Hemophagocytic lymphohistiocytosis poses a substantial socio-economic burden in China

To the Editor: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease characterized by immune overstimulation and hyperinflammatory response.^[1] Although the prognosis is poor, with a high mortality rate of up to 58% in critically ill patients,^[2] the treatment for HLH is potentially curative. Active HLH treatment involves immunosuppressive induction therapy, followed by hematopoietic stem-cell transplant (HSCT).^[3] This treatment has potentially high value, because progressive HLH can lead to the failure of multiple organs if left untreated, but at a very high cost. Although HSCT has been included in the medical insurance reimbursement list in China, coverage for HLH remains limited, and patients often face substantial out-of-pocket expenses, particularly for self-paid medications. Consequentially, patients with HLH will experience a very significant burden of the expenditure for medical care as well as the disease itself. A certain proportion of patients might also give up HSCT treatment due to unaffordability. Furthermore, the medical management of HLH, especially for the HSCT treatment, needs multiple hospital admissions, which unquestionably would impact patients’ lives in meaningful and costly ways.

We conducted this study to quantify the direct and indirect costs and the potential impact of HLH on employment status and household income. As such, this may be informative for medical care providers in determining preferred treatment modalities and optimal reimbursement policies.

The study included patients with HLH who met the following criteria: (1) hospitalized for HLH at Beijing Friendship Hospital between May 1, 2022, and July 31, 2022; (2) received continuous treatment throughout the entire duration of the disease; (3) completed the questionnaires reporting the cost related to HLH, as well as changes in employment status and income. This study was approved by the Institutional Research Board of Beijing Friendship Hospital, Capital Medical University (Approval Number 2022-P2-384-01). All patients gave informed consent.

Data of each patient were collected from electronic medical records (EMRs) and patient interviews before hospital discharge. Patients’ EMRs collected clinical information, including demographic characteristics, medical history, diagnostic tests, and therapeutic procedures. The direct and indirect costs, employment status changes, and annual household income were assessed by person-to-person investigation using custom questionnaires. The definitions of direct and indirect costs and changes in employment status were provided in Supplementary Method 1, http://links.lww.com/CM9/C860.

Categorical variables were summarized by numbers and percentages, and continuous variables by medians with quartiles. Annual income differences after HLH onset was compared using the paired Mann–Whitney U-test. A logistic regression model was built to identify the factors influencing employment termination. A generalized linear model was used to identify factors associated with the length of work loss. All analyses used SAS version 9.4 (SAS Inc., Cary, NC, USA). A two-sided P value <0.05 was defined as statistical significance.

A total of 102 patients were included. Patients with HLH were primarily female (54/102, 52.94%), with a mean age of 34 years. Among theses patients, Epstein–Barr virus (EBV) composed 40.20% (41/102), infection of other virus composed 20.59% (21/102), rheumatoid/immune composed 18.63% (19/102), and unknown etiology composed 13.73% (14/102), while the left 3.92% (4/102), 1.96% (2/102), and 0.98% (1/102) were primary HLH, pregnancy, and tumor etiology, respectively [Supplementary Tables 1–2, http://links.lww.com/CM9/C860].

The direct cost for HLH across the entire cohort was $67,064.08 (interquartile range: $40,238.45–$149,031.30), with diagnosis and treatment accounting for $7,078.99 and $59,612.52, respectively. Appropriately, 45.56% ($30,551.42/$67,064.08) of the direct cost was paid out of pocket [Supplementary Table 3, http://links.lww.com/CM9/C860]. Moreover, direct costs increased with the treatment duration. In particular, the direct cost was $93,144.56 for patients on follow-up and $55,886.74 for patients on treatment. Regarding etiology, patients with EBV infection had the highest direct cost ($93,889.72), whereas patients with unknown etiology had the lowest ($55,886.74). Regarding regional differences, the direct cost for patients in the Northeast ($119,225.04) was nearly two times higher than those in the East region ($67,064.08). The direct cost was slightly higher among patients with an annual household income greater than $10,000.00 ($77,496.27) and among those with a college degree or higher ($75,260.80) [Supplementary Table 4, http://links.lww.com/CM9/C860].

