Postdengue chronic fatigue syndrome in an adolescent boy

Abstract

Chronic fatigue syndrome (CFS) is often preceded by a viral illness and has recurrent ‘flulike’ symptoms which include a wide spectrum of musculoskeletal and neurological clinical features. The condition is also known as myalgic encephalomyelitis and systemic exertional intolerance syndrome. CFS has been reported following dengue among adult patients. We report the case of an 11-year-old boy who developed CFS following recovery of dengue haemorrhagic fever (DHF). The reported child was initially managed as for DHF and was clinically asymptomatic on post-discharge day 3. He was re-admitted after 3 weeks with severe joint pains, myalgia and unbearable headache. As his symptoms persisted, he was investigated in-depth. All investigations were normal except mild elevation of liver functions. The diagnosis of CFS secondary to DHF was made by exclusion of differential diagnosis. At 1-year follow-up, patient continues to have symptoms after treatment with physiotherapy and nutrition counselling.

Background

Dengue which is recognised as a common yet neglected tropical disease by the WHO prevails in many tropical countries.¹ While most patients with symptomatic dengue have undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF) or dengue shock syndrome, a number of atypical presentations of dengue have been reported in literature.^{2 3} Atypical systemic features are seen when various organ systems are involved in dengue and these features have been incorporated to describe ‘expanded dengue syndrome’.⁴

In adults with dengue fever, convalescent phase can be prolonged with persistent fatigue for 2–4 weeks.⁵ Several adult studies from Central and South America and South-East Asia reported unusually prolonged phase of fatigue following recovery of dengue fever.^6–8 However, the presence of unusually prolonged fatigue is a diagnostic challenge to paediatricians given the rarity of this entity in the paediatric age group and the need for ruling out differential diagnosis of unexplained fatigue.

The Centres for Disease Control and the CFS (chronic fatigue syndrome) International Study Group defined CFS in adults and children based on presence of three symptoms and at least one of two additional manifestations.⁹ The three classic symptoms include presence of substantial reduction in the ability to engage in pre-illness levels of activity, postexertional malaise and unrefreshing sleep. Presence of orthostatic intolerance and cognitive impairment are additional manifestations. These symptoms need to be present for more than 6 months in at least half the time with moderate or severe intensity to make a definitive diagnosis of CFS. In addition to fatigue which does not relieve with rest, patients with CFS often report of myalgia, arthralgia, headache and swallowing difficulties. The authors of this report have described a child who had prolonged fatigue leading to CFS following initial recovery of DHF and discuss the diagnostic challenges of this unusual and rare phenomenon in the paediatric age group.

Case presentation

An 11-year-old boy presented with the fever, body ache, arthralgia and headache for 3 days duration. Dengue NS1 antigen was positive on day 3 of illness and the same day blood counts revealed normal white cell (6.4×10³/cumm) and platelet counts (256×10³/cumm). He was initially managed by the general practitioner with paracetamol and oral fluids.

On day 4 of illness, he developed abdominal pain, vomiting and loose stools and was admitted for in-patient management. He was given intravenous fluids in addition to oral fluids to maintain vital signs as vomiting and loose stools were profuse. On day 5 of illness, he developed severe abdominal pain and in-ward ultrasound demonstrated bilateral pleural effusions, and thicken gall bladder. On physical examination, he was ill, febrile (39.5°C) and had red eyes with mild watery discharge. His body mass index was 21 kg/m². Vital signs were: blood pressure—100/60 mm Hg, pulse rate—120 beats/min, capillary refill time <2 s with warm peripheries. Abdominal examination revealed right hypochondrial tenderness and hepatomegaly (3 cm). His investigations revealed that white cell—10.5×10³, Hb—142 g/L, platelet—120×10³, alanine transaminase (ALT)—254 U/L, aspartate transaminase (AST)—325 U/L. DHF was diagnosed based on clinico-radiological findings and monitoring was intensified as for critical phase.

