COVID-19 is probably the greatest pandemic of our generation, with more than 16 million people infected and over 650,000 deaths worldwide so far. COVID 19 pandemic is currently in its second phase in India. Thousands of people are still dying every day. New cases however are on the decline. Secondary infections are increasingly being reported now from admitted patients (the proportion of patients with secondary infections range from 5% to 30%). Such cases are on the rise due to prolonged admission and indwelling devices.
Bacterial infections associated with COVID-19 may be:
- Co-infections- Microbiologically confirmed bacterial infection ( occurring ≤2 days after admission) is termed co-infection.
- Secondary infections- Microbiologically confirmed bacterial infection(occurring >2 days after admission) is termed secondary infection.
The high mortality in severely ill COVID-19 patients is thought to be at least in part due to secondary infections in addition to viral replication in the lower Respiratory tract leading to severe lung injury and ARDS.
Of all COVID deaths, 50% have had some secondary infections. Even coinfections are associated with worse outcomes. In the case of secondary infections after COVID, the case fatality rate goes up to the order of 50-56%. Hence it has to be taken very seriously and differentiated from worsening COVID19 pneumonia per se.
Profile of secondary infections in COVID 19
1) Bacterial (about 72%).
2) Viral (about 19%).
3) Fungal (about 14%).
However, it is strange that bacterial infections, though most common, get the least importance. Fungal superinfections are now very well known after COVID 19, like so-called Black fungus and white fungus, yellow fungus etc.
Bacterial infections in COVID
- Such infections can either be coinfections or more commonly secondary infections. 78% of these infections arise in hospitals.
- People having more secondary bacterial infections include :
- Critically ill patients.
- Those on steroids and IL6 antagonists.
- Those having prolonged ICU admission with a central line, mechanical ventilation and other indwelling devices.
- Those on antibiotics for some time.
One large study from the US documented that early empiric antibiotic therapy was used in 56.6% (965/1705) patients hospitalised with COVID-19, whereas only 3.5% (59/1705) of patients had a confirmed community-onset bacterial co-infection. Male sex, older age, heart diseases, hypoproteinemia, corticosteroid and proton-pump inhibitors are independent risk factors of secondary infections following COVID-19.
The site of such infections includes lungs(due to ventilator), Bloodstream, Urinary tract.
A study from France found that in patients with SARS-CoV-2 infection requiring mechanical ventilation for ARDS, early coinfection (samples taken within 24 h after intubation) with bacterial pathogens occurred in 13 (27.7%) of the patients, with co-infection with multiple pathogens in five patients (10.6%). Coinfection plays an important role in the occurrence and development of SARS-CoV-2 infection by raising the difficulties of diagnosis, treatment, the prognosis of COVID-19, and even increasing the disease symptom and mortality. Such coinfections are caused usually by S. aureus, S. pneumoniae, Legionella pneumophila, H. influenza and Mycoplasma pneumoniae.
Role of many factors behind co-infection
Gu et al recently discovered that the intestinal bacterial diversity of patients with COVID-19 is significantly reduced; there is a relative abundance of opportunistic pathogens like Streptococcus, Rothia, Veillonella, and Actinomyces spp., while the relative counts of beneficial symbionts such as Blautia, Romboutsia, Collinsella, and Bifidobacterium spp., is lower. This may be a factor. Currently, antibiotic use is high (74·5%) among patients with COVID-19 who are admitted to intensive care units, making culture-based microbiological testing of coinfections less sensitive.
A study has described both active and latent TB as a risk factor for COVID-19 infection, from Shenyang, China. TB diagnosis was based on an interferon-gamma release assay on peripheral blood. Not only were patients with active or latent TB more susceptible, but the symptom progression of the COVID infection was more rapid and more severe. Hence all patients with COVID-19 infection should be tested for TB.
Coinfection with TB and SARS CoV-2 is of particular concern due to several reasons:
- Firstly, diagnosis of TB is likely to be missed due to non-specific clinical features in both (TB & COVID-19) and the lack of radiological findings specific to TB.
