Cardiovascular complications of Streptococcus pneumoniae bacteraemia
- Michelle M de Leau and
- Remko S Kuipers
- Heart Center, department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
- Correspondence to Dr Remko S Kuipers; R.S.kuipers@olvg.nl
Abstract
The incidence of Streptococcus pneumoniae bacteraemia has risen due to a worldwide increase in immunocompromised patients and antibiotic resistance. We describe three patients who experienced severe, including cardiovascular, complications of pneumococcal bacteraemia. Cardiovascular complications related to pneumococci may run a fulminant course. However, some of these life-threatening complications (eg, endocarditis and aortitis) may long remain unnoticed or be misdiagnosed and therefore delay correct treatment. We review the literature with regards to the incidence, diagnosis and treatment of these rare but possibly lethal and hence important cardiovascular complications.
Background
Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium, and commensal coloniser of the nasopharyngeal cavity. It is the main cause of sinusitis, otitis media, meningitis and community acquired pneumonia.1 2 Together with Escherichia coli and Staphylococcus aureus, it is one of the most important causes of bacteraemia.3 Even in the antibiotic era, about 25%–30% of patients with pneumococcal pneumonia develop bacteraemia.4 5 Pneumococcus, dependent on the serotype, is a virulent and invasive organism. Multiple organs might become involved secondary to bacteraemia. Several mechanisms have been described to explain pneumococcal translocation across vascular endothelial cells, the blood-brain barrier and even their entrance into myocardial cells.6
In the preantibiotic era, some of these invasive complications were quite common. In 1885, William Osler already noted the frequent concurrence of pneumonia, endocarditis and meningitis.7–9 This triad was eventually named ‘Austrian Syndrome’ after pathologist Richard Heschl who first described the association of these coexisting infections in 1862, and physician Robert Austrian who described it as a syndrome related to pneumococcus infection.10 11 Involvement of the vasculature, such as the aorta, and right sided heart valves were considered rare events even in this time.7 Since the development of antibiotics and pneumococcal vaccination, these complications have almost disappeared. However, with increasing prevalence of drug-resistant micro-organisms together with an increasing number of immunocompromised patients, the incidence of unusual invasive pneumococcal infections is on the rise again.1 12
An analysis of 325 cases of pneumococcal bacteraemia13 revealed pneumonia to be the most common complication (observed in 80% of patients), followed by meningitis (8%), endocarditis (2%) and peritonitis (1.2%). After exclusion of pneumonia and meningitis, Taylor et al 1 showed arthritis (16%), peritonitis (12%), endocarditis (8%) and ophthalmic infections (8%) to be the most prominent invasive pneumococcal complications, followed by renal and urinary tract infections (8%), osteomyelitis (5%), genital tract (5%), soft tissue (notably cellulitis: 2,5%) and central nervous infections (notably brain abscesses: 2.2%). A combination of several of these rare complications regularly occurs. For example, in patients with pneumococcal vertebral osteomyelitis, concurrent meningitis (18%) and endocarditis (14%) were shown to be relatively common.14 Comparably, although Austrian Syndrome has been described to occur in only 0.9–7.8 cases per 10 million people each year,15 its incidence reaches 26% in patients with infective endocarditis (IE).16 In patients with infected aortic aneurysms, 9% had concurrent endocarditis.
We present three cases of rare, but life-threatening invasive cardiovascular complications of pneumococcal bacteraemia in immunocompromised patients. Although rare, awareness of these severe complications among physicians might reduce morbidity and mortality in cases of pneumococcal bacteraemia.
Case presentation
Case 1: aortitis, endocarditis, osteomyelitis and cellulitis in the setting of alcoholism
A 49-year-old patient with a history of suicidal depression, polyneuropathy, spinal stenosis and alcoholism, presented to our hospital with fever and cold chills. He had been experiencing increasing pain in his back during the previous few months for which he had been ingesting increasing amounts of alcohol (up to several bottles of wine per day) and benzodiazepines (60–80 mg diazepam per day), while eating less and losing weight. He was an active smoker and did not use intravenous drugs. On admittance, he appeared ill and was haemodynamically unstable (for clinical characteristics: see table 1). Chest examination revealed normal heart sounds and slight right-sided pulmonary crackles. Further examination exposed a large area of erythema on his right upper leg, measuring 15×30 cm with local swelling of the skin. Next to this lesion, petechiae were noted on 10×10 cm surface area. Palpation of the spine was not painful.
