Laboratory findings

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Ocular and atypical manifestations

Ocular manifestations are also common (Meduri 2020). In a case series from China, 12/38 patients (32%, more common in severe cases) had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. Two patients had positive PCR results from conjunctival swabs (Wu 2020). The retina can also be affected, as has been shown using optical coherence tomography (OCT), a non-invasive imaging technique that is useful for demonstrating subclinical retinal changes. Twelve adult patients showed hyper-reflective lesions at the level of the ganglion cell and inner plexiform layers more prominently at the papillomacular bundle in both eyes. Since their initial report, the authors have extended their findings to more than 150 patients, demonstrating an absence of blood flow within the retinal lesions of “many” patients (Marinho 2020). However, in another study of 25 patients with severe or critical disease in a study from Brazil, only three (12%) manifested convincing retinal changes (micro-hemorrhages, flame-shaped hemorrhage and nerve fiber layer infarcts). These retinal changes were likely secondary to clinical intercurrences or co-morbidities (Lani-Louzada 2020). Other new and sometimes puzzling clinical presentations have emerged (and will emerge) in the current pandemic. There are case reports of non-specific symptoms, especially in the elderly population, underlining the need for extensive testing in the current pandemic (Nickel 2020).

The most evident laboratory findings in the first large cohort study from China (Guan 2020) are shown in Table 2. On admission, lymphocytopenia was present in 83,2% of the patients, thrombocytopenia in 362%, and leukopenia in 33,7%. In most patients, C-reactive protein was elevated to moderate levels; less common were elevated levels of alanine aminotransferase and D-dimer. Most patients have normal procalcitonin on admission.

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Table 2. Percentage of symptoms in first large cohort study from China (Guan 2020). Disease severity was classified according to American Thoracic Society (Metlay 2019) guidelines

Clinical symptoms All Severe Disease NonSevere

Fever, % Cough, % Fatigue, % Sputum production, % Shortness of breath, % Myalgia or arthralgia, % Sore throat, % Headache, % 88.7 91.9 88.1 67.8 70.5 67.3 38.1 39.9 37.8 33.7 35.3 33.4 18.7 37.6 15.1 14.9 17.3 14.5 13.9 13.3 14.0 13.6 15.0 13.4

Chills, % Nausea or vomiting, % Nasal congestion, % Diarrhea, % 11.5 15.0 10.8 5.0 6.9 4.6 4.8 3.5 5.1 3.8 5.8 3.5

Abnormalities on X-ray, % 59.1 76.7 54.2 Abnormalities on CT, % 86.2 94.6 84.4

WBC < 4,000 per mm3, % 33.7 61.1 28.1 Lymphocytes < 1,500 per mm3, % 83.2 96.1 80.4 Platelets < 150,000 per mm3, % 36.2 57.7 31.6 C-reactive protein ≥ 10 mg/L, % 60.7 81.5 56.4 LDH ≥ 250 U/L, % 41.0 58.1 37.1 AST > 40 U/L, % 22.2 39.4 18.2 D-dimer ≥ 0.5 mg/L, % 46.6 59.6 43.2

Inflammation

Parameters indicating inflammation such as elevated CRP and procalcitonin are very frequent findings. They have been proposed to be important risk factors for disease severity and mortality (Chen 2020). For example, in a multivariate analysis of a retrospective cohort of 1590 hospitalized subjects with COVID-19 throughout China, a procalcitonin > 0.5 ng/ml at admission had a HR for mortality of 8,7 (95% CI: 3,4-22,3). In 359 patients, CRP performed better than other parameters (age, neutrophil count, platelet count) in predicting adverse outcome. Admission serum CRP level was identified as a moderate discriminator of disease severity (Lu 2020). Of 5279 cases confirmed in a large medical center in New York, 52% of them admitted to hospital, a CRP > 200 was more strongly associated (odds ratio 5.1) with critical illness than age or comorbidities (Petrilli 2019).

