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Case of the Month

August 2018

A rare case of Salmonella Enteritidis meningitis in an HIV-infected patient


Dr Roxanne Rule, Dr Mohamed Said; Department of Medical Microbiology, University of Pretoria; Tshwane Academic Division, National Health Laboratory Services (NHLS)

Background

A 34-year-old man presented to the emergency department at a tertiary hospital in Pretoria on 6 June 2018 with a one-month history of headache and constitutional symptoms (non-productive cough, fever, loss of weight, and generalised body pain). A relative accompanying the patient reported that his symptoms had worsened over the preceding week, notably the fever and headache. In addition to the headache, the patient developed neck pain and then became confused. He had no history of vomiting, convulsions or skin rash. His relative was unable to comment on whether he had had a recent diarrhoeal illness.
There was no travel history of note. The patient was unemployed, and no household contacts had been ill.

Past medical history revealed that the patient was diagnosed with HIV about two years before admission. His CD4 count on admission was 2 cells/μl. The most recent HIV viral load available was 49 925 copies/ml in December 2017. His relative reported that the patient was taking fixed dose combination antiretroviral therapy (tenofovir, emtricitibine and efavirenz) but added that the patient was poorly adherent and had recently stopped treatment. There was no history of prior opportunistic infections.

Upon further enquiry as to social habits, the patient was reported to be an intravenous and inhalational drug user, and frequently used nyaope (a street drug cocktail containing antiretroviral drugs, heroin, marijuana and other substances). There was no history of alcohol use.

On arrival to hospital, he appeared acute on chronically ill but was haemodynamically stable with a blood pressure of 102/60, heart rate of 65 beats/min, oxygen saturation of 97% on room air, respiratory rate of 19 breaths/min and temperature of 36°C. His serum glucose level was 6.6 mmol/l.

Severe oral candidiasis was noted on general examination. On neurological examination, he was noted to be confused with a Glasgow coma scale (GCS) score of 12/15 and meningism, but no focal neurological deficits. The rest of the physical examination was unremarkable.

A chest X-ray showed no abnormalities.

Question 1: What differential diagnosis should be considered in this patient?

Answer to Question 1

  • Infectious causes of meningitis:
    • Cryptococcal meningitis
    • Bacterial meningitis
      • Tuberculous meningitis
      • Streptococcus pneumoniae
      • Neisseria meningitidis
      • Haemophilus influenzae
      • Listeria monocytogenes
      • Gram negative bacilli
      • Neurosyphilis
    • Parasitic causes:
      • Toxoplasmosis
    • Viral meningitis
      • Cytomegalovirus
      • Herpes simplex virus
      • Enteroviruses
      • Varicella zoster virus
  • Non-infectious causes: Toxins, drug overdose, trauma

    Empiric broad spectrum antibiotic therapy with ceftriaxone (2 g 12 hourly IVI) was initiated. Adjunctive intravenous corticosteroid therapy (dexamethasone 8 mg 8- hourly) was also administered, despite cryptococcal meningitis being included in the differential diagnosis. Other treatment included prophylactic trimethoprim-sulfamethoxazole (2 tablets daily per os), vitamin B complex supplementation (2 tablets daily per os) and pyridoxine supplementation (25 mg daily per os). Prophylactic heparin (40 mg daily subcutaneously) was added to prevent the development of deep venous thrombosis.

    A lumbar puncture was performed on admission (including CSF cryptococcal tests), along with blood cultures, a full blood count, renal and liver function tests, serum cryptococcal antigen, rapid plasma reagin, and inflammatory markers.

Question 2: Describe the typical findings in cerebrospinal fluid parameters with bacterial meningitis, cryptococcal meningitis, viral meningitis and TB meningitis

Answer to Question 2

The full blood count showed a mild normocytic hypochromic anaemia with Hb of 10.3g/dL, a white cell count of 10.53 x 109/L with a neutrophilia of 8.49 x 109/L, and a platelet count of 460 x 109/L. C-reactive protein and erythrocyte sedimentation rate values were elevated at 130 mg/L and 125 mm/hr respectively. Renal function tests revealed an elevated urea of 13.5 mmol/L with a normal creatinine of 80 μmol/L. The electrolytes were within normal range. Liver function tests revealed a mild elevation in aspartate transaminase (51 U/L) and gamma-glutamyl transferase (92 U/L). Serum cryptococcal antigen and rapid plasma reagin were both negative. Hepatitis B surface antigen was also negative.

Two blood culture bottles were collected on admission. The aerobic bottle grew a coagulase negative Staphylococcus (blood culture flagged positive after 22 hours) and was considered a contaminant. The partner bottle (a paediatric bottle) yielded no growth after 5 days of incubation.

On day two, following the consultant ward round, it was decided to initiate anti-tuberculosis therapy in light of an elevated cerebrospinal fluid adenosine deaminase level (>120 U/L) [note: it is not clear if CSF Gram stain results were considered at the time that this decision was made]. Gene Xpert Ultra on the same specimen was negative. Rifafour, at a dose of 4 tablets daily per os, was started.

