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  • v.2020; 2020

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A Curious Case of Dengue Fever: A Case Report of Unorthodox Manifestations

Raja shakeel mushtaque.

1 Jinnah Post Graduate Medical Center, Karachi, Pakistan

Syed Masroor Ahmad

Rabia mushtaque.

2 National Institute of Cardiovascular Diseases, Karachi, Pakistan

Shahbano Baloch

Dengue is the major cause of arthropod-borne viral disease in the world. It presents with high fever, headache, rash, myalgia, and arthralgia and it is a self-limiting illness. Severe dengue can occur in some cases resulting in dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). We present a case of a 32-year-old male patient of high-grade fever, bilateral subconjunctival hemorrhages, swelling on hands and lips, and nasal bleeding. After investigations, he was diagnosed with dengue fever and it was observed that he developed systemic fungal infection secondary to Candida tropicalis infection. The patient's bone marrow biopsy showed hemophagocytic activity. He also developed hepatitis E infection while hepatitis A, B, or C serology profile showed no active infection. The bilateral iliopsoas hematoma was also observed on CT scan manifested by decreased power in bilateral lower limbs and pain in the right leg. The patient was treated in the hospital with antibiotics (ceftriaxone 2 g once daily for 14 days) and antifungal (fluconazole 200 mg per oral initially for one day then 100 mg daily for 13 days) medicines, and his condition improved on discharge. There is evidence of variable presentations of dengue fever after the disease burden is increased, and thus, diagnosing with such manifestations can be very challenging.

1. Background

Dengue is the foremost cause of arthropod-borne viral disease in the world and due to severe muscle aches. It is transmitted through Aedes mosquito and commonly found in tropical and subtropical parts of the world. The incidence of dengue has substantially increased over the past few decades [ 1 ]. It was estimated in a study that 3.9 billion people are at risk of infection with dengue viruses in the world and Asia is the most affected part [ 2 ]. A seasonal pattern of dengue linked to climate. In Pakistan, the highest dengue cases are reported during July-September due to more rainfall, optimum temperature, and humid environment which are ideal for breeding of Aedes mosquitoes [ 3 ]. Last year, the outbreak was first reported on 8 July 2019 in Peshawar city. A total of 47,120 confirmed cases of dengue fever, including 75 deaths, were reported during the outbreak period in the entire country [ 4 ].

Dengue fever is caused by one of the four distinct serotypes (DENV 1-4) of single-stranded RNA Flavivirus genus [ 5 ]. Infection caused by one serotype results in lifelong immunity to that serotype, but not to others. Dengue fever (DF) presents with high fever, headache, rash, myalgia, and arthralgia, and case fatality is less than 1%. Severe dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) are accompanied by thrombocytopenia, vascular leakage, and hypotension [ 5 ]. DSS is characterized by systemic shock, which can be fatal with case fatality high as 12% to 44% [ 6 ].

There are few atypical manifestations of dengue fever growing with rising disease burden, often missed and sometimes difficult to comprehend the case collectively. In this case report, we will discuss atypical manifestations observed in dengue fever patients.

A 32-year-old male patient, married, with no previous comorbidities presented through the emergency room with complaints of fever for 8 days, bilateral subconjunctival hemorrhages, and swelling of hands and lips for 3 days and 1 episode of nasal bleed one day back. Fever was high grade, continuous, and associated with rigors/chills and generalized body ache. The patient developed bilateral conjunctival hemorrhages that were all of sudden, not associated with any trauma. The patient also had swelling on both hands and lips, which progressed over the 3 days. He also had one episode of nasal bleeding that was all of sudden and 1-2 teaspoons in quantity. He also had a tingling sensation in both lower limbs and difficulty in walking. He denied any history of bleeding from other parts of the body or any vomiting. He denied any previous hospitalization or any drug intake or any substance abuse. Her family came from a middle‐class background, he was sexually active with his wife, and he denied any chronic illness in his family.

3. Examination

A middle-aged male patient, ill-looking but oriented with time, place, and person. His vitals at the time of examination were blood pressure of 110/80 mmHg and pulse of 82/min regular, and the respiratory rate was 20/min. He was febrile (101°F), anemic, and jaundiced, while his hands and legs were mildly edematous, and lips were mildly swollen up and bilateral subconjunctival hemorrhage was noted. His abdomen was soft, slightly tender over the right hypochondrium, and mildly distended, and the liver was enlarged 3 cm below the right costal margin, firm, and nonnodular. On auscultation of the chest, there was normal vesicular breath sounds bilaterally except decreased breath sounds over the right base. The examination of the cardiovascular system was unremarkable.

On neurological examination, his GCS was 15/15, there were no signs of meningeal irritation, pupils were 3 mm bilaterally equally reactive to light and accommodation, and cranial nerves were intact. On motor examination, muscle bulk and tone were normal. Power in the lower limb was reduced, but normal in the upper limbs. Medical Research Council (MRC) grade in the right lower extremity was hip flexion 3/5 and extension 3/5, hip abduction 4/5 and adduction 4/5, and leg flexion 3/5 and extension 3/5 and dorsiflexion and plantar-flexion 5/5 strength bilaterally. MRC grade in the left lower extremity was hip flexion 4/5 and extension 4/5, hip abduction 5/5 and adduction 5/5, and leg flexion 4/5 and extension 4/5 and dorsiflexion and plantar-flexion 5/5 strength bilaterally. Additionally, there was a pain in the distribution of dermatome L2, L3, and L4 on the right lower limb. Deep tendon reflexes on the right lower cannot be performed due to pain, although they were normal and 2+ on the left side, and planters were bilaterally downgoing. The sensation was intact throughout, and the cerebellar examination was normal.

4. Differential Diagnosis

As this patient presented with high-grade fever, subconjunctival hemorrhage, nasal bleeding, and hepatosplenomegaly, a provisional diagnosis of viral hemorrhagic fever was made. The other differentials included malaria, viral hepatitis, and leptospirosis.

5. Investigation

Baseline laboratory investigations are shown in Table 1 , and hepatitis virology and autoimmune work are given in Table 2 . Serum dengue NS-1 antigen was positive while the MP-ICT was negative. Peripheral smear of CBC showed a leukoerythroblastic picture. Platelet clumps were observed, and anisocytosis, poikilocytosis, polychromasia, macrocytes, nucleated RBC, myelocytes, and metamyelocytes were seen.

Baseline laboratory investigations.

Hb: hemoglobin; MCV: mean corpuscular volume; TLC: total leukocyte count; GGT: gamma-glutamyltransferase; ALT: alanine transaminase; ALP: alkaline phosphatase; INR: international normalization ratio; APTT: activated partial thromboplastin time; LDH: lactate dehydrogenase; ESR: erythrocyte sedimentation rate.

Hepatitis virology and autoimmune workup.

IgM: immunoglobulin M; IgG: immunoglobulin G; HBsAg: hepatitis B surface antigen; ANA: antinuclear antibodies.

Urine analysis was suggestive of urinary tract infection (nitrate 1+, leukocytes: 40–50/HPF, RBC: 20–25/HPF, epithelial cells: ++/HPF, and casts: nil), but no organism grew on culture studies. The blood culture grew Candida tropicalis , which was sensitive to fluconazole and voriconazole. His bone marrow biopsy report showed preserved trilineage hematopoiesis along with the hemophagocytic activity. Leptospirosis serology was unremarkable.

Computed tomography (CT) scan of the chest and abdomen revealed bilateral pleural effusions with adjacent patchy consolidations and hepatosplenomegaly along with moderate ascites was noted. Diffuse thickening of bilateral iliopsoas muscles was also noted with areas of internal necrosis and ill-defined heterogeneous enhancement. His ultrasound Doppler of both legs was unremarkable except mild soft-tissue edema.

7. Treatment and Follow-Up

The patient was started on intravenous antibiotics (ceftriaxone 2 g once daily for 14 days) and antifungal (fluconazole 200 mg per oral initially for one day then 100 mg daily for 13 days). He was symptomatically managed with intravenous fluids (0.9% normal saline), antipyretics (paracetamol), and antiemetics (inj. gravinate[dimenhydrinate]). He improved with the treatment. He was discharged home after three weeks. At the time of discharge, his fever was subsided, bilateral hand and feet swelling subsided, and subconjunctival hemorrhage resolved, but he still complained of pain during walking and lower limb weakness. On the first clinic follow-up visit, his leg pain and weakness improved.

8. Discussion

This patient's complete blood picture showed increased total leukocyte count (TLC): 25.2 (neutrophils 40% and lymphocytes 57%), and later, the blood culture was positive for Candida tropicalis . The phenomenon of bacteremia in dengue has been identified and can occur simultaneously with various organisms like Streptococcus pneumoniae , E. coli , Salmonella species, Shigella sonnei , Klebsiella species, Enterococcus faecalis , Moraxella lacunata , Staphylococcus aureus , Haemophilus influenzae , Candida tropicalis , Mycobacterium tuberculosis , Mycoplasma , or Herpesviruses [ 7 ]. Candida tropicalis normally inhabit the skin and intestinal tract. There is evidence of intestinal mucosal injury in patients with dengue infection. Therefore, the vulnerability of intestinal mucosa due to dengue virus infection may lead to the transfer of organisms into the bloodstream [ 8 ].

The peripheral smear of complete blood count of this patient showed the leukoerythroblastic picture, and bone marrow biopsy showed preserved trilineage hematopoiesis along with the hemophagocytic activity. Hemophagocytic lymphohistiocytosis (HLH) (also known as “hemophagocytic syndrome”) is a hyperinflammatory condition characterized by sustained activation of the mononuclear phagocytic system that may result in a severe hyperinflammatory response. Epstein–Barr virus (EBV-HLH) is a recognized cause of acquired HLH [ 9 ], but it has also been reported as a complication of dengue. In a retrospective study carried out in Malaysia, adult patients with severe dengue showed HLH in twenty-one patients of 180 (12%) [ 10 ]. In another study, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died [ 11 ]. HLH was not found to be associated with a particular type of dengue virus. These patients had a longer duration of fever and were more likely to have anemia, hepatomegaly, and elevated liver transaminases than controls.

In this case report, there was no active infection of hepatitis A or B or C infection, but the patient had acute hepatitis E infection as shown by hepatitis virology and autoimmune workup in Table 2 . The presenting signs and symptoms were overlapping between viral hepatitis and dengue fever, and thus, it could be hard to challenging diagnosis in an endemic area. In one study, it was found that women were infected with dengue virus and hepatitis E virus simultaneously [ 12 ]. Another study was conducted in India found that a young man was infected with dengue, HEV, and Leptospira at the same time [ 13 ]. In epidemic regions, a physician should be vigilant for identifying such coinfections.

Our patient had decreased hip flexion and extension, hip abduction and adduction, and leg flexion and extension on the right leg, while on the left side, hip flexion and extension and leg flexion and extension were affected. There was also the pain in the distribution of dermatome L2, L3, and L4 on the right lower limb. On CT scan, there was diffuse thickening of the bilateral psoas muscle and iliacus muscles noted with areas of internal necrosis and ill-defined heterogeneous enhancement noted, pointing towards bilateral iliopsoas hematoma. Iliopsoas hematomas have also been associated with compressive femoral neuropathy due to the long course of the femoral nerve. Iliopsoas hematoma is usually caused by trauma in patients on anticoagulation/antiplatelet therapy or in those with hemophilia [ 14 ]. In 1939, Tallroth first ever explained the occurrence of spontaneous hemorrhage in the iliopsoas muscle followed by an injury to the femoral nerve in a hemophilia patient. Muscle hematomas are a rare complication of dengue fever. Only a few cases have been reported in the literature of spontaneous muscle hematomas in DHF reported by Ammer et al. [ 15 ], Ganeshwaran et al. [ 16 ], Ganu and Mehta [ 17 ], Koshy et al. [ 18 ], and Kumar et al. [ 19 ]. The hematoma could have resulted from thrombocytopenia and deranged international normalization ratio (INR), thus resulting in hemorrhage.

9. Learning Points

  • Bacteremia or systemic fungal infections can occur in dengue fever. Thus, it should be looked at with high suspicion to avoid morbidity and mortality.
  • Hemophagocytic lymphohistiocytosis (HLH) can occur in dengue fever and can cause high mortality.
  • Coinfection of dengue fever can occur with hepatitis E and cause overlapping symptoms which can cause a challenging situation for a physician to diagnose.
  • Dengue fever can present with bilateral iliopsoas muscle hematoma with femoral nerve palsy. This phenomenon was only reported a few times.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

  • Case report
  • Open access
  • Published: 18 December 2018

Series of 10 dengue fever cases with unusual presentations and complications in Sri Lanka: a single centre experience in 2016

  • S. A. M. Kularatne 1 ,
  • Udaya Ralapanawa   ORCID: orcid.org/0000-0002-7416-7984 1 ,
  • Chamara Dalugama 1 ,
  • Jayanika Jayasinghe 1 ,
  • Sawandika Rupasinghe 1 &
  • Prabashini Kumarihamy 2  

BMC Infectious Diseases volume  18 , Article number:  674 ( 2018 ) Cite this article

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Dengue has global importance as a dreaded arboviral infection. It has 4 serotypes of epidemiological imporatnce. The classification denotes two clinical spectrums- dengue fever (DF) and dengue haemorragic fever (DHF). Most cases are stereotype and amenable to fluid resuscitation. However, unusual manifestations cause fatalities and often overlooked. This study describes 10 such dengue cases to fill the knowledge gaps.

Case presentation

All 10 patients presented to the Teaching Hospital, Peradeniya, Sri Lanka during mid-year epidemic of dengue in 2016. The mean age is 27 years (range 12-51 years) comprising 6 females and 4 males. The group had 7 DHF, 3 DF and 2 primary dengue infections who predominantly had severe bleeding into gut. Other potentially life threatening problems were acute severe hepatitis, severe septic shock, myocarditis, erratic rapid plasma leak, intracranial bleeding, diarrhoea and decompenstaed dengue shock due to 3rd space fluid leak. Blood transfusions and other empirical therapeutic methods were used apart from meticulous fluid management to suit issues of each patient. Bedside ultrasound scanning helped early detection of critical phase. All recovered fully.

Conclusions

Dengue is an extremely challenging infection to treat in the globe today. Above unusual presentation and complications could be fatal, if not detected early where therapeutic window period is very short. Clinicians need awareness of these problems which are not uncommon, but underreported and often overlooked. The clinical management of each patient was described for the purpose sharing the experiences.

Peer Review reports

Dengue is the most common arboviral infection in the Southeast Asia. Dengue virus has four related but antigenically distinct serotypes: DENV-1, DENV-2, DENV-3, and DENV-4 [ 1 ]. The global burden of dengue has increased in recent decades causing huge impact on both human health and the national economics [ 1 , 2 , 3 ] . Dengue infection has a diverse clinical presentation ranging from asymptomatic subclinical infection to severe multi-organ involvement [ 3 ]. Although, vascular plasma leak is the commonest manifestation, dengue can manifest in multitude of unusual presentations due to organ dysfunction that can carry high mortality [ 2 , 3 ]. Early detection of such manifestations and prompt action could avert the adverse outcome where clinicians need knowledge and experience. Aim of this case series is to present 10 such unusual dengue cases managed in a single hospital over 1 year period. These patients presented to Teaching Hospital, Peradeniya (THP), Sri Lanka in 2016 and recovered fully following problem based tailored management.

Case 1: (erratic rapid plasma leak during early critical phase)

A 22-year-old female admitted to THP with a one-day history of fever proceeded by frontal headache of 3 days. On admission, she had arthralgia, myalgia, mild postural dizziness and nausea. She has passed urine normal amount. She was hemodynamically stable with a blood pressure of 96/64 mmHg without a postural drop. Abdomen was soft and non-tender. Clinically, she did not have evidence of plasma leak. Her blood test was positive for dengue NS1 antigen. On 3rd day of fever, ultra sound scan of abdomen detected thin rim of free fluid in the hepato-renal pouch and moderate gall bladder wall oedema with mild pericholycystic fluid. She did not have pleural effusion or ascites. Neither she had postural drop of blood pressure, tachycardia or right hypochondrial tenderness. However, her haematocrit has risen from 33 to 38%. In a flash, within the next 6 h, she developed significant ascites (moderate) and bilateral moderate pleural effusions with a reduction of urine output. She had fluctuation of urine output and blood pressure and required several normal saline boluses and Dextran-40 along with frusemide to maintain vital parameters. Sixty percent of her calculated fluid quota was utilized in the 1st 12 h of tentative critical phase. Her clinical status gradually improved within the next 3 days. But, there was delayed resolution of effusion and ascites. Her serum albumin level dropped during the critical phase and took days reverse. Her recovery was uneventful and discharged on day 6 of the hospital stay. She had erratic rapid leaking of plasma into serous cavities during critical phase.

Case 2: (severe hepatitis with increased transaminases and gross ascites after critical phase)

A previously healthy 39-year-old female, admitted to the THP with a history of fever for 4 days. She had nausea, vomiting, arthralgia, myalgia and headache. She did not have any bleeding manifestations or abdominal pain. On examination, she had mild dehydration with low volume pulse. Blood pressure was 100/80 mmHg in supine position and 90/80 mmHg on standing. Right lung base was stony dull on percussion and had absent breath sounds. Ultrasound scan revealed a right sided plural effusion with free fluid in the abdomen. The patient was managed as critical phase of dengue haemorrhagic fever (DHF) with meticulous titration of fluids according to the haematocrit values. She remained hemodynamically stable with a stable haematocrit values during the critical phase. On day 7 of illness, dengue serology showed positive IgM and IgG titers. After completion of critical phase on 7th day of the illness, she complained of abdominal pain and back pain. Clinical examination found s mild icterus and tense ascites. Laboratory investigations revealed a marked rise in liver enzyme levels (ALT 204 to 1391 u/L and AST 505 to 4519 u/L) with an INR of 1.9. Diagnosis of acute hepatitis leading into acute liver failure was made and viral hepatitis was excluded by doing hepatitis A IgM, hepatitis B surface antigen and hepatitis C IgM which were negative. She denied self-medication with high doses of paracetamol. Further, she was treated with intravenous N acetyl cysteine 150 mg/hour infusion as an empirical treatment. Her low albumin level was corrected with intravenous human albumin administration. Antibiotics including oral metronidazole and intravenous ceftriaxone was administered at the same time to cover bacterial infections. She was given intravenous vitamin K for 3 days to prevent clotting factor depletion whilst monitoring liver transaminases and clotting parameters. Finally she was discharged on 12th day of the illness with near normal liver transaminases and normal clotting profile without residual free fluids in her abdomen. Further follow of after 21 days revealed completely normal liver biochemistry.

Case 3: (DEN 2, intracranial Haemorrhage in DHF)

A19- year-old male, previously healthy university student admitted to THP having a febrile illness with arthralgia and myalgia for 5 days duration. On the way to the hospital, the patient had postural dizziness and fainting attack causing impact on the forehead. Soon after admission, he developed a generalized tonic-clonic seizure which lasted for 5 min with post ictal drowsiness. On examination, he was not pale but had conjunctival hemorrhages. He had a contusion over the forehead due to fall. He was hemodynamically stable with a blood pressure of 126/90 mmHg and a pulse rate of 92 beats per minute without clinical evidence of plasma leaking. Ultrasound scan revealed a thin rim of free fluid in the abdomen. Dengue NS 1 antigen and Dengue Ig M and IgG both were positive. Serotype of dengue was identified as DEN 2. Diagnosis of DHF entering into critical phase was made and commenced intense monitoring with administration of intravenous and oral fluid according to guidelines, Meanwhile, the patient was found to be drowsy but arousable without having any lateralizing neurological deficits. Both optic fundi were normal. Non-contrast CT brain revealed bilateral frontal lobe hyperdense areas with mild cerebral oedema with minimal midline shift, suggestive of intra-cranial hemorrhages. His clotting parameters were within the normal limits. He was transfused with platelets to keep the platelet count more than 50 × 10 6 /L and managed conservatively with adequate intravenous fluids, intravenous antibiotics and antiepileptic drugs. He was started on intravenous phenytoin sodium and later converted to oral phenytoin. Cerebral oedema was managed with intravenous dexamethasone and intravenous mannitol. He was administered with intravenous tranexamic acid to retard further bleeding. Critical phase was uneventful. His headache and drowsiness improved over the next 5 days and discharged with oral antiepileptics.

Case 4: (DEN 1 causing myocarditis and DHF together)

A-17-year-old previously healthy female presented to THP with a history of fever for 2 days associated with body aches and nausea. She didn’t have any abdominal pain, bleeding manifestations or postural symptoms. On examination, she was flushed and febrile but was not pale or icteric. She was mildly dehydrated. Blood pressure was 100/70 mmHg, pulse rate 100 beats/min and capillary refilling time (CRFT) was less than 2 s. On abdominal examination, there was no free fluid. Lung fields were clear on respiratory system examination. Other systems examination was normal.

Her NS1 antigen was positive and serotype was identified as DEN1. She was managed as dengue fever with continuous monitoring. On the 3rd day of fever, she complained of retrosternal chest pain and undue tiredness. At that time her cardiovascular system examination was normal and electrocardiogram (ECG) showed acute T wave inversion in V2-V5 leads. Troponin I was negative and 2D echo showed global left ventricular hypokinesia and mild impairment of LV function. Ejection fraction was 40–45%. She was treated as having dengue fever complicated by myocarditis. Intravenous hydrocortisone 200 mg 8 hourly was administered for 2 days to reduce myocardial inflammation. On the 4rd day following admission, she complained of abdominal pain and ultrasound scanning revealed free fluid in hepato-renal pouch. Blood pressure was 100/70 mmHg, pulse rate 70 bpm, and CRFT was less than 2 s. She was taken to High Dependency Unit (HDU) and was managed as having DHF complicated with myocarditis with continuous monitoring and with careful administration of fluid to avoid fluid overload. She was discharged on day 7 of illness after recovering from critical phase of dengue fever. She was advised on limiting physical activities. During the follow up on day 14 of the illness, ECG showed reversal of T inversions. Echocardiogram showed improvement of left ventricular function with an ejection fraction of 55%.

Case 5: (acute GI bleeding and hepatitis in DF)

A-22-year old previously healthy male admitted to THP with a history of on and off fever for 10 days associated with 3 bouts of hematemesis and melaena. On examination, his pulse rate was 88 beats/m, blood pressure was 90/60 mmHg and CRFT was less than 2 s and lungs were normal. Abdomen was soft and there was no detectable free fluid. Rest of the examination was unremakable. Serology for dengue IgM and IgG were positive on admission. His liver enzymes were high on admission (AST 840 U/L and ALT 560 U/L) with a high INR value of 2.1. His complete blood count showed 11.5 g/dl of haemoglobin and platelet count of 144 × 10 9 /l. Ultrasound examination of abdomen did not show any evidence of leaking thus, DHF was excluded. Hence, the patient was managed as in primary dengue fever with bleeding manifestations. Intravenous fluids were given along with tranexamic acid and vitamin K to reduce bleeding. Intravenous infusion of omeprazole was continued for 24 h and converted to twice day intravenous boluses. He was started in intravenous N acetyl cysteine infusion as liver transaminases were high. His symptoms resolved within the next few days, with symptomatic management.

