|Year : 2023 | Volume
| Issue : 2 | Page : 45-52
Dengue-COVID-19 overlap: A single-center prospective observational study in a tertiary care setting in India
Shital Patil1, Sham Toshniwal2, Uttareshvar Dhumal3, Ganesh Narwade1
1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Department of Internal Medicine, NIMS Medical College, Jaipur, Rajasthan, India
3 Department of Radiodiagnosis, MIMSR Medical College, Latur, Maharashtra, India
|Date of Submission||01-Dec-2022|
|Date of Decision||25-Feb-2023|
|Date of Acceptance||12-Mar-2023|
|Date of Web Publication||13-Jul-2023|
Prof. Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Dengue-COVID-19 overlap is a mixture of both diseases sharing few similarities in pulmonary and extrapulmonary involvement. Although dengue fever is more commonly reported in tropical settings, very little literature is available regarding dengue-COVID-19 overlap in Indian context. Due to high prevalence of both diseases later being pandemic disease, and overlapping laboratory and clinical parameters, we have conducted a study to observe dengue-COVID-19 overlap in Indian settings in tertiary care hospitals. Methods: This prospective, observational study included 600 COVID-19 cases with dengue nonstructural protein 1 or dengue immunoglobulin (Ig) M positive, with lung involvement documented and categorized on high-resolution computerized tomography (CT) thorax at entry point. All cases were subjected to dengue IgG antibody titers and dengue IgM/IgG antibody titer analysis after 12 weeks of discharge from the hospital. Results: Dengue-COVID-19 overlap was documented in 16.33% (98/600) of cases. CT severity has documented a significant correlation with dengue-COVID-19 overlap cases (P < 0.00001). Hematological evaluation, white blood cell count, and platelet count were having a significant association with dengue-COVID-19 overlap (P < 0.0076 and P < 0.00001, respectively). Clinical parameters as hypoxia have a significant association with dengue-COVID-19 overlap (P < 0.00001). Inflammatory markers such as interleukin-6, C-reactive protein, and lactate dehydrogenase have a significant association in dengue-COVID-19 overlap (P < 0.00001), respectively. In study of 600 cases of “dengue COVID 19 overlap”, post COVID lung fibrosis was documented in 92/600 cases. Serological assessment between dengue IgM/IgG antibody and COVID antibody titers has a significant association with post covid lung fibrosis (P < 0.00001). Conclusions: Dengue-COVID-19 overlap is clinical syndrome with overlapping clinical and laboratory workup of both the illnesses. High index of suspicion is must in all COVID cases in tropical settings where dengue is endemic, and all cases with leucopenia and thrombocytopenia with fever should be screened for dengue serology. False-positive dengue serology or dengue antigen cross-reactivity is known to occur in underlying COVID-19 illness, and have impact on clinical outcome as it will result in delay in COVID appropriate treatment initiation and many cases require intensive care unit treatment due to progressed COVID pneumonia.
Keywords: Antigenic mimicry, COVID-19, dengue-COVID-19 overlap, post-COVID lung fibrosis
|How to cite this article:|
Patil S, Toshniwal S, Dhumal U, Narwade G. Dengue-COVID-19 overlap: A single-center prospective observational study in a tertiary care setting in India. J Assoc Pulmonologist Tamilnadu 2023;6:45-52
|How to cite this URL:|
Patil S, Toshniwal S, Dhumal U, Narwade G. Dengue-COVID-19 overlap: A single-center prospective observational study in a tertiary care setting in India. J Assoc Pulmonologist Tamilnadu [serial online] 2023 [cited 2023 Sep 30];6:45-52. Available from: https://www.japt.in//text.asp?2023/6/2/45/381419
Dengue and COVID-19 are viral illnesses with overlapping clinical and laboratory features, usually underestimated due to high prevalence and lack of suspicion in tropical settings. In the present study, 16.33% of cases were diagnosed to have dengue-COVID-19 overlap and having a significant impact on clinical and radiological outcome.
