Neisseria elongata subsp elongata infective endocarditis following endurance exercise

Abstract

A 31-year-old Argentinian woman presented with a 3-week history of fever, night sweats, myalgia and lethargy following a work trip to Uganda where she ran a marathon. Malarial screens were negative but C reactive protein, erythrocyte sedimentation rate and neutrophil count were raised and she was anaemic. A new pansystolic murmur was heard over the mitral valve and the transthoracic echocardiogram showed a large vegetation (>1 cm) with at least moderate mitral regurgitation. Blood cultures grew Neisseria elongata, subsp elongata treated initially with ceftriaxone then oral ciprofloxacin to complete 4 weeks of treatment. CT scan revealed a wedge-shaped area of low attenuation in the spleen in keeping with a splenic infarct. Seven days postadmission, the patient underwent a successful mitral valve repair. Recovery was complicated by a likely embolic infarct in the right frontal lobe, but the patient was discharged 12 days postoperative with no neurological sequelae.

Background

A literature review reveals only 22 reported cases of infective endocarditis (IE) due to Neisseria elongata (N. elongata):19 due to subsp nitroreducens, 2 due to subsp elongata and 1 due to subsp glycolytica. Although considered to be a commensal bacterium of the nose and pharynx, N. elongata can be the cause of significant disease in humans.

Case presentation

A 31-year-old Argentinian woman, residing in the UK, presented to the accident and emergency department (A&E) with a 3-week history of fever, night sweats, myalgia and lethargy with nausea and headache. She had travelled to Uganda 6 weeks previously for her job with a charitable organisation. While there, she was fit enough to run a marathon and felt well on her return. She began to feel unwell 3 weeks after her return and was advised by her general practitioner to attend A&E for a malarial screen. Examination was normal and she had two negative malarial screens in the travel clinic a week later. A course of amoxicillin initially improved her symptoms but she then continued to deteriorate and was admitted through A&E.

On admission, the temperature was 37.3°C, O₂ saturation was 95% on air, heart rate (HR) was 102 bpm and blood pressure was 99/60 mm Hg. On examination, there was a new pansystolic murmur, loudest over the left sternal edge and apex and radiating to the axilla. There was a Janeway lesion on the plantar surface of the right foot with no splinter haemorrhage or splenomegaly. There was no significant medical history and no history of invasive investigations, intravenous drug use or dental work.

Investigations

C reactive protein (CRP) was 146.3 (<5 mg/L), erythrocyte sedimentation rate was 36 (1–15 mm/h) and neutrophils 6.84 (2.2–6.3×10⁹/L). Her white blood cell count was normal but she had normocytic anaemia—red blood cell count 3.05 (3.8–5.8×10⁹/L), haemoglobin 83 (115–155 g/L). Chest X-ray was normal and ECG showed SR with an RSR pattern. Three sets of blood cultures taken at the travel clinic grew fastidious Gram-negative rods. Transthoracic echocardiogram showed a large vegetation (>1 cm) on the posterior mitral valve (MV) leaflet with prolapse of the leaflet and at least moderate mitral regurgitation. A diagnosis of MV IE was made. To delineate anatomy and assess suitability for valve repair, transoesophageal echocardiography was performed which confirmed previous findings (figure 1).

Figure 1.

(A) Four-chamber view TOE showing a 1.1 cm vegetation on a posterior leaflet of MV and (B) a colour flow image showing significant mitral regurgitation. (C) Surgical view TOE showing large vegetation on a posterior leaflet of the MV (AL, anterior leaflet; Ao, aorta; AV, atrioventricular; LA, left atrium; LV, left ventricle; MV, mitral valve; PL, posterior leaflet; TOE, transoesophageal echocardiogram).

Differential diagnosis

Non-specific symptoms of headache, malaise, myalgia, anaemia and fever following a recent travel history to a high-risk malarial country raise a suspicion of malarial infection. However, fever in the context of a new murmur is IE until proven otherwise. A definite diagnosis is made according to the Duke criteria (box 1) with either two major, one major and three minor criteria or all five minor criteria necessary for a diagnosis.

Box 1. Duke criteria for infective endocarditis.

