Emergence of disseminated infections due to nontuberculous mycobacteria in non-HIV-infected patients, including immunocompetent and immunocompromised patients in a university hospital in Taiwan

doi:10.1016/j.jinf.2005.10.009

Journal of Infection

Volume 53, Issue 2, August 2006, Pages 77-84

https://doi.org/10.1016/j.jinf.2005.10.009 Get rights and content

Summary

Objectives

Although disseminated nontuberculous mycobacteria (NTM) infection has been increasingly reported in patients with AIDS, this condition is still considered rare in non-HIV-infected patients.

Methods

We retrospectively reviewed the medical records of non-HIV-infected patients treated at National Taiwan University Hospital from January 1997 to December 2004 to search for epidemiological trends in disseminated NTM infection. Data analyzed included etiology, demographic characteristics, underlying disease, initial symptoms and signs, treatment, and outcomes.

Results

Disseminated NTM infections occurred in 15 non-HIV-infected patients during the study period. The mean age of these patients was 51 years (range 13–80). Among these patients, eight were males, and eight had various immunocompromised conditions. Fever was an initial presentation in 12 patients (80%). Diagnosis was made by positive blood (seven patients) or bone marrow culture (five patients) in the majority (73%) of patients. Infectious etiologies included Mycobacterium avium complex (MAC) in eight, rapidly growing mycobacteria (RGM) in four and Mycobacterium kansasii in three. The mean time from initial presentation to initiation of anti-NTM therapy was 130 days (ranged from 9 days to 17 months). Mortality was highest in patients with M. kansasii (100%), followed by RGM (25%) and MAC (12.5%).

Conclusions

Although disseminated NTM infection is an emerging condition among patients without HIV infection, it is a condition which is associated with immune deficiency. A high level of clinical suspicion should be maintained for avoiding delayed diagnosis, especially in patients with underlying immunosuppression. Blood culture might play an important role in the early diagnosis of disseminated NTM disease. Early diagnosis can lead to appropriate diagnosis and reduce mortality.

Introduction

Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, readily isolated from water, soil, domestic and wild animals, milk, and foods.¹ NTM infection is commonly acquired from environmental sources including water and soil.² These bacteria are not always pathogenic when isolated from human samples, and the identification of which isolates are pathogenic, contaminants or colonizers is based on internationally recognized criteria.3, 4 These organisms have been implicated in an increasing number of human diseases around the world. The increase in AIDS prevalence in developed countries has contributed to a rise in NTM infection.5, 6, 7 However, increasing vigilance and awareness of these bacteria as human pathogens, improvements in methods of detection and culture, and increased population of immunocompromised hosts have also contributed to the apparent increase in disease burden.3, 4

Most disseminated diseases due to NTM have been reported in patients with AIDS, especially in those with advanced immunosuppression.8, 9, 10 Disseminated NTM infection in non-HIV-infected hosts is rare and is associated with various immunosuppressive conditions (e.g. renal or cardiac transplantation, chronic corticosteroid use, and leukemia).11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 Mycobacterium haemophilum,¹¹ Mycobacterium avium complex,12, 13 Mycobacterium kansasii,¹⁴ Mycobacterium chelonae,15, 16, 17, 18 Mycobacterium scrofulaceum,12, 19 Mycobacterium abscessus,²⁰ Mycobacterium gordonae²¹ have been reported to cause disease in this setting. While disseminated M. avium complex infection typically presents as a fever of unknown origin,¹¹ M. kansasii, M. chelonae, M. abscessus and M. haemophilum etiologies are associated with the presentation of multiple subcutaneous nodules or abscesses.11, 12, 16, 17, 18

This study investigated epidemiologic trends in disseminated NTM infection in non-HIV-infected patients treated at National Taiwan University Hospital (NTUH) from 1997 through 2004. Our investigation also considered the potential impact of several events which occurred during this period on the incidence, presentation, and diagnosis of disseminated NTM. These included the upsurge of the HIV endemic, increasing use of immunosuppressive agents to treat patients with cancer and improvements in mycobacterial culture systems.

Section snippets

Definition of disseminated NTM infection

Because of the lack of an accepted strict case definition for disseminated NTM, we adapted the following definition originally developed for the diagnosis of tuberculosis.²² Disseminated NTM infection was defined as isolation of NTM from blood or bone marrow, from a liver biopsy specimen, or from specimens from two or more noncontiguous sites such as respiratory tract, lymph node, ascites, pleural effusion, pericardial effusion, joint fluid and cerebral spinal fluid (CSF). Patients with NTM

Clinical features

From January 1997 to December 2004, a total of 15 patients met the case definition for disseminated NTM (Fig. 1). The clinical features of these patients are summarized in Table 1. The mean age of patients was 51 years (ranged from 13 to 80 years). Of the 15 patients with disseminated NTM infection, three (20%) had solid organ malignancy. Four (27%) patients had received immunosuppressive therapy, including glucocorticosteroid treatment and cancer chemotherapy prior to initial symptoms.

