{"product_id":"is-chronic-fatigue-after-a-bacterial-infection-caused-by-a-hidden-infection","title":"Is Chronic Fatigue After a Bacterial Infection Caused by a Hidden Infection?","description":"\u003cp\u003eThis review article examines whether chronic fatigue syndrome that follows a bacterial infection is caused by a hidden, dormant infection. The authors reviewed 119 scientific references. The authors found no evidence that subjective symptoms such as fatigue, headache, and muscle pain are linked to dormant bacteria or to the asymptomatic carriage of live bacteria. They conclude that antibiotic treatment is not required for latent infections, with two exceptions: latent syphilis and latent tuberculosis, where treatment prevents progression to serious later stages of disease.\u003c\/p\u003e\n\n\u003ch1\u003eIs Chronic Fatigue After a Bacterial Infection Caused by a Hidden Infection?\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: What Is Chronic Fatigue Syndrome?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Researchers Conducted This Review\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#qfs\"\u003eQ Fever Fatigue Syndrome\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lyme\"\u003eLyme Disease and Post-Treatment Lyme Disease Syndrome\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#brucella\"\u003eBrucella Infection and Post-Infectious Fatigue\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#dormant\"\u003eDormant Bacteria and Latent Infection: A Reversible State\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#staph\"\u003eStaphylococcus aureus Bone and Joint Infection\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#syphilis\"\u003eLatent Syphilis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#latent-lyme\"\u003eLatent Lyme Disease\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#tuberculosis\"\u003eLatent Tuberculosis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#rickettsiosis\"\u003eRickettsiosis and the Brill-Zinsser Disease\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of This Review\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eA review of 119 references found no evidence linking post-bacterial infection chronic fatigue syndrome to dormant bacteria or asymptomatic carriage of live bacteria.\u003c\/li\u003e\n\u003cli\u003eAntibiotic treatment is not required for latent infections, except latent syphilis and latent tuberculosis, where treatment prevents progression to serious later stages.\u003c\/li\u003e\n\u003cli\u003eFinding bacterial DNA in blood does not prove live bacteria are present; DNA can persist after successful antibiotic treatment, and some patients with positive tests had no symptoms.\u003c\/li\u003e\n\u003cli\u003eDoctors should rule out other physical and psychiatric causes and be alert to persistent active infection masquerading as chronic fatigue, as misdiagnosis can be fatal.\u003c\/li\u003e\n\u003cli\u003ePsychological trauma may be part of the subjective symptoms, and post-infectious chronic fatigue syndrome could be due to unknown microorganisms, requiring further research.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: What Is Chronic Fatigue Syndrome?\u003c\/h2\u003e\n\n\u003cp\u003eChronic fatigue syndrome is defined by unexplained disability combined with a group of non-specific subjective symptoms. These symptoms include fatigue, headache, musculoskeletal pain (pain in muscles and bones), neurocognitive disorders (problems with thinking and memory), sleeping disorders, mood disorders, and even respiratory tract disorders (breathing problems).\u003c\/p\u003e\n\n\u003cp\u003eChronic fatigue syndrome represents a major public health problem. However, its causes remain poorly understood. Post-infectious chronic fatigue syndrome (fatigue that follows an infection) has been reported after viral infections. These include Epstein-Barr virus infection, Chikungunya virus infection, and hepatitis A and B infections.\u003c\/p\u003e\n\n\u003cp\u003eFor bacterial infections, post-infectious chronic fatigue syndrome may be suspected after brucellosis, Q fever caused by \u003cem\u003eCoxiella burnetii\u003c\/em\u003e, and Lyme disease caused by \u003cem\u003eBorrelia burgdorferi\u003c\/em\u003e group bacteria (Borreliae). However, no evidence of a progressive infection can explain chronic fatigue syndrome. Specifically, there is no clinical or biological inflammatory syndrome, no evidence of bacterial multiplication, and no evidence that antibiotics work.\u003c\/p\u003e\n\n\u003cp\u003ePost-infectious chronic fatigue syndrome therefore remains a crucial and unsolved issue. The question currently raised is whether latent infection (a hidden, inactive infection) could be responsible for the subjective syndrome. This question is especially relevant in the case of post-treatment Lyme disease syndrome.