AIDS Research and Therapy

Yang et al. AIDS Res Ther (2017) 14:24

DOI 10.1186/s12981-017-0150-2

RESEARCH Open Access

Molecular diagnosis of central nervous

system opportunistic infections and mortality
in HIV‑infected adults in Central China
Rongrong Yang1†, Hong Zhang1†, Yong Xiong1*, Xien Gui1, Yongxi Zhang1, Liping Deng1, Shicheng Gao1,
Mingqi Luo1, Wei Hou2 and Deyin Guo2

Abstract 
Background:  CSF PCR is the standard diagnostic technique used in resource-rich settings to detect pathogens of
the CNS infection. However, it is not currently used for routine CSF testing in China. Knowledge of CNS opportunistic
infections among people living with HIV in China is limited.
Methods:  Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral and fungal etiolo-
gies. Pathogen-specific primers were used to detect DNA from cytomegalovirus (CMV), herpes simplex virus (HSV),
varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6) and John Cunningham virus (JCV)
via real-time polymerase chain reaction (PCR).
Results:  Cryptococcal meningitis accounted for 63.0% (34 of 54) of all causes of meningitis, 13.0% (7/54) for TB, 9.3%
(5/54) for Toxoplasma gondii. Of 54 samples sent for viral PCR, 31.5% (17/54) were positive, 12 (22.2%) for CMV, 2 (3.7%)
for VZV, 1 (1.9%) for EBV, 1 (1.9%) for HHV-6 and 1 (1.9%) for JCV. No patient was positive for HSV. Pathogen-based
treatment and high GCS score tended to have a lower mortality rate, whereas patients with multiple pathogens infec-
tion, seizures or intracranial hypertension showed higher odds of death.
Conclusion:  CNS OIs are frequent and multiple pathogens often coexist in CSF. Cryptococcal meningitis is the most
prevalent CNS disorders among AIDS. The utility of molecular diagnostics for pathogen identification combined with
the knowledge provided by the investigation may improve the diagnosis of AIDS related OIs in resource-limited
developing countries, but the cost-efficacy remains to be further evaluated.
Keywords:  AIDS, Central nervous system diseases, Cerebrospinal fluid

Background causes of neurologic diseases in HIV/AIDS patients in

Central nervous system (CNS) infectious is a major cause developing countries [4–8]. In China, lumbar puncture
of morbidity and mortality among people living with (LP) is a routine practice and cerebrospinal fluid (CSF)
human immunodeficiency virus (HIV) [1, 2]. Sympto- is commonly collected for patients with suspected diag-
matic neurological diseases happened in about 40–70% of nosis of CNS infection. However, the available and fre-
HIV/AIDS patients during the course of their illness [1], quently-used means of diagnosis are generally limited to
and about 10–20% HIV/AIDS patients have neurologic CSF routine and biochemical tests, Gram stain, India ink
symptoms as an initial manifestation [2, 3]. Studies indi- stain, cryptococcal antigen (CrAg) detection, and bacte-
cated that opportunistic infections are the most common rial/fungal cultures. As a result, country-specific data
in our hospital regarding prevalence of CNS disorders
*Correspondence: [email protected]
are sparse, and many patients remain misdiagnosed and
†
Rongrong Yang and Hong Zhang contributed equally to this article inadequately treated.
1
Department of Infectious Diseases, Zhongnan Hospital of Wuhan In resource-rich settings, the standard diagnostic tech-
University, 169 Donghu Road, Wuhan 430071, China
Full list of author information is available at the end of the article
nique used to identify the presence of viral, parasitic, and

