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CASE REPORT
Year : 2022  |  Volume : 25  |  Issue : 11  |  Page : 1931-1935

Fatal cryptococcal meningitis in the Non-HIV infected: A case report


1 Department of Medical Microbiology, University of Benin Teaching Hospital; Department of Medical Microbiology, School of Medicine, University of Benin, Benin City, Nigeria
2 Department of Medicine, University of Benin Teaching Hospital, Benin City, Nigeria

Date of Submission27-Mar-2022
Date of Acceptance30-Aug-2022
Date of Web Publication18-Nov-2022

Correspondence Address:
Dr. I I Osaigbovo
Department of Medical Microbiology, University of Benin Teaching Hospital, Benin City
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_217_22

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   Abstract 


Cryptococcal meningitis (CM) is underreported in the immunocompetent, the disease being more commonly associated with advanced human immunodeficiency virus (HIV) disease. We report the diagnosis, management, and eventual fatal outcome of CM in a non-HIV-infected man. Late presentation, delayed diagnosis, difficulties in accessing medications, and raised intracranial pressure (ICP) were contributory to his demise. Detailed history, a high index of suspicion, and laboratory workup coupled with prompt antifungal therapy and aggressive ICP management are essential for better outcomes.

Keywords: Case report, cryptococcal antigen, cryptococcal meningitis, intracranial pressure


How to cite this article:
Osaigbovo I I, Igetei S, Omiunu O J. Fatal cryptococcal meningitis in the Non-HIV infected: A case report. Niger J Clin Pract 2022;25:1931-5

How to cite this URL:
Osaigbovo I I, Igetei S, Omiunu O J. Fatal cryptococcal meningitis in the Non-HIV infected: A case report. Niger J Clin Pract [serial online] 2022 [cited 2022 Nov 30];25:1931-5. Available from: https://www.njcponline.com/text.asp?2022/25/11/1931/361451




   Introduction Top


The fungus Cryptococcus is the most common cause of meningitis in adults living with human immunodeficiency virus (HIV) and accounts for 223,100 new cases and more than 181,000 deaths globally per year, three quarters of which occur in sub-Saharan Africa.[1] With the advent of highly active antiretroviral therapy, the relative burden of cryptococcal meningitis (CM) among people without HIV infection is on the rise.[2] In the United States of America, up to 20% of cases of cryptococcosis occur in phenotypically “normal” and otherwise clinically non-immunocompromised.[3] However, documentation in Africa remains patchy.

The objective of this report is to describe a case of CM in an apparently immunocompetent Nigerian man.


   Case Report Top


In January, 2020, a 28-year-old Nigerian male school teacher was referred from a private health facility to our hospital, which is an academic tertiary centre, with complaints of recurrent frontal, throbbing headaches and vomiting of 7 weeks, fever of 1 week, and irrational talk of a day's duration. The headaches, which began insidiously, were moderate to severe in intensity, each episode lasting up to 18 h a day. They affected his daily activities and were transiently relieved by analgesics. The headaches later worsened with associated diplopia and neck stiffness necessitating presentation at the referring centre. His clinical status did not improve despite intravenous antibiotics and, thus, he was referred. There was no associated hemiparesis, dysarthria, facial deviation, seizures, or loss of consciousness. No history of ear pain, ear discharge, chronic cough, drenching night sweats, weight loss, or contact with anyone with chronic cough preceeded presentation. He did not report any recent travel to states within the Nigerian meningitis belt. There was no history of psychoactive drug use or psychiatric illness. He was not diabetic and his retroviral status had not been ascertained.

On examination, the Glasgow Coma scale (GCS) was 13. His pupils were round, central, normal in size, and reactive to light. There was neck stiffness and both Kerning's and Brudzinski's signs were positive. Muscle bulk and tone were normal and he was able to move all limbs. Reflexes were also normal. Cranial nerve, sensation, co-ordination, and gait assessments were deferred because of his confused state. His pulse was of normal volume and regular at 88 beats per min, blood pressure was 130/80 mmHg, and the cardiovascular examination revealed no abnormalities.The respiratory system and abdominal examinations were not remarkable. An assessment of meningoencephalitis was made to rule out tuberculous meningitis.