\u003c\/p\u003e\n\n\u003cp\u003eHowever, medical experience with stubborn infections, relapses, and reactivations raises important questions. Doctors have observed bone and joint infections appearing even decades after the primary infection. This observation suggests that some bacteria could persist in a dormant stage. These dormant bacteria remain quiet and alive, without causing any clinical symptoms.\u003c\/p\u003e\n\n\u003cp\u003eSeveral factors can promote reactivation of dormant bacteria. These factors include immunosuppression (a weakened immune system) and pregnancy. However, sometimes no reactivation factor can be identified at all.\u003c\/p\u003e\n\n\u003cp\u003eSome bacterial infections occur in several stages, with latency periods in-between some stages. This is the case for Lyme disease, tuberculosis, and syphilis. The primary infection is self-limiting (resolves on its own), but if left untreated, the disease can quietly progress to secondary or tertiary (later-stage) manifestations.\u003c\/p\u003e\n\n\u003cp\u003eFinally, the identification of pathogenic bacteria in asymptomatic and healthy individuals is known as asymptomatic carriage. Asymptomatic carriage has led researchers to re-interrogate Koch's postulates, the classic rules for proving that a specific germ causes a specific disease.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Researchers Conducted This Review\u003c\/h2\u003e\n\n\u003cp\u003eTo find out whether latent infections, dormant bacteria, or asymptomatic carriage may have a role in post-infectious chronic fatigue syndrome, the authors performed a literature review. They searched the Medline and Google Scholar databases.\u003c\/p\u003e\n\n\u003cp\u003eThe search had no language restriction and no restriction of publication time or status. The authors used the following keywords:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eDormant bacteria\u003c\/li\u003e\n  \u003cli\u003eLatent infection\u003c\/li\u003e\n  \u003cli\u003ePost-infectious chronic fatigue syndrome\u003c\/li\u003e\n  \u003cli\u003eChronic fatigue syndrome\u003c\/li\u003e\n  \u003cli\u003eAsymptomatic carriage\u003c\/li\u003e\n  \u003cli\u003ePost-treatment Lyme disease syndrome\u003c\/li\u003e\n  \u003cli\u003ePost-Q fever fatigue syndrome\u003c\/li\u003e\n  \u003cli\u003eLatent tuberculosis\u003c\/li\u003e\n  \u003cli\u003e\u003cem\u003eMycobacterium tuberculosis\u003c\/em\u003e\u003c\/li\u003e\n  \u003cli\u003e\n\u003cem\u003eBrucella\u003c\/em\u003e spp.\u003c\/li\u003e\n  \u003cli\u003e\u003cem\u003eTropheryma whipplei\u003c\/em\u003e\u003c\/li\u003e\n  \u003cli\u003e\n\u003cem\u003eBartonella\u003c\/em\u003e spp.\u003c\/li\u003e\n  \u003cli\u003e\u003cem\u003eStaphylococcus aureus\u003c\/em\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eA total of 119 references were included in the final qualitative synthesis.\u003c\/p\u003e\n\n\u003ch2 id=\"qfs\"\u003eQ Fever Fatigue Syndrome\u003c\/h2\u003e\n\n\u003cp\u003eQ fever fatigue syndrome (QFS) was first described in 1992. It is a health challenge because it is responsible for impaired quality of life and absenteeism (missing work). QFS is characterized by subjective symptoms lasting for at least six months after acute Q fever.\u003c\/p\u003e\n\n\u003cp\u003eQFS is responsible for significant disability in daily living. It is associated with neither objective symptoms nor organic lesions (physical damage to organs). The diagnosis should rule out other physical and psychiatric causes of chronic fatigue syndrome.\u003c\/p\u003e\n\n\u003cp\u003eQFS also does not correlate with the levels of anti-\u003cem\u003eC. burnetii\u003c\/em\u003e phase I IgG (a type of antibody against the bacteria). These antibody levels are insufficient and erroneous for concluding whether the infection persists or does not persist.\u003c\/p\u003e\n\n\u003cp\u003eIn the Netherlands, after the 2007–2011 epidemiological outbreaks, QFS developed in 20% of patients who had been diagnosed with acute Q fever. This compared with 4% of healthy controls. In Australia, QFS developed in 28% of patients who had been diagnosed with acute Q fever, versus 0% of controls.\u003c\/p\u003e\n\n\u003cp\u003ePentillas et al. provided the first broad description of QFS in Australia. However, their report can be questioned because they included patients presenting with objective symptoms, such as diarrhea and swollen superficial lymph nodes.\u003c\/p\u003e\n\n\u003cp\u003eJust like post-treatment Lyme disease syndrome (PTLDS), the persistence of living microbes has been suggested to be involved in QFS. However, this has never been confirmed. A fundamental and dangerous confusion may thus be observed between latent infections and QFS.\u003c\/p\u003e\n\n\u003cp\u003eThis confusion leads to misdiagnosing persistent \u003cem\u003eC. burnetii\u003c\/em\u003e latent infection. This is illustrated by a fatal case recently reported by Sudocheva et al. A 19-year-old man was diagnosed with post-Q fever fatigue syndrome and died from disseminated \u003cem\u003eC. burnetii\u003c\/em\u003e infection 10 years after acute Q fever infection. \u003cem\u003eC. burnetii\u003c\/em\u003e was identified by immunohistochemistry (IHC) and polymerase chain reaction (PCR) targeting the COM1 and IS1111 sequences in all post-mortem investigated organs.