Disseminated Mycobacterium lentiflavum Responsible for Hemophagocytic Lymphohistocytosis in a Man with a History of Heart Transplantation

Abstract

Mycobacterium lentiflavum is a nontuberculous, slowly growing mycobacterium usually recognized as a contaminant. Here, we report a case of disseminated M. lentiflavum infection responsible for hemophagocytic lymphohistocytosis in a heart-transplanted man.

CASE REPORT

In June 2013, a 65-year-old man was admitted to the medical intensive care unit (ICU) of North Hospital in Marseille (France) for coma in the context of pancytopenia and fever. He had a medical history of heart transplantation for ischemic heart failure (2006), moderate renal failure, an abdominal aortic aneurysm treated with endoprothesis in 2011, and recurrent stays in Senegal.

He presented with a 1-year history of a chronic fever, splenomegaly, and pancytopenia. Fever developed in early June 2012 and was associated with a poor general condition and a loss of 9 kg in body weight. The patient was receiving tacrolimus and mycophenolate as maintenance immunosuppression regimens. All etiological evaluations for infectious diseases, including tropical diseases and solid and hematologic malignant diseases, were negative. Histological analysis of the liver and bone marrow showed granuloma without caseous necrosis. Oral corticotherapy (prednisolone at 20 mg/day) was initiated in mid-September for idiopathic granulomatosis disease, and tacrolimus was switched to cyclosporine. The patient's fever rapidly disappeared, and his general condition improved.

In March 2013, the patient was hospitalized for recurrent fever despite corticosteroid treatment. Medullar analysis again presented similar results, showing granuloma without caseous necrosis and persistence of the inflammatory syndrome. Blood cultures, including mycobacterial blood culture (MGIT; Becton, Dickinson, Le Pont-de-Claix, France), were performed but showed negative results. Fecal analysis detected acid-fast bacilli (AFB) with a negative DNA probe for Mycobacterium tuberculosis complex. A few weeks later, culture of feces yielded colonies identified as M. lentiflavum by partial rpoB gene sequencing as previously described (1), but no specific treatment was introduced because this was considered a nonpathogenic agent. The dose regimen of cyclosporine was decreased, and mycophenolate mofetil was stopped to restore the patient's immunity (CD4⁺ T cells = 121/mm³).

In May 2013, the patient traveled to Dakar, Senegal. After 1 week, he presented with spontaneous ecchymosis, gingivorrhagia, epistaxis, diarrhea, and fever. He was treated with ciprofloxacin and amoxicillin-clavulanic acid. Three days later, he presented with a sudden right-sided hemiplegia. The patient was transferred to an ICU in Marseille due to neurological worsening. Upon arrival, orotracheal intubation was performed because the patient was comatose. Cerebral computed tomography showed a capsulothalamic hematoma with intraventricular extension and mass effect without neurosurgical indication. Blood counts showed pancytopenia with anemia (hemoglobin [Hb] = 7.1 g/dl), major thrombocytopenia (platelet = 8,000/mm³), and lymphocytopenia (lymphocytes = 110/mm³; CD4⁺ T cells = 50/mm³). Biochemical results revealed renal failure (creatinine = 225 μmol/liter) and a nonspecific inflammatory syndrome with hyperferritinemia (1,051 μg/liter). Bone marrow aspiration showed hemophagocytosis, which led to a diagnosis of hemophagocytic lymphohistocytosis. Tests for hemorrhagic fever, paludism, leptospirosis, and leishmaniosis were all negative. We then performed bronchoalveolar lavage (BAL) and blood and bone marrow cultures and started treatment with empirical antibiotics. After 5 days, AFB were identified in the bone marrow, feces, and BAL fluid, and rpoB PCR sequencing (1) detected M. lentiflavum in the bone marrow specimen. Specific antibiotherapy was introduced with the combination of rifabutin (600 mg/day), ethambutol (1,000 mg/day), clarithromycin (1,000 mg/day), and amikacin. This antibiotherapy was based on the usual therapy for M. lentiflavum infection and was not based on susceptibility testing because identification was made by PCR and susceptibility testing was not yet available. As a result, the patient's platelet level increased to 57,000/mm³. Unfortunately, his renal failure worsened, and no sign of conscious recovery was noted after 10 days without sedation. End-of-life care was performed, and the patient died after 11 days in the ICU. Biological sampling and postmortem biopsy of the liver and lung were performed, revealing disseminated M. lentiflavum in the liver (AFB, culture, and rpoB PCR sequencing), lung, and feces (rpoB PCR sequencing).

The introduction of comparative 16S rRNA gene sequencing has enabled recognition of the distinctive characteristics of most nontuberculous mycobacteria (NTM), which has also led to the discovery of new species (2). Mycobacterium lentiflavum is a nontuberculous, slowly growing mycobacterium that was discovered in 1996 by Springer et al. (2); those authors isolated the organism from a diabetic patient with thoracic spondylodiscitis. Similarly to other NTM, M. lentiflavum has been isolated from soil and water samples around the world. However, links between environmental sources and human disease have not yet been demonstrated (3).

Since 1996, there have been almost 47 reports of M. lentiflavum infections responsible for different disease manifestations depending on the host immune status (Table 1) (2–21). Interestingly, our report describes the first case of hemophagocytic lymphohistocytosis (HLH) due to M. lentiflavum. HLH is often associated with infections, especially viral infections (22), and although it is less common, HLH may also occur in the setting of bacterial infections, including tuberculosis; however, M. lentiflavum-related HLH has not yet been described.

TABLE 1.

