|Year : 2019 | Volume
| Issue : 2 | Page : 110-114
Opportunistic infections occurring in renal transplant recipients in tropical countries
Krishan Lal Gupta, Sahil Bagai, Kiran Joshi, Manish Rathi, Harbir Singh Kohli, Vivekanand Jha, Vinay Sakhuja, Ashish Sharma, Mukut Minz, Arunaloke Chakrabarti
Department of Nephrology, Renal Transplant Surgery and Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||02-Aug-2018|
|Date of Acceptance||10-Jan-2019|
|Date of Web Publication||28-Jun-2019|
Dr. Krishan Lal Gupta
Department of Nephrology, Renal Transplant Surgery and Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Introduction: Renal transplant recipients now have better graft survival rates, but continue to develop opportunistic infections. The present study was aimed at finding the incidence of opportunistic infections in the tropical environment in live-related transplant recipients. Materials and Methods: The study was carried out retrospectively with the help of medical records at a tertiary care hospital in North India from 2006 to 2010. The demographic and transplant details were noted, and data were analyzed for any possible risk factor. Results: A total of 1270 patients were studied, of which 231 infectious episodes were detected in 196 (15.4%) patients. Within 1 month, 11.7% of patients had infection, whereas 68.4% of patients had at least one infectious episode within the first 6 months of transplant. Bacterial infection (5.9%) followed by tuberculosis (4.9%), viral (3.8%), and fungal (2.1%) were the infections encountered. Aspergillosis (32.1%) was the most common fungal infection, followed by candidiasis and mucormycosis. The most common site of involvement was lung (26.4%), followed by urinary tract (13.0%). The overall patient survival was nearly 90%. Only 20% of patients had functional graft on follow-up in whom the graft was directly involved by a particular infection. Conclusions: Posttransplant infections continue to affect graft and patient survival. Higher rates are seen in the first 6 months posttransplant.
Keywords: Infection, mucormycosis, renal, transplant, tuberculosis
|How to cite this article:|
Gupta KL, Bagai S, Joshi K, Rathi M, Kohli HS, Jha V, Sakhuja V, Sharma A, Minz M, Chakrabarti A. Opportunistic infections occurring in renal transplant recipients in tropical countries. Indian J Transplant 2019;13:110-4
|How to cite this URL:|
Gupta KL, Bagai S, Joshi K, Rathi M, Kohli HS, Jha V, Sakhuja V, Sharma A, Minz M, Chakrabarti A. Opportunistic infections occurring in renal transplant recipients in tropical countries. Indian J Transplant [serial online] 2019 [cited 2019 Aug 25];13:110-4. Available from: http://www.ijtonline.in/text.asp?2019/13/2/110/261840
| Introduction|| |
The steady improvement in short-term success rates in renal transplant patients has translated into better long-term success rates and a large number of patients with long functioning renal transplants. Due to advances in the medical management, the life span of transplant recipients has increased but at the cost of being more prone to infectious complications in the posttransplant period. Posttransplant infections rank second as the cause of death in patients with allograft function. Renal transplant recipients are prone to develop a variety of infectious complications including bacterial, viral, fungal, and parasitic infections. The degree of net immunosuppression and various comorbid conditions predisposes to the development of these infections. However, there is limited information on the etiology and course of posttransplant infections in tropical countries.
It is estimated that infections complicate the course of 50%–70% of transplant recipients in tropical countries, with mortality ranging from 20% to 60%. In spite of new antimicrobials, infection rate following transplant has not decreased.
