Case of steroid refractory dengue myositis responsive to intravenous immunoglobulins

Abstract

Dengue is an arbovirus infection that usually presents with the symptoms of high-grade fever, myalgia and rash. Dengue is spread by the Aedes aegypti mosquito and frequent outbreaks are being reported in regions like Pakistan, India and Sri Lanka. Although muscle ache is quite common with dengue fever, overt myositis is of very rare occurrence. Here, we report a case of a young girl who presented to us with serologically confirmed dengue infection, and having bilateral upper and lower limb weakness. Her raised creatine kinase, along with her electromyography pattern was suggestive of myositis. Her condition was steroid-resistant and responded only to intravenous immunoglobulin. She was discharged in a stable condition.

Background

Dengue infection is caused by an RNA virus belonging to the genus Flavivirus and is prevalent in tropical and subtropical regions in the world.¹ It is transmitted by the Aedes aegypti mosquito predominantly. Dengue infection has an incubation period of 4–10 days and in most cases presents as a high-grade fever associated with severe myalgia hence the term bone-breaking disease. These symptoms are often preceded by retro-orbital pain.² The most frequent biochemical derangement associated with dengue infection is that of thrombocytopenia; although leucopenia has also been reported in several cases. Most of the cases are usually uncomplicated and the symptoms subside in about 7 days’ time; however, the infection can complicate into dengue shock syndrome or dengue haemorrhagic fever. Dengue virus has four serotypes, and subsequent infection with a different serotype greatly increases the chances of major complications due to cytokine storm.³ Dengue is generally treated with supportive management like antipyretics, intravenous fluids and platelets transfusion when indicated.

We present a case of dengue myositis and quadriparesis which was refractory to steroids and only responded to intravenous immunoglobulin (IVIG).

Case presentation

A young girl in her early teens, with no documented chronic medical conditions and no history of dengue infection, presented to the outpatient department with complaints of high-grade fever associated with chills, myalgia, arthralgia, headache and retro-orbital pain. Additionally, she had severe tenderness in both upper and lower extremities and was unable to walk.

The patient had reportedly developed fever 4 days before presenting to us and was found to have dengue NS1 (rapid test) positive. Fever was intermittent, high grade (102 °F), and was relieved by oral acetaminophen. On the fourth day of symptoms onset, she started experiencing progressive weakness in both lower limbs associated with excruciating pain. The patient was initially able to walk with support. However, within the next 24 hours she was unable to walk, and also started experiencing pain and weakness in both upper extremities, and was subsequently brought to the hospital. Her review of systems was normal and did not report any respiratory, cardiovascular, gastrointestinal or urinary complaints. Her medical, surgical and family history was unremarkable. She denied recent travel or any medication use other than acetaminophen.

On examination she was found pale-looking with normal body mass index, lying on the examination couch in mild to moderate distress. At the time of admission, assessment of vital signs revealed a temperature of 100°F, blood pressure of 80/50 mm Hg, a pulse of 110 beats per minute, a respiratory rate of 21 breaths per minute and an oxygen saturation of 95% at room air. General physical examination was significant for anaemia, non-pitting oedema of both upper and lower extremities, and marked tenderness to touch, more pronounced in the lower limbs than the upper extremities. No petechial haemorrhages or any skin rash were observed. Respiratory and cardiovascular examinations were unremarkable. No tenderness or visceromegaly was appreciated on abdominal examination. On central nervous system examination, the patient was well oriented, and her Glasgow Coma Scale was 15/15. Motor examination revealed normal muscle bulk in all four limbs. Tone and deep tendon reflexes could not be appreciated due to severe tenderness. Plantar reflexes were normal bilaterally. Power was 2/5 in the lower limbs and 4/5 in the upper limbs bilaterally. Bowel and bladder control was intact, cranial nerves were intact and no other neurological signs were observed.

