Infection

, Volume 40, Issue 4, pp 463–468

Mycobacterium szulgai: an unusual cause of disseminated mycobacterial infections

Authors

    • Department of Pathology, Division of MicrobiologyThe Johns Hopkins University, School of Medicine, Johns Hopkins Bayview Medical Center
  • K. Dionne
    • Department of Pathology, Division of MicrobiologyThe Johns Hopkins University, School of Medicine, The Johns Hopkins Hospital
  • C. Ellis
    • Department of PathologyThe Johns Hopkins University, School of Medicine, The Johns Hopkins Hospital
  • A. Duffield
    • Department of PathologyThe Johns Hopkins University, School of Medicine, The Johns Hopkins Hospital
  • K. C. Carroll
    • Department of Pathology, Division of MicrobiologyThe Johns Hopkins University, School of Medicine, The Johns Hopkins Hospital
  • N. M. Parrish
    • Department of Pathology, Division of MicrobiologyThe Johns Hopkins University, School of Medicine, The Johns Hopkins Hospital
Correspondence

DOI: 10.1007/s15010-011-0213-6

Cite this article as:
Riedel, S., Dionne, K., Ellis, C. et al. Infection (2012) 40: 463. doi:10.1007/s15010-011-0213-6

The incidence of nontuberculous mycobacterial infections in the USA has significantly increased during the past three decades, specifically after the advent of HIV/AIDS [14]; however, the incidence of tuberculosis in the United States is low when compared to developing countries. For most of the nontuberculous mycobacteria (NTM), the pathogenicity and clinical relevance are poorly understood. Likewise, the role of in vitro susceptibility testing of NTM isolates related to the approach of patient care management remains a topic of debate, despite the fact that consensus guidelines for optimal diagnosis, treatment, and prevention for NTM infections were published in 2007 [5]. This fact is mainly related to the limited number of cases caused by certain NTM species and is further related to some variability in antimicrobial resistance profiles. Mycobacterium szulgai was first described in 1972; since then, it has been repeatedly recognized as a cause of pulmonary infections that often clinically and radiologically resemble patterns of disease caused by M. tuberculosis [69]. Based on a recent case of a fatal M. szulgai infection in a patient with disseminated disease and underlying hematologic malignancy in our institution, we reviewed the current literature with regard to epidemiology, diagnosis, and treatment approaches for M. szulgai infections. The infection in our patient was unrecognized for an undetermined amount of time, prior to presentation to our hospital. Our literature review identified only a few case reports and no comprehensive review of the subject was identified.

The patient’s current and past medical history: A 59-year-old Caucasian male patient presented to our institution with progressive unintentional weight loss and fatigue over a period of the prior 12 months. The patient’s past medical history was otherwise significant for hypertension, hyperlipidemia, a thyroidectomy for papillary thyroid carcinoma, and a laminoforaminotomy. Two months prior to his current presentation, the patient was diagnosed with an upper respiratory tract infection, for which he was treated with a course of azithromycin. However, there was only marginal improvement of his symptoms. Subsequently, the patient self-medicated with penicillin for an unknown duration and dosing schedule. On a subsequent visit to another emergency room, a chest computed tomography (CT) scan showed bullous changes of the basal lobe of the right lung, a 2.5-cm right hilar lymph node, and a 6-mm precarinal lymph node. At that time, the patient received treatment with oral corticosteroids for the presumptive diagnosis of sarcoidosis. He also required more frequent transfusions with leukoreduced, packed red blood cells (RBC), and weekly Epoetin α injections for a significantly more symptomatic anemia. A colonoscopy, performed as part of the diagnostic work-up for the persistent and recurrent anemia, was without significant pathologic findings.

Diagnostic procedures: Upon admission to our hospital, the patient presented with profound anemia: hemoglobin 6.4 g/dl, hematocrit 19%, mean corpuscular volume (MCV) 90 fL, mean corpuscular hemoglobin (MCH) 30.3 pg, white blood cell (WBC) count 15,820/mm3, platelets count 3,000/mm3. A repeat bone marrow biopsy showed a persistent high-grade myelodysplastic syndrome (Fig. 1a) with 5–10% myeloblasts and prominent hemophagocytosis, as well as a prominent histiocytic infiltrate (Fig. 1b). The Epstein–Barr virus (EBV) IgG antibody test was positive. Additional laboratory studies, including Mycoplasma pneumoniae IgM and IgG antibodies, EBV capsid IgM and IgG antibodies, cryoglobulins, warm and cold auto-antibodies, indirect Coombs test, beta-2 microglobulin, and serum protein electrophoresis, were negative or within normal limits. Blood, respiratory, and urine cultures were performed but were negative for the growth of organisms. A repeat bone marrow biopsy was performed on day 14 of hospitalization and showed progression to acute myeloid leukemia and prominent hemophagocytosis. Bacteriology and mycobacteriology cultures were also performed on this bone marrow specimen. A repeat chest CT scan showed multilobular consolidation with focal nodular lesions and prominent hilar lymphadenopathy. Repeat respiratory, blood, and urine cultures remained negative.
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Fig. 1

