Disseminated tuberculosis (TB) is a severe form of TB characterized by the widespread hematogenous dissemination of Mycobacterium tuberculosis (M. tuberculosis) to multiple organs [1]. Extrapulmonary TB, including disseminated TB, makes up 15-20% of all TB cases in South Korea. Disseminated TB is estimated to account for a small fraction, approximately 1-5%, of these extrapulmonary cases [2]. This condition is predominantly observed in immunocompromised individuals, particularly those infected with the human immunodeficiency virus (HIV), a well-established risk factor for disseminated TB [1,3]. Older children, adolescents, and adults with normal immune function have a low risk of developing TB following TB infection (the lifetime risk of developing TB is 5-10% [4]. Furthermore, disseminated TB rarely occurs in immunocompetent individuals, particularly in the absence of identifiable risk factors. Renal TB, an extrapulmonary manifestation of TB, is also uncommon and typically presents after significant renal damage has occurred [1,5]. The coexistence of disseminated and renal TB in healthy adults without apparent immunosuppressive conditions presents a unique clinical challenge, with few cases reported in the literature [6,7]. Most cases of disseminated TB have been documented in patients with HIV, diabetes mellitus, malnutrition, or other forms of immunosuppression [8]. Some studies have shown that disseminated TB occurs in up to 20% of patients with advanced HIV infection, whereas its incidence in immunocompetent individuals is markedly lower.

Idiopathic CD4 lymphocytopenia (ICL), a rare disorder characterized by the unexplained depletion of CD4+ T-cells in the absence of HIV infection or other known immunodeficiencies, has been identified as a potential risk factor for severe infections, including TB [9]. However, reports of disseminated TB in patients with ICL are sparse, making this case particularly notable.

Herein, we describe a rare case of disseminated TB with renal involvement in a previously healthy 35-year-old man with an unexplained depletion of CD4+ T-cells. This case underscores the need to consider TB in the differential diagnosis of unexplained systemic symptoms in patients with CD4+ T-cell depletion, regardless of their HIV status.

A previously healthy 35-year-old man presented with a 2-month history of intermittent gross hematuria, dysuria, and a 2 kg weight loss. Two weeks before admission to our hospital, he was treated with empirical antibiotics for cystitis at a local urology clinic without improvement in symptoms. An enhanced abdominal computed tomography (CT) scan performed 10 d prior was highly suggestive of multiorgan TB involvement, including the kidneys, intestines, and lymph nodes (Fig. 1A-C). Upon admission, the patient was alert, with a temperature of 36.2℃, blood pressure of 116/75 mmHg, and a pulse rate of 70 beats/min. Physical examination revealed tenderness in the lower right quadrant of the abdomen. Laboratory findings were as follows: white blood cell count, 5,900/μL (normal, 4,000-10,000); C-reactive protein level, 1.7 mg/dL (normal, 0.0-0.3); erythrocyte sedimentation rate, 78 mm/h (normal, 0-20); alkaline phosphatase level, 283 IU/L (normal, 104-338); alanine aminotransferase level, 17 IU/L (normal, 4-44); aspartate aminotransferase level, 14 IU/L (normal, 8-38); and creatinine level, 0.9 mg/dL (normal, 0.8-1.3). Urinalysis revealed microscopic hematuria and pyuria. Chest CT revealed an active pulmonary TB lesion (Fig. 1D). However, the patient denied any history of TB exposure and did not exhibit any respiratory symptoms. Additionally, he had received the Bacille Calmette-Guerin vaccine during childhood. On the 5th day of hospitalization, urine and blood cultures showed no bacterial growth, but polymerase chain reaction testing for M. tuberculosis and acid-fast bacilli staining on a urine specimen were positive. On the 6th day of admission, colonoscopy revealed active intestinal TB involving the terminal ileum and ileocecal valve (Fig. 2A). TB-polymerase chain reaction tests of sputum and ileal ulcer tissues obtained via colonoscopy were also positive. Based on these findings, the patient was diagnosed with disseminated TB, and induction therapy with anti-TB drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) was initiated. Antimicrobial-susceptible Mycobacterium tuberculosis was identified in urine, sputum, and intestinal tissue a month after discharge. Further laboratory tests showed the following results (Table 1): HIV antigen/antibody test, negative; testosterone level, 5.46 ng/mL (normal, 5.40-40.00); 25-OH vitamin D level, 25.8 ng/mL (normal, >10); immunoglobulin (Ig) A, 215 mg/dL (normal, 84-438); IgM, 134 mg/dL (normal, 57-288); IgG, 1,275 mg/dL (normal, 680-1,620); CD4+ T-cell count, 278/μL. CD3+ T-cell, CD19 B-cell, and CD16+ CD56 natural killer cell counts were within the normal ranges. The patient received anti-TB medication for 6 months and fully recovered without renal failure during the 1-year follow-up period. However, his CD4+ T-cell count did not improve.

