Fungal Infections — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr Daniel Okafor, 34 years old, hospitality worker, recently arrived from a sub-Saharan African country 2 years ago. [1] />

Presenting complaint: Admitted to hospital with a 3-week history of progressive headache, photophobia, low-grade fever, and increasing confusion. Over the last 3 days his family reports he has become drowsy and has vomited twice. [1] />

HIV history: Diagnosed with HIV 4 months ago at a sexual health check, but he has not yet started antiretroviral therapy (he was lost to follow-up after the diagnosis). Most recent CD4 count 24 cells per microlitre, viral load 220,000 copies per mL. He had oral thrush 2 months ago. [1] />

Current presentation:

• Fever to 38.4 degrees, heart rate 102, blood pressure 114/72, respiratory rate 18, oxygen saturation 97 per cent on room air.
• Glasgow Coma Scale 14 (confused but obeying commands). Neck stiffness present. No focal limb weakness. Papilloedema on fundoscopy. Cranial nerves intact apart from a subtle left abducens palsy. [1] />

Investigations on admission:

• Full blood count: haemoglobin 108 g/L, white cell count 6.2 x 10^9 per litre, platelets 180 x 10^9 per litre. CD4 24. HIV viral load 220,000.
• Electrolytes, renal and liver function normal. CRP 42. Lactate 1.4.
• CT brain before LP: no mass lesion, no hydrocephalus, mild leptomeningeal enhancement.
• Lumbar puncture: opening pressure 38 cm of water. CSF 120 white cells per microlitre (lymphocyte predominant), glucose 1.2 mmol per litre (serum 5.6), protein 1.4 g per litre. India ink positive. CSF cryptococcal antigen titre 1 to 4096. Serum cryptococcal antigen positive. CSF culture pending but consistent with Cryptococcus neoformans.
• Chest X-ray: clear. [1] />

Past history: HIV (untreated), one episode of oral candidiasis. No prior opportunistic infections. No tuberculosis. No allergies. [1] />

Social history: Lives with his partner and two young children. Works as a kitchen hand. Non-smoker, does not drink alcohol. Sexually active with his male partner (HIV-negative); condoms used inconsistently. Keen to start treatment and return to work. No recent travel. No obvious pigeon or bird exposure. [1] />

Candidate's structured presentation (model)

SASPOP opening statement: [1]

"Mr Daniel Okafor is a 34-year-old hospitality worker, recently arrived from sub-Saharan Africa, with untreated HIV and a CD4 count of 24, who presents with a 3-week history of progressive subacute headache, photophobia, fever, and confusion, and is found to have cryptococcal meningitis with a markedly raised opening pressure of 38 cm of water, papilloedema, and a subtle left sixth nerve palsy. He was diagnosed with HIV 4 months ago but was lost to follow-up and has not started antiretroviral therapy. The clinical picture is the classic indolent presentation of cryptococcal meningitis in advanced cellular immunodeficiency, and the raised intracranial pressure is the single most important determinant of his early prognosis." [1] />

Structured problem list: [1]

1. Cryptococcal meningitis with raised intracranial pressure (opening pressure 38 cm of water) — the central and immediately life-threatening problem; raised ICP is the biggest determinant of early mortality.
2. Untreated advanced HIV (CD4 24, viral load 220,000) — the underlying immunodeficiency; ART must be started but the timing is critical to avoid IRIS.
3. Neurological compromise (GCS 14, papilloedema, sixth nerve palsy) — reflects the raised ICP and the basilar meningitis; mandates active ICP management and close monitoring.
4. Risk of secondary complications — IRIS after ART, immune reconstitution unmasking other opportunistic infections, and the long-term cognitive and visual sequelae of cryptococcal meningitis.
5. Public health and psychosocial — partner notification and HIV testing, ART adherence support, and the social and occupational impact of a prolonged treatment course. [1] />

Integrated management plan

1. Raised intracranial pressure — the immediate priority: [1] />

The single most important determinant of early mortality in cryptococcal meningitis is the raised intracranial pressure, more than the antifungal choice. His opening pressure is 38 cm of water (markedly elevated; the threshold for intervention is 25 cm of water). The IDSA 2010 cryptococcal guideline is explicit: perform daily therapeutic lumbar punctures to drain CSF and reduce the opening pressure to below 20 cm of water (or by 50 per cent) [1]. I will repeat the LP daily and drain sufficient CSF to halve the pressure or bring it below 20 cm, and I will monitor his GCS, headache, vomiting, and papilloedema as clinical markers of response. If the pressure cannot be controlled with serial LPs, I will arrange a ventricular shunt or external ventricular drain in consultation with neurosurgery. Corticosteroids, mannitol, and acetazolamide have no role — corticosteroids worsen outcomes in HIV-associated cryptococcal meningitis, and mannitol and acetazolamide have not been shown to help. I will monitor his vision, because optic nerve compression from raised ICP can cause permanent blindness.

