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Intracranial pressure management in patients with human immunodeficiency virus-associated cryptococcal meningitis in a resource-constrained setting

Background Cryptococcal meningitis (CCM) is the leading cause of meningitis in people living with HIV (PLWH) in sub-Saharan Africa (SSA). The mortality and morbidity associated with CCM remain high. Combination of antifungal therapy, diligent management of intracranial pressure (IP) and the correct timing of the introduction of antiretroviral therapy (ART) minimise the risk of mortality and morbidity. The absence of spinal manometers in many healthcare centres in SSA challenges the accurate measurement of cerebrospinal fluid (CSF) pressure and its control. Objectives We hypothesised that four lumbar punctures (LPs) in the first week of the diagnosis and treatment of CCM would reduce IP such that in-hospital mortality and morbidity of HIV-associated CCM (HIV/CCM) would be significantly reduced. Methods We conducted a retrospective study to assess whether receipt of four or more LPs in the first week of the diagnosis and treatment with combination antifungal therapy of HIV/CCM would be associated with the reduction of in-hospital mortality in adult PLWH. Results From 01 January 2016 to 31 December 2016, 116 adult patients were admitted to the Dora Nginza District Hospital in Zwide, Port Elizabeth, South Africa. After exclusion of 11 (two were younger than 18 years, two had missing hospital records and seven demised or left the hospital before 7 days of hospitalisation), 105 patients were included in the analysis. The mean age was 39.4 (standard deviation [s.d.] ± 9.7) years, 64.8% were male. All were PLWH. A total of 52.4% had defaulted ART and 25.7% were ART naïve. Forty-three patients received four or more LPs (mean = 4.58 [± 0.96]) in the first week of hospitalisation with an associated in-hospital mortality of 11.6% (n = 5/43) compared with 62 patients who received less than four LPs (mean = 2.18 [± 0.80]) with an in-hospital mortality of 29% (n = 18/62) and a relative risk of 0.80 (95% CI, 0.66–0.97), p = 0.034. Conclusion In the current study of adult PLWH presenting to hospital with HIV/CCM, four or more LPs in the first 7 days following admission and the initiation of treatment were associated with a 17.4% reduction in absolute risk of in-hospital mortality and a 20% reduction in relative risk of in-hospital mortality. This mortality difference was noted in patients who survived and were in hospital at the time of the 7-day study census and persisted until the time of hospital discharge.


Background
Cryptococcal meningitis (CCM) accounts for up to 60% of meningitis in adult persons living with HIV (PLWH) in many African countries including South Africa (SA). 1,2 Those with CD4 cell counts < 100 cells/µL are particularly at risk. 3 Mortality is high -reaching levels of 70% in sub-Saharan Africa (SSA). 3 Altered mental state at presentation, older age, high cerebrospinal fluid (CSF) fungal burden and high peripheral white cell count predict mortality in antiretroviral therapy (ART) naïve patients. 4 Although the availability of ART has led to a decrease in HIV-associated CCM (HIV/CCM) in high-income countries, 5 the condition remains responsible for 10% -20% of HIV-related deaths in SSA. 6 Notwithstanding improved access to ART, many remain outside of care or on failing treatment and at risk of opportunistic disease. 7 Background: Cryptococcal meningitis (CCM) is the leading cause of meningitis in people living with HIV (PLWH) in sub-Saharan Africa (SSA). The mortality and morbidity associated with CCM remain high. Combination of antifungal therapy, diligent management of intracranial pressure (IP) and the correct timing of the introduction of antiretroviral therapy (ART) minimise the risk of mortality and morbidity. The absence of spinal manometers in many healthcare centres in SSA challenges the accurate measurement of cerebrospinal fluid (CSF) pressure and its control.

Objectives:
We hypothesised that four lumbar punctures (LPs) in the first week of the diagnosis and treatment of CCM would reduce IP such that in-hospital mortality and morbidity of HIV-associated CCM (HIV/CCM) would be significantly reduced.

Methods:
We conducted a retrospective study to assess whether receipt of four or more LPs in the first week of the diagnosis and treatment with combination antifungal therapy of HIV/CCM would be associated with the reduction of in-hospital mortality in adult PLWH.
Results: From 01 January 2016 to 31 December 2016, 116 adult patients were admitted to the Dora Nginza District Hospital in Zwide, Port Elizabeth, South Africa. After exclusion of 11 (two were younger than 18 years, two had missing hospital records and seven demised or left the hospital before 7 days of hospitalisation), 105 patients were included in the analysis. The mean age was 39.4 (standard deviation [s.d.] ± 9.7) years, 64.8% were male. All were PLWH. A total of 52.4% had defaulted ART and 25.7% were ART naïve. Forty-three patients received four or more LPs (mean = 4.58 [± 0.96]) in the first week of hospitalisation with an associated in-hospital mortality of 11.6% (n = 5/43) compared with 62 patients who received less than four LPs (mean = 2.18 [± 0.80]) with an in-hospital mortality of 29% (n = 18/62) and a relative risk of 0.80 (95% CI, 0.66-0.97), p = 0.034.

Conclusion:
In the current study of adult PLWH presenting to hospital with HIV/CCM, four or more LPs in the first 7 days following admission and the initiation of treatment were associated with a 17.4% reduction in absolute risk of in-hospital mortality and a 20% reduction in relative risk of in-hospital mortality. This mortality difference was noted in patients who survived and were in hospital at the time of the 7-day study census and persisted until the time of hospital discharge. Keywords: cryptococcal meningitis; HIV; antifungal therapy; antiretroviral therapy; in-hospital mortality; adult PLWH.

