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Inflammatory Markers or ‘Composite Index’ in COVID-19 as ‘Point Of Care Test’: Which One is the Best Choice to Tackle Dragon!

June 2023
Research Journal of Medical Sciences 5(3):53-62

June 2023
5(3):53-62

DOI:10.36346/sarjms.2023.v05i03.002

Authors:

Shital Patil

VENKATESH CHEST HOSPITAL AND CRITICAL CARE CENTER

Gajanan Gondhali

Maharashtra Institute of Medical Sciences and Research

COVID-19 is first corona virus related global pandemic after SARS and MERS and due to rapid evolution of pandemic fast track developments in diagnostics, monitoring and treatment options and vaccine developments has occurred to prevent its significant impact on mortality and morbidity. COVID-19 infection involves a complex interplay of the immunological and inflammatory responses. Inflammatory parameters are closely linked to the COVID-19 severity and mortality. Inflammatory parameters could be used to predict the transition from mild to severe/critical infection in patients of COVID-19. Numerous Inflammatory markers were analysed and used as point of care test to predict severity of illness, monitoring of illness, treatment planning and predicting final outcomes such as CRP, LDH, IL-6, D-dimer and ferritin. Robust data of these inflammatory markers is available and proved crucial in predicting pathophysiological trends such as cytokine storm, coagulation abnormalities, oxygenation status and response to therapy. Isolated assessment of inflammatory markers in absence of clinical and radiological parameters were observed as ‗double edged weapon‘ due to overestimation and its impact on health burden and underprediction resulting into progression of illness and resultant poor outcome and increased health care cost. Composite index is combination clinical, radiological and laboratory inflammatory marker assessment. Combination of any two abnormalities were observed crucial role in early suspicion, diagnosis, monitoring, and recognition of complications, management and disposition of patients. Composite index rather than single biomarkers may provide more reliable information. Availability and cost issues cannot be ignored. It would be impossible for clinicians to consolidate and critically analyse the enormous data that is continuously added to the COVID-19 literature to extract practically useful information for the benefit of patients. Still, as of now Composite index should be considered as ‗point of care test‘ to honour successful treatment outcome and prevent mortality and morbidity due to this ‗Dragon Pandemic‘.

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ISSN 2664-3987 (Print) & ISSN 2664-6722 (Online)

South Asian Research Journal of Medical Sciences

Abbreviated Key Title: South Asian Res J Med Sci

| Volume-5 | Issue-3 | May-Jun -2023 | DOI: 10.36346/sarjms.2023.v05i03.002

International License (CC BY-NC 4.0) which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use

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CITATION: Shital Patil, Gajanan Gondhali (2023). Inflammatory Markers or ‗Composite Index in COVID-19 as ‗Point

Of Care Test‘: Which One is the Best Choice to Tackle Dragon!. South Asian Res J Med Sci, 5(3): 63-77.

Review Article

Inflammatory Markers or ‘Composite Index’ in COVID-19 as ‘Point

Of Care Test’: Which One is the Best Choice to Tackle Dragon!

Shital Patil1*, Gajanan Gondhali2

1Associate Professor& Head, Pulmonary Medicine, MIMSR Medical College & Venkatesh Chest Hospital, Latur,

Maharashtra State, India

2Professor, Internal Medicine, MIMSR Medical College, Latur, India

*Corresponding Author: Shital Patil

Associate Professor& Head, Pulmonary Medicine, MIMSR Medical College & Venkatesh Chest Hospital, Latur, Maharashtra State,

India

Article History

Received: 14.05.2023

Accepted: 10.06.2023

Published: 14.06.2023

Abstract: COVID-19 is first corona virus related global pandemic after SARS and MERS and due to rapid evolution

of pandemic fast track developments in diagnostics, monitoring and treatment options and vaccine developments has

occurred to prevent its significant impact on mortality and morbidity. COVID-19 infection involves a complex interplay

of the immunological and inflammatory responses. Inflammatory parameters are closely linked to the COVID-19

severity and mortality. Inflammatory parameters could be used to predict the transition from mild to severe/critical

infection in patients of COVID-19. Numerous Inflammatory markers were analysed and used as point of care test to

predict severity of illness, monitoring of illness, treatment planning and predicting final outcomes such as CRP, LDH,

IL-6, D-dimer and ferritin. Robust data of these inflammatory markers is available and proved crucial in predicting

pathophysiological trends such as cytokine storm, coagulation abnormalities, oxygenation status and response to therapy.

