COVID-19

Look For:

Emergency warning signs for severe COVID-19 include trouble breathing, persistent pain or pressure in the chest, new confusion or inability to arouse, and bluish lips or face.

Signs and symptoms of illness vary, and some people with COVID-19 infection can be relatively asymptomatic. Most patients; however, will experience one or more of the following over the course of disease:

• Fever or chills
• Sore throat
• Congestion or rhinorrhea
• Myalgias
• Headache
• Nausea or vomiting
• Diarrhea
• Cough
• Dyspnea
• Fatigue
• New-onset anosmia or ageusia

Children and infants may additionally present with ocular manifestations such as conjunctival secretions, conjunctival congestion, ocular pruritus, and eye rubbing (ie, viral conjunctivitis).

Other signs and symptoms include anorexia, sputum production, repeated shaking with chills, arthralgia, confusion, and hemoptysis. More severe disease has caused in some patients neurologic manifestations such as microembolic stroke, encephalopathy, agitation, delirium, and corticospinal tract signs. See below for further discussion of variant presentations.

Lymphopenia, neutrophilia, elevated serum alanine aminotransferase and aspartate aminotransferase levels, elevated lactate dehydrogenase, high C-reactive protein, and high ferritin levels may be associated with greater illness severity. Some patients rapidly deteriorate 1 week after illness onset.

Most patients admitted to the hospital with laboratory-confirmed COVID-19 infection receive a diagnosis of pneumonia. The most common CT abnormality detected in COVID-19 pneumonia is ground glass opacity. Distribution of CT abnormalities is typically peripheral, and linear consolidations may be observed on CT several days after disease onset.

Other complications included acute respiratory distress syndrome (ARDS) and shock. Uncommon complications include acute kidney injury, acute cardiac injury (cardiomyopathy, myocarditis), secondary infection, and rhabdomyolysis. Aplastic anemia rarely has been associated with COVID-19.

A large review of US Department of Veterans Affairs patient records suggests that individuals infected with SARS-CoV-2 were at greater risk of developing type 2 diabetes within a year, even those with mild or asymptomatic infection, although risk increased with severity of illness.

Children:

• A multisystem inflammatory syndrome (MIS-C) potentially linked to COVID-19 has been reported in children and young adults; clinical features include Kawasaki-like and toxic shock syndrome-like presentations.
• Primary COVID-19 infection in children seems to most commonly manifest as a mild respiratory illness or be asymptomatic. Severe primary COVID-19 illness in children has been uncommonly reported; children with significant preexisting comorbidities are at higher risk.

Gastrointestinal symptoms of COVID-19:

While the majority of symptomatic COVID-19 patients present with respiratory symptoms of cough, shortness of breath, and sore throat, some patients may concurrently present with digestive symptoms (diarrhea, nausea, and vomiting and/or abdominal pain); a subset of patients may present with only digestive symptoms.

In patients with diarrhea, symptoms can last for 1-14 days (5 days on average). In some cases, digestive symptoms such as diarrhea can be the initial presenting symptoms of COVID-19 in patients who may later develop respiratory symptoms or fever. Patients with digestive symptoms appear to have a longer duration between symptom onset and viral clearance and are more likely to have fecal samples positive for SARS-CoV-2 compared with those with respiratory symptoms.

COVID-19-associated coagulopathy:

COVID-19-associated coagulopathy is primarily characterized by elevations in fibrinogen and D-dimer levels. These elevations are generally in parallel with elevations in inflammatory markers such as C-reactive protein. Other markers of coagulation such as prothrombin time (PT) and partial thromboplastin time (PTT) are not generally elevated, and platelet counts are only mildly low (100 000 range), unlike standard sepsis-associated disseminated intravascular coagulation (DIC). Some COVID-19 patients can progress to a more fulminant DIC picture with severe tissue damage.

Development of DIC in COVID-19 is an extremely concerning finding, as it is associated with extremely poor prognosis. While there is controversy around the efficacy of therapeutic anticoagulation in the absence of documented venous thromboembolism (VTE) or atrial fibrillation, the growing consensus is that COVID-19 patients with moderate illness who are hospitalized but not in the intensive care unit (ICU) and have an elevated D-dimer (? twice the upper limits of normal) will benefit from therapeutic anticoagulation. At least a prophylactic dose of low molecular weight heparin (LMWH) is recommended for all hospitalized patients with COVID-19. Despite the development of coagulopathy, COVID-19 infection is only rarely complicated by bleeding.

COVID-19-associated cytokine release syndrome:

In addition to the bilateral diffuse alveolar injury that marks severe cases of COVID-19, these cases demonstrate a sustained decrease in lymphocytes compared with more mild cases as well as increased levels of inflammatory cytokines such as interleukin (IL)-6, IL-10, IL-2, and interferon (IFN)-?. This “cytokine storm” results in the development of cytokine release syndrome (CRS), which is characterized by a marked increase in vascular permeability with the development of severe vasoplegia and systemic hypotension, noncardiogenic pulmonary edema, and persistent fevers.

Acute COVID-19-associated cardiovascular complications:

Emerging evidence suggests that, like other viruses, COVID-19 can affect the heart, sometimes severely. This is more frequently seen in hospitalized patients, but increasing evidence raises the concern that even those who are not hospitalized with serious COVID-19 illness can experience cardiac injury. Cardiovascular effects can include but are not limited to arrhythmia, myocarditis, acute coronary syndrome, and cardiomyopathy.