Case 6: (DEN 2 primary infection and bleeding into GIT and GUT)

A-12-year old previously well female child was transferred to THP from a private hospital due to fever for 5 days associated with melena, haematemesis and haematuria with passage of blood clots. She did not have abdominal pain or any other warning signs of dengue on admission.

On examination, she was ill looking, adequately hydrated and GCS was 15/15. Blood pressure was 125/75 mmHg, pulse rate was 90 beats per minute and capillary refilling time was less than 2 s. On respiratory examination lungs were clear and on abdominal examination the abdomen was soft and non tender. Rest of the clinical examination was normal. Both NS1 and IgM were positive and dengue PCR revealed serotype of DEN 2. Ultrasound examination of abdomen did not show any evidence of plasma leaking. She was managed as having primary dengue fever with bleeding manifestations. Her liver enzymes were only mildly elevated (AST 87 u/L and ALT 56 u/L) with a normal clotting profile. Complete blood count revealed hemoglobin of 7 g/dl and platelet count of 17 × 10 9 /μL. Due to low haemoglobin, she was transfused with 1 pint of blood and 4 units of platelets. Her symptoms resolved within the next few days.

Case 7: (DEN 2, severe diarrhoea, DHF, profound shock, sepsis and occult bleeding, need of massive transfusion)

A 14-year-old boy presented to THP with a history of fever for 2 days along with headache, arthralgia and myalgia. He did not complain of abdominal pain and did not have bleeding manifestations or any other warning symptoms. On examination, blood pressure was 110/70 mmHg and pulse rate was 100 beat per minute and capillary refilling time was less than 2 s. The abdomen was soft and non-tender and there was no free fluid. Lung fields were clear on respiratory system examination. Rest of the examination was normal. His NS-1 was positive and the PCR appeared as DEN 2 serotype. The patient was managed as having dengue fever. He continued to have fever spikes for 4 days following admission. On the 5th day following admission, he developed postural dizziness, vomiting and heavy diarrhoea. On examination, he was febrile, dehydrated, flushed and had warm peripheries. Blood pressure was 90/60 mmHg, pulse rate was 130 beats per minute and a capillary refilling time of 2 s. Ultrasound examination of abdomen revealed free fluid in the hepato-renal pouch with increased gall bladder wall thickness. He was clinically diagnosed as having DHF complicated with septic shock and gastroenteritis. He was taken to HDU and critical phase monitoring commenced. His c-reactive protein was high 112 mg/dl. Broad-spectrum intravenous antibiotics (ceftriaxone and metronidazole) were started cover the sepsis after taking blood and urine cultures. Within about 1 h, the patient deteriorated significantly and continued to have vomiting and diarrhoea. Blood pressure dropped to 60/30 mmHg and the pulse rate increased to 120 beats/min. Several fluid boluses were given including normal saline and IV Dextran 40. The haematocrit value dropped from 36 to 30 and patient went into decompensated shock with no urine output. He needed continuous transfusion of whole blood amounting to 9 pints over 20 h to maintain blood pressure and urine output. However, there were no obvious bleeding sites. Further, intravenous noradrenaline infusion supported the blood pressure. Gradually patient improved with fluid, blood, antibiotics and vasopressors. He was given intravenous antibiotics for total of 7 days. Vasopressor was gradually weaned off. He was plethoric during convalescence due to over transfusion and was discharged on day 8 of admission.

Case 8 (presenting as dysentery and in compensated shock in DHF)

A previously well 36-year-old Buddhist monk presented to THP with a history of a febrile illness with generalized malaise for 4 days duration. His main complaint was vomiting and diarrhea of same duration. He did not have any postural symptoms, bleeding manifestations or abdominal pain at presentation. On examination, he was febrile and was not pale or icteric. Blood pressure was 120/100 mmHg with a pulse rate of 110 beats per minute and capillary refilling time of 2 s. On respiratory system examination, there was bilateral plural effusion and on examination of the abdomen there was shifting dullness. Other systems examination was normal. Ultrasound examination of abdomen revealed moderate amount of free fluid in the abdomen. Blood and urine were taken for investigations. His NS 1 antigen was positive, and serotype was identified as DEN 2. The patient was immediately taken to HDU and was managed as compensated shock of dengue hemorrhagic fever. Initial investigations revealed a platelet count of 15 × 10 9 /l, and haematocrit of 57%. With meticulous fluid management he recovered. Thus, this patient had clinical picture of dysentery associated with DHF presenting at the peak of critical phase.

Case 9: (occult leaking of plasma leading to undetected decompensated shock)

A 51-one-year-old previously healthy female admitted with a history a febrile illness with arthralgia and myalgia for 4 days. Her NS1 antigen was positive on admission. She was ill and complained of postural dizziness and abdominal pain. On examination, she was ill looking, dehydrated and had bluish cold peripheries. She had central cyanosis and collapsed superficial veins. Her supine blood pressure was recorded as 90/80 mmHg and standing blood pressure was unable to measure due to severe postural symptoms. Capillary refilling time was prolonged, and her respiratory rate was 24 breaths per minute. Lungs were clear and clinically there was no evidence of free fluid in abdomen and pleura. She did not pass urine for 12 h. She was clinically diagnosed to have dengue haemorrhagic fever with decompensated shock. Then she was admitted to the HDU and critical phase management was started. Ultrasound scan of the abdomen did not show free fluid in peritoneal cavity despite patient was possibly in the peak of plasma leaking. However, 12 h after admission, repeat ultrasound scan showed thin rim of free fluid in the hepatorenal pouch. She was resuscitated with boluses of crystalloids and colloids., She became hemodynamically stable gradually and took about 8 h to gain warm peripheries. Fluid management and monitoring was continued, and her symptoms improved within the next 2 days. Although she went in to decompensated shock due to DHF, she had minimum detectable amount free fluid in the abdomen in the later phase of leaking.

Case 10: (DF complicating severe septic shock)

A 34-year-old female presented with a febrile illness with arthralgia and myalgia for 2 days duration. Her Dengue NS1 was positive. Her hemodynamic parameters were stable on admission. She was having continuous fever on day 6 of illness. There was no evidence of hemoconcentration or plasma leak and managed as uncomplicated dengue fever. She was kept on intravenous saline infusion at a slower rate. On 6th day of fever she developed cough and shortness of breath. Auscultation of lungs heard crepitations in bases. Over next 6 h she was not improving despite continuous infusion of normal saline and commencing antibiotics. Later, she became agitated and restless and was confused. She had warm peripheries despite blood pressure of 80/40 mmHg which further dropped to 60/30 mmHg. She had pulse rate of 108 beats/ min. There were widespread coarse crackles in the both lung fields involving all 3 zones. Her oxygen saturation dropped to 85% on room air. Her haematocrit remained within normal range. To counter the shock, she was given more intravenous normal saline, Dextran 40 and 2 units of blood transfusion. Then, she developed pulmonary oedema and required CPAP in the intensive care unit with high flow oxygen and intravenous frusemide. Patient was treated with intravenous meropenum 1 g 8 hourly and metronidazole. She had very high CRP and procalcitonin levels suggestive of severe sepsis. After 6 h of resuscitation her blood pressure got stabilized and she recovered completely over next 5 days. She was diagnosed as dengue fever complicated by septic shock probably originating from lungs even though, dengue shock syndrome (DSS) was contemplated at the outset.

Discussion and conclusion

Our case series compiles summaries of 10 confirmed dengue cases with wide array of unusual manifestation which are potentially fatal, in a single centre (THP) in the central hills of Sri Lanka. All these patients presented during mid-year outbreak of dengue in 2016 when serotype transition occurring from DEN 1 to DEN 2 that finally led to a massive outbreak of DEN 2 in 2017 in Sri Lanka. In these cases, females (n,6) out number males (n,4) and 7 patient had DHF. Out of 3 patients who had DF, 2 developed severe GI bleeding while other one developed severe septic shock that was mistaken for dengue shock syndrome (DSS) initially. Other unusual manifestations highlighted are hepatic dysfunction, myocarditis, erratic plama leak, ICH, occult blood loss, decompensated shock etc. Early detection of these manifestation and taking appropriate clinical decisions such as blood transfusions, antibiotics, and other empirical treatments saved all lives.

Most such manifestations of dengue infection are underreported, under recognized or not casually linked to dengue fever. Therefore, vigilance and anticipation are needed in managing dengue beyond the most common stable type of plasma leak in DHF.

Common life threatening complications related to DF and DHF include hepatic dysfunction leading to acute fulminant hepatic failure [ 3 ], musculoskeletal complications such as myositis and rhabdomyolysis [ 4 ], acute renal failure [ 5 ], cardiac complications such as myocarditis [ 6 ], life threatening bleeding such as gastrointestinal and intracranial bleeding [ 7 ], endocrine complications such as precipitating diabetic ketoacidosis [ 8 ] and neurological complications such as Guillain Barre syndrome and encephalopathy [ 9 ]. Early identification and early approach for appropriate management strategies are important to reduce morbidity and mortality of such cases. Better understanding of the disease dynamics has improved the outcome over time but still timely diagnosis and management is a challenge.

This case series comprises primary dengue infection, dengue fever (DF) and dengue hemorrhagic fever (DHF) all associated with unusual manifestaions. Importantly some life-threatening complications were observed in both primary dengue infection and DF without leaking. Patients in cases 1,2,3,4,7,8 and 9 developed DHF whereas patients in cases 5, 6 and 10 had DF. Some presented with bleeding manifestations while the others developed complications mentioned above.

Dengue can present with a diverse clinical spectrum ranging from asymptomatic infection or simple undifferentiated fever to DHF with multiorgan failure. Pathological hallmark of dengue hemorrhagic fever is increased capillary permeability with extravasation of fluids during the critical phase of dengue fever [ 3 , 10 ]. The onset of critical phase is determined by clinically or radiologically demonstrable pleura effusion or ascites and/or evidence of hemoconcentration as shown by increased haematocrit in serial measurements [ 3 , 11 ]. The critical phase lasts for a period of 24–48 h in which rate of plasma leak gradually peaks and comes down to the baseline. But this typical pattern is not appreciated all the time. Case 1 describes a young erratic leaker. His plasma leak peaked within 1st 12 h of critical phase evidenced by rapidly rising haematocrit and rapidly developing pleural effusions and ascites necessitating use of more than 60% of fluid quota within first 12 h. This type erratic leaker needs to be identified early with frequent monitoring of clinical parameters and haematocrit and fluid need to be titrated accordingly. The same patient had obvious fluid leak into peritoneal cavity and pleural spaces with hypoalbunaemia and took time for reabsorption. Case 9 describes a female who presented with decompensated shock. She had evidence of hemoconcentration with a high haematocrit. But on presentation clinically and ultrasonically she had no objective evidence of plasma leak into serous cavities. This highlights that although plasma leak is describes as selective to pleural, pericardial and peritoneal cavities, there can be substantial amount of fluid leaking in to 3rd space of unknown sites. Absence of objective fluid leak should not delay the treating physician making a diagnosis of DHF in the presence of evidence of intravascular volume depletion and hemoconcentration. However, frequent use of ultrasound examination has enhanced early detection of plasma leak. In THP, ultrasound scanners are available in the wards where dengue patients are treated to do bedside scaning without mobilizing patients to scanning rooms.

Liver dysfunction is a well-recognized feature in both dengue fever and DHF. Patients with dengue fever complaining of abdominal pain, nausea, vomiting and anorexia should alert the physician of the possibility of liver involvement [ 12 ]. Aetio-pathogenesis in liver dysfunction in dengue fever is yet to be elucidated. Direct effects of the virus or host immune response on liver cells, circulatory compromise, metabolic acidosis and/or hypoxia caused by hypotension or localized vascular leakage inside the liver are possible mechanisms postulated to explain the liver dysfunction [ 13 , 14 ]. Case 2 describes patient with DHF developing acute liver failure and case 5 describes a patient with DF without leaking developing liver dysfunction, coagulopathy and gastrointestinal bleeding. Both cases were successfully managed with adequately maintaining the hydration status and intravenous N acetyl cysteine. NAC scavenges free radicals, improves antioxidant defense and acts as a vasodilator to improve oxygen delivery and consumption [ 15 ]. However, efficacy of NAC needs to be validated with further studies.

Bleeding manifestations are seen both in dengue fever and dengue hemorrhagic fever. Despite the name, cardinal feature that differentiate dengue fever from DHF is not hemorrhage but leaking. The underlying mechanisms responsible for bleeding in dengue infections remain poorly understood. Thrombocytopenia is universal in DHF and most of the patients with DF [ 16 ]. Platelet functions is abnormal in acute dengue fever mainly due to impaired ADP mediated platelet aggregation [ 17 ].Isarangkura et al. reported that platelet survival is less in acute dengue fever [ 18 ]. Mild prolongation of prothrombin time and activated partial thromboplastin times with reduction in fibrinogen levels were reported in some studies in patients without liver involvement [ 19 , 20 ]. Patients with prolonged shock with multi-organ dysfunction and those with acute liver failure had major gastrointestinal bleeds contributed by deranged clotting and gut ischemia. Case 5 describes a patient with DF without leaking who had normal platelets with severe liver involvement leading to coagulopathy and gastrointestinal bleeding. In contrast in case 6, a primary DF patient developed severe gastrointestinal bleeding needing blood and platelet transfusions. Her liver enzymes were marginally elevated and had a normal clotting profile. Her main risk factor for a gastrointestinal bleed, haematuria was low platelet count.

Intracranial hemorrhage in dengue fever is a rare but a grave complication. Mechanism of intracranial bleeding is still not clearly described, it is postulated that it could be due to the interplay between coagulopathy, platelet dysfunction, thrombocytopenia, and vasculopathy [ 21 , 22 ]. In our patient described in case 3 presented in the peak of leaking with postural symptoms. On admission, his platelet count was16 × 10 9 /μl. He had history of a fall with head impact and soon after admission patient sustained a generalized tonic clonic fit. Later he was found to have bilateral frontal lobe hemorrhages. This could be either traumatic following the fall or could be spontaneous which might have caused the fall. Management of an ICH in a dengue patient is controversial as the causative factors such as vasculopathy and platelet dysfunction are usually still present and irreversible while surgery is undertaken. No studies have been performed on place for surgery for ICH in dengue fever. Low platelets are the main risk factor for an ICH in dengue fever. There is no consensus on when to transfuse platelets and place for primary prophylaxis. Some studies have recommended prophylaxis platelet transfusions when the platelet count is very low [ 23 , 24 ]. In 2011, Kurukularatne et al. strongly concluded that prophylactic platelet transfusion is associated with hazards and wastage without any hematological benefit and therefore, should not be adopted as a routine clinical practice [ 25 ]. Our patient received platelet transfusion as a secondary prophylactic measure as the platelet count was very low.

Dengue fever and DHF are associated with a wide spectrum cardiac complication. Kularatne et al. showed that 62.5% of 120 adults with dengue fever had an abnormal electrocardiogram [ 26 ]. Most cardiac complications are clinically mild and self-limiting, therefore, they are under diagnosed [ 27 ]. Myocardial involvement in dengue is yet to be fully described, but it can be due to direct viral invasion of the myocardium or cytokine mediated immune injury [ 28 ]. In case 4, young patient had evidence of myocarditis in ECG and left ventricular global hypokinesia in the 2D Echo. She was managed conservatively with meticulous fluid management and with a short course of steroids. Theoretically, steroids help to reduce inflammation of myocardium, thus improving contractility. Her follow up Echo in 2 weeks showed normalization of left ventricular systolic function.

Clinically considerable proportion of dengue patients who presented to the hospital can have bacterial co-infection [ 29 ]. Bacterial co-infection can be easily overlooked in the dengue epidemic setting. Delay in diagnosis and delay in anti-microbial therapy will have adverse outcome. Bacteremia in dengue fever is mainly Gram negative. It is probably caused by the breakdown of the intestinal mucosal barrier in severe dengue infection. In Case 7, the patient had DHF complicated with septic shock. The focus of sepsis is probably the gut, as he had diarrhoea and sepsis developed during leaking phase and gut ischemia probable led to breach in mucosal defense and gram-negative sepsis. Low blood pressure in tachycardia could have been easily overlooked attributing to dengue shock syndrome, but the disproportionately high pulse rate and warm peripheries in the background of shock alerted the treating physician of the possible underlying sepsis. Prompt use of antibiotics and judicious use of vasopressors were lifesaving. It is intriguing that he needed massive transfusions to maintain his blood pressure and save the life. This case provide empirical evidence for blood transfusion sever dengue infection Moreover, Case 10 describes a patient developed dengue fever and septic shock probably originating from the lung. Patient was treated with blood transfusion and intravenous crystalloids and colloids to overcome the shock which resulted in pulmonary edema. Judicious use of vasopressors is important in such instance to prevent volume overload. Supportive respiratory care over many hours maintained the oxygenation. The Case 8 describe presentation of dengue predominantly with diarrhea that might mislead the clinician as bacillary dysentery.

Lessons learnt from managing difficult cases of dengue as we presented here need sharing. Similar cases or situations may be happening at any given time in the globe as dengue is mostly seen everywhere. These clinical observations needs explanation on pathophysiological basis, but the knowledge about pathology and pathophysiology in dengue needs further improvement. Better treatment options are needed to improve the outcome of dengue.

Abbreviations

Adenine di-Phosphate

Alanine transaminase

Aspartate transaminase

Continuous Positive Airway Pressure

Capillary Refilling Time

Dengue virus serotype 1

Dengue Haemorrhagic Fever

Full Blood Count

High Dependency Unit

Intra Cranial Haemorrhage

N-Acetyl Cysteine

Polymerase chain reaction

Packed Cell Volume

Teaching Hospital Peradeniya

Halstead SB. Dengue. CurrOpin Infect Dis. 2002;15(5):471–6.

Article   Google Scholar  

Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med. 2005;353:924–32.

Article   CAS   Google Scholar  

Kularatne SAM. Dengue fever. BMJ. 2015;351:h4661. https://doi.org/10.1136/BMJ.h4661 .

Article   PubMed   Google Scholar  

Dalugama C, Ralapanawa U, Jayalath T. Dengue myositis and review of literature. Clin Case Rep Res Trials. 2017;2:16–8.

Google Scholar  

Lizarraga KJ, Nayer A. Dengue-associated kidney disease. J Nephropathol. 2014;3(2):57–62 http://doi.org/10.12860/jnp.2014.13.

PubMed   Google Scholar  

Wali JP, Biswas A, Chandra S, Malhotra A, Aggarwal P, Handa R, Wig N, Bahl VK. Cardiac involvement in dengue haemorrhagic fever. Int J Cardiol. 1998;64(1):31–6.

Kumar R, Prakash O, Sharma BS. Intracranial hemorrhage in dengue fever: management and outcome: a series of 5 cases and review of literature. Surg Neurol. 2009;72(4):429–33.

Dalugama C, Gawarammana IB. Dengue hemorrhagic fever complicated with transient diabetic ketoacidosis: a case report. J Med Case Rep. 2017;11(1):302.

Ralapanawa DM, Kularatne SA, Jayalath WA. Guillain-Barre syndrome following dengue fever and literature review. BMC Res Notes. 2015;8:729. https://doi.org/10.1186/s13104-015-1672-0 .

Article   PubMed   PubMed Central   Google Scholar  

Stephenson JR. Understanding dengue pathogenesis: implications for vaccine design. Bull World Health Organ. 2005;83:308–14.

PubMed   PubMed Central   Google Scholar  

Guidelines on Management of Dengue Fever and Hemorrhagic Fever in adults: Epidemiology Unit, Ministry of Health; 2012. http://www.epid.gov.lk/web/images/pdf/Publication/guidelines_for_the_management_of_df_and_dhf_in_adults.pdf

Karoli R, Fatima J, Siddiqi Z, Kazmi KI, Sultania AR. Clinical profile of dengue infection at a teaching Hospital in North India. J Infect Dev Ctries. 2012;6:551–4.

Itha S, Kashyap R, Krishnani N, Saraswat VA, Choudhuri G, Aggarwal R. Profile of liver involvement in dengue virus infection. Natl Med J India. 2005;18:127–30.

Kularatne SAM, Imbulpitiya IVB, Abeysekera RA, Waduge R, Rajapakse RPVJ, Weerakoon KGAD. Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. BMC Infect Dis. 2014;14:141.

Sklar GE, Subramaniam M. Acetylcysteine treatment for non-acetaminopheninduced acute liver failure. Ann Pharmacother. 2004;498–500(23):38.

World Health Organization. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd edi ed. Geneva: WHO; 1997. http://www.who.int/csr/resources/publications/dengue/Denguepublication/en/

Srichaikul TA, Nimmannitya SU, Sripaisarn T, Kamolsilpa MA, Pulgate CH. Platelet function during the acute phase of dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 1989;20(1):19–25.

CAS   PubMed   Google Scholar  

Isarangkura P, Tuchinda S. The behavior of transfused platelets in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 1993;24:222–4.

Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg. 1977;26(5):975–84.

Funahara Y, Shirahata A, Setiabudy-dharma RA. DHF characterized by acute type DIC with increased vascular permeability. Southeast Asian J Trop Med Public Health. 1987;18(3):346–50.

Cam BV, Fonsmark L, Hue NB, Phuong NT, Poulsen A, Heegaard ED. Prospective case-control study of encephalopathy in children with dengue hemorrhagic fever. Am J Trop Med Hyg. 2001;65:848–51.

Puccioni-Sohler M, Soares CN, Papaiz-Alvarenga R, Castro MJ, Faria LC, Peralta JM. Neurologic dengue manifestations associated with intrathecal specific immune response. Neurology. 2009;73:1413–7.

Makroo RN, Raina V, Kumar P, Kanth RK. Role of platelet transfusion in the management of dengue patients in a tertiary care hospital. Asian J Transfus Sci. 2007;1:4–7.

Dutta AK, Biswas A, Baruah K, Dhariwal AC. National guidelines for diagnosis and management of dengue fever/dengue haemorrhagic fever and dengue shock syndrome. J Indian Med Assoc. 2011;109:30–5.

Kurukularatne C, Dimatatac F, Teo DL, Lye DC, Leo YS. When less is more: can we abandon prophylactic platelet transfusion in dengue fever? Ann Acad Med Singap. 2011;40:539–45.

Kularatne SAM, Pathirage MMK, Kumarasiri PVR, Gunasena S, Mahindawanse SI. Cardiac complications of a dengue fever outbreak in Sri Lanka, 2005. Trans R Soc Trop Med Hyg. 2007;101(8):804–8.

Satarasinghe RL, Arultnithy K, Amerasena NL, Bulugahapitiya U, Sahayam DV. Asymptomatic myocardial involvement in acute dengue virus infection in a cohort of adult Sri Lankans admitted to a tertiary referral Centre. Br J Cardiol. 2007;14:171–3.

Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, Imbert P, Pecarere JL, Vergez-Pascal R, Watter P, Maniez-Montreuil M. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg. 1993;48(3):324–31.

