Prospective case-control analysis of the aetiologies of acute undifferentiated fever in Vietnam

Figures & data

Figure 1. Flowchart of the enrolment of patients with AUF.

Table 1. Clinical characteristics of the patients with AUF (n = 378).

Characteristics	Frequency	Percentage
Forest exposure^a	41	11.1
Comorbid conditions
Alcohol abuse	1	0.3
Basedow	1	0.3
Chronic renal failure	2	0.5
Diabetes	1	0.3
Essential thrombocytopenia	1	0.3
Gout	1	0.3
Hypertension	27	7.1
Pregnancy	4	1.1
Headache	306	81.0
Dizziness^b	141	37.5
Disappetite^b	205	54.5
Nausea^c	68	18.1
Vomiting^c	34	9.1
Diarrhoea^c	46	12.3
Sore throat	65	17.2
Breathlessness^c	4	1.1
Cough	115	30.4
Chest pain^c	7	1.9
Abdominal pain^c	50	13.3
Back pain^c	105	28
Muscle pain^c	166	44.3
Joint pain^d	59	15.8
Rash^c	16	4.3
Haemorrhage^d	9	2.4
Eschar	12	3.2
Hepatomegaly^⁑	3	0.8
Splenomegaly^⁑	2	0.5
Lymphadenopathy^e	15	4.0
	Mean	Standard deviation
Peak body temperature (°C)	39.2	0.8
	Median	Interquartile range
Fever duration (days)	5	4–6
White blood cell count (k/µL)	6.9	5–9.1
Neutrophil (k/µL)	4.8	2.9–6.4
Lymphocyte (k/µL)	1.3	0.8–1.9
Monocyte (k/µL)	0.6	0.4–0.9
Hemoglobin (g/dL)	13	12–14
Platelet count (k/µL)	176.5	133–223
Aspartate aminotransferase (IU/L)^f	31.5	23–61.5
Alanine aminotransferase (IU/L)^f	26.5	15.5–49.5

Notes: ^⁑Clinicians assessed the patients clinically and confirmed by ultrasound.

^aData are missing in 7 cases; ^bdata are missing in 2 cases; ^cdata are missing in 3 cases; ^ddata are missing in 4 cases; ^edata are missing 1 case; ^fdata are missing in 86 cases.

Table 2. Aetiologies detected in whole blood, plasma and urine.

Aetiologies	AUFs (n = 378)	Controls (n = 384)	p-value
Leptospira (qPCR), n (%)	18 (4.8)	3 (0.8)	<.001
Rickettsia, n (%)	41 (10.8)	1 (0.3)	<.001
O. tsutsugamushi, n (%)	21 (5.5)	0
qPCR + IFA (n)	8^a	–
qPCR only (n)	11^a	0
IFA only (n)	2	–
R. typhi, n (%)	18 (4.8)	0
qPCR + IFA (n)	4	–
qPCR only (n)	6	0
IFA + WB (n)	1	–
IFA only (n)	7	–
R. felis, n (%)	2 (0.5)	1 (0.3)
qPCR + IFA (n)	0	–
qPCR only (n)	2^b	1
IFA only (n)	0	–
Dengue virus (qRT-PCR), n (%)	29 (7.7)	2 (0.5)	<.001
DEN-1, n (%)	22 (5.8)	0
DEN-2, n (%)	2 (0.5)	0
DEN-4, n (%)	5 (1.3)	2 (0.5)

Notes: qPCR = real-time polymerase chain reaction, qRT-PCR = real-time reverse-transcription polymerase chain reaction, IFA = indirect immunofluorescence assay, WB = western blot.

^aFour cases were positive in both eschar and whole blood specimens.

^bOne case was positive in only the blood specimen, and one case was positive in only the eschar specimen.

Figure 2. Detected pathogens and their frequency in throat swabs from patients with AUF and controls in central Vietnam.

Table 3. Aetiologies detected in throat swab specimens.

Aetiologies	AUFs (n = 378)	Controls (n = 384)	p-value
Influenza
Influenza A, n (%)	65 (17.2)	0	<.001
Influenza B, n (%)	14 (3.7)	0	<.001
Parainfluenza 1, n (%)	1 (0.3)	0	.32
Parainfluenza 4, n (%)	0	1 (0.3)	.32
Enterovirus, n (%)	8 (2.1)	0	.004
Adenovirus, n (%)	18 (4.8)	4 (1.0)	.002
Rhinovirus, n (%)	0	4 (1.0)	.05
RSV A/B, n (%)	2 (0.5)	5 (1.3)	.27
Coronavirus
CoV 229E, n (%)	2 (0.5)	6 (1.6)	.16
CoV NL63, n (%)	1 (0.3)	3 (0.8)	.32
CoV OC43, n (%)	1 (0.3)	0	.32
CoV HKU1, n (%)	0	2 (0.5)	.16
M. pneumoniae, n (%)	3 (0.8)	1 (0.3)	.31
S. aureus, n (%)	18 (4.8)	28 (7.3)	.14
H. influenzae
H. influenzae B, n (%)	4 (1.1)	4 (1.0)	.98
H. influenzae non-type B, n (%)	69 (18.3)	57 (14.8)	.21
S. pneumoniae, n (%)	50 (13.2)	41 (10.7)	.28
K. pneumoniae, n (%)	109 (28.8)	100 (26.0)	.39
M. catarrhalis, n (%)	6 (1.6)	6 (1.6)	.97
Bordetella spp., n (%)	0	2 (0.5)	.16
C. pneumoniae, n (%)	0	1 (0.3)	.32