Patient characteristics
| Case 1 | Case 2 | Case 3 | |
| Gender | Male | Female | Male |
| Age (years) | 49 | 58 | 61 |
| Temperature (degrees Celsius) | 38.6 | 38.6 | 40 |
| Heart rate (beats/min) | 105 | 110 | 93 |
| Blood pressure (mm Hg) | 75/60 | 86/50 | 133/69 |
| Respiratory rate (breaths/min) | 17 | 28 | n.a. |
| Saturation (at room air or × L O2) | 99% | 98%+4 L O2 | 95% |
| Underlying condition(s) | Alcoholism | Diabetes type 2 | Hypogammaglobulinaemia |
| Chronic pancreatitis | Alcohol |
Laboratory results are shown in table 2. The ECG showed sinus rhythm at 98 beats/min, without abnormalities. Chest radiography disclosed an enlarged mediastinum and prominent right heart border, but no signs of a pleural effusion or infiltration. The patient was admitted with a working diagnosis of sepsis secondary to cellulitis. He received fluid resuscitation and antibiotic treatment with intravenous flucloxacillin 1000 mg four times daily. After initiation of antibiotic therapy, swelling and redness of the leg decreased rapidly. On hospital day 3 blood cultures yielded growth of Streptococcus pneumoniae. Due to severe back pain, MRI was performed. This showed, aside from the previously known spinal canal stenosis at L3, pathological staining of the L4 vertebral body and surrounding tissue, and two small abscesses, paravertebral and epidural, suggesting focal spondylitis and spondylodiscitis. Additionally, a saccular aneurysm of the thoracic aorta with increased signal intensity of the surrounding tissue was revealed, thought to be a mycotic aneurysm. Finally, increased signal intensity was shown around the aortic bifurcation, with localised wall thickening, suggestive of local aortitis. Subsequently, CT angiography confirmed these diagnoses (figure 1A). Flucloxacillin dose was increased to 6 g daily and endovascular surgery of both lesions was performed without further delay. Transthoracic followed by transesophageal echocardiography revealed severe tricuspid insufficiency and a large mobile structure on the non-septal leaflet of the tricuspid valve, measuring 24×21 mm (figure 1B). After antibiotic treatment for 14 days, fever was absent but the C reactive protein (CRP) remained elevated (68 mg/L) and signs of right-sided heart failure appeared. Diuretics were started. Cardiothoracic surgery was postponed until the patient was stable and 4 weeks of intravenous antibiotic treatment was completed. A large vegetation was attached to the non-septal cusp, which was removed and the tricuspid valve was reconstructed with implantation of an Edwards 30 mm ring with good result. After a total period of 6 weeks of antibiotic treatment, the patient was discharged.
Case 1. A saccular aneurysm of the descending aorta (A) on CT angiography and a large vegetation on the tricuspid valve (B) on transesophageal echocardiography. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.
Laboratory results
| Case 1 | Case 2 | Case 3 | Reference | |
| Haemoglobin (mmol/L) | 4.4 | 5.3 | 7.4 | (8.5–11.0) |
| WCC (109/L) | 15.4 | 8.8 | 20.4 | (4.0–10.0) |
| Platelets (109/L) | 61 | 81 | 138 | (150–400) |
| ESR (mm/hour) | 114 | n.a. | 90 | (1–10) |
| CRP (mg/L) | 192 | 213 | 236 | (<10) |
| Sodium (mmol/L) | 125 | 137 | 125 | (135–147) |
| Potassium (mmol/L) | 3.4 | 3.9 | 3.3 | (3.5–5.0) |
| Creatinine (umol/L) | 69 | 43 | 148 | (59–104) |
| Urea (mmol/L) | 7.5 | 6.3 | 11.6 | (2.1–7.1) |
| Alkaline phosphatase (IU/L) | 269 | 195 | 29 | (35–52) |
| Lactate dehydrogenase (IU/L) | 342 | 343 | 184 | (<248) |
| ALAT (IU/L) | 79 | 22 | 33 | (<45) |
| ASAT (IU/L) | 94 | 32 | 22 | (<35) |
| yGT (IU/L) | 256 | 118 | 44 | (<55) |
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ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; n.a., not available; WCC, white cell count; yGT, gamma-glutamyl-transferase.
