
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12410-3
10.1016/j.heliyon.2024.e36379
e36379
Case Report
DENV-1 infection with rhabdomyolysis in an adolescent: A case report and review of challenge in early diagnosis and treatment
Putri Anastasia ab
Arunsodsai Watcharee c
Hattasingh Weerawan c
Sirinam Salin salin.sir@mahidol.ac.th
c⁎
a Thai Travel Clinic, Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
b Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
c Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
⁎ Corresponding author. salin.sir@mahidol.ac.th
22 8 2024
15 9 2024
22 8 2024
10 17 e3637914 2 2024
14 8 2024
14 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Dengue infection is a well-known tropical disease that has become a global health issue. The clinical characteristics of dengue range from asymptomatic to severe, which can involve multiple organs and challenge management. Rhabdomyolysis in dengue infection is a rare condition described in children and adolescents. Herein, we present the case of a young adolescent with autism spectrum disorder who had a dengue virus serotype 1 infection complicated by rhabdomyolysis, which was not detected based on its typical manifestations. Rhabdomyolysis is recognized as one of the manifestations of expanded dengue syndrome and is associated with significant morbidity and mortality, especially if acute kidney injury develops. These coexisting conditions should be carefully considered, particularly in patients with underlying medical issues that may contribute to a worse prognosis. The early diagnosis and management of patients with dengue complicated by rhabdomyolysis is challenging and should be widely acknowledged. The detection of potential complications and appropriate fluid balance are essential to achieve a better prognosis.

Highlights

• Rhabdomyolysis poses a challenge in dengue management.

• Dengue complicated by rhabdomyolysis requires delicate fluid treatment.

• The early detection of muscle lysis and myoglobinuria can alleviate kidney injury.

Keywords

Dengue
Rhabdomyolysis
Dengue-induced muscular complication
Tropical disease
Case report
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pmc1 Introduction

Dengue is caused by dengue viruses (DENVs), which are transmitted by Aedes mosquitoes. It is endemic in tropical and subtropical areas due to urbanization and increased transportation. Dengue disease has also become a health issue in temperate regions, particularly for people visiting the tropics who are at significant risk, as a result of a substantial number of trips for business and tourism [1,2]. In terms of the clinical manifestations, dengue infection can be asymptomatic or symptomatic with various symptoms including acute-onset fever, nausea, body and retroorbital pain, abdominal pain, lethargy, and bleeding. Furthermore, it can have severe symptoms with multiple organ involvement, which makes its management more challenging. Muscle-related complications have occasionally been reported in dengue infection [[3], [4], [5]]. Rhabdomyolysis, characterized by the breakdown of skeletal muscles resulting in elevated creatinine phosphokinase (CPK), has been studied in different perspectives including viral-induced rhabdomyolysis. However, it is uncommonly described in patients with dengue. Despite dengue being recognized as a major global health problem, only limited number of case reports and clinical study discussing rhabdomyolysis were found. CPK is not routinely tested unless there is significant clinical suspicion. Nevertheless, symptoms which characterized rhabdomyolysis do not provide high sensitivity for early detection [6]. Rhabdomyolysis can cause significant complications such as acute kidney injury (AKI). Some patients require renal replacement therapy and die. Previous studies have investigated the incidence of AKI among patients with dengue. Results showed that rhabdomyolysis led to AKI in 15.6─35.8 % of cases, both adults and children, and that it was an independent risk factor for AKI [[7], [8], [9], [10], [11]]. However, the mortality rate of patients with dengue complicating rhabdomyolysis has not yet been fully elucidated due to limited study. One study in adult dengue found that it can be up to 11.1 % [12].

While rhabdomyolysis is well-known for requiring early aggressive fluid hydration to alleviate serious consequences, intravenous volume administration is recommended for patients with warning signs [13]. Due to several challenges in the early diagnosis and management of dengue infection complicated by rhabdomyolysis, this article presents the clinical course of a young adolescent with neurodivergence who had dengue virus serotype 1 (DENV-1) infection complicated by rhabdomyolysis during the febrile stage but who did not present with the typical triad of rhabdomyolysis manifestation. Furthermore, we reviewed the challenge in diagnosis and treatment of these two conditions, which have differences in details regarding the fluid therapy, based on the recent literatures.

2 Case presentation

A 13-year-old female with 4-day fever, agitation, leukopenia, and elevated creatine phosphokinase (CPK) levels (3343 U/L) without discolored urine was referred to our hospital for appropriate management. The patient had autism spectrum disorder and was treated with risperidone, topiramate, benzhexol, diazepam, and haloperidol. At two weeks before admission, she was admitted to the mental health institution due to aggressive behavior. However, during behavioral training, she developed high-grade fever and agitation, which required intermittent restraint. Based on the initial laboratory tests conducted on day 4 of the illness, the patient had low leukocyte levels and elevated CPK levels as mentioned earlier. The parents denied travel history within the last month or a history of dengue infection. The family did not report genetic or muscular diseases of their members.