\u003c\/p\u003e\n\n\u003cp\u003eMarmion et al. also reported two cases of patients misdiagnosed with chronic fatigue syndrome instead of persistent \u003cem\u003eC. burnetii\u003c\/em\u003e endocarditis (infection of the heart lining). One of these cases was fatal. These three cases argue in favor of long-term latent and asymptomatic \u003cem\u003eC. burnetii\u003c\/em\u003e infection.\u003c\/p\u003e\n\n\u003cp\u003eThis infection is different from QFS because it only affects patients presenting with subjective signs and symptoms, with no detected living bacteria. Experimental studies on tissues distinguished living bacteria from dead bacteria using fluorescence in situ hybridization targeting the bacterial ribonucleic acid.\u003c\/p\u003e\n\n\u003cp\u003eBecause \u003cem\u003eC. burnetii\u003c\/em\u003e was not isolated from blood samples in cases of QFS, persistent \u003cem\u003eC. burnetii\u003c\/em\u003e cell components are probably residues of the original heavy seeding during bacteremia (bacteria in the blood). These components are not a renewed production of viable bacteria.\u003c\/p\u003e\n\n\u003cp\u003eThe long-term persistence of non-viable \u003cem\u003eC. burnetii\u003c\/em\u003e cell components, including antigens or DNA, is the sole biological finding currently correlating with these subjective symptoms. The circulation of these bacterial cell components could result in altered cell immunity and altered cytokine production.\u003c\/p\u003e\n\n\u003cp\u003eCytokines are signaling molecules that control inflammation. The subsequent ongoing production of pro-inflammatory cytokines could then be responsible for fatigue.\u003c\/p\u003e\n\n\u003cp\u003ePatients presenting with QFS were described as differing in the frequency of HLA-DRB1*11 carriage and the 2\/2 genotype of the IFN-γ intron 1 microsatellite when compared with controls. In addition, the cytokine release pattern of peripheral blood monocyte cells of QFS patients was reported as abnormal. This pattern showed increased IL-6 release, a decreased level of IL-2 release, and increased INF-γ and CXCL10 production.\u003c\/p\u003e\n\n\u003cp\u003eJust like PTLDS, it is unknown whether QFS is a direct consequence of non-viable or viable bacteria, or whether its origin is psychological. Predictors of QFS are contradictory. Factors such as female sex and young adult age have been associated with QFS. The severity of the acute illness, as well as pre-existing health problems and hospitalization, have been reported as QFS predictors.\u003c\/p\u003e\n\n\u003ch2 id=\"lyme\"\u003eLyme Disease and Post-Treatment Lyme Disease Syndrome\u003c\/h2\u003e\n\n\u003cp\u003ePost-treatment Lyme disease syndrome (PTLDS) is characterized by the late onset of musculoskeletal symptoms and antibiotic treatment failures. PTLDS is estimated to affect 10 to 20% of patients treated with antibiotics effective against Lyme disease.\u003c\/p\u003e\n\n\u003cp\u003ePTLDS is a public and political challenge compared with \u003cem\u003eC. burnetii\u003c\/em\u003e infection. However, few studies have been conducted to identify \u003cem\u003eB. burgdorferi\u003c\/em\u003e cell components or to understand the physiological and immune mechanisms involved in PTLDS.\u003c\/p\u003e\n\n\u003cp\u003ePicha et al. performed a study with \u003cem\u003eB. burgdorferi\u003c\/em\u003e-infected patients. They identified \u003cem\u003eB. burgdorferi\u003c\/em\u003e DNA up to six months after the administration of an effective antimicrobial treatment. However, this result does not indicate the presence of living bacteria. All patients with a positive \u003cem\u003eB. burgdorferi\u003c\/em\u003e PCR did not present with subjective symptoms.\u003c\/p\u003e\n\n\u003cp\u003eAutoimmune diseases are believed to be involved in patients diagnosed with PTLDS. Maccallini et al. hypothesized that such patients exhibited autoimmunity against α-enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase.\u003c\/p\u003e\n\n\u003cp\u003eCabello et al. explained that in the absence of sterilizing immunity, a strong antibody response was observed. They suggested that \u003cem\u003eB. burgdorferi\u003c\/em\u003e is located in a niche where it could be protected from the adaptive immune response. The extracellular matrix, rich in collagen such as tendon and ligaments, was suspected to be the niche of \u003cem\u003eB. burgdorferi\u003c\/em\u003e in mice.\u003c\/p\u003e\n\n\u003cp\u003eCrossland et al. recently identified persistent non-viable Borrelia in the central nervous system, joint-associated tissues, and urinary bladder of rhesus macaques following doxycycline therapy. Hodzic et al. demonstrated that after ceftriaxone therapy in a mouse model, \u003cem\u003eB. burgdorferi\u003c\/em\u003e could not be cultured from tissues. However, low copy numbers of specific DNA sequences could be detected two, four, and eight months after treatment completion.