The 2008 USRDS report showed an increase in hospitalization rates for infection from 5.9 per 100 patient-years in 2001–2003 to 6.5 per 100 patient-years in 2004–2006. The spectrum of infections also differs in tropical countries as opposed to the Western world due to the endemicity of certain infections. Furthermore, other factors such as unhygienic conditions, hot and humid environment, overcrowding, malnutrition, and late presentation account for such high rates in developing countries. At present, the literature in this field is not vast. Hence, there is a need of study to document the various infectious complications following renal transplant and their outcome in tropical countries. This would probably help in early identification of these infections and their prompt treatment would lead to improved outcome.
| Materials and Methods|| |
This was a cross-sectional observational study carried out retrospectively with the help of medical records of the patients admitted at a tertiary care hospital in North India from 2006 to 2010. Patients received a triple-drug regimen including tacrolimus (Tac) 0.1 mg/kg in two divided doses; hydrocortisone 100 mg intraoperatively followed by dexamethasone 4 mg on postoperative days 1 and 2 followed by prednisolone 0.5 mg/kg from day 3 postoperatively for the first 14 days, tapered gradually to 5–10 mg/day over the next 2 months; and mycophenolate 2 g/day in divided doses (an equivalent dose of mycophenolic acid sodium was 720 mg twice a day). The demographic details, type of immunosuppression, rejection episodes, and treatment given during the rejection episodes (nature of immunosuppressive medication) were noted for all patients.
Various comorbid conditions (immunosuppressive agents, hyperglycemia, hepatitis, chronic liver disease, and immunomodulating viral infections) were evaluated. The correlation (if any) was analyzed between infections and the nature of immunosuppression and comorbidities.
At our center, all chronic kidney disease-end-stage renal disease patients are routinely administered hepatitis B and pneumococcal vaccines, the course of which is usually completed 1 month before transplant. Hepatitis B vaccination (40 mcg) is usually offered in four doses at 0, 1, 2, and 6 months. Pneumococcal vaccine is given as a combination of conjugate and polysaccharide vaccines. Pneumococcal conjugate vaccine (Prevnar-13) is followed by pneumococcal polysaccharide vaccine (Pneumovax-23) after 8 weeks. A booster of Pneumovax-23 is given after every 5 years.
| Results|| |
A total of 1270 patients were studied, of which 231 infectious episodes were detected in 196 (15.4%) patients during the study period. Multiple infectious episodes were detected in 17 patients (two episodes in 14 patients and three episodes in three patients) at different time points requiring more than one admission following transplantation. The mean age of the patients in the study was 38 years, and 85% of the patients were male [Table 1].
Within 1 month, 11.7% of patients had infection, whereas 68.4% of patients had at least one infectious episode within the first 6 months posttransplant. Bacterial infections constituted the most common type of infection in the posttransplant (5.9%) period. Tuberculosis (TB) (4.9%), viral (3.8%), and fungal (2.1%) were the other infections seen.
The most common organ involvement was by lung (26.4%), followed by urinary tract infection (UTI) (13.0%), disseminated disease (11.7%), pyrexia of unknown origin (PUO) (7.8%), graft (6.5%), pleural effusion (5.6%), gut/liver (4.8%), central nervous system (2.6%), paranasal sinuses (2.2%), bone, and perigraft collection (1.3%) [Table 2].
The overall incidence of bacterial infections among renal transplant recipients was found to be 5.9%. Overall, among all bacterial infections, UTI was the most common, followed by pneumonia. UTI was the most common infection within the 1st month following transplantation, whereas bacterial pneumonias were predominant after 6 months of transplantation.
The overall incidence of fungal infections among renal transplant recipients was found to be 2.2%. Aspergillosis (32.1%) was the most common fungal infection, followed by candidiasis and mucormycosis. Overall, zygomycosis and aspergillosis accounted for about 50% of all the fungal infections. The peak incidence of fungal infections was detected after 6 months following transplantation. In 89.3% of cases, fungal infections involved a single site (the most common being lungs), while disseminated infection was seen in 10.7% of cases.
Risk factor for fungal infection in our study was hepatitis (29%), post-transplant diabetes mellitus (17.9%), type 2 diabetes mellitus (14.3%), and cytomegalovirus (CMV) infection (7%). Tac-mycophenolate mofetil (MMF) protocol, age >40 years, and mortality were independently associated with the occurrence of fungal infection.