Among patients who experienced losses due to missed work, the median duration of work absence was 11 months, with a median monthly income reduction of $856.93. Other indirect costs were driven predominantly by food and accommodation ($1490.31), followed by transportation ($745.16), nursing workers ($429.21), and health and nutrition products ($149.03). Notably, 78.43% (80/102) of patients received care provided by relatives and friends. The absence from work was 7 months, with a monthly reduced income of $894.19 for these care providers.

On average, patients experienced a 20% reduction in annual household income after HLH onset, from $14,903.13 to $11,922.50. This reduction was higher for patients with EBV infection ($8941.88/$14,903.13, 60%), those on treatment ($7600.6/$14,903.13, 51%), those with low levels of education ($5119.23/$10,804.77, 47.38%), and annual income ≤$10,000 USD ($4470.94/$5961.25, 75.00%) [Supplementary Figure 1 and Supplementary Table 5, http://links.lww.com/CM9/C860].

Among the 61 patients who reported working full-time before HLH onset, there were 41 with employment status changes and 17 with employment termination. Patients who received a college education were less likely to switch to employment termination than those with an education level less than college (odds ratio [OR] = 0.08; 95% confidence interval [CI]: 0.02–0.30). [Supplementary Tables 6–8, http://links.lww.com/CM9/C860].

On average, the duration of absence from work was 11 months for patients with HLH. Statistically, the duration of absence was longer for patients with EBV infection (median 12 months) than those with other infection etiology (median 3 months) (P = 0.01). Moreover, the absence duration was significantly higher for patients with frequent hospital admissions. Notably, the median absence duration was 12 months for patients with hospital admission ≥6 times and 7 months for those with <6 times admission [Supplementary Table 9, http://links.lww.com/CM9/C860].

The study added to the cost-of-illness literature by demonstrating the substantial economic burden of HLH in China. The median direct cost reached $67,064.08, of which nearly half (45.56%) was paid out of pocket. Indirect costs were driven primarily by productivity loss, with over two-thirds of employed patients experiencing employment changes and 27.87% terminating employment. Overall, annual household income declined by approximately 20% following HLH onset.

Direct cost accounted for the largest share of the total cost of HLH. This direct cost was approximately five times the China’s per capita GDP. It is well-known that patients with cancer have more expensive therapy, such as radiotherapy, chemotherapy, and targeted therapy, leading to a high economic burden.^[4] The predicted annual expenditure for lung cancer patients with comorbidity and their noncomorbid counterparts was $9192.70 and $6087.38 in China.^[5] Notably, our study demonstrated that the medical costs of HLH are comparable or even higher than that of cancer. Given the life-threatening nature of HLH, its high recurrence risk, and the need for intensive treatment such as prolonged hospitalization and potential HSCT, disease management requires substantial medical resources, thereby resulting in exceptionally high healthcare expenditures.

Although most direct costs are accrued immediately following HLH onset, indirect cost components will regularly be incurred for a longer period. Compared with cancer patients who were absent from work for 1.5–3.5 months, the absence days for HLH employees were notably higher for 11 months. Indeed, missed wages for HLH constituted a significant component of indirect costs in our study, and this income decrease might continue for quite a while.

Furthermore, HLH was associated with substantial income loss, underscoring its profound socioeconomic impact. The financial consequences were particularly pronounced among patients with EBV-related disease and those undergoing ongoing treatment, likely reflecting the severe clinical course and intensive care requirements of these subgroups. Notably, household income declined by up to 75% among patients with an annual household income below $10,000, indicating a disproportionate burden on economically disadvantaged households. In addition, higher rates of employment termination were observed among patients with lower educational attainment, further highlighting the socioeconomic vulnerability of this population.

There are several noted limitations. First, recall bias may exist in the data collection, especially regarding the costs and days off work. Second, we only calculated the costs closely related to HLH. However, we did not calculate the cost of conditions that are comorbid or secondary to the disease, which also has a strong economic impact on HLH management. As such, the cost of HLH may be even higher.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81901982 and 82370185) and the Beijing Natural Science Foundation (No. 7262031).

Conflicts of interest

None.

Supplementary Material

cm9-139-1885-s001.docx ^{(3.4MB, docx)}