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DLI Induced by Herbal Medicine: What Are the Characteristics of DLI due to Herbal Medicines?

  • Mitsuhiro AbeEmail author
  • Kenji Tsushima
  • Koichiro Tatsumi
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Part of the Respiratory Disease Series: Diagnostic Tools and Disease Managements book series (RDSDTDM)

Abstract

In many countries, herbal medicine has been developed and is currently practiced. Herbal medicine involves the use of the stalks, roots, leaves, flowers, and berries of several different plant species for medical treatment. Many practitioners believe that herbal medication has no side effects because of its natural origin. Thus, herbal medication has been used for a long time with little awareness of its side effects. However, there is an increasing incidence of interstitial pneumonia due to a drug-induced lung injury (DLI), which could be induced by common drugs. Moreover, increasing cases of bronchiolitis obliterans and pulmonary hypertension are being reported; further, these are drug-induced conditions. Clinicians should be more aware of DLI symptoms caused by herbal medication and interrogate patients regarding their use of herbal medication and supplements as well as prescription drugs.

Keywords

Herbal medicine Drug-induced lung injury (DLI) Shosaikoto (SST) 

13.1 Introduction

Generally, herbs are plants that are used for flavoring food and drugs. Broadly, “herbs” can be the leaves, roots, flowers, seeds, resin, bark, berries, or other segments of a plant. Some herbs have strong side effects and are toxic in large doses. “Herbal medicine” involves the use of herbs for medical treatment. Herbal medicine has a long tradition that has evolved independently over many years in different regions worldwide.

Since the nineteenth century, the bioactive components of herbs used in herbal medicine have been identified and extracted to synthesize a drug formulation. In the twentieth century, evidence-based medical research to evaluate the effects of drugs in large clinical trials has become mainstream. Along with this development, the practice of conventional herbal medicine has decreased.

However, recently, the use of herbal medication to treat certain diseases has been increasing. For example, herbal medicine is being used increasingly to augment the efficacy of chemotherapy and reduce toxicity [1], extend the survival of patients with uterine cervical cancer [2], and reduce postoperative ileus [3].

Many herbs are not readily identified as medication. People can obtain these herbs without visiting a clinic or hospital. Therefore, it is difficult to accurately recognize the market size and side effects of herbal medicine.

Typically, herbal medication is considered a probable cause of adverse events [4]. For example, aconitum (monkshood), which is often used in Chinese herbal medicine, is highly toxic (lethal dose, 0.2–1 g). Aconitum is usually heat-detoxified. Many other herbal drug formulations also have some toxic properties.

As the practice of herbal medicine increases, side effects are being increasingly reported. In this regard, the consumption of healthy and natural foods is just as important as the ingestion of prescription drugs in influencing patient health. To diagnose side effects accurately, we should always consider these side effects. Moreover, we should ask patients sufficiently and understand the characteristics of DLI in each drug.

13.2 Diagnosis of DLI Related to Herbal Medication

There is no special method to diagnose a DLI associated with the use of herbal medication. The Japanese Respiratory Society has proposed five diagnostic criteria for a DLI [4] (Table 13.1): (1) a patient history of ingestion of a drug that induces a lung injury, (2) the clinical manifestations reported as drug-induced lung injury, (3) other causes of the clinical manifestations are excluded, (4) the clinical manifestations improve after drug discontinuation, and (5) the exacerbation of the clinical manifestations after resuming drug administration. Resuming drug administration to identify the causative drug is usually not recommended; however, it is acceptable if the patient requires the drug, and a reasonable level of safety is assured.
Table 13.1

Diagnostic criteria for DLIs [4]

1.

History of ingestion of a drug that is known to induce lung injury

Specifically inquire about the following when taking the patient’s history: over-the-counter (OTC) drugs, health foods, and illegal narcotic drugs/antihypnotic drugs

2.

The clinical manifestations have been reported to be induced by a drug

The clinical manifestations include clinical findings, imaging findings, and pathological features

3.

Other causes of the clinical manifestations could be ruled out

Differentiation from infection, cardiogenic pulmonary edema, exacerbation of an underlying disease, etc.

4.

Improvement of the clinical manifestations after drug discontinuation

Spontaneous remission or remission in response to an adrenocorticosteroid

5.

Exacerbation of the clinical manifestations after resuming drug administration

Resuming drug administration to identify if the causative drug is not generally recommended but is acceptable if the patient requires the drug and safety is assured

The drug lymphocyte stimulation test (DLST) is sometimes helpful in the diagnosis of a DLI. 3H-thymidine uptake by lymphocytes is measured as a stimulating index. The DLST has a positivity rate of 66.9% in patients with drug-induced pneumonia [4, 5]. The rate of drug-induced pneumonia due to herbal medication is 67.6% [5]. However, the results of the DLST should be interpreted with caution for several reasons. First, the DLST is performed in vitro; therefore, the results may be inconsistent with the in vivo condition. Second, the administration procedure is not well established; therefore, the results of the DLST can be different at different institutions. Third, false-positive or false-negative reactions often occur when the DLST is used as a diagnostic test for a DLI, regardless of whether herbal medication is involved. Moreover, herbal medicine includes several plant components (Table 13.2). Some of these components cannot be absorbed in the intestine. A DLST test is performed in vitro; therefore, the component that is not present in the blood in vivo can react with the lymphocytes in vitro (i.e., a false-positive result). For example, Sho-Saiko-To (SST) can directly stimulate lymphocytes, thereby resulting in a false-positive result [4, 6]. Nakayama reported that a DLST for SST was positive in 27.5% of healthy controls [6]. Therefore, we need to carefully consider the result of a DLST in patients suspected with a DLI due to herbal medication.
Table 13.2

