Clinical Infectious Diseases BRIEF REPORT
Angiostrongylus cantonensis Is an Important Cause of Eosinophilic Meningitis in Southern Vietnam Angela McBride,1,7,a Tran Thi Hong Chau,1,a Nguyen Thi Thu Hong,1,a Nguyen Thi Hoang Mai,1 Nguyen To Anh,1 Tran Tan Thanh,1 Tran Thi Hue Van,2 Le Thi Xuan,2 Tran Phu Manh Sieu,3 Le Hong Thai,4 Ly Van Chuong,4 Dinh Xuan Sinh,4 Nguyen Duy Phong,4 Nguyen Hoan Phu,4 Jeremy Day,1,5 Ho Dang Trung Nghia,6 Tran Tinh Hien,1,5 Nguyen Van Vinh Chau,4 Guy Thwaites,1,5 and Le Van Tan1 Oxford University Clinical Research Unit, 2University of Medicine and Pharmacy, 3Nguyen Trai Hospital, and 4Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; 5Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom; 6Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam; 7University College London Hospitals, United Kingdom. 1
We utilized polymerase chain reaction (PCR) to demonstrate that Angiostrongylus cantonensis was responsible for 67.3% of 55 cases of eosinophilic meningitis from a cohort of 1,690 adult patients with CNS infection at a tertiary hospital in southern Vietnam. Longer duration of illness, depressed consciousness, and peripheral blood eosinophilia were associated with PCR positivity. Keywords. Angiostrongylus cantonensis; eosinophilic meningitis; Vietnam.
Angiostrongylus cantonensis (or “rat lung worm”) is responsible for most infectious cases of eosinophilic meningitis (EM) worldwide. A. cantonensis is endemic to Southeast Asia and the Pacific islands, but in recent years human cases have been reported from increasingly diverse locations [1–3]. Although the definitive host is the Rattus rat, humans are most frequently infected by direct ingestion of molluscan intermediate hosts (e.g., raw snails) [4]. The characteristic eosinophilic reaction occurs when parasitic larvae die in the central nervous system (CNS) of dead-end human hosts. Diagnosis is usually presumed on the basis of epidemiological risk together with cerebrospinal fluid (CSF) eosinophilic pleocytosis, but adjunctive serological assays are available in some centers. Real-time polymerase chain reaction (PCR) has recently been developed for
Received 14 December 2016; editorial decision 14 January 2017; accepted 1 February 2017; published online February 4, 2017. a Alphabetically listed and contributed equally to the manuscript. Correspondence: A. McBride, Oxford University Clinical Research Unit, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam ([email protected]). Clinical Infectious Diseases® 2017;64(12):1784–7 © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/cix118
1784 • CID 2017:64 (15 June) • BRIEF REPORT
A. cantonensis, but it is not yet routinely used in clinical practice, especially in resource-limited settings. Patients are usually treated with a combination of albendazole and corticosteroids, but the degree of additional benefit conferred by antihelminthic therapy is uncertain [5]. To date there have been only 8 published cases of human angiostronglyiasis from Vietnam [6]. Herein, we present the clinical features, diagnostic results by A. cantonensis real-time PCR, treatment, and in-hospital outcomes of 69 adults with EM in southern Vietnam. METHODS
Between June 2008 and January 2014, a prospective descriptive study aimed at improving the diagnosis of CNS infections was conducted in an adult infectious diseases ward at the Hospital for Tropical Diseases, a tertiary referral hospital for southern Vietnam. Human immunodeficiency virus (HIV)-negative patients aged ≥15 years and suspected to have a CNS infection by the admitting physician were eligible for inclusion. Demographics, clinical features, laboratory results, management, and outcome were recorded. Routine CSF analysis included cell count, leucocyte differential by giemsa staining, protein, lactate and glucose analysis, gram stain and bacterial culture, india ink, and ZiehlNeelson staining. Additional investigations included mycobacterial and fungal culture, GeneXpert for Mycobacterium tuberculosis, cryptococcal lateral-flow assay (IMMY, Norman, OK 73071, USA), Japanese encephalitis virus specific immunoglobulin M (IgM), real-time PCR for herpes simplex virus, and brain imaging when clinically indicated. Clinical outcomes were assessed at discharge on the basis of survival and residual symptoms relative to those on admission (recorded as: complete recovery, partial recovery, no recovery). From the above cohort, we selected all patients with EM (defined as eosinophils ≥10% of the total CSF leucocyte count) for further analysis. We performed retrospective real-time PCR for A. cantonensis and conventional PCR for Gnathostoma spinigerum on stored CSF, with positive controls for each assay [3, 7]. We created a specificity panel from culture materials (n = 5) and CSF with other PCR-confirmed CNS pathogens (n = 26) (Supplementary Table 1). Statistical analysis was conducted using Stata (Stata Release 9. College Station, Texas, USA). The study was approved by the Scientific and Ethical Committee of the Hospital for Tropical Diseases, Vietnam, and the Oxford University Tropical Research Ethics Committee, United Kingdom. Written informed consent was obtained from the patient or from a family member if the patient was unconscious.
