Pleurodynia (formerly called Bornholm disease) is a form of viral myalgia defined by the sudden occurrence of lancinating chest pain or abdominal pain, commonly associated with fever, malaise, and headaches. It is usually an uncommon complication of coxsackievirus B infection; however, cases of pleurodynia secondary to other enteroviruses have been reported (eg, enteric cytopathogenic human orphan [ECHO] virus). Coxsackievirus B is an RNA Enterovirus, which usually causes an asymptomatic or brief upper respiratory tract or gastroenteric infection. In rare cases, other severe sequelae of coxsackievirus B infection develop, including meningitis and carditis.[1]
Diagnosis of pleurodynia is made on clinical grounds. Negative serology does not rule out the disease. No specific treatment exists. The pain typically lasts 1 to 4 days, although pain lasting as long as 45 days has been described.[2] Management is supportive and includes nonsteroidal anti-inflammatory drugs (NSAIDs) for pain and pleurisy (if present) or peripheral nerve block (eg, intercostal nerve) with 1% lidocaine (Xylocaine) infusion.
Also see the article Coxsackieviruses.
For patient education resources, see the Lungs Center and Coxsackievirus Infection.
The striated muscle is the actual anatomic structure targeted by the coxsackievirus B and is responsible for the attacks of severe chest pain. Therefore, the term pleurodynia may be a misnomer because only some patients with the condition actually develop pleuritis (ie, inflammation of the pleural surface). In patients with pleurodynia, the striated intercostal muscles necrose, which explains the frequent elevations in serum creatine kinase levels. Some of the more chronic sequelae, such as myocarditis, dermato-polymyositis, chronic fatigue syndrome, and possibly, juvenile-onset diabetes type I, are believed to be immune mediated.
The virus has an incubation time of 1 week in the gastrointestinal tract and then, through hematogenous dissemination, involves the target organs, most commonly the skeletal muscles but also the central nervous system (CNS) (ie, meningitis, encephalitis) and myocardium (ie, carditis with or without associated pericarditis). Coxsackievirus B can be recovered in the stool or pharynx for up to 2 weeks after the resolution of the symptoms.
The classic etiologic agent for pleurodynia is coxsackievirus B, serotypes B1, B2, B3, B4, and B5,[3] which are small, nonenveloped RNA viruses, in which an icosahedral capsid encloses the single-stranded RNA genome. Other nonpolio enteroviruses, including echoviruses type 6 and 19, coxsackievirus A, and human parechovirus type 3 (HPeV3),[4] are also reported to cause syndromes very similar to that of coxsackievirus B infection, including pleurodynia.
A rare case of echovirus 1-caused pleurodynia was reported in a 31 year old woman in the Netherlands who fell is a few days after returning from a 1 month backpacking trip to Thailand, Indonesia and Malaysia. The cause was determined by stool culture and confirmed by polymerase chain reaction (PCR) and direct genotyping.[5]
Humans are the only known reservoir of the enteroviruses; transmission occurs via the fecal-oral route. The incubation time is usually 2-5 days. Potential risk factors for the transmission of the enteroviruses are poor sanitation and overcrowding. Intrafamilial spread is common.
Coxsackievirus B was present in 24% of the 18,000 enteroviruses isolated and reported in the United States from 1970-1979.[6] The estimated number of nonpolio enteroviral symptomatic infections is 5-10 million per year. In regions of temperate climate, the infection is seasonal, with about 90% of infections occurring in the summer and early fall, and sometimes infections occur in epidemics.
Antibodies to coxsackievirus B serotypes are present in 75% of the population in developed countries. In the tropical and subtropical climate areas, the prevalence of the enteroviral infections is year-round.
Males are more commonly affected than females.
The incidence of coxsackievirus B infection in neonates is 1 in 2000 live births. Coxsackievirus B infection occurs most commonly in children younger than 15 years; half of these patients are younger than 5 years, and 30% are younger than 1 year. The disease is rare in patients older than 60 years. However, pleurodynia most commonly affects adults infected with the virus, with fewer than 10% of cases occurring in patients younger than 20 years. Of 372 prospectively studied children aged 4-18 years with nonpolio enteroviral infections, only 3% developed pleurodynia.[7] In contrast, 30 of 78 mostly adult patients with coxsackievirus B-associated cardiac disease had pleurodynia.[8] Therefore, the location of pain is believed to be predominantly abdominal in children and thoracic in adults.
The prognosis for pleurodynia is good, with complete recovery in most cases. The return to normal health may be gradual after a period of weakness and fatigue. No deaths are reported as a direct result of pleurodynia. The severity of the coxsackievirus B infection is highest in infants and children. In infants who develop coxsackievirus B infection, 10% die, usually within the first 4 weeks of life most commonly from cardiac involvement. Fulminant hepatic failure, sepsis syndrome, and severe CNS involvement with seizures and apnea are also potential complications in this age group.[9]
Direct complications of pleurodynia are rare. Splinting from pain may result in atelectasis and shortness of breath.
