient was admitted to Hospital because of abdominal pain and intestinal bleeding requiring blood transfusion. CT scan showed a solid lesion in the right colon (Figure 2f), surrounded by multiple enlarged lymph nodes, with a radiologic appearance of a colon cancer; colonscopy showed a large mass in the proximal ascending colon, which was biopsied. However, in the following days the patient developed peritonitis and caecal perforation that required emergency laparotomy and right hemicolectomy. Histological examination of a 7 cm wide sessile, centrally excavated, heteroplasia in the ascending colon and of peritoneal lymphonodes showed malakoplakia of the intestine and of perivisceral lymph nodes [23]. A similar histological picture was disclosed by an echo-guided biopsy of a 2.5 cm wide lesion of the chest wall. Patient noticed also the appearance of subcutaneous nodules on her face (Figure 2g) and reappearance of the thigh lesion and R. equi was isolated from both the thigh lesion and blood samples. Based on antibiogram, patient was started again on imipenem, levofloxacin and vancomicin; intravenous azythromicin was added after 3 weeks. Vancomicin was stopped after 4 weeks for severe thrombocytopenia, imipenem replaced by ertapenem after 7 weeks and levofloxacin suspended after 8 weeks. After a total of 14 weeks, intravenous treatment was substituted with oral azythromicin and rifabutin. In June 2010, patient's conditions were improved, with disappearance of the skin lesions, volume reduction of the thigh lesion and lymph nodes at CT scans and no abnormalities in lungs and brain. Multiple biopsies on a control EGDS did not confirm the presence of gastric lymphoma. Despite virological suppression, there was no immunological improvement (74 CD4+ cells count/μL).

In August 2010, patient was admitted to hospital for important headache, CT and MRI disclosed multiple brain contrast-enhancing lesions, associated with cerebral oedema (Figure 2h, i). Intravenous imipenem and amykacin were started together with mannitol and dexamethasone, followed by clinical improvement. Systemic spread of rhodococcosis was excluded by a total body CT scan. After 21 days treatment was changed to meropenem and azythromicin and, after 10 weeks, to ertapenem alone. MRI follow-up showed progressive reduction of cerebral lesions, despite occurrence of seizures in December 2010, for which antiepileptic therapy was started.