The overall incidence of TB among renal transplant recipients was found to be 4.9%. TB was the second most common (bacterial being the most common) infection after 6 months after transplantation.
There were a total of 63 episodes of TB of which 51 (81%) were seen after 6 months of transplantation, 10 (16%) were seen between 2nd and 6th months of transplantation, while 2 (4%) were seen within the 1st month of transplantation. The most common organ involved by TB was lungs followed by pleura.
In 31 (49·2%) cases, we had histopathological or microbiological proof of TB. Empirical anti-TB treatment (ATT) was given to 32 (50.8%) patients of whom 13 had exudative, lymphocytic effusions (with high adenosine deaminase levels), and 10 had radiological lesions highly suggestive of TB, while 9 had PUO that responded to ATT. These patients were treated with isoniazid (INH), ciprofloxacin, ethambutol, and pyrazinamide for initial 3 months, followed by INH, ciprofloxacin, and ethambutol for subsequent 15 months. Symptomatic relief and radiological resolution of lesions were taken as response to therapy.
A total of 48 (38.8%) patients had viral infection. The most common viral infection encountered was CMV (19 [38.8%]), followed by herpes (18 [36.7%]) and BK virus (BKV) (11 [22.4%]). Herpes infection was the most common viral infection within 1-month posttransplant period. Herpes and CMV infection occurred in equal numbers from the 2nd to 6th months. However, post 6 months, CMV was the most dominant viral infection. Six (54.5%) of all patients with BKV had evidence of BKV nephropathy.
Anti-thymocyte globulin use, calcineurin-inhibitor (CNI)/MMF protocol, and new-onset graft dysfunction were independently associated with an increased risk of viral infection.
Graft outcome (n= 15)
For the estimation of graft loss, the patients who died and lost to follow-up were excluded, and only those patients were included in whom graft was directly affected by a particular infection. Only 20% of patients had functional graft on follow-up in whom the graft was directly involved by a particular infection.
| Discussion|| |
According to literature, infections complicate the course of 50%–75% of transplant recipients in tropical countries, with mortality ranging from 20% to 60%. Infections posttransplantation are a cause of significant morbidity and mortality. In developing countries, infections are encountered much more common than in the West. In this study, we display a spectrum of infection encountered at different time intervals posttransplantation.
Of 1270 patients, 231 infectious episodes were detected in 196 patients which meant that 15.4% of patients had at least one episode of infection. The overall mortality rate due to the infections in the current study was 11.2%.
Bacterial infections (5.9%) were the most common infection encountered in this study, which is consistent with previous studies. UTI was the most common bacterial infection constituting 86.7% of bacterial infections within the 1st month of transplantation, while bacterial pneumonias were predominant (41.2%) after 6 months of transplantation. UTI constituted 13% of all the infections following transplantation. A study by Gupta et al. confirmed the same. In another study by Jha, UTI was seen to be the most common infection posttransplant period.
In one study from India, Gupta et al. retrospectively analyzed 228 transplant recipients (190 males, 38 females). Overall, the incidence of UTI was 22.3%, and it accounted for 32.8% of all infective episodes.
Bacterial pneumonias constituted 35.5% of all cases of bacterial infections seen posttransplantation in this study. In a previous study, at our center, bacterial infection of lungs was observed in 18% of patients in the 1st year after transplantation.
The overall incidence of fungal infections among renal transplant recipients in this study was found to be 2.1%. At our center, previously (in an autopsy study), we found the incidence to be around 9.8%. Other centers from India have reported a figure ranging from 2.5% to 19%. The diagnosis of fungal infection was based on histopathological examination of the involved organ. In another study, Patel and Paya reported an incidence of 5%. Autopsy incidence of fungal infections is higher because these infections are difficult to diagnose during life.
Overall, zygomycosis and aspergillosis accounted for about 50% of all the fungal infections. This is consistent with a previous report (autopsy study) from our center in which these fungal infections accounted for 52% of all fungal infections. In one recent study from India, invasive fungal infections were the most common pathogens, amounting to 55% of all infections.
