Infections in Renal Transplant Recipients - medIND

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JIACM 2007; 8(4): 316-23

Infections in Renal Transplant Recipients L Umesh*, E Mahesh**, Alind Kumar***, K Punith****, K Lalitha*****, G Suman*****

Abstract Infection is a major and severe penalty of immunosuppression and is associated with high mortality. In order to prevent the occurrence of infection, one should know the commonest types of infection in that particular group of patients. Hence an attempt was made to find out the present trend of infections and their incidence in renal transplant patients. The study was conducted at MS Ramaiah Hospitals, Bangalore. All the patients who underwent renal transplantation between 2002 and 2005 were followed-up for the study. Sixty-two patients who satisfied the inclusion criteria were followed for a period of 48 months. Urinary tract infection (36.11%) was the most common infection seen in the post-transplant period followed by candidiasis (16.62%) and tuberculosis (13.89%). The occurrence of acute gastroenteritis (p < 0.05) and pneumonia (p < 0.05) was statistically more in patients aged less than 40 years. Urinary tract infection (p < 0.01) was significantly higher in patients more than 40 years. Except for urinary tract infection (p < 0.05), the occurrence of all other infections in either sex had no statistical significance. Candidiasis was statistically found more in diabetics compared to non-diabetics in the pre-transplant period (p < 0.01).

Introduction Infection is a major and severe penalty of immunosuppression and is associated with high mortality. Renal transplant patients have poor resistance to infections because of immunosuppressive therapy. In a study done by Tam et al in 1980 - 1984, 87% of the renal transplant patients developed one or the other infection during a mean follow-up of 16 months1. Viale et althroughhisstudyfoundthatbacteria(inparticular Enterobacteriaceae, non-fermenting Gram-negative bacilli and Enterococcus spp) and Candida spp are a frequent cause of urinary tract infection in the early post-transplantation phase. Cytomegalovirus (CMV) is a frequent infectious complication (20 - 60% of patients) whose risk is enhanced by mycophenolate mofetil2. Alangaden et al conducted a study on infectious complications after kidney transplantation analysing the current epidemiology and associated risk factors. The study suggests that the use of newer immunosuppressive agents in recent years is associated with some changes in the epidemiology of post-transplant infections. 127 infections were reported in 65 patients, consisting of urinary tract infection (UTI) (47%), viral infections (17%), pneumonia (8%), and surgical wound infections (7%). UTI was the most

common infection in all post-transplant periods. Enterococcus spp. (33%) and Escherichia coli (21%) were the most prevalent uropathogens. Of six patients with cytomegalovirus infection, none had tissue-invasive disease3. With the advances in science and recent developments in medicine, there has been a great deal of improvement in immunosuppression and this has brought about a great impact on the changing pattern of infection and diseases in renal transplant patients. In order to prevent the occurrence of infection, one should know the commonest types of infection in that particular group of patients. Hence an attempt will be made to find out the present trend of infections and their incidence in renal transplant patients.

Aims and objectives To study the proportion of various infections in post renal transplant patients by retrospective record analysis.

Methodology Study setting ?

MS Ramaiah Memorial Hospital, Bangalore.

* Professor and Head, ** Assistant Professor, *** Lecturer, Department of Nephrology, MS Ramaiah Memorial Hospital; **** 8th Term Student, ***** Lecturer, Department of Community Medicine, M S Ramaiah Medicall College, Msrit Post, New Bel Road, Bangalore - 560 054, Karnataka.

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MS Ramaiah Medical Teaching Hospital, Bangalore.

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The duration of follow-up ranged from 6 months to 4 years.

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All patients were on standard triple immunosuppressant drug therapy constituting cyclosporine, prednisolone, and mycophenolate mofetil.

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Case definition for various infections occurring in the post-transplant period was considered using standard protocol (Annexure 1).

Study group ?

Records of patients who have undergone renal transplant from 1st January 2002 to 31st December 2005 (48 months).

Total number of patients followed-up – 62 Inclusion criteria ?

Records of patients who have received renal allograft from 1st January 2002 to 31st December 2005.

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Records of patients who had a minimum 3 follow-up check-ups after the transplant.

Results Socio-demographic profile of the study subjects

Exclusion criteria

Table I: Age and sex distribution of the study subjects.

