Multiple Simultaneous Infections With Nontuberculous Mycobacteria in the Setting of GATA2 Mutation and Myelodysplastic Syndrome.

GATA2 mutation can result in profoundly reduced monocytes, dendritic cells, natural killer cells, and B cells, and is associated with a predisposition for recurrent and disseminated nontuberculous mycobacterial (NTM) infections and myelodysplasias. Herein, we describe a unique case of 3 simultaneous disseminated NTM infections in a patient with GATA2 mutations.

The incidence of infections caused by nontuberculous mycobacteria (NTM) is increasing worldwide due to acquired or iatrogenic immunosuppression [1, 2]. In this report, we share our experience with an unusual case of 3 simultaneous disseminated NTM infections in a patient with guanine-adenine-thymine-adenine 2 (GATA2) mutation and myelodysplastic syndrome.

CASE REPORT

An 81-year-old man was admitted for scattered skin abscesses. His comorbidities included coronary artery bypass, arthroplasties, and sensorineural hearing deficit. His sister had leukemia at age 65. Family history was otherwise unremarkable. He developed fevers of 6 months duration. He later had transaminitis and anemia. A liver biopsy showed mildly active hepatitis with focal lobular histiocyte clusters/small granulomas. Nodular skin lesions appeared over his forehead, extremities, and gluteal region (Figure 1). Chest computed tomography (CT) showed scattered pulmonary nodules. A positron emission tomography CT showed fluorodeoxyglucose-avid lesions in skin and soft tissue, brain, and lungs. A punch biopsy of skin demonstrated dense granulomatous and suppurative inflammation and stained positive for acid-fast bacilli using acid-fast and Fite stains. Tissue cultures grew Mycobacterium abscessus complex, identified by matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI-TOF MS). However, he grew Mycobacterium avium complex (species avium) and Mycobacterium simiae from separate blood cultures. The microbiology laboratory confirmed no identification errors. Mycobacterium abscessus complex grew from typical dry and nonchromogenic colonies and M simiae grew from typical translucent yellow colonies. Both M avium and M simiae isolates were confirmed via 16s ribosomal RNA (rRNA) Sanger sequencing.

Figure 1.

A and B, Scattered pulmonary nodules (red arrow). C, Single isolated brain nodule (red arrow). D, Nodular skin lesion over lateral elbow with ulcerated center. E, Right wrist swelling and redness; magnetic resonance imaging of the wrist with and without intravenous contrast (not shown) revealed marked synovitis at the radiocarpal joint and extensor and flexor tenosynovitis. F, Nodular skin lesion over the forehead.

The patient had monocytopenia and lymphopenia. Bone marrow biopsy showed evidence of chronic myeloid neoplasm, rare circulating blasts, and marked hypercellularity, with features of myelodysplastic syndrome (MDS) with multilineage dysplasia with approximately 5% bone marrow blasts and 2% circulating blasts. Cytogenetic testing demonstrated complex changes; of 20 metaphases, 4 had t(1;6)(q21;p21) and all metaphases had a (13;14) constitutional Robertsonian translocation (the latter is not a clonal abnormality). Next-generation sequencing was performed on extracted DNA from bone marrow aspirate and core biopsy as previously described at our center (OncoHeme, Mayo Clinic) [3]. This revealed 2 GATA2 gene variants: Chr3(GRCh37):g.128204894_128204895del, NM_001145661.1(GATA2):c.546_547del; p.Pro183* (6% allele frequency) and Chr3(GRCh37):g.128200134CCTT>C; NM_001145661.1(GATA2):c.1168_1170delAAG; p.Lys390del (56%). Mutations in ASXL1, MPL, and U2AF1 were also detected.