Diagnostic sampling, including lumbar puncture to obtain cerebrospinal fluid (CSF) for microscopy, culture and sensitivity (M/C/S), GeneXpert MTB/RIF (Cepheid Sunnyvale, CA, United States) and chemistry, and venepuncture for full blood count (FBC), electrolytes/urea/creatinine, retroviral screen, and random blood glucose, was performed. A brain computerised tomography (CT) scan was also performed. He was commenced on therapy with intravenous (IV) 5% dextrose saline 500 ml supplemented with 5 ml of vitamin B complex 8 hourly; IV vancomycin 1 g 12 hourly; IV dexamethasone 8 mg stat then 6 mg 8 hourly for 3 days; IV cefotaxime 2 g 12 hourly; IV acyclovir 500 mg in 200 ml of normal saline 8 hourly and anti-tuberculous medications (tabs rifampicin 600 mg daily, tabs isoniazid 300 mg daily, tabs pyrazinamide 1.2 g daily, tabs tthambutol 800 mg daily, and tabs pyridoxine 25 mg daily).

Imaging and laboratory results

The brain CT scan was essentially normal. The retroviral screen done using Determine HIV-1/2 Ag/Ab Combo (Abbot, United States) lateral flow assay (LFA) was negative for HIV 1 and 2. The FBC showed a reduced lymphocyte differential of 17.9% (reference range 25–50%) but other parameters were normal. CSF microscopy showed increased white cells but no organisms were detected on the Gram stain. Indian ink stain was not performed because CM was not considered in the differential diagnosis. Gene-Xpert of the CSF did not detect Mycobacterium tuberculosis. Chemistry reported markedly elevated protein of 184.8 mg/dl and low glucose of 29 mg/dl with a concomittant random blood glucose of 127 mg/dl. However, bacterial culture yielded no growth after incubation for 48 h and culture plates were discarded.

On day 3, clinical microbiology was consulted on account of the non-response to antibiotics and negative culture despite clinical and chemistry parameters suggestive of meningitis. A serum cryptococcal antigen test was done using non-routine cryptococcal antigen (CrAg) LFA test (Immy Diagnostics, Norman, United States) donated for screening in HIV patients. The result was positive [Figure 1]. The patient's archived CSF was tested using the test strips and was also positive, confirming the diagnosis of CM. There was no residual sample to stain with Indian ink or repeat the culture. On further probe, the patient's wife disclosed recently moving to a house opposite a large poultry 3 months before presentation, confirming that he took ill a month later.
Figure 1: Cryptococcal antigen lateral flow assay of the patient's serum showing a positive test

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Management and clinical course

Induction therapy with IV amphotericin B deoxycholate (AmB) 50 mg into 500 ml of 5% dextrose water over 3 h daily and IV fluconazole 1.2 g daily was immediately commenced. The antibacterial and antituberculous medications were discontinued. However, on review by day 4, he was unable to perceive light and bilateral lateral rectus nerve palsy was noted. An assessment of complicated CM in an apparently immunocompetent adult was made. On day 6, after the second dose of intravenous AmB, patient complained of feeling cold and developed respiratory difficulty. He was commenced on oxygen via nasal prongs and later face mask. By day 7, his clinical condition worsened with blood pressure of 170/110 mmHg and persistent tachycardia. Electrocardiogram showed sinus tachycardia. The GCS dropped to 7/15. An assessment of raised ICP was made and therapeutic lumbar puncture planned. However, patient continued to deteriorate until his demise on day 8.


   Discussion Top


Cryptococcus species are cosmopolitan yeasts found in environments worldwide.[4] C. neoformans and C. gattii are the chief pathogens in humans.[3] Cryptococcosis results when the aerosolized spores and/or dessicated yeast cells are inhaled by susceptible individuals.[4],[5] It may involve any organ, including bone, prostate, skin, eyes, and liver but typically manifests as an acute pneumonia or a highly fatal meningitis arising from the yeast's predilection for the central nervous system.[4],[6]