| Introduction|| |
Coronavirus-related global pandemic (COVID-19), declared by the World Health Organization (WHO) in March 2020, caused by novel coronavirus SARS-CoV-2 resulted in significant mortality morbidity, with impact on health-care systems globally resulting in shortage of resources to manage rapidly growing pandemic. Dengue fever is an arboviral vector-borne disease with four antigenic variants, and as per the WHO figures, dengue has shown a significant increase in disease burden in all parts of the world causing 100–400 million infections each year with more than 50% in tropical settings. Asian countries are significantly affected by COVID 19 pandemic and dengue fever is endemic due to favorable geographical trends in tropical settings. Hence, concurrent occurrence is more possible along with predicted antigenic cross reactivity and resurgence of both diseases is expected in future.,, COVID-19 and dengue both are viral diseases sharing clinical and laboratory similarities and increase in chances of underestimation resulting in delay in diagnosis if proper laboratory workup and specific diagnostic tests are not performed. Antigenic cross-reactivity resulted in false-positive results, and will manifest significantly in patient view and public health due to increased disease burden and poor outcomes due to delay in diagnosis and treatment.,
COVID-19 pandemic is a big health concern in dengue-endemic areas due to overlapping of clinical and laboratory features and its challenging job for critical care physicians for correct diagnosis and management of both the diseases.,, Many case reports and case series published the concurrent COVID-19 and dengue co-infections,, which has been associated more mortality than isolated single infection., Both viral diseases share may pathogenic and clinical features, as antibody-dependent enhancement phenomenon has been documented in both dengue and COVID-19 which is the reason for overlapping nature of both the disease and behaving like “two sides of same coin.” Both are RNA viruses and shown similar pathologic pathways as cytokines and chemokine release, altering the integrity of the vascular endothelium leading to vasculopathy, coagulopathy, and capillary leak.
In present study, we have documented COVID-19 pneumonia cases with concurrent dengue-like manifestations and dengue serology positivity, i.e., either nonstructural protein (NS1) or immunoglobulin (Ig) M antibody positive, and we have followed these cases for 12 weeks to exactly confirm dengue-COVID overlap.
| Methods|| |
This was a prospective, observational study conducted in Venkatesh Chest Hospital, and Pulmonary Medicine, MIMSR Medical College, Latur, during May 2021 to March 2022, to find out “COVID-dengue overlap” in diagnosed COVID-19 pneumonia cases admitted in critical care unit. Total 600 cases were enrolled in the study after Institutional Review Board (IRB) approval and written informed consent of the patient [Figure 1].
|Figure 1: Flow of the study. RT-PCR = Reverse transcriptase-polymerase chain reaction, CRP = C-reactive protein, HRCT = High-resolution computerized tomography|
Click here to view
COVID-19 patients, confirmed with reverse transcriptase-polymerase chain reaction (RT-PCR), above the age of 18 years, hospitalized in the study centers, including those with comorbidities, and irrespective of severity and oxygen saturation were included in the study.
Those not willing to give consent, not able to perform follow-up dengue and COVID-19 antibody titers, and cases who died during hospitalization or before 12 weeks of discharge from hospital and patients <18 years of age were excluded from the study.
This study is approved by the IRB/Ethics Committee of MIMSR Medical College, Venkatesh Chest Hospital, and Critical Care Center, Latur, India (approval No. VCC/104-2020–2021; approval date: May 31, 2021).
All study cases were undergone the following assessment before enrolling in study
The COVID 19 RT PCR test was performed on nasopharyngeal samples collected with all standard institutional infection control policies. If the first RT-PCR test results were negative and radiological features were clearly documenting pneumonia, then we have repeated RT PCR test on nasopharyngeal samples and finally enrolled all cases with positive COVID 19 RT PCR test. High resolution computerized tomography (HRCT) thorax used to assess the severity of lung involvement as per COVID 19 Reporting and Data System (CO RADS) and categorized as mild, if score 15 or 15–25. Clinical assessment, routine biochemistry, and haematological workup done in all study cases. Laboratory parameters-hemoglobin, renal functions, blood sugar level, liver functions, electrocardiogram. All cases were undergone dengue serology, and cases either dengue NS1 or dengue IgM positive were finally enrolled. Viral inflammatory markers such as CRP, ferritin, lactate dehydrogenase, and interleukin 6 (IL 6) were done in all cases as a protocol. Entry point inflammatory markers were utilized as an assessment tool for the severity of illness with clinical parameters. If inflammatory markers analysis were normal at the entry point, then repeat analysis was done on the day of discharge from the hospital, or done during hospitalization, if the clinical course deteriorates. If inflammatory markers analysis were abnormal at the entry point, we repeated on every 72 h as the follow up to assess severity, progression of illness, and also titer utilized to assess response to medical treatment in cases with Dengue-COVID-19 overlap. Normal and abnormal parameter readings were considered as per pathological laboratory standard. COVID-19 antibody titers and dengue IgM and IgG titers and follow-up HRCT thorax were done at 12 weeks or 3 months of discharge from the hospital [Figure 1].
