16.9.4 Cardiovascular syphilis 3539 Krishna Somers

16.9.4 Cardiovascular syphilis 3539 Krishna Somers

16.9.4  Cardiovascular syphilis 3539 16.9.4  Cardiovascular syphilis Krishna Somers ESSENTIALS Clinicians need to be aware of cardiovascular syphilis in patients at risk of infection, with the time taken from initial infection to clin- ical manifestation ranging from 10 to 25 years, although this is ac- celerated in patients with HIV infection. Inadequate or interrupted antibiotic therapy may confound the development of cardiovascular syphilis and make diagnosis difficult. Presentation may be with (1)  asymptomatic aortitis; (2)  aortic regurgitation—​the commonest manifestation resulting from annular dilatation of the aortic ring and eventually affecting 70% of patients with untreated syphilis; (3) coronary ostial stenosis; (4) aneurysm of the aorta; or (5) a combination of these. Syphilitic aortitis must be included in the differential diagnosis of aortic regurgitation in older people and those with predisposing factors. Diagnosis—​serological testing is the mainstay:  latent or inad- equately treated syphilis should be suspected with the finding of a positive non​specific treponemal serological test (e.g. rapid plasma reagin) and a positive specific treponemal antibody test (e.g. Treponema pallidum haemagglutination), but negative serology does not absolutely exclude infection with T. pallidum, particularly in an immunocompromised host. Management—​parenteral penicillin remains the treatment of choice for cardiovascular syphilis: the World Health Organization and European and United States guidelines recommend benzathine benzylpenicillin 2.4 × 106 units administered once weekly for 3 weeks by the intramuscular route. Modern imaging technology with MRI and three-​dimensional CT enables innovative surgical approaches in the repair of syphilitic aortitis. Introduction At the beginning of the 20th century cardiovascular syphilis ac- counted for 5–​10% of deaths due to cardiovascular disease. The in- stitution of public health measures—​early recognition of syphilis and treatment with penicillin since the 1940s—​produced a sharp decline in its incidence and hence in the tertiary manifestations and mortality from cardiovascular and neurosyphilis. The rarity of syphilitic aortitis in recent times has led to pub- lication of a succession of case reports describing challenges in diagnosis and management. With the re-​emergence of syph- ilis in both developed and developing countries, particularly in South East Asia and sub-​Saharan Africa, delayed cardiovascular complications of syphilis are likely to be seen with increasing frequency. Syphilis remains a major cause of ascending aortic aneurysm. An increased rate of infection with the causative organism, Treponema pallidum, prevails in sexually promiscuous individuals, intravenous drug abusers, men who have unsafe sex with men, sex workers trafficked from ‘east to west’, clients of sex workers, and so-​ called bridging populations, such as men who have both male and female sexual partners. Increase in syphilis infection rates among homosexual men is well documented in several cities in the United States of America and also in Europe, Canada, and Australia. As the syphilis epidemic continues to develop it is anticipated that increasing numbers of patients will present with cardiovascular or neurological tertiary syphilis in future decades. Clinicians need to be aware of cardiovascular syphilis in groups considered to have been at risk of infection. Inadequate or inter- rupted antibiotic therapy may confound the development of cardio- vascular syphilis and make diagnosis difficult. Pathogenesis and pathology of cardiovascular syphilis Syphilis is spread through body fluids and is usually acquired by sexual contact with an infected person. Men who have sex with men need to be aware that syphilis can be transmitted through oral sex. In the preantibiotic era, 50–​75% of partners of persons with primary or secondary syphilis were liable to become infected. Spontaneous healing of the early lesions of primary and secondary syphilis is fol- lowed by a long latent period, the time taken from initial infection to clinical manifestation of cardiovascular syphilis ranging from 10 to 25 years. The 2-​year mortality rate after diagnosis of untreated syphilitic aneurysm is about 80%. T. pallidum has a predilection for small vessels, especially in the aorta and the nervous system. In tertiary syphilis, obliterative end- arteritis of the vasa vasorum of the media and the adventitia of the aorta is characterized by the presence of an inflammatory cuff com- posed of lymphocytes and plasma cells around the affected vessels, causing ischaemic necrosis of collagen and elastic tissue in the aortic media. Syphilis classically involves the proximal ascending aorta, presumably because the vasa vasorum are more plentiful in that region. The pathological hallmark of syphilitic aortitis is ‘tree-​barking’, a description of longitudinal wrinkling of the aortic intima resulting from contraction of fibrous scars in the aortic media. Fibrosis of the media in the proximal ascending aorta results in dilatation of the aortic root and aneurysm formation, leading to aortic re- gurgitation, the most common complication of syphilitic aortitis afflicting 20 to 30% of patients. A  rarer form of cardiovascular syphilis is ‘gummatous’ myocarditis, which is usually diagnosed post-​mortem. Clinical presentation Cardiovascular syphilis may present in one of four forms, but the features may be mixed. • Asymptomatic aortitis—​the most prevalent form, and usually diagnosed at necropsy with the unexpected finding of character- istic ‘tree-​barking’ of the aortic intima. • Aortic regurgitation—​the commonest manifestation of cardio- vascular syphilis that results from annular dilatation of the aortic valve ring in syphilitic aortitis affecting the ascending aorta (the valve cusps remain normal); 70–​80% of patients with untreated syphilis eventually develop aortic regurgitation.

