Disseminated Mycobacterium peregrinum and Mycobacterium avium infection in a patient with AIDS: A case report and review of literature.

Disseminated nontuberculous mycobacterial infections are frequently recognized in patients living with human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS) and Mycobacterium avium-intracellulare complex (MAIC) is the most common species. Mycobacterium peregrinum is a rapidly growing mycobacterium that accounts for 1-2% of community-acquired and healthcare-associated infections. It mainly causes skin and soft tissue infection. Disseminated infection by M. peregrinum has never been reported in patients with AIDS. We describe a case of disseminated co-infection of M. peregrinum and M. avium in a 33-year-old male with newly diagnosed AIDS, and review the literature regarding M. peregrinum infection. The patient's bone marrow culture grew M. peregrinum and his blood culture grew M. avium. The diagnosis of disseminated co-infection of M. peregrinum and M. avium was confirmed. Disseminated infection due to M. peregrinum is rare and diagnosis can be challenging. Due to limited case numbers, there is no treatment guideline for M. peregrinum nowadays. Further study is warranted for better understanding M. peregrinum related infections.

Background

Nontuberculous mycobacteria (NTM) are universal in the environment, including soil, animals, household water, aquatic systems, and healthcare water systems [1]. NTM comprise more than 150 species and are further divided into slowly growing mycobacteria (SGM) and rapidly growing mycobacteria (RGM) [1], [2]. Around 50 species are considered human pathogens. Among people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (PLWHA), disseminated NTM infections are more frequently recognized and Mycobacterium avium-intracellulare complex (MAIC) is the most common species [3]. M. peregrinum is a RGM and belongs to the M. fortuitum complex. Skin and soft tissue infection, pneumonia, bacteremia (catheter-related and primary infection), implantable cardioverter device infection, and tonsillar abscess by M. peregrinum have been reported, in which skin and soft tissue infection is the most common form of infection [3], [4], [5], [6], [7], [8], [9], [10], [11]. Disseminated infection by M. peregrinum is rare as M. fortuitum complex rarely causes disseminated infections compared to other pathogenic RGM, especially M. chelonae and M. abscessus [1]. Here we report a case of disseminated co-infection of M. peregrinum and M. avium in a patient with AIDS. To our best knowledge, this is the first HIV-infected patient reported to have disseminated M. peregrinum infection, provoking us to review literature of this bacterium.

