Blood and Biochemistry Clues Separate Confirmed COVID-19 From Suspected Cases

When the COVID-19 pandemic swept across the globe, one of the most persistent practical problems facing clinicians was not treatment but diagnosis. Reverse-transcriptase polymerase chain reaction, or RT-PCR, remains the reference standard for confirming infection with SARS-CoV-2, yet the assay is far from perfect in real-world conditions. It requires specialized equipment, takes time to return results, and can produce false negatives, particularly when swabs are collected late in the course of illness or from poorly sampled sites. In settings with limited laboratory infrastructure, these constraints are magnified, and physicians are often left treating patients whose infection status remains uncertain. A new study from Yemen now adds to a growing body of evidence that routine blood tests, cheap and widely available, may help distinguish patients with genuinely confirmed disease from those with similar symptoms but negative swabs.

Researchers at Hadhramout University in Mukalla, Yemen, conducted a retrospective cross-sectional study of 106 patients admitted to the COVID-19 isolation centers at Ibn-Sina Hospital between 1 December 2021 and 30 October 2022. The cohort comprised 63 men and 43 women with a mean age of 58.3 years, and all participants had presented with clinical suspicion of COVID-19 and undergone SARS-CoV-2 RT-PCR testing on nasal or oropharyngeal swabs. Of these, 58 patients, or 54.72 percent, tested positive and were classified as confirmed cases, while 48 patients, or 45.28 percent, tested negative and were classified as suspected cases. To guard against false negatives, patients with initial negative results were retested within 48 to 72 hours, a precaution the authors argue strengthens the reliability of the negative classification.

The study, published in Acta Biochimica Polonica, was designed to compare a panel of routine hematological and biochemical parameters between the two groups. The investigators extracted demographic, clinical, hematological, and biochemical data from electronic medical records and analyzed complete blood counts alongside random blood glucose, alanine transaminase, aspartate transaminase, lactate dehydrogenase, gamma-glutamyl transferase, C-reactive protein, and ferritin. Patients with known liver disease, renal disease, hematological disorders, autoimmune diseases, or malignancies were excluded, since any of these conditions could independently distort the laboratory picture and confound the comparison.

The hematological findings were striking. Compared with the RT-PCR-negative group, patients with confirmed COVID-19 had significantly higher hemoglobin, hematocrit, red blood cell counts, and white blood cell counts. Their neutrophil counts were markedly elevated, while lymphocyte and eosinophil counts were significantly reduced. This pattern, combining neutrophilia with lymphopenia and eosinopenia, mirrors what has been described repeatedly in confirmed COVID-19 cases worldwide and is thought to reflect the systemic inflammatory response triggered by SARS-CoV-2. Lymphopenia in particular has emerged as one of the most consistent hematological signatures of the disease, and reduced eosinophil levels have been linked to inflammatory activity and delayed recovery in prior reports.

Not every measured parameter moved in the same direction. Mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet counts, monocyte counts, and basophil counts showed no statistically significant differences between the two groups. This selectivity is itself informative, suggesting that the laboratory changes associated with confirmed infection are not a nonspecific derangement of the blood but a characteristic pattern concentrated in the white cell differential and in the oxygen-carrying components. The authors note that hemoglobin and hematocrit were higher in the confirmed group, consistent with some previous studies, although other investigations have reported declining hemoglobin with increasing disease severity, a discrepancy the researchers attribute to differences in disease stage, patient characteristics, and underlying comorbidities.

The biochemical results were equally revealing. Serum levels of lactate dehydrogenase, gamma-glutamyl transferase, C-reactive protein, and ferritin were all significantly higher in the RT-PCR-positive group, with P values below 0.001 for each comparison. Random blood glucose was also elevated in the confirmed cases. By contrast, the liver transaminases ALT and AST did not differ significantly between the groups, despite earlier literature documenting hepatic involvement in COVID-19, with some studies reporting elevated transaminase activity in a substantial proportion of patients during the course of illness. The authors suggest that elevated LDH likely reflects tissue injury and systemic inflammation, while increased GGT points toward hepatobiliary involvement, though they acknowledge that previous findings on GGT in COVID-19 have been inconsistent, with some studies reporting no difference between confirmed and suspected cases.

