Chronic pain and infection: mechanisms, causes, conditions, treatments, and controversies

Acute pain

Infection can cause pain via numerous mechanisms. Acutely, pain is a core symptom of infection, and could result directly from somatic (eg, septic arthritis) or visceral (eg, appendicitis) tissue invasion, or nerve injury (eg, acute herpes zoster neuritis) and the accompanying inflammatory process.

Chronic pain

Molecular mimicry and other immune mechanisms

Figure 1 shows the various mechanisms by which chronic pain can occur after infection. Inflammation after infection might cause an abnormal immune response that triggers acute and chronic neuropathic, nociceptive, or nociplastic pain. In Guillain-Barré syndrome, immunoglobulin G induced, painful peripheral neuropathy affects between 55% and 89% of individuals, with two thirds of patients experiencing a viral (eg, Epstein-Barr virus, Zika virus) or bacterial (eg, Campylobacter jejuni) infection within the preceding six weeks.10–12 The precise mechanisms for axonopathy are unclear, but evidence points to mimicry of axolemmal surface molecules (gangliosides) by microbial antigens (lipopolysaccharides), leading to an antibody mediated attack on the nerve axolemma. Other immune related painful conditions in which molecular mimicry is postulated to have a role include multiple sclerosis, reactive arthritis, inflammatory bowel disease, and Lyme disease. Similarly, infection could trigger autoimmune related pain via epitope spreading and bystander activation. In epitope spreading (also known as antigen spreading), endogenous epitopes develop secondary to the release of self-antigens during inflammation.13 Bystander activation is characterized by autoreactive B and T cells that are activated in an antigen independent manner.14

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Figure 1

Mechanisms of chronic pain after infection

Varicella zoster virus

Varicella zoster virus is responsible for chickenpox and shingles. After a primary infection, it lies dormant in a dorsal root or cranial ganglion and reactivates upon a decline in immunity. Pain can be spontaneous, paroxysmal, or evoked (eg, allodynia), and acute reactivation typically causes nociceptive (vesicular rash) and neuropathic (acute radiculitis) pain.

Postherpetic neuralgia is the most common and one of the most serious complications of acute infection with varicella zoster virus, and is defined as pain persisting more than 90 days after the onset or healing of the vesicular rash.37 Mechanisms include nerve root inflammation and ectopic discharges, peripheral sensitization, and central sensitization (eg, loss of inhibitory neurons, glial cell activation), deafferentation in the affected dermatome, and central nervous system reorganization (eg, alterations in brain metabolism, decreased grey matter, and sympatho-afferent coupling).38

Postherpetic neuralgia can eventually develop in approximately half of the individuals infected with varicella zoster virus.37 Risk factors include older age, prodromal pain, severe acute pain or rash, marked immunosuppression, and diabetes.37 39 40 Because greater acute pain and rash severity might indicate increased neural damage,40 41 treatment of varicella zoster virus and resultant acute pain could reduce the incidence of postherpetic neuralgia. Strategies have included antiviral treatment, steroids, non-steroidal anti-inflammatory drugs, neuropathic analgesics, local anesthetics, epidural steroids, and neuromodulation.42–46 However, these treatments have yielded mixed results for the prevention and treatment of postherpetic neuralgia. Vaccination is the most effective means of preventing postherpetic neuralgia, reducing risk by up to 67%, and vaccinated patients who do develop the disorder have less severe symptoms.47

Human immunodeficiency virus (HIV)

More than 30 million individuals worldwide are infected with HIV type 1 (HIV-1) or 2 (HIV-2),48 although this number is likely an underestimate because of poor access to healthcare among populations at risk.49 50 Six strains of HIV-1 account for the vast majority of infections globally.51 HIV-2 is characterized by lower transmissibility and is uncommon outside West Africa.51 52

