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Case of the Month 

April 2021

Tamsin Lovelock1, Jantjie J Taljaard1, Jan Loot Pretorius2, Arifa Parker1

1 Division of Infectious Diseases, Department of Medicine, Stellenbosch University and Tygerberg Hospital

2 Worcester Hospital

Word Count: 1184

Case Presentation

A 15-year-old grade 8 scholar first presented to Worcester Hospital in January 2021. She had been unwell for several months with fatigue, joint pain and skin rashes. Examination revealed pallor, a typical malar rash, Raynaud’s phenomenon and a general appearance of chronic illness. No swollen or tender joints were documented, although the patient reported arthralgias. Investigations revealed Coombs positive anaemia, proteinuria and mild renal dysfunction. A presumptive diagnosis of systemic lupus erythematosus (SLE) was made and she was discharged home on prednisone 40mg daily pending results of an autoimmune workup.

She subsequently presented to Worcester Hospital again in February 2021 with fever and swollen, painful knees. Autoimmune workup confirmed SLE with positive anti-nuclear, anti-dsDNA, anti-RNP and anti-Smith antibodies and low complement levels.   Her arthritis was initially attributed to a lupus flare. Chloroquine was initiated and prednisone continued. The left knee was very warm to touch and exquisitely tender. She remained pyrexial and CRP was markedly elevated at 233mg/L, and there was concern of sepsis. Joint aspirate yielded frank pus, confirming septic arthritis. The patient was initiated on ceftriaxone but later changed to ciprofloxacin in response to a culture result of non-typhi Salmonella (NTS) species on urine, blood and joint aspirate. She was transferred to Tygerberg Hospital on 1 March for specialist management of her lupus. Multiple specimens were sent for culture during her admission:


Date

Specimen

Culture result

11/02/2021

Urine

Salmonella (non-typhi)

11/02/2021

Blood

No growth

18/02/2021

Joint aspirate

Salmonella (non-typhi)

20/02/2021

Blood

Salmonella (non-typhi)

03/03/2021

Blood

No growth

04/03/2021

Stool

Salmonella negative

18/03/2021

Blood

Salmonella (non-typhi)

22/03/2021

Joint aspirate

Salmonella (non-typhi)

Current management

She is receiving oral ciprofloxacin for 6- 8 weeks and her arthritis has settled well on treatment. Her left knee sustained severe joint damage and she will likely require arthroplasty to regain full function. Her mobility and function is currently improving with physiotherapy and she is attending school at the hospital. Prednisone has been weaned to 5mg daily and further immunosuppressive therapy has been avoided. Renal biopsy is planned but has been deferred.


Discussion:

This case lends itself to discussion of 2 important topics- septic arthritis and invasive non-typhoidal Salmonella


1. Septic arthritis in the immunocompetent and immunocompromised host


Septic arthritis is an orthopaedic emergency.  Timely diagnosis is important to prevent disabling joint damage. Clinical presentation may be subtle in immunocompromised patients, and an infectious aetiology for arthritis may be overlooked in patients known with a rheumatologic condition.

Arthrocentesis should be performed when there is any suspicion of septic arthritis and usually yields a purulent aspirate with predominant neutrophilia. Visualizing organisms on gram stain or culture confirms septic arthritis.


What are the risk factors for septic arthritis?


Septic arthritis most frequently arises from haematogenous seeding of microorganisms to joints, thus many of the risk factors for septic arthritis are those which increase the risk of bacteraemia. These include older age, diabetes mellitus, chronic organ failures, immunosuppression and intravenous drug use. However, preexisting joint disease remains the most significant predisposing factor for septic arthritis. Abnormal joints are more likely to become a septic focus following bacteraemia and patients with joint disease are more likely to undergo joint surgery and intra-articular injection of corticosteroids, which may also increase risk for septic arthritis.

Septic arthritis infrequently results from penetrating injury or contiguous spread from overlying skin or soft tissue infection. A fifth of patients with septic arthritis will have no predisposing clinical conditions.

What are the likely pathogens?


Historically, Neisseria gonorrhoeae was the most common cause of septic arthritis, but in the post-antibiotic era this has been superseded by Staphylococcus aureus. S aureus is a common cause of bacteraemia and the organism possesses multiple virulence factors which facilitate entry into joint tissues and bone. Methicillin resistant S aureus is becoming increasingly common. β-haemolytic streptococci are the second most commonly isolated organisms, predominantly groups A, C, F and G.