Isolated assessment of inflammatory markers in absence of clinical and radiological parameters were observed as ‗double

edged weapon‘ due to overestimation and its impact on health burden and underprediction resulting into progression of

illness and resultant poor outcome and increased health care cost. Composite index is combination clinical, radiological

and laboratory inflammatory marker assessment. Combination of any two abnormalities were observed crucial role in

early suspicion, diagnosis, monitoring, and recognition of complications, management and disposition of patients.

Composite index rather than single biomarkers may provide more reliable information. Availability and cost issues

cannot be ignored. It would be impossible for clinicians to consolidate and critically analyse the enormous data that is

continuously added to the COVID-19 literature to extract practically useful information for the benefit of patients. Still,

as of now Composite index should be considered as ‗point of care test‘ to honour successful treatment outcome and

prevent mortality and morbidity due to this ‗Dragon Pandemic‘.

Keywords: COVID-19, CRP, IL-6, LDH, Ferritin, D-Dimer, Long COVID, post covid lung.

INTRODUCTION

The ongoing pandemic of severe acute respiratory syndrome by coronavirus 2 (SARS-CoV-2) continues to pose

several diagnostic and therapeutic challenges. First reported from Wuhan in China in December 2019, the World Health

Organization on February 11, 2020 officially named this infection, coronavirus disease 2019 (COVID-19) and the virus

as SARS-CoV-2 (1). It was declared as a pandemic on March 11, 2020 [1]. After the virus‘ genome was sequenced, the

virus was given the name severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by the International

Committee on Taxonomy of Viruses. It shared genetic ancestry with the coronavirus outbreak that caused the SARS

epidemic of 2003 [2]. As of today, more than 500 million people have been infected and more than six million have died

globally.

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

Acute inflammation in the lungs is a complex pathophysiological mechanism involving inflammatory mediators

such as cytokines and chemokines, which stimulate the macrophages in the alveoli, leading to poor regulation of the

immune system. In humans, the clinical progression of the novel coronavirus-induced disease exists in a triphasic form.

The clinical features in first phase include fever, dry cough, myalgia, and other systemic infections that are likely to be

increased by the replication of the virus and cell necrosis. The associated feature of the second phase is the onset of IgG

immunoglobulins conversion, correlated with the decrease in viral replication. During this phase, uncontrolled viral

replication occurs causing severe worsening of symptoms. The exact hypothesis behind this might be the severe damage

to alveoli caused by over exuberant immune response of the host. In nCOVID-19-infected patients, the major patient

population recovered after two weeks, but one-third of the patients progressed to the third phase, which is characterized

by severe lung inflammation leading to ARDS, i.e., acute respiratory distress syndrome [3, 4].

The virus causing nCOVID-19 belongs to a family of viruses known as Coronaviridae. Coronaviruses can be

classified in four genera: alpha, beta, gamma, and delta. Human CoV belong to either alpha or beta. Gamma and delta

CoV tend to infect birds. The coronaviruses affecting humans are of seven types, as depicted in Table 1. Among them,

the highly pathogenic corona viruses are SARS CoV, MERS CoV, and SARS CoV-2. They cause severe pneumonia in

humans by infecting the lower respiratory tract, which causes diffuse alveolar damage, resulting in increased morbidity

and mortality [3, 5].

Table 1: Types of coronaviruses affecting human

S. No

Type

229E (alpha coronavirus)

NL63 (alpha coronavirus)

OC43 (beta coronavirus)

HKU1 (beta coronavirus)

MERS-CoV (beta coronavirus)

SARS-CoV (beta coronavirus)

SARS CoV-2 (novel coronavirus)

The nCOVID-19 virus has a round, enveloped structure with a diameter of approximately 80 to 120 nm and

contains a positive genome of single stranded RNA of 31 kb size [6]. Structure of severe acute respiratory syndrome

coronavirus-2 (SARS-CoV-2), an enveloped virus with single-stranded positive-sense (+sense) RNA taking four

principal proteins, including membrane (M) and spike (S) glycoproteins, in addition to nucleocapsid (N) and envelope

(E) proteins forming peplomer on the surface of the virion giving the structure a crown-like appearance as shown in

Figure 1 [7].

