Infection belongs to the most common complications after human stem cell transplantation (HSCT) and constitutes one of the major causes of transplantation-related mortality. Immune deficiency, which persists after HSCT for over a year, can be the cause of an atypical and sometimes abrupt course of infectious diseases, characterized by rapid multi-organ spread of pathogens and their resistance to treatment. Severe infections at later stages after transplantation (100 days after HSCT) are observed in 40–80% of patients(1). Infections caused by atypical intracellular opportunistic bacteria (including Listeria spp., Nocardia spp. or Bartonella spp.), which are usually responsible for late post-transplantation infections, pose a diagnostic challenge. Since their culture is difficult, the results are usually negative. Serological tests are not suitable due to insufficient antibody production, and molecular assays are of limited sensitivity which additionally decreases with the duration of infection(2). Treatment is therefore often based only on the clinical diagnosis(3). This article presents the crucial role of ultrasound imaging in the establishment of a clinical diagnosis of bartonellosis (i.e. cat scratch disease) and implementation of effective therapy in a patient after allogenic HSCT with severe atypical infection involving multiple organs.
A seven-year-old girl received HSCT from an unrelated donor due to severe aplastic anemia. The post-transplantation period was uneventful with normal return of hematopoietic activity. After five months, during which the patient received immunosuppressive therapy, she was admitted to hospital due to fever with no other significant signs. The C-reactive protein (CRP) level was 65 mg/l. Multiple bacterial cultures, microbiological and parasitological tests as well as molecular tests for infections with pneumotrophic viruses, cytomegalovirus or Epstein-Barr virus were negative. Imaging examinations of the chest, abdomen and paranasal sinuses (US, CT, MRI) revealed no changes. Empirical broad-spectrum antibiotic therapy, which was modified several times, and anti-fungal treatment were ineffective. Hectic fever with 3–4 peak episodes up to 39–40°C daily persisted for 4 weeks and CRP reached 195 mg/l. Repeated microbiological and molecular tests extended to detect atypical pathogens were still negative.
In the fourth week of hospitalization, abdominal US, CT and MRI revealed multiple disseminated changes in the spleen (Fig. 1 A), liver and kidneys with morphology resembling abscesses. The lesions were round or oval, homogeneously hypoechoic/hypodense with the size from several to several dozen millimeters; they were not found to be vascularized. Subcapsular foci deformed the splenic outline. Contrast-enhanced CT revealed peripheral enhancement. US showed deformation of vessels around the foci and hyperechoic contrasting intrusions within the lesions, which grew and multiplied over time (Fig. 1 B). The patient's parents did not consent to a diagnostic biopsy. Exclusion of other infections, no response to antibacterial and antifungal treatment, information about pet exposure provided by the parents as well as a typical radiological image of the lesions led to a probable diagnosis of bartonellosis.
Ultrasound image of the splenic manifestation of suspected bartonellosis: A. disseminated, oval, anechoic and non-vascularized lesions 4 weeks after the onset of fever; B. more numerous lesions, most of which contain hyperechoic intrusions; some neighboring lesions fuse – 16th day of treatment; C. regression of the lesions with residual irregular calcifications – after 12 months of treatment
Long-term combined treatment was implemented: azithromycin and amikacin, followed by doxycycline and amikacin as well as ciprofloxacin and co-trimoxazole. Fever subsided, CRP was observed to normalize and the lesions within organs regressed gradually. Within the subsequent weeks, the patient developed similar painless and non-inflammatory nodules in the cervical lymph nodes, subcutaneous tissue of the arm and thyroid gland (Fig. 2 A) with no new foci in the abdominal organs. Microbiological tests of biopsies collected from the superficial lesions were negative. US revealed that lesions in the organs and soft tissues showed a typical evolution pattern: their size increased to 10–20 mm and sometimes they fused with one another. Hyperechoic intrusions appeared within them (Fig. 1 B, 2 B) and developed into calcifications (Fig. 1 C, 2 C). Subsequent treatment with azithromycin alternately with cotrimoxazole, which lasted for approximately a year, led to the regression of all organ and subcutaneous foci leaving multiple calcifications. After a year from the conclusion of the therapy, the girl was healthy and remained in a very good physical condition
Ultrasound image of thyroid involvement in the course of suspected bartonellosis: A. a single oval, anechoic lesion that alters the outline of the gland in the 15th week of treatment; B. presence of a hyperechoic intrusion in the center; no new lesions – 28th day of treatment; C. calcification of the lesion after 12 months of treatment
Cat scratch disease, caused by Bartonella henselae, is typically manifested by localized skin lesions, enlarged regional lymph nodes and fever. In immunocompromised patients, the disease can have a severe, systemic course and affect internal organs, usually the liver, spleen and subcutaneous tissue. The pathogenesis of B. henselae infection is associated with the induction of pathological angiogenesis. The multi-focal proliferation of capillary endothelia with the formation of cavernous spaces filled with blood and necrotic tissue results in the development of multiple disseminated nodular lesions in affected organs, which is referred to as peliosis hepatis/lienalis. In imaging, these lesions are multiple, homogeneous and hypoechoic/hypodense, and resemble abscesses or granulomas. The detectability of Bartonella infection in immunocompromised patients can be significantly underestimated, which is indicated by the common occurrence of this pathogen. Antibodies against B. henselae are found in 81% of cats and in 19–48% of people in the general European population(4).
Life-threatening multi-organ infection after hematopoietic stem cell transplantation requires rapid therapeutic intervention even when the microbiological confirmation of its etiology is not possible. A probable infection with Bartonella can be suspected if at least two of four criteria are met: 1) history of cat exposure; 2) detection of antibodies against Bartonella; 3) presence of multiple hypoechoic/ hypodense hepatic lesions in imaging; 4) granulomatous or angiomatous lesions with additional positive staining for Bartonella (5). A certain diagnosis requires isolation of Bartonella from cultures or detection of its genetic material. Psarros et al.(6) have collected data about 29 cases of bartonellosis in solid organ transplant recipients. These patients presented disseminated organ lesions with similar features to those observed in our patient. B. henselae infection was confirmed in only 13 cases. In the remaining 16 patients, the diagnosis was based on the clinical picture. Rostad et al.(7) have reported the presence of the same ultrasound image of hepatic or splenic involvement in bartonellosis in 24 organ transplant recipients. Moreover, other authors have also presented a similar manifestation of multi-organ bartonellosis(8–10).
We have not found comparable descriptions of hepatic and splenic imaging that could be observed in the course of other bacterial or parasitic infections. Such lesions could be present in candidiasis, which was unlikely in our patient considering the progression of the disease despite intensive anti-fungal therapy, negative microbiological tests and effective treatment targeted to atypical bacteria.
Since it is difficult to conduct microbiological tests in the course of infections caused by atypical pathogens in immunocompromised patients, repeated ultrasound examinations are useful in the diagnostic process of infective changes in organs. In the case presented above, a clinical diagnosis of bartonellosis was established on the basis of an ultrasound image, which enabled effective therapy.
Conflict of interests
The authors report no conflict of interests.