See KC, Phua J, Yip HS, Yeo LL, Lim TK. Identification of concurrent bacterial infection in adult patients with Dengue. Am J Trop Med Hyg. 2013;89(4):804–10 http://doi.org/10.4269/ajtmh.13-0197.

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S. A. M. Kularatne, Udaya Ralapanawa, Chamara Dalugama, Jayanika Jayasinghe & Sawandika Rupasinghe

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Kularatne, S.A.M., Ralapanawa, U., Dalugama, C. et al. Series of 10 dengue fever cases with unusual presentations and complications in Sri Lanka: a single centre experience in 2016. BMC Infect Dis 18 , 674 (2018). https://doi.org/10.1186/s12879-018-3596-5

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  • Expanded dengue syndrome
  • Fulminant liver failure
  • Myocarditis
  • Septic shock
  • Dengue shock syndrome

BMC Infectious Diseases

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case study of dengue fever

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Dengue hemorrhagic fever presenting as encephalitis: a case report

  • W S Weerasinghe   ORCID: orcid.org/0000-0002-0041-2350 1 &
  • Arjuna Medagama 2  

Journal of Medical Case Reports volume  13 , Article number:  278 ( 2019 ) Cite this article

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Dengue fever and dengue hemorrhagic fever incidence is increasing in Sri Lanka, especially among the young population. Uncommon presentations of this common illness make diagnostic dilemmas and can delay standard treatment which leads to unfavorable outcomes.

Case presentation

An 18-year-old Sri Lankan Sinhalese boy presented with a history of 1 day of fever and an episode of seizure followed by left-side hemiparesis. He was diagnosed to have dengue complicated by dengue hemorrhagic fever and recovered with minimal residual weakness. He presented with neurological symptoms; cerebrospinal fluid analysis, electroencephalogram, and magnetic resonance imaging showed evidence of encephalitis. Positive dengue antigen and antibody in serum and cerebrospinal fluid with the exclusion of other possible etiologies confirmed parainfectious dengue encephalitis. He was started on sodium valproate 200 mg 8 hourly and made a slow neurological recovery with mild residual weakness (grade 4+ power) in his left upper limb at 2 months with intensive supervised physiotherapy.

Standard national guideline-based management of dengue illness has significantly reduced its mortality rates in Sri Lanka. However, uncommon presentations of a common illness often cause diagnostic dilemmas. Hence, reporting of these presentations and knowing the epidemiologic patterns of the disease help physicians to arrive at the correct diagnosis even though they do not have sophisticated serological investigations. Overall, this can improve the quality of health care and reduce mortalities, especially in a resource-poor setup.

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Dengue fever (DF) is a leading cause of morbidity in Sri Lanka and 185,688 suspected cases of dengue were reported to the Epidemiology Unit, Ministry of Health from all over the island during 2017 [ 1 ]. Approximately 41% of dengue cases were reported from the Western Province of Sri Lanka.

The first serologically confirmed case of dengue was reported in 1962 and the first documented dengue outbreak occurred in 1965–1966 [ 2 ]. DF and dengue hemorrhagic fever (DHF) comprise the bulk of symptomatic illness while dengue encephalitis is a rare entity (around 4 to 21%) [ 3 ].

We report the case of a previously well 18-year-old Sri Lankan Sinhalese boy, resident of a dengue endemic area, who presented with a 1-day history of high fever and tonic-clonic movements of the left upper and lower limbs later converting into a generalized tonic-clonic (GTC) seizure to the Teaching Hospital Peradeniya, Sri Lanka. The fever was high grade without chills but associated with arthralgia, myalgia, headache, and vomiting. The seizures commenced on the evening of the first day of the illness, lasted for 10 minutes and were associated with postictal drowsiness. A persistent left-sided face, arm, and leg weakness was apparent as the postictal drowsiness improved. There were no associated sensory symptoms and the weakness was more pronounced in his face and upper limb. There was no associated abdominal pain, postural dizziness, reduced urine output, or any bleeding tendency. There was no recent history of vaccination and no skin rashes. He had been investigated following a head injury 10 months back. He presented after a road traffic accident with mild drowsiness without any focal neurological weakness and a non-contrast computed tomography (NCCT) scan of his brain had been normal. He was completely well on discharge and no long-term neurological symptoms were evident until this incident. His past medical history was unremarkable with no history of epilepsy or collagen vascular diseases.

A general examination revealed a temperature of 38.33 ºC (101 ºF) but was otherwise unremarkable. A neurologic examination revealed our patient to be drowsy but arousable, without signs of meningism. A conscious level corresponding to Glasgow Coma Scale (GCS) of 10/15 (E-4, V-1, M-5) was present with horizontal gaze palsy to the left, and normally reactive pupils of 3 mm. A cranial nerve examination revealed facial nerve palsy of upper motor neuron type on the left with flaccid paralysis of his left upper limb (power 0/5) and diminished left lower limb (power 2/5) power. Deep tendon reflexes were diminished on the left with hypotonia. Plantar response was extensor on the left side. No cerebellar signs were apparent.

His vital signs were stable with a pulse rate of 100 beats per minute (bpm) and blood pressure of 107/70 mmHg. No right hypochondriac tenderness or murmurs were present, and the rest of the examination was unremarkable.

Initial investigations are summarized in Table  1 . An urgent NCCT of his brain revealed no evidence of infarction or intracerebral hemorrhage (ICH). An interval NCCT and contrast-enhanced computed tomography (CECT) scan was also performed and did not show any infarction, cerebral abscess, or space-occupying lesion. We performed a lumbar puncture (LP) and cerebrospinal fluid (CSF) was colorless and clear: total white blood cell (WBC), 03 cells/mm 3 (lymphocytes); red blood cell (RBC), 00 cells/mm 3 ; CSF protein, 250 mg/L; CSF sugar, 3.4 mmol/l; random blood sugar (RBS), 5.7 mmol/l; CSF Gram stain and bacterial cultures were negative. CSF viral studies were not performed due to the small volume of CSF being available at the first LP and a repeat attempt was not made in the context of dropping platelet (PLT) counts.

Electroencephalography (EEG) performed on the following day showed generalized slow waves with a burst of activity in the right frontotemporal region compatible with organic brain disease (Fig.  1 ).

figure 1

An electroencephalograph showing generalized slow waves with burst of activity in right frontotemporal region

A magnetic resonance imaging (MRI) of his brain was performed which showed abnormal high intensity subcortical white matter and cortical gray matter in right frontoparietal and temporal lobes in T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) images with some faint meningeal enhancement appreciated in right frontotemporal area suggestive of right-sided meningoencephalitis (Fig.  2 ).

figure 2

Magnetic resonance (fluid-attenuated inversion recovery) images with some faint meningeal enhancement appreciated in right frontotemporal area

A presumptive diagnosis of viral encephalitis was made, and he was started on intravenously administered acyclovir 500 mg 8 hourly and intravenously administered ceftriaxone 2 g 12 hourly with intravenously administered dexamethasone 4 mg 8 hourly and sodium valproate 200 mg 8 hourly. Supportive care with nasogastric feeding, urine catheterization, and intravenously administered fluids was also started, and he was continuously monitored within the high dependency unit to identify clinical or biochemical deterioration.

On the fifth day of illness, fever was still present, neurological signs remained unchanged, and rising liver transaminases were noted, that is, aspartate aminotransferase (AST) of 4918 U/L and alanine aminotransferase (ALT) of 2987 U/L, together with leukopenia and thrombocytopenia (WBC, 3770 cells/μl; PLT, 23,000 cells/μl). A peripheral blood film was found to be compatible with a viral infection without features of microangiopathic hemolytic anemia (MAHA).

The marked rise in transaminases together with leukopenia and thrombocytopenia prompted a fresh search for an alternative diagnosis and serum dengue nonstructural protein 1 (NS1) [ 4 ] antigen was performed which was positive. Testing CSF for dengue Immunoglobulin M (IgM) with enzyme-linked immunosorbent assay (ELISA) antibody and NS1 antigen was not possible at this moment as the initial CSF sample was inadequate. The viral studies performed considering the possible neurotrophic viruses in the serum on the seventh day of the illness and varicella-specific IgM, cytomegalovirus (CMV) IgM, and Epstein–Barr virus (EBV) IgM (ELISA method) were negative. Serum antibody testing for enterovirus and coxsackievirus was not feasible in the government sector and our patient could not afford to take the test from the private sector.

National guidelines [ 5 ]-directed dengue monitoring and management were commenced. On day 5 of the illness a rising pack cell volume (PCV), with ultrasonographic evidence of free fluid in the hepatorenal pouch and gallbladder wall edema corresponding to plasma leakage of dengue critical phase, was found. Table  2 demonstrates the laboratory results during the hours spent in the critical phase. He made a full recovery from dengue critical phase 48 hours after confirming DHF. Serum dengue IgM was positive on day 7 of the illness but IgG was negative.

He made a slow recovery with mild residual weakness (grade 4+ power) in his left upper limb at 2 months with intensive supervised physiotherapy.

Considering his slow recovery, a CSF analysis was repeated at 2 months and showed total WBC, 04 cells/mm 3 (lymphocytes); RBC, 00 cells/mm 3 ; CSF protein, 540 mg/L; CSF sugar, 3.4 mmol/L; RBS, 5.7 mmol/L; adenosine deaminase (ADA), 3.0 U/L; CSF Gram stain and bacterial cultures were negative. Dengue IgG (ELISA) was positive in CSF and IgM (ELISA) was negative. Since full virologic profile was not performed in the first presentation, CSF was also tested for other neurotrophic viruses such as herpes simplex virus (HSV) by polymerase chain reaction (PCR), HSV-1 and HSV-2 antibodies, Japanese encephalitis (JE) antibody, enterovirus, and coxsackievirus. All the CSF studies and serum for human immunodeficiency virus (HIV) screening were negative. A repeat EEG was also performed, and it was normal (Fig.  3 ).

figure 3

Normal electroencephalograph

He had been followed up at our medical clinic since discharge, where a gradual improvement in his weakness was evident. After 12 months of follow-up, he showed remarkable recovery of his neurologic functions without any residual weakness.

Discussion and conclusion

Dengue is the commonest arthropod-borne viral infection in humans [ 6 ]. It is caused by a family of positive, single-stranded, enveloped ribonucleic acid (RNA) viruses called Flaviviridae , genus Flavivirus [ 7 ]. There are four closely related but antigenically different serotypes of the virus that can cause dengue (DEN-1, DEN-2, DEN-3, DEN-4). Dengue has a wide spectrum of infection outcomes (asymptomatic to symptomatic). Symptomatic illness can vary from undifferentiated fever (viral syndrome), DF, DHF, and dengue with unusual manifestations such as isolated organopathies [ 5 , 8 ].

Expanded dengue syndrome/isolated organopathy is an entity in which some patients present with unusual manifestations of organ involvement with or without fluid leakage [ 5 ]. Encephalitis and meningoencephalitis have been found in 4–21% of cases of dengue [ 3 ]. This wide variation in the prevalence of encephalitis most likely reflects differences in the populations studied and the use of different criteria to define dengue encephalitis. Distinguishing dengue encephalitis from other types of central nervous system (CNS) involvement is also challenging [ 3 ].

Dengue is classically thought to be a non-neurotropic virus but DEN-2 and DEN-3 are the most frequently involved serotypes in neurotropism [ 9 , 10 , 11 ]. Dengue encephalopathy is a secondary manifestation of the DF frequently associated with multisystem derangement found later in the course of the illness, which is thought to be due to an immune-mediated inflammatory response of the body [ 12 ]. Conversely, encephalitis occurs due to direct invasion of the virus and occurs in the viremic phase of the illness as in this patient. Although it is a rare occurrence, autopsy studies have proved the presence of virus antigen in brain parenchymal cells using immunoperoxidase stain [ 13 ].

There were many reported cases of dengue encephalitis and other neurological manifestations by Kularatne et al. from Sri Lanka [ 14 ], by Misra et al . from India [ 15 ], and Solomon et al . from Vietnam [ 16 ]. All of them had neurological symptoms with signs such as headache, confusion, seizures, hemiparesis, and even coma. Some of them described EEG changes and MRI changes depending on the area of the brain involved.

Bhoi et al. [ 17 ] studied a cohort of 21 patients with dengue encephalitis in a study conducted to evaluate MRI and computed tomography (CT) changes and showed hyperintensities in MRI of brains involving bilateral parietal region, corona radiata, internal capsule, centrum semiovale bilaterally, basal ganglia, and thalamus. Carod-Artal et al. [ 18 ] summarized findings of eight autopsy studies reported on fatal cases of dengue with neurological involvement which showed histopathologic patterns of cerebral edema, congestion, hemorrhage, perivascular lymphocytes infiltration, and even necrosis of the brain matter. There are many case reports and studies found in the literature proving that various parts of the brain can be affected in different ways [ 19 , 20 , 21 ]. MRI of our patient’s brain showed hyperintensities in subcortical white matter and cortical gray matter in right frontoparietal and temporal lobes, and some faint meningeal enhancement in the right frontotemporal area. These lesions are compatible with the clinical signs shown. The interesting fact is that none of them follow a uniform pattern which helps a clinician to suspect dengue by looking at MRI or CT.

Carod-Artal et al. [ 18 ] proposed three criteria to define dengue encephalitis. They are: the clinical signs and symptoms of CNS involvement; demonstration of dengue virus RNA, IgM, or NS1 antigen in CSF; and CSF pleocytosis without other neuroinvasive pathogens. The literature also showed that the presence of dengue antibody in CSF can be considered a piece of firm evidence of CNS invasion, but the practical difficulty in performing a LP in a patient with dengue was also highlighted [ 22 ]. Most of the cases reported in the literature [ 23 ] were based on clinical diagnosis of encephalitis followed by serological confirmation of dengue infection and exclusion of the other neurotropic viruses such as HSV, CMV, EBV, JE, enterovirus, and coxsackievirus [ 24 ]. MRI or CT is nonspecific but often provided valuable clues for further investigations and CSF studies. This fact further highlights the need for more evidence and studies to access the sensitivity and specificity of these investigations to diagnose dengue encephalitis.

A wide variety of symptoms are documented in the literature as the initial presentation of dengue. Sometimes it is very difficult to suspect dengue encephalitis by history, examination, and initial investigations, as in this patient. This kind of atypical presentation of DF can lead to diagnostic delays and adverse patient outcomes.

This case report emphasizes the importance of considering dengue as a differential diagnosis in a patient with features of encephalitis especially in a background of dengue epidemic and endemicity, as it changes the monitoring and management. Dengue NS1 antigen is an affordable investigation in developing countries like Sri Lanka and is sometimes available in the government sector. A combination of clinical signs and other basic investigations like WBC, PLT, PCV, and liver enzymes will provide clues to diagnosis and the proper monitoring of the patient to prevent the life-threatening complication of dengue illness in an atypical presentation like this. Another important fact is that although we have national guidelines to manage DF, we must individualize the plan of management for this kind of patient.

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Abbreviations

Adenosine deaminase

Alanine aminotransferase

Aspartate aminotransferase

Beats per minute

Contrast-enhanced computed tomography

Cytomegalovirus

Central nervous system

Cerebrospinal fluid

Computed tomography

Dengue fever

  • Dengue hemorrhagic fever

Epstein–Barr virus

Electroencephalography

Enzyme-linked immunosorbent assay

Fluid-attenuated inversion recovery

Glasgow Coma Scale

Generalized tonic-clonic

Human immunodeficiency virus

Herpes simplex virus

Intracerebral hemorrhage

Japanese encephalitis

Lumbar puncture

Microangiopathic hemolytic anemia

Magnetic resonance imaging

Non-contrast computed tomography

Nonstructural protein 1

Polymerase chain reaction

Pack cell volume

Red blood cell

Random blood sugar

T2-weighted

White blood cell

Epidemiology Unit, Ministry of Health, Sri Lanka, Dengue update. http://www.epid.gov.lk/web/attachments/article/146/Fact_Sheet_WH_Dengue_UPDATED.pdf . Accessed 16 Jan 2018.

Vitarana T, Jayakuru WS, Withane N. Historical Account of Dengue Haemorrhagic Fever in Sri Lanka. WHO/SEARO Dengue Bull. 1997;21:117–8.

Google Scholar  

Domingues RB, Kuster GW. Diagnosis and Management Neurologic Manifestations Associated with Acute Dengue Virus Infection. J Neuroinfectious Dis. 2014;5(1):1–5.

Solanke V, Karmarkar M, Mehta P. Early dengue diagnosis: Role of rapid NS1 antigen, NS1 early ELISA, and PCR assay. Trop J Med Res. 2015;18(2):95.

Article   Google Scholar  

Epidemiology Unit, Ministry of Health, Sri Lanka, Publications, Guidelines on Management of DF / DHF in Adults. http://www.epid.gov.lk/web/images/pdf/Publication/guidelines_for_the_management_of_df_and_dhf_in_adults.pdf . Accessed 11 June 2018.

Kumar, Clark. In: Kumar P, Clark M, editors. Kumar and Clark’s Clinical Medicine, 8th Edition. Oxford: Saunders Ltd; 2012. p. 106–7.

Centers for Disease Control and Prevention, Viral Hemorrhagic Fevers, Flaviviridae . https://www.cdc.gov/vhf/virus-families/flaviviridae.html . Accessed 5 Feb 2018.

Dalugama C, Shelton J, Ekanayake M, Gawarammana IB. Dengue fever complicated with Guillain-Barré syndrome: A case report and review of the literature. J Med Case Rep. 2018;12(1):12–5.

Soares C, Puccioni-Sohler M. Dengue encephalitis: Suggestion for case definition. J Neurol Sci. 2011;306(1–2):165.

Lum LC, Lam SK, Choy YS, George R, Harun F. Dengue encephalitis: a true entity? Am J Trop Med Hyg. 1996;54(3):256–9.

Article   CAS   Google Scholar  

Dhenni R, Karyanti MR, Putri ND, Yohan B, Yudhaputri FA, Ma’roef CN, et al. Isolation and complete genome analysis of neurotropic dengue virus serotype 3 from the cerebrospinal fluid of an encephalitis patient. PLoS Negl Trop Dis. 2018;12(1):e0006198.

Herath HMM, Hewavithana JS, De Silva CM, Kularathna OAR, Weerasinghe NP. Cerebral vasculitis and lateral rectus palsy - two rare central nervous system complications of dengue fever: two case reports and review of the literature. J Med Case Rep. 2018;12(1):1–6.

Nogueira RMR, Filippis AMB, Coelho JMO, Sequeira PC, Schatzmayr HG, Paiva FG, et al. Dengue virus infection of the central nervous system (CNS): a case report from Brazil. Southeast Asian J Trop Med Public Health. 2002;33(1):68–71.

CAS   PubMed   Google Scholar  

Kularatne SAM, Pathirage MMK, Gunasena S. A case series of dengue fever with altered consciousness and electroencephalogram changes in Sri Lanka. Trans R Soc Trop Med Hyg. 2008;102(10):1053–4.

Misra UK, Kalita J, Syam UK, Dhole TN. Neurological manifestations of dengue virus infection. J Neurol Sci. 2006;244(1–2):117–22.

Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LTT, Raengsakulrach B, et al. Neurological manifestations of dengue infection. Lancet. 2000;355(9209):1053–9.

Bhoi SK, Naik S, Kumar S, Phadke RV, Kalita J, Misra UK. Cranial imaging findings in dengue virus infection. J Neurol Sci. 2014;342(1–2):36–41.

Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. Lancet Neurol. 2013;12(9):906–19.

Kalita J, Misra UK. EEG in dengue virus infection with neurological manifestations: A clinical and CT/MRI correlation. Clin Neurophysiol. 2006;117(10):2252–6.

Hegde V, Aziz Z, Kumar S, Bhat M, Prasad C, Gupta AK, et al. Dengue encephalitis with predominant cerebellar involvement: Report of eight cases with MR and CT imaging features. Eur Radiol. 2015;25(3):719–25.

Li G-H, Ning Z-J, Liu Y-M, Li X-H. Neurological Manifestations of Dengue Infection. Front Cell Infect Microbiol. 2017;7:449.

Chen WJ, Hwang KP, Fang AH. Detection of IgM antibodies from cerebrospinal fluid and sera of dengue fever patients. Southeast Asian J Trop Med Public Health. 1991;22(4):659–63.

Withana M, Rodrigo C, Chang T, Karunanayake P, Rajapakse S. Dengue fever presenting with acute cerebellitis: A case report. BMC Res Notes. 2014;7(1):1–3.

Meyer HM, Johnson RT, Crawford IP, Dascomb HE, Rogers NG. Central nervous system syndromes of “viral” etiology. Am J Med. 1960;29(2):334–47.

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Weerasinghe, W., Medagama, A. Dengue hemorrhagic fever presenting as encephalitis: a case report. J Med Case Reports 13 , 278 (2019). https://doi.org/10.1186/s13256-019-2201-x

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case study of dengue fever

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Clinical predictors of severe dengue: a systematic review and meta-analysis

  • Tsheten Tsheten   ORCID: orcid.org/0000-0002-8071-5721 1 , 2 ,
  • Archie C. A. Clements 3 , 4 ,
  • Darren J. Gray 1 ,
  • Ripon K. Adhikary 1 ,
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  • Kinley Wangdi 1   na1  

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Severe dengue is a life-threatening complication; rapid identification of these cases, followed by adequate management is crucial to improve the clinical prognosis. Therefore, this study aimed to identify risk factors and predictors of severe dengue.

A literature search for studies reporting risk factors of severe dengue among individuals with dengue virus infection was conducted in PubMed, Scopus and Web of Science database from inception to December 31, 2020. Pooled odds ratios ( ORs ) for patients’ demographic characteristics, co-morbidities, and warning signs were estimated using an inverse variance heterogeneity model.

We included 143 articles in the meta-analysis from a total of 13 090 articles retrieved from the literature search. The risk factors of severe dengue were: being a child [ OR  = 1.96; 95% confidence interval ( CI ): 1.22–3.13], secondary infection ( OR  = 3.23; 95% CI : 2.28–4.57), and patients with pre-existing diabetes ( OR  = 2.88; 95% CI : 1.72–4.81) and renal disease ( OR  = 4.54; 95% CI : 1.55–13.31). Warning signs strongly associated with severe disease were increased haematocrit with a concurrent decrease in platelet count ( OR  = 5.13; 95% CI : 1.61–16.34), abdominal pain ( OR  = 2.00; 95% CI : 1.49–2.68), lethargy ( OR  = 2.73; 95% CI : 1.05–7.10), vomiting ( OR  = 1.80; 95% CI : 1.43–2.26), hepatomegaly ( OR  = 5.92; 95% CI : 3.29–10.66), ascites ( OR  = 6.30; 95% CI : 3.75–10.60), pleural effusion ( OR  = 5.72; 95% CI : 3.24–10.10) and melena ( OR  = 4.05; 95% CI : 1.64–10.00).