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Records of patients who haven’t had a minimum 3 follow-up check-ups after the transplant.

Age group

Males No. (%)

Females No. (%)

Total No. (%)

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Less than 30

7

7

13 (22.6)

In presence of an infection, the same was excluded during analysis of the incidence of that infection in all the patients during the post-transplant period.

31 to 40

8

2

10 (16.1)

41 to 50

17

5

22 (35.5)

51 to 60

12

1

13 (21)

Source of information

61 to 70

3

0

3(4.8)

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Medical Record Department, MS Ramaiah Memorial Hospital.

Total

47

15

62 (100)

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Medical Record Department, MS Ramaiah Medical Teaching Hospital.

Most of the transplanted patients were between the ages of 41 to 60 years. Out of the study population, 47 (75.8%) were males and 15 (24.2 %) were females.

Study design – Descriptive study Method of data collection: Retrospective record analysis.

Methodology ?

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All the 62 patients’ records were reviewed upto June 2006 so that the last case was at least reviewed for a minimum period of 6 months. These included 35 patients who received living related renal allograft and 27 patients who underwent living unrelated transplantation at our centre. All these patients had functioning grafts for more than 6 months. The pre-transplant tuberculin test was negative in all of them.

Journal, Indian Academy of Clinical Medicine

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Table II: Underlying disease of the patients who underwent renal transplantation. Basic disease

Number of patients affected

Chronic glomerulonephritis with end-stage renal disease

18

Chronic renal failure with end-stage renal disease

14

Chronic glomerulonephritis with Chronic renal failure with end-stage renal disease

11

Chronic glomerulonephritis

11

Chronis renal failure

8

42 of the patients were having end-stage renal disease with chronic glomerulonephritis and/or chronic renal failure at the time of transplantation.

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Table III: Occurrence of various infections during the study period Infections

No.ofmonthsoffollow-up

Acutegastroenteritis Acutehepatitis*

0-6 7-12 (n=62) (n=51) 4(6.5) 1(1.9) 1(1.6) 1(1.9)

Cytomegalovirus Candidiasis HepatitisC Herpessimplex Herpeszoster

5(8.1) 11(17.7) 4(6.5) 1(1.6) 7(11.3)

3(5.8) 1(1.9) 1(1.9) 0(0) 0(0)

13-24 25-36 (n=33) (n=15) 0(0) 0(0) 0(0) 1(6.6) 0(0) 0(0) 0(0) 0(0) 0(0)

Pneumonia 3(4.8) 0(0) 2(6.1) Tuberculosis 10(16.1) 0(0) 0(0) Urinarytractinfection 23(37.1) 2(3.9) 1(3.1) Total 59(81.94) 9(12.5) 3(4.16) Figures in parenthesis indicate percentages

0(0) 0(0) 0(0) 0(0) 0(0)

aged less than 40 years. Urinary tract infection (p < 0.01) was significantly higher in patients more than 40 years. Other infections showed no particular age preference.

Total 5(6.9) 3(4.16) 8(11.11) 12(16.62) 5(6.9) 1(1.38) 7(9.72)

0(0) 5(6.9) 0(0) 10(13.89) 0(0) 26(36.11) 1(1.38) 72(100)

The occurrence of at least one infection in the posttransplant period in patients less than 40 years old was found to be higher than that which occurred in age group more than 40 years. However, it was not found to be statisticallysignificant. Table V: Comparison of occurrence of infection between males and females Infection

Males N=47

Females N=15

Chi-Square value

Acutegastroenteritis

3(6.4)

2(13.3)

0.741

Acutehepatitis*

3(6.4)

0(0.0)

1.006

Candidiasis

8(16.9)

4(26.6)

0.678

* 59 subjects were followed during the study (3 patients had hepatitis Binfectionbeforestudy).

Cytomegalovirus HepatitisCinfection

6(12.8) 3(6.4)

2(13.3) 2(13.3)

0.003 0.741

Most of the infections were found to occur in the first six months of post-transplant period. In the second year followup period, only 2 cases of pneumonia and one case of tuberculosis was reported while in the third year follow-up, there was only one case of acute hepatitis reported. Between 37 to 48 months, four patients were followed-up and no infections were reported by them.

