Profile and acute mortality outcome of patients admitted with cryptococcal meningitis to an urban district hospital in KwaZulu-Natal, South Africa

Abstract

Background: Cryptococcal meningitis (CCM) is one of the leading causes of early mortality in human immunodeficiency virus (HIV)-infected patients. This study was part of a clinical audit aimed at improving care for patients with CCM at an urban district hospital in South Africa.

Method: The clinical records of patients (age > 13 years) admitted to the hospital with a diagnosis of CCM between June 2011 and December 2012 were retrospectively reviewed. Descriptive statistics and chi-square analysis were generated with EpiInfo^™ 7.1.2.0. Ninety-five per cent confidence intervals were reported, where appropriate.

Results: Of the 127 patients admitted with CCM, only 97 (76.4%) knew their HIV status. Only 44.8% (43/96) of those who knew that they were HIV-positive were on antiretroviral therapy (ART). Seventeen of the 25 patients (68%) previously treated for CCM had defaulted on their fluconazole treatment and only 60% (15/25) were on ART. CCM-related mortality at two weeks was 55.9% (71/127). A high cerebrospinal fluid (CSF) fungal load, CD4 count < 100 cells/mm³ and poor CSF inflammatory response were associated with increased mortality risk. However, only the association between poor CSF inflammatory response and mortality was statistically significant (p = 0.03).

Conclusion: Acute CCM-related mortality remains high. The number of patients who do not know their HIV status, the number of HIV-positive patients who are not on ART, the high level of nonadherence to their fluconazole medication and the proportion of patients who are not on ART after at least one previous CCM episode indicate that there is a need to develop comprehensive strategies aimed at encouraging HIV testing and improving the retention of patients with regard to HIV care and support.

Keywords:

• acute mortality
• cryptococcal meningitis
• Cryptococcus neoformans
• district hospital
• KwaZulu-Natal

Introduction

In spite of the recent rapid scale-up of access to antiretroviral therapy (ART) in sub-Saharan Africa, mortality from human immunodeficiency virus (HIV)-related opportunistic infections remains high, largely because patients present late with advanced immune suppression.¹

With approximately one million new cases every year² and mortality rates as high as 70% in some resource-limited settings,^3,4 HIV-associated cryptococcal meningitis (CCM) is a major public health problem,⁵ and one of the leading causes of morbidity and early mortality in people living with HIV.⁶ Currently, CCM is the most common cause of microbiologically confirmed cases of adult meningitis in South Africa, accounting for 63% of microbiological diagnoses.⁷

To improve the management and reduce mortality associated with CCM, the South African National Department of Health and the Southern African HIV Clinicians Society published context-relevant CCM treatment guidelines in 2006 and 2008, respectively.^8,9 These guidelines advocated induction therapy with amphotericin B, followed by consolidation with oral fluconazole in view of the non-availability of flucytosine in South Africa.^8,9 The guidelines also recommended that HIV counselling and testing (HCT) services should be offered to patients diagnosed with CCM⁹ in line with the recognition of CCM as an acquired immune deficiency syndrome (AIDS)-defining illness and with a view to initiating those patients infected with HIV on lifelong ART.^10,11

In keeping with reports from other public hospitals in South Africa,^1,12,13 CCM is a common AIDS-defining illness that is seen at the hospital where this study was conducted.¹⁴ Routine clinical observations at the hospital suggest that mortality outcomes in patients admitted with CCM are high. This study was conducted with the aim of documenting the profile and mortality outcomes of patients admitted with CCM as part of a clinical audit aimed at improving the management of CCM at the hospital.

Method

This was a retrospective descriptive study carried out at an urban district hospital in KwaZulu-Natal, South Africa.

The clinical records of patients (age > 13 years) admitted with a proven diagnosis of CCM between 1 June 2011 and 31 December 2012 were retrospectively reviewed to document patient profiles, patient management and the acute mortality outcome of CCM. A diagnosis of CCM, based on a positive India ink, positive cryptococcal latex agglutination test, or a positive culture of Cryptococcus neoformans, was essential for inclusion in this study. Patient records were identified using the hospital’s admission, transfer and discharge register, clinical records, mortality records and laboratory data accessed from the National Health Laboratory Service (NHLS) database. Data on coexisting opportunistic infections were based on patients’ clinical records and history, or on clinicians’ observations and clinical entries at the time of admission.