CM commonly has a sub-acute presentation with fever, malaise, headache, vomiting, meningeal signs, seizures, and cranial nerve palsies as features.[7] Although AIDS-related cases represent the bulk of disease burden worldwide, non-HIV-related CM accounts for a substantial proportion of cases in developed countries such as the United States of America.[2],[3] Most non-HIV cases have immunosuppression from other causes, including transplants, prolonged corticosteroid therapy, haematologic malignancies, and autoimmunity.[3] Non-HIV, non-transplant (NHNT) CM has also been reported in diabetics and in individuals with no obvious underlying conditions.[3],[8] In sub-Saharan Africa, non-HIV-related cryptococcosis has been sparsely documented; thus, the contribution to the burden of CM in the region is unknown.[7],[9],[10],[11] The index case emphasises the need to consider CM in the non-HIV patient and the importance of aggressive management of raised intracranial pressure and appropriate antifungal therapy in the successful management of CM.

As illustrated by our report, the index of suspicion for CM by both clinical and laboratory staff is typically low once HIV has been ruled out, resulting in delayed and often missed diagnosis in non-HIV patients.[2] According to Pappas et al.,[3] the mean time to diagnosis is significantly longer among NHNT compared to HIV-positive and organ transplant recipients (68 days vs. 22 and 26 days, respectively). The time from initial symptoms to diagnosis is also significantly different for immunocompromised and normal patients (34 days vs. 81 days, respectively), showing a substantial delay in diagnosing CM among the immunocompetent. From the laboratory angle, the fungus may be difficult to discern with conventional Gram stain microscopy because of the presence of a thick capsule surrounding the organism.[12] Using a negative staining technique that employs Indian ink highlights the encapsulated yeast in 42–86% of cases, depending on the burden of the infecting pathogen.[13] Furthermore, although Cryptococcus is readily recoverable from CSF and blood cultures, growth may only become apparent after approximately 72 h of incubation and may take up to 7 days, whereas most meningitis-causing bacterial pathogens would grow within 24 to 48 h. Thus, for laboratorians to examine CSF with Indian ink and also retain cultures long enough to detect growth of Cryptococcus in clinical specimens, an index of suspicion is required, often by express clinician request or prompting from the clinical information provided on the requisition. The strait jacketed association of cryptococcal disease with HIV/AIDS coupled with lack of simple diagnostic tools such as the CrAg LFA makes the prospects of prompt detection in the immunocompetent extremely dire. The development of the CrAg LFA has revolutionized the diagnosis of HIV-associated CM. It is a rapid, sensitive, and specific diagnostic test that can be used in both laboratories and at the point of care to detect cryptococcal antigen in both serum and CSF.[14] This simple tool is, however, only available in 13% of tertiary facilities in Nigeria and is used almost exclusively in HIV care.[15] The test used for diagnosis in this case was one of a donated lot, limited in quantity, and placed in our facility by the Medical Mycology Society of Nigeria after a training event, ironically, to enhance screening for CrAg in advanced HIV disease.[16]

Therapy for CM is mostly guided by experience from treating HIV patients. There have been no randomized controlled trials to define the optimum regimen in the non-HIV infected.[9],[17] Despite therapy, mortality rates in HIV-seronegative individuals with CM are high, up to 30% in developed countries. The preferred regimen for NHNT patients with CM, as recommended by the Infectious Diseases Society of America (IDSA), is an induction therapy of AmB (0.7–1.0 mg/kg per day) combined with 5-flucytosine (100 mg/kg per day) for at least 4 weeks.[17] Toxicity from AmB can complicate treatment so the liposomal form is preferred but this is not readily available and where available costs are prohibitive.[18] Of note, even AmB was not stocked in our hospital pharmacy. There were challenges in procuring the drug locally and the patient's relatives had to order for additional doses from out of town. Flucytosine, also, is not readily available in most of sub-Saharan Africa;[18],[19] therefore, an alternative regimen of amphotericin B with fluconazole was used in the index case. Poor access to antifungal medications is a recognized challenge to the management of systemic fungal infections in sub-Saharan Africa.

Besides antifungal therapy, aggressive management of raised ICP is just as crucial to successful outcomes in CM because elevated ICP is an important risk factor for early mortality and late morbidity. The goal of ICP treatment in CM is to reduce fungal burden quickly and to prevent long-term neurological deficits such as visual impairment as observed in the index case, hearing impairment, hemiplegia, and permanent change in mental status. The IDSA recommends repeated lumbar punctures if the CSF pressure is ≥25 cm of CSF, followed by ventriculoperitoneal shunting for refractory cases.[18] Lack of instruments for measuring CSF pressure constitutes a challenge to detecting and managing raised intracranial pressure in resource-limited settings.[19] Nevertheless, therapeutic lumbar puncture to reduce the ICP was considered in the index case but was not performed early enough to prevent the patient's demise.