Case presentation

A 33-year-old male visited our Hematology Clinic in April 2021 due to anemia for one year after receiving colon polypectomy a year ago. He also had chronic watery diarrhea after flu-like symptoms 2 months ago. Physical examinations only revealed pale conjunctivae. His hemogram showed pancytopenia with a white blood cell count of 1.7 × 109/L, a hemoglobin level of 3.9 g/dL (reticulocyte index: 0.12), and a platelet count of 134,000/μL. Folate, vitamin B12, and lactate dehydrogenase levels were within normal range. Protein electrophoresis disclosed a chronic inflammation pattern with decrease of albumin and polyclonal increase of gamma globulin (albumin 1.7 g/dL, total protein 5.7 g/dL). Ferritin level was 3,212 ng/mL. The patient was transferred to our Emergency Department on April 26, 2021. Fever with a body temperature 39 °C was noted at triage. His C-reactive protein (CRP) level was 45.75 mg/L. Two sets of blood cultures yielded serogroup D Salmonella enterica. Stool analysis showed positive fecal occult blood test. Abdominal ultrasonography found hepatosplenomagaly. Bone marrow biopsy disclosed normal cellularity and iron stores, without granuloma or malignant cells. His HIV antigen/antibody combination test was positive, with an absolute CD4 T cell count of 16 cells/µL and a HIV RNA viral load of 338,610 copies/mL. Biktarvy™ (bictegravir, emtricitabine and tenofovir alafenamide) was started on April 29. Pancytopenia gradually improved after treatment. The other virology survey revealed 358 copies and 755 copies of CMV DNA/ml and EBV DNA/mL, respectively. Ganciclovir was prescribed and CMV DNA was not detectable after a 2-week course of treatment. For chronic diarrhea, colonofiberscopy showed an ulcerative mass involving ileocecal valve, cecum, and terminal ileum. Biopsy disclosed ulcer only. Repeated colonofiberscopy with biopsy found acute colitis without granuloma, malignancy, crypt abscess, viral inclusion body or parasite. For salmonellosis with elevated alkaline phosphatase (604 U/L), whole-body 18fluorodeoxyglucose positron-emission tomography/computed tomography (18FDG PET/CT) was arranged for metastatic infection evaluation, which incidentally found prominent left mesenteric lymph nodes and lesions over left adrenal gland, stomach, and ascending colon. Esophagogastroduodenoscopy for the stomach lesion revealed superficial gastritis only. As lymphoma was highly suspected and fever persisted without definite infectious focus since May 19, bone marrow aspiration and biopsy were arranged again on June 02 and showed no evidence of malignancy or lymphoma cells. Bone marrow culture was also sent this time. Abdominal CT was arranged for lymphoma survey and showed multiple enlarged lymph nodes at mesentery, para-aortic and porta hepatis areas, an ill-defined, infiltrated and hypodense lesion (about 3 cm) at segment 5 of liver, diffuse wall thickening of jejunum and focal wall thickening of ileum. Echo-guided biopsy of liver tumor showed fatty liver with scattered tiny granulomas and many acid fast bacilli with Ziehl-Neelsen stain. One set of sputum mycobacterial culture yielded M. avium. Rifabutin (300 mg per day), ethambutol (1200 mg per day) and clarithromycin (500 mg twice a day) were started for suspected disseminated MAIC infection. Biktarvy™ was shifted to Triumeq™ (dolutegravir, abacavir and lamivudine) to avoid drug-drug interaction with rifabutin. Bone marrow in Myco/F Lytic culture medium disclosed growth of mycobacteria after 6 days of incubation and the mycobacterium was identified to be M. peregrinum by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) Biotyper system (Bruker Daltonics), with scores ranging from 2.17 to 2.41. Rifabutin was discontinued and levofloxacin (750 mg administered intravenously once a day) was added. Dexamethasone was prescribed for suspected immune reconstitution inflammatory syndrome (IRIS). Fever subsided and CRP level was normalized 3 weeks after addition of levofloxacin. The patient was discharged with clarithromycin, ethambutol and levofloxacin. However, after one and a half months, progressive leukopenia (white blood cell count: 3.2 × 109/L), anemia (hemoglobin: 6.5 g/dL) and elevated CRP level (89.9 mg/L) were noted at our outpatient clinic follow-up. Fever was noted upon admission. As treatment failure was a concern, we tried to regrow the previous M. peregrinum isolate from the stock culture and get the antimicrobial susceptibility profile, but the isolate failed to regrow. According to the previous antimicrobial susceptibility profiles of M. peregrinum in our hospital, trimethoprim-sulfamethoxazole, ciprofloxacin, moxifloxacin, amikacin, tigecycline, clarithromycin, linezolid and imipenem showed good in vitro activities against this bacterium. Thus, for a better disseminated M. peregrinum infection control, amikacin (500 mg twice a day), ciprofloxacin (500 mg administered orally twice a day) and clarithromycin (500 mg twice a day) were prescribed. However, his fever persisted and then dexamethasone was given for suspected IRIS. He responded well to amikacin-containing antibiotic regimen and steroid, with a normal CRP level 10 days later. He was discharged with clarithromycin, ciprofloxacin and linezolid (600 mg twice a day). Six weeks after his discharge, the hospital Central Laboratory informed about M. avium growth from his blood culture obtained eight weeks ago. We intended to inform the patient about his condition and suggest admission, but the patient had been hospitalized at another medical center to manage his abdominal pain. Colonofiberscopy there showed an obstructive lesion at hepatic flexure. Lymphadenopathy over left neck and inguinal region was also observed. Pathology report of these lesions led to a diagnosis of Kaposi’s sarcoma with visceral involvement. His serum HHV-8 DNA level was 595,000 copies/mL. He received chemotherapy with doxorubicin hydrochloride liposome and was still hospitalized at the time of writing. The timeline of the case is presented in Fig. 1.