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Yang et al. AIDS Res Ther (2017) 14:24 Page 2 of 7

specific bacterial infection of the CNS disorders is CSF (CT) or magnetic resonance imaging (MRI) for patients
polymerase chain reaction (PCR); however, in China in with a focal brain lesion or suspected brain hemorrhage.
HIV-infected patients, CSF PCR is not currently used But whether the imaging examination ultimately used
for routine tests. The prevalence data regarding CNS depends on the patients’ or their family members’ will-
infectious diagnosed via PCR in China was particularly ingness and attitude.
absent at present. In this study, CSF samples were tested
for CMV, HSV, VZV, EBV, HHV-6 and JCV via PCR. The CSF testing
prevalence of CNS OIs in HIV-infected Chinese adults All CSF samples were collected via lumbar puncture and
and their impact on patient outcomes were determined. stored at −20 °C for molecular diagnostics. DNA was iso-
lated by using the easyMAG Instrument (bioMérieux).
Methods Primers amplifying a conserved sequence of viral DNA
Patients population polymerase (BALF5) gene and a fluorogenic probe were
This hospital-based study was conducted at Zhongnan used at a primer concentration of 0.9  μM and a probe
Hospital of Wuhan University, China, between 1 Decem- concentration of 0.25  μM. Amplification was carried
ber 2012 and 30 September 2014. Patients were eligible out in an ABI PRISM 7900 HT Sequence Detector (PE
for the study if they had: (1) confirmed with HIV infec- Applied Biosystems) and the standard curve was created
tion; (2) three or more symptoms of meningitis and/or with Sequence Detection System software by plotting the
encephalitis (headache, seizure, nausea/vomiting, altera- CT values against known CMV, EBV, JCV, VZV, HHV-6,
tion in consciousness, photophobia, or a focal neurologi- HSV or TB-DNA concentrations. The assay has a detec-
cal deficit); and (3) agreed to do a lumbar puncture(LP), tion limit of 500 genome equivalents/ml.
as determined by the attending physician. Exclusion cri-
teria for enrollment included: (1) patients with delirium, Statistical analysis
such as sepsis due to a non-neurological infection or Continuous data are presented as mean ± standard devi-
metabolic abnormality; (2) patients with peripheral neu- ation (for normally distributed variables) or median and
ropathy and psychosis rather than medical explanation interquartile range or IQR (for variable influenced by
for their symptoms; or (3) patients with a documented extreme values). Categorical data are presented as num-
immunosuppressive except for HIV infection or neuro- bers with proportions. P-values were 2-sided and consid-
surgical illness. Meningitis was diagnosed if there was a ered statistically significant if  <0.05. Statistical analyses
combination of meningeal irritation symptoms and signs were performed using SPSS for Windows, version 19.0
and the presence of more than five white blood cells in (SPSS, Chicago, IL).
CSF obtained by lumbar puncture. Exclusion criteria
included malignancies, various inflammatory conditions, Results
sarcoidosis, and infectious secondary to procedures. Patient characteristics
Meningoencephalitis was defined as any brain parenchy- In this study, 57 patients with CNS diseases out of 658
mal involvement (e.g. seizures), behavioral change, con- hospitalized AIDS (≥14  years old) were admitted to
fusion, dysphasia and other cortical deficits, with signs Zhongnan Hospital of Wuhan University with a com-
of meningeal irritation. Encephalitis was defined as fever plaint of new or recurrent neurological or psychiatric
with altered sensorium with CSF pleocytosis and raised symptoms were included (Fig.  1). Of these 57 patients,
protein with or without focal neurological signs in whom complete clinical information was available in 54 (94.7%).
malaria, bacterial or fungal meningitis were excluded. Forty-one cases of meningitis, six cases of encephalitis
Trained radiologists and neurologists were also invited and seven cases of meningoencephalitis were found in
to help identifying patients with a suspected diagnosis this series. Characteristics of the 54 patients are shown
of meningitis, encephalitis or meningoencephalitis. The in Table 1. The mean age was 38 years and 64.8% of par-
study was approved by Zhongnan Hospital of Wuhan ticipants were male. The main occupational population
University Ethics Committee. was farmer (70.4%). And the main HIV acquisition route
Demographic information, such as age, gender, mari- was sexual contact (79.6%). At the time of enrollment, a
tal status, risk factors, duration between HIV infection median duration of 45  days was observed. The median
and hospital admission, clinical features and past medi- ­CD4+ T cell count was 31 cells/μl.
cal history were collected on a standardized report form
by the trained physician. In China, lumbar puncture (LP) Pathogen(s) detecting in CSF
is routine practice for patients with a suspected CNS Pathogens were detected in 47 (87.0%) CSF samples. The
infection prior to antibiotic treatment. Other impor- number of patients diagnosed with one or more patho-
tant medical assessment were computed tomography gens is shown in Table  2. Cryptococcus neoformans was
Yang et al. AIDS Res Ther (2017) 14:24 Page 3 of 7