Conclusions

Our meta-analysis identified children, secondary infection, diabetes and renal disease(s) as important predictors of severe dengue. Our finding also supports the predictive ability of the WHO warning signs to identify severe dengue. These findings are useful for clinicians to identify severe dengue for management and timely interventions.

case study of dengue fever

In 2010, it was estimated that there were 390 million dengue infections, of which 96 million manifested clinically [ 1 ] with severe dengue resulting in 21 000 deaths worldwide [ 2 ]. Asia bears 70% of this global burden [ 1 ]. The incidence of dengue has surged dramatically with an eightfold increase over the last two decades, from 505 430 cases in 2000 to over 2.4 million in 2010, and 4.2 million in 2019 [ 3 ]. The increase in dengue incidence has been associated with explosive outbreaks and geographical expansion to new areas [ 3 ].

Dengue is an arboviral infection caused by a dengue virus (DENV) belonging to the Flaviviridae family. Four antigenically and genetically distinct DENV serotypes (DENV1–4) have been described to co-circulate around the world and cause human infections [ 4 ]. The infection leads to a wide spectrum of clinical manifestations from asymptomatic infection to life threatening severe dengue or dengue shock syndrome (DSS) [ 1 ]. In many Asian countries, severe dengue is the leading cause of hospitalization among children and the case fatality rate (CFR) is about 5% on average [ 5 ].

There is no specific treatment and the dengue vaccine [CYD-TDV (Dengvaxia ® )] is licensed only in 20 countries [ 6 ]. The vaccine is not yet approved for younger children due to low efficacy and safety reasons [ 7 ]. In a randomized controlled, multicentre, phase III trial, the efficacy of CYD-TDV was reported at ~ 56% against virologically confirmed dengue among children in countries in the Asia–Pacific region [ 8 ]. Only adults aged 9–45 years living in an area of ≥ 70% dengue prevalence, and whose serostatus is positive for past dengue infection are recommended for immunization [ 6 ]. Due to the challenges associated with the need to collect information on the burden and seroprevalence profiles of the local population, and the recent reports of vaccine-related severe dengue and deaths, the use of the dengue vaccines is not widespread [ 9 ]. Therefore, rapid identification of severe cases and appropriate clinical management remains the mainstay to avoid dengue-related case fatalities. This includes monitoring for plasma leakage and initiating intravenous fluid replacement to prevent shock and death [ 10 ]. A rational approach of case management through proper understanding of the determinants of severe dengue is key to improving clinical outcomes [ 11 ].

This systematic review and meta-analysis aimed to identify predictors of severe dengue. Such knowledge will be useful to clinicians for targeting at-risk groups of severe dengue for initiating prompt interventions to save lives.

Search strategy

The methods and results of the systematic review and meta-analysis are reported in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Additional file 1 ) [ 12 ]. No protocol was registered for this systematic review and meta-analysis.

Three databases, PubMed, Scopus and Web of Science, were searched from inception to December 31, 2020, for relevant articles. Key search terms were “dengue”, “dengue haemorrhagic fever”, “dengue shock syndrome” or “severe dengue”. The detailed search strategy is provided in Additional file 2 . In addition, a backward citation search using the reference lists of relevant studies were reviewed for additional studies that may not have been captured using the search terms.

Eligibility criteria

This review was undertaken to identify predictors of severe dengue based on the patient’s demographic characteristics, comorbidities, and presentation of warning signs; therefore, the inclusion criteria were: (1) observational studies (cross-sectional, case control, or cohort study designs) conducted in humans; (2) which compared severe dengue and non-severe dengue cases; and (3) reported patients’ demographic characteristics (i.e., age, sex, ethnicity, socio-economic class, region/location, and primary or secondary dengue infection), co-morbidities [i.e., asthma, chronic obstructive pulmonary disease (COPD), visual impairment, cardiovascular diseases (CVD), diabetes, obesity and overweight, hearing loss, cancer, oral health, alcohol use disorder, and haemoglobin disorders like thalassemia and sickle cell disease], and/or clinical warning signs [i.e., abdominal pain, vomiting, enlarged liver size, pleural effusion, ascites, gum bleeding, epistaxis, lethargy, melena, increase in haematocrit with concurrent decrease in platelet count, gastrointestinal (GI) bleeding, hematemesis and skin bleeding]. Exclusion criteria included: (1) case reports, case series, reviews, or letters; (2) in vitro and animal studies; (3) conference presentations; and (4) studies where patient outcomes were not separated into severe and non-severe dengue.

The classification of the severity of dengue of the selected studies was done either with the World Health Organization (WHO) 1997 or the revised WHO 2009 dengue case classification. The WHO 1997 dengue case classification categorized dengue into dengue fever (DF), dengue haemorrhagic fever (DHF) (i.e., grade I & II) and dengue shock syndrome (DSS) (i.e., grade III & IV) [ 5 ]. While the WHO 2009 dengue case classification categorized dengue into dengue without warning signs (DWoWS), dengue with warning signs (DWWS), and severe dengue (SD) [ 10 ]. In this review, we defined severe dengue as DSS according to the WHO 1997 dengue case classification and SD according to WHO 2009 dengue case classification. A detailed description of the WHO 1997 and 2009 dengue case classification along with the case definition of severe dengue used in this study are presented in Table 1 .

Selection of studies and data extraction

All retrieved articles from the three databases (PubMed, Scopus and Web of Science) were imported into EndNote X7.7.1 (Clarivate Analytics, Philadelphia, PA, USA) and duplicates were removed. Then studies were screened by title and abstract in Rayyan ( http://rayyan.qcri.org/ ). Using Rayyan, articles selected by title and abstract also underwent full text screening for the final selection. The screening process was conducted by two independent reviewers (TT and RKA) and any discrepancies during the selection of studies were resolved through discussion and consensus following independent evaluation by another author (KW).

The same two reviewers (TT and RKA) extracted the data of the eligible articles. Differences in the extracted data were resolved by consensus between the reviewers. The following information was extracted: name of the first author, WHO dengue case classification type (guideline 1997 or 2009), country name, recruitment time, study design/size, study population (children, adults or mixed), median/mean age, infection type (primary or secondary), warning signs (i.e., abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleed, lethargy, liver enlargement, and increase in haematocrit with a concurrent decrease in platelets), co-morbidities (i.e., asthma, COPD, CVD, hypertension, diabetes, obesity, cancer, sickle cell disease), and the severity of disease (severe and non-severe dengue). When available, adjusted estimates were extracted, otherwise unadjusted estimates were calculated.

Quality assessment

The quality of the studies was assessed using the MethodologicAl STandards for Epidemiological Research (MASTER) scale [ 13 ]. This scale has 36 bias safeguards that were categorized into seven methodological standards or equivalence [ 13 ]. These standards reflect initial and ongoing equivalence in equal recruitment, equal retention, equal ascertainment, equal implementation, equal prognosis, sufficient analysis and temporal precedence. The studies were rated as ‘1” or “0” depending on the presence or absence of each of these safeguard items. Safeguards not relevant to the studies were rated “0”. Similar to the screening and data extraction process, two independent reviewers (TT & RKA) conducted the assessment and any discrepancies were resolved by the consensus and involvement of another author (KW).

Data analysis

The pooled odds ratios ( OR s) with 95% confidence intervals ( CI ) comparing severe and non-severe dengue for each predictor was estimated using the inverse variance heterogeneity (IVhet) model [ 14 ]. Heterogeneity between studies was assessed using the Cochran Q and the I 2 test statistics. Levels of heterogeneity were categorized according to the I 2 index as low (< 25%), low to moderate (25% to < 50%), moderate to high (50% to < 75%) or high (≥ 75%). The same Cochran Q statistic was used to assess heterogeneity in the sub-group analysis.

Sub-group analyses were conducted to compare the differential effect based on (1) WHO dengue case classification of disease severity (1997 vs 2009), and (2) children and adults to identify risk factors specific to an age group. We defined participants under the age of 20 years as children and as adults otherwise. This classification was based on the definition in the studies, with some studies reporting 19 years as children. Studies reporting only children or adults were excluded from the age predictor analysis. A minimum of four studies per strata was required for sub-group analysis.

For sensitivity analysis, a bias-adjusted (quality-effect model) meta-analysis was performed using the score generated from the MASTER Scale. The scores of all safeguards generated as described above were added and converted into a relative rank between 0 and 1 by dividing the cumulative score of each study by the highest score. We included these quality ranks into the model to estimate bias-adjusted pooled effect sizes as a sensitivity analysis [ 15 ].

The publication bias was assessed using the Doi plot and LFK index bias [ 16 ]. LFK values beyond ± 1 were considered to be indicative of asymmetry and suggest the presence of publication bias [ 16 ]. The analysis was performed in the statistical program Stata 16 (College Station, TX: StataCorp LLC) using metan and lfk modules.

Literature search

A total of 13 090 records were retrieved from the initial search. After removing 3629 duplicates, 9461 records were screened by titles and abstracts. Subsequently, 501 articles were included for full-text review, of which 143 articles remained and were included in the systematic review and meta-analysis (Fig.  1 ). Studies included in this study are presented in Additional file 3 .

figure 1

Screening and selection of studies

Characteristics of the studies

Included studies were reported from the WHO regions as follows: South-East Asia ( n  = 74, 51.8%), Western Pacific ( n  = 34, 23.1%), Americas ( n  = 26, 18.2%), Eastern Mediterranean ( n  = 7, 4.9%), Europe ( n  = 2, 1.4%) and Africa ( n  = 1, 0.7%), respectively. Most of the studies were cross-sectional ( n  = 81, 56.6%) followed by cohort ( n  = 36, 25.2%) and case–control studies ( n  = 26, 18.2%). In 59 studies, only children were included, while 36 studies reported only adults, both children and adults were reported in 47 studies, and one study did not provide information on the age of the participants. Dengue severity was classified using the WHO 2009 dengue case classification in 85 (59.4%) studies, while the rest used the WHO 1997 dengue case classification (Table 2 ).

Socio-demographic predictors including sex, age and primary/secondary infection variables were reported in 114, 87, and 29 studies, respectively. Diabetes was the most reported co-morbidity in 10 studies, followed by hypertension in nine studies, obesity in five studies, and one each of CVD and renal disease in four studies. Other co-morbidities including asthma, pulmonary disease or sickle cell disease were not adequately reported to be analysed further. Finally, warning signs of severe dengue were reported as follows: abdominal pain ( n  = 55 studies), vomiting ( n  = 53 studies), enlarged liver size ( n  = 47 studies), pleural effusion ( n  = 25 studies), ascites ( n  = 22 studies), gum bleeding ( n  = 12 studies), epistaxis ( n  = 11 studies), lethargy ( n  = 10 studies), melena ( n  = 9 studies), increase in haematocrit with concurrent decrease in platelet count ( n  = 7 studies), gastrointestinal (GI) bleeding ( n  = 5 studies), hematemesis ( n  = 5 studies) and skin bleeding ( n  = 4 studies).

Quality of the studies

The quality of the studies was assessed against each of the 36 safeguard items. Accordingly, the studies met all the pre-defined eligibility criteria and were from the same population and timeframe. Similarly, the attrition rate and missing values were either below 20% or non-existent in 143 studies. The procedures for data collection of covariates and outcomes were reliable and objective in 142 studies. Overall, the least deficient standards across studies were equal prognosis (88.6%), equal implementation (64.6%) and equal retention (59.4%). Temporal precedence was the most deficient standard across the studies (1.5%) (Additional file 4 ). This might be because most of the studies included in the review used cross-sectional designs where there is no temporal dimension.

Quantitative analysis

Demographic characteristics.

Children were positively associated with the development of severe disease as compared to adults ( OR  = 1.96, 95% CI : 1.22–3.13). Progression to severe dengue did not show a significant difference by sex ( OR  = 1.20, 95% CI : 0.79–1.82). Secondary dengue infection was found to be significantly associated with the development of severe disease ( OR  = 3.23, 95% CI : 2.28–4.57) (Table 3 ).

Co-morbidities

Diabetes ( OR  = 2.88 95% CI : 1.72–4.81) and renal disease(s) ( OR  = 4.85, 95% CI : 1.08–21.66) were associated with severe dengue. However, other co-morbidities including hypertension ( OR  = 1.82, 95% CI : 0.98–3.37), CVD ( OR  = 2.27, 95% CI : 0.38–13.71), and obesity ( OR  = 0.76, 95% CI : 0.41–1.40) were not significantly associated with the severe disease (Table 3 ).

Warning signs

The definition of warning signs varied across the studies. Only one study defined abdominal pain as severe enough to warrant medical attention [ 17 ]. Persistent vomiting was defined in four ways: vomiting with signs of dehydration [ 18 , 19 , 20 ], ≥ 2 episodes of vomiting associated with fatigue or requiring intravenous fluid [ 17 ], at least six episodes of vomiting in 24 h [ 21 ] or vomiting during ≥ 2 consecutive days [ 22 ]. Similarly, liver enlargement was defined as > 2 cm in the midclavicular line in three studies [ 23 , 24 , 25 ]. No studies provided a definition of lethargy.

Progression to severe dengue was associated with a concurrent increase in haematocrit and decrease in platelet count compared to normal values ( OR  = 5.13, 95% CI : 1.61–16.34), abdominal pain ( OR  = 2.00, 95% CI : 1.49–2.68), lethargy ( OR  = 2.73, 95% CI : 1.05–7.09), vomiting ( OR  = 1.80, 95% CI : 1.43–2.26) and enlarged liver ( OR  = 5.92, 95% CI : 3.29–10.65) (Table 3 ).

Studies have used different definitions for mucosal bleeding and clinical fluid accumulation. Some studies used specific conditions like epistaxis [ 26 , 27 ] or gum bleeding [ 28 , 29 ] to refer to mucosal bleeding, while others have grouped them as mucosal bleeding [ 30 , 31 ]. Similarly, clinical fluid accumulation was defined as ascites [ 24 , 32 ] or pleural effusion or combined as clinical fluid accumulation [ 17 , 33 ]. Here, we presented only specific conditions rather than the grouped variable. In terms of clinical fluid accumulation, both ascites ( OR  = 6.94, 95% CI : 3.75–10.60) and pleural effusion ( OR  = 5.72, 95% CI : 3.24–10.10) were significantly associated with severe dengue. In terms of mucosal bleeding, hematemesis ( OR  = 12.35, 95% CI : 4.97–30.72) was significantly associated, while gum bleeding ( OR  = 2.00, 95% CI : 0.86–4.66) and epistaxis ( OR  = 1.85, 95% CI : 0.72–4.70) were not significantly associated with severe dengue. In addition, GI bleeding ( OR  = 9.49, 95% CI : 2.75–32.70) and melena ( OR  = 4.05, 95% CI : 1.69–10.00) were also found to be positively associated with severe disease (Table 3 ). The forest plots are presented in additional file 5 .

Subgroup analysis

All predictors that were significantly associated in the main analysis also showed similar results in the stratified analysis using the WHO 1997 and 2009 dengue case classifications. These included age groups, secondary infection, abdominal pain, vomiting, enlarged liver size, ascites, pleural effusion, hematemesis and melena. Similar to the main analysis, sex, epistaxis and gum bleeding were not significant in the stratified analysis (Additional file 6 ).

In the subgroup analysis by age, only adult females were significantly associated with severe dengue (relative to adult males, OR  = 2.12, 95% CI : 1.13–3.97) (Additional file 7 ). Due to a limited number of studies, sub-group analysis could not be performed for all predictors in the co-morbidities category, GI bleeding, and increase in haematocrit values with a concurrent decrease in platelet count.

Sensitivity analysis

In the sensitivity analysis, when using the quality effects model, all pooled estimates were found to be consistent with the main analysis (Additional file 8 ).

Publication bias

The Doi plot and LFK index revealed major asymmetries for the estimates of age group (LFK = -3.83), CVD (LFK = 2.92), renal disease(s) (LFK = -3.13), hypertension (LFK = 5.05), vomiting (LFK = 1.94), lethargy (LFK = 3.7), gum bleeding (LFK = 2.04), melena (LFK = 2.4), skin (LFK = 5.47) and GI bleeding (LFK = -2.05). A moderate to high heterogeneity of the studies might have accounted for asymmetries in these estimates (Table 3 and Additional file 9 ).

In this systematic review and meta-analysis, we found that the main predictors for severe dengue were being a child, secondary dengue infection, pre-existing co-morbidities [i.e., diabetes and renal disease(s)] and the presence of warning signs (i.e., increase in haematocrit with concurrent decrease in platelet count, abdominal pain, lethargy, vomiting, hepatomegaly, ascites, pleural effusion and melena). Most of these studies were reported from countries in the WHO-South-East Asia region.

Although there has been a shift in the incidence of DF towards older age groups [ 34 ], severe dengue continues to be an important cause of significant morbidity and mortality in children since it was first reported in the 1950s in South-East Asia [ 35 ]. Previous studies have demonstrated an increased risk of severe dengue or dengue shock syndrome in children and these conditions have been known to be common causes of hospitalization and mortality in tropical regions [ 36 , 37 ]. The risk of severe dengue can be explained by greater vascular permeability in children [ 38 ]. Dengue shock results from a sudden generalized increase in microvascular permeability with less microvascular reserve to accommodate extraneous factors [ 38 ]. Therefore, clinicians should pay special attention to children in recognizing the severity of the disease and providing appropriate interventions on time. Such a strong positive association of severe disease with children also supports the delivery of future vaccines and therapeutics to pre-school and school-going children to achieve the greatest impact on disease burden.

Similar to the other reported studies [ 39 ], we found a strong association between secondary dengue infection and severe dengue. This pathogenesis might be related to antibody-dependent enhancement (ADE) in secondary infection with a different DENV serotype, where the pre-existing heterotypic antibodies bind to form immune complexes with virions without neutralizing it [ 40 ]. These virus-immune complexes facilitate virus entry and enhanced virus replication in the FcγR (fragment crystallizable gamma receptors)-bearing cells, such as monocytes, dendritic cells and macrophages. The internalized DENV particles then initiate an immune cascade which results in the evasion of innate immunity, such as the inhibition of type-1 interferon, and subsequently leads to vascular leakage and severe disease [ 40 , 41 ]. Further, cytokine levels are also assumed to be elevated in secondary dengue infection [ 42 ]. Cytokines like vascular cell adhesion molecule-1 (VCAM-1) facilitate chemotaxis by mediating the adhesion of lymphocytes and cells of the innate immune system to the vascular endothelium [ 43 ]. Other cytokines such as vascular endothelial growth factor-A (VEGF-A) enhance vascular permeability and activate the coagulation system by upregulating the production of tissue factors [ 44 , 45 ]. Finally, biosynthesis of other pro-inflammatory cytokines such as interleukins (IL-6, IL-7, IL-8 and IL-10) facilitates an increased synthesis of DENV RNA (ribonucleic acid) and suppresses the host mediated and adaptive immune responses [ 41 , 46 ]. However, it is important to note that the severity may be affected by certain DENV serotypes; the other meta-analysis study reported severe disease in secondary infection with DENV-2, 3 and 4 [ 39 ]. To provide accurate management of dengue, clinicians should rely on tests that detect both recent and past infections.

Our study also found a significantly higher risk of severe dengue due to pre-existing co-morbidities like diabetes and renal disease. This finding supports the need for hospitalization and monitoring of dengue patients with pre-existing co-morbidities [ 10 ]. Although no clear mechanism was postulated, in diabetes, patients with suboptimal glycaemic control (HbA1c ≥ 7%) were found to be strongly associated with severe dengue than were patients with adequate glycaemic control and without other co-morbidities [ 47 ]. In advanced diabetes, micro and macro-vascular functions are impaired, which might lead to increased plasma leakage and subsequently progress to severe dengue [ 48 , 49 ]. In chronic kidney disease(s), pro-inflammatory cytokines are markedly elevated, which might cause vascular injury in dengue virus infection [ 50 ]. In addition, the uraemia associated with kidney disease induces endothelium dysfunction and contributes to greater vascular damage with dengue infection [ 51 ].

Patients with warning signs have to be admitted into the hospital for close monitoring and intravenous fluid therapy administration [ 10 ]. These interventions can reduce the frequency of patients progressing to severe dengue and deaths. However, none of the studies so far have comprehensively studied all warning signs identified by the WHO. Some studies [ 52 ] used thrombocytopenia and elevated thrombocytopenia separately to assess the risk of developing severe disease. However, these parameters have to be interpreted with other concurrent laboratory results. For example, an increase in haematocrit with a concurrent decrease in platelet count is an important warning sign.

As expected, our study found all warning signs to be positively associated with severe dengue excepting cutaneous and mucosal bleeding (epistaxis and gum bleeding). Notably, gastrointestinal bleeding/melena was significantly associated with severe disease. A previous study on the clinical predictors of severe dengue also found similar findings [ 53 ]. Similar to a previously published study [ 52 ], fluid accumulation, vomiting and abdominal pain was found to be positively associated with the severe disease in this study. In addition, lethargy, abdominal pain, vomiting and hepatomegaly were strongly associated with an increase in haematocrit with a concurrent decrease in platelet count. None of the meta-analyses in the past have pooled this estimate, possibly due to a low number of studies.

The findings of this study should be interpreted in the context of some limitations. We were not able to consider the role of viremia, dengue virus serotypes, genetic, biomarker and other clinical parameters besides warning signs as predictors of severe dengue. Second, we were unable to analyse different co-morbidities such as sickle cell disease and bleeding disorders despite our broad search strategy. These disorders could affect the progression to severe disease and possible outcomes. Third, there was inconsistent reporting of heart diseases which made it difficult to assess these conditions individually as potential predictors, rather we combined different heart conditions into a single group. Fourth, many studies did not report adjusted effect sizes, and we based our pooled result on crude effect sizes. These might have overestimated the pooled effect sizes due to potential confounders. This is of particular concern with smaller studies and therefore our results need to be interpreted with caution. Fifth, limiting papers published in English might have influenced the precision of the pooled estimates. Importantly, most of the studies were from the South-East Asia region and the Pacific region, which bears more than 75% of the global burden of dengue. Sixth, we did not include biomarkers of severe dengue. Finally, we found both heterogeneity and publication bias in the included studies. These might be related to variations in study design, sample sizes, recruitment processes and exposure/outcome measurement across different studies. However, we conducted subgroup analysis and sensitivity analysis to account for these variations and tested the robustness of our results.

Our meta-analysis identified children, secondary infection, diabetes and renal disease(s) as important predictors of severe dengue. We also confirmed the predictive ability of all warning signs of severe dengue identified by the WHO. All warning signs were significantly associated with severe disease excepting mucosal and cutaneous bleeding. The knowledge generated from this study will help clinicians to identify early warning signals of severe dengue leading to timely interventions of dengue cases. Future studies using novel biomarkers and point of care methods including ultrasonography will be useful in predicting the onset of severe dengue.

Availability of data and materials

The datasets used and/or analysed during the current study are included this published article and the additional files, all of which are also available in the public domain.

