Tuberculous Osteomyelitis in the Ulna of a Patient

135

□ CASE REPORT □

Tuberculous Osteomyelitis in the Ulna of a PatientUndergoing Hemodialysis

Yuka Nakazawa 1, Tomoya Nishino 1, Atsushi Mori 1, Tadashi Uramatsu 1,2, Yoko Obata 1,3,

Hideyuki Arai 1, Hideyuki Hayashi 4, Shoko Tsukasaki 5, Yoshiaki Muraya 6, Yuichi Inoue 6,

Yoshihiro Yamamoto 1 and Shigeru Kohno 1

Abstract

A 76-year-old woman on hemodialysis (HD) presented with pain and swelling in the left wrist and fore-

arm. The osteomyelitis occurred in the part of the ulna adjacent to the arteriovenous fistula. Mycobacteriumtuberculosis was identified in pus obtained from the left forearm, leading to a diagnosis of tuberculous osteo-

myelitis. The patient was treated with anti-tuberculous drugs and her symptoms improved. In this study, we

report a case of tuberculous osteomyelitis occurring in the ulna, which is not the usual site of predilection for

tuberculosis infection. As HD patients exhibit a high frequency of extrapulmonary tuberculosis, tuberculous

osteomyelitis should be considered in the differential diagnosis of infectious osteomyelitis. In addition, it may

be useful to perform stab cultures at an early stage in order to diagnose tuberculous osteomyelitis.

Key words: tuberculous osteomyelitis, ulna, hemodialysis, arteriovenous fistula, Mycobacterium tuberculosis

(Intern Med 52: 135-139, 2013)(DOI: 10.2169/internalmedicine.52.8437)

Introduction

Tuberculosis (TB) is the leading cause of illness and

death in many countries and has become a global public

health problem. Moreover, decreased immunity in end-stage

renal disease (ESRD) patients results in a high prevalence

and mortality rate of TB in this population compared to that

observed in the general population (1, 2).

Extrapulmonary TB, either isolated or associated with

pulmonary TB, has been reported to occur in approximately

60-80% of patients undergoing hemodialysis (HD) (3-6). Pa-

tients with extrapulmonary TB often present with many non-

specific symptoms such as general malaise, poor appetite,

low-grade fever, weight loss, night sweats and lymphadeno-

pathy (2, 7). It is particularly difficult to differentiate tuber-

culous osteomyelitis from bacterial osteomyelitis or bone tu-

mors. Therefore, there is an average time gap of 3-6 months

between the first appearance of symptoms and diagno-

sis (8-11). This held true in the present case, as six months

were required to reach a diagnosis of tuberculous osteomye-

litis. At the onset of symptoms, the patient experienced pain

and swelling of the left wrist and forearm. Magnetic reso-

nance imaging (MRI) showed osteolytic changes and ab-

scess formation in the left ulna. Based on these findings, we

first suspected a diagnosis of pyogenic osteomyelitis caused

by bacteria. The results of a culture test of the pus dis-

charged from the disintegrated skin of the left forearm were

positive for M. tuberculosis, and the patient was definitively

diagnosed with tuberculous osteomyelitis. To the best of our

knowledge, there have been no previous reports of tubercu-

lous osteomyelitis occurring in the ulna of an HD patient.

Even though the ulna is not a site of predilection for TB in-

fection, tuberculous osteomyelitis should be considered in

the differential diagnosis of infectious osteomyelitis in

ESRD patients.

１The Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan, ２Division of Blood Purification, Nagasaki Uni-

versity Hospital, Japan, ３Medical Education Development Center, Nagasaki University Hospital, Japan, ４Department of Radiology and Radiation

Biology, Nagasaki University Graduate School of Biomedical Sciences, Japan, ５Tanaka Clinic, Japan and ６Isahaya Health Insurance General

Hospital, Japan

Received for publication June 21, 2012; Accepted for publication September 23, 2012

Correspondence to Dr. Tomoya Nishino, [email protected]

