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Clinical Meetings at RH Year 2008

2008 Clinical Meeting TMH - Where is the Breach?

Drs WAN Chi-kin & KWOK Yuk-lung
Department of Medicine & Geriatrics
Tuen Mun Hospital


A 26-year-old Chinese lady, who enjoyed good past health, presented with persistent fever and cough for 2 months. Her chest X-ray (CXR) on admission showed bilateral nodular infiltrates (Figure 1). The computer tomography (CT) of the chest and abdomen showed bilateral patchy consolidation with upper lobe predominant but no abdominal lesion except mild splenomegaly (Figure 2). Blood test showed progressive pancytopenia, while the renal and liver function tests were normal. Two bone marrow examinations showed normal inflammatory response without abnormal cellularity nor granuloma formation. Extensive bacteriology investigations were negative initially, and autoimmune markers and tumor markers were also negative. Bronchoscopy showed normal endoscopic findings and collected specimen were all negative for bacterial and mycobacterial culture. Board spectrum antibiotics including clavunate/amoxicillin, Piperacillin/tazobactam, carbopenams, amikacin, vancomycin and levofloxacin had been given but without clinical response; fever and abnormal pulmonary infiltrates persisted. Empirical anti-tuberculosis chemotherapy including isoniazid, rifampacin and ethambutol were given after 4 weeks of unrewarding treatment, together with medium dose systemic corticosteroid for presumed of extensive tuberculous pulmonary involvement. Fever subsided but only for 4 days and relapsed just after stopping steroid.


Patient developed painful erythematous papules in right lower limb (Figure 3) at week 6. Skin biopsy showed poorly formed granuloma with Ziehl Neelsen stain positive for acid-fast bacilli (Figure 4). At this point, bone marrow culture confirmed Mycobacterium Chelonae infection, sensitive to imipenem, amikacin and clarythromycin and resistant to doxycyclin and levofloxacin. Skin biopsy as well as blood culture were also positive subsequently for the same organism of similar sensitivity pattern (ST). Sensitivity-guided antibiotic regime with imipenem, amikacin plus clarythromycin was initiated.


However, the patient continued to deteriorate with progression of pulmonary consolidation, skin eruptions and pancytopenia. She later developed massive pericardial effusion. Pericardiocentesis was required to relieve cardiac tamponade. Pericardial fluid culture again grew Mycobacterium Chelonae with the same ST pattern.

Underlying immunodeficiency was suspected. Tests for human immuno-deficiency virus (HIV) infection were performed thrice but were all negative. Anti-interferon-γantibody was negative, T cell function test was requested but declined as the blood sample was taken during extreme cytopenia. Granulocyte-colony-stimulating-factor (GCSF), Buffy-coat transfusion and immunoglobulins were prescribed as salvage therapy, but the results were disappointing.

She later acquired nosocomial pneumonia with septic shock and severe respiratory failure. There was no response to further courses of broad-spectrum antibiotics and vigorous supportive care in the Intensive Care Unit. She deteriorated into multi-organs failure and finally succumbed 4 months after hospitalization.

In summary, this is a case of disseminated Mycobacterium Chelonae infection involving the blood, bone marrow, pericardium, skin, and probably the lungs, which was refractory to sensitivity guided anti-mycobacterium chemotherapy and died of the infection. No specific primary or acquired immunodeficiency could be identified.

Discussion
Non-Tuberculosis Mycobacterium (NTM) infection is uncommon. The Center of Disease Control (CDC) estimated that the incidence was about 1.8 case of NTM/100,000 population. Disseminated NTM infections were even rarer and primarily occurred in immunocompromised patients. About 5.5% of acquired immuno-deficiency syndrome (AIDS) patients suffered from disseminated NTM infection. Mycobacterium Avium Complex (MAC) accounted most of them (96%), while M. Chelonae only accounted for 0.3% of the cohort.

The most relevant primary immunodeficiency that leading to mycobacterium infection is Type I cytokine pathway defect. The pathway consists of Interferon-gamma-receptor (IFN-γ-R), STAT 1 signal transudation and Interleukin-12/Interleukin-12-receptor (IL-12/IL -12R).

When phagocytes encounter mycobacterium, IL-12 is released which stimulates T-helper (Th) cells and Nature Killer (NK) cells to produce IFN-γ, which binds to IFN-γ receptor on phagocyte and initiate bactericidal process (Figure 5).


There was no reported cases of IFN-γproduction deficiency. But there was a small number of reported cases of natural occurring antibodies again IFN- γthat leading to low IFN-γlevel and predisposition to NTM infection . IFN-γ-R2 defect was less common than IFN-γ-R1 defect, and STAT 1 deficiency was even rarer. There were 60 reported cases of IFN-γ-R1 defect, 38 of which were partial deficiencies of dominant inheritance (DP). The other 22 cases were complete deficiency of IFN-γ-R1 of recessive inheritance (RC) ’ . In general, RC form (complete deficiency) presented earlier with more severe infections, especially fast grower NTM with a poorer survival (Table 1). DP form was usually less severe with a better prognosis, but the frequency of NTM osteomyelitis was higher (Table 1). Only 4 reported cases suffered from INF-γ-R2 defect with similar phenotypes with IFN-γ-R1 deficiencies. Three cases have been reported to have STAT 1 defect with universal Mycobacterium Bovis infection after Bacillus Calmette-Guérin (BCG) vaccination during infancy and responded well to anti-microbial chemotherapy .


Both IL-12 production deficiency and IL-12 receptor defect have been reported. There were 16 patients diagnosed to have IL-12 production deficiency, 12 had M. Bovis BCG infection and 5 had Salmonella infection. Ten of them had local and curable infection but 6 patients died of severe infections . Fifty eight patients have been reported to have IL-12 receptor defect, 29 of them had M. Bovis BCG infection, 29 patients had salmonellae infection and 8 of them acquired other NTM infections. IL-12 receptor defect had a better overall prognosis than IL-12 production deficiency (mortality 10% vs. 37%) . Another entity of immunodeficiency is idiopathic CD 4+ lymphocytopenia, which is a reproducible depletion of CD 4+ cells (< 300 cmm) in the absence of HIV infection or other known causes of immunodeficiency according to CDC definition. Fifty patients have been reported to fulfill these criteria and 4 of them suffered from NTM infection, all of which were MAC infections .

There is no randomized controlled trial comparing alternative treatment strategies in refractory disseminated NTM infection in patients with specific related primary immunodeficiencies. There were only sparse experiences in small case series. The most commonly used treatment was IFN-γrepletion. Squires, et al is the pioneer to use INF-γplus anti-NTM chemotherapy to treat 6 MAC bacteremic AIDS patients. The IFN-γtreatments were preliminarily stopped because of clear decline in mycobacteremia . Steven M. Holland, et al also treated 7 MAC patients without AIDS, resulting in clear improvement in clinical parameters . However, patients with complete deficiency of INF-γ receptor demonstrated absolute refractoriness to INF-γ stimulation in vivo and in vitro . There were some other reported successful cases treated with INF-α, IL-12, GM-CSF and bone marrow examination . For cases with disseminated NTM infection without obvious immunosuppression, specific deficiencies in the Type I cytokine pathway should be suspected, albeit these conditions are rare.

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