Articles

Correlating Diagnostic Reports Of COVID-19 For Rationale Therapeutic Regimen, A Pathologist And Pulmonologist Perspective

Author: Dr. G. Venkata Lakshmi

MBBS, MD (Pulmonary Medicine), Consultant Pulmonologist, Sriram Clinics, Manikonda

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Abstract

The outbreak of novel Coronavirus Disease 2019 (COVID-19) currently spread worldwide with around 209 countries reporting the events. The early detection of COVID-19 infection is crucial to provide the targeted therapy for management of COVID-19. Real time polymerase chain reaction (RT-PCR) is the gold standard for detection of the COVID-19 infection, however, there are chances of negative results as well. There is urgent need for more accurate, and precise detection tests with faster results and thereby a rational therapeutic approach could be established. Along with detection, other laboratory findings (D-dimer, C- Reactive Protein (CRP), platelets, serum ferritin, Lactate Dehydrogenase (LDH), transaminases etc.) also play a significant role in detecting the level of infection in COVID-19 patients as suggested by various studies. In addition, to improve the healthcare infrastructure, there is also need of certified laboratories, equipment, and well-trained healthcare professionals to avoid any unnecessary error. So far various clinical trials are conducted for therapeutic approach, yet, no particular drug or therapy is registered for management of COVID-19. The symptomatic treatment along with managing the condition with standard of care is the current practice for management of COVID-19 and the development of vaccine has shown a ray of hope.

Keywords: COVID-19, Therapeutic regime, Haematological laboratory tests, Case study

 

Introduction

In Wuhan, China, the first case of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in December 2019. Since then, a total of 150,989,419 cases are recorded globally, with 3.17 million deaths so far [1, 2] and the counting is increasing daily. The actual number of deaths due to COVID-19 may be due to limited testing and problems associated with the attribution of the cause of death [3]. The epidemiological characteristics of COVID-19 were found as similar to the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) (4). However, the mortality rate was different (COVID-19: 2.08% versus SARS-CoV: 10.87% versus MERS-CoV: 34.77%) and despite this, COVID-19 is more contagious [4, 5]. The increasing severity of COVID-19 can be explained by three stages: early stage (flu-like symptoms due to viral infection, developing viral pneumonia), second stage (pulmonary inflammation and coagulopathy, increased level of inflammatory biomarkers), and third stage (fibrosis) [6].

During the first wave of COVID-19, the situations were different and various methods and medicines were tried for the management of COVID-19 with changing symptoms and diagnosis in accurate manner. From the first wave in 2020, many things were learned about the clinical course, prognostic inflammatory markers, disease complications, and mechanical ventilation strategy. However, the pathophysiology of COVID-19 is poorly understood. In the second wave, early diagnosis along with the laboratory testing were conducted to manage the patients with COVID-19. The scientists are working relentlessly to find the treatment for COVID-19. The vaccine was also developed and vaccination at large scale started globally to protect the patients. However, the initial laboratory findings play a major role and cannot be neglected. When dealing with infectious diseases, complete blood counts (CBCs) play an important role. The article focus on the different laboratory tests for diagnosis and use of rationale therapeutic regimen for management of COVID-19.

 

Diagnostic Approach

Diagnosis of COVID-19

The diagnosis for SARS-CoV-2 can be accomplished by detecting the virus or the immune response against viral agent. As a direct diagnosis, RT-PCR is the most commonly used molecular test for which samples are collected from the nose and/or throat with a swab [7]. Molecular tests can detect virus in the sample by amplifying viral genetic material at the detectable levels. Within a few days of exposure or when symptoms are visible, a molecular test is used to confirm an active infection [7].

Apart from this, antigen-based immunoassays are also used as virus detection method. For the sensitivity and specificity, the use of more than one antigens in the assays is essential, therefore, molecular assays or immunoassays prefer more than one specific SARS-CoV-2 target [8]. During infection, viral antigens and antibodies are detectable at different periods and detection time depends on several factors including viral features, individual patient variability, and applied test. Hence, for accurate diagnosis, it is very important to select an appropriate diagnostic test within the correct timing of infection [8, 9].

