A Multiorgan System Disease
The lungs are a major target for SARS-CoV-2. However, SARS-CoV-2 also causes injury to many other organ systems, such as the heart, kidneys, and liver. Understanding that COVID-19 is a multiorgan system disease is crucial to its clinical management.
The spectrum of COVID-19’s clinical presentation is wide, from no or minimal symptoms to severe viral pneumonia with respiratory failure, multiorgan system dysfunction, sepsis, and death. Up to 40 to 45% of those infected are asymptomatic when tested for the virus, many of whom remain asymptomatic, but nevertheless shed the virus from the upper respiratory tract and are capable of transmitting the virus to others (1). Other patients become symptomatic with a mean incubation period of about 5 days, ranging between 2 and 14 days, after exposure (2).
Fortunately, about 80% of those infected will have mild disease, which can be managed on an outpatient basis; 15% with more severe disease (dyspnea, hypoxia, or > 50% lung involvement on imaging) will require hospitalization, and another 5% with critical disease (respiratory failure, shock, or multiorgan system dysfunction) will require ICU admission (3). The case fatality rate globally is about 4%, but it varies based on demographic characteristics of the local population. All ages are susceptible to infection, but the severity and risk of death is increased in older people, in the poor, in Black and Latino populations, and in those with certain pre-existing co-morbidities, such as obesity, diabetes, hypertension, and lung and cardiovascular disease.
Some infected people who are entirely asymptomatic may nevertheless have a low blood oxygen saturation, called “silent hypoxia,” and may have evidence of lung involvement on chest imaging when these studies are done, for example, when the patient is seen in an ER for an unrelated problem such as trauma (4). Hypercapnia (elevated blood CO2) is rare in these patients, which may explain why patients with COVID-19 may not complain of shortness of breath until their pulmonary disease is far advanced and hypoxia is severe.
Fever, chills, fatigue, dry cough, anorexia, myalgia, diarrhea, and sputum production are common symptoms. Loss of smell (anosmia) and loss of taste (dysgeusia) are also commonly reported. Sore throat, nasal congestion, and rhinorrhea are less common. Some individuals remain afebrile. Others have mild symptoms for 8 to 9 days, until sudden onset or worsening of shortness of breath (dyspnea) prompts an ER visit. Ventilatory support may be needed shortly after the onset of dyspnea (median, 2.5 days).
Cardiac involvement is indicated by elevated levels of troponin and abnormalities on electrocardiograms and heart ultrasounds (5). SARS-CoV-2 infection may destabilize previously asymptomatic coronary atherosclerotic plaques or may cause blood clots to form in coronary vessels, resulting in obstruction of coronary arterial blood flow. Myocarditis due to SARS-CoV-2 has been suspected but not proven with biopsy.
not so far been described. While early reports suggested that patients with COVID-19 have a high incidence of cardiac arrests and arrhythmias, a study of 700 consecutive patients admitted to the Hospital of the University of Pennsylvania over 9 weeks concluded that cardiac arrhythmias were likely due to systemic illness and not solely the direct effects of the COVID-19 infection (6).
Some patients develop proteinuria and acute renal insufficiency. About 15% to 30% of patients with COVID-19 in the ICU require renal replacement therapy. On post-mortem examination, proximal acute tubular injury has been seen on kidney histology, with coronavirus-like particles in the cytoplasm of proximal tubular epithelium and podocytes, sites of known ACE2 expression (7). Liver involvement is indicated by elevated levels of serum alanine aminotransferase and aspartate aminotransferase.
COVID-19 frequently is complicated by a coagulopathy, with elevated levels of D-dimer, but unlike disseminated intravascular coagulation (DIC) associated with sepsis, significant bleeding is unusual, the prothrombin time and partial thromboplastin time are normal or mildly prolonged, the fibrinogen level is often increased, and the platelet count is normal or mildly decreased (8, 9, 10). Reports describe a high frequency of venous thromboembolism and lung pathology that shows marked microvascular thrombosis linked to extensive alveolar and interstitial inflammation, which suggests that clotting is contributing to the respiratory failure in these patients.
Neurologic impairment is common in COVID-19. A nationwide study in the UK found COVID-19 patients diagnosed with altered mental status, new-onset psychosis, neurocognitive (dementia-like) impairment, and an affective disorder (11). Patients have also been reported with encephalitis and positive CSF PCR for SARS-CoV-2 (12) and acute necrotizing encephalopathy (13). COVID-19 may cause ischemic stroke; such patients have been found to be younger, had worse symptoms, and were at least seven times more likely to die than people who had a stroke not associated with COVID-19 (14). Patients requiring prolonged mechanical ventilation and/or ICU stays may experience symptoms including chronic fatigue, altered cognitive ability, PTSD, and affective disorders.
Lymphopenia is the most common laboratory finding in hospitalized patients with COVID-19 and has been associated with severe disease. Marked elevation of serum ferritin occurs in patients with severe COVID-19, complicated by “cytokine storm,” which is defined by the excessive and uncontrolled release of pro-inflammatory cytokines (IL-2, IL-6, IL-10, and TNF-α) and inflammatory markers such as C-reactive protein and erythrocyte sedimentation. “Cytokine storm” in COVID-19 appears later in the hospital course reportedly after an initial clinical improvement, and is associated with worsening damage to the lungs, multiorgan failure, and unfavorable prognosis.