Case 2: Austrian Syndrome in the setting of diabetes and chronic pancreatitis
A 58-year-old woman with type 2 diabetes and chronic pancreatitis presented to our hospital with reduced consciousness and respiratory failure. She had been coughing for a few days and had lost >6 kg in weight over the previous 6 months. Three days before presentation, she left the hospital against medical advice after being admitted for a flare of her recurrent pancreatitis. After she had left the hospital, a blood culture had revealed the presence of S. pneumoniae. Since there were no clinical signs of infection, antibiotics were withheld, but the general practitioner was instructed to start antibiotics in case of fever. On arrival, she was taking oxycodone, oxycontin, supplemental medication for pancreatic insufficiency and hydrochlorothiazide. She was an active smoker but denied drinking alcohol. On the day of readmission, she was found on the floor and was transported by ambulance to our emergency department. She appeared cachectic and ill with decreased consciousness (E2M4V1) (see table 1). Further examination revealed neck stiffness, a systolic cardiac murmur and decreased breathing sounds over the right-lower lung with diffuse rhonchi. Laboratory results are shown in table 2. The ECG showed a sinus tachycardia of 123 beats/min without other abnormalities. A CT thorax showed bilateral consolidation (figure 2A). A CT brain showed no abnormalities. She was transferred to the intensive care unit (ICU) with a working diagnosis of bilateral pneumococcal pneumonia with respiratory failure and concurrent meningitis secondary to pneumococcal bacteraemia. She was intubated and received haemodynamic support, high-dose cefotaxime and steroids. Cerebrospinal fluid analysis confirmed a bacterial infection. Four separate blood cultures were positive for S. pneumoniae. The culture of cerebrospinal fluid showed no growth, but was taken after initiation of antibiotics. Transesophageal echocardiography (figure 2B) revealed a large vegetation of 24*12 mm on P2P3 of the mitral valve and severe regurgitation due to perforation. Coronary angiography was performed which revealed significant two vessel obstruction. Despite a high embolic risk because of the large vegetation size, surgery was postponed due to haemodynamic and respiratory instability. After 2 weeks of intravenous antibiotic therapy, no embolic events had occurred, concurrent mitral valve replacement and coronary artery bypass grafting were performed without periprocedural complications. She recovered well. Antibiotic therapy with cefotaxime was continued for a total of 6 weeks, fever remained absent and CRP low. She was discharged.
Case 2. Right-sided pneumonia (A) on CT and a large vegetation on P2P3 of the mitral valve (B) on transesophageal echocardiography. For abbreviations see Figure 1.
Case 3: arthritis, osteomyelitis and aortitis in the setting of multiple myeloma
A 61-year-old man presented to ED after experiencing severe pain in his left ankle with concurrent fevers. Besides hypertension, for which he used lisinopril and hydrochlorothiazide, he reported no significant medical history. He did not have a history of tobacco use, but reported moderate alcohol intake. At presentation, he was haemodynamically stable (see table 1) but appeared ill and somnolent. His left ankle was swollen, red and motion was antalgic. Further examination revealed no abnormalities. Laboratory results are shown in table 2. A diagnostic puncture of the ankle joint was performed and 20 cm3 of purulent fluid was aspirated. The aspirate, as well as urine and blood cultures, tested positive for S. Pneumoniae. Echocardiography showed no signs of endocarditis. The patient was treated with flucloxacillin 6 g/day for septic pneumococcal arthritis but fever remained. A PET-CT was performed (figure 3) exhibiting fluorodeoxyglucose (FDG)-uptake along the descending aorta on the level of L2–L3 with expansion to the vertebral column. Also, there was disseminated infection with high FDG uptake in the left knee, left ankle, right iliac bone and several muscles (right-sided adductor brevis, gluteus maximus on both sides, left subscapularis and right scalenus). In addition, exaggerated FDG uptake was shown in his bone marrow. A CT abdomen showed slight dilatation of the infrarenal aorta (33 mm) and periaortal infiltration from the kidney arteries down to the femoral bifurcation, suggestive of aortitis. Also, a lytic lesion of the right iliac bone was revealed. The patient was treated with high-dose penicillin, 12 million units per day. An endovascular aneurysm repair was performed 9 days after presentation because of an expected high risk of aortic rupture. Surgery and postoperative recovery were uncomplicated. After 6 weeks of intravenous antibiotic therapy, the patient was discharged. Further analysis of the lytic lesion in the right iliac bone revealed a multiple myeloma for which he was successfully treated in an outpatient setting after recovery of his infection.
Case 3. Radioisotope activity on PET-CT suggesting aortitis (upper arrow) and vertebral (lower arrow) osteomyelitis (A), activity located at the ileal bone was later found to be a multiple myeloma (B) and arthritis of the knee (C).
Outcome and follow-up
At present, on average 7 years later, all patients are alive. In our first patient, the tricuspid prosthesis is functioning well, but he has been institutionalised because of psychological problems. In the second patient, there has been no recurrence of endocarditis or meningitis and the prosthetic mitral valve is functioning well. Our last patient has been intensively treated, including an autologous stem cell transplant, for multiple myeloma. At present, he has fully recovered.
