Brain abscess following kidney transplantation: A single centre observational study from North India

Abstract

Background

Amongst the infections in kidney transplant recipients, brain abscess represents an uncommon life-threatening complication. Mortality continues to be high despite improvements in diagnostics and therapeutics.

Method

We conducted an observational study, describing the incidence, presentation, implicating pathogen, management and outcome of brain abscess following kidney transplantation at our centre.

Result

Amongst the 1492 patients who underwent kidney transplantation at our centre between June 1991 and January 2023 (cumulative follow-up: 4936 patient-years), five females and four males, developed brain abscesses. The incidence proportion (risk) is 0.6% with an incidence rate of 6.03 cases per 1000 patient years. The median duration from transplant to development of brain abscess was 5 weeks (range: 4 weeks to 9 years). The commonest presentation was a headache. A definitive microbiological diagnosis was established in eight out of nine patients. The commonest implicated organism was a dematiaceous fungus, Cladophialophora bantiana (3 patients, 33.3%). Despite the reduction in immunosuppression, surgical evacuation and optimal medical therapy, five (55.55%) patients succumbed to their illness.

Conclusions

Brain abscesses following kidney transplantation is an uncommon, life-threatening condition. It usually occurs in the early post-transplant period and the presentation is often subtle. Unlike immunocompetent individuals, a fungus is the most common causative organism in those with solid organ transplants. The management includes a reduction in immunosuppression, early antimicrobial therapy, and surgical decompression.

Introduction

Kidney transplant recipients (KTRs) are susceptible to a wide range of opportunistic infections including bacterial, viral, fungal, protozoal and parasitic.¹ This is attributed to the presence of multiple comorbidities, infection by immunomodulatory viruses, and the influence of immunosuppression. Despite rigorous screening, regular follow-up, use of prophylactic agents, advancement in diagnostics, and the presence of modern therapeutics, infections continue to be common and are a major cause of mortality.^{1, 2, 3} This is especially so in resource-poor tropical countries, with multiple endemic infectious agents coupled with limited health care resources.³ Amongst infections in KTRs, brain abscess is a dreaded complication with high mortality.^{4, 5, 6, 7} The clinical presentation is often subtle requiring a high index of suspicion. While the usual aetiology of brain abscess in immunocompetent hosts is bacterial, fungi predominate in the immunocompromised. The origin of this fungal infection is thought to be hematogenous dissemination from a primary site often the lungs, resulting in arteritis, thrombosis and infarcts.⁸

The management involves a combination of supportive care, reduction in immunosuppression (RIS), surgical drainage and empiric broad antimicrobial cover based on the presumptive agent. The antimicrobial spectrum is narrowed once the implicating pathogen is isolated. The therapy in KTRs is hampered by the paucity of guiding literature, the presence of atypical organisms, immunocompromised status, fear of drug-related nephrotoxicity, and the presence of multiple comorbidities along with a poor baseline functional status. The outcome data in KTRs is scarce; the mortality and the long-term neurological sequelae even in immunocompetent hosts continue to be high.⁹ The study was conceptualized to fill the void in the existing literature.

Material and methods

Study design

This is was retrospective, single-centre, hospital-based observational study involving KTRs with brain abscesses.

Study protocol

The study was conducted, at a tertiary-level teaching hospital located in North India. Approval was obtained from the hospital-based ‘Institutional Ethics Committee’ and good clinical care guidelines as per the ‘Declaration of Helsinki’ were adhered to. Consent from patients was obtained before inclusion in the study. We retrospectively analysed the medical records of 1492 patients who had undergone kidney transplantation from Mar 1991 to Jan 2023. The data was retrieved from the departmental record and the hospital information system. The data collated include demographic profile, comorbidities, degree of human leucocyte antigen mismatch, immunosuppression protocol, clinical presentation, laboratory parameters, incriminating pathogen, therapeutic modality, response to therapy and the outcome.

Study subjects

All patients who had undergone kidney transplantation at the centre within the predefined period.

Diagnostic criteria

Brain abscess was defined as a central area of necrotic debris visualized as a hypodense area on computed tomography (CT) imaging, or magnetic resonance imaging (MRI) with a surrounding area of contrast enhancement. The causative organism was identified using microbiological techniques including culture and appropriately stained histopathology specimen. In those where the abscess was deemed surgically unapproachable, ancillary supportive evidence was used Fig. 1.