\u003c\/p\u003e\n\n\u003cp\u003eInterestingly, Iyer et al. demonstrated in vitro (in the laboratory) that \u003cem\u003eB. burgdorferi\u003c\/em\u003e could not be cultured three days after ceftriaxone antibiotic treatment. However, positive \u003cem\u003eB. burgdorferi\u003c\/em\u003e DNA was detected up to 56 days after antibiotic treatment.\u003c\/p\u003e\n\n\u003cp\u003eThese results are at odds with experimental data reported by Caskey et al. These researchers showed the inability of doxycycline to kill quiescent \u003cem\u003eB. burgdorferi\u003c\/em\u003e, which newly developed after antimicrobial therapy. The lack of studies in humans does not allow scientific support for the responsibility of quiescent \u003cem\u003eB. burgdorferi\u003c\/em\u003e or dormant bacteria in PTLDS.\u003c\/p\u003e\n\n\u003ch2 id=\"brucella\"\u003eBrucella Infection and Post-Infectious Fatigue\u003c\/h2\u003e\n\n\u003cp\u003eChronic fatigue syndrome after \u003cem\u003eBrucella\u003c\/em\u003e infection has been reported in patients with poor health, musculoskeletal pain, depression, or anxiety without any infectious focus of the disease. However, the definition and description of persistent subjective symptoms after brucellosis is often mistaken for chronic brucellosis.\u003c\/p\u003e\n\n\u003cp\u003eHistorically, antigen therapy was suggested to patients presenting with chronic brucellosis following antibiotic therapy. The term \"post-brucellosis fatigue syndrome\" could be more appropriate. This term would differentiate subjective symptoms without detectable organic lesions following infection from chronic persistent \u003cem\u003eBrucella\u003c\/em\u003e infection.\u003c\/p\u003e\n\n\u003cp\u003eSome studies focused on post-brucellosis disease. The persistent detection of \u003cem\u003eBrucella\u003c\/em\u003e spp. DNA after an effective antibiotic therapy was initially related to relapses. Castano et al. recently identified the presence of \u003cem\u003eBrucella\u003c\/em\u003e spp. DNA in the blood and serum of patients presenting with persistent focalized infection, with non-focal disease, and with subjective symptoms.\u003c\/p\u003e\n\n\u003cp\u003eThis finding was even observed in the group of asymptomatic subjects with a history of brucellosis, but not in the control group. The authors reported that the proportion of individuals with \u003cem\u003eBrucella melitensis\u003c\/em\u003e DNA was significantly higher in symptomatic non-focal disease patients than in asymptomatic subjects. Symptomatic non-focal disease patients are patients with subjective symptoms and without an identified focus.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eBrucella abortus\u003c\/em\u003e has been widely used to study chronic fatigue syndrome in animal models. An impaired mouse running activity has been described when animals were inoculated with \u003cem\u003eB. abortus\u003c\/em\u003e antigens. Potential oxidative stress and immunological activation, as assessed by an increase in tumor necrosis factor alpha, are involved in chronic fatigue syndrome induced by \u003cem\u003eB. abortus\u003c\/em\u003e.\u003c\/p\u003e\n\n\u003cp\u003eWhether for \u003cem\u003eBrucella\u003c\/em\u003e spp., \u003cem\u003eC. burnetii\u003c\/em\u003e, or \u003cem\u003eB. burgdorferi\u003c\/em\u003e, the persistence of bacterial DNA copies in blood samples remains poorly understood. We do not know if these DNA sequences are associated with subjective symptoms and the expression of viable dormant bacteria.\u003c\/p\u003e\n\n\u003ch2 id=\"dormant\"\u003eDormant Bacteria and Latent Infection: A Reversible State\u003c\/h2\u003e\n\n\u003cp\u003eIn 1944, Joseph Bigger laid the founding stone of the concept of \"dormant bacteria\" with a microbiological definition. He observed that penicillin lysed a growing population of \u003cem\u003eStaphylococcus\u003c\/em\u003e spp. However, only a small proportion survived. These surviving bacteria were not resistant to antibiotics and were not in a fission stage.\u003c\/p\u003e\n\n\u003cp\u003eThis data suggested that penicillin was only effective in dividing bacteria. \"Dormant bacteria\" are characterized by a non-growing and non-replicating stage. They are viable but unable to grow on usual culture media. They are also tolerant to stress, including stress-induced antibiotics.\u003c\/p\u003e\n\n\u003cp\u003eConsequently, dormant bacteria could be responsible for antibiotic treatment failure to eradicate the infection. At the \"dormant\" stage, bacteria are also non-virulent and bypass the innate immune system response. These bacteria could return to growth and normal activity when original conditions are restored.\u003c\/p\u003e\n\n\u003ch2 id=\"staph\"\u003eStaphylococcus aureus Bone and Joint Infection\u003c\/h2\u003e\n\n\u003cp\u003eSince the description of \u003cem\u003eS. aureus\u003c\/em\u003e as a \"dormant\" bacterium, mechanisms used to achieve its intracellular persistence have been partially identified. The \u003cem\u003eS. aureus\u003c\/em\u003e small colony variant (SCV) is a quiescent metabolic state related to persistence, recurrence, and antibiotic resistance.