Fig. 1  Study profile

Table 1  Patient demographics (N = 54) also detected VZV (3.7%), JCV (1.9%), EBV (1.9%) and
Feature No (%) HHV-6 (1.9%) in this patient population. No case of HSV
were detected by PCR.
Age (years), mean (SD) 38 (11.2)
Male 35 (64.8) Results of PCR positive pathogen(s) detected by other
Occupation methods
 Farmers 38 (70.4) Of the 34 cases with cryptococcus, three were negative
 Clerk 8 (14.8) on India Ink (8.8%), and four were negative on CrAg
 Businessman 4 (7.4) (11.8%).
 Others 4 (7.4) Of five PCR diagnosed toxoplasmosis in this series,
HIV transmission route all responded clinically and radiographically within four
 Sex 43 (79.6) weeks of initiation of pyrimethamine and clindamycin
 Blood donation/transfusion 6 (11.1) combination therapy.
 IDU 2 (3.7) Among the 12 CMV-DNA positive patients, 8 (66.7%)
 Unknown 3 (5.6) serum samples were negative for CMV-DNA and the
Days since HIV diagnosis, median (IQR) 45 (1–732) average level of CMV-DNA in CSF was 2.80  ±  1.15
CD4+ T cells/μl, median (IQR) 31 (21–83) ­Log10copies/ml.
SD standard deviation Among five patients diagnosed toxoplasmosis, brain
CT or MRI was used for four patients. The representative
the most common pathogen found (63.0%) and the most ring enhancing lesions were found in all the four patients.
common copathogen (22.2%). There were high rates of For the EBV-DNA positive patient, mass lesions were
detection of CMV (22.2%) and tuberculosis (13.0%). We not found. For the JCV-DNA positive patient, typical

Table 2  Characteristics of patients with CSF pathogen(s)

Pathogens Individual CSF prevalence 1 pathogen No. of cases 2 pathogens No. of cases 3 pathogens No. of cases

Cryptoa 34/54 (63.0%) Crypto 22 Crypto/CMV 7 Crypto/TB/CMV 2

Crypto/VZV 1 Crypto/TB/HHV-6 1
Crypto/JCV 1
CMV 12/54 (22.2%) CMV 2 CMV/TB 1
TB 7/54 (13.0%) TB 3
Toxop 5/54 (9.3%) Toxop 5
VZV 2/54 (3.7%) VZV 1
JCV 1/54 (1.9%) JCV 0
EBV 1/54 (1.9%) EBV 1
HHV-6 1/54 (1.9%) HHV-6 0
HSV 0/54 (0%) HSV 0
Total 63 pathogens 34/54 (63.0%) 10/54 (18.5%) 3/54 (5.6%)
Yang et al. AIDS Res Ther (2017) 14:24 Page 4 of 7