Diagnosis of dengue infection
- Dengue NS1 antigen: Rapid detection technique also called as qualitative screening test which analyzes the presence of nonstructural protein NS1 antigen in blood and serum (SD Dengue Duo, Standard Diagnostics, Germany)
- Dengue IgG and IgM: Qualitative IgM and IgG antibody assays were performed by immune-chromatography strip method (SD Dengue Duo, Standard Diagnostics, Germany), with a sensitivity and specificity of 94.2% and 96.4%, respectively
- Diagnosis of SARS-CoV-2 infection by RT-PCR: Qualitative screening of the SARS-CoV-2 virus, performed on nasopharyngeal swab samples as fully automated RT-PCR on Cobas 6800 instrument (Roche Molecular Diagnostics, USA).
Case definitions used in the present study
- Dengue-COVID-19 overlap: COVID-19 RT-PCR-positive cases with serology detected dengue NS1 with or without IgM antibody with clinical and laboratory parameters correlated with concurrent possibility of both illnesses
- False dengue or antigenic mimicry: Initially presented with dengue-COVID-19 overlap, and later on in course of illness during follow-up analysis of these cases at 12 weeks shown dengue IgM or dengue IgG antibody negative
- Concurrent COVID-dengue illness: Initially presented with dengue-COVID-19 overlap, and later on in course of illness during follow-up analysis of these cases at 12 weeks shown dengue IgM or dengue IgG antibody positive
- COVID-dengue immune senescence: Initially presented with dengue-COVID-19 overlap, and later on in course of illness during follow-up analysis of these cases at 12 weeks shown dengue IgM and dengue IgG antibody negative and COVID antibody test negative or weakly positive.
The statistical analysis was performed using Chi-square test in R-3.4 is available as a Free Software under the terms of the (Free Software Foundation's GNU General Public License in source code form, Vienna, Austria). Significant values of χ2 were seen from probability table for different degrees of freedom required. P value was considered statistically significant if it was below 0.05 and highly significant in case if it was <0.001.
| Results|| |
In study of total 600 COVID 19 pneumonia cases, dengue COVID 19 overlap was documented in 16.33% (98/600) of cases. Cases between 18-95 age group were enrolled, of which 60% (360/600) cases were above 50 year age and 40% (240/600) cases were below 50 year age. In gender distribution in the study group, male population was 70.33% (422/600) and females were 29.66% (178/600). The main symptoms in the study group were shortness of breath in 79% of cases, fever in 71%, cough especially dry in 48% of cases & fatigability in 79% of cases. Clinical assessment documented tachycardia in 72% of cases, tachypnea in 24% of cases and oxygen desaturation on 6 min walk in 29% of cases. Hematological parameters were having a significant association in COVID-19 cases with and without dengue overlap as like abnormal white blood cell count (P < 0.0076) and abnormal platelet count [P < 0.00001, [Table 1]] Clinical parameters like hypoxia have a significant association in COVID-19 cases with and without dengue overlap [P < 0.00001, [Table 1]]. Inflammatory marker analysis such as IL-6 (P < 0.00001), CRP (P < 0.00001), and LDH (P < 0.00001) has documented a significant association in COVID-19 cases with and without dengue overlap [Table 1].