\u003c\/p\u003e\n\n\u003cp\u003eSmall colonies are also distinguished from usual \u003cem\u003eS. aureus\u003c\/em\u003e colonies on agar plates by their decreased pigmentation and reduced hemolysis. \u003cem\u003eS. aureus\u003c\/em\u003e SCVs are then characterized by a low metabolic activity.\u003c\/p\u003e\n\n\u003cp\u003eProctor et al. showed that \u003cem\u003eS. aureus\u003c\/em\u003e SCVs settled in an intracellular niche. They also showed that 25% of the initial inoculum switched to SCVs.\u003c\/p\u003e\n\n\u003cp\u003eIn humans, \u003cem\u003eS. aureus\u003c\/em\u003e SCVs were recovered from abscess, bone and joint, blood, catheters, heart, and respiratory tract. All presented auxotrophic defects accounting for their low metabolic activities. Auxotrophic means the bacteria require specific nutrients to grow.\u003c\/p\u003e\n\n\u003cp\u003eNon-professional phagocytic cells such as endothelial cells, epithelial cells, fibroblasts, osteoblasts, and keratinocytes were identified as host cells for intracellular persistence of \u003cem\u003eS. aureus\u003c\/em\u003e SCVs. In vitro, keratinocytes and endothelial cells infected with \u003cem\u003eS. aureus\u003c\/em\u003e SCVs did not present any sign of damaged cells. This was unlike cells infected with the usual \u003cem\u003eS. aureus\u003c\/em\u003e, which underwent cell apoptosis or necrosis. This data supports the role of these cells as latent niches for \u003cem\u003eS. aureus\u003c\/em\u003e infection.\u003c\/p\u003e\n\n\u003ch2 id=\"syphilis\"\u003eLatent Syphilis\u003c\/h2\u003e\n\n\u003cp\u003e\u003cem\u003eTreponema pallidum\u003c\/em\u003e is responsible for syphilis. It is characterized by its ability to invade the human body and escape the immune system. It is also characterized by a latent stage following the secondary stage and preceding the tertiary stage of the infection.\u003c\/p\u003e\n\n\u003cp\u003eEarly latent syphilis is defined by a positive serology without clinical symptoms. Late latency may start one or two years after exposure and may last up to several decades. It is estimated that 15–40% of untreated individuals develop tertiary syphilis. Tertiary syphilis is characterized by cardiac, neurological, skin, and bone involvement. It can cause destructive syphilitic gumma, hemiparesis (weakness on one side of the body), aphasia (loss of ability to speak), and aortitis (inflammation of the aorta). It can also cause aortic aneurysm, and congestive heart failure or coronary disease.\u003c\/p\u003e\n\n\u003cp\u003eAs a global worldwide re-emerging disease, latent \u003cem\u003eT. pallidum\u003c\/em\u003e infection is still challenging physicians because of two critical complications. In immunocompromised hosts, malignant syphilis has been described as a severe cutaneous complication of syphilis in AIDS patients. The authors recently observed neurological syphilis involvement in HIV-infected patients with low CD4 level (less than 350\/mm³).\u003c\/p\u003e\n\n\u003cp\u003eThese reports demonstrated that immunosuppression is a factor promoting awakening of the latent form. Pregnant women presenting with latent syphilis can transmit the infection in utero. This has led to recent dramatic outbreaks of congenital syphilis in Australia and the United States.\u003c\/p\u003e\n\n\u003cp\u003eThe detection of \u003cem\u003eT. pallidum\u003c\/em\u003e DNA in patients with latent stage of the disease was only observed in blood and ear scraping. Only former animal studies aimed to understand \u003cem\u003eT. pallidum\u003c\/em\u003e quiescent surviving.\u003c\/p\u003e\n\n\u003cp\u003eOne century ago, Pearce and Brown described the rabbit's large and indurated lymph nodes (inguinal, popliteal, submental, auricular, axillary, and large flank) as the latent niches of the bacterium. Inoculation of the emulsion of resected asymptomatic lymph nodes induced the development of syphilis in previously uninfected animals.\u003c\/p\u003e\n\n\u003cp\u003eIn another experimental work, Collart et al. showed that corticosteroids reactivated latent syphilis in two of 12 rabbits. During this latent stage, the authors pointed out the morphological transformation of Treponema. \u003cem\u003eT. pallidum\u003c\/em\u003e is supposed to survive extracellularly, in areas rich in connective tissues and relatively inaccessible to circulating immune cells (tunica albuginea, tunica media of the aorta, testes).\u003c\/p\u003e\n\n\u003cp\u003eCerebrospinal fluid and lymphoid sites act as reservoirs for spirochetes, and maintain the disease in a quiescent state. The latent stage is characterized by the absence of symptoms. Reactivation may be promoted by immunosuppression or other hitherto unknown factors.\u003c\/p\u003e\n\n\u003ch2 id=\"latent-lyme\"\u003eLatent Lyme Disease\u003c\/h2\u003e\n\n\u003cp\u003e\u003cem\u003eB. burgdorferi\u003c\/em\u003e infection is characterized by symptom-free stages. Several years may go by between the early localized and late disseminated stages. There is no documented case of bacterial presence at the latent stage. Reports rather focus on descriptions of the secondary or tertiary stage of the infection.