case study of dengue fever

• 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.

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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

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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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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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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 .

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.

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

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 .

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.

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.

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Acknowledgements

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Northwest General Hospital & Research Centre, Peshawar, Pakistan

Syed Muhammad Owais & Khatira Wahid

Quaid e Azam International Hospital, Rawalpindi, Pakistan

Farrukh Ansar

Khyber Medical College, Peshawar, Pakistan

Muhammad Saqib

James Cook University Hospital, Middlesbrough, UK

Khalid Rashid

University of Sunderland, Sunderland, England, UK

Maroof International Hospital, Islamabad, Pakistan

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Health Services Academy, Islamabad, Pakistan

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Contributions

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.

Corresponding author

Correspondence to Muhammad Saqib .

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The care of patient described in this case report was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient before any clinical procedures were performed. All personal and identifying information has been de-identified to protect the privacy of the patient. A CARE checklist is provided in Fig.  5 .

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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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Volume 30, Number 1—January 2024

Research Letter

Autochthonous dengue fever in 2 patients, rome, italy.

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Since August 2023, outbreaks of dengue virus (DENV) infection have occurred in Italy. We report 2 autochthonous case-patients and their extended follow-up. Despite persistent DENV detected in blood by PCR, results for antigenomic DENV RNA were negative after day 5, suggesting that a 5-day isolation period is adequate to avoid secondary cases.

Dengue virus (DENV) infection is the most prevalent arthropodborne viral disease in humans, caused by 4 DENV serotypes widely spread in tropical and subtropical regions and transmitted mainly by Aedes mosquitoes ( 1 ). Aedes albopictus mosquitoes colonizing every continent except Antarctica has led to an increase in areas of Europe at risk for Aedes -borne viruses ( 2 , 3 ). During August–October 2023, a total of 68 case-patients who had DENV infection and no travel link were reported in Italy, 36 (53%) in Lombardia and 32 (47%) in Lazio; all had a good clinical condition ( 4 , 5 ). We report 2 autochthonous case-patients who had DENV infection and prolonged viral shedding during a follow-up period of 28 days after symptoms onset.

On August 31, a 46-year-old man (case-patient 1) and a 48-year-old woman (case-patient 2) who were living in Rome, Italy, and had no history of recent international travel or of yellow fever vaccination were referred to the National Institute for Infectious Diseases L. Spallanzani in Rome for history of fever. Both persons were on holiday during August 14–21. On August 27, eighty km south of Rome, where 1 imported DENV case was previously reported, case-patient 1 had a 2-day history of fever with bilateral conjunctivitis and a face and trunk macular rash, and case-patient 2 had a 1-day history of fever with myalgia and arthralgia. No major concurrent illnesses were present.

At admission, we tested the 2 patients for DENV nonstructural protein 1 (NS1) and IgM and IgG by using fluorimetric rapid assays (Standard F Dengue NS1 Ag FIA and Standard F Dengue IgM/IgG FIA; SD Biosensor, https://www.sdbiosensor.com ) ( 6 ). For both patients, rapid assays were positive for DENV NS1 antigen only, which is considered an early marker for acute DENV infection ( 7 ). Results for chikungunya virus, HIV, hepatitis B virus, and hepatitis C virus were negative. Hematologic analyses showed platelet values within reference limits but leukopenia (minimum 2,760 cells/mm 3 for case-patient 1 and 1,850 cells/mm 3 for case-patient 2; reference range 4,000–11,000 cells/mm 3 ) and lymphocytopenia (minimum 750 cells/mm 3 for case-patient 1 and 230 cells/mm 3 for case-patient 2; reference range 1,000–4,800 cells/mm 3 ).

Case-patient 1 had continuous fever (maximum temperature 38.5°C) until day 8, skin macular rash and lymphopenia until day 9, and lowest platelet level (98,000 cells/mm 3 ) on day 9. Case-patient 2 had fever (maximum temperature 38.7°C), headache, myalgia, arthralgia, and lymphopenia until day 7.

We performed molecular and serologic analyses during the 28-day follow-up period ( Appendix ). DENV-specific reverse transcription PCR on plasma and blood samples collected within 3 days after symptom onset yielded positive results, enabling us to identify a DENV-3 infection ( 8 ). Plasma samples remained positive until day 9 for case-patient 1 and day 8 for case-patient 2. Blood samples were positive at day 17 for case-patient 1 and day 16 for case-patient 2. Saliva sample results were positive until day 9 for case-patient 1 and day 8 for case-patient 2. Positive urine samples were observed only at day 9 for case-patient 1 and day 16 for case-patient 2. Ocular swab specimens remained negative for both patients. At the end of the 28-day follow-up period, all samples were negative in the DENV molecular assay.

We analyzed serum and saliva samples by using an immunofluorescence assay to detect DENV-3–specific IgM, IgG, and IgA at serologic and mucosal levels ( Appendix ). IgM appeared in serum samples by day 6 and seroconversion of IgG by day 9 in both case-patients. In saliva, IgM, IgG, and IgA were always negative for case-patient 1, and a positive result was obtained for IgA at day 8 for case-patient 2, suggesting an absent/poor antibody response at the mucosal level for these patients.

To determine whether the DENV genome in plasma/blood samples was associated with active viral replication, we measured levels of antigenomic DENV RNA (negative-strand) ( Appendix ) by using a DENV type 3–specific forward primer because we considered it to be an indirect marker of ongoing viral replication ( 9 ). Both patients had antigenomic DENV RNA during the acute phase of infection (i.e., day 3), and case-patient 2 was positive for antigenomic DENV RNA until day 5. Thereafter, despite prolonged viral persistence detected by reverse transcription PCR in plasma/blood until day 16, the antigenomic DENV RNA test results were always negative, suggesting absence of ongoing active viral replication. Patients were discharged at day 9 (case-patient 1) and day 8 (case-patient 2) in good clinical condition.

DENV-infected patients can transmit the virus to Aedes mosquitoes if bitten after symptom onset. Therefore, patients should use precautionary measures to reduce the risk for transmission (i.e., sleeping alone) during the first 7 days of febrile illness.

Our results suggest that prolonged viral shedding is not always a marker of ongoing replication in blood, and that the 5-day isolation period might be adequate to prevent transmission ( 10 ). This observation is relevant for nonendemic countries to limit generation and spread of autochthonous cases.

Dr. Vita is a research scientist at the National Institute for Infectious Diseases Lazzaro Spallanzani, Rome, Italy. Her primary research interests are chronic and emerging acute infections.

L.B. and S.V. analyzed results and wrote and edited the article; C.M. and D.L. performed serologic testing; E.S. and G.S. performed molecular testing; A.D., P.C., and A.C. enrolled patients and edited the article; F.V., F.M., and E.G. reviewed and edited the article; and E.N. and E.L. conceptualized, reviewed, and edited the article.

Acknowledgments

This study was supported by the Ministero della Salute: Ricerca Corrente, Linea 1.

This study was conducted in accordance with the Declaration of Helsinki and protocol code no. 70 and approved on December 17, 2018, by the institutional review board of the National Institute for Infectious Diseases, L. Spallanzani, Istituto di Ricovero e Cura a Carattere Scientifico, according to which the study protocol did not provide informed consent by patients because no additional samples were taken other than those used for diagnostic purposes. Data for biologic samples collected for diagnostic purposes were used only after their complete anonymization. Analysis of genetic data was not provided.