The lack of speciation and definitive exclusion of immunocompromise limit the contributions of the index report to the understanding of epidemiology of CM in NHNT patients in Africa. As there was no isolate from culture, we are unable to comment on the exact species of Cryptococcus responsible for this case. C. neoformans, which causes disease in both immunocompromised and immunocompetent hosts, accounts for over 80% of CM in Africa, according to a recent systematic review.[20] However, infections caused by C. gattii, more commonly associated with immunocompetent patients, are also on the rise. Both Cryptococcus species have been associated with pigeons and poultry and the history of a recent move to a house close to a large poultry in the index case was, therefore, significant as an exposure risk. Although our patient was HIV negative and apparently immunocompetent, the differential white cell count showed a relative lymphopaenia suggesting a possible compromise to the immune system that was not investigated further by doing a CD4 count or other immunological profiling studies as these were not available. CM has been reported in patients with idiopathic CD4 lymphopaenia, a rare condition characterized by an unexplained deficit of circulating CD4 T cells leading to increased risk of serious opportunistic infections.[21],[22] This rare condition is defined as a CD4 count of less than 300 cells/μl or less than 20% of all lymphocytes for two readings at least 6 weeks apart in the absence of HIV infection or other secondary causes.[21] It is not impossible that this condition was present in the index case. However, a review of cryptococcosis in patients with idiopathic CD4 lymphopaenia suggested that a favorable outcome (cured or improved) may be more common than in previously normal patients with CM and no predisposing factors.[21] Although brain CT may be normal in immunocompetent patients with CM, it is more common to have an aggressive inflammatory response that is evident on imaging.[10] The normal brain CT in the index case may, therefore, support an immunosuppressive condition other than HIV infection.


   Conclusion Top


This case exemplifies the course of CM in the non-HIV patient that is often characterized by late presentation and delayed diagnosis fueled by a justified, though myopic, association of CM with HIV-infected persons. A high index of suspicion, detailed history, and laboratory workup are essential if the disease is to be promptly detected. The outcome is worsened by late identification, sub-optimal antifungal therapy, and failure to aggressively control ICP, all of which contributed to the fatal outcome in this case. This can be averted by the astute clinician's risk assessment and prompt consideration of CM in the differential diagnosis whether or not the patient is infected with HIV.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, et al. Global burden of disease of HIV-associated cryptococcal meningitis: An updated analysis. Lancet Infect Dis 2017;17:873-81.  Back to cited text no. 1
    
2.
Marr KA, Sun Y, Spec A, Lu N, Panackal A, Bennett J, et al. A multicenter, longitudinal cohort study of cryptococcosis in human immunodeficiency virus-negative people in the United States. Clin Infect Dis 2020;70:252-61.  Back to cited text no. 2
    
3.
Pappas PG. Cryptococcal infections in non-HIV-infected patients. Trans Am Clin Climatol Assoc 2013;124:61-79.  Back to cited text no. 3
    
4.
Edwards HM, Cogliati M, Kwenda G, Fisher MC. The need for environmental surveillance to understand the ecology, epidemiology and impact of Cryptococcus infection in Africa. FEMS Microbiol Ecol 2021;97:fiab093. doi: 10.1093/femsec/fiab093.  Back to cited text no. 4
    
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Walsh NM, Botts MR, McDermott AJ, Ortiz SC, Wüthrich M, Klein B, et al. Infectious particle identity determines dissemination and disease outcome for the inhaled human fungal pathogen cryptococcus. PLoS Pathog 2019;15:e1007777. doi: 10.1371/journal.ppat. 1007777.  Back to cited text no. 5
    
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Kronstad JW, Attarian R, Cadieux B, Choi J, D'Souza CA, Griffiths EJ, et al. Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. Nat Rev Microbiol 2011;9:193-203.  Back to cited text no. 6
    