On day 6 of illness, he became more ill and irritable and developed severe abdominal tenderness with significant melena, but no other bleeding manifestations were seen and vital sign were within normal limits. Haematological parameters showed leucocytosis (white cell—15×10³/ cumm), anaemia (Hb—8.2 g/dL) and thrombocytopenia (platelet—48×10³/ cumm). C-reactive protein (CRP) was elevated (12 mg/dL). Acute bleeding was managed with blood and platelet transfusions. Since he continued to have high fever, diarrhoea, leucocytosis and elevated CRP, he was commenced on intravenous ceftriaxone as for secondary bacterial infection although blood and urine cultures yielded no growth. Both dengue IgG and IgM antibodies were positive on day 7 of illness. While he was on supportive care as for dengue fever and intravenous antibiotics, he recovered from all medical symptoms and was discharged on day 14 of illness. He was reviewed with platelet count in the out-patient clinic in 3 days, found to be asymptomatic and advised to follow additional home rest for 3 weeks before he could resume schooling.

At baseline, he reported normal levels of activity. He has been playing with his school mates every day in the playground prior to admission and never had reported tiredness. He walked to ward on the day of admission with no difficulty from Outpatient Department which is almost 300 m from the ward. However, on discharge, he was feeling tired. At reviewed in 3 days, he showed some improvement in tiredness and did not report any symptoms. As most patients recover from dengue infection feel tired, we usually suggest them to rest for 3 weeks and almost all of them are free from any tiredness after this period. Exceptionally, the reported child had multiple symptoms and readmitted after 3 weeks with the help of wheel chair as he could not walk as earlier. He was re-admitted with severe joint pains, myalgia and unbearable headache for 1-week duration. He had lost appetite, and felt loss of energy. His sleep quality was disturbed by physical symptoms. He was reluctant to continue schooling and daily activities as he felt increasingly tired. Physical examination disclosed that he was less active and sleepy although all system examination was otherwise completely normal. He was subsequently investigated for incapacitating fatigue and other non-specific systemic symptoms. Table 1 shows the timeline of symptoms over the course of illness.

Table 1.

The timeline of symptoms over the course of illness

Acute stage of the disease			Prodromal period	Chronic stages of disease
Febrile stage	Critical stage	Recovery stage	Up to 3 weeks	3 months	6 months	1 year
1–4 days	5–7 days	8–14 days
Fever	Severe abdominal pain	Increased appetite	Severe joint pains	Persisting joint pains	Persisting joint pains	Slight improvement in joint pain
Vomiting	Hepatomegaly	Urine output increased	Myalgia	Myalgia	Myalgia	Significant improvement in myalgia
Headache	Ill looking	Feeling of well being	Unbearable headache	Persisting headache in the same severity	Persisting headache in the same severity	Significant improvement in headache
Arthralgia	Irritability	Sleep improved	Sleep disturbances	Sleep disturbances	Sleep disturbances	No sleep disturbance
Body ache	Pleural effusion and ascites	Air entry improved and abdominal swelling reduced	Uninterested in activities and food intakes	Uninterested in activities and food intakes	Uninterested in activities and food intakes	Improvement in daily activities
Abdominal pain	Unstable vital signs (narrowed pulse pressure, tachycardia, prolong capillary refilling time)	Vital signs became stable	Poor concentration in studies and watching televisions	Poor concentration in studies and watching televisions	Poor concentration in studies and watching televisions	Showed some interest in education and hobbies
Vomiting	Melena	No bleeding manifestations	Fatigue	Difficult to walk due to body ache	Reluctant to walk	Can walk to school with minimal tiredness for less than 30 min
Loose stools			Mostly bed bound	Uninterested to talk to family members	Still not interested to talk to family members	Spend some time with family and friends

Investigations

Investigation revealed normal white cells (85×10³/cumm), platelets (425×10³/cumm), normal morphology of cells in blood film examination, ALT (42 U/L), AST (50 U/L), serum bilirubin, serum calcium, serum proteins, CRP (<6 mg/L), erythrocyte sedimentation rate (ESR) (15 mm/hour). Renal function and urine analysis were normal. Urine, sputum, blood, stool and CSF cultures were normal. Sputum examination for acid fast bacilli was normal. Epstein-Barr virus, influenza, HIV, cytomegalovirus, hepatitis B, hepatitis C and mycoplasma serology were normal. Thyroid function test, 08:00 serum random cortisol levels, and fasting serum glucose levels were normal. Serology for coeliac disease and stool calprotectin were negative. ANA (anti-nuclear antibodies), pANCA, cANCA, complements, immunoglobulin, rheumatoid factor and ASOT (anti-Streptolysin O titre) were also within normal range. Ultrasound abdomen, 2 D-echocardiogram, chest X-ray, CT brain and MRI brain were normal. In addition, electroencephalography, electromyography, nerve conduction studies (NCS) and muscle biopsy had been normal. Bone marrow aspiration and trephine biopsy also had been normal. Mantoux test had been within normal limits (less than 10 mm). He was referred to child and adolescent psychiatrist and evaluation did not reveal any comorbid psychiatric diagnosis. The reported child had body aches, arthralgia, headache and sleep disturbances co-occurring with incapacitating fatigue for 6 months following recovery from dengue fever and no alterative explanations for these symptoms were available despite focused history and physical examination and extensive immunological, serological, microbiological, radiological and endocrinological evaluation. The diagnosis of postdengue CFS was confirmed by exclusion of other differential diagnosis for CFS and confirmation of diagnosis based on international diagnostic criteria⁹ by the multidisciplinary team including paediatrician, neurologist, rheumatologist, haematologist psychiatrist and endocrinologist. Table 2 shows the results of laboratory investigations during acute and chronic stages of CFS.

