Coxsackie Virus Infections
Coxsackie refers to a collection of closely related viruses classified among the enteroviruses, namely those that cause infection after being taken in orally with contaminated food or water and then multiply in the intestines (entero = intestinal). The coxsackie viruses were named after the town Coxsackie, New York. A strain of this virus was discovered there during the investigation of an epidemic that occurred in 1948 alongside a polio epidemic (polio being another enterovirus). The coxsackie viruses are divided into two major subgroups, labeled A and B. There are 23 known coxsackie A viruses that usually cause only enteric diseases, and 6 known coxsackie B viruses, which are the ones of greatest concern because of their ability to cause serious diseases beyond the intestinal tract. Coxsackie B3 has been found to be one of the main causes of certain debilitating or life-threatening diseases, such as viral myocarditis.
The coxsackie virus apparently produces few or no symptoms in most instances, but it can cause a commonly occurring intestinal disease, with abdominal distress and diarrhea. Even when symptomatic, the resulting disease is usually a relatively mild one, which might be referred to as "intestinal flu." It most often occurs in late summer or early autumn and is consistent with what the Chinese call "summer heat syndrome," which usually manifests as an intestinal disorder accompanied by muscle aches and/or headaches, and fever. Rarely, the coxsackie virus can cause a more severe disease.
It has been suggested that most people experience coxsackie infections at some time, and they are particularly prevalent in infants and young children, and, to a lesser extent, adolescents, with first onset related largely to the hygienic conditions (lack thereof) in which the child lives. The disease symptoms appear between 2 and 10 days after exposure, and are gone within a few days, similar to the experience of the common cold or influenza, but with intestinal symptoms. It is thought that a partial immunity to coxsackie viruses develops in most children exposed to it, so that symptomatic disease is rare or even milder for adults.
In some cases, however, the virus escapes the intestinal tract to cause serious disease. In children, coxsackie may go on to produce viral meningitis and it has been proposed, on the basis of epidemiological evidence, that coxsackie and other enteroviruses (such as ECHO) may be among the causes of childhood insulin-dependent diabetes. In adults, viral myocarditis and dilated cardiomyopathy can occur if the virus infects the heart muscle. Coxsackie B viruses are estimated to be responsible for at least 50% of the cases of infection-caused heart diseases. For reasons yet unknown, the cardiac disease caused by this virus mainly occurs in middle-aged men, with onset occurring, on average, around age 42. The cardiac disease becomes apparent about two weeks after exposure to the virus.
The early symptoms of the coxsackie-induced cardiac myopathy include some generalized viral symptoms-fever, fatigue, malaise-with the addition of chest pains. As the virus enters the heart cells, the immune system attacks and damages both infected and normal heart cells; the affected individual feels severe fatigue when there is significant impairment of heart function. In most cases, the disease is resolved spontaneously without any treatment, though some permanent heart damage may have occurred. But, in about 20% of the cases, there can be progressive disease or recurrence of symptoms; the heart damage can be extensive, causing arrhythmias, weakened left ventricular functions, and, in the worst cases, heart failure requiring heart transplantation. In these severe cases, cardiac disease progression persists after the virus is long gone: the immune system continues to damage the heart.
Effective medical therapies have yet to be worked out for viral myocarditis; one approach is to administer anti-inflammatory or immunosuppressive drugs during the early stage of the disease to impair the immune attack and resulting inflammatory response that damages the heart. Patients are usually told to rest, as the damaged heart does not withstand the demands for vigorous activity.
Coxsackie infections are recognized as health problems in modern China, contributing to the high rates of childhood intestinal disease, meningitis, and, for adults, myocarditis. These infections are the subject of some research into the potential value of Chinese herbs. The main strategies are to inhibit viruses with the heat clearing herbs, of which sophora root (kushen) appears to be the most promising agent, and to bolster the resistance to the disease and limit its damaging effects to the heart with qi tonics, for which astragalus (huangqi) and ginseng (renshen) appear particularly valuable.
At the Shanghai Second Medical University (13, 15), it was reported that animal studies showed prolonged survival of mice with coxsackie-induced myocarditis when given sophora root. On that basis, the affiliated Renji Hospital began using sophora for treating this condition in humans (14, 19), using the injection form of the extract. It was claimed that coxsackie B virus RNA clearance (evaluated by PCR test) was dose dependent and that all 76 patients treated in the study group had relief of arrhythmia. Further, there were improvements in ejection fraction, stroke volume, cardiac output, and cardiac index, while left ventricular mass and its index were decreased significantly. The anti-coxsackie antibodies returned to normal titer after five months of therapy. Sophora has also been administered in the treatment of heart arrhythmias from various causes, so it may provide direct symptomatic relief, as well as its antiviral activity, in yielding the observed effects. A coordinating group for sophora research at the Beijing Medical University has reported on sophora's rapid effects for tachycardia (13).
In a recent rat study at the Shanghai Second Medical University (2), sophora root was found to inhibit Coxsackie B3 replication in myocardial cells. The herb and its alkaloid components (matrine and oxymatrine) appear to have broad antiviral effects, with inhibition of hepatitis B in mice (20), hepatitis C both in vitro (16) and in clinical trials (17), and significant inhibition of respiratory syncytial virus in vitro (18).
According to the book Antiviral Compounds from Plants (3), flavones may have an inhibitory effect on coxsackie viruses; in particular, a flavone isolated from Agastache rugosa (huoxiang) was said to be effective, though it needed to be used in very high dosage if given for systemic infection (e.g., cardiac infection) due to poor absorption from the intestines. Agastache is one of the key herbs for treating summer heat syndrome (especially in the formula Huoxiang Zhengqi San); the condition is sometimes referred to as "common cold in summer," though most cases are intestinal diseases that from contaminated food and water. Until recently, China had no refrigeration and limited food sterilization, leading to a high level of intestinal diseases during the warm months. Sophora also contains flavone components, mainly isoflavones.