Table 4. Clinical characteristics of scrub typhus, murine typhus, leptospirosis, dengue fever, influenza and other respiratory viral infections.

Characteristics	Scrub typhus (n = 19)	Murine typhus (n = 18)	Leptospirosis (n = 12)	Dengue fever (n = 28)	Influenza (n = 33)	Nonflu RVI (n = 14)
Age (years)^a	47.4 (18.4) ε γ	42.7 (17.3) λ	35.4 (18.3)	35.3 (16.1) γ	43.6 (21.3) ‡	28.6 (16.1) ε λ ‡
Forest exposure, n (%)	9 (47.4) α β γ δ ε	0 α	1 (8.3) β	3 (11.1)^cγ	0 δ	1 (7.1) ε
Fever duration (days)^b	7.5 (5–9.5) δ	8.5 (6–10) ζ η θ λ	5.5 (4–7) ζ	6 (5–7) η σ	5 (4–6) δ θ σ	5 (4–6) λ
Peak T°(°C)^a	39.2 (0.7)	39.8 (0.8) θ	39.5 (1.1)	39.6 (0.7) σ	39.0 (0.7) θ σ	39.2 (0.8)
Headache, n (%)	18 (94.8) β γ	17 (94.4) ζ η	8 (66.7) β ζ	18 (64.3) γ η	26 (78.8)	11 (78.6)
Nausea, n (%)	1 (5.3)	3 (16.7)	3 (25)	6 (21.4)	9 (27.3)	4 (28.6)
Vomiting, n (%)	1 (5.3)	3 (16.7)	1 (8.3)	2 (7.1)	3 (9.1)	2 (14.3)
Diarrhoea, n (%)	0	2 (11.1)	2 (16.7)	3 (10.7)	5 (15.2)	1 (7.1)
Sore throat, n (%)	1 (5.3)	2 (11.1)	3 (25)	4 (14.3)	9 (27.3)	4 (28.6)
Cough, n (%)	6 (31.6) δ	5 (27.8) θ	1 (8.3) π	3 (10.7) σ	21 (63.6) δ θ π σ ‡	3 (21.4) ‡
Abdominal pain, n (%)	5 (26.3)	5 (27.8)	2 (16.7)	5 (17.9)	8 (24.2)	3 (21.4)
Muscle pain, n (%)	11 (57.9)	8 (44.4)	6 (50)	10 (35.7)	11 (33.3)	7 (50)
Joint pain, n (%)	7 (36.8) γ δ ε	5 (27.8) λ	2 (16.7)	4 (14.3) γ	4 (12.1) δ	0 ε λ
Rash, n (%)	1 (5.3)	3 (16.7) η θ	1 (8.3)	0 η	0 θ	0
Haemorrhage, n (%)	0	0	0	2 (7.4)^c	1 (3.0)	0
Eschar, n (%)	9 (47.4) α β γ δ ε	0 α	0 β	0 γ	0 δ	0 ε
Lymphadenopathy, n (%)	8 (42.1) γ δ ε	1 (5.6)	1 (8.3)	1 (3.6) γ	0 δ	0 ε
WBC (k/µL)^b	8.2 (5.5–9.1) γ δ	6.3 (5.0–7.9) η	7.4 (6.8–8.5) μ π	4.3 (3.0–6.2) γ η μ ϕ	5.4 (3.8–7) δ π ‡	8.0 (5.7–9.8) ϕ ‡
PLT (k/µL)^b	140.5 (103.5–204)	133.5 (116.5–187) η λ	165.5 (134.5–200.5) μ	118 (65.5–147.5)η μ σ ϕ	165 (132–189) σ	199.5 (153–228) λ ϕ
AST (IU/L)^b	125 (67–157) α β γ δ ε	73.5 (34–109) α θ λ	44 (23–66) β	38 (26–74) γ σ	25 (21–29) δ θ σ	39 (16–47) ε λ
ALT (IU/L)^b	106 (77–141) α β γ δ ε	50 (27–121) α θ λ	44 (18–53) β	29 (22–45) γ σ	15 (13–27) δ θ σ	26 (13–37) ε λ

Notes: Nonflu RVI = noninfluenza respiratory viral infection.