The lumbar puncture yielded the following findings:
  • The cerebrospinal fluid was purulent on macroscopic appearance;
  • The cell count, India ink and cryptococcal antigen tests could not be performed due to the viscosity of the specimen;
  • Gram stain showed numerous Gram-negative bacilli.
  • Protein was high at 9.90 g/L, with CSF glucose level of 0.1 mmol/L
Routine culture procedures were followed, with the cerebrospinal fluid specimen inoculated on blood agar, chocolate agar and MacConkey agar plates. Flat, dry, non-lactose fermenting bacterial colonies were cultured. On agglutination, these tested positive for Group D with the Wellcolex Colour Salmonella Agglutination (Remel, London, UK) test. The identification of the culture was then confirmed as Salmonella group with the Vitek 2 (bioMérieux, France) automated identification system. Serotyping was performed according to the Kauffman White scheme which revealed the organism to be Salmonella Enteritidis.

Question 3: How does invasive infection with non-typhoidal Salmonellae (NTS) occur in HIV-infected patients?

Answer to Question 3

NTS are transmitted through contaminated food or water, contact with animals, and in some cases contact with infected humans. The infectious dose ranges from 103 - 106 organisms. Once ingested, NTS colonise the terminal ileum and colon. A fraction of NTS invade intestinal epithelial cells resulting in intestinal inflammation. NTS exploit this gut mucosal inflammatory response and are able to out-compete the normal gut flora. Crossing the epithelium results in a bacteraemia, following which the NTS enter and survive within macrophages and dendritic cells. This may result in a bloodstream infection or other foci of extraintestinal disease Additionally, persistence in macrophages in systemic tissues can result in recrudescence of invasive disease.

Increased risk for invasive NTS HIV-infected patients can be attributed to a number of immunological defects: Firstly, it has been shown that a significant reduction in gut CD4 T-cells occurs with HIV infection, especially interleukin 17 producing T-cells (Th17 cells) which play a crucial role in gut mucosal defence and stimulation of the innate immune system. With a reduction of Th17 cells, translocation and invasion into the blood stream may occur. Secondly, intracellular persistence of the organism and recrudescence of invasive NTS infection occurs due to dysregulated cytokine production. Finally, the presence of IgG antibodies against NTS lipopolysaccharide has been shown to impair the killing mechanisms of other, effective antibodies directed against outer membrane proteins through competition.

Question 4: What are the risk factors for invasive NTS infections?

Answer to Question 4

  • Extremes of age
  • Immunosuppression
    • Common variable immunodeficiency (inherited)
    • HIV infection
    • Malignancies (particularly lymphoproliferative)
    • Immunosuppressive therapy
    • Malnutrition
  • Malaria
  • Sickle cell disease
  • Anaemia
  • Achlorhydria or hypochlorhydria

On day three of admission (8 June 2018), the patient’s condition deteriorated, with a decrease in GCS score to 10/15. At this point, his antibiotic therapy was changed to meropenem 2 g to be infused over 4 hours 8 hourly to cover for an extended spectrum β-lactamase producing Salmonella species. Antimicrobial susceptibility was not yet available at this time.

Question 5: What is the treatment of choice for NTS meningitis?

Answer to Question 5

Therapy should be guided by antimicrobial susceptibility testing. The agent of choice is ceftriaxone, but in cases where the isolate is resistant to ceftriaxone, meropenem is advised. Therapy for at least 3 weeks is recommended. This form of invasive NTS disease typically has a high case-fatality ratio (20%-60%) despite appropriate treatment.

With phenotypic antimicrobial susceptibility testing methods, using Vitek 2 and confirmed by Etest (bioMérieux, France), the isolate was found to be susceptible to both ceftriaxone (Etest MIC = 0.064 µg/ml) and ciprofloxacin (Etest MIC = 0.023 μg/ml). The isolate was also susceptible to the carbapenems, with MICs of <=0.5 μg/ml for ertapenem, and <=0.25 μg/ml for both imipenem and meropenem on Vitek 2.

After discussing the antimicrobial susceptibility results with the treating clinician, he was switched back to ceftriaxone 2g 12 hourly IVI on day 6 of admission (11 June 2018). Unfortunately, despite appropriate antimicrobial treatment, the patient succumbed to his illness and died later the same day.

References

  1. Feasey NA, Dougan G, Kingsley RA, Heyderman RS, Gordon MA. Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet. 2012 June;379: 2489 – 2499
  2. Crump JA, Sjölund-Karlsson M, Gordon MA, Parrye CM. Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections. Clin Microbiol Rev. 2015 Oct;28(4):901-937
  3. Le-Bury G, Niedergand F. Defective phagocytic properties of HIV-infected macrophages: how might they be implicated in the development of invasive Salmonella Typhimurium? Front Immunol 2018, 9;531:1-12
  4. Haselbeck AH, Panzner U, Im J, Baker S, Meyer CG, Marks F. Current perspectives on invasive nontyphoidal Salmonella disease. Curr Opin Infect Dis 2017, 30:498-503
  5. Uche IV, MacLennan CA, Saul A. A systematic review of the incidence, risk factors and case fatality rates of investive nontyphoidal Salmonella disease in Africa (1966-2014). PLoS Negl Trop Dis 2017, 11(1):e0005118.
  6. Tunkel AR, van de Beek D, Scheld WM. Acute meningitis. In: Bennett JE, Doli R, Blaser MJ, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadephia, United States of America: Elsevier Saunders, 2015:1097-1137

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