Pathological Test for COVID-19

1. Nucleic Acid Amplification Test: NAATs such as RT-PCR for SARS-CoV-2 are designed to detect viral RNA NAATs for SARS-CoV-2 specifically identify the RNA (ribonucleic acid) sequences that comprise the genetic material of the virus. It works by amplifying first and making many copies of the virus’s genetic material, if any is present in a person’s specimen and detect very small amounts of SARS-CoV-2 RNA in a specimen, making these tests highly sensitive for diagnosing COVID-19 [10].
2. Saliva Testing: Saliva tests are easy, more comfortable than nasal swabs and need 10-12 minutes to make enough spit to fill the tube, but they are not good option for those with low saliva production, such as very young children or those who have suffered a stroke [11].
3. Inflammatory Biomarkers: COVID-19 disease is associated with significantly increased leukocytes, neutrophils, infection biomarkers [such as CRP, procalcitonin (PCT) and ferritin] and cytokine levels [IL-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] and decreased lymphocyte counts [12].
4. Lung Pathology: Lungs are the main organ that are infected and abnormal changes involves edema, epithelial damage, and capillaritis/endothelialitis, and combined with microthrombosis. Patients with respiratory insufficiency exhibit exudative diffuse alveolar damage (DAD) and Pneumocyte type 2 hyperplasia, with superinfection and other comorbidities. The early disease stage of severe COVID-19 is characterized by high viral load, lymphopenia, more of pro-inflammatory cytokines and hypercoagulability, increased D-dimers and more frequency of thrombotic and thromboembolic events, and cytokine levels tend to decrease according to severity of disease [13].
5. Computed Tomography and CT scan: Chest CT scans are non-invasive and involve many X-rays at different angles across a patient’s chest to produce cross-sectional images [14]. The X-rays are analysed by radiologists to look for any abnormal features, if any that can lead to a diagnosis [15]. The symptoms CT scans features of COVID-19 are vast and depend on the stage and severity of infection after the onset of symptoms. For example, in one study it was seen that more frequent normal CT findings (56%) in the early stages of the disease (0–2 day) with a maximum lung involvement peaking at around 10 days after the onset of symptoms [16]. The most common hallmark features of COVID-19 include bilateral and peripheral ground-glass opacities (areas of hazy opacity) [16] and consolidations of the lungs (fluid or solid material in compressible lung tissue). In another study it was found that ground-glass opacities, a disorder that cause scarring of lung tissue are most prominent 0–4 days after symptom onset. Based on these features, several retrospective studies have shown that CT scans have a higher sensitivity of 86–98% and improved false negative rates compared to RT-PCR. The main caution of using CT for COVID-19 is that the specificity is low (25%) because the imaging features overlap with other viral pneumonia [17].

 

COVID-19 Test and their Significance

Early and accurate detection of COVID-19 infection is very important for providing targeted therapy and it also reduce unnecessary use of other drugs, like there was a lot of steroid usage during the second wave and that's what possibly may have contributed to the higher incidence of infections, treatment costs, and morbidity [7]. As far as CBC is concerned, high level of CRP, reduced hematocrit, lower red blood cells (RBCs), low levels of platelets count, increased leucocytes, increased levels of inflammatory biomarkers (CRP, ferritin, IL-6, IL-1, and D-dimer) indicate the presence of infection that lead to fatigue and dyspnea in COVID-19 patients [6, 9]. In COVID-19 patients with comorbid conditions, the abnormal hemoglobin, hematocrit, RBCs, lead to inability of bone marrow to produce enough RBCs to supply oxygen and gaseous exchange is further deteriorated due to lung damage by COVID-19 [4].

A systemic review revealed that laboratory tests reported within a median of 6 days after symptoms were a crucial evidence to understand the abnormalities in COVID-19 patients [6]. Lymphocytopenia, high CRP and D dimer levels were detected in majority of COVID-19 patients while few patients (less than 10) also had other relevant markers (ferritin, IL-6, IL-1, cardiac enzymes, and coagulation tests) [6]. Due to the abnormalities based on laboratory findings, the decision and timing to use the antiviral agents and ant-inflammatory drugs lead a great dilemma for the treating physician.