Gram negative bacilli are important in the elderly and in immunocompromised hosts. Escherichia coli is commonly found but Listeria, Klebsiella, Salmonella, Enterobacter, and Proteus species are also important. Pseudomonas aeruginosa is also significant in patients with a history of intravenous drug use.

In the immunocompromised host, Staphylococcal and Streptococcal infections remain the most important causes overall, but gram negatives and unusual or opportunistic organisms will be more common than in immunocompetent hosts.

What is the management of septic arthritis?


Management of septic arthritis consists of both joint drainage and antimicrobial therapy.

Drainage is important for source control and to limit damage to the joint and can be achieved by needle aspiration or by arthroscopy or open drainage in theatre. Surgical drainage is preferred when repeated joint aspiration is not feasible or fails to control the infection.

Empiric antimicrobial therapy should be initiated without delay. A suggested empiric regimen for community acquired septic arthritis in an immunocompetent host:

 

Cloxacillin 2g IVI 6 hourly

OR

Ceftriaxone 1g IVI daily 

 

A suggested empiric regimen in the immunocompromised or hospitalized patient (when MRSA or GNB may be suspected):

Cefepime 2g IVI 8 hourly

AND

Vancomycin 1g IVI 12 hourly 

 

Antimicrobial therapy must be de-escalated as soon as an organism is identified and directed therapy should be continued parenterally for a minimum of 2 weeks, followed by oral therapy for an additional 1 to 2 weeks. Hard to treat pathogens, persistent immunosuppression or concomitant osteomyelitis or endocarditis may necessitate a longer duration of therapy.

2. Invasive non-typhoidal Salmonella

In contrast to Salmonella typhi and paratyphi, where the only reservoir is humans, NTS may be found in many animals and is most frequently transmitted to humans via contaminated food or water or may be acquired directly from animals or their environment.   NTS is endemic in Africa and contributes significantly to the burden of disease in sub-Saharan Africa.

What is the spectrum of disease of NTS?

Infection with non-typhoidal Salmonella (NTS) typically results in self-limiting gastroenteritis in immunocompetent hosts. The presence of NTS bacteraemia or extra-intestinal disease should therefore raise suspicion for immunosuppression. Invasive NTS is a common cause of a blood stream infection in HIV but is also commonly identified in other immunocompromised populations. Salmonella species invade macrophages but are resistant to phagocytic killing and can survive and replicate intracellularly leading to disseminated disease and acting as a reservoir of infection. For this reason, invasive NTS is particularly prevalent in conditions with impaired macrophage function including malaria, bilharzia, sickle-cell disease and glucocorticoid use.

There is no pathognomonic clinical presentation and NTS has been isolated from almost every anatomical location. The diagnosis must be suspected and may be overlooked in the absence of cultures.

What are the principles of management of invasive NTS disease?

Management of invasive NTS disease includes surgical drainage and source control of local disease if present, combined with appropriate antimicrobial therapy. Fluoroquinolones (ciprofloxacin 400mg IVI 12 hourly) are the usual first choice due to good intracellular penetration and high oral bioavailability, allowing transition to oral therapy. A third-generation cephalosporin (ceftriaxone 2g IVI daily) is a reasonable alternative. Susceptibility testing is important as resistance to both quinolones and cephalosporins has been documented.

How long should antimicrobial therapy be continued?

Two weeks of appropriate antibiotics are adequate for uncomplicated NTS bacteraemia in the immunocompetent host but immunocompromised patients require prolonged therapy for 4 to 6 weeks as NTS is a hardy organism which can establish a reservoir in the reticuloendothelial system and be difficult to eradicate.

Recommended reading

Ohl CA. Infectious arthritis of native joints. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia: Elsevier; 2020. p1400-17

Wang DA, Tambyah PA. Septic arthritis in immunocompetent and immunosuppressed hosts. Best Pract Res Clin Rheumatol. 2015 Apr;29(2):275-89. doi: 10.1016/j.berh.2015.05.008. Epub 2015 Jun 16. PMID: 26362744.

Pegues DA, Miller SI. Salmonella species, including Salmonella typhi. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia: Elsevier; 2020. P2725-36

Mahon BE, Fields PI. Invasive Infections with Nontyphoidal Salmonella in Sub-Saharan Africa. Microbiol Spectr. 2016 Jun;4(3). doi: 10.1128/microbiolspec.EI10-0015-2016. PMID: 27337467.

GBD 2017 Non-Typhoidal Salmonella Invasive Disease Collaborators. The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019 Dec;19(12):1312-1324. doi: 10.1016/S1473-3099(19)30418-9. Epub 2019 Sep 24. PMID: 31562022; PMCID: PMC6892270.

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