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DOI: 10.3201/eid3001.231508

Original Publication Date: November 15, 2023

1 These authors equally contributed to this article.

Table of Contents – Volume 30, Number 1—January 2024

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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  

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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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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.

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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 30 , 670–674 (2024). https://doi.org/10.1038/s41591-024-02798-x

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Factors contributing to in-hospital mortality in dengue: insights from national surveillance data in mexico (2020–2024).

1. Introduction

2. materials and methods, 4. discussion, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Ríos-Bracamontes, E.F.; Mendoza-Cano, O.; Lugo-Radillo, A.; Ortega-Ramírez, A.D.; Murillo-Zamora, E. Factors Contributing to In-Hospital Mortality in Dengue: Insights from National Surveillance Data in Mexico (2020–2024). Trop. Med. Infect. Dis. 2024 , 9 , 202. https://doi.org/10.3390/tropicalmed9090202

Ríos-Bracamontes EF, Mendoza-Cano O, Lugo-Radillo A, Ortega-Ramírez AD, Murillo-Zamora E. Factors Contributing to In-Hospital Mortality in Dengue: Insights from National Surveillance Data in Mexico (2020–2024). Tropical Medicine and Infectious Disease . 2024; 9(9):202. https://doi.org/10.3390/tropicalmed9090202

Ríos-Bracamontes, Eder Fernando, Oliver Mendoza-Cano, Agustin Lugo-Radillo, Ana Daniela Ortega-Ramírez, and Efrén Murillo-Zamora. 2024. "Factors Contributing to In-Hospital Mortality in Dengue: Insights from National Surveillance Data in Mexico (2020–2024)" Tropical Medicine and Infectious Disease 9, no. 9: 202. https://doi.org/10.3390/tropicalmed9090202

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Dengue infection in India: A systematic review and meta-analysis

Affiliations.

• 1 Department of Epidemiology, National Institute of Epidemiology, Chennai, Tamil Nadu, India.
• 2 School of Public Health, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
• 3 Campbell Collaboration, New Delhi, India.
• 4 Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, India.
• PMID: 30011275
• PMCID: PMC6078327
• DOI: 10.1371/journal.pntd.0006618

Introduction: Dengue is the most extensively spread mosquito-borne disease; endemic in more than 100 countries. Information about dengue disease burden, its prevalence, incidence and geographic distribution is critical in planning appropriate control measures against dengue fever. We conducted a systematic review and meta-analysis of dengue fever in India.

Methods: We searched for studies published until 2017 reporting the incidence, the prevalence or case fatality of dengue in India. Our primary outcomes were (a) prevalence of laboratory confirmed dengue infection among clinically suspected patients, (b) seroprevalence in the general population and (c) case fatality ratio among laboratory confirmed dengue patients. We used binomial-normal mixed effects regression model to estimate the pooled proportion of dengue infections. Forest plots were used to display pooled estimates. The metafor package of R software was used to conduct meta-analysis.

Results: Of the 2285 identified articles on dengue, we included 233 in the analysis wherein 180 reported prevalence of laboratory confirmed dengue infection, seven reported seroprevalence as evidenced by IgG or neutralizing antibodies against dengue and 77 reported case fatality. The overall estimate of the prevalence of laboratory confirmed dengue infection among clinically suspected patients was 38.3% (95% CI: 34.8%-41.8%). The pooled estimate of dengue seroprevalence in the general population and CFR among laboratory confirmed patients was 56.9% (95% CI: 37.5-74.4) and 2.6% (95% CI: 2-3.4) respectively. There was significant heterogeneity in reported outcomes (p-values<0.001).

Conclusions: Identified gaps in the understanding of dengue epidemiology in India emphasize the need to initiate community-based cohort studies representing different geographic regions to generate reliable estimates of age-specific incidence of dengue and studies to generate dengue seroprevalence data in the country.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Fig 1. Flow diagram showing the article…

Fig 1. Flow diagram showing the article selection in the systematic review on dengue in…

Fig 2. Distribution of median age of…

Fig 2. Distribution of median age of laboratory confirmed dengue cases by year of study,…

Fig 3. Prevalence (proportion) of laboratory confirmed…

Fig 3. Prevalence (proportion) of laboratory confirmed dengue among clinically suspected patients in India.

Fig 4. Seroprevalence of dengue in India.

Error bars indicate 95% confidence intervals. Diamonds show…

Fig 5. Studies reporting case fatality ratio…

Fig 5. Studies reporting case fatality ratio among laboratory confirmed dengue cases in India.

Fig 6. Proportion of secondary infection among…

Fig 6. Proportion of secondary infection among laboratory confirmed dengue cases in India.

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Fig 7. Proportion of severe dengue infections…

Fig 7. Proportion of severe dengue infections among laboratory confirmed dengue cases in India.

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Research Article

A systematic review of dengue outbreak prediction models: Current scenario and future directions

Roles Data curation, Project administration, Writing – original draft, Writing – review & editing

Affiliation School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

Roles Data curation, Project administration, Writing – review & editing

Roles Conceptualization, Supervision, Writing – review & editing

Roles Data curation, Project administration, Visualization, Writing – review & editing

Roles Supervision, Visualization, Writing – review & editing

Roles Conceptualization, Writing – original draft, Writing – review & editing

Affiliation Department of Virology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Roles Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

• Xing Yu Leung, 
• Rakibul M. Islam, 
• Mohammadmehdi Adhami, 
• Dragan Ilic, 
• Lara McDonald, 
• Shanika Palawaththa, 
• Basia Diug, 
• Saif U. Munshi, 
• Md Nazmul Karim

• Published: February 13, 2023
• https://doi.org/10.1371/journal.pntd.0010631
• Peer Review
• Reader Comments

Dengue is among the fastest-spreading vector-borne infectious disease, with outbreaks often overwhelm the health system and result in huge morbidity and mortality in its endemic populations in the absence of an efficient warning system. A large number of prediction models are currently in use globally. As such, this study aimed to systematically review the published literature that used quantitative models to predict dengue outbreaks and provide insights about the current practices. A systematic search was undertaken, using the Ovid MEDLINE, EMBASE, Scopus and Web of Science databases for published citations, without time or geographical restrictions. Study selection, data extraction and management process were devised in accordance with the ‘Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies’ (‘CHARMS’) framework. A total of 99 models were included in the review from 64 studies. Most models sourced climate (94.7%) and climate change (77.8%) data from agency reports and only 59.6% of the models adjusted for reporting time lag. All included models used climate predictors; 70.7% of them were built with only climate factors. Climate factors were used in combination with climate change factors (13.4%), both climate change and demographic factors (3.1%), vector factors (6.3%), and demographic factors (5.2%). Machine learning techniques were used for 39.4% of the models. Of these, random forest (15.4%), neural networks (23.1%) and ensemble models (10.3%) were notable. Among the statistical (60.6%) models, linear regression (18.3%), Poisson regression (18.3%), generalized additive models (16.7%) and time series/autoregressive models (26.7%) were notable. Around 20.2% of the models reported no validation at all and only 5.2% reported external validation. The reporting of methodology and model performance measures were inadequate in many of the existing prediction models. This review collates plausible predictors and methodological approaches, which will contribute to robust modelling in diverse settings and populations.

Author summary

Dengue is considered as a major public health challenge and a life-threatening disease affecting people worldwide. Over the past decades, numerous forecast models have been developed to predict dengue incidence using various factors based on different geographical locations. Dengue transmission appears to be highly sensitive to climate variability and change, however quantitative models used to assess the relationship between climate change and dengue often differ due to their distribution assumptions, the nature of the relationship and the spatial and/or temporal dynamics of the response. We performed a systematic review to examine current literature surrounding existing quantitative models based on development methodology, predictor variable used and model performance. Our analysis demonstrates several shortcomings in current modelling practice, and advocates for the use of real time primary predictor data, the incorporation of non-climatic parameters as predictors and more comprehensive reporting of model development techniques and validation.