A postviral syndrome, also called fatigue-dysphoria syndrome, is described in children who were seropositive for coxsackievirus B and who complained of fatigue, weakness, sore throats, and dysphoria. This syndrome may also complicate the patient's recovery.
In rare cases, coxsackievirus B infection may be complicated by carditis,[10] aseptic meningitis, constrictive pericarditis, orchitis, myalgic encephalomyelitis, severe neonatal encephalitis with seizures,[11] hemorrhagic conjunctivitis, hepatitis, pancreatitis, and juvenile-onset diabetes mellitus.
Dilated cardiomyopathy is a complication of viral myocarditis. It may be acute or related to severe muscle necrosis, or it may occur several years later, possibly due to chronic inflammation and fibrosis as a result of an immune-mediated process.[10]
Pleurodynia should be considered in all cases of acute and subacute chest pain that present in the ER or in internal medicine, cardiology, or cardiothoracic surgery outpatient clinics. The onset of chest pain is acute. During attacks, the pain is severe, intense, and excruciating, lasting seconds to a minute. Pain is paroxysmal, occurring in attacks separated by minutes to hours. Severe attacks can result in difficulty breathing. The thoracic pain is usually over the lower ribs and is unilateral, but it can also occur over the front, back, or substernal area. Between attacks, patients usually have a constant, dull, pleuritic chest pain. A very important quality of the pain is its direct relationship to sneezing, coughing, laughing and deep breathing, which can cause the patient to look tachypneic and even diaphoretic.[12] The pain typically lasts 1 to 4 days, although pain lasting as long as 45 days has been reported.[2]
Patients can present with a wide range of signs and symptoms including the following[12] :
While the diagnosis of pleurodynia is made on clinical grounds, several laboratory studies are useful. Negative serology does not exclude the disease. Virus isolation from stool, pleural fluid or the pharynx is most specific, but not sensitive, test and can render a positive result for up to 2 weeks after resolution of symptoms. Coxsackie virus B1-B6 is the most common isolated variant.[12] Necrosis of the striated intercostal muscles is visible. in histologic studies. Rarely, adjacent pleural inflammation results in a small exudative pleural effusion.
Coxsackie B virus infection can be diagnosed by isolation of the virus in cell culture, detection of virus RNA via polymerase chain reaction (PCR) or serologic evaluation of viral antibodies.[14]
Serum creatine kinase is usually elevated because of muscle necrosis. The white cell count ranges from mild leukopenia to mild leukocytosis. Although seldom performed for the diagnosis of pleurodynia per se, tissue diagnosis can be made by direct detection of the viral antigen or by isolation of RNA virus-specific sequences. Depending on the clinical presentation and suspicion for serositis caused by systemic lupus erythematosus, an antinuclear antibody test can be performed.
Primary monkey kidney cells or embryonic lung fibroblasts are the standard cells used for isolation and identification of coxsackievirus B. The addition of Buffalo green monkey kidney cells may increase the sensitivity of this method. Viral growth occurs in 1-4 days, causing a cytopathic effect on the host cells, resulting in rounded, refractile cells that eventually lyse. The cultures may be performed from various clinical specimens, dictated by the presence of clinical symptoms.
Throat viral cultures are more sensitive than urine viral cultures and confirm 33% of the enteroviral infections studied. Throat culture findings were positive for coxsackievirus B in 45% of the patients presenting with pleurodynia. Blood cultures are useful in children younger than 3 months. Stool cultures have a higher yield than rectal swabs. Having multiple culture specimens may also increase the yield of virus recovery in culture.
A positive enteroviral culture result must be interpreted in light of the clinical context and the history of polio immunization. After vaccination with the live attenuated oral polio vaccine, viral culture results from both throat and stool specimens may remain positive for enteroviruses for several months. Similarly, patients with asymptomatic infections may shed the virus for months after they acquire the infection.
Cerebrospinal fluid (CSF) viral cultures have limited clinical utility in the management of enteroviral meningitis due to poor sensitivity (65-75%), high cost, and long turnaround time.
Using specific antibodies, these tests are used to further confirm and delineate the type of enterovirus isolated from cell culture.
Molecular methods may soon replace viral culture and neutralization assays used to isolate and type enteroviruses. Viral culture and neutralization assays are reliable but time-consuming and costly methods.
Reverse transcriptase PCR (RT-PCR) is now an established technique for the detection of viral nucleic acids, especially from specimens with a low viral load that may be associated with false-negative cell culture results.[15] In the CSF, RT-PCR has better sensitivity than viral culture. In children, RT-PCR for throat specimens was also more sensitive than viral culture. Another advantage is the rapid turnaround time, which has resulted to improved health care costs, especially in the management of enteroviral meningitis.[16, 17]
Commercial diagnostic RT-PCR kits are available for the identification of coxsackievirus B RNA. One disadvantage of RT-PCR is that the virus serotype cannot be identified. Additional restriction fragment length polymorphism (RFLP) assays may provide a simple strategy to identify the virus subtype.[18]
Reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay is a rapid, in vitro technique based on viral RNA amplification, targeting highly conserved regions in 5’ URT gene. In one study of 150 CSF and stool samples, the results were compared with those from RT-PCR. RT-LAMP assay showed high sensitivity and specificity in isolating and typing coxsackieviruses.[19]
Specific antibodies against enteroviral groups and serotypes are commercially available, but their application has thus far been limited to fluorescent staining and detection of viral antigens in cell cultures, rather than clinical specimens.