\u003c\/p\u003e\n\n\u003cp\u003eSeveral animal models tried to identify the persistent niche of \u003cem\u003eB. burgdorferi\u003c\/em\u003e. However, most of these models focused on explaining PTLDS in mice, dogs, and macaques. These models provided evidence of persistent bacteria by immunofluorescence and PCR after antibiotic therapy.\u003c\/p\u003e\n\n\u003cp\u003eAs previously discussed, the presence of \u003cem\u003eB. burgdorferi\u003c\/em\u003e DNA does not indicate bacterial viability. As \u003cem\u003eB. burgdorferi\u003c\/em\u003e is probably present at a latent stage before the tertiary stage of the infection, its niche has not been identified.\u003c\/p\u003e\n\n\u003cp\u003eAlthough speculative works using mathematical models studied dormant properties of \u003cem\u003eB. burgdorferi\u003c\/em\u003e in vitro and in vivo, only migratory birds have been reported as able to carry \u003cem\u003eB. burgdorferi\u003c\/em\u003e at a latent stage for several months. Moreover, immunosuppression has not been described as favoring the reactivation of \u003cem\u003eB. burgdorferi\u003c\/em\u003e. It has also not been described as influencing the acute phase of the infection.\u003c\/p\u003e\n\n\u003cp\u003eThis was anecdotally described for \u003cem\u003eB. miyamotoi\u003c\/em\u003e reactivation in a patient presenting with follicular lymphoma treated with chemotherapy. Finally, evidence for latent Lyme disease reactivation in immunocompromised patients is scarce.\u003c\/p\u003e\n\n\u003ch2 id=\"tuberculosis\"\u003eLatent Tuberculosis\u003c\/h2\u003e\n\n\u003cp\u003e\u003cem\u003eM. tuberculosis\u003c\/em\u003e is a global health challenge, with 10.4 million new cases diagnosed in 2016 and 1.3 million deaths. It has been estimated that one third of the global population carries latent \u003cem\u003eM. tuberculosis\u003c\/em\u003e infection. This represents an enormous reservoir of potential tuberculosis cases. Initial infection usually occurs during childhood.\u003c\/p\u003e\n\n\u003cp\u003eThe infection is almost kept under control by the immune system and leads to disease in only 10% of cases. Hundreds of millions of tuberculosis reactivation cases are expected in future decades, representing a public health challenge.\u003c\/p\u003e\n\n\u003cp\u003eThe term \"latent tuberculosis\" was coined by Clemens von Pirquet (the inventor of the tuberculin skin test, or TST) in 1907. He described children with a positive TST presenting without any clinical symptoms. The current definition of latent tuberculosis combines a positive TST or positive interferon gamma release assay without clinical nor active radiological signs of the disease.\u003c\/p\u003e\n\n\u003cp\u003ePatients presenting with latent tuberculosis cannot transmit the disease but are subject to reactivation. The estimated lifetime risk of reactivation in developed countries is 2 to 23%.\u003c\/p\u003e\n\n\u003cp\u003eReactivation of \u003cem\u003eM. tuberculosis\u003c\/em\u003e is triggered when the host's immune response is weakened or suppressed. Patients with high risk of reactivation have HIV co-infection, lymphoma, leukemia, neck cancer, or underwent transplantation or chemotherapy, or received TNF-alpha inhibitor treatment. Patients with a moderate risk of reactivation are patients with diabetes mellitus and patients treated with systemic glucocorticoids.\u003c\/p\u003e\n\n\u003cp\u003eNon-replicating \u003cem\u003eM. tuberculosis\u003c\/em\u003e mycobacteria were observed within adipocytes (fat cells). In that location, they exhibited increased resistance to isoniazid and a diminished resistance to pyrazinamide. This result is consistent with the hydrophilic property of isoniazid. Furthermore, Ayyappan et al. showed that in experimentally infected rabbits, \u003cem\u003eM. tuberculosis\u003c\/em\u003e modulated the adipocyte signalling differently according to the latent or active infections.\u003c\/p\u003e\n\n\u003cp\u003eNonetheless, animal models tried to reproduce latent \u003cem\u003eM. tuberculosis\u003c\/em\u003e infection. However, none was truly contributory and representative, as \"latency\" was drug-induced.\u003c\/p\u003e\n\n\u003ch2 id=\"rickettsiosis\"\u003eRickettsiosis and the Brill-Zinsser Disease\u003c\/h2\u003e\n\n\u003cp\u003e\u003cem\u003eRickettsia prowazekii\u003c\/em\u003e is responsible for epidemic typhus and is transmitted by body lice. It has deeply marked the history of medicine, war, famine, and migration. In addition to its typical presentation including abrupt fever, rashes, and headaches, recurrent presentations of epidemic typhus have been reported, such as Brill-Zinsser disease.\u003c\/p\u003e\n\n\u003cp\u003eFirst described in 1934, Brill-Zinsser disease is unrelated to louse infestation. The article text provided for this review ends at this point in the discussion of Brill-Zinsser disease.