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. 2025 Jun 24;19(6):e0013207. doi: 10.1371/journal.pntd.0013207

Unveiling fatal risk factors: Predicting hemophagocytic lymphohistiocytosis in SFTS patients

Bo Zhang 1,*, Jia-le Gong 1, Hao-long Zeng 1, Qin Liao 1
Editor: Richard A Bowen,2
PMCID: PMC12186921  PMID: 40554617

Abstract

Background

Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic infectious disease with high mortality, and hemophagocytic lymphohistiocytosis (HLH) is one of the rare fatal complications of SFTS. Early prediction of the occurrence of HLH and the identification of prognostic factors in SFTS patients with HLH are crucial for effective clinical management.

Methods

Univariate and multivariate logistic regression were used to analyze the demographic characteristics, clinical manifestations at admission and laboratory parameters of 272 SFTS patients. The ROC curve was used to calculate the optimal critical value of each index based on the survival outcomes of patients, and the kinetic characteristics of laboratory markers predicting the prognosis of patients with HLH were analyzed.

Results

Decreased platelet count, reduced ALT/AST ratio, elevated LDH, and increased DD were identified as independent risk factors for HLH in SFTS patients. Age, fibrinogen (FIB), and procalcitonin (PCT) were independent risk factors for mortality in SFTS patients with HLH (P < 0.05). The combination of these three factors can effectively predict patient prognosis (AUC = 0.903). Patients aged ≥64 years, with FIB ≤ 2.23 g/L, and PCT ≥ 0.9 ng/ml exhibited higher mortality rates. The dynamic characteristics of PCT and FIB levels significantly differed between the survival and death groups in SFTS patients with HLH.

Conclusion

Early laboratory indicators can timely identify HLH complications in SFTS patients. Close monitoring of elderly patients and regular assessment of PCT and FIB levels can effectively reduce mortality.

Author summary

SFTS is a zoonotic disease with high mortality. While research has implicated HLH as a leading fatal complication of SFTS, the majority of these studies have focused on isolated cases, lacking comprehensive correlation analysis. This study identifies a decreased alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio, along with elevated levels of LDH and DD, as independent predictors of HLH development in patients with SFTS. Additionally, age ≥ 64 years, fibrinogen levels ≤2.23 g/L, and procalcitonin levels ≥0.9 ng/mL collectively serve as significant prognostic markers for mortality in cases of SFTS complicated by HLH. Continuous monitoring of fibrinogen and procalcitonin levels enhances the real-time assessment of disease progression, facilitating timely interventions to reduce mortality.

Introduction

Severe Fever with Thrombocytopenia Syndrome (SFTS) is a zoonotic infectious disease caused by SFTS virus (SFTSV) [1–2]. The most common clinical symptoms of SFTS include fever, thrombocytopenia, leukopenia, and gastrointestinal abnormalities [3]. Since its initial report in China in 2010, the disease has been documented in various countries and regions worldwide [4]. The WHO has listed SFTSV as one of the nine most dangerous pathogens that require prompt attention [5]. In severe cases, SFTSV infection can lead to immune dysfunction, cytokine storm, and endothelial injury, potentially resulting in hemorrhage or multiple organ failure, with a mortality rate ranging from 2.8% to 47% [3,6]. Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory response syndrome triggered by abnormally activated macrophages and cytotoxic T cells. The disease progresses rapidly and can cause systemic tissue and organ damage within a short period. Without timely and effective intervention, the prognosis for patients is extremely poor [7]. Previous studies have shown that HLH is one of the fatal complications of SFTS, and it is considered a key factor that increase the risk of death in SFTS patients [8–11]. However, these studies are mainly isolated case reports without any correlation analysis.Therefore, this study analyzed the demographic characteristics, clinical features and laboratory parameters of SFTS patients with HLH at admission, and examined the early predictive factors and prognostic factors of patients with HLH, to promote the early detection of HLH complications and improve the survival rate of patients.

Materials and methods

Ethics statement

This study was approved by the Ethics Committee of Tongji Hospital of Huazhong University of Science and Technology (NO.TJ-IRB20230632). The study was performed in accordance with the Declaration of Helsinki. Due to the retrospective design, patient informed consent was waived.

Patients

We gathered hospitalized SFTS patients at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2020 to April 2024. SFTSV infection was confirmed by detecting SFTSV RNA in EDTA-anticoagulated plasma through polymerase chain reaction or next-generation sequencing. Patients with co-infections of hepatitis C virus, hepatitis B virus, or human immunodeficiency virus (HIV), as well as those with malignant tumors or autoimmune diseases, were excluded.

Collection and analysis of clinical data

Clinical data were collected through the Medical Data Retrieval and Application Platform of Tongji Hospital in Wuhan, China. The data included demographic information, underlying diseases, clinical symptoms, laboratory test results, treatment methods, and prognosis. Laboratory tests included routine blood markers, biochemical indicators, inflammatory markers, cardiac markers, coagulation markers, and cytokines. Routine blood markers were determined using the Sysmex XN 2000 automated hematology analyzer.

The analysis of blood biochemical markers was conducted utilizing the Roche fully automated biochemical analyzer, encompassing liver function indicators—alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total cholesterol (T-CHOL), and lactate dehydrogenase (LDH)—as well as kidney function indicators, including urea, creatinine, uric acid, and bicarbonate. Furthermore, specific inflammatory markers, namely interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), procalcitonin (PCT), and ferritin, were also quantified. Some cardiac markers were detected using the Abbott chemical analyzer. Coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), and D-dimer (DD) were measured using Stago coagulation analyzers. Serum levels of interleukin-1β (IL-1β), interleukin-2 receptor (IL-2R), interleukin-8 (IL-8), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α) were determined using the SIEMENS Immulite 1000 solid-phase two-site chemiluminescent immunoassay. All laboratory test results from the time of admission to discharge were collected for all confirmed SFTS patients.

