ABSTRACT.
Chikungunya is a mosquito-borne disease mainly characterized by fever with polyarthralgia. Currently, liver complications of chikungunya remain rarely described. This study assesses the prevalence, severity, and risk factors of liver involvement, and the association between liver involvement severity and prognosis. We conducted a retrospective cohort study at two referral centers for tropical infectious diseases—the Hospital for Tropical Diseases and Bamrasnaradura Infectious Diseases Institute in Thailand—from January 2016 to April 2021. The study included 400 patients diagnosed with chikungunya. Of them, 254 (63.5%) were female with a mean age of 41.5 ± 14.1 years, and 98.5% of them presented with fever with arthralgia. Gastrointestinal presentations included nausea or vomiting (n = 62, 15.5%), diarrhea (n = 33, 8.3%), and abdominal pain (n = 4, 1%). Of 88 patients with available liver function tests, 39.8% had hepatitis (abnormal alanine aminotransferase levels), of whom 5.7% had moderate hepatitis. Nausea or vomiting is a clinical risk factor associated with liver involvement (adjusted odds ratio, 5.17; 95% CI, 1.20–22.34). Liver involvement was usually observed during the first 2 weeks of illness and resolved eventually. None of the patients experienced severe hepatitis, liver failure, or death caused by a liver problem. In conclusion, most of the patients with chikungunya did not have significant liver involvement. In those patients with severe liver injury, coexisting causes should be considered.
INTRODUCTION
Chikungunya is a mosquito-borne disease occurring across many countries, especially in tropical regions. Its name originates from the language of Makonde, an ethnic group living in Tanzania, and it means “that which bends up” or “to become contorted,” which refers to the clinical position of patients to relieve the joint pain caused by the disease.1
Chikungunya is caused by Chikungunya virus (CHIKV), the virus of the genus Alphavirus from the family Togaviridae. CHIKV is a positive-sense single-stranded enveloped RNA virus and is transmitted to humans by the bite of mosquitoes such as Aedes aegypti and Aedes albopictus. By phylogenetic analysis, CHIKV has four lineages: West African, East/Central/South African, Indian Ocean, and Asian.
This disease has various clinical presentations, and the most common are fever and polyarthralgia with joint pain.2 Atypical presentations include skin rash and renal and systemic involvement, including liver involvement.3,4 In severe cases, patients may experience life-threatening conditions, such as liver failure (3% in atypical chikungunya cases),5 which is the cause of death. Chikungunya infection and liver involvement were reported previously during the outbreaks in Island of La Reunion in 2005 and 2006, India in 2016, and Bangladesh in 2017.5–10
In 2019 and 2020 in Thailand, the incidence of chikungunya was 17.32 and 16.40 cases/100,000 population, respectively,11 indicating a dramatic increase from that of 2009 to 2018 (0.02–5.42 cases/100,000 population).12 The prevalence of liver involvement was varied because of limitations in the different characteristics of patients (hospitalized, referred, and outpatient), disease severity, disease phase, small sample size, and inclusion of co-infections or other causes of liver involvement. In severe cases, life-threatening conditions, including liver failure, and even death may occur. Despite the increased global incidence of chikungunya, studies about liver involvement in adult patients with chikungunya remain insufficient, with several study limitations. Therefore, we aimed to determine the prevalence and severity of liver involvement in chikungunya cases, the risk factors of liver involvement, and the association between severity and disease prognosis.
MATERIALS AND METHODS
Study design.
This retrospective cohort study evaluated the prevalence, severity, risk factors of liver involvement, and the association of liver involvement severity with prognosis in adult patients with chikungunya who met the inclusion/exclusion criteria at the Hospital for Tropical Diseases (HTD), Faculty of Tropical Medicine, Bangkok, Thailand, and the Bamrasnaradura Infectious Diseases Institute (BIDI) between January 2016 and April 2021. From the medical records, demographic data, disease history, physical examination results, laboratory findings, and treatment outcomes were recorded (Supplemental Table S1).
Study population.