section 16  Cardiovascular disorders 3540 • Coronary ostial stenosis—​occurs in up to 30% of cases of cardio- vascular syphilis, and frequently coexists with aortic regurgitation as a complication of aortitis affecting the proximal ascending aorta. • Syphilitic aneurysm of the aorta—​the least common manifest- ation of cardiovascular syphilis, occurring in 10–​15% of patients with untreated syphilis; usually saccular but may be fusiform, and can occur as solitary aneurysm anywhere along the aorta, with characteristic radiographic appearance of dilatation. Aortic regurgitation With typical location of syphilitic disease in the ascending aorta, the murmur of syphilitic aortic regurgitation may be more prominent along the right sternal edge, in contrast to the left side in rheumatic aortic regurgitation. Transthoracic echocardiography will demon- strate that the aortic regurgitation is a result of dilatation of the aortic root (Fig. 16.9.4.1). Patients with syphilitic aortitis of the ascending aorta die of heart failure resulting from aortic valve regurgitation. Coronary ostial stenosis Angina or acute myocardial infarction may be the first presentation of syphilitic heart disease, even in younger patients (Fig. 16.9.4.2), and may also result from associated coronary atherosclerosis. In the South African literature in the 1980s there were several reports of acute myocardial infarction and death due to syphilitic ostial sten- osis (see ‘Syphilis and HIV infection’, next); hence patients found at coronary angiography to have bilateral coronary ostial stenosis but no distal coronary disease should be screened for syphilis, especially if they have known risk factors. Syphilitic aneurysm Nearly one-​half of the cases of syphilitic aneurysm occur in the as- cending aorta, 30–​40% in the aortic arch, and the remainder in the descending aorta. Mural thrombus, often with calcification, may obliterate the lumen of an aneurysm. Aneurysm of the aortic arch may compress and erode contiguous structures, such as a bronchus, resulting in pulmonary atelectasis; great veins, with presentation of superior mediastinal obstruction; the left recurrent laryngeal nerve, causing cough and hoarseness; and the vertebral bodies or sternum, causing pain. Aneurysm of the aortic arch may also produce tracheal tug, stridor, and dysphagia. Sternal erosion may be an early mani- festation of syphilitic aortitis, as the junction between the ascending aorta and the aortic arch is near to the sternum, and massive aortic aneurysm may present as a pulsatile swelling in the right anterior thoracic cage. Rupture of an aortic aneurysm (70% of cases) into a bronchus—​resulting in massive and fatal haemoptysis—​or into the pleural space or pericardium may be the first clinical manifestation of syphilitic aneurysm. Although extremely rare, tertiary syphilis should be considered in the differential diagnosis of thoracic aneurysms, even in the setting of atherosclerotic disease in older subjects. Patients with syphilitic aneurysm of the thoracic aorta, if untreated, have a mean life expect- ancy of 6 to 9 months from the onset of symptoms. Aneurysm of the abdominal aorta due to syphilitic aetiology is rare and (if asymptomatic) of unknown prognosis, but it may pre- sent with lumbar or abdominal pain and—​extremely rarely—​as spontaneous aortocaval fistula. Diagnosis A high index of suspicion is required to make the diagnosis in a patient found to have aortic regurgitation or aortic aneurysm, but syphilitic disease should be considered, especially if the patient belongs to a group at high risk of syphilitic infection or is elderly with a suggestive background risk factor, such as birth in a country where diagnosis and treatment of syphilis are likely to have been inadequate. With appropriate questioning a history of syphilis and its treatment may be obtained, but patients will often not volunteer such information. The diagnosis of syphilitic aortitis is often over- looked because atherosclerosis has greatly surpassed it as a cause of aortic aneurysm (Fig. 16.9.4.3). Laboratory investigation Serological testing is the mainstay of diagnosis. Rapid plasma re- agin is currently the most widely available non​specific treponemal test: if positive in high titre, it may indicate latent or inadequately (b) (a) LV AoV LA Fig. 16.9.4.1  Transthoracic echocardiography of a 61-​year-​old woman with syphilitic aortitis. (a) Apical long-​axis view of the left ventricle in mid-​diastole. The aortic valve leaflets are closed. The diameter of the ascending aorta is 4.8 cm (normal <3 cm) with the dilatation extending to the arch. AoV, aortic valve; LA, left atrium LV, left ventricle. (b) Apical long-​axis colour Doppler study in mid-​diastole showing severe aortic regurgitation.