Discussion
We have presented three patients with pneumococcal bacteraemia and a variety of concomitant complications. Due to timely recognition and treatment, all patients survived.
Mortality rates from pneumococcal bacteraemia generally range between 5%and 20% according to the country, underlying conditions and the presence of antibiotic resistant strains,17 but can rise up to 50%, even in Western societies.18 Mortality is lowest when bacteraemia is associated with pneumonia only, but increases when extrapulmonary foci are present.13 19 Since the discovery of penicillin, the introduction of vaccines, appropriate use of antibiotics, improved imaging techniques, and multidisciplinary management, complicated invasive pneumococcal disease has become rare, decreasing from 15% to 20% of cases to less than <10%.16 20 The most important risk factor for pneumococcal bacteraemia is alcoholism9 13 21 22 since it gives rise to functional asplenia or hyposplenism,23 possible aspiration during intoxication22 and a decreased inflammatory response.24 In Austrian Syndrome, its frequency has been reported to be as high as 28%.12 In fact, alcoholism historically completed the tetrad of associated conditions.25 Other (uncorrected) risk factors include liver disease, (functional) asplenia, pregnancy, influenza, older age, male sex, cigarette smoking and the many comorbidities and medication associated with immunodeficiency, such as chronic pulmonary disease, diabetes mellitus, chronic renal failure, corticosteroids, HIV infection and malignancies.12 16 26–29
Pneumococcal endocarditis
1%–2% of patients with pneumococcus infection develop IE and its annual incidence is estimated at 2 cases/million people.6 13 30 31 Pneumococcal endocarditis often runs a fulminant course with large thrombus formation and rapid valvular destruction, necessitating early and aggressive surgical intervention.32 The aortic valve is mostly affected.10 16 33 Right-sided endocarditis occurs in 5%–15%.16 21 In very few cases, valves on both sides of the heart are affected, either as a result of bacteraemia or from direct migration of pneumococci through the atrial septum.12 Right-sided endocarditis is a frequent complication of intravenous drug abuse. In one case series, more than 85% of patients with right sided IE were abusing drugs.34 Also, alcoholism and right-sided cardiac catheters are known risk factors.21 Finally, alcoholic liver disease, immunosuppression, previous (notably congenital) heart disease and splenectomy/asplenia seem to be the most important underlying conditions in patients with pneumococcal IE.16 In case of pneumococcal endocarditis, a definite diagnosis is often delayed since stigmata are often absent or occur late during disease. Besides, a diagnosis of right-sided endocarditis might also remain undetected since classical signs such as cardiac murmurs, petechiae and splinter haemorrhages are often absent.35 More specific symptoms such as pleuritic chest pain, shortness of breath, cough and haemoptysis can occur. Suspicion of tricuspid endocarditis has been suggested in the presence of ‘the Tricuspid Syndrome’, which consists of recurrent pulmonary events, microscopic haematuria and anaemia. However, only anaemia was observed in our patient with right sided endocarditis. Treatments of choice for IE are culture-specific intravenous antibiotics for an extended period of time, according to local practice and resistance.36 Indications for valve replacement or surgery are failure of antibiotic treatment with persistent fever or inadequate source control, myocardial extension of the infection, prevention of systemic embolism and heart failure secondary to valve dysfunction.36 Cardiac surgery in case of pneumococcal endocarditis is performed in about half of patients, mostly within 1 week.16 The average in-hospital mortality rate, even in the antibiotic era, is 20%–50%. Meningitis (OR 4.3), peripheral and cerebral embolism are the most important risk factors for mortality.16 31
Pneumococcal aortitis
Infectious aortitis is a rare complication of a pneumococcal bacteraemia (0.6%), representing 0.5%–1.3% of all operated aneurysms.1 37 Salmonella sp and Staphylococcus aureus are the most common microbial agents of infectious aortitis. However, in a more recent study, S. pneumoniae was described as an emerging pathogen and was found in 36% of patients presenting with infectious aneurysms.38 The abdominal aorta is mostly affected (54%), followed by the descending aorta (30%) and the ascending aorta (15% of patients).37 39 We found no cases where both descending and abdominal aorta were involved, as in our patient (case 1). Clinical manifestations of infected aortitis are fever (present in 73% of patients), local pain (in 65%, generally related to the site of infection) and less often a palpable pulsatile mass (3%–50%).37–39 A predisposing factor for aortitis is atherosclerosis, which facilitates bacterial seeding and attachment to the intimal surface of the weakened blood vessel. CT and MR angiography are mostly used for non-invasive investigation.40
