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Critical Care Medicine

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Post-COVID Secondary Infections

Secondary infections post-COVID-19 have been reported since the beginning of the pandemic, however in recent months the frequency and type of secondary infections have increased. Some of these secondary infections are becoming increasingly life-threatening, especially in vulnerable populations.

Recent research has highlighted the long-term damage and dysfunction that SARS-CoV-2 has on the immune system, even after mild COVID infections. It has been previously documented that COVID-19 infection can cause long-lasting immunocompromised state, likely from T-cell activation and exhaustion.

Researchers reported in a study published in April 2023 in the journal Immunity, that their "findings suggest that SARS-CoV-2 infection damages the CD8+ T cell response, an effect akin to that observed in earlier studies showing long-term damage to the immune system after infection with viruses such as hepatitis C or HIV."

The risks of secondary infections from SARS-CoV-2 increases with subsequent COVID infections as immune dysfunction increases.

Current research has so far identified multiple bacterial, viral, and fungal infections that are directly attributed to COVID-19 infection, and many more that have circumstantial evidence that suggests that COVID-19 may be associated with the infections.

Covid-Associated Bacterial Infections

Antimicrobial Resistance

The COVID-19 pandemic has likely altered other pathogens, including bacteria and fungi, potentially increasing the incidence of antimicrobial resistance. During the COVID-19 pandemic, there were improper uses of antimicrobials either in healthcare institutions or in communities, which in turn played a role in the increase in antimicrobial resistance.

It has been documented that about 72% of COVID-19-admitted patients were treated with antimicrobials, whereas solely 8% of these patients had bacterial or fungal co-infection. Additionally, antimicrobials were used early in the pandemic in the absence of other therapeutics on many severe hospitalized COVID-19 patients with which there were desperate attempts to find symptomatic relief for these patients. On top of the inappropriate use of antimicrobials, the increased and universal use of biocides (disinfectants) probably encouraged more indirect increases in antimicrobial resistance.

Since early 2020, this situation has expanded globally and might have supported the evolution of extremely resistant microorganisms, which might have played a critical role in worsening the status of some patients, especially those who were admitted to intensive care units (ICUs). Many patients with severe COVID-19 infections developed deadly bacterial and fungal secondary/co-infections, often referred to as "superinfections".

Antibiotic Resistance

A systematic review published in 2022 in the International Journal of Environmental Research and Public Health found that the most commonly reported resistant Gram-negative bacteria were:

  • Acinetobacterbaumannii
  • Klebsiella pneumonia
  • Escherichia coli
  • Pseudomonas aeruginosa

A. baumannii and K. pneumonia were highly resistant to tested antibiotics compared with E. coli and P. aeruginosa. Moreover, K. pneumonia showed high resistance to colistin.

The most commonly reported Gram-positive bacteria were:

  • Staphylococcus aureus
  • Enterococcus faecium

The resistance of E. faecium to ampicillin, erythromycin, and Ciprofloxacin was high.

The authors concluded that self-antibiotic medication, empirical antibiotic administration, and antibiotics prescribed by general practitioners were the causes of increased antibiotic resistance during the COVID-19 pandemic.

A study published in PLOS Global Publich Health in 2022 of 318 COVID patients found that antibiotics were prescribed were heavily prescribed for all COVID-19 patients, with severe disease correlated to increased usage:

  • 93.72% (209) of mild cases
  • 92.45% (49) of moderate cases
  • 96.15% (25) of severe cases
  • 100% (16) of critical cases


Antifungal Resistance

One of the mechanisms for the resistance is fungi tend to produce elevated amount of enzymes that are the main target for azole group and other antifungal drugs, hence preventing the suppression of metabolic reactions. Another mechanism used is the modification of the arrangement of targeted enzyme that minimize the attachment efficacy of azole significantly.