Table 1. Demographic Details, Clinical Features, Results of Laboratory Investigations, Treatment Received and Outcome at Discharge for All Patients with Eosinophilic Meningitis, A. cantonensis PCR Positive Patients and A. cantonensis PCR Negative Patients
Characteristic
All eosinophilic meningitis cases (n = 69)
A. cantonensis PCR positive patients (n = 37)
A. cantonensis PCR negative patients (n = 18)
P valuea
Age, years
31 (21−44)^
33 (23−44)^
22 (18−35)^
.053
Male
51 (59.4)
20 (54.1)
11 (61.1)
.624
Duration of illness, days
12 (7−20)^
14 (10−20)^
9 (5−14)^
.027
Snail ingestion
20 (29.0)
11 (29.7)
4 (22.2)
.557
History of fever
58 (84.1)
32 (86.5)
15 (83.3)
.756
Headachea
63 (96.9)
33 (97.1)
17 (100.0)
.475
Vomitingb
39 (62.9)
20 (62.5)
10 (55.6)
.630
Confusionc
18 (30.0)
9 (30.0)
3 (17.7)
.351
Blurred visiond
5 (8.6)
5 (16.7)
0 (0.0)
.084
Speech difficultyd
3 (5.2)
2 (6.7)
0 (0.0)
.291
Abdominal paine
5 (8.2)
5 (15.6)
0 (0.0)
.095
Clinical History
Examination GCS 15
.150 47 (68.1)
25 (67.6)
15 (83.3)
13−14
7 (10.2)
3 (8.1)
3 (16.7)
9−12
6 (8.7)
2 (5.4)
0 (0.0)
6−8
9 (13.1)
7 (18.9)
0 (0.0)
.036
Fever ≥38°C
26 (37.7)
16 (43.2)
6 (33.3)
.481
Neck stiffness
50 (72.5)
26 (70.3)
14 (77.8)
.557
Unilatera cranial nerve palsy
6 (8.7)
4 (10.8)
2 (11.1)
CN VI
4 (5.8)
3 (8.1)
1 (5.5)
CN VII
2 (2.9)
1 (2.7)
1 (5.5)
Bilateral cranial nerve palsy
3 (4.4)
2 (5.4)
1 (5.5)
CN III & CN VI
1 (1.4)
1 (2.7)
0 (0.0)
CN VI & CN VI
1 (1.4)
1 (2.7)
0 (0.0)
CN VI & CN VII
1 (1.4)
0 (0.0)
1 (5.5)
Hemiplegiaf
2 (3.2)
1 (3.0)
1 (5.9)
Paraplegiaf
2 (3.2)
2 (6.1)
0 (0.0)
Convulsionsg
1 (1.7)
1 (3.2)
0 (0.0)
Blood tests Hemoglobin g/dL
13.8 (12.9−14.8)^
13.7 (12.9−14.6)^
13.8 (13.2−15.4)^
.326
Leucocyte count ×109/L
11.4 (8.9−14.6)^
10.8 (8.3−14.0)^
12.1 (9.6−15.8)^
.226
Neutrophils (%)
62.1 (51.5−75.0)^
56.6 (50.1−69.0)^
67.9 (56.4−83.9)^
.018
Lymphocytes (%)
14.9 (9.5−20.8)^
18.0 (11.3−23.4)^
10.2 (8.4−17.6)^
.027
Eosinophils (%)
13.5 (4.9−20.1)^
15.0 (7.6−23.7)^
4.2 (1.1−16.3)^
.014
Platelets ×109/L
307 (259−358)^
302 (260−365)^
320 (268−355)^