Fig. 1

Timeline of the case.

We tested the antimicrobial susceptibility profiles for the M. avium isolates. The minimum inhibitory concentration (MIC) ranges and interpretation were shown in Table 1. Both M. avium isolates were resistant to levofloxacin, ciprofloxacin, ethambutol and linezolid (the antimicrobial agents prescribed to treat M. peregrinum for this patient). Only amikacin and clarithromycin were effective against both M. peregrinum and M. avium to treat mycobacterial infection for the patient.

Table 1

Antibiotic susceptibility and interpretation of the Mycobacterium avium isolates.

Antibiotics	MIC range (µg/mL)	Interpretation
Clarithromycin	2	S
Rifabutin	0.5	S
Ethambutol	8	R
Isoniazid	4	–
Moxifloxacin	2	S
Rifampin	16	R
Trimethoprim-sulfamethoxazole	4/76	R
Amikacin	16	S
Linezolid	32	R
Ciprofloxacin	16–32	R
Streptomycin	32	–
Doxycycline	32	–
Ethionamide	2.5	–

MIC: minimum inhibitory concentration. S: susceptible. I: intermediate. R: resistant

Discussion

Although NTM are ubiquitous in the environment, only some of them are pathogenic in humans and are mostly SGM (about 82% of cases) [2]. These NTM can cause opportunistic infections in both immunocompromised and immunocompetent patients, with various clinical manifestations. There are four main clinical syndromes: pulmonary infection, skin and soft tissue infection, lymphadenitis, and disseminated infection. Though there is no clear-cut definition for disseminated NTM infection, a consensus seems to be reached among most literatures that disseminated NTM infection is defined as isolation of NTM from blood or bone marrow [12], [13], [14]. Some literature also included isolation of NTM from liver biopsy or from ≥ 2 noncontiguous organs as disseminated infection [13], [14], [15]. Disseminated NTM infections are mainly found in patients with immunodeficiency, such as AIDS and leukemia/lymphoma, and in those with genetic defects or mutations (for examples, Mendelian susceptibility to mycobacterial disease, nuclear factor κB essential modulator mutation, signal transducer and activator of transcription 1 deficiency) or presence of anti-interferon-γ autoantibodies or anti-granulocyte–macrophage colony-stimulating factor antibodies [14], [15]. In PLWHA, 70% to 94.6% of disseminated NTM infections were caused by MAIC [12], [13], [15].

To the best of our knowledge, this is the first description of a disseminated M. peregrinum infection in a patient with AIDS. M. peregrinum, a RGM and member of M. fortuitum complex, accounts for 1 to 2% of RGM infections [1]. A total nineteen publications were reviewed on the PUBMED and MEDLINE databases and there were 21 cases (including our case) reporting M. peregrinum infection. The demographic characteristics, infection sites, antimicrobial susceptibilities and outcomes were summarized in Table 2. Skin and soft tissue was the most commonly infected site (n = 11, 52.4%) and 54.5% of the cases (6/11) were related to surgical site or artificial-device related infections, similar clinical behavior as other members in the M. fortuitum complex [1]. Catheter-related bloodstream infection, pneumonia, lymphadenitis, tonsillar abscess, and infective endocarditis by M. perergrinum have also been reported [2], [3], [5], [6], [7], [10], [16], [17], [18]. Nine cases (42.9%) were recorded to be immunocompromised. But M. peregrinum could also cause sporadic invasive infections in immunocompetent patients. Pneumonia caused by M. peregrinum have been reported in two patients (2/4, 50%) who were previously healthy [7], [18]. With increasing numbers of NTM infections in the last four decades and improvement in methods of identifying different NTM species, a rise in M. peregrinum infection is anticipated and physicians should be aware of the clinical significance of M. peregrinum.

Table 2

Previous reports of Mycobacterium peregrinum infections.

