Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition characterized by the rapid onset of widespread inflammation [1]. In the context of dengue fever, ARDS is a critical complication that can lead to severe outcomes if not managed promptly and effectively [2-4]. Dengue fever is caused by the dengue virus, transmitted by Aedes mosquitoes. The virus can cause a wide range of symptoms, from mild febrile illness to severe forms like Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) [3]. A hallmark of severe dengue is increased vascular permeability, resulting in plasma leakage, hemoconcentration, pleural effusion, and, in severe cases, pulmonary edema. Inflammation and increased permeability of the lung capillaries lead to fluid accumulation in the alveoli (air sacs), impairing gas exchange and causing hypoxemia (low blood oxygen levels) [4,5].

Patients with ARDS in the setting of dengue may present with severe dyspnea, tachypnea, cyanosis, diffuse crackles on lung auscultation, and signs of other severe dengue complications, such as shock or hemorrhage [6,7]. ARDS in dengue fever is a life-threatening condition requiring prompt recognition, supportive management, and careful consideration of the underlying dengue infection to improve patient outcomes.

Ethical Clearance

The protocol was approved by the Institutional Ethical Review Board. Informed consent was obtained from all participants.

Type of Study

Prospective Study: According to specific inclusion criteria, 2256 patients with fever (presenting within 5-7 days of onset with a body temperature above 100°F at the time of blood sample collection) and fulfilling the case definition criteria of dengue fever (DF) and dengue hemorrhagic fever (DHF) as defined by the WHO were included in the study [8,9].

Clinical and demographic data were collected through patient interviews or their attendants and meticulous physical examination by their treating physician. ARDS was diagnosed based on Berlin’s definition: acute onset of respiratory distress within one week of a known clinical insult, bilateral lung opacities on chest radiograph that are not due to effusions, lobar/lung collapse, or nodules; respiratory failure not fully explained by cardiac failure or fluid overload; and presence of severe hypoxemia, characterized by a PaO2/FiO2 ratio <= 300 with PEEP or CPAP >= 5 cm H2O. Bedside echocardiography was performed on all patients to exclude the cardiac origin of edema [8-10]. Patients with ARDS secondary to sepsis, pneumonia, malaria, scrub typhus, or other etiologies were excluded.

Two blood samples were collected from each patient. One blood sample was sent on ice to the molecular laboratory for the detection of dengue viruses, the NS1 antigen, and IgM and IgG antibodies. The second sample was used for a complete blood hemogram and other investigations, such as the Widal test, malarial test by card and peripheral smear, Chikungunya test by card method, and typhus fever test. The clinical basis for diagnosing dengue virus infection was based on WHO definitions [8].

Reports of hematological investigations, dengue serology, and data obtained from daily follow-ups were analyzed. Hospitalized patients were categorized into Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome according to the WHO severity grading scale. Blood indices were initially measured on a continuous scale and then categorized based on clinically meaningful cut-offs. Thrombocytopenia was defined as a platelet count <100,000 cells/mm³. A hematocrit >20% rise was considered raised⁸. Similarly, leukopenia was defined as a white cell count <4000 cells/mm³.

Viral RNA was extracted from serum samples using the QIAamp Viral RNA mini kit (Qiagen, Germany) according to the manufacturer’s instructions [9]. Extracted RNA was stored at −70°C or immediately used for amplification. Real-time polymerase chain reaction (RT-PCR) was performed in one tube using a universal primer and a one-step RT kit. The NS1 antigen and IgM and IgG antibodies were detected with ICT. The test kit used was the dengue NS1 antigen and antibody Combi Card supplied by J. Mitra and Co. Pvt Ltd. (New Delhi, India) [8,9].

Statistical Analysis

Data were analyzed using Epi-info software. Categorical data were presented in terms of numbers and percentages and analyzed using the Z test for proportions and the Chi-square test.

The study on dengue cases involved 2256 patients, with a distribution of 62.6% males and 37.4% females. The patients' demographics showed that 60.1% were from rural areas, and 39.9% were from urban areas (Table-1). Their ages ranged from 2 to 44 years.

Table 1: Patient Demographics.

RT-PCR Testing and Dengue Positivity

Out of the 2256 clinically suspected dengue cases:

• 1306 tested positive by RT-PCR.
• 950 tested negative. (Table-2)

Table 2: RT-PCR Testing Results.

Clinical Features of RT-PCR-Positive Dengue Cases

Among the 1306 RT-PCR positive cases:

• Fever: Present in all patients (38°C to 40°C) (Table-3).
• Retro-orbital pain: 85.9%
• Flushing: 77.5%
• Rashes: 84.8%
• ARDS: 9.7%
• Splenomegaly: 27.5%
• Ascitis: 20.3%
• Encephalopathy: 3.4%

Table 3: Clinical Features of RT-PCR-Positive Dengue Cases.

Serotype Distribution

Out of the 1306 positive cases:

Single DENV Serotype Infections: 798 cases

• DENV-2: 392 cases (54.2%)
• DENV-3: 218 cases (29.2%)
• DENV-1: 114 cases (8.3%)
• DENV-4: 74 cases (8.3%)

Concurrent DENV Serotype Infections: 608 cases

• DENV-2 and DENV-3: 67.8%
• DENV-1 and DENV-3: 16.7%
• DENV-2 and DENV-4: 11.1%
• DENV-3 and DENV-4: 5.6% (Table-4).

Table 4: Serotype Distribution among RT-PCR Positive Case.

Classification of Dengue Cases

Among the 1306 RT-PCR positive cases:

• Classical Dengue Fever: 660 cases (50.5%)
• Dengue Hemorrhagic Fever: 376 cases (28.8%)
• Dengue Shock Syndrome: 270 cases (20.7%) (Table-5).

