Disseminated Rhodococcus equi infection in a patient with Hodgkin lymphoma

Introduction. Rhodococcus (R) equi is an opportunistic, uncommon human pathogen that causes mainly infection in immunocompromised hosts. The disease is usually presented as subacute pneumonia that is mostly cavitary and sometimes bacteremic. Case report. We reported the extremly rare case of a 43-year-old woman with Hodgkin lymphoma, who developed R. equi pulmonary infection after recieving multiple courses of chemotherapy. Secondary, the patient developed bacteremia, leading to sepsis and dissemination of R. equi infection in many extrapulmonary sites. At addmission the patient was febrile, tachypnoic, tachycardic, hypotensive, with facial edema, splenomegaly, positive meningeal signs, left hemiparesis and paraparesis. Laboratory data included erythrocyte sedimentation rate (ESR) > 140 mm/h, C-reactive protein (CRP) 143.0 mg/L, red blood cells (RBC) 2.14 × 1012/L, whyite blood cells (WBC) 2.8 × 109/L, lactate dehydrogenase (LDH) 706 U/L, serum albumin 26 g/L, sodium 127 mmol/L and potassium 2.7 mmol/L. Blood culture and culture of sputum and empyema were positive for R. equi. Imaging studies demonstrated a large right cavitary pneumonia and abscess, empyema, pericarditis, mediastinal and intra-abdominal lymphadenopathy, brain and psoas abscesses, osteomyelitis and spondylodiscitis. The patient recovered completely after a 12-month treatment with combinations of parenteral and oral antibiotics (meropenem, vancomycin, teicoplanin, ciprofloxacin, rifampicin, macrolides etc), including drainage of abscesses and empyema. Eight years after completition of the treatment the patient was without recurrence of R. equi infection and lymphoma. Conclusion. Since the eradication od R. equi is very difficult, it is very important to make the diagnosis and initiate appropriate antibiotic therapy as soon as possible.

We reported an extremely rare case of disseminated R. equi infection in a patient with Hodgkin lymphoma who was successfully treated with antibiotics and drainage of abscesses.To the best of our knowledge, this is the first documented case of R. equi infection in Serbia.