Mycobacterium abscessus complex has historically proven itself to be more difficult to treat; hence, antibiotics were tailored toward M abscessus complex while retaining at least 2 drugs active against M avium and M simiae (see Table 1 for susceptibilities): oral azithromycin 500 mg daily and intravenous (IV) imipenem 1 g twice daily, IV tigecycline 50 mg daily, and IV amikacin 15 mg/kg 3 times weekly. Amikacin target peak (Cmax) and trough levels were 35–45 µg/mL and <5 µg/mL, respectively. Imipenem was later switched to IV cefoxitin 3 g every 12 hours due to concern for drug-induced thrombocytopenia. Constitutional symptoms persisted and new skin lesions appeared. Amikacin Cmax target was increased to 45–60 µg/mL and oral clofazimine 50 mg daily was added. After start of treatment, repeat mycobacterial blood cultures remained negative. Skin lesions stabilized and fevers resolved, and he was discharged to a transitional care unit. The anticipated therapeutic program was 2–3 months of a 5-drug regimen followed by 9–10 months continuation with 2–3 drugs (oral azithromycin, oral clofazimine, with or without oral linezolid or IV cefoxitin). After discharge, the patient gradually declined and became transfusion dependent. He was not a candidate for bone marrow transplant. He was later transitioned to comfort care, antibiotics were stopped, and he eventually succumbed to his illness after 3 months of treatment.

Table 1.

Antimicrobial Susceptibility Test Results for Isolated Nontuberculous Mycobacteria and Our Therapeutic Approach

Antimicrobial Agent	Mycobacterium abscessus Complex		Mycobacterium avium		Mycobacterium simiae
	MIC, µg/mL	Interpretation	MIC, µg/mL	Interpretation	MIC, µg/mL	Interpretation
Amikacin	16	S	8	S	16	S
Amikacin (liposomal inhaled)	…	…	8	S	…	…
Cefoxitin	64	I	…	…	…	…
Ciprofloxacin	>4	R[a]	…	…	>8	R[a]
Clarithromycin	0.25	S[b,c]	2	S[c]	4	S[c]
Clofazimine	0.25	NI	0.12	NI	0.12	NI
Doxycycline	>8	R	…	…	>8	R
Imipenem	16	I	…	…	…	…
Linezolid	8	S	32	R	32	R
Minocycline	…	…	…	…	>8	R
Moxifloxacin	4	R	>4	R	1	S
Rifabutin	…	…	…	…	1	S
Rifampin	…	…	…	…	>4	R
Tigecycline	0.25	NI	…	…	…	…
Tobramycin	16	R	…	…	…	…
TMP-SMX	4/76	R	…	…	>4/76	R

Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; NI, no interpretation; R, resistant; S, susceptible; TMP-SMX, trimethoprim-sulfamethoxazole.

Ciprofloxacin and levofloxacin are interchangeable, but both are less active in vitro than moxifloxacin.

No inducible clarithromycin resistance detected.

Clarithromycin is the class representative for the macrolides (ie, clarithromycin, azithromycin, and roxithromycin).

DISCUSSION

GATA2 gene is located on chromosome 3q21 and encodes a master transcription factor that is key to the proliferation and maintenance of hematopoietic stem cells and lymphatic angiogenesis [4, 5]. GATA2 mutations can lead to a state of haploinsufficiency [5]. Immunodeficiency with increased susceptibility to human papillomavirus and NTM, and a predisposition to MDS/acute myeloid leukemia, protein alveolar proteinosis, and lymphedema is the clinical hallmark [6]. However, patients with GATA2 mutations demonstrate clinical heterogeneity (Supplementary Figure 1). Mutations at different locations of GATA2 lead to different syndromic phenotypes such as monocytopenia and M avium complex (MonoMAC) syndrome, Emberger syndrome, and dendritic cell, monocyte, B, and NK lymphoid deficiency syndrome [5]. Symptoms mostly occur in adolescence to early adulthood [6]. In 1 series, the median age at disease onset was 18.6 years, and the probability of remaining without symptoms at age of 40 years was as low as 8% [7]. This high penetrance was also seen in another study where only 7% of individuals with GATA2 mutations remained asymptomatic during follow-up [6]. To date, >100 different germline GATA2 mutations were reported in >400 cases [5]. Mutations can be grouped into 3 types: (1) missense mutations and in-frame deletions in the C-terminal zinc finger domain; (2) nonsense mutations, frameshifts, and large deletions resulting in null alleles; and (3) mutations in regulatory enhancer region of intron 5 [6]. Mutations that affect GATA2 transcript integrity can lead to severe disease while regulatory mutations that preserve transcript integrity may have variable penetrance and later disease onset [5, 6].