Fig. 1.

Institutional management algorithm for brain abscess in kidney transplant recipient.

Management protocol

The Institutional management algorithm is depicted in Table 1. The management algorithm included the following diagnostic and therapeutic interventions.

• (a)An initial clinical examination directed towards finding the source of infection including otitis media, sinusitis, dental infection, infective endocarditis, and systemic infection.
• (b)An attempt towards establishing the aetiology using non-invasive investigations; these included blood and urine cultures, serum beta-D-glucan, serum galactomannan, serum procalcitonin, interferon-gamma release assay (IGRA) for mycobacterium tuberculosis, and cerebrospinal fluid study (CSF) studies including culture.
• (c)RIS involved stopping the antiproliferative agent (mycophenolate-mofetil or azathioprine) and a reduction in the dose of tacrolimus to achieve a trough level of 3–6 ng/ml.
• (d)The initial empiric antimicrobial therapy included a broad-spectrum cover for bacterial and fungal infections. The therapy included a combination of vancomycin or teicoplanin along with third-generation cephalosporins or carbapenems and intravenous liposomal amphotericin. The therapy was modified appropriately following the identification of the pathogen.
• (e)A neurosurgical consultation for early intervention; intervention was planned based on the location, numbers, accessibility, and abscess characteristics. The sample obtained was subjected to an appropriate culture and histopathological examination.

Table 1.

Demographic profile of kidney transplant recipients with brain abscess.

Patient Number	Patient-1	Patient-2	Patient-3	Patient-4	Patient-5	Patient-6	Patient-7	Patient-8	Patient-9
Age (years)	28	29	27	37	34	12	30	31	16
Gender	F	F	F	M	F	M	M	F	M
Basic Disease	CGN	CIN	CGN	CGN	CGN	CAKUT	CGN	CGN	CAKUT
Other co-morbidities	None	None	None	Chronic hepatitis C	None	None	None	None	None
Donor Relation	Father	Mother	Mother	Sister	Mother	Mother	Father	Deceased donor	Grandmother
HLA mismatch (HLA A, B, DRB1)	3	2	2	2	3	3	2	Not available	3
ABOc/ABOi	ABOi	ABOc	ABOi	ABOc	ABOi	ABOc	ABOc	ABOc	ABOc
Induction therapy	IL2RA	IL2RA	IL2RA	IL2RA	IL2RA	IL2RA	Nil	rATG	rATG
Maintenance	T/M/P	T/M/P	T/M/P	T/M/P	T/M/P	T/M/P	T/M/P	T/M/P	T/M/P
Tacrolimus (C0) Level (ng/ml)	10.24	11.10	10.76	10.11	10.70	11.13	8.10	3.20	10.39
History of preceding allograft rejections	None	TCMR IB + ABMR	None	None	None	None	TCMR IA + ABMR	None	None
Baseline Creatinine (mg/dl)	0.9	0.7	0.7	1.0	0.9	0.5	1.2	1.2	2.3

Abbreviations: M, male gender; F, female gender; CGN, chronic glomerulonephritis; CIN, chronic tubulointerstitial nephritis; CAKUT, congenital abnormality of kidney and urinary tracts; ABOc, ABO compatible transplant; ABOi, ABO incompatible transplant; IL2RA, interleukin 2 receptor antagonist (Basiliximab); rATG, rabbit antithymocyte globulin; T/M/P, tacrolimus, mycophenolate mofetil, prednisolone; TCMR, T-cell mediated renal allograft rejection; ABMR, antibody-mediated renal allograft rejection.

Results

A total of 1492 patients including 1266 blood group compatible and 226 incompatible, with a mean age of 34.04 ± 10.52 years underwent kidney transplantation between Mar 1991 to Jan 2023 at the centre. The mean follow-up was 39 ± 46 months (cumulative: 4936 patient-years). Nine patients including five females and four males, with a mean age of 27.11 ± 8.1 years developed brain abscesses. The incidence rate is 6.03 per 1000 patient-years. The demographic and baseline characteristics are depicted in Table 1. The donors were predominantly live-related; the transplant was blood-group compatible in six, and incompatible in three patients. Those undergoing blood group incompatible kidney transplant received 200 mg of intravenous rituximab, 3 weeks prior to the performance of the transplantation. The induction therapy included Basiliximab in six, rabbit anti-thymocyte globulin (rATG) in two and nil in one patient. The maintenance immunosuppression included tacrolimus, mycophenolate mofetil and prednisolone. The departmental protocol mandates tacrolimus trough levels of 10–12 ng/ml in the first 3 months, 5–10 ng/ml during 3–12 months, and 3–5 ng/ml after 12 months. Two patients had mixed allograft rejection prior to the detection of brain abscess. Both responded favourably to the administration of rATG (cumulative dose: 4.5 mg/kg) and five sessions of therapeutic plasma exchange along with intravenous immunoglobulin (0.2 gm/kg following plasma exchange).