Intern Med 52: 135-139, 2013 DOI: 10.2169/internalmedicine.52.8437

136

Table.　Laboratory Data on Admission

RBC 362×104 Na 142 mEHb 10.5 K 4.4 mEPlt 33.1×104 Cl 104 mEWBC 6,600 Ca 10.6

Neut 67.4 % BUN 44ym 18.8 % Creatinine 8.6

Mon 9.0 % TP 6.8Eosi 3.9 % 2.8Baso 0.9 % T-Cho 182

T-Bil 0.3PT 86.9 % AST 13PT(INR) 1.10 5APTT 28.3 sec 157Fibrinogen 491 -GTP 18

163ESR 1hr 48 mm Glucose 126

2hr 60 mm CRP 1.74RBC: red blood cells, Hb: hemoglobin, Plt: platelets, WBC: whiteblood cells, Neut: neutrocytes, ym: lymphocytes, Mon: monocytes, Eosi: eosinophils, Baso: basophils, PT: prothrombin time, INR: international normalized ratio, APTT: activated partial thromboplastin time, ESR: erythrocyte sedimentation rate, Na: sodium, K: potassium, Cl: chrolide, Ca: calcium, BUN: blood urea nitrogen, TP: total protein,

B: albumin, T-Cho: total cholesterol, T-Bil: total bilirubin, AST: aspartate aminotransferase, A T: alanine aminotransferase, P: alkaline phosphatase, -GTP: -glutamyltransferase, H: lactate dehydrogenase, CRP: C-reactive protein

Figure　1.　Radiographs of the left forearm region on ob-tained admission and 18 months after the initiation of treat-ment. A. A radiograph of the left forearm region obtained on admission showing fractures in the distal end of the left ulna with osteolytic changes. B. A radiograph of the left forearm region obtained 18 months after the initiation of treatment showing bone reconstruction and formation of the ulna.

Case Report

The patient was a 76-year-old woman without a history of

TB. She began to undergo HD in January 2005 due to

ESRD caused by benign glomerulosclerosis. Since then, she

had undergone HD three times a week at a nearby hospital.

Since December 2006, she had experienced pain in her left

wrist and forearm. In March 2007, she developed worsening

pain and swelling in the left wrist and forearm and pre-

sented with a low-grade fever and elevated levels of white

blood cells (WBCs) and C-reactive protein (CRP). A diag-

nosis of bacterial cellulitis was suspected, and antibiotics

(amoxicillin, levofloxacin and minocycline hydrochloride)

were administered. After receiving antibiotic treatment, the

patient showed a slight improvement in her symptoms; how-

ever, the elevated levels of WBCs and CRP did not return to

normal. She was admitted to our hospital in April 2007 for

further examination and treatment.

On admission, the patient’s height was 153 cm, her dry

weight was 59.8 kg, her body temperature was 36.2℃ and

her blood pressure was 191/83 mmHg. Upon physical ex-

amination, she showed redness and swelling on the distal

side of the left forearm. The laboratory data were as fol-

lows: WBCs, 6,600/μL; neutrophils, 67.4%; lymphocytes,

18.8%; monocytes, 9.0%; CRP level, 1.74 mg/dL; erythro-

cyte sedimentation rate (ESR) 1 h/2 h, 48/60 mm; total pro-

tein (TP) level, 6.8 g/dL; albumin level, 2.8 g/dL; and Ca

level, 10.6 mg/dL. These data indicated the presence of a

mild inflammatory reaction, hypoalbuminemia and hypercal-

cemia (Table). Radiographs of the left forearm revealed a

fracture with osteolytic changes at the distal end of the ulna

(Fig. 1A). MRI revealed bone destruction in the left ulna

(Fig. 2A, B), and the bone marrow showed low signal inten-

sity on T1-weighted images with fluid accumulation in the

surrounding soft tissue (Fig. 2A). On the basis of these re-

sults, we suspected the presence of bacterial osteomyelitis

and abscess formation.