To probe the relationships among these markers more deeply, the team performed Pearson correlation analysis within the RT-PCR-positive group. C-reactive protein correlated positively with AST, ALT, LDH, and GGT, and ferritin showed similar positive correlations with all four enzymes. The strongest associations were seen between the inflammatory markers and LDH and GGT, hinting at a coupling between systemic inflammation and the tissue or hepatobiliary injury these enzymes signal. This interlocking pattern of inflammation and organ-associated enzyme release reinforces the idea that the biochemical disturbances of COVID-19 are not isolated abnormalities but components of a coordinated pathological process.

The most consequential result emerged from the multivariable logistic regression analysis. When the significant biochemical variables were entered into a single model, only two markers remained independently associated with RT-PCR positivity: LDH, with an odds ratio of 1.008 per unit increase and a 95 percent confidence interval of 1.002 to 1.013 and a P value of 0.004, and GGT, with an odds ratio of 0.949, a 95 percent confidence interval of 0.903 to 0.997, and a P value of 0.039. CRP, despite its dramatic univariate elevation in confirmed cases, did not retain independent significance in the model. The direction of the GGT association, with higher values slightly reducing the odds of RT-PCR positivity, is counterintuitive and underscores the complexity of interpreting these markers in a multivariable framework.

The authors are careful to frame these findings appropriately. Because the study was retrospective and cross-sectional, the observed associations between LDH, GGT, and RT-PCR positivity cannot be interpreted as evidence of predictive or causal relationships. The regression model was built primarily from available laboratory parameters and did not account for all potential clinical confounders such as age, comorbidities, and disease severity, meaning residual confounding cannot be excluded. Moreover, the RT-PCR-negative group, though retested to reduce false negatives, was not systematically screened for alternative respiratory pathogens or other inflammatory conditions, so some of these patients may have had other infections or inflammatory diseases that influenced their laboratory profiles. The single-hospital design and modest sample size further limit generalizability, and clinical outcomes such as oxygen requirement, intensive care admission, and mortality were not available for all patients and could not be assessed.

Despite these caveats, the study offers a practical message for resource-constrained settings. The constellation of higher white cell and neutrophil counts, lower lymphocyte and eosinophil counts, and elevated LDH, GGT, CRP, and ferritin provides a recognizable laboratory fingerprint of confirmed COVID-19 that can be generated with standard hospital analyzers. In places where RT-PCR capacity is limited or turnaround times are long, such patterns may support clinical judgment while definitive testing is pending. The researchers call for prospective multicenter studies with larger cohorts, comprehensive clinical characterization, appropriate adjustment for confounding factors, and evaluation of patient outcomes to confirm these findings and determine whether LDH and GGT can ultimately earn a place alongside RT-PCR in the diagnostic toolkit for COVID-19 and beyond.

Subject of Research: Hematological and biochemical differences between RT-PCR-positive and RT-PCR-negative patients with suspected COVID-19 in Yemen

Article Title: Hematological and biochemical alterations in patients with suspected COVID-19 infection with negative and positive RT-PCR swabs

Article References: Hematological and biochemical alterations in patients with suspected COVID-19 infection with negative and positive RT-PCR swabs. (n.d.). https://doi.org/10.3389/abp.2026.16764

Image Credits: AI Generated

DOI: 10.3389/abp.2026.16764

Keywords: COVID-19, SARS-CoV-2, RT-PCR, lactate dehydrogenase, gamma-glutamyl transferase, CRP, ferritin, lymphopenia, neutrophilia, Yemen, biomarkers, retrospective study