Extrapulmonary Involvement of Mycobacterial Infections in
Dialysis Patients
A.F. Oner-Eyuboglu, M.S. Akcay, H. Arslan, B. Demirhan, and A.F. Kalpaklioglu
E ND-STAGE renal disease (ESRD) leads to changes in
host defense mechanisms, particularly impairment of
cellular immunity, that causes higher incidence of mycobac-
terial infections as compared to general population.1 In
areas where tuberculosis (TB) is endemic, the incidence of
mycobacterial infections in chronic renal failure patients is
reported to be 10 times higher.2 Reactivation of the dor-
mant microorganisms due to deficient host defense is
suggested to be the main cause of mycobacterial infection in
ESRD patients.3 Furthermore in these patients, extra pul-
monary involvement of mycobacterial infections appears to
be more frequent than isolated pulmonary disease. How-
ever, because extrapulmonary manifestations usually
present in atypical forms, diagnosis can be delayed or
missed entirely.4
In western countries the association between ESRD and
mycobacterial infections is well documented, particularly
TB. However, information is scanty on this patient popula-
tion in regions where TB is endemic, mainly due to the lack
of yearly statistical records. Turkey is one country where TB
remains an important cause of morbidity and mortality; to
date, no large studies have been carried out with regard to
the incidence of mycobacterial infection in CRF patients in
Turkey. In this descriptive study, we analyzed data of 36
patients who were diagnosed with mycobacterial infection
from a total of 407 at our center over a 15-month period.
METHODS
This descriptive study was carried out on 407 chronic renal failure
(CRF) patients on dialysis at Baskent University Hospital. We
reviewed the hospital records and outpatient follow-up of 36 of
these patients who developed mycobacterial disease during the
period from April 1997 through September 1998. Routine investi-
gations on patients suspected of having mycobacterial infection
included a whole blood picture, biochemical profile, chest x-ray,
tuberculin skin testing (PPD), sputum smear (Ziehl-Neelsens
stain), and culture (on Loewenstein-Jensen media) for acid-fast
bacilli. When the investigations were inconclusive and mycobacte-
rial infection was still strongly suspected, patients underwent more
invasive diagnostic procedures including biopsy and culture of
tissue from suspected sites. Diagnosis of mycobacterial infection
was based on two criteria: (1) demonstration of mycobacterium on
a smear or a culture, and (2) demonstration of caseating granulo-
mata or acid fast staining bacilli on histologic examination. In the
presence of fever of unknown origin or where there were symptoms
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Transplantation Proceedings, 31, 31993201 (1999)
and clinical findings of TB, mycobacterial infection was considered
likely.
Patients tuberculin sensitivity was measured after 72 hours of
administration of 5 units of polysorbate 80 stabilizied PPD. Indu-
ration of 10 mm in diameter was considered a positive response,
while that 10 mm of induration was labeled negative. Anergy was
defined as the absence of induration of 2 mm in diameter.
The treatment protocol for all patients consisted of a 9- to
12-month therapy with isoniazid (INH) 5 mg/kg/d, rifampicin
(RMP) 10 mg/kg/d, pyrazinamide (PZA) 20 mg/kg/d, ethambutol
(EMB) 20 mg/kg/d, or ciprofloxacin 1000 mg/d. Duration of
follow-up ranged from 2 to 15 months.
The clinical charts of the 36 patients diagnosed with mycobacte-
rial infection were viewed for demographic information, duration
of CRF, presence of coexisting disease other than CRF, sites of
involvement, clinical characteristics of the disease, chest x-ray
findings, methods of diagnosis, drug treatments used and related
toxicities, and clinical outcome.
RESULTS
Patient Population
Between April 1997 and September 1998, mycobacterial
infection was diagnosed in 36 of the 407 CRF patients, the
incidence being 8.8%. This group included 18 men and 18
women with a mean age of 39.8 2.4 years. The mean
SD duration of dialysis at the time of diagnosis was 74.9
105.8 days. The underlying renal disease could not be
determined in most of these patients. Three patients had
received a renal transplant but had returned to dialysis
therapy due to graft rejection. Six individuals had a history
of previous TB. Four of these six patients had radiologic
evidence of TB (residual fibrotic lesions and calcifications
on chest x-ray) and none had a history of close contact with
a pulmonary TB patient. The mean time interval between
the start of symptoms and diagnosis of mycobacterial
infection was 30.6 37.7 days with a range of 20 days to 11
months. Of the 36 patients, 13 had a history of coexisting
disease in addition to CRF: amyloidosis (n 3), hepatitis B
From the Departments of Pulmonary Diseases (A.F.O.E.,
M.S.A., A.F.K.), Microbiology (H.A.)and Department of Pathology
(B.D.), Baskent University, Ankara, Turkey.