Upon admission, the patient was alert but could not communicate verbally because of her baseline condition of autism. The physical examination was unremarkable, except for the high fever. A complete blood count showed the following results: hemoglobin level, 10.5 g/dL; hematocrit level, 35 %; white blood cell count, 7060 cells/mm3; and platelet count, 333,000 cells/mm3. Hemolysis was not observed on the peripheral blood smear. The patient tested positive for dengue non-structural protein 1 antigen (NS1Ag) and negative for immunoglobulin G (IgG) and IgM dengue antibodies. A diagnosis of dengue fever with rhabdomyolysis was established. At initiation, the patient had been administered half of the maintenance volume of intravenous normal saline solution to maintain vitals and urine output. The neuropsychiatric medications were temporarily discontinued to prevent further muscle injury. On day 5 of the illness, the hematocrit decreased to 32.9 %. The CPK level increased to 10,510 U/L, and her serum creatinine level was 0.81 mg/dL (Fig. 1). Her electrolyte levels were within the normal range, except for mild acidosis. Urinalysis showed a pH of 5.5, and the urine dipstick test revealed the presence of blood (3+), but not protein. However, red blood cells (RBCs) were not found in the urine. Chest radiography showed no abnormalities.Fig. 1 Clinical course of the patient.

Fig. 1

The patient's serum CPK level reached its peak at 16,233 U/L on day 6 of the illness and the urinalysis showed a persistent pH of 5.5 and the presence of blood 2+ to 3+ without RBCs. Therefore, myoglobinuria was suspected, and treatment with urine alkalization was initiated by administering a maintenance volume of normal saline solution with sodium bicarbonate, which resulted in a gradual increase in urine pH. The peak hematocrit was observed on day 7 of the illness at 35.8 %, while the downward trend in CPK levels began on day 9 of the illness, reaching a level of 2754 U/L. The patient's highest serum creatinine level reached 0.92 mg/dL before decreasing to a normal level at 0.63 mg/dL. Her fever persisted until day 8 of the illness and then declined. A reverse transcription polymerase chain reaction tested on the blood sample collected on day 8 of the illness revealed dengue virus serotype 1 (DENV-1). The blood culture showed no bacterial growth. There was no significant increase in hematocrit levels. The lowest platelet count was 88,000 cells/mm3. Thereafter, it returned to normal levels. The urine output had been consistently normal since admission, and the patient did not present with urine discoloration despite the presence of significant urinary blood on the dipstick tests. The hematocrit on day 11 of the illness showed a level of 30.1 %, reflecting a rise of at least 18.9 % from the baseline. The kidney and bladder ultrasonography results on day 11 of the illness were normal, with only small bilateral pleural effusions noted by the radiologist. Nevertheless, the patient's medical condition improved, and she was then discharged the same day (Fig. 1). Based on the outpatient follow-up results, the patient's symptoms had recovered within a week. The CPK level gradually decreased to the normal level. The platelet count, electrolytes, and urine analysis results were unremarkable, although mild anemia was persistently observed. Taking a history and blood count profile, iron deficiency anemia was suspected. Therefore, a therapeutic trial of oral iron was given, which showed a successful response.

3 Discussion

3.1 Presentation of rhabdomyolysis in dengue infection

Viral infection is the leading cause of rhabdomyolysis in children. Previous studies have reported that influenza A, not dengue virus, is the most frequent viral cause of rhabdomyolysis [6]. The classic triad of symptoms of rhabdomyolysis include myalgia, muscle weakness, and tea-colored urine. However, only <10 % of patients present with these symptoms, and more than 30 %─50 % of patients do not complain of myalgia or muscle weakness. Thus, a diagnosis is made based on an elevated CPK level and urinary myoglobin levels [6]. A serum CPK level five times greater than the upper limit (≥1000 U/L) supports the diagnosis of rhabdomyolysis [14,15]. Mild dengue fever or low-grade dengue hemorrhagic fever were reported to show high CPK ranging from 7800 up to 742,900 U/L, requiring early aggressive hydration, with cases developing AKI and even resulting in death [[16], [17], [18], [19], [20], [21]]. Notably, in previous case reports, dengue patients who were detected to have high CPK presented signs of severe kidney failure, or dark urine, which means significant myoglobinuria has already been released [[16], [17], [18], [19], [20], [21], [22], [23], [24]]. Some patients were later diagnosed with severe rhabdomyolysis despite dark urine observed earlier [21,24]. Our patient had neither urine discoloration nor any signs of severe dengue or kidney insufficiency. Furthermore, she did not complain of muscle tenderness because of her underlying condition. The clinical clue was that this patient presented with risk factors for elevated CPK levels, such as receiving neuropsychiatric medication and restraint, while having a fever from infection [25]. Urine analysis can be used to detect the presence of blood in the dipstick test in the absence of red blood cells to prevent myoglobin-induced AKI.

