MAJOR ARTICLE

Disseminated Nontuberculous Mycobacterial

Infection in Patients Who Are Not Infected
with HIV in Thailand
Ploenchan Chetchotisakd,1 Sasisopin Kiertiburanakul,2 Piroon Mootsikapun,1 Susun Assanasen,3

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Romanee Chaiwarith,4 and Siriluck Anunnatsiri1
1
Srinagarind Hospital, Khon Kaen University, Khon Kaen, 2Ramathibodi Hospital and 3Siriraj Hospital, Mahidol University, Bangkok,
and 4Chiang Mai University Hospital, Chiang Mai University, Chiang Mai, Thailand

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 charac-
teristics, 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, do-
mestic and wild animals, milk, and other items [1].
NTM were believed to represent environmental con-
tamination or colonization; only during the 1950s were
NTM recognized as potential pathogens [2]. These or-
ganisms have since been implicated in a large and in-
creasing number of infections in both immunocom-
petent and immunocompromised hosts, mostly
HIV-infected patients, throughout the world [3–9].
Received 18 February 2007; accepted 2 May 2007; electronically published 5
July 2007.
Reprints or correspondence: Dr. Ploenchan Chetchotisakd, Srinagarind Hospital,
Dept. of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002,
Thailand (ploencha@kku.ac.th).
Clinical Infectious Diseases 2007; 45:421–7
 2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4504-0003$15.00
DOI: 10.1086/520030
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 [9]. However, we recently described
a group of patients in Thailand whose disease mani-
festation was a previously unrecognized clinical entity
characterized by chronic bilateral lymphadenopathy
due to rapidly growing mycobacteria (RGM). This in-
fection often progresses to dissemination and, in severe
cases, can be fatal. This syndrome is not due to HIV
infection or other recognized underlying diseases [10].
Most of the patients were coinfected with other op-
portunistic pathogens, including Salmonella, Crypto-
coccus, Penicillium, and Histoplasma species, and had
reactive skin diseases, especially Sweet syndrome. A
similar group of patients was also reported from a uni-
versity hospital in Bangkok, Thailand [11]. In recog-
nition of the increasing significance of this unique

Disseminated NTM without HIV Infection • CID 2007:45 (15 August) • 421
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 di-
agnosis 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.
METHODS
Patient population. All incident cases of disseminated NTM
infection were seen at Srinagarind Hospital, Khon Kaen Uni-
versity, 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 11 organ or positive results of
blood culture); any sites of NTM infection with reactive skin
diseases, such as Sweet syndrome, pustular psoriasis, general-
ized pustulosis, or erythema nodosum; or combined oppor-
tunistic 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 di-
agnosed during 1999–2004 were included for retrospective and
prospective reviews except for patients from Srinagarind Hos-
pital, 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 in-
volvement, 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 Uni-
versity Hospital was done using the standard methods and tests
recommended by Murray [12]. Most of the isolates at Srina-
garind 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 dis-
eases was based on pathological findings coupled with a neg-
ative 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 char-
acterized by either erythematous papules, nodules, or plaques
422 • CID 2007:45 (15 August) • Chetchotisakd et al.
and histopathological findings showing an upper dermal infil-
trate of mature neutrophils [13]. Acute generalized exanthem-
atous pustulosis is defined by the combination of fever; neu-
trophilia; 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 ne-
crosis of keratinocytes [14]. Pustular psoriasis is differentiated
from acute, generalized exanthematous pustulosis by the clin-
ical findings of more generalized distribution of pustular lesions
and histopathologic findings demonstrating subcorneal and/or
intraepidermal pustules, papillomatosis, and acanthosis [15].
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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 [16].
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.
RESULTS
There were 129 patients with disseminated NTM infection en-
rolled 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 immunosup-
pressive agents, disseminated cancer, malnutrition, radiother-
apy, or chronic renal disease. The demographic characteristics,
occupations, underlying diseases, and places of birth are pre-
sented 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 dis-
eases: 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 gov-
ernment officer (18%), housewife (10%), laborer (10%), pri-
vate business (6%), and other occupations (10%). The majority
of the patients (81%) lived in the northeast of Thailand, 10%
Table 1. Demographic characteristics, occupations, and under- other opportunistic infections, mostly of the kind associated
lying diseases for patients with disseminated nontuberculous my- with cell-mediated immune defects (table 3). Except for herpes
cobacterial infection in Thailand. zoster, all were diagnosed by positive results of culture. The
most common infection was salmonellosis (32 cases), almost
Value
Characteristic (n p 129) all of which presented with Salmonella bacteremia and some
with other organ involvements (i.e., pneumonia, psoas abscess,
Age, years
Mean  SD 46.52  13.67
and spondylitis); 3 patients had 2 episodes of bacteremia each.
Range 7–80 Other infections were herpes zoster (11 cases; some had re-
No. of male/female patients 67/62 current episodes), cryptococcosis (8 cases; presented with men-
Underlying disease 15 (12) ingitis, osteomyelitis, septic arthritis, and cellulitis), penicilliosis
Diabetes mellitus 3 (8 cases; presented with skin abscesses, epidural abscess, pneu-
Malignancy 3 monia, and disseminated infection), histoplasmosis (5 cases;
Thalassemia 2 presented with lymphadenitis, pneumonia, and skin abscess),