Diagnosis of HLH

The diagnosis of HLH was based on HLH-2004 criteria [12], requiring the presence of at least 5 out of the following 8 criteria: (1) Fever: body temperature > 38.5°C, lasting > 7 days; (2) Splenomegaly; (3) Cytopenia (involving two or three lineages of peripheral blood): hemoglobin < 90 g/L, platelets < 100 × 10^9/L, neutrophils < 1.0 × 10^9/L, and not due to decreased bone marrow hematopoiesis; (4) Hypertriglyceridemia and/or hypofibrinogenemia: triglycerides >3 mmol/L or above the age-matched 3 standard deviations, fibrinogen <1.5 g/L or below the age-matched 3 standard deviations; (5) Hemophagocytes found in bone marrow, spleen, liver, or lymph nodes; (6) Elevated serum ferritin: ferritin ≥ 500 μg/L; (7) Decreased or absent NK cell activity; (8) Elevated sCD25 (soluble interleukin-2 receptor).

Statistical analysis

Statistical analyses were conducted using GraphPad Prism version 9.5 (San Diego, CA, USA) and SPSS version 26.0 (Chicago, IL, USA). Normally distributed continuous data were presented as mean ± standard deviation (SD) and compared between two groups using Student’s t-test. Non-normally distributed continuous data were shown as median (IQR) and compared using the Mann-Whitney test. Categorical data were expressed as frequency (%) and compared using the Chi-square test. Univariate analyses assessed differences in demographic characteristics, clinical manifestations, and laboratory parameters for HLH occurrence. Factors with P < 0.05 in univariate analysis were further evaluated as independent risk factors for HLH using multivariable logistic regression. Kaplan-Meier curves and log-rank tests were employed for survival analysis. Receiver operating characteristic (ROC) curves determined maximum values, sensitivity, specificity, and optimal cutoff values. Univariate and multivariate logistic regression models analyzed prognostic factors in SFTS patients with concurrent HLH. Statistical significance was set at P < 0.05.

Results

Demographic and clinical characteristics of SFTS patients

A total of 272 SFTS patients were included in this study, with 148 females and 124 males. The median age was 65 (IQR,57-71) years. Among these patients, 53 were in the HLH group and 219 were in the non-HLH group. The demographic and clinical characteristics of the SFTS patients are shown in Table 1. There were no significant differences in age and gender between the two groups. Compared to non-HLH SFTS patients, those in the HLH group had fewer diarrhea symptoms upon admission (P = 0.037). However, the onset time for patients in the HLH group was shorter (P = 0.011), and they required more treatments such as corticosteroids (P = 0.013), intravenous immunoglobulin (P = 0.01), and continuous renal replacement therapy (P < 0.001). Additionally, the mortality rate was higher in the HLH group (P = 0.026).

Table 1. Demographic and clinical features of SFTS patients on admission.

Parameters Total (n = 272) Non-HLH group (n = 219) HLH group (n = 53) P-value
Sex, N (%) 0.797
Female 148(54.4) 120(54.8) 28(52.8)
Male 124(45.6) 99(45.2) 25(47.2)
Age, Y, median (IQR) 65.0
(57.0,71.0)		 66.0
(57.0,70.0)		 64.0
(56.0,71.0)		 0.598
Area, N (%) 0.400
Urban area 38 (14.0) 33 (15.1) 5 (9.4)
Rural area 234 (86.0) 186 (84.9) 48 (90.6)
Season of onset, N (%) 0.875
Spring and summer 154 (56.6) 125 (57.1) 29 (54.7)
Autumn and winter 118 (43.4) 94 (42.9) 24 (45.3)
Symptoms, N (%)
Fever 242(89.0) 192(87.7) 50(94.3) 0.164
Muscular soreness 56(20.6) 47(21.5) 9(17.0) 0.469
cough 44(16.2) 38(17.4) 6(11.3) 0.285
Weakness 129(47.4) 108(49.3) 21(39.6) 0.205
Inappetence 87(32.0) 68(31.1) 19(35.9) 0.502
Nausea 54(19.9) 42(19.2) 12(22.6) 0.571
Vomiting 66(24.3) 53(24.2) 13(24.5) 0.960
Abdominal pain 35(12.9) 32(14.6) 3(5.7) 0.081
Diarrhea 106(39.0) 92(42.0) 14(26.4) 0.037
Headache and dizziness 91(33.5) 70(32.0) 21(39.6) 0.289
Consciousness disorder 15(5.5) 12(5.5) 3(5.7) 0.959
Comorbidities, N (%)
hypertension 96(35.3) 78(35.6) 18(34.0) 0.821
Diabetes mellitus 73(26.8) 54(24.7) 19(35.9) 0.099
Cerebrovascular diseases 39(14.3) 30(13.7) 9(17.0) 0.541
Lung disease 12(4.4) 9(4.1) 3(5.7) 0.622
Chronic kidney disease 8(2.9) 7(3.2) 1(1.9) 0.613
Therapy, N (%)
Corticosteroid 193(71.0) 148(67.6) 45(85.0) 0.013
Intravenous immunoglobulin 88(32.3) 63(28.8) 25(47.2) 0.010
continuous renal replacement therapy 75(27.6) 49(22.4) 26(49.1) <0.001
Respiratory support 48(17.7) 37(16.9) 11(20.8) 0.508
History of tick bite, N (%) 81(29.8) 68(31.1) 13(24.5) 0.352
Time from onset to admission,d,median (IQR) 7.0
(5.0,8.0)		 7.0
(5.0,9.0)		 6.0
(4.0,7.0)		 0.011
Duration of hospital admission,d,median (IQR) 8.0(4.0,12.0) 7.0(5.0,12.0) 9.0(4.0,13.0) 0.497
Outcome, N (%) 0.026
Survival 179(65.8) 151(69.0) 28(52.8)
Deceased 93(34.2) 68(31.0) 25(47.2)
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Laboratory parameter analysis of SFTS patients at admission