Figure 1: Structure of novel coronavirus, SARS-CoV-2

Mode of host entry and infective life cycle of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

virus. The COVID-19 pathogenesis includes direct cytotoxicity of virus in ACE2 (angiotensin-converting enzyme 2)-

expressing cells; Renin-Angiotensin-Aldosterone System (RAAS) dysregulation secondary to virus-mediated ACE2

downregulation; immune response dysregulation; damage to the endothelial cells and thromboinflammation; and tissue

fibrosis (Figure 2) [8].

1. The interaction between the angiotensin-converting enzyme 2 (ACE2) receptor and S-protein leads to the

attachment of the virus

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

2. The entry of virus conducted by endocytosis and/or by

3. Membrane fusion of virus

4. Translation of virus RNA leads to produce proteins 1a & 1ab

5. Proteolysis of proteins results in non-structural proteins and replicase-transcriptase complex (RTC)

6. Synthesizing the new viral RNA (-sense) and the viral proteins

7. The association of the viral particle

8. Release of virus through exocytosis.

Figure 2: The life cycle of nCOVID-19 in human cells [8]

The heterogeneous course of COVID-19 disease is unpredictable, with most patients presenting with mild, self-

limiting symptoms. The virus infection commonly starts with flu-like symptoms and can be asymptomatic or may have a

minor to severe development. Despite this, up to 30% of patients require hospitalization, and up to 17% of them need

intensive care support for acute respiratory distress syndrome (ARDS), hyper-inflammatory responses, and multiorgan

failure [9, 10].

The common features observed in critically ill nCOVID-19 patients are-

1. Respiratory failure

2. Sudden worsening of disease around 1–2 weeks after onset

3. High level of inflammatory mediators including CRP (C-reactive proteins) and pro-inflammatory cytokines like

interleukins, tumor necrosis factor (TNFα), etc.

4. Damaged immune system presented by the atrophy of lymph nodes and spleen, also reduction in the

lymphocytes level

5. Elevated levels of infiltrated immune cells like monocytes, macrophages found in lung lesions

6. Hypercoagulation, vasculitis, and multiple organ damage

Genetic makeup of corona virus was determining factor for overall outcome in first and second wave, first was

classical ‗Wuhan variant virus‘ and second one was mutant ‗Delta variant‘ corona virus; and as mutant in second wave

was associated with increased morbidity and mortality. In both the waves, covid pathophysiology were same i.e.,

immune activation, inflammatory, thrombogenic and direct viral affection to lungs and extrapulmonary tissues. Covid-19

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

is corona virus related disease, its etiological agent discovered in middle of 20th century, its epidemics-pandemics has

created health burden in early 21st century; but evidences are coming up with its correlation with ―Russian or Asiatic flu‖

of late 19th century [11-15].

Available inflammatory markers in COVID-19 pneumonia:

Now the robust data is available for role of various inflammatory markers in initial assessment of cases which

are associated with direct or indirect virus-related lung injury. Apart from lung involvement, proportionate number of

cases were shown systemic manifestations due to activation of inflammatory pathway and inflammatory surge resulting

in to pulmonary and extrapulmonary effects which have significant impact on final outcome. All these effects can be

easily picked up by timely analysis of inflammatory markers. Now these markers are also called as ‗inflammatory

biomarkers.‘ Various inflammatory markers such as CRP, Ferritin, LDH, D-dimer and IL-6 were exuberantly used

during workup of COVID-19 cases worldwide and reported their valuable role in initial assessment, predicting severity,

guiding or triaging hospitalization, predicting need of interventions during hospitalization, analysing final outcome,

predicting post recovery outcome and possibility of long covid manifestations. But more misinformation was reported

regarding inflammatory markers in COVID-19 pneumonia and reported as Infodemic during this pandemic [16].

COVID-19 pneumonia is heterogeneous disease with variable effect on lung parenchyma, airways and

vasculature leading to long term effects on lung functions which occurred as a resultant pathophysiological effects of

immune activation pathway and direct virus induced lung damage. In COVID-19 pneumonia pathophysiology constitutes

different pathways like immune activation, inflammatory, thrombogenic and direct viral affection to lungs and

extrapulmonary tissues presenting with pulmonary and extrapulmonary manifestations [17-19]. COVID-19 infection is

accompanied by vigorous immune and inflammatory response that causes severe lung damage to limit the entry of

oxygen to the bloodstream, resulting in long-term breathlessness and severe complications including renal failure.