Recent studies also revealed that hematological parameters significantly altered in patients with COVID-19 [18, 19]. It was also reported high levels of transaminases and LDH in Chinese patients with COVID-19 [20]. Another study concluded that low WBC count, significantly higher CRP, Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and LDH were observed in COVID-19 patients [19], while no associations were observed between platelets counts and the disease [19]. In present cases of COVID-19, low platelets count was an alarming trend and in line with what was reported by Cheng et al. These laboratory tests might help in detecting false-positive/negative RT-PCR tests and can also provide the significant level of infection.

 

Pulmonologist on Correct Therapeutic Regimen

Currently there is no registered therapy for management of COVID-19 patients and vaccine has limited availability. The management of COVID-19 patients is based on supportive therapy and symptomatic treatment trying to prevent the respiratory failure [7, 20]. Optimal supportive care with oxygen for severely ill patients and those with comorbid conditions; and more advanced respiratory support system (ventilation) for patients who are critically ill are the current approach for managing COVID-19 patients. Use of dexamethasone, a corticosteroid can reduce the length of time on a ventilator and save lives of patients with severe and critical illness [7]. The results from WHO’s “Solidarity Trial” indicted little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients by using the treatment with remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens [7, 21].

As per WHO guidelines, hydroxychloroquine is unable to offer any benefit for treatment of COVID-19 and WHO does not recommend self-medication with any medicines, including antibiotics, as a prevention or cure for COVID-19 [7]. Most of the data showing the pharmacological intervention is based on the drugs used during SARS-CoV or MERS-CoV pandemics. At present several clinical trials for possible treatments are ongoing based on the use of antiviral, anti-inflammatory and immunomodulatory drugs, cell therapy, antioxidants and other therapies [22]. The current growing interest of clinical trials and therapy is the use of anti-inflammatory molecules such as tocilizumab, a monoclonal antibody against IL-6R, which was used in Wuhan for management of COVID-19 patients and is being investigated in Italy. Though it seems promising, yet data are limited to claim the benefits and draw a meaningful conclusion. Other potential candidates are anti-IL-17, interferon, and treatment with mesenchymal stromal cells. As the vaccine is available now and global vaccination is ongoing, the management of the COVID-19, hopefully, would be more promising in coming times.

 

Clinical Trial on Therapy of COVID-19

RECOVERY is an international randomised clinical trial investigating treatments beneficial for hospitalized COVID-19 patients (figure 1). Treatment scope includes medicines like Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Colchicine, IV Immunoglobulin (children only), Convalescent plasma, Synthetic neutralizing antibodies (REGN-COV2), Tocilizumab, Aspirin, Baricitinib, Infliximab, Empagliflozin or Anakinra (children only) preventing death in patients with COVID-19 [23].

 

Study Details Study type - Interventional (Clinical Trial) Estimated enrolment - 45000 participant Allocation - Randomized Actual study start date - March 19, 2020 Estimated primary completion date - December 2021 Estimated study completion date - December 2031

 

Figure 1: Details on RECOVERY, an international randomised clinical trial investigating treatments beneficial for hospitalized COVID-19 patients

 

Case Study on COVID-19 patient

52-year-old man (with medical history of Thyroid, Obesity and no other comorbidity) was tested positive after 10 days of 1st dose of vaccine and presented with symptoms (Running nose, Cough, Breathlessness and Fever). First four to five days’ symptoms were not so severe however after sixth / seventh days’ patient’s condition changed from mild to severe. During this time patient tried to get hospital admission; however due to non-availability, both treating doctor and patient decided to follow strict dietary, medicine and physio regime at home with the help of family members. During these days as the patient condition was changing from Mild to severe, Doctor advised to undertake blood reports and CT at regular interval helping in prescribing as per changing health condition. Apart from medicine following regimen was asked to be followed:

• Gargle and Steam – at least three to five times with boiled and cool water at room temperature
• Dietary regimen – Regular food, Fruits and Fluid (3 L/day) is important to sustain and revive the body to come out of Chronic Fatigue Syndrome (table 1)
• Therapeutic regimen – Divided in two parts initial days and other for maintenance till the report result in negative (table 1)
• Health Monitoring Chart – Every two hours (Temp., SpO2, BP, FBS and Symptoms) and Diagnostic reports as available (table 2)

 