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe central finding of this review is that post-bacterial infection chronic fatigue syndrome is not a latent infection. The subjective symptoms described in post-infectious chronic fatigue syndromes remain misunderstood. There is no evidence suggesting that such symptoms could be related to dormant bacterial infection or to carriage of viable bacteria.\u003c\/p\u003e\n\n\u003cp\u003ePsychological trauma may be part of these subjective symptoms. Post-infectious chronic fatigue syndrome could nonetheless be due to unknown microorganisms.\u003c\/p\u003e\n\n\u003cp\u003eThis distinction matters greatly for patients. When doctors and patients confuse latent infection with post-infectious fatigue syndrome, serious consequences can follow. The review describes a fatal case where a young man was diagnosed with post-Q fever fatigue syndrome but actually had disseminated \u003cem\u003eC. burnetii\u003c\/em\u003e infection. Two other patients were misdiagnosed with chronic fatigue syndrome instead of persistent \u003cem\u003eC. burnetii\u003c\/em\u003e endocarditis, and one of those cases was fatal.\u003c\/p\u003e\n\n\u003cp\u003eAt the same time, the review makes clear that antibiotic treatment is not required for latent infections. The two exceptions are latent syphilis and latent tuberculosis infection. In these two cases, treatment prevents progression to the secondary or tertiary stage of the disease after the primary infection.\u003c\/p\u003e\n\n\u003cp\u003eThe review also explains why finding bacterial DNA in a patient's blood does not prove that live bacteria are present. Studies in Q fever, Lyme disease, and brucellosis all found bacterial DNA after antibiotic treatment. However, DNA detection does not indicate bacterial viability. Some patients with positive DNA tests had no symptoms at all.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of This Review\u003c\/h2\u003e\n\n\u003cp\u003eThis article is a literature review, not a new clinical trial. The authors synthesized existing scientific data rather than generating new experimental results.\u003c\/p\u003e\n\n\u003cp\u003eThe authors note that the persistence of bacterial DNA copies in blood samples remains poorly understood across all the bacteria studied. Researchers do not know whether these DNA sequences are associated with subjective symptoms and the expression of viable dormant bacteria.\u003c\/p\u003e\n\n\u003cp\u003eFor PTLDS specifically, the lack of studies in humans does not allow scientific support for the responsibility of quiescent \u003cem\u003eB. burgdorferi\u003c\/em\u003e or dormant bacteria. Most persistent-niche research has been conducted in animal models such as mice, dogs, and macaques, not in people.\u003c\/p\u003e\n\n\u003cp\u003eAnimal models of latent tuberculosis were also limited. None was truly contributory and representative, because \"latency\" in those models was drug-induced rather than occurring naturally.\u003c\/p\u003e\n\n\u003cp\u003ePredictors of QFS are contradictory, and it remains unknown whether QFS is a direct consequence of non-viable or viable bacteria, or whether its origin is psychological.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations\u003c\/h2\u003e\n\n\u003cp\u003eBased on this review, the following points are important for patients and their doctors:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003eAntibiotic treatment is not required for latent infections in general. The two exceptions are latent syphilis and latent tuberculosis infection, where treatment prevents progression to later, serious stages of disease.\u003c\/li\u003e\n  \u003cli\u003eFinding bacterial DNA in the blood does not prove that live bacteria are present. DNA can persist after successful antibiotic treatment.\u003c\/li\u003e\n  \u003cli\u003eDoctors should carefully rule out other physical and psychiatric causes before diagnosing post-infectious chronic fatigue syndrome.\u003c\/li\u003e\n  \u003cli\u003eDoctors should be alert to the possibility of persistent, active infection (such as \u003cem\u003eC. burnetii\u003c\/em\u003e endocarditis) masquerading as chronic fatigue syndrome, because misdiagnosis can be fatal.\u003c\/li\u003e\n  \u003cli\u003ePsychological trauma may be part of the subjective symptoms of post-infectious chronic fatigue syndrome, and this possibility deserves attention.\u003c\/li\u003e\n  \u003cli\u003ePost-infectious chronic fatigue syndrome could be due to unknown microorganisms, and further research is needed.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eIs chronic fatigue after a bacterial infection caused by a hidden, dormant infection?\u003c\/h3\u003e\n\u003cp\u003eA review of 119 scientific references found no evidence that subjective symptoms such as fatigue, headache, and muscle pain are linked to dormant bacteria or to asymptomatic carriage of live bacteria. The authors conclude that post-bacterial infection chronic fatigue syndrome is not a latent infection, though its cause remains poorly understood.