α, β, γ, δ, ε, ζ, η, θ, λ, μ, π, ς, σ, ϕ, ‡ significant difference (p < .05) in proportions (chi-square or Fisher’s exact test) or means/medians (Kruskal–Wallis test):

α Scrub typhus vs. Non-ST RI, β Scrub typhus vs. Leptospirosis, γ Scrub typhus vs. Dengue fever, δ Scrub typhus vs. Influenza, ε Scrub typhus vs. Noninfluenza RVI, ζ Murine typhus vs. Leptospirosis, η Murine typhus vs. Dengue fever, θ Murine typhus vs. Influenza, λ Murine typhus vs. Noninfluenza RVI, μ Leptospirosis vs. Dengue fever, π Leptospirosis vs. Influenza, ς Leptospirosis vs. Noninfluenza RVI, σ Dengue fever vs. Influenza, ϕ Dengue fever vs. Noninfluenza RVI, and ‡ Influenza vs. Noninfluenza RVI.

^aMean (standard deviation), ^bmedian (interquartile range).

^cData are missing in 1 case.

Figure 3. Eschar on the right face of a patient with Rickettsia felis infection in central Vietnam. Eschar on the right face (a), close-up view of the eschar (b).

Table 5. Causes and probable causes of AUF.

Diagnosis	n	%
One-pathogen detection (n = 144)
Causes
Rickettsial infections	40	10.6
Orientia tsutsugamushi	20
Rickettsia typhi	18
Rickettsia felis	2
Dengue	28	7.4
Leptospira	12	3.2
Influenza	33	8.7
Influenza A	26
Influenza B	7
Adenovirus	9	2.4
Enterovirus	5	1.3
Probable causes
Respiratory syncytial viruses	1	0.3
Haemophilus influenzae non-type B	2	0.5
Klebsiella pneumoniae	11	2.9
Moraxella catarrhalis	2	0.5
Streptococcus pneumoniae	1	0.3
Two-pathogen codetection (n = 51)
Causes
Orientia tsutsugamushi + Leptospira	2	0.5
Leptospira + RVI	4	1.1
Leptospira + Influenza A	1
Leptospira + Influenza B	2
Leptospira + Adenovirus	1
Dengue + Adenovirus	1	0.3
Influenza + RBI	27	7.1
Influenza A + Haemophilus influenzae non-type B	5
Influenza B + Haemophilus influenzae non-type B	1
Influenza A + Streptococcus pneumoniae	4
Influenza B + Streptococcus pneumoniae	1
Influenza A + Klebsiella pneumoniae	12
Influenza B + Klebsiella pneumoniae	3
Influenza A + Staphylococcus aureus	1
Other RVI + RBI	4	1.1
Enterovirus + Haemophilus influenzae type B	1
Enterovirus + Haemophilus influenzae non-type B	1
Adenovirus + Streptococcus pneumoniae	2
Probable causes
Human coronavirus 229E + Streptococcus pneumoniae	1	0.3
2 RBIs	12	3.2
Streptococcus pneumoniae + Haemophilus influenzae non-type B	3
Streptococcus pneumoniae + Klebsiella pneumoniae	1
Klebsiella pneumoniae + Haemophilus influenzae non-type B	5
Klebsiella pneumoniae + Mycoplasma pneumoniae	1
Mycoplasma pneumoniae + Haemophilus influenzae non-type B	1
Staphylococcus aureus + Haemophilus influenzae non-type B	1
Three-pathogen codetection (n = 22)
Causes
Influenza A + RPIs	16	4.2
Influenza A + Human coronavirus OC43 + Klebsiella pneumoniae	1
Influenza A + Staphylococcus aureus + Haemophilus influenzae non-type B	1
Influenza A + Staphylococcus aureus + Klebsiella pneumoniae	1
Influenza A + Haemophilus influenzae non-type B + Klebsiella pneumoniae	6
Influenza A + Haemophilus influenzae non-type B + Streptococcus pneumoniae	5
Influenza A + Streptococcus pneumoniae + Klebsiella pneumoniae	2
Adenovirus + RPIs	5	1.3
Adenovirus + Enterovirus + Haemophilus influenzae non-type B	1
Adenovirus + Streptococcus pneumoniae + Haemophilus influenzae non-type B	2
Adenovirus + Klebsiella pneumoniae + Haemophilus influenzae type B	1
Adenovirus + Streptococcus pneumoniae + Klebsiella pneumoniae	1
Probable causes
Mycoplasma pneumoniae + Streptococcus pneumoniae + Klebsiella pneumoniae	1	0.3

Note: RVI: respiratory viral infection, RBI: respiratory bacterial infection, RPIs: respiratory pathogen infections.