.905
Creatinine µmol/L
61 (49−73)^
58 (48−69)^
63 (49−74)^
.204
Serum glucose g/dL
5.4 (4.8−6.5)^
5.3 (4.8−6.2)^
5.4 (4.9−6.4)^
.930
Sodium mmol/L
132 (129−139)^
133 (129−137)^
132 (130−136)^
.896
Potassium mmol/L
3.8 (3.5−4.2)^
3.8 (3.5−4.3)^
3.8 (3.2−3.9)^
.238
23 (17−33)^
22 (14−36)^
26 (18−31)^
.590
Clear
24 (34.8)
10 (27.0)
9 (50.0)
Turbid
42 (60.9)
25 (67.6)
9 (50.0)
3 (4.4)
2 (5.4)
CSF investigations Opening pressure cmH20 CSF appearance
Bloodstained CSF leucocyte count cells/mm3
.180
564 (347−1015)^
516 (374−856)^
0 (0.0) 786 (575−978)^
.208
CSF eosinophils (%)
39 (27−52)
39 (28−48)
42 (30−58)
.394
CSF protein g/dL
0.8 (0.5−1.2)^
0.9 (0.6−1.1)^
0.7 (0.5−1.2)^
.693
CSF protein>0.5 g/dL
55 (80.8)
30 (81.1)
CSF glucose g/dL
2.5 (1.9−2.8)^
2.4 (2.0−2.7)^
CSF/blood glucose
Angiostrongylus cantonensis Is an Important Cause of Eosinophilic Meningitis in Southern Vietnam Angela McBride,1,7,a Tran Thi Hong Chau,1,a Nguyen Thi Thu Hong,1,a Nguyen Thi Hoang Mai,1 Nguyen To Anh,1 Tran Tan Thanh,1 Tran Thi Hue Van,2 Le Thi Xuan,2 Tran Phu Manh Sieu,3 Le Hong Thai,4 Ly Van Chuong,4 Dinh Xuan Sinh,4 Nguyen Duy Phong,4 Nguyen Hoan Phu,4 Jeremy Day,1,5 Ho Dang Trung Nghia,6 Tran Tinh Hien,1,5 Nguyen Van Vinh Chau,4 Guy Thwaites,1,5 and Le Van Tan1 Oxford University Clinical Research Unit, 2University of Medicine and Pharmacy, 3Nguyen Trai Hospital, and 4Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; 5Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom; 6Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam; 7University College London Hospitals, United Kingdom. 1
We utilized polymerase chain reaction (PCR) to demonstrate that Angiostrongylus cantonensis was responsible for 67.3% of 55 cases of eosinophilic meningitis from a cohort of 1,690 adult patients with CNS infection at a tertiary hospital in southern Vietnam. Longer duration of illness, depressed consciousness, and peripheral blood eosinophilia were associated with PCR positivity. Keywords. Angiostrongylus cantonensis; eosinophilic meningitis; Vietnam.