After performing curettage of the left ulnar lesion, we

scheduled placement of a continuous perfusion drain. How-

ever, since the arteriovenous fistula used for vascular access

was located ipsilateral to the lesion, there were risks for

massive bleeding during the procedure and for infection

spreading to the arteriovenous fistula and subsequently to

the patient’s entire body. Therefore, we performed surgery

to close the arteriovenous fistula. After surgery, pus dis-

charge was observed from the disintegrated skin surrounding

the swollen region of the left forearm. To identify the spe-

cific pathogen causing the osteomyelitis, we performed a

culture test and a polymerase chain reaction (PCR) test on

the pus. The results of Gram and Ziehl-Neelsen staining

were negative; however, the culture and PCR test results

were positive for M. tuberculosis. Based on these findings,

the patient was diagnosed with tuberculous osteomyelitis of

the left ulna. Therefore, we cancelled the planned drainage

and initiated treatment with anti-tuberculous drugs (rifam-

picin, 450 mg/day; isoniazid, 300 mg/HD day; and strepto-

mycin, 0.5 g/twice a week; via intramuscular injection). We

also assessed the patient for pulmonary TB using chest radi-

ography and computed tomography; however no pulmonary

lesions were found. Four weeks after the initiation of anti-

mycobacterial treatment, the patient began to show de-

creased inflammation and improved imaging findings on

both radiography and MRI (Figs. 1B, 2C, D). The patient

received 15 months of anti-mycobacterial treatment (rifam-

picin, 450 mg/day; isoniazid, 300 mg/HD day; streptomycin,

0.5 g/twice a week; via intramuscular injection) and thus far


137

Figure　2.　MRI images of the left forearm obtained on admission and eight weeks after the initia-tion of treatment. On admission, bone destruction was observed in the metaphysis of the left ulna. The surrounding marrow presented a low signal on a T1-weighted image. Fluid accumulation was also observed in the surrounding soft tissue. New bone formation was observed and fluid accumula-tion was decreased in the soft tissue eight weeks after the initiation of treatment. A. A T1-weighted image (T1WI) obtained on admission; B. A T2-weighted image (T2WI) obtained on admission; C. A T1WI obtained eight weeks after the initiation of treatment; and D. A T2WI obtained eight weeks after the initiation of treatment.

has shown no evidence of relapse.

Discussion

The incidence of TB among HD patients is reported to be

6-25 times higher than that observed in the general popula-

tion (2). Moreover, the mortality rate of HD patients with

TB is 17-75% (1). A common finding associated with ure-

mia is impaired immunity, including disorders of T-

lymphocyte growth and activation, lymphopenia and de-

creased antigen-specific humoral immunity mediated by T-

lymphocytes (12). In addition, several factors specific for

HD patients, such as malnutrition, anemia, vitamin D defi-

ciency and hyperparathyroidism, may further contribute to

impaired immunity (13-16). Therefore, HD patients are con-

sidered to have high susceptibility to TB, and latent TB is

52.5 times more likely to be reactivated in patients with re-

nal failure than in the general population (1, 17).

Extrapulmonary TB, either isolated or associated with

pulmonary TB, has been reported to occur in approximately

60-80% of HD patients. The most common forms of ex-

trapulmonary TB are lymphadenitis, gastrointestinal, bone,

genitourinary, peritoneal, pleural, pericardial and miliary

TB (3-6). Osteoarticular TB has been reported to account

for 12.5% of extrapulmonary TB cases in HD patients. The

most common site of osteoarticular TB is the spine, ac-

counting for 56% of all cases, followed by joints. Tubercu-

lous osteomyelitis occurring in the long bones, as was ob-

served in our patient, is uncommon (18). Although the

mechanisms by which M. tuberculosis reaches bone are un-

known, the pathogen is thought to do so hematogenously, as

it commonly grows within the marrow cavity. In most cases,

osteoarticular TB is caused by an endogenous reactivation of

M. tuberculosis from a latent lesion. Usually, these lesions

remain inactive; however, they can reactivate when cellular

immunity is decreased (19, 20). In the present case, no pul-

monary lesions were found. Therefore, in the present case,

tuberculous osteomyelitis likely developed from an already

infected focus of the previously disseminated ulnar region.

However, another possible pathogenesis in this case is that


138

reactivated M. tuberculosis, as a result of decreased immu-

nity due to advanced age and ESRD, moved to the left ulna

via the blood stream and became associated with the arte-

riovenous fistula.

Since tuberculous osteomyelitis does not generally present

with any characteristic imaging findings or clinical manifes-

tations, it is difficult to differentiate between bacterial osteo-

myelitis and bone tumors. Therefore, an average time of 3-6

months passes from the first appearance of symptoms to di-

agnosis. As possible points of differentiation between bacte-

rial osteomyelitis and tuberculous osteomyelitis, Monach et

al. reported that patients with tuberculous osteomyelitis pre-

sent with a low-grade fever and exhibit so-called “cold ab-

scesses” that are without local redness or warmth (21).