Investigations

Initial complete blood count revealed pancytopenia. White cell count was 1900×10⁹/L, serum platelet was 1 17 000×10⁹/L and haemoglobin (Hb) was 10.8 g/L. At the time of admission, acute phase reactants were markedly raised. Erythrocyte sedimentation rate was 120 mm/hour, and creatine phosphokinase (CPK) was 8858 U/L. HIV, hepatitis B and C tests were negative. Thyroid profile, serum urea, creatinine and urinalysis were all reported normal. ECG and serum troponin levels were normal. Stool analysis did not report any ova, cyst or parasite. Urine microscopy showed 0–1 Red blood cells (RBC)/High Power Field (HPF), 3–5 White Blood Cells (WBC)/High Power Field (HPF), few epithelial cells and absent granular casts. Urine myoglobin levels were not measured. Malaria and rapid influenza diagnostic tests were negative. Blood cultures came out negative. Nerve conduction test (NCS) and electromyography (EMG) were planned. NCS reported all tested nerves of the upper and lower limbs with normal distal latency, amplitude and conduction velocity. EMG of both upper and lower limbs was consistent with myopathic configuration including early recruitment and small amplitude action potentials with positive sharp waves of the motor unit; suggestive of inflammatory muscle disorder. Arterial and venous systems of both lower limbs showed normal flow, wave formation and good compressibility. No evidence of thrombosis was seen during the scan. An extensive autoimmune profile was done to rule out potential autoimmune causes of inflammatory myopathy which included serum anti-nuclear antibodies (ANA), anti-histidyl-tRNA syntase (anti-Jo-1), anti-polymyositis/scleroderma -75 (anti-PM/Scl-75), anti-polymyositis/scleroderma -100 (anti-PM/Scl-100), anti- signal recognition particle (anti-SRP), anti-glycyl (anti-EJ), anti-isoleucyl (anti-OJ), anti-threonyl (anti-PL-7), anti-alanyl (anti-PL-12), anti-Mi-2 nuclear antigen (alpha and beta), anti-Melanoma differentiation-associated gene 5 (anti-MDA-5), anti-transcription intermediary factor 1 (anti-TIF-1γ), anti-nuclear matrix proteint-2 (anti-NXP-2), anti-Ku complex antibody, and anti-small ubiquitin-like modifier 1-activating enzyme (anti-SAE-1). Results for all the antibody tests were negative. Anti- 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody test was not done due to unavailability in local labs. It is associated with statins use which our patients had not used for any reason.

Differentials

Our patient’s history, physical examination, NCS and EMG tests all favoured the diagnosis of myositis. Deep venous thrombosis was ruled out based on normal Doppler scan. An extensive investigation was performed to identify the cause of myositis. Her serum CPK levels were high; however, serum urea/creatinine and urinalysis ruled out any rhabdomyolysis. A workup for the endemic, seasonal, and most common parasitic, bacterial and viral aetiologies were done including malaria, influenza, hepatitis B and C. All of which were negative and thus ruled out. Stool analysis did not report any ova, cyst or parasite. Negative blood cultures ruled out bacterial causes. An autoimmune profile was done to rule out potential autoimmune causes of inflammatory myopathy. Although muscle biopsy was not done, EULAR/American College of Rheumatology criteria for idiopathic inflammatory myopathies suggested a probable inflammatory myopathy with a score of 2.8 and a probability value of 7%. The variables which were included in determining the value were the patient’s age, the pattern of weakness, absence of rash, dysphagia, negative serology and high CPK levels. Fungal causes of myositis are usually reported in immunocompromised, chemotherapy receiving patients, which was not the case in our patient. Therefore, after ruling out other differentials, given her most recent diagnosis of dengue infection in the ongoing season of dengue, we diagnosed the case as dengue myositis.

Treatment

The patient was started on intravenous fluids, empiric antibiotics for any concomitant bacterial infection, acetaminophen, intravenous tramadol and a prophylactic dose of enoxaparin. She continued having fever spikes for up to 3 days after admission and was afebrile thereafter. The antibiotics thereafter were stopped. Her serum Hb level which was 10.8 g/L on admission, had dropped to 6 g/L over the next 3 days, attributable to haemodilution from aggressive intravenous hydration, and menorrhagia aggravated somehow by thrombocytopenia. Two pints of red cell concentrate were transfused to correct the anaemia. As the patient was not responding to conservative management both in terms of clinical symptoms and worsening CPK levels, a decision was made to start the patient on steroids. Methylprednisolone pulse therapy was initiated to blunt the inflammatory response at a dose of 1 gm/day. However, no clinical improvement was observed. On the fifth day of admission, the patient was started on IVIG (2 gm/kg), which was administered at a rate of 0.4 gm/kg/day over 5 days.