Inflammatory markers (ferritin/LDH) could be useful as a predictor for COVID-19 mortality and respiratory failure and

could help the physicians to discern at-risk COVID-19 patients to facilitate early treatment. Elevated LDH increases the

odds of severe COVID-19 disease and mortality among ICU-admitted patients.

Role of CRP in COVID-19 pneumonia:

The laboratory of Oswald Avery first documented ‗CRP‘ as inflammatory protein released in serum of patients

with acute infections and later on labelled as ‗acute phase reactant‘. Robust data is available regarding its role in

infections, inflammatory, ischemic, and traumatic tissue injuries, and malignancy, whilst the advent of sensitive

quantitative immunoassays in the 1970s greatly enhanced its clinical utility. In 1974, Kaplan and Volanakis [20] and

Siegel et al., [21] reported ‗pro-inflammatory‘ role of CRP. CRP can be used as marker of inflammation in COVID-19

pneumonia‘s can be used as inflammatory marker and help in analyzing infective and non-infectious causes, surgical,

post operative, inflammatory conditions as rheumatoid, gout and venous thromboembolism. Data of CRP in severe H1N1

viral pneumonia is available and a number of recent series have reported an association between CRP and COVID-19

disease severity [22-25].

CRP is easily available, sensitive, reliable, cost effective, and universally acceptable inflammatory marker in

COVID-19 pneumonia. CRP has very crucial role in COVID-19 pneumonia in predicting severity of illness, especially

‗follow up titters‘ have significant role in step-up or step-down interventions in critical care setting. Correlating CRP

with variables as duration of illness, oxygenation status and timing of BIPAP/NIV has important role in predicting

outcome. CRP titer has significant association in predicting progression of pneumonia and we have documented that

proportionate number of COVID-19 cases with mild variety on CT thorax with normal initial CRP has progressed to

critical course. Authors [22-25] have also documented that serial or follow up CRP titers has played crucial role along

with other inflammatory markers. Authors have observed rising CRP titers, especially in second week of illness indicates

nosocomial bacterial infection and guided in targeting antibiotic treatment accordingly. CRP follow‑up titer can help in

predicting progression of COVID pneumonia and assessing risk of post‑COVID lung fibrosis [22-25].

LDH in COVID-19 pneumonia:

In last few decades, LDH has been analyzed as prognostic marker in hematology and oncology, in hemolytic

anemia, in megaloblastic anemias, Hodgkin disease and non-Hodgkin lymphoma and leukemias [26] Elevated LDH

levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis due to hypoxia, the latter being

associated with high tumor burden. LDH has many subtypes, 1-5 released by erythrocytes, heart and skeletal muscles, its

isolation usually done as major component and subtyping is not routinely required [26]. Severe infections including

interstitial pneumonia or ARDS (acute respiratory distress syndrome) may cause tissue damage induced by cytokine

production with subsequent release of LDH into the bloodstream [26-28]. As 5% of COVID-19 Pneumonia cases require

intensive care unit treatment including mechanical ventilation and these patients are at high risk of death. Therefore,

markers with high positive predictive value for early prediction of ARDS will help in decreasing mortality [28]. In

inflammatory panel evaluation, LDH has very good association with direct lung damage and significantly raised in more

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

widespread tissue injury [27, 28]. In a recently published study on a large case-series of COVID-19 patients, documented

high serum concentrations of LDH was associated with more chance of death due to pneumonia [29].

LDH is an easily available, sensitive & reliable, cost effective, and universally acceptable inflammatory marker

in COVID-19 pandemic. Correlating LDH with variables like duration of illness, oxygenation status and timing of

BIPAP/NIV at entry point is important to have satisfactory treatment outcome. LDH titer has significant associations

with predicting progression of pneumonia, as proportionate number of pneumonia cases with mild variety on CT thorax

and normal initial LDH has progressed to critical course which were documented with help of rising titers and we have

documented follow-up rising titers has played crucial role with other inflammatory markers like LDH & ferritin [30-32].

LDH rising titers in the second week of illness indicates nosocomial bacterial infection and target therapy accordingly.

Also decreasing LDH titers has been assessed and analyzed with improved oxygenation status and excellent response to

treatment and decreased underlying inflammation. LDH titer can help in predicting progression of COVID-19

pneumonia, and assessing risk of post covid lung fibrosis if LDH titer is persistently high in these cases and proportionate

number of cases with normal or abnormal LDH at entry point were predicted with underlying fibrosis or ongoing

inflammation and necrosis of lung parenchyma if LDH is persistently high. LDH titer can guide antifibrotic treatment

response in follow-up post covid care setting [30-32].