With the development of antiretroviral treatments, the prognosis of HIV infection has markedly improved and many patients have a near-normal lifespan. However, antiretroviral drugs rarely eliminate the virus entirely. As a consequence of chronic infection, more than 50% of individuals with HIV develop chronic non-cancer associated pain.53 54 Painful peripheral neuropathy is one of the most common symptoms, with the most form having a characteristic stocking-and-glove distribution.53 55 HIV can directly cause neural damage via certain components of its viral envelope, such as glycoprotein 120, that induce axonal degeneration, inflammatory cytokine release, and increased oxidative stress.56 57 Earlier generations of antiretroviral drug treatments were associated with distal polyneuropathies,53 possibly through the upregulation of inflammatory cytokines, microglial activation, and direct neuroinflammation.58 59 Cohort studies performed before the advent of highly active antiretroviral treatments found an increased incidence and severity of polyneuropathy in individuals who are immunosuppressed and with higher viral loads, with some evidence that effective treatment might be associated with improvement in pain and other neurological symptoms.60 61

HIV infection is also associated with a greater risk of concomitant nociceptive or nociplastic pain. Patients with HIV commonly report abdominal pain, chest pain, musculoskeletal pain, and headaches,53 55 and are at higher risk of developing fibromyalgia.55 How HIV directly leads to these symptoms is unclear, but mechanisms similar to the development of neuropathic pain, including central and peripheral sensitization and psychosocial factors (eg, social isolation or stigma), are likely to be involved.55

Herpes simplex virus

The vast majority of people worldwide are infected with either herpes simplex virus type 1 (HSV-1) or 2 (HSV-2).62 Infection occurs through contact with mucosal surfaces or abraded skin. Although acute symptoms might occur,63 most individuals are asymptomatic.62 HSV-1 and HSV-2 enter sensory ganglia and establish lifelong latency.62 64 Cycles of dormancy and reactivation can occur, most commonly at mucocutaneous sites63 64 (eg, vesicular lesions at the vermilion border of the mouth, herpetic whitlow in medical and dental professionals’ fingers), often with prodromal burning, itching, or pain.63

Highly morbid painful neurological manifestations can occur. HSV-1 is associated with encephalitis63 65 and herpes keratitis, which presents with ocular pain and is one of the leading causes of infectious blindness in the world.66 Owing to its ability to establish latency in the cranial ganglia, HSV-1 might also lead to Bell’s palsy, which is sometimes characterized by pain.65 HSV-2 is associated with meningitis, ascending thoracic or lumbosacral myelitis, and lumbosacral radiculitis, and might have a synergistic relation in causing these symptoms in patients with HIV.65 HSV-1 and HSV-2 might also cause central spontaneous pain via glial activation, although the incidence and mechanism(s) are unclear.64 Antiviral drug treatments could reduce the severity and duration of symptoms, but do not eradicate the virus.

Hepatitis C virus

Hepatitis C virus is a member of the Flaviviridae family with up to 190 million individuals worldwide infected.67 68 The virus replicates up to 10 trillion copies per day without a proofreading mechanism, leading to numerous genetic variants that prevent the host’s immune system from eradicating it.67 Hepatitis C virus has the distinction of being the hepatitis virus with the most known extrahepatic manifestations,69 including arthralgia, lymphoma, type diabetes, and chronic kidney disease. Most of these conditions are independently associated with chronic pain.

The virus is also the leading cause of mixed cryoglobulinemic vasculitis, which can lead to a distal sensory or sensorimotor peripheral neuropathy that presents with painful paresthesias.69 70 Peripheral neuropathy can occur independently of cryoglobulinemia and might be more strongly associated with older age and the duration of infection with hepatitis C virus.68 71 Evidence also suggests that the virus can elevate levels of inflammatory cytokines such as interleukin 6, contributing to hyperesthesia and possibly centrally mediated pain.72

