ABOUT FIDSSA

Case of the Month

February 2023

Eiman Alblooshi, Pediatric infectious disease fellow, UKZN

Reviewed by Prof. Moherndran Archary, UKZN.

Case Presentation:

B.A is a 12-year-old boy, living with HIV and virologically suppressed since 2020 after being changed to a Dolutegravir based antiretroviral therapy regimen. He was started on ART in 2012, with a long history of prior immunological and virological failure. He presented to the hospital with a 4-day history of vomiting, headache and blurred vision.

In Emergency Department: he was febrile, tachycardic and drowsy.  His Glasgow Coma Scale was 10/15. He had neck stiffness with positive Kernig’s sign.

Considering the clinical picture of fever associated with neurological deterioration and meningitic signs, a meningitis was high on the list of differentials.

Initial investigations: 
  • Cerebral CT scan: Unremarkable with no evidence of an intracranial lesion or hydrocephalus

Laboratory results:

Lumbar puncture results:

  • CSF specific tests:
  • Gram stain : yeast and 1+leukocytes
  • CrAg : positive
  • CSF Culture : sent
  • TB GeneXpert: negative

 

The results confirmed the diagnosis of cryptococcal meningitis (CM) in this patient.

B.A received 2 weeks of Amphotericin B deoxycholate and fluconazole (flucytosine was not available). He improved clinically and discharged home to continue fluconazole at a dose of 6mg/kg/day. 

B.A presented to the hospital after 4 weeks with fever, severe headache, photophobia and neck stiffness. His physical examination was showing signs of meningitis. The family reported adherence  to current treatment. 

A lumbar puncture was repeated and showed the following results:

  • Opening pressure was not performed
  • Gram stain: Leukocytes 2+, no bacteria, no yeast observed
  • CSF analysis: clear, colorless
    • Glucose: 1.2 mmol/L
    • Protein:1.16 g/L (0.15-0.45)
    • Polymorphs: 28 /uL
    • Lymphocytes: 2 /uL
  • CrAg: positive
  • CSF GenXpert : not detected
  • CSF Culture: Sent for bacterial and fungal culture (both came back negative later)

On repeated Labs: CD4 count : 540 cells/mm3 (26.6%) , HIV VL: LTDL

CSF culture from the first admission was reviewed and cultured Cryptococcus gatii and Cryptococcus laurentii.

Differential Diagnosis:

The possible differential diagnosis for CM Symptomatic relapse include:

Management

The management of cryptococcal meningitis is divided into 3 phases:

  • Induction phase (2 weeks)
  • Consolidation Phase (Further 8 weeks)
  • Maintenance (Secondary prophylaxis)

Combination antifungal therapy has improved outcomes and antifungal monotherapy should be avoided. Flucytosine containing treatment regimens have higher survival rates. Cryptococcus species are intrinsically resistant to  Echinocandins (echinocandins).  

World Health Organization (WHO) guidelines:

https://www.who.int/publications/i/item/9789240052178


  • At the first presentation: B.A received 2 weeks of Amphotericin B deoxycholate 1 mg/kg/day IV and fluconazole 12mg/kg/day followed by fluconazole 6mg/kg/day (consolidation phase).

  • Second presentation: the problem list was as following:
    •  Symptoms of meningitis with positive CSF analysis and negative culture on repeated CSF.
    •    Initial CSF CX grew C. Gatii and C. Laurentii
    • The clinical deterioration presented at the same time of CD4 count improvement.
    • CrAg tests remain positive for weeks to months after cryptococcal meningitis has been treated. and cannot be relied on to diagnose a Cryptococcal meningitis relapse. The gold standard test is a CSF fungal culture which was negative on the second admission.

Final diagnosis

Can cryptococcal meningitis occur in virally suppressed patient?

Yes, because the risk factor to develop Cryptococcal meningitis is not the presence of an HIV infection, but a low number of CD4 T-cells (increasing risk when CD4+ < 350/mm3). 

Cryptococcal meningitis can accur in:

  • Immunodeficient patients: cellular immunodeficiency, post organ-transplant and patients on immunosuppressive medication.
  • Immunocompetent patients.
  • Congenital/transplacental cryptococcal infection is also reported.

