Bupleurum: Sho-Saiko-To and Interstitial Pneumonia

Table of Contents

1. What Sho-Saiko-To Is
2. What Interstitial Pneumonia Is
3. The 73-Patient Review
4. Which Ingredient? Skullcap, Licorice and Bupleurum
5. The National Database Signal
6. The Interferon Warning
7. How a Herbal Cause Is Tested: The DLST Problem
8. The Same Formula and the Liver
9. What the Record Means, and What It Does Not
10. Questions Worth Raising With a Clinician
11. Terms Used on This Page
12. Key Research Papers
13. Connections

What Sho-Saiko-To Is

A 2006 case report from Taipei Veterans General Hospital describes xiao chai hu tang (syo-saiko-to in Japanese) as a mixture of seven herbal components: bupleurum root, pinellia tuber, scutellaria (Chinese skullcap) root, jujube fruit, ginseng root, licorice root and ginger rhizome, first prepared in the Han dynasty (206 BC–AD 220) for what Chinese medicine called "Shaoyang" patterns, which the authors link to respiratory, gastrointestinal and liver-and-bile diseases (J Chin Med Assoc 2006).

In Japan, the formula became a standardized prescription medicine. A 2000 review describes shosaikoto as "used clinically to treat patients with chronic hepatitis or cirrhosis in Japan," and reports its effects on immune cells called macrophages in animal studies. A 2010 systematic review of Chinese trials, discussed on the Saikosaponins and the Liver page, gathered 16 randomized trials of the formula in chronic hepatitis B.

That clinical setting matters for the lung story: the people most likely to take the formula were older adults with long-standing viral liver disease, many of whom were also candidates for interferon treatment.

What Interstitial Pneumonia Is

The lungs' air sacs (alveoli) are separated by thin walls of tissue called the interstitium, through which oxygen passes into the blood. In interstitial pneumonia, or pneumonitis, those walls become inflamed and thickened. People typically notice a dry cough, breathlessness and sometimes fever. On a CT scan the inflamed areas often look like hazy "ground glass."

Many things cause it, including infections, autoimmune disease, inhaled dusts and moulds (hypersensitivity pneumonitis), and a long list of medicines. Drug-induced cases often improve when the drug is stopped, sometimes with steroid treatment, but a minority progress to severe lung injury. The site's Interstitial Lung Disease page covers the condition in general.

The 73-Patient Review

The most complete clinical picture comes from a 2017 review in Respiratory Investigation. The authors searched PubMed and Japan's main medical abstracts database for articles published from 1996 to 2015 describing pneumonitis caused by Japanese herbal medicines, and assembled 73 patients from 59 articles (7 in English, 52 in Japanese).

• Which formulas: sho-saiko-to was the most frequently implicated (26% of patients), followed by sairei-to (16%), seishin-renshi-in (8%) and bofu-tsusyo-san (8%).
• Who: the mean age was 63.2 years (range 7 to 89); 44 patients were men and 29 women.
• When: 65 patients (89%) developed pneumonitis within three months of starting the herbal medicine.
• What it looked like: bilateral ground-glass shadows on chest CT, and an excess of lymphocytes with a low CD4/CD8 T-cell ratio in fluid washed from the lungs (bronchoalveolar lavage), were common findings.
• Outcomes: 26 patients (36%) recovered after simply stopping the herbal medicine. The rest needed immune-suppressing treatment; 13 (18%) needed mechanical ventilation; three (4%) died, two of whom showed diffuse alveolar damage at autopsy.

The authors concluded that "most events are non-severe," but that critical cases occur and clinicians need to be alert, especially early in treatment and with formulas known to cause the reaction.

Which Ingredient? Skullcap, Licorice and Bupleurum

The 2017 review made an observation that is easy to miss: the implicated formulas "commonly contain ougon (skullcap) and kanzo (liquorice)." Ougon is the Japanese name for Scutellaria baicalensis root, the Chinese skullcap in sho-saiko-to; kanzo is licorice root.

A 2022 case report in a Japanese internal-medicine journal describes sairei-to as "minor bupleurum decoction plus poria powder with five herbs," so the second most implicated formula contains the whole of sho-saiko-to, and it states that "Saiko (bupleuri radix) and Ougon (skullcap) are suspected as the crude agents associated with lung injury" (Internal Medicine, 2022).

Neither observation proves which herb is the cause; suspicion falls on both bupleurum and skullcap, with licorice also common to the implicated formulas. It does mean that "bupleurum causes pneumonitis" is not a statement the evidence supports. What the evidence supports is that certain multi-herb Kampo formulas, led by sho-saiko-to, are associated with the reaction. None of the sources reviewed here reports pneumonitis from bupleurum root taken alone, and none excludes it either.

The site's Chinese skullcap and licorice pages describe those two herbs in their own right.