Case Report
A 43-year-old woman was admitted to the Clinic for Infectious and Tropical Diseases of Military Medical Academy, Belgrade due to disseminated R. equi infection on April 8, 2004.She became ill on February 2001 with the appearance of fever, malaise and enlarged lymph nodes in the right inguinal region.At that period of time, the patient worked hard as a lawyer, for several months, at a farm near the village she lived in.One year later, a generalized lymphadenopathy occurred and the Hodgkin lymphoma was diagnosed.After 7 cycles of chemotherapy, in October 2002, the patient developed high fever, chills, cough, and severe pain in the right hemithorax.On chest radiography loose shadow in the right lung with pleural effusion was registered.Despite the implementation of various parenteral and peroral antibiotics in a multiple short courses, the progression of acquired pneumonia in the right lung was registered and the permanent deterioration of general condition.
Chemotherapy was discontinued in March 2003.In order to maintain intra-abdominal lymphadenopathy radiotherapy was performed.In the following period, in addition to high temperature and expectoration of the purulent sputum, a pain in the left hip occurred.Computed tomography showed the presence of a large abscess and pneumonia in the right lung, pleural effusion on the right side and paraaortic lymphadenopathy of more than 2 cm.Magnetic resonance imaging registered progressive spondylodiscitis L2/L3 and psoas abscess at the left side (Figure 1).
During July, 2003 pathohistological examination of the material obtained by biopsy of the right pulmonary infiltration showed pulmonary malacoplakia.In late 2003 blood culture and cultures of the sputum and pleural empyema were positive on R. equi.Prolonged use of parenteral antibiotics according to the antibiogram with blood transfusions, human albumin and other replacement therapy resulted in improvement of the patient's general condition, normalization of body temperature and marked regression of the right pulmonary infiltration.However, on February 2004 the patient developed to allergic reaction to vancomycin and soon after, hemolytic anemia occured.By the end of March, new relapse was registred.According to high fever, dizziness, headache, nausea, vomiting, cough, expectoration of purulent sputum, hemoptysis and chest pain, a positive meningeal signs were detected.Computerized tomography (CT) scan showed large nodular lesion with cavitation in right lung.This lesion was in a close contact with the vena cava superior, pericard and right hilus.An oval lesion 10 cm in diameter has also been registred in the basal region of the chest, that was in contact with right chest wall and destruction of left ribs 9 and 10 (Figure 2).A lumbar puncture was not performed because of the presence of lumbar spine abscess collection.At that time the patient was addmitted to the Blood culture and sputum and empyema cultures were positive for R. equi.R. equi was sensitive to macrolides, rif-ampicin, fluoroquinolons, glicopeptids, carbapenems, amikacin and amoxicilin-clavulaxate, but resistentant to cefalosporins, piperacillin-tazobactam, clindamycin, amoxicillin and gentamicin.
Infiltration connected with right hilus and nodular lesion in posterobasal region of the right lung, diameter of 9 cm, were registred on chest radiography examination.Radiography of LS spine showed pathologic fracture of L2 corpus with a wedge-shaped deformation (Figure 3).
Pericardial effusion of 1.4 cm was registred on ehocardiography and splenomegaly of 16 cm on the abdominal ultrasound.CT scan of the brain showed hypodense zones 4 mm in diameter in crus posterior of the right capsula interna and left olive, which did not change their caracteristics after intravenous addmission of the contrast.
Immediately after addmission the therapy with meropenem and rifampicin started.After 7 days ciprofloxacin and amikacin were added.After 14 days amikacin was excluded and teicoplanin was added (Table 1).During the first month the patient recieved immunoglobulins, human albumin, fresh A combined antibiotic treatment was continued also including meropenem, ciprofloxacin, vancomycin, rifampicin, trimethoprim-sulfamethoxazole and lincomycin.By the end of August 2004, drainage of abscess collection diameter of 10 cm in the left psoas was performed (Figure 5).A parenteral antibiotical therapy was continiued for six months more and than was changed with peroral antibiotics (rifampicin, azithromycin, roxithromycin, eritromycin, linkomycin, clarithromycin, ciprofloxacin, trimethoprim-sulfamethoxazole) up to 12 months.At discharge from the Clinic, on February 1, 2005, the patient was in good general condition with lumbar pain and normal laboratory values.Four months later, MRI of the lumbar spine showed cured spondylodiscitis L2/L3 with kyphosis deformity.There were no signs of paravertebral infection (Figure 6).
Five months after therapy cessation, CT scan showed scared lesions in basal paracardial regions of the right lung and incapsulated liquid collection 4 cm in diameter in the posterobasal region of the same lung.Mediastinal lymph nodes were not enlarged (Figure 7).
Eight years after treatment cessation the patient was without recurrence of R. equi infection and lymphoma.Meanwhile, fluid collection in the right lung was completely and spontaneously regressed (Figure 8).