IL-6 in COVID-19 pneumonia:

Various biomarkers, especially inflammatory markers like C-reactive protein (CRP), ferritin, fibrinogen, D-

dimer and Interleukin 6 (IL-6) are associated with COVID-19 progression. According to known evidence, IL-6 is

superior to CRP and other markers of inflammation in predicting respiratory failure in COVID-19. IL-6 appears to be the

most important driver of immune dysregulation and ARDS in COVID-19 [33-34]. There is a substantial body of

evidence linking the IL-6 concentration to the severity of disease and unfavourable outcome of COVID-19. Herold et al.

examined the predictive value of various cytokines and concluded that IL-6 is the best predictor of severe COVID-19

[35]. Authors have documented that IL-6 > 80 pg/mL the predicts respiratory failure and need for mechanical ventilation

[35]. Chen et al. found cut-off 80 pg/mL of IL-6 differentiates the survivors from the non-survivors [36]. The direct role

of IL-6 in COVID-19 pathogenesis is further supported by findings that IL-6 inhibition improves the prognosis of severe

COVID-19 [37].

IL-6 is easily available, sensitive, reliable, cost effective, and universally acceptable inflammatory marker in

COVID-19 pneumonia. IL-6 has very crucial role in COVID-19 pneumonia in predicting severity of illness, especially

‗follow up titers‘ have significant role in step-up or step-down interventions in critical care setting. Correlating IL-6 with

variables as duration of illness, oxygenation status and timing of BIPAP/NIV has important role in predicting outcome

[38-40]. IL-6 titer has significant associations with predicting progression of pneumonia, as proportionate number of

pneumonia cases with mild variety on CT thorax and normal initial IL-6 has progressed to critical course and we have

documented follow up titers has played crucial role with other inflammatory markers, and many times in second week of

illness rising titers indicates nosocomial bacterial infection and targeting treatment accordingly. IL-6 follow-up titer can

help in predicting progression of COVID pneumonia, and assessing risk of post covid lung fibrosis [38-40].

D-Dimer in COVID-19 pneumonia:

In COVID-19 pneumonia pathophysiology constitutes different pathways like immune activation, inflammatory,

thrombogenic and direct viral affection to lungs and extrapulmonary tissues. COVID-19, the pandemic disease caused by

infection with the novel virus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) can now be added to the

already extensive list of conditions that may be associated with elevated D-dimer. The discovery that D-dimer may be

elevated in COVID-19 was first reported by physicians in Wuhan, China where the epidemic started. A study of 191

patients with covid-19, who were hospitalized in Wuhan during January 2020 at the outset of the pandemic, revealed that

D-dimer was elevated in many of these patients and the magnitude of the elevation was greatest in those who did not

survive [41]. Fibrin degradation products (FbDP) are a highly heterogeneous group of soluble fragments that appear in

the circulation as a result of two simultaneous physiological processes: 1) Coagulation, resulting in the conversion of

soluble fibrinogen into insoluble stabilized fibrin by the enzymes thrombin and factor XIIIa, 2) Fibrinolysis, resulting in

the dissolution of the fibrin clot by the enzyme plasmin. The D-dimer fragment is the terminal product of this process

[42]. A number of subsequent studies conducted around the world have confirmed that D-dimer is elevated in those with

severe COVID-19 and highest in those who are most critically ill and those who do not survive. Much COVID-19

research over the past months has been directed at understanding the significance of D-dimer elevation and the COVID-

19 related coagulopathy that is presumed responsible for the elevation [41]. D-dimer has been extensively investigated

for the diagnosis, monitoring, and treatment of venous thromboembolism (VTE) for which it is used routinely [43]. D-

dimer levels are also elevated in conditions of chronic inflammation, such as active malignancy, rheumatoid arthritis,

sickle cell disease, and asthma [44]. In the setting of covid-19, D-dimer has been reported to be higher in subjects who

are critically ill or those who expire [45-47].