This review collates methodological approaches adopted in the modelling practices in the field across current literature. This will provide an evidence-based framework for upgrading future modelling practice to develop more accurate predictive models with robust techniques. In turn, this also provided an opportunity for the effective distribution of limited public health resources to prepare for demand.

Citation: Leung XY, Islam RM, Adhami M, Ilic D, McDonald L, Palawaththa S, et al. (2023) A systematic review of dengue outbreak prediction models: Current scenario and future directions. PLoS Negl Trop Dis 17(2): e0010631. https://doi.org/10.1371/journal.pntd.0010631

Editor: Husain Poonawala, Tufts Medical Center, UNITED STATES

Received: July 5, 2022; Accepted: January 29, 2023; Published: February 13, 2023

Copyright: © 2023 Leung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors declare that they have no conflicts of interest.

Introduction

Dengue fever is one of the fastest-spreading mosquitos-borne disease primarily of tropical and subtropical regions and is caused by various dengue virus strains [ 1 , 2 ]. In 2017 alone, over 100 million people were estimated to have acquired the infection, contributing to a globally increasing burden of disease [ 3 ]. Although most infections are mild, dengue shock syndrome and dengue haemorrhagic fever are severe forms of infections and can be fatal [ 4 , 5 ]. The case-fatality rate can be as high as 20% in the absence of prompt diagnosis and lack of specific antiviral drugs or vaccines [ 6 , 7 ], particularly in resource-limited settings. When an outbreak is particularly large, the influx of severe dengue cases can overwhelm the health system and prevent optimal care. Dengue also imposes an enormous societal and economic burden on many of the tropical countries where the disease is endemic [ 8 ]. An accurate prediction of the size of the outbreak and trends in disease incidence early enough can limit further transmission [ 5 ], and is likely to facilitate planning the allocation of healthcare resources to meet the demand during an outbreak.

Vector-borne pathogens characteristically demonstrate spatial heterogeneity—a result of spatial variation in vector habitat, climate patterns and subsequent human control actions [ 9 – 11 ]. The interplay of human, climate and mosquito dynamics give rise to a complex system that determines the pattern of dengue transmission, which in turn influences the potential for outbreak [ 12 ]. These relationships have been explored over the decades in the development of predictive models worldwide. Models vary widely in their purposes [ 13 – 15 ] and settings [ 16 – 21 ]. Many of these models excel at different tasks, however for a prediction model to be efficient, it requires a systematic, self-adaptive and generalizable framework capable of identifying weather and population susceptibility patterns across geographic regions. The scientific community has not yet agreed upon a model that provides the best prediction. The selection of predictors for the existing models is also quite heterogeneous. Some models rely solely on climate variables [ 16 ], some include vector characteristics [ 17 , 18 ] others use population characteristics [ 19 – 21 ]. A wide range of statistical techniques are used with varying degrees of accuracy and robustness among the existing models [ 16 – 21 ].

Clarity in the documentation of the model development processes and model performance are essential for ensuring the robustness of the prediction [ 22 ], which is scarce as many of the existing models have not yet been systematically appraised. Given the disparate approaches, a focused synthesis and appraisal of the existing models, along with their building techniques and factor catchments, is required. Carefully establishing these details will provide the foundation for updating and developing robust models in future. This study aimed to systematically review all published literature that reported quantitative models to predict dengue outbreaks, revealing several shortcomings in the usage of real time primary predictive data and non-climatic predictors in the development of models, as well as inadequate reporting of techniques, model and performance measure validation.

Search strategy and selection criteria

This systematic review’s aim, search strategy and study selection process were devised in accordance with the seven items in the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (‘CHARMS’) framework [ 23 ]. CHARMS framework is a systematic review tool, devised to facilitate and guide the methodological aspects the systematic review of prediction modelling studies, ranging from question development, appraisal of studies, and data extraction thereof. Detail of the CHARMS checklist can be found elsewhere [ 23 ]. The review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (‘PRISMA’) guidelines [ 24 ], and was registered in PROSPERO (CRD42018102100).

A literature search was conducted from inception until October 2022 using the electronic databases of Ovid MEDLINE, Embase, Scopus and Web of Science to obtain the information on the statistical models for predicting the number of dengue cases based on climatic factors. Google Scholar and the bibliography of included papers were also searched. The search strategies were developed under the guidance of an information specialist from Monash University Library. For the purposes of this study, dengue fever or dengue haemorrhagic fever or dengue shock syndrome were considered as a single entity “dengue”. Search strategy included Medical Subject Headings (‘MeSH’) and keyword terms including “dengue”, “severe dengue,” “weather,” “climate change,” “model,” “predict,” and “forecast.” The detailed search strategy and history are presented in S1 Table .

The review included studies focused on (1) prognostic prediction models which aim to review models predicting future events, (2) incidence of dengue fever or dengue haemorrhagic fever cases, (3) models to be used to predict the number of cases prior to an outbreaks, (4) models intended to inform public health divisions of future dengue outbreaks, (5) models with no restrictions on the time span of prediction and (6) prediction model development studies without external validation, or with external validation in independent data. Peer-reviewed original articles that presented a model and were available as full-text articles were considered eligible if they focused on predicting the number of dengue cases or an outbreak based on number of dengue incidence. Articles that focused on updating previously developed models were only included if they presented an updated version of the model. Articles which dealt exclusively with dengue in international travellers, or which only analyse the correlation between climate parameters and dengue cases without presenting a prediction model were excluded. Furthermore, articles which used models for predicting the population of dengue vectors (e.g., Aedes aegypti or Aedes albopictus ) as well as articles which only offer susceptible-infected-recovered modelling stochastic or transmission rates modelling were excluded. Articles which presented a model only dealing with spatial or temporal components of dengue risk were considered ineligible. Conference proceedings, book chapters, abstracts or letters were also excluded. Titles and abstracts of the retrieved articles were screened independently by two reviewers (RMI, MMA). Two review team members (LM, XYL) then retrieved the full text of those potentially eligible studies and independently assessed their eligibility. Disagreements were resolved by a third reviewer (MNK). A detailed study selection process is illustrated in the PRISMA flow diagram ( Fig 1 ) [ 24 ].

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https://doi.org/10.1371/journal.pntd.0010631.g001

Data analysis

Based on the data extraction fields of the CHARMS framework [ 23 ], a standardised table was developed to extract data from the selected studies for assessment of quality and evidence synthesis. The data extraction table consists of eleven domains, each with a specific item, that extract data from the reports of the primary forecasting model. Key information extracted from the included articles were period and geographical region, sources of data, outcomes to be predicted, modelling covariates variables, sample size, statistical techniques, model performances, model evaluation, and key findings. Information regarding handling and/or reporting of missing data was also extracted. Each paper was independently reviewed by two reviewers (MMA, XYL) and discrepancies were resolved through discussion with each other or with a third reviewer (SP) where necessary.

Extracted data from the selected studies were summarised and the key information about the methodological characteristics of these models were tabulated. Descriptive statistics were generated based on model characteristics and comparative methodological features such as outcome types, target population, data sources and predictor selection techniques. All statistical analyses were performed using Stata (version 17.0).