The list of components of herbal medicines in Japan that has been reported to cause drug-induced IP

 

bakumondoto

bofutsushosan

boiogito

daikenchuto

daisaikoto

gorinsan

goshajinkigan

hangeshashinto

hochuekkito

junchoto

keigairenngyoto

baimo

           

bakumondo

          

biwayou

           

boi

  

        

bofu

 

        

bosho

 

         

botampi

      

    

borei

           

bukuryo

     

    

bushi

      

    

byakugo

           

byakujutu

 

         

byakushi

          

chikujo

           

chimo

           

chimpi

        

  

chotoko

           

daio

    

    

 

gomin

           

goshitsu

      

    

hakka

          

hange

   

  

   

ireisen

           

jikoppi

           

jio

     

  

kankyo

   

   

   

karokon

           

kasseki

     

     

kanzo

 

  

 

keigai

          

keihi

      

    

kikyou

          

kijitsu

    

    

kobei

          

kobushi

           

koboku

         

 

kujin

           

kyokatsu

           

kyonin

         

 

mao

 

         

mashin

         

 

mokutsu

     

     

ninjin

  

   

  

obaku

          

ogi

  

     

  

ogon

 

  

 

 

oren

       

  

renniku

           

rengyo

          

ryukotsu

           

ryutan

           

saiko

    

   

 

saishin

           

sanshishi

     

    

sansho

   

       

sanshuyu

      

    

sanyaku

      

    

sekko

 

         

senkyu

          

shakuyaku

    

    

shazenshi

     

    

shishi

           

shokyo

  

 

   

  

shoma

        

  

sohakuhi

           

sojutsu

  

     

  

soyo

           

takusha

     

    

taiso

 

 

  

  

temmondo

           

tennansho

           

toki

     

  

tonin

         

 
 

nijutsuto

otsujito

orengedokuto

ryutanshakanto

saibokuto

saikokaryukotsuboreito

saikokeisikannkyoto

saikokeishito

sammotsuogonto

baimo

         

bakumondo

         

biwayou

         

boi

         

bofu

   

     

bosho

         

botampi

         

borei

     

  

bukuryo

   

   

bushi

         

byakugo

         

byakujutu

        

byakushi

         

chikujo

         

chimo

         

chimpi

        

chotoko

         

daio

 

   

   

gomin

         

goshitsu

         

hakka

   

     

hange

   

 

 

ireisen

        

jikoppi

         

jio

   

    

kankyo

      

  

karokon

      

  

kasseki

         

kanzo

 

 

 

keigai

         

keihi

     

 

kikyou

         

kijitsu

         

kobei

         

kobushi

        

koboku

    

    

kujin

        

kyokatsu

        

kyonin

         

mao

         

mashin

         

mokutsu

   

     

ninjin

    

 

 

obaku

  

     

ogi

         

ogon

oren

  

     

renniku

         

rengyo

   

     

ryukotsu

     

   

ryutan

   

     

saiko

 

  

 

saishin

         

sanshishi

  

     

sansho

         

sanshuyu

         

sanyaku

         

sekko

         

senkyu

   

     

shakuyaku

   

   

 

shazenshi

   

     

shishi

         

shokyo

   

 

 

shoma

 

       

sohakuhi

         

sojutsu

        

soyo

    

    

takusha

   

     

taiso

    

 

 

temmondo

         

tennansho

        

toki

 

 

     

tonin

         
 

sanoshashinto

seihaito

seishinrenshiin

shakuyakukanzoto

shin’iseihaito

shosaikoto

shoseiryuto

unseiin

yokukansan

baimo

 

       

bakumondo

 

 

    

biwayou

    

    

boi

         

bofu

         

bosho

         

botampi

         

borei

         

bukuryo

 

     

bushi

         

byakugo

    

    

byakujutu

         

byakushi

         

chikujo

 

       

chimo

    

    

chimpi

 

       

chotoko

        

daio

        

gomin

 

    

  

goshitsu

         

hakka

         

hange

     

  

ireisen

         

jikoppi

  

      

jio

       

 

kankyo

      

  

karokon

         

kasseki

         

kanzo

 

 

 

keigai

         

keihi

      

  

kikyou

 

       

kijitsu

         

kobei

         

kobushi

         

koboku

         

kujin

         

kyokatsu

         

kyonin

 

       

mao

      

  

mashin

         

mokutsu

         

ninjin

  

  

   

obaku

       

 

ogi

  

      

ogon

 

 

 

oren

      

 

renniku

  

      

rengyo

         

ryukotsu

         

ryutan

         

saiko

     

  

saishin

      

  

sanshishi

    

  

 

sansho

         

sanshuyu

         

sanyaku

         

sekko

    

    

senkyu

       

shakuyaku

   

  

