Impact of the COVID-19 pandemic on the volume of laboratory testing

AUTORI

ABSTRACT

Impact of the COVID-19 pandemic on the volume of laboratory testing

Introduction: this single-center retrospective analysis was aimed to investigate the burden of coronavirus disease 2019 (COVID-19) pandemic on utilization of laboratory resources.
Methods: a retrospective analysis was conducted in the database of the Management Control Unit of the Pederzoli hospital in Peschiera del Garda (Verona, Italy), to retrieve information on the volume of total and some specific laboratory tests performed in the year range 2018-2022.
Results: the mean yearly volume of total tests has increased by 10% during the pandemic compared to the pre-pandemic period, by 5% without considering SARS-CoV-2 diagnostic tests. The peak over the reference year 2018 was reached in 2021 (+19%, +12% without SARS-CoV-2 tests), but the volume remained high in 2022 (+16%; +11% without SARS-CoV-2 tests). The requests for D-dimer, vitamin D, blood culture, lactate dehydrogenase (LDH) and thyroid stimulating hormone (TSH) tests increased in the pandemic period (between 19-57%), those of white blood cell count (WBC) count, plasma glucose and creatinine remained almost unvaried (between -3% to 2%), whilst those for cardiac troponin T (cTnT) and prostate specific antigen (PSA) declined (-17% and -19%, respectively).
Conclusion: the COVID-19 pandemic has had remarkable impact on laboratory activity, by increasing the demand for certain tests whose increment has remained even after the emergency period, and by decreasing the demand for other tests perhaps attributable to social limitations and modified demography (i.e., death of older people).

INTRODUCTION
In addition to causing an immense number of severe infections and a considerable number of deaths all around the world, the still ongoing coronavirus disease 2019 (COVID-19) pandemic has also generated a remarkable impact on human society, global economy and healthcare (1). Specifically, COVID-19 has led to a surge in demand for healthcare services, especially in specific areas such as emergency departments, intensive care units (ICU) respiratory care and diagnostic facilities, thus generating a notable strain on healthcare resources, including staff and equipment. The COVID-19 pandemic has also been associated with disruption of routine care, inducing cancellation or postponement of a substantial number of healthcare activities such as preventive care visits, diagnoses, and treatments of many acute and chronic conditions (1).
As specifically concerns medical laboratories, the management of the COVID-19 pandemic has required a substantial increase in laboratory activities including for diagnosing the viral infection (2), predicting the clinical progression of illness by means of a number of specific laboratory tests (3), and monitoring vaccine efficacy (4). Clinical laboratories have needed to quickly scale up their testing capabilities to meet a remarkably increased demand, thus encompassing an increase of expenditures for instrumentation, test reagents and other supplies, as well as for recruiting new personnel to sustain the enhanced activity.
Earlier evidence has been provided that the number of some specific laboratory tests had considerably increased during (and/or due to) the pandemic (5,6), though to the best of our knowledge, a specific analysis on the cumulative impact of COVID-19 on laboratory testing volume is lacking. Thus, this single-center retrospective analysis was aimed to define the burden that COVID-19 has placed on overall laboratory testing.

METHODS
This single-center retrospective analysis was conducted at the Laboratory Medicine Service of the Pederzoli Hospital (Peschiera del Garda, Verona). The facility is a private hospital affiliated with the national healthcare system, covering an area in the north-west province of Verona with around 200 000 inhabitants. The hospital has around 350 beds and is equipped with an emergency department (ED), an ICU, surgical and medical wards, and a service of laboratory medicine, which also operates stats (24/7) with general and specialized testing. The laboratory is also a referral provincial center for SARS-CoV-2 diagnostics. The specific analysis in this work entailed a retrospective search in the database of the Management Control Unit of the hospital to retrieve information on the volume of laboratory tests performed between the years 2018 and 2022, considering the years 2018-2019 as pre-pandemic and those between 2020-2022 as pandemic, respectively. The data retrieved included the number of all tests performed each year in the laboratory, as well as the volume of some specific tests that were arbitrarily selected as “sentinel” analyses to identify specific trends, as follows: SARS-CoV-2 diagnostics tests (both molecular and antigen) D-dimer, serum vitamin D (Vit D), blood culture, plasma lactate dehydrogenase (LDH), serum thyroid stimulating hormone (TSH), white blood cell (WBC) count, plasma glucose, plasma creatinine, cardiac troponin T (cTnT) and serum prostate specific antigen (PSA). The raw data were entered into an Excel Worksheet, then graphically plotted and analyzed. This retrospective study was conducted in accordance with the Declaration of Helsinki, under the terms of relevant local legislation, using completely anonymized data.

