Background.Disseminated nontuberculous mycobacterial (NTM) infection is an emerging infectious disease worldwide that occurs mostly in immunocompromised hosts. Disseminated NTM infection is uncommon in persons who are not infected with human immunodeficiency virus (HIV). Recently, we described a group of non–HIV-infected Thai patients whose disease manifestation was a previously unrecognized clinical entity characterized by chronic bilateral lymphadenopathy due to rapidly growing mycobacteria. Most of the patients had coinfection with other opportunistic pathogens and reactive skin diseases. Therefore, in recognition of the increasing significance of this unique disease due to NTM in our country, we initiated a study to assess the prevalence, clinical characteristics, and geographic variations of this disease.
Methods.There were 129 cases of disseminated NTM infection identified from 4 university hospitals located in major areas throughout Thailand. All patients but 1 were adults. Only 12% of patients had underlying diseases. The majority of the patients (81%) lived in the northeast of Thailand.
Results.The most common organ involved was the lymph node (89%), followed by skin and soft tissue (26%), lung (19%), and others. Fifty-nine patients (46%) had 81 episodes of coinfection with other opportunistic infections (e.g., salmonellosis, 32 cases; cryptococcosis, 8 cases; penicilliosis, 8 cases; histoplasmosis, 5 cases). Seventy-seven patients had 86 episodes of reactive skin diseases (e.g., Sweet syndrome, 60 cases; pustular psoriasis, 6 cases; erythematous pustulosis, 5 cases).
Conclusions.These findings suggest a cell-mediated immune defect in these patients that needs to be further investigated. This study strongly suggests that the prevalence of NTM infection in Thailand is increasing. To our knowledge, this is the largest study of disseminated NTM infection among non–HIV-infected patients.
Nontuberculous mycobacteria (NTM) are ubiquitous organisms that are readily isolated from soil, water, domestic and wild animals, milk, and other items . NTM were believed to represent environmental contamination or colonization; only during the 1950s were NTM recognized as potential pathogens . These organisms have since been implicated in a large and increasing number of infections in both immunocompetent and immunocompromised hosts, mostly HIV-infected patients, throughout the world [3,4,5,6,7,8–9].
The syndromes caused by NTM in non–HIV-infected patients are typically pulmonary, unilateral cervical lymph node (in children), limited cutaneous, or, in rare cases, disseminated . However, we recently described a group of patients in Thailand whose disease manifestation was a previously unrecognized clinical entity characterized by chronic bilateral lymphadenopathy due to rapidly growing mycobacteria (RGM). This infection often progresses to dissemination and, in severe cases, can be fatal. This syndrome is not due to HIV infection or other recognized underlying diseases . Most of the patients were coinfected with other opportunistic pathogens, including Salmonella, Cryptococcus, Penicillium and Histoplasma species, and had reactive skin diseases, especially Sweet syndrome. A similar group of patients was also reported from a university hospital in Bangkok, Thailand . In recognition of the increasing significance of this unique disease due to NTM in our country, we initiated a study to assess the burden of such disease in Thailand. Diagnosis of NTM disease is based on the results of mycobacterial culture, which is available only in university hospitals and some of the national institutes for treatment of pulmonary tuberculosis. Almost all cases of extrapulmonary NTM are referred for diagnosis and management through a university hospital.
The aims of our study were to assess the prevalence, clinical characteristics, and conditions associated with the disease and to describe its geographic variations.
Patient population.All incident cases of disseminated NTM infection were seen at Srinagarind Hospital, Khon Kaen University, Khon Kaen; Ramathibodi Hospital, Mahidol University, Bangkok; Siriraj Hospital, Mahidol University, Bangkok; and Chiang Mai University Hospital, Chiang Mai. Inclusion criteria were defined as follows: NTM lymphadenitis; disseminated NTM infection (involvement of >1 organ or positive results of blood culture); any sites of NTM infection with reactive skin diseases, such as Sweet syndrome, pustular psoriasis, generalized pustulosis, or erythema nodosum; or combined opportunistic infections either at the same time or subsequently (e.g., salmonellosis, penicilliosis, histoplasmosis, cryptococcosis, or melioidosis). Exclusion criteria were defined as follows: NTM infection in the lung only, nosocomial NTM infection, or HIV antibody positivity. All patients whose NTM infection was diagnosed during 1999–2004 were included for retrospective and prospective reviews except for patients from Srinagarind Hospital, who were seen from February 1994 to April 2006. The medical records of all study patients were reviewed; information on the age, sex, place of birth, underlying diseases, organ involvement, coinfection, and reactive skin diseases were recorded.