This case highlights the rare occurrence of disseminated TB in an immunocompetent individual with CD4+ T-cell depletion. Despite the lack of typical risk factors, the patient developed severe multiorgan TB, emphasizing the need to consider TB in the differential diagnosis of systemic symptoms in patients with unexplained CD4+ T-cell depletion. Although disseminated TB is most commonly associated with immunocompromised conditions, such as HIV infection, diabetes mellitus, or immunosuppressive therapy, it is an uncommon and clinically challenging diagnosis in immunocompetent individuals. 3 In this case, a 35-year-old man presented with disseminated TB affecting the kidneys, intestines, and lymph nodes, coupled with an unexplained depletion of CD4+ T-cells. The absence of traditional TB risk factors, such as HIV infection or immunosuppressive treatment, makes this case particularly noteworthy.

Similar cases of disseminated TB have been reported in immunocompetent individuals; however, these are extremely rare. For instance, some studies have described cases of disseminated TB in immunocompetent adult [10-12], but these patients did not have the associated CD4+ T-cell depletion observed in our case. This difference underscores the unique aspect of our patient’s condition, which aligns more closely with TB cases in HIV-positive individuals, where CD4+ T-cell depletion is a significant factor. Although a few cases of opportunistic infections due to CD4+ T-cell depletion without HIV infection have been reported, a low CD4+ T-cell count is associated with severe forms of extrapulmonary TB, especially in those not infected with HIV. Reports have suggested that CD4+ T-cell counts below 300/μL are associated with more severe and widespread forms of TB, even in the absence of HIV. This aligns with our findings, as our patient had a CD4+ T-cell count of 278/μL, which may have facilitated the widespread dissemination of the infection.

It is worth considering ICL as a potential underlying condition. Although it could not be definitively diagnosed in this case, persistent CD4+ T-cell depletion raises this possibility. This patient met all Centers for Disease Control and Prevention criteria for ICL: 1) CD4+ T-cell depletion (absolute CD4+ T-cell counts <300 cells/μL or <20% of total lymphocytes at a minimum of two separate time points measured at least 6 weeks apart), 2) seronegativity for HIV infection, and 3) absence of any defined immunodeficiency or therapy associated with CD4+ T-cell depression [13]. ICL is an exceptionally rare disorder, with fewer than 300 cases reported globally since it was first identified [13]. The rarity of ICL has limited systematic clinical studies, with existing research primarily consisting of case reports, small series, and retrospective cohorts. Although genomic data are expected to uncover new genetic causes, the cause of ICL remains unclear, even in infants diagnosed with lymphopenia through T-cell receptor excision circle screening [13]. Patients with ICL are at a heightened risk of opportunistic infections, including mycobacterial infections, although most documented cases involve pathogens other than TB [9]. The most common opportunistic infections were severe skin or anogenital human papillomavirus-related disease (29%) and cryptococcosis (24%). Other opportunistic infections include nontuberculous mycobacterial infections, cytomegalovirus diseases, Pneumocystis jirovecii pneumonia, candidiasis, and aspergillosis [13]. In our patient, persistent CD4+ T-cell depletion despite successful TB treatment suggests that individuals with ICL may have an underlying vulnerability to severe TB, similar to that observed in advanced HIV infection. In addition, Lisco et al. [13] reported that patients with CD4 lymphocytopenia have opportunistic infections and cancers, leading to clinical monitoring and individualized approaches for antimicrobial prophylaxis. This patient may have required prophylactic antibiotics and regular cancer monitoring.

Given the rarity of disseminated TB in immunocompetent individuals, particularly those with CD4+ T-cell depletion of unknown origin, this case emphasizes the importance of considering TB in the differential diagnosis of patients presenting with systemic symptoms and unexplained immunodeficiency. Although our patient had no respiratory symptoms and only a minimal pulmonary TB burden, he initially presented with renal symptoms of disseminated TB; airborne precautions were not implemented because of unawareness of his active pulmonary TB status. This case also suggests that ICL, although rare, may predispose individuals to severe TB, similar to advanced HIV infection. Clinicians should remain vigilant for TB in patients presenting with unusual immune profiles, even in the absence of traditional risk factors, and should consider early CD4+ T-cell count assessment as part of the diagnostic workup. Timely recognition and treatment of TB in such cases are crucial for preventing complications and improving patient outcomes. Additionally, this study highlights the importance of considering TB as a differential diagnosis in South Korean adults presenting with gross hematuria, even in the absence of typical risk factors.