We recruited patients diagnosed with chikungunya according to the International Classification of Diseases, 10th revision, at HTD and BIDI from January 2016 to April 2021. Recruited patients met the following inclusion criteria: age ≥ 15 years, symptoms of fever, and confirmed laboratory diagnosis of chikungunya. The confirmed laboratory diagnosis of chikungunya included positive real-time reverse transcription–polymerase chain reaction chikungunya, positive chikungunya IgM, or seroconversion of chikungunya IgG. Quantification of chikungunya viral genomes was performed using methods described previously.13 Serological tests were conducted by immunochromatographic assay for the detection of IgM/IgG antibodies against the chikungunya virus (STANDARD Q Chikungunya IgM/IgG Test; SD BIOSENSOR, Korea). We excluded those with co-infection by other tropical diseases, comorbidities with other causes of liver failure, no laboratory-confirmed diagnosis, or another diagnosis.
Data collection.
The demographic, illness history, and physical examination data were reviewed at the first visit. The patients came to the hospital with fever. We collected the laboratory findings, including those from liver function test (LFTs) and clinical courses, obtained during treatment and follow-up. The treatment outcomes were retrieved from the last follow-up visit. LFT was investigated, and alanine aminotransferase (ALT) levels were monitored for liver involvement. Using the operative definition of the highest ALT level fore each patient, we classified the severity of liver involvement as normal, ALT level < 35 IU/L; mild hepatitis, ALT level of 35 to 105 IU/L; moderate hepatitis, ALT level of 106 to 350 IU/L; and severe hepatitis, ALT level > 350 IU/L).14 In patients without LFT results, we evaluated liver involvement according to clinical data and laboratory findings. Furthermore, we classified the patients into four groups: symptomatic acute liver failure, impeding liver failure, symptomatic hepatitis, and no evidence of hepatitis (Supplemental Tables S2 and S3).
Prognosis evaluation.
We evaluated the prognosis of the disease according to the clinical courses, fever clearance time, and treatment outcome.
Statistical analysis.
Statistical data were analyzed using SPSS Statistics for Windows (version 25; IBM Corp., Armonk, NY). Continuous data are presented as a mean with the SD (for normally distributed data) or a median with a range (for non-normally distributed data); categorical data are presented as numbers and percentages.
In the statistical analysis, the categorical variables were tested for association using the χ2 test or Fisher’s exact test, as appropriate. For continuous variables, we used Student’s t-test for those with normal distribution, and the Mann–Whitney U test for those with non-normal distribution. The association of the risk factors of liver involvement was evaluated by logistic regression. Statistical data were analyzed using a two-tailed test; P < 0.05 was considered statistically significant.
RESULTS
Between January 2016 and April 2021, 590 patients were diagnosed with chikungunya according to the International Classification of Diseases, 10th revision, of which 349 were from HTD and 241 from BIDI. However, 190 patients were excluded because of chronic chikungunya arthritis (n = 117), absent laboratory-confirmed diagnosis of chikungunya (n = 57), Dengue virus (DENV) co-infections (n = 9), and another diagnosis (n = 7). Ultimately, 400 eligible patients (with fever and a laboratory-confirmed diagnosis of chikungunya) were included in the analysis (Figure 1). The mean patient age was 45.1 ± 14.1 years, with the eldest at 87 years and the youngest at 15 years. The female-to-male ratio was 1.7:1. The prominent age ranges were 35 to 44 years (24.5%) and 45 to 54 years (24%). In addition, three patients (0.8%) had chronic liver disease, and 22 (5.5%) had a history of alcohol consumption. Prominent comorbidities were hypertension (15.3%), diabetes mellitus (9.3%), and dyslipidemia (8.8%) (Table 1). The median duration of fever from onset to hospital admission was 3.5 days (range, 2–30 days). Most of the patients presented with arthralgia (98.5%). Gastrointestinal presentations were nausea or vomiting (15.5%), diarrhea (8.3%), and abdominal pain (1%). The prominent sign was rash (n = 190, 47.5%). On abdominal examination, abdominal tenderness (n = 8, 2%) and hepatomegaly (n = 3, 0.8%) were detected (Table 2).
Figure 1.
Flow of the study. ALT = alanine aminotransferase; CCA = chronic chikungunya arthritis; ICD-10 = International Classification of Diseases, 10th revision; IPD = inpatient department; LFT = liver function test; OPD = outpatient department.
