Pilot Quasi-Randomized Controlled Study of Herbal Medicine Hochuekkito as an Adjunct to Conventional Treatment for Progressed Pulmonary <i>Mycobacterium avium</i> Complex Disease

<div><p>Introduction</p><p>Hochuekkito, a traditional herbal medicine, is occasionally prescribed in Japan to treat patients with a poor general condition. We aimed to examine whether this medicine was beneficial and tolerable for patients with progressed pulmonary <i>Mycobacterium avium</i> complex (MAC) disease.</p><p>Methods</p><p>This pilot open-label quasi-randomized controlled trial enrolled 18 patients with progressed pulmonary MAC disease who had initiated antimycobacterial treatment over one year ago but were persistently culture-positive or intolerant. All patients continued their baseline treatment regimens with (n = 9) or without (n = 9) oral Hochuekkito for 24 weeks.</p><p>Results</p><p>Baseline characteristics were generally similar between the groups. Most patients were elderly (median age 70 years), female, had a low body mass index (<20 kg/m²), and a long-term disease duration (median approximately 8 years). After the 24-week treatment period, no patient achieved sputum conversion. Although the number of colonies in sputum tended to increase in the control group, it generally remained stable in the Hochuekkito group. Radiological disease control was frequently observed in the Hochuekkito group than the control group (8/9 vs. 3/9; p = 0.05). Patients in the Hochuekkito group tended to experience increase in body weight and serum albumin level compared with those in the control group (median body weight change: +0.4 kg vs. −0.8 kg; median albumin change: +0.2 g/dl vs. ±0.0 g/dl). No severe adverse events occurred.</p><p>Conclusions</p><p>Hochuekkito could be an effective, feasible adjunct to conventional therapy for patients with progressed pulmonary MAC disease. Future study is needed to explore this possibility.</p><p>Trial Registration</p><p>UMIN Clinical Trials Registry <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000011622&language=E" target="_blank">UMIN000009920</a></p></div

Comparison of treatment status at the time of registration between patients in the Hochuekkito and control groups.

<p>Data are expressed as number of patients.</p><p>RFP  =  rifampicin (10 mg/kg/day); EB  =  ethambutol (15 mg/kg/day); CAM  =  clarithromycin (15–20 mg/kg/day); LVFX  =  levofloxacin (10 mg/kg/day).</p><p>*Aminoglycosides (Kanamycin or Streptomycin: 15 mg/kg two/three times per a week) and/or fluoroquinolones.</p>†<p>Minimum inhibitory concentration to CAM >32 µg/ml by the broth microdilution method.</p

Comparison of baseline characteristics in the Hochuekkito and control groups.

<p>Data are expressed as the number of patients or median (with observed range: minimum, maximum). All p values are for comparisons between the two groups and were obtained by Fisher's exact test, Pearson's test, or Mann-Whitney U test as appropriate.</p><p>BMI  =  body mass index; CRP  =  C-reactive protein; ESR  =  erythrocyte segmentation rate; CAT  =  chronic obstructive pulmonary disease assessment test.</p><p>*Semi-quantitative scoring system: 0 (no colonies), 1 (1–9 colonies), 2 (10–49 colonies), 3 (50–99 colonies), 4 (100–199 colonies), 5 (200–299 colonies), 6 (300–399 colonies), 7 (400–499 colonies), and 8 (≥500 colonies).</p>†<p>Chronic obstructive pulmonary disease assessment test score ranging from 0 to 40. A higher score means more severe symptoms <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104411#pone.0104411-Jones1" target="_blank">[11]</a>.</p

Comparison of secondary endpoints between the Hochuekkito and control groups over the 24-week treatment period.

<p>CAT  =  chronic obstructive pulmonary disease assessment test; BW  =  body weight; ALB  =  albumin; CRP  =  C-reactive protein; ESR  =  erythrocyte segmentation rate.</p><p>*Chronic obstructive pulmonary disease assessment test score ranging from 0 to 40. A higher score means more severe symptoms <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104411#pone.0104411-Jones1" target="_blank">[11]</a>.</p

Changes in sputum findings over the 24-week treatment period.

<p>The number of MAC colonies in the sputum cultures of patients in the Hochuekkito (a) and control (b) groups. All p values were determined by using Wilcoxon signed-rank test. MAC  =  <i>Mycobacterium avium</i> complex. *Semi-quantitative scoring system: 0 (no colonies), 1 (1–9 colonies), 2 (10–49 colonies), 3 (50–99 colonies), 4 (100–199 colonies), 5 (200–299 colonies), 6 (300–399 colonies), 7 (400–499 colonies), and 8 (≥500 colonies).</p

Changes in radiological findings over the 24-week treatment period.

<p>Radiological assessment was performed by comparing chest X-ray images before and after treatment.</p

Kaplan-Meier survival curves of all-cause mortality.

<p>Overall cumulative 5-year mortality was 24.4%. (A) Patients with ScAb-ILD (dotted line) had worse survival than those with SSc-ILD (dashed line) (p = 0.011). (B) In patients with ScAb-ILD, those with extensive disease (dashed line) had worse survival than those with limited disease (solid line) (p = 0.015). (C) In patients with SSc-ILD, those with KL-6 ≥ 1000 U/mL (dashed line) had worse survival than those with KL-6 < 1000 U/mL (solid line) (p = 0.049). (D) The survival curves for patients with each type of autoantibody were not significantly different (p = 0.905 for comparison between anti-scleroderma-70 and anti-U1 RNP antibody, p = 0.089 for comparison between anti-scleroderma-70 and anti-centromere antibody, and p = 0.137 for comparison between anti-U1 RNP and anti-centromere antibody).</p

Analysis of factors associated with mortality.

<p>Analysis of factors associated with mortality.</p

Changes in forced vital capacity (FVC) during follow-up.

<p>(A) SSc-ILD (B) ScAb-ILD (C) Regression lines were calculated by solving the linear mixed-effects model. Baseline FVC (intercept) with ScAb-ILD (mean, 2.574 L [95% CI: 2.313–2.835]) was significantly higher than that with SSc-ILD (mean, 2.191 L [95% CI: 1.974–2.407]) (p = 0.027). The declining slopes of FVC between both groups were not significantly different (SSc-ILD: mean, -0.03979 L year^-1 [95% CI: -0.05449 to -0.02509]; ScAb-ILD: mean, -0.03740 L year^-1 [95% CI: -0.06446 to -0.01034] (p = 0.878).</p

HRCT scans of cyst formation.

<p>(A-B) HRCT scan demonstrates cyst formation (arrowheads) with pulmonary fibrosis, traction bronchiectasis, and architectural distortion in two patients with SSc-ILD. There is no continuity between the cysts and traction bronchiectasis. (C) HRCT scan shows cysts (arrowheads) with opacity separated from the pleura in a patient with MCTD-ILD.</p