Author	Year	Country	Age	Gender	Immunocomprosed status	Foreign body/procedure	Type of infection (specimen)	Susceptible	Resistant	Antibiotics	Duration of treatment	Intervention	Mortality
Ishii [20]	1998	Japan	45	M	–	–	Skin and soft tissue (skin tissue)	NA	NA	SPFX, MIN	7 weeks	–	Survived
Pagnoux [21]	1998	France	30	F	DM	Continuous subcutaneous insulin infusion	Skin and soft tissue (abscess)	AN, CIP, IMP, CLR	NA	CIP, IMP, AN	3 months	surgical drainage	Survived
Rodríguez-Gancedo [5]	2001	Spain	38	M	Myelomonocytic leukemia	Hickman catheter	Bacteremia (blood)	AN, VA, CIP	ERM, TCN, GM, TOB, IMP, MEM, CAZ, CXM, CTX, CEF, PCN, OX, AMC, SXT, CHL, CC, RIF	VA	NA	catheter removal	Survived
Koscielniak [10]	2003	Germany	1.2	M	Interferon-gamma receptor-1 deficiency	–	Lymphadenitis (lymph node)	IMP, CPM	NA	IMP, CPM	1 year	bone marrow transplantation	Survived
Marie [6]	2005	France	68	M	Polymyositis treated with infliximab	–	Pneumonia (sputum, gastric aspiration products and BAL)	NA	NA	RIF, INH, EMB, PZA	NA	–	Dead
Sakai [3]	2005	Japan	30	F	AIDS (CD4 count: 8 cells/µl)	–	Tonsilar abscess (abscess)	AN, CIP, IMP, CLR	PCN, AM, ERM, VA, CZ, anti-tuberculous drugs	IMP, CLR	6 weeks	drainage	Survived
Short [22]	2005	USA	74	M	–	Automatic implantable cardioverter defibrillator	Skin and soft tissue, bacteremia (wound, blood)	AN, CIP, IMP, CLR, DOX, GAT, LZD, MEM, TOB	NA	–	–	ICD removal	Survived
Rivera-Olivero a[23]	2006	Venezuela	NA	NA	NA	Mesotherapy	Skin and soft tissue (biopsy/aspirates)	NA	NA	AN, CIP	4–5 months	NA	Survived
Tsolia [16]	2006	Greece	2	M	Interferon-gamma receptor-1 deficiency	–	Lymphadenitis (lymph node, gastric aspirate)	AN, CLR, CIP	RIF	AN, CLR, CIP	at least 1 year	–	No improvement
Appelgren [24]	2008	Sweden	40	M	NA	–	Skin and soft tissue (wound)	NA	NA	AN, CLR, CIP	3 months	–	Survived
Nagao [4]	2009	Japan	58	F	NA	Artificial sheets for chest wall reconstruction	Skin and soft tissue (pus)	AN, IMP, LVX	CLR, DOX	AN, IMP, LVX	5 weeks	Artificial sheet removal	Survived
Swahata [7]	2010	Japan	24	M	–	–	Pneumonia (sputum)	AN, CLR, LVX, EMB	INH	CLR, LVX, EMB	NA	–	Survived
Torres-Duque [17]	2010	Colombia	17	F	–	Mechanical aortic valve	Infective endocarditis (blood, sputum)	NA	NA	AN, IMP, CLR, SXT, RIF, DOX	12 months	Biological aortic valve replacement	Survived
Kamijo [25]	2012	Japan	83	M	–	–	Skin and soft tissue (skin tissue)	NA	NA	MIN	28 weeks	–	Survived
Todorova [18]	2015	Bulgaria	72	M	–	–	Pneumonia (sputum)	NA	INH	RIF, INH, EMB, PZA	NA	–	Survived
Wachholz [8]	2016	Brazil	53	F	Psoriasis (not using immunosuppressive therapy)	–	Skin and soft tissue (skin tissue)	NA	NA	DOX	30 days	–	Survived
Lazo-Vasquez [11]	2020	USA	59	F	–	Dual-chamber permanent pacemaker	Skin and soft tissue (wound)	AN, AZI, FOX, CIP, CLR, GM, IMP, LZD, MIN, MXF, TGC, SXT	AMC, FEP, CTX, CRO, DOX, TOB	AN, IMP, LZD, MXF, SXT	4 months	Pacemaker removal	Survived
Pérez-Alfonzo [9]	2020	Venezuela	13	F	–	Dental procedure	Skin and soft tissue and lymphadenitis (skin tissue and lymph node)	NA	NA	AN, CIP	19 weeks	Debridment and surgical removal of lymph node	Survived
Rolan [2]	2020	Argentina	40	F	Autoimmune uveitis under mycophenolate	–	Pneumonia (sputum)	AN, CIP, CLR, LZD	NA	CIP, CLR	6 months	–	Survived
Present study	2021	Taiwan	33	M	AIDS	–	Bone marrow (bone marrow)	NA	NA	LVX, CLR, EMB	Still under treatment	–	Survived