Among 270 cases of dengue shock syndrome, 185 cases had concurrent infection with dengue serotypes 2 &3, and 35 cases with serotypes 1&3.

Table 5: Classification of Dengue Cases.

Severe Dengue Cases with ARDS

127 patients with severe dengue developed ARDS and all 127 cases had concurrent infection with different serotypes. 110 cases had concurrent infection with dengue serotypes 2 & 3 and 17 cases had concurrent infection with dengue serotypes 1 &3. The key clinical observations included:

• Acute onset of rapid breathing and severe hypoxemia.
• Abdominal pain, vomiting, and petechial rash.
• No hypotension upon admission.
• Lab abnormalities: thrombocytopenia and elevated aminotransferases (AST higher than ALT).
• Bilateral pulmonary opacities on chest radiograms, normal echocardiograms (Table-6).

Table 6: Severe Dengue Cases with ARDS.

Treatment and Outcomes for ARDS Patients

• Initial Treatment: Oxygen via a non-rebreathing mask, then transfer to PICU for mechanical ventilation.
• Mechanical Ventilation: Required for 12 patients due to severe respiratory distress.
• Fluid Management: Restrictive fluid strategy with crystalloids.
• Improvement: Gradual improvement in oxygenation, with a median duration of mechanical ventilation of 4 days (IQR 2-6 days).

Complications:

• Ventilator-associated pneumonia: 9 patients.
• Sepsis: 5 patients, required antibiotic escalation.
• Gross hematuria: 4 patients, required platelet transfusion.

Outcome: One patient died, median hospital stay was 8 days (IQR 8-10 days) (Table-7).

This study comprehensively analyzes the clinical features, serotype distribution, and management of dengue cases, particularly those with severe manifestations such as ARDS.

Table 7: Outcomes for ARDS Patients.

This study's findings on dengue demographics, clinical features, serotype distribution, and severe cases align with and add to existing literature on dengue epidemiology and management. Here, we compare our results with those from other relevant studies to highlight similarities, differences, and unique contributions.

Our study found that 62.6% of the dengue cases were male, and 60.1% were from rural areas. These findings are consistent with other studies, such as those by Gupta, Arya [1,2], which also reported a higher incidence of dengue among males and rural populations. The higher male prevalence could be attributed to greater outdoor exposure, increasing the risk of mosquito bites. The rural predominance underscores the need for improved vector control and healthcare access in these areas.

The 57.9% positivity rate for dengue by RT-PCR in our study is comparable to the rates reported by Hasan [3], who found a 55% positivity rate among suspected cases. This high positivity rate highlights the effectiveness of RT-PCR as a diagnostic tool, as supported by other studies [4], which emphasize its critical role in early and accurate dengue detection, aiding in timely intervention and management.

The clinical features observed in our study, including fever (100%), retro-orbital pain (85.9%), flushing (77.5%), and rashes (84.8%), align with those reported by studies such as Gubler, Halstead [5,6]. These studies also noted fever as a universal symptom, with other common manifestations being retro-orbital pain and rash. The occurrence of severe manifestations like ARDS (9.7%), splenomegaly (27.5%), ascites (20.3%), and encephalopathy (3.4%) in our study parallels findings from Rigau-Pérez [7], indicating the diverse and severe clinical spectrum of dengue.

Our study identified DENV-2 as the most prevalent serotype (54.2% of single infections), followed by DENV-3 (29.2%). Similar serotype distributions have been reported by other studies, such as those by Bharaj [9,10] and Anker, which also found DENV-2 and DENV-3 to be dominant during outbreaks. The high rate of concurrent infections (46.6%) in our study, with DENV-2 and DENV-3 being the most common combination, is consistent with findings by Cummings [11], who reported significant rates of coinfection, contributing to increased disease severity and complications. Among 127 cases of severe dengue cases with ARDS, 86.6% of the patients showed the presence of concurrent infection with dengue serotypes 2 & 3.

The classification of dengue cases in our study into classical dengue fever (50.5%), dengue hemorrhagic fever (28.8%), and dengue shock syndrome (20.7%) is comparable to the categorization used in studies by Nimmannitya, WHO [8,12], which also reported similar distributions. The high percentage of severe cases highlights the need for effective clinical management and monitoring protocols, as Wills emphasized [13].

Our focus on 127 severe dengue cases with ARDS reveals critical clinical insights. The presentation of ARDS symptoms, including rapid breathing, severe hypoxemia, and lab abnormalities such as thrombocytopenia and elevated aminotransferases, aligns with findings from studies by Lee, Murray [14,15]. These studies also noted similar clinical presentations and complications in severe dengue cases, underscoring the importance of early recognition and intensive care management.

The management of ARDS in dengue patients in our study involved initial oxygen therapy, followed by mechanical ventilation for most patients, reflecting protocols outlined in studies by WHO, Trung [8,16]. The use of a restrictive fluid strategy and crystalloids aligns with recommendations from studies by Bethell [17] and Hanafusa [18], which emphasize cautious fluid management to prevent fluid overload.

The median duration of mechanical ventilation in our study was 4 days, with a median hospital stay of 8 days. These findings are consistent with those reported by Lee [14], who also observed similar durations of ventilation and hospitalization. The low mortality rate (0.8%) in our study compares favorably with rates reported in other studies, such as those by Murray [15], highlighting the effectiveness of intensive care protocols in improving patient outcomes.

This study provides a comprehensive analysis of dengue cases, aligning with and extending findings from existing literature. The high incidence of severe cases associated with DENV-2 and DENV-3 serotypes, the prevalence of concurrent infections, and the critical need for effective clinical management strategies are key points of emphasis. Future research should focus on understanding the pathophysiology of concurrent infections and improving preventive measures to reduce the burden of dengue in endemic regions.

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