This poses challenges in clinical and laboratory diagnosis of COVID, and have a bearing on clinical management and patient outcomes.
The scope of this document is to provide clear guidelines on prevention and treatment of co-infections of COVID with diseases like Dengue, Malaria, Seasonal Influenza (H1N1), Leptospirosis, Chikungunya etc.
As per the World Health Organization (WHO) case definition, a COVID case may present with:
• Acute onset of fever AND cough; OR
• Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general weakness/ fatigue, headache, myalgia, sore throat, coryza, dyspnoea, anorexia/ nausea/ vomiting, diarrhoea, altered mental status.
This case definition, although sensitive, is not very specific. Seasonal epidemic-prone diseases, as cited in the foregoing paragraphs may all present as febrile illness, with symptoms that mimic COVID-19. If there is a coinfection, then apart from the febrile illness there may be constellation of signs and symptoms that may lead to difficulty in diagnosis. A comparative analysis of disease onset, symptoms, signs, warning signs, complications and diagnosis is given at Annexure.
APPROACH TO DIAGNOSIS OF SUSPECTED CO-INFECTION
A high index of suspicion must be maintained for epidemic prone diseases (e.g. Dengue, Malaria, Chikungunya, Seasonal influenza, Leptospirosis) prevalent in a particular geographic region during monsoon and post-monsoon seasons. Bacterial co-infections must also be suspected in moderate or severe cases of COVID-19 not responding to treatment.
It must be borne in mind that malaria/ dengue can coexist with other infections, and thus confirmation of malaria/dengue infection does not rule out the possibility of the patient not suffering from COVID-19. Similarly, a high index of suspicion of malaria/ dengue must be there when a fever case is diagnosed as COVID-19, particularly during the rainy and post rainy season in areas endemic for these diseases.
Both COVID-19 and Seasonal Influenza present as Influenza-Like Illness (ILI)/ SARI, hence all ILI/SARI cases in areas reporting COVID-19 cases must be evaluated and tested for both COVID-19 and Seasonal Influenza, if both viruses are circulating in population under consideration.
Chikungunya presents with acute onset of moderate to high grade continuous fever and malaise followed by rash, myalgia and arthralgia. Respiratory failure may ensue in late stages. Co-infection with COVID-19 may be suspected in Chikungunya endemic areas, in the months of monsoon.
Leptospirosis apart from it presenting as febrile illness, has also the tendency to manifest as acute respiratory illness, leading to respiratory distress and shock. In areas where Leptospirosis is known to cause outbreaks during monsoon/ post monsoon, the possibility of coinfection should be considered.
Scrub typhus is known to be prevalent in foothills of Himalayas viz Jammu & Kashmir, Himachal Pradesh, Sikkim, Manipur, Nagaland, Meghalaya, etc. However, in recent past, scrub typhus outbreaks have also been reported from Delhi, Haryana, Rajasthan, Maharashtra, Uttarakhand, Chhattisgarh, Tamil Nadu and Kerala. The clinical picture consists of sudden high-grade fever, severe headache, apathy, myalgia and generalized lymphadenopathy. A maculopapular rash may appear first on the trunk and then on the extremities and blenches within a few days. The patients may develop complications that include interstitial pneumonia (30 to 65% of cases), meningoencephalitis and myocarditis. Scrub typhus infection may co-exist with COVID-19.
Few patients with COVID-19 experience a secondary bacterial infection. In such cases, empiric antibiotic therapy as per local antibiogram needs to be considered.
Despite the possibility of above-mentioned co-infections, in present times of the pandemic, approach to diagnosis for COVID-19 essentially remains the same. Testing protocol as per MoHFW/ICMR guidelines will be followed. However, in addition, further tests for a likely co-infection will also be undertaken, whenever suspected.
While each of these infections are antigenically distinct with specific serological responses, yet in the eventuality of co-infections, cross reactions (resulting in false-positive / false-negative results) cannot be totally ruled out, especially if the testing kits used are not having requisite sensitivity and specificity. Hence the tests recommended by ICMR (for COVID-19) and that recommended by the concerned programme divisions (NVBDCP for vector borne diseases [Malaria, Dengue, Chikungunya]) and NCDC (Seasonal Influenza, Leptospirosis, Scrub Typhus)] needs to be followed. Availability of rapid diagnostic kits for malaria, dengue, scrub typhus should be ensured in such COVID treatment facilities.
The table below summarizes the various (confirmatory) test to be undertaken for possible coinfections.
Management of co-infection of COVID-19 with dengue, Influenza and bacterial co-infections may however be challenging and are dealt with in greater detail here.
Management of COVID-19 and Dengue co-infection Pathogenesis
Dengue Fever and COVID-19 share many pathogenic and clinical features which might make it very difficult to differentiate the two infections. The phenomenon of ADE (Antibody-Dependent Enhancement) has been described for both dengue virus as well as for SARS-CoV-2 virus resulting in escalation in degree of infection and number of complications. Both being RNA viruses they share certain common features in pathogenesis, eventually leading to subsequent cytokines and chemokine release and also affecting the integrity of the vascular endothelium leading to vasculopathy, coagulopathy and capillary leak. Various mechanisms can explain the signs and symptoms observed in coinfected patients but most will have the following, (i) Antibody-dependent enhancement (ADE), (ii) Cytokine Storm, (iii) Vasculopathy and (iv) Coagulopathy.
The clinical features of both the infections are overlapping, both present as acute febrile illness of short duration and may have thrombocytopenia and shortness of breath, although respiratory symptoms are more common in COVID-19 and bleeding manifestations more common in Dengue. Routine testing for both diseases shows leucopenia or normal leucocyte count. Decrease in platelet count which is a defining feature of dengue infection but can also be seen in significant number of covid cases. There are reports in literature, where dengue serology was positive initially and later on, it was found that cases were positive by RT-PCR for COVID-19 thereby suggesting that dengue serology can be falsely positive in COVID-19 patients. Therefore, there is a need to rely on more specific tests for each disease like throat swab RTPCR for COVID-19 and ELISA based Dengue NS1 Antigen or serology test for dengue diagnosis. Serum sample for NS1 antigen within first 5 day of onset of fever were negative in above study suggesting that positive dengue serology was more likely to be false positive result and not co-infection. Hence, one needs to be careful while making diagnosis of co-infection.
There are now enough evidences to support that severe dengue is associated with cytokine storm and high levels of various circulating cytokine are associated with poor outcome in most cases. COVID19 infects alveolar epithelial cells leading to pneumonia and ARDS, it also infects monocytes/macrophages leading to cytokine storm associated with multi organ failure and death. This cytokine storm seen in severe cases has led to increased use of steroids and other immunosuppressive therapy in moderate to severe cases.
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