Table 1.
Demographic data of the study population
| Parameter | No. of cases (N = 400) | Cases with available liver function test results (n = 88) | P value | |
|---|---|---|---|---|
| Cases with liver involvement (n = 35) | Cases without liver involvement (n = 53) | |||
| Age, years; mean ± SD | 45.1 ± 14.1 | 47.6 ± 14.2 | 44.8 ± 17.1 | 0.822 |
| Age group, years; n (%) | ||||
| 15–24 | 30 (7.5) | 1 (2.9) | 7 (13.2) | 0.138 |
| 25–34 | 66 (16.5) | 7 (20.0) | 5 (9.4) | 0.208 |
| 35–44 | 98 (24.5) | 5 (14.3) | 9 (17.7) | 0.141 |
| 45–54 | 96 (24.0) | 10 (28.6) | 10 (18.9) | 0.288 |
| 55–64 | 78 (19.5) | 7 (20.0) | 12 (22.6) | 0.768 |
| ≥ 65 | 32 (8.0) | 5 (14.3) | 10 (18.9) | 0.576 |
| Gender, n (%) | ||||
| Male | 146 (36.5) | 19 (54.3) | 20 (37.7) | 0.126 |
| Female | 254 (63.5) | 16 (45.7) | 33 (62.3) | – |
| Chronic liver disease, n (%) | 3 (0.8) | 2 (5.7) | 1 (1.9) | 0.560 |
| Alcohol consumption, n (%) | 22 (5.5) | 4 (11.4) | 1 (1.9) | 0.079 |
| Underlying disease, n (%) | ||||
| DM | 37 (9.3) | 5 (14.3) | 11 (20.8) | 0.441 |
| Hypertension | 61 (15.3) | 6 (17.1) | 15 (28.3) | 0.229 |
| HIV infection | 4 (1.0) | 1 (2.9) | 1 (1.9) | 1.000 |
| Dyslipidemia | 35 (8.8) | 4 (11.4) | 6 (11.3) | 1.000 |
| Allergic rhinitis | 9 (2.3) | 1 (2.9) | 0 (0) | 0.565 |
| Hyperthyroidism | 6 (1.5) | 1 (2.9) | 2 (3.8) | 1.000 |
| Gout | 5 (1.3) | 0 (0) | 0 (0) | – |
Table 2.
Clinical presentation and laboratory findings
| Parameters | No. of cases (N = 400) | Cases with available LFT results (n = 88), n | P value | |
|---|---|---|---|---|
| Cases with liver involvement (n = 35) | Cases without liver involvement (n = 53) | |||
| Fever at first visit, no. of days; median (min–max) | 3.5 (2–30) | 4 (2–8) | 4 (2–30) | 0.941 |
| Clinical manifestation, n (%) | ||||
| Arthralgia | 394 (98.5) | 35 (100) | 53 (100) | – |
| Nausea/vomiting | 62 (15.5) | 10 (28.6) | 12 (12.6) | 0.530 |
| Abdominal pain | 4 (1.0) | 1 (2.9) | 0 (0) | 0.398 |
| Diarrhea | 33 (8.3) | 4 (11.4) | 29 (7.9) | 0.514 |
| Cough/rhinorrhea | 50 (12.5) | 4 (11.4) | 7 (13.2) | 1.000 |
| Physical sign, n (%) | ||||
| Pale conjunctiva | 5 (1.3) | 1 (2.9) | 3 (5.7) | 1.000 |
| Icteric sclera | 2 (0.5) | 0 (0) | 0 (0) | – |
| Rash | 190 (47.5) | 10 (28.6) | 20 (37.7) | 0.375 |
| Abdominal tenderness | 8 (2.0) | 1 (2.9) | 2 (3.8) | 1.000 |
| Hepatomegaly | 3 (0.8) | 2 (5.7) | 1 (1.9) | 0.560 |
| Arthritis | 3 (0.8) | 0 (0) | 0 (0) | – |
| Complete blood count | ||||
| Hemoglobin, mg/dL; mean ± SD | 13.3 ± 1.6 | 13.9 ± 1.6 | 13.1 ± 1.9 | 0.044 |
| Hematocrit, %; median (min–max) | 40.3 (25.0–55.0) | 42.0 (31.0–50.2) | 40.0 (28.0–54.6) | 0.046 |
| WBC count, cells/mm3, median (min–max) | 4,900 (1,500–25,400) | 5,200 (2,400–12,300) | 4,900 (1,600–25,400) | 0.976 |
| Platelet count, × 103/mm3; median (min–max) | 206.0 (19.8–507.0) | 200.0 (76.0–298.0) | 176.0 (49.0–448.0) | 0.609 |
LFT = liver function test; max = maximum; min = minimum; WBC = white blood cell.