The initial search yielded 6553 studies. After duplicates were removed, 3244 studies were screened for titles and abstracts. This led to 153 studies for full text review, and 64 that strictly met the inclusion criteria ( Fig 1 ), 16 of these studies reported multiple models. A total of 99 models from 64 selected studies were identified. Characteristics of the models including, year, country and source of data used, predictors and outcome of the models, overall model development technique and model performance related variables are summarised in Table 1 [ 14 , 15 , 17 – 21 , 25 – 81 ].

https://doi.org/10.1371/journal.pntd.0010631.t001

Table 2 presents the sources of data used for modelling. Most of the models (90.7%) sourced dengue incidence data from surveillance and 44.3% used registry data, while 34.0% also used hospital or laboratory data. While most (94.7%) of the models used climate data from government agency reports, only around 22.1% of the models used data from the meteorological stations in real-time. Climate change data was also sourced mostly (77.8%) from government agency reports, only 11.1% used international environmental agency data and 22.2% used local environmental agency report. Half (50.0%) of the models used vector data from entomological surveillance and 25.0% used vector data from laboratory sources. Around 83.8% of the models were built based on the sample from general population, 16.2% used only urban samples. Around 46.9% of the models used monthly aggerate data, over a third (29.3%) used weekly aggregate data and 23.2% used daily aggregated data of the predictors. The majority (59.6%) of the models incorporated reporting time lag adjustment. Although 17.2% of the models addressed the missing data, 30.3% did not address the issue, while the majority (52.5%) did not specifically report the missing value. Around 80.8% of the models were intended to predict the number of dengue cases and 19.2% focused on predicting dengue outbreaks, based on predetermined case number threshold.

https://doi.org/10.1371/journal.pntd.0010631.t002

Table 3 summarises the statistical methods adopted by the prediction models. Modelling techniques were broadly categorised under two genres, statistical models (60.6%) and machine learning (39.4%). The statistical models were broadly comprised of linear regression models (18.3%), time series/autoregressive models (26.7%), Poisson regression models (18.3%) and generalized additive models (16.7%). Neural networks models (23.1%), random forest models (15.4%), and ensemble models (10.3%) were types of machine learning models used.

https://doi.org/10.1371/journal.pntd.0010631.t003

All theoretically plausible predictors were considered as candidate predictors in 71.7% of models and pre-selection of predictors based on unadjusted association with the model outcome was considered in 28.3% of models. Reporting of essential modelling techniques was heterogeneous– 84.8% of models reported model performance, 58.6% reported model calibration and 47.5% reported model discrimination. Among the performance metrices, Root Mean Squared Error (‘RMSE’) (11.1%), Mean Squared Error (‘MSE’) (7.3%), Mean Absolute Percentage Error (‘MAPE’) (5.1%), and Receiver Operating Characteristic (‘ROC’) (5.1%) were notable. Of these models, most (75.8%) reported the internal validation alone, only 5.2% reported both internal and external validation and 20.2% reported no validation at all. The validation techniques included: split sample validation (development and validation) (20.3%), cross validation, which involves resampling of the derivation sample (40.5%) and performance metrics (29.1%).

Table 4 presents the factors used for prediction models. All of the models included in the review used climate predictors in their model. Among the climate predictors: humidity (77.4%), temperature (95.2%) and rainfall (81.0%), were used in most models. Windspeed and direction (27.4%), precipitation (15.5%) and sunshine (10.7%) were among other notable climate factors. Considering the similarity of the description of factors, climate change and environmental factors were collapsed in to one category under climate change. Overall, 18.2% of the models used climate change and/or environmental predictors. El Nino-Southern Oscillation (‘ENSO’), Southern Oscillation Index (‘SOI’), Oceanic Nino Index (‘ONI’), hydric balance and vegetation index were among the key climate change predictors. Vegetation Index and enhanced vegetation index were among the key environmental factors reported.

https://doi.org/10.1371/journal.pntd.0010631.t004

Vector-related predictors were included in 8.1% of models, and the key vector related predictors were container index, Breteau index, adult productivity index, breeding percentage and mosquito infection rate. Demographic predictors were included in 8.1% of models, and key demographic predictors were, population size, population density, area under the urban settlement, access to piped water, education coverage and GDP per capita ( Table 4 ).

The combination of the predictors used in the model are depicted in Fig 2 . While majority (70.7%) of the models were built solely on climate predictors, none of the models used the combination of all four (climate, climate change, vector and demography) categories of predictors. The combination of climate, climate change and demographic predictors was used in 3.1% of the models and the combination of climate and climate change predictors were used in 13.4% models. Among other notable combinations were, climate and vector predictors (6.3%) and climate and demographic predictor (5.2%).

https://doi.org/10.1371/journal.pntd.0010631.g002

This systematic review evaluated 99 dengue outbreak prediction models from 64 studies, predicting the number of dengue cases or outbreaks from a variety of settings and populations. Our review identified, three major area of inadequacy in the current modelling practices. Firstly, use of secondary predictor data—acquired from reports—were quite prevalent among models. Secondly, as data for other non-climate variables were not included in the majority of the models, they failed to capture a holistic view of dengue development in the prediction process. Lastly, inadequacy in the reporting of methodology, model validation and performance measures were quite prevalent in the existing prediction models. One positive aspect seen in the current modelling practice is the shift toward robust modelling technique, such as use of machine learning algorithm and autoregressive time series techniques.

While effective treatments and prevention measures are still being developed, an early warning system for an epidemic has the potential to reduce the toll of severe disease on the health system and population [ 82 ]. Developing a clearer understanding of the factors affecting dengue transmission is an important step towards mitigating the impact of the disease on health systems and on communities at large. Early prediction of dengue incidences or alerts regarding impending outbreak may contribute to the health system preparedness through effective resource mobilization and creating public awareness. Such predictions also have policy implications, as epidemiological evidence generated through modelling feeds the policy making process and facilitates the prioritization of interventions, such as vector control and environmental modification particularly in regard to climate change [ 83 ]. Considering dengue is a mosquito-borne disease, the majority of outbreak prediction models focus on climate dependency of mosquito breeding and dengue transmission [ 4 – 7 ]. While many models have been successful in predicting relative cases of dengue in real settings, incorrect prediction results have been observed in several included studies. For example, a model by Adde et al. [ 26 ] was unable to forecast a dengue outbreak in 2001–2005 with the use of climate data from 1991–2000. One of the potential reasons for their inaccurate prediction is the geo-spatial variation of climate and environment within regions. In their study, the decision to include vastly heterogenous geographical areas led to variation in model prediction, which—be due to exclusion of non-climatic factors—may be the explanation of the poor performance in many of the earlier prediction models could. An increasing number of later models appears to incorporate a wide range of vector parameters as well as demographic parameters. Chang et al. pointed out that, entomological (vector) factor combined with other meteorological (climate) factors, have better prediction performance, and their prediction accuracy is often higher than that of climate predictors alone [ 21 ].

For dengue incidence data, the majority of the models relied on reports from government organizations based on notifiable data. Notification involves passive surveillance, where there is potential for systematic underreporting along with varying time lag. Modelling with data from active surveillance or real-time study may minimize such limitations. A considerable number of models did not consider the time lag affecting the prediction, which may be responsible for possible delays in weather affecting mosquito vectors and subsequently viruses. Due to the nature of dengue disease dynamics, failure to address time lag in model development is likely to affect prediction accuracy. Critical points in the natural history of disease timeline those may generate time lag may start with mosquito development, and subsequently also during acquisition and amplification virus in mosquitoes, mosquito host behaviour (i.e. biting and feeding pattern) and the incubation period of the virus in the human body [ 12 , 48 ]. Some studies have found a positive correlation between climate variables with time-lags at several points in the natural history of disease timeline [ 48 , 53 ]. Therefore, the adjustment for the time lags while predicting dengue is indispensable, especially when meteorological data is used [ 12 ].