Discussion
R. equi is an opportunistic pathogen well described in veterinary science as a causative agent of pneumonia and sepsis in domestic animals, and a leading cause of chronic pneumonia in foals less than six months of age 1,2 .However, its role in the etiology of human diseases is much less known.Human R. equi infection was described in 1967 for the first time in a patient with autoimmune hepatitis, who suffered from cavitary pneumonia after immunosupressive treatment 3 .In the next 15 years only 12 cases of this illness have been reported.After that, the frequency of R. equi in- fection begins to increase along with the increasing number of immunocompromised hosts, particularly the number of AIDS patients 4,[19][20][21] .R. equi has been isolated from almost each specimen and tissue of domestic and wild animals.It has been isolated from soil on 50%-90% farms on each continent, except Antarctic.Concentration of R. equi is especially high in feces of horses.From that reason direct and indirect contact with domestic animals could have an important role in development of human R. equi infection.The infection occurs through inhalation, ingestion and inoculation 1,2,[22][23][24] .We assume that the presented patient acquired R. equi infection most probably by inhalation, working at the farm of horses.However, we are not sure when the infection actually occurred.
Like the other authors, we assume that regional lymphadenitis was caused by dissemination of R. equi infection from the primary focus 20,25 .However, we are not absolutely sure what was the role of R. equi infection in the development of mediastinal and intra-abdominal lymphadenopathy in the presented patient.Namely, chemotherapy of Hodgkin lymphoma was interuppted when the patient had significant mediastinal and intraabdominal lymphadenopathy, and this lymphadenopathy just withdrew after a long-term of a combined antibiotical therapy.This indicates that the most likely cause of lymphadenitis was R. equi.
The most important factor in the development of R. equi infection is impaired cellular immunity.This is confirmed by the results of the study conducted in HIV positive persons, which showed that R. equi infection is more common in patients with blood CD4 + lymphocytes count less than 100/mm 3 .For that reason the disease is more frequent in the patients with AIDS and on immunosuppressive therapy after solid organ or bone marrow transplantation, but very rare in healthy immunocompetent persons 6,7,8,20,26,27 .This explains why there was continuous impairment of lung inflammatory process in the presented patient and why the dissemination of R. equi infection appeared.However, the delayed diagnosis and inadequate antibiotic therapy has also contributed to the frequent relapses and dissemination of the disease.Namely, bacteriemia, relapses and dissemination of the infection also registered after chemotherapy cessation and making the diagnosis.According to data from the literature, relapses, bacteriemia and visceral dissemination of R. equi infection rarely occures in HIV negative persons in contrast to the patients with AIDS 4,14,16,[27][28][29][30] .
Clinical manifestations of R. equi infection may be different, but the disease is usually manifested with respiratory symptoms and signs.The most frequent form of R. equi infection is chronic, progressive, granulomatous and necrotizing inflammation which is cavitary in 2/3 of the patients.The other manifestations of respiratory infection are nodular infiltrates which can be complicated by lung absesses, empyema, pleural effusion and spontaneous pneumothorax 6,7,8,20,27 .Extrapulmonal R. equi infection can be primary and secondary, and usually is a late manifestation of initial lung infection as was the case in our pa-tient.It is a multisistemic or local disease, usually presented as sepsis, fever of unknown origin, cerebral abscess, meningitis, pericarditis, osteomyelitis, subcutaneous abscess, regional lymphadenitis, mastoiditis, or wound infection 18,25,27,[31][32][33][34][35][36] .Because of the delayed diagnosis and treatment, frequent bacteriemias and dissemination of R. equi infection, almost all of these manifestations were seen in our patient.However, we should not forget that in such cases disease progression is registred in about 10% of patients, despite adequate therapy 4,20,27 .
Optimal treatment regimen and optimal duration of antibiotic therapy in patients with R. equi infection are not exactly defined.Combined antibiotic treatment is the cornerstone of the therapy for R. equi infection, but surgical incision and drainage of abscess formation can also be useful.Treatment of severe forms of the disease should start with combined parenteral antibiotics and after clinical and laboratory improvement should switch to a combined peroral antibiotic therapy, we also applied [37][38][39][40][41][42][43] .Because of high incidence of bacteriemia and large bacterial inoculum it is necessary to apply adequate combination of antibacterial drugs with bactericidal activity, with simultaneous application of lipophilic antibiotics with good intracellular penetration.It is believed that antibiotics combination which includes carbapenems (meropenem, imipenem), glycopeptides (vancomycin, teicoplanin), macrolides and rifampicin can be optimal 4,20,27,[37][38][39][40][41][42][43] .That was the way we started and continued antibiotic treatment for exactly one year, that resulted in a complete success.Some authors recommend combinations with two or even more antibiotics with intracellular activity, while the others put accent on the bactericidal antimicrobial agents, especially during the initial phase of treatment [37][38][39][40][41][42][43] .We appreciated the views of both authors and conducted the treatment with four antimicrobial drugs, guided by antibiogram, in a long period of time.After careful consideration, we anticipated that there was no allergic reaction to vancomycin in our patient, actually it was "red woman" phenomenon, so we continued the treatment with glycopeptides sucessfully.At the same time great attention was paid to the volume replacement therapy and to the fact that drainage of large abscess collection in those with R. equi infection should be done whenever possible.

Conclusion
Human R. equi infection is a very rare disease usually affecting those with severe immunodeficiences.The delayed diagnosis is very frequent, despite the advances in knowledge about the causative agent.The most important step in making diagnosis is a clinical suspition of the disease and after that, microbiological analyses from the adeqate specimens.Since it is almost impossible to eradicate R. equi, it is very important to make a diagnosis and start therapy as soon as possible.Antimicrobial therapy is based on a combination of antibacterial drugs with bactericidal activity and drugs with good intacellular penetration and applied for a long period of time.

Fig. 1 -
Fig. 1 -Magnetic resonance imaging of the lumbar spine in the presented patient with disseminated R. equi infection: progressive spondylodiscitis L2/L3 and psoas abscess of the left side.

Fig. 2 -Fig. 3 -
Fig. 2 -Computed tomography of the chest in the presented patient: large cavitary pneumonia and abscess in the right lung.

Fig. 4 -Fig. 5 -
Fig. 4 -Computed tomography of the chest in the presented patient with disseminated R. equi infection after a month of combined antibiotic therapy.