Table 1: Diet chart and therapeutic regimen during COVID-19 infection

Time	Morning	Afternoon	Evening	Therapeutic regimen
Early (7am, 1pm, 7pm)	Fruits (Watermelon/ Melon/ Papaya/ Orange)	Cottage cheese/ Chicken/ Lentils/ Fish, Roti, Rice	Lentils/ Mutton/ Cottage cheese/ Egg, Roti, Rice	Initial days: Doxycycline cap BD Apixaban 2.5mg BD for 2 weeks Favipiravir 1st day 1800mg BD, 2 to 6 day onwards 800mg twice a day Immunity supplement one tab for one month Vitamin C two tab BD for one month Dexamethasone 4mg TID Perinorm 10mg
Late (9am, 11am, 5pm, 9pm)	Two boiled eggs Paratha/ Idli/ Omelet Hot Turmeric Milk	Salad, Cottage cheese/ Green leafy, Sprouts/ Boiled lentils	Hot Turmeric Milk	Maintenance till negative report: Dexamethasone 4mg twice a day Ecosprin OD for one month Immunity supplement for month once a day Vitamin C BD for one month Phytosomal curcumin one tab twice a day for 3 months Vitamin C 2 tab BD for one month

 

Table 2: Health monitoring chart of COVID-19 infected patient

Date Apr-May 2021

Symptoms

RT-PCR Test

SPO2 value

Temp.

CRP (HSCRP)<3.00 mg/ml

D-Dimer (Phytometery)  <1.00 µg / ml

HbA1c (HPLC)  Below 5.7%

Ferritin (C.L.I.A) 22-322 ƞg/ml

LDH (Colometric Lactae to pyruat)                          125 – 220 u/l

CT Chest

BP

FBS

Therapeutic regimen

Remarks

10 Apr

Sneezing, Running nose

RTPCR positive N1 / RdRp gene CT – 19, N2 / N Gene CT - 19

97-98

98.2

127/89

102

11 Apr

Sneezing, Running nose, Low grade fever

95-98

99.8

Doxycycline cap - BD x 5days Apixaban 2.5mg BD X 2 weeks Vitamin D3 cap - Once a week Pantoprazole + Domperidone - BD X 2 weeks Favipiravir - 1st day 1800mg - BD, 2-6 day onwards 800mg - BD Cetrizine- BD X 3 days Immunity supplement - one-tab x one month Vitamin C - two tabs. x BD X one month

12 Apr

Sneezing, Running nose, Fever

95-97

98.5-100

23.76

2.49

5.8

400

Elevated GGT & SGPT, GFR - 79

13 Apr

Sneezing, Running nose, Fever

95-96

98.4-100

Multivitamin + Zinc - OD x 15 days Apixaban 2.5mg BD X 2 weeks Vitamin D3 cap - Once a week Famotidine - OD X 30 days Favipiravir - Continue Dexamethasone - 4mg BD

14 Apr

Feeling better, symptoms subsided (No- fever/cough, Nasal congestion improved)

95-96

normal

15 Apr

Sneezing, Running nose, Fever, Frequent hiccups

95-97

normal

5.7

2.68

6.04

486

9/25 (CO-RADS 6) ground glass opacification, diffusely secreted along bilateral lung field.

Dexamethasone- 4mg TID Donase nasal spray - 2 puffs in each nostril X BD Perrinorm - 10mg X BD Acetylcystine - 600mg X BD X 5 days

Significantly elevated GGT & SGPT, Elevated - Blood urea, Blood Urea nitrogen, Vit B12-716pg/ml, Vit D total19.7ng/ml

16 Apr

Fever, Severe cough, Frequent hiccups, Black sputum

95-96

98.4-99

17 Apr

Chest congestion, Severe cough, Frequent hiccups, Black brown sputum thrice in a day with cough

86-91

99

62.82

0.79

5.2

995

13/25 (CO-RADS 6) multifocal patchy, ground glass opacification, diffusely secreted along bilateral lung field.

