The clinical course of COVID-19, caused by the SARS-CoV-2 virus, varies widely, ranging from asymptomatic infection to severe illness requiring mechanical ventilation and leading to death. A person’s risk for developing a severe form of the disease is strongly linked to specific host characteristics and external factors. These risk factors increase the likelihood of progressing to severe illness, hospitalization, or mortality once a person is infected. Understanding these elements is essential for identifying vulnerable populations and guiding public health strategies and individual medical decisions.
Age and Immunological Changes
Advanced age represents one of the strongest, independent risk factors for severe COVID-19 outcomes. This vulnerability is rooted in two interconnected biological phenomena: immunosenescence and inflammaging. Immunosenescence describes the gradual deterioration of the immune system’s function that occurs as a natural part of aging, compromising the body’s ability to mount an effective defense against new pathogens.
This age-related decline includes a reduction in the number and function of naive T-cells and B-cells, which are necessary to recognize and respond to a novel virus like SARS-CoV-2. The adaptive immune response becomes slower and less potent, leading to delayed viral clearance. Simultaneously, older individuals experience inflammaging, a state of chronic, low-grade systemic inflammation characterized by elevated levels of pro-inflammatory signaling molecules.
When SARS-CoV-2 infection occurs, this pre-inflamed state primes the immune system for an exaggerated response. The immune system often overreacts, leading to a dysfunctional process sometimes described as a “cytokine storm,” where excessive inflammatory mediators cause widespread damage to the lungs and other organs. Risk for severe disease begins to increase noticeably around age 50 and accelerates significantly past age 65, correlating with the progression of these immunological changes.
Specific Chronic Health Conditions
The presence of chronic health conditions significantly compounds the risk of severe COVID-19 by introducing underlying physiological stress and inflammation. These comorbidities span multiple organ systems, contributing unique vulnerabilities to the body’s ability to withstand the viral assault.
Cardiovascular and Metabolic Vulnerabilities
Cardiovascular diseases, including hypertension and heart failure, increase the risk of severe outcomes due to compromised vascular health and reduced cardiac reserve. While the virus can damage heart tissue, pre-existing strain on the circulatory system means these patients are less able to cope with the demands of a severe respiratory infection. Diabetes, particularly Type 2, is a major risk factor, as poor glycemic control contributes to systemic inflammation and immune cell dysfunction. High blood sugar levels impair the function of immune cells, hindering the body’s initial response to the virus.
Obesity is a complex and potent risk factor, operating through both mechanical and inflammatory mechanisms. Excess adipose tissue, especially abdominal fat, physically restricts the diaphragm and lungs, diminishing respiratory capacity and making it harder to maintain oxygen levels during pneumonia. Adipose tissue is metabolically active, secreting numerous pro-inflammatory substances, which contributes to a chronic inflammatory state. This chronic inflammation, combined with increased expression of the ACE2 receptor in fat cells, creates an environment ripe for viral replication and an exacerbated inflammatory response, often leading to a prothrombotic state and increased risk of blood clots.
Respiratory and Other Organ Conditions
Chronic obstructive pulmonary disease (COPD) is a risk factor because it leads to permanent airway obstruction and damage, severely limiting the lung’s functional reserve. For these patients, even a mild viral infection can quickly overwhelm the compromised respiratory system, leading to respiratory failure. Moderate-to-severe asthma also places individuals at higher risk of hospitalization, likely due to chronic airway inflammation and reduced lung capacity.
Conditions affecting organ function outside the cardiovascular and respiratory systems also increase severity risk. Chronic kidney disease (CKD) impairs the body’s ability to regulate fluid, electrolyte balance, and waste products, and is associated with chronic immune activation and inflammation. Similarly, chronic liver disease, which often results in poor nutritional status and immune dysregulation, is associated with a higher likelihood of severe illness and mortality following SARS-CoV-2 infection.
Immunosuppression and Medical Treatments
A compromised immune system, whether due to an underlying illness or necessary medical treatment, significantly alters the body’s response to SARS-CoV-2. These patients often face a dual challenge: a reduced ability to clear the virus and a diminished capacity to benefit from vaccination.
Immunosuppressive medications, such as high-dose systemic corticosteroids, are a primary concern, as they broadly suppress the inflammatory response required to fight the virus. Their use for chronic conditions can leave the patient vulnerable during the initial viral replication phase. Similarly, chemotherapy and certain biological agents, like B-cell-depleting drugs used for autoimmune diseases or cancer, reduce the number of immune cells critical for generating a long-lasting antibody response.
Active cancer, particularly hematological malignancies like leukemia or lymphoma, is strongly associated with severe COVID-19 because the disease and its treatments destroy or disable immune cells. Patients receiving recent chemotherapy may have a significantly higher risk of severe clinical events. Individuals with poorly controlled or advanced HIV/AIDS also face elevated risk, particularly those with a low CD4 T-cell count (typically below 350 cells per cubic millimeter). This low count signifies a functionally impaired immune system, making it harder to fight the virus and leading to a higher chance of severe breakthrough infection.
Socioeconomic and Environmental Factors
Beyond clinical health status, a person’s environment and socioeconomic position play a substantial role in determining the risk of severe COVID-19. These factors influence exposure risk, access to preventive measures, and the quality and timeliness of medical care.
Crowded living conditions, such as those found in multi-generational homes or dense urban housing, inherently increase the risk of household transmission and higher initial viral dose exposure. Occupational exposure is another major driver of risk, with essential workers in high-contact roles (e.g., public transit, food processing, or healthcare) facing unavoidable daily contact. These working conditions make physical distancing difficult and increase the probability of infection.
Systemic health disparities also translate directly into poorer COVID-19 outcomes, particularly for racial and ethnic minority populations. These disparities are rooted in socioeconomic disadvantages, lower rates of health insurance, and reduced access to timely, high-quality primary care, which leads to higher rates of underlying chronic conditions.
Delayed treatment, often due to lack of sick leave or financial barriers, means many individuals only seek care when the disease has already progressed to a severe stage. Lifestyle factors also contribute, as current or former smoking and vaping directly damage the lung lining and impair respiratory function, reducing the body’s reserve capacity and increasing the severity of viral pneumonia.