Angiostrongylus cantonensis (or “rat lung worm”) is responsible for most infectious cases of eosinophilic meningitis (EM) worldwide. A. cantonensis is endemic to Southeast Asia and the Pacific islands, but in recent years human cases have been reported from increasingly diverse locations [1–3]. Although the definitive host is the Rattus rat, humans are most frequently infected by direct ingestion of molluscan intermediate hosts (e.g., raw snails) [4]. The characteristic eosinophilic reaction occurs when parasitic larvae die in the central nervous system (CNS) of dead-end human hosts. Diagnosis is usually presumed on the basis of epidemiological risk together with cerebrospinal fluid (CSF) eosinophilic pleocytosis, but adjunctive serological assays are available in some centers. Real-time polymerase chain reaction (PCR) has recently been developed for
Received 14 December 2016; editorial decision 14 January 2017; accepted 1 February 2017; published online February 4, 2017. a Alphabetically listed and contributed equally to the manuscript. Correspondence: A. McBride, Oxford University Clinical Research Unit, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam ([email protected]). Clinical Infectious Diseases® 2017;64(12):1784–7 © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/cix118
1784 • CID 2017:64 (15 June) • BRIEF REPORT
A. cantonensis, but it is not yet routinely used in clinical practice, especially in resource-limited settings. Patients are usually treated with a combination of albendazole and corticosteroids, but the degree of additional benefit conferred by antihelminthic therapy is uncertain [5]. To date there have been only 8 published cases of human angiostronglyiasis from Vietnam [6]. Herein, we present the clinical features, diagnostic results by A. cantonensis real-time PCR, treatment, and in-hospital outcomes of 69 adults with EM in southern Vietnam. METHODS
Between June 2008 and January 2014, a prospective descriptive study aimed at improving the diagnosis of CNS infections was conducted in an adult infectious diseases ward at the Hospital for Tropical Diseases, a tertiary referral hospital for southern Vietnam. Human immunodeficiency virus (HIV)-negative patients aged ≥15 years and suspected to have a CNS infection by the admitting physician were eligible for inclusion. Demographics, clinical features, laboratory results, management, and outcome were recorded. Routine CSF analysis included cell count, leucocyte differential by giemsa staining, protein, lactate and glucose analysis, gram stain and bacterial culture, india ink, and ZiehlNeelson staining. Additional investigations included mycobacterial and fungal culture, GeneXpert for Mycobacterium tuberculosis, cryptococcal lateral-flow assay (IMMY, Norman, OK 73071, USA), Japanese encephalitis virus specific immunoglobulin M (IgM), real-time PCR for herpes simplex virus, and brain imaging when clinically indicated. Clinical outcomes were assessed at discharge on the basis of survival and residual symptoms relative to those on admission (recorded as: complete recovery, partial recovery, no recovery). From the above cohort, we selected all patients with EM (defined as eosinophils ≥10% of the total CSF leucocyte count) for further analysis. We performed retrospective real-time PCR for A. cantonensis and conventional PCR for Gnathostoma spinigerum on stored CSF, with positive controls for each assay [3, 7]. We created a specificity panel from culture materials (n = 5) and CSF with other PCR-confirmed CNS pathogens (n = 26) (Supplementary Table 1). Statistical analysis was conducted using Stata (Stata Release 9. College Station, Texas, USA). The study was approved by the Scientific and Ethical Committee of the Hospital for Tropical Diseases, Vietnam, and the Oxford University Tropical Research Ethics Committee, United Kingdom. Written informed consent was obtained from the patient or from a family member if the patient was unconscious.