The majority of included models were built on conventional regression techniques. According to recent literature, the time series technique is particularly considered effective in predicting the highly auto-correlated nature of dengue infection [ 84 , 85 ]. Machine learning techniques are employed in around 40% of the included models, and is particularly prevalent among the recently developed models. Batista et al. confirmed superiority with ML techniques demonstrating a lower error rate compared to the conventional statistics-based model in predicting dengue cases. In the age of big data, this technique can leverage data availability and in addition to being non-parametric in nature, can also provide some leeway in terms of strict assumption [ 86 ]. Random forest, neural networks, gradient boosting and support vector algorithms are notable subsets of machine learning algorithms, which have made significant contributions to several areas of public health, particularly in the forecasting of infectious diseases like malaria [ 87 ] and COVID-19 [ 88 ], and may have similar utility for making dengue outbreak predictions. Although machine learning in gaining popularity, future modelling in this area may benefit from using mechanistic models [ 89 ]. This modelling technique have played an essential role in shaping public health policy over the past decades [ 90 ]. Mechanistic models have the potential to provide additional insight regarding precise dynamics of the transmission and infection of dengue. As these models highlight underlying processes that drive the patterns. These models can particularly aid in the prediction through incorporating the observed trajectory of vectors.

In the modelling process, generating an algorithm or equation is only part of the process. It is not complete unless its performance has been assessed considering discrimination [ 91 ] and calibration [ 92 ], both internally and using the population outside of what it is developed from, respectively. Among the existing models examined, reporting of the discrimination and calibration is very low. Without knowledge of model performance through validation in both source populations and populations other than where it was developed, objective evaluation of models is difficult [ 93 ]. Predictive models can be of great value only if there is certainty of its accuracy, that is, how precisely the model can predict an outcome in real world [ 94 ]. In the majority of the published models, real-world validation has not been performed or reported. Generally, models are unlikely to predict as well in real-world samples as it would in the derivation sample; this validity shrinkage can often be quite substantial. Hence, future models should report a mechanism of estimating and reporting potential validity shrinkage as well as predictive validity in real world data [ 95 , 96 ].

In a substantial proportion of the models that reported validation, the original dataset was randomly split into the development and validation subset. Although this approach is widely used in many model validation settings, there are some setbacks when using smaller operational sample sizes, as split-sample analyses give overly pessimistic estimates of model performance and are accompanied by large variability [ 97 ]. Bootstrapping is generally considered to be the preferred internal validation method in predictive models [ 98 , 99 ]. Interestingly, bootstrapping was not used in any of the models in included studies, instead cross-validation technique was adopted in most of them. External validation, on the other hand, was used only in very few included studies. This is despite the fact that external validation is considered pivotal to model development and a key indicator of model performance through highlighting applicability to participants, centres, regions or environments [ 23 ]. The external validation is particularly essential for model redevelopment, where the original model is adjusted, updated, or recalibrated based on validation data to improve performance [ 100 ]. This update may include adjusting the baseline risk (interception or hazard) of the original model, adjusting the weight or regression coefficient of the predictor, adding new predictors, or removing existing predictors from the model.

This review has a number of strengths–specifically, the use of the CHARMS checklist [ 23 ], designed for the assessment of the applicability of the prediction models. In addition, inclusion and exclusion criteria were strictly followed, and database searches were conducted by an expert librarian. However, there are a few limitations of the review–the models in this review are not explicitly rated based on quality or performance due to the lack of accepted criteria for rating the quality of forecasting models. In addition, although calibration was reported in several studies, calibration measures lack clarification, which may impact the overall evaluation of the model performance. The model performance could not be compared across methodological approaches in quantitative synthesis because of a lack of model performance data, and those that did provide data are mostly generated from internal validation data which may result in overfitting.

In conclusion, failure to use of real time primary predictor data, failing to incorporate non-climatic parameters as predictor and insufficient reporting of model development techniques, model validation and performance measure were the major inadequacies identified in the current modelling practice. The paradigm shift towards robust modelling techniques, such as the use of machine learning algorithms and autoregressive time series, is a significant positive trend in contemporary model practices. The findings of this review have the potential to lay the groundwork for improved modelling practices in the future. These findings will contribute to robust modelling in different settings and populations and have important implications for the planning and decision-making process for early dengue intervention and prevention.

Supporting information

S1 table. search strategy for ovid medline, as performed in october 2022..

https://doi.org/10.1371/journal.pntd.0010631.s001

S2 Table. PRISMA checklist.

https://doi.org/10.1371/journal.pntd.0010631.s002

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• v.13(4); 2019 Apr

Trends in dengue research in the Philippines: A systematic review

Kristal an agrupis.

Institute of Child Health and Human Development, National Institutes of Health, University of the Philippines, Manila, Philippines

Michelle Ylade

Josephine aldaba, anna lena lopez, jacqueline deen, associated data.

All relevant data are within the manuscript and its Supporting Information files.

Dengue is an important public health problem in the Philippines. We sought to describe the trends in dengue research in the country. We searched four databases and identified published studies on dengue research in the Philippines during the past 60 years. We reviewed 135 eligible studies, of which 33% were descriptive epidemiologic studies or case series, 16% were entomologic or vector control studies, 12% were studies on dengue virology and serologic response, 10% were socio-behavioral and economics studies, 8% were clinical trials, 7% were on burden of disease, 7% were investigations on markers of disease severity, 5% were on dengue diagnostics, and 2% were modeling studies. During the last decade, dengue research in the Philippines has increased and evolved from simple descriptive studies to those with more complex and diverse designs. We identified several key topics where more research would be useful.

Author summary

Dengue is a disease caused by four separate but related viruses transmitted by mosquitos. In this systematic review, we aimed to describe dengue research in the Philippines, where the disease is of great concern, to better understand the types of dengue research and the main findings and important gaps. We identified 135 studies that described dengue research in the Philippines during the past 60 years. Our review showed that in the early years, dengue studies were mainly simple descriptive studies and case reports. Recently the types of investigations have become more complex and diverse, reflecting advancement in local research capacity and infrastructure but more research activity would be beneficial in several areas.

Introduction

Dengue is a mosquito-borne, acute febrile illness that is an important public health problem in tropical countries. In the early 1950’s, the disease was described in the Philippines as hemorrhagic fever or infectious acute thrombocytopenic purpura [ 1 , 2 ]. Dengue continues to cause considerable concern in the country because of its widespread endemicity, the minimal success of vector control strategies, the possibility of severe disease caused by sequential infection by a different serotype, the potential for fatal outcomes and the consequent social and economic burden. The four dengue virus serotypes circulate in the country where the disease is predominantly reported among children [ 3 ].

Findings from dengue studies could provide policy-makers with information needed for rational decision-making regarding dengue preventive and control efforts. The focus of dengue research may vary widely. This could include basic laboratory research, the estimation of dengue seroprevalence and incidence; the assessment of risk factors for severe disease; the quantification of its economic burden; the elucidation of local transmission and epidemiology; the development of improved diagnostic tests or the evaluation of interventions.