 

shazenshi

  

      

shishi

 

  

    

shokyo

 

   

   

shoma

    

    

sohakuhi

 

       

sojutsu

        

soyo

         

takusha

         

taiso

 

   

   

temmondo

 

       

tennansho

         

toki

 

     

tonin

         

〇 always including, △ sometimes including

13.3 DLI due to Herbal Medication

13.3.1 Characteristics of a DLI due to Herbal Medication

Generally, any unfavorable medical occurrence in a patient or a subject of clinical investigation administered a pharmaceutical product is referred to as an adverse event (AE). A DLI is an AE that occurs specifically in the pulmonary system [7]. A DLI can be classified into several different types based on clinicoradiological features such as the clinical course, laboratory findings, and radiological findings (Table 13.3) [4]. Several pathognomonic findings of a DLI have been reported in patients administered with herbal medication.
Table 13.3

Main clinical types and histological diagnoses of DLIs (in contrast to common diffuse pulmonary diseases)

Main lesion site

Clinical disease type

Histological diagnosis

1. Alveolar and interstitial regions

Acute respiratory distress syndrome (ARDS)

Diffuse alveolar damage (DAD)

Idiopathic interstitial pneumonias (IIPs)

 

  Acute interstitial pneumonia (AIP)

Diffuse alveolar damage (DAD)

  Idiopathic pulmonary fibrosis (IPF)

Usual interstitial pneumonia (UIP)

  Nonspecific interstitial pneumonia (NSIP)

Nonspecific interstitial pneumonia (NSIP)

  Desquamative interstitial pneumonia (DIP)

Desquamative interstitial pneumonia (DIP)

  Cryptogenic organizing pneumonia (COP)

Organizing pneumonia (OP)

  Eosinophilic pneumonia (EP)

Eosinophilic pneumonia (EP)

  Hypersensitivity pneumonia (HP)

Hypersensitivity pneumonia (HP)

Granulomatous interstitial lung diseases

Granulomatous interstitial pneumonia

Pulmonary edema

Pulmonary edema

Capillary leak syndrome

Pulmonary edema

Pulmonary alveolar proteinosis

Alveolar proteinosis

Diffuse alveolar hemorrhage

Alveolar hemorrhage

Bronchial asthma

Bronchial asthma

2. Airway

Bronchiolitis obliterans syndrome (BOS)

Bronchiolitis obliterans (BO)

Pulmonary artery embolism

Pulmonary artery embolism

3. Blood vessels

Vasculitis

Vasculitis

Pulmonary hypertension

Pulmonary hypertension

Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease

4. Pleura

Pleuritis

Pleuritis

The most common pathognomonic of a DLI due to herbal medication is interstitial pneumonia. However, recently, other symptoms such as bronchiolitis obliterans and pulmonary arterial hypertension have been associated with herbal medication-related DLI [8, 9].

In Japan, approximately 140 types of herbal drug formulations have been covered by insurance. Many herbal medicines that are used to treat chronic diseases are sometimes ineffective. Nonetheless, herbal medication has been generally considered an unlikely cause of adverse reactions [4]. The first case of interstitial pneumonia due to herbal medication was reported in 1989 [10]. This patient was administered Sho-Saiko-To (SST) for treatment of chronic hepatitis. Thereafter, interstitial pneumonia has been diagnosed in an increasing number of patients receiving herbal medication.

13.3.2 Interstitial Pneumonia (IP)

Drug-induced IP is the most common characteristic of a DLI and is classified into two types: cytotoxic and allergic drug-induced IP [11].

Cytotoxic drug-induced IP involves multiple mechanisms, including reactive oxygen species (ROS) synthesis, decreased deactivation of metabolites in the lung, impaired alveolar-repair mechanisms, and release of various cytokines [12]. Additionally, cytotoxic drug-induced IP shows a diffuse alveolar damage (DAD) pattern and often presents as a severe clinical manifestation with a lethal outcome. Chemotherapeutic agents, antirheumatic drugs, and amiodarone are typical agents that cause cytotoxic drug-induced IP. However, cytotoxic drug-induced IP due to herbal medication has not been reported. Cases of allergic drug-induced IP often improve with corticosteroid treatment. However, some cases of allergic drug-induced IP have resulted in deaths; therefore, some of these cases may involve conditions other than allergic drug-induced IP.

As mentioned previously, the first report of IP due to herbal medication involved SST in 1989 [10], which occurred in Japan. SST consists of seven types of herbs, saiko (Bupleurum scorzonerifolium), ogon (Scutellaria baicalensis), hange (Pinellia ternata), shokyo (Zingiber officinale), taiso (Ziziphus jujube), ginseng (Panax ginseng), and kanzo (Glycyrrhiza uralensis). SST improved liver function in patients with chronic active hepatitis in a double-blind randomized study [13]. Some studies report that only two SST components (ogon and hange) were positive in a DLST [10, 14]. However, another study found that all seven components were positive in a DLST [15]. Shimodaira reported in 2000 that ogon, kanzo, and shokyo are commonly involved in lung injury after a review of 488 patients administered with herbal medication [16].

