ABSTRACT
Objective: To estimate the incidence of chest
infections in renal allograft recipients, the mortality of lung infections, the
incidence of Tuberculosis, its common presenting features, and determine
significant risk factors for such infections.
Methods:
Over an eighteen
month period (January 2001 to July 2002),
100 kidney graft recipients were checked for any past or present history of
chest infection. All the recipients acquired their graft from living related or
unrelated donors. The study was
conducted in Al-Shaheed Adnan Hospital Centre for kidney disease and
transplantations in Medical city, Baghdad Teaching Hospital and Al-Karama
Teaching Hospital. Statistical analyses were carried out using Chi square test
and Yate's correction wherever needed. A P value of less than 0.05 was taken as
significant.
Results: Bacterial pneumonia was the commonest pulmonary infection
(n=13, 32.5%) followed by the probable acute viral bronchitis (n=10, 25%), pulmonary tuberculosis (n=9, 22.5%) and fungal
infection in five (n=5, 12.5%), nocardiosis in two and candidacies in three
recipients. The mortality from chest infections including pulmonary tuberculosis
in renal allograft recipients was seven (17.5%) recipients.
Conclusion:
Pulmonary tuberculosis
should be included in the differential diagnosis of infections causing fever of
unknown origin in the renal transplant patients, especially in endemic areas.
Leucopenia and diabetes mellitus were significant risk factors for serious
pulmonary infections. Unrelated donor is
also a risk factor for serious post renal transplant recipient pulmonary
infections including tuberculosis which presents with high grade intermittent fever.
Key words: Chest infections, Renal transplant, Tuberculosis
JRMS
December 2009; 16(3): 20-25
Introduction
Bacterial infections usually occur in the
first month following transplantation, and technical issues related to the
procedure can play an important etiological role.(1)
Pulmonary infections were less common in patients treated with cyclosporine
(CsA) compared to those receiving Azathioprine (probably due to the fact, that
Azathioprine may cause leukocytopenia).(2,3) However,
there seems to be an increased risk in patients treated with anti-lymphocyte
globulin (ALG) or monoclonal
antibody (OKT3) for acute rejection(4)
or in the course of induction therapy.(5,6) Some
studies(4,7,8) could
demonstrate more frequent pulmonary infections when the monoclonal
antibody (OKT3 ) was used.
Currently the use of cyclosporine A (CsA)
combined with low dose steroids has resulted in decrease in the incidence of
post renal transplant opportunistic infection.(9,10)
Beyond six months, in patients with well
functioning allograft who are on stable maintenance immunosuppressant the
pattern of infection is similar to that in the general population.(11-13)
In general, during the first
postoperative months, bacterial pneumonias predominate. Two to four months
after transplantation, pneumonia is caused by both opportunistic and bacterial
pathogens. Patients with stable graft function on minimal immunosuppression beyond one year contract primarily bacterial pneumonia.(13-15) However, the time table of infection in
tropics may be some what different with sixth month milestone not demarcating
the risk of the opportunistic versus conventional infection(16)
(Table I).
Mycobacterial disease should be considered
in any patient with fever of unknown aetiology(17) and positive tuberculin test is included in
the risk factors for reactivation of tuberculosis in renal allograft recipient.(18) Mycobacterial infection, although suggested by
many to be common in haemodialysis patients has seldom been reported in the
literature prior to 1996 and most reports have described a small number of cases.(19,20)
In the past two years five reports have
emerged from developing countries suggesting either a resurgence or greater recognition of this
infection.(21,22) Since
the prevalence of tuberculosis in end stage renal disease and kidney graft recipients patients is high
in developing countries, the insight gained into the diagnosis and treatment of
Mycobacterium tuberculosis, in these patients will be of value to nephrologists.(23,24)
Method
Over an eighteen months period (January
2001 to July 2002), 100 kidney graft recipients were checked for any past or
present history of chest infection. All the recipients had their graft from living
related or unrelated donors.