The details of the clinical presentation, lesion characteristics, and management are enumerated in Table 2. The most common clinical presentation was dull persistent headache without fever or focal neurological deficit; two patients presented with seizures and one presented with visual disturbance. The median duration from transplant to detection of brain abscess was 5 weeks (range: 4 weeks to 9 years). Brain abscess was detected in the early post-transplant period in all but one patient; patient-8, developed a left frontal lobe abscess nine years post-transplantation. No specific predisposition could be elicited for the late-onset brain abscess. The initial diagnosis was established using CT imaging or an MRI. The imaging showed variable-sized lesions, perilesional oedema, mass effect and a predilection for the frontal lobe (Fig. 2). The neuroimages for three patients could not be retrieved. A definitive microbiological diagnosis could be established in 8 out of 9 patients; the location of the lesion in patient number 6 precluded neurosurgical approach and the diagnosis was based on CSF showing a lymphocyte predominant exudative picture with an adenosine deaminase level of 32 U/L and a positive IGRA for tuberculosis. In the absence of an unequivocal diagnosis, he was treated with both antitubercular therapy as well as liposomal amphotericin. The common implicating organisms included C. bantiana (3 patients, 33.3%), Aspergillus fumigatus (2 patients, 22.2%); F. pedrosoi, Cryptococcus neoformans and Mycobacterium tuberculosis were seen in one patient each.

Table 2.

Clinical presentation, management and outcome of kidney transplant recipients with brain abscess.

Patient	Patient-1	Patient-2	Patient-3	Patient-4	Patient-5	Patient-6	Patient-7	Patient-8	Patient-9
Presentation	Headache	Headache	Headache and vomiting	Visual disturbance	Focal seizure	Headache and vomiting	Headache	Headache and vomiting	Generalized seizures
Time from transplant	4 weeks	4 weeks	5 weeks	10 weeks	8 weeks	4 weeks	20 weeks	9 years	5 weeks
Location of the lesion	Left occipital lobe	Right parietal and temporal lobe	Left frontal lobe	Left parietal lobe	Right frontoparietal lobe	Right lentiform nucleus and gangliocapsular region	Bilateral frontal lobe	Left frontal lobe	Left frontal lobe
Culture/Stain	C. bantiana	C. bantiana	Fonsecaea pedrosoi	Aspergillus Fumigatus	Aspergillus Fumigatus	Not established	C. bantiana	Cryptococcal neoformans	Tuberculosis
Surgical management	Craniotomy and excision of the lesion.	Craniotomy and excision of the lesion.	Burr-hole and aspiration of the lesion.	Left parieto- occipital craniotomy and decompression of the lesion.	Right frontal burr-hole and aspiration of the lesion.	None	Burr-hole and aspiration of the lesion.	None	Burr-hole Left and aspiration of the lesion.
Medical management
(a) RIS	MMF withdrawn and dose of tacrolimus reduced.	MMF withdrawn and dose of tacrolimus reduced.	MMF and tacrolimus withdrawn.	MMF and tacrolimus withdrawn.	MMF withdrawn and dose of tacrolimus reduced.	MMF withdrawn and dose of tacrolimus reduced.	MMF withdrawn and dose of tacrolimus reduced.	MMF withdrawn and dose of tacrolimus reduced.	MMF withdrawn and dose of tacrolimus reduced.
(b) Therapy	AmB + Posaconazole	AmB + Posaconazole	AmB + Voriconazole	AmB + Voriconazole	AmB + Voriconazole	AmB + ATT	AmB + Posaconazole	AmB + Fluconazole	ATT
Rejections following RIS	TCMR IA	Nil	Nil	TCMR IA	Nil	Nil	ABMR	Nil	Nil
Patient Outcome	Recovered	Death	Death	Death	Recovered	Recovered	Death	Recovered	Death
Discharge Serum creatinine (mg/dl)	1.8	–	–	–	1.79	0.5	–	2.1	–

Abbreviations: RIS, reduction in immunosuppression; AmB, Intravenous liposomal amphotericin B; ATT, antitubercular therapy (rifampicin, isoniazid, pyrazinamide and ethambutol); TCMR, T cell-mediated renal allograft rejection; ABMR, antibody-mediated allograft rejection.