Covid-Associated Viral Infections

An article published on May 12, 2023 on the preprint server medRxiv looked at real-time U.S. nationwide EHR data from January 1, 2010 through January 31, 2023 to assess whether COVID-19 contributed to the surge of RSV infections and hospitalizations in young children in fall 2022. After examining EHR data for over 29 million medical visits from children 0-5 and over 13 million medical visits for children 0-1, the authors concluded that prior COVID-19 infection increased risk for unspecified bronchiolitis (of which RSV is the most common cause) in both 2021 and 2022.

"Patients infected with COVID-19 can have long-lasting changes in both innate and lymphocyte based immune functions, precisely the systems most engaged in defense against respiratory viruses. These findings further support our hypothesis that COVID-19 had adverse impact on the immune and respiratory systems of children, making them susceptible to severe respiratory viral infections from RSV and other viruses."

Covid-Associated Virus Reactivation

Reactivation is the process by which a latent (inactive) virus switches to a lytic (active) phase of replication. There are a few relevant human viruses that have another phase of replication, usually referred to as the ‘latent phase’ – in other words, the virus lays dormant in this latent phase of replication. Latent infections have the ability to be reactivated into a lytic form. The ability to move back and forth from latent to lytic infections helps the virus spread from infected individuals to uninfected individuals.

Many viruses have a propensity to cause latent infections. The majority of these viruses are from the family of Herpesviridae:
  • Herpes simplex virus (HSV)-1
  • Herpes simplex virus (HSV)-2
  • Varicella zoster virus (VZV)
  • Epstein–Barr virus (EBV)
  • Cytomegalovirus (CMV)
  • Human herpesvirus (HHV)-6
  • Human herpesvirus (HHV)-7
  • Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV)-8.

Other viruses that are capable of latent phases are:

  • Human polyomavirus 2 (also referred to as JC Virus, John Cunningham Virus, or VCV)
  • Human polyomavirus 2 (also referred to as the BK Virus)
  • Adenoviruses
  • Parvovirus B19 (also referred to as Fifth Disease)
  • Adeno-Associated Viruses (AAV)

Current research is also trying to determine whether SARS-CoV-2 (COVID-19) is capable of latent phases. If this turns out to be the case, it is possible that once a person has been infected with SARS-CoV-2, the virus may live in their body indefinitely, possibly reactivating at a later time, including with unique symptoms (i.e. the Varicella Zoster Virus which causes chicken pox can be reactivated years or decades after initial infection and cause Shingles (Herpes Zoster)).

Covid-19 Associated Fungal Infections

COVID-19-associated fungal infections can lead to severe illness and death. COVID-19 likely increases the risk for fungal infections because of its effect on the immune system and because treatments for COVID-19 (like steroids and other drugs) can weaken the body’s defenses against fungi. The most commonly reported fungal infections in patients with COVID-19 include aspergillosis, invasive candidiasis, and mucormycosis (sometimes referred to by the misnomer ”black fungusexternal icon.”) Fungal infections resistant to antifungal treatment have also been described in patients with severe COVID-19.

Moreover, a distinctive immune-cell event that is observed in patients with COVID-19 is the decrease of T-cell populations, especially in patients with severe disease. Decline of lymphocyte counts can be accompanied by defective function. Severe lymphepenia has been established as a factor predicting the risk of invasive mold disease in patients with hematological malignancies.

Covid-19 Associated Pulmonary Aspergillosis (CAPA).

Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported.

Scientists are still learning about aspergillosis (infections caused by the fungus Aspergillus) in people with severe COVID-19. In the past, scientists thought aspergillosis occurred almost entirely in people with severely weakened immune systems. However, aspergillosis has been increasingly reported in patients without weakened immune systems but who have severe respiratory infections caused by viruses, including influenza. Several recent reports describe COVID-19-associated pulmonary aspergillosis (CAPA).

Covid-Associated Mucormycosis

Mucormycosis (previously called zygomycosis) is a rare but serious angio-invasive infection caused by a group of fungi called mucormycetes. 

Mucormycosis mainly affects people who are immunocompromised, or patients already infected with other diseases. High risk groups include people with diabetes (especially diabetic ketoacidosis), solid organ transplantation, neutropenia (low neutrophils, a type of white blood cells), long-term systemic corticosteroid use, and iron overload (hemochromatosis). The risk is high for people living with HIV, and those using immunomodulating drugs, including the anti-fungal voriconazole in some high-risk groups. 