2. Induction antifungal therapy — amphotericin B plus flucytosine: [1] />

The standard induction, per the IDSA 2010 guideline, is liposomal amphotericin B 3 to 4 mg/kg/day intravenously plus flucytosine 25 mg/kg orally every 6 hours (100 mg/kg/day) for at least 2 weeks [1]. The addition of flucytosine accelerates CSF sterilisation and improves survival; it is never used alone (rapid resistance) and requires renal dose adjustment and peak-level monitoring (2-hour post-dose, target below 100 mg/L) to avoid bone-marrow suppression. The AMBITION-cm trial (2022) demonstrated that a single high-dose liposomal amphotericin B 10 mg/kg on day 1, combined with 14 days of flucytosine and fluconazole (1200 mg/day), was non-inferior to the standard 7-day amphotericin B deoxycholate plus flucytosine regimen, with fewer adverse events [2] — and this regimen is now endorsed by WHO, though I would discuss with my infectious diseases team whether the single-dose regimen is appropriate here given his markedly raised pressure. The ACTA trial (2018) showed that 1 week of amphotericin plus flucytosine was as effective as 2 weeks, and that fluconazole plus flucytosine was a reasonable oral alternative [3]. I will monitor his renal function, electrolytes (potassium and magnesium wasting from amphotericin), full blood count (flucytosine marrow suppression), and infusion reactions, and I will repeat the CSF culture weekly to document sterilisation.

3. Consolidation and maintenance: [1]

After a successful induction (clinical improvement, falling CSF cryptococcal antigen, sterile CSF culture), he transitions to consolidation with fluconazole 400 to 800 mg/day orally for at least 8 weeks, then maintenance (secondary prophylaxis) with fluconazole 200 mg/day. In HIV-associated cryptococcal meningitis, the maintenance continues until the CD4 is above 100 to 200 for at least 6 months on antiretroviral therapy — at which point it can be safely stopped. I will monitor the CD4 and viral load quarterly. [1] />

4. Antiretroviral therapy — timing and IRIS: [1]

I will defer antiretroviral therapy for 2 to 4 weeks after the start of antifungal induction. The rationale is that immediate (same-day or very early) ART precipitates a high rate of immune reconstitution inflammatory syndrome (IRIS) — a paradoxical worsening as the recovering immune system reacts to residual or killed Cryptococcus — and randomised trials have shown that immediate ART increases early mortality without improving long-term outcome. The deferral allows the antifungal to reduce the organism burden before immune recovery begins. I will start a standard first-line regimen (tenofovir, emtricitabine or lamivudine, and dolutegravir) once the deferral period has passed. I will counsel him and his partner about the risk of IRIS (new or worsening headache, fever, lymphadenitis) and the importance of reporting it promptly. [1] />

5. Monitoring for complications and other opportunistic infections: [1] />

Because cryptococcal meningitis and advanced HIV predispose to other complications, I will screen for and monitor: CMV (retinitis, colitis) with a CMV PCR if any visual or gastrointestinal symptom arises; PJP prophylaxis with co-trimoxazole (CD4 below 200); toxoplasmosis (prophylaxis is covered by co-trimoxazole); disseminated mycobacterial infection (MAC, TB) with appropriate cultures if he deteriorates; and strongyloides (he is from a tropical area — serology and treatment with ivermectin before steroids if needed). I will monitor the serial CSF cryptococcal antigen titre, the renal function and electrolytes, and the neurological examination. [1] />

6. Partner notification and public health: [1]

His HIV-negative partner must be offered HIV testing and counselling, and consideration of pre-exposure prophylaxis if he remains negative. I will involve the sexual health service and the HIV liaison nurse for partner notification, education, and adherence support. I will discuss Mr Okafor's preferences around disclosure to his family and his workplace, and I will arrange psychosocial support. [1] />

Examiner discussion questions

Q1: "His opening pressure was 38 cm of water. Walk me through exactly what you would do at the bedside to manage this, and what you would NOT do." [1] />

