Introduction 

Tietze syndrome is a rare, benign inflammatory disorder affecting the costal cartilage found at the function of the ribs and sternum. It can be characterised by localised pain and swelling but is often misdiagnosed as other conditions. Tietze syndrome has no known cause and is spontaneous, however, researchers have found potential links to infectious agents, such as bacteria and viruses. In this article, we explore the possible associations using existing medical literature, case studies and their hypothesised mechanisms of infection-related onset. 

Understanding Tietze syndrome

Initially discovered by Alexander Tietze in 1921, the syndrome affects individuals between ages 20-50, with no distinction between genders, ethnicity or geography. Typical symptoms include pain in the upper chest due to cartilage inflammation between the ribs and breastbone. Specifically, the cartilage tips between the first 10 upper ribs where they connect to the breastbone (sternum), and is often called the costal cartilage. The joints where the tips connect also contain cartilage. Tietze syndrome is commonly mistaken for costochondritis, which refers to general inflammation of the cartilage in the rib cage. However, Tietze syndrome is more specific, as it affects only one of the top four ribs and spreads to the shoulder and arm. It also presents noticeable swelling, which can be aggravated by movement, coughing or deep breathing. The causes are unclear but theories range from mechanical stress and microtrauma to inflammatory or infectious triggers.¹

Infectious hypotheses: Could bacteria or viruses play a role?

The body’s immune system is reliant upon inflammation, which manifestss as redness, swelling, heat and pain. These components contain and eliminate pathogens and trigger tissue repair. The damaged cells release chemical signals, histamines and prostaglandins, stimulating the inflammatory response. The chemicals cause blood vessels to widen, increasing blood flow to the affected area. Swelling is the result of more permeable blood vessels. These allow increased flow of fluid, proteins and immune cells to leave affected tissues. Furthermore, the white blood cells, such as neutrophils and macrophages, move to the site of inflammation where they engulf and destroy the pathogen. Once the infection has cleared, the tissues repair and the inflammatory response subsides.² This inflammatory response can be triggered by viral or bacterial infections which may contribute to or resemble Tietze Syndrome. 

Viral triggers and theories 

Enteroviruses are single-stranded RNA viruses which are the basis of several diseases. They can cause a range from mild illnesses, such as respiratory infections to central nervous system infections, such as meningitis. Examples of enteroviruses are:

• Polioviruses 
• Echoviruses 
• Coxsackieviruses 

These viruses are known for causing inflammation of the thoracic region (chest area), especially in myocarditis and pericarditis, which involve inflammation of the muscles surrounding the heart. Case studies have shown that enteroviruses can trigger localised cartilage inflammation in the ribs, resembling Tietze Syndrome.³

Herpesviruses are chronic inflammatory disorders, such as rheumatoid arthritis and lupus. The Epstein-Barr virus is associated with chronic fatigue syndrome and fibromyalgia. These conditions are known to have the characteristic inflammation of Tietze Syndrome. In herpesviruses, there are various mechanisms which stimulate the immune response, including the innate immune response and inflammasome signalling, leading to localised inflammation. The reactivation of herpesvirus is currently under research for chest wall inflammation.⁴

Characteristics of Tietze Syndrome are commonly presented as symptoms of influenza and SARS-CoV-2 (COVID-19). These viral infections have prolonged inflammatory responses even after recovery. Individuals have reported persistent chest pain, specifically musculoskeletal inflammation, leading to question its contribution to Tietze Syndrome. Enhanced activation of chemical signals (known as cytokine storms) by these viruses leads to localised inflammation of the costal cartilage. 

Bacterial involvement and theories 

Bacterial infections are potential players in Tietze Syndrome, due to the activation of the immune response and the consequent inflammatory reaction in cartilage tissues. 

The bacterium mycoplasma pneumonia is known for its respiratory infections and links to several inflammatory syndromes, such as reactive arthritis and pneumonia. The bacteria attaches itself to the cells in the walls of the respiratory tract. Here, they damage cells by producing agents, such as hydrogen peroxide and superoxide. Consequently, an inflammatory response is activated against this injury. Prolonged presence causes a cough to develop from damaged respiratory cells.⁵ As a result, Tietze Syndrome can develop. 

Streptococcus and Staphylococcus are well-known bacteria involved in a multitude of inflammatory conditions. They are currently the leading cause of antibiotic resistance. Group A streptococcal infections enter through the skin and throat. The majority of these are mild infections:

• Cellulitis - infection in the deep tissues beneath the skin. 
• Sore throat - pain and discomfort in the throat
• Strep throat - infection in tonsils and throat 

Severe infections contain a greater inflammatory response which impacts the whole body:

• Inflamed tissues in the joints and heart 
• Bloodstream infections 
• Scarlet fever 
• Toxic shock syndrome⁶

The Staphylococcus aureus infection is the most common human infection. Several areas of the body are affected by this bacterium:

• Skin infection around the body, mouth or nose 
• Inflammation around bones causes pain 
• Damage to heart valves which risks heart failure 
• Pneumonia in the lungs 
• Blood poisoning 
• Inflammation in the chest, collection of pus⁷

These bacteria cause extreme elevations of the immune response and thus inflammation, which can extend to the cartilage in the ribs resulting in the Tietze syndrome. 