Reports of COVID-19-associated mucormycosis have been increasing in frequency since early 2021, particularly among patients with uncontrolled diabetes.

COVID-19-associated mucormycosis is a major public health problem in India. COVID-19-associated mucormycosis cases have also been seen outside of India, including in the United States, although much less commonly. Uncontrolled diabetes and overuse of steroids for COVID-19 treatment are important risk factors.

Covid-Associated Candida auris (CACa)

Candida auris (C. auris) is a type of fungus that can cause serious illness in hospitalized patients. Infections with this fungus can be difficult to treat. C. auris only recently appeared in the United States, and public health officials are researching more about how it is spread.

Candida auris (C. auris) is an emerging fungus that can cause outbreaks of severe infections in healthcare facilities. In the United States, it has most commonly spread in long-term care facilities caring for people with severe medical conditions. However, since the start of the COVID-19 pandemic, outbreaks of C. auris have been reported in COVID-19 units of acute care hospitals. These outbreaks may be related to changes in routine infection control practices during the COVID-19 pandemic, including limited availability of gloves and gowns, reuse or extended use of these items, and changes in cleaning and disinfection practices. Screening for C. auris colonization, an important part of containment efforts, has been more limited as healthcare facilities and health departments have been responding to COVID-19.

The incidence of COVID-19-associated candidiasis (CAC) is increasing, resulting in a grave outcome among hospitalized patients with COVID-19. The most alarming condition is the increasing incidence of multi-drug resistant Candida auris infections among patients with COVID-19 worldwide.

According to a CDC analysis published in April 2023 in Annals of Internal Medicine, clinical cases of C. auris, grew 95 percent from 2020 to 2021. Overall, 3,270 infections were reported in the U.S. from 2016 — when the first clinical case was reported — through 2021. Additionally, the number of cases that were resistant to antifungal drugs tripled from 2019 to 2021. Infections in the US increased from 476 clinical cases in 2019 to 1,471 in 2021.

Covid-19 Associated Invasive Fungal Rhinosinusitis (AIFR)

Fungal infections of the paranasal sinuses are in fact a spectrum of diseases rather than one distinct entity. As such, there has been much published on the classification of fungal rhinosinusitis (FRS). These are invasive or non-invasive, dependent on the potential of the fungal hyphae to invade the tissues through the epithelium (invasive) in comparison to the infection being confined to the superficial epithelium (non-invasive). As its name suggests, invasive FRS can result in dramatic tissue invasion through mucosa, bone, neurovascular structures and surrounding organs.

Systemic corticosteroids have been proven to reduce mortality in specific subgroups of patients with COVID‐19, with the greatest efficacy observed in individuals who require invasive mechanical breathing. Nonetheless, systemic corticosteroids depress the immune system, predisposing patients to invasive fungal rhinosinusitis. This results in a high rate of deadly fungal infection affecting the nose and paranasal sinuses, with the rhino–orbito–cerebral presentation being the most prevalent.

The COVID‐19‐associated AIFR differs from that of the non‐COVID‐19 in both existences of some remarkable risk factors and high incidence rate. The upregulation of inflammatory cytokines and reduced cell‐mediated immunity with decreasing levels of CD4+ and CD8+ cells might both be related to COVID‐19. Further contributing variables to the COVID‐19‐linked AIFR include steroid‐induced hyperglycemia, diabetic ketoacidosis, elevated iron levels, immunosuppression from COVID‐19, excessive steroid dosages, and immunomodulators, and reduced white blood cells phagocytic activity. Additionally, extended hospitalization with or without mechanical ventilators and low oxygen levels both increase the risk of AIFR. Compared to non‐COVID‐19 individuals, the incidence of AIFR is noticeably higher in immunocompromised, diabetic, renal, and hepatic dysfunction patients, as well as those with cardiac illnesses, bronchial asthma, and obesity.