Herpeszoster

4(8.5)

3(20.0)

1.499

Herpessimplex

1(2.1)

0(0.0)

0.324

Pneumonia

3(6.4)

2(13.3)

0.741

7(14.9) 23(48.9)

3(20.0) 3(20.0)

0.219 3.910

Table IV: Comparison of occurrence of infections in various age groups. Infection Acutegastroenteritis Acutehepatitis*

0to40years N=24 4(16.7%) 1(4.2%)

Above40years N=38 1(2.6%) 2(5.3%)

Chi-square value 3.908 0.038

Candidiasis Cytomegalovirus HepatitisCinfection Herpeszoster Herpessimplex

3(12.5%) 2(8.3%) 2(8.3%) 4(16.7%) 0(0.0)

9(23.7%) 6(15.8%) 3(7.9%) 3(7.9%) 1(2.6%)

1.179 0.728 0.004 1.130 0.642

Pneumonia Tuberculosis Urinarytractinfection

4(16.7%) 2(8.3%) 5(20.8%)

1(2.6%) 8(21.1%) 21(55.3%)

3.908 1.759 7.161

Figures in parenthesis indicates percentages * 59 subjects were followed during the study (3 patients had hepatitis Binfectionbeforestudy).

The occurrence of acute gastroenteritis (p < 0.05) and pneumonia (p < 0.05) was statistically more in patients

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Tuberculosis Urinarytractinfection

Figures in parenthesis indicate percentages * 59 subjects were followed during the study (3 patients had hepatitis Binfectionbeforestudy).

Except for urinary tract infection (p < 0.05), the occurrence of all other infections in either sex had no statistical significance. When occurrence of at least one infection in the study period was considered, the occurrence was higher in males compared to females. However, it was not statistically significant. Candidiasis was statistically found more in diabetics compared to non-diabetics in the pre-transplant period (p < 0.01). Otherwise the difference in occurrence of all other infectionswasstatisticallynotsignificantinthetwogroups. The difference in the occurrence of at least one infection in the post-transplant period in patients who were diabetic before transplantation was found to be statistically not significant when compared to subjects who were nondiabetic.


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Table VI: Comparison of occurrence of infections in study subjects who were diabetics and non-diabetics in the pre-transplant period.

included cyclosporine, mycophenolate mofetil and prednisolone.

Infection

On follow-up of these patients, the following pattern of infection was found to prevail in the study population.

Diabetics N = 44

Non-diabetics Chi-square N = 18 value

Acutegastroenteritis

1(5.6)

4(9.1)

0.215

Acutehepatitis*

0(0.0)

3(6.8)

1.290

Candidiasis

8(44.8)

4(9.1)

10.22

Cytomegalovirus

2(11.1)

6(13.6)

0.072

HepatitisCinfection

1(5.6)

4(9.1)

0.215

Herpeszoster

0(0.0)

7(15.9)

3.228

Herpessimplex

0(0.0)

1(2.3)

0.416

Pneumonia

0(0.0)

5(11.4)

2.225

Tuberculosis

3(16.7)

7(15.9)

0.005

Urinarytractinfection

11(61.1)

15(34.1)

3.830

A. Bacterial infections 1. Urinary tract infection Urinary tract infection stood as the major morbidity to the renal transplant patients. The occurrence rate was 37.1 per cent. Of these, one case reported with recurrent urinary tract infection of two episodes. The first episode was in the first six months and the second episode was in the second post-transplant year. Of this, nearly 90 per cent of the cases were reported in the first six months of post-transplant period. The occurrence was statistically significant in males and in patients over 40 years of age (p < 0.05). Similar results were seen in the study done by Viale2 and Date et al4.

Figures in parenthesis indicate percentages * 59 subjects were followed during the study (3 patients had hepatitis Binfectionbeforestudy).

Table VII: Overall mortality pattern among the study subjects during 2002 to 2005. Status Totalno.ofpatientsfollowed-up

2. Tuberculosis

Number (Percentage)

Tuberculosis was the second common infection in the post-transplant patients during the follow-up period. The overall occurrence rate was 16.1 per cent. All the cases occurred in the first six months of follow-up. Sakhuja et al5, Hallet al6, Qunibiet al7, and Dateet al4 have obtained similar results in their respective studies.