Since the first report in 1989, the number of reports of drug-induced IP due to SST has increased. More than 100 cases have been reported in 10 years [17]. Ten people with SST-induced IP have died, and this condition has become a serious social problem in Japan. Suzuki reported the clinical characteristics of SST-induced IP (Table 13.4) [17]. The period of onset of SST-induced IP was longer (78.9 ± 121.0 days) than that for non-herbal drug-induced IP. The proportion of SST-induced IP patients that was positive for the hepatitis C virus (HCV) antibody was 75.7%. Laboratory findings indicated high lactic dehydrogenase enzyme (LDH) and C-reactive protein (CRP) levels, hypoxemia, and a high proportion of lymphocytes in the bronchoalveolar lavage fluid. Chest computed tomography (CT) findings indicated that ground-glass opacity was 29.2% and air-space consolidation was 45.8%.
Table 13.4

Clinical features of Sho-Saiko-To-induced interstitial pneumonia

Age (years)

64.5 ± 8.2

Male/female

69/31

Underlying disease

Chronic hepatitis

52 (52%)

Cirrhosis of the liver

29 (29%)

Liver dysfunction

18 (18%)

Others

1 (1%)

Period to onset (day)

78.9 ± 121.0 (n = 80)

Duration of administration after the onset (day)

6.9 ± 9.3 (n = 84)

First symptom

Cough

87.6%

Dyspnea

85.9%

Fever

79.8%

Laboratory findings

Hematology/serology

  White blood cell

7823 ± 3324/mm3 (n = 77)

  Eosinophils

246 ± 288/mm3 (n = 56)

  LDH

681 ± 310 IU/L (n = 74)

  CRP

5.3 ± 4.9 mg/dL (n = 53)

Arterial blood gas

  PaO2

48.5 ± 13.0 Torr (n = 76)

  PaCO2

33.5 ± 6.3 Torr (n = 71)

Bronchoalveolar lavage (n = 17)

  Macrophage

38.0 ± 28.6%

  Lymphocytes

46.2 ± 29.2%

  Neutrophils

12.4 ± 16.6%

  Eosinophils

3.2 ± 3.5%

  CD4/CD8 ratio

0.61 ± 0.51%

Radiological findings

Chest X-ray (n = 41)

  Ground-glass opacity

58.5%

  Infiltration

26.8%

  Ground-glass opacity + infiltration

14.6%

Chest CT (n = 24)

  Ground-glass opacity

29.2%

  Air-space consolidation

45.8%

  Ground-glass opacity + air-space consolidation

4.2%

  Nodular shadow

16.7%

LDH lactic dehydrogenase enzyme, CRP C-reactive protein, CT computed tomography

Additionally, Sato characterized patients with SST-induced IP [18]. A comparison of the survivors and non-survivors revealed a significant difference in the prevalence of pulmonary complications such as idiopathic pulmonary fibrosis, duration of treatment after onset, degree of hypoxemia, prevalence of liver cirrhosis, positive proportion of HCV antibody, and CRP values.

A delay in the discontinuation of SST administration can result in death. Although the treatment response for allergic drug-induced IP is generally positive, cytotoxic mechanisms may result in death.

Fibroblasts produce inflammatory cytokines (such as IL-1, IL-6, and IL-8) in vitro in response to stimulation by SST, and this reaction is stronger in fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis (IPF) than in healthy individuals [19]. Furthermore, the proportion of patients with SST-induced IP that were positive for HCV antibody was high. Interferon (IFN) production due to viral infection either may be involved in the onset of drug-induced IP or may increase its severity.

In Japan, SST is frequently reported as the causative agent of an AE involving IP compared to other herbal medicines. An AE that involved IP has been reported for 25 species of herbal medicines, including SST [20]. Some IP patients use multiple herbal medicines, while others develop IP after herbal medicine use was discontinued. We should recognize that all herbal medicines pose a risk for developing drug-induced IP.

13.3.3 Bronchiolitis Obliterans

An outbreak of bronchiolitis obliterans in association with Sauropus androgynus (Sauropus albicans) was reported in Taiwan in Lancet in 1996 [8]. Sauropus androgynus (SA) is a plant from the Euphorbiaceae family. This plant grows to a height of approximately 1.5 m. The leaves of this plant are eaten as a vegetable particularly in Malaysia, Indonesia, and Vietnam. SA has been imported into Taiwan from these countries since 1982. Some people believe that SA can be used for weight management, especially young and middle-aged women in Southeast Asia who regularly consume SA. The characteristic DLI due to herbal medicine is reported as only IP. Therefore, the 1996 report of bronchiolitis obliterans as a new pathognomonic of a DLI due to SA was of interest of many researchers.