Tuberculosis is an illness caused by the tuberculosis bacteria, characterised by its serious effects on the lungs, causing musculoskeletal complications. When investigating Tietze syndrome, underlying tuberculosis infections must be considered, especially in immunocompromised individuals. ⁸ Persistent coughing and chest pain are known potential triggers of Tietze syndrome. 

Lyme disease is caused by the bacteria Borrelia burgdorferi. This is found on infected ticks and transmitted by their bite. As a result, the body suffers from:

•  Severe fever
•  Swollen glands
• Areas of numbness 
• Rash 
• Face paralysis⁹

The bacteria affects the connective tissue and immune regulation leading to chest wall pain and inflammation similar to Tietze Syndrome. 

Immune response and autoimmune considerations 

After looking at the external triggers of the immune response, it is essential to explore the internal mechanisms which link infection to Tietze Syndrome. 

Molecular mimicry is when pathogens contain proteins similar to human tissue structures. The immune system cannot distinguish between the host and foreign cell, resulting in the destruction of both the pathogen and host cells. This mechanism is found in streptococcus infections which stimulate the immune system to attack the joint and heart tissues.¹⁰ The costal cartilage may become a false target in this process, leading to the inflammation and swelling of Tietze Syndrome. 

The aftermath of an infection can result in prolonged inflammatory responses, despite the pathogen’s removal. The dysregulated immune system, following an infection, can cause persistent cartilage inflammation. This is seen across COVID-19 patients, known as ‘long COVID’, where the body has a long-term inflammatory imprint. The failure to resolve the inflammation causes recurrent symptoms.¹¹ 

The potential genetic component of Tietze syndrome involves cytokines.¹³ Cytokines are the immune system's signal for stimulating inflammation. In some cases, the immune response produces an excess of cytokines. This is called cytokine release syndrome (CRS), where the immune system overreacts and causes an imbalance of cytokines. This puts the costal cartilage at risk of inflammation.¹² People can be genetically predisposed to CRS by mutated human leukocyte antigen. The gene is linked to autoimmune and inflammatory diseases found on chromosome 6, and it helps the immune system distinguish between the body’s cells and a pathogen.

Diagnosis and differential considerations

Initially, Tietze Syndrome presents itself as acute chest pain. This brings into consideration a broad range of potential conditions, where doctors will first rule out a heart attack. Next, they carefully examine the chest through several imaging techniques:

• CT scan 
• MRI
• Ultrasound 
• EKG
• Biopsy¹

Despite deep investigation, Tietze Syndrome is often misdiagnosed as costochondritis. This condition is associated with multiple ribs, 2 through 5. While Tietze syndrome is more localised, only one rib is inflamed. Clinicians will look for significant swelling and inflammation in ultrasounds, which is not observed in costochondritis. Furthermore, visible swelling can be observed in Tietze syndrome, differentiating it from costochondritis.¹⁴ Other possible differential diagnoses include:

• Chest trauma-associated fractures 
• Rheumatoid arthritis 
• Gastroesophageal reflux 
• Lupus 
• Fibromyalgia¹⁴ 

Treatment approaches and implications 

As Tietze Syndrome is a self-limiting disease, it resolves itself within a few weeks. Treatments include conservative therapies and reassurance that the disease will pass with no permanent effects. Oral or topical anti-inflammatory agents are used to dampen the aggravated immune cells, and these include opioids or acetaminophen. If these non-steroidal medications do not bring relief, local anaesthetics are used, which can be administered in combination with steroids. A less popular route is cartilage resecting, which is done in severe cases but is still not recommended. Treatment and management are delivered on a case-by-case basis.¹⁴ Immuno-therapies are a new path of treatment under investigation which could provide an individualistic approach. Clinical trials are able to assess the specific agents in each infection which contribute to the occurrence of Tietze Syndrome. 

Summary

There is a lack of understanding of the causes of Tietze Syndrome. Due to its quick resolution time, it is challenging to produce definitive causal links, however theories are under investigation. Existing evidence shows infection as a potential contributor to costal cartilage inflammation. To establish these hypotheses, extensive immunological research is required to study the exact mechanism through which infections trigger the condition. Understanding the infectious origins of Tietze syndrome can provide valuable insights into post-infectious syndromes and immune dysregulation in inflammatory responses.