”Dengue-COVID-19 overlap” as per CT severity scoring was documented as 52/84 in mild CT severity cases, 32/184 in moderate CT severity cases, and 14/332 in severe CT severity cases [P < 0.00001, [Table 2]]. In study of 600 cases of “dengue COVID 19 overlap,” post COVID lung fibrosis was documented in 92 cases. Total 90 cases with post covid lung fibrosis were having negative dengue serology and only 2 cases were having positive dengue serology in all COVID-19 RT PCR positive cases. [P < 0.004, [Table 3]] In a study of 98 cases of “COVID-dengue overlap,” serological assessment in dengue IgM/IgG and COVID antibody titers was documented in significant association [P < 0.00001, [Table 4]].
|Table 4: Actual serological assessment in COVID-dengue overlap and COVID-19 with dengue coexistent pathology (n=490) follow-up at 12 weeks|
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| Discussion|| |
Prevalence of “dengue-COVID-19 overlap” in present study
In this study, of total 600 COVID-19 pneumonia cases confirmed by COVID-19 RT-PCR test, “COVID-dengue overlap” was documented in 16.33% (98/600) of cases after positive dengue NS1/IgM antibody analysis. This will be the first study in Indian context in enrolling and analyzing a greater number of cases having COVID-dengue overlap. Dengue became endemic in Asian countries due to trading industry and transportation services in the last century due to movement of people., Presently, majority of the Asian countries are badly affected with COVID-19 pandemic and resulted in socioeconomic crisis due to significant disease burden in compromised health sector.,,,, India is one of the most affected countries due to COVID-19 with ranked second and third in number of affected cumulative cases and deaths, respectively. Now, most of the South East Asia region has documented full-blown COVID-19 pandemic with more cases and deaths in comparison to the rest of the world.,,
In the present study, we have observed many cases where treatment was initiated in consideration of dengue fever due to overlap of common symptoms of fever and similar laboratory findings. These cases were evaluated for COVID-19 after new symptoms such as cough or shortness of breath during the course of illness in an indoor unit. We have documented positive COVID-19 RT PCR results with lung parenchymal involvement on HRCT thorax. Authors, Tsheten et al., Chen et al., and Kembuan, documented similar findings. We have also observed that clinical worsening or requirement of oxygen supplementation due to fall in oxygen saturation was a reason to investigate for underlying COVID-19 in primary dengue hospitalizations, and vice versa. Authors, Estofolete et al., Mahajan et al., Bicudo et al., Rodriguez-Morales et al., Tsheten et al., Pontes et al., and Ratnarathon et al., documented similar observation. As both diseases share same pathophysiologic mechanism resulting into clinical laboratoryfeatures for thrombocytopenia and leucopenia. Hematological manifestations asthrombocytopenia and leucopenia observed either due to decreased production becauseof bone marrow suppression or increase immune mediated consumption., Otherplausible mechanism would be immune complex mediated and autoantibody dependentplatelet destruction which is known in dengue and now documented in COVID-19.,
”Dengue-COVID-19 overlap:” Is it an “antigenic mimicry?”
In a study of 98 cases of “dengue-COVID-19 overlap,” serological assessment at 12 weeks in dengue IgM/IgG and COVID antibody titers documented a significant association (P < 0.00001). In the present study of these 98 cases with COVID-dengue overlap, antigenic cross-reactivity has been documented initially in 32 cases, i.e. false-positive dengue NS1 without dengue antibody titer documentation at 12-week follow-up. Few studies have documented similar observation.,,
”Dengue-COVID-19 overlap” documentation needs a high index of suspicion due to overlapping clinical and laboratory markers and concurrent double infection complicates either disease clinical outcome. All cases with dengue NS1 and or IgM antibody positives need COVID-19 to be ruled out due to the possibility of concurrent both illnesses. We especially recommend scenarios with abnormal chest radiograph during hospitalization or dengue cases with abnormal adventitious sounds during auscultation clinically. Few studies, have similar observations collaborating with our study.
”Dengue-COVID-19 overlap:” Is it a coexistent two different viral genotypic disease?
In a study of 98 cases of “dengue-COVID-19 overlap,” actual serological assessment in dengue IgM/IgG antibody and COVID IgG antibody titers at 12 weeks was documented in significant association (P < 0.00001), i.e., 66 cases with dengue overlap syndrome were having coexistent dengue and COVID-19 diseases. Initially, Dengue-COVID-19 overlap was considered an important health issue in high dengue burden setting in tropical countries in South East Asia region ongoing covid pandemic. As the pandemic grew across the globe irrespective of Dengue trends, now Dengue-COVID-19 overlap is considered a global health issue of concern. Various studies,,, documented similar observation.