The peak incidence of fungal infections was detected after 6 months following transplantation. Rubin's timetable suggests that the majority of fungal infections occur within 6 months in patients; however, this has not been the case in the tropics. John showed that fungal infections occur at all time points, crossing the 6-month milestone even in those who have no extra immunosuppression. Our study also confirmed the same finding.
In this study, no association was observed between fungal infection and hyperglycemia. This is in contrast to previous studies where a significant correlation between fungal infections and chronic liver disease and hyperglycemia was shown. Age more than 40 years emerged as one of the predisposing factors for the risk of fungal infections in this study.
As expected, angioinvasive fungal infections turned out to be the most important risk factor for mortality (100% in this study) on account of their severity. This is consistent with a study done by Song et al.
The diagnosis of TB was based on the following criteria: (1) demonstration of mycobacterium on smear or culture, (2) demonstration of caseating granuloma on histological examination, or (3) therapeutic response to ATT in patients with (a) fever and apical or miliary infiltration on chest skiagram or exudative pleural effusion with lymphocytic pleocytosis or (b) pyrexia of undetermined etiology when extensive investigations had yielded no clue.
The overall incidence of TB among the entire renal transplant recipient was found to be 4.9%. The incidence of TB was found to be 27.3% among all the infectious episodes (the second most common after bacterial infections). At our center, previously, we had observed 36 cases of TB in 305 renal transplant recipients (11.8%) over an 8-year period. In another study from South India, the authors have reported an incidence of 13.3% among 1414 renal transplant recipients. The decline in an incidence of TB may be due to more careful screening for TB before transplantation.
In this study, the infection was limited to the thoracic cavity (pleuropulmonary TB) in 52.3% (which emerged as the most common site), whereas it was disseminated in 6% of cases [Table 3].
At our center (in a previous study), the infection was limited to the thoracic cavity in 41.7% and a single extrapulmonary site in 11.1%, while it was disseminated in 27.8% of cases. In a study from another center also, the most common presentation was pleuropulmonary (28%–50%), followed closely by disseminated disease (20%–60%) and fever of unknown origin (20%–40%). Our conclusion is consistent with these results except the fact that we found lesser number of cases of disseminated TB. We found a significant association between CNI (Tac/CSA)-Aza protocol and higher incidence of TB (P = 0.002). This may be related to higher number of TB cases seen in azathioprine era and importantly to reduction in the overall incidence of TB in MMF (recent) time period.
The incidence of viral infection in our study was 3.8%. The most common viral infection encountered was CMV (19 [38.8%]). The diagnosis of CMV disease was made on the basis of patient having fever, graft dysfunction, leukopenia, and hepatic dysfunction, with evidence of typical CMV inclusions on biopsy of involved organ accompanied by CMV pp65 antigenemia and/or significant titers of CMV DNA polymerase chain reaction (PCR) in the peripheral blood. “Graft dysfunction with CMV antigenemia” was diagnosed when patients had evidence of recent deterioration in graft function accompanied by CMV pp65 antigenemia and/or significant titers of CMV DNA PCR in the peripheral blood and when these patients' graft function improved on follow-up with ganciclovir therapy. We did not perform a graft biopsy in these patients.
CMV disease was seen in this study in 18.5% of cases. CMV pp 65 positivity in peripheral blood (with no evidence of CMV disease) was detected in 18.5% of cases. CMV infections occur in up to 65% of kidney transplant recipients, and 14%–46% of infections are reportedly symptomatic. In a study by John from Vellore, CMV disease occurred in 20% of patients. However, lack of data on the pretransplant serologic status of donors and recipients makes any judgment on the nature of CMV disease in tropical countries as merely speculative. The most common mode of presentation of CMV disease was disseminated infection (seen in 63% of cases). This is consistent with our past (autopsy) data in which the disease was disseminated in 50% of cases [Table 4].
