Disseminated Mycobacterium avium complex infection presenting as superior vena cava syndrome in a patient with anti-interferon-gamma autoantibody: a case report

Abstract

Background

Superior vena cava (SVC) syndrome is primarily associated with malignancy, with infectious etiologies being less common. Tuberculosis is the most common infectious cause of SVC syndrome (SVCS). There has been no report of SVCS caused by nontuberculous mycobacteria (NTM). Here, we present a case of SVCS caused by disseminated Mycobacterium intracellulare in a patient who was previously healthy and subsequently tested positive for anti-interferon gamma autoantibodies.

Case presentation

A 38-year-old woman with no significant past medical history presented with a 3-month history of fever, progressive dyspnea, productive cough, and weight loss. She also reported a one-year history of ulcerative wounds on her right ankle and chest wall. On examination, she exhibited fever, tachycardia, tachypnea, facial and bilateral upper extremity edema, and cervical lymphadenopathy. Chest computed tomography revealed a 4-cm right paratracheal mass, causing SVC obstruction, and suspicious lytic lesions in the thoracic bones. Radiologic imaging of the right ankle showed an osteolytic lesion. Tissue specimens from lymph node biopsy and ankle wound demonstrated positive staining for acid-fast bacilli. While awaiting culture results, an anti-interferon gamma autoantibody assay was performed and returned positive. Mycobacterial culture subsequently identified M. intracellulare. Empiric therapy for NTM infection was initiated with imipenem and azithromycin. Following species identification, treatment was switched to a combination of azithromycin, rifampin, ethambutol, and levofloxacin. Clinical symptoms and imaging findings gradually resolved following the treatment.

Conclusion

Nontuberculous mycobacterial (NTM) disease is a rare cause of superior vena cava syndrome. In cases of disseminated NTM infection, a thorough evaluation for associated underlying conditions, particularly adult-onset immunodeficiency (AOID), linked to anti-IFN-γ autoantibodies, is essential.

Background

Superior vena cava syndrome (SVCS) resulted from a blockage of blood flow through the superior vena cava. The etiology of this obstruction can be an intraluminal thrombus, direct tumor infiltration of the vessel wall, or external compression from adjacent structures. Malignancy, particularly lung cancer and lymphoma, is the most common cause of SVCS. However, increasing number of cases are being reported in relation to intravascular devices [1–3]. While tuberculosis is a known, but rare, cause of SVCS, there have been no prior report of non-tuberculous mycobacterial (NTM) disease causing this condition [4]. Anti-interferon gamma (IFN-γ) autoantibodies are an increasingly recognized cause of adult-onset immunodeficiency (AOID), particularly among previous healthy individuals in Southeast Asia [5, 6]. This condition predisposes patients to severe, recurrent, and disseminated infections by intracellular pathogens, most notably NTM [5–7]. The clinical presentations of disseminated NTM in AOID patients often includes fever, localized or generalized lymphadenopathy, arthralgia, and chronic cough [6–8]. We present a case of SVCS caused by disseminated Mycobacterium intracellulare in a patient who was previously healthy and subsequently tested positive for anti-interferon gamma autoantibodies.

Case presentation

A 38-year-old previously healthy Asian female presented to the outpatient department with a five-day history of fever, a productive cough, and dyspnea on exertion. She reported a low-grade fever and productive cough three months prior to this visit, with the shortness of breath worsening over the last two weeks. She also had chronic ulcerative wounds on her right ankle and chest wall for one year. Despite a normal appetite, she had lost six kilograms in the past month. She had no headaches or other significant symptoms. She had no history of smoking, alcohol use, taking any medication, including immunosuppressants or herbal remedies. She had no prior documented history of recurrent infections. Upon initial assessment, her vital signs were as follows: a body temperature of 38.2 °C, a heart rate of 122 beats/min, a blood pressure of 113/83 mmHg, and a respiratory rate of 24 breaths/min with an oxygen saturation of 95% on room air. The physical examination revealed she was underweighted (36 kg), had facial edema, an enlarged and firm right cervical lymph node (2.5 cm), and rubberry bilateral axillary lymph nodes (4 cm). Her jugular venous pressure was elevated to the mandible, and superficial veins on the right side of the neck were visibly dilated. Pemberton’s sign was negative. Lung auscultation revealed inspiratory wheezing and rhonchi in both lungs. Additionally, she had multiple ulcerative wounds on her chest wall and right ankle.