3.2 Dengue-complicated rhabdomyolysis and the risk of acute kidney injury

Excessive myoglobin released from damaged muscle cells can cause renal tubular injury, resulting in AKI. The pathophysiology of AKI in rhabdomyolysis is multifactorial, involving vasoconstriction, hypovolemia, direct myoglobin toxicity, and intraluminal cast formation [15]. A previous report described a patient with dengue infection who developed severe AKI and rhabdomyolysis and underwent biopsy. Results revealed positive staining for myoglobin deposit in the kidney tubules, and the histological findings indicated acute tubular necrosis [26]. Based on in vitro study, dengue can cause muscle damage by direct invasion [27].

To decrease the risk of severe kidney injury in patients with rhabdomyolysis, the early detection of elevated creatine phosphokinase (CPK) levels and myoglobinuria is important. The risk of developing AKI may increase in the presence of coexisting conditions such as sepsis and dehydration [28]. In previous case reports, patients usually presented with elevated CPK levels as evidenced by manifestations including dark-colored urine, decreased urine output, and elevated serum creatinine levels, which are the late markers of AKI [29]. The cutoff for creatine kinase levels in AKI has not been established. Some studies have found creatine kinase levels ranging from 5000 to 15,000 U/L may be associated with an increased risk of renal injury, and a CPK level of >15,000 U/L with an increased risk of renal replacement therapy [15]. It should be emphasized that the nephrotoxic agent in rhabdomyolysis is in fact myoglobin, not directly from elevating CPK. However, myoglobin measurement is not available in every medical center. Urinary blood of ≥2+ on the dipstick test could indicate a higher probability of developing rhabdomyolysis-associated acute kidney injury [10].

To the best of our knowledge, the proportion of pediatric patients (aged <18 years) with dengue complicated by rhabdomyolysis is low. However, some of them died [24]. Table 1 shows the characteristics of the patients under the age of 18 with dengue infection complicated by rhabdomyolysis [21,24,30]. Notably, our patient was the youngest to present with dengue infection complicated by rhabdomyolysis, showing a moderate to severe rise of CPK, which is associated with the risk of kidney injury.Table 1 Rhabdomyolysis with dengue infection in patients under the age of 18.

Table 1No.	Year	Age	Presenting symptoms	Dengue result	CPK level(U/L)	Clinical progression	Treatment	Outcome	Reference	
1	2015	16	Fever, periorbital pain, headache, fatigue at the lower extremities, vomiting	Positive
DEN-1
PCR	1549	Circulatory failure (narrow pulse pressure), high creatinine level	Fluid resuscitation and symptomatic treatment	Improved without sequelae	[30]	
2	2015	17	Fever, poor appetite	Negative dengue antigen, weekly positive dengue IgM, positive dengue IgG	151,760	Hemoconcentration, thrombocytopenia, right pleural effusion, severe hepatitis, coagulopathy, encephalopathy, respiratory failure, dark urine, heavy proteinuria, acute kidney injury	Cautious fluid treatment, blood transfusion, respirator, hemodialysis	Dead	[24]	
3	2022	17	Fever, headache, intense body pain, generalized muscle weakness, red-brown urine	Positive dengue NS1Ag	285,200	Hemoconcentration, high creatinine levels with oliguria and hypertension, deranged liver function	Judicious intravenous fluid therapy, alkalinization, balancing fluid intake and output	Improved without sequelae	[21]	

