A Gut Feeling: Inflammatory Disease Revealed During Immune Reconstitution

Question: A 34-year-old man with human immunodeficiency virus (HIV) infection presented with progressive night sweats, weight loss, and abdominal distention. He initially came to the United States 3 years earlier as a refugee from Eastern Europe and reported multiple years of fatigue, fluctuating erythematous rashes, and intermittent fevers. Five months before presentation, he was diagnosed with HIV (viral load 105,000 copies/mL, CD4 T-cells 11 cells/μL) and started on antiretroviral therapy (ART) with emtricitabine, tenofovir, and bictegravir. Two months after starting ART, he developed abdominal discomfort, drenching night sweats, and progressive wasting with a 30-pound weight loss over the next 3 months. On examination, he was afebrile with abdominal distention. Abdomen was diffusely tender with palpable hepatosplenomegaly. Full-body positron emission tomography demonstrated increased fluorodeoxyglucose uptake in the mesenteric lymph nodes and proximal small intestine (Figures A and B). Capsule endoscopy showed severe inflammatory changes, including a diffuse nodular mucosa with erythema, edema, and ulcerations throughout the duodenum and jejunum (Figures C and D). Esophagogastroduodenoscopy was performed with biopsies of the affected areas within the small intestine. Kinyoun stain of a touch prep showed acid-fast–positive organisms within macrophages (Figure E). Hematoxylin and eosin stain demonstrated small bowel mucosa with sheets of histiocytes in the lamina propria but no malignant cells (Figure F). Fite stain identified large quantities of acid-fast–positive bacilli (Figure G). Silver stain was negative for fungal organisms. Small intestine biopsy cultures grew Mycobacterium avium complex (MAC) consistent with disseminated MAC. Antibiotic treatment with azithromycin and ethambutol was started and rifabutin was added later, but symptoms progressed. He continued to have night sweats and severe abdominal distension for another 2 months despite antibiotic therapy. His course was then complicated by bilateral lower extremity venous thromboses and severe hypercalcemia (peak 13.2 mg/dL) leading to recurrent hospitalizations for obstructing nephrolithiasis. His white blood cell count was normal, but he had anemia (hemoglobin 10.0 g/dL), and thrombocytosis (platelets 413 × 103/μL). Albumin was low at 2.4 g/dL; C-reactive protein was mildly elevated at 16.1 mg/L. He had intermittent hyponatremia to 127 mEq/L and increased creatinine to 1.7 mg/dL. Liver function tests were normal. Repeated CD4 T-cell count was 84 cells/μL, and HIV viral load was 118 copies/mL after 8 months of ART. What is your diagnosis and how will you manage the patient? Look on page 543 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. In this individual with advanced HIV and persistent severe inflammatory symptoms despite ART and antibiotic therapy for disseminated MAC, the differential diagnosis includes: 1) inadequate antibiotic therapy owing to resistant mycobacteria or poor intestinal absorption; 2) an unrecognized opportunistic infection, such as histoplasmosis or AIDS-defining malignancy, including lymphoma or Kaposi sarcoma herpesvirus (KSHV); or 3) immune reconstitution inflammatory syndrome (IRIS) driven by disseminated MAC. Importantly, IRIS is a diagnosis of exclusion, and a thorough evaluation for other etiologies is essential before initiating immunosuppressive therapy. Antibiotic susceptibility testing confirmed that the pathogen was susceptible, and drug levels were measured and confirmed adequate antibiotic absorption. Biopsy of the small intestine and a lymph node showed no evidence of lymphoma or fungal infection. KSHV serologies and polymerase chain reaction also were negative. There are no universally accepted diagnostic criteria for IRIS, but key clinical features are supportive of the diagnosis, including a low CD4 T-cell count (usually <100 cells/μL) at the time of HIV diagnosis, evidence of ART initiation with an improving CD4 T-cell count and decreasing HIV viral load, a clinical presentation consistent with an infectious or inflammatory condition, and the exclusion of alternative etiologies.2Sereti I. Sheikh V. Shaffer D. et al.Prospective international study of incidence and predictors of immune reconstitution inflammatory syndrome and death in people living with human immunodeficiency virus and severe lymphopenia.Clin Infect Dis. 2020; 71: 652-660Crossref PubMed Scopus (32) Google Scholar The dramatic hypercalcemia was also suggestive, because diffuse granulomatous inflammation can occur in severe mycobacterial infections. Hypercalcemia in this setting occurs from increased production of 1,25(OH2) vitamin D3 (calcitriol) within granulomas leading to greater calcium absorption.1Sharma O.P. Hypercalcemia in granulomatous disorders: a clinical review.Curr Opin Pulm Med. 2000; 6: 442-447Crossref PubMed Scopus (224) Google Scholar Therefore, in the setting of severe progressive inflammatory symptoms and a detailed negative evaluation for alternative etiologies, treatment with prednisone 1 mg/kg daily was initiated for mycobacterial IRIS. IRIS occurs as a pathologic inflammatory response against an underlying infection or tumor during immune reconstitution after suppression of HIV replication. Mycobacterial infections (tuberculosis or non-tuberculous mycobacteria) are commonly associated with IRIS, but IRIS can also develop against cryptococcus and viral infections such as cytomegalovirus (CMV) and varicella zoster virus (VZV).2Sereti I. Sheikh V. Shaffer D. et al.Prospective international study of incidence and predictors of immune reconstitution inflammatory syndrome and death in people living with human immunodeficiency virus and severe lymphopenia.Clin Infect Dis. 2020; 71: 652-660Crossref PubMed Scopus (32) Google Scholar Two forms of IRIS exist: 1) paradoxical, which represents the worsening of a previously known infection despite adequate treatment after initiation of ART; and 2) unmasking, which occurs in a patient with a subclinical infection at the time of HIV diagnosis and becomes apparent only after ART initiation in the setting of immune reconstitution.3Quinn C.M. Poplin V. Kasibante J. et al.Tuberculosis IRIS: pathogenesis, presentation, and management across the spectrum of disease.Life (Basel). 