RESULTS
The total number of tests performed in the local laboratory medicine service was 1.029 million in 2018, 1.080 million in 2019, 1.053 million in 2020, 1.225 million in 2021 and 1.198 million in 2022, respectively. Excluding the number of SARS-CoV-2 diagnostic tests (including both molecular and antigenic: 41 920 in 2020, 68 760 in 2021 and 58 498 in 2022, respectively), the total number of tests was 1.011 million in 2020, 1.156 million in 2021 and 1.140 million in 2022, respectively. The specific trend is shown in Table 1 and Figure 1.
Overall, the mean yearly volume of total tests has increased by 10% during the pandemic compared to the pre-pandemic period, by 5% without considering SARS-CoV-2 diagnostic tests (Figure 2). The peak over the reference year 2018 was reached in 2021 (+19%; +12% without SARS-CoV-2 tests), but the volume of tests remained still considerably higher than this baseline in 2022 (+16%; +11% without SARS-CoV-2 tests). The trend followed by the sentinel analyses is also shown in Table 1 and Figure 1. Specifically, the volume of D-dimer, serum Vit D, blood culture, plasma LDH and serum TSH displayed a notable increase throughout the pandemic period (i.e., between 19-57%), the volume of WBC count, plasma glucose and creatinine remained almost unvaried (between -3% to 2%), whilst that of cTnT and serum PSA displayed a visible decline during the pandemic period (-17% and -19%, respectively). Unlike other tests which showed an incremental change during the pandemic and a peak in 2021, Vit D displayed a peculiar and continuously augmenting trend, with the highest value reached in 2022 (+95%).

