Sticky Business: a syndrome of mucoid bacterial spread

Abstract

A 70-year-old man presented with acute wrist pain concerning for septic arthritis. Shortly thereafter, he developed acute monocular vision loss and was diagnosed with endogenous endophthalmitis. Subsequent imaging revealed numerous visceral abscesses and a mycotic abdominal aortic aneurysm. Cultures, in conjunction with the clinical syndrome, were strongly suggestive of hypervirulent Klebsiella pneumoniae syndrome (hvKP). hvKP syndrome may present with multiple sites of infection or subsequent metastatic spread may develop; the liver, lungs, central nervous system and eye are most commonly involved. Prompt source control and intravenous antibiotic therapy leads to a cure in the majority of patients. This case highlights the risk factors, presentation, management and prognosis of this disease as well as its increasing incidence in North America and Europe.

Background

Originally described in East Asia, hypervirulent Klebsiella pneumoniae syndrome (hvKP) has become a well-recognised clinical syndrome in North America and Europe. Metastatic Klebsiella infection has been described in virtually all organs but has a propensity for the liver, lungs, central nervous system (CNS) and eye. Diabetes mellitus is frequently associated with invasive hvKP, although this syndrome has been known to affect otherwise healthy individuals. Aggressive source control and prolonged intravenous antibiotics are typically curative, although permanent morbidity (eg, blindness) may occur in some patients. Greater awareness of hvKP will lead to more effective diagnosis and management of this increasingly recognised clinical syndrome.

Case presentation

A 70-year-old man presented to the emergency department with 10 days of worsening left wrist pain. There was no history of trauma, recent illness or prior joint symptoms. He had not seen a physician for more than 30 years and had no known medical history. There was no history of smoking, alcohol use or injection drug use. He had emigrated from Guam but had no recent travel outside California. He also described polyuria and polydipsia but denied constitutional symptoms, fever, chills, nausea, vomiting, light-headedness, chest pain or shortness of breath.

Temperature was 36.7°C, blood pressure was 137/82 mm Hg, pulse was 117 beats/min, respirations were 22 breaths/min and oxygen saturation was 97% on room air. On examination, he was in no apparent distress. His cardiopulmonary and abdominal examination was normal. His left wrist and hand were swollen, erythematous, and range of motion was limited due to severe pain (figure 1). No sensory deficits were noted and 2+pulses were present. He was admitted to the hospital for further evaluation.

Figure 1.

Erythematous and edematous left hand and wrist.

Investigations

Laboratory studies were notable for a leucocyte count of 20.8×10⁹/L (normal: 4–10×10⁹/L) with neutrophilic predominance, creatinine of 1.57 mg/dL (baseline unknown) and blood glucose level of 507 mg/dL (normal: <126 mg/dL). Joint aspiration of the left wrist was attempted, but no fluid could be collected. Given concern for sepsis, he was started on intravenous fluids and empiric vancomycin and piperacillin/tazobactam.

Within 12 hours of admission, he developed acute painless monocular vision loss in the left eye. He had no other neurological deficits, and MRI of the brain was normal. Ophthalmology was consulted and diagnosed endogenous endophthalmitis, given the clinical context of probable systemic infection and ocular findings of conjunctival chemosis, hypopyon, and diffuse haze and debris obscuring retinal view. Aqueous and vitreous cultures were sent for confirmation. Subsequently, CT of the chest, abdomen and pelvis showed multiple subcentimeter cavitary nodules in the lungs, multiple liver abscesses measuring up to 3.8 cm (figure 2A), multiple perinephric abscesses measuring up to 3 cm and a 3.2 cm prostatic abscess. A 2.3 cm mycotic aneurysm of the infrarenal aorta with evidence of aortitis and contained rupture was also present (figure 2B). Transthoracic and transoesophageal echocardiograms were negative for endocarditis. Further studies were notable for a haemoglobin A1c of 10.4% (normal: <6.5%) and blood cultures were positive for gram-negative bacilli (pending speciation).

Figure 2.