Outcome and follow-up

Noticeable clinical improvement was seen after the first two doses of immunoglobulin. There was a significant reduction in the intensity of pain. Power in the upper limbs improved to 5/5. Following the third dose, lower limbs power improved to 3/5 and the patient was able to walk with support. After completion of immunoglobulin therapy, power in the lower extremities had further improved to 4/5. Serum CPK levels peaked at 11 051 U/L on the fifth day of admission, After IVIG therapy serum CPK levels started to decline precipitously, and gradually returned to normal levels over the next few days. Our patient had regained a near-normal level of mobility. Platelet count showed a downward trend till day 5 of admission, reaching a low of 57 400×10⁹/L, and subsequently returned to physiological levels after IVIG therapy (table 1). Renal function remained normal throughout the hospital stay. Renal function and serum electrolytes only had minor derangements, which resolved within 3 days of admission (table 2). Finally, our patient recovered fully and was discharged on the 13th day of admission. The patient was not given any maintenance dose of immunoglobulin as is usually given in several other causes of myositis in adolescence.

Table 1.

Lab Parameters

	Day 5*	Day 8	Day 10	Day 11	Day 13	Day 17
	Day 1**	Day 3	Day 5	Day 6	Day 8	Day 12
White cell count	19003×109/L	35003×109/L	55003×109/L		61003×109/L	72003×109/L
Haemoglobin	10.8 g/L	6.9 g/L	8.9 g/L		9.6 g/L	11.3 g/L
Haematocrit	31.3%	20.6%	25.1%		28.1%	33.8%
Platelets	1 17 000×109/L	77 000×109/L	57 000×109/L	86 000×109/L	1 99 000×109/L	4 00 000×109/L

Day 1 (lower row**) corresponds to first day of hospital admission and day 5 (upper row*) of symptom onset.

Table 2.

Parameters

	Day 5**	Day 8	Day 10	Day 11	Day 13	Day 15	Day 17
	Day 1**	Day 3	Day 5	Day 6	Day 8	Day 10	Day 12
CPK	8858 U/L	6357 U/L	11 051 U/L		2570 U/L	382 U/L	169 U/L
Creatinine (0.49–0.84)***	1 mg/dL	1.2 mg/dL	0.9 mg/dL	0.7 mg/dL	0.6 mg/dL	0.5 mg/dL	0.4 mg/dL
Urea	38 mg/dL	81 mg/dL	79 mg/dL	67 mg/dL	53 mg/dL	40 mg/dL	28 g/dL

Lower row** (day 1) corresponds to first day of hospital admission and upper row* (day 5) of symptom onset. Normal range*** of serum enzymatic creatinine for a young girl in her early teens.

Discussion

Dengue infection is caused by an RNA virus belonging to the genus Flavivirus. Dengue infection outbreaks are frequently reported in areas like Pakistan, India and Sri Lanka. According to a WHO estimate, the approximate incidence of dengue infection is 390 million cases per year. Although 129 countries are at risk of dengue infection, Asian countries represent 70% of the disease burden.⁴

The majority of dengue infections are either subclinical or present with influenza-like illness with symptoms of high-grade fever, myalgia and nausea. Blood workup of the majority of patients reveals thrombocytopenia and in some cases leucopenia.⁵ The strong association of dengue with that of thrombocytopenia means that traditionally a lot of focus has been around that. However, with the passage of time, it has been realised that we need to see dengue infection beyond mere thrombocytopenia. It has been reported that dengue affects various other systems and a literature review reveals cases of myositis,⁶ myocarditis,⁷ encephalitis⁸ and Guillain-Barré syndrome⁹ associated with dengue infection.

