Causes

Evidence suggesting that some CFS cases may not be due to a virus:

• Most cases of CFS occur sporadically. They occur in individuals and do not appear to be contagious.
• There is no evidence that CFS is spread through casual contact, such as shaking hands or coughing, or by intimate sexual contact.
• No single virus has been implicated in chronic fatigue syndrome. Well-designed studies of patients who met strict criteria for chronic fatigue syndrome and of patients with idiopathic chronic fatigue have not found an increased incidence of any specific infections.

Immune System Abnormalities

CFS has sometimes been referred to as the "chronic fatigue immune dysfunction syndrome." A number of studies have found many irregularities of the immune system. Some components appear to be overreactive, whereas others appear to be underreactive, but no consistent picture has emerged to explain CFS as a disease of the immune system. Again, the theory of subgroups may explain the significant heterogeneity among patients.

Allergies. Some, although not all, studies have reported that a majority of CFS patients have allergies to foods, pollen, metals (such as nickel or mercury), or other substances. One theory is that allergens, like viral infections, may trigger a cascade of immune abnormalities leading to CFS. (Most allergic people, in any case, do not have CFS.) Some research indicates that people with both allergies and emotional disorders, such as anxiety or depression, may be more vulnerable to the effects of the inflammatory response. This is a harmful overreaction of the immune system that can cause fatigue, joint aches, and fever as well as hormone and brain chemical disturbances.

One theory that may help tie in some of the various factors common to CFS suggests that allergies, stress, and infections may deplete a chemical in the body called adenosine triphosphate (ATP). This chemical stores energy in cells, and studies have reported a deficiency in many CFS patients. Supporting this theory was a study in which patients reported reduced CFS symptoms after they took a vitamin-like supplement called NADH, which increases ATP levels.

Autoimmune Abnormalities. The risk profile for chronic fatigue syndrome is similar to the risk profiles for a number of autoimmune diseases, such as lupus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis. These disorders also have early symptoms resembling CFS. Common to such diseases are the presence of high levels of autoantibodies, immune factors that mistakenly attack the patient's own cells. Studies are inconsistent, however, in reporting the presence of autoantibodies in CFS, and the disease is unlikely to be due to autoimmunity.

Overactive Immune System. Various studies have reported imbalances in various immune factors, importantly white blood cells called T cells, which serve as infection fighters in the immune system.

The result of some T-cell abnormalities is to produce an excess of inflammatory substances called cytokines, which has been observed in some CFS patients. Excess amounts of cytokines cause inflammation and damage in the cells of the body and play an important role in many chronic diseases. This activity also produces fatigue, muscle aches, and other symptoms of CFS. Nevertheless, not all studies have reported elevated cytokine levels in CFS patients.

Low Blood Pressure

Some studies have observed that a subgroup of patients who fit the strict criteria for chronic fatigue syndrome also has a condition known as neurally mediated hypotension (NMH). NMH causes a dramatic drop in blood pressure when standing up, even for as short a time as 10 minutes. Its immediate effect can be lightheadedness, nausea, and fainting. A less severe hypotension condition known as postural orthostatic tachycardia syndrome (POTS) is also associated with CFS. An estimated 30% of CFS patients may have POTS, and some experts believe that the key to understanding CFS will eventually be found in understanding orthostatic intolerance. To further confound the issue, different CFS patients display different types of orthostatic intolerances.

Some experts suggest that such events may be due to impaired blood flow in CFS patients, which might affect the leg and arm muscles. (This in turn might account for muscle fatigue in these patients.) Evidence suggests, however, that blood flow is not abnormal in CFS patients, with or without NMH.

In any case, not all CFS patients experience NMH or POTs. In fact, some studies have reported no higher incidence of NMH in chronic fatigue patients. More research is needed to determine how or if these conditions are associated.

Psychologic Factors

Psychological, personality, and social factors are strongly associated with chronic fatigue in most, but not all, patients. The complex relationship between physical and emotional factors has yet to be fully understood, however. Studies have not found any consistent association between emotional or personality disorders and CFS to explain a causal role. Psychological factors, then, are unlikely to be a primary cause of CFS. They may play a role in increasing susceptibility to onset or perpetuation of the disorder. Certainly, in many cases, CFS promotes psychological and social dysfunction.

Chemicals and Environmental Toxins

In another subgroup of patients, chronic fatigue and pain has been associated with exposure to various chemicals and environmental toxins, such as solvents, pesticides, or heavy metals (cadmium, mercury, or lead). Of note, some reports in Sweden have suggested that mercury found in dental preparations may trigger processes that might cause CFS in susceptible patients. However, most experts believe that dental amalgam is entirely safe. The most publicized example is Gulf War syndrome. Still, most people have been exposed to toxic chemicals at some point during their lives, and it is very difficult to determine specific chemicals that might be particularly dangerous. It is not clear, then, to what extent chemicals may cause CFS. A recently described condition called multiple chemical sensitivity may produce the same symptoms or even occur with CFS.