”COVID-dengue immune senescence:” Is it a natural trend or worrisome pattern in ongoing pandemic?
In study of 98 cases of 'Dengue-COVID-19 overlap', actual serological assessment between dengue IgM/IgG antibody and COVID-19 IgG antibody titers at 12 weeks of illness were negative in 32 and 40 cases respectively (p<0.00001). In a study of these cases in follow-up, 28 cases were showing negative both COVID and dengue antibody titers. Negative antibody titer is really a concern and it would suggest “weak antigen–antibody memory link” and issue of great research being all such cases again become virgin to catch reinfection due to COVID-19.
Author Nalbandian A et al observed evolution of acute COVID-19 illness usually lasting for 4 weeks and mentioned that beyond this time virus isolation from respiratory samples is rare. They also reported the highest viral load during the first 2 weeks of illness and it decreases to baseline in four weeks with exemption in few cases where viral load can be documented till 6 weeks to 60 days. Confounding factors associated with persistence of virus for longer duration in selected cases is area of research. Serological assessment of IgM antibodies in COVID-19 cases, titer increases during the first week with peaks at around 2 week of illness and then disappears over two to four weeks. Serological assessment of IgG antibody in COVID-19 cases, titer starts rising by the end of first week and remains elevated and detectable level till 90 days of infection. Still, exactly protective value of these antibodies in preventing reinfections is not clearly known.
Raafat N et al observed evolution of acute Primary Acute Dengue infection and mentioned that NS1 and viral RNA has been documented in the first week of illness till the first 5 days of infection. Serological assessment of IgM antibody in dengue infection as earliest picked up during 3-5 days of illness and remains detectable for several weeks to months. Serological assessment of IgG antibody in dengue infection is usually detected at the end of acute phase or 10 days of illness and remains detectable for several years which is an indicator of immunological memory. While, in secondary dengue infection, IgG antibody rises earlier than IgM. Recent studies,,, have documented the role of neutralizing antibodies in these infections which will disappear after 3 months. Long et al observed a short lasting serological stage and early waning of humoral immunity in dengue illness. They have reported that 40% percent of asymptomatic individuals after clinical illness became seronegative and 12.9% of the symptomatic cases after clinical illness became negative for IgG in the early convalescent phase of dengue infection. Wu et al. mentioned the doubtful role of these neutralizing antibodies in protection from future infections due to various variants, and really how much they protect us from reinfection is not known at present.
We have further analyzed these 14 cases, and documented that all these 14 cases were having mild lung involvement on CT thorax imaging, which means that more immunopathological nature of coronavirus disease leading to short-lasting humoral immunity and ultimately “short-lasting immune memory” or “viral escape from immune restoration phenomenon” by altering and targeting “immune escape pathway” which will hide the COVID-19 antigen presentation and sensing to memory T-cells of host and developing protective antibodies for same.
Other important observations in the present study
Hematological parameters were having a significant association in COVID-19 cases with and without dengue overlap, especially normal and abnormal white blood cell count (P < 0.0076) and normal or abnormal platelet count (P < 0.00001). Possible mechanisms associated with similar observations would be the immunological nature of Dengue-COVID-19 overlap' syndrome.
Clinical parameters like oxygen saturation at entry point, i.e., with or without hypoxia, have a significant association in COVID-19 cases with and without dengue overlap (P < 0.00001). Rational for similar observation in scenarios with isolated dengue, isolated covid-19 and Dengue-covid overlap cases would be lung parenchymal involvement. Due to inflammatory surge and lung parenchymal damage, these cases with covid-19 and Dengue-covid-19 overlap were having hypoxia.