Initial laboratory investigation showed anemia (hemoglobin 7.6 g/dL), marked leukocytosis (WBC count 31,390 cells/µL) with a high neutrophil count (87.8%), thrombocytosis (858,000 cells/µL), and elevated alkaline phosphatase (184 U/L). Other laboratory tests, including random capillary glucose and serum tumor marker, were within normal limits. A chest computed tomography (CT) revealed a 4-cm right paratracheal mass causing superior SVC obstruction, extensive thoracic lymphadenopathies (mediastinum, right hilum, axillary), and multiple osteolytic lesions in the clavicles, right acromion, and right scapular body (Fig. 1A). There were some small nodular consolidations in the left lower lung zone. Radiography imaging of the right ankle also revealed an osteolytic lesion in her right fibula. The blood test for anti-HIV antibody was negative. Tissue specimens from her cervical lymph node, chest wound, and ankle wound were sent for pathology. The results showed no evidence of malignancy or granuloma, but acid-fast bacilli were found in the lymph node and ankle wound specimens. Direct PCR on the lymph node sample was positive for non-tuberculous mycobacteria. While waiting for mycobacterial culture, a test for anti-interferon gamma (IFN-γ) autoantibody was performed and came back positive, with an OD of 3.22, indicating an underlying adult-onset immunodeficiency (AOID). Anti-IFN-γ auto-Abs concentrations in serum were measured using enzyme-linked immunosorbent assay (ELISA). The relative concentration of anti-IFN-γ auto-Abs was described as the optical density (OD) of the patient’s sample compared to that of a healthy control, and an OD of at least 1 was considered a positive result [9].

Fig. 1.

Chest computed tomography (CT) scan. A The initial CT scan on admission showed the paratracheal mass (orange arrow) compressing the superior vena cava (blue arrow). B A follow-up chest CT scan one month after treatment revealed a decrease in size of the right paratracheal mass. C A follow-up chest CT scan six months after treatment demonstrated a further reduction in the size of the paratracheal mass and thoracic lymph nodes

Ten days later, cultures from the lymph node, chest, and ankle wound all grew M. intracellulare, with drug susceptibility test (DST) showing susceptibility to clarithromycin and amikacin. Sputum and blood cultures showed no other pathogens. Initially, the patient was given intravenous piperacillin-tazobactam for suspected obstructive pneumonia, However, once NTM disease was suspected based on the PCR result, the antibiotics were changed to intravenous imipenem and azithromycin. After a positive anti IFN-γ autoantibody test, intravenous tigecycline and oral clofazimine were added to broaden coverage for both rapid and slow growing NTM. Finally, after the specific identification of M. intracellulare, the antibiotics regimens were adjusted to a combination of oral azithromycin (500 mg/day), rifampicin (300 mg/day), ethambutol (600 mg/day), and levofloxacin (750 mg/day).

After two weeks of intravenous antimycobacterial treatment, the patient’s fever, dyspnea, and facial edema gradually improved. She was discharged on a regimen of oral azithromycin, rifampicin, ethambutol, and levofloxacin. Azithromycin, ethambutol, and rifabutin/rifampicin is the standard regimen for severe disseminated MAC [10]. However, given the findings of osteolytic lesions at multiple sites, which confirmed chronic osteomyelitis, levofloxacin was added to the regimen because of its ability to penetrate bone tissue. A follow-up six months later showed significant improvement: no more shortness of breath or edema, and her ulcerative wounds were healing. A follow-up chest CT scan after one month (Fig. 1B) and six months after treatment revealed a reduction in size of the paratracheal and thoracic lymph nodes (Fig. 1C). Due to self-reported skin rash, levofloxacin was discontinued two months after the initiation. She is currently taking oral azithromycin (500 mg/day), rifampicin (450 mg/day), and ethambutol (600 mg/day), with a planned treatment duration of at least two to four years or until the complete resolution of lymphadenopathies. The entire timeline of diagnosis and treatment is summarized in lFig. nul.