Table 2.

Findings of laboratory investigations during acute and chronic stages of chronic fatigue syndrome

Investigation	Acute stage					Chronic fatigue
	D3	D5	D6	D14	D17	3 weeks	3 months	6 months	1 year
White cell (103/cumm)	6.4	10.5	15	7.0	6.8	8.5	8.4	9.2	8.8
Platelet (103/cumm)	256	120	48	154	452	425	325	258	256
Haemoglobin (g/dL)	12.1	14.2	8.2	11.2	12	12.1	11.8	12	11.4
ALT (U/L)	48	254	284	64	44	42	40	38	28
AST (U/L)	52	325	387	72	42	50	48	40	20

ALT, Alanine transaminase; AST, aspartate transaminase.

Differential diagnosis

CFS is diagnosed by ruling out differential diagnosis including both medical conditions and psychiatric diagnoses. Those who have symptoms for less than 6 months duration are likely to have either acute, self-limited fatigue or prolonged fatigue.⁹ Chronic fatigue (for more than 6 months) which does not have a significant impact over daily routines makes the diagnosis of idiopathic chronic asthenia more likely over CFS.¹⁰ Focused history and physical examination are key to rule out differential medical and psychiatric conditions. Psychiatric evaluation is crucial to rule out depression, schizophrenia, eating disorders, anxiety disorder, bipolar disorder, somatoform disorders, sleep disorders and substance abuse disorders as fatigue could be precipitated by these psychiatric comorbidities. A number of viral illnesses as well as other medical conditions can lead to fatigue thus these differential causes should be ruled out before the aetiology of CFS is determined. Differential medical causes include endocrinological (adrenal insufficiency, thyroid disorders, diabetes mellitus, calcium disorders), infective (Epstein-Barr virus, influenza, hepatitis B, C, tuberculosis, HIV, giardiasis, enterovirus, Q fever, toxoplasmosis, brucellosis), gastrointestinal (coeliac disease, irritable bowel syndrome, inflammatory bowel disease), rheumatological (systemic lupus erythematosis (SLE), rheumatoid arthritis, polymyositis), neuromuscular causes (multiple sclerosis, myasthenia gravis, myopathies and neuropathies) and malignancies (Hodgkin’s lymphoma and pituitary tumours).

Treatment

He has been following up multidisciplinary clinic for psychological counselling, physiotherapy and dietary management. School was informed to encourage regular exercise.

Occupational therapy was targeted to his routine activities of daily living such as bathing, dressing, playing and watering in his home garden. Further, he was trained for walking in varied distances and assessed for his running ability gradually. He has been receiving active and passive physiotherapy along with hydrotherapy. His father was trained to do active physiotherapy at home and now he can walk for 0.5 km with minimal tiredness to school, and he is able to do all his routine activities after 1 year of illness. Playing with mates is still difficult and causes muscle pains and tiredness. He has been on monthly visits to outpatient multidisciplinary clinic. He is also being under follow-up with psychologist, rheumatologist and paediatrician for further management of these symptoms.

Outcome and follow-up

He was unable to do his routine sports and could not walk to school at 6 months postdiagnosis. He was reviewed at 1-year postdiagnosis and showed some improvement and reported that he was not feeling tired while engaging in daily activities although he could not walk for more than half an hour unlike before the onset of CFS. Headache has disappeared now with gradual improvement over 1 year. He has some interest in education and has been sleeping well; watching drama in television and talking to friends. Rheumatologist suggested continuing physiotherapy at home while receiving a healthy, balanced diet.