The study was conducted prospectively and
retrospectively in Al-Shaheed Adnan Hospital Centre for kidney disease and transplantations
in Medical city, Baghdad Teaching Hospital and Al-Karama Teaching Hospital.
Triple immuno-suppresion drug therapy (Cyclosporine A, Azathioprine and
Steroid) was given to all the kidney graft recipients during the induction of
immunosuppression and sometimes during the maintenance phases.
Data of chest infection were taken from
patients’ files for those patients who were checked retrospectively. The
patients' ages ranged 14-65 years. Among the patients who were studied 40 had
chest infection and among the latter nine had pulmonary tuberculosis.
Twenty six patients were male and 14 were
female. The data were obtained from patients during their routine follow
up.
Most
of those patients with pulmonary infection had a serious systemic infection and
stayed in the intensive care unit of renal transplant for several days or
weeks. All such patients underwent septic work up for infections in the post transplant
period-namely blood, urine and sputum cultures for bacteria, Fungi and
mycobacterium (Acid fast bacilli). Four patients underwent fiberoptic
bronchoscopy for bronchial washing/brushing for culture.
Laboratory work up for pulmonary tuberculosis
such as sputum or bronchoalveolar lavage for acid fast bacillus, tuberculin
skin testing were done When initial work up was negative and the problem
persisted despite three days of hospitalization with definitive radiological
findings persisting and in cases where presumptive diagnosis of tuberculosis
was made. Pleural fluid aspiration and pleural biopsy were done when considered
appropriate. The follow up ranged from three days to seven weeks with a mean of
32 days (median 28 days). Diagnosis of pulmonary infection in certain instances
(three patients) was based on therapeutic Trial (Anti -TB) where investigations
failed to reveal basic microbiological diagnosis. Leucopoenia was treated with
Azathioprine withdrawal, blood transfusion and changing the dose of steroid in
appropriate cases. Some results of analysis are expressed as mean ±SD
(Standard Deviation) and compared with Mobia Indian and Hyderabad (HS) studies.
Statistical analysis was carried out
using Chi square test and Yate's correction wherever needed. A P value of less
than 0.05 was taken as significant.
Results
Of the 100 patients who were studied, 40 patients
developed pulmonary infection. Five patients with fungal infection (12.5%)
(nocardiosis in two and candidiasis in three) as proved by sputum culture were
leucopenic and
the patient with Cytomegalovirus (CMV) as (proved by seroconversion) also was
leucopenic. Nine patients had Pulmonary Tuberculosis and two thirds of them (n=6,
66.6%) had their graft from unrelated donors.
We found that patients who have Diabetes
Mellitus and leucopenia were at a high risk of getting post transplant
pulmonary infection (Table II).
Table I. The characteristics of post transplant chest infections
|
Infectious disease of the chest
|
Sex
|
Duration of Renal Transplant
|
Donor/recipient relationship
|
|
|
m
|
f
|
<3m/y
|
>3m/y
|
R.D
|
UR.D
|
|
1. Pneumonia
|
6
|
7
|
3
|
10
|
4
|
9
|
|
2. TB
|
8
|
1
|
2
|
7
|
3
|
6
|
|
3. Fungal infection
|
3
|
2
|
2
|
3
|
1
|
4
|
|
4. Pneumocystic carini pneumonia
|
2
|
0
|
2
|
0
|
1
|
1
|
|
5. CMV
|
0
|
1
|
0
|
1
|
0
|
1
|
|
6. Acute bronchitis (viral)
|
7
|
3
|
8
|
2
|
0
|
10
|
Table II. Risk factors for post-transplant serious infections
|
Renal transplant Pt.
|
Total
|
Sex
|
Diabetes
|
Leucopenia <4000/cmL
|
Renal dysfunction CS.cr.>1.1
|
Age>40yr.
|
|
Hyderabad study (HS)
|
142
|
Male=97 Female=45
|
44(32.8%)
|
18(12.22%)
|
43(28.16%)
|
59(41.5%)
|
|
Baghdad study (BS)
|
100
|
Male=52 Female=48
|
32(32%)
|
56(56%)
|
60(60%)
|
10(10%)
|
|
Pulmonary inf. HS
|
27
|
Male=16 Female=11
|
12(44.4%)
|
8(29.6%)*
|
11(40.01%)
|
15(55.5%)
|
|
Pulmonary inf. BS
|
40
|
Male=26 Female=14
|
20(50%)
|
10(25%)**
|
28(70%)
|
5(12.5%)
|
|
Pulmonary inf.