The mean age of the 23 women in this 1996 report by Lai [8] was 39 years (range, 21–52 years). SA is usually cooked in most Southeast Asian countries; however, 23 patients drank juice from uncooked SA. The mean estimated total amount of ingested SA per person was 8–16 kg (range, 2–21 kg) over a mean of approximately 10 weeks (range, 2–13 weeks). Table 13.5 shows the clinical features of SA-induced bronchiolitis obliterans. Progressive dyspnea (23 patients) and persistent cough (21 patients) were the predominant symptoms on presentation; these features developed approximately 14 weeks after SA ingestion. Physical examination revealed decreased breathing sounds and tachypnea with wheezing in 3 patients and crackles in 17 patients. The use of the accessory muscles was observed in 19 patients. No abnormality was detected in the complete blood count, serum biochemistry, serum alpha-1 antitrypsin concentration, urine analysis, and electrocardiography.
Table 13.5

Clinical features of Sauropus androgynous-induced bronchiolitis obliterans

Total number

23 (male 0/female 23)

 

Mean age (range)

39 (21–52)

 
 

Number (proportion)

 

Symptoms

  Progressive dyspnea

23 (100%)

 

  Cough

21 (91%)

 

  Sputum

8 (34%)

 

  Oral ulcer

9 (39%)

 

  Palpitation

17 (73%)

 

  Insomnia

12 (52%)

 

Physical examination

  Decreased breath sounds

3 (13%)

 

  Tachypnea

3 (13%)

 

  Wheezing

3 (13%)

 

  Crackles

17 (73%)

 

  Using of accessory muscles

19 (82%)

 
 

Mean (SD)

% predicted

Blood arterial gas

  pH

7.43 (±0.03)

 

  PaCO2 (Torr)

39.0 (±6.7)

 

  PaO2 (Torr)

72.0 (±12.0)

 

  SpO2 (%)

94 (±3)

 

Spirometry

  FEV1 (L)

0.66 (±0.20)

26%

  FVC (L)

1.52 (±0.36)

51%

  TLC (L)

4.12 (±0.51)

95%

  RV (L)

2.34 (±0.45)

177%

  DLCO (mL min−1 mmHg−1)

12.1 (±4.1)

49%

SD standard deviation, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, RV residual volume

Malaysians have consumed SA for a long time; however, there are no reports of related side effects. In contrast, in Taiwan, several side effects have been reported, which may be due to a difference in the amounts of consumed SA [21]. Taiwanese people consume about 150 g of SA as opposed to about 100 ~ 200 g consumed by Malaysians.

One study reported that papaverine, which is a component of SA, results in the development of bronchiolitis obliterans [22]; however, this is questionable. Wang reported that a more accurate histopathological classification of SA-associated lung disease is constrictive obliterative bronchitis/bronchiolitis with the participation of T-lymphocytes, macrophages, mast cells, eosinophils, and fibroblasts in its morphogenesis of the bronchioles or bronchi. The persistent accumulation of inflammatory cells was predominantly mediated by continued blood flow to the site of injury, eventually resulting in the irreversible fibrosis of the bronchioles and bronchi <3 mm in diameter. Obliterative arteriopathy was suspected of being only an indirect contributing factor [23].

In SA-induced bronchiolitis obliterans, respiratory failure sometimes progresses after SA ingestion has been discontinued. Moreover, corticosteroid therapy and immunosuppressive agents are usually administered; however, the condition is often resistant. Therefore, lung transplantation should be considered for treatment [24, 25]. This clinical course is not typically recognized as a DLI.

13.3.4 Pulmonary Arterial Hypertension

The Evian Conference in 1998 [9] reported that some drugs are the risk factors for the development of pulmonary arterial hypertension (PAH). In addition, these drugs were categorized into four types based on their incidence rate.

This categorization was followed by additional modification at the Venice meeting in 2003 [26], the Dana Point conference in 2008, and the Nice meeting in 2013 (Table 13.6) [27]. In this drug categorization scheme, “definite” indicates the demonstration of an association between a drug and PAH in large multicenter epidemiologic studies. “Likely” indicates the demonstration of such an association by a single-center case-control study or a multiple-case series. “Possible” indicates a demonstration of such an association based on case series, registries, or expert opinions. Finally, “unlikely” indicates that a drug has been studied in epidemiological studies and an association with PAH was not demonstrated [26, 27, 28].
Table 13.6

Risk factors for pulmonary arterial hypertension

Definite

Possible

Likely

Unlikely

Aminorex

Cocaine

Amphetamines

Oral contraceptives

Fenfluramine

Phenylpropanolamine

l-tryptophan

Estrogen

Dexfenfluramine

St. John’s Wort

Methamphetamines

Cigarette smoking

Toxic rapeseed oil

Chemotherapeutic agents

Dasatinib

 

Benfluorex

Interferon α and β

SSRI

Amphetamine-like drugs

SSRI selective serotonin reuptake inhibitor

Some of these drugs that pose a risk for the development of PAH are related to herbal medication (e.g., toxic rapeseed oil, cocaine, St. John’s wort, and methamphetamine).

13.3.4.1 Toxic Rapeseed Oil

In 1981, in Madrid, Spain, the outbreak of toxic oil syndrome (TOS) was caused by the ingestion of a type of oil that was fraudulently sold as olive oil [29]. More than 15,000 children and adults were hospitalized in Madrid, complaining of fever, dyspnea, cough, skin rash, and a spectrum of gastric and neurologic symptoms. Approximately 300 died shortly after the onset of the disease, and a larger number developed a chronic disease [30].

PAH is one of the symptoms of TOS, showing an estimated frequency of 1 ~ 3% [30]. Garcia-Dorado D studied 38 patients with PAH due to toxic rapeseed oil [31], where the mean pulmonary arterial pressure of the patients was 40 ± 9 mmHg and the mean pulmonary to systemic vascular resistance ratio (Rp/Rs) was three times that of normal individuals (0.45 versus 0.15). However, cardiac index, pulmonary capillary wedge pressure, and left ventricular end-diastolic pressure remained within the normal range.