The laboratory parameter results of SFTS patients at admission are presented in Table 2. Compared to non-HLH patients, SFTS patients with HLH exhibited significant differences in hematological markers, liver function markers, coagulation markers, inflammatory indicators, and cytokine markers. Hematological parameters showed that SFTS patients in the HLH group had lower counts of lymphocytes, monocytes, white blood cells, and platelets than those in the non-HLH group (P < 0.05). Biochemical markers indicated that SFTS patients with HLH had higher levels of ALT, AST, and LDH, but a lower ALT/AST ratio compared to those without HLH. Coagulation indicators revealed significant differences in APTT, TT, FIB, and DD between the two groups (P < 0.05), with FIB being lower in the HLH group. Inflammatory markers such as ferritin and PCT levels were significantly higher in the HLH group compared to the non-HLH group (P < 0.001), and cytokines IL6, IL2R, and IL10 were also elevated in the HLH group. These findings suggest that the differences in these markers may be associated with secondary HLH in SFTS patients.

Table 2. The comparison of laboratory parameters in SFTS patients with and without HLH.

Parameters Total(n = 272) Non-HLH group (n = 219) HLH group (n = 53) p
Blood routine indicators
WBC, × 109/L 3.16[1.81,5.93] 3.29[1.89,6.01] 2.45[1.61,4.21] 0.044
Lymphocyte, × 109/L 0.57[0.37,0.93] 0.62[0.39,0.96] 0.45[0.32,0.85] 0.038
Monocyte, × 109/L 0.13[0.08,0.33] 0.15[0.08,0.37] 0.09[0.06,0.13] 0.002
Neutrophil, × 109/L 1.94[1.15,4.26] 2.06[1.18,4.65] 1.72[1.00,3.33] 0.168
Platelet, × 109/L 47.0[32.0,64.0] 50.0[33.0,68.0] 33.0[25.0,52.0] <0.001
RBC, × 1012/L 4.29 ± 0.68 4.31 ± 0.69 4.22 ± 0.67 0.400
Hemoglobin,g/L 129.36 ± 20.55 129.64 ± 20.40 128.23 ± 21.09 0.655
Blood biochemistry indicators
ALT, U/L 86.0[52.0,162.0] 80.0[48.0,151.0] 116.0[70.0,193.0] 0.011
AST, U/L 243.0[108.0,441.0] 208.0[97.0,383.0] 357.0[224.0,677.0] <0.001
ALT/AST ratio 0.38[0.28,0.54] 0.39[0.29,0.56] 0.32[0.22,0.45] 0.016
Total protein, g/L 60.77 ± 6.17 61.02 ± 6.29 59.73 ± 5.55 0.172
Albumin, g/L 32.56 ± 4.76 32.73 ± 4.82 31.87 ± 4.43 0.239
Albumin/globulin ratio 1.18 ± 0.24 1.18 ± 0.24 1.17 ± 0.25 0.843
TBIL, μmol/L 8.3[6.0,11.6] 8.3[6.0,11.9] 7.9[5.3,10.3] 0.185
DBIL, μmol/L 4.3[3.0,6.7] 4.4[3.1,6.8] 3.8[2.9,6.5] 0.256
ALP, U/L 74.0[58.0,108.0] 73.0[58.0,109.0] 75.0[58.0,98.0] 0.910
γ-Glutamyl transferase,U/L 40.0[25.0,88.0] 41.0[25.0,97.0] 38.0[22.0,82.0] 0.307
LDH, U/L 744.0[445.0,1282.0] 727.0[425.0,1220.0] 926.0[634.0,1474.0] 0.008
Potassium,mmol/L 4.07[3.63,4.44] 4.04[3.57,4.49] 4.10[3.71,4.38] 0.574
Sodium,mmol/L 134.1[130.8,136.6] 134.4[130.8,136.9] 133.0[130.4,134.4] 0.011
Chlorine,mmol/L 100.7[97.6,103.0] 100.8[97.8,103.2] 100.29[96.4,102.5] 0.157
Calcium,mmol/L 1.96[1.88,2.05] 1.97[1.88,2.07] 1.94[1.87,2.04] 0.388
Urea, mmol/L 5.97[4.20,8.85] 5.90[3.90,8.80] 6.00[4.66,9.00] 0.400
Creatinine, μmol/L 83.0[65.0,113.0] 81.0[64.0,113.0] 89.0[68.0,117.0] 0.201
Uric acid, mmol/L 252.0[195.0,331.0] 249.0[192.0,327.0] 266.0[210.0,333.0] 0.552
HCO3 − , mmol/L 19.55 ± 3.56 19.69 ± 3.56 18.99 ± 3.50 0.196
eGFR, mL/min/1.73m2 74.8[51.9,90.7] 75.1[52.4,92.5] 73.3[49.5,83.0] 0.155
Lactic acid,mmol/L 1.62[1.27,2.18] 1.59[1.26,2.17] 1.74[1.27,2.20] 0.532
Glucose, mmol/L 7.80[6.51,9.95] 7.98[6.57,10.10] 7.40[6.30,9.67] 0.364
Lipase, IU/L 185.5[105.5,345.8] 170.4[98.7,336.9] 217.5[125.3,377.4] 0.077
Amylopsin, U/L 88.0[54.0,132.0] 85.0[52.3,131.0] 96.0[62.0,147.0] 0.320
CK,U/L 509.0[229.0,1371.0] 509.0[206.0,1410.0] 500.0[246.0,1371.0] 0.731