Related deaths in HS
|
11
|
Male=5 Female=6
|
4(36.36%)
|
3(27.27%)
|
4(36.36%)
|
2(18.1%)
|
|
Pulmonary inf.
Related deaths in BS
|
7
|
Male=4 Female=3
|
4(57.1%)
|
5(71.4%)
|
3(42.8%)
|
2(28.56%)
|
|
|
|
P=0.057
|
P=0.03
|
P= 0.0001
|
P=0.14
|
P=0.73
|
Significant on Chi-square test analysis
* Hyderabad study (HS) =
P< 0.001 **Baghdad study (BS) =
P<0.000
Table III
demonstrates the demographics of our patients.
Forty patients (26 males, 14 females) were diagnosed as having post
transplant chest infection which is compared with the result of the Mutubia study
held in Pakistan.
The mean age of our renal transplant patients was 25.2±6.6 (14-65) years. The
prevalence of Tuberculosis in our patients was 9/40 (22.5%). The onset of the
symptoms was 3-24 (10.2±6.6) months after renal transplantation.
Table IV show the features consistent with
pneumonitis (cough, sputum, fever, fine crackles, radiological opacity or
dyspnoea) necessitating hospitalization were observed in two patients among
those having tuberculosis (TB). While some of these clinical features were seen
in the remaining seven patients: two third had anorexia, nausea and fever, one
third had dry cough and fever, and pleuritic chest pain.
Table V shows the results according to the
investigation that were done to our patients compared with those in the Mobia
Indian study (MS). Pleural effusion was
seen in 4/9 of our patients with TB and pulmonary infiltrate was seen in 5/9
patients. Positive sputum for Acid Fast Bacillus (AFB) was seen in only one of
our patients Exudative pleural fluid was seen in three out of four (75%) of our
patients.
Discussion
In our study, bacterial
pneumonia
was the
commonest pulmonary infection (n=13, 32.5%) followed by the probable acute
viral bronchitis (n=10/40, 25%), pulmonary tuberculosis (n=9, 22.5%) and fungal
infection (n=5, 12.5%) (Nocardiosis in two and candidiasis in three).
Pneumocytis
carinii pneumonia (PCP) was
diagnosed on clinical bases and response to treatment, because of shortage of
diagnostic tests. Though the clinical
findings were not of any diagnostic value per se, the combination of
respiratory failure with interstitial shadowing and few auscultatory lung
signs, which are characteristically due to PCP,
were seen only in two patients in our series with gratifying outcome.
Candida and nocardiasis were the cause of
pulmonary infection in five
patients (12.5%) and they were
the commonest fungal infection in this study. These findings were comparable to
other studies.(25)
A previous study in Iraq by Dr. Ibrahim, summarized
that nocardia asteroids and Candida albicans were the major opportunistic
pathogen for development of pulmonary infection in renal transplant patients.(26)
Table III. Demographic characteristic of patients with pulmonary
tuberculosis in renal transplantation (compared with Mutubai Pakistan study)