Fig. 2.

Timeline of diagnosis and treatment

Discussion and conclusions

This case report highlights a rare and unusual presentation of disseminated M. intracellulare infection causing superior vena cava syndrome (SVCS) in a previously healthy patient. The patient was subsequently diagnosed with adult-onset immunodeficiency (AOID) associated with anti-interferon gamma (IFN-γ) autoantibodies. While SVCS is predominantly caused by malignancies, infectious causes, though uncommon, remain clinically important [1–4]. Historically, tuberculosis was the main infectious cause of SVCS, but its prevalence has decreased substantially due to effective treatment. This has shifted the focus to other pathogens such as nontuberculous mycobacteria (NTM) [2–4]. NTM infections, particularly in disseminated form, typically affect individuals with immunosuppressive conditions such as cancer, organ transplants, and AIDS. However, they are now being recognized more often in individuals with AOID linked to anti IFN-γ autoantibody [6–8, 11]. IFN-γ is a key cytokine that activates macrophage and is crucial for eliminating intracellular pathogens. The presence of anti-IFN-γ autoantibody compromises cellular immunity, making a person susceptible to disseminated intracellular pathogens such as Salmonella spp., Talaromyces marneffei, and NTM [12–14].

Over the past two decade, AOID has been increasingly reported in Southeast and East Asia, where it is more common among middle-aged women [5, 15]. The predominant NTM species also differ by the region: rapidly growing NTM, particularly M. abscessus, are more common in Southeast Asia, while MAC, including M. intracellulare, are more often found in non-Asian countries [5, 6, 13]. Disseminated NTM in AOID typically presents with a prolonged fever, generalized lymphadenopathy, osteolytic lesions, or disseminated skin lesions [8, 11]. Our case is notable because it highlights disseminated NTM as rare infectious cause of SVCS, a complication facilitated by anti-IFN-γ autoantibody-mediated immunodeficiency. While previous report of disseminated MAC in AOID have shown presentations similar to ours (e.g., lung mass, osteolytic lesions), SVC obstruction was not observed [16]. The patient’s presentation with a large mediastinal mass due to disseminated NTM, which resulted in SVCS, is a unique and rarely reported manifestation. However, this case report may not be representative of how AOID patients typically presents and should not lead to an underestimation of more common etiologies of SVC syndrome.

In conclusion, disseminated NTM is strongly associated with underlying immunodeficiency, particularly AOID associated with anti IFN-γ autoantibody, which is increasingly recognized in Southeast Asia. While SVC syndrome is typically caused by malignancy, our case demonstrated that, in rare instances, it can result from an infectious etiology like disseminated NTM. Our findings broaden the clinical spectrum of this immunodeficiency, underscoring the critical need for prompt identification of underlying immunological abnormalities to facilitate timely therapeutic intervention and enhance patient prognosis.

Abbreviations

SVC

Superior vena cava

SVCS

Superior vena cava syndrome

NTM

Nontuberculous mycobacteria

MAC

Mycobacterium avium

AOID

Adult-onset immunodeficiency

CT

Computed tomography

IFN-γ

Interferon gamma

Authors’ contributions

T.P. and N.A. contributed to data acquisition, data interpretation, and drafting and revision of the manuscript. S.P. contributed to data acquisition, and revision of the manuscript, P.N. contributed to data acquisition, interpretation specific to the microbiological diagnosis, drafting and revision of the manuscript. All authors have read and approved the final version of the manuscript to be submitted for journal publication.

Funding

Open access funding provided by Mahidol University. The authors received no funding for this work.

Data availability

All data during this study are included in this article.

Declarations

Ethics approval and consent to participate

The patient clinical and demographic data were collected in accordance with the guidelines set forth by the Siriraj Institutional Review Board of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. The patient profiled in this report gave written informed consent to be studied and reported upon in this case report.

Consent for publication

The patient gave written informed consent for their personal or clinical details along with any identifying images to be published in this study.

Competing interests

The authors declare no competing interests.