white matter changes were found, which was consistent The most common viral pathogen causing meningitis
with the PCR for JCV. is CMV and that the most common bacterial pathogen
Among 12 CMV-DNA positive patients, brain CT or is TB. Our finding highlighted the utility of molecular
MRI was used for 6 patients and none was found with diagnostics for improving pathogen identification for
brain parenchymal lesion. CNS infections.
The HIV epidemic has caused a marked increase in
Risk factors associated with mortality cases of cryptococcal meningitis such that it has become
In our study population, the total mortality rate was the leading cause of meningitis among patients living
22.2% (12/54). Table 3 summarizes the potential risk fac- with HIV [9–11]. We found that cryptococcal meningi-
tors of death in our study population. The odds of death tis caused the majority of meningitis among hospitalized
together with 95% confidence intervals were reported for AIDS patients, which accounted for 63.0% of all causes
each covariate. In the multivariate analysis, pathogen- of meningitis in this study. In a review, the total crypto-
based treatment and high glasgow coma scale (GCS) coccal meningitis prevalence was 52.0% in sub-Saharan
score were associated with lower odds of death. Con- Africa [12]. Our relatively high prevalence may be attrib-
versely, patients with multiple pathogens infection, sei- utable to different methodologies and tests used for
zures or intracranial hypertension showed higher odds of assessing prevalence; differences in host factors; or geo-
death. graphic variations in the epidemiology of cryptococcal
meningitis.
Discussion The prevalence of toxoplasma gondii in this study are
This hospital-based study provides information about the higher than previously reported from a study in Zambian
spectrum of pathogens causing CNS infections and mor- [13]. In our study population, the median ­CD4+ T-cell
tality among people living with HIV in Zhongnan Hospi- count was 31 cells/μl and all were newly diagnosed with
tal of Wuhan University in central China. The spectrum HIV and without any prophylaxis treatment, whereas in
of HIV-associated central nervous system disorders may Zambian [13] study, the enrollment C ­ D4+ T-cell count
be influenced by differences in the epidemiology. was 81 cells/μl in men and 99 cells/μl in women, and 118
We identified a microbiologic diagnosis for clinical (35.6%) patients were on cART for a median duration
meningitis in a cohort of HIV-infected Chinese inpa- of 240 days. The patient population and the presence of
tients. Our data suggested that the most common patho- anti-Toxoplasma treatment may account for the high pre-
gen causing meningitis is Cryptococcus neoformans. sent of Toxoplasma gondii.

Table 3  Variables associate with death in univariate and multivariate analysis

Variable Univariate analysis Multivariate analysis
Odds ratio (95% CI) P value Odds ratio (95% CI) P value

Categorical
 Male 0.58 (0.30–1.32) 0.26
 cART status 0.48 (0.30–2.22) 0.56
 Multiple pathogens 0.33 (0.14–0.56) <0.0001 0.46 (0.26–0.74) 0.002
 Cryptococcal meningitis 1.32 (0.80–2.34) 0.22
 CMV 1.21 (0.58–2.33) 0.74
 Tuberculosis 0.63 (0.88–3.26) 0.30
 EBV 0.70 (0.44–1.33) 0.23
 Other pathogens 0.85 (0.44–1.63) 0.53
 Pathogen-based treatment 5.7 (2.0–17.6) <0.0001 4.8 (2.4–16.5) 0.001
 Seizures 0.87 (0.33–1.42) 0.08 0.52 (0.36–0.98) 0.04
 Intracranial hypertension 0.27 (0.18–0.84) 0.04 0.33 (0.22–0.84) 0.03
 Disturbance of consciousness 0.67 (0.43–1.04) 0.06 1.00 (0.46–2.18) 0.99
Continuous
 Age 0.36 (0.14–0.89) 0.08 0.56 (0.32–1.02) 0.25
 GCS 0.22 (0.12–0.32) <0.0001 0.42 (0.21–0.80) 0.001
 CD4 count 0.66 (0.45–1.24) 0.68
GCS Glasgow coma scale
Yang et al. AIDS Res Ther (2017) 14:24 Page 5 of 7