Inflammatory marker analysis was documented a significant association in COVID-19 cases with and without dengue overlap as abnormal IL-6 (P < 0.00001), abnormal CRP (P < 0.00001), and abnormal LDH (P < 0.00001). Rationale for the similar findings were more immunological nature illness in dengue-covid-19 overlap cases as compared to isolated COVID cases. Also, other possible mechanisms would be more lung parenchymal involvement in isolated covid-19 than in dengue-covid-19 overlap cases which would very well correlate with raised inflammatory markers IL-6, CRP, and LDH. We used LDH as a marker of assessment of oxygen status and hypoxia, and observed grossly raised it with predominant lung involvement as documented in a previous study.
”Dengue-COVID-19 overlap” as per CT severity scoring was documented as 52/84 in mild CT severity cases, 32/184 in moderate CT severity cases, and 14/332 in severe CT severity cases (P < 0.00001). Plausible mechanism for these observations would be either antigenic cross-reactivity or mimicry in dengue-covid-19 overlap cases. As immunological phenomenon showed reversal in majority and considered as transient type. We have observed immunological phenomena and lung involvement doesn't follow the same pattern. Cases with mild covid were shown predominant overlap with dengue serology, while cases without overlap were shown more advanced lung disease or high CT severity. CT documented mild lung involvement in cases with prolonged fever, and these cases were initially documented as dengue and later on diagnosed as concurrent COVID-19 coinfection in many cases and few cases were shown antigenic cross-reactivity. While, in majority of moderate-to-severe COVID-19 cases on HRCT thorax, proportionately high number of cases were having antigenic cross-reactivity and only small proportion of cases were having concurrent COVID-dengue coinfection.
In a study of 98 cases of “COVID-dengue overlap,” post-COVID lung fibrosis was documented in 2 cases while 251 COVID patients with negative dengue serology documented post-COVID lung fibrosis in 90 cases (P < 0.004). Plausible mechanism would be the reversible nature of immunological phenomenon in dengue-covid-19 disease which has resolved over a period of 12 weeks. We have observed that these cases with reversible nature were having minimal or lesser lung parenchymal involvement and usually, these cases have more extrapulmonary features or manifestations. As disease progressed to 12 weeks of illness and chances of antigenic cross-reactivity, decreased and isolated COVID cases were predominant category showing lung fibrosis and we have confirmed these cases with antibody titer analysis.
Some Issues needs further research and remains unsolved (observations in present study which needs global research):
- Dengue-COVID-19 overlap and antigenic mimicry scenario was documented in the second wave, i.e., delta variant of coronavirus, and less frequently documented with Wuhan variant coronavirus of the first wave. Is there any antigenic cross-reactivity with genetic makeup of coronavirus is behaving selectively, really, we don't know, and further workup is required?
- Whether Immunological phenomenon documented in dengue-COVID-19 overlap is reversible, transient or persistent? and/or prerequisite for certain autoimmune rheumatological syndromes in post-COVID illness cases which has been documented in all clinical settings, needs further workup
- How much dengue will impact in ongoing COVID-19 pandemic in spite of increase in cost of care of both the illnesses with fatigued manpower and health system? or we should prepare for both the diseases as top priority in incoming few years with rising trends of various variants of coronavirus? Time will decide, but as of now, Lancet Commission also warrants COVID-dengue as a hot topic of medical research and disease of concern for medical experts across the globe due to shared common pathophysiological and biological pathways.
| Conclusions|| |
Dengue-COVID-19 overlap is clinical syndrome with overlapping clinical and laboratory workup of both the illnesses. High index of suspicion is must in all COVID cases in tropical setting where dengue is endemic, and all cases with leucopenia and thrombocytopenia with fever should be screened for dengue serology. False-positive dengue serology or dengue antigen cross-reactivity is known to occur in underlying COVID-19 illness, and have impact on clinical outcome as it will result in delay in COVID appropriate treatment initiation and many cases require intensive care unit treatment due to progressed COVID pneumonia.
COVID-dengue antigenic cross-reactivity has a significant association with lung fibrosis as resultant pathophysiological effect of immune activation pathway, and these cases were required longer oxygen supplementation and antifibrotics in follow-up. “Dengue-COVID-19 overlap” is very frequently documented in tropical setting and disease of concern in critical care setting, as natural trend of this entity is different and having impact on clinical outcome if diagnosis is delayed. Both diseases may behave like “two sides of same coin,” and rational for coexistent pathology is still not known and needs further research.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]