Understanding Tuberculosis-Linked Hemophagocytic Lymphohistiocytosis: A Systematic Review of Key Insights

Study Selection and Characteristics

In this study, 211 patients were analyzed. Out of these, 61.6% were male, averaging 39.62 years in age. Geographically, 20.7% of reports were from India, with an additional 23.34% involving patients of Indian descent. The United States contributed 10.3%, where 36.2% were non-US nationals. Japan accounted for 9.4%, alongside cases from England, France, and Spain, many involving immigrants.

Previous Infectious Diseases

A history of prior infections was found in 34 patients (17.43%). Tuberculosis (TB) was noted in 7.2% of cases. Suspected Epstein-Barr Virus (EBV) infection appeared in 15 cases (7.7%), while Cytomegalovirus (CMV) suspicion was present in eight patients (4.1%). Additionally, 8.7% had HIV, and 6.7% had other infections, like COVID-19.

Comorbidities

Immunodeficiency occurred in 28.2% of cases. About 20% of patients used immunomodulatory drugs. Cancer was present in 8.2%, hematological disorders in 3.1%, and rheumatologic diseases in 9.2%. Cardiovascular issues affected 11.3%, pulmonary diseases 3.1%, diabetes 10.8%, and renal disease 13.3%.

Signs and Symptoms at Presentation

Fever was recorded in 97% of cases, with an average temperature of 39.06 °C. Respiratory symptoms appeared in 29.1% of patients, lymphadenopathy in 25.4%, and Central Nervous System (CNS) symptoms in 13.6%. Other symptoms included icterus (14.1%), skin rash (11.3%), edema (8.7%), and bleeding (12.7%).

HLH Diagnosis

Most studies based HLH diagnosis on clinical evidence. Of the 207 cases, 135 (65.2%) met the HLH 2004 criteria. H-scores were calculated for many cases. Genetic analyses revealed IFN-γ receptor deficiency and mutations in GZMB and PRF1.

TB Diagnosis

TB was diagnosed through histology, molecular tests, and acid-fast staining. Among 179 patients, 22.3% had lung-only TB, 28.5% had extrapulmonary TB, and 46.4% had both. Miliary TB was noted in 155 cases (82%).

Time and Priority

The median hospitalization for survivors was 38.5 days. In the deceased group, median time from admission to death was 21 days. Postmortem diagnoses revealed TB in 12.7% and HLH in 1.9% of patients.

Mortality

The overall mortality rate was 39%. There was a significant age difference between survivors and deceased, with older patients showing higher mortality. Platelet counts and LDH levels were lower in deceased patients.

Treatment Approaches

Only patients who received HLH-specific treatment survived, with all 11 who did not receiving no treatment succumbing. Treatment outcomes varied significantly between groups receiving different therapies.

ATT and HLH Treatment Received

Among patients receiving both ATT and HLH treatment, the mortality rate was 26.8%. Treatments included classic and salvage ATT regimens, as well as various HLH-specific therapies.

Therapeutic Plasma Exchange

Therapeutic plasma exchange was utilized in six patients, resulting in an 83.3% survival rate. It was effective in managing multiple complications.

Treatment in Pregnancy

In two cases of TB-HLH during pregnancy, both mothers and newborns survived with appropriate treatments.

Risk of Bias Assessment

Using a quality assessment tool, most cases showed moderate to good quality. A small percentage had lower quality scores.

Conclusion

This study highlights the demographics, clinical features, and outcomes of patients with tuberculosis-associated hemophagocytic lymphohistiocytosis (TB-HLH). It underscores the need for timely diagnosis and effective treatment strategies to improve survival rates.