Triglyceride, mmol/L 2.30[1.62,3.22] 2.23[1.67,3.13] 3.02[1.46,3.79] 0.190
Total cholesterol, mmol/L 2.93[2.47,3.50] 2.95[2.48,3.51] 2.83[2.29,3.41] 0.327
Coagulation markers
PT,s 12.9[12.3,13.7] 12.9[12.2,13.7] 13.2[12.6,14.2] 0.077
APTT,s 56.6[46.3,68.4] 55.1[45.1,66.6] 62.4[54.7,85.7] <0.001
TT,s 24.6[20.8,35.1] 23.9[20.7,31.7] 31.9[22.2,50.6] 0.003
Fibrinogen, g/L 2.52[2.23,3.03] 2.58[2.29,3.05] 2.36[2.10,2.75] 0.024
D-dimer, μg/mL FEU 3.53[1.69,7.68] 2.85[1.53,6.81] 6.08[3.74,12.71] <0.001
Cardiac Markers
Myoglobin,ng/mL 207.0[112.5,508.7] 207.0[115.6,505.3] 189.5[109.2,567.6] 0.974
CK-MB,ng/mL 3.3[1.7,7.5] 3.3[1.8,7.7] 3.1[1.3,7.5] 0.607
hs-cTnI,pg/mL 107.3[32.8,295.1] 111.2[33.2,347.8] 72.6[29.4,211.3] 0.144
NT-proBNP,pg/mL 616.0[249.0,1405.0] 640.4[259.9,1440.5] 514.4[199.7,1244.0] 0.360
Inflammatory indicators
Ferritin, μg/L 9986.4[3358.5,25591.0] 8354.4[2705.7,22989.0] 19733.0[7569.7,45124.0] <0.001
hsCRP, mg/L 6.3[2.0,16.6] 5.9[1.8,16.8] 7.7[4.2,13.1] 0.138
PCT, ng/mL 0.40[0.14,1.15] 0.33[0.13,0.93] 0.90[0.42,2.00] <0.001
Cytokine indicators
IL-6, pg/mL 53.92[19.68,125.70] 45.70[15.72,122.10] 84.45[49.90,143.30] 0.009
IL-2R, U/mL 1281.0[964.0,1856.0] 1257.0[943.6,1739.0] 1479.0[1138.0,2077.0] 0.040
IL-8, pg/mL 43.4[21.4,117.0] 38.180[20.5,114.0] 51.0[25.6,128.0] 0.403
IL-10, pg/mL 60.0[15.4,141.8] 48.0[13.2,129.0] 100.0[53.5,181.0] 0.002
IL-1β, pg/mL 7.6[5.0,15.2] 7.6[5.0,14.6] 7.2[5.0,17.9] 0.827
TNF-α, pg/mL 29.7[17.8,55.9] 28.5[16.7,52.8] 31.5[21.4,67.4] 0.190
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Abbreviations: ALP, alkaline phosphatase; ALT, alanine minotransferase; CK,Creatine phosphokinase;APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; DBIL, direct bilirubin; eGFR, estimated glomerular filtration rate; FEU, fibrinogen equivalent unit; hsCRP, high-sensitivity C-reactive protein; IBIL, indirect bilirubin; IL, interleukin; LDH, lactate dehydrogenase; PCT, procalcitonin; PT, prothrombin time; RBC, red blood cell; TBIL, total bilirubin; TNF-α, tumor necrosis factor-α; TT, thrombin time; WBC, white blood cell;hs-cTnI,High-Sensitivity Cardiac Troponin I;CK-MB,Creatine Kinase Myocardial Band; NT-proBNP,N-terminal pro-brain natriuretic peptide;

Independent risk factor analysis for HLH in SFTS patients

To identify independent risk factors for HLH occurrence in SFTS patients, we conducted a univariate logistic regression analysis of demographic characteristics, clinical presentations at admission, and laboratory parameters between the two groups. The analysis revealed that the time from onset to admission, diarrhea, platelet count, ALT/AST ratio, LDH, APTT, FIB, DD, ferritin, and IL-10 were significant factors associated with HLH in SFTS patients. Further multivariate logistic regression analysis indicated that a reduced platelet count (OR 0.966 [0.947, 0.985], P = 0.001), decreased ALT/AST ratio (OR 0.016 [0.001, 0.338], P = 0.008), elevated LDH (OR 1.001 [1.001, 1.002], P = 0.001), and increased DD (OR 1.088 [1.033, 1.146], P = 0.001) are independent risk factors for HLH occurrence in SFTS patients. Diarrhea was identified as a protective factor against HLH in SFTS patients (OR 0.434 [0.211, 0.895], P = 0.024). Although ferritin levels differed between the two groups (P=0.002), there was no significant correlation between ferritin levels and HLH occurrence in SFTS patients (OR 1.000). Specific results are shown in Table 3.

Table 3. Univariate and multivariate Logistic regression analysis of SFTS patients with concurrent HLH.