We reviewed published studies on dengue research in the Philippines during the past 60 years. The objective of the review is to better understand the trends in dengue research and the findings from these studies. The results of the review could provide an impression of local capacity and infrastructure for dengue research and help determine important knowledge gaps. These gaps need to be identified since research interest and support for funding can only be achieved if scientists, decision makers and other stakeholders are able to understand developments related to the disease and recognize areas where more information is needed.

The Philippines is an archipelago of 7,107 islands and is located in the western Pacific Ocean in Southeastern Asia. The population of the Philippines in 2015 was 100,981,437 [ 4 ]. Philippine health status indicators show that the country lags behind most of Southeast and North Asia in terms of health outcomes [ 5 ]. Communicable diseases continue to be major causes of morbidity and mortality in the country. Health care in the Philippines is provided through a mixed public-private system.

This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [ 6 ]. In June 2018, we searched articles on PubMed, the Cochrane Library, ScienceDirect and the Health Research and Development Information Network (HERDIN) from 1 January 1958 to 31 December 2017 combining MeSH and free-text terms for the following: dengue, “dengue fever”, “hemorrhagic fever”, “dengue hemorrhagic fever”, “dengue shock syndrome”, DF, DHF, DSS and Philippines without any language or age restrictions. The search on HERDIN, an electronic database of health research in the Philippines, was done to ensure that articles from local journals not indexed on international databases are included. The completed PRISMA checklist ( S1 Table ) is shown in the Supporting information. There is no protocol for this systematic review.

The articles were compiled in Endnote (Thomson Reuters, San Francisco, CA, USA). Titles and abstracts were screened for eligibility. Published articles on dengue research in the Philippines and on Filipinos that reported objectives, methods and results or descriptive epidemiologic and case reports were included.

We excluded unpublished articles, studies that were not focused on dengue or not focused on the Philippines, those reporting aggregated results from various countries or analysis of a global or regional collection of viral isolates and specimens from which findings specific to the Philippines could not be retrieved, those reporting the same data from another publication (duplicates), reviews and updates (not original research), meeting or news reports, program descriptions, commentaries, guidelines on dengue (prevention, treatment or diagnosis) and studies on expatriates and non-Filipinos. Towards the goal of assessing the broad picture of dengue research in the Philippines, we included studies that met the basic standard requirements and did not exclude studies based on methodology or risk of bias or selective reporting.

The relevant full papers were downloaded and reviewed in detail. Information from each eligible paper was extracted and entered into an Excel spread sheet (Microsoft Office 2007, Seattle, WA, USA). These included the study title, the year of publication, the journal, the study site primary location, type of study, brief methods and study findings. The summary measures were descriptive.

We compared the annual number of Philippine-related dengue publications with other markers. As a measure of economic growth in the country, we assessed the Philippine Gross Domestic Product (GDP) per capita (in current US dollars) in 1960 (the earliest year data was available) and in 2017 [ 7 ]. For comparison, we also obtained the annual number of publications worldwide on PubMed combining the terms: dengue, “dengue fever”, “hemorrhagic fever”, “dengue hemorrhagic fever”, “dengue shock syndrome”, DF, DHF, DSS, from 1958 to 2017, without location, language or age restrictions.

We identified 836 published articles on dengue research in the Philippines during the past six decades ( Fig 1 ). We removed 77 duplicates and screened the titles and abstracts of 759 articles, of which 624 (82%) were excluded and 135 (18%) full text articles were downloaded and reviewed. The 135 articles were classified as follows: 44 (33%) descriptive epidemiologic studies or case series [ 8 – 51 ], 21 (16%) entomologic or vector control studies [ 52 – 72 ], 16 (12%) studies on dengue virology and serologic response [ 73 – 88 ], 13 (10%) socio-behavioral and economics studies [ 89 – 101 ], 11 (8%) clinical trials [ 102 – 112 ], 10 (7%) on burden of disease [ 113 – 122 ], 10 (7%) investigations on markers of disease severity [ 123 – 132 ], 7 (5%) on dengue diagnostics [ 133 – 139 ], and 3 (2%) modeling studies [ 140 – 142 ]. The majority (102/135, 76%) of the dengue research locations were in Metro Manila.

We assessed the annual number of Philippine dengue studies, by study type and year of publication, and compared this with the annual number of dengue publications worldwide ( Fig 2 ). There were very few articles on dengue research in the Philippines published during the early decades but an increasing annual number in recent years, peaking at 19 articles in 2016. This was associated with an increase in the Philippine GDP per capita from $254 in 1960 to $2,989 in 2017. In comparison, there was a dramatic rise in the annual number of worldwide dengue publications from around 900 articles in 1958 to over 20,000 in 2017 ( Fig 2 ).

Descriptive epidemiologic studies and case series

The most common studies during the 1960’s were descriptive and these types of studies continue to be published in recent years. The 44 publications included in this category described demographic, clinical and laboratory findings in Filipino patients with suspected or confirmed dengue in hospital or community settings [ 8 – 51 ]. One study of 100 patients who died of clinically-diagnosed dengue hemorrhagic fever reported necropsy findings of intravascular thrombosis and hemorrhages; dengue virus (DENV) was isolated in 32 per cent of the patients [ 18 ]. A re-analysis of dengue experimental infection studies in the 1920’s allowed the calculation of an average incubation period for dengue infection of about 6 days [ 33 ]. One article described the dengue prevention and response strategies applied after a natural disaster, Typhoon Haiyan that occurred in 2013 [ 44 ] while another paper characterized hospital admissions to a tertiary care hospital, including dengue cases, after the typhoon [ 47 ]. Five studies assessed the correlation between dengue fever and climate or weather patterns [ 34 , 35 , 40 , 41 , 51 ]. Longer-term comparative reporting and analysis of dengue fever from around the country would be useful to assess geographic and temporal epidemiologic patterns, risk factors for severe disease, variations in clinical management and changes in case-fatality rates.

Entomologic and vector control studies

These studies help improve our understanding of the dengue vectors, which could be useful in developing effective control strategies. Of the 21 articles in this category [ 52 – 72 ], six investigated dengue mosquito vector key breeding sites and potential interventions [ 52 , 56 – 58 , 60 , 64 ], three described the response to or efficiency of vector control measures introduced in communities [ 54 , 59 , 61 ], five assessed the larvicidal activity of various agents against Aedes aegypti [ 55 , 62 , 65 , 68 , 70 ], three explored the characteristics and behavior of Ae . aegypti or Ae . albopictus [ 63 , 67 , 72 ], one quantified vertical transmission of dengue viruses in Ae . aegypti [ 66 ], two described the population and genetic changes of Ae . aegypti populations during the dry and wet seasons [ 53 , 69 ] and one investigated the role of different water-holding containers on the development of Ae . aegypti [ 71 ]. As newer strategies become available (e.g. mosquito sterilization and Wolbachia -based approaches), it will be important to investigate these vector control methods in the country.