Discussion

This study investigated the epidemiological trends in non-HIV patients with disseminated NTM infection at a university hospital during an eight-year period. Comparison of our data from a previous study at this hospital revealed that the number of non-AIDS patients meeting the case definition for disseminated NTM at NTUH increased dramatically from only one during a previous period between 1992 and 1996,²⁶ to 15 during the following eight years of the present study. There are several possible

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Though there is no clear-cut definition for disseminated NTM infection, a consensus seems to be reached among most literatures that disseminated NTM infection is defined as isolation of NTM from blood or bone marrow [12–14]. Some literature also included isolation of NTM from liver biopsy or from ≥ 2 noncontiguous organs as disseminated infection [13–15]. Disseminated NTM infections are mainly found in patients with immunodeficiency, such as AIDS and leukemia/lymphoma, and in those with genetic defects or mutations (for examples, Mendelian susceptibility to mycobacterial disease, nuclear factor κB essential modulator mutation, signal transducer and activator of transcription 1 deficiency) or presence of anti-interferon-γ autoantibodies or anti-granulocyte–macrophage colony-stimulating factor antibodies [14,15].
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Clinical diseases caused by non-tuberculous mycobacterial infections include lymphadenitis, skin and soft tissue infections, pulmonary disease, and disseminated infection (figure 1). Although disseminated non-tuberculous mycobacterial infections are opportunistic in patients with overt immunodeficiency, such as the late stages of HIV infection, hairy cell leukaemia, and individuals taking specific immunosuppressive therapies,6–8 refractory or recurrent non-tuberculous mycobacterial infections, especially of the airways, are also seen in otherwise healthy individuals. Patients with immunodeficiencies, whether primary or acquired, often have poor responses to antimicrobial drugs alone.
Non-tuberculous mycobacteria cause a broad range of clinical disorders, from cutaneous infections, such as cervical or intrathoracic lymphadenitis in children, to disseminated infections at all ages. Recognition of the underlying immune defect is crucial for rational treatment, preventive care, family screening, and, in some cases, transplantation. So far, at least seven autosomal mutations (in IL12B, IL12RB1, ISG15, IFNGR1, IFNGR2, STAT1, and IRF8) and two X-linked mutations (in IKBKG and CYBB), mostly presenting in childhood, have been reported to confer susceptibility to disseminated non-tuberculous mycobacterial infection. GATA2 deficiency and anti-interferon γ autoantibodies also give rise to disseminated infection, typically in late childhood or adulthood. Furthermore, isolated pulmonary non-tuberculous mycobacterial infection has been increasing in prevalence in people without recognised immune dysfunction. In this Review, we discuss how to detect and differentiate host susceptibility factors underlying localised and systemic non-tuberculous mycobacterial infections.
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Emergence of disseminated infections due to nontuberculous mycobacteria in non-HIV-infected patients, including immunocompetent and immunocompromised patients in a university hospital in Taiwan

Summary

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Definition of disseminated NTM infection

Clinical features

Discussion

J Infect

Am J Med

Am J Med

Nontuberculous mycobacteria and associated diseases

Am Rev Respir Dis

Agents of newly recognized or infrequently encountered mycobacterial diseases

Clin Microbiol Rev

Diagnosis and treatment of disease caused by nontuberculous mycobacteria

Am Rev Respir Dis

Diagnosis and treatment of disease caused by nontuberculous mycobacteria

Am J Respir Crit Care Med

Prevalence of Mycobacterium avium complex infection in AIDS

Scand J Infect Dis

Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients

J Infect Dis

An epidemiologic analysis of Mycobacterium avium complex disease in homosexual men infected with human immunodeficiency virus type 1

Clin Infect Dis

Clinical manifestations of AIDS in the era of pneumocystis prophylaxis

N Engl J Med

Mycobacterium avium complex infection in acquired immunodeficiency syndrome

N Engl J Med

Mycobacterium haemophilum. An emerging pathogen

Eur Clin Microbiol Infect Dis

State of the art: nontuberculous mycobacteria and associated diseases

Am Rev Respir Dis

Disseminated infection with Mycobacterium avium-intracellulare

Medicine