The baseline median values of platelet count, aspartate aminotransferase (AST) level, alanine transaminase (ALT) level, and total bilirubin were 206,000/mm3 (range, 19,800–507,000/mm3), 31 IU/L (range, 11.0–178.0 IU/L), 26.5 IU/L (range, 5.0–182.0 IU/L), and 0.5 ± 0.2 mg/dL, respectively. During the period of admission and follow-up, 18 patients (4.5%) had thrombocytopenia (platelet count < 100,000/mm3). AST and ALT levels increased during the first week of illness and decreased during the second week. Day of fever, platelet count, and LFT result (e.g., total bilirubin, AST, and ALT) showed no correlation (Figure 2).
Figure 2.
Association between the day of fever and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelet count, and total bilirubin. IPD = inpatient department; OPD = outpatient department.
The clinical features associated with liver involvement were nausea or vomiting (2.5%) and bleeding (1.0%). During the follow-up period, the main complications were aphthous ulcer (2.8%), rash (0.5%), and lymphadenopathy (1.3%). After the administration of antipyretics, analgesics, and fluid rehydration, illness was alleviated in all affected patients, and none died.
Prevalence and severity of liver involvement.
Of the 400 participants, 88 had available LFT results. The AST level ≥ 35 IU/L increased in 36 patients (40.9%), whereas the ALT level ≥ 35 IU/L increased in 35 patients (39.8%) (Figure 1). Furthermore, one patient (1.1%) had an abnormal total bilirubin level (> 1.2 mg/dL), and another one (1.1%) had an abnormal alkaline phosphatase level (> 147 IU/L). Those with increased ALT levels ≥35 IU/L were identified as having liver involvement.
In 312 patients without LFT results, liver involvement was evaluated using their clinical features, such as symptoms, signs, and other laboratory findings. None had symptomatic liver failure, impending liver failure, or symptomatic hepatitis (Figure 1). Therefore, the prevalence of liver involvement was 39.8%, which comprised those with available LFT results. In the group with liver involvement, liver involvement was found mostly on days 4 to 6 of fever (34.3%), followed by days 7 to 9 (31.4%), days 1 to 3 (28.6%), and days 16 to 18 (5.7%).
Risk factors associated with liver involvement.
The association of clinical features and laboratory findings with liver involvement was evaluated by logistic regression. In the multivariate analysis, age group of 25 to 34 years and nausea or vomiting were associated with liver involvement (adjusted odds ratio, 25.06 and 5.17, 95% CI, 1.38–453.45 and 1.20–22.34, respectively) (Table 3).
Table 3.