16.9.4  Cardiovascular syphilis 3541 treated disease and be used to gauge response to treatment, but false positives are not uncommon: it is always positive in patients with non​venereal treponematosis, and it may be negative in car- diovascular syphilis. Specific treponemal antibody tests such as T.  pallidum haemagglutination (TPHA) detect antibodies to T. pallidum-​specific antigen and are almost always positive in car- diovascular syphilis, indicating prior infection with this organism. However, negative serology does not absolutely exclude infection with T.  pallidum, particularly in an immunocompromised host. Latent syphilis, defined by the presence of positive serological tests in the absence of clinical evidence of syphilis, may progress to car- diovascular and gummatous manifestations of tertiary syphilis. Even when confirmatory tests are not readily available, treatment should be initiated on suspicion of diagnosis. The diagnostic gold standard remains direct identification of T. pallidum in clinical specimens obtained at surgery. Polymerase chain reaction assay can provide definite diagnosis of spirochaetal infection when biopsy material is available. Syphilitic aortitis is often diagnosed on histological examination of the aneurysmal wall in patients who undergo resection of an ascending aortic aneurysm. Between 10 and 20% of patients with cardiovascular syphilis have coexisting neurosyphilis, hence cerebrospinal fluid examination is recommended. Recent case-​based reports propose the usefulness of 18F-​fluorodeoxyglucose positron emission spectroscopy (FDG-​ PET)/​CT for the assessment of extent of disease and response to treatment in syphilitic aortitis. Syphilis and HIV infection Syphilis promotes the transmission of HIV infection, and these infections can interact with each other. Cardiovascular syph- ilis develops more quickly in patients who are HIV seropositive (40 months from the time of primary infection) compared to those who are HIV seronegative (102 months), suggesting that coinfection with HIV hastens progression to late syphilis, perhaps due to im- munosuppression. Even though new cases of cardiovascular syphilis remain rare, it has been suggested that the decline of tertiary syphilis (a) (b) Fig. 16.9.4.2  Coronary angiogram of a 40-​year-​old Indonesian man who presented with severe, central chest pain. Note tapering of the aortic root (a, thin arrows), left main coronary artery stump (a, large arrowhead), and 90% ostial lesion of the right coronary artery (b, arrow). Emergency coronary artery grafting was performed. Serology obtained afterwards proved positive for syphilis. From Tong SYC, et al. (2006). MJA, 184, 241–​3. © Copyright 2006. The Medical Journal of Australia. Fig. 16.9.4.3  Chest radiograph showing aneurysm of the ascending aorta in an elderly man with cardiovascular syphilis. Note the typical linear calcification in the wall of the dilated ascending aorta. Atherosclerotic aneurysm of the ascending aorta in diffuse atherosclerotic disease may present a similar picture, although calcification—​when present—​is usually limited to the aortic knuckle and descending aorta.

section 16  Cardiovascular disorders 3542 in males in the 1990s could be attributed to mortality from AIDS. But at the same time, there has been an increase in the prevalence of infectious syphilis, with many cases undiagnosed. As a general principle, consideration of one sexually transmissible infection should lead to consideration of another. After appropriate consent, any person with syphilis should be studied for antibodies to HIV and hepatitis B virus, and vice versa, and contacts traced for evidence of infection. Medical treatment In spite of discrepancies in dosage regimens, international con- sensus supports the use of parenteral penicillin as first-​line treat- ment for all stages of syphilitic infection. T. pallidum has remained sensitive to penicillin despite more than 60 years of its use in the treatment of syphilis. A standard course cures most patients, al- though some authorities have recorded serological failure rates as high as 25%. It is thought that tertiary syphilis requires a longer course of treat- ment than early syphilis, since the treponemes may be dividing very slowly in the later stage of infection. The World Health Organization and European and United States guidelines recommend treatment of cardiovascular syphilis with benzathine benzylpenicillin 2.4 × 106 units administered once weekly for 3 weeks by the intramuscular route. United Kingdom guidelines propose 750 mg procaine benzyl penicillin once daily for 17 days by the intramuscular route. The Australian recommendation for the treatment