13.3.4.2 Cocaine

Long-term cocaine abuse causes left ventricular hypertrophy and systolic dysfunction [32]. In addition, many adverse cardiovascular events have been reported (e.g., dysrhythmias, endocarditis, and aortic dissection or rupture) [33, 34].

Moreover, pulmonary granulomatosis and pulmonary artery hypertension have been documented in chronic users of cocaine [35, 36, 37].

Significant reduction of the pulmonary vascular bed owing to the granulomatous process may result in pulmonary hypertension. The granulomatous process may be caused by insoluble agents that adulterate the addictive drug [36, 37].

Yakel DL Jr. (1995) measured the systolic pulmonary artery pressure (PAP) of 13 chronic intravenous cocaine users (aged 33.3 years; range, 23–41 years). Eight subjects had an elevated PAP (>30 mm Hg), three of whom had a PAP >40 mmHg [37].

13.3.4.3 St. John’s Wort (Hypericum perforatum)

St. John’s wort (Hypericum perforatum) is an herb of European origin that is perennial, bears yellow flowers, and is available worldwide.

St. John’s wort is currently used for treating depression. A meta-analysis in 1996 [38] revealed that extracts of St. John’s wort are more effective than placebo for the treatment of mild to moderately severe depression. Further, a double-blind randomized controlled trial [39] carried out in the United States was unable to demonstrate the efficacy of St. John’s wort compared to placebo and sertraline—a selective serotonin reuptake inhibitor [SSRI]).

Hyperforin, one of the main components of the St. John’s wort, increases synaptic serotonin and norepinephrine concentrations via an indirect and yet unknown mechanism [40]. Increasing synaptic serotonin and norepinephrine concentrations may be related to PAH, similar to SSRIs. In fact, an SSRI is categorized as a “definite” cause of PAH [28, 41].

13.3.4.4 Methamphetamine

Methamphetamine is synthesized from ephedrine extracted from Ephedra sinica. This plant has been used in China for more than 5000 years to stimulate circulation and for its antipyretic and antitussive properties. Ephedrine, which is the main ingredient of Ephedra sinica, was discovered by N. Nagai in 1885.

Ephedrine acts on parts of the sympathetic nervous system (SNS). The main mechanism of ephedrine is an indirect stimulation of the adrenergic receptor system through increasing the activity of norepinephrine at the postsynaptic α-adrenergic and β-adrenergic receptors. Although the action of ephedrine is less potent than that of adrenaline, its activation time is 7–10 times longer. Hence, ephedrine is used as a bronchodilator and vasopressor.

In contrast, methamphetamine is a strong agonist of trace amine-associated receptor 1 (TAAR1). Activated TAAR1 increases cyclic adenosine monophosphate (cAMP) production and completely inhibits the uptake of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) in the plasma membrane [42, 43]. Moreover, methamphetamine induces efflux of neurotransmitters via the vesicular monoamine transporters (VMAT) [44]. Currently, methamphetamine is used to treat conditions such as narcolepsy and depression; however, it is strictly restricted worldwide because of its addictive nature and irritation to the central nervous system.

The proportion of stimulant use (amphetamines, methamphetamines, or cocaine) was investigated in 340 patients with idiopathic PAH, chronic thromboembolic PH (CTEPH) or PAH that was associated with other risk factors. A history of stimulant use was found in 28.9% of the patients diagnosed with idiopathic PAH, compared to 3.8% for the patients with PAH and a known risk factor, and 4.3% for patients with CTEPH [45].

Methamphetamines potently act on norepinephrine and dopamine transporters and rarely affect the serotonin transporter. Both serotonin and norepinephrine have vasoconstrictive and growth-modulating effects on smooth muscle cells, suggesting a possible involvement of methamphetamines in the development of PAH [46, 47].

Y. Sakurai reported a case of pulmonary hypertension due to bofutsushosan. Ephedra is a component of bofutsushosan [48]; thus, ephedra is probably involved in the development of PAH.

13.3.5 Pulmonary Arterial Thrombosis

Demonstrating a relationship between an administered drug and the development of pulmonary arterial thrombosis is difficult.

Yigit M reported a 41-year-old woman with a pulmonary embolism while on a high-dose course of panax tablets that contain extracts of Tribulus terrestris, Avena sativa, and Panax ginseng [49]. However, the pathophysiological mechanism of pulmonary embolism has not been demonstrated.

13.4 Therapy and Prognosis of a DLI due to Herbal Medication

There is no special treatment to protect against a DLI due to herbal medication. The Japanese Respiratory Society has proposed a treatment for DLI [4]. Any drug that is suspected of causing a DLI should be immediately discontinued in all cases. If continued treatment is necessary, the suspected drug should be replaced by one that is less likely to induce a lung injury.