Microbiological studies.In this study, NTM were divided into rapidly growing mycobacteria (RGM) and slowly growing mycobacteria (SGM). RGM are defined as organisms that grow in ⩽7 days on subculture. Species delineation of mycobacteria at Siriraj Hospital, Ramathibodi Hospital, and Chiang Mai University Hospital was done using the standard methods and tests recommended by Murray . Most of the isolates at Srinagarind Hospital were sent to Siriraj Hospital to identify the species, and some were sent to the Microbiology Laboratory at the National Institutes of Health (Bethesda, MD), but some of the isolates were not available for speciation.
Reactive skin diseases.The diagnosis of reactive skin diseases was based on pathological findings coupled with a negative result of culture for mycobacteria and other pathogens. Sweet syndrome is characterized by a constellation of symptoms and findings: fever, neutrophilia, and painful skin lesions characterized by either erythematous papules, nodules, or plaques and histopathological findings showing an upper dermal infiltrate of mature neutrophils . Acute generalized exanthematous pustulosis is defined by the combination of fever; neutrophilia; numerous nonfollicular sterile pustules occurring on a diffuse, edematous erythema predominantly in the folds and/or on the face; and histopathologic studies revealing spongiform subcorneal and/or intraepidermal pustules, edema of papillary dermis, vasculitis, exocytosis of eosinophils, and/or focal necrosis of keratinocytes . Pustular psoriasis is differentiated from acute, generalized exanthematous pustulosis by the clinical findings of more generalized distribution of pustular lesions and histopathologic findings demonstrating subcorneal and/or intraepidermal pustules, papillomatosis, and acanthosis . Erythema nodosum is characterized by painful, subcutaneous erythematous nodules commonly located symmetrically on ventral aspect of lower extremities, with histological findings compatible with septal panniculitis .
Testing for HIV antibodies.Screening for antibodies to HIV was performed using the following US Food and Drug Administration–approved test kits: HIV Ag/Ab Combo Assay (Abbott Laboratories) at Srinagarind Hospital, Ramathibodi Hospital, and Siriraj Hospital and Cobas Core Anti HIV 1/HIV2 EIA DAGS (Roche Diagnostics) at Chiang Mai University Hospital. Western blots were not performed for patients with negative results of screening tests.
There were 129 patients with disseminated NTM infection enrolled in the study (94 from Srinagarind Hospital, 26 from Ramathibodi Hospital, 5 from Siriraj Hospital, and 4 from Chiang Mai University Hospital). All of the patients had at least 1 negative result of an HIV antibody test, and most of them had repeated negative test results. In addition, none of the patients had other known conditions associated with acquired immunodeficiency, such as receipt of steroid or immunosuppressive agents, disseminated cancer, malnutrition, radiotherapy, or chronic renal disease. The demographic characteristics, occupations, underlying diseases, and places of birth are presented in table 1. All patients but 1 were adults, with mean age of 47 years (range, 7–80 years). Persons of both sexes were equally affected. The majority of patients did not have any underlying disease. Only 15 patients (12%) had underlying diseases: diabetes (3 patients), malignancy (3 patients), thalassemia (2 patients), and other diseases (7 patients). Information on occupation and place of birth were not available for patients from Siriraj Hospital, so these data were based on data for 124 persons. The most common occupation among the patients with information available was farmer (46%), followed by government officer (18%), housewife (10%), laborer (10%), private business (6%), and other occupations (10%). The majority of the patients (81%) lived in the northeast of Thailand, 10% of patients lived in the north, 9% of patients lived in the central part of Thailand, and only 1 patient lived in the south. The geographic distribution of all patients is show in figure 1.
The most common organ involvement was lymph node (89%), followed by skin and soft tissue (26%), lung (19%), bone and joint (18%), liver (15%), spleen (9%), sinus and tonsil (8%), and CNS (7%). Twenty-one patients had positive results of blood cultures. Other organs involved were breast (3 cases) and peritoneum, pleura, tongue, small bowel, and bone marrow (1 case each). The organs involved in these patients are summarized in table 2.