a Antemortem biopsy of hypercellular bone marrow with atypical megakaryocytes with b histiocytic infiltrate. c Representative tissues from autopsy demonstrating histiocytic infiltrate in bone marrow, bowel, lung, and liver

Treatment and hospital course: While being evaluated for a possible hematopoietic stem cell transplant, the patient was treated with transfusions of multiple RBC units and lenalidomide. After a brief 3-day period of improvement, the patient’s symptoms suddenly deteriorated, while being treated with methylprednisolone, I.V. immunoglobulin, hydroxychloroquine, and aminocaproic acid. The patient was transferred to the intensive care unit (ICU) and received broad-spectrum antimicrobial therapy, including vancomycin (1 g I.V. q12 h) and piperacillin/tazobactam (4.5 g I.V. q6 h). Subsequently, azithromycin and meropenem were added to the treatment regimen. For treatment of the underlying leukemia, high-dose cyclophosphamide was started, in conjunction with continued, frequent transfusions with RBCs, platelets, and fresh-frozen plasma (FFP).

During the following 7 days, the patient’s clinical status continued to deteriorate, and he developed significant cardiopulmonary insufficiency and acute renal failure. The patient expired 20 days after admission to the hospital. The autopsy confirmed the clinical and bone marrow diagnosis of an acute myeloid leukemia with myelodysplasia-related changes, and hemophagocytic lymphohistiocytosis (HLH). Additional findings were a prominent histiocyte-rich infiltrate in the bone marrow, the lungs, the periportal regions of the liver, and in several sections of the intestinal wall. Histochemical stains for acid-fast bacilli (AFB) and fungi on select sections of lung, liver, and bone marrow tissues were negative. Twelve days postmortem, M. szulgai was identified from the culture of the bone marrow biopsy specimen.

We reviewed hematoxylin and eosin (H&E) stains as well as a panel of immunohistochemistry stains and an AFB stain from the antemortem bone marrow biopsy.

The previous findings of this bone marrow biopsy were confirmed (Fig. 1a, b); notably, the AFB stain was negative. Prominent hemophagocytosis, consistent with HLH, was noted on the bone marrow aspirate. The review of the autopsy slides (H&E and AFB stains) demonstrated prominent histiocytic infiltrates in several tissues (Fig. 1c). Multiple lymph nodes were entirely replaced by a histiocytic infiltrate that extended into the perinodal fat and was largely necrotic (Fig. 2a). Abundant AFB-positive organisms were noted in additional sections of the hilar lymph nodes (Fig. 2b), but organisms were not identified in the other tissues. Silver stains for fungi (Grocott methenamine silver [GMS]) were negative.
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Fig. 2

a Extensive necrosis of the lymph nodes (hematoxylin and eosin; H&E). b Special stain for acid fast bacilli (AFB), demonstrating organisms (400×)

The BACTEC 960 Middlebrook medium for the detection of mycobacterial growth was used for the antemortem bone marrow sample that was submitted for culture. Once positive, an aliquot from the broth was inoculated onto Middlebrook agar and incubated at 30°C. Non-amplified probes (Accuprobe, GenProbe) for M. tuberculosis, M. avium complex, M. kansasii, and M. gordonae were negative. Growth of the organism on Middlebrook agar demonstrated a scotochromogenic organism with a prominent yellow pigment (Fig. 3). Using high-performance liquid chromatography (HPLC, Sherlock® Mycobacteria Identification System, MIDI, Newark, DE, USA), the organism was identified as M. szulgai. Antimicrobial susceptibility testing showed the organism to be susceptible to amikacin (minimum inhibitory concentration, MIC ≤ 1 μg/ml), ciprofloxacin (MIC = 0.5 μg/ml), clarithromycin (MIC = 0.12 μg/ml), ethambutol (MIC = 1 μg/ml), rifampin (MIC ≤ 0.12 μg/ml), rifabutin (MIC ≤ 0.25 μg/ml), streptomycin (MIC ≤ 1 μg/ml), and trimethoprim–sulfamethoxazole (MIC ≤ 0.12/2.4 μg/ml). The MICs were also low for linezolid (≤1 μg/ml) and moxifloxacin (0.5 μg/ml), although no uniform guidelines exist at this time for the interpretation of the MIC results for these organism–drug combinations [10].
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Fig. 3