Abbreviations

Antibody-dependent enhancement

Case fatality rate

Chronic obstructive pulmonary disease

Cardiovascular diseases

Chimeric yellow fever virus—DENV tetravalent dengue vaccine

Dengue virus

Dengue fever

Dengue haemorrhagic fever

Dengue without warning signs

Dengue with warning signs

Dengue shock syndrome DSS

Fragment crystallizable gamma receptors

Gastrointestinal bleeding

Haematocrit

Inverse variance heterogeneity model

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Ribonucleic acid

  • Severe dengue

Vascular cell adhesion molecule-1

World Health Organization

Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, et al. The global distribution and burden of dengue. Nature. 2013;496:504–7.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Thomas SJ, Endy TP. Vaccines for the prevention of dengue: development update. Hum Vaccin. 2011;7:674–84.

Article   CAS   PubMed   Google Scholar  

World Health Organization: Dengue and severe dengue. https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue . Accessed July 07 2021.

Weaver SC, Vasilakis N. Molecular evolution of dengue viruses: contributions of phylogenetics to understanding the history and epidemiology of the preeminent arboviral disease. Infect Genet Evol. 2009;9:523–40.

World Health Organization. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd edition. Geneva 1997.

World Health Organization. Revised SAGE recommendation on use of dengue vaccine. 2018. https://www.who.int/immunization/diseases/dengue/revised_SAGE_recommendations_dengue_vaccines_apr2018/en/ . Accessed July 09 2021.

The Lancet Infectious D: the dengue vaccine dilemma. Lancet Infect Dis. 2018;18:123.

Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, Luong CQ, Rusmil K, Wirawan DN, Nallusamy R, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014;384:1358–65.

Tsheten T, Gray DJ, Clements ACA, Wangdi K. Epidemiology and challenges of dengue surveillance in the WHO South-East Asia Region. Trans R Soc Trop Med Hyg. 2021;115:583–99.

Article   PubMed   Google Scholar  

World Health Organization: Dengue guidelines for diagnosis, treatment, prevention and control: New Edition. World Health Organization: Geneva. In . ; 2009.

World Health Organization. Background paper on dengue vaccine. https://www.who.int/immunization/sage/meetings/2018/april/2_DengueBackgrPaper_SAGE_Apr2018.pdf . Accessed July 10 2021.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Moher D. Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement. J Clin Epidemiol. 2021;134:103–12.

Stone JC, Glass K, Clark J, Ritskes-Hoitinga M, Munn Z, Tugwell P, Doi SAR. The MethodologicAl Standards for Epidemiological Research (MASTER) scale demonstrated a unified framework for bias assessment. J Clin Epidemiol. 2021;134:52–64.

Doi SA, Barendregt JJ, Khan S, Thalib L, Williams GM. Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model. Contemp Clin Trials. 2015;45:130–8.

Doi SA, Thalib L. A quality-effects model for meta-analysis. Epidemiology. 2008;19:94–100.

Furuya-Kanamori L, Barendregt JJ, Doi SAR. A new improved graphical and quantitative method for detecting bias in meta-analysis. Int J Evid Based Healthc. 2018;16:195–203.

Sreenivasan P, Geetha S, Sasikala K. Development of a prognostic prediction model to determine severe dengue in children. Indian J Pediatr. 2018;85:433–9.

Thanachartwet V, Oer-Areemitr N, Chamnanchanunt S, Sahassananda D, Jittmittraphap A, Suwannakudt P, Desakorn V, Wattanathum A. Identification of clinical factors associated with severe dengue among Thai adults: a prospective study. BMC Infect Dis. 2015;15:420.

Article   PubMed   PubMed Central   Google Scholar  

Rafi A, Mousumi AN, Ahmed R, Chowdhury RH, Wadood A, Hossain G. Dengue epidemic in a non-endemic zone of Bangladesh: clinical and laboratory profiles of patients. PLoS Negl Trop Dis. 2020;14:e0008567.

Aung KL, Thanachartwet V, Desakorn V, Chamnanchanunt S, Sahassananda D, Chierakul W, Pitisuttithum P. Factors associated with severe clinical manifestation of dengue among adults in Thailand. Southeast Asian J Trop Med Public Health. 2013;44:602–12.

PubMed   Google Scholar  

Mercado ES, Espino FE, Perez ML, Bilar JM, Bajaro JD, Huy NT, Baello BQ, Kikuchi M, Hirayama K. HLA-A*33:01 as protective allele for severe dengue in a population of Filipino children. PLoS ONE. 2015;10:e0115619.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Carrasco LR, Leo YS, Cook AR, Lee VJ, Thein TL, Go CJ, Lye DC. Predictive tools for severe dengue conforming to World Health Organization 2009 criteria. PLoS Negl Trop Dis. 2014;8:e2972.

Prasad D, Bhriguvanshi A. Clinical profile, liver dysfunction and outcome of dengue infection in children: a prospective observational study. Pediatr Infect Dis J. 2020;39:97–101.

Wakimoto MD, Camacho LAB, Gonin ML, Brasil P. Clinical and laboratory factors associated with severe dengue: a case-control study of hospitalized children. J Trop Pediatr. 2018;64:373–81.

Hoffmeister B, Suttorp N, Zoller T. The revised dengue fever classification in German travelers: clinical manifestations and indicators for severe disease. Infection. 2015;43:21–8.

Sahu AK, Aggarwal P, Ekka M, Nayer J, Bhoi S, Kumar A, Luthra K. Assessing the serum chymase level as an early predictor of dengue severity. J Med Virol. 2021;93:3330–7.

Zhang H, Xie Z, Xie X, Ou Y, Zeng W, Zhou Y. A novel predictor of severe dengue: the aspartate aminotransferase/platelet count ratio index (APRI). J Med Virol. 2018;90:803–9.

Hanafusa S, Chanyasanha C, Sujirarat D, Khuankhunsathid I, Yaguchi A, Suzuki T. Clinical features and differences between child and adult dengue infections in Rayong Province, Southeast Thailand. Southeast Asian J Trop Med Public Health. 2008;39:252–9.

Falconar AK, Romero-Vivas CM. Simple prognostic criteria can definitively identify patients who develop severe versus non-severe dengue disease, or have other febrile illnesses. J Clin Med Res. 2012;4:33–44.

PubMed   PubMed Central   Google Scholar  

Sabeena S, Chandrabharani K, Ravishankar N, Arunkumar G. Classification of dengue cases in southwest India based on the WHO systems—a retrospective analysis. Trans R Soc Trop Med. 2018;112:479–85.

Article   Google Scholar  

Duangmala T, Lumbiganon P, Kosalaraksa P. Unusual clinical manifestations of dengue infection in children in a tertiary care hospital in northeast Thailand. Asian Biomed. 2014;8:97–103.

Md Sani SS, Han WH, Bujang MA, Ding HJ, Ng KL, Amir Shariffuddin MA. Evaluation of creatine kinase and liver enzymes in identification of severe dengue. BMC Infect Dis. 2017;17:505.

Hegazi MA, Bakarman MA, Alahmadi TS, Butt NS, Alqahtani AM, Aljedaani BS, Almajnuni AH. Risk factors and predictors of severe dengue in saudi population in Jeddah, Western Saudi Arabia: a retrospective study. Am J Trop Med Hyg. 2020;102:613–21.

Egger JR, Coleman PG. Age and clinical dengue illness. Emerg Infect Dis. 2007;13:924–5.

Ooi E-E, Gubler DJ. Dengue in Southeast Asia: epidemiological characteristics and strategic challenges in disease prevention. Cad Saude Publica. 2009;25:S115–24.

Anders KL, Nguyet NM, Chau NV, Hung NT, Thuy TT, le Lien B, Farrar J, Wills B, Hien TT, Simmons CP. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. Am J Trop Med Hyg. 2011;84:127–34.

Teixeira MG, Siqueira JB Jr, Ferreira GL, Bricks L, Joint G. Epidemiological trends of dengue disease in Brazil (2000–2010): a systematic literature search and analysis. PLoS Negl Trop Dis. 2013;7:e2520.

Gamble J, Bethell D, Day NP, Loc PP, Phu NH, Gartside IB, Farrar JF, White NJ. Age-related changes in microvascular permeability: a significant factor in the susceptibility of children to shock? Clin Sci (Lond). 2000;98:211–6.

Article   CAS   Google Scholar  

Soo K-M, Khalid B, Ching S-M, Chee H-Y. Meta-analysis of dengue severity during infection by different dengue virus serotypes in primary and secondary infections. PLoS ONE. 2016;11:e0154760–e0154760.

Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, Balmaseda A, Harris E. Antibody-dependent enhancement of severe dengue disease in humans. Science. 2017;358:929–32.

Narayan R, Tripathi S. Intrinsic ADE: the dark side of antibody dependent enhancement during dengue infection. Front Cell Infect Microbiol. 2020;10:580096.

Chaturvedi UC, Agarwal R, Elbishbishi EA, Mustafa AS. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol. 2000;28:183–8.

Murgue B, Cassar O, Deparis X. Plasma concentrations of sVCAM-1 and severity of dengue infections. J Med Virol. 2001;65:97–104.

Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–5.

Mangione JN, Huy NT, Lan NT, Mbanefo EC, Ha TT, Bao LQ, Nga CT, Tuong VV, Dat TV, Thuy TT, et al. The association of cytokines with severe dengue in children. Trop Med Health. 2014;42:137–44.

Soo KM, Khalid B, Ching SM, Tham CL, Basir R, Chee HY. Meta-analysis of biomarkers for severe dengue infections. PeerJ. 2017;5:e3589.

Lee IK, Hsieh CJ, Lee CT, Liu JW. Diabetic patients suffering dengue are at risk for development of dengue shock syndrome/severe dengue: emphasizing the impacts of co-existing comorbidity(ies) and glycemic control on dengue severity. J Microbiol Immunol Infect. 2020;53:69–78.

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ . 1998;317:703–713.

Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–12.

Pecoits-Filho R, Heimbürger O, Bárány P, Suliman M, Fehrman-Ekholm I, Lindholm B, Stenvinkel P. Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis. 2003;41:1212–8.

Aznar-Salatti J, Escolar G, Cases A, Gómez-Ortiz G, Anton P, Castillo R, Revert L, Ordinas A. Uraemic medium causes endothelial cell dysfunction characterized by an alteration of the properties of its subendothelial matrix. Nephrol Dial Transplant. 1995;10:2199–204.

Sangkaew S, Ming D, Boonyasiri A, Honeyford K, Kalayanarooj S, Yacoub S, Dorigatti I, Holmes A. Risk predictors of progression to severe disease during the febrile phase of dengue: a systematic review and meta-analysis. Lancet Infect Dis. 2021;21:1014–26.

Zhang H, Zhou YP, Peng HJ, Zhang XH, Zhou FY, Liu ZH, Chen XG. Predictive symptoms and signs of severe dengue disease for patients with dengue fever: a meta-analysis. BioMed Res Int. 2014;2014:359308.

CAS   PubMed   PubMed Central   Google Scholar  

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Luis Furuya-Kanamori and Kinley Wangdi are joint senior authors

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Department of Global Health, Research School of Population Health, College of Health and Medicine, Australian National University, Canberra, Australia

Tsheten Tsheten, Darren J. Gray, Ripon K. Adhikary & Kinley Wangdi

Royal Centre for Disease Control, Ministry of Health, Thimphu, Bhutan

Tsheten Tsheten

Telethon Kids Institute, Nedlands, Australia

Archie C. A. Clements

Curtin University, Perth, Australia

UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia

Luis Furuya-Kanamori

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TT, LFK and KW conceived this study. TT, RKA and KW screened the studies and extracted the data from the eligible studies. TT undertook literature review and drafted the manuscript. LFK and TT analysed the result. KW helped in the drafting and revision of manuscript. DJG and ACAC were involved in the critical revision of manuscript. All authors read and approved the final manuscript.

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Supplementary Information

Additional file 1..

PRISMA Checklist for systematic reviews and meta-analysis

Additional file 2.

Search strategy used in the review of literature

Additional file 3.

Studies included in the review and meta-analysis

Additional file 4.

Quality assessment of the studies using a MASTER Scale

Additional file 5.

Forest plots with pooled OR of progression to severe dengue with potential predictors

Additional file 6.

Subgroup analysis using WHO classification for demography, co-morbidities and clinical warning signs of dengue severity

Additional file 7.

Subgroup analysis using age groups for demography and warning signs of severe dengue

Additional file 8.

Additional file 9..

Doi plots and LFK values used to assess publication bias

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Tsheten, T., Clements, A.C.A., Gray, D.J. et al. Clinical predictors of severe dengue: a systematic review and meta-analysis. Infect Dis Poverty 10 , 123 (2021). https://doi.org/10.1186/s40249-021-00908-2

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Unforeseen complications: a case of dengue shock syndrome presenting with multi-organ dysfunction in a subtropical region

  • Syed Muhammad Owais 1 ,
  • Farrukh Ansar   ORCID: orcid.org/0000-0002-9056-5245 2 ,
  • Muhammad Saqib   ORCID: orcid.org/0000-0003-3645-6416 3 ,
  • Khatira Wahid 1 ,
  • Khalid Rashid   ORCID: orcid.org/0000-0002-4771-6896 4 , 5 &
  • Hassan Mumtaz   ORCID: orcid.org/0000-0003-2881-2556 6 , 7  

Tropical Medicine and Health volume  51 , Article number:  39 ( 2023 ) Cite this article

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Metrics details

Dengue fever, a viral illness transmitted by the Aedes mosquito, is capable of causing a range of serious complications, including fulminant hepatic failure, renal dysfunction, encephalitis, encephalopathy, neuromuscular and ophthalmic disorders, seizures, and cardiomyopathy.

Case description

This report details the case of a 30-year-old lactating woman with no notable medical history who presented to the emergency department with symptoms of high-grade fever, altered mental status, and seizures. Upon imaging, bilateral infarcts in the thalami and cerebellar hemispheres were observed, consistent with cerebellitis and dengue encephalitis.

Patient treatment and outcome

The patient was admitted to the intensive care unit and received appropriate treatment. Following a critical phase and successful patient stabilization, she was transferred to a high dependency unit for a week before being discharged with recommendations for follow-up care.

This case illustrates the broad spectrum of complications that can arise as a result of dengue infection and the importance of timely diagnosis and management in improving patient outcomes. Further investigation is required to better understand the mechanisms underlying these complications and to formulate specific guidelines for the prevention and treatment of dengue shock syndrome.

Introduction

Dengue fever is a viral infection transmitted by the Aedes mosquito. It is caused by one of four serotypes of the dengue virus (DENV 1–4). The dengue virus belongs to the Flaviviridae family of ribonucleic acid (RNA) viruses [ 1 ]. Dengue is an endemic disease in tropical and subtropical countries, putting almost four billion people worldwide at risk. The prevalence of dengue has rapidly increased in the Southeast Asian region in recent years. It is important for people living in or traveling to areas where dengue is prevalent to take precautions to protect themselves from mosquito bites and to seek medical attention if they develop symptoms of dengue fever [ 2 ]. Dengue shock syndrome (DSS) is the most severe manifestation of dengue infection and can have a mortality rate of up to 20% if not treated appropriately. DSS is characterized by a rapid drop in blood pressure, leading to shock and organ failure. Early diagnosis and management of DSS is crucial for improving patient outcomes. It is important for healthcare providers to be aware of the signs and symptoms of DSS and to initiate prompt treatment in order to prevent complications and reduce mortality [ 1 ]. It has been suggested that there are over 350 million reported cases of dengue and 22,000 related deaths worldwide each year [ 3 ]. Generally, dengue infection is characterized by a high-grade fever accompanied by rigors, chills, body aches, and a transient macular rash. However, in rare cases, complicated dengue infection can lead to severe complications such as fulminant hepatic failure, renal dysfunction, encephalitis, encephalopathy, neuromuscular and ophthalmic disorders, seizures, and cardiomyopathy [ 4 ]. Severe hepatic involvement associated with dengue infection is very rare. According to a large retrospective cohort study from the Hospital for Tropical Disease in Thailand, the incidence of acute liver failure in symptomatic dengue patients was less than 0.5%, but it had a significant mortality rate of 66%. This highlights the importance of early diagnosis and management of dengue infection in order to prevent complications and reduce mortality [ 5 ].

Case presentation

A 30-year-old lactating mother in subtropical South Asia with no significant past medical or surgical history presented to the emergency room with chief complaints of high-grade fever, altered mental status, and seizure. High grade and intermittent fever had been present since five days prior to admission, accompanied by rigors and chills. The patient’s mental status altered gradually starting with a loss of orientation and progressing to complete obtundation. The patient also experienced abrupt localized seizure in her lower limbs every half to one hour, without generalized tonic–clonic seizures or tongue bites. The patient did not have any bowel or bladder incontinence.

Physical examination revealed body temperature of 101 ºF, blood pressure of 99/64 mmHg, pulse of 144/min, oxygen saturation of 94% on room air, a respiratory rate of 36/min and a Glasgow Coma Scale score of 5/15 with a fixed constricted pupil. A malar rash on the face, palmar erythema, left lower extremity focal seizures, prolonged capillary refill, cold, clammy, and mottled skin were observed. The rest of the physical examination was unremarkable. The patient's random blood glucose was 180 mg/dl, and there were no signs of meningismus. Blood test revealed a hemoglobin level of 12.7 g/dL, a platelet count of 105 × 10 9 /L, and neutrophils of 27.5 × 10 9 /L. The alanine transaminase was 1394 U/L, C-reactive protein was 19.2 mg/dL, creatinine was 1.79 mg/dL, activated partial thromboplastin time was 61.7 s, procalcitonin was 0.00835 mg/dl, and Troponin I was raised at 0.00012168 mg/dl.

An echocardiography report showed an ejection fraction of 35–39% with mild pulmonary hypertension and moderate left ventricular systolic dysfunction. A brain computed tomography (CT) scan showed hypodensity in both the thalami and cerebellar hemispheres, suggesting bilateral thalamic and cerebellar infarcts and a possibility of cerebellitis and encephalitis. Grey–white matter differentiation appeared intact, and there was no evidence of a focal mass, midline shift, or hematoma. A brain magnetic resonance imaging (MRI) showed bilateral, almost symmetrical, high signals on T2-weighted and fluid-attenuated inversion recovery images in the thalami cerebellar hemispheres and bilateral cerebral cortices, which indicated the possibility of encephalitis or postictal ischemic changes. An enhanced CT scan of the chest and abdomen showed bilateral basal atelectasis, hepatomegaly, a distended gallbladder and enlarged bilateral iliacus muscles with internal hyperdense and hypodense areas suggesting the possibility of bilateral iliacus hematomas with some liquefaction.

The patient was diagnosed as sepsis, metabolic acidosis (evident from serum bicarbonate levels of 18 mEq/L, arterial pCO2 of 29 mmHg and a pH of 7.23), respiratory distress, acute kidney injury, heart failure due to myocarditis, acute liver injury and possible brain edema. Sudden onset of high-grade fever, systemic symptoms with multiple organ failure and local endemic situation arose the possibility of dengue shock syndrome although normal platelet count and absence of petechial rashes on the body were not compatible.

Further investigation revealed positive dengue non-specific antigen 1 (Dengue NS1 Ag) and positive dengue immunoglobulin M antibody (Dengue IgM Ab)done using qualitative Wondfo© One Step Dengue NS1 Antigen kits. A graphical summary of the case as well as the table of investigations can be seen in Fig.  1 .

figure 1

Summary of the case ( a ) and table of investigations ( b ). *Only the deranged values have been reported; Dengue NS1 Ag: dengue non-specific antigen 1; Dengue IgM Ab: dengue immunoglobulin M antibody

The patient was admitted to the intensive care unit and intravenous fluids were started (3% normal saline, 100 ml/h) with 0.10 μg/kg/min of norepinephrine. Mechanical ventilation was initiated due to the patient's deteriorating respiratory status, suspected secondary bacterial infection and herpes encephalitis, intravenous antibiotics (ceftriaxone 1 g/12 h and azithromycin 500 mg/day) and acyclovir (400 mg/8 h). In addition, the patient received intravenous insulin (0.1 units/kg/h) to maintain normal blood sugar levels and intravenous vasopressin (0.01 units/min) to maintain optimal blood pressure (above 120 mmHg systolic and above 80 mmHg diastolic) on the first day of admission. The patient soon started responding to treatment with gradual improvement in consciousness and laboratory findings.

The patient's renal function was monitored closely, and hemodialysis was initiated on the first day of admission. The patient's liver function was also monitored, and she received intravenous N -acetylcysteine and a low-fat diet. N-acetylcysteine (NAC) was administered in a specific dosing regimen. Initially, a bolus dose of 150 mg/kg body weight was administered, followed by a maintenance dosage of 12.5 mg/kg/h over a duration of 4 h. Subsequently, the maintenance dosage was adjusted to 6.25 mg/kg/h and continued for up to 72 h.

The patient's condition improved gradually over the next few days, and the mechanical ventilation was discontinued on the fourth day of admission. The patient was transferred to the high dependency unit for further management and stayed there for a week. After satisfactory echocardiography (revealing ejection fraction of 59% with a cardiac output 6.0 L per minute and a heart rate of 80 beats per minute, indicating a normal cardiac profile) and CT scan results (resolution of thalamic and cerebellar involvement seen on previous CT scans), the patient was discharged and advised to follow-up. CT scan and MRI images taken before recovery are shown in Figs.  2 and  3 , respectively. CT scan of the brain, revealed bilateral thalamic and cerebellar infarcts, suggesting brain involvement. Additionally, a magnetic resonance imaging (MRI) of the brain showed abnormal signals in the thalami, cerebellar hemispheres, and bilateral cerebral cortices, indicating the presence of dengue encephalitis or postictal ischemic changes. These imaging findings support the diagnosis of neurological involvement in the patient.

figure 2

CT scan showing bilateral thalamic and cerebellar hypodensities ( a , b ); patient details are hidden to protect patient privacy

figure 3

MRI scan showing bilateral thalamic and cerebellar infarcts ( a – c ); patient details are hidden to protect patient privacy

The patient was conscious towards the end of day 1 and slowly improved function. There was a mild residual muscle weakness in the proximal thigh muscles which improved in the subsequent days. This could be due to the lower limb seizures that were observed in the initial phase of admission. There were no signs of muscle paralysis observed in the patient. A recovery CT scan done on day 4 showed resolution of brain findings seen on CT previously as shown in Fig.  4 .

figure 4

CT scan of the brain after recovery showing resolution of all findings seen on previous CT scan; patient details are hidden to protect patient privacy

The relationship between dengue fever and neurological manifestations was first described in 1976, and multiple studies since then have shown that dengue fever can be associated with neurological complications [ 6 , 7 ]. Neurological manifestations of dengue fever can include headaches, irritability, alteration of consciousness, insomnia, and focal neurological deficits. These manifestations may be associated with encephalitis and seizures [ 6 ]. Dengue fever presents various neurological manifestations that can be classified into three distinct categories. The first category involves direct neurotropism, leading to conditions such as encephalitis, meningitis, myelitis, and myositis. The second category encompasses systemic complications, which include encephalopathy, stroke, and hypokalemic paralysis. Lastly, there are post-infectious or immune-mediated manifestations, such as acute disseminated encephalomyelitis (ADEM), Guillain–Barré syndrome (GBS), and optic neuritis [ 8 ].

