/ / EN
JOINT WEBSITE OF THE HONG KONG THORACIC SOCIETY AND THE CHEST DELEGATION HONG KONG AND MACAU
back to home

Clinical Meetings at RH Year 2001

2001 - A Lady With Generalized Lymphadenopathy

Dr. KY Wong, Dr. KS Yee, Dr. YC Chan, TB & Chest Unit, Wong Tai Sin Hospital

Case History
A 42-year-old lady presented in October 1998 with fever, chills and right cervical lymphadenopathy. She enjoyed good past health and worked in a garment factory. There was no significant family or travel history. She was admitted to an acute hospital and was investigated as a case of pyrexia of unknown origin. Blood results revealed hypochromic, microcytic anaemia with haemoglobin of 6.5 g/dl. The rest of the blood results were as follows:

• WBC=16, platelet=580
• Hb pattern: normal
• ESR=l00
• ALP =119, AST=44, ALT=43
• albumin=32, globulin=52
• Fe=2 (L), TIBC=4l(L), Ferritin=118(N)

CXR was clear and both upper and lower GI endoscopies revealed no abnormalities. Bone marrow examination showed normal iron store with mild reactive plasmacytosis only. CT abdomen and pelvis demonstrated gallstone in gallbladder neck with prominent common bile duct and a benign-looking linear calcified shadow in liver pedicle. Right cervical lymph node biopsy revealed many caseating tuberculoid granulomas but Ziehl-Neelsen stain did not show any acid-fast bacilli (AFB). At that juncture the diagnosis was tuberculous (TB) lymphadenopathy. Anti- TB drugs (isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (M) were started on 23.1.99 and the patient was then transferred to WTSH. The salient physical findings upon arrival were bilateral cervical lymphadenopathy and erythema nodosum over both shins. Despite the above treatment, she continued to have high swinging fever and persistent leucocytosis. Septic workup was negative. Moreover, she could not tolerate the anti-TB drugs due to the development of skin rash, gastrointestinal upset and arthralgia. Pyrazinamide-induced fever was also suspected and the fever settled after withdrawal of this drug.

The previous lymph node (LN) culture then yielded Mycobacterium Chelonae but no sensitivity testing was done. The patient refused to repeat LN biopsy or LN aspirate. A swab of the discharge from the previous LN biopsy wound was sent for further culture. Ofloxacin and amikacin were added. This was subsequently complicated by extensive erythematous rash with areas of excoriation. She was eventually put on ofloxacin, clarithromycin and HRM. She remained afebrile since then; however, the leucocytosis (WBC=20), anaemia (Hb=8) and lymphadenopathy persisted. Other investigation results included diffuse increase in serum IgG, IgA and IgM level, negative ANF, RF and anti-HIV. In April 1999 she had tonsillar pain and the ENT surgeon diagnosed tonsillitis and a course of Augmentin@ was given and she was discharged. One month later she was admitted to QMH Surgical Unit for increasing pain from enlarging cervical lymph nodes and drug eruptions. A battery of investigations was done:

• Bone marrow aspirate/trephine biopsy: trilineage hyperplasia, the blast count was not increased, no granuloma formation; clonality study was normal; Ph chromosome was negative
• Bone marrow clot for ABF: negative
• Lymphocyte proliferation assay: no significant abnormality
• Lymphocyte subset profile by flow cytometry: no significant abnormality (normal number and % of B-cells/T -cells/NK cells; CD4:CD8 ratio: within normal limits)
• Neutrophil function: normal NBT
• Anti-toxoplasma antibody: negative
• Penicillium marneffei serology: negative