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Totalno.ofdeaths

6(9.6)

No.ofdeathsduetosepticaemia

5(8.06)

No.ofdeathsduetomyocardialinfarction

1(1.61)

The major cause of death in the study subjects was septicaemia accounting for 83.33 per cent of deaths.

3. Pneumonia The occurrence rate of pneumonia was 9.6 per cent. Though the infection was reported all through the study period, 50 per cent of the cases were reported in the first six months. The results are similar to studies done by Davis8, Rubinet al9, and Dateet al4.

More than four-fifths of the deaths were during the first six months following transplantation. Patients who survived through first year following transplant had good prognosis intermsofsurvival.

4. Acute gastroenteritis

Discussion Sixty-two patients were transplanted during the period 2002 - 2005. Among these, 47 were male and 15 were females; 38 were more than 40 years old and 24 were less than 40. 44 patients had diabetes mellitus as a co-morbid condition. All the patients were put on the standard triple drug therapy for immunosuppression following the operation which


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The overall occurrence rate was 8.1% with eighty per cent of the cases occurring in the first six months. Viale et al2 have seen similar results in their study.

B. Viral infections 1. Cytomegalovirus infection

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Cytomegalovirus infection was the third most common

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morbidity associated with transplantation. The overall incidence was 12.9 per cent. All the cases were reported during the first year of follow-up with more than 60 per cent of the cases in the first six posttransplant months. These results are similar to the ones in the study done by Rubin et al9 and Guerin et al10. 2.

Herpes zoster Herpes zoster was one of the major morbid conditions recorded during the study. The overall occurrence rate was 11.3 per cent. All these cases were reported in the first six months of follow-up. Prakashet al11 and Chugh et al12 have reported similar results from their study.

period. The results are similar to those reported by AlMohaya et al14. While most of the infections showed no particular age preference, the occurrence of acute gastroenteritis, pneumonia, and urinary tract infection was statistically more in patients aged more than 40 years (p < 0.05). Except for urinary tract infection, the occurrence of all other infections in either sex had no statistical significance. Candidiasis was statistically found more in diabetics compared to nondiabetics in the pre-transplant period. Otherwise the difference in occurrence of all other infections was statistically not significant in the two groups.

Prognosis 3.

Hepatitis C The occurrence rate and pattern of hepatitis C infection was similar to acute gastroenteritis. The overall occurrence of hepatitis C was 8.1 per cent. 80 per cent cases of hepatitis C infection occurred in the first six months of follow-up. Pedroso et al13 have obtained these results from their study.

During follow-up, 6 patients expired (9.6% of the total followed-up patients), the major cause of death in them being septicaemia (83.33% of the total deaths). 5 out of the total 6 deaths (83.33%) occurred in the first six months of post-transplant period and all the deaths occurred in the firstyearoffollow-up.

Summary and conclusion 4.

Acute hepatitis The overall occurrence rate of acute hepatitis was 4.8 per cent. Of the three cases, two occurred during the first year following transplantation. One isolated case was reported during the third year follow-up. Similar results have been reported by Dateet al4 and Davis8 from their studies.

5.

Herpes simplex Only one case of herpes simplex was recorded in the follow-up. The occurrence rate was 1.6 per cent. The case was reported in the first six months post-transplant period similar to most other infections. Prakashet al11 and Chugh et al12 have reported similar results from theirstudies.

C. Fungal infections 1.

Candidiasis Twelve cases of candidiasis were reported during the study period. The occurrence rate was 16.62 per cent. All the cases were in the first year of post-transplant

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Sixty two renal transplant patients were followed between the periods of 2002 to 2005 to study the pattern of occurrence of infections following transplantation. Of the sixty two, forty seven (75.8%) were males and fifteen (24.2%) were females. Most of the patients (61.6%) were between the ages of 31 to 60 years. When a pre-transplant evaluation for infections was done on these patients, four (6.5%) were infected by cytomegalovirus and three (4.8%) were hepatitis B positive. These were not considered as an infection during the study period. Urinary tract infection was the most common bacterial infection encountered during the study. It occurred significantly more in patients aged more than 40 years old (p < 0.01) and showed male sex preponderance (p < 0.05). Tuberculosis was the second common bacterial infection, but age, sex or presence of diabetes had no influence on its occurrence. The other common bacterial infections were pneumonia and acute gastroenteritis, both occurring significantly higher in patients less than 40 years (p < 0.05).