Major criteria

Positive blood culture

• Typical organism in two separate cultures or

• Persistently positive blood cultures, for example, 3, >12 h apart (or majority if >4)

Endocardium involvement:

• Positive echocardiogram (vegetation, abscess, dehiscence of prosthetic valve) or

• New valvular regurgitation (change in murmur not sufficient)

Minor criteria

• Predisposing heart conditions or intravenous drug use

• Fever >38°C

• Vascular signs, for example, septic emboli, Janeway lesions

• Immunological signs, for example, Roth spots, Osler's nodes, glomerulonephritis

• Positive blood culture not meeting a major criterion or serological evidence of active infection with an organism consistent with infective endocarditis

Treatment

Amoxicillin was discontinued and she was started on ceftriaxone 2 g once daily. The next morning, she was given a stat dose of gentamicin due to spiking temperature (38.1°C, HR 105 bpm) as per microbiology advice and started on a regular dose of 60 mg two times per day. Since she did not have any evidence of embolisation, she was planned for initial antimicrobial treatment and surgery after the infection was under control.¹

On day 4 postadmission, the oxidase-positive, catalase-negative organism was identified as Neisseria spp. Partial sequencing of 16S ribosomal RNA subsequently identified it as N. elongata and further phenotypic testing confirmed that this was N. elongata subsp elongata (glucose negative and negative for nitrate reduction).² Provisional susceptibility testing results showed that the minimum inhibitory concentration (MIC) of ceftriaxone for the organism just exceeded the clinical breakpoint for Neisseria spp (MIC 0.19 mg/L compared with 0.125 mg/L, EUCAST clinical breakpoint guidelines)³ but was susceptible to ciprofloxacin. Ceftriaxone was discontinued and the patient switched to oral ciprofloxacin 500 mg two times per day. She remained afebrile and the CRP continued to fall (51). The patient then began reporting swelling and tenderness in the left arm down to the hand with severe left upper quadrant pain. A CT scan of the abdomen and pelvis showed a wedge-shaped area of low attenuation in the spleen in keeping with a splenic infarct.

Since there was evidence of embolic phenomena, she underwent urgent MV surgery and the MV was repaired. Surgeons removed the MV vegetation entirely via a medial sternotomy and repaired a posterior leaflet perforation with a CorMatrix patch. Neochordae were reconstructed with Gore-Tex and implanted into the leaflet. A 28 mm Edwards Physio ring was used for annuloplasty and a competent MV was obtained. The patient remained stable postsurgery and continued to recover well until day 10 when she started to report numbness in the left hand and leg. An urgent head CT showed a focal area of hyperdensity in the right frontal lobe in keeping with an embolic infarct. Her symptoms had subsided by the time she returned from the scan and was discharged at 12 days postoperative with no neurological symptoms to complete a course of treatment with oral ciprofloxacin as an outpatient.

Discussion

The patient had N. elongata subsp elongata IE as defined by the modified Duke criteria, with one major and three minor criteria present.⁴

N. elongata is a Gram-negative, rod-shaped commensal bacterium that resides in the human pharynx, respiratory secretions and blood and consists of three subspecies separated according to their biochemical differences. These are N. elongata subsp glycolytica, N. elongata subsp elongata and N. elongata subsp nitroreducens.⁵ Although considered non-pathogenic, clinical case studies have identified the N. elongata spp as rare causes of invasive human infection, including osteomyelitis, septicaemia and IE.⁶ More recently, a case of IE complicated by spondylodiscitis has been reported.⁷ Case reports from the UK, Europe, the USA, Canada and Australia have implicated all three subspecies in human infection.⁶

N. elongata induced IE typically causes acute febrile IE with large vegetations and has been reported to cause systemic embolic events, congestive heart failure, myocardial abscess and valvular damage.^{6 8–12} Despite treatment with heparin following a splenic infarct and possible embolic event in the left arm, the patient went on to develop an embolic cerebral infarct, though with no enduring neurological sequelae. This highlights the importance of adequate prophylactic anticoagulation therapy when IE due to N. elongata is suspected.