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Covid-19 is associated with acute pain in 20% to >60% of patients admitted to hospital, with the most common complaints being myalgia or arthralgia, headache, and sore throat (>25%); followed by chest pain, spinal pain, abdominal pain, and non-headache neurological symptoms.73–75 These symptoms can result from a combination of factors, including a hypervigilant immune response, fever, deconditioning, and direct viral invasion (arthralgia, myositis, myocarditis or chest pain).75 76 Although SARS-CoV-2 is not primarily neurotropic, the virus binds to angiotensin converting enzyme 2 receptors in the central and peripheral nervous system, and has been linked to myelitis, Guillain-Barré syndrome, and peripheral neuropathy.75 77 As with other viral mediated illness, neuropathic pain can be triggered by immune mechanisms, antiviral treatment, or direct viral invasion, and carries a higher incidence in those individuals with pre-existing risk factors (eg, diabetes).78 About 5-15% of patients admitted to hospital with covid-19 will present with abdominal pain, which might be secondary to viral binding to angiotensin converting enzyme 2 receptors in the gastrointestinal tract, lymphadenopathy, referred pain from the lungs, or visceral distension.75

In one observational study, the presence of acute pain was paradoxically found to mitigate against death and intensive care, which was attributed to the activation of neurotransmitters involved in pain modulation and distraction.74 In another case-control study, patients who experienced myalgia during acute covid-19 had a greater likelihood of having musculoskeletal pain seven months after covid-19 infection that those who did not have myalgia (odds ratio 1.41, 95% confidence interval 1.04 to 1.90).79 Several studies have found chest pain, headache, myalgias, and arthralgias to be present in over 20% of surviving patients with covid-19, 60 days after infection, with neuropathy, spinal pain, and abdominal pain reported less frequently.80 Since patients in these studies did not have measurable viral loads, the cause of these symptoms is likely immunological or a psychological triggering event.5

Borrelia burgdorferi (Lyme disease)

Lyme disease results from infection with several Borrelia species including burgdorferi, afzelii, and garinii. Pain can appear immediately after infection (stage 1 includes, for example, localized pain and constitutional symptoms), days to weeks after infection (stage 2 includes, for example, severe headache, myalgias and arthralgias), and during a controversial stage 3, which can range from months to years after infection and has been postulated to be secondary to central sensitization.81 82

About 10-20% of patients with infection develop post-treatment Lyme disease syndrome, which entails unequivocal evidence of infection and appropriate treatment. However, in one analysis of seven observational and retrospective studies including 1902 patients in endemic areas, 50-88% of enrolled patients had no evidence of Borrelia infection.83 The cause is most likely autoimmune, with high antibodies to Borrelia burgdorferi found in some patients with reactive arthritis.83 84 Diffuse pain is a hallmark, with over 75% of individuals reporting headache, arthralgias, myalgias, neuropathic pain, and widespread pain most consistent with nociplastic pain. Similar to other nociplastic conditions, sensory hyperarousal, cognitive deficits, fatigue, and sleep dysfunction also affect most individuals with post-treatment Lyme disease syndrome.85 Although antibiotics are frequently prescribed and have been found in some studies to provide subjective benefit,85 86 the Centres for Disease Control and Prevention recommends against their routine use based on high quality trials.87

Mycobacterium leprae (leprosy)

Leprosy, also known as Hansen’s disease, causes 250 000 infections worldwide annually, with Brazil, India, and Indonesia accounting for 80% of cases.88 The bacterium responsible for leprosy, Mycobacterium leprae, is morphologically indistinguishable from Mycobacterium tuberculosis. In 1982, the World Health Organization developed a simple classification system, which categorizes patients as having paucibacillary (<5 lesions) or multibacillary (>6) leprosy, reflecting the tissue burden of the infection.89