COVID-19 Symptoms in Children
Most children are asymptomatic or exhibit mild symptoms when infected with COVID-19, but in late April 2020, some children were first noted to have what has become to be called multisystem inflammatory syndrome in children (MIS-C), a new COVID-19 presentation, which has some features similar to Kawasaki disease (but, unlike Kawasaki disease, occurs in an older age group), staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes (15).
Affected children (age 2 to 16 years) have prolonged fever, fatigue, sore throat, headache, abdominal pain, and vomiting, with multiorgan involvement (eg, cardiac, gastrointestinal, renal, hematologic, dermatologic, neurologic), which progress rapidly to shock and organ dysfunction. A study in England included 58 patients with MIS-C and found that all the children presented with fever and nonspecific symptoms which included abdominal pain, diarrhea, vomiting, rash, and conjunctival injection, each occurring in about 50% of patients (16). Unlike adults with COVID-19, only a third have respiratory symptoms. Most have left ventricular systolic dysfunction, and some have coronary artery dilatation or aneurysms. Lab results show elevated C-reactive protein (CRP), elevated ferritin, lymphopenia, and elevated D-dimer, and some have elevated troponin and brain natriuretic peptide (BNP) levels, suggesting cardiac injury. Some have elevated serum creatinine. Some require circulatory or respiratory support or rarely extracorporeal membrane oxygenation.
As of January 8, 2021, there were 1,659 cases in the US that met the case definition for MIS-C, with 26 deaths; 99% of cases tested positive for SARS CoV-2, with the remaining 1% exposed to someone with COVID-19. Most of the children developed MIS-C 2 to 4 weeks after infection with SARS-CoV-2, and more than 70% of cases occurred in children who are Hispanic or Latino or Black, Non-Hispanic (17).
Most patients have received intravenous immune globulin treatment, and some were treated with intravenous steroids and heparin. Serology testing should be performed prior to administering IVIG or any other exogenous antibody treatments.
Patients younger than 21 years of age who meet the CDC MIS-C criteria (18) should be reported to the local, state, or territorial health department. The CDC MIS-C criteria are:
COVID-19 Long-Term Complications
COVID-19 is usually a short-term illness. Those with mild symptoms typically recover in about 2 weeks, while those with severe or critical disease recover in 3 to 6 weeks. However, in some patients, debilitating symptoms persist for weeks or even months. In some of these patients, symptoms have never gone away.
Many studies have documented lingering damage to many organs or systems, including lungs, heart, brain, kidneys, and vascular system, in patients infected with SARS-CoV-2. The damage seems to be caused by severe inflammatory responses, thrombotic microangiopathy, venous thromboembolism, and oxygen deprivation. Organ damage has been documented to persist in the lungs, the heart, the brain, and the kidneys, even in some people who initially had only mild symptoms. The slow pace of recovery readily explains the duration of what has come to be called the “post-COVID syndrome.” Some people may also be suffering from post-intensive care syndrome, a group of symptoms that sometimes occur in people who were patients in an intensive care unit and that involves muscle weakness, balancing problems, cognitive decline, and mental health disturbances observed after discharge from critical care that usually involved a prolonged period of mechanical ventilation (19).
Persistence of symptoms also occurred after infection with another coronavirus, SARS-CoV-1, the virus that caused the severe acute respiratory syndrome (SARS) epidemic in 2002–2003. The persisting symptoms resemble chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Persistent fatigue, muscle pain, depression, and disrupted sleep prevented patients with SARS in Toronto, most of whom were healthcare workers, from returning to work for up to 20 months after infection (20). Forty percent of 233 survivors of SARS in Hong Kong were reported to have chronic fatigue after about 3 to 4 years, and 27% met the criteria outlined by the Centers for Disease Control and Prevention (CDC) for CFS/ME (21). Many remained unemployed and have experienced social stigmatization (22).
CFS/ME-like illness, in which some people get better quickly but others remain sick for prolonged periods, has followed many other infectious diseases. Examples include influenza, Epstein-Barr virus infection (infectious mononucleosis—23), brucellosis, Q fever (Coxiella burnetii infection—24), Ebola virus infection (25), and Ross River virus infection (26).
The persisting illness following COVID-19 also is said to resemble CFS/ME (27), and people with post-COVID-19 syndrome have given themselves the name “long-haulers.” However, there is no clear picture of what constitutes post-COVID-19 syndrome. Without a formally accepted definition of post COVID-19 syndrome, it is difficult to assess how common it is, how long it lasts, who’s at risk for it, what causes it, what its pathophysiology is, and how to treat and prevent it. But several studies are now beginning to define this group of patients.