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Annexure 1 Case definitions for various infections occurring in post renal transplant individuals Table I: Common bacterial infections and their manifestations18. Organisms

System involved

Manifestations

Diagnostic criteria

Escherichiacoli

GIT

Acute gastroenteritis

1 . Stool culture positive for the organism.

GUS

Urinary tract infection

1 . Urine culture positive for the organism.

RS

Pneumonia

1 . Gram stain of sputum shows the presence of organism.

CNS

Meningitis

Haemophilus influenzae

2 . Sputum culture shows growth of organism. 1 . CSF examination shows features of bacterial infection. 2 . Gram stain of CSF shows the presence of organism. Klebsiella

Listeria monocytogenes

GIT

Acute gastroenteritis

1 . Stool culture positive for the organism.

GUS

Urinary tract infection

1 . Urine culture positive for the organism.

CNS

Meningitis Meningoencephalitis

1 . CSF examination shows features of bacterial infection. 2 . Gram stain of CSF shows the presence of organism.

Streptococcus pneumoniae

RS

Pneumonia

1 . Sputum shows Gram-stain positive for the organism. 2 . Sputum culture shows growth of the organism.

Mycobacterium

CNS

Meningitis Meningoencephalitis

1 . CSF examination shows features of tuberculosis infection. 2 . Gram stain of CSF shows the presence of organism.

RS

Tuberculosis

1 . Ziehl-Neelsen staining shows presence of acid-fast bacilli. 2 . Sputum culture shows growth of tubercle bacilli.

Table II: Common viral infections and their manifestations19. Organisms

Systems involved

Manifestations

Diagnostic criteria

Cytomegalovirus

CNS

Hepatitis B

GIT

Meningitis Meningoencephalitis Acute hepatitis

1 . CSF Examination showing features of viral infection. 1 . Hbs Ag positive 2 . HBV-DNA positive 3 . Anti-HBc positive 4 . Anti-HBs positive

Hepatitis C

GIT

Acute hepatitis

1 . Anti-HCV antibodies 2 . HCV RNA positive

Herpes simplex

GIT

Oesophagitis

1 . Clinical features

Skin CNS

Fever,blister Encephalitis

2 . Tzanck smear showing presence of intranuclear inclusion bodies and multinucleated giant cells. 3 . Specific HSV-2 serology

Varicella zoster

CNS

Encephalitis

1 . Clinical features

Post-herpetic neuralgia

2 . Direct immunofluoroscent antibody. 3 . Multinucleated giant cell on Tzank smear of the material from vesicle base.


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Table III: Common fungal infections and their manifestations20. Organisms

Systems involved

Candida albicans

GIT

1. Oralcandidiasis 2. Oesophagitis

CNS

1. Meningitis 2. Biopsy will show intraepithelial pseudomycelia 2. Meningo-encephalitis of Candida albicans. 3. Encephalitis

Skin

1. Muco-cutaneous candidiasis

RS

1. Broncho-pulmonary aspergillosis 2. Disseminated aspergillosis

Aspergillosis

Cryptococcus

CNS

Manifestations

Diagnostic Criteria 1. Wet preparation using potassium hydroxide shows spores and non-septate mycelia.

1. Detection of galactomanan by ELISA. 2. Isolation of the organism from the biopsy tissue. 3. CT scan showing characteristics of aspergillosis invasion.

1. Meningitis 1. Cryptococcal capsular antigen in the CSF. 2. Meningoencephalitis 2. Demonstration of Cryptococcal capsular antigen in CSF culture.

Table IV: Common protozoal infections and their manifestations21. Organisms

Systems involved

Manifestations

Diagnostic criteria

Toxoplasma gondii

CNS

Meningitis

1. Positive Sabin-Feldman dye test

Meningo-encephalitis

2. Positive IgM and IgG antibodies for Toxoplasma gondii.

Encephalitis

3. Cysts or trophozoites of Toxoplasma gondii in specimen

Gastroenteritis

1. Presence of trophozoites or cysts of Entamoeba histolyticain stool

Entamoeba histolytica

GIT

Table V: CSF findings in normal individuals and various types of meningitis22. Features