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Other 7 and melioidosis (4 cases; all presented with pneumonia). These
None 114 (88) infections either preceded, were concurrent with, or followed
a
Occupation
the NTM infection. Ten patients had 11 episode of NTM in-
Farmer 57 (46)
fection by different species (table 4).
Government officer 22 (18)
Seventy-seven patients had 86 episodes of reactive skin dis-
Housewife 13 (10)
Laborer 12 (10)
eases (table 5); the most common was Sweet syndrome (60
Private business 7 (6) cases; most were recurrent episodes), followed by pustular pso-
Other 13 (10) riasis (6 cases), acute generalized exanthematous pustulosis (5
a
Geographic distribution of place of birth cases), erythema nodosum (4 cases), and other types of reactive
Northeast Thailand 100 (81) skin disease (11 cases). The pathology of Sweet syndrome,
North Thailand 12 (10)
Central Thailand 11 (9)
South Thailand 1 (1)

NOTE. Data are no. (%) of patients, unless otherwise indicated.

a
Data are for 124 patients.

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 sum-
marized 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 fortui-
tum, 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, My-
cobacterium malmoense, and Mycobacterium haemophilum; and Figure 1. Geographic distribution of patients with disseminated non-
9 were other species. tuberculous mycobacterial infection in Thailand. Data were available for
Fifty-nine patients (46%) had 81 episodes of coinfection with 124 cases (96%).

Disseminated NTM without HIV Infection • CID 2007:45 (15 August) • 423
Table 2. Organ involvement in 129 patients with disseminated The majority of patients in this study (81%) were living in
nontuberculous mycobacterial infection in Thailand. the northeast of Thailand. The high prevalence from this area
might be partially explained by the fact that the majority of
No. of patients
patients (73%) were reported from Srinagarind Hospital, which
Organ involvement (n p 129)
is the tertiary care hospital in the northeast. However, a sig-
Lymph node 115
nificant number of patients from this part of the country were
Skin and soft tissue 34
seen at the other 2 hospitals in Bangkok. Only 1 patient had
Lung 25
Bone and joint 23
a place of birth in the southern part of Thailand. The uneven
Blood 21 geographic distribution of patients needs to be further eluci-
Liver 19 dated in an epidemiological and genetic study. Genetic factors
Spleen 12 among northeastern Thai people may play some role in the
Sinus and tonsil 10 susceptibility of these patients to these opportunistic infections.
CNS 9 From the epidemiological data, the acquisition of infection can-

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Other 8 not be associated solely with patients’ occupations, because
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.
DISCUSSION
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 [17]. However, we recently described 16 patients with
disseminated RGM infection who presented with chronic bi-
lateral lymphadenopathy, opportunistic coinfections, and re-
active skin diseases [10]. A similar group of patients was also
described at a university hospital in Bangkok [11]. Further-
more, 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.
Table 3. Proven coinfections in 59 patients with disseminated
nontuberculous mycobacterial infection in Thailand.
Coinfection No. of cases
Salmonellosis 32
Cryptococcosis 8 7
Penicilliosis 8 blood, and pleural fluid) and M. abscessus (LN)
farming was the most common occupation among these pa-
tients, 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 [10]. All patients
but 1 were adults with negligible underlying diseases who pre-
sented 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 [18–22]. Skin and soft-tissue
infection were also common. The diagnosis of skin involvement
Table 4. Patients with disseminated nontuberculous mycobac-
terial (NTM) infection who had 11 episode of NTM infection, by
species.
Patient Mycobacterium species identified (organ[s] involved)
1 Mycobacterium gordonae (LN), Mycobacterium absces-
sus (LN), and Mycobacterium tuberculosis (LN)
2 Mycobacterium fortuitum (LN) and M. abscessus (LN)
3 M. abscessus (LN) and SGM (bone marrow)
4 RGM (LN) and Mycobacterium simiae (LN, sinuses)
5 Mycobacterium avium complex (LN and blood), Myco-
bacterium chelonae (LN), and M. abscessus (LN)
6 M. chelonae, (LN, leg tissue, and blood), M. simiae
(blood), and M. avium complex (lacrimal gland)
Mycobacterium scrofulaceum (bronchoalveolar lavage,

Histoplasmosis 5 8 Mycobacterium kansasii (blood and lung) and Mycobac-

terium nonchromogenicum (bone marrow)
Herpes zoster 11 a
9 SGM-1 (LN) and SGM-2 (LN)
Melioidosis 4
10 SGM (blood and joint) and RGM (LN and blood)
Tuberculosis 4
Other bacteria 5 NOTE. Pathogens are listed in the sequence in which they were identified
Other 4 in each patient. LN, lymph node; RGM, rapidly growing mycobacteria; SGM,
slowly growing mycobacteria.
Total 81 a
SGM-1 and SGM-2 refer to 2 different episodes of SGM infection.