Parameters Univariate Multivariate
OR 95%CI P OR 95%CI P
Diarrhea 0.496 [0.254,0.966] 0.039 0.434 [0.211,0.895] 0.024
Platelet 0.969 [0.953,0.985] <0.001 0.966 [0.947,0.985] 0.001
ALT/AST ratio 0.179 [0.038,0.835] 0.029 0.016 [0.001,0.338] 0.008
APTT 1.014 [1.004,1.025] 0.008 1.019 [0.997,1.041] 0.097
Fibrinogen 0.587 [0.368,0.934] 0.025 0.630 [0.366,1.087] 0.097
DD 1.101 [1.054,1.151] <0.001 1.088 [1.033,1.146] 0.001
Time from onset to admission 0.894 [0.805,0.992] 0.035 0.907 [0.813,1.012] 0.081
LDH 1.001 [1.000,1.001] <0.001 1.001 [1.001,1.002] 0.001
Ferritin 1.000 [1.000,1.000] <0.001 1.000 [1.000,1.000] 0.002
IL-10 1.002 [1.000,1.004] 0.030 1.001 [0.999,1.004] 0.363
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Prognostic analysis of SFTS patients with HLH

An analysis of the clinical characteristics of 272 SFTS patients indicated that the presence of HLH was statistically significantly associated with patient mortality. Kaplan-Meier curve analysis showed that the 28-day survival rate of SFTS patients was also higher in those without HLH, with a statistically significant difference in mortality (HR = 1.635, 95% CI [0.967-2.764], P = 0.031), as shown in Fig 1. Among the 53 SFTS patients with concurrent HLH, they were categorized into a survival group (28 cases) and a death group (25 cases) based on outcomes. The demographic characteristics, clinical presentations at admission, and laboratory parameters of the two groups are detailed in S1 Table. Univariate and multivariate logistic regression analyses of differential indicators at admission suggested that age, FIB, and PCT are independent risk factors for mortality in SFTS patients with concurrent HLH, with specific results shown in Table 4.

Fig 1. (A) Kaplan-Meier survival curves showing 28-day survival rates between the two groups;(B) ROC analysis of death risk factors in SFTS patients with HLH.

Fig 1

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Abbreviations: AUC, area under the curve; A-F-P, combination of Age, Fib (fibrinogen), and PCT (procalcitonin).

Table 4. Univariate and multivariate Logistic regression analysis of prognosis of SFTS patients with HLH.

Parameters Univariate Multivariate
OR 95%CI P OR 95%CI P
Age 1.159 [1.064,1.261] 0.001 1.208 [1.073,1.359] 0.002
FIB 0.278 [0.096,0.808] 0.019 0.155 [0.038,0.636] 0.010
PCT 1.804 [1.029,3.163] 0.039 2.990 [1.041,8.588] 0.042
ALT/AST ratio 0.016 [0.0,0.602] 0.025 0.020 [0.000,2.578] 0.115
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Further analysis using ROC curves revealed significant findings. Age (AUC = 0.804), FIB (AUC = 0.741), and PCT (AUC = 0.761) were important indicators for mortality in SFTS patients with concurrent HLH. The combination of these three indicators demonstrated good diagnostic value for predicting mortality in SFTS patients with concurrent HLH (AUC = 0.903,Fig 1B). Based on the ROC curve, the optimal cutoff values for each indicator were calculated based on the survival outcomes of the patients(as shown in S2 Table), and the data was grouped. Kaplan-Meier survival curve analysis of the 28-day survival rate indicated that age ≥ 64 years (P = 0.001, Fig 2A), FIB ≤ 2.23 g/L (P = 0.023, Fig 2B), and PCT ≥ 0.9 ng/ml (P = 0.009, Fig 2C) are associated with poor prognosis.

Fig 2. Kaplan-Meier survival curves demonstrated 28-day survival rates in SFTS patients with HLH based on varying levels of (A) age, (B) FIB, and (C) PCT.

Fig 2

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Dynamic characteristics of risk factors for mortality in SFTS patients with HLH

We further observed the dynamic changes in risk factors from admission to 20 days of hospitalization in SFTS patients with concurrent HLH. In the death group, PCT levels continued to rise after admission, whereas in the survival group, PCT levels gradually increased after admission but started to decline around day 8 post-admission, as shown in Fig 3A. The FIB levels in the death group consistently decreased after admission and fell below the reference range, while the survival group’s FIB levels slightly decreased after admission and then gradually rose, remaining within the normal reference range, as shown in Fig 3B. We also observed the ferritin levels in SFTS patients with concurrent HLH. Apart from differences in the levels, both groups showed an initial increase followed by a decrease. The results are shown in S1 Fig.

Fig 3. Dynamic characteristics of (A) FIB and (B) PCT between the survival and deceased groups of SFTS patients with HLH.

Fig 3

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The dotted line represents the biological reference interval.The biological reference range for PCT is less than 0.5 ng/mL; the biological reference range for FIB is 2-4 g/L.Data are presented as median (IQR). ns = no significance, *P < 0.05.

Discussion

SFTS is a severe viral disease with high morbidity and mortality. HLH, a rare and life-threatening condition, can be triggered by various viruses, including human herpesvirus, hemorrhagic fever viruses (dengue, Ebola, hantavirus), human immunodeficiency virus, and SARS-CoV-2 [13–14]. Reports indicate that SFTSV infection can also trigger HLH, leading to higher mortality [10]. Therefore, evaluating prognostic factors available at patient admission is crucial for clinicians to make timely and effective management decisions.