Address reprint requests to Oner-Eyuboglu A. F, MD, Baskent
University Hospital, Department of Pulmonary Diseases, 1.
Cadde, No: 77 Kat: 4, Bahcelievler, 06490, Ankara, Turkey.
0041-1345/99/$see front matter
PII S0041-1345(99)00686-7
3199
3200
and C (n 4), coronary artery disease (n 3), nephrotic
syndrome (n 1), and ovarian cyst (n 1).
Clinical Presentation
Malaise (58.3%) and fever (52.8%) were the most frequent
symptoms followed by anorexia and weight loss (27.8%),
palpable lymph nodes (22.2%), nausea (19.4%), night
sweats (11.1%), and hemoptysis (8.3%). Patients with pleu-
ral and peritoneal thickening or fluid also had cough,
pleuritic pain, and abdominal distension. Only one patient
was asymptomatic at the time of diagnosis.
The predominant disease localization was extrapulmo-
nary in 24 patients (66.7%), the majority (n 14, 40.5%)
presenting with lymphadenitis. Cervical lymph nodes were
affected in five patients, abdominal nodes in four, medias-
tinal nodes in three, and axillary nodes in three cases. The
urinary tract and bone were the sites involved in the
remaining patients. Isolated pulmonary disease was diag-
nosed in five (13.9%) patients. Seven individuals presented
with multiple organ involvement: lung and pleura (n 2,
5.6%), lung and lymph nodes (n 5, 13.9%). Miliary
mycobacterial infection was present in three patients with
an incidence of 8.3%.
PPD Skin Test, Microbiological and
Pathologic Identification
Tuberculin reactivity was positive in 10 patients (27.8%),
negative in 4 patients (11.1%), and anergic in the remaining
19 (52.8%) patients. PPD results of three patients (8.3%)
were unknown. Acid-fast smears (Ziehl Neelsens stain)
were positive only in three patients (one sputum smear, two
urine sample). Eleven patients (30.6%) were diagnosed
with TB by culturing Mycobacterium tuberculosis in Lowen-
stein-Jensen culture media. In the remaining 22 cases
(61.11%), identification of acid-fast bacilli and/or caseous
granulomas on histopathologic examination of tissue biop-
sies confirmed the mycobacterial infection. Cultures for
atypical mycobacteria could not be obtained under our
labratory conditions. Of these 36 patients, 19 had abnormal
chest x-rays. Four patients radiographs revealed infiltra-
tions that indicated more recent infection, five patients had
calcifications and scar lesions that indicated older infec-
tions, three had pleural effusion, and seven presented
enlargement at the hilar and/or mediastinal region.
Treatment and Outcome
Because we were unsuccessful in isolating atypical myco-
bacterial agents, all the patients were treated as if they had
TB and were thus initially give four-drug therapy. The
initial regimen consisted of INH, RMP, PZA, EMB/cipro-
floxacine. After 2 months of this treatment, patients con-
tinued on INH and RMP for 9 to 12 months. Toxicity
secondary to the use of antituberculosis drugs occured in six
(16.1%) patients: three developed hepatotoxicity, one de-
veloped hyperuricasidemia, and two had peripheric neurop-
athy. In each of these cases, we interrupted the therapy for
ONER-EYUBOGLU, AKCAY, ARSLAN ET AL
a period, and then continued once the abnormal parame-
ters returned to normal levels. Dose reduction was neces-
sary in six patients. In six patients we had to stop EMB and
replaced it with ciprofloxacine because of gastrointestinal
irritation, eye and ear problems. Currently, 23 patients are
still on therapy, seven have completed therapy, two patients
died during treatment and 1 patient refused to continue
after 3 months of the regimen.
DISCUSSION
Mycobacterial disease in Turkey continues to be an impor-
tant cause of morbidity and mortality. However, to date no
large study has been done on the incidence of these
infections in CRF patients. The incidence of TB is very high
in Turkey, estimated at 31.5 cases per 100,000 in 1997
(unpublished data). Cengiz observed that the overall inci-
dence of mycobacterial infections was 23% in a 12-year
follow up study at a dialysis center.5 Our data confirmed
this finding, with an incidence of 8.6%, 273 times higher
than the average for the general population.