Studies have shown that clinical isolates are usually fully susceptible to amoxicillin, gentamicin, cephalosporins and ciprofloxacin but with variable sensitivity to penicillin and trimethoprim. The reduced susceptibility of this strain to ceftriaxone highlights the importance of checking the susceptibility profile carefully in individual cases. Ciprofloxacin is an exceptional oral treatment option for selected cases of IE (usually of the HACEK group) because of its excellent bioavailability and has been used to treat N. elongata IE.¹³ Despite antibiotic treatment, 12 of the 23 cases have required surgical treatment for congestive heart failure (6), abscess (4) and/or embolic events (4). The indications for valve surgery include acute heart failure, uncontrolled infection and vegetation >1 cm to reduce the risk of stroke.

Recent dental work and a history of valvular disease (endocarditis, valvular damage or rheumatic fever) have been identified as risk factors for N. elongata IE.¹¹ One case study has also suggested that N. elongata subsp nitroreducens IE can originate from skin infections.¹⁴ In this case, we were unable to identify any traditional risk factors for the development of IE. However, exhaustive exercise has been shown to interfere with immunity and cause transient immunosuppression.¹⁵ In concordance with this, epidemiological studies show that runners are at greater risk of developing upper respiratory tract infections during the first 2 weeks following competitive endurance races.¹⁶ Taking this into consideration, we postulate that endurance exercise (such as a marathon) causing immunological compromise is a risk factor for IE. This is the first case report of IE caused by a commensal pathogen that is potentially linked to endurance exercise.

Following marathon training, several components of the immune system show a decrease in number and function, reflecting the physiological stress that the body is experiencing.^{17 18} There is neutrophilia and lymphopenia with a steep drop in natural killer (NK) and T cells in the blood. There is also a decrease in NK cell cytotoxic activity and T-cell function as well as a reduction in nasal and salivary IgA concentration and nasal neutrophil phagocytosis. NK cells, neutrophils and macrophages show the greatest decrease in response to marathon running and these changes are thought to be mediated by an exercise-induced elevation in stress hormone and cytokine concentrations as well as alterations in body T, increased blood flow and dehydration.^{17 19} This immune dysfunction usually lasts between 3 and 72 h, depending on which immunological component is being measured, providing an ‘open window’ during which infections can take hold.

A handful of studies attempting to understand the differences and interactions between commensal and pathogenic Neisseria, in which N. elongata is used as a model, have been published.^20–22 Regardless, publication of clinical case studies of N. elongata infection continue to be an important way of adding to our understanding of its pathogenesis and informing management in the clinical setting.

Patient's perspective.

• I began feeling unwell at work and went home early. I felt tired and feverish, so stayed home the next day and rested. I then visited the general practitioner (GP) and was told to go to accident and emergency department (A&E) for a malarial check. This was negative and was told to rest for a few days at home. I did, but was not improving, so I returned to my GP who prescribed me with amoxicillin for flu. After 2–3 days I started feeling better and went back to work. But when my course of amoxicillin ended, the fever started returning in the evening. Again I spent 3 days at home and tried going back to work. But I was in a meeting shivering from cold and sweating, so went straight to the Hospital for Tropical illnesses in Euston, where someone listened to my heart for the first time and they heard a murmur. The younger doctor suspected endocarditis, and suggested I was admitted, but his supervisor said it was too unlikely and sent me home to rest until the cultures were ready. The next day my fever hit 39 for the first time, so we called the night emergency GP. I mentioned endocarditis and he sent me to the A&E at King’s. From there on I was very well taken care of and in great hands. I was relieved that they were able to repair the vegetation and not have to get a biological or mechanical valve. I’m also extremely relieved that the embolic infarcts did not have long-term consequences, as not being able to move my hand for 3 h was the scariest thing of all.

Learning points.

• Immunosuppression caused by endurance exercise may be a risk factor for infective endocarditis (IE) caused by Neisseria elongata.

• While considered a commensal organism of the nose and pharynx, N. elongata is known to be a cause of significant disease in humans.

• N. elongata IE is associated with high embolic risk and early surgery should be recommended, especially if there are other indications for valve surgery (eg, perforation, severe mitral regurgitation).

• Detailed susceptibility testing is required.

• Mitral valve repair is feasible in patients with IE and it should be considered.

• Further study of N. elongata is important to understand its pathogenesis in humans.