There were 99 cases due to RGM and 34 due to SGM. Sixty-six of 99 RGM pathogens were available for identification: 45 were Mycobacterium abscessus 11 were Mycobacterium fortuitum 9 were Mycobacterium chelonae and 1 was Mycobacterium thermoresistibile. Of the 27 of 35 SGM pathogens available for identification, 9 were Mycobacterium avium complex; 2 each were Mycobacterium simiae, Mycobacterium scrofulaceum and Mycobacterium szulgai; 1 each was Mycobacterium kansasii, Mycobacterium malmoense and Mycobacterium haemophilum; and 9 were other species.
Fifty-nine patients (46%) had 81 episodes of coinfection with other opportunistic infections, mostly of the kind associated with cell-mediated immune defects (table 3). Except for herpes zoster, all were diagnosed by positive results of culture. The most common infection was salmonellosis (32 cases), almost all of which presented with Salmonella bacteremia and some with other organ involvements (i.e., pneumonia, psoas abscess, and spondylitis); 3 patients had 2 episodes of bacteremia each. Other infections were herpes zoster (11 cases; some had recurrent episodes), cryptococcosis (8 cases; presented with meningitis, osteomyelitis, septic arthritis, and cellulitis), penicilliosis (8 cases; presented with skin abscesses, epidural abscess, pneumonia, and disseminated infection), histoplasmosis (5 cases; presented with lymphadenitis, pneumonia, and skin abscess), and melioidosis (4 cases; all presented with pneumonia). These infections either preceded, were concurrent with, or followed the NTM infection. Ten patients had >1 episode of NTM infection by different species (table 4).
Seventy-seven patients had 86 episodes of reactive skin diseases (table 5); the most common was Sweet syndrome (60 cases; most were recurrent episodes), followed by pustular psoriasis (6 cases), acute generalized exanthematous pustulosis (5 cases), erythema nodosum (4 cases), and other types of reactive skin disease (11 cases). The pathology of Sweet syndrome, which is shown in figure 2A, consists of a neutrophilic infiltrate of the dermis; in contrast, the pathology of NTM-involved skin infection was suppuration and granulomatous inflammation in the reticular dermis, as shown in figure 2B.
In the past, NTM infections in non–HIV-infected patients were considered to be uncommon in Thailand. There were only 38 cases reported before 1991, and most of these were due to lung infection . However, we recently described 16 patients with disseminated RGM infection who presented with chronic bilateral lymphadenopathy, opportunistic coinfections, and reactive skin diseases . A similar group of patients was also described at a university hospital in Bangkok . Furthermore, we noticed an increasing number of patients infected not only with RGM but also with other NTM and who had a similar clinical presentation. These findings led us to conduct this study. Our study strongly suggests that the prevalence of NTM infection in Thailand is increasing. To our knowledge, this is the largest study of disseminated NTM infection among non–HIV-infected patients.
The majority of patients in this study (81%) were living in the northeast of Thailand. The high prevalence from this area might be partially explained by the fact that the majority of patients (73%) were reported from Srinagarind Hospital, which is the tertiary care hospital in the northeast. However, a significant number of patients from this part of the country were seen at the other 2 hospitals in Bangkok. Only 1 patient had a place of birth in the southern part of Thailand. The uneven geographic distribution of patients needs to be further elucidated in an epidemiological and genetic study. Genetic factors among northeastern Thai people may play some role in the susceptibility of these patients to these opportunistic infections. From the epidemiological data, the acquisition of infection cannot be associated solely with patients' occupations, because farming was the most common occupation among these patients, and it is also the most prevalent among Thai people who live in the northeast of Thailand. NTM is a ubiquitous environmental organism to which universal exposure is inevitable.
This study confirmed our previous report about the unique presentations of disseminated RGM infection . All patients but 1 were adults with negligible underlying diseases who presented with chronic bilateral cervical lymphadenitis and whose infection progressed to involve other organs. Our cases are unlike the more common form of NTM lymphadenitis reported worldwide, which occurs almost exclusively with SGM in healthy children with localized disease, unilateral involvement, and minimal systemic symptoms [18,19,20,21–22]. Skin and soft-tissue infection were also common. The diagnosis of skin involvement was made on the basis of positive results of culture or granulomatous inflammation noted by skin biopsy. Most of the skin involved was the overlying skin of the infected lymph nodes. A significant number of patients had positive blood culture results, indicating severe immunosuppression in these patients.