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

D-Dimer is easily available, and universally acceptable inflammatory marker, which has documented very

crucial role in COVID-19 pneumonia in predicting severity of illness, and assessing response to treatment during

hospitalization. D-Dimer has important role during interventions in intensive care unit, as follow up titers have

significant role in step-up or step-down interventions in critical care setting. Correlating D-dimer with variables like

duration of illness, oxygenation status and timing of BIPAP/NIV at entry point is important to have satisfactory treatment

outcome [48-50]. D-Dimer titer has significant associations with predicting progression of pneumonia, as proportionate

number of pneumonia cases with mild variety on CT thorax and normal initial D-Dimer has progressed to critical course

and we have documented follow up titers has played crucial role with other inflammatory markers, and many times in

second week of illness rising titers indicates ongoing coagulation abnormality, worsening of pneumonia, and increased

inflammatory burden which will help to target therapy accordingly. D-Dimer follow-up titer can help in predicting

progression of COVID pneumonia, and assessing risk of post covid lung fibrosis [48-50].

Ferritin in COVID-19 pneumonia:

The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19

has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis

and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and

biochemical tests in disease diagnosis and management [51]. Ferritin is highly ubiquitous iron binding protein first

isolated in 1937 from horse spleen, since then its isolation methodology and role as acute phase reactant and role as

marker of inflammation has been evolved over decades. Various inflammatory markers like Ferritin, LDH, CRP, IL-6

and D-Dimer have been evaluated in this pandemic and now robust data is available regarding its usefulness in analyzing

severity, decision making in critical cases, assessing response to interventions, predicting outcome.

Cytokine syndrome is defined as ‗A group of conditions sharing same pathological mechanisms with different

etiologies, causing massive release of pro-inflammatory cytokines resulting into aberrant activation of immune and

coagulation systems‘ [52]. Cytokine storms have direct association with raised ferritin level and indirectly it will help in

predicting ongoing inflammatory surge resulting in cytokine storm. cytokine storm is most dreadful event in

pathophysiology of COVID-19 pneumonia and ultimately it will lead to either direct cytokine induced lung injury

manifesting as ALI/ARDS or extrapulmonary systemic secondary haemophagocytic lymphohistiocytosis. [53] Studies

have documented significantly raised ferritin with other inflammatory markers in COVID-19 pneumonia [54] and now

COVID-19 has been included in conditions causing Hyperferritinemia [53]. Ferritin analysis found to be very crucial in

this COVID-19 pneumonia, apart from routine inflammatory marker, its usefulness as marker of underlying

immunosuppression [55]. Additionally, it is useful in predicting severity of illness in patients suffering with comorbidity

as Diabetes mellitus and in geriatric cases and marker of increased morbidity in these cases [56-57].

Ferritin is easily available, sensitive & reliable, cost effective, and universally acceptable inflammatory marker

in COVID-19 pandemic. Robust data of Ferritin is available in bacterial infection, and it can be utilized in this COVID-

19 pneumonia pandemic for initial assessment before planning of treatment in indoor setting in comparison with other

inflammatory markers and CT severity. Ferritin has very crucial role in covid-19 pneumonia in predicting severity of

illness, especially follow up titers have significant role in step-up or step-down interventions in critical care setting.

Correlating Ferritin with variables like duration of illness, oxygenation status and timing of BIPAP/NIV at entry point is

important to have satisfactory treatment outcome [58-61].

Ferritin titer has significant associations with predicting progression of pneumonia, as proportionate number of

pneumonia cases with mild variety on CT thorax and normal initial Ferritin has progressed to critical course and we have

documented follow up titers has played crucial role with other inflammatory markers, and many times in second week of

illness rising titers indicates nosocomial bacterial infection and target therapy accordingly. Ferritin titer can help in

predicting progression of COVID pneumonia, and assessing risk of post covid lung fibrosis, also follow up titers in

suspected lung fibrosis case can be monitored underlying lung inflammation with this easily available marker [58-61].

Inflammatory markers, antigenic mimicry and COVID-19 dengue overlap:

COVID-19 pandemic is a big health concern in dengue endemic areas due to overlapping of clinical and

laboratory features and its challenging job for critical care physicians for correct diagnosis and management of both the

diseases [62-64] Many case reports and case series published the concurrent COVID-19 and dengue co-infections, which

has been associated more mortality than isolated single infection [64-65]. Both viral diseases share may pathogenic and

clinical features, as Antibody Dependent Enhancement phenomenon (ADE) has documented in both dengue and

COVID-19 which is the reason for overlapping nature of both the disease and behaving like ‗two sides of same coin.‘

Both are RNA viruses and shown similar pathologic pathways as cytokines and chemokine release, altering the integrity

of the vascular endothelium leading to vasculopathy, coagulopathy and capillary leak [66].