Mycobacterium szulgai grown on Middlebrook 7H11 agar at 37°C. This organism is a scotochromogen when grown at this temperature; note the characteristic yellow pigment

NTM have been increasingly recognized as pathogens throughout the world, capable of causing pulmonary and extrapulmonary site infections in both immunocompetent and immunocompromised patients [1, 4, 6, 7]. The impact of NTM on morbidity and mortality in HIV and AIDS patients has resulted in a growing interest in these organisms [2, 4, 5]. Unfortunately, the pathogenicity and clinical relevance of many NTM species remains poorly understood. M. szulgai is a slow-growing mycobacterium and produces a yellow–orange pigment; the organism is scotochromogenic when grown at 37°C, but photochromogenic at 25°C [11]. Biochemical characteristics that help distinguish M. szulgai from other scotochromogenic NTM are Tween 80 hydrolysis, catalase activity, nitrate reductase and urease activities, and the lack of acid phosphatase activity [1]. However, the identification of M. szulgai based on these phenotypic characteristics alone is somewhat difficult, and the preferred method of identification is by either 16S rRNA gene sequencing or by HPLC of mycolic acid [10].

Most often, the organism has been reported to cause pulmonary infections that clinically and radiologically resemble the patterns of disease caused by M. tuberculosis, but infections of bone, soft tissue, and lymph nodes have also been described [1, 8, 12, 13]. Infections in immunocompetent patients remain mostly localized; the majority of disseminated infections due to M. szulgai have been reported in HIV/AIDS or otherwise severely immunocompromised patients [6, 1315]. The patient presented in our case had a known diagnosis of myelodysplastic syndrome (MDS). He presented initially with worsening anemia and thrombocytopenia, and, ultimately, progressed to acute myeloid leukemia with concomitant HLH. The patient experienced an acute and rapid decline of his condition and, ultimately, expired as a consequence of multi-organ failure. M. szulgai was identified from a bone marrow biopsy that was obtained 12 days prior to the patient’s death. Further complicating the diagnosis of NTM in our patient was the concurrent HLH. Hemophagocytic syndrome is a severe hyperinflammatory condition that can present as either a primary (genetic) or secondary syndrome, due to infection, hematologic malignancies, or rheumatologic diseases [16]. Secondary HLH is most often associated with EBV infections; however, HLH in association with other microbial pathogens has also been described [17, 18]. To our knowledge, this is also the first report of a hemophagocytic syndrome associated with M. szulgai infection.

We found at least three case reports describing an association of hematopoietic malignancies and infection with NTM and, specifically, M. szulgai (Table 1); however, patients had more localized infections, and, to our knowledge, this is the first report of disseminated M. szulgai infection in a patient with a hematologic malignancy [1921]. While the AFB tissue stains in our case confirmed the presence of AFB only in lymphnodes, the histopathologic changes observed in other tissue sections (Fig. 1c) suggest the possibility of further dissemination of the organism, despite negative AFB stains. The incidence of mycobacterial infections in patients receiving bone marrow transplants (BMTs) appears to be low. In a 20-year retrospective review, Roy and Weisdorf reported a rate of 0.49% mycobacterial infections following BMT [16]. In patients with hematologic malignancies and BMT, infections due to NTM are often difficult to diagnose because concomitant clinical factors such as severe immunosuppression and neutropenia can mask the febrile response and granulomatous tissue reaction.
Table 1

Comparison of various case reports on Mycobacterium szulgai and other nontuberculous mycobacteria (NTM) infections

Cited reference

NTM infection site and/or site of organism recovery

Co-morbidity

Patient age (years) and gender

Treatment

Outcome

Meyer and Gelman [20]

M. szulgai; (skin, nodules/lesion on hand, forearm, and elbow; osteomyelitis of phalanges)

Chronic lymphocytic leukemia (prior chemotherapy)

66, female

Isoniazid, rifampin, and ethambutol (duration: 1 year)

Complete resolution of infection and no recurrent skin or bone lesions

Nakada et al. [21]

M. szulgai; (bone marrow, sputum, and BAL)

Myelodysplastic syndrome (refractory anemia); hemophagocytosis

64, male

Clarithromycin (duration: unknown)