DISCUSSION
The ongoing COVID-19 pandemic has generated a considerable impact on laboratory testing, triggering an almost unprecedented demand for new tests for diagnosing the infection, as well as of conventional diagnostic testing for patient monitoring, prognostication and therapeutic follow-up.
This straightforward concept is clearly reflected by the results of our retrospective, observational analysis. In particular, we found that the cumulative volume of tests performed by the local laboratory facility had increased by 10% during the COVID-19 pandemic, reaching the peak in 2021, but remaining still considerably higher in the last complete pandemic year 2022 compared to the reference year 2018. This figure needs to be interpreted according to the current definition of appropriateness, encompassing the use of the right test, using the right technology, at the right time, for the right patient, with the right costs and for the right outcome (7). In turn, inappropriateness not only entails the (clinically) unjustified test request, but also, and perhaps more importantly, avoidance to request a laboratory test when this would be otherwise needed throughout the clinical spectrum of disease (8). Thus, the increased demand that we have seen for certain “sentinel analyses” is likely attributed to the COVID-19 emergency, while the variation of other tests may be due to different reasons that will be addressed in the following sections of this discussion.
The first and most obvious test to be discussed is certainly D-dimer. Incontrovertible evidence has already been provided that COVID-19 is associated with a considerably enhanced risk of developing venous thromboembolism (VTE), especially pulmonary thrombosis (9). The diagnostic approach to VTE, irrespective of the underlying causes, places D-dimer at the top of the diagnostic reasoning (10), and it is hence not surprising that the demand for this test may have dramatically increased throughout the pandemic. This evidence is in keeping with previous reports, which have also emphasized similar increases in the volume of D-dimer tests (5,6).
Serum Vit D is the second test that displayed the most striking increase among those that we have selected for our analysis, though its trend is seemingly differed from that of others. Specifically, the volume of Vit D tests performed has displayed a constant increase throughout the pandemic, without showing the typical decline in 2022 of other COVID-19 related tests such as D-dimer and plasma LDH. There may be reasonable explanations for this finding. First, evidence has been provided that Vit D may interplay with many infectious diseases, including COVID-19 (11). Specifically, a recent meta-analysis has concluded that Vit D administration may reduce the risk of ICU admission (standardized mean difference, 0.28; 95%CI, 0.20-0.39) and death (standardized mean difference, 0.49; 95%CI, 0.34-0.72) in patients with COVID-19 (12). Almost identical findings have been reported by another meta-analysis published by D’Ecclesiis et al. (13). Thus, the increase volume seen for this biomarker in the first two years of the pandemic can be reasonably explained by the need to assess Vit D status and identifying potential insufficiency or deficiency, leading the way to its administration for reinforcing the immune system (14). The revision of the recent indication for supplementation in the general population is a second reason that may explain increased testing demand over time, including the recent year 2022. With implementation of the UK Scientific Advisory Committee on Nutrition on Vitamin D and health recommendations, the Italian pharmacy agency has recently revised the current indications for Vit D administration, extending the plateau of potential recipients to people with Vit D levels below <12 ng/mL (i.e., <30 nmol/L) (15). It is hence predictable that the increase in the volume of Vit D tests will be retained for the foreseeable future. Blood culture is the third test which displayed a considerable increase during the pandemic period. There is indeed a reasonable explanation for this finding, represented by the fact that COVID-19 patients are at increased risk of developing both localized (i.e., pulmonary) and systemic infections. As shown by the meta-analysis of Calderon et al. (16), there is an over 10% prevalence of bacterial co-infection in patients with COVID-19, the presence of which is also associated with a worse outcome, increasing the risk of intensive care requirement and death. Thus, routine performance of blood culture in COVID-19 patients with severe illness has now become a new standard of care (17), and potentially explains the incremental trend in demands that we observed over the past 5 years. Likewise to D-dimer, plasma LDH is widely used for predicting the clinical course of COVID-19 illness, whereby its value is a significant predictor of developing severe/critical illness, up to death (18). It is hence not surprising that the volume of requests for this important laboratory test may also have increased throughout the pandemic. The reason for the trend observed for TSH is less clear. We