Cryptococcus lives as a yeast in the environment. Humans and animals can become infected after inhaling airborne, dehydrated yeast cells or spores, which travel through the respiratory tract and enter the lungs. The environment inside the host body signals the progression of the infection to disseminate and infect other organs like CNS.

Our patient showed a viro-immunological discordance (supressed viral load with low CD4 count). These immunological discordant responses among people living with HIV have reported in 13 to 29% of patients. 

The risk factors for viro-immunological discordance are:

  • Younger age
  • Poor HIV treatment adherence
  • Male gender
  •  Low baseline CD4+ count
  • Hepatitis C co-infection. 

Discordance response increases the risk for:

  • opportunistic infections
  • stroke, liver and kidney failure, meningitis and endocarditis. 

Cryptococcus gatii and Cryptococcus laurentii. 

The major pathogenic species in the genus Cryptococcus are Cryptococcus neoformans and Cryptococcus gattii. Previously, C. gattii infection was restricted to tropical and subtropical regions. However, outbreaks have been recorded in North America. C. gattii shows higher level of heteroresistance to fluconazole compared to C. neoformans.

Cryptococcus species other than C. neoformans and C. gattii were previously considered to be non-pathogenic to humans; however, opportunistic infections associated with rare Cryptococcus spp., such as Cryptococcus laurentii and Cryptococcus albidus, are increasingly being reported.

C. laurentii has been reported that is has various levels of fluconazole resistances.

Does our patient need a change of his management in the second admission?

C. laurentii infections are rare and a standard treatment has not yet been established.

NIH Guideline for adults and adolescents with cryptococcal meningitis relapse recommend the following:

  • Testing:
    • Cryptococcus isolates should undergo antifungal susceptibility testing.
  • Review induction phase:
    • Patients who failed fluconazole monotherapy should be switched to amphotericin B, with or without flucytosine.
    • Those initially treated with amphotericin B formulation should remain on this agent until clinical response occurs.
    • Liposomal amphotericin B or amphotericin B lipid complex is better tolerated and has greater efficacy than the deoxycholate formulation and should be considered when initial treatment with other regimens fails.
  • Confirm response to new regimen:
    • Verify CSF culture sterility at the completion of re-induction therapy.
  • Recommendations for Consolidation therapy:
    • Fluconazole at a higher dose of 1,200 mg per day and optimization of ART.
    • Posaconazole, voriconazole, and isavuconazole—have activity against Cryptococcus spp. in vitro and may have a role in salvage therapy, but no specific advantages over fluconazole unless in vitro susceptibility testing indicates high-level fluconazole resistance.
    •  In case of decreased azole-susceptibility ( >16 µg/mL MIC for fluconazole):
      • Adjunctive weekly amphotericin B administration during consolidation therapy.
      • Higher doses of fluconazole (1,200 mg per day) in combination with flucytosine also may be considered.

Does our patient has IRIS?

Although the patient was virologically supressed upon initial admission, his initial CD4 count was low showing viro-immunological discordance. After cryptococcal meningitis treatment the CD4 count improved. The temporal association of clinical deterioration with immune reconstruction in absence of microbiological relapse indicating paradoxical IRIS. 

Immune Reconstitution Inflammatory Syndrome (IRIS) refers to a collection of inflammatory disorders, predominantly related to infectious processes that manifest after the initiation of antiretroviral therapy (ART) and can be classified as unmasking or paradoxical. 

Common Scenarios of HIV Immune Reconstitution Inflammatory Syndrome (IRIS) 

“Unmasking” IRIS

  • Occult, subclinical opportunistic infection
  • Unmasked by immune recovery following ART initiation
  • Infectious pathogen typically detectable 

“Paradoxical” IRIS 

  • Clinical recrudescence of a successfully treated infection
  • Symptomatic relapse despite initial clinical improvement and continued microbiologic treatment success.
  • Antigen driven immune activation, often with a robust immune response in the setting of few or no detectable organisms.
  • Culture may be sterile due to effective opportunistic infection treatment

 