A data extraction tool was developed to collect the demographic data and clinical profile, including HIV status, ART status, CD4 count, cerebrospinal fluid (CSF) findings and mortality outcomes. Data were captured onto an Excel^® spreadsheet and analysed descriptively using EpiInfo^™ 7.1.2.0. Chi-square analysis was carried out and 95% confidence intervals (CIs) were reported, where appropriate.

Ethical approval was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (Ref BE086/12) and from the hospital management.

Results

One hundred and twenty-seven patients with proven CCM, based on the aforementioned diagnostic criteria, were admitted to the hospital during the study period. The demographic and clinical data of these patients are shown in Table 1. Just over half of the patients were men. Only 97/127 (76.4%) of the patients were aware of their HIV status, and 96/127 (75.6%) reported that they were HIV-positive. Less than 50% of those who knew that they were HIV-positive prior to admission with CCM were on ART. Of the 74 patients with a known CD4 count, 54 (73%) had a CD4 cell count < 100 cells/mm³, 13 (17.6%) had a CD4 cell count 100–200 cells/mm³ and seven (9.5%) had a CD4 count > 200 cells/mm³.Tuberculosis (n = 61, 48.0%) was the most common coexisting opportunistic infection reported in the patients. Twelve (9.4%) patients had more than one concurrent opportunistic infection. Common presenting features included a headache (n = 118, 92.2%), meningism (n = 93, 73.2%), vomiting (n = 67, 52.8%) and photophobia (n = 52, 40.9%). 16.4% (n = 21) of the patients presented with non-specific symptoms, such as loss of appetite, nausea, malaise and generalised body pain.

Table 1: The demographic and clinical profile of patients admitted with cryptococcal meningitis

Characteristics	n (%)
Age (years) mean ± standard deviation	36 ± 9.8
Gender	(n = 127)
Male	65 (51.2)
Female	62 (48.8)
Self-reported HIV status on admission	(n = 127)
Positive	96 (75.6)
Negative	1 (0.8)
Unknown HIV status	30 (23.6)
ART status of HIV-positive patients on admission	(n = 96)
On ART	43 (44.8)
Not on ART	47 (49.0)
Defaulted on ART	6 (6.3)
Known CD4 count (cells/mm^3) (n = 74)
CD4 < 100	54 (73.0)
CD4 100–200	13 (17.6)
CD4 > 200	7 (9.5)
CD4 count (cells/mm^3) median (IQR)	45 (21–115)
Duration of ART before cryptococcal meningitis diagnosis, if known	(n = 27)*
< 1 month	6 (22.2)
1–3 months	11 (40.7)
> 3 months to 6 months	5 (18.5)
> 6 months to 1 year	2 (7.4)
1–3 years	3 (11.1)
Coexisting opportunistic infection at cryptococcal meningitis diagnosis
Tuberculosis	61 (48.0)***
Oral candidiasis	22 (17.2)***
Oesophageal candidiasis	4 (3.1)***
Kaposi sarcoma	2 (1.6)***
Other**	3 (12.3)***
No opportunistic infection reported	50 (39.4)***

ART: antiretroviral therapy, CD4: cluster of differentiation, HIV: human immunodeficiency virus, IQR: interquartile range

* actual sample was less than 43 owing to the unknown duration of the highly active antiretroviral therapy in 16 patients

** One case each with genital warts, genital ulcer disease and herpes ophthalmicus

*** Total number > 127 and total percentage > 100, owing to the coexistence of multiple opportunistic infections

All the 31 (24.4%) patients who reported their HIV status on admission as “negative” or “unknown” were referred for HCT. Twenty-three of these patients tested positive for HIV, one declined to be tested and seven died before the test could be carried out.

Twenty-five patients (25/127, 19.7%) had previously been treated for at least one episode of CCM, and 68% of them (17/25) had defaulted on their fluconazole medication after the last episode of CCM. Only 60% (15/25) of these patients were on ART at the time they presented with a repeat episode of suspected CCM.