In this study, we conducted a comprehensive analysis of the clinical features and laboratory markers of SFTS patients. Our findings suggest that diarrhea may reduce the risk of HLH in SFTS patients (OR=0.434). Previous research has reported a higher prevalence of diarrhea among surviving SFTS patients [15], whereas other studies have shown that diarrhea increases the risk of death in SFTS patients [16]. Therefore, the role of diarrhea in SFTS remains controversial. Further examination of the prognosis of SFTS patients with HLH showed no significant difference in the presence of diarrhea symptoms at admission between survivors and non-survivors. We propose that this finding may be due to the shorter duration from symptom onset to hospitalization in cases complicated by HLH, along with prompt fluid infusion therapy following admission, which may have alleviated prognostic differences. In the analysis of laboratory markers, SFTS patients with HLH exhibited significant differences in blood routine markers, liver function markers, coagulation markers, inflammatory indicators, and cytokine markers. HLH patients typically exhibit pancytopenia due to cytokine storm, macrophage activation, bone marrow suppression, and increased hemophagocytosis [17–19], which explains why SFTS patients complicated by HLH demonstrate significantly lower leukocyte, lymphocyte, monocyte, and platelet counts compared to non-HLH cases. Critical SFTS patients can rapidly develop into multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation (DIC) [5]. This study also suggests that ALT, AST, LDH, and DD are significantly increased in SFTS patients with HLH. In SFTS patients, a decreased ALT/AST ratio and elevated LDH levels typically reflect the extent of tissue injury and cellular destruction, which are considered as markers of poor prognosis in SFTS patients [20–21]. Notably, SFTS patients with HLH exhibit higher ALT, AST, and LDH levels, along with a lower ALT/AST ratio, all of which collectively signal worse prognosis. In patients with HLH upon admission, the elevation of APTT, TT, and DD, as well as the decrease of FIB, may be related to the inflammatory response and excessive activation of the immune system in SFTS patients [22]. In SFTS patients complicated with HLH, the coagulation abnormalities may present dynamic evolutionary characteristics: in the early stage, the coagulation indexes are mainly characterized by hypocoagulation; however, with the aggravation of endothelial injury, microvascular thrombosis may occur in the later stage, ultimately progressing to DIC [23].This study shows that a decreased ALT/AST ratio, elevated LDH, and increased DD are independent risk factors for HLH in SFTS patients. Ferritin and PCT, as inflammatory biomarkers, demonstrate significant clinical value in the early prognostic assessment of SFTS patients [24]. Studies have confirmed that elevated PCT levels are significantly associated with increased mortality in SFTS patients, particularly during the acute phase of the disease, where changes in PCT levels can serve as important indicators for evaluating prognosis [20,24]. Notably, extremely elevated ferritin levels in HLH patients have been clearly identified as predictors of disease severity and poor prognosis [25]. The results of this study indicate that SFTS patients complicated with HLH have significantly higher ferritin and PCT levels compared to non-HLH patients, suggesting that ferritin and PCT may hold important clinical significance in disease severity and prognosis. However, the multivariate regression analysis suggested no correlation between ferritin levels and the occurrence of HLH in SFTS patients. Some studies argue that the diagnostic value of serum ferritin levels for HLH in adults may not be clear, as other conditions can also activate macrophages to produce ferritin [26]. A study establishing an SFTSV infection model in mice also indicated significant increases in megakaryocytes in the spleen and bone marrow early in the infection [27]. Additionally, an autopsy of a deceased SFTS patient showed significant infiltration of activated macrophages and increased hemophagocytes in the liver, spleen, and bone marrow, suggesting that ferritin levels could significantly increase in the early stage of of SFTS infection [11]. Research indicates that high serum IL-6 and IL-10 levels at admission are independent risk factors for in-hospital mortality in SFTS patients [28]. Notably, when SFTS is accompanied by HLH, the combined rise in IL-6, IL-2R, and IL-10 can worsen the cytokine storm [29]. Thus, monitoring cytokines during the acute phase may help guide immunomodulatory therapy to control inflammation and evaluate patient prognosis..

Some case reports suggest that concurrent HLH is a critical factor for mortality in SFTS patients [3,18]. This study further analyzes the prognosis of SFTS patients with concurrent HLH, confirming an increased mortality rate in these patients. Previous studies have established that age is an independent risk factor for mortality in SFTS patients, potentially related to lower immune function, higher infection rates, and higher complication rates in the elderly [16,30]. Additionally, reports indicate that age is associated with the prognosis of HLH patients [31], consistent with our findings. Studies have shown that the PCT level at admission is a key indicator for predicting the prognosis of SFTS patients, and its increase is usually related to bacterial infection, one of the main causes of death in SFTS patients [11,32]. In SFTS patients, the elevated PCT level may be caused by multiple factors, including immune system overactivation, systemic inflammatory response following HLH, and bacterial infection itself. Beyond systemic inflammation, PCT may worsen SFTS by activating coagulation pathways, with research linking elevated PCT levels to coagulation dysfunction in these patients [33]. In COVID-19 cases, higher PCT levels correlate with disease severity and coagulopathy, potentially indicating DIC [34–35]. SFTS-associated DIC patients also show increased inflammatory markers such as IL-6 and CRP, which, like PCT, may be crucial in DIC development [36]. This study suggests that PCT may be an independent risk factor for death in SFTS patients with HLH. Moreover, fibrinogen, as an independent risk factor for the prognosis of HLH patients, may drive fulminant hyperinflammatory response syndrome after HLH with SFTS patients, resulting in liver dysfunction, DIC, and fibrinolysis [37]. Therefore, monitoring the levels of PCT and fibrinogen is of great significance for evaluating the prognosis of SFTS patients and guiding clinical treatment.