Table 1. Demographic Details, Clinical Features, Results of Laboratory Investigations, Treatment Received and Outcome at Discharge for All Patients with Eosinophilic Meningitis, A. cantonensis PCR Positive Patients and A. cantonensis PCR Negative Patients
Characteristic
All eosinophilic meningitis cases (n = 69)
A. cantonensis PCR positive patients (n = 37)
A. cantonensis PCR negative patients (n = 18)
P valuea
Age, years
31 (21−44)^
33 (23−44)^
22 (18−35)^
.053
Male
51 (59.4)
20 (54.1)
11 (61.1)
.624
Duration of illness, days
12 (7−20)^
14 (10−20)^
9 (5−14)^
.027
Snail ingestion
20 (29.0)
11 (29.7)
4 (22.2)
.557
History of fever
58 (84.1)
32 (86.5)
15 (83.3)
.756
Headachea
63 (96.9)
33 (97.1)
17 (100.0)
.475
Vomitingb
39 (62.9)
20 (62.5)
10 (55.6)
.630
Confusionc
18 (30.0)
9 (30.0)
3 (17.7)
.351
Blurred visiond
5 (8.6)
5 (16.7)
0 (0.0)
.084
Speech difficultyd
3 (5.2)
2 (6.7)
0 (0.0)
.291
Abdominal paine
5 (8.2)
5 (15.6)
0 (0.0)
.095
Clinical History
Examination GCS 15
.150 47 (68.1)
25 (67.6)
15 (83.3)
13−14
7 (10.2)
3 (8.1)
3 (16.7)
9−12
6 (8.7)
2 (5.4)
0 (0.0)
6−8
9 (13.1)
7 (18.9)
0 (0.0)
.036
Fever ≥38°C
26 (37.7)
16 (43.2)
6 (33.3)
.481
Neck stiffness
50 (72.5)
26 (70.3)
14 (77.8)
.557
Unilatera cranial nerve palsy
6 (8.7)
4 (10.8)
2 (11.1)
CN VI
4 (5.8)
3 (8.1)
1 (5.5)
CN VII
2 (2.9)
1 (2.7)
1 (5.5)
Bilateral cranial nerve palsy
3 (4.4)
2 (5.4)
1 (5.5)
CN III & CN VI
1 (1.4)
1 (2.7)
0 (0.0)
CN VI & CN VI
1 (1.4)
1 (2.7)
0 (0.0)
CN VI & CN VII
1 (1.4)
0 (0.0)
1 (5.5)
Hemiplegiaf
2 (3.2)
1 (3.0)
1 (5.9)
Paraplegiaf
2 (3.2)
2 (6.1)
0 (0.0)
Convulsionsg
1 (1.7)
1 (3.2)
0 (0.0)
Blood tests Hemoglobin g/dL
13.8 (12.9−14.8)^
13.7 (12.9−14.6)^
13.8 (13.2−15.4)^
.326
Leucocyte count ×109/L
11.4 (8.9−14.6)^
10.8 (8.3−14.0)^
12.1 (9.6−15.8)^
.226
Neutrophils (%)
62.1 (51.5−75.0)^
56.6 (50.1−69.0)^
67.9 (56.4−83.9)^
.018
Lymphocytes (%)
14.9 (9.5−20.8)^
18.0 (11.3−23.4)^
10.2 (8.4−17.6)^
.027
Eosinophils (%)
13.5 (4.9−20.1)^
15.0 (7.6−23.7)^
4.2 (1.1−16.3)^
.014
Platelets ×109/L
307 (259−358)^
302 (260−365)^
320 (268−355)^
.905
Creatinine µmol/L
61 (49−73)^
58 (48−69)^
63 (49−74)^
.204
Serum glucose g/dL
5.4 (4.8−6.5)^
5.3 (4.8−6.2)^
5.4 (4.9−6.4)^
.930
Sodium mmol/L
132 (129−139)^
133 (129−137)^
132 (130−136)^
.896
Potassium mmol/L
3.8 (3.5−4.2)^
3.8 (3.5−4.3)^
3.8 (3.2−3.9)^
.238
23 (17−33)^
22 (14−36)^
26 (18−31)^
.590
Clear
24 (34.8)
10 (27.0)
9 (50.0)
Turbid
42 (60.9)
25 (67.6)
9 (50.0)
3 (4.4)
2 (5.4)
CSF investigations Opening pressure cmH20 CSF appearance
Bloodstained CSF leucocyte count cells/mm3
.180
564 (347−1015)^
516 (374−856)^
0 (0.0) 786 (575−978)^
.208
CSF eosinophils (%)
39 (27−52)
39 (28−48)
42 (30−58)
.394
CSF protein g/dL
0.8 (0.5−1.2)^
0.9 (0.6−1.1)^
0.7 (0.5−1.2)^
.693
CSF protein>0.5 g/dL
55 (80.8)
30 (81.1)
CSF glucose g/dL
2.5 (1.9−2.8)^
2.4 (2.0−2.7)^
CSF/blood glucose