Aortitis might originate from three different routes: (1) the hematogenous spread of pathogens or septic emboli to a pre-existing aneurysm, (2) from extension from a contiguous site of infection, such as endocarditis or osteomyelitis, and (3) from direct inoculation (eg, after aortic surgery).41 42 In many cases however, the route of infection will remain unknown since, as in our patients with concurrent aortitis and osteomyelitis, infection of one another could be by either hematogenous spread, local infiltration or both (see figure 3). In the preantibiotic era, 90% of aortic infections were mycotic aneurysms, since they resulted from septic emboli secondary to concurrent left-sided endocarditis.43 Pre-existing aneurysms that become infected in case of bacteraemia should officially be referred to as ‘arteritis’ (and not mycotic aneurysms),41 42 Consequently, our first case would be an example of ‘aortitis’ and not of a mycotic aneurysm, since septic emboli that cross the pulmonary circulation from a right-sided endocarditis seem a less plausible explanation than either bacteraemia or local infiltration from concurrent osteomyelitis. In clinical practice, the source of aortic infection is often uncertain.37 39 In about half of patients (41%–67%), no source of infection is found, suggesting that the endarteritis might have originated in the vasculature, secondary to bacteraemia itself. Sites of hematogenous spread are the respiratory tract (20%–22%), endocarditis (6%–19%), septic arthritis (3%) and spondylodiscitis (3%), while cellulitis and urinary tract infections have also been described.37 44
Finally, aneurysm formation can be surprisingly rapid. It has been reported that aortic aneurysms, secondary to pneumococcal aortitis can be formed within 1 week of presentation.45 Infected aortitis, if left untreated, has a poor outcome which is partly dependent on the infectious pathogen. Gram-positive micro-organisms, such as pneumococcus, are associated with a 10% risk of rupture and 50% mortality rate.46 Freely ruptured infected aortic aneurysms have a 63%–100% mortality.40 47 At first presentation, 7%–24% of infected aortic aneurysms have ruptured, whereas another 47%–61% show contained or impending rupture.40 Specific management is dependent on the individual case, but medical treatment alone has proven inferior to immediate surgery.40 Once aortitis is suspected, it should be surgically managed as soon as possible, together with any infected sites in the vicinity, such as an abscess or osteomyelitis.38 Surgery should even be considered in a patient in shock, since shock might very well signal imminent or ongoing aortic rupture.22 37 38 Mortality associated with non-surgical management approaches 90%.39 Prolonged culture-specific intravenous antibiotic therapy in combination with conventional or endovascular surgery is the recommended treatment. This combined therapy reaches survival rates of 70%–100%.37 39 The mortality rate is 16%–38% for conventional surgery37 and 10% for endovascular stent repair.48 However, the latter is more often complicated by persistent infection. Late endovascular graft-related complications occur in 23%.The 12-month survival was only 39% in a group complicated by persistent infection, compared with 94% in the group that was free of infection.48 The latter shows the importance of concurrent antibiotic treatment, especially after endovascular surgery.
Timely recognition and prevention of cardiovascular complications
In case of pneumococcal bacteraemia, we advocate a multidisciplinary approach to these patients to improve the chance of a timely recognition and treatment of the possibly lethal complications of infection. Finally, our cases raise the question whether (more) immunocompromised patients, for example, those who abuse alcohol, should be included in preventive pneumococcal vaccination programmes.30 Moreover, a recent review showed that some immunocompromised patients, such as our last patient with multiple myeloma, might even need prophylactic intravenous immunoglobulins, since over half of these patients fail to demonstrate a protective level of antibody titre after vaccination to S. pneumoniae.28
Conclusion
The incidence of unusual invasive pneumococcal infections is likely to increase with increasing prevalence of drug resistant micro-organisms and immunocompromised patients. As illustrated by our cases, this can result in life-threatening cardiovascular complications. Therefore, prevention, timely recognition and immediate treatment of these complications is vitally important.
Learning points
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The incidence of Streptococcus pneumonia bacteraemia is rising due to both an increasing number of immunocompromised patients and antibiotic resistance.
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Endocarditis due to S. pneumonia often remains unnoticed until severe destruction of the heart valves has occurred.
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Aortitis due to S. pneumonia has a very high mortality rate.
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Clinical symptoms of aortitis are non-specific and the diagnosis is often delayed.
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In case of pneumococcal bacteraemia, the concurrent presence of several invasive complications is not unusual and should be considered.
Footnotes
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Contributors Both authors wrote, reviewed and accorded the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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