Cytomegalovirus is a ubiquitous agent that can cause of immunodepression, being shed from activated B-cells
infection at any time during the course of life and com- trafficking into the CSF during meningitis. Further inves-
monly infects individuals from diverse geographical tigation on the significance of EBV in the CSF is needed.
and socio-economic backgrounds [14, 15]. By serology, Quantitative and comparison values from the CSF and
a study reports that 93.9% of the HIV infection patients serum is necessary to distinguish those with CNS lym-
were positive for anti-CMV IgG antibody [16]. But in phoma from those with non-pathogenic presence of EBV.
most patients, the diseases caused by CMV is so mild HIV strain and host susceptibility factors were thought
that it is overlooked. AIDS patients are commonly posi- to be less tendentious to infection by JCV, the pathogen
tive for CMV when sick with other illnesses. Diagno- of progressive multifocal leukoencephalopathy (PML).
sis of CMV infection from tissue biopsies is considered Indeed, the JCV CSF-positive patient had neurological
the gold standard with specificity for histopathological symptoms consistent with PML. The sole JCV-DNA pos-
evaluation near 100% but with low sensitivity (23.2%) itive patients received brain imaging examination, white
[17]. In this study through PCR for CMV-DNA, 12 out matter changes were found, which was consistent with
of 54 (22.2%) CSF samples were positive. Whether the the PCR for JCV.
CMV is truly pathogenic or simply an innocent bystander Seroprevalence of CNS HSV infection has previously
remains to be further identified. Among the 12 patients been documented at 47.2% in an urban Zambian popu-
with CMV-DNA positive in CSF, 8 (66.7%) serum sam- lation [20]. However, HSV DNA was not detected in
ples were negative for CMV-DNA and the average level any CSF samples in our study population. This is likely
of CMV-DNA in CSF was 2.80  ±  1.15  Log10  copies/ml. because the sample in our series is small and because our
Among 12 CMV-DNA positive patients, brain CT or study used a different detection method (HSV-DNA PCR
MRI was used for six patients. None patient was found in CSF) as the Zambian population [20] (HSV IgG ELISA
with brain parenchymal lesion. These features supported in serum).
a low CMV burden which is combination with the nega- In our study population, the total mortality rate
tive PCR in the blood favored the argument of CMV was 22.2% (12/54). This rate of mortality is lower than
being a bystander. reported in Zambian at the beginning of the AIDS epi-
Cerebral toxoplasmosis is a very relevant neurologi- demic [13]. Our study was not designed for long-term
cal disease in individuals with AIDS [18]. In this study, follow-up. It is possible that death occurred in the post-
toxoplasma is the fourth most common pathogen in CNS hospitalization period due to loss of follow-up, poor
disorders. Among five patients diagnosed toxoplasmosis, compliance with treatment, and poor access to emer-
brain CT or MRI was used for four patients. The repre- gency health services. As expected, the actual mortality
sentative ring enhancing lesions were found in all the four was higher than 22.2%.
patients. The limited data imply PCR for the diagnosis of Our study shows that numerous pathogens can be
toxoplasmosis was accurate and reliable. Of 5 PCR diag- found in the CSF of HIV-infected patients presenting
nosed toxoplasmosis in this series, all responded clini- with neurological symptoms in China, and the mor-
cally and radiographically within four weeks of initiation tality of this population is very high. There was a high
of pyrimethamine and clindamycin combination therapy. prevalence of co-infection in the CSF, indicative of
Although DNA positive in serum or cerebrospinal fluid severe immunodepression in this population. This find-
can be diagnosed as Toxoplasma infection, the policy of ing warrant a more in dept study in the future since in
empiric treatment of suspected Toxoplasma encephalitis resource-limited settings, patients present with advance
is still satisfactory and recommendable. For patients with immunodepression and the high morbidity and mortal-
AIDS and suspected Toxoplasma encephalitis, early diag- ity associated with this condition will continue to bring
nosis and initiation of empiric treatment and antiretrovi- great challenges to clinicians. Multiple pathogens infec-
ral therapy are important for good prognosis. tion in CNS disorder patients will be an important topic
EBV is consider to be associated with primary CNS to assess with further study in larger cohorts and with
lymphoma in HIV infected patient, though further diag- subsequent validation of results.
nostics for evaluation are lacking in this study. Detec- Diagnostic testing for a broad array of CSF pathogens
tion of EBV DNA from a CSF sample may represent may be helpful in resource-limited settings to avoid
replication of EBV within B lymphocytes, and it was unnecessary treatments and achieve better prognosis.
also closely related to an increased risk of death [19]. For TB diagnosis, the Xpert MTD/RIF assay is a fully
Neuroimaging was not obtained as part of this study. automated nucleic acid amplification testing (NAAT)
However, in the EBV PCR-positive patients with neu- that can deliver a result for MTB and rifampin resist-
roimaging, mass lesions were not found. Therefore, we ance in about 2  h. On the basis of studies in countries
speculated that EBV might be a non-pathogenic marker with high tuberculosis burden, Xpert has been endorsed
Yang et al. AIDS Res Ther (2017) 14:24 Page 6 of 7