Table 2 shows the CSF parameters of the patients included in the study. Fifty-seven per cent (n = 71) of the patients had a CSF white blood cell count (WBC) of < 20 cells/ml.

Table 2: An indication of patients’ cerebrospinal fluid parameters at diagnosis

Cerebrospinal fluid parameters	n (%)	Total
Cerebrospinal WBCs		n = 124***
Cerebrospinal WBCs < 20 cells/ml	71 (57.3)
Cerebrospinal WBCs ≥ 20 cells/ml	53 (42.7)
Cerebrospinal Indian ink stain		n = 125***
Yeasts observed	117 (93.6)
Yeasts not observed*	8 (6.4)
Cerebrospinal microscopy (yeast burden)**		n = 80***
Nil	1 (1.3)
1+ (scanty)	34 (42.5)
2+ (moderate)	28 (35.0)
3+ (numerous)	18 (22.5)
Cerebrospinal chemistry
Glucose (mmol/l) median (IQR)	1.8 (1.1–2.7)
Protein (g/l) median (IQR)	0.78 (0.49–1.43)

IQR: interquartile range, WBCs: white blood cells

* Diagnosis based on the cryptococcal latex antigen test and/or cerebrospinal culture of Cryptococcus neoformans

** Not routinely performed in the laboratory

*** Missing data from the laboratory

Acute mortality (percentage of patients who died within 14 days of CCM diagnosis) was 55.9% (71/127). The median time to death from diagnosis was four days [interquartile range (IQR) 2–9]. The association between CSF WBC count < 20 cells/ml and increased risk of death within 14 days was statistically significant [odds ratio (OR) 2.2, 95% CI: 1.1–4.6, p = 0.03). Patients with a heavy cryptococcal burden (reported as numerous yeasts seen on microscopy) at diagnosis were three times more likely to die within 14 days of diagnosis of CCM (OR 3.2, 95% CI: 0.9–10.7, p = 0.06). Even though a CD4 count < 100 cells/mm³ was associated with a 1.6 times increased acute mortality risk, the association was not statistically significant (OR 1.6, 95% CI: 0.6–4.6, p = 0.3). The role of elevated CSF opening pressure at diagnosis was not assessed because baseline opening pressure was measured in only 2 (1.6%) patients.

Discussion

This study provides insight into the burden of CCM in patients admitted to a district hospital in KwaZulu-Natal, South Africa. The average age of our patients (36 years) was similar to that reported in patients in other studies from sub-Saharan Africa,^{11,12,15–17} with CCM, like HIV, predominantly affecting the productive population of South Africa. Contrary to data from other studies^11,12 where females predominate, there were slightly more males than females in this patient group. This may be owing to the fact that in general, men are less likely than their female counterparts to routinely access HCT services^18,19 before the development of an AIDS-defining opportunistic infection, such as CCM. The routine integration of HCT services into antenatal programmes offers women more opportunities to routinely test for HIV than men.¹⁸ Furthermore, men’s reluctance to routinely access HIV services may be owing to peculiar masculine socialisation relating to HIV-associated fear and stigma.¹⁹ Therefore, it is important that the health services find creative solutions to encourage all individuals, but in particular, men, to test and to know their HIV status if this pattern is to be reversed.

While more than three quarters (75.6%) of the patients knew that they were HIV-positive on diagnosis of CCM, it is of concern that less than half (44.8%) of these patients were on ART at the time they presented with an AIDS-defining illness. This finding is consistent with those of other studies in which the substantial loss to follow-up of patients diagnosed with HIV in sub-Saharan Africa and their poor retention in care were reported.²⁰ Therefore, while it is commendable that all of the patients with unknown or negative HIV status were referred for HCT services, optimal in-patient HIV services might not necessarily translate into long-term retention in care.¹¹ Another potential impact of poor follow-up was reflected in the fact that only 60% of the patients with a symptomatic relapse of CCM were on ART, and 68% had defaulted on their fluconazole treatment at the time they presented with another episode of CCM. The burden of symptomatic CCM relapse is similar to that described in patients seen at another public sector hospital in South Africa where 23% of CCM cases were due to relapse episodes and where 43% of patients had defaulted on their fluconazole prophylaxis.¹⁷ The established link between poor retention in care and poor survival outcome with HIV infection has led to calls for innovative strategies aimed at ensuring sustainable systems to follow-up patients diagnosed with HIV infection.²¹

