Abstract
Tuberculosis-associated hemophagocytic lymphohistiocytosis (TB-HLH) is a rare and life-threatening complication of tuberculosis infection. Early recognition and treatment of TB-HLH is crucial for improving outcomes. Treatment typically involves a combination of antituberculosis therapy and immunosuppressive therapy to control the immune system's overreaction. In this report, we present the case of a 53-year-old ambulance driver who was diagnosed with TB-HLH. His CT scan revealed splenic abscesses, hepatomegaly and bilateral lung consolidation. He subsequently developed multiorgan failure, including acute respiratory distress syndrome (ARDS), transaminitis and bone marrow dysfunction. The clinical course and simultaneous increase in serum ferritin raised the suspicion of HLH. His Hscore was 254, indicating a high probability of hemophagocytic syndrome. TB diagnosis was confirmed by positive endotracheal TB GeneXpert and bone marrow aspiration (BMA) which detected acid-fast bacilli organisms. The patient was promptly started on anti-TB, dexamethasone and IVIG. The patient responded well to treatment and made a full recovery without any lasting complications. This case highlights the importance of promptly recognising HLH and identifying the underlying cause. In critically ill patients, it is crucial not to delay HLH-specific treatment while working up for differential diagnosis.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a rare hematologic disorder characterized by uncontrolled immune response resulting in multiorgan damage.1 HLH can be primary due to genetic disorder or secondary due to an acquired condition such as neoplastic or infectious diseases. TB is still a public health problem in Malaysia. We report a case of HLH associated with disseminated TB in an immunocompetent healthy man. This case highlights the importance of an aggressive diagnostic approach, high clinical suspicions, and early therapeutic intervention for successful outcomes.
Case report
A 53-year-old man of Melanau ethnic origin, from Sibu, Sarawak, presented to us with a 1-week history of fever and abdominal discomfort. He was an active smoker with underlying hypertension who worked as an ambulance driver. Physical examination revealed a healthy man with normal vital parameters, except for tachycardia and fever. Dull percussion was noted on Traube's space with mild tenderness over the bilateral hypochondriac area. He was treated with multiple courses of antibiotics for infection, but there was no clinical improvement. Cultures, including blood, urine, and sputum, were all sterile. Initial chest X-ray (CXR) and pulmonary tuberculosis workups were all unremarkable. However, he continued to be febrile and eventually developed multiorgan failure, acute respiratory distress syndrome (ARDS), transaminitis and bone marrow dysfunction.
The laboratory test results revealed severe pancytopenia with a haemoglobin level of 6.9 g/dL, white blood cell count of 3.7×109/L, and platelet count of 29×109/L. The patient also had elevated CRP and ESR levels at 232 mg/L and 109 mm/hr, respectively. Furthermore, the patient had transaminitis, high ferritin levels (16,368 ug/L), and raised triglyceride levels (3.34 mmol/L). A leucoerythroblastic picture with severe anaemia and thrombocytopenia was evident in the full blood picture. Autoimmune and biohazard screening tests were negative. Serological tests for cryptococcal antigen, immunofluorescent assay melioidosis, cytomegalovirus and HIV were negative. Echocardiography showed no vegetations.
Given these findings, the clinical suspicion of HLH was raised, which was supported by a high Hscore of 254. Repeated CXR (Fig 1a) showed bilateral diffuse airspace opacities. CT thorax demonstrated bilateral mixed ground glass opacities and confluent areas of consolidations predominantly in bilateral upper lobes associated with several enlarged mediastinal lymph nodes (Fig 1c, d). CT abdomen showed splenic abscesses and mild hepatomegaly (Fig 1e). Bone marrow aspiration (BMA) showed hemophagocytic activity (Fig 2a, b) and acid-fast bacilli organism (Fig 2c). Endotracheal aspirate for TB GeneXpert was positive.
Interim chest X-ray, CT thorax and abdomen. (a, b) Interim CXR following treatment shows improving bilateral airspace opacities. (c) CT Thorax in lung window axial view demonstrates bilateral mixed ground glass opacities and confluent areas of consolidations (black arrows) predominantly in bilateral upper lobes associated with several enlarged mediastinal lymph nodes (white arrows) observed in the mediastinal window axial view (d). (e) Contrast-enhanced CT abdomen in coronal view shows hypodense lesions near the splenic hilum (black arrow) which are suggestive of splenic abscesses.
Bone marrow biopsy. (a, b) Bone marrow aspirate slides (May Grunwald-Giemsa stain) show hemophagocytic activities (green arrow) with various stages of granulocytes and late normoblast engulfed within the cytoplasm of the macrophages. (c) Auramine staining for BMA sample shows acid-fast bacilli organism (black arrow).
The patient was started on a tapering regimen of dexamethasone as per the HLH protocol and also received anti-TB treatment. Due to overt sepsis with leukopenia, etoposide was not administered. Instead, he was given intravenous immunoglobulin (total 2 g/kg) over 5 days. Significant improvements in the patient's clinical condition, CXR, ferritin levels and bone marrow function were observed after one week of treatment with high doses of steroids and anti-TB drugs (Fig 1a, b, Fig 3, Fig 4). Dexamethasone was tapered off during his stay and he was discharged home well after 68 days of admission. Anti-TB treatment was planned for a total duration of 9 months.
The trend of biochemical parameters (haemoglobin, white cells, platelets and CRP) during the disease course.
Ferritin trend during the disease course. Day 0 is the first day of hospitalisation, and the timing of various diagnostic and treatment approaches are marked in the graph.
Discussion
HLH is a rare syndrome characterised by intense immune and inflammatory system activity and the prognosis of this disease is poor. Studies have reported a mortality rate of 50–70%, regardless of its underlying cause.2 HLH can be classified into primary and secondary forms, with the latter resulting from various underlying conditions including infections, malignancies and autoimmune disorders.3 HLH presents as fever of unknown origin with elevated ferritin levels and multi-organ involvement. The HScore has been developed as a tool to aid in diagnosis.
Hyperferritinemia and marrow failure are the key indicators in the diagnosis of HLH. A BMA demonstrating hemophagocytosis is essential for diagnosis and to rule out secondary causes of HLH such as underlying malignant disorders. Fasting hypertriglyceridemia and/or hypofibrinogenemia can also be detected in HLH. Diagnosing HLH is challenging due to variable clinical presentations and lack of specificity of clinical and laboratory findings.4
HLH is associated with various infections, including viral, fungal and parasitic infections.5 TB-HLH is most often seen in immunocompromised patients.6 In Malaysia, where TB prevalence is high, TB-HLH should be considered, especially among healthcare workers. TB-HLH has a high mortality rate as immunosuppressive treatments can exacerbate the course of TB. Combination therapy with etoposide and corticosteroids is often used to treat HLH, and the addition of intravenous immunoglobulin (IVIG) may also be considered due to its anti-inflammatory potential.7 The patient in our case demonstrated significant improvement in CXR, respiratory function and biochemical markers following treatment with a combination of steroids, IVIG and anti-TB drugs.
In conclusion, TB-HLH should be considered in patients with risk factors for TB presenting with clinical or laboratory findings consistent with HLH. Extensive workup for TB should be carried out including the use of Xpert MTB/RIF Ultra, which is more sensitive than other tests for paucibacillary sputum.8 This case highlights the importance of early initiation of HLH treatment as well as treating the underlying cause of HLH. Clinicians should be aware that HLH can be a potential complication of TB.
- © Royal College of Physicians 2023. All rights reserved.
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