In our case, the patient belonged to a subtropical region of South Asia and presented with altered mental status, seizure, and low Glasgow Coma Scale score, which were indicative of neurological involvement. This was supported by a CT scan showing bilateral thalamic and cerebellar infarcts due to possible brain edema, possibly indicating cerebellitis and dengue encephalitis. Myocarditis and cardiac dysfunction are rare but recognized complications of dengue fever. Earlier studies have reported on these complications, but did not specify which serotype was most commonly associated with them. More recent studies, however, have suggested that dengue virus serotype 2 (DENV-2) may be particularly implicated in causing myocardial dysfunction in children. Cardiac complications of dengue fever tend to manifest early in the disease course, and common electrocardiographic changes include T-wave inversion. These findings have been described in the literature previously [ 9 ]. In the current case, our patient was suspected to have myocarditis, which was later confirmed by the presence of a raised Troponin I level and a low ejection fraction on echocardiography. Acute kidney injury (AKI) is a significant complication that can occur in patients with dengue fever, particularly in those who are hospitalized for extended periods of time. The etiology of AKI in dengue fever is not fully understood, but proposed mechanisms include rhabdomyolysis, hemodynamic instability, acute glomerular injury, and hemolysis, all of which can lead to tubular necrosis, thrombotic microangiopathy, and acute glomerulopathy. Unfortunately, patients with dengue fever who develop renal complications such as AKI have a higher mortality rate. There are currently no specific recommendations for the treatment of AKI in dengue patients, and treatment typically involves conventional renal replacement therapy [ 10 ]. Dengue fever can affect the liver, which is the most commonly affected organ in patients with this infection. Liver involvement can range from mild elevation of hepatic transaminases to severe acute liver failure. The mechanisms behind liver injury in dengue fever are not fully understood, but may include hypoxic liver injury due to shock, direct virological attack on hepatocytes, and immunological damage to the liver. The management of acute liver injury in dengue fever can be challenging, as there are few guidelines available on the best approach. In the past, some studies have suggested that the use of NAC as an antidote for acetaminophen toxicity may be beneficial in the management of acute liver failure in dengue fever, as it has been associated with reduced mortality and high transplant-free survival, particularly when used in the early stages of the disease [ 11 ]. In our case, the administration of NAC was based on evidence from a recent meta-analysis conducted by Walayat et al. [ 12 ], which highlighted the significant improvement in overall survival associated with NAC, even in cases of non-acetaminophen-related acute liver failure [ 12 ]. The underlying pathophysiology of dengue fever involves a complex interplay between the virus and host-specific factors. The dengue virus replicates inside host cells, triggering the release of immune-mediated destruction and cytokines. While there is increased vascular permeability, plasma leakage is typically confined to the pleural and peritoneal cavities and does not result in generalized edema. The development of hemorrhagic diathesis is thought to be caused by liver damage that leads to decreased secretion of coagulative factors and albumin. The virus also replicates in the adrenal gland, contributing to sodium loss and hypotension. The presence of petechiae, which are small red or purple spots on the skin, is likely due to capillary fragility, thrombocytopenia, and cytokines that disrupt vascular integrity [ 13 , 14 ]. In dengue infection, both thrombosis and brain edema are potential mechanisms underlying the vascular involvement observed in cerebellitis and dengue encephalitis. Thrombosis can occur due to endothelial dysfunction and increased vascular permeability, leading to impaired blood flow and infarction in cerebral blood vessels. Meanwhile, the inflammatory response triggered by dengue fever can cause brain edema through the release of cytokines and immune mediators, resulting in increased blood–brain barrier permeability and fluid accumulation in the brain tissue. Brain edema can subsequently compress surrounding vessels and compromise blood flow, potentially leading to ischemic events and infarction [ 15 ]. It is evident from the CT images that the patient in our case most probably had ischemic changes due to brain edema that resolved in the subsequent days as evident in follow-up recovery brain CT scan which shows no residual findings.

Our patient presented to the emergency department with encephalopathy leading to coma, a neurological complication of dengue fever. There is a difference between encephalopathy and encephalitis in dengue virus infection which can be seen in Table 1 .

Upon examination, the patient was found to be in shock, as indicated by tachycardia, tachypnea, hypotension, cold, clammy, and mottled skin, and prolonged capillary refill. The presence of palmar erythema and malar rash may have been due to the physiological effects of pregnancy. Initially, the absence of petechiae and a good platelet count led us to suspect a case of non-dengue viral sepsis. However, dengue antigenic testing eventually revealed a positive result. This case is unique in that it involved multiple organ involvement mimicking viral sepsis, but without evidence of petechiae and a relatively good platelet count given the patient's condition. The diagnosis of dengue infection was ultimately reached through extensive testing and an astute clinical approach.

The patient was suffering from acute liver injury, acute kidney injury (AKI), heart failure (myocarditis), hypernatremia, and possible brain edema. While previous reports have described similar complications of dengue fever, this case is unusual in that it involved all of these complications simultaneously [ 16 , 17 , 18 ]. Our treatment regimen was in accordance with the guidelines provided by the Centers for Disease Control and Prevention [ 19 ]. Our treatment approach was also informed by based on the findings of multiple randomized controlled trials studied by Kalayanarooj et al. [ 20 ]. In the management of our patient, we focused on restoring and maintaining intravascular volume for sufficient end-organ perfusion. To this end, we administered intravenous fluids and norepinephrine to improve hemodynamics and normalize blood pressure, as well as antibiotics to control sepsis. We did not use beta blockers to lower the patient's heart rate, but closely monitored it instead. Other treatments included oral proton pump inhibitors to prevent stress ulcers, whole-nutrition in the form of Ensure®, compression stockings to prevent deep vein thrombosis, and any other necessary medications. There are many reasons why our case is unique. First, the case presents a unique and rare combination of serious complications of dengue fever, including dengue encephalitis, suspected myocarditis, acute kidney injury, and acute liver failure. This is an unusual presentation of dengue fever that has not been widely reported in the literature and would be of interest to healthcare professionals and researchers studying this disease. Second, the case report provides a detailed account of the patient's clinical presentation, diagnostic workup, and management, including the specific treatment strategies employed to address each of the complications. This information would be valuable to other healthcare professionals caring for patients with dengue fever and could inform future clinical practice. Finally, the successful management of the patient's multiple serious complications and the patient's eventual recovery make this an informative and inspiring case report that would be of interest to a wide audience. More interdisciplinary and evidence-based studies are required to make guidelines and decide on diagnosis and optimum fluid management in dengue infections complicated by encephalopathy in lactating women with dengue infection complicated by multiple complications. The guidelines are essential to facilitate management and prevent any adverse outcomes.

figure 5

CARE checklist

In conclusion, dengue fever presented in our case with a wide range of complications involving various organs, such as the brain, kidneys, liver, and myocardium. These complications ranged from encephalitis and seizures to acute kidney injury and myocarditis. It is important for healthcare professionals to be aware of the potential complications of dengue fever and to promptly diagnose and manage them in order to improve patient outcomes.

Patient’s own perspective

The patient reported “As a young, healthy mother, I never expected to wind up in the intensive care unit struggling for my life. But that's exactly what happened when I contracted dengue fever. It all started with a high fever came on suddenly. I figured I had just caught a bug and would be feeling better soon, but my condition only seemed to get worse. Before long, I was experiencing changes in my mental status. When I arrived at the hospital, I was rushed to the emergency department for evaluation. The doctors told me that I had dengue fever and that it had caused complications, including brain inflammation. They immediately started me on treatment and transferred me to the intensive care unit. The next few days were a blur. I remember being hooked up to a lot of machines and feeling very weak and tired. My family was by my side, and the doctors and nurses were all very kind and compassionate, but I was in a lot of pain and was barely able to communicate. Eventually, I started to improve. I was transferred to a high dependency unit and was able to receive more targeted care. After a week, I was finally stable enough to be discharged from the hospital. Looking back, I am grateful to have survived this terrifying experience. But I also hope that others can learn from my story and take the necessary precautions to protect themselves from dengue fever. If you're traveling to an area where dengue is prevalent, be sure to use insect repellent and take other precautions to avoid mosquito bites. And if you do start to feel sick, don't wait to seek medical attention. Early diagnosis and treatment can make all the difference.”

Availability of data and materials

The data collected and analyzed during this case report are available upon request, subject to ethical and legal considerations. All data will be de-identified to protect the privacy of the patient.

Khetarpal N, Khanna I. Dengue fever: causes, complications, and vaccine strategies. J Immunol Res. 2016;2016:6803098. https://doi.org/10.1155/2016/6803098 . ( Epub 2016/08/16 ).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Tropic Dis. 2012;6(8):e1760. https://doi.org/10.1371/journal.pntd.0001760 . ( Epub 2012/08/11 ).

Article   Google Scholar  

Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496(7446):504–7. https://doi.org/10.1038/nature12060 . ( Epub 2013/04/09 ).

Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. Lancet Neurol. 2013;12(9):906–19. https://doi.org/10.1016/s1474-4422(13)70150-9 . ( Epub 2013/08/21 ).

Article   PubMed   Google Scholar  

Kye Mon K, Nontprasert A, Kittitrakul C, Tangkijvanich P, Leowattana W, Poovorawan K. Incidence and clinical outcome of acute liver failure caused by dengue in a hospital for tropical diseases, Thailand. Am J Trop Med Hygiene. 2016;95(6):1338–44. https://doi.org/10.4269/ajtmh.16-0374 . ( Epub 2016/12/09 ).

Peter S, Malhotra N, Peter P, Sood R. Isolated Bell’s palsy - an unusual presentation of dengue infection. Asian Pac J Trop Med. 2013;6(1):82–4. https://doi.org/10.1016/s1995-7645(12)60207-7 . ( Epub 2013/01/16 ).

Article   CAS   PubMed   Google Scholar  

Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Raengsakulrach B, et al. Neurological manifestations of dengue infection. Lancet. 2000;355(9209):1053–9. https://doi.org/10.1016/s0140-6736(00)02036-5 . ( Epub 2000/04/01 ).

Kulkarni R, Pujari S, Gupta D. Neurological manifestations of dengue fever. Ann Indian Acad Neurol. 2021;24(5):693–702. https://doi.org/10.4103/aian.AIAN_157_21 .

Article   PubMed   PubMed Central   Google Scholar  

Kularatne SA, Pathirage MM, Medagama UA, Gunasena S, Gunasekara MB. Myocarditis in three patients with dengue virus type DEN 3 infection. Ceylon Med J. 2006;51(2):75–6. https://doi.org/10.4038/cmj.v51i2.1362 . ( Epub 2006/12/22 ).

Oliveira JF, Burdmann EA. Dengue-associated acute kidney injury. Clin Kidney J. 2015;8(6):681–5. https://doi.org/10.1093/ckj/sfv106 . ( Epub 2015/11/28 ).

Suganthan N, Sakthilingham G, Kumanan T. Dengue fever complicated with acute liver failure: a case report of expanded dengue syndrome and literature review. SAGE Open Med Case Rep. 2020. https://doi.org/10.1177/2050313x20913428 .

Walayat S, Shoaib H, Asghar M, Kim M, Dhillon S. Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review. Ann Gastroenterol. 2021;34(2):235–40. https://doi.org/10.20524/aog.2021.0571 .

Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev. 2009;22(4):564–81. https://doi.org/10.1128/cmr.00035-09 . ( Epub 2009/10/14 ).

Sellahewa KH. Pathogenesis of dengue haemorrhagic fever and its impact on case management. ISRN Infect Dis. 2013;2013:571646. https://doi.org/10.5402/2013/571646 .

Adane T, Getawa S. Coagulation abnormalities in Dengue fever infection: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2021;15(8):e0009666. https://doi.org/10.1371/journal.pntd.0009666 .

Arora S, Nathaniel SD, Paul JC, Hansdak SG. Acute liver failure in dengue haemorrhagic fever. BMJ Case Rep. 2015. https://doi.org/10.1136/bcr-2015-209443 . ( Epub 2015/05/27 ).

Lee I-K, Lee W-H, Liu J-W, Yang KD. Acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients. Int J Infect Dis. 2010;14(10):e919–22. https://doi.org/10.1016/j.ijid.2010.06.011 .

Vachvanichsanong P, Thisyakorn U, Thisyakorn C. Dengue hemorrhagic fever and the kidney. Arch Virol. 2016;161(4):771–8. https://doi.org/10.1007/s00705-015-2727-1 . ( Epub 2015/12/25 ).

Dengue clinician guide. Centers for Disease Control and Prevention; 2023. https://www.cdc.gov/dengue/resources/dengue-clinician-guide_508.pdf . Accessed 8 Jan 2023.

Kalayanarooj S, Rothman AL, Srikiatkhachorn A. Case management of dengue: lessons learned. J Infect Dis. 2017;215(suppl_2):S79–88. https://doi.org/10.1093/infdis/jiw609 .

Hendarto SK, Hadinegoro SR. Dengue encephalopathy. Acta Paediatr Jpn. 1992;34(3):350–7. https://doi.org/10.1111/j.1442-200x.1992.tb00971.x .

Borawake K, Prayag P, Wagh A, Dole S. Dengue encephalitis. Indian J Crit Care Med. 2011;15(3):190–3. https://doi.org/10.4103/0972-5229.84896 .

Angibaud G, Luaute J, Laille M, Gaultier C. Brain involvement in Dengue fever. J Clin Neurosci. 2001;8(1):63–5. https://doi.org/10.1054/jocn.2000.0735 .

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Quaid e Azam International Hospital, Rawalpindi, Pakistan

Farrukh Ansar

Khyber Medical College, Peshawar, Pakistan

Muhammad Saqib

James Cook University Hospital, Middlesbrough, UK

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SMO, FA and MS were lead authors and wrote the majority of the paper. FA conceived the study and contributed significantly to the design and planning of the study as well. MS was involved in the data collection and analysis, and contributed to the interpretation of the results as well. SMO, KR, KW and HM provided critical review and feedback on the manuscript. All authors contributed to the writing and editing of the final manuscript and approved the submitted version.

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Correspondence to Muhammad Saqib .

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Owais, S.M., Ansar, F., Saqib, M. et al. Unforeseen complications: a case of dengue shock syndrome presenting with multi-organ dysfunction in a subtropical region. Trop Med Health 51 , 39 (2023). https://doi.org/10.1186/s41182-023-00530-y

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case study of dengue fever

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  • Published: 06 February 2024

Severe disease during both primary and secondary dengue virus infections in pediatric populations

  • Charu Aggarwal 1   na1 ,
  • Hasan Ahmed 2   na1 ,
  • Pragati Sharma 1 ,
  • Elluri Seetharami Reddy 1 , 3 ,
  • Kaustuv Nayak 1 ,
  • Mohit Singla 4   na2 ,
  • Deepti Maheshwari 1 ,
  • Yadya M. Chawla 1 ,
  • Harekrushna Panda 1 ,
  • Ramesh Chandra Rai   ORCID: orcid.org/0000-0002-8008-3904 1 ,
  • Sivaram Gunisetty 1 , 5 ,
  • Lalita Priyamvada 5 ,
  • Siddhartha Kumar Bhaumik 5 ,
  • Syed Fazil Ahamed   ORCID: orcid.org/0000-0002-1909-5893 6 ,
  • Rosario Vivek   ORCID: orcid.org/0000-0001-9384-2079 6 , 7 ,
  • Priya Bhatnagar 1 , 8 ,
  • Prabhat Singh 1 ,
  • Manpreet Kaur 1 ,
  • Kritika Dixit 1 ,
  • Sanjeev Kumar   ORCID: orcid.org/0000-0002-8181-3999 1 ,
  • Kamal Gottimukkala 1 ,
  • Keshav Saini   ORCID: orcid.org/0000-0002-8072-2024 1 ,
  • Prashant Bajpai 1 ,
  • Gopinathan Pillai Sreekanth   ORCID: orcid.org/0000-0002-0278-8642 1 ,
  • Shobha Mammen 9 ,
  • Anand Rajan 9 ,
  • Valsan Philip Verghese 10 ,
  • Asha Mary Abraham 9 ,
  • Paresh Shah 11 ,
  • Kalichamy Alagarasu   ORCID: orcid.org/0000-0003-1401-8589 11 ,
  • Tianwei Yu 12 , 13 ,
  • Carl W. Davis 14 ,
  • Jens Wrammert 5 ,
  • Aftab Ansari   ORCID: orcid.org/0000-0003-4607-7268 14 ,
  • Rustom Antia   ORCID: orcid.org/0000-0001-7991-614X 2 ,
  • Sushil Kumar Kabra 4 ,
  • Guruprasad R. Medigeshi   ORCID: orcid.org/0000-0001-5333-9743 15 ,
  • Rafi Ahmed   ORCID: orcid.org/0000-0002-9591-2621 14 , 16   na3 ,
  • Rakesh Lodha   ORCID: orcid.org/0000-0003-2608-1163 4   na3 ,
  • Anita Shet   ORCID: orcid.org/0000-0002-7204-8164 6 , 17   na3 ,
  • Anmol Chandele   ORCID: orcid.org/0000-0002-5702-7170 1   na3 &
  • Kaja Murali-Krishna   ORCID: orcid.org/0000-0002-6275-1710 1 , 5 , 14   na3  

Nature Medicine ( 2024 ) Cite this article

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  • Dengue virus
  • Viral infection

Dengue is a global epidemic causing over 100 million cases annually. The clinical symptoms range from mild fever to severe hemorrhage and shock, including some fatalities. The current paradigm is that these severe dengue cases occur mostly during secondary infections due to antibody-dependent enhancement after infection with a different dengue virus serotype. India has the highest dengue burden worldwide, but little is known about disease severity and its association with primary and secondary dengue infections. To address this issue, we examined 619 children with febrile dengue-confirmed infection from three hospitals in different regions of India. We classified primary and secondary infections based on IgM:IgG ratios using a dengue-specific enzyme-linked immunosorbent assay according to the World Health Organization guidelines. We found that primary dengue infections accounted for more than half of total clinical cases (344 of 619), severe dengue cases (112 of 202) and fatalities (5 of 7). Consistent with the classification based on binding antibody data, dengue neutralizing antibody titers were also significantly lower in primary infections compared to secondary infections ( P  ≤ 0.0001). Our findings question the currently widely held belief that severe dengue is associated predominantly with secondary infections and emphasizes the importance of developing vaccines or treatments to protect dengue-naive populations.

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case study of dengue fever

Data availability

All the raw data analyzed are provided as source files in the main text and in the extended data material. Individual de-identified data for age, sex and clinical disease classification are provided as source data in the supplementary information. Source data are provided with this paper.

Bhatt, S. et al. The global distribution and burden of dengue. Nature 496 , 504–507 (2013).

Article   CAS   PubMed   PubMed Central   Google Scholar  

World Health Organization. Dengue Guidelines for Diagnosis, Treatment, Prevention and Control (WHO, 2009).

Farrar, J. J. et al. Dogma in classifying dengue disease. Am. J. Trop. Med. Hyg. 89 , 198–201 (2013).

Article   PubMed   PubMed Central   Google Scholar  

Srikiatkhachorn, A. et al. Dengue—how best to classify it. Clin. Infect. Dis. 53 , 563–567 (2011).

Halstead, S. B. et al. Dengue hemorrhagic fever in infants: research opportunities ignored. Emerg. Infect. Dis. 8 , 1474–1479 (2002).

Guzmán, M. G. et al. Epidemiologic studies on Dengue in Santiago de Cuba, 1997. Am. J. Epidemiol. 152 , 793–799 (2000).

Article   PubMed   Google Scholar  

Halstead, S. B., Scanlon, J. E., Umpaivit, P. & Udomsakdi, S. Dengue and chikungunya virus infection in man in Thailand, 1962–1964. IV. Epidemiologic studies in the Bangkok metropolitan area. Am. J. Trop. Med. Hyg. 18 , 997–1021 (1969).

Article   CAS   PubMed   Google Scholar  

Winter, P. E. et al. Recurrence of epidemic dengue hemorrhagic fever in an insular setting. Am. J. Trop. Med. Hyg. 18 , 573–579 (1969).

Nunes, P. C. G. et al. 30 years of dengue fatal cases in Brazil: a laboratorial-based investigation of 1047 cases. BMC Infect. Dis. 18 , 346 (2018).

Rosen, L. The Emperor’s New Clothes revisited, or reflections on the pathogenesis of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 26 , 337–343 (1977).

Halstead, S. B., O’Rourke, E. J. & Allison, A. C. Dengue viruses and mononuclear phagocytes. II. Identity of blood and tissue leukocytes supporting in vitro infection. J. Exp. Med. 146 , 218–229 (1977).

Ng, J. K. et al. First experimental in vivo model of enhanced dengue disease severity through maternally acquired heterotypic dengue antibodies. PLoS Pathog. 10 , e1004031 (2014).

Katzelnick, L. C. et al. Antibody-dependent enhancement of severe dengue disease in humans. Science 358 , 929–932 (2017).

Cuzzubbo, A. J. et al. Comparison of PanBio Dengue Duo IgM and IgG Capture ELISA and Venture Technologies Dengue IgM and IgG Dot Blot. J. Clin. Virol. 16 , 135–144 (2000).

Vaughn, D. W. et al. Rapid serologic diagnosis of dengue virus infection using a commercial capture ELISA that distinguishes primary and secondary infections. Am. J. Trop. Med. Hyg. 60 , 693–698 (1999).

Vazquez, S., Hafner, G., Ruiz, D., Calzada, N. & Guzman, M. G. Evaluation of immunoglobulin M and G capture enzyme-linked immunosorbent assay Panbio kits for diagnostic dengue infections. J. Clin. Virol. 39 , 194–198 (2007).

Murhekar, M. V. et al. Burden of dengue infection in India, 2017: a cross-sectional population based serosurvey. Lancet Glob. Health 7 , e1065–e1073 (2019).

de Silva, A. Safety of dengue vaccine? Clin. Infect. Dis. 76 , 371–372 (2023).

Clapham, H. E. & Wills, B. A. Implementing a dengue vaccination programme—who, where and how? Trans. R. Soc. Trop. Med. Hyg. 112 , 367–368 (2018).

Article   Google Scholar  

Thomas, S. J. Is new dengue vaccine efficacy data a relief or cause for concern? NPJ Vaccines 8 , 55 (2023).

Chandele, A. et al. Characterization of human CD8 T cell responses in dengue virus-infected patients from India. J. Virol. 90 , 11259–11278 (2016).

Gunisetty, S. et al. Analysis of dengue specific memory B cells, neutralizing antibodies and binding antibodies in healthy adults from India. Int. J. Infect. Dis. 84S , S57–S63 (2019).

Kar, M. et al. Isolation and molecular characterization of dengue virus clinical isolates from pediatric patients in New Delhi. Int. J. Infect. Dis. 84S , S25–S33 (2019).