Mutations in GATA2 can be germline or somatic. Germline mutations follow an autosomal dominant pattern of inheritance, and their clinical manifestations typically occur in family cohorts, although sporadic cases have been described [8]. Patients may present with primary bone marrow failure syndrome, such as aplastic anemia or MDS [5]. Alternatively, they may present with acute myeloid leukemia at a young age. Patients typically have hypocellular bone marrow, which contrasts with the hypercellular bone marrow usually seen with de novo MDS [6]. Up to 80% of patients with germline GATA2 mutations may develop such hematologic malignancies [7]. Patients may also have a simultaneous or stand-alone primary immunodeficiency syndrome with profoundly reduced monocytes, dendritic cells, NK cells, and B cells [5]. Reported rates for NTM infections vary widely [7, 9, 10]. For example, in early studies of MonoMAC syndrome, up to 78% of patients had NTM infections [9]. On the other hand, a much lower rate of 15% NTM infections was detected in a larger and more contemporary study of germline GATA2 mutations [7]. In the latter study, the estimated risk for all mycobacterial infection was 9% at age 20 years and 42% at age 40 years [7].

In contrast to germline mutations, somatic GATA2 mutations are acquired after conception. They are poorly described in the literature but may occur in 1%–4% of patients with sporadic myeloid malignancies [11]. Prior studies have detected clinical and flow cytometric features of immunodeficiency in patients with somatic GATA2 mutations and myeloid malignancies, indicating that GATA2 mutations may exert pleiotropic effect on terminal immune lineages that alters immunity even when acquired later in life and may produce a similar immunophenotype as germline mutations [5]. For example, up to 41% of patients with somatic GATA2 mutations and myelodysplasia developed invasive fungal infections in a prior series [11]. Along the same lines, somatic GATA2 mutations are theoretically expected to increase the risk for NTM infection similar to germline mutations, yet the currently limited literature cannot support this association. Several NTM species were reported in patients with GATA2 mutations, but these reports mostly do not elaborate on the type of mutation (Supplementary Table 1). We found only 1 report of a patient with confirmed somatic GATA2 mutation and probable mycobacterial infection in the setting of MDS [12]. The patient had a hypercellular bone marrow and a trinucleotide GATA2 deletion c.1168_1170delAAG; p.Lys390del and a co-mutation in ASXL1, similar to our patient. Infection was not confirmed by culture. However, the patient improved after empiric mycobacterial treatment.

The conventional method for determining whether GATA2 mutation is somatic is to perform a skin fibroblast GATA2 analysis [5]. Mutations not found on skin fibroblasts are acquired after birth [5]. Our patient did not undergo skin testing and so we are unable to fully confirm the nature of his GATA2 mutations. Nonetheless, given our patient’s age at disease onset, we have a strong suspicion that his GATA2 mutations were somatic.

This is a unique case of disseminated infection with 3 different NTMs in an elderly patient with GATA2 mutations, likely somatic. This is also the first report of M simiae infection in the setting of GATA2 mutations. Molecular testing was used to confirm identification of the different mycobacterial species. MALDI-TOF MS has been effectively used for the rapid identification of NTMs but still lacks the nuances of identifying M avium complex to the species level. Alternatively, 16S rRNA Sanger sequencing is a phylogenetic tool that helps distinguish members within the avium complex while adding confidence to the identification of M avium and M simiae. Unfortunately, disseminated infection in the setting of hematologic malignancy led to a poor outcome in our patient despite aggressive antimicrobial therapy.

Continued research is needed to improve understanding of the complex association/overlap between immunologic deficiencies and NTM infections and their expected outcomes. Clinicians should maintain an index of suspicion for mycobacterial infections in patients with myelodysplasias.

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