originally included this test along with plasma glucose, creatinine and WBC, as an ideal marker of non-COVID-19 related tests, such that the observation of a visible increase over time, especially during the past 2 years of the pandemic, cannot be easily explained. We propose two possible explanations. The first is directly linked to the reduced care access seen during the earlier period of the pandemic, due to both lockdown and patient hesitation to frequent public places, although the decline we have seen in the first year of the pandemic was almost negligible (i.e., -1% in 2020) (19). Therefore, a second explanation that may be more pertinent concerns the fact that COVID-19 is a potential cause of thyroid injury, both during the acute phase (20), as well as in the convalescent phase in patients developing long-COVID (21). Thus, routine monitoring of thyroid function may become an appropriate practice in COVID-19 patients, especially those with more severe forms of illness. The trend displayed by other routine tests such as plasma glucose, creatinine and WBC had, as predicted, displayed no exceptional changes. These tests may be occasionally used for monitoring COVID-19; however, they cover a much broader array of clinical indications (22). Interestingly, all these tests displayed a modest increase in 2021, when some residual COVID-19 patients were admitted to the local hospital, albeit such variations were so modest that the influence of chance cannot be ruled out. Unlike other tests, cTnT displayed a gradually decreasing trend throughout the pandemic. Although the initial decline in the year 2020 could be likely attributed to a considerably lower number of hospitalizations for acute coronary syndrome as recorded in many worldwide countries (23), the following trend remained almost unchanged, with volumes of tests for this biomarker persistently 13-15% lower compared to the pre-pandemic period. This finding may be biased by the fact that the risk of cardiac ischemia increases with ageing, and the COVID-19 outbreak has caused the death of a still untold numbers of older adults worldwide, thus reducing the relative burden of cardiac disorders within the general population (24). The trend followed by PSA overlaps with that of cTnT, thus being potentially explained by similar reasons. During the early period of the pandemic, especially when many governments adopted strict measures of infection containment (i.e., lockdowns, curfews, limitations of hospital access to emergency situations and so forth), the demand for screening tests had dramatically dropped (25), including that for PSA, as shown by earlier reports (26). A partial recovery has been observed in the years following the 2020, however, we have noticed that the volume of PSA testing has remained ~20% lower compared to the pre-pandemic period. Whether such reduction may also reflect a lower demand due to death of many older patients who may have potentially been assessed for prostate cancer and related diseases (i.e., prostate hyperplasia) will need to be addressed by more specific population analysis. In conclusion, the results emerged from this retrospective observation analysis are in keeping with those previously published by Durant et al. (i.e., local increase of COVID-19 related diagnostic test and substantial decrease of others) (27) and Singh et al. (28) (i.e., underuse of laboratory tests typically requested for managing chronic diseases), thus paving the way to some important considerations. First, in general, we confirm that COVID-19 has had a considerable impact on laboratory resources, generating unprecedented demand for general and specialized diagnostic testing, coupled with the need of implementing new analytical techniques and/or instrumentations. Beside those tests specifically used for diagnosing acute SARS-CoV-2 infection, the usage of some COVID-19 related test (i.e., D-dimer, plasma LDH, blood culture) has certainly increased during the pandemic, however the long-tail of such trends has persisted. While the usage of non-strictly COVID-19 related tests has not varied considerably throughout the pandemic, the volume of Vit D and TSH (two quite expensive analyses) increased over time, continuing throughout the year 2022. This variation is perhaps attributable to other clinical practices that may have led to an increased need of obtaining the values of these biomarkers, as well as (potentially) a certain degree of inappropriateness. The lower demand seen for cTnT and PSA likely reflects an underutilization during the early period of the pandemic, but may now also reflect the fact that the plateau of stakeholders (i.e., mostly older people) has substantially decreased. Although this analysis may help laboratory managers and healthcare administrators to acknowledge the important impact that outbreaks of infectious diseases may pose on the availability of human, technical and economic resources, our results are only temporarily attributable to the COVID-19 and may be biased by type and location of the hospital center considered, thus potentially limiting their widespread generalizability. CONFLICT OF INTEREST None.