The cervical wound discharge culture subsequently yielded M. Chelonae. TB drugs were then stopped and imipenam/cilastin (Tienam@), clarithromycin and ofloxacin were added consecutively since early June 1999. Her right axillary lymph node started to shrink after 5 days of Tienam@ and other lymph node regions also responded slowly. Figure 1 shows the CT thorax of the patient, demonstrating lymph node enlargement in March 2000 before Tienam@ administration and shrinkage of the lymphadenopathy after treatment. The WBC also normalized. Later the sensitivity results showed that the M. Chelonae was pan-resistant to multiple antibiotics except Tienam@. Tienam@ was given for a total of 12 weeks followed by clarithromycin and ofloxacin. Unfortunately one week later her lymphadenopathy and fever recurred and Tienam@ was re-introduced. Over the next year her disease became Tienam@ dependent, although various antibiotics combinations were tried. Meanwhile, extensive immunologic studies were done:

• Adult onset of heterozygous chronic granulomatous disease and AIDS were excluded.
• α-interferon release assay induced by PHA and M. chelonae was normal.
• Lymphocyte proliferation assay, neutrophil function, T-cells production of interleukin-12 upon stimulation and interferon (IFN) gamma receptor mutation study all showed no significant abnormality.

Gamma IFN and GM-CSF (granulocyte-macrophage colony stimulating factor) were added consecutively to Tienam@but both regimens failed to control the disease. At one point, the patient felt discouraged and sought herbalist's advice, which was in vain. Finally early this year, she returned with diffuse lymphadenopathy and agreed to a prolonged course of Tienam@(500mg q6h, at least 6 months) as suggested by microbiologists. The lymphadenopathy slowly responded. Figure 2 shows the time-course of her disease.

Discussion
Mycobacterium chelonae is a fast-growing Runyon group IV organism (1). M. chelonae, M. fortuitum and M. abscessus together account for more than 80% of the clinical isolates of rapidly growing mycobacteria. Friedmann, in 1903, first isolated M. chelonae from the lungs of two sea turtles (Chelonia corticata).

Epidemiology
As one of the rapidly growing mycobacteria (RGM), M. chelonae is ubiquitous and can be recovered from soil and natural water supply. Investigations of nosocomial outbreaks using DNA fingerprinting pulsed-field gel electrophoresis have demonstrated tap water, ice prepared from tap water, processed tap water used for dialysis, and distilled water used for preparing solution such as gentian violet as the sources. Table 1 shows the known species of RGM and Table 2 lists the common clinical diseases ofRGM.

Clinical Diseases Caused by M Chelonae
As shown in Table 1, chronic lung infection by M. chelonae is uncommon. Yew et al reported a case of M. chelonae being isolated in the trans bronchial biopsy of a 73-year old lady with bronchiectasis and worsening chest symptoms (2). The patient responded well to 2 weeks of amikacin and 10 weeks of Tienam@' RJ Wallace reported 100 cases of M. chelonae chelonae infections identified over 10 years in University of Texas Health Center (3). 53% had disseminated cutaneous infection, 35% localized cellulitis, abscess, or osteomyelitis and 12% were catheter infections. The underlying conditions with disseminated infection included organ transplantation, rheumatoid arthritis, and autoimmune disorders. 92% involved corticosteroid use. Corticosteriod and chronic renal failure were risk factors for catheter infections while trauma and medical procedures were risk factors for localized infection. 6% of patients with disseminated disease did not show any evidence of underlying immunosuppressive disorder.

M Chelonae Lymphadenitis
Lymphadenitis is the main presentation in M. chelonae infection. It is more commonly recognized in young children, occurring mostly in healthy children<12 years old (4). The regions involved are submandibular, submaxillary, cervical or pre-auricular, and are generally unilateral (95%) and non-tender. Other nodal groups outside the head and neck may be involved occasionally. Treatment is by local excision of the affected lymph node. Incision and drainage is usually not recommended because of higher recurrence, risk of fistulae formation with chronic drainage.

