A 70-Year-Old Woman Receiving Immunosuppressive Therapy Presenting With Iliopsoas Abscess, Pulmonary Miliary Tuberculosis, and Secondary Hemophagocytic Lymphohistiocytosis

Introduction

Tuberculosis (TB) infection is a major global health concern with a diverse spectrum of clinical presentations, especially among immunocompromised individuals [1]. Despite advances in diagnostic strategies, TB diagnosis can be delayed or missed due to its variable manifestations and the absence of a definitive point-of-care test [2]. As a result, clinicians frequently rely on a combination of bacteriological, clinical, and radiological evidence, supported by immunological assays, to establish the diagnosis of TB [2]. This is particularly challenging in patients receiving immunosuppressive therapies, where atypical presentations are more likely [3].

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by abnormal immune activation, leading to symptoms such as persistent fever, cytopenias, organomegaly, and coagulopathies [4]. Although infectious diseases are recognized triggers for HLH, its development as a complication of disseminated TB is relatively rare [5]. The unpredictable and potentially fatal course of TB-associated HLH, even with appropriate antituberculosis therapy, posed significant therapeutic challenges [6,7].

Iliopsoas abscesses can be classified as either primary (without an identifiable source of infection) or secondary (arising from contiguous spread from adjacent structures, such as the vertebrae or gastrointestinal tract) [8]. In spinal TB, “cold abscesses” typically form in the paravertebral region due to vertebral body destruction [9]. However, in rare cases involving immunocompromised patients, primary iliopsoas abscesses can develop as a result of hematogenous dissemination in the setting of miliary TB [10,11]. A previous case report described the rare coexistence of HLH and a muscle abscess in miliary tuberculosis, with diagnosis delayed due to minimal pulmonary findings [12].

This report describes the case of a 70-year-old woman with rheumatoid arthritis receiving long-term immunosuppressive therapy who presented with an iliopsoas abscess, pulmonary miliary tuberculosis, and secondary HLH. It emphasizes the importance of considering this life-threatening complication early to guide timely diagnosis and management.

Case Report

A 70-year-old Japanese woman presented with low-grade fever and loss of appetite for 10 days, and worsening exertional dyspnea, nonproductive cough, and chills for 3 days. She also reported an unintentional 3 kg weight loss during the past 3 weeks. She denied any recent travel history or known sick contacts. Her medical history was notable for rheumatoid arthritis, for which she had been receiving immunosuppressive therapy including golimumab and iguratimod for 8 years. She had no known history of TB exposure, previous TB infection, prior TB testing, or other chronic illnesses. On presentation, her vital signs showed a temperature of 38.6°C and oxygen saturation of 97% while receiving 1 L/min of oxygen via nasal cannula. Physical examination was notable for bilateral coarse crackles at the lung bases. There was no evidence of lymphadenopathy. The remainder of the examination was unremarkable. Initial laboratory evaluation revealed pancytopenia, with a white blood cell count of 2700/μL (reference range: 4000–9000/μL), hemoglobin 9.3 g/dL (reference range: 13.5–18.0 g/dL), and platelet count 123 000/μL (reference range: 150 000–350 000/μL). She also had transaminitis, with aspartate aminotransferase 141 U/L (reference range: 13–33 U/L) and alanine aminotransferase 86 U/L (reference range: 8–42 U/L), as well as elevated lactate dehydrogenase 485 U/L (reference range: 119–229 U/L). Inflammatory markers were elevated, including C-reactive protein 10.1 mg/dL (reference range: 0–0.29 mg/dL), ferritin 626.2 ng/mL (reference range: 8–429 ng/mL in females), and soluble interleukin-2 receptor (sIL-2R) 6160 U/mL (reference range: 120–600 U/mL). Coagulation studies were notable for mild prolongation, with a prothrombin time–international normalized ratio of 1.25 (reference range: 0.9–1.14) and activated partial thromboplastin time of 47.8 s (reference range: 24–40 s). The T-Cell Spot Test for Tuberculosis returned positive (Table 1).

Other infectious workup – including severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR), HIV antibody testing, and blood cultures – was negative. Given the clinical suspicion for TB, 3 consecutive sputum samples were examined for acid-fast bacilli (AFB) smears, all of which were negative. AFB smears of gastric aspirate samples were subsequently performed, which were also negative (Table 2) [13]. A TB PCR was not available at our institution.