of all forms of tertiary syphilis is benzylpenicillin 1.8 g intravenously 4-​hourly for 15 days. Doxycycline, 100 mg by mouth twice daily for 28 days, is recom- mended by the United States Centers for Disease Control in those with penicillin allergy; United Kingdom guidelines suggest that doxycycline 200 mg twice daily for 28 days is preferable. An unusual feature in the antibiotic treatment of syphilis is the Jarisch–​Herxheimer reaction. The mechanism of the reaction, which takes the form of malaise and fever within 24 h of penicillin treatment, is uncertain and may be due to release of endotoxins from the massive death of treponema. In patients with cardiovascular syphilis, the Jarisch–​Herxheimer reaction can be avoided by pred- nisolone 10–​20 mg three times daily for 3 days, starting 24 h before commencement of penicillin therapy. Established aortic aneurysm and aortic regurgitation cannot be reversed or halted by medical treatment. All patients with cardiovascular syphilis require clinical and sero- logical follow-​up 6 and 12 months after treatment. Syphilis serology is often difficult to interpret after treatment, as post-​treatment trepo- nemal tests usually remain positive even after completion of suc- cessful treatment. Treatment failure could be indicated by failure of non​specific treponema antibody titres to decline fourfold within 6 months of treatment. There is a higher rate of syphilis treatment failure in HIV-​positive patients. Surgical treatment Digital subtraction aortography, MRI, or three-​dimensional CT scanning enables visualization of the anatomy of syphilitic aortitis and can inform surgical strategy (Fig. 16.9.4.4). The aortic valve, if it is involved, may be replaced by a prosthetic valve if there is normal aortic tissue upstream. Alternatively, a Bentall procedure, which in- volves replacement of the ascending aortic arch, may be the surgical treatment of choice. Coronary ostial lesions have been convention- ally treated, with favourable results, using internal mammary grafts or in combination with saphenous vein grafting. Isolated aortic aneurysm may be treated with endovascular stent graft repair, especially in patients with comorbidities who may be at high risk for open surgery, provided the lesion is considered anatomically suitable with adequate proximal and distal vessels. Conventional surgery, combined with endovascular repair, may be tried in the patients with syphilitic aortic aneurysm involving the aortic arch and the descending thoracic aorta, with the 30-​day mor- tality of such intervention ranging from 5 to 10%. FURTHER READING Bodhey NK, et al. (2003). Early sternal erosion and luetic aneurysms of thoracic aorta. Eur J Cardiothorac Surg, 28, 499–​501. Cheng TO (2001). Syphilitic aortitis is dying but not yet dead. Catheter Cardiovasc Interv, 52, 240–​1. Feier H, et  al. (2012). Coronary ostial stenosis in a young patient. Circulation, 125, e367–​8. Goh BT (2005). Syphilis in adults. Sex Transm Infect, 81, 448–​52. Goldstein B, Carroccio A, Ellozy SH (2003). Combined open and endovascular repair of a syphilitic aortic aneurysm. J Vasc Surg, 38, 1422–​5. Hook EW 3rd (2017). Syphilis. Lancet, 389, 1550–​7. Jackman JD, Radolf JD (1989). Cardiovascular syphilis. Am J Med, 87, 425–​33. Kennedy JLW, Barnard JJ, Prahlow JA (2006). Syphilitic coronary ostial stenosis resulting in acute myocardial infarction and death. Cardiology, 105, 25–​9. Fig. 16.9.4.4  Three-​dimensional left-​profile reconstruction of the thoracic aorta and adjacent structures in a 51-​year-​old man with the finding, on routine chest radiography, of an aortic aneurysm that proved to be syphilitic. From de Cannière D, et al. (1999). 21st century imaging for a 19th-​century disease. Circulation, 100, 884–​5.

16.9.4  Cardiovascular syphilis 3543 Maharajan M, Sampath Kumaar G (2005). Cardiovascular syphilis in HIV infection: a case-​controlled study at the Institute of Sexually Transmitted Diseases, Chennai, India. Sex Transm Infect, 81, 361. Parkes R, et al. (2004). Review of current evidence and comparison of guidelines for effective syphilis treatment in Europe. Int J STD AIDS, 15, 73–​88. Roberts WC, et al. (2015). Syphilis as a cause of thoracic aortic an- eurysm. Am J Cardiol, 116, 1298–​303. Tomey MI, Murthy VL, Beckman JA (2011). Giant syphilitic an- eurysm:  a case report and review of the literature. Vasc Med, 16, 360–​4. Tong SYC, Haqqani H, Street AC (2006). A pox on the heart: five cases of cardiovascular syphilis. MJA, 184, 241–​3. Treglia G, et al. (2013). Usefulness of 18F-​FDG PET/​CT in disease ex- tent and treatment response assessment in a patient with syphilitic aortitis. Clin Nucl Med, 38, e185–​7.