In the absence of HIV infection and immunosuppressive disorder, M. chelonae rarely affects adults. Chetchotisakd et al recently reported 16 cases of chronic bilateral cervical lymphadenopathy due to RGM in 'immunocompetent hosts' (5) Twelve had RGM involvement of other organs: sinuses (6), lungs (4), liver (4), spleen (3), skin (3), bone and joints (2), tonsils (2). All the patients were HIV negative, one patient had low CD4 count and eight patients had episodes of prior infection with other opportunistic pathogens (salmonellosis, penicilliosis, TB, melioidosis, cryptococcosis). These suggest that cell-mediated immunity is defective in these patients. Reactive skin manifestations including Sweet's syndrome, erythema nodosum and generalized pustulosis were found in nine patients. M.chelonae/abscessus were isolated in six patients. Only one patient had complete response without relapse after 24 months of amikacin and clarithromycin. Imipenam, amikacin, clarithromycin, kanamycin and cefoxitin in various combinations were given to the other five patients. One patient had relapse after complete response. The remaining four patients just had partial response and one of them, without history of prior opportunistic infection, died. M. abscessus (confirmed by HPLC) was isolated in ten patients. With various antibiotic combinations, there were seven partial responses, one complete response, one complete response with relapse and one death. The author concluded that RGM was a new clinical entity of disseminated infection. This infection should be considered when patients have chronic granulomatous lymphadenitis with progressive involvement of other organs or develop concomitant reactive skin disease.

Anti-microbial Treatment of M chelonae
Isolates of M.chelonae are notoriously drug-resistant. The commonly used antibiotics (sensitivities in parentheses) are: amikacin (70%), imipenem (60%), clarithromycin (100%), tobramycin (100%), doxycycline (25%) and ciprofloxacin (25%). Rapid development of resistance to clarithromycin following monotherapy for disseminated M. Chelonae infection was reported in 1994. According to the American Thoracic Society Official Statement, susceptibility testing of the rapid growers should not be performed on the standard anti-TB agents (6). They should be tested against antibacterial drugs including amikacin, doxycycline, imipenem, the fluoroquinolones, a sulfonamide, cefoxitin and clarithromycin. The treatment of nontuberculous mycobacteria cervical lymphadenitis is primarily by surgical excision alone, with 95% cure rate. A clarithromycin-containing regimen should be considered for patients with extensive disease or poor response to surgery. In general, treatment of nonpulmonary rapidly growing mycobacteria should include drugs such as amikacin and clarithromycin, based on in-vitro susceptibility tests. However, there is no controlled clinical trial with regard to the duration of treatment. For serious disease, a minimum of 4 months of therapy is necessary to provide a high likelihood of cure. For bone infections, 6 months of therapy is recommended. Surgery is generally indicated with extensive disease, abscess formation, or where drug therapy is difficult.

References
  1. Wolinsky E. Nontubercu1ousmycobacteria and associated diseases. Am Rev Respir Dis 1979; 119(1):107-159.
  2. Yew WW,Lau KS, Tse WK, Wong CF. Imipenem in the treatment of lung infections due to Mycobacterium fortuitum and Mycobacterium che1onae:further experience. C1inInfect Dis 1992; 15(6):1046-1047.
  3. Wallace RJ, Brown BA, Onyi GO. Skin, soft tissue, and bone infections due to Mycobacterium che1onaeche1onae:importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to oral antimicrobials other than clarithromycin. J Infect Dis 1992; 166(2):405-412.
  4. Wright JE. Non-tuberculous mycobacterial lymphadenitis. Aust N Z J Surg 1996; 66(4):225-228.
  5. Chetchotisakd P, Mootsikapun P, Anunnatsiri S, Jirarattanapochai K, Choonhakam C, Chaiprasert A, Dbo1 PN, Wheat LJ, Davis TE. Disseminated infection due to rapidly growing mycobacteria in immunocompetent hosts presenting with chronic lymphadenopathy: a previously unrecognized clinical entity. Clin Infect Dis 2000; 30(1):29-34.
  6. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association. Am J Respir Crit Care Med 1997; 156(2Pt 2):SI-25.
Top