Efficacy & safety of <i>Carica papaya</i> leaf extract (CPLE) in severe thrombocytopenia (≤30,000/μl) in adult dengue – Results of a pilot study

Severe thrombocytopenia in dengue often prompts platelet transfusion primarily to reduce bleeding risk. In India, about 11–43% of dengue patients report receiving platelet transfusions which is considered scarce and expensive especially in resource limited settings. Herein, we evaluated the efficacy and safety of Carica papaya leaf extract (CPLE) in the management of severe thrombocytopenia (≤30,000/μL) in dengue infection. 51 laboratory confirmed adult dengue patients with platelet counts ≤30,000/μL were randomly assigned to either treatment (n = 26) or placebo (n = 24) group. By day 3, CPLE treated patients reported significantly (p = 0.007) increased platelet counts (482%± 284) compared to placebo (331%±370) group. In the treatment group, fewer patients received platelet transfusions (1/26 v/s 2/24) and their median time for platelets to recover to ≥ 50,000/μL was 2 days (IQR 2–3) compared to 3 days (IQR 2–4) in placebo. Overall, CPLE was safe and well tolerated with no significant decrease in mean hospitalization days. Plasma cytokine profiling revealed that by day 3, mean percent increase in TNFα and IFNγ levels in treatment group was less compared to that observed in placebos; (TNFα: 58.6% v/s 127.5%; p = 0.25 and IFNγ: 1.93% v/s 62.6% for; p = 0.12). While a mean percent increase in IL-6 levels occurred in placebos (15.92%±29.93%) by day 3, a decrease was noted in CPLE group (12.95%±21.75%; p = 0.0232). Inversely, CPLE treated patients reported a mean percent increase compared to placebo by day 3 (143% ±115.7% v/s 12.03%± 48.4%; p = 0.006). Further, by day 3, a faster clearance kinetics of viral NS1 antigenemia occurred–mean NS1 titers in treatment group decreased to 97.3% compared to 88% in placebos (p = 0.023). This study demonstrates safety and efficacy of CPLE in increasing platelet counts in severe thrombocytopenia in dengue infections. A possible immunomodulatory and antiviral activity may be attributed to CPLE treatment. These findings merit validation in larger prospective studies. Trial registration Name of the registry: Clinical Trials Registry—India (CTRI) Registration No.: CTRI-REF/2017/02/013314登革热重症血小板减少症患者通常需输注血小板以降低出血风险。在印度，约11%~43%的登革热患者接受过血小板输注，而在资源受限的医疗环境中，血小板输注被认为稀缺且昂贵。本研究评估了番木瓜叶提取物（Carica papaya leaf extract, CPLE）用于治疗登革热感染所致重症血小板减少症（血小板计数≤30000/μL）的有效性与安全性。本研究共纳入51例经实验室确诊的成人登革热患者，其血小板计数均≤30000/μL，按随机原则分为治疗组（n=26）与安慰剂组（n=24）。至第3天，治疗组患者的血小板计数较基线升高482%±284，显著高于安慰剂组的331%±370（p=0.007）。治疗组需输注血小板的患者更少（1/26 vs 2/24），其血小板恢复至≥50000/μL的中位时间为2天（四分位距2~3），而安慰剂组为3天（四分位距2~4）。总体而言，CPLE安全性良好，耐受性佳，平均住院天数无显著变化。血浆细胞因子谱分析显示，至第3天，治疗组肿瘤坏死因子α（TNFα）与干扰素γ（IFNγ）水平的平均增幅低于安慰剂组：TNFα为58.6% vs 127.5%（p=0.25），IFNγ为1.93% vs 62.6%（p=0.12）。安慰剂组白细胞介素6（IL-6）水平至第3天平均升高15.92%±29.93%，而CPLE组则出现下降（12.95%±21.75%；p=0.0232）。与之相反，至第3天，CPLE组的平均增幅为143%±115.7%，显著高于安慰剂组的12.03%±48.4%（p=0.006）。此外，至第3天，治疗组的病毒NS1抗原血症清除更快——治疗组的平均NS1滴度降至基线的97.3%，而安慰剂组为88%（p=0.023）。本研究证实，CPLE可有效升高登革热重症血小板减少症患者的血小板计数，且安全性良好。CPLE可能具有免疫调节与抗病毒活性。上述发现尚需在更大规模的前瞻性研究中验证。试验注册：注册机构名称为印度临床试验注册库（Clinical Trials Registry—India, CTRI），注册编号为CTRI-REF/2017/02/013314。