Gritintus - 5ml X TID Stop Favipiravir due to elevated LFT, KFT

Significantly elevated GGT & SGOT, Elevated - Blood urea, Blood Urea nitrogen, Tried hospital admission, but no bed was available

18 Apr

Chest congestion, cough, sore throat fever, Black brown sputum thrice in a day with cough

86-91

99

Dexamethasone – 8mg X BD Levofloxacin - 750mg X BD X 7 days Phytosomal curcumin - one tab x BD x 0ne month

19 Apr

Chest congestion, cough, fever, Black brown sputum thrice in a day with cough

89-91

99

20 Apr

Chest congestion, Severe cough, Slight fever, Black brown sputum thrice in a day with cough

93-95

98.6

21 Apr

Chest congestion, Cough, Yellow sputum once in a day

94-96

normal

120/70

134

MPD - 16mg x BD

Lung exercises with Spirometer thrice daily for 5 min. each time

22 Apr

Chest congestion, Less cough, Yellow sputum once in a day

94-96

98.6

6.6

0.75

145/84

130

MPD - 16mg x BD

Elevated GGT & SGPT, GFR - 101

23 Apr

Chest congestion, Less cough, Yellow sputum once in a day

95-96

98.2

130/80

149

MPD - 16mg x BD

24 Apr

Chest congestion, Less cough, Yellow sputum once in a day

95-98

Normal

117/74

145

Dexamethasone 4mg for BD

25 Apr

No Chest congestion, No breathlessness, No Sputum

95-98

Normal

134/87

138

Dexamethasone 4mg for BD

26 Apr

No Chest congestion, No breathlessness, No Sputum

96-98

normal

124/77

133

Dexamethasone 4mg for BD

27 Apr

Felling normal, Lethargic Fatigue

96-98

Normal

0.1

2.8

6.5

413

260

116/78

101

Dexamethasone 4mg for BD

Elevated blood urea and Nitrogen

28 Apr

Felling normal, Lethargic Fatigue

97-98

Normal

120/67

99

Dexona 2mg for BD

29 Apr

Felling normal, Lethargic Fatigue

97-98

Normal

126/77

105

Dexona  1mg for BD

30 Apr

Felling normal, Lethargic Fatigue

96-98

Normal

8.5

5.2

6.83

437

451

135/81

116

Dexona 0.5mg for BD

Slightly elevated blood urea and Nitrogen, Vit B12 - 1135pg/ml, Vit D 24.55ng/ml, IL6 5pg/ml

1 May

Less Fatigue

97-98

Normal

109/65

90

Dexona 0.5mg for OD

Rehab started, Daily Yoga excersises - Prayanam, Suryanaskar, Small red spots on hand & arms

9 May

Normal

97-98

Normal

6.7

0.9

6.6

272

337

113/73

92

Ecosprin - OD X One month Vitamin D3 cap - Once a week for one year Immunity supplemet - one-tab x one month Phytosomal curcumin - one tab. X BD X three months Vitamin C - two tabs. x BD X one month

Red spots disappeared, LFT & KFT normal, IgG - 13.8

17 May

Normal

RT PCR Negative, 2nd dose of vaccine

96-97

normal

131/84

112

 

Abbreviations – SpO2: peripheral capillary oxygen saturation, CRP: C-reactive protein, D-dimer: domain dimer, HbA1C: Glycated haemoglobin, LDH: Lactate dehydrogenase BP: blood pressure, FBS: Fasting blood sugar, GGT: Gamma-glutamyl transferase, SGPT: serum glutamic-pyruvic transaminase, GFR: Glomerular filtration rate, SGOT: Serum glutamic-oxaloacetic transaminase.

 

Conclusion

An early diagnosis of the infection is essential part of preventing the current outbreak of the pandemic. Correct sampling within appropriate time of infection is very significant for accurate and precise diagnosis. In current scenario, RT-PCR is a gold standard and antibody-based immunological tests are practical and easy-to-use methods for rapid screening. However, RT-PCR has a long turnaround time and can show false negative results as well. Although, the current diagnostic measures can detect COVID-19, still, there is urgent need for more practical, accurate, and precise detection tests, which could provide faster results and thereby a rational therapeutic approach could be established. Along with that, other laboratory findings also play a significant role in detecting the level of infection in COVID-19 patients as suggested by various studies. Hence, the role of therapeutic medication and laboratory testing in COVID-19 infection cannot be neglected.

 

 

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