3.3 Management of co-existing dengue and rhabdomyolysis

Vascular permeability is the main pathophysiology reflecting the dengue outcome [31]. During the febrile stage, clinically significant plasma leakage has not yet played a role but can begin subtly due to endothelial dysfunction as early as 3 days after the onset of illness [32]. For dengue treatment, the patients should have their volume status carefully evaluated. Not only is poor clinical outcome related to volume depletion, but volume overload is also a significant factor in dengue morbidity and mortality [31,33]. Fluid replacement therapy should be administered cautiously to prevent complications once extravasation develops. To detect evidence of vascular permeability, several clinical aspects are suggested. Blood pressure and urine output are essential parameters to monitor. Hematocrit is an important laboratory marker to detect evidence of critical plasma leakage. While a hematocrit rise of ≥20 % from baseline is defined as hemoconcentration in dengue hemorrhagic fever (DHF), a modest rise of 10─20 % may indicate early plasma leakage that requires attention [31,34]. Chest radiograph and ultrasound including abdomen can be helpful in early documenting evidence of pleural effusion and ascites, although not always necessary for acute management if other clinical data are sufficient for decision making. Kaagaard et al. found that pleural effusion was discovered in nearly 20 % of uncomplicated dengue cases [35]. Therefore, it is generally recommended to administer low-volume or just enough fluid to maintain adequate circulation, preferring a downward adjustment of the fluid volume [13,31,36]. Some approaches suggest strictly giving intravenous fluid only in cases of moderate to severe dehydration, with a volume of only one-fourth to half of maintenance fluid during the febrile stage [31,37]. In contrast, early treatment with a large volume of intravenous fluid is generally recommended for rhabdomyolysis to achieve higher urine output and reduce the complications of myoglobin-induced kidney injury and the need for dialysis. The fluid administration regimen, preferably an isotonic solution, has varied among adult and pediatric patients. Adult patients are initially given 1.5 L of fluid per hour, whereas pediatric patients are suggested to receive a bolus of 20 mL/kg followed by twice the maintenance volume, aiming to achieve at least thrice the normal urine output [38]. Fluid administration within the first 6 hours after muscle injury was found to decrease the risk of AKI [39]. Therefore, the early detection of myolysis in patients with dengue can provide guidance for fluid management and improve patient prognosis. Rhabdomyolysis, which cannot always be detected solely by clinical symptoms, is not commonly recognized as a warning sign of dengue. This complication requires in-hospitalized management to prevent serious consequences. Some cases can develop significant muscle lysis during the febrile stage and are under-detected until the condition worsens. Delayed recognition of high CPK resulted in re-hospitalizations, AKI, and death [17,20,21,24]. However, the concern regarding whether every rhabdomyolysis patient would benefit from high-volume fluid treatment, given the varied causes of this condition and the patient's context, hasn't been prospectively proven. The treatment guidelines for fluid therapy in dengue complicated by rhabdomyolysis have not yet been well established.

Nevertheless, our patient was administered with IV fluid to correct the initial dehydration when CPK started to rise. The initial physical examination did not exhibit clinically significant pleural or peritoneal effusion. Chest X-ray and serial complete blood count were performed to monitor critical plasma leakage. Sequential urinalysis was performed to detect the presence of blood without red blood cells in the urine dipstick test, which considered myoglobinuria that could affect the management. Therefore, the intravenous fluid was increased when the patient's urine dipstick tested positive for blood without red blood cells. Urine output was maintained at least 1 mL/kg/hour and kept monitoring the CPK levels, renal function, electrolyte levels and urine analysis. Alkalization was initiated in our patient to correct the acidic urinary pH and decrease the risk of myoglobin cast formation. Urine alkalization increases myoglobin solubility among acidotic patients. Still, there is not enough evidence supporting the use of this treatment in rhabdomyolysis [6,15].

4 Conclusion

Rhabdomyolysis poses a challenge for patients with dengue infection, particularly in the pediatric population, owing to its subtle clinical symptoms and the non-routine nature of laboratory-based diagnosis. Given the potential for worsening outcomes in both dengue and rhabdomyolysis, it requires cautious consideration. Patients with pre-existing conditions or risk medications, such as ours, are at risk of developing acute kidney injury. To facilitate the early detection of muscle lysis and myoglobinuria in patients with dengue, routine non-invasive urine analysis and/or serum CPK assessment are recommended if available. Timely identification can heighten awareness of appropriate fluid therapy in patients with dengue complicating rhabdomyolysis, emphasizing the need to tailor the fluid treatment as there is no one-size-fits-all general recommendation. Overall, clinical monitoring and maintaining fluid balance for a specific treatment goal at a certain time point are important keys to mitigate morbidity and mortality in the management of these co-existing conditions.

Ethics statement

The study was approved by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University, under protocol TMEC 24-007, and the director of the Hospital for Tropical Diseases Bangkok. A written informed consent of the patient's guardian for the publication of clinical data included in the manuscript was obtained. The study complies with all regulations.

Data availability statement

The data of the patient is not registered in any publicly available repository. They are available on reasonable request.

Funding

None.

CRediT authorship contribution statement

Anastasia Putri: Writing – original draft, Data curation. Watcharee Arunsodsai: Writing – review & editing. Weerawan Hattasingh: Writing – review & editing. Salin Sirinam: Writing – review & editing, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Pimolpachr Sriburin, TROP-PED Diagnostic Center for the laboratory test.
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