INFECTIONS CONTRIBUTE TO THE ONSET AND/OR MAINTENANCE OF CFS
A number of pathogens (bacteria, viruses) have been associated with CFS. Some studies have suggested that infections (particularly viral infections) could act as triggering factors for the disease; other studies tend to support the idea that infections may rather be opportunistic and develop as a consequence of impaired immunity. In any case, persistent infections in CFS patients can contribute to the maintenance of the disease and to the worsening of the symptoms.
HUMAN HERPESVIRUS 6
HHV-6 has a very high prevalence (close to 100% of the world’s population has been exposed). It is transmitted mainly by saliva. Transmission occurs usually within the first two years of life; primary infection is often associated with a febrile condition and sometimes with the onset of roseola (exanthem subitum). Two variants of the virus are known, HHV-6A and HHV-6B. HHV-6 is mainly lymphotropic, infecting a broad range of immune cells including T cells, monocytes, NK cells; however the virus can also infect many other tissues such as brain or liver.
HHV-6 has immunomodulatory effects, including suppression of T-cell proliferation and alteration of cytokine production. This immunosuppression may favor the development or progression of other viral infections such as CMV, EBV or HIV.
Several studies have reported a possible link between HHV-6 and multiple sclerosis (MS). Expression of HHV-6 proteins is observed at the site of MS lesions; cell-free HHV-6 DNA has been detected in the serum of MS patients. Reactivation of HHV-6 is also suspected to contribute to the pathogenesis of CFS.
HUMAN HERPESVIRUS 7
HHV-7 is closely related to HHV-6. Primary infection with HHV-7 usually occurs later in childhood than HHV-6 infection; it can also cause exanthem subitum. HHV-7 may have a narrower tropism than HHV-6: the virus efficiently infects and replicates in CD4+ cells; it can be found in brain tissue but at a lower frequency than HHV-6.
It has been suggested that HHV-7 could reactivate HHV-6 from latency. Increased prevalence has been reported in people with autoimmune disease.
CYTOMEGALOVIRUS
CMV is transmitted through close personal contact (saliva, blood, breast milk, semen…). 20% of children are already infected before puberty; infection is then common during adolescence. Finally 40 to 100% of the general population will show evidence of prior exposure.
Primary CMV infections in newborns can lead to severe complications, but in older children and adults, primary infection is usually asymptomatic. After infection CMV remains latent in the host and can be reactivated when the immune system is severely impaired. Reactivation of the virus can target the central nervous system (acute encephalitis), damage the retina or have dermatologic manifestations (rash, ulcerative lesions). A pathogenic role of CMV in irritable bowel disease is suspected.
EPSTEIN-BARR VIRUS
EBV (HHV-4) infects more than 90% of the world’s adult population. It is transmitted by salivary contact; the virus first replicates in the epithelium of the oropharynx before infecting B lymphocytes where it will persist for life in a latent state. Primary infection typically occurs within the first years of life and is generally asymptomatic. In developed countries however, primary infection is sometimes delayed until late adolescence, and may then result in mononucleosis.
In most individuals persistence of the virus has no consequences; in some people however EBV is associated with the development of cancer. EBV infections were first found to be associated with Burkitt’s lymphoma (a common cancer affecting children in certain regions of Africa) and have been implicated in Hodgkin’s disease, non-Hodgkin’s lymphoma, and nasopharyngeal carcinoma (in specific Asian regions).
In addition to cancer, EBV has been linked to various immune diseases. By infecting T and NK cells, EBV can cause hemophagocytic syndrome (EBV-AHS).
There is evidence that multiple sclerosis may sometimes occur as a consequence of an EBV infection. Serum antibodies to EBV antigens are found in a subset of CFS patients; since EBV infections can lead to infectious mononucleosis, whose acute symptoms are similar to those of CFS, EBV was once proposed to be the primary causative agent.
MYCOPLASMA PNEUMONIAE
Mycoplasmas are atypical bacteria that live as intra- or extracellular parasites. Mycoplasmas can be transmitted through aerosols (M. pneumoniae, M. fermentans, both of which are found in the saliva); sexual transmission is also frequent (M. genitalium). Acute M. pneumoniae infections cause pneumonia, bronchitis; chronic infection in the lungs can exacerbate other respiratory diseases such as asthma. Mycoplasmas can disseminate from their primary infection site to other organs. Central nervous system can be a target, resulting in encephalitis; attack on the joints and development of arthritis is also frequent.
Mycoplasma infections are particularly frequent in CFS patients. Using PCR detection, M. fermentans was found in 34% of CFS patients, versus 8% of healthy controls. Another study showed that more than two third of CFS patients (versus 5.6% of controls) were infected by at least one mycoplasma species (M. fermentans, M. pneumoniae, or M. hominis). This high prevalence may result from the immunodepression typically observed in CFS (low NK activity); however persistent mycoplasma infections can in turn contribute to the etiology of the disease by eliciting a chronic inflammatory response.
CHLAMYDIA TRACHOMATIS AND CHLAMYDIA PNEUMONIAE
Chlamydiae are bacterial intracellular pathogens which cause widespread infections in humans. C. trachomatis is the world’s most common sexually transmitted bacterial pathogen. C. pneumoniae, which is transmitted via respiratory secretions, causes pneumonia. The percentage of people displaying positive serology to C. pneumoniae is high, reaching 80% in adults. Chlamydial organisms have the capacity to enter a particular growth stage characterized by reticulate bodies that divide very slowly and can persist in cells for a long time. This results in a chronic infection, which, by inducing a sustained inflammatory response, can lead to a number of serious pathologies.
- Chlamydia pneumoniae
Acute C. pneumoniae infections cause pneumonitis; chronic persistence of the pathogen in the lungs has been linked to chronic obstructive pulmonary disease, asthma, and even lung cancer. In the lungs, C. pneumoniae can infect alveolar macrophages and spread to other organs via the blood. Infection can be directly transferred to vascular endothelial cells, leading to chronic endothelium inflammation that favors atherogenesis. Chlamydia infection stimulates the migration of monocytes through the blood-brain barrier, promoting inflammation of the central nervous system. An increased prevalence of C. pneumoniae infections has been reported in CFS patients.
- Chlamydia trachomatis
C. trachomatis has a tropism for both conjunctival and urogenital epithelial cells. Ocular infections cause conjunctivitis, that frequently evolve to trachoma. Urogenital infections cause acute urethritis. Like C. pneumoniae, C. trachomatis can disseminate away from the site of primary infection. Several days after a genital infection, certain patients develop acute inflammatory arthritis; this is caused by C. trachomatis organisms that have reached the joint via circulating monocytes. A portion of these patients will then develop chronic arthritic disease. Persistent, chronic chlamydial infections may have little or no apparent symptoms. Though, they continue to elicit a chronic inflammation that will eventually cause disease. This of course strongly warrants screening for infections. Monocytes appear as common host cells for persistent organisms, and major effectors of systemic dissemination. PCR testing in whole blood is therefore an adequate approach for the detection of Chlamydia infections.