Enzyme-linked immunosorbent assay (ELISA) is more sensitive than the neutralization test and can be used as a screening tool, followed by the neutralization test for confirmation. ELISA using an enteroviruses group–specific monoclonal antibody may detect early immunoglobulin M (IgM) antibody secreted during coxsackievirus B infection. The test is more sensitive than the neutralization tests and can be used as a screening tool, followed by the neutralization test. The specificity is not extremely high because the antibodies cross-react with other enteroviruses such as hepatitis A virus.[20, 21]
The neutralization assay measures the ability of the serum to antagonize the viral infectivity in cell culture. The cytopathic effect-based neutralization test (Nt-CPE) and the plaques reduction neutralization test (PRNT) are the most common methods for quantifying the neutralizing antibody titers.[22, 23] Although the tests are expensive and laborious, a more specific finding of a positive ELISA result followed by a negative neutralization test result usually signifies an enteroviral infection other than that caused by coxsackievirus B. An efficient neutralization test based on the enzyme-linked immunospot assay (Nt-ELISPOT) has shortened the testing period from 7 days to approximately 20 hours, with good correlation (r2=0.9462) between the Nt-ELISPOT and the Nt-CPE assays. This modified Nt-ELISPOT would allow for faster specimen processing in coxsackievirus B vaccine trails, which require testing of a large number of serum specimens.[24]
A chest radiograph is usually obtained to exclude other causes of chest pain. In pleurodynia, the findings on chest radiography can be normal, or the radiograph may show a small amount of ipsilateral pleural effusion or adjacent atelectasis from splinting. The atelectasis can be linear or in the form of bibasilar consolidation. Infrequently, the coxsackievirus B infection causes pneumonia, with a radiographic pattern of fine perihilar opacities.
No specific treatment for pleurodynia exists. Management is supportive and includes nonsteroidal anti-inflammatory drugs (NSAIDs) for pain and pleurisy (if present) or peripheral nerve block (eg, intercostal nerve) with 1% lidocaine (Xylocaine) infusion. Aspirin should be avoided in children because of the potential to develop Reye syndrome.
Several experimental antiviral treatments have been tested in animal models, as follows:
Patients must receive follow-up care with their primary care providers to ensure that other potential coxsackievirus B-associated complications are diagnosed and managed in a timely manner.
Coxsackievirus B may be transmitted to the fetus during pregnancy by transplacental route or during delivery. During pregnancy, the outcomes of coxsackievirus B infection depend on the timing of infection during the age of gestation. Two independent studies reported higher prevalence of coxsackievirus B infection in women experiencing a miscarriage than in women delivering at term or receiving a voluntary termination before 13 weeks gestation. IgM antibody against coxsackie virus B1-5 or semi-nested RT-PCR positive for coxsackievirus B3 in the placental tissue were significantly higher, by 42% and 57.1%, respectively, than in women in the control group.[30, 31] It may also be related to increased incidence of congenital heart defects, and early-onset insulin-dependent diabetes mellitus.
Transmission of ECHO virus to neonates has also been reported during delivery, by an orofecal route. Similarly to coxsackievirus B, it may cause severe systemic infection in the neonate, such as aseptic meningitis, hepatitis, gastroenteritis, and viral pneumonitis.[32]
Common hygiene measures aid in the prevention of the oral-fecal transmission of coxsackievirus B. Encourage proper hygiene measures in the patient's household to avoid intrafamilial spread of the virus.
An outbreak of pleurodynia among high school football players was traced to contaminated water; therefore, avoid direct oral contact with common drinking or ice containers in favor of individual water containers and ice packs.[33]
Coxsackievirus B is a small RNA virus that lacks a lipoprotein envelope and, hence, may be resistant to physical and chemical inactivation, including 70% alcohol or 1% quaternary ammonium compounds. Sodium hypochlorite at a concentration of 3120 ppm, at a contact time of 5 minutes, was sufficient to completely inactivate different Enterovirus strains.[34] Good sterilization techniques that include ethylene oxide have been shown to inactivate the virus on electrophysiologic catheters.[35]
Nonsteroidal anti-inflammatory drugs and analgesics are used for the symptomatic relief of pleurodynia.
Clinical Context: Exerts anti-inflammatory effect via inhibition of cyclooxygenase, resulting in decreased formation of prostaglandins and thromboxanes from arachidonic acid. Also may inhibit synthesis and/or actions of other local inflammatory mediators and leukocyte migration. Analgesic effect is thought to result from the drug's action on peripheral pain impulse transmission and on pain receptor modulation.
Clinical Context: For relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.
Clinical Context: For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but it may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, eg, inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation and various cell membrane functions. They are used for symptomatic relief of pleurodynia.[36]