Mycobacterium intracellulare-Related Immune Reconstitution Syndrome in an HIV Patient: A Case Report

Immune reconstitution syndrome (IRIS) is an uncommon complication seen in patients living with human immunodeficiency virus (HIV) characterized by the decline in a pre-existing condition or a new diagnosis of a masked disease. It is associated with a significant inflammatory component that occurs after starting antiretrovirals, being most frequent in those with severe immunosuppression. Thereby, different types of opportunistic diseases such as non-tuberculous mycobacteria are more frequent in this group of patients, especially those with low lymphocyte counts of below 50 cells/µL. Here, we present the case of an HIV-positive patient who developed lymphadenitis caused by Mycobacterium intracellulare as an unmasked IRIS after initiating treatment for HIV.


Introduction
It is well known that highly active antiretroviral therapy (HAART) leads to immunovirological control in the treatment of human immunodeficiency virus (HIV) infection, decreasing the frequency of opportunistic diseases and improving survival. However, it is associated with different complications such as the immune reconstitution syndrome (IRIS). IRIS was first described as being related to an increase in localized nontuberculous mycobacteria after the introduction of treatment with zidovudine in the early 1990s [1].
Here, we present the case of an HIV-positive patient who developed lymphadenitis caused by Mycobacterium intracellulare as an unmasked IRIS after initiating treatment for HIV.

Case Presentation
A 22-year-old heterosexual male with a history of daily tetrahydrocannabinol use was diagnosed with HIV in 2019. He was lost to follow-up after the first medical visit but returned in May 2020 when he decided to start HAART with tenofovir disoproxil 300 mg + efavirenz 600 mg + emtricitabine 200 mg; suspending it three days later because of marked intolerance with no reintroduction after this episode. Later, he was hospitalized in June 2020 with a new diagnosis of meningeal cryptococcosis treated with amphotericin B and fluconazole. In the July 2020 follow-up, he initiated abacavir 600 mg + lamivudine 300 mg + dolutegravir 50 mg with good adherence and tolerance, achieving undetectable viral load ( Table 1).  In November 2020, he required admission to a hospital for a month due to a left cervical mass with tenderness and an ulcer with active suppuration (Figure 1).

FIGURE 1: Left cervical mass with ulceration.
A contrast computed tomography (CT) of the neck revealed a left lymphadenopathy conglomerate with central hypodensity and loss of the cleavage plane with the adjacent muscular structures ( Figure 2). Chest projection showed small mediastinal and axillary lymphadenopathies with no involvement of the lung parenchyma.

CT: computed tomography
A fine-needle aspiration biopsy was performed. The results showed negative Gram staining and bacterial culture. The acid-fast bacilli smear was positive (++), but the polymerase chain reaction assay GeneXpert MTB/RIF was negative. The patient started antituberculous treatment (rifampicin 600 mg qd + isoniazid 300 mg qd + pyrazinamide 1,200 mg qd + ethambutol 1,100 mg qd), prednisone 40 mg qd for two weeks, and an adjustment of dolutegravir dosage (50 mg bid) due to the possible interactions with rifampicin. During the next few months, there was no clinical response, despite the fact that the patient was adherent to his treatment, and drug interactions were ruled out, triggering the possibility of non-tuberculous mycobacteria. This was confirmed by the definitive culture results and a new molecular test (GenoType) isolating Mycobacterium intracellulare with an absence of rrl and rrn gene mutations (macrolide and aminoglycoside sensibility). With these new findings, the treatment was switched to rifampicin 600 mg qd + ethambutol 1,200 mg qd + azithromycin 500 mg qd, and no further use of steroids was necessary. Rapid response was seen within a month during the follow-up visit.

Discussion
Multiple infectious agents and pathological processes are related to IRIS ( Table 2), hindering the efforts for a universal definition. However, there is a temporal association between the initiation of HAART and the onset of symptoms, with patients presenting with a reduction in the HIV viral load and a rise in the CD4 lymphocyte count, the latter not being a necessary condition [2].  In a meta-analysis involving a total of 13,103 patients from 54 studies, Muller et al. found IRIS incidence at an average of 16.1% with a mortality of 4.5%. They also identified a difference in the etiologies: 37.7% cytomegalovirus retinitis, 19.5% meningeal cryptococcosis, 16.7% progressive multifocal leukoencephalopathy, 15.7% tuberculosis, and 6.4% Kaposi sarcoma [3].

Names of organisms
Despite the heterogeneity of this syndrome, some risk factors have been described that help the identification of these patients: a rapid decline in the viral load (in the first three months), an initial CD4 count lower than 50 cells/µL, early initiation of HAART in patients with the concomitant opportunistic disease, and no previous HAART exposure [2]. IRIS has the following two patterns classified by the clinical presentation: paradoxical IRIS, wherein symptoms and signs of an opportunistic infection briefly improve but reappear or worsen despite treatment, and unmasked IRIS, wherein a new opportunistic infection not previously diagnosed appears after HAART with excessive inflammation [4].
Different infectious etiologies related to IRIS has been described such as Mycobacterium intracellulare, a slow-growing and ubiquitous microorganism in the environment belonging to the Mycobacterium avium complex (MAC), which typically affects individuals with HIV in advanced stages of the disease, especially with CD4 lymphocyte counts less than 50 cells/µL [5]. In these patients, both paradoxical and unmasked IRIS have been reported, presenting atypically with high focal inflammation, the most frequent manifestations being peripheral lymphadenitis, thoracic-pulmonary, and intra-abdominal disease [6].
Unlike Mycobacterium tuberculosis infection, non-tuberculous mycobacterial (NTM) infections are not mandatory to report, hindering the understanding of epidemiological behavior. Henkle [8].
The onset of symptoms is usually slow, with patients initially presenting with constitutional symptoms (fever, night sweats, weight loss, abdominal pain, diarrhea, and malaise), which may be absent or can be associated with anemia, hepatosplenomegaly, and lymphadenopathy. Regarding lymphadenitis, the growth of the lymph nodes begins painlessly, evolving with the production of pus [9]. Imaging findings are usually non-specific: solid and hypoechoic nodes are identified on ultrasound or hypodense with a necrotic center on CT [10].
Lymphadenitis diagnosis is based on cultures (positivity range from 50% to 80%), molecular test, or histopathological findings, typically caseating granulomas. The presence of acid-alcohol-resistant bacilli is variable, and infection by Mycobacterium tuberculosis must be ruled out [11].
Treatment is based on a macrolide plus ethambutol and/or rifampicin with a duration ranging between six to twelve months, depending on clinical evolution and sometimes requiring surgical management. MACrelated IRIS in HIV patients is based on surgical and antimicrobial management, the continuation of antiretroviral therapy, and the use of systemic corticosteroids, generally when it presents with painful lymphadenopathy [12].

Conclusions
IRIS is a condition that must be considered at the time of antiretroviral therapy initiation, especially in patients with marked immunosuppression. Despite not being a frequent disease, non-tuberculous mycobacterial infections should not be forgotten, especially when molecular identification tests for tuberculosis are negative.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.