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Acknowledgements

This work was supported by National Institutes of Health grant no. ICIDR 1UO1A/115654; Department of Biotechnology (DBT), Government of India grant nos. BT/PR5132/MED/15/85/2012 and BT/PR8470/med/29/726/2013; and NIH-DBT Human Immunology Project Consortium grant no. AI090023. G. Medigeshi is supported by the Wellcome Trust-DBT India Alliance Intermediate fellowship (no. IA/S/14/1/501291). S. Kumar is supported by the DBT/Wellcome Trust India Alliance Early Career Fellowship grant no. IA/E/18/1/504307. The authors thank N. Khanna (International Centre for Genetic Engineering and Biotechnology (ICGEB)) for discussions, W. M. Orenstein (Emory Vaccine Center) for critical review of the manuscript, and S. Singh and A. Singh (ICGEB) for technical support.

Author information

These authors contributed equally: Charu Aggarwal, Hasan Ahmed.

Deceased: Mohit Singla

These authors jointly supervised this work: Rafi Ahmed, Rakesh Lodha, Anita Shet, Anmol Chandele, Kaja Murali-Krishna.

Authors and Affiliations

ICGEB Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

Charu Aggarwal, Pragati Sharma, Elluri Seetharami Reddy, Kaustuv Nayak, Deepti Maheshwari, Yadya M. Chawla, Harekrushna Panda, Ramesh Chandra Rai, Sivaram Gunisetty, Priya Bhatnagar, Prabhat Singh, Manpreet Kaur, Kritika Dixit, Sanjeev Kumar, Kamal Gottimukkala, Keshav Saini, Prashant Bajpai, Gopinathan Pillai Sreekanth, Anmol Chandele & Kaja Murali-Krishna

Department of Biology, Emory University, Atlanta, GA, USA

Hasan Ahmed & Rustom Antia

Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India

Elluri Seetharami Reddy

Division of Pediatric Pulmonology and Intensive Care, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

Mohit Singla, Sushil Kumar Kabra & Rakesh Lodha

Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA, USA

Sivaram Gunisetty, Lalita Priyamvada, Siddhartha Kumar Bhaumik, Jens Wrammert & Kaja Murali-Krishna

Division of Infectious Diseases, St. John’s Research Institute, St. John’s National Academy of Health Sciences, Bengaluru, India

Syed Fazil Ahamed, Rosario Vivek & Anita Shet

The University of Trans-Disciplinary Health Sciences & Technology, Bengaluru, India

Rosario Vivek

TERI school of advanced studies, New Delhi, India

Priya Bhatnagar

Department of Clinical Virology, Christian Medical College, Vellore, India

Shobha Mammen, Anand Rajan & Asha Mary Abraham

Pediatric Infectious Diseases, Department of Pediatrics, Christian Medical College, Vellore, India

Valsan Philip Verghese

Department of Molecular Virology, National Institute of Virology, Pune, India

Paresh Shah & Kalichamy Alagarasu

Rollins School of Public Health, Emory University, Atlanta, GA, USA

Shenzhen Research Institute of Big Data, School of Data Science, The Chinese University of Hong Kong, Shenzhen, Guangdong, China

Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA

Carl W. Davis, Aftab Ansari, Rafi Ahmed & Kaja Murali-Krishna

Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India

Guruprasad R. Medigeshi

Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA

International Vaccine Access Centre, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

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Contributions

M.S., S.F.A., R.V., S.M., A.R., V.P.V., A.M.A., S.K.K., R.L. and A.S. carried out patient recruitment and follow-up. C.A., H.A., P. Sharma, H.P., K.N., R.C.R., D.M., S.G., L.P., S.K.B., S.F.A., R.V., E.S.R., Y.M.C., P. Bhatnagar, P. Singh, M.K., K.D., S.K., K.G., K.S., P. Bajpai, G.P.S., P. Shah, A.K., T.Y., C.W.D., R. Antia and G.R.M. performed the experiments, analysis and interpretation. J.W., A.A., A.M.A., S.K.K., R. Ahmed, R.L., A.S., A.C. and K.M-K. were involved in study design, analysis and interpretation. C.A., H.A., R. Ahmed, R.L., A.S., A.C. and K.M-K. prepared the paper.

Corresponding authors

Correspondence to Rafi Ahmed , Rakesh Lodha , Anita Shet , Anmol Chandele or Kaja Murali-Krishna .

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Nature Medicine thanks Eng Eong Ooi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended data fig. 1 similar frequency of severe disease in primary versus secondary cases that were distinguished using stringent igm/igg ratios..

Pie charts show the frequency of Severe Dengue (SD), Dengue with warning signs (DW) and Dengue infection without warning signs (DI) cases in primary versus secondary dengue infections that were distinguished using more stringent IgM/IgG ratios indicated on left. The number of patients in each group is indicated below the pie chart. For all three classification methods, the proportion of severe disease was not significantly different between primary and secondary cases (p > 0.78, two-sided Fisher’s exact test). The 95% confidence interval for the percentages indicated in the pie charts are as below: IgM/IgG >1.32, primary: DI- 5.4-11.6, DW-53.4-64.4, SD-27.9-38.5, Secondary: DI- 6.7-13.1, DW-52.8-63.6, SD-27.4-37.6; IgM/IgG >1.4: primary: DI- 5.7-12.1, DW-52.2-63.5, SD-28.5-39.3, secondary: DI- 6.4-12.6, DW-53.8-64.4, SD-26.9-36.9; IgM/IgG >1.78: primary: DI- 5.8-13.0, DW-50.5-62.9, SD-28.7-40.6 and secondary: DI- 6.3-12.0, DW-54.8-64.6, SD-27.0-36.3 (Wilson CI).

Source data

Extended data fig. 2 frequency of severe disease in primary versus secondary dengue infections using who 1997 and who 2009 disease classification..

Data from a subset of the patients from the AIIMS Delhi site where disease severity was classified using both WHO 2009 and WHO 1997 criteria. a , Data shown by WHO 1997 disease classification. Pie charts show the frequency of the cases with dengue shock syndrome (DSS), dengue hemorrhagic fever (DHF); or dengue fever (DF) among a subset of dengue confirmed children that are recruited from AIIMS site among all cases (n = 171), primary dengue cases (n = 66) and secondary dengue cases (n = 105). DSS case frequency is not significantly different between the primary and secondary dengue infections, (p = 0.106, two-sided Fisher’s exact test). b , Data shown by WHO 2009 disease classification among the same group of the patients from panel a. Pie charts show the frequency of the cases with severe dengue (SD), dengue with warning signs (DW); or dengue infection without warning signs (DI) among all cases, primary dengue cases or secondary dengue cases. Severe dengue case frequency was not significantly different between the primary and secondary dengue infections, (p = 0.344, two-sided Fisher’s exact test).

Extended Data Fig. 3 Dengue specific responses in infants (≤1-year-old).

a , Scatter plot shows dengue specific IgM and IgG index values by capture Elisa (Panbio) for dengue confirmed infants (n = 34). p values were calculated using two-sided Mann-Whitney U tests b , Neutralizing antibody titers to the indicated infecting virus serotype in dengue confirmed infants where the infecting serotype was determined (n = 26). c . Scatter plots show dengue specific IgM index values by Panbio Capture ELISA among the infants with different grades of disease severity. Severe dengue (SD, n = 22); Dengue with warning signs (DW, n = 12). Note that there are no Dengue infection without warning signs (DI) cases since all the hospitalized infants were either SD or DW cases. p values (p = 0.087) were calculated using two-sided Mann-Whitney U tests. Non-significant p values (>0.05) are indicated as n.s. d . Scatter plots show neutralizing activity against the indicated infecting dengue virus serotypes among the infants with different grades of disease severity. Severe dengue (SD, n = 15); Dengue with warning signs (DW, n = 11). Note that there are no DI cases since all of the hospitalized infants were either SD or DW cases. p values (p > 0.999) were calculated using two- sided Mann-Whitney U tests. Non-significant p values (>0.05) are indicated as n.s.

Extended Data Fig. 4 Neutralization responses were below detection or significantly lower for infecting serotype in the primary dengue cases compared to secondary dengue cases.

Neutralizing antibody titers against the infecting virus serotype in primary (n = 38) and secondary (n = 50) from a subset of the patients from 2b, where the infecting serotype was identified. p values were calculated using Mann-Whitney U test.

Supplementary information

Supplementary information.

Individual-level data for age, sex and clinical disease classification.

Reporting Summary

Supplementary data.

Source data for individual-level data in the Supplementary Information.

Source Data Fig. 1

Similar frequency of severe disease in pediatric patients with primary versus secondary dengue infections.

Source Data Fig. 2

Comparison of neutralizing antibody responses between cases with primary and secondary dengue infection.

Source Data Extended Data Fig. 1

Similar frequency of severe disease in primary versus secondary cases that were distinguished using stringent IgM/IgG ratios.

Source Data Extended Data Fig. 2

Frequency of severe disease in primary versus secondary dengue infections using WHO 1997 and WHO 2009 disease classification.

Source Data Extended Data Fig. 3

Dengue specific responses in infants (≤1 year old).

Source Data Extended Data Fig. 4

Neutralization responses were below detection or significantly lower for infecting serotype in the primary dengue cases compared to secondary dengue cases.

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Aggarwal, C., Ahmed, H., Sharma, P. et al. Severe disease during both primary and secondary dengue virus infections in pediatric populations. Nat Med (2024). https://doi.org/10.1038/s41591-024-02798-x

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case study of dengue fever

As temperatures rise, dengue fever infections keep surging around the world

Scientists say mosquito-transmitted viral infection could impact more regions thanks to climate change.

case study of dengue fever

Social Sharing

This story is part of CBC Health's Second Opinion, a weekly analysis of health and medical science news emailed to subscribers on Saturday mornings. If you haven't subscribed yet, you can do that by  clicking here .

In Bangladesh, roughly 300,000 people have been infected with dengue this year during the country's worst-ever outbreak of the mosquito-transmitted disease. By mid-November, the death toll hit close to 1,500, as hospitals in the densely populated South Asian country struggled to cope with the surge in patients.

Neighbouring India is also experiencing more and more outbreaks , along with Sri Lanka to the south, where 60,000 cases of dengue have been reported just this year. In Mexico , cases rose more than 330 per cent in 2023 compared to 2022, and Argentina, Bolivia, Brazil, and Peru are also reporting high rates of infections.

The disease — known as "breakbone fever," due to the severe muscle and joint pains it can cause — is also appearing far beyond its usual range in tropical and subtropical climates.

Dozens of dengue cases not tied to travel abroad have been reported across several European countries, including Italy, France, and Spain. Chad, a landlocked country at the crossroads of North and Central Africa, experienced its first known outbreak this year. Meanwhile several U.S. states announced locally acquired cases in recent months, including the country's first known infections in California .

The explosive spread of dengue, through the mosquitos known for carrying the virus, offers a case study in how climate change, human movement, and rising temperatures are all coaligning to fuel the expansion of potentially deadly threats to human health. And, scientists warn, even countries like Canada that have avoided dengue's wrath could experience local transmission of the virus in the decades ahead.

"The frequency of outbreaks is ever increasing," Himmat Singh, a scientist at the National Institute of Malaria Research in New Delhi, told the British Medical Journal . "Mosquitoes are evolving as humans have pushed them to adapt."

WHO scientists ring alarms

While eye-catching climate impacts such as extreme weather events and heat waves will be front and centre at the first dedicated Health Day being held on Sunday at COP28, the World Health Organization (WHO) recently warned our changing climate is also "catalyzing a surge in infectious diseases like dengue" and is calling for health-focused climate action from global governments.

  • Second Opinion Why insect-transmitted illnesses are emerging threats in Canada and beyond

The organization's chief scientist, Dr. Jeremy Farrar, told Reuters in October that he expects dengue will become a major threat in the southern U.S, southern Europe, and new parts of Africa this decade — as warmer temperatures create the conditions for the mosquitoes carrying the infection to spread.

Dengue virus is transmitted by the Aedes aegypti mosquito, a tropical species which also spreads the viruses behind diseases such as Zika, chikungunya, and yellow fever. 

"They harbour a lot of these nasty viruses," said virologist Stephen Barr, an associate professor in Western University's department of microbiology and immunology. "What researchers know is that the traits these mosquitoes have, that are favourable for spreading these viruses, occur in the range of temperatures from about 24 to 29 C."

A man in a blue jacket, pants and cap stands in a yard, with clothes hanging on a line behind him, as he holds a long metal machine spraying fog.

The species can survive year-round when temperatures are warm enough, and females lay their eggs in areas of shallow, stagnant water, which can mean spaces as small as household containers, potted plants, or even a bottle cap. 

"Once the mosquito habitat is established, it only takes one or two people to bring the virus into that habitat for the mosquito to [spread it]," said Dr. Amila Heendeniya, a clinical infectious diseases physician at the Winnipeg Regional Health Authority and an assistant professor at the University of Manitoba. 

  • CBC Explains Peru is enduring its worst dengue outbreak ever. Is El Niño making it worse?

Researchers say warming temperatures and shifts in rainfall patterns due to climate change are creating ideal conditions for these mosquitoes to breed, particularly in areas such as Bangladesh where monsoon-level rain is being reported earlier in the season .

In Pakistan, there has been an ongoing dengue epidemic since 2011, said Dr. Imran Hassan Khan, chair of the country's Dengue Expert Advisory Group. The mosquitoes appear to be adapting to a longer rainy season, and now likely live throughout homes where they can infect people with this virus at any time of day, he explained.

"We're unable to eradicate it," he added. "It's impossible to eradicate it."

Rates of the disease have risen eight-fold around the world in the last two decades, WHO figures suggest. Scientists also suspect far more cases are going unreported, given the wide range of potential symptoms, from internal bleeding, organ failure and death on the severe end, all the way to mild ailments or even no symptoms at all.

case study of dengue fever

Insect-borne infections on the rise thanks to climate change

2nd infections can be worse than the 1st.

One of the most alarming aspects of dengue's rapid rise is that one exposure to the virus doesn't protect you from infection with a different serotype — and can actually mean your second round is worse. 

There are four distinct serotypes of dengue, explained Thais dos Santos, advisor for surveillance and control of arboviral diseases at the Pan American Health Organization (PAHO). 

"In terms of immunity, they act as four distinct viruses," she said, adding that one dengue infection is thought to provide life-long immunity to that specific serotype, but not the others. "Once you get that secondary infection it has been well-documented that you're more likely to have severe symptoms."

  • The urban mosquito is thriving farther north than it's ever been, and scientists are worried

The mechanism at play is known as "antibody-dependent enhancement," in which the antibodies against dengue produced by someone's immune system fall to a low range. Research suggests that leads to a domino effect where the few antibodies still left are able to bind to the virus, pull it into cells, and give it space to replicate — but their level remains too low to actually kill those invaders. 

"Your body starts fighting it, but not really properly," explained Heendeniya, who said that haywire immune response leads to an increased risk of internal bleeding and hemorrhagic fever.

  • Release the mosquitos! How 5 billion bugs will help fight dengue fever in Brazil

Why that reaction happens with dengue to a degree not seen in many other infections is still not fully understood, but researchers note what's clear is that it complicates the use of vaccines. Two commercially available dengue vaccines are being used by various countries, but most global guidance recommends only vaccinating children in high-risk areas who have had a prior confirmed infection , given there's also a risk for severe disease if someone catches dengue after immunization.

"I think we're still trying to understand a lot of those mechanisms, and everyone's immune system is going to be different… there's so much we still don't know," said Barr.

A hand with tongs and mosquitos in a lab dish.

Half of world's population now at risk

Questions about how dengue operates are now more pressing as climate change and widespread human migration are expected to fuel its continued spread, with potentially dire consequences. Already, roughly half of the world's population is now at risk , with an estimated 100 to 400 million infections occurring every year, the WHO has said.

"For the longest time, dengue was considered an 'emerging' infectious disease," Heendeniya said. "I would say it has already emerged."

  • More types of mosquito discovered in Yukon — that's 33 and counting

Modelling studies also project wider expansion of the virus within specific countries. One paper in the Lancet Planetary Health , for instance, projected a higher risk of dengue through much of mainland China by the year 2100.

As for Canada, the dengue virus isn't found in mosquitos here — at least not yet. But Barr warns that could change. Local transmission in countries such as France and Croatia was only reported for the first time in 2010, WHO data shows .

  • Fears the dengue vaccine could worsen infection sparks review by WHO

Canada's historically colder climate hasn't provided the conditions for these mosquitoes to thrive year-round, Barr said. However, an adult Aedes aegypti was found in a trap in Ontario for the first time in 2017 , a discovery health officials believe signaled the species is now becoming established.

Rising temperatures, Barr warned, could make this country more hospitable, and if more of these mosquitoes hitch a ride here, locally-acquired dengue infections in the years ahead could become a real possibility.

"Dengue is always a plane ride away," he said.

ABOUT THE AUTHOR

case study of dengue fever

Senior Health & Medical Reporter

Lauren Pelley covers health and medical science for CBC News, including the global spread of infectious diseases, Canadian health policy, pandemic preparedness, and the crucial intersection between human health and climate change. Two-time RNAO Media Award winner for in-depth health reporting in 2020 and 2022. Contact her at: [email protected]

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  • Case report
  • Open access
  • Published: 26 August 2020

A case report of dengue hemorrhagic fever complicated with diabetic ketoacidosis in a child: challenges in clinical management

  • V. Thadchanamoorthy 1 &
  • Kavinda Dayasiri 2  

BMC Pediatrics volume  20 , Article number:  403 ( 2020 ) Cite this article

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Metrics details

Diabetic ketoacidosis (DKA) is a common presentation of type 1 diabetes mellitus (T1DM) precipitated by various bacterial and viral infections. Dengue infection is no exception for this and can be a precipitating factor for DKA. The presentation of DKA with dengue haemorrhagic fever (DHF) has been reported in adults. However, it is very rarely observed in children.

Case presentation

We present the case of a paediatric patient who was previously healthy and subsequently, developed polyuria (above 3 ml/kg/hour), irritability and high blood glucose (724 mg/dl) during the critical phase of DHF. DKA was diagnosed with DHF and managed successfully with insulin and intravenous fluids. He recovered without complications and discharged home with follow up being arranged at the endocrinology clinic.

Conclusions

When both DHF and DKA present together in a patient, meticulous monitoring of glycaemic control as well as fluid management is required to reduce the potential risk for severe complications of both conditions. Since there are no similar paediatric case reported in the literature, this case report might inspire paediatricians to anticipate the possibility of DKA in children with DHF.

Peer Review reports

Dengue has a wide spectrum of clinical manifestations which may be mild to severe and can be severe enough to cause death due to dengue shock syndrome. Worldwide estimates suggest that annual incidence of dengue fever and DHF has been 100 million and 500,000 respectively. Ninety percent of DHF cases are children under 15 years old [ 1 , 2 ]. Dengue fever similar to other viral infections is known to precipitate diabetic ketoacidosis in patients with diabetes. Both insulin dependent and independent diabetes can increase the release of pro-inflammatory cytokines and intensify the risk of plasma leakage in dengue fever. Acute pancreatitis is a rare complication of severe dengue infection, which could be a contributory factor for diabetic ketoacidosis. The clear understanding of the comorbidity and mortality between the two diseases is vital in patient management during acute illness.

There is only limited research evidence with regard to actual fluid requirement during critical phase of dengue haemorrhagic fever as plasma leakage is dynamic and can occur at different rates across the critical phase [ 3 ]. Therefore, current practice of fluid management in DHF depends, to a greater extent, on expertise of the managing clinicians and a number of assumptions regarding evolution of plasma leakage. Urine output is considered as a reliable indicator of haemodynamic stability in patients with DHF and maintaining urine output between 0.5–1 ml/kg/hour is considered appropriate to prevent both shock and fluid overload that carry high risk of mortality. However, it is crucial that clinicians are mindful of potential confounding factors such as hyperglycemia. As a patient with dengue fever presents with hyperglycemia, urine output becomes an unreliable indicator of haemodynamic status and patient might have polyuria even during shock [ 4 ]. We report a child who was initially admitted for dengue fever and subsequently developed DHF associated with polyuria and irritability needing more fluids to maintain vital signs during the critical period of DHF. He was ultimately diagnosed as having type − 1 diabetes mellitus associated diabetic ketoacidosis with DHF. The report enlightens the importance of consideration of differential causes for surprisingly high urine output in patients with DHF associated shock and clinical decision making based on meticulous overall haemodynamic assessments. Management of this patient would be a thought-provoking and challenging task for clinicians and their teams.

A 13-year-old previously healthy boy was admitted with fever, generalized body ache, headache, cough and mild diarrhea for 4 days and abdominal pain and vomiting for 2 days. His urine output was satisfactory. Dengue NSI antigen done on day 3 febrile illness was positive. He had no history of thirst, weight loss, and increased frequency of urination. On examination he was febrile (99.5F), ill looking, and flushed but was rational and heamodyanamically stable. Blood pressure had been 100/70 mmHg with pulse pressure of 30 mmHg. Pulse was of good volume and rate had been 155 / minute. His Complete Blood Count showed leukopenia (WBC- 1.5 × 10 3 / cumm), and thrombocytopenia (platelet count - 100 × 10 3 /cumm). Haemoglobin was 13 g/dL, and haematocrit was 38. Random blood glucose on admission was 104 mg/dl. Abdominal examination showed 3 cm hepatomegaly and there was no clinical evidence of pleural effusion. He was provisionally diagnosed as having DHF and haemodynamic monitoring was commenced while he was on oral rehydration fluids at rate of 75 ml per hour. The child tolerated oral rehydration fluids well and did not need intravenous fluids including dextrose solutions.

On day five, he started to deteriorate with low volume pulse, tachycardia (rate of more than 180/min), cold clammy extremities and narrow pulse pressures whilst on intravenous 0.9% saline (4 ml/kg/hour) and oral fluids (1 ml/kg/hour). Clinical examination of lungs showed slight reduction of air entry on right side with vesicular breathing and no added sounds were heard. However, his urine output remained surprisingly satisfactory (more than1.5 mL/kg/hour). In addition, he became more irritable, thirsty, tachypnoic and had severe generalized abdominal tenderness whilst on two units of 0.9% saline 10 mL/kg boluses followed by 5 mL/kg/hour infusions. He continuously had disproportionately increased urine output (more than 2 mL/kg/hour) and pulse pressure varied between 15 to 20 mmHg. His Complete Blood Count showed WBC - 4.5 × 10 3 (N − 60 %, L-34%), haemoglobin - 16 g/dL, platelets - 60x10 3 mm/l, and haematocrit - 48. C-reactive protein (CRP) was elevated (12 mg/dl). Renal functions (Na- 140 mmol/L, K-4.3 mmol/L, serum creatinine 0.9 mg/dl) were normal apart from raised blood urea (60 mg/dL). Liver functions were deranged (Alanine transaminase − 240 IU/L, Aspartate transaminase-546 IU/L). Serum amylase was normal (44 U/L) Chest X-ray was normal apart from mild haziness all over the lungs. Ultrasound revealed mild ascites and bilateral pleural effusions. Capillary blood glucose was 724 mg/dl. He was transferred from local hospital to intensive care unit (ICU), in the tertiary care hospital for further management of diabetic ketoacidosis co-occurring with DHF. As he had high fever with unstable haemodynamic parameters and CRP was elevated, he was commenced broad spectrum empirical intravenous antibiotics. However, antibiotics were stopped following negative blood cultures.