by the World Health Organization and widely deployed resources, whether CSF PCR should be prioritized needs
[21–28]. In contrast to other NAATs, Xpert can be per- to consider the patients’ economic ability.
formed on-demand by personnel with minimal training
[28, 29]. The present study supports analysed suggesting
Abbreviations
that Xpert implementation in the United States is effi- CNS: central nervous system; AIDS: acquired immunodeficiency syndrome;
cient and cost-effective [30]. Therefore, in resource-lim- CMV: cytomegalovirus; EBV: Epstein-Barr virus; JCV: JC polyomavirus; VZV:
ited countries, establishment of Xpert is one of the ways varicella-zoster virus; HHV-6: human herpesvirus 6; HSV: herpes simplex
viruses; CSF: cerebrospinal fluid.
to attempt improving the clinical diagnosis level about
TB infection in CNS among AIDS patients. Authors’ contributions
Our study had some limitations. First, the generaliza- RRY, HZ and YX devised the study, advised on data analysis and participated in
interpreting the data and reviewing the manuscript. XE Gi,YXZ, LPD, SCG and
bility of our research finding is limited. Since our hospital MQL advised on data analysis and participated in interpreting the data and
is the sole comprehensive hospital well-known for AIDS reviewing the manuscript. WH and DYG participated in its design and coordi-
treatment in Hubei province, we can make some general nation and helped to draft the manuscript. All authors read and approved the
final manuscript.
assumptions regarding CNS infection in a province in
China. Second, the number of specific pathogens for PCR Author details
1
testing was limited and there are other possible etiolo-  Department of Infectious Diseases, Zhongnan Hospital of Wuhan University,
169 Donghu Road, Wuhan 430071, China. 2 Basic Medical College of Wuhan
gies of CNS infection, but were not assessed in our study. University, Wuhan, China.
Last but not least, the detection samples associated with
the study were limited to CSF, which may be incomplete Acknowledgements
We would like to acknowledge and thank all staff in the Department of Infec-
for diagnosis since pathogens can present in the CSF tious Diseases, Zhongnan Hospital of Wuhan University.
transiently. For many types of CNS infections, serologic
detection on the presence of virus-specific IgM antibod- Competing interests
The authors declare that they have no competing interests.
ies in serum or a rise in antibody titer can be useful; this
study did not include serologic assays. Availability of data and materials
In this series, in addition to the molecular testing, The datasets supporting the conclusions of this article are included within the
article and in Fig. 1.
Cryptococcus can be diagnosed with India Ink and CrAg,
TB can be diagnosed with Xpert, and Toxoplasmosis Ethics approval and consent to participate
can frequently be managed using an empirical strat- This clinical study was conducted according to the principles expressed in the
Declaration of Helsinki. The ethics committee of Zhongnan Hospital of Wuhan
egy. Meanwhile, some pathogens such as EBV and JCV University approved the study and patient confidentiality was maintained
have no specific, effective treatment, while others such by de-identification of patient data and use of a unique ID number for each
as CMV and HHV-6 require specialized therapies that patient.
Written consent forms were obtained from the patients after gave them
are frequently unavailable in a resource limited setting. appropriate information.
Disease burden, economic pressure, health resource and
severity of diseases are critical factors which can effect Funding
This study was supported by the National Science and Technology Major
the cost-efficacy of running a molecular laboratory. In Project of China (2014ZX10001003).
China, we believed that the molecular testing can only be
recommended under conditioned circumstances, rather Publisher’s Note
than prioritized under all circumstances. Springer Nature remains neutral with regard to jurisdictional claims in pub-
In conclusion, this study provides baseline data regard- lished maps and institutional affiliations.

ing the etiology distribution of CNS infections among Received: 18 January 2017 Accepted: 20 April 2017
hospitalized patients living with HIV/AIDS in a compre-
hensive Chinese hospital. It reported that the most etiol-
ogy was cryptococcal meningitis (63.0%). Even as high as
22.2% of CMV DNA positive rate was found in this study,
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