Although past studies have reported no significant in-
crease in the incidence of mycobacterial infections in
dialysis patients6 compared to the general population, our
results are consistent with those of more recent research.2,3
Many case reports in literature discuss mycobacterial infec-
tions (particularly TB) in CRF patients, but there are few
studies that involve large series.2,8 Our descriptive study
was carried out on data that we collected over a 15-month
period from 407 CRF patients who were on regular dialysis
program. Of these 407, 36 patients were infected with
mycobacterium. In Rutskys study, collected over 8 years,
mycobacteriosis developed in 9 of 885 CRF patients.2 In
Kwans study eight of 209 CRF patients developed myco-
bacterial infection within 2 years.1 When compared to the
previous studies, our data represent the largest series
published so far which is collected in only 15 months. This
result could be explained by the reactivation of infection
induced by depressed cellular immunity in this patient
group. Also, because TB is endemic in Turkey, physicians
greater awareness and suspicion of mycobacterial infection
(particularly TB) in CRF patients and the more aggressive
evaluation of this type of the infection could explain its high
incidence.
A high frequency of predominantly extrapulmonary in-
volvement of mycobacterial infection in CRF patients has
been noted in the literature.3,4,8 Our results confirmed
these findings, with an incidence of 66.7%. Lymph node
involvement was predominant followed by that of serous
membranes. Isolated pulmonary involvement occured in
only four patients. The reasons for the predominance of
extrapulmonary disease are unclear but age and ethnic
background have been highlighted to be responsible.7 Be-
cause TB is endemic in Turkey, and mean age of our
patients was relatively young at 39.8 12.4 years, we
believe that other host factors are operating. These could
include reactivation of dormant TB bacilli in extrapulmo-
EXTRAPULMONARY MYCOBACTERIAL INFECTION
nary organs, or infection with nontuberculosis mycobacte-
ria.
A high incidence of infection with nontuberculosis my-
cobacteria has been noted in CRF patients who have
extrapulmonary disease involvement.9 Our results are lim-
ited in this respect, since we were unable to isolate atypical
mycobacteria in our laboratory. Had this been possible, we
would have been better informed about the development of
atypical mycobacteriosis. M. tuberculosis was isolated in
only one-third of our patient population but the remaining
was M. tuberculosis culture (negative) patients, suggesting
the presence of non tuberculous mycobacterial disease.
In majority of our patients, mycobacterial infection was
diagnosed (12 months) prior to or early in, the course of
dialysis.2 We observed that development of mycobacterial
infection occured within the first 3 years of dialysis therapy.
This finding is consistent with the observation that azotemia
causes impairment of cellular immunity in CRF patients.2,7
All of our cases were diagnosed as mycobacterial infection
within the first year of onset of symptoms. This likely
reflects our high index of suspicion of such infections, as has
been suggested in the literature. Like others, we found
malaise, fever, anorexia weight loss were the most common
features of dialysis-associated mycobacterial infections.7,10
Conflicting results appeared concerning the PPD skin test.
Some investigators have claimed that consistently negative
skin test result from impairment of patients cellular immu-
nity,2,7 whereas others have reported positive tests in 62%
of their cases.5 In our series, 52.8% of the patients were
anergic and 11.1% were negative, suggesting that PPD skin
test results should not be accepted as a significant diagnos-
tic test in immunocompromised patients. First line treat-
ment included the antimycobacterial drugs including INH,
3201
RMP, PZA, EMB. Patients generally tolerate and respond
well to therapy. Because most of our patients are still
receiving treatment, our experience in this regard cannot be
fully interpreted. Only one of our patients died due to
miliary TB. This rate contrasts to previous reports that have
indicated a high mortality of mycobacterial infections5,8 but
is consistent with another study done in Turkey.5
In conclusion, patients with CRF, and especially those on
long-term dialysis, should be considered to be at signifi-
cantly high risk for mycobacterial infection. In areas where
TB is endemic, a careful evaluation of CRF patients for
evidence of mycobacterial infection and close follow-up to
facilitate early detection is essential. Aggressive extrapul-
monary evaluation is necessary in cases who have a high
index of suspicion for mycobacterial infection.
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