Regarding drug-induced IP, treatment should be determined using PaO2 (Table 13.7). The most common type of drug-induced IP due to herbal medication is the allergic type; thus, most patients will have a good response to steroid therapy. However, ten patients with SST-induced IP have died in Japan [17]. Therefore, it is important to note that delayed diagnosis and treatment of a drug-induced IP due to herbal medication could result in death.
Table 13.7

Proposed classification and treatment strategy for drug-induced interstitial pneumonia and acute lung injury [4]

Degree of severity

PaO2

Treatmenta

Mild

≧80 Torr

Discontinuation of the suspected drug

Moderate

≧60 Torr, <80 Torr

Discontinuation of the suspected drug

Adrenocorticosteroid therapy

Severe

<60 Torr

(PaO2/FiO2 < 300)

Discontinuation of the suspected drug

mPSL pulse therapy for 3 days and then continuous adrenocorticosteroid administration

aThe treatment information is provided for reference only. When a patient rapidly resolves after discontinuation of the suspected drug or responds to adrenocorticosteroid therapy, the dose of the steroid should be reduced

Bronchiolitis obliterans due to Sauropus androgynus is irreversible and resistant to treatment, similar to idiopathic bronchiolitis obliterans. Lung transplantation is the only solution for patients in the advanced stage of this disease. Some patients with bronchiolitis obliterans due to Sauropus androgynous have successfully received a lung transplant [24, 25]. Therefore, early detection and treatment are important.

13.5 Conclusion

Herbal medication is rarely suspected to be involved in a DLI. A detailed inquiry of the patients is important because some DLIs resulting from the use of herbal medication are irreversible.