However, in the present case, redness and swelling were ob-

served on the distal side of the left forearm, which is an un-

common site of tuberculous osteomyelitis. Another differen-

tial point is that hypercalcemia is observed in 2.3-51% of

TB patients, although the prevalence of hypercalcemia in pa-

tients with TB varies widely (13). Hypercalcemia in TB pa-

tients is considered to be caused by an increased production

of 1,25(OH)2D3, which enhances calcium absorption in

granulomatous lesions (22). It is important to note that our

patient was not administered drugs, such as calcium carbon-

ate or active vitamin D, that can elevate the serum Ca lev-

els. In addition, the patient did not have secondary hyper-

parathyroidism, malignant tumors or any granulomatous dis-

eases other than TB. After the administration of anti-

tuberculous treatment, the patient’s levels of serum Ca de-

creased and became normal (Ca; 9.0 mg/dL). Therefore, the

hypercalcemia observed in the present case may have been

caused by the tuberculous osteomyelitis.

Regarding the early diagnosis of extrapulmonary tubercu-

losis in HD patients, there are some points that should be

considered. First, as extrapulmonary TB is common in HD

patients, the possibility for tuberculosis should be always

considered. Second, because appropriate specimens may be

difficult to obtain from some sites, acquiring bacteriological

confirmation is often more difficult for extrapulmonary TB

than for pulmonary TB. Moreover, relatively few M. tuber-culosis organisms are present in extrapulmonary sites, and

identification of acid-fast bacilli in specimens obtained from

these sites using microscopy is infrequent. Therefore, per-

forming PCR tests for TB in addition to cultures and histo-

pathological examinations of tissue specimens, such as those

that may be obtained with needle aspiration or biopsies, as

diagnostic tests for extrapulmonary TB is recom-

mended (23). Third, the tuberculin skin test exhibits poor

sensitivity in HD patients. Recently, many reports have in-

vestigated the usefulness of the QuantiFERON-TB test

(QFT) as a tool for diagnosing TB (2). Although we did not

perform a QFT in our patient because the practice had not

been widely adopted at the time of treatment, QFTs might

be useful for making future diagnoses. Therefore, enhanced

awareness of TB in HD patients along with providing earlier

diagnosis and treatment may improve the outcomes of infec-

tion in these patients.

Regarding the treatment of tuberculous osteomyelitis,

multidrug therapy using three to four drugs for six to 12

months or more is recommended, while surgical drainage is

not usually recommended as an initial therapy (24). In the

present case, 15-month treatment with rifampicin, isoniazid

and streptomycin resulted in improvements in the patient’s

inflammatory reaction and imaging findings, and no recur-

rence has since been reported. We selected this treatment

regimen for the patient, although it was not the standard

protocol, because the patient was elderly and had defective

cellular and humoral immunity caused by ESRD and HD.

Additionally, she showed gradual improvements on imaging

tests.

In this case, the osteomyelitis occurred in the part of the

ulna adjacent to the arteriovenous anastomotic region. Gen-

erally, patients on HD are at an increased risk of developing

infections and bacteremia. The incidence rate of bacteremia

ranges from 0.04 to 0.55/1,000 patient-days for arte-

riovenous grafts or arteriovenous fistulae (25). Most cases of

infectious arthritis and osteomyelitis in HD patients are most

likely caused by bacteremia (26). Al-Nammari et al. re-

ported that the incidence of microbiologically proven infec-

tious arthritis in HD patients is under 0.5% per year (27).

The majority of bacteremia and infectious osteomyelitis

cases are caused by Gram-positive organisms; Staphylococ-cus aureus and S. epidermidis are the responsible organisms

in approximately 70% of cases (28, 29). Therefore, at first,

we suspected a diagnosis of osteomyelitis caused by bacte-

ria, and the patient was treated with antibiotics. In addition,

considering the location of the lesion, the risk that the infec-

tion might spread throughout the patient’s entire body or

that the arteriovenous fistula might rupture was high. There-

fore, we also performed closure surgery on the arteriovenous

fistula in order to prevent dissemination of the infection.

When an arteriovenous fistula is located adjacent to a lesion

of infectious osteomyelitis, closure of the fistula and recon-

struction of the arteriovenous fistula in the contralateral limb

should be considered.

The number of HD patients is increasing worldwide, in-

cluding in Japan; therefore, we speculate that the incidence

of TB among HD patients will also increase in the future.

Therefore, when HD patients develop infectious osteomyeli-

tis, it is important to determine if the infection is caused by

M. tuberculosis. Furthermore, it is also necessary to perform

a stab culture or a PCR test for M. tuberculosis at an early

stage in patients with infectious osteomyelitis who show a

poor response to antibiotic therapy.

The authors state that they have no Conflict of Interest (COI).

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Tuberculous Osteomyelitis in the Ulna of a Patient