AIDS, acquired immunodeficiency syndrome; AM, ampicillin; AMC, amoxicillin-clavulanic acid; AZI, azithromycin; CC, clindamycin; CEF, cephalotin; CHL, chloramphenicol; CLR, clarithromycin; CPM capreomycin; CRO, ceftriaxone; CTX, cefotaxime; CXM, cefuroxime; CZ, cefazolin; DM, diabetes mellitus; DOX, doxycycline; EMB, ethambutol; ERM, erythromycin; FEP, cefepime; FOX, cefoxitin; GAT, gatifloxacin; GM, gentamicin; IMP, imipenem; INH, isoniazid; LZD, linezolid; MEM, meropenem; MIN, minocycline; MXF, moxifloxacin; NA, not available; OX, oxacillin; RIF, rifampin; SPFX, sparfloxacin; SXT, trimethoprim-sulfamethoxazole; TCN tetracycline; TGC, tigecycline; VA, vancomycin

a This is a retrospective study in which Mycobacterium peregrinum were identified in 2 patients.

As previously mentioned, the majority of disseminated NTM infections in PLWHA is caused by MAIC. These patients with disseminated MAIC infections are usually presented as prolonged fever without obvious origin, weight loss, fatigue, abdominal pain, chronic diarrhea and hepatosplenomegaly [19]. Other opportunistic infections or common malignancies in AIDS patients share similar clinical manifestations. Our patient also presented with resembling symptoms, leading to an initial tentative diagnosis of disseminated MAIC infection. It is unlikely to differentiate between these two NTM infections by clinical symptoms. Empiric treatment will be initiated for MAIC after excluding tuberculosis if there is evidence of mycobacterial growth from specimens. Drugs effective against MAIC include macrolides, ethambutol, rifabutin, fluoroquinolones and amikacin [19]. For M. peregrinum, amikacin, ciprofloxacin, clarithromycin, imipenem and linezolid showed good in vitro activities (Table 2). Although we cannot differentiate between disseminated MAIC and M. peregrinum infections before species identification, both can be inhibited by macrolides, fluoroquinolones and amikacin. But accurate identification of the isolate is still crucial for definite diagnosis and appropriate treatment regimen. The treatment duration for disseminated MAIC infection is at least 12 months [19]. Due to small numbers of disseminated M. peregrinum infection, there is no recommendation for treatment duration. In Table 2, the duration of treatment for M. peregrinum infection varied between different sites. For disseminated infection, it was at least 12 months. The IDSA guidelines suggest lifelong treatment for disseminated MAIC infection in patients with AIDS unless they restore their immunity. The treatment duration of disseminated M. peregrinum infection should be individualized according to the patient’s immune status. Fortunately, the prognosis of M. peregrinum infection seems to be good with mortality documented in only one patient [6].

Conclusion

We presented a disseminated M. peregrinum infection in a patient with AIDS. Disseminated infection due to this bacterium is rare and patients affected are usually immunocompromised. Due to limited cases, there is no treatment guideline for M. peregrinum nowadays. Most physicians chose macrolides, fluoroquinolones, imipenem or amikacin as combination therapy for M. peregrinum infection. Larger numbers of isolates and cases are warranted to provide more information about the clinical features, antimicrobial susceptibility pattern and prognosis of this species.

Ethics statement

This study was approved by the Institution Review Board (IRB) of Chang Gung Medical Foundation (IRB No.: 202101410A3). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.