Risk factors associated with liver involvement (N = 88)
| Variable | Cases with liver involvement (n = 35), n (%) | Cases without liver involvement (n = 53), n (%) | Adjusted odds ratio (95% CI) | P value |
|---|---|---|---|---|
| Male | 19 (54.3) | 20 (37.7) | 1.90 (0.60-5.99) | 0.276 |
| Age, years | ||||
| 15–24 | 1 (2.9) | 7 (13.2) | Ref. | – |
| 25–34 | 7 (20.0) | 5 (9.4) | 25.06 (1.38–453.45) | 0.029 |
| 35–44 | 5 (14.3) | 9 (17.0) | 5.66 (0.29–112.20) | 0.256 |
| 45–54 | 10 (28.6) | 10 (18.9) | 8.80 (0.55–141.30) | 0.125 |
| 55–64 | 7 (20.0) | 12 (22.6) | 4.78 (0.29–78.18) | 0.273 |
| ≥65 | 5 (14.3) | 10 (18.9) | 14.10 (0.63–314.22) | 0.095 |
| Diabetes mellitus | 5 (14.3) | 11 (20.8) | 1.55 (0.33–7.25) | 0.579 |
| Hypertension | 6 (17.1) | 15 (28.3) | 0.52 (0.13–2.12) | 0.361 |
| Clinical signs, symptoms, and laboratory results | ||||
| Nausea/vomiting* | 10 (28.6) | 12 (22.6) | 5.17 (1.20–22.34) | 0.028 |
| Diarrhea | 4 (11.4) | 12 (22.6) | 0.21 (0.04–1.08) | 0.062 |
| Rash | 10 (28.6) | 20 (37.7) | 0.56 (0.14–2.08) | 0.374 |
| Anemia† | 6 (17.1) | 16 (30.2) | 0.37 (0.06–2.21) | 0.278 |
| Leukopenia‡ | 18 (51.4) | 32 (60.4) | 0.62 (0.21–1.82) | 0.385 |
| Thrombocytopenia§ | 5 (14.3) | 6 (11.3) | 2.88 (0.55–15.99) | 0.210 |
Ref. = reference.
Presented as a baseline in the disease history.
Hemoglobin level < 12 mg/dL in females or < 13 mg/dL in males.
White blood cells < 4,500 cells/mm3.
Platelet count <100 × 103/mm3.
Severity of liver involvement and prognosis.
Of the 400 participants, 32 (8.0%) had clinical features associated with complications involving the liver, skin, and mucous membrane detected during the treatment period. In this group, 23 patients (74.2%) were female, with a mean age of 40.9 ± 16.1 years. Complications included nausea or vomiting (n = 10, 31.3%), bleeding (n = 4, 12.5%), rash (n = 11, 34.4%), oral aphthous ulcer (n = 2, 6.3%), and lymphadenopathy (n = 5, 15.6%). Bleeding was mostly not life-threatening (e.g., coffee-ground color, epistaxis, and bleeding from the gums).
DISCUSSION
In this hospital-based retrospective cohort study, data were collected from the medical records of the patients who had fever and a laboratory-confirmed diagnosis of chikungunya at HTD and BIDI. The demographics, disease history, physical examination and laboratory results, clinical course, complications, and treatment outcome were analyzed.
Regarding age at presentation, the mean age of the patients (N = 400) was 45.1 ± 14.1 years, which is less than that in the survey conducted on the Island of La Reunion (55.7 ± 12.7 years).15 Half of their patients (n = 194, 48.5%) were 35 to 54 years old. The Island of La Reunion study15 was conducted only in the emergency department, and the clinical features of the patients were more severe, especially in the older age group, than in our study, which collected data from various departments, including the outpatient, inpatient, and emergency departments. Thus, the severity of clinical features in our patients was varied, and the mean age group was younger than that of the Island of La Reunion study.15 These observations might affect the clinical outcomes and mortality rate (Table 4).
Table 4.