In a retrospective cohort of > 1000 patients diagnosed with COVID-19, major arterial or VTE events, major adverse cardiovascular events, and symptomatic VTE were common in hospitalized patients despite high use of thromboprophylaxis. Patients in ICUs were most affected, although hospitalized non-ICU patients were also at risk. ARDS was strongly associated with increased risk.

Skin and oral mucosal manifestations of COVID-19 (not a common finding):

Several main mucocutaneous manifestations of COVID-19 have been described:

• Pernio-like lesions on the acral surfaces (also known as “COVID toes,” pseudo-chilblains, and acute acro-ischemia), including erythema, edema, vesiculation, and purpura of the toes, fingers, feet, and hands. Lesions may be painful, itchy, or asymptomatic. Feet seem to be affected more frequently than hands. These manifestations occurred in younger individuals late in disease course and usually followed a milder illness. PCR is often negative in these patients, and the timing of onset may be an explanation. Viral particles have been demonstrated within endothelial cells of affected areas, supporting that this cutaneous finding is a direct effect of the virus as opposed to quarantine-induced lifestyle changes (eg, inactivity and ongoing cold exposure in unheated homes). However, some debate remains on this subject; it is possible that some individuals have chilblain-like lesions as a result of infection with SARS-CoV-2 and some have true chilblains as a result of lifestyle changes in the setting of a global pandemic. Cryofibrinogenemia has been found in two-thirds of a series of 54 patients with COVID-related chilblains; further studies are needed to support cryofibrinogens as a potential pathogenetic factor.
• A vesicular eruption with lesions all in the same stage (as opposed to chickenpox). In some cases, vesicles coalesce and become hemorrhagic. This manifestation occurred predominantly in middle-aged patients with moderate disease severity and lasted around 10 days. Itch was a common associated symptom.
• An urticarial eruption.
• A macular or papulosquamous eruption. Also classed in this group are cases with a perifollicular distribution, some that are erythema multiforme-like, some that are pityriasiform, and some that manifest secondary purpura as well. For both the urticarial and maculopapular eruptions, itch is frequent, and patients tend to present with more severe disease. In the largest study of skin manifestations of COVID-19, rash was present at the onset of other symptoms and lasted about 6-8 days.
• Livedo or retiform purpura. Transient livedo has been seen in milder illness, but livedo racemosa or retiform purpura that may be complicated by skin necrosis may be seen in individuals with severe disease. A series of 4 such cases with these skin findings manifested evidence of a thrombotic state, including high D-dimer levels and suspected pulmonary emboli. Purpuric pressure ulcers have also been reported in hospitalized patients. Risk factors included obesity, impaired mobility due to critical illness, incontinence, and malnutrition, and their presence seems to be independent of thrombotic vasculopathy.
• Oral cavity findings may include lingual papillitis, glossitis, Kawasaki-like syndrome, oral ulcers including aphthous, hemorrhagic, and necrotic ulcers, and mucositis. Dysgeusia and burning may accompany these findings. Macular and petechial enanthems of the palate have been reported in a minority of patients. A single case of herpes simplex virus-like vesicles on and around the lips has been reported. Other lesions reported included pustules, bullae, maculopapular enanthema, and erythema multiforme-like lesions.

Other less frequent findings included a purpuric flexural exanthem and an enanthem. Rare cases resembling leukocytoclastic vasculitis have been observed. There has been a case of unilateral laterothoracic exanthem linked to COVID-19. Reported COVID-19-induced nail changes include the “red half-moon nail sign,” where a red border to the lunula is seen in active disease. Beau lines and onychomadesis have been reported after resolution of COVID-19, and a greenish fluorescence of the proximal nails has been reported over favipiravir therapy. Periungual desquamation is seen in MIS-C.

A study reporting data from an international registry of individuals with confirmed COVID-19 found that the most commonly associated dermatologic finding was a morbilliform eruption. Pernio-like lesions were the second most common and were generally associated with mild disease. The least common skin finding in patients with COVID-19 was livedo reticularis; this was seen only in patients with severe COVID-19.

As more is learned about the long-term effects of COVID-19 in some individuals (postacute sequelae of SARS-CoV-2 [PASC], so-called “long-haulers”), durable cutaneous manifestations have been observed. While morbilliform and urticarial eruptions were found to resolve within days, one study of an international registry found that 6.8% of those with chilblain-like lesions have persistence greater than 60 days. Papulosquamous eruptions of COVID-19 have generally been reported to resolve within a few weeks, but a case of a patient with such an eruption for 70 days has been reported in an international registry.

Impact of skin color on clinical presentation: Erythema is more readily appreciated in lighter skin colors. In darker skin colors, a deep red, maroon, or violaceous hue may be seen. In lighter skin colors, purpura may appear bright red, deep red, maroon, or violaceous. Purpura in darker skin colors will appear deep red, maroon, violaceous, or deep brown.

Imaging:

• Typical chest CT findings include multifocal bilateral ground glass opacities with patchy consolidations, peripheral subpleural distribution, and posterior part or lower lobe predilection. Less commonly, crazy-paving pattern or air bronchogram sign was observed. Pure consolidation, reversed halo sign, or pleural effusion was uncommonly detected.
• Pure ground glass opacity lesions can be an early presentation of COVID-19 pneumonia.
• Chest CT is superior to chest x-ray in early detection of COVID-19 pneumonia, but both have low specificity for the diagnosis.

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