|
Number
|
Mutubai study
|
BS
|
|
1. Total No.
|
109
|
40
|
|
2. Patient with TB
|
16(14.6%)
|
9(22.2%)
|
|
3. Age years mean ± SD
|
33.4 ± 11.9
|
25.2±6.6
|
|
4. Sex ratio M:F
|
3:1
|
2:1
|
|
5. Time of RT (in months) when TB detected
|
6.5 ± 4.8 (1-18)
|
10.2±6.6 (3-24)
|
Table IV. Clinical symptoms of pulmonary tuberculosis in renal transplant
patients
|
RT
|
Number
|
%
|
|
1. Loss of appetite / nausea
|
6
|
60.5
|
|
2. Fever persistent low grade / high intermittent
|
3 and 5
|
33.3 and 55
|
|
3. Dry cough
|
3
|
33
|
|
4. Pleural pain
|
2
|
22
|
Table V. Diagnostic procedures performed
in pulmonary tuberculosis patients after renal transplantation (compared with
Mobia study)
|
Diagnostic
procedures
|
M.S N=16
|
B.S N=9
|
|
1. CXR: Plural effusion Pulmonary infiltration
|
3(18.7%) 4(25%)
|
4(44.4%) 5(55.5%)
|
|
2. Suptum for AFB
|
3(18.7%)
|
1(11.1%)
|
|
3. Pleural fluid analysis: exudative transudative
|
3/3(100%) 0(0%)
|
3/4(75%) 1/4(25%)
|
|
4. pleural biopsy
|
3/4(75%)
|
2/4(50%)
|
|
5. Bronchial lavage smear for AFB
|
1/1(100%)
|
2/4(50%) |
Cytomegalovirus (CMV) disease was quite uncommon and because of the lack of diagnostic facilities it was suspected in one patient but the diagnosis
could not be established other than that positive high titers of IgM antibody
to CMV were detected in this patient.
The table also shows that those patients who
received their grafts from unrelated donors, developed post RT pulmonary TB in
a higher percentage (n=6, 66.6%), probably these recipients are more liable for
graft rejection and therefore needed higher doses of immunosuppressive therapy.
Table II shows that recipients who are at
increased risk for infection include those who have leucopenia and diabetes mellitus.
In our series of lung infection,
leucopoenia was present in 56/100 (56%) and 10/40 (25%) of leucopenics had serious
pulmonary infection, among those with serious pulmonary infections 7/10 (70%)
has significant leucopoenia with WBCs<1000 c/ml.
Patients with leucopoenia at an early stage
may have asymptomatic lung infection, they necessitate periodic radiological
screening, and early diagnosis has gratifying outcomes. Though diabetes was
found to be significant risk factor for
serious post transplant pulmonary
infections (P<0.03) it was comparable with others,(27)
however leucopoenia was found to be a significant risk factor for all kinds of
serious infections including pulmonary ones (P<0.0001).
As compared with the Hyderabad study which concluded that age, gender,
diabetes, and impaired renal functions, are not significant risk factors for
post transplant infection, we found in our study that diabetes mellitus and leucopenia
were significant risk factors for post transplant infections.
As the outcome is related to precise
diagnosis, the diagnostic material for cytological study and culture are
important.(28) The specimens for diagnostic work up are
sputum, bronchoalveolar lavage, pleural fluid aspirate in addition to blood
culture and serodiagnosis. The order of
such sample analysis depends upon the case, diagnostic set up, time of
presentation, and initial work up results. In most of our cases, patients
received broad spectrum antibiotics from the first day and depending upon the
initial work up, treatment that begun was either continued (in case of
improvement) or changed In case of no improvement with negative microbiological
reports, patients were given a trial of antituberculous drugs and/or antifungal
therapy based on presumptive possible diagnosis.
Seven out of the 40 patients died (17.5%)
and the causes were as the follows; lung abscess in two patients (28.75%),
undiagnosed in four patient (57.1%) and disseminated tuberculosis in one
patient (14.2%). Out of the deaths, four patients died within three weeks of
hospitalization. The cause of death could be attributed to delay in treatment
in four patients one of them is the patient who died with disseminated TB.