- Secondly, this disease itself or the use of immunomodulators in moderate-severe COVID-19 may lead to reactivation of latent TB in high endemic areas like India.
- Thirdly, pre-existing TB disease and underlying lung condition will affect the clinical categorization (for severity) of COVID19.
- Co-existing active TB disease may predispose to severe illness.
- Lastly, there is a possibility of drug-drug interactions (e.g. Rifampicin and Lopinavir/ritonavir) as well as additive hepatotoxicity (remdesivir) due to simultaneous use of anti-tubercular drugs and available COVID-19 therapeutic options.
These infections usually occur 5 -11 days after admission. Bloodstream infections are the most frequent, followed by pneumonia, tracheobronchitis and urinary tract infection (8%) that are caused by a wide spectrum of Gram-positive (55%) and Gram-negative bacteria (30%) as well as fungi (15%).
Why secondary bacterial infection is common in COVID?
- Due to profound immunosuppression caused by COVID-19.
- Steroid therapy in severe cases and use of IL-6 inhibitors. Steroids can also aggravate diabetes.
- Severe COVID-19 cases are mostly Diabetic and hence immunocompromised.
- Impaired ability of the host to clear bacterial pathogens owing to release of specific cytokines like IL-10, IL-6, IL-17 and IL-23; reduced dendritic cells function, macrophages, natural killer cells, CD4+ and CD8+ T-cells.
- Platelets are activated in COVID-19, and cause:
- A. Upregulation of expression of CD62P, which, in turn, interacts with its counter-ligand, P-selectin glycoprotein ligand-1 (PSGL-1), expressed on neutrophils, monocytes, T lymphocytes and vascular endothelium.
- Intravascular formation of heterotypic aggregates between platelets with neutrophils, monocytes, and T cells, resulting in inappropriate leukocyte activation and microvascular occlusion.
- Augmentation of formation of platelet/neutrophil and platelet/monocyte aggregates via binding of cell surface-expressed platelet factor 4 (PF4, also known as chemokine CXCL4) with the leukocyte integrin, CR3.
- TGF-β-mediated polarization of immunosuppressive M2-like macrophages, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).
Severe SARS-CoV-2 infection causes multiple damages in the lungs, which can largely decrease the oxygen and carbon dioxide diffusion capacities. The disruption of surfactant and the sloughing of cells into the airways may provide access and a rich source of nutrients, promoting rapid bacterial growth. In almost all severe cases, SARS-CoV-2 infection results in pneumonia and the inflamed fluid-filled alveolar tissue now is an ideal habitat for bacterial growth for pathogens including P. aeruginosa and S. aureus.
Tests for pneumonia
- Multiplex PCR for coinfections.
- For coinfections: Biofire/Filmarray seems to be good (specificity an issue)
- Culture and VITEK.
- Post mortem histopathology.
- Imaging for secondary or concomitant bacterial pneumonia
- Legionella coinfection: Urine antigen test can be done, and detection of Legionella spp. DNA from BAL fluid by PCR.
- In the case of urine tests for Legionella spp., to exclude a false-positive antigen test result, a specific urine sample can be retested after boiling for 5 min and centrifugation, which retains positivity.
- For Mycoplasma, ELISA or Growth on PPLO Broth and PPLO agar can be tried.
- For fungi: CT /HRCT chest detects fungal hyphal margin and air-fluid level well (mostly Aspergillus spp.).
- Proper antibiotics have to be chosen based on susceptibility data.
- A peculiar entity: Patients with ventilator-associated tracheobronchitis often lack the classic signs of secondary bacterial pneumonia, may have increased secretions and low-grade fevers and can be difficult to wean from ventilatory support. The evidence to support antibacterial therapy for this clinical entity is limited and warrants a judicious case-based analysis.
Note: The article is based on inputs from Dr Sayan Bhattacharyya, MD Microbiology ( PGIMER Chandigarh) Assistant Professor, Department of Microbiology, All India Institute of Hygiene and Public Health, Kolkata, Chief Editor, Eastern Journal of Medical Sciences.