The National Database Signal

A 2020 study in SAGE Open Medicine analysed reports of drug-induced interstitial lung disease in the Japanese Adverse Drug Event Report database from 2004 to 2018. Using a measure called the reporting odds ratio (how much more often a lung reaction is reported with one drug than with all others in the database), it ranked the drugs with the strongest signal:

• temsirolimus 18.3; gefitinib 17.8; sho-saiko-to 16.3 (95% confidence interval 11.8–22.4); sai-rei-to 14.5 (11.7–18.2); osimertinib 12.5; amiodarone 10.9.

Two of the top four entries were herbal formulas containing bupleurum, sitting among cancer drugs and the heart drug amiodarone that are well known for lung toxicity. The median time from starting sho-saiko-to to the lung reaction was 33 days (interquartile range 13.5–74.0), and for sai-rei-to 35 days. A data-mining technique found that the risk rose when sho-saiko-to (or amiodarone) was combined with older age; the authors concluded that older people receiving sho-saiko-to "should be carefully monitored."

A reporting odds ratio is a signal, not a rate. It cannot say how many users develop the reaction, because the database records reports, not users. It does say that, relative to other medicines in Japan, sho-saiko-to is reported with this reaction unusually often.

The Interferon Warning

Interferon alfa, an injected immune-signalling protein, was for many years the backbone of treatment for chronic hepatitis C, and interferon itself can cause interstitial pneumonia. The overlap of patients — people with chronic viral hepatitis — meant many could be offered both interferon and sho-saiko-to.

In September 2008, Japan's Pharmaceuticals and Medical Devices Agency published Safety Information No. 250 on interstitial pneumonia from interferon preparations. The label text it reproduced for these preparations states that "as there have been many reports of interstitial pneumonia occurring from the concomitant administration of Shosaikoto, the concomitant should be avoided," and similar wording appears for other interferon alfa products (PMDA Safety Information No. 250).

That is a regulator's labelling statement, reported here as a fact about the label. It concerns a specific combination in a specific era of hepatitis C treatment; a 2015 review notes that an interferon-free tablet regimen has since produced high cure rates, including in people who had not responded to interferon. The site's Hepatitis C page covers current treatment.

How a Herbal Cause Is Tested: The DLST Problem

Proving that a herbal formula caused a lung reaction is hard. One tool used in Japan is the drug lymphocyte stimulation test (DLST): a patient's white blood cells are exposed to the suspect drug in a dish to see whether they react.

A 2007 Japanese study examined three patients with pneumonitis attributed to shosaikoto. Two were positive for hepatitis C antibodies, all three showed a hypersensitivity-pneumonitis pattern on high-resolution CT, and all three recovered well. Only one had a positive DLST to shosaikoto. The striking finding came from healthy volunteers: 27.5% of healthy controls also tested positive to shosaikoto in the DLST. The authors concluded the test "showed high false-positive rate" for this formula, though comparing how the response changed with drug concentration might separate true from false positives.

For readers, the lesson is that a positive lab test does not by itself prove the formula caused a given case, and a negative one does not rule it out. The case-series evidence rests mainly on timing and recovery after stopping.

The Same Formula and the Liver

Sho-saiko-to was given for liver disease, yet it also appears in reviews of herbal liver injury. A 2000 review in Public Health Nutrition listed it among Chinese herbal medicines with reported hepatotoxicity and noted that "the picture is confused further by demonstrations of hepatoprotective properties for some components." A 2015 compilation counted syo saiko to and xiao chai hu tang among 28 herbs and mixtures for which liver-injury causality had been established by a standard scale or a positive re-exposure.

The 2006 Taipei case describes a 52-year-old woman who developed weakness, fatigue and dark urine after drinking a xiao chai hu tang decoction for six weeks; viral tests were negative, a biopsy showed acute hepatitis, and her liver tests returned to normal two months after stopping. A 2000 Lancet review of herb–drug interactions also listed lower blood levels of prednisolone, a steroid sometimes used to treat drug-induced pneumonitis, when taken with the formula.

What the Record Means, and What It Does Not

• It is real. Dozens of published cases, a strong national reporting signal, and a regulatory label statement all point the same way.
• It is usually reversible, sometimes not. About a third of published cases recovered on stopping alone; a minority needed ventilation and a few died.
• It is early. Nearly nine in ten cases began within three months; the median in the database was about a month.
• It concentrates in older people and, historically, in people with viral hepatitis on interferon.
• It is a formula finding. The data do not isolate bupleurum; skullcap and licorice are common to the implicated formulas.
• It is not a rate. No source reviewed here gives the proportion of users affected.

The research raises the clearest concern for older adults, people with chronic liver disease, and anyone combining sho-saiko-to with interferon. The interferon label text quoted by the regulator instructs that patients be told to contact a physician immediately if cough or breathlessness occurs.