In ICU, he had moderate to severe metabolic acidosis with arterial blood gas showing pH -7.17, pCO2-23 mmHg, pO2- 75 mmHg, HCO3- 12mmo/l and base excess-(− 14). Urine ketone bodies were positive. Blood ketones were not performed due to unavailability of this investigation in the hospital. He was resuscitated with dextran 40 with the dose of 10 ml/ kg once. Then he was started 0.9% saline with soluble insulin infusion at 0.1 u/kg/hour and blood glucose was monitored hourly until glucose levels dropped between 200 and 328 mg/dl. Intravenous fluid (0.9%saline) was adjusted between 5 and 7 ml/kg/h depending on the vital signs. We did not administer intravenous dextrose as it might have worsened hypovolaemia by the ongoing plasma leakage, producing more hydrostatic pressure and also producing osmotic diuresis. Instead child was advised to take foods which contained complex carbohydrate. Fluids were adjusted hourly according to pulse pressure which was more than minimum 20 mmHg and capillary refilling time was maintained below 2 s. The management was not guided both by urine output which had been more than expected and pulse rate due to presence of high fever. In addition, potassium was added to fluids as serum electrolyte revealed Na-140 mmol/L, and K-3.0 mmol/L while on insulin. As he improved after 24 h of critical period, his fluids and insulin were reduced to half. He was not commenced intravenous bicarbonate as repeat arterial blood gas showed improved findings (pH 7.32, PCO2-30 mmHg, PO2-80 mmHg, HCO2–18, Base excess (− 8)) following correction of dehydration and glucose with insulin. The lowest platelet count was 12x10 3 and renal function had been within normal range on the day 6 of illness. Intravenous Insulin was changed to subcutaneous insulin after 48 h of critical period and urine ketone bodies were noted to be negative.

After 72 h of ICU care, he was transferred to medical ward where he was continued on subcutaneously insulin and food according to dietician’s advice. Blood glucose, urine ketone body, renal functions, liver functions and hematological parameters were repeated until they were normalized. His HbA1C was 5.1% and Glutamic acid decarboxylase autoantibody had been positive (22 IU/L). Other type 1 diabetes related autoantibodies could not be performed due to limited financial resources in patient’s family. Both IgM and IgG dengue antibodies were positive on day 7 and dengue infection was notified to infection control team of the local hospital. Intravenous antibiotic was discontinued after 5 days with normal CRP. He was discharged after 2 weeks of hospital stay with the postprandial blood sugar being 146 mg/dl and fasting blood sugar being 100 mg/dl. Follow up was arranged at the endocrinology clinic. He was reviewed after 6 months and 1 year in the paediatric clinic and found to have been in good health and HbA1C was within normal range (5.3–5.5%). He is currently on insulin pump therapy under the care of paediatrician, paediatric endocrinologist and dietician. His growth and school performance had been within normal limits at one-year follow up.

Discussion and conclusions

We report the case of this young boy who was initially admitted with dengue fever but subsequently developed DKA during the critical period of DHF. The rarity of this co-incidence in the paediatric age group and unexpected challenges in management of this child might inspire paediatricians. Altered haemostasis and plasma leakage have been two important pathophysiological mechanisms in DHF. Vascular leakage is caused by a transient increase in vascular permeability due to endothelial dysfunction and subsequent occurrence of haemoconcentration. The elevation of hematocrit greater than 20% is typically used as a cut-off to define the presence of leakage in dengue [ 5 ]. In patients with vascular leakage, excess intravenous fluid therapy can aggravate fluid accumulation and precipitates respiratory distress while substandard fluid treatment can cause shock. The osmotic diuresis in DKA results in large volume depletion. Typical total body water deficit among patients with DKA is 100 mL/kg of body weight, and the deficit becomes even higher with fluid loss in the phase of fluid leakage in DHF. Therefore, continuous monitoring and careful use of intravenous fluids are crucial in the management of patients with both DHF and DKA. The initial fluid therapy would be isotonic solutions to maintain satisfactory tissue perfusion and urine output should be at least 0.5 mL/kg/hour whilst insulin infusion is running. Intravenous fluids can be reduced gradually when plasma leakage decreases towards the end of the critical period which is usually signposted by an increase in urine output or decrease in hematocrit [ 6 ]. The reported child developed DKA during the critical period of DHF. We followed combined national and international guidelines for management of DKA and DHF. We managed the child with isotonic fluids and dextran 40 to restore the hypovolaemia. In addition, we were also guided by previous reports of dengue presenting with diabetes in adults [ 4 , 7 ] as we could not find any reported cases in children. Literature reported in adults had been mainly dengue infection diagnosed in patients with insulin independent diabetes mellitus (type 2).

DHF was considered as a trigger factor for DKA in this patient who had previously undiagnosed diabetes mellitus. There were few case reports of dengue triggering diabetic ketoacidosis [ 4 , 7 , 8 ]. Supradish et al. reported the case of a 16-year-old Thai girl who presented in dengue shock showing signs of severe dehydration and ascites [ 7 ] and one other review article reported that those who had diabetes were two and half times as likely to have dengue hemorrhagic fever [ 9 ] The physiopathology of dengue hemorrhagic fever leads to amplification of the immune response following presence of heterotypic antibodies against a serotype of the dengue virus at the time of new infection [ 10 ]. Thus Type 1 diabetes mellitus is commonly associated with autoimmunity and the immune system may be persistently activated with signs of inflammation in tissues and capillaries, and is more likely to lead to inflammation and liberation of pro-inflammatory cytokines in tissues, particularly in the endothelium, explaining the higher risk of plasma leak in dengue fever [ 11 ].

Although ideal total body water deficit is 100 mL/kg in children with severe DKA, the actual deficit increases more than ideal deficit in the presence of fluid leakage. Both DHF related shock and fluid deficit due to DKA were managed in this patient with 0.9% saline with frequent monitoring of blood glucose, blood gases and haemodynamic parameters including pulse rate, and pulse pressure. Fluid intake was adjusted to keep urine output at least 0.5 mL/kg/hour and pulse pressure at least 20 mmHg. Early recognition of DKA and DHF are crucial in preventing complications related to both conditions.

The reported patient had hypovolaemia with surprisingly high urine output during the critical phase of DHF due to concurrent DKA. This situation in critical phase of DHF made fluid management more difficult even with central venous pressure monitoring. Fluids were adjusted every hour with insulin dose until the child reached recovery phase with meticulous blood glucose monitoring. As the reported child tolerated food well, cooperated with the management and was conscious throughout the critical period, he made a rapid and complete recovery of both complications without needing invasive monitoring. Meticulous non-invasive monitoring in the intensive care needed more human resources and added more mental stress to clinicians and their team who treated this child.

We further could not use any invasive monitoring to adjust the fluid management as his platelet had been low although invasive monitoring was available in the tertiary care hospital. This was another challenge the clinicians faced during fluid management as he had a high chance of internal bleeding while inserting the central cannulas. Fortunately, the child did not have bleeding at any time of illness and non-invasive monitoring sufficed. As this patient was admitted to local hospital where patient had been managed with limited facilities including human resources, timely diagnosis of coexisting diabetic mellitus was a challenge in the management of this child and possibly contributed for a delay in transfer to the intensive care unit. However, the diagnosis of diabetic ketoacidosis was made without much delay, and the child improved without developing any unacceptable complications. The authors recommend that urine output should be carefully reviewed in all patients with DHF on individual basis and differential causes for discordant urine output should be identified and managed without delay to prevent complications.

Dengue can rarely present with various atypical endocrinological manifestations in children. Every clinician must anticipate DKA in children with disproportionately high urine output during dengue infection even though it is rare in children. Scrupulous and frequent monitoring is an important step in identifying co-morbidities and treating these children. We were channeled with contradicting findings of urine output and vital parameters to make the diagnosis successfully.

Availability of data and materials

The data that support the findings of this case report are available from Medical Records Department, Batticaloa Teaching Hospital, but restrictions apply to the availability of these data, which were used under license for the current report and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of Medical Records Department, Batticaloa Teaching Hospital, Sri Lanka.

Abbreviations

Dengue haemorrhagic fever

Diabetic ketoacidosis

Alanine transaminase

Aspartate transaminase

Haemoglobin A 1C

Intensive Care Unit

Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Review Dengue viral infections. Postgrad Med J. 2004;80:588–601. https://doi.org/10.1136/pgmj.2004.019638 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Kularatne SA. Dengue fever. BMJ. 2015;351:h4661. https://doi.org/10.1136/bmj.h4661 .

Article   CAS   PubMed   Google Scholar  

Kularatne SA, Weerakoon KG, Munasinghe R, Ralapanawa UK, Pathirage M. Trends of fluid requirement in dengue fever and dengue haemorrhagic fever: a single centre experience in Sri Lanka. BMC Res Notes. 2015;8:130. Published 2015 Apr 8. https://doi.org/10.1186/s13104-015-1085-0 .

Article   PubMed   PubMed Central   Google Scholar  

Dalugama C, Gawarammana IB. Dengue hemorrhagic fever complicated with transient diabetic ketoacidosis: a case report. J Med Case Rep. 2017;11(1):302. Published 2017 Oct 28. https://doi.org/10.1186/s13256-017-1476-z .

Srikiatkhachorn A, Spiropoulou CF. Vascular events in viral hemorrhagic fevers: a comparative study of dengue and hantaviruses. Cell Tissue Res. 2014;355:621–33. https://doi.org/10.1007/s00441-014-1841-9 .

World Health Organization. WHO Guidelines Approved by the Guidelines Review Committee. In: Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. Geneva: WHO Press; 2009. p. 1–144.

Google Scholar  

Supradish PO, Rienmanee N, Fuengfoo A, Kalayanarooj S. Dengue hemorrhagic fever grade III with diabetic ketoacidosis: a case report. J Med Assoc Thail. 2011;94:0–40.

Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes. A consensus statement from the American Diabetes Association. Diabetes Care. 2006;29:2739–48. https://doi.org/10.2337/dc06-9916 .

Figueiredo MA, Rodrigues LC, Barreto ML, et al. Allergies and diabetes as risk factors for dengue hemorrhagic fever: results of a case control study. PLoS Negl Trop Dis. 2010;4(6):e699. Published 2010 Jun 1. https://doi.org/10.1371/journal.pntd.0000699 .

Halstead SB. The pathogenesis of dengue: molecular epidemiology in infections disease. Am J Epidemiol. 1981;114(5):632–48. https://doi.org/10.1093/oxfordjournals.aje.a113235 .

Brown JM, Wilson TM, Metcalfe DD. The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy. 2008;38(1):4–18. https://doi.org/10.1111/j.1365-2222.1997.tb00665.x .

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Acknowledgements

We would like to thank Dr. K. Dharshini, Consultant Endocrinologist, and Dr. N. Yogananth, Consultant Anaesthetist.

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Thadchanamoorthy, V., Dayasiri, K. A case report of dengue hemorrhagic fever complicated with diabetic ketoacidosis in a child: challenges in clinical management. BMC Pediatr 20 , 403 (2020). https://doi.org/10.1186/s12887-020-02300-9

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Severe Dengue Fever with Haemolytic Anaemia-A Case Study

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  • 1 Department of Medicine, Melaka Manipal Medical College, Melaka 75150, Malaysia. [email protected].
  • 2 Consultant oncohematologist, 633 Gov. Carlos Canaco Rd., B5, Tamung, Guam 96913, USA. [email protected].
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Dengue fever, the most common arthropod-borne viral infection in South East Asia, is increasing in prevalence due partially to increased awareness and better diagnostic methods. While haematologic complications, such as cytopeniae and bleeding, may occur in severe dengue infection due to a variety of aetiologies, reports of haemolytic anaemia in dengue fever are scant. We report a case of severe dengue fever with haemolytic anaemia following the critical phase of infection.

Keywords: haemolytic anaemia; severe dengue fever.

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  • Case Reports

Wild Places, Clean Energy

The Planet Needs Solar Power. Can We Build It Without Harming Nature?

Today’s decisions about how and where to set up new energy projects will reverberate for generations.

case study of dengue fever

Catrin Einhorn reported from the grasslands north of Flagstaff, Ariz. Photos and video by Nina Riggio.

First in a series on how the energy transition affects wildlife.

For pronghorn, those antelope-like creatures of the American West, this grassland north of Flagstaff is prime habitat. It gives the animals the food and conditions they need to survive fall and winter.

But for a nation racing to adopt renewable energy, the land is prime for something else: solar panels. The sun shines strong, the terrain is flat and high-voltage transmission lines are already in place from a decommissioned coal plant. Energy collected here could speed to major metropolitan regions across the West, part of a colossal wave of clean power needed to stave off the worst effects of global warming.

Animals need humans to solve climate change. But they also need places to live. Loss of habitat is the top driver of a staggering global decline in biodiversity, the variety of life on earth. The boom in solar, set to be the fastest-growing energy source in the United States, is predicted to fence off millions of acres across the nation, blanketing them in rows of glassy squares.

The good news for wildlife is that there are ways for solar developers to make installations less harmful and even beneficial for many species, like fences that let some animals pass, wildlife corridors, native plants that nurture pollinators, and more.

But at this pivotal moment, as solar farms sprout across the country, those measures often go unused. Among the reasons: a patchwork of local and state regulations governing large-scale solar, not enough research on how animals interact with it, and an absence of federal guidelines on siting or design.

“We’re faced with two truths: We have a climate change crisis, but we also have a biodiversity crisis,” said Meaghan Gade, a program manager at the Association of Fish & Wildlife Agencies. “We have to be mindful that there’s wildlife that are dependent on these habitats, and we have to be smart and thoughtful about how we’re doing this deployment so that we can hold both of those crises at the same time.”

Eighty percent of states rely on voluntary approaches to minimize impacts to species and habitat, according to the association . As developers race ahead, the decisions they make today will reverberate for decades.

On the grassland north of Flagstaff, a ranching family, solar developers and state wildlife biologists have come together to try out solutions on the fly. One sunny day last fall, a helicopter descended over a herd of pronghorn streaking across shrubby grasslands near the site of a planned solar farm.

A wide shot of a helicopter closing in on a herd of pronghorn. The animals are darting along a plain of yellowish grass, with green mountains in the background.

Wildlife biologists chased down pronghorn to attach GPS collars in October near Flagstaff, Ariz.

A person in an orange shirt and black helmet attaches a collar to a captured and tied pronghorn.

The collars will help researchers understand how pronghorn and other animals interact with energy infrastructure.

Pronghorn are exceptional for their combination of speed and endurance. If there was a global mammal marathon, a pronghorn would probably win.

Even though they look like antelopes, they’re more closely related to giraffes. While Arizona’s pronghorn population is stable, it’s a small fraction of the species’ historic numbers.

A net shot from the helicopter, a buck fell and a wrangler jumped out. He tied the buck’s feet and a biologist blindfolded the heaving animal, hoping to calm him. Monitoring his temperature for signs of dangerous distress, they worked quickly to attach a tag to his ear and a GPS collar around his neck.

The collar will track how he responds to the solar farm, which will be broken up into sections. Fifteen corridors ranging from a quarter-mile to more than a half-mile will offer habitat and passage for pronghorn, mule deer and elk.

A moment later the pronghorn galloped away, an unknowing participant in an experiment in coexistence.

case study of dengue fever

‘There’s Always Competing Interests Out There.’

On the surface, the most wildlife-friendly practice might seem obvious.

“If you start with a site that has really no conservation value — it’s cleared, it’s degraded, whatever — then everything you do at that point is a win,” said Liz Kalies, an ecologist who studies clean energy for the Nature Conservancy and works in North Carolina, where forests have been felled to make way for solar.

Pollinators like bees, for example, can benefit from solar facilities that replace crops treated with pesticides, especially when the new installations include native species ( nearby crops can benefit, too ). In Kentucky, a solar farm is going up at the site of a former coal mine .

About a dozen glassy solar panels on a field of yellowish grass. They are surrounded by a tall chain-link fence.

A solar farm in North Carolina with chain-link fencing.

Kate Medley for The New York Times

But for developers, it’s not so easy. Getting permits and financing for work on former industrial sites can be tricky because of risks like leftover toxic waste. Rural communities sometimes oppose the conversion of agricultural areas to solar, arguing that arable land should be protected for food security and to maintain the economic health of farming towns.

And critically, developers need to be able to move the electricity, which makes the availability of transmission infrastructure paramount to any site.

“While it would be nice to think that there’s all of these low-conflict areas that developers could just go build on and everybody would leave them alone, in reality that’s not how things work,” said Tom Vinson, vice president of policy and regulatory affairs at the American Clean Power Association, which represents utility-scale solar developers. “There’s always competing interests out there.”

Potential solar sites are so ecologically varied that federal guidelines on wildlife and habitat wouldn’t be appropriate, he said. And solar developers already take precautions for animals and plants that are protected under the Endangered Species Act, the intensive care unit for wildlife.

case study of dengue fever

Permeable Fences Make Good Neighbors

All kinds of energy development exact a toll on all kinds of plants and animals.

Oil and natural gas reduce habitat and can cause pollution, including catastrophic spills. They also drive climate change, which is expected to replace habitat loss as the leading threat to the world’s biodiversity in future decades.

Wind turbines come with bird and bat collisions, though many of those deaths can be minimized , and the infrastructure doesn’t take up much space. Anecdotes abound of elk and pronghorn strolling around turbines or napping in their shade.

Solar farms need a lot more land per unit of energy. While they’re projected to take up a tiny fraction of the area dedicated to agriculture, they come on top of that, and on top of land occupied by cities, towns, roads and all kinds of industries.

Up to a third of potential solar development in the United States could overlap with areas that have high value for wildlife movement, according to one study , as animals move to adapt to climate change. (Rooftop and other small-scale solar can go a long way to taking pressure off big installations, but U.S. energy demand would still require a surge in large-scale projects.)

One way to reduce solar’s damage is wildlife-friendly fencing.

A short video of a reddish fox urinating on a post at a solar site and then darting through a chain-link fence with wide spacing.

Nature calls at a solar site in North Carolina.

The Nature Conservancy

National electricity codes require fencing to protect people from electrical hazards and infrastructure from damage. Simply replacing the conventional chain-link version with fencing that has wider gaps will let creatures like foxes scamper through. Raising the bottom of a fence off the ground, to offer a few inches of passage, accomplishes the same thing.

In Florida, a combination of four- and six-foot fencing allows panthers and deer to jump into many of Florida Power and Light’s solar facilities, said Jack Eble, a company spokesman. Wooden supports that shore up fences let medium-sized animals crawl over, and larger openings at the bottom give access to small animals.

“We have not experienced any issues with wildlife damaging solar panels or other solar-related infrastructure to date,” Mr. Eble said.

case study of dengue fever

Fencing that’s raised slightly off the ground allows animals, in this case a coyote in North Carolina, to pass through.

A black-and-white image of a bobcat slipping through a fence at night amid tall grass.

Chain-link fences with wider gaps are used for small and midsized wildlife, like this bobcat in Tennessee.

But so far, wildlife friendly fencing is not commonly used, according to Josh Ennen, a senior scientist at the Renewable Energy Wildlife Institute, a nonprofit collaboration that seeks to find solutions to wildlife conflicts and is mostly funded by industry.

Developers are often unfamiliar with the options for wildlife-friendly fencing, and it may not be easily available. Furthermore, many worry it will backfire if federally protected animals use the permeable fencing to wander onto the site. Suddenly, developers would have to worry about fines for driving over, say, a baby desert tortoise.

Regulations can get in the way, too. Around the country, solar facilities are subject to a disparate patchwork of local and state rules, some of which require specific kinds of fencing.

These challenges need to be solved quickly, biologists and wildlife advocates say.

“It’s not something we can easily retrofit,” Dr. Kalies said. “Developers don’t want to tear down a fence once it’s up.”

A Trade-Off for the Future

At Babbitt Ranches, the solar farm’s fencing will be raised off the ground for smaller animals like rabbits. Pronghorn, mule deer and elk will be kept out because of the developer’s concerns that they could damage equipment or hurt themselves. For those animals, they’re planning the corridors.

Long known for Hereford cattle and quarter horses, Babbitt Ranches stretches over 700,000 acres of private and leased public land. Transmission lines have drawn a crowd of clean energy developers, and the first wind turbines have already gone up.

Clenera, a solar developer, approached the ranch in 2018. For Babbitt’s president, Bill Cordasco, the idea of a large solar project was appealing both financially and morally. It would bring in revenue for the family business while helping reduce climate risks for future generations. But he knew the pronghorn relied on that land. Mr. Cordasco wanted to find a solution that would meet everyone’s needs, including the pronghorn.

“If you guys aren’t interested in working through this pronghorn deal, it ain’t going to happen,” he recalled telling Clenera during their first in-person meeting.

Bill Cordasco, wearing jeans and a blue, long-sleeved shirt, sitting on the ground in a forest clearing.

Bill Cordasco, president of Babbitt Ranches.

A right hand pointing at a map entitled “pronghorn and mule deer corridor use.” It appears to be spread out in the bed of a pickup truck.

A map showed how pronghorn and deer movements intersect with planned renewable energy projects.

Clenera was interested.

State wildlife officials already had data from earlier GPS collaring, so they knew how pronghorn and mule deer moved through the area. A renewable energy ordinance passed by Coconino County gave additional teeth to the importance of maintaining wildlife linkages in solar facilities.

A back-and-forth over the site design led to adding migration corridors and closing off some dead-end areas where animals could have gotten trapped or disoriented. Developers and wildlife officials discussed the pros and cons of quarter-mile versus half-mile corridors. (Would the smaller ones be wide enough for the animals to use? Would the larger be worth a significant increase in the overall footprint?) In the end, everyone agreed on the range of different corridors, creating a kind of natural experiment.

The miles of additional high-voltage cable and the extra fencing required to break big sections of solar panels into smaller ones make the project more expensive, Clenera officials said, though they declined to say how much. Mr. Cordasco also asked them to help fund long-term studies on the impact of the solar farm on wildlife migration.

“It’s a lot of money,” said Tom Fitzgerald, vice president of development at Clenera. “That’s also the cost of getting all of the stakeholders to get behind you and to support your project, and to pay to be a contributing member of any community.”

Jeff Gagnon, a biologist with the Arizona Game and Fish Department who oversaw the collaring effort, was thrilled to have his agency’s advice taken seriously. He focuses on habitat connectivity, and while dozens of solar projects have come to his agency for review, he said, developers often disregard or minimize their recommendations.

“They can take it or leave it,” he said.

This time, he pointed out, Mr. Cordasco made sure things went differently.

Mr. Cordasco knows the pronghorn he loves could be negatively affected, but he believes the damage will be minimized and the trade-off will be worth it for generations of people and wildlife to come.

“When you make these bigger decisions,” Mr. Cordasco said, “you have to have a very long-term view.”

A long pronghorn crossing a dirt road lined with trees and telephone poles. The sky is big and clear blue.

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