References

  • Garcia-Rubio, R., de Oliveira, H. C., Rivera, J., & Trevijano-Contador, N. (2020). The fungal cell wall: Candida, Cryptococcus, and aspergillus species. Frontiers in Microbiology, 10. https://doi.org/10.3389/fmicb.2019.02993
  • World Health Organization. (n.d.). Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. World Health Organization. Retrieved September 5, 2022, from https://www.who.int/publications-detail-redirect/9789240052178
  • Li, S. S., & Mody, C. H. (2010). Cryptococcus. Proceedings of the American Thoracic Society, 7(3), 186–196. https://doi.org/10.1513/pats.200907-063al
  • Hailu, G. G., & Wasihun, A. G. (2021). Immunological and virological discordance among people living with HIV on highly active antiretroviral therapy in Tigray, Northern Ethiopia. BMC Infectious Diseases, 21(1). https://doi.org/10.1186/s12879-021-06206-4
  •  Govender, N. P., Meintjes, G., Mangena, P., Nel, J., Potgieter, S., Reddy, D., Rabie, H., Wilson, D., Black, J., Boulware, D., Boyles, T., Chiller, T., Dawood, H., Dlamini, S., Harrison, T. S., Ive, P., Jarvis, J., Karstaedt, A., Madua, M. C., … Wake, R. (2019). Southern African HIV clinicians society guideline for the prevention, diagnosis and management of cryptococcal disease among HIV-infected persons: 2019 update. Southern African Journal of HIV Medicine, 20(1). https://doi.org/10.4102/sajhivmed.v20i1.1030  
  • Zuma, P., Ramsamy, Y., Mlisana, K., & Archary, M. (2020). Serum cryptococcal antigen testing in immunosuppressed HIV-positive children and adolescents. Pediatric Infectious Disease Journal, 39(3), 217–220. https://doi.org/10.1097/inf.0000000000002538
  • K Musubire, A. (2013). Diagnosis and management of cryptococcal relapse. Journal of AIDS & Clinical Research, 01(S3). https://doi.org/10.4172/2155-6113.s3-003
  • Morales-López, S. E., & Garcia-Effron, G. (2021). Infections due to rare Cryptococcus species. A literature review. Journal of Fungi, 7(4), 279. https://doi.org/10.3390/jof7040279
  • Cano, E. J., Yetmar, Z. A., & Razonable, R. R. (2020). Cryptococcus Species Other Than Cryptococcus neoformans and Cryptococcus gattii: Are They Clinically Significant? Open Forum Infectious Diseases, 7(12). https://doi.org/10.1093/ofid/ofaa527
  • Bernal-Martinez, L., Gomez-Lopez, A., Castelli, M. V., Mesa-Arango, A. C., Zaragoza, O., Rodriguez-Tudela, J. L., & Cuenca-Estrella, M. (2010). Susceptibility profile of clinical isolates of non-Cryptococcus neoformans/non-Cryptococcus gattii Cryptococcus species and literature review. Medical Mycology, 48(1), 90–96. https://doi.org/10.3109/13693780902756073
  • Smith, N., Sehring, M., Chambers, J., & Patel, P. (2017). Perspectives on non-neoformanscryptococcal opportunistic infections. Journal of Community Hospital Internal Medicine Perspectives, 7(4), 214–217. https://doi.org/10.1080/20009666.2017.1350087  
  • Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Cryptococcosis | NIH. (n.d.). Retrieved September 5, 2022, from https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
  • Mahomed, N., & Reubenson, G. (2017). Immune reconstitution inflammatory syndrome in children. South African Journal of Radiology, 21(2). https://doi.org/10.4102/sajr.v21i2.1257
  • Boulware, D. R., Callens, S., & Pahwa, S. (2008). Pediatric HIV immune reconstitution inflammatory syndrome. Current Opinion in HIV and AIDS, 3(4), 461–467. https://doi.org/10.1097/coh.0b013e3282fe9693  
  • Mahomed, N., & Reubenson, G. (2017). Immune reconstitution inflammatory syndrome in children. South African Journal of Radiology, 21(2). https://doi.org/10.4102/sajr.v21i2.1257  


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