\u003c\/p\u003e\n\u003ch3\u003eDo I need antibiotics for a latent infection?\u003c\/h3\u003e\n\u003cp\u003eThe review states that antibiotic treatment is not required for latent infections in general. There are two exceptions: latent syphilis and latent tuberculosis, where treatment prevents progression to serious later stages of disease. For other latent infections, antibiotics are not indicated based on this review.\u003c\/p\u003e\n\u003ch3\u003eDoes finding bacterial DNA in my blood mean I still have a live infection?\u003c\/h3\u003e\n\u003cp\u003eNo. The review explains that finding bacterial DNA in the blood does not prove that live bacteria are present. Studies in Q fever, Lyme disease, and brucellosis all found bacterial DNA after antibiotic treatment, but DNA detection does not indicate bacterial viability. Some patients with positive DNA tests had no symptoms at all.\u003c\/p\u003e\n\u003ch3\u003eCan chronic fatigue syndrome be mistaken for a persistent infection?\u003c\/h3\u003e\n\u003cp\u003eYes, and the consequences can be serious. The review describes a fatal case where a young man was diagnosed with post-Q fever fatigue syndrome but actually had disseminated C. burnetii infection. Two other patients were misdiagnosed with chronic fatigue syndrome instead of persistent C. burnetii endocarditis, and one of those cases was fatal.\u003c\/p\u003e\n\u003ch3\u003eWhat should doctors rule out before diagnosing post-infectious chronic fatigue syndrome?\u003c\/h3\u003e\n\u003cp\u003eDoctors should carefully rule out other physical and psychiatric causes before diagnosing post-infectious chronic fatigue syndrome. They should also be alert to the possibility of persistent, active infection, such as C. burnetii endocarditis, masquerading as chronic fatigue syndrome, because misdiagnosis can be fatal.\u003c\/p\u003e\n\u003ch3\u003eCould psychological factors play a role in post-infectious chronic fatigue syndrome?\u003c\/h3\u003e\n\u003cp\u003eThe review notes that psychological trauma may be part of the subjective symptoms of post-infectious chronic fatigue syndrome, and this possibility deserves attention. It also states that post-infectious chronic fatigue syndrome could be due to unknown microorganisms, and further research is needed to understand its cause.\u003c\/p\u003e\n\u003ch3\u003eHow common is post-treatment Lyme disease syndrome?\u003c\/h3\u003e\n\u003cp\u003ePost-treatment Lyme disease syndrome is estimated to affect 10 to 20 percent of patients treated with antibiotics effective against Lyme disease. It is characterized by the late onset of musculoskeletal symptoms and antibiotic treatment failures. The review notes that few studies have been conducted to understand the mechanisms involved.\u003c\/p\u003e\n\u003ch3\u003eI was diagnosed with post-infectious chronic fatigue syndrome after Q fever or Lyme disease — when should I seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eSeek a second opinion when fatigue, headache, or muscle pain lasting at least six months after a bacterial infection is labelled post-infectious chronic fatigue syndrome without other physical and psychiatric causes being ruled out first. Persistent active infection such as C. burnetii endocarditis can masquerade as chronic fatigue syndrome, and misdiagnosis has been fatal. A positive bacterial DNA test does not prove live bacteria are present, and antibiotic treatment is not required for latent infections except latent syphilis and latent tuberculosis. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Post-bacterial infection chronic fatigue syndrome is not a latent infection\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Cléa Melenotte, Michel Drancourt, Jean Pierre Gorvel, Jean Louis Mège, Didier Raoult\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e Aix-Marseille University, IRD, MEPHI, IHU Méditerranée Infection, AP–HM, 13385 Marseille cedex 05, France; and Aix-Marseille University, CNRS, Inserm, CIML, 13288 Marseille cedex 09, France\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eJournal:\u003c\/strong\u003e Médecine et maladies infectieuses (Med Mal Infect)\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication details:\u003c\/strong\u003e Received 31 July 2018; accepted 15 January 2019. Published by Elsevier Masson SAS. DOI: https:\/\/doi.org\/10.1016\/j.medmal.2019.01.006\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eArticle type:\u003c\/strong\u003e Review article\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eNote:\u003c\/strong\u003e This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare professional.\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807298437276,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-is-chronic-fatigue-after-a-bacterial-infection-caused-by-a-hidden-infection-hero.png?v=1792041713","url":"https:\/\/diagnosticdetectives.com\/sv\/products\/is-chronic-fatigue-after-a-bacterial-infection-caused-by-a-hidden-infection","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}