Compilation of the clinical and abnormal laboratory features related to liver involvement
| Parameter | Borgherini et al.9* | Staikowsky et al.7† | Thiberville et al.10* | Reller et al.15* | Srikirin et al.‡ |
|---|---|---|---|---|---|
| Location and date | La Reunion, 2005–2006 | La Reunion, 2006 | La Reunion, 2007 | Sri Lanka, 2007 | Thailand, 2016–2021 |
| Total no. of patients | 157 | 274 | 76 | 797 | 400 |
| CHIKV-positive patients, % | 100 | 65.7/12.4 | 71.1 | 3.5 | 100 |
| Genotype/lineage | IOL | IOL | IOL | IOL | ECSA |
| Age, year (mean or median) | 57.9 (mean) | 55.0 (mean) | 40.0 (mean) | 41 (median) | 45.1 (mean) |
| Male-to-female ratio | 1.2 | 1.1/0.6 | 1.7 | 6.8 | 0.6 |
| Days after symptom onset | 2.1 | 1.8/6.2 | 1.2 | 3.0 | 3.5 |
| Fever, % | 89.0 | 19.4/0.0 | 100 | 100 | 76.5 |
| Arthralgia, % | 96.0 | 98.8/96.8 | 100 | 71.0 | 98.5 |
| Rash, % | 40.1 | 47.8/67.7 | 30–50 | 11 | 47.5 |
| Digestive symptoms,§ % | 47.1 | 63.3/85.3 | 13–44 | 11–38.0 | 8.3–15.5 |
| Aphthous ulcer, %) | – | – | – | – | 2.8 |
| Bleeding, % | 6.4 | 1.1/8.8 | 8.0 | – | 1.0 |
| Lymphadenopathy, % | 8.9 | 8.9/29.4 | – | 18.0 | 1.3 |
| High ALT level, % | 11.5 (ALT > 65 IU/L) | 7.2 (ALT > 65 IU/L) | 14.0 (ALT > 45 IU/L) | – | 39.8‖ (ALT ≥ 35 IU/L) |
| Mean or median WBC count, cells/mm3 | 5,153 ± 2,198 (mean) | 5,431 ± 2,139/5,199 ± 2,554 (mean) | – | 4,500 (median) | 4,400¶ (median) |
| Mean or median platelet count, × 103/mm3 | – | 174.2 ± 56.0/ 173.7 ± 62.2 (mean) | – | 181.0 (median) | 199.0# (median) |
| Thrombocytopenia, % (< 100 × 103 platelets/mm3) | 9.5 | – | 24.0 | – | 4.5 |
| Mortality rate, % | 3.2 | 0 | 0 | 0 | 0 |
ALT = alanine transaminase; ECSA = East/Central/South African; CHIKV = Chikungunya virus; IOL = Indian Ocean Lineage; WBC = white blood cell.
These studies reported the baseline laboratory results of patients.
This study reported values for viremic/postviremic patients.
Our study.
Digestive symptoms included abdominal pain, nausea or vomiting, and diarrhea.
Among 88 patients with available liver function test.
Median of lowest WBC count.
# Median of lowest platelet count.
In our study, the majority of the patients with chikungunya were female (63.5%), which differs from previous studies conducted on the Island of La Reunion (61.9%)7 and in Bangladesh (47.2%).8 Our study was conducted at HTD and BIDI, which are situated in Bangkok, the capital city of Thailand; and Nonthaburi Province, the province near Bangkok. Both sites have similar circumstances, such as urbanization, easy access to the health-care system, and no significant differences in culture and socioeconomics between men and women, making the female proportion in this study different from previous studies.
Gastrointestinal manifestations of chikungunya.
Regarding nausea or vomiting associated with hepatocellular injury, 15.5% of our patients with chikungunya presented with nausea or vomiting. Gastrointestinal disturbance symptoms such as nausea or vomiting are common, reported as approximately 14.0% to 43.3% in a previous study7,9,10,15 (Table 4). In terms of severity, patients with clinical nausea or vomiting were significantly more prone to be hospitalized than those without nausea or vomiting (32.8% versus 12.6%, P < 0.001). Nausea or vomiting is the cause of volume depletion, thus requiring fluid replacement therapy.
Moreover, diarrhea was reported in 8.3% of our patients compared with 2.0% to 28.9% in previous studies.16–19 The range was wide because of the difference in the number of populations, epidemic lineage strain, and recall bias about diarrhea in each study. Regarding the need for hospitalization, patients with diarrhea were more likely to be closely monitored as inpatients rather than outpatients (19.0% versus 6.4%, P = 0.040). Other gastrointestinal signs such as abdominal tenderness and hepatomegaly occurred in only 2.0% and 0.8% of our patients, respectively; none had splenomegaly. However, these results are underreported because 39.3% of the patients did not have records about hepatomegaly or splenomegaly.
Prevalence of liver involvement.
The ALT level was selected to determine liver involvement because ALT is a specific enzyme representing hepatocellular injury.14 This study defined an abnormal ALT level of ≥ 35 IU/L as liver involvement. Of the 400 participants, only 88 (22.0%) had available LFT results. Of these 88 patients, 39.8% had abnormal ALT levels, with mild hepatitis (ALT, 35–105 IU/L) at 34.1% and moderate hepatitis (ALT, 106–350 IU/L) at 5.7% (Figure 1). Liver involvement presented within 1 to 2 weeks of the illness and resolved eventually.