Discussion

CFS which is also known as myalgic encephalomyelitis and systemic exertional intolerance syndrome is identified as a collection of symptoms and signs of fatigue related to muscular and neurological systems. Muscular symptoms comprise muscle weakness with or without pain. Although these symptoms have been observed among hospitalised adult patients following dengue infection and this presentation has been rarely reported in children. Older age, female sex and presence of chills are reported risk factors.⁶ Most patients develop acute onset symptoms of fatigue within days or weeks following the triggering agent and experience a gradual decline in their functional capacity. A minority of patients develops insidious onset symptoms and functional decline may take several years.¹¹ The incidence of fatigue following dengue infection is lower compared with other infections such as Epstein-Barr virus (38%–40%), and Q-fever (31%).^{12 13}

Although the precise aetiology remains ambiguous, it is thought that altered cytokine production, autonomic system and hypothalamo–pituitary–adrenal axis dysfunction during the postinfection period are implicated in pathophysiology of postdengue fatigue syndrome.⁶ The altered immune function results in an inversion of the CD4/CD8 ratio and an overproduction of cytokines, such as C3a and C5a that cause an immune-mediated damage to the endothelial cells. This triggers a complex phenomenon through the hypothalamic–pituitary–adrenal axis and the autonomic nervous system and leads symptoms and signs of fatigue related to immune, endocrine, musculoskeletal and neurological systems, possibly, to result in the clinical phenomenon of fatigue following dengue infection.¹⁴

A study which assessed clinical profiles and incidence of postdengue CFS reported body aches, poor concentration, headache, giddiness, poor sleep, insomnia or excess sleepiness, feeling of low-grade fever muscle pain, joint pain, sore throat, headache, tender lymph nodes and anxiety as its clinical features.^{6 15} As children often report non-specific symptoms, it is an exceptionally challenging task for the paediatrician to investigate these children in-depth. However, investigations might rule out other potentials differential diagnoses of CFS.

Evidence suggests that older patients with CFS demonstrate a very different course as compared with younger patients.¹⁶ Older patients were reported to have more fatigue and depression, greater autonomic dysfunction (reduced parasympathetic function and increased sympathetic function), and more prolonged left ventricular ejection times.¹⁶ In this child, physical symptoms such as joint pains and myalgia were main symptoms while depression was not a major symptom. However, he demonstrated lack of interest in social activities such as playing and having time-outs with family members due to symptoms of fatigue and weakness.

Although there is substantial evidence on treatment of CFS in adults, there is limited evidence of management of children. The main mode of treatment for CFS is behavioural approach which is focused at encouraging regular exercise, healthy diet and sleep patterns and resumption of normal activity.¹⁷ Cognitive behavioural therapy showed positive effects on self-perception of fatigue, social adjustment, depression and anxiety among adult patients with CFS in a large randomised trial.¹⁸ Exercise therapy may have positive effects on fatigue in adults compared with passive therapies.¹⁹ Although several pharmacological agents have been trialled to assess positive effects on fatigue, none of the pharmacological therapies have been found to be effective in long-term management of fatigue.²⁰ Children with chronic pain need to be reviewed regularly by pain management team and opiates should be avoided due to risk of dependence. Children with comorbid mood and eating disorders need specific treatment.

The symptoms continue to persist and disrupt quality of life for many years in a minority of children.²¹ School time lost during first 4 years following onset of CFS predicts the long-term outcome of CFS.²² Severe chronic fatigue in children can lead to marked functional handicapping.²³ Therefore, it is important that all children with CFS are carefully reviewed and managed jointly by paediatrician, psychologist, physiotherapist, pain management team, dietician, social worker and general practitioner to ensure complete resolution of symptoms.

Learning points.

• Postdengue chronic fatigue syndrome (CFS) is a challenging diagnosis to the paediatrician and rarely reported in children.

• Children who recover from dengue fever merit follow-up for complete resolution of symptoms.

• All children with CFS following dengue fever need to be carefully reviewed and managed jointly by paediatrician, psychologist, physiotherapist, pain management team, dietician, social worker and general practitioner until complete recovery.

Ethics statements

Patient consent for publication

Parental/guardian consent obtained.