424 • CID 2007:45 (15 August) • Chetchotisakd et al.

Table 5. Reactive skin diseases in 77 patients with dissemi- patients in those reports [10, 11, 25, 26] were also included in
nated nontuberculous mycobacterial infection in Thailand. this study, and almost all of the cases were associated with
NTM infection. In this cohort of patients, Sweet syndrome was
Reactive skin disease No. of cases
the most common reactive dermatosis. The majority of patients
Sweet syndrome 60 had Sweet syndrome as their first presentation along with cer-
Pustular psoriasis 6
vical lymphadenopathy. Their skin disease tended to recur dur-
Acute generalized erythema-
tous pustulosis 5 ing the course of infection. Some had different episodes of other
Erythema nodosum 4 reactive skin diseases, such as pustular psoriasis, acute gener-
Other 11 alized exanthematous pustulosis, and erythema nodosum. Po-
Total 86 lyarteritis nodosa and leucocytoclastic vasculitis have been re-
ported in conjunction with Sweet syndrome [28]. These reactive
was made on the basis of positive results of culture or gran- skin diseases usually respond to treatment with systemic
corticosteroids.

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ulomatous 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 lym-
phoproliferative diseases, or solid-organ malignancies [13]. 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 [13]. Sweet syndrome has been rarely described in
NTM infection [23, 24]. However, recently, several case series
have been reported from Thailand [10, 11, 25–27]. Most of the
It is remarkable that these patients were also infected with
other intracellular pathogens such as Salmonella species, Cryp-
tococcus neoformans, Penicillium marneffei, Histoplasma capsu-
latum, 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 cell-
mediated immune dysfunction; however, the mechanisms un-
derlying the immune defect in these patients are not under-
stood. The common obvious causes of cell-mediated immune
defects were not identified in these patients: HIV infection,
immunosuppressive therapy, high-dose steroid use, or mal-
nutrition. In our previous report, 11 of 12 patients had CD4+

Figure 2. A, Pathology of Sweet syndrome, consisting of a neutrophilic infiltrate of the dermis. B, Pathology of nontuberculous mycobacteria–
involved skin involving suppuration and granulomatous inflammation in the reticular dermis.

Disseminated NTM without HIV Infection • CID 2007:45 (15 August) • 425
cell counts determined; all but 1 had CD4+ cells in the normal
range (580–1890 cells/mm3) [10].
Genetic causes of susceptibility to mycobacteria and other
intracellular pathogens are due to defects in the type 1 cytokine
pathway [29–31]. However, almost all of the patients we de-
scribe 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 immunode-
ficiency syndrome.
Recently, in 11 cases from 4 reports [32–35], anti–IFN-g
autoantibodies have been associated with disseminated NTM
and other infections. In all cases, high-affinity inhibitory anti–
IFN-g IgG autoantibodies were demonstrated. Kampmann et
al. [34] and Patel et al. [35] showed that these antibodies are
biologically active by blocking the IFN-g–dependent up-reg-
ulation of TNF-a and IL-12 and blocking the induction of
IFN-g–inducible genes. Interestingly, 8 of their patients were
of Asian descent (5 were Filipino, 1 was Taiwanese, 1 was Viet-
namese, and 1 was Thai) and presented with disseminated my-
cobacterial infection (most had lymphadenitis), which was pre-
dominantly due to RGM. Furthermore, 2 Taiwanese and 1
Singaporean patients have been reported to have cervical lym-
phadenitis due to M. fortuitum and M. chelonae, and all of these
patients also presented with Sweet syndrome [24, 27, 36]. Ding
et al. [37] have reported NTM lymphadenitis in 12 Taiwanese
persons, of whom 7 were adults. Anti–IFN-g IgG autoanti-
bodies were also present in 5 anonymous serum samples ob-
tained from our patients tested (Holland SM, personal com-
munication). We hypothesize that some of the patients who
we describe have the same antibody defects. However, we can-
not 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-g IgG autoantibodies.
Here, we report the largest study of disseminated NTM in-
fection among non–HIV-infected patients and confirm our re-
port 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 opportu-
nistic infections.
Acknowledgments
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.
426 • CID 2007:45 (15 August) • Chetchotisakd et al.
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