Intracranial pressure management in patients with human immunodeficiency virus-associated cryptococcal meningitis in a resource-constrained setting
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The initial (induction phase) management of HIV/CCM requires the following: (1) combination antifungal therapy including IV amphotericin B and oral flucytosine (first week only) and high-dose oral fluconazole 1200 mg daily (second week), after that an 8-week consolidation phase of oral fluconazole 800 mg daily, (2) control of raised intracranial pressure (rIP) with therapeutic lumbar punctures (LPs) to maintain the 'opening-pressure' (CSF-OP) at < 25 cm of water and (3) minimising the risk of immune reconstitution inflammatory syndrome (IRIS) by delaying the initiation of ART until 4 to 6 weeks after the start of antifungal therapy. 8,9,10,11,12 In the absence of a spinal manometer, the SA guidelines for the prevention, diagnosis and management of CCM recommend performing an LP to remove 20 mL -30 mL of CSF if the symptoms and signs of rIP are present. 12 However, in clinical practise only 23% -30% of CCM patients with signs and symptoms receive 'therapeutic' LPs. 13,14 A symptom guided approach has the potential to miss asymptomatic patients who might benefit from therapeutic LPs.
We hypothesised that four or more LPs in the first 7 days of treatment could facilitate CSF drainage and reduce inhospital mortality in PLWH and HIV/CCM in a resource constrained setting where there are no spinal manometers. We, therefore, conducted a single centre retrospective cohort study to determine the impact on in-hospital mortality of four or more LPs in the first 7 days of antifungal therapy compared with PLWH/CCM who received fewer than four LPs.

Study design
The study was designed as a retrospective cohort review of PLWH/CCM admitted to the department of medicine at the Dora Nginza Hospital from 01 January 2016 to 31 December 2016. The Dora Nginza Hospital is a district hospital located in the Zwide township of the Nelson Mandela Bay Municipality (Port Elizabeth), SA. The Nelson Mandela Bay region has a population of 1 152 115 and an unemployment rate of 36.6%. 15 The internal medicine department consists of a 120-bed unit without access to intensive or high care services and with limited access to radiological imaging apart from plain chest radiography.

Study population
Clinical notes, discharge summaries and death notification registries were reviewed to identify patients who received a primary or secondary diagnosis of CCM.

Data collection
A standardised data collection form was prepared. This included patient demographic details, comorbidities, history of previous CCM, data of concurrent tuberculosis (TB) and details of the index admission. Patients' folders were checked for the results of therapeutic LPs and to document the indications for the procedure. The National Health Laboratory Services (NHLS) computer records were accessed for admission bloods, CD4 count, HIV viral load (VL) and CSF results. Identifying patient material was anonymised at the time of the collection and storage of data.

Ethical consideration
Approval to conduct the study was obtained from Walter Sisulu University Human Research Committee. Ethical clearance number: 027/2018.

Clinical characteristics of the study population
From 01 January 2016 to 31 December 2016, a total of 116 patients received a diagnosis of CCM. After exclusion of 11 (two were younger than 18 years, two had missing hospital files/records and seven demised or left the hospital before 7 days of hospitalisation), 105 patients were available for study analysis (Figure 1). Patients who received ≥ 4 LPs in the first 7 days had an inhospital mortality rate of 11.6% (n = 5/43), whereas those with < 4 LPs in the first 7 days had in-hospital mortality of 29% (n = 18/62). This represents a 17.4% absolute risk reduction of in-hospital mortality and a relative risk of 0.80 (95% CI, 0.66-0.97, p = 0.034), namely a 20% relative risk reduction of in-hospital mortality (Figures 2 and 3). Patients who received four or more LPs in the first 7 days received a mean of 4.58 (s.d. ± 0.96) LPs in the first week of treatment.   http://www.sajhivmed.org.za Open Access

Discussion
In this retrospective study of patients with HIV/CCM, receipt of four more LPs in the first week of diagnosis and treatment was associated with reduced in-hospital mortality. These findings inform the recorded 98.2% compliance of hospital staff with local guideline-based treatment of CCM with combination antifungal therapy.
Raised intracranial pressure develops in most PLWH with HIV/CCM and portends a poor prognosis if not adequately treated. 16 Lumbar punctures and CSF drainage have been shown to be effective in managing CCM related rIP. 17 Alternatives such as acetazolamide or corticosteroids have no role in the management of HIV/CCM. 18,19 Despite the increased prevalence of rIP, therapeutic LPs are seldom instituted even when symptoms and signs of rIP are present. 13,16 In a clinical audit by Adeyemi and Ross, only 23% of patients with CCM related headaches received therapeutic LPs despite 82% of patients receiving analgesia for their pain. 13 Similarly, Rolfes et al. report that only 30% of the 248 patients in their cohort received therapeutic LPs. 14 This was despite the fact that therapeutic LPs were associated with a 69% improvement in survival. 14 In our study we report a 17.4% absolute risk reduction of in-hospital mortality following intervention with four or more LPs in the week of diagnosis and treatment.
Spinal manometers are recommended for the measurement of rIP. In resource limited settings spinal manometers are seldom available. Instead, guidelines recommend using tubing from intravenous giving-sets. 20  The optimal management of CCM consists of a triad of (1) combination antifungal therapy, (2) intracranial pressure (IP) management with CSF drainage and (3) immune reconstitution with ART after completion of 4 to 6 weeks of combination antifungal therapy to avoid CCM-IRIS. 12 This study provides evidence that rIP in HIV/CCM can be managed without recourse to spinal manometers.
The limitations of this study include it's retrospective and single centres design. Also, we do not have data on the volume of CSF removed and survival beyond the index hospitalisation.
In conclusion, this study shows that PLWH/CCM can be effectively managed in centres with limited access to spinal manometers. We have shown that ≥ four LPs with CSF drainage in the first 7 days of hospitalisation improves early survival.