Fig. 2.

The MRI image of the patient showing. (A) (Patient- 1) An irregular ring-enhancing lesion with a crenated margin measuring 20 × 15 × 18.6 cm is seen in the left occipital lobe (B) (Patient- 2) A well-demarcated enhancing lesion involving the right parietal and temporal lobe with perilesional oedema causing a midline shift. (C) (Patient- 3) A well-defined enhancing lesion with irregular walls is seen in the left frontal lobe with significant perilesional oedema and mass effect. (D) (Patient- 4) A well-defined enhancing lesion involving the left cuneus, precuneus region of the parietal lobe and splenium of the corpus callosum with perilesional oedema. (E) (Patient- 5) A well-defined enhancing lesion measuring 12 × 15 × 20 mm in the right frontoparietal lobe with perilesional oedema and mass effect. (F) (Patient- 6) Two co-located well-defined enhancing thick wall lesions in the right lentiform nucleus with perilesional oedema.

The initial management included stabilization, RIS, and initiation of empiric antimicrobials including antibacterial and antifungal agents as per the protocol detailed above. Liposomal amphotericin was administered in a dose of (3–5 mg/kg/day). Neurosurgical intervention was performed in all but 2 patients; in one (patient-6), the location of the lesion near the brain stem precluded a surgical approach, while in the other (patient-8), the diagnosis was already established following CSF analysis. In those with C. bantiana or Aspergillus-related brain abscess, a second-generation triazole was added to liposomal amphotericin. All patients underwent serial neuroimaging at monthly intervals, and the liposomal amphotericin was continued till the lesion regressed (mean cumulative dose 19.6 ± 2.2 gm); the triazole was continued for an additional 6 months or till the lesions disappeared, whichever was later. Those with mycobacterial tuberculosis-related abscesses received oral rifampicin, isoniazid, pyrazinamide and ethambutol for 3 months, followed by 9 months of rifampicin and isoniazid.

Three patients developed biopsy-proven allograft rejection following RIS; two developed T-cell mediated rejection (TCMR), Banff class 1 A and one had acute antibody-mediated rejection (ABMR). Those with TCMR were treated with pulse intravenous methylprednisolone (500 mg for 3 days), following which one responded with normalization of serum creatinine while the other did not and progressed to a dialysis-dependent state before his demise. The patient with ABMR was treated with plasmapheresis and IVIg; he showed an initial favourable response before succumbing to his illness. Despite aggressive therapy, 5 out of the 9 (55.5%) patients died.

Discussion

A brain abscess is a focal suppurative process within the brain parenchyma. The lesion starts as a localized area of cerebritis, which evolves into a focal collection of pus with a well-vascularized capsule. The organism invades the brain either by direct spread from contiguous sites like otitis media, sinusitis and dental infection or through hematogenous spread following systemic infection. In up to 10–35% of immunocompetent individuals with brain abscesses no primary source or condition can be identified; similar data for KTRs is not available.^10,11 None of our patients had any identifiable local or systemic focus of infection.

All our patients were young with brain abscesses being detected in the early post-transplant period. The incidence proportion for brain abscesses in our study was 0.6% which is higher than the 0.36% reported by another comparable large study.⁸ The early onset is attributed to the higher net immunosuppression in the immediate post-transplant period, while the higher incidence in our cohort is likely due to the prevailing tropical environment.⁶ The clinical presentation of brain abscesses is variable and often subtle; it may become evident later once the abscess grows larger and the surrounding oedema increases. The classical triad of fever, headache and focal neurological deficit is seen in around 20% of immunocompetent individuals with 25% presenting with seizures.⁹ All our patients were afebrile and none presented with the classical triad. In our study, the commonest presentation was headache (6 patients, 66.66%) and seizures (2 patients, 22.22%). It is hence imperative that minor symptoms that are otherwise disregarded be given due credence in KTRs.