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Owuor OH, Chege P. Cryptococcal meningitis in a HIV negative newly diagnosed diabetic patient: Acase report. BMC Infect Dis 2019;19:5. doi: 10.1186/s12879-018-3625-4.  Back to cited text no. 7
    
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Nsenga L, Kajjimu J, Olum R, Ninsiima S, Kyazze AP, Ssekamatte P, et al. Cryptococcosis complicating diabetes mellitus: A scoping review. Ther Adv Infect Dis 2021;8:20499361211014769. doi: 10.1177/20499361211014769.  Back to cited text no. 8
    
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Mitha M, Naicker P, Mahida P. Disseminated cryptococcosis in an HIV-negative patient in South Africa: The elusive differential diagnosis. J Infect Dev Ctries 2010;4:526-9.  Back to cited text no. 9
    
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Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: A comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-positive and HIV-negative patients. Clin Infect Dis 1997;24:131-4.  Back to cited text no. 10
    
11.
Kabangila R, Groß U, Mshana SE. Disseminated cryptococcosis in a HIV-negative patient: Case report of a newly diagnosed hypertensive adult presenting with hemiparesis. Med Mycol Case Rep 2018;22:4-7.  Back to cited text no. 11
    
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Bottone EJ. Cryptococcus neoformans: Pitfalls in diagnosis through evaluation of gram-stained smears of purulent exudates. J Clin Microbiol 1980;12:790-1.  Back to cited text no. 12
    
13.
Rajasingham R, Wake RM, Beyene T, Katende A, Letang E, Boulware DR. Cryptococcal meningitis diagnostics and screening in the era of point-of-care laboratory testing. J Clin Microbiol 2019;57:e01238-18. doi: 10.1128/JCM.01238-18.  Back to cited text no. 13
    
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Osaigbovo II, Bongomin F. Point of care tests for invasive fungal infections: A blueprint for increasing availability in Africa. Ther Adv Infect Dis 2021;8:20499361211034266. doi: 10.1177/20499361211034266.  Back to cited text no. 14
    
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Osaigbovo II, Oladele RO, Orefuwa E, Akanbi OA, Ihekweazu C. Laboratory diagnostic capacity for fungal infections in Nigerian tertiary hospitals: A gap analysis survey. WAJM 2021;38:1065-71.  Back to cited text no. 15
    
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Oladele RO, Jordan A, Akande P, Akanmu SA, Akase IE, Aliyu S, et al. Tackling cryptococcal meningitis in Nigeria, one-step at a time; the impact of training. PLoS One 2020;15:e0235577. doi: 10.1371/journal.pone.  Back to cited text no. 16
    
17.
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2010;50:291-322.  Back to cited text no. 17
    
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Kneale M, Bartholomew JS, Davies E, Denning DW. Global access to antifungal therapy and its variable cost. J Antimicrob Chemother 2016;71:3599-606.  Back to cited text no. 18
    
19.
Oladele RO, Bongomin F, Gago S, Denning DW. HIV-associated cryptococcal disease in resource-limited settings: A case for “prevention is better than cure”? J Fungi (Basel) 2017;3:67. doi: 10.3390/jof3040067.  Back to cited text no. 19
    
20.
Nyazika T, Kamtchum-Tatuene J, Kenfak-Foguena A, Robertson VJ, Verweij PE, Meis JF, et al. Prevalence and Mortality of Cryptococcal Meningitis in Africa from 1950 to 2017 and Associated Epidemiological Mapping of C. neoformans and C. gattii Species Complexes: A Systematic Review and Meta-Analysis. Available at SSRN: http://dx.doi.org/10.2139/ssrn.3393702. Accessed February 12, 2022 [Last accessed on 2019 May 24].  Back to cited text no. 20
    
21.
Zonios DI, Falloon J, Huang CY, Chaitt D, Bennett JE. Cryptococcosis and idiopathic CD4 lymphocytopenia. Medicine (Baltimore) 2007;86:78-92.  Back to cited text no. 21
    
22.
Eshwara VK, Garg R, Chandrashekhar GS, Shaw T, Mukhopadhyay C. Fatal cryptococcusgattii meningitis with negative cryptococcal antigen test in a HIV-non-infected patient. Indian J Med Microbiol 2018;36:439-40.  Back to cited text no. 22
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