The COVID-19 pandemic has had a severe impact with millions of deaths worldwide . In dengue-endemic regions, the situation is aggravated by socio-economic aspects and the occurrence of epidemic arboviruses . In addition to the first case reported in Brazil, also in the Federal District , SARS-CoV-2/DENV co-infection cases were reported in other tropical and developing countries, where these infections are also considered a defying public health problem [13,14,15]. The co-infection cases described to date, together with the 13 cases reported herein, highlight the difficulty in reaching the final diagnosis, since both diseases share similar signs, symptoms and laboratory features. These obstacles in the diagnostic process can be detrimental to the patient’s condition and increase the burden on the healthcare system, especially in the context of the COVID-19 pandemic, as these are diseases with substantial morbidity and mortality .
The precise diagnosis of COVID-19 alone is already a significant challenge in clinical practice as the differential diagnosis with influenza and other respiratory infections must be considered. This problem is reflected in the number of deaths by respiratory diseases reported between March and November of 2020 in Brazil, where a 1225% increase in acute respiratory distress syndrome (ARDS) and a 40% increase in undetermined deaths (deaths linked to respiratory diseases, but not conclusive) can be seen when compared to the same period in 2019 . In this sense, other endemic febrile diseases complicate the clinical picture even further.
The differential diagnosis problem with febrile diseases becomes evident after analyzing the cases reported here, where the similarities between symptoms in the initial stages of COVID-19 and dengue fever, or asymptomatic presentation of one of them, delayed the diagnosis of concomitant infections (Table 2). Even retro-orbital pain, a symptom usually associated with dengue, is being commonly reported in COVID-19 cases . In the context of this case series, at the start of the pandemic dengue fever was usually the first diagnosis contemplated by physicians (Fig. 2), and co-infection with SARS-CoV-2 was, therefore, determined with delay. Fortunately, during the course of the pandemic, healthcare professionals started to consider the possibility of concomitant infections in the initial diagnosis, as highlighted in Fig. 2.
As dengue fever and COVID-19 require different clinical management, incorrect or delayed diagnosis can have serious consequences . The use of anticoagulants is especially concerning since they are frequently used in COVID-19 patients to protect against thrombotic events, but should be avoided in all patients with dengue fever, as they can increase the risk of thrombocytopenia and even trigger Reyes syndrome, a rare condition characterized by hepatitis and encephalopathy . Furthermore, several factors, such as hypertension, diabetes, obesity and old age, that are associated with poor prognosis in COVID-19 , may also complicate dengue fever. Some of these factors are present in the co-infected patients reported here, and in previously reported cases .
Some clinical and epidemiological clues can aid differential diagnosis. Generally, the seasonality is opposite: respiratory infections are usually reported in winter whereas dengue is usually in summer. However, COVID-19 cases in Brazil do not follow a clear seasonal pattern, as commonly observed for influenza and other respiratory viruses. It is not yet clear whether COVID-19 will become seasonal or will continue to spread throughout the year, especially because of its stability in comparison to other respiratory viruses (such as influenza) and the presence of an immunologically-susceptible population . Meanwhile, public health policies and individual countermeasures are in place to mitigate the spread.
The usual findings of thrombocytopenia and lymphopenia are common in both diseases [20, 21]. However, cavitary effusions and bleeding are not commonly observed in COVID-19, which should raise suspicion, even with pulmonary clear ground-glass opacities typical of such infection. The diagnosis of COVID-19 during a pandemic might impact and lead to a reduction in the number of dengue cases diagnosed, contributing to underdiagnosis and delayed fluid interventions, which are lifesaving in severe dengue cases . Official reports issued by the Brazilian Ministry of Health showed a decrease in the number of dengue cases and deaths compared to 2019, possibly fueled by resource and personnel allocation to SARS-CoV-2 diagnosis in Brazil , which could have led not only to under-reporting of cases and deterioration in surveillance, but also a worsening in control interventions .
An additional limitation is mainly related to the serological response of these infections. The low specificity of some rapid tests and commercial kits designed to detect IgM antibody for DENV cross-reactivity must be considered . In addition, the possibility of a hospital-acquired SARS-CoV-2 infection is also a factor to be taken into consideration in patients hospitalized due to severe dengue.
Regarding cross-reactivity, confirmatory diagnosis via RT-PCR for DENV would be ideal. However, in the context of clinical practice, confirmation by RT-PCR is frequently not the most common approach as clinical management of dengue fever is decided primarily on signs and symptoms . IgM ELISA or NS1 tests are often preferred as they are more available, and more affordable, in dengue-endemic regions [25,26,27]. In addition, the serological sample collection time offers more flexibility, while the higher stability of immunoglobulins facilitates transportation .
In addition, although it is known that clinical manifestations can vary according to serotype , in the Federal District, RT-PCR results are only released in up to 12 working days , by which time the symptoms have already subsided in the majority of cases . Therefore, health professionals often use serological tests to confirm dengue diagnosis. That said, information about the circulating serotypes can be obtained from the weekly regional epidemiological bulletins that register the infrequently reported serotype identification. Between January and September of 2020, these bulletins reported 312 DENV-1 and 16 DENV-2 serotype identifications in the residencial areas of the patients included in the present study . Nonetheless, lack of identification of the dengue serotype is a limitation of this study as it has clinical and epidemiological significance . An experimental design incorporating the RT-PCR test for DENV should be considered for future studies.