Myositis due to dengue infection could range in severity from self-limiting to fatal, as indicated by a case series of seven patients suffering from dengue myositis in which three patients had respiratory muscle involvement, out of which two patients succumbed to the disease; however, others recovered over the subsequent weeks.¹⁰ Another review of 34 cases of dengue myositis revealed that dengue myositis occurred mainly in the younger population with a mean age of 24.6 years, it had a mean duration of weakness of 9.4 days, and it predominantly affected men. Out of those 34, 3 patients died while the rest had an unremarkable recovery.¹ Our patient had generalised muscle tenderness and decreased power, which was more pronounced in the lower limbs. However, respiratory muscles were spared.

The exact mechanism of myositis in dengue is not known; however, the literature review suggests that a direct invasion by the virus itself could be responsible. There is also a suggestion that disruption of calcium homeostasis could be responsible for rhabdomyolysis.¹¹ One of the key things that need further exploration is that of a possible autoimmune component due to cellular tropism that might be responsible for myositis. It is even possible that it might be a combination of all these.

Dengue myositis is usually diagnosed by key clinical features including muscle tenderness and weakness along with raised CPK levels.^{1 10} However, EMG and muscle biopsy could also provide supportive evidence. All of these features were clearly evident in our patient.

Although in majority of patients, dengue myositis would resolve spontaneously with conservative management, some of the refractory cases do need corticosteroids.^{12 13} Clinicians use them to blunt the inflammatory response and when they consider that the immune response contributes to the disease process. The clinical outcome of corticosteroids in dengue myositis varies considerably based on literature, with some showing therapeutic advantages while others reporting no benefit. In a review, steroid’s role in dengue shock syndrome could not be manifested probably due to underpowered study, and the need for larger studies was felt. Similarly, steroid did not have any significant effect in early symptomatic dengue to prevent dengue mortality, complications or Intensive care unit admissions¹⁴ Another review also suggested the need for more and large trials. They concluded that steroids can be beneficial but their effects varies based on the stage of the dengue infection, dose and duration of steroid to sustain therapeutic blood level of corticosteroids, and recommended use of steroid with higher receptor affinity.¹⁵ Our literature review did not reveal any case of dengue myositis that was refractory to steroids as seen in our patient. Our patient responded to IVIG therapy after a failed trial of corticosteroid therapy. We believe that the proposed mechanism could be the neutralising effect of immunoglobulin on autoantibodies formed against myocytes due to cellular tropism. However, there is still a need for further research work to be carried out in this regard, both in terms of the efficacy of immunoglobulin as a potential treatment, as well as its possible mechanism of action.

The literature review of the cases so far suggests that a high CPK count, involvement of respiratory muscles and secondary renal failure holds major prognostic significance.^{1 10 16} However, until the exact mechanism of muscle injury is found, it would be very difficult to predict the prognosis and treatment of the patient. Hence it is important that more such cases are reported with special significance given to the way cases were managed.

Patient’s perspective.

I had high fever. It was dengue season which is common in our region. After testing I was diagnosed with dengue and reassured that I need only symptomatic therapy. However, to my surprise my disease took a turn, and it got severe to the point that I could not walk. The pain was unbearable. I thought maybe I have been wrongly diagnosed and expressed my concerns. I am glad the doctors did an extensive investigation and concluded that it is rare, but I have dengue myositis. They said I would need steroid therapy, and everything would be fine afterwards. However, things did not improve. I and my family were thinking to change hospital or see some other doctors. Finally, the doctor proposed and explained to me IVIG as a treatment choice. I trusted him, and we proceeded with this option. To my surprise, I recovered remarkably. The pain was gone. Soon I could walk once again. It was a tough journey. I am glad I made it through.

Learning points.

• Given the high prevalence rate of dengue fever in southeast Asia and tropical regions, dengue myositis should always be considered in patients presenting with high-grade fever, myalgia and muscle weakness.

• Severe tenderness of the involved muscles, high serum CPK levels, positive dengue serology and an otherwise normal neurological examination are the hallmark features of the condition; and may aid the clinician in differentiating dengue myositis from other causes of acute muscle weakness.

• Even though dengue myositis is a self-resolving condition, intravenous immunoglobulin is a potential treatment option in steroid-refractory cases, and needs to be further evaluated.

Ethics statements

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