Coinfections among COVID-19 patients: A need for combination therapy?

Dear Editor,

We have read the review of Lai et al. about coinfections among COVID-19 patients with great interest. They emphasized that the prevalence of coinfections varies among the studies, while it could be up to 50% among non-survivors.

Viral coinfections, especially with influenza are challenging since COVID-19 pandemic coincided with the local circulation of influenza in many countries. Although the measures taken for COVID-19 pandemic, decreased the influenza cases as well (Fig. 1 ), influenza is still a health care problem especially for certain risk groups. We have recently reported 6 COVID-19 patients coinfected with influenza and reviewed 28 previously reported cases. A review of 14 studies reporting viral coinfecting respiratory pathogens estimated that 3% of hospitalized COVID-19 patients were also coinfected with another respiratory virus; respiratory syncytial virus (16.9% of detections) being the most prevalent one, followed by influenza A (15.5%). This analysis also showed that coinfected COVID-19 patients were more likely to die than patients who were not coinfected.

Figure 1

Rate of influenza positivity among patients admitting to sentinel influenza centers in 2018–2019 (dashed line) and in 2019–2020 (solid line) seasons in Europe. X-axis shows the weeks of the year and y-axis shows rate of influenza positivity (%).

Coinfection of influenza with COVID-19 may change the epidemiologic, clinical and radiologic features (Table 1 ).2, 3, 4 A study from Wuhan, China reported 93 COVID-19 patients, 44 (47.3%) of whom were coinfected with influenza. Although fatality rates between COVID-19 monoinfected (47%) and coinfected (48%) patients were comparable, the critically ill COVID-19 patients with influenza exhibited more severe inflammation and organ injury, and were more prone to cardiac injury.

Table 1

Characteristics of influenza, COVID-19 and coinfection of influenza-COVID-19.1, 2, 3, 4, 5

	Influenza	COVID-19	Influenza-COVID-19 Coinfection
Epidemiology	Prevalent from December to April in northern hemisphere; June to October in southern hemisphere, significantly decreases during summer	It emerged in China in December 2019 and spread rapidly across the world within 3 months. The pandemic is on the rise in many countries. Hot weather (summer) alone does not seem to stop the spread of the disease.More clustered (2 or more cases reported in same small area, such as home, office, etc.)	The studies from China including the period January–February 2020, reported coinfection rates of 2.7–57% among COVID-19 patients and 49% among critically ill COVID-19 patients. A study from Turkey including the period of March to May detected the influenza coinfection as 0.54%. Studies from the United States including the period of March to April, reported the coinfection rates of 0.08–0.9%.
Prevalence	≈1 billion people are infected annually	As of 2 July 2020, 17,660,523 patients have been reported	Among influenza patients, COVID-19 coinfection rate is 0.08–57%
Seasonality	Seasonal	Unknown	Follows influenza's seasonality: Higher (2–57%) when influenza is circulating.Lower (0.08–0.9%) when influenza season is over.
Incubation time	1–4 days	2–14 days	Unknown. Probably depends which virus is taken first (or at the same time)
Clinical Features
Signs & Symptoms	Fever (higher), cough, dyspnea, fatigue, sputum, GI symptoms, myalgia, hemoptysis	Fever, cough, sputum, dyspnea, fatigue (more), GI symptoms (more), myalgia, hemoptysis	Mostly like those of COVID-19 patients
Laboratory	Higher levels of lactate dehydrogenase	Higher levels of D-dimer, CRP, ferritin, procalcitonin, troponin, prolonged prothrombin time
Organ involvement other than lungs		COVID-19 patients are more susceptible to thrombosis, and liver and kidney damages.
Radiology
Lesion Distribution	Central	Balanced predomination	Mostly like those of COVID-19 patients
Lobe predomination	Inferior	Nonspecific and peripheral
Lesion margin	Vague	Both vague (54%) and clear (46%)
GGO involvement pattern	Cluster-like GGO	Combination of GGO and consolidation opacities and patchy GGO
Lesion contour	Non-shrinking	Shrinking
Bronchial wall thickening	None	33%
Outcome-Case fatality rate	0.05–0.1%	3.86%	Not available
Impact of influenza vaccine	The effectiveness depends on several host factors and on antigenic matches between the vaccine and circulating viruses. It reduces the risk of illness by between 40% and 60% among the overall population	Higher influenza vaccine uptake in the elderly was found to be associated with less COVID-19 deaths.	Influenza vaccine may prevent influenza coinfection among COVID-19 patients.

GGO: ground-glass opacity.

Furthermore, Marín-Hernández et al. conducted a study investigating the relationship between elderly individuals who received the influenza vaccination and the percentage of COVID-19 deaths in Italy. They found a moderate-to-strong negative correlation between influenza vaccination and COVID-19 deaths among elderly meaning that where there were higher influenza vaccination rates, fewer deaths from COVID-19 occurred. This study may suggest the negative role of influenza on COVID-19 disease course indirectly.

Comparison of thorax computed tomogram (CT) of 13 patients with COVID-19 and 92 with influenza reported that following 6 parameters were found significantly different between influenza and COVID-19 patients: lesion distribution (central in influenza; non-specific/peripheral in COVID-19), lobe predomination (inferior in influenza; balanced predomination in COVID-19), lesion margin (vague in influenza; both vague and clear in COVID-19), ground-glass opacity (GGO) involvement pattern (cluster-like GGO in influenza; combination of GGO and consolidation opacities and patchy GGO in COVID-19), lesion contour (non-shrinking in influenza; shrinking in COVID-19) and bronchial wall thickening (none in influenza; 1/3 in COVID-19)2.

Then, Liu et al. compared CT findings of 122 patients confirmed with COVID-19 and 48 patients confirmed with influenza and confirmed the predilection of peripheral distribution, GGO with consolidation, and bronchiolar wall thickening in COVID-19. Additionally, the study showed that, compared with the influenza group, the COVID-19 group was more likely to have interlobular septal thickening but less likely to have nodules, tree-in-bud sign, and pleural effusion. Thus, thoracic CT may help to distinguish findings of COVID-19 and those of influenza (Table 1).

Among COVID-19 guidelines, only Canadian and Turkish guidelines recommend adding oseltamivir, a neuraminidase inhibitor. Neuraminidase inhibitors are used in the prophylaxis and treatment of influenza A and B infections. They are ineffective against COVID-19. They reduce the mortality of patients with influenza, especially those admitted to the intensive care unit. The effectiveness of oseltamivir in reducing the mortality of patients with influenza is related to the timing: the drug was found effective before the onset of respiratory failure. The patients in critical condition who took the drug showed no benefit in improving the disease. Therefore, neuraminidase inhibitors, oseltamivir or zanamivir, should be initiated rapidly when influenza co-infection is considered among COVID-19 patients.

Accumulating data suggest that influenza coinfection is undiagnosed and underestimated and is likely to associate with a higher mortality. Although influenza is decreasing during this pandemic because of the measures, clinicians should keep alert COVID-19 patients with influenza coinfection. Combination therapy (adding oseltamivir) should be considered in COVID-19 patients with CT findings suggesting influenza coinfection and/or when there is local circulation of influenza.