Although sensory loss, visual impairment and disfigurement are more notorious, neuropathic pain is present in about 35% (range 11-66%) of patients. with leprosy90–92 The bacterium can enter the nervous system via endothelial cells or transmigration of infected monocytes, showing an affinity for Schwann cells. The type of neuropathic pain varies based on disease burden, with the ulnar and peroneal nerves commonly affected in paucibacillary leprosy, while advanced stages frequently result in a diffuse symmetrical polyneuropathy that often includes the facial and trigeminal nerves.92 In addition to neuropathic pain, patients with leprosy also experience nociceptive pain from tissue invasion (eg, skin, nose, testicles) and disfigurement, with lifetime prevalence rates ranging from 15 to >40%.93–95 Patients with leprosy also have disproportionate psychological distress including ostracization and stigmatization, which can exacerbate pain. Although corticosteroids are often used to treat acute neuritis from leprosy, a systematic review found no evidence for long term superiority over placebo for nerve function.93 96 Because most neuropathology in leprosy is immunological, nerve injury and neuropathic pain can occur before, during, or after antibiotic treatment.97

Group A streptococcus

In acute rheumatic fever, oropharyngeal group A streptococcus infection triggers an autoimmune response resulting in inflammation and organ damage.98 Most patients who develop rheumatic fever are aged between 5 and 15 years, with Streptococcus pyogenes being the most implicated bacterial strain. In one large database study of 1470 children, 50% of rheumatic fever hospital admissions presented with primary arthritis without carditis, 26% presented with arthritis and carditis, 24% presented with chorea, and 6.5% showed both chorea and carditis.99 Recurrences are common in rheumatic fever, especially in younger individuals. Considered by many to be a prototypical autoimmune condition, rheumatic fever can manifest as a prolonged pain syndrome that includes reactive polyarthritis, skin involvement, carditis, vasculitis, and chorea, which might result in associated neurologic symptoms including pain.98 100 About 5% of patients with untreated, group A streptococcus pharyngitis develop rheumatic fever, with early antibiotic treatment reducing the risk substantially. Prophylactic antibiotics are recommended to prevent recurrences.101

Treponema pallidum

Treponema pallidum is a spiral-shaped bacterium belonging to the phylum Spirochaetes, with subspecies that each cause a distinct disease (T pallidum subspecies endemicum, T carateum, and T pallidum subspecies pertenue cause bejel, pinta, and yaws, respectively).102 103 These subspecies are serologically and morphologically indistinguishable,103 104 spread by direct contact through dermal microabrasions or mucosal membranes, and form painful mucocutaneous ulcers. However, T pallidum subspecies pallidum, the causative agent of syphilis, is unique in being transmissible via blood and is most commonly spread through sexual contact.

Humans are the only known natural host of T pallidum subspecies pallidum.102 With the introduction of penicillin, the incidence of syphilis declined considerably in the mid-20th century.105 However, cases have steadily increased over the past 20 years in association with unsafe sexual practices (eg, unprotected sexual contact, promiscuity), with WHO estimating 12 million new cases annually across the globe.102

On infection, systemic dissemination occurs within hours, and a painless chancre—the characteristic sign of primary syphilis—appears within three weeks.102 Within three months, secondary syphilis occurs, which is characterized by a disseminated maculopapular rash and protean findings105 that can be associated with pain and discomfort, including lymphadenopathy, mucosal lesions, gastritis,106 hepatitis,107 glomerulonephritis,108 and pulmonary abscesses.109 After a latent period that is usually less than a year, tertiary syphilis begins. Neurologic manifestations are most common (eg, paresthesias, paresis, and ataxia from tabes dorsalis,102 vision loss,110 and cognitive impairments105), followed by cardiovascular complications (eg, aortic aneurysm and myocarditis) and granulomatous nodules known as gummas.102 105 Regardless of the stage of infection, penicillin is the treatment of choice,105 although even with bacterial eradication, pain could persist when organ damage is severe.