The CDC conducted a multistate telephone survey in April and June 2020 of non-hospitalized adults who had a positive reverse transcription–polymerase chain (RT-PCR) test for SARS-CoV-2 infection (28). Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Of 274 respondents symptomatic at the time of PCR testing, about one third reported not having returned to their usual state of health when interviewed 2 to 3 weeks after testing. Of younger persons, aged 18 to 34 years, with no chronic medical conditions, 20% had not returned to their usual state of health. However, older age and presence of multiple chronic medical conditions were more commonly associated with prolonged illness, which was present in 26% of those aged 18 to 34 years, 32% of those aged 35 to 49 years, and 47% of those aged 50 years or older. Fatigue (71%), cough (61%), and headache (61%) were the most frequently reported symptoms. These findings indicate that COVID-19 can result in prolonged illness even among people with milder outpatient illness, including young adults. This finding is particularly concerning as outbreaks are emerging on college campuses.
In another study in Rome, Italy of 143 patients (mean age 57 years) after about a 2-week-hospitalization for COVID-19, many patients still struggled with symptoms 60 days on average after onset of their illness; 87% still had at least one symptom, and 55% had 3 or more symptoms (23). Quality of life had worsened for 44%, with fatigue (53.1%), difficulty breathing (43%), joint pain, (27%) and chest pain (22%) persisting in many. None had fever or any signs or symptoms of acute illness.
Much information, however, that characterizes the post-COVID-19 syndrome’s demographics, time-course, and symptomatology has been generated and analyzed by long-haulers themselves who belong to the online Body Politic COVID-19 Support Group and who have expertise in research, survey design, and data analysis. The online survey they developed and targeted to those whose symptoms persisted for more than 2 weeks received 640 responses from April 21 to May 2, 2020 (29).
The respondents were predominately young (63% between the ages of 30 to 49 years), white (77%), and female (77%), and live in the United States (72%) or the U.K. (13%). Most were never hospitalized, or, if hospitalized, never admitted to an ICU or placed on a ventilator, so their cases technically counted as “mild.” Many were seen in an emergency department/urgent care facility but were not admitted. All respondents were included, regardless of SARS-CoV-2 RT-PCR testing status. In about 25%, the RT-PCR was positive; but almost 50% of participants never were tested because testing during those months (March and April 2020) was often limited to people hospitalized with severe respiratory problems, their symptoms were said to be “classic,” making testing unnecessary at a time when PCR testing kits were in short supply, or testing was denied because their symptoms did not match preset criteria.
Another 25% of respondents tested negative, but a negative result does not mean these people didn’t have COVID-19. Some negative tests were likely false-negative results, which occur up to 30 percent of the time (30). Others were tested relatively late in the course of their illness, at a time when virus may no longer be detectable (31). In the survey, respondents with negative RT-PCR test results were in fact tested a week later than those with positive test results.
The reported symptoms were diverse and spanned the respiratory tract, and the neurological, cardiovascular, gastrointestinal, and various other systems. The top 10 symptoms, reported by 70% or more respondents, included shortness of breath, tightness of the chest, fatigue, chills or sweats, body aches, dry cough, “elevated temperature” (98.8 to 100° F), headache, and brain fog/difficulty concentrating. Extreme fatigue to the point of preventing someone from getting out of bed, severe headache, fever (above 100.1° F), and loss of taste or smell were reported by 40 to 50% of respondents. Seventy percent (70%) experienced fluctuations in the type and 89% in the intensity of symptoms over the course of being symptomatic. Some patients noted that symptoms came back or intensified with physical activity or were strongest in the evening. About 70% had been physically fit before the onset of symptoms, but 70% reported being sedentary after the onset of symptoms.
About 10% of respondents had recovered in, on average, about 4 weeks. The 90% who had not recovered experienced symptoms for an average of 40 days. A large proportion of respondents experienced symptoms for 5 to 7 weeks. The chance of full recovery by day 50 was estimated to be smaller than 20%.
Results of surveys such as this, however, are subject to bias. Respondents to surveys might differ from non-respondents; for example, there might have been gender bias in that women might more likely join support groups and complete online surveys; patients with more severe illness might be unable to respond or be unable to recall events accurately. Online surveys may also be skewed toward more affluent, younger, and more computer savvy respondents and omit economically disadvantaged minorities, the homeless, those lacking broadband access and computers, and those fearful of responding, such as undocumented migrants.
Since issuing their report, the Body Politic COVID-19 Support Group team has met with staff from the Centers for Disease Control and Prevention and the World Health Organization (32) and issued a second survey to fill in gaps in their first report; examine antibody testing results, neurologic symptoms, and the role of mental health; and increase geographic and demographic diversity (33).
Many long-haulers report their persisting symptoms are being downplayed. They are told they are perhaps exaggerating, imagining, or even inventing their life-altering illness. Simple physical activities, like getting out of bed, grooming, preparing simple meals, and showering, can be exhausting for some. Being unable to care for themselves and their families, being unable to work, and losing income and possibly employer-based health insurance bring additional burdens. Healthcare planners and policy makers must prepare to meet the needs of the many people that have been affected by this illness and their families while ongoing studies investigate causes and ways to mitigate the post-COVID syndrome.
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