One of the qi tonic herbs that has been researched for coxsackie-induced cardiomyopathy is astragalus. The work has been done by a team at the Shanghai Medical College and its associated hospitals. Studies with mice have suggested that astragalus protects the heart muscle (4, 5) and even inhibits the viral activity (6, 7). In one of the early mouse studies (8), the combination of the heart nutrients taurine (an amino acid) and coenzyme Q10 with the Chinese herb astragalus was said to reduce the mortality due to coxsackie B3 viral myocarditis. The active ingredients in astragalus include flavonoids and saponins.
Clinical evaluations of astragalus-based therapies have also begun, but on a small scale. Kang Er Xin number 1 is a recipe used to treat viral myocarditis (9). It consists of lonicera, astragalus, and ophiopogon. The formula is designed to clear away heat and toxin, supplement qi, and nourish yin. A clinical study with 26 patients was carried out with this formula in a cross-over design using coenzyme Q10 as the control treatment, and monitoring left ventricular function. Treatment time was two weeks, with favorable results on heart function and its related symptoms in which the herb therapy was deemed superior to coenzyme Q10. An experimental study in support of the clinical trial showed that the formula inactivated coxsackie B3 in vitro, protected the heart cells in mice (preventing attack by coxsackie B3), and promoted interferon production.
The cardiac formula Shengmai San, comprised of ginseng, schizandra, and ophiopogon, has been reported to be helpful in recovering heart function in patients with viral myocarditis and dilated cardiomyopathy (10, 11). Like sophora, ginseng is well known as a treatment for arrhythmia, but its active constituents differ: ginseng saponins are the effective component. A preparation for heart arrhythmia due to cardiomyopathy made at the Shanghai Penta Ocean Medical and Health Care Food Company is Fufang Sishenyin Chongji (Modified Formulation of Four Shen Drink in Granules) made with ginseng (renshen), salvia (danshen), adenophora (shashen), and sophora (kushen). The herbs are extracted and combined with sugar granules to make an instant tea, to be consumed three times per day. Salvia is frequently used in the treatment of cardiovascular diseases.
Minor Bupleurum Combination (Xiao Chaihu Tang) has been evaluated in animal models of coxsackie-induced myocarditis (22, 23) with findings suggesting that the herbs regulate T-lymphocyte subsets and antibodies involved in the attack against the cardiac cells, speed clearance of the virus, and protect the heart. This formula includes ginseng, jujube, and bupleurum with saponin components, and scute with flavonoids; licorice contains both types of compounds. The formula is commonly used in treatment of viral hepatitis. Scute (Scutellaria baicalensis; see Figure 1) has been shown to inhibit influenza, HIV, and respiratory syncytial in vitro.
The preparation Xinkang Shui (Heart Protecting Oral Liquid) was developed as a heart protectant that has been used for treating adriamycin cardiotoxicity (24). It has further been tested in laboratory animals for cardiac protection against both coxsackie B virus (25) and ischemic myocardial damage (26), and applied clinically for treating arrhythmias (27). The formula (not fully revealed) includes astragalus, ginseng and scute (in common with Minor Bupleurum Combination), raw rehmannia, and taraxacum.
The development of clinical knowledge in this field is relatively limited; only tentative recommendations can be made. Of the herbs mentioned, sophora is the most studied as a broad spectrum anti-infection agent and antiarrhythmic that might be a reasonable component of therapy during the time when the virus is active. Scute (huangqin) may also be an additional useful antiviral. Astragalus and ginseng are valued as heart protective agents; they are widely used in China, and appear to have direct application to myocarditis based on pharmacology studies and limited clinical evaluations. Taurine and coenzyme Q10 are among the best known of the heart protective agents in the West, so their use could be recommended, especially in light of their negligible toxicity (in addition to taurine, the amino acid carnitine is a heart protectant). Preliminary tests show that taurine transport into heart cells is inhibited by coxsackie B3 infection (21).
A brief summary of in vitro findings published in Modern Study and Application of Materia Medica (1), lists hu-chang, belamcanda, isatis leaf, loranthus, and osmunda (Osmunda japonica, a fern mainly used in Japanese cuisine) as effective agents for coxsackie virus. Of these, isatis and hu-chang are used extensively as antiviral agents. Isatis leaf (daqingye) is obtained primarily from Isatis indigotica (see Figure 2), but also from Polygonum tinctorium, and Baphicacanthus cusia, each of these herbs being from a different plant family. They all have in common the ingredients indican and indirubin. Isatis was shown to inhibit several viruses in vitro, including encephalitis B, mumps, and influenza. It has been used clinically in treatment of many epidemic disorders; measles, hepatitis, and herpes simplex, in addition to the three previously mentioned. Qingdai, an extract of the leaves of the same plants that are used or isatis leaf, contains 5-8% indigo. It is indicated for the treatment of various epidemic diseases, including those that cause chest pain (6).
Hu-chang is obtained from Polygonum cuspidatum (see Figure 3), which contains a number of anthraquinones, such as emodin, physcion, and chrysophanol, and the stilbene derivative resveratrol (this compound is an ingredient in red grapes that is thought to be responsible for some of the health benefits of red wine). In vitro studies showed that the herb extract could inhibit several viruses including influenza, herpes simplex, adenovirus, polio, coxsackie A and B, EHCO, and encephalitis B. Isatis leaf, hu-chang, and sophora (for more information about the latter; see the START article: Sophora) are all used in the treatment of viral hepatitis in China; in addition, they are all used in formulas for treatment of sore throat due to various infections.
Figure 2:Isatis indigotica.
Figure 3:Polygonum cuspidatum.