Herpes (18 [36%]) was the second most common viral infection seen in our study, of which 14 (77.8%) had herpes zoster, 2 (11.11%) had Epstein–Barr virus, and 2 (11.1%) had herpes simplex. BKV incidence was seen in 11 (22.4%) patients in our study. Six (54.5%) patients out of the 11 had BKV nephritis. The diagnosis of BKV nephritis was made on the basis of light microscopy showing typical viral inclusions on graft biopsy accompanied by BK viremia (as documented by significant titers of BKV DNA PCR in blood) or SV40 immunostain positivity on biopsy. All these patients were on triple immunosuppression (Tac, mycophenolate, and steroids) at the time of diagnosis, and immunosuupression was altered once BKV was diagnosed and antiproliferatives were completely stopped. Four patients also required reduction in Tac dose to half.
In a study by Dadhania et al., BKV was seen to affect 10% of all transplant recipients. We do not perform regular screening of BKV (by viral DNA PCR assays in peripheral blood) on follow-up due to cost constraints. We have been looking for BKV by screening of peripheral blood for viremia only in patients of unexplained graft dysfunction for the last 1 year only. Hence, some cases of unexplained graft dysfunction in the past might in fact be cases of BKV nephropathy that have gone undetected. Hence, we possibly have got low prevalence of BKV nephritis (as compared to Western data) seen in the current study.
| Conclusion|| |
Post transplant infections are a common occurence in post transplant phase. Aggressive management is required to salvage the graft kidney. Bacterial infection and tuberculosis dominate amongst infections.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Karuthu S, Blumberg EA. Common infections in kidney transplant recipients. Transplant Proc 1994;26:2072-4.
Jha V, Chugh S, Chugh KS. Infections in dialysis and transplant patients in tropical countries. Kidney Int 2000;57:S85-93.
Snyder JJ, Israni AK, Peng Y, Zhang L, Simon TA, Kasiske BL, et al.
Rates of first infection following kidney transplant in the United States. Kidney Int 2009;75:317-26.
US Renal Data System: Annual Data Report; 2008. Available from: http://www.usrds.org/adr
. [Last accessed on 2008 Dec 15].
John GT. Infections after renal transplantation in India. Transplant Rev 1999;13:183-91.
Gupta RK. Opportunistic infections in renal allograft recipients. Transplant Proc 2007;39:731-3.
Gupta G, Unruh ML, Nolin TD, Hasley PB. Primary care of the renal transplant patient. J Gen Intern Med 2010;25:731-40.
Jha V. Post-transplant infections: An ounce of prevention. Indian J Nephrol 2010;20:171-8.
] [Full text]
Gupta S. Urinary tract infection in renal allograft recipients. J Nephrol 1996;9:207-10.
Gupta KL. Fungal infections and the kidney. Indian J Nephrol 2001;11:147-54. [Full text]
Tharayil John G, Shankar V, Talaulikar G, Mathews MS, Abraham Abraham M, Punnakuzhathil Thomas P, et al.
Epidemiology of systemic mycoses among renal-transplant recipients in India. Transplantation 2003;75:1544-51.
Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev 1997;10:86-124.
Song Y, Qiao J, Giovanni G, Liu G, Yang H, Wu J, et al.
Mucormycosis in renal transplant recipients: Review of 174 reported cases. BMC Infect Dis 2017;17:283.
Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis among renal transplant recipients in India. Transplantation 1996;61:211-5.
John GT, Shankar V, Abraham AM, Mukundan U, Thomas PP, Jacob CK, et al.
Risk factors for post-transplant tuberculosis. Kidney Int 2001;60:1148-53.
Kashyap R, Shapiro R, Jordan M, Randhawa PS. The clinical significance of cytomegaloviral inclusions in the allograft kidney. Transplantation 1999;67:98-103.
Dadhania D, Snopkowski C, Ding R, Muthukumar T, Chang C, Aull M, et al.
Epidemiology of BK virus in renal allograft recipients: Independent risk factors for BK virus replication. Transplantation 2008;86:521-8.
[Table 1], [Table 2], [Table 3], [Table 4]