Normal

Bacterial meningitis

Viral meningitis

Tubercular meningitis

Naked eye appearance

Clear and colourless

Cloudy or frankly purulent

Clearorfaintly turbid

Turbid, forms coagulum on standing

CSF pressure

60 - 150 mm Hg

> 180 mm Hg

> 250 mm Hg

> 300 mm Hg

Cells

0 - 4 lymphocytes/ mclitre

1000 - 10000 neutrophils/mc litre

10 - 100 mononuclear cells/mclitre

100 - 1000 mononuclear cells/mclitre

Proteins

15 - 45 mg/dl

Markedly raised

Raised

Raised

Glucose

50 - 80 mg/dl

Markedly reduced

Normal

Reduced

Bacteriology

Sterile

Causative organism present

Sterile

Tubercle bacilli present

The viral infections recorded during the study period were cytomegalovirus infection (12.9%), herpes zoster (11.3%), hepatitis C (8.1 %), acute hepatitis (4.8%) and herpes simplex (1.6%). The occurrence of these infections was not influenced by the age, sex and presence of diabetes as a co-morbid condition.

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Candidiasis (16.62%) was the only fungal infection noted in the renal transplant patients during the study period. Though age and sex had no bearing on the disease occurrence, it was significantly higher in patients who had diabetes as a co-morbid condition before the transplantation (p < 0.01).


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Nearly 82 per cent of the infection occurred in the first six months of post-transplant period and upto 94 per cent infection occurred in the first year. This can be attributed to the high levels of immunosuppression achieved in the early post-transplant period as a measure to prevent graft rejection. Of the 6 deaths which occurred in the follow-up period, 83.3 per cent were due to septicaemia. 83.3 per cent of the total deaths occurred in the first six months of followup and all the deaths were in the first year following the transplantation.

References 1 .

2 . 3 .

4 .

5 .

Tam PC, Li MK, Wong KK. Infections in post transplant patients. Journal of Hong Kong Medical Association 1987; 39 No.2. Viale P, Scudeller L. Infectious complications after renal transplantation. G Ital Nefrol 2004; 21 (Suppl 26): S48-52. Alangaden GJ, Thyagarajan R, Gruber SA. Infectious complications after kidney transplantation: current epidemiology and associated risk factors.Clin Transplant 2006;20(4):401-9. Date A, Vaska K, Vaska PHet al. Terminal infections in renal transplant patients in a tropical environment.Nephron 1982;32(3):253-7. Sakhuja Vinay, Jha Vivekanand, Varma Premet al. The high incidence of tuberculosis among renal transplant


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recipients in India.Transplantation 1996; 61 (2): 211-5. 6 .

Hall CM, Willcox PA, Swanepoel CR et al. Mycobacterial infection in renal transplant recipients.Chest Vol. 106: 435-9.

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Qunibi WY, al-Sibai MB, Taher Set al. Mycobacterial infection after renal transplantation – report of 14 cases and review of the literature.Q J Med 1990; 77 (282): 1039-60.

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Davis Connie L. Post transplant infections, Henrich, William L, Bennet William M. Atlas of the diseases of kidney; Blackwell publishers; Vol. 5: page 10.1-10.40.

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Rubin RH, Wolfson JS, Cosimi AB, Tolkoff-Rubin NE. Infection in the renal transplant recipient.Am J Med 1981; 70 (2): 405-11.

10. Guerin C, Pozzétto B, Berthoux FC, Gaudin OG. Incidence of Cytomegalovirus Infections in Renal Transplant Patients Treated With Conventional or Cyclosporin Therapy. Nephrol Dial Transplant 1988; 3: 77-80. 11. Prakash J, Singh S, Prashant GK et al. Mucocutaneous lesions in transplant recipient in a tropical country. Transplant Proc 2004; 36 (7): 2162-4. 12. Chugh KS, Sharma SC, Singh V et al. Spectrum of dermatological lesions in renal allograft recipients in a tropical environment. Dermatology 1994; 188 (2): 108-12. 13. Pedroso S, Martins L, Fonseca Iet al. Impact of hepatitis C virus on renal transplantation: association with poor survival. Transplant Proc2006;38(6):1890-4. 14. Al-Mohaya MA, Darwazeh A, Al-Khudair W. Oral fungal colonisation and oral candidiasis in renal transplant patients: the relationship to Miswak use.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 93 (4): 455-60.

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