References

  1. 1.
    McCulloch M, See C, Shu XJ, et al. Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. J Clin Oncol. 2006;24:419–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Takegawa Y, Ikushima H, Ozaki K, et al. Can Kampo therapy prolong the life of cancer patients? J Med Invest. 2008;55:99–105.CrossRefPubMedGoogle Scholar
  3. 3.
    Itoh T, Yamakawa J, Mai M, et al. The effect of the herbal medicine dai-kenchu-to on post-operative ileus. J Int Med Res. 2002;30:428–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Kubo K, Azuma A, Kanazawa M, et al. Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig. 2013;51:260–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Kondo A. Drug-induced pneumonitis. Kekkaku. 1999;74:33–41.PubMedGoogle Scholar
  6. 6.
    Nakayama M, Bando M, Hosono T. Evaluation of the drug lymphocyte stimulation test (DLST) with shosaikoto. Arerugi. 2007;56:1384–9.PubMedGoogle Scholar
  7. 7.
    ICH harmonized tripartite guideline; clinical safety data management: definitions and standards for expedited reporting. [Internet]. In: The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH). 1994. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf.
  8. 8.
    Lai RS, Chiang AA, MT W, et al. Outbreak of bronchiolitis obliterans associated with consumption of Sauropus androgynus in Taiwan. Lancet. 1996;13:83–5.CrossRefGoogle Scholar
  9. 9.
    Fishman AP. Clinical classification of pulmonary hypertension. Clin Chest Med. 2001;22:385–91.CrossRefPubMedGoogle Scholar
  10. 10.
    Tsukiyama K, Tasaka Y, Nakajima M, et al. A case of pneumonitis due to sho-saiko-to. Nihon Kyobu Shikkan Gakkai Zasshi. 1989;27:1556–61.PubMedGoogle Scholar
  11. 11.
    Pietra GG. Pathologic mechanisms of drug-induced lung disorders. J Thorac Imaging. 1991;6:1–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Matsuno O. Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches. Respir Res. 2012;31:13–39.Google Scholar
  13. 13.
    Hirayama C, Okumura M, et al. A multicenter randomized controlled clinical trial of Shosaiko-to in chronic active hepatitis. Gastroenterol Jpn. 1989;24:751–9.Google Scholar
  14. 14.
    Katou K, Mori K. Autoimmune hepatitis with drug-induced pneumonia due to Sho-saiko-to. Nihon Kokyuki Gakkai Zasshi. 1999;37:641–6.PubMedGoogle Scholar
  15. 15.
    Hatakeyama S, Tachibana A, Morita M. Five cases of pneumonitis induced by sho-saiko-to. Nihon Kyobu Shikkan Gakkai Zasshi. 1997;35:505–10.PubMedGoogle Scholar
  16. 16.
    Suzuki H, Kumada H, Sato A, et al. Guidelines of Sho-saiko-to/Xiao-Chaihu-Tang treatment in patients with chronic hepatitis C. J Tradit Med. 2000;17:95–100.Google Scholar
  17. 17.
    Sato A, Toyoshima M, Kondo A, et al. Pneumonitis induced by the herbal medicine Sho-saiko-to in Japan. Nihon Kyobu Shikkan Gakkai Zasshi. 1997;35:391–5.PubMedGoogle Scholar
  18. 18.
    Suganuma H, Sato A, Tamura R, et al. Effects of interferon-alfa and the herbal medicine Sho-saiko-to on cytokine production and lung fibroblast proliferation. A pilot study. Curr Ther Res. 1994;55:1551–61.CrossRefGoogle Scholar
  19. 19.
    Information about the case report that a side effect is suspected. [Internet]. In: Pharmaceuticals and Medical Devices Agency (PMDA), Japan. http://www.info.pmda.go.jp/fsearchnew/jsp/menu_fukusayou_base.jsp.
  20. 20.
    Shimodaira H, Nozaki M, Kwon Y, et al. Analysis of adverse reaction in Kampo-medicines using JADER database of PMDA. Jpn J Drug Inform. 2014;16:16–22.Google Scholar
  21. 21.
    Hsiue TR, Guo YL, Chen KW, et al. Dose-response relationship and irreversible obstructive ventilatory defect in patients with consumption of Sauropus androgynus. Chest. 1998;113:71–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Svetlecic J, Molteni A, Herndon B. Bronchiolitis obliterans induced by intratracheal papaverine: a novel animal model. Lung. 2004;182:119–34.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang JS, Tseng HH, Lai RS, et al. Sauropus androgynus-constrictive obliterative bronchitis/bronchiolitis--histopathological study of pneumonectomy and biopsy specimens with emphasis on the inflammatory process and disease progression. Histopathology. 2000;37:402–10.CrossRefPubMedGoogle Scholar
  24. 24.
    Hsu H, Chang H, Su J, et al. Lung transplantation in Sauropus androgynus consumption patients in Taiwan. Transplant Proc. 1998;30(7):3393–4.CrossRefPubMedGoogle Scholar
  25. 25.
    Hsu H, Chang H, Goan Y. Intermediate results in Sauropus androgynus bronchiolitis obliterans patients after single lung transplantation. Transplant Proc. 2000;32:2422–3.CrossRefPubMedGoogle Scholar
  26. 26.
    Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S–12S.CrossRefPubMedGoogle Scholar
  27. 27.
    Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.CrossRefPubMedGoogle Scholar
  29. 29.
    MacGregor GA, Smith SJ, Markandu ND, et al. Moderate potassium supplementation in essential hypertension. Lancet. 1982;2:567–70.CrossRefPubMedGoogle Scholar
  30. 30.
    Gelpí E, de la Paz MP, Terracini B, et al. The Spanish toxic oil syndrome 20 years after its onset: a multidisciplinary review of scientific knowledge. Environ Health Perspect. 2002;110:457–64.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Garcia-Dorado D, Miller DD, Garcia EJ, et al. An epidemic of pulmonary hypertension after toxic rapeseed oil ingestion in Spain. J Am Coll Cardiol. 1983;1:1216–22.CrossRefPubMedGoogle Scholar
  32. 32.
    Brickner ME, Willard JE, Eichhorn EJ, et al. Left ventricular hypertrophy associated with chronic cocaine abuse. Circulation. 1991;84:1130–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Richards JR, Garber D, Laurin EG, et al. Treatment of cocaine cardiovascular toxicity: a systematic review. Clin Toxicol (Phila). 2016;54:345–64.CrossRefGoogle Scholar
  35. 35.
    Oubeid M, Bickel JT, Ingram EA, et al. Pulmonary talc granulomatosis in a cocaine sniffer. Chest. 1990;98:237–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Arnett EN, Battle WE, Russo JV, et al. Intravenous injection of talc-containing drugs intended for oral use. A cause of pulmonary granulomatosis and pulmonary hypertension. Am J Med. 1976;60:711–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Yakel DL Jr, Eisenberg MJ. Pulmonary artery hypertension in chronic intravenous cocaine users. Am Heart J. 1995;130:398–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Linde K, Ramirez G, Mulrow CD, et al. St John’s wort for depression--an overview and meta-analysis of randomised clinical trials. BMJ. 1996;313:253–8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287(14):1807.CrossRefGoogle Scholar
  40. 40.
    Leuner K, Kazanski V, Müller M, et al. Hyperforin--a key constituent of St. John’s wort specifically activates TRPC6 channels. FASEB J. 2007;21:4101–11.CrossRefPubMedGoogle Scholar
  41. 41.
    Fox BD, Azoulay L, Dell’Aniello S, et al. The use of antidepressants and the risk of idiopathic pulmonary arterial hypertension. Can J Cardiol. 2014;30:1633–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Miller GM. The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem. 2011;116:164–76.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Xie Z, Miller GM. A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain. J Pharmacol Exp Ther. 2009;330:316–25.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sulzer D, Sonders MS, Poulsen NW, et al. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75:406–33.CrossRefPubMedGoogle Scholar
  45. 45.
    Chin KM, Channick RN, Rubin LJ. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest. 2006;130:1657–63.CrossRefPubMedGoogle Scholar
  46. 46.
    Tseng YT, Padbury JF. Expression of a pulmonary endothelial norepinephrine transporter. J Neural Transm. 1998;105:1187–91.CrossRefPubMedGoogle Scholar
  47. 47.
    Montani D, Seferian A, Savale L. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013;22:244–50.CrossRefPubMedGoogle Scholar
  48. 48.
    Sakurai Y, Tanabe N, Sekine A, Al e. Spontaneously remitted pulmonary arterial hypertension associated with the herbal medicine “bofutsushosan”. Intern Med. 2013;52:1499–502.CrossRefPubMedGoogle Scholar
  49. 49.
    Yigit M, Cevik E. A rare cause of pulmonary embolism: panax. Am J Emerg Med. 2015;33:311.e1–2.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Mitsuhiro Abe
    • 1
    Email author
  • Kenji Tsushima
    • 1
  • Koichiro Tatsumi
    • 1
  1. 1.Department of Respirology, Graduate School of MedicineChiba UniversityChibaJapan

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