Summary of published clinical features of 48 patients with M. lentiflavum infection in order of publication from 1996 to 2014^a

Reference or source	Sex(es)	Age	Disease and site of infection	Immune status	PD	Therapy	Outcome
2	F	85 yrs	Spondylodiscitis (T9–T10)	Normal	No	ISO, RFB, 6 mos; ISO, RFB, PZM, 3 mos	Improved
4	M	42 mos	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
	M	33 mos	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
5	M	49 yrs	Lung	AIDS	No	CLR, ETH, RFB	Cured
6	F	61 yrs	Lung	Immunosuppressed*	COPD	RFB, ETH, CLR, CIP	AFB+
	M	4 yrs	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
	M	45 yrs	Lung, liver, bone	AIDS	No	RFB, CLR, ETH, CIP	Improved
7	M	19 mos	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
8	F	52 yrs	Synovitis, blood	Immunosuppressed**	No	LVX, CLR	Died
9	M	71 yrs	Lung	Normal	TB	RFB, ETH, ISO, PZM, CLR	AFB+
10	F	45 yrs	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
11	F	67 yrs	Lymphadenitis	Normal	No	Surgical excision	NA
	F	38 yrs	Ascites	Normal	No	NA	NA
	F	36 yrs	Lung, skin abscess	AIDS	No	NA	NA
	F	35 yrs	Pleural effusion	Normal	No	RFB, ISO, PZM, ETH	Improved
12	F	67 yrs	Lung	Normal	TB	CLR, RFB, ETH, CIP	AFB+
13	M	49 yrs	Lung	Immunosuppressed*	No	CIP, AZM, ETH	NA
	M	66 yrs	Lung	Immunosuppressed*	No	CLR, ETH	Died
14	M	18 mos	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
	M	14 yrs	Lung and pleural effusion	Immunosuppressed*	No	CLR, AMK, CRO 5 mos	Improved
	M	87 yrs	Lung and pleural effusion	Normal	No	CLR, LVX, RFB	Improved
15	M	48 yrs	Skin ulceration	AIDS	No	ISO, ETH, LVX	NA
16	M	69 yrs	Lung	Normal	TB	None	AFB−
17	F	44 yrs	Lung	Normal	TB	CLR, OFX, AMK	Improved
3	F	43 yrs	Liver, blood, lymph nodes	AIDS	No	ISO, RFB, PZM, CLR, ETH	Improved
	F	85 yrs	Lung	Normal	No	RFB, ETH, CLR	Improved
	F	20 mos	Cervical lymphadenitis	Normal	No	Surgical excision	Cured
18	M	34 yrs	Ileitis	AIDS	No	NA	NA
19	M	5 yrs	Cervical lymphadenitis	Normal	No	Surgical excision, CLR 1 mos	Cured
20	F	54 yrs	Lung	Normal	TB	NA	NA
21	9 F/8 M	12–34 mos	Cervical lymphadenitis	Normal	No	Surgical excision ± medical treatment	Cured
G. Thomas	M	65 yrs	Lung, liver, bone marrow, feces	Immunosuppressed	No	RFB, ISO, ETH, AMK	Died

^aF, female; M, male; AMK, amikacin; AZM, azithromycin; CIP, ciprofloxacin; CLR, clarithromycin; CRO, ceftriaxone; ETH, ethambutol; ISO, isoniazid; LVX, levofloxacin; OFX, ofloxacin; PZM, pyrazinamide; RFB, rifabutin; COPD, chronic obstructive pulmonary disease; TB, tuberculosis; AFB, acid-fast bacilli; PD, pulmonary disease; *, immunosuppressed cancer patients; **, antisynthetase syndrome; NA, not available.

The diagnosis of M. lentiflavum is difficult. M. lentiflavum is phylogenetically related to other slow-growing NTM species, such as M. genavense and M. simiae (2), and traditional biochemical tests poorly differentiated M. lentiflavum from these closely related NTM species, which led to misclassification before the advent of molecular diagnosis (13). It is also important to accurately assess the clinical significance of the isolate because, similarly to other NTM species, M. lentiflavum has often been reported as a harmless contaminant. Our report clearly illustrates this difficulty. Indeed, we first detected M. lentiflavum in the feces and did not consider it as a pathogenic agent. Unfortunately, the patient presented with a disseminated form of this infection a few months later. A study by Safdar and Han (13) evaluated a total of 12 isolates from immunosuppressed cancer patients and identified M. lentiflavum-related disease in only 2 patients. Moreover, M. lentiflavum is highly resistant to almost all antimycobacterial drugs. Therefore, when possible, antimicrobial susceptibility testing should be performed prior to treatment (23, 24).

Finally, we performed a brief review of the literature and identified three main clinical presentations of M. lentiflavum infection (Table 1) (2–21). First, in young children (n = 24) and, rarely, in adults (n = 2), M. lentiflavum can be responsible for lymphadenitis, most often, cervical lymphadenitis, and these cases demonstrate a good outcome after surgical removal alone. Second, in immunosuppressed patients, M. lentiflavum can be responsible for lung disease (n = 5) but can also produce a disseminated form with multiple or atypical organ involvement (n = 7). Third and more recently, M. lentiflavum was described as a potential pathogenic agent in immunocompetent patients, usually with a medical history of respiratory problems, and the agent responsible for lung disease in most of these cases (n = 8/10).

In conclusion, despite the difficulty in assessing the clinical significance of M. lentiflavum, this mycobacterium should be considered a significant opportunistic pathogen, especially in immunocompromised patients and transplanted patients. Moreover, HLH is rare but can be a severe manifestation of disseminated M. lentiflavum infection.