Discogenic spine pain

Studies have shown that over 40% of herniated discs might be infected with bacteria, with the most common organism being the anaerobic bacterium Cutibacterium acnes.142 In one meta-analysis by Ganko et al of nine studies with various methodologies (one included cervical discs), seven studies included patients with radiculopathy or herniated disc and two included patients with disc degeneration. The researchers found a higher infection rate in degenerated discs than in non-degenerated discs (37.4% v 5.9%; odds ratio 6.077, 95% confidence interval 1.426 to 25.901).143 However, a large subsequent case-control study (n=812 total samples) that included operated cervical and lumbar discs found no difference in infection rates between symptomatic and control discs.144 A 2018 prospective study found a 32.5% infection rate in 80 patients who underwent single level discectomy for sciatica, with a positive association between infection and endplate signal changes, but not for the degree of disc degeneration.145 In another prospective study of 32 patients who underwent cervical discectomy and fusion, positive cultures were found in 25% of patients and 13.6% of discs, which was higher than the positive rate in controlled muscle biopsies (12.5%).146 In this sample, coagulase-negative Staphylococcus was the most common microbe.

Studies have sought to evaluate the efficacy of antibiotic treatment for discogenic pain. In a review by Gilligan et al, two of four observational studies and two of three randomized controlled trials (n=413) reported benefit.142 In the randomized trials, the two positive studies treated patients with Modic type 1 endplate changes for 100 days with amoxicillin-clavulanic acid and reported benefit at one year or end of treatment,147 148 while the negative study treated patients with Modic type 1 and type 2 changes with only amoxicillin for 3 months and reported no meaningful benefit at one year.149 Collectively, these results suggest that a small percentage of patients with infection-associated disc pathology might benefit from antibiotic treatment, but the heterogeneity of spine pain and lack of antibiotic penetrance could hinder results.

Inflammatory bowel disease

Inflammatory bowel disease includes Crohn’s disease, which can affect any part of the gastrointestinal tract, and ulcerative colitis, which is limited to the colon. Evidence suggests that a subset of patients with inflammatory bowel disease develops symptoms secondary to an autoimmune response that targets natural gut microbiota or fails to control invasive commensal or pathogenic organisms.150 151 In a computational analysis of a dataset from people with inflammatory bowel disease, Hassouneh et al found 34 bacterial species with concentrations at least twofold higher than that of control samples, and eight species that were less than half as abundant.152 That many of these bacteria are implicated in immune modulation and inflammation suggests the relation between microbes and immune system impairment might be bidirectional.

Numerous studies have established higher prevalence rates of organisms (such as Mycobacterium avium subspecies paratuberculosis, adherent invasive E coli, Campylobacter species, Clostridium difficile, and cytomegalovirus) in patients with inflammatory bowel disease than in control patients, with minimal differences in disease stage or type of inflammatory bowel disease. Other research, including a meta-analysis examining 58 studies with various designs, found a protective effect for Helicobacter pylori.153 One mechanism by which microbes can cause inflammatory bowel disease is via dysregulation of pattern recognition receptors, which include toll-like receptors and C type lectin receptors.154

The clinical pain presentation of inflammatory bowel disease varies according to phenotype. Abdominal pain, typically described as crampy and colicky, affects about 60% of patients, and is more common in Crohn’s disease. Crohn’s disease affects the entire gastrointestinal tract, so painful oral ulcers can occur, with a prevalence of around 30%.155 Tenesmus might occur in both Crohn’s disease and ulcerative colitis but is more common in the ulcerative colitis. Rheumatological manifestations affect up to 30% of patients with inflammatory bowel disease and are more common in Crohn’s disease, with one meta-analysis of 71 observational studies finding an average prevalence of 13% for peripheral arthritis, 10% for sacroiliitis, 3% for ankylosing spondylitis, and lower rates for enthesitis and dactylitis.156 Other painful manifestations might include cholangitis and hepatitis, ocular involvement, carditis, and dermatological involvement, in which the cumulative prevalence is up to 30%.157