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Some studies have suggested that the dynamic change of interleukin-6 (IL-6) levels and other cytokines can be used as a marker in disease monitoring in patients with severe COVID-19 (Chi 2020, Zhang 2020). In a large study of 1484 patients, several cytokines were measured upon admission to the Mount Sinai Health System in New York (Del Valle 2020). Even when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of 231 patients. The authors propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. There is also one study suggesting that serum cortisol concentration seems to be a better independent predictor than other laboratory markers associated with COVID-19, such as CRP, D-dimer, and neutrophil to leukocyte ratio (Tan 2020).

Hematological: Lymphocytes, platelets, RDW

Lymphocytopenia and transient but severe T cell depletion is a well-known feature of SARS (He 2005). In COVID-19, lymphopenia is also among the most prominent hematological features. Lymphopenia may be predictive for progression (Ji 2020) and patients with severe COVID-19 present with lymphocytopenia of less than 1500/µl in almost 100% of cases (Guan 2020). It’s not only the total lymphocyte count. There is growing evidence for a transient depletion of T cells. Especially the reduced CD4+ and CD8+ T cell counts upon admission were predictive of disease progression in a larger study (Zhang 2020). In another large study on COVID-19 patients, CD3+, CD4+ and CD8+ T cells as well as NK cells were significantly decreased in COVID-19 patients and related to the severity of the disease. According to the authors, CD8+ T cells and CD4+ T cell counts can be used as diagnostic markers of COVID-19 and predictors of disease severity (Jiang 2020). Beside T cells, B cells may also play a role. In 104 patients, a decrease in B cells was independently associated with prolonged viral RNA shedding (Hao 2020). Another common hematological finding is low platelet counts that may have different causes (Review: Xu 2020). A meta-analysis of 24 studies revealed a weighted incidence of thrombocytopenia in COVID-19 patients of 12,4% (95% CI 7,9%–17,7%). The meta-analysis of binary outcomes (with and without thrombocytopenia) indicated an association between thrombocytopenia and a 3-fold enhanced risk of a composite outcome of ICU admission, progression to acute respiratory distress syndrome, and mortality (Zong 2020). Cases of

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hemorrhagic manifestation and severe thrombocytopenia responding to immunoglobulins fairly quickly with a sustained response over weeks have been reported (Ahmed 2020). Red blood cell distribution width (RDW) is another component of complete blood counts that quantifies the variation of individual red blood cell (RBC) volumes and has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. In a large cohort study including 1641 adults diagnosed with SARS-CoV-2 infection and admitted to 4 hospitals in Boston (Foy 2020), RDW was associated with mortality risk in Cox models (hazard ratio of 1.09 per 0,5% RDW increase and 2.01 for an RDW > 14,5% vs ≤ 14,5%). However, there are also cohorts in which hematological parameters such as thrombocytes, neutrophil-to-lymphocyte ratio or D-dimers do not allow prediction of patient outcome (Pereyra 2020). These routine parameters, despite giving guidance on the overall health of the patient, might not always accurately indicate COVID-19-related complications.

Cardiac: Troponin

Given the cardiac involvement especially in severe cases (see above), it is not surprising that cardiac parameters are frequently elevated. A meta-analysis of 341 patients found that cardiac troponin I levels are significantly increased only in patients with severe COVID-19 (Lippi 2020). In 179 COVID-19 patients, cardiac troponin ≥ 0.05 ng/mL was predictive of mortality (Du 2020). Among 2736 COVID-19 patients admitted to one of five hospitals in New York City who had troponin-I measured within 24 hours of admission, 985 (36%) patients had elevated troponin concentrations. After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (0,03-0,09 ng/mL) were significantly associated with death (adjusted HR: 1,75, 95% CI 1,37-2,24) while greater amounts (> 0,09 ng/dL) were significantly associated with higher risk (adjusted HR 3,03, 95% CI 2,42-3,80). However, it remains to be seen whether troponin levels can be used as a prognostic factor. A comprehensive review on the interpretation of elevated troponin levels in COVID-19 has been recently published (Chapman 2020).