To confirm the relationship between FIB and PCT levels and the prognosis of SFTS patients with HLH. We found that the mortality rate was higher in patients older than 64 years, with FIB levels ≤ 2.23 g/L and PCT levels ≥ 0.9 ng/ml at admission. The combination of these three indicators could predict the prognosis of patients effectively. Further observation of the dynamic changes in FIB and PCT revealed significant differences between the death and survival groups in SFTS patients with HLH.In the survival group, FIB decreased slightly after admission and then increased within the reference range. However, in the death group, FIB levels continued to decline, consistent with existing research reports [38]. Additionally, the PCT level in the death group continued to rise, which has also been observed in other studies when observing deceased SFTS patients [24]. Therefore, continuous monitoring of the two indicators during hospitalization could provide valuable insights into disease progression and patient prognosis.

This study also has some limitations.Although the HLH-2004 criteria remain the most widely used standard for HLH diagnosis, they have certain limitations. Parameters such as hemophagocytosis, serum NK cell activity, and sCD25 concentration are not routinely measured, which may lead to underdiagnosis. Additionally, variability in physicians’ diagnostic criteria and documentation practices may introduce potential bias. Some SFTS patients, particularly those with complex presentations or in early stages of the disease, might not meet all diagnostic criteria, resulting in missed diagnoses; The retrospective nature of this study may not capture all relevant variables. For instance, the duration and severity of diarrhea during hospitalization were not consistently recorded, which could influence outcome assessments; The unequal sample sizes between SFTS patients with and without HLH might affect the statistical power of our comparisons. Although we adjusted for known confounders using multivariate regression, residual confounding may persist. Future studies with larger cohorts are needed to address this limitation; Retrospective data may not fully account for dynamic variables such as viral load fluctuations [39,40] and individual immune status [41,42], which could impact HLH development and prognosis in SFTS patients. Prospective studies are warranted to better control for these factors; Geographic differences in viral strains and genotypes may influence SFTS outcomes [43]. Whether specific genotypes affect HLH incidence or prognosis in SFTS patients remains unclear and requires further investigation.

Conclusions

We found that a decreased ALT/AST ratio, increased LDH levels, and elevated DD levels are independent risk factors for HLH in SFTS patients. Age, FIB, and PCT are independent risk factors for mortality in SFTS patients with HLH. Combining these three indicators can effectively predict patient prognosis. Patients aged ≥64 years, with FIB ≤ 2.23 g/L and PCT ≥ 0.9 ng/mL at admission, have a higher mortality rate. Additionally, dynamic monitoring of FIB and PCT levels can better reflect disease progression, aiding doctors in timely intervention and reducing patient mortality.

Supporting information

S1 Table. Comparison of clinical characteristics and laboratory markers at admission for SFTS patients with HLH between the Surviving and Deceased Groups.

(DOCX)

pntd.0013207.s001.docx (32.7KB, docx)
S2 Table. ROC Curve Analysis for Predicting Death in SFTS Patients with HLH.

(DOCX)

pntd.0013207.s002.docx (12.9KB, docx)
S1 Fig. Fig Dynamic characteristics of ferritin between the survival and deceased groups of SFTS patients with HLH.

(TIF)

pntd.0013207.s003.tif (403.9KB, tif)

Acknowledgments

The authors thank all the donors and patients for participating in this study.

Data Availability

The data supporting the findings of this study are available within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0013207.r002

Decision Letter 0

Andrea Marzi

Jun 01 2025

PNTD-D-24-01931

Unveiling Fatal Complications: Predicting Hemophagocytic Lymphohistiocytosis in SFTS Patients

PLOS Neglected Tropical Diseases

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Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods:

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The objectives for this paper – identifying predictive biomarkers for HLH and markers for. HLH mortality – are clearly stated. There are no citations provided for the methods section, however, and therefore it is difficult to ascertain whether the methods used were appropriate or if they were novel to the manuscript. Additionally, in 102, the author refers to a “big data platform”, please provide the specific data platform. The n-size for the total population and the population that were HLH positive appear appropriate to address the objective of this manuscript.

Results:

-Does the analysis presented match the analysis plan?

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-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The analysis presented matches the analysis plan. The results are clear and completely presented. The figures do appear slightly blurry, and this should be fixed before publication, but the content of the figures is clear.

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Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The conclusions drawn are clearly supported by the data presented. The authors additionally contextualize their findings within the larger body of research or attempt to explain how their work disagrees with prior studies (i.e., the diarrhea results). The authors do discuss some limitations to their work, and while some are very clear, such as markers that could have been studied, some are far too vague. Specifically, the authors should expand on the phrase “influencing factors may not have been included”. Overall, this manuscript has significant public health relevance, as it provides critical diagnostic criteria and relationships between them to predict HLH.

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: ※Minor comments:

1.What is the full name of APTT in line 113?

2.It is necessary to correct the usage of spacing in the manuscript, as there were many errors (line 114, 121, 123, 125, 127, 151~155, Table 1~3, 166, 169, 171, 190~195, and etc…). For example: in table 1 '(n=272)', the letter 'n' should be italicized, and there should be a single space between each character like ‘(n = 272)’.

Reviewer #2: (No Response)

Reviewer #3: In general, the paper should be reviewed for grammatical errors, such as in Line 90, which should say “We gathered hospitalized SFTS patients…”

Summary and General Comments:

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: ※Major comments:

1.The authors of this study provide insufficient explanation regarding the changes in the blood coagulation mechanism associated with increased procalcitonin (PCT) levels. The hypothesis that PCT elevation worsens the prognosis of SFTS patients by enhancing systemic inflammation lacks sufficient supporting evidence. Providing a discussion on the correlation between PCT and disseminated intravascular coagulation (DIC) would strengthen the argument. Additional explanation in the Discussion section is essential.