"At the diagnostic lumbar puncture, after measuring the opening pressure of 38 cm of water, I would drain sufficient CSF to reduce the pressure to below 20 cm of water (or by 50 per cent, whichever is lower) — typically 15 to 25 mL. I would then recheck the closing pressure. The IDSA 2010 guideline recommends repeating this daily — a therapeutic lumbar puncture every day — until the opening pressure is stable below 20 cm of water for several days [1]. I would monitor his GCS, headache, vomiting, and papilloedema as clinical markers, and his visual acuity and visual fields, because optic nerve compression from raised ICP can cause permanent blindness. If the pressure cannot be controlled with serial LPs (refractory raised pressure, or rapid re-accumulation), I would arrange a ventricular shunt or an external ventricular drain in consultation with neurosurgery. What I would NOT do is give corticosteroids — they have been shown to worsen outcomes in HIV-associated cryptococcal meningitis and have no role in managing the raised ICP. I would NOT give mannitol or acetazolamide, which have not been shown to help. And I would NOT attribute a rising pressure to 'the antifungal not working' and change the antifungal — the pressure is a mechanical problem of CSF outflow obstruction by the capsule and the fungal burden, and it is managed mechanically. The single most important determinant of his early survival is the ICP control, not the antifungal choice."

Q2: "Why is the timing of antiretroviral therapy so critical here, and what evidence underpins the deferral?" [1] />

"The timing of ART in HIV-associated cryptococcal meningitis is one of the clearest examples of where doing the right thing too early causes harm. If ART is started on the same day or within the first week of antifungal induction — while the organism burden is still high and the cryptococcal antigen is driving a brisk inflammatory response — the recovering immune system mounts an exuberant reaction to the residual or killed Cryptococcus, producing immune reconstitution inflammatory syndrome (IRIS). IRIS in this setting presents as worsening meningitis, rising intracranial pressure, lymphadenitis, and new pulmonary infiltrates, and it can be fatal. Randomised trials — notably the CRYPTOIMMUNO study and the analyses derived from the ACTA programme — showed that immediate ART increased early mortality, predominantly from IRIS, without improving long-term viral suppression or survival. The current IDSA 2010 and WHO recommendations are to defer ART for 2 to 4 weeks after the start of antifungal induction. This window allows the amphotericin and flucytosine to reduce the organism burden before the immune system begins to recover, which lowers the IRIS risk without compromising the long-term benefit of ART. I would start a standard first-line ART regimen (tenofovir, emtricitabine, dolutegravir) at the 2 to 4 week mark, and I would counsel Mr Okafor and his partner about the IRIS risk and the importance of reporting any new or worsening symptom promptly." [1] />

Q3: "How do the AMBITION and ACTA trials change the induction regimen you would use, and would you apply them here?" [1] />

"The AMBITION-cm trial, published in the New England Journal of Medicine in 2022, randomised patients with HIV-associated cryptococcal meningitis to either a single high-dose liposomal amphotericin B 10 mg/kg on day 1 plus 14 days of flucytosine and fluconazole, or the standard WHO regimen of amphotericin B deoxycholate plus flucytosine for 7 days followed by fluconazole [2]. The single-dose regimen was non-inferior for all-cause mortality at 10 weeks (24.8 per cent vs 28.7 per cent) and was associated with significantly fewer grade 3 or 4 adverse events (50.0 per cent vs 62.3 per cent), predominantly less anaemia and nephrotoxicity. The AMBITION regimen has been endorsed by WHO and is transforming induction in resource-limited settings where the toxicity and monitoring burden of daily amphotericin is a major barrier. The ACTA trial, published in Clinical Infectious Diseases in 2018, showed that 1 week of amphotericin B plus flucytosine was as effective as 2 weeks, and that an oral regimen of fluconazole plus flucytosine was a reasonable alternative where amphotericin is not available [3]. For Mr Okafor, in a well-resourced setting, I would discuss with my infectious diseases team whether to use the standard 2-week liposomal amphotericin plus flucytosine induction (the IDSA 2010 default, with robust data and familiarity) or the AMBITION single-dose regimen (which reduces toxicity and the duration of hospital admission and IV therapy). Given his markedly raised opening pressure and his neurological compromise, I would lean toward the standard liposomal amphotericin B plus flucytosine regimen for the first week at least, with daily therapeutic LPs, and then re-evaluate. The AMBITION regimen is most clearly transformative in resource-limited settings; in a well-resourced setting the choice is individualised with the ID team."