Thus, the prevalence of liver involvement in this study was 39.8%, which is greater than previous studies (7.2%–14.0%).5,7–9 The strain of CHIKV and the different cutoff points of liver involvement may explain the greater prevalence in our study. Khongwichit et al.17 reported that the main CHIKV strain in large-scale outbreaks in Thailand in 2018 and 2019 was the East/Central/South African mutation E1-K211E and E2-V264A, which were not the Indian Ocean lineage strain reported in a previous study.16 Hence, different strains could obtain different results of liver involvement in adult patients with chikungunya. In our study, liver involvement was defined as an ALT level ≥ 35 IU/L, and the cutoff point was less than that in previous studies, which defined liver involvement as an ALT level > 45 IU/L or > 65 IU/L. If the cutoff point of liver involvement in our study was set at an ALT level > 65 IU/L, the prevalence of liver involvement was 18%, similar to the results of previous studies (Table 4).
Severity of liver involvement.
This study found patients with mild and moderate hepatitis; none had severe hepatitis. Borgherini et al.9 found ALT levels of > 65 IU/L and > 50 IU/L in 11.5% and 5.1% of patients, respectively. Economopoulou et al.5 reported 610 atypical chikungunya cases, 8.0% of which showed liver involvement (hepatic insufficiency, 4.0%; subacute hepatitis, 1.0%; and toxic hepatitis, 3.0%). The severity of liver involvement varied because patient characteristics in each study were different. Regarding our patients’ characteristics, they had acute fever approximately 1 week before hospitalization, most had no liver involvement, and those with liver involvement only had mild-to-moderate hepatitis. In previous studies,5–7,9,10 patients were prone to high morbidity, mortality, and liver involvement, including referred patients, those who were hospitalized, and those who had atypical presentations. When comparing the severity of liver involvement between DENV and CHIKV infection, the abnormal ALT level recorded in our study undermined the evaluation, because only 22% of the eligible patients had available LFT results, especially mild hepatitis, which can occur even in asymptomatic patients. DENV infection can result in a more severe liver involvement than CHIKV infection because DENV could cause a direct viral effect on hepatocytes or dysregulation of the host’s immune response.18 CHIKV mainly invades macrophages, dendritic cells, and endothelial cells of the liver; it does not invade the hepatocytes directly, as does DENV.19
Severity and prognosis of the disease.
Of the 32 patients with interesting clinical courses associated with liver involvement or complications, 10 (31.3%) had available LFT results, five of whom (15.6%) had mild hepatitis. Given this low number of patients, the association between liver involvement severity and clinical studies or complications was not evaluated. Between DENV, CHIKV, and Zika virus, DENV has shown a predominance of liver involvement and a tendency toward bleeding.19,20
Considering the retrospective cohort study design, some limitations were found. The prevalence of liver involvement could be confounded by DENV, hepatitis A, hepatitis C, other tropical diseases, and drug-induced hepatitis, which were not tested or documented in the medical records. Because of the lack of clinical data about hepatomegaly and splenomegaly, and the use of the operative criteria as noted earlier, the prevalence of liver involvement in our study was underestimated, especially in asymptomatic patients with mild hepatitis. In addition, the data collected during the follow-up period might have been affected by recall bias, especially the setting of the clinical courses or complications that disappeared during follow-up.
In conclusion, the prevalence of liver involvement in adult patients with chikungunya at HTD and BIDI from January 2016 to April 2021 was 40%, with abnormal LFT results. A few patients presented with hepatomegaly, but none had jaundice. The liver involvement found was mild and moderate hepatitis. Nausea or vomiting were clinical risk factors associated with liver involvement. After treatment completion, all patients with liver involvement attained good prognosis and outcome. In studying cases of chikungunya with severe liver injury, other causes of liver injury should be considered.
Supplemental files
ACKNOWLEDGMENTS
We express our gratitude to the HTD staff, Department of Clinical Tropical Medicine, and BIDI for all their support with data collection, analysis, and suggestions for interesting issues in this study.
Note: Supplemental tables appear at www.ajtmh.org.
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