Neuroimaging including contrast-enhanced computed tomography or magnetic resonance imaging provides vital information regarding the size, location and number of abscesses. Various MRI sequences have been proposed to distinguish abscess from cerebral tumour and metastasis. Following confirmation of the brain abscess by imaging, a microbiological identification using histopathology and culture is obligatory for the administration of appropriate antimicrobials. Pending the culture and histopathology examination, the initial therapy is empiric, guided by the existing literature. While pyogenic brain abscesses predominate in the immunocompetent, non-bacterial causes such as fungi and tuberculosis are more common in solid organ transplant recipients.^8,9 In their series of 5 KTRs with brain abscesses from India, the authors noted the aetiology to be fungal in three, mycobacterium tubercular in one, and staphylococcus aureus in one.⁵ In another study involving solid organ transplant recipients, the authors noted fungi, Nocardia and Toxoplasma to be the commonest implicated organisms.⁸ Our study noted a predominance of fungal infections, particularly C. bantiana. This rare neurotropic dematiaceous fungus is being increasingly recognised as an aetiology for brain abscesses in the immunocompromised host.^{12, 13, 14} Geographic factors have also been reported to influence the nature of the organism.⁶ Surprisingly despite the immunocompromised status and the abundance of latent and manifest tuberculosis in the tropics, only one patient in our cohort had a tubercular aetiology.

A delay in the initiation of antimicrobial therapy often results in poor outcomes and empiric therapy should be started as early as feasible.^15,16 In our series, we used a broad-spectrum antibiotic cover along with intravenous amphotericin. The therapy was modified once the aetiological agent was identified. The recommended therapy for C. bantiana, the commonest pathogen identified in our study includes a combination of amphotericin and flucytosine. These medications have many limitations; while amphotericin is limited by poor penetrability, nephrotoxicity and electrolyte disturbances, the use of flucytosine is associated with bone marrow toxicity The second-generation triazoles including voriconazole and posaconazole have a broad antifungal spectrum including for C. bantiana and represent an attractive therapeutic add-on antimicrobial.¹⁷ In our patients, once the fungal aetiology was confirmed, a second-generation triazole was added to amphotericin and the systemic antibiotics were discontinued. The therapy was prolonged but well tolerated by the patients. Neurosurgical intervention including stereotactic aspiration is imperative for lesion decompression and identification of the causative organism. The surgical excision which is commonly performed for bacterial abscesses is often less effective in fungal brain abscesses as the fungal hyphae often penetrate and extend beyond the fibrous capsule.¹⁸

The net immunosuppression cannot be quantified and the quantum of RIS is often driven by the physician's experience. RIS is a dual-edged sword, a higher net immunosuppression will cause disease flare while if lower, can potentially result in allograft rejection. The RIS practised by our centre included discontinuation of antiproliferative agents and reduction in calcineurin inhibitor, while simultaneously increasing the dose of steroids. The increased dose of steroid reduced vasogenic oedema while maintaining the net immunosuppression. Following RIS, three of our patients developed biopsy-proven allograft rejection. The therapy of allograft rejection in such a scenario remains undefined. We restricted the therapy of TCMR to methylprednisolone and acute ABMR to plasmapheresis and IVIg. Steroid unresponsive TCMR was not administered rATG, similarly, we did not administer rescue therapy to those with treatment unresponsive ABMR despite the presence of significant microvascular inflammation.

The morbidity and mortality associated with brain abscess remains unacceptably high. The therapy entails prolonged administration of antimicrobials with its attendant toxicity impairing the health-related quality of life. The mortality in solid organ transplants has been reported to be as high as 86%.^5,8 C. bantiana, the commonest aetiological organism in our series also carries a similar grave prognosis.^{12, 13, 14,19} Our study noted a mortality rate of 55.55% despite optimal medical and surgical intervention.

To conclude brain abscess in KTRs is an uncommon infection with high mortality. Unlike immunocompetent hosts, the predominant implicating organism in KTRs is fungus. The key to successful treatment includes a high index of suspicion, prompt diagnosis, RIS, surgical debulking and prolonged antimicrobial therapy.

Limitation of the study

The major limitation of the study includes its retrospective nature and being a single-centre study.

Disclosure of competing interest

The authors have none to declare.