Resolution of the infection

Doutre et al. [19]

M. malmoense; (skin nodules/lesion on forearm)

Myelodysplastic syndrome; transfusions; corticosteroid therapy

75, female

Surgical excision of lesions; doxycycline, rifampin, ethambutol (duration: 3 months)

Resolution of lesions with no recurrence of the infection

Gur et al. [14]

M. szulgai; (multifocal osteomyelitis and skin lesions; generalized lymphadenopathy)

N/A

18, male

Isoniazid, rifampin, ethambutol (duration: 2 years)

Temporary improvement after 2 years of therapy; but then recurrent foci of osteomyelitis

Tappe et al. [13]

M. szulgai; (osteomyelitis, right metacarpal, and skin lesions on forearm and chest)

HIV/AIDS; pneumonia

36, male

Clarithromycin, ethambutol, ciprofloxacin (duration: 1 year)

Complete resolution of skin lesions and overall improvement of general condition

Hurr and Sorg [26]

M. szulgai; (osteomyelitis, mandible, and lymphadenopathy)

Rheumatoid arthritis and long-term corticosteroid therapy

68, female

Surgical resection of lymph node and jaw lesion; isoniazid and rifampin

Lost for follow-up, since patient discontinued antimicrobial therapy after 1 month

BAL bronchoalveolar lavage

It is commonly accepted that NTM are ubiquitous in the environment [15]. However, no large-scale studies have been conducted to date that conclusively identified environmental sources for infections due to M. szulgai. Some studies have suggested an association of M. szulgai with snails and tropical fish [22, 23]. Based on a number of case reports of M. szulgai infections and the identification of likely environmental sources, several risk factors for acquisition of the organism with subsequent clinically symptomatic infection have been identified. In HIV-positive and AIDS patients, M. szulgai has been reported to cause pulmonary infections as well as disseminated infections, most commonly, osteomyelitis [9, 15, 23]. In the HIV-negative patient population, M. szulgai more commonly affects middle-aged or elderly men, causing pulmonary infections initially manifesting as a rather indolent disease [1, 24]. Preexisting, chronic lung disease (e.g., chronic obstructive pulmonary disease [COPD]), cigarette smoking, and high-level alcohol consumption have been identified as risk factors for developing pulmonary infections due to M. szulgai [22, 25, 26]. Evidence of person-to-person transmission has never been proven [1]; however, the acquisition of the organism from environmental sources, e.g., aquatic reservoirs, seems highly likely. While acquisition of the organism most likely occurs via the inhalation of aerosolized droplets, the degree of host susceptibility defines the extent of infection [27].

Considering the risk factors reported in the literature, our patient only had a history of occasional smoking and may not have had any other predisposition for pulmonary NTM disease. Notably, however, the history of recurrent pulmonary infections with limited response to antimicrobial therapy could suggest a preexisting exposure and infection due to M. szulgai. The concurrent and previous chest CT scan findings also support this conclusion. Given the current recommendations for the treatment of NTM infections, our patient did receive, at some point, antimicrobial treatment with agents that are considered to be appropriate against M. szulgai. However, the patient never received a three-to-four-drug regimen as recommended by the ATS/IDSA guidelines [5], and, likewise, the length of treatment was below the recommended 12-month time interval. The approach for treatment described in the consensus guidelines and other studies recommends the use of a three-to-four-drug regimen that includes isoniazid, ethambutol, and rifampin, with the possible addition of clarithromycin [5, 28, 29]. Treatment for 9–12 months depending on the extent of the clinical disease may be necessary. However, in vitro resistance to the three primary drugs in addition to clarithromycin and ciprofloxacin has been previously described [15, 26, 28].

In conclusion, we report a fatal case of disseminated M. szulgai infection in a patient with myelodysplastic syndrome with rapid progression to acute myeloid leukemia. The patient was significantly immunosuppressed due to the underlying hematologic condition and immunosuppressive therapy he received. This case illustrates the importance of considering pulmonary and/or disseminated infections due to NTM in immune-suppressed patients with known preexisting pulmonary disease, especially in the setting of suboptimal or absent clinical response to standard antimicrobial therapy. Due to the delayed growth of NTM in the currently available broth and solid media, surgical pathology samples should be carefully examined for the presence of microorganisms, including NTM, and appropriate stains for these organisms may be warranted at an early stage in the diagnostic evaluation of tissue sections from immunocompromised patients.

Conflict of interest

None.

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© Springer-Verlag 2011