2020; 10: 262PubMed Google Scholar,4Wilson E.M.P. Sereti I. Immune restoration after antiretroviral therapy- the pitfalls of hasty or incomplete repairs.Immunol Rev. 2013; 254: 343-354Crossref PubMed Scopus (104) Google Scholar Unmasking mycobacterial IRIS was most consistent with our case, and it was likely this patient had occult disseminated MAC for several months before diagnosis. Disseminated MAC is common in advanced HIV (CD4 T-cells <50 cells/μL) with an incidence of 20% to 40%, and individuals are frequently exposed via the gastrointestinal (GI) tract, leading to high rates of stool colonization.5Nightingale S.D. Byrd L.T. Southern P.M. et al.Incidence of Mycobacterium avium–intracellulare complex bacteremia in human immunodeficiency virus-positive patients.J Infect Dis. 1992; 165: 1082-1085Crossref PubMed Scopus (522) Google Scholar,6Chin D.P. Hopewell P.C. Yajko D.M. et al.Mycobacterium avium complex in the respiratory or gastrointestinal tract and the risk of Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection.J Infect Dis. 1994; 169: 289-295Crossref PubMed Scopus (149) Google Scholar Although the GI tract is often the portal of entry, diffuse intestinal involvement is rare, but when it does occur, the duodenum is frequently involved (80%).7Corti M. Palmero D. Mycobacterium avium complex infection in HIV/AIDS patients.Expert Rev Anti Infect Ther. 2008; 6: 351-363Crossref PubMed Scopus (60) Google Scholar Characteristic findings include nodular inflammation with fine white mucosal lesions as visualized in our patient, which were likely accentuated from the severe inflammatory presentation. Risk factors for IRIS include disseminated infection, low CD4 count at diagnosis, and possibly genetic factors.3Quinn C.M. Poplin V. Kasibante J. et al.Tuberculosis IRIS: pathogenesis, presentation, and management across the spectrum of disease.Life (Basel). 2020; 10: 262PubMed Google Scholar,8Rocco J.M. Laidlaw E. Galindo F. et al.Mycobacterial immune reconstitution inflammatory syndrome in HIV is associated with protein-altering variants in hemophagocytic lymphohistiocytosis-related genes.J Infect Dis. 2023; 228: 111-115Crossref PubMed Scopus (2) Google Scholar C-Reactive protein was minimally elevated in our patient, but it is a poor marker of disease severity in mycobacterial IRIS.9Rocco J.M. Laidlaw E. Galindo F. et al.Severe mycobacterial immune reconstitution inflammatory syndrome (IRIS) in advanced human immunodeficiency virus (HIV) has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression.Clin Infect Dis. 2023; 76: e561-e570Crossref PubMed Scopus (5) Google Scholar There are no FDA-approved treatments for mycobacterial IRIS, although guidelines recommend those with mild to moderate symptoms can be treated initially with non-steroidal anti-inflammatory drugs (NSAIDs).10Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Developed by the National Institutes of Health, the Centers for Disease Control and Prevention, and the HIV Medicine Association of the Infectious Diseases Society of America Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV—A Working Group of the NIH Office of AIDS Research Advisory Council (OARAC).https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-newGoogle Scholar In those with more severe inflammation or symptoms unresponsive to NSAIDs, treatment with corticosteroids, usually with 1 mg/kg prednisone daily, can improve symptoms and morbidity. Severe mycobacterial IRIS with inflammation refractory to corticosteroid therapy has been reported, and in these settings blocking tumor necrosis factor α or interleukin-6 could be considered.9Rocco J.M. Laidlaw E. Galindo F. et al.Severe mycobacterial immune reconstitution inflammatory syndrome (IRIS) in advanced human immunodeficiency virus (HIV) has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression.Clin Infect Dis. 2023; 76: e561-e570Crossref PubMed Scopus (5) Google Scholar Prednisone initiation provided rapid symptomatic improvement in fevers and night sweats with resolution of hypercalcemia. Antibiotics were also broadened to include moxifloxacin and tedizolid as corticosteroids increased the overall net state of immunosuppression. His abdominal symptoms and malaise began to slowly resolve, and his weight increased to baseline over the course of 4 months while prednisone was slowly weaned. Careful monitoring for new opportunistic infections is essential throughout treatment with corticosteroids owing to the severe immunocompromised state. Our patient developed both VZV reactivation and CMV retinitis during corticosteroid treatment. Both were rapidly identified and treated with complete resolution. By 6 months, his symptoms had resolved completely, allowing him to return to work. Mycobacterial infections in HIV can cause diffuse GI infiltration with an occult presentation and minimal elevation of inflammatory markers. Weight loss and night sweats despite HIV suppression with ART require investigation for opportunistic infections and malignancies. Mycobacterial IRIS should be considered in those with low CD4 counts and persistent or worsening symptoms despite appropriate anti-mycobacterial therapy.