Questions Worth Raising With a Clinician

The findings above suggest several questions that people taking, or considering, sho-saiko-to or related formulas may find useful to discuss with the clinician who knows their history:

• Does the formula contain bupleurum, Chinese skullcap or licorice, and is it one of the formulas named in the Japanese reports?
• How does it fit with any current interferon or other immune-modifying treatment?
• What baseline lung and liver information exists, given that the published reactions involved both organs?
• Which symptoms (for example, new cough, breathlessness or fever) would prompt a check, given that most published lung reactions began within the first three months?
• How does it interact with steroids such as prednisolone, which a 2000 review reports at lower blood levels alongside the formula?

These are information points drawn from the research, not instructions; decisions belong to the patient and their clinician.

Terms Used on This Page

• Interstitial pneumonia / pneumonitis: inflammation of the tissue walls between the lung's air sacs.
• Ground-glass attenuation: hazy grey areas on a CT scan, a common sign of that inflammation.
• Bronchoalveolar lavage: rinsing part of the lung with fluid through a thin tube and examining the cells washed out.
• CD4/CD8 ratio: the balance between two kinds of T lymphocytes; the 2017 review found it low in the lung fluid of many patients.
• Diffuse alveolar damage: widespread injury to the air sacs seen under the microscope, found at autopsy in two of the fatal cases.
• Reporting odds ratio: how much more often a reaction is reported with one drug than with all others in a database; a signal, not a rate.
• DLST: drug lymphocyte stimulation test, in which a patient's white cells are exposed to a suspect drug in the laboratory.
• Interferon alfa: an injected immune-signalling protein formerly central to hepatitis C treatment.

Key Research Papers

1. Enomoto Y Md, Nakamura Y Md PhD, Enomoto N Md PhD, et al. Japanese herbal medicine-induced pneumonitis: A review of 73 patients. Respiratory investigation. 2017;55(2):138-144. PubMed PMID: 28274529
2. Matsumoto K, Nakao S, Hasegawa S, et al. Analysis of drug-induced interstitial lung disease using the Japanese Adverse Drug Event Report database. SAGE open medicine. 2020;8:2050312120918264. PubMed PMID: 32528682
3. Nakayama M, Bando M, Hosono T, et al. [Evaluation of the drug lymphocyte stimulation test (DLST) with shosaikoto]. Arerugi = [Allergy]. 2007;56(11):1384-9. PubMed PMID: 18059152
4. Stickel F, Egerer G, Seitz HK. Hepatotoxicity of botanicals. Public health nutrition. 2000;3(2):113-24. PubMed PMID: 10948380
5. Teschke R, Zhang L, Long H, et al. Traditional Chinese Medicine and herbal hepatotoxicity: a tabular compilation of reported cases. Annals of hepatology. 2015;14(1):7-19. PubMed PMID: 25536637
6. Teschke R. Traditional Chinese Medicine Induced Liver Injury. Journal of clinical and translational hepatology. 2014;2(2):80-94. PubMed PMID: 26357619
7. Fugh-Berman A. Herb-drug interactions. Lancet (London, England). 2000;355(9198):134-8. PubMed PMID: 10675182
8. Qin XK, Li P, Han M, et al. [Xiaochaihu Tang for treatment of chronic hepatitis B: a systematic review of randomized trials]. Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine. 2010;8(4):312-20. PubMed PMID: 20388470
9. Inoue M. Shosaikoto as a potential antiatherosclerotic agent. Drug news & perspectives. 2000;13(7):407-12. PubMed PMID: 12937613
10. Rino Y, Yukawa N, Yamamoto N. Does herbal medicine reduce the risk of hepatocellular carcinoma? World journal of gastroenterology. 2015;21(37):10598-603. PubMed PMID: 26457019
11. Li X, Li X, Huang N, et al. A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2018;50:73-87. PubMed PMID: 30466994
12. Zhou P, Shi W, He XY, et al. Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics. Pharmaceutical biology. 2021;59(1):1480-1489. PubMed PMID: 34714209

PubMed Topic Searches

1. PubMed: Shosaikoto interstitial pneumonia
2. PubMed: Kampo-induced pneumonitis
3. PubMed: Interferon and shosaikoto
4. PubMed: Herbal drug-induced interstitial lung disease

Connections

• Heart, Liver and Metabolic Herbs — the parent category
• Bupleurum (Chai Hu) — the main topic page
• Bupleurum Benefits Deep Dive — the hub for all four articles
• Saikosaponins and the Liver
• Xiao Yao San and Mood Research
• Chai Hu in Traditional Chinese Medicine
• Interstitial Lung Disease — the condition
• Hypersensitivity Pneumonitis — the CT pattern in the DLST cases
• Pulmonary Fibrosis — where severe lung inflammation can lead
• Hepatitis C — the interferon setting
• Chinese Skullcap — ougon, common to the implicated formulas
• Licorice — kanzo, the other common ingredient
• Ginseng — a sho-saiko-to ingredient