Prone chest radiography on admission showed diffuse hazy opacities with indistinct pulmonary vascular markings throughout both lungs, consistent with fine micronodular and ground-glass–like changes (Figure 1). High-resolution chest computed tomography (HRCT) at the level of the right upper lobe showed randomly distributed tiny nodules throughout both lungs. Although some centrilobular opacities were also present, most of the nodules were not clearly related to the secondary pulmonary lobules (Figure 2A). HRCT at the level of the left lower lobe demonstrated thickening of the interlobular septa. Faint ground-glass opacities were also seen in the perihilar regions (Figure 2B). Coronal contrast-enhanced computed tomography (CT) obtained at the same time as Figure 2A and 2B showed a round, well-circumscribed fluid-density lesion with a distinctly enhancing capsule within the right iliacus muscle, suggesting an abscess. No paraspinal lesion or fluid collection was identified, and there was no evidence of spinal destruction (Figure 3). CT-guided aspiration of the right iliacus muscle lesion yielded serous fluid. Gram stain revealed no bacteria or leukocytes, and acid-fast staining was negative.

The patient was initially treated empirically with intravenous ampicillin-sulbactam and azithromycin for a presumed bacterial muscle abscess and community-acquired pneumonia. As her respiratory status deteriorated, she required mechanical ventilation on hospital day 4. A follow-up HRCT obtained 4 days after the initial scan (Figure 2B) showed progression of ground-glass attenuation along the bronchovascular bundles, with increased interlobular septal thickening (Figure 4). Traction bronchiectasis was noted in association with volume loss (Figure 4). Given these radiologic findings, bronchoscopy with bronchoalveolar lavage (BAL) was performed. AFB stains of the BAL fluid were negative, but the sample was sent for culture. TB PCR testing on BAL fluid was not available at our institution. Cytological examination of the BAL fluid revealed inflammation predominantly composed of monocytes, with no signs of malignancy or multinucleated giant cells. PCR tests for cytomegalovirus and Pneumocystis jirovecii were also negative.

Persistent fever (>38.5°C), bicytopenia, elevated ferritin, and elevated sIL-2R met 4 diagnostic criteria for HLH-2024 [4]. On hospital day 10, bone marrow biopsy showed an increased number of macrophages and histiocytes phagocytizing erythrocytes (Figure 5), confirming the diagnosis of HLH according to the HLH-2024 criteria [4].

On hospital day 11, upon diagnosis of HLH, her cytopenia and multi-organ failure were worsening. A multidisciplinary team including hematology, infectious disease, pulmonology, and internal medicine concluded to initiate HLH-94 protocol therapy, acknowledging the potential risk of exacerbating active infections such as the iliopsoas abscess and pneumonia [14]. Dexamethasone was administered at 10 mg/m2 daily for the first week, and etoposide was given at a dose of 150 mg/m2 per dose. On hospital day 16, the Mycobacterium culture from the right iliacus muscle aspirate grew Mycobacterium tuberculosis. Subsequently, mycobacterial cultures of blood, BAL, and urine – obtained on hospital day 4 after worsening respiratory status – yielded Mycobacterium tuberculosis, establishing the microbiologic diagnosis of miliary TB. Based on these culture results, the pulmonary lesions and the iliopsoas abscess were determined to be manifestations of miliary TB.

After the diagnosis of miliary TB was confirmed, standard antituberculosis therapy with rifampin, isoniazid, ethambutol, and pyrazinamide was promptly initiated. Despite immunosuppressive therapy following the HLH-94 protocol, broad-spectrum antimicrobial coverage, and timely initiation of standard antituberculosis therapy, the patient developed progressive multi-organ failure and died, considered to be due to progression of both miliary TB and HLH, and cytotoxic adverse effects from etoposide, and an autopsy was declined (Table 3).

Discussion

This case highlights 2 important clinical lessons. First, clinicians should consider tuberculosis in the differential diagnosis of immunosuppressed patients who present with multiple clinical conditions, including an iliopsoas abscess and HLH. Both conditions are nonspecific and can obscure the underlying etiology, particularly when typical pulmonary findings are absent. Second, in the management of TB-associated HLH, antituberculous therapy remains the cornerstone of treatment, while the use of adjunctive HLH-directed immunomodulatory therapies should be individualized due to limited evidence.

This case aligns with a growing body of evidence showing that immunosuppressed patients, particularly those on TNF-α inhibitors for autoimmune conditions, are at elevated risk for miliary TB and HLH [14,15]. Meta-analyses have shown that TNF-α inhibitors significantly increase the risk of active TB in patients with rheumatoid arthritis, with drugs such as infliximab, adalimumab, and golimumab associated with a higher risk compared to etanercept [16]. Our patient was also receiving iguratimod, which may have contributed to development of the infection [17].