In this study, pulmonary infection
continues to be a common complication of immunosuppression (n=40, 40%) with
high mortality (n=7, 17.2%). Increased awareness and aggressive approach is
required to prevent such fatalities. Renal dysfunction (n=28, 70%) as well as
age and gender were not the major factors in deciding the outcome in pulmonary
infection. Leucopenia (n=10, 25%) and diabetes mellitus (n=20, 50%), with P values
of P=0.0001 and 0.03 respectively, were significant risk factors for all
serious pulmonary infection. Diagnostic problem with delay in appropriate
therapy was a significant predictive factor of death and fatalities were high
in chest infection occurring within the first six months.
The present study underlines the role of
infections in the morbidity and mortality in renal transplant recipients and
highlights the risk of nosocomial exposure hazards if corrective steps are not
undertaken. The hazards of leucopenia, diabetic host and immunomodulating
viruses also look important in this analysis of causation and mortality of
pulmonary infection. The high incidence of post transplant pulmonary TB in our
study is similar to that reported from other centres in developing countries.(29)
In
Iraq and India the prevalence of TB in the general population is 20-25 times
higher than in developed countries and it is 7-8 times higher in end stage
renal disease (ESRD) patients compared to the general population.(29)
In this study the prevalence of TB in
renal transplant patient is 9/40 (22.2%) which is comparable to findings in
other developing countries such as India and Pakistan(30)
and Turkey.(31)
Table III compares the demographic
characteristics of patients with post transplant pulmonary TB in our study with
that in the Mutubai study in Pakistan which shows that the onset of post transplant
pulmonary infections occur later (10.2±6.6 compared 6.5±4.8 months) which may
be due to that the patients become more exposed to the sources of infections as
they come more in contact with the community.
The most common presenting signs of TB in
renal transplant patients in this study (Table IV) were fever and weight
loss. High grade intermittent fever was
most common in renal transplant patients in our study (55%), and in (68%) of renal
transplant patients with TB in Pakistan
by Naqvi et al.(32) and in 63% of patients in India by Sakhuja et
al.(33) In renal transplant patients TB could easily be
mistaken for other common infections, such as Cytomegalovirus
(CMV), that can present with intermittent spiking fever. Further, fever of
unknown origin was seen, only in renal transplant patients necessitating
empiric anti TB therapy.(32,33)
There were nine patients with TB who had
invasive and non invasive investigations. Six of such patients were diagnosed
based on: direct sputum exam in one patient (1/9, 11.1%), bronchoalveolar
lavage in two patients (2/4, 50%), pleural fluid analysis in one patient (1/4, 25%),
histological diagnosis of pleural biopsy in two patients (2/4, 50%) and therapeutic
response to anti TB trial in three patients (3/9, 33.3%). The mortality in such group was one who had
disseminated TB out of nine patients with TB (11.1%) (Table V).
Our results were comparable with those of the
Mobia Indian study; both revealed that the sputum yield is less positively for
acid fast bacillus (AFB) in patients on immunosuppression therapy (1/9, 11.1%) compared with the Mobia
study (3/16, 18.7%).
Pulmonary TB was the most common form of
the disease in renal transplant patients. It presented as either infiltrates or
effusions,(34,35) our results are comparable with those of
others.
Whether post transplant pulmonary
tuberculosis is a reactivation or new infection in our patients is unknown. The
recent molecular epidemiology techniques have shown that reinfection rather
than reactivation of TB occur in immune comprised hosts.(35)
Conclusions
Bacterial pneumonia is the commonest
pulmonary infection (13/40, 32.5%) followed by the probable acute viral
bronchitis (10/40, 25%), pulmonary tuberculosis (9/40, 22.2%) and fungal
infection in five (5/40, 12.5%) with Nocardiosis in two patients and
candidiasis in three.
Tuberculosis presents with high grade
intermittent fever in renal transplant patients. Tuberculosis should be
included in the differential diagnosis of infections causing fever of unknown
origin in the kidney graft recipients, especially in endemic areas.
Leucopenia and diabetes mellitus were
significant risk factors for all serious pulmonary infections. Unrelated donors
are risk factor for post renal transplant pulmonary infections.
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