Sweet syndrome is a reactive skin disease that usually occurs in association with various infections, inflammatory or lymphoproliferative diseases, or solid-organ malignancies . The pathogenesis of the syndrome remains unclear. It has been thought to be a hypersensitivity reaction to various antigens, a reaction to immune complexes, or associated with certain cytokines . Sweet syndrome has been rarely described in NTM infection [23, 24]. However, recently, several case series have been reported from Thailand [10, 11, 25,26–27]. Most of the patients in those reports [10, 11, 25, 26] were also included in this study, and almost all of the cases were associated with NTM infection. In this cohort of patients, Sweet syndrome was the most common reactive dermatosis. The majority of patients had Sweet syndrome as their first presentation along with cervical lymphadenopathy. Their skin disease tended to recur during the course of infection. Some had different episodes of other reactive skin diseases, such as pustular psoriasis, acute generalized exanthematous pustulosis, and erythema nodosum. Polyarteritis nodosa and leucocytoclastic vasculitis have been reported in conjunction with Sweet syndrome . These reactive skin diseases usually respond to treatment with systemic corticosteroids.
It is remarkable that these patients were also infected with other intracellular pathogens such as Salmonella species, Cryptococcus neoformans, Penicillium marneffei, Histoplasma capsulatum, Burkholderia pseudomallei and varicella-zoster virus, as well as with Mycobacterium tuberculosis and other NTM. The coinfections preceded, were concomitant with, or succeeded the NTM infections. These findings strongly suggest cellmediated immune dysfunction; however, the mechanisms underlying the immune defect in these patients are not understood. The common obvious causes of cell-mediated immune defects were not identified in these patients: HIV infection, immunosuppressive therapy, high-dose steroid use, or malnutrition. In our previous report, 11 of 12 patients had CD4+ cell counts determined; all but 1 had CD4+ cells in the normal range (580–1890 cells/mm3) .
Genetic causes of susceptibility to mycobacteria and other intracellular pathogens are due to defects in the type 1 cytokine pathway [29,30–31]. However, almost all of the patients we describe were adults, and none were related to or lived with a family member who had the same infection. These findings suggest the possibility of an acquired immunodeficiency in our patients. NTM infections in these patients may be only one manifestation of this apparently acquired cellular immunodeficiency syndrome.
Recently, in 11 cases from 4 reports [32,33,34–35], anti–IFN-γ autoantibodies have been associated with disseminated NTM and other infections. In all cases, high-affinity inhibitory anti–IFN-γ IgG autoantibodies were demonstrated. Kampmann et al.  and Patel et al.  showed that these antibodies are biologically active by blocking the IFN-γ–dependent up-regulation of TNF-α and IL-12 and blocking the induction of IFN-γ–inducible genes. Interestingly, 8 of their patients were of Asian descent (5 were Filipino, 1 was Taiwanese, 1 was Vietnamese, and 1 was Thai) and presented with disseminated mycobacterial infection (most had lymphadenitis), which was predominantly due to RGM. Furthermore, 2 Taiwanese and 1 Singaporean patients have been reported to have cervical lymphadenitis due to M. fortuitum and M. chelonae and all of these patients also presented with Sweet syndrome [24, 27, 36]. Ding et al.  have reported NTM lymphadenitis in 12 Taiwanese persons, of whom 7 were adults. Anti–IFN-γ IgG autoantibodies were also present in 5 anonymous serum samples obtained from our patients tested (Holland SM, personal communication). We hypothesize that some of the patients who we describe have the same antibody defects. However, we cannot yet discern whether the autoantibodies are causes or effects of disseminated NTM infection in this population. A large cohort study on natural history, phenotype, and genetics in these patients is underway to delineate the pathophysiology and genetics of anti–IFN-γ IgG autoantibodies.
Here, we report the largest study of disseminated NTM infection among non–HIV-infected patients and confirm our report of a new clinical entity of disseminated NTM infection. The syndrome consists of chronic NTM lymphadenitis with progressive involvement of other organs; concomitant reactive skin disease, especially Sweet syndrome; and other opportunistic infections.
We thank all medical staffs and laboratory technicians who were involved in the study, as well as who cared for the patients. We also thank Dr. Steven M. Holland for reviewing and editing this manuscript.
Potential conflicts of interest.All authors: no conflicts.
- communicable diseases, emerging
- hospitals, university
- immunocompromised host
- mycobacterium infections
- mycobacterium infections, atypical
- opportunistic infections
- salmonella food poisoning
- skin disorders
- sweet's syndrome
- lymph nodes
- salmonella infection
- pathogenic organism
- pustular psoriasis
- hiv infection
- predominantly t-cell defect
- rapid-growing mycobacteria
- infection due to penicillium marneffei
- soft tissue