2."In Table 1&2, which compares non-HLH and HLH patients, the HLH-classified group shows increased APTT and TT, decreased fibrinogen, and increased D-dimer, all indicating reduced blood coagulation activity. This could suggest that SFTS patients diagnosed with HLH may have impaired coagulation function, potentially leading to a lower incidence of DIC. However, as the authors mentioned in lines 268–269, critical SFTS patients are at high risk due to progression to DIC and MODS, which seems contradictory. Furthermore, as seen in the outcome data, patients classified as HLH show a significantly higher mortality rate. The authors appear to have skipped an in-depth discussion of this discrepancy and moved directly to analyzing risk factors in HLH-classified SFTS patients. A more thorough discussion of Table 1&2 is essential to provide a clearer interpretation of these findings.

3.Based on the title of the paper, one might anticipate that the research focuses on distinguishing HLH among SFTS patients. However, the precise final conclusion of this study is the identification of important factors for assessing the risk of SFTS patients classified as HLH. Therefore, I believe it is necessary to revise the title.

Reviewer #2: (No Response)

Reviewer #3: Zhang and their collaborators set out to identify biomarkers to predict HLH in SFTS patients and, further, predict mortality amongst HLH patients. This work involved comprehensive blood panels and statistical analysis on 272 SFTS patients from Tongji Hospital. Their analysis identified that platelet counts, ALT/AST ratios, LDH, and DD were all predictive risk factors for HLH. They also determined that Age, fibrinogen (FIB), and procalcitonin (PCT) were all strong predictors of mortality due to HLH. These results allowed the authors to establish diagnostic thresholds that can be used by other doctors when treating SFTS and SFTS-HLH patients. On its face, this paper is a significant step forward towards understanding and combating SFTS. However, this paper is not without issues, some of which are major and some minor, that must be addressed before it is accepted. The primary issue that requires significant revisions is that the authors failed to provide any citations within the methods section. I am unable to determine whether the methods used are novel or adapted from existing work due to the absence of citations, which makes it impossible to evaluate the study's originality and reproducibility. The secondary issue is that the limitation section, particularly when discussing confounding factors, is too vague to be interpreted appropriately. Once these two issues are addressed, I see no reason why this manuscript should not be accepted.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Attachment

Submitted filename: PNTD-D-24-01931_reviewer_submitted.pdf

pntd.0013207.s004.pdf (104.5KB, pdf)
PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0013207.r004

Decision Letter 1

Andrea Marzi

Jul 03 2025

PNTD-D-24-01931R1Unveiling Fatal Risk Factors: Predicting Hemophagocytic Lymphohistiocytosis in SFTS PatientsPLOS Neglected Tropical Diseases Dear Dr. Zhang, Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript within 30 days Jul 03 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosntds@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pntd/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers '. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes '.

* An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript '.

If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Richard A. Bowen, DVM PhD

Academic Editor

PLOS Neglected Tropical Diseases

Andrea MarziSection EditorPLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

Additional Editor Comments : Thank you for modifying your manuscript to address reviewer comments - I think we both agree that it is significantly improved. I would ask that you make two further minor revisions if possible:

1) Figures 1 and 2 remain low quality and will not be good for publication - are you able to re-create them in a higher quality form? The new Figure 3 looks much improved.

2). The precision of numbers in tables is excessive and unnnecessary. For example: Table 1, first 2 lines have Females as 148 (54.412) and Males as 45.558. Please change these to 54.4 and 45.6% respectively. Please do the same for all of the numbers presented in your tables, restricting all figures to 1 number after the decimal point. Thank you - that will improve readability. Journal Requirements:

1) Thank you for stating "All authors declare that there is no conflict interest." If you have no competing interests to declare, please state "The authors have declared that no competing interests exist"

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

Figure resubmission: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. If there are other versions of figure files still present in your submission file inventory at resubmission, please replace them with the PACE-processed versions. Reproducibility: To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0013207.r006

Decision Letter 2

Andrea Marzi

Dear Mr Zhang,

We are pleased to inform you that your manuscript 'Unveiling Fatal Risk Factors: Predicting Hemophagocytic Lymphohistiocytosis in SFTS Patients' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Richard A. Bowen, DVM PhD

Academic Editor

PLOS Neglected Tropical Diseases

Andrea Marzi

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

***********************************************************

Thank you for modifying your manuscript in response to reviewer and editor suggestions. It will be a valuable contribution to the field.

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Comparison of clinical characteristics and laboratory markers at admission for SFTS patients with HLH between the Surviving and Deceased Groups.

    (DOCX)

    pntd.0013207.s001.docx (32.7KB, docx)
    S2 Table. ROC Curve Analysis for Predicting Death in SFTS Patients with HLH.

    (DOCX)

    pntd.0013207.s002.docx (12.9KB, docx)
    S1 Fig. Fig Dynamic characteristics of ferritin between the survival and deceased groups of SFTS patients with HLH.

    (TIF)

    pntd.0013207.s003.tif (403.9KB, tif)
    Attachment

    Submitted filename: PNTD-D-24-01931_reviewer_submitted.pdf

    pntd.0013207.s004.pdf (104.5KB, pdf)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pntd.0013207.s005.docx (219.4KB, docx)
    Attachment

    Submitted filename: Response_to_Reviewers_auresp_2.docx

    pntd.0013207.s006.docx (219.4KB, docx)

    Data Availability Statement

    The data supporting the findings of this study are available within the manuscript and its Supporting Information files.

    Articles from PLOS Neglected Tropical Diseases are provided here courtesy of PLOS

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