Studies on dengue virology and serologic response

In 1960, an article described how viruses isolated from specimens collected in Manila (12 from human sera and 2 from wild-caught mosquitoes) were adapted to suckling mice and shown to be dengue viruses [ 73 ]. This was followed by the publication of 15 studies on virologic and serologic aspects of dengue in the Philippines [ 74 – 88 ]. These included one from 1974 reporting how antibody assessments of sera collected from nine participants of dengue experimental infection studies in the 1920’s showed that DENV 1 and 4 were transmitted in these experiments [ 75 ]. Several studies described the isolation of various dengue serotypes circulating in the community [ 76 , 77 , 79 , 81 , 84 ]. A paper compared the nucleotide and amino acid sequences of the nonstructural-1 gene of dengue virus serotype 3 isolated in Metro Manila [ 78 ] and another described the molecular epidemiology of DENV 2 [ 82 ]. Two studies assessed the presence of dengue antibodies among monkeys in the Philippines suggesting possible sylvatic transmission cycles [ 80 , 86 ]. In another study, flow cytometric analysis of peripheral blood samples from clinically suspected dengue cases found that B cells are a major replication site for dengue viruses [ 83 ]. More recent studies described the continued circulation of a single genotype of DENV 2 in the Philippines [ 87 ] and the modulatory effects of compounds on dengue virus infected cells [ 88 ]. Continued monitoring of the circulating dengue viruses in the Philippines would help in understanding better the epidemiology of the disease.

Socio-behavioral and economics studies

Together with epidemiologic studies that quantify the incidence and seroprevalence of disease, socio-behavioral and economic research provides information on how dengue impacts affected communities. There were nine dengue socio-behavioral studies [ 89 – 93 , 95 , 96 , 98 , 100 ]. Six assessed dengue-related knowledge and preventive practices in different communities [ 89 , 90 , 92 , 93 , 96 , 98 ]. Two were multi-country studies that included the Philippines and used questionnaires and focus group discussions to assess policymakers’ views on dengue and the need for a dengue vaccine [ 91 ] and health care providers’ use of dengue clinical guidelines [ 95 ]. One documented anecdotal use of a local herb in the treatment of dengue [ 100 ]. In light of the recent dengue vaccination controversy in the country, a study on policymakers’ understanding of dengue's complicated pathophysiology and immunologic responses would be useful in addressing unresolved issues and also for considering what would be needed when implementing future dengue control strategies.

There were four economics studies [ 94 , 97 , 99 , 101 ]. One published in 2008, prior to the licensure of the first dengue vaccine, used a contingent valuation survey and found a high willingness to pay and household demand for a dengue vaccine [ 94 ]. In another study, investigators assessed the economic and disease burden of dengue in 12 Southeast Asian countries [ 97 ]. For the Philippines, they calculated the direct cost for each hospitalized and ambulatory dengue case (in 2010 US dollars) of $177 and $47, respectively, plus indirect costs of $36 and $17, respectively. In a later publication, an annual average of 842,867 clinically diagnosed dengue cases in the Philippines was estimated, with direct medical costs (in 2012 US dollars) of $345 million ($3.26 per capita) [ 99 ]. The potential cost-effectiveness of a dengue vaccination program was discussed in another paper [ 101 ]. It will be useful to estimate the economic benefits of new dengue control methods in the country, as they become available.

Clinical trials

Of the 11 publications on dengue-related clinical trials, four were on therapeutic interventions [ 102 – 105 ] and seven were on vaccine trials [ 106 – 112 ]. The therapeutic interventions assessed included a hemostatic agent [ 102 ], fluids [ 103 ] and immunoglobulin [ 104 , 105 ]. Multi-country randomized controlled trials of candidate dengue vaccines included study sites in the Philippines and the seven papers we identified reported on vaccine safety, immunogenicity and efficacy [ 106 – 108 , 110 – 112 ], as well as concomitant dengue and MMR vaccination [ 109 ]. As newer dengue vaccines and therapeutics become available, it will be important to investigate these interventions in the country.

Burden of disease

Ten studies assessed the burden of dengue infections [ 113 – 122 ]. A study from 1992 reported an attack rate of 0.2 dengue cases per 1,000 population for the period of July to December 1990 in Zamboanga city [ 113 ]. On a national scale, the annual dengue surveillance data from the Philippines (included among other countries in the World Health Organization Western Pacific Region) showed dengue fever notification rates of 1.5 per 1,000 population in 2010, 1.3 per 1,000 population in 2011 and 1.9 per 1,000 population in 2012 [ 115 , 116 , 118 ]. Another paper quantified epidemiologic trends in dengue disease burden in 5 Asian countries, including the Philippines, over a 30-year period using data from DengueNet and the WHO [ 122 ]. The estimated dengue incidence and mortality in the Philippines increased by 24% and 29%, respectively, but the authors acknowledged that implementation of more sensitive surveillance methods over the study period may have contributed to a reporting bias. These data provide an overall picture but are based on routine passive notification, often of clinically diagnosed cases, and may be weakened by incomplete reporting and delays.

Among the burden of disease articles, incidence of laboratory-confirmed symptomatic dengue infections were estimated in several prospective surveillance studies that actively followed a cohort for acute febrile illness [ 114 , 117 , 119 – 121 ]. Incidence was calculated using the number of new cases arising from the defined cohort as the numerator and the years of observation time contributed by each person in the cohort as the denominator. Table 1 shows the estimated incidence of laboratory-confirmed symptomatic dengue infections from the articles. In the first study, Capeding and co-workers followed 4,441 healthy infants; and dengue infection was confirmed by serotype specific reverse transcriptase-polymerase chain reaction (RT-PCR) in acute-phase sera and dengue IgM/IgG enzyme linked immunosorbent assay (ELISA) in paired acute and convalescent phase sera [ 114 ]. The incidence of symptomatic (clinically apparent) infant dengue infections was 16 per 1,000 person-years ( Table 1 ), of which hospitalized episodes occurred at 8 per 1,000 person-years. Serologic testing of serial blood samples from a subset of 250 infants without reported febrile illnesses in 2007 showed an incidence of clinically-inapparent dengue infections (defined as a > 4-fold rise in dengue virus 50% plaque-reduction neutralization titers between two time points with a monotypic pattern), that was 6-fold higher than that of symptomatic infections at 103 per 1,000 person-years (95% CI 64–155). Second, in a multi-center study, 300 healthy children 2 to 14 years at two sites in the Philippines were actively followed for febrile illness and dengue was confirmed using a nonstructural protein 1 (NS1) antigen ELISA in acute serum samples and IgM/IgG ELISA in both acute and convalescent samples [ 117 ]. The incidence of confirmed symptomatic dengue infections was 34 per 1,000 person-years ( Table 1 ). In the third study, 854 participants 6 months to over 50 years of age underwent active fever surveillance and annual serological assessment [ 119 ]. Acute sera were tested by dengue PCR and acute/convalescent samples by dengue IgM/IgG ELISA to identify symptomatic infections while enrolment and 12-month samples were tested by dengue hemagglutination inhibition assay to identify subclinical infections. The incidence of symptomatic dengue infection was 16 per 1,000 person-years ( Table 1 ) and clinically inapparent dengue infections occurred at 70 per 1,000 person-years (95% CI 54–90). Symptomatic dengue rarely occurred in those older than 15 years. Fourth, two articles reported the incidence of virologically-confirmed dengue in the control group of a multi-center phase 3 trial of a dengue vaccine, including 1,166 participants 2 to 16 years of age at two Philippine study sites [ 120 , 121 ]. The children were followed for acute febrile illness and dengue infection was confirmed by means of both NS 1 antigen and RT-PCR assays. The incidence of symptomatic dengue infection was 66 per 1,000 person-years ( Table 1 ), of which hospitalized episodes occurred at 7 per 1,000 person-years (95% CI 4–12). In comparison with the national data described above, these incidence data provide a more accurate estimate of the burden of dengue because of the active surveillance in a defined cohort and the laboratory-confirmation of cases. But they are limited by having been conducted at only three sites (Laguna, Metro Manila and Cebu) in the country. The wide differences in incidence of laboratory-confirmed symptomatic dengue infections in the studies ( Table 1 ) are due to the different age groups in the cohort and varying time periods (dengue has seasonal and cyclical epidemic patterns) but may also reflect variations in the dengue force of infection across the sites. Additionally, differences in fever detection methods and diagnostic confirmatory tests may have contributed to the variation in the incidence estimates.