The treatment of pain in inflammatory bowel disease depends on presentation. Antidepressants and opioids should be considered for flares of visceral pain, although chronic opioid use could paradoxically worsen abdominal pain. Given the high co-prevalence rates of depression, anxiety, and other psychiatric illnesses, psychotherapy can be considered.158 Systematic reviews have found evidence for antibiotics in both Crohn’s disease and ulcerative colitis, but paradoxically, the use of antibiotics in childhood could increase the risk for future inflammatory bowel disease.159 160 Immunomodulatory drugs such as azathioprine, methotrexate, and tumor necrosis factor alpha inhibitors have shown effectiveness.161

Myalgic encephalomyelitis or chronic fatigue syndrome

Myalgic encephalitis or chronic fatigue syndrome is a poorly understood clinical condition characterized by post-exertional malaise lasting at least six months, associated with variable symptoms of neurological, immune, endocrine, or autonomic dysfunction.20 162 163 The diagnosis is controversial, with no universally accepted diagnostic criteria.164 The term "chronic fatigue syndrome" was originally proposed as an alternative to "chronic Epstein-Barr syndrome" to describe the symptom complex of chronic fatigue presenting with other (often painful) symptoms, including sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias.165 Myalgic encephalomyelitis refers to a specific neuro-immunological condition, and has been suggested to be clinically distinct from chronic fatigue syndrome,166 but most practitioners use the two terms synonymously or in combination.163 Although painful symptoms were prominent in earlier case definitions of chronic fatigue syndrome,165 167 more recent clinical diagnostic criteria have de-emphasized pain, which is not required for diagnosis.20 168 Nevertheless, pain remains a common symptom in patients with myalgic encephalitis or chronic fatigue syndrome, and many nociplastic pain conditions (eg, fibromyalgia, temporomandibular disorder, irritable bowel syndrome, migraine) are comorbidities.162

No single cause has been identified for myalgic encephalitis or chronic fatigue syndrome, but immunological, psychological, neurobiological, neuroendocrine, genetic or epigenetic, circulatory, and infectious cause are the most commonly proposed categories, with viral infections implicated in up to 50% of cases in some studies.17 169 170 In some instances, categories can overlap, for example, infectious diseases leading to autoimmune mechanisms. Myalgic encephalitis or chronic fatigue syndrome often presents sporadically, but outbreaks do occur, often in association with viral-like illnesses, suggesting infection as a possible trigger.17 Various epidemiological studies have associated the disorder with Epstein-Barr virus, cytomegalovirus, human herpes viruses 6 or 8, parvovirus B19, enteroviruses, lentivirus, and bacteria such as mycoplasma, Borrelia species, and Coxiella burnetii.17 Covid-19 infection has been associated with the development of prolonged symptoms similar to those found in myalgic encephalitis or chronic fatigue syndrome.171

Infection can trigger an autoreactive process in susceptible individuals, leading to autoimmune responses against energy metabolic processes in the brain and muscle.170 Cytokine signatures have also been causally linked to illness severity of myalgic encephalitis or chronic fatigue syndrome,172 and infection both inside and outside the brain could cause increased production of proinflammatory cytokines, leading to immune mediated dysfunction of the nervous system and energy metabolism.173 Given these proposed relations, use of antiviral and immunomodulatory drugs has been suggested to treat the disorder, but such use is off-label.174 Antiviral drugs such as acyclovir, valacyclovir, and rintatolimod appear to have limited efficacy in treating myalgic encephalitis or chronic fatigue syndrome and can be considered in patients who are seropositive for specific viruses, but evidence is limited by flawed study design and conflicting results.175 Immunomodulatory drugs including corticosteroids, cyclophosphamide, and rituximab have failed to show broad benefit in patients with myalgic encephalitis or chronic fatigue syndrome.175 176 These studies highlight the heterogeneous nature of the disorder and emphasize the importance of developing multimodal, precision medicine approaches to treatment.175 176