(A) Coronal view of the CT abdomen and pelvis with contrast demonstrating a 3.8 cm abscess in segment 4b of the liver (arrow). (B) Axial view of the CT abdomen and pelvis with contrast demonstrating a 2.3  cm lobulated saccular mycotic aneurysm with surrounding inflammation (arrow), consistent with aortitis.

Differential diagnosis

This case involves an immunocompetent host with multifocal abscesses in the liver, lungs, prostate, joint and anterior chamber of the eye. The differential diagnosis for this clinical presentation includes several bacterial species in addition to gram-negative bacilli. Disseminated fungal infection would be very unlikely in the absence of profound immunosuppression, an indwelling vascular catheter or other prosthetic device.

Staphylococcus aureus may form intra-abdominal abscesses, and the patient’s initial articular manifestation raises concerns that this began as a primary joint or soft-tissue infection with haematogenous spread, a common clinical progression for S. aureus. Even in the absence of endocarditis, as is suggested by negative echocardiogram, metastatic spread and abscess formation may occur in up to 30% of S. aureus bacteraemia.¹ However, S. aureus abscesses due to haematogenous spread are mostly limited to the bones, joints, kidneys and lungs, lacking the extensive intra-abdominal manifestations seen in this case.

The Streptococcus anginosus group has also been implicated in disseminated infection leading to abscess formation in the brain, lung, liver, kidney and soft-tissues; cases of endogenous endophthalmitis secondary to liver abscess have also been reported.^{2 3} However, most case reports (92%) of S. anginosus infections involve metastatic abscess formation in the CNS, the absence of which makes this pathogen less likely in this patient.³

K. pneumoniae is also known to cause intra-abdominal abscesses with widespread metastasis. The hvKP syndrome involves multifocal infection manifesting most commonly with endophthalmitis, meningitis, lung abscess and liver abscess.⁴ In the context of the gram-negative culture results, this was considered to be the most likely aetiology for this patient. In comparison, Escherichia coli and other Enterobacteriaceae generally do not present in this widely disseminated pattern in immunocompetent hosts.

Other bacterial pathogens less commonly implicated in intra-abdominal infections with metastatic spread include Group C and D Streptococcus spp., non-typhoidal Salmonella spp., Nocardia spp and Listeria monocytogenes.

Treatment

Blood cultures grew K. pneumoniae and the patient was started on a 6-week course of intravenous ceftriaxone based on antimicrobial susceptibility testing, which demonstrated pansensitivity. He underwent emergent repair of the mycotic aortic aneurysm, CT-guided drainage of the liver abscesses, intravitreal antibiotic injection in the left eye, and incision and drainage of the left wrist. In addition, he received treatment and counselling for his diabetes mellitus.

Outcome and follow-up

Cultures from the liver and aqueous humour also grew K. pneumoniae, supporting the diagnosis of hvKP syndrome. The patient improved on antibiotic therapy once source control was achieved and he was scheduled for repeat CT chest, abdomen and pelvis to evaluate for interval improvement of the abscesses. On discharge, his visual acuity was stable but limited to hand motion in the left eye.

Discussion

hvKP syndrome describes a community-acquired bacterial infection that classically begins as a pyogenic liver abscess (in the absence of biliary tract disease) with subsequent haematogenous dissemination to distant organs.^{5 6} The most common extrahepatic manifestations are endophthalmitis, meningitis and lung abscess, which may also occur without hepatic involvement.