In our case, the pathophysiology underlying the development of HLH was likely multifactorial. The combination of TNF-α inhibitor use, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) therapy, impaired residual cytotoxic function, and persistent antigenic stimulation from TB appears to have disrupted immune regulation and driven a cytokine storm characterized by interferon-γ, IL-6, and IL-18 [4]. This hyperinflammatory response subsequently led to pathological activation of macrophages, ultimately resulting in the development of HLH, which is considered the most likely underlying mechanism [4]. HLH secondary to TB, although rare, requires prompt recognition and treatment, as delayed diagnosis is associated with poor outcomes [5,7]. Because approximately half of HLH cases are associated with concomitant infections, treatment decisions are often challenging [18]. Prior reports have emphasized the difficulty in distinguishing whether a patient’s presentation reflects infection itself or an underlying HLH process [19]. The HLH-94 protocol was originally designed for primary HLH in the pediatric population, and its use in patients with active TB remains controversial, as immunosuppressive therapy can exacerbate infection [20]. As the therapeutic effect of antituberculosis treatment requires time to manifest, the importance of providing adequate immunosuppressive therapy in the early phase to control the cytokine storm has also been emphasized [21]. In TB-associated HLH, a systematic review demonstrated that antituberculosis therapy combined with HLH-specific treatments – including corticosteroids, intravenous immunoglobulin, etoposide, cyclosporine, and other immunosuppressive agents – was associated with reduced mortality compared with antituberculosis therapy alone [13]. In this case, based on rapidly progressive multi-organ failure likely due to HLH, we initiated treatment according to the HLH-94 protocol, and subsequently added antituberculosis therapy as soon as the diagnosis was established, aiming to achieve both infection control and immune hyperactivation suppression.

Another notable aspect of this case is the presentation of an iliopsoas abscess as a rare extrapulmonary manifestation of miliary TB in conjunction with HLH. Musculoskeletal manifestations of TB are reported to be rare, accounting for approximately 3% of all TB cases [22]. Iliopsoas abscesses in tuberculosis are typically described as “cold abscesses,” which arise from vertebral destruction due to spinal TB and extend into the paraspinal region [11,12]. In our case, however, there were no findings suggestive of vertebral involvement, and the lesion was located within the iliacus muscle. Therefore, this abscess was considered a primary iliopsoas abscess likely caused by hematogenous dissemination of Mycobacterium tuberculosis. A recent systematic review demonstrated that TB-HLH can manifest in various extrapulmonary forms; however, none of the 211 patients included exhibited musculoskeletal involvement [13]. Only a single case report has described the coexistence of HLH and a muscle abscess in the course of miliary TB [12]. Notably, the elderly patient lacked symptoms or imaging findings suggestive of active pulmonary TB, which delayed the diagnosis until later in the clinical course, when the disease had rapidly progressed [12]. Similarly, in our case, there was initially a lack of typical pulmonary findings. In addition, the presence of an iliopsoas abscess mimicked bacterial or other inflammatory etiologies and further obscured the underlying diagnosis. Therefore, in immunosuppressed patients presenting with multiple clinical manifestations such as iliopsoas abscesses and HLH, clinicians should consider TB in the differential diagnosis, even when typical pulmonary lesions are absent.

The clinical implications of this case report are particularly relevant for the management of immunosuppressed patients with atypical presentations of infection [23]. The substantially increased risk of TB associated with TNF-α inhibitor therapy and csDMARDs in patients with rheumatoid arthritis, as demonstrated in large meta-analyses, underscores the importance of vigilant screening and monitoring for TB before and during biologic treatment [17]. Moreover, when HLH and unusual extrapulmonary findings such as muscle abscesses occur in these patients, clinicians should maintain a high index of suspicion for TB [13]. Prompt application of AFB studies and timely initiation of antituberculosis therapy can facilitate diagnosis and improve outcomes, as delayed recognition of TB-HLH is associated with high morbidity and mortality [15]. In our case, TB was considered early in the differential diagnosis. However, all initial acid-fast stains were negative, and the diagnosis was only confirmed when TB cultures returned positive. This delayed the initiation of antituberculous therapy and allowed progression of miliary TB [14]. Despite receiving both standard antituberculosis therapy and HLH-94 protocol therapy, the patient ultimately died. The severe immune dysregulation from HLH, progression of TB, and possible cytotoxicity from etoposide likely all contributed to the poor outcome.

Conclusions

In immunosuppressed patients presenting with multi-organ involvement, such as iliopsoas abscess and HLH, clinicians should maintain a high index of suspicion for miliary TB and pursue proactive diagnostic evaluation. For TB-associated HLH, antituberculous therapy is the essential treatment. Adjunctive immunomodulatory therapies should then be considered on an individualized basis and guided by multidisciplinary discussion.