Q4: "He is originally from sub-Saharan Africa. What other opportunistic infections must you consider, and how does that shape your workup?" [1] />

"Advanced HIV in a patient from sub-Saharan Africa carries a broad differential of opportunistic infections beyond cryptococcosis, and the workup must be active rather than reactive. Tuberculosis is the leading consideration — I will send sputum for acid-fast bacilli and mycobacterial culture (and a GeneXpert if available), and I will image the chest; TB can coexist with cryptococcal meningitis and is itself a cause of chronic meningitis. Toxoplasma gondii encephalitis causes ring-enhancing brain lesions in HIV with CD4 below 100 — the CT was reassuring here (no mass lesion), but I will maintain a low threshold to image again if he develops a focal deficit or seizures. Cytomegalovirus (retinitis, colitis, encephalitis) is screened with a CMV PCR if visual or gastrointestinal symptoms arise. Pneumocystis pneumonia is prevented by the co-trimoxazole prophylaxis I will start. Disseminated Mycobacterium avium complex presents with fever, weight loss, and anaemia at CD4 below 50. Strongyloides stercoralis is critical — he is from a tropical area, and strongyloides hyperinfection under immunosuppression (or when he starts ART and the immune response shifts) is fatal in over half of cases and presents as polymicrobial Gram-negative sepsis from larvae carrying enteric bacteria out of the gut; I will send strongyloides serology and treat with ivermectin if positive, before any steroid use. Talaromyces (Penicillium) marneffei is an important consideration in patients from South-East Asia rather than sub-Saharan Africa, but Histoplasma is relevant in both regions and I will send urine and serum Histoplasma antigen if he has any pulmonary or cutaneous feature. The principle is to actively screen rather than wait for a symptom, because coinfection changes both the diagnostic and the therapeutic plan." [1] />

Q5: "How will you communicate this complex plan to him and his partner, and what are the key shared decision-making points?" [1] />

"I will sit down with both of them, ideally with an interpreter if there is any language barrier (his English may be functional but medical complexity benefits from his first language), and explain clearly. I will tell them that the fungus has caused an infection of the lining of his brain, that the pressure inside his head is high and that this is the most dangerous part of the illness, that we are draining fluid from his spine every day to bring the pressure down, and that we are giving him two antifungal medications through the drip to kill the fungus. I will explain that we will start the HIV medicines in a few weeks rather than immediately, because starting them too early can cause a dangerous reaction as his immune system wakes up — and that this is a deliberate, evidence-based decision, not a delay. I will explain the expected timeline — weeks of hospital treatment, months of tablets at home, close follow-up — and that the outlook is better with treatment than without, but that cryptococcal meningitis is a serious illness with a significant mortality. I will ask about his goals — return to work, his family, his partner's health, his values around intensity of treatment — and I will arrange a family meeting with the infectious diseases, HIV, and nursing teams. I will address the partner notification and testing sensitively, with the sexual health service. I will give written information, a clear point of contact, and a plan for what to do if things change. The communication is part of the treatment — a patient who understands the plan adheres to it, recognises complications early, and comes back when it matters." [1] />

Q6: "What is his long-term prognosis and follow-up plan once he recovers?" [1] />

"With optimal therapy, the mortality of HIV-associated cryptococcal meningitis is approximately 10 to 20 per cent in well-resourced settings, and higher in resource-limited settings and in those with a high fungal burden, altered mental status at presentation, or uncontrolled raised ICP. Mr Okafor's presenting features — a GCS of 14, a markedly raised opening pressure, and a high CSF antigen titre — place him in a higher-risk group, which is why the ICP control and the induction are so critical. If he survives the acute episode, his long-term outlook depends on immune reconstitution with ART: once his CD4 rises above 100 to 200 for at least 6 months on ART, he can stop the fluconazole maintenance, and his risk of cryptococcal relapse falls dramatically. His long-term follow-up includes: ART adherence support and quarterly CD4 and viral load monitoring; fluconazole maintenance until immune reconstitution; co-trimoxazole for PJP prophylaxis until the CD4 is above 200; annual influenza and pneumococcal vaccination; routine monitoring for IRIS in the first months after ART; and attention to the cognitive and visual sequelae of cryptococcal meningitis (some patients have residual cognitive impairment or visual loss despite optimal therapy). I will involve the HIV service, the infectious diseases service, and the general practitioner in a shared-care model, and I will give him and his partner a clear written summary of the plan." [1] />