We derived data on dengue seroprevalence in Filipinos from two studies that conducted baseline serologic assessments prior to fever surveillance [ 119 , 120 ]. First, among participants over 6 months of age in Cebu City, dengue seroprevalence assessed by hemagglutination inhibition assay increased sharply with age [ 119 ]. The proportion of participants with a multitypic dengue serologic profile was 40% in the 6 month to 5-year-old age group compared to 99% in the 31 to 50 year olds. Second, baseline dengue seropositivity prior to vaccination, assessed in 604 Filipino children by plaque-reduction seroneutralization assay, was 78% overall and 58%, 75%, 86% and 93% in the 2–4, 5–8, 9–12 and 13–16 year old age group, respectively [ 120 ].

Investigations on markers of disease severity

Ten studies looked for associations between biomarkers and clinical presentation of dengue disease. Eight studies assessed levels of various immune-related or enzymatic biomarkers [ 123 – 127 , 130 – 132 ], while two evaluated the potential role of adiposity [ 128 , 129 ]. More research is needed to better understand the host characteristics that contribute to dengue disease severity.

Dengue diagnostics

There are several methods available for the diagnosis of dengue fever, including virus isolation, detection of viral components (RNA or antigen) and serological assays. In the Philippines, RT-PCR is the confirmatory test of choice but RT-PCR is expensive and time consuming, requires technical expertise and high-level laboratory equipment and does not provide immediate results that could be used for patient care. Dengue rapid diagnostic tests are used at the point-of-care but have insufficient sensitivity and specificity. We found seven published studies that assessed various dengue diagnostic tests, including ELISA [ 133 – 135 , 138 ], fluorogenic real-time RT-PCR [ 136 ] and rapid diagnostic tests [ 137 , 139 ]. The gold standard used for comparison in these studies was conventional RT-PCR. Definitive diagnosis of dengue is important for the clinical management of patients, disease surveillance and outbreak investigations. A dengue diagnostic assay with sufficient sensitivity and specificity, that is less cumbersome than RT-PCR and with results immediately available for clinical care would be very useful.

Modeling studies

There were three studies that used modeling techniques to estimate dengue burden and describe disease patterns [ 140 – 142 ]. Using historical epidemiological, environmental, socio-economic and climate data, one study developed prediction models for future dengue incidence in the Philippines [ 140 ]. From an analysis of 18 years of dengue surveillance reports in eight countries in Southeast Asia, including the Philippines, investigators found strong patterns of synchronous dengue transmission across the entire region coinciding with elevated temperatures associated with anomalies in Pacific Ocean surface temperatures (Oceanic Niño index) [ 141 ]. Another study estimated 794,255 annual dengue episodes and a disease burden of 535 DALYs per million population in the Philippines extrapolated from passive routinely-collected data compared with results from a prospective community-based cohort study at one site [ 142 ]. Modeling studies may be useful in the evaluation of dengue interventions or control studies that become available in the future, especially when field studies are not feasible.

We report on published, dengue research in the Philippines during the past 60 years. During the last decade, there have been an increasing number of dengue studies in the Philippines. From the 1960’s to the 1990’s, the studies were mainly descriptive epidemiologic assessments and case series, but during the recent years, the types of investigations have become more complex and diverse. We believe this reflects advancement in local research capacity and infrastructure. The improvement has coincided with an increase in annual GDP per capita. Globally, there has also been an upsurge in dengue-related publications over the recent decades, probably due to an increasing interest in dengue together with its geographic expansion, more research publications from dengue-endemic countries, the assessment of recently developed strategies against the disease, as well as the proliferation of medical journals.

Despite the increase in dengue research in the Philippines, we identified several dengue knowledge gaps. The vast majority were descriptive short-term hospital- or community-based studies. A longer-term comparative assessment of dengue epidemiologic patterns by site and year would be useful to understand the bigger picture of dengue in the country. As newer vector control methods and vaccine and therapeutic interventions become available, it will be important to investigate these strategies in the country. Sociobehavioral, economics and modeling studies related to these future interventions would be important to assess their impact. More studies on basic laboratory research, including continued monitoring of the circulating dengue viruses in the country and dengue serologic response would help to provide a better understanding of dengue epidemiology in the country. The incidence and seroprevalence data are available from a few sites and it is not known whether this is generalizable to other areas of the country.

Aside from these important research areas, it is essential that basic dengue information and updated findings be communicated to policymakers, health workers, academics and other stakeholders. Researchers may need to liaison with the media to avoid miscommunication to the general public. This is especially important to avoid issues arising from misunderstanding when new control measures are implemented. Perhaps the recent controversy that surrounded the dengue vaccination program could have been avoided by prior detailed communication and education for more informed decision-making.

There are several limitations of this review. First, although we searched four databases (including a local repository), it is possible that some publications were missed. Second, there was some overlap in topics covered by some papers and we selected the main theme covered in the classification and assessment of results. Third, although the majority of the articles (117/135 or 87%) included a Filipino author affiliated with a Philippine institution, foreign collaborators led many of the projects for which much of the laboratory work and data analysis were done outside the Philippines. Although dengue research capacity and infrastructure in the Philippines appears to have significantly increased during the recent decades, we are not able to exactly quantify the improvement. As local investigators gain more experience in developing proposals, obtaining grants and implementing research, we hope that more dengue projects will be lead by Filipino scientists. Fourth, this review on identifying dengue research gaps is just one step towards defining specific questions of interest on dengue in the Philippines. There needs to be a fuller engagement of scientists, policymakers and the public and the development of a continuing method to assess the evolving dengue research needs of the country.

The importance of dengue research is justified by the data showing a significant burden of the disease. These studies indicated a symptomatic laboratory-confirmed dengue incidence of 16 to 66 per 1,000 person-years (depending on the age group, the year when the study was done, the intensity of the surveillance method and the diagnostic method), while the incidence of hospitalized dengue was estimated at 7 to 8 per 1,000 person-years. Furthermore, clinically inapparent or asymptomatic dengue infections occur quite frequently, many folds higher than symptomatic dengue, due to the intense transmission of the virus. The available incidence and seroprevalence data confirm the high endemicity of dengue infections in the country, which results in a heavy socio-economic burden.

The epidemiology of dengue varies in different geographical areas around the world. Describing what is happening in the Philippines can provide a template for other dengue-endemic areas. A standardized protocol could be developed from this and other reviews [ 143 ] for those who wish to conduct a similar activity in other dengue-endemic countries. Publishing data on the research needed to improve health care delivery is part of the communication that is central and key to successful implementation of public health programs. This is particularly true in the Philippines where dengue vaccination has recently been in the limelight when it was introduced in 2016 and stopped the year after. Initial introduction and subsequent events that resulted in highly controversial issues were partly due to misunderstanding of dengue's complicated pathophysiology and immunologic responses.

In conclusion, this review showed that dengue studies in the country have increased in number and evolved from simple to more complicated types of investigations. We identified several important areas for increased research efforts. Studies such as this can help raise awareness on the significance of the disease and the need for better treatment and preventive strategies.

Supporting information

Funding statement.

The author(s) received no specific funding for this work.

Data Availability