BIBLIOGRAFIA

1. El-Sadr WM, Vasan A, El-Mohandes A. Facing the New Covid-19 Reality. [Editorial] N Engl J Med 2023;388:385-7.
2. Lippi G, Salvagno GL, Mattiuzzi C. Guida sintetica alla diagnostica della malattia da coronavirus 2019 (COVID-19). [Editorial] Biochim Clin 2020;44 Supp 1 SS3-4.
3. Negrini D, Danese E, Henry BM, Lippi G, Montagnana M. Artificial intelligence at the time of COVID-19: who does the lion’s share? Clin Chem Lab Med 2022;60:1881-6.
4. Lippi G, Sciacovelli L, Trenti T, Plebani M. Kinetics and biological characteristics of humoral response developing after SARS-CoV-2 infection: implications for vaccination. [Editorial] Clin Chem Lab Med 2021;59:1333-5.
5. Favaloro EJ, Lay M, Mohammed S, Vong R, Pasalic L. Pathology utilisation during COVID-19 outbreaks beyond viral testing: routine coagulation and D-dimer testing. Pathology 2023;55:155-9.
6. Lippi G, Perilli V. Has “D-Dimeritis” Worsened during the Coronavirus Disease 2019 Pandemic? Semin Thromb Hemost. 2023 Jan 24. doi: 10.1055/s-0043-1761464. Epub ahead of print.
7. Lippi G, Bovo C, Ciaccio M. Inappropriateness in laboratory medicine: an elephant in the room? Ann Transl Med 2017;5:82.
8. Lippi G, Plebani M. A modern and pragmatic definition of Laboratory Medicine. Clin Chem Lab Med 2020;58:1171.
9. Lippi G, Favaloro EJ. What We Know (and Do not Know) Regarding the Pathogenesis of Pulmonary Thrombosis in COVID-19. Semin Thromb Hemost 2023;49:27-33.
10. Lippi G, Mullier F, Favaloro EJ. D-dimer: old dogmas, new (COVID-19) tricks. Clin Chem Lab Med. 2022 Jul 14. doi: 10.1515/cclm-2022-0633. Epub ahead of print.
11. Targher G, Pichiri I, Lippi G. Vitamin D, thrombosis, and hemostasis: more than skin deep. Semin Thromb Hemost 2012;38:114-24.
12. Argano C, Mallaci Bocchio R, Natoli G, Scibetta S, Lo Monaco M, Corrao S. Protective Effect of Vitamin D Supplementation on COVID-19-Related Intensive Care Hospitalization and Mortality: Definitive Evidence from Meta-Analysis and Trial Sequential Analysis. Pharmaceuticals (Basel) 2023;16:130.
13. D’Ecclesiis O, Gavioli C, Martinoli C, Raimondi S, Chiocca S, Miccolo C et al. Vitamin D and SARS-CoV2 infection, severity and mortality: A systematic review and meta-analysis. PLoS One 2022;17:e0268396.
14. Abu Fanne R, Moed M, Kedem A, Lidawi G, Maraga, Mohsen F. et al. SARS-CoV-2 Infection-Blocking Immunity Post Natural Infection: The Role of Vitamin D. Vaccines (Basel) 2023;11:475.
15. Agenzia Italiana del Farmaco (AIFA). Nota 96 per la prescrizione di farmaci a base di Vitamina D. Available at: https://www.aifa.gov.it/-/vitamina-d-chiarimenti-sulla-nota-96. (Last accessed, February 28, 2023).
16. Calderon M, Gysin G, Gujjar A, McMaster A, ing L, Comandé D. Bacterial co-infection and antibiotic stewardship in patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis 2023;23:14.
17. Sieswerda E, de Boer MGJ, Bonten MMJ, Boersma WG, Jonkers RE, Aleva RM. Recommendations for antibacterial therapy in adults with COVID-19 – an evidence based guideline. Clin Microbiol Infect 2021;271:61-6.
18. Fialek B, Pruc M, Smereka J, Jas R, Rahnama-Hezavah M, Denegri A et al. Diagnostic value of lactate dehydrogenase in COVID-19: A systematic review and meta-analysis. Cardiol J 2022;29:751-8.
19. Lippi G, Henry BM, Bovo C, Sanchis-Gomar F. Health risks and potential remedies during prolonged lockdowns for coronavirus disease 2019 (COVID-19). Diagnosis (Berl) 2020;7:85-90.
20. Darvishi M, Nazer MR, Shahali H, Nouri M. Association of thyroid dysfunction and COVID-19: A systematic review and meta-analysis. Front Endocrinol (Lausanne) 2022;13:947594.
21. Lui DTW, Tsoi KH, Lee CH, Yan Cheung CY, Yi Fong CH, Lee ACH, et al. A prospective follow-up on thyroid function, thyroid autoimmunity and long COVID among 250 COVID-19 survivors. Endocrine. 2023 Jan 3:1–12. doi: 10.1007/s12020-022-03281-8. Epub ahead of print.
22. Favaloro EJ, Lippi G. Recommendations for Minimal Laboratory Testing Panels in Patients with COVID-19: Potential for Prognostic Monitoring. Semin Thromb Hemost 2020;46:379-82.
23. Araiza-Garaygordobil D, Montalto C, Martinez-Amezcua P, Cabello-Lopez A, Gopar-Nieto R, Alabrese R, et al. Impact of the COVID-19 pandemic on hospitalizations for acute coronary syndromes: a multinational study. QJM 2021;1149:642-7.
24. Sorrell JM. Losing a Generation: The Impact of COVID-19 on Older Americans. J Psychosoc Nurs Ment Health Serv 2021;59:9-12.
25. Battisti F, Falini P, Gorini G, Sassoli de Bianchi P, Armaroli P, Giubilato P. et al. Cancer screening programmes in Italy during the COVID-19 pandemic: an update of a nationwide survey on activity volumes and delayed diagnoses. Ann Ist Super Sanita 2022;58:16-24.
26. Ferrari A, Sanchis-Gomar F, Mattiuzzi C, Henry BM, Lippi G. Is COVID-19 impacting prostate cancer screening? A survey of prostate-specific antigen test requests during a local outbreak. EJIFCC 2021;32:69-77.
27. Durant TJS, Peaper DR, Ferguson D, Schulz WL. Impact of COVID-19 Pandemic on Laboratory Utilization. J Appl Lab Med 2020;5:1194-205.
28. Singh IR, Dowlin M, Chong TH, Nakamoto JM, Hilborne LH. Changes in Test Volumes During Coronavirus Disease 2019 (COVID-19): A Laboratory Stewardship Opportunity. Arch Pathol Lab Med 2021;145:821-4.