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Many Covid-19 deaths were caused by secondary infections

During the Covid-19 pandemic, many scientists argued that cytokine storms – overwhelming inflammations driving multiple organ failures – were the main cause of death in critically ill patients. However, according to a new study led by Northwestern University that applied machine learning to medical record data, secondary bacterial infections were a leading cause of death among Covid-19 patients.

The analysis revealed that nearly half of the patients who required mechanical ventilation developed bacterial pneumonias, highlighting the need to identify and aggressively treat secondary infections in ICU patients.

“Our study highlights the importance of preventing, looking for, and aggressively treating secondary bacterial pneumonia in critically ill patients with severe pneumonia, including those with Covid-19,” said senior author Benjamin Singer, a professor of Pulmonary Medicine at Northwestern University and a pulmonary and critical care physician at Northwestern Medicine.  

“Those who were cured of their secondary pneumonia were likely to live, while those whose pneumonia did not resolve were more likely to die. Our data suggested that the mortality related to the virus itself is relatively low, but other things that happen during the ICU stay, like secondary bacterial pneumonia, offset that.” 

Moreover, according to Singer, the “cytokine storm theory” arguing that most of Covid fatalities were caused by massive inflammation driving multiple organ failure is false. “If cytokine storm were underlying the long length of stay we see in patients with Covid-19, we would expect to see frequent transitions to states that are characterized by multi-organ failure. That’s not what we saw,” he explained.

The study involved 585 patients in the intensive care unit (ICU) of the Northwestern Memorial Hospital with severe pneumonia and respiratory failure, including 190 Covid patients. 

The experts designed a new machine learning approach called CarpeDiem that groups similar ICU patient-days into clinical states based on electronic health record data. This groundbreaking approach – based on the concept of daily rounds by the ICU team – helped researchers clarify how complications such as secondary bacterial infections impacted the course of illness.

In addition, the patients or their surrogates consented to enroll in the Successful Clinical Response to Pneumonia Therapy (SCRIPT) study, an observational trial aiming to identify new biomarkers and therapeutic pathways for patients with severe pneumonia. As part of this trial, an expert panel of ICU physicians analyzed lung samples to better understand the outcomes of secondary pneumonia events.

“The application of machine learning and artificial intelligence to clinical data can be used to develop better ways to treat diseases like Covid-19 and to assist ICU physicians managing these patients,” explained lead author Catherine Gao, an instructor in Pulmonary and Critical Care Medicine at Northwestern University and a Northwestern Medicine physician.

“The importance of bacterial superinfection of the lung as a contributor to death in patients with Covid-19 has been underappreciated because most centers have not looked for it or only look at outcomes in terms of presence or absence of bacterial superinfection, not whether treatment is successful or not,” added co-author Richard Wunderink, the leader of the Successful Clinical Response in Pneumonia Therapy Systems Biology Center at Northwestern.

In future studies, the scientists plan to integrate molecular data from the already collected samples with machine learning approaches to clarify why some patients are cured of pneumonia and others not, while also expanding the datasets currently used to make better predictions that could improve the care of critically ill patients.

The study is published in the Journal of Clinical Investigation.  

More about Covid-19 and secondary infections

Covid-19, caused by the SARS-CoV-2 virus, primarily affects the respiratory system and can lead to severe pneumonia and respiratory distress. In some cases, Covid-19 can also lead to secondary infections. 

Secondary infections are infections that occur as a result of an individual’s weakened immune system or the complications arising from the primary infection. In the context of Covid-19, secondary infections can involve bacterial, fungal, or viral pathogens. Some common secondary infections associated with Covid-19 include:

Bacterial infections

Patients with severe Covid-19, particularly those who are hospitalized or on ventilators, may be at a higher risk of developing bacterial infections. These can include ventilator-associated pneumonia (VAP) or bloodstream infections. Common bacterial pathogens involved are Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae.

Fungal infections

Covid-19 patients, especially those with weakened immune systems or underlying health conditions like diabetes, may be more susceptible to fungal infections. One notable example is the emergence of Covid-19-associated mucormycosis, also known as “black fungus.” This infection is caused by the fungi from the Mucorales order and can lead to severe complications if not treated promptly.

Viral infections 

In some cases, patients with Covid-19 may also be co-infected with other respiratory viruses, such as influenza or respiratory syncytial virus (RSV). These co-infections can potentially exacerbate the severity of the illness and further strain the patient’s immune system.

Preventing secondary infections in Covid-19 patients 

Infection control practices

Strict adherence to infection control measures in healthcare settings, such as hand hygiene, the use of personal protective equipment (PPE), and isolation protocols, is crucial to prevent the spread of infections among patients and healthcare workers.

Antibiotics and antifungal medications

The appropriate use of antibiotics and antifungal medications is crucial in the management of secondary infections. However, it is essential to ensure that these drugs are used judiciously to prevent the development of antibiotic resistance.


Vaccines for preventable diseases, such as influenza and pneumococcal pneumonia, can help reduce the risk of secondary infections in Covid-19 patients.

Close monitoring

Healthcare professionals should closely monitor Covid-19 patients, especially those with severe cases or underlying health conditions, for any signs of secondary infections. Early diagnosis and treatment can significantly improve outcomes.

Patient education

Educating patients and their caregivers about the signs and symptoms of secondary infections can help in the early identification and management of these complications.

By Andrei Ionescu, Staff Writer

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