First described in Taiwan in 1986, hvKP spreads to other areas in the Asian Pacific Rim and is now seen in the USA, Canada and Europe.^{5 7 8} Our review of the literature demonstrated over 800 reported cases worldwide, but as this condition is not reportable, a more accurate assessment of disease incidence cannot be made.⁵ While the mode of transmission has not been established, it is thought to involve colonisation of the gastrointestinal tract. A liver abscess subsequently develops via bacterial translocation across the intestinal epithelium or ascension up the biliary tree.^{5 6}

Risk factors for hvKP include Asian ethnicity or immigration from the Asian Pacific Rim, although it is unclear whether this represents endemicity versus genetic predisposition.4 5 9 10 Men are more commonly affected than women.^{5 8} Diabetes mellitus has been reported in 60%–93% of patients with invasive hvKP and is thought to be an independent risk factor for metastatic complications.^{8 11–13} However, as more is discovered about the specific virulence factors involved in hvKP strains, this association has been called into question.^{6 9} This syndrome may also develop without identifiable risk factors in young, otherwise healthy patients.^{5 6}

Compared with ‘classical’ K. pneumoniae, bacterial strains in hvKP have developed the ability to increase production of capsular polysaccharides, augmenting resistance to complement, antibiotic peptides and phagocyte activity.⁶ These properties confer a mucoid phenotype to the bacterial colonies, which are often described as ‘hypermucoviscous’ K. pneumoniae when grown on agar plates.⁶ Other contributing virulence factors include an increased ability to produce aerobactin (a bacterial siderophore) and colibactin (a molecule which mediates DNA damage).⁴ It has been proposed that detection of these virulence genes be used to develop laboratory markers for hvKP strains as a diagnostic test; a recent study described greater than 95% accuracy for identifying five virulence genes, which has promising applications in the clinical management of this syndrome.¹⁴

The clinical presentation of hvKP is directly related to the specific organs involved, though constitutional symptoms are present in the majority of patients.^{5 10} In the classical pathogenesis involving a primary liver abscess, the disease is often subclinical until secondary organs are affected. Endophthalmitis generally presents with painful ocular swelling, redness, and blurred vision and can be bilateral in up to 25% of patients.⁶ Thus, this case represents an atypical (painless) manifestation of the disease. Pulmonary manifestations include bilateral cavitary nodules that disproportionally affect the lower lobes. Central nervous symptoms complications include meningitis and brain abscess. Other reported sites of metastasis include the skin and soft-tissue, prostate, ascites and spleen.⁶ This is in contrast to ‘classical’ K. pneumoniae, where the infection is often limited to the primary focus (eg, pyelonephritis) even in the setting of bacteraemia. In this case, the osteoarticular and vascular complications represent rare manifestations of this syndrome.

Most hvKP strains are sensitive to cephalosporins, which is the preferred antibacterial agent, though aminopenicillins, carbapenems, fluoroquinolones and aminoglycosides have also been used successfully; most hvKP is ampicillin resistant.5 6 8 9 However, there have been several reports of extended-spectrum beta-lactamase- (ESBL) and carbapenemase-producing K. pneumoniae in the literature, so antimicrobial resistance may be of increasing concern.^{4 15} Duration of treatment is generally 4–6 weeks after source control, which may require confirmation by repeat cross-sectional imaging. Endophthalmitis should be treated with combined intravitreal and intravenous antibiotics. Strict blood glucose control may reduce the risk of metastatic complications.⁵

Overall mortality is 5%, but rates vary depending on organ involvement.⁵ The worst prognosis occurs with necrotising fasciitis or pulmonary involvement, with mortality rates reaching nearly 50%.⁶ Significant morbidity has also been reported in patients with ocular involvement, with some case series estimating permanent visual impairment or blindness in 70%–85% of these patients.^{5 8 9}

Learning points.

• Hypervirulent Klebsiella pneumoniae (hvKP) is an increasingly recognised clinical syndrome in North America and Europe.

• In hvKP, bacteria have developed additional virulence factors that confer resistance to host immune defences as well as a mucoid phenotype. Several biomarkers have been shown to have high diagnostic accuracy for hvKP virulence genes, which may be used in the future to direct clinical management.

• hvKP syndrome may present with multiple sites of infection or subsequent metastatic spread after the initiation of therapy; common sequelae include endophthalmitis, meningitis, lung abscess and liver abscess.

• Frequently described risk factors for this infection include diabetes mellitus and East Asian ethnicity.

• Most hvKP strains are cephalosporin sensitive, but clinicians should be aware of the potential for ESBL- and carbapenemase-producing strains.