It is not uncommon for patients diagnosed with CCM to have other opportunistic infections when presenting for care. Eighty per cent of patients diagnosed with HIV-associated CCM were reported as having concurrent opportunistic infections in Durban.¹² Similarly, the majority of our patients (61.4%) had another opportunistic infection at the time they were diagnosed with CCM. The pattern observed in this study is similar to that in a previous report from South Africa, with tuberculosis and oral candidiasis being the most common opportunistic infections.¹² This highlights the need for clinicians to be vigilant about other opportunistic infections when managing patients with CCM.

Although the CD4 count was only available in 74 patients, with a median CD4 count of 45 cells/mm³ (IQR 21–115), and 73% of these patients having a CD4 cell count < 100 cells/mm³, the degree of immunodeficiency in patients admitted with CCM in this study was similar to that previously reported in other settings.^11,16 A study conducted in Cape Town in 2005 reported a median CD4 cell count of 49 cells/mm³ (IQR 21–71) in patients diagnosed with CCM, and a CD4 count of 49 cells/mm³ (IQR 16–86) was reported from a study conducted at a district hospital in rural KwaZulu-Natal in 2007.¹¹ Other pointers to advanced CCM disease and the severity of immunodeficiency in our patients at presentation included the high rate of CSF India ink positivity (93.6%) and the poor CSF inflammatory response [CSF white blood cell (WBC) count < 20 cells/ml] seen in 57.3% of these patients. India ink positivity is a reflection of a heavy fungal burden and a CSF WBC count < 20 cells/ml is a marker of poor host inflammatory response.²² Similar to findings in other reports,^22,23 there was a statistically significant association between poor CSF inflammatory response and acute mortality. Patients with a poor CSF inflammatory response were more than twice as likely to die within 14 days. Univariate analysis from this study also showed that patients with a heavy fungal burden and a low CD4 cell count were at increased risk of death within 14 days. However, these associations were not statistically significant. In view of the small study sample, these results need to be treated with caution.

In spite of excellent inpatient guidelines for the management of CCM, significant mortality continues to occur.²⁴ High mortality associated with acute CCM has been reported²⁴ previously, and the mortality outcome from this study was comparable with a mortality outcome of 30–70% reported in routine care in sub-Saharan Africa,^3,4,11 but higher than that reported in clinical trials in which severe cases of CCM were excluded.²² Thus, strategies aimed at the prevention or early diagnosis of CCM need to be explored if mortality rates are to be reduced.^25,26 These findings lend credence to calls for the preemptive screening and treatment of subclinical cryptococcal disease at the time of ART initiation.^25,27 Routine screening of patients with a CD4 count < 100 cells/mm³ for cryptococcaemia and pre-emptive treatment with fluconazole have been started in Gauteng and Western Cape provinces,²⁸ and consideration needs to be given to the further rapid roll-out of this initiative to reduce the in-hospital mortality associated with CCM.²⁹ Further studies are needed to assess the impact of this practice on CCM-associated mortality in routine care settings.

Limitations

Given that only patients seen at one district hospital were included in this study, the results may not be generalisable to other district hospitals. The retrospective nature of the study design made it impossible for the researchers to control the quality of the recorded information in the patient files. Some records were incomplete and information may have been incorrectly recorded, thus introducing the possibility of information bias. The reasons for the nonadherence to fluconazole or the failure to initiate ART after the initial CCM episode were not explored in this study. These represent important areas that warrant further research.

Conclusion

The above limitations notwithstanding, data from this study provide insight into the burden of CCM in patients admitted to a district hospital. This study also highlighted the high mortality associated with CCM in routine care settings, and supports the need for innovate strategies to be developed and implemented if CCM-associated mortality is to be reduced. The number of HIV-positive patients who were not on ART, the level of nonadherence to fluconazole treatment and the proportion of patients who were not on ART after a previous diagnosis of CCM, indicate weaknesses within the health system, and the need to develop comprehensive strategies aimed at improving the retention of patients in care.

Acknowledgements

The authors thank the medical record staff and NHLS laboratory manager at the hospital for facilitating access to the patient records.