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

Dengue-COVID-19 overlap is clinical syndrome with overlapping clinical and laboratory workup of both the

illnesses. High index of suspicion is must in all covid cases in tropical setting where dengue is endemic; and all cases

with leukopenia and thrombocytopenia with fever should be screened for dengue serology. False positive dengue

serology or dengue antigen cross-reactivity is known to occur in underlying COVID-19 illness, and have impact on

clinical outcome as it will result in delay in covid appropriate treatment initiation and many cases require intensive care

unit treatment due to progressed covid pneumonia. Covid-dengue antigenic cross-reactivity has significant association

with lung fibrosis as resultant pathophysiological effect of immune activation pathway; and these cases were required

longer oxygen supplementation and anti-fibrotics in follow up. ‗Dengue-COVID-19 overlap‘ is very frequently

documented in tropical setting and disease of concern in critical care setting; as natural trend of this entity is different and

having impact on clinical outcome if diagnosis is delayed. Both diseases may behave like ‗two sides of same coin‘, and

rational for coexistent pathology were still undetermined [67-69].

Inflammatory markers during initial assessment, monitoring, targeting interventions and predicting final

outcome in COVID-19 pneumonia:

Studies have documented that inflammatory marker titer has significant association with duration of illness

(DOI) in COVID-19 pneumonia cases [22-25, 30-32, 38-40, 48-50, 58-61]. Authors have also documented that

proportionate number of cases with duration of illness < 7 days and many cases with duration of illness >15 days were

having normal inflammatory markers titer, while pneumonia cases between 7-14 days of illness were having abnormal or

raised inflammatory markers titer. Rational for this observation is not known, may be inflammatory response pattern is

different, and authors have correlated CRP pattern with other inflammatory markers like IL-6 and D-dimer and

documented that these two markers raised parallel to CRP [22-25, 30-32, 38-40, 48-50, 58-61].

Studies have reported that BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care

setting has significant association with inflammatory marker titer. Authors have documented higher inflammatory marker

titer in cases requiring ventilatory support than requiring high flow nasal canula or just oxygen supplementation, thus it

will help in predicting severity timely to and help in analyzing disease severity [22-25, 30-32, 38-40, 48-50, 58-61].

Studies have reported that inflammatory marker titer has significant association with oxygen saturation in

COVID-19 pneumonia cases [22-25, 30-32, 38-40, 48-50, 58-61]. Various authors have documented similar to our

observation in their studies, mentioned that hypoxia and infection are best triggers of inflammation and synergistic

effects of both lead to significant rise in CRP titer which indicates advanced disease [22-25, 30-32, 38-40, 48-50, 58-61].

Studies have documented that Timing of BIPAP/NIV requirement during course of COVID-19 pneumonia in

critical care setting has significant association with inflammatory marker titer [22-25, 30-32, 38-40, 48-50, 58-61].

Numerous studies have observed positive correlation of inflammatory marker titer with ventilatory requirement and

underlying pathophysiology of ARDS in these cases, and timely CRP titer analysis helped in predicting ‗timings of

ventilatory support‘ requirement [22-25, 30-32, 38-40, 48-50, 58-61].

Studies have documented that Follow-up inflammatory marker titer during hospitalization as compared to entry

point abnormal inflammatory marker titer has significant association in post-covid lung fibrosis [22-25, 30-32, 38-40, 48-

50, 58-61, 70-72]. Rational for similar observation is exaggerated inflammatory response due to advanced lung

inflammation and necrosis resulting in overproduction of inflammatory cytokines linked to elevated inflammatory

marker titer in severe patients with COVID‐19. Cytokines has ‗double edge sword effect‘ i.e., cytokines have protective

role in controlling infection, while in hyperactive state, cytokines will cause exaggerated lung inflammation and lung

parenchymal damage and resultant lung fibrosis and possible explanation for this is significantly raised inflammatory

marker titer in cases with lung fibrosis than without lung fibrosis [22-25, 30-32, 38-40, 48-50, 58-61,70-72].

Studies have reported that Follow-up inflammatory marker titer during hospitalization as compared to entry

point normal inflammatory marker titer has significant association in post-covid lung fibrosis [22-25, 30-32, 38-40, 48-

50, 58-61, 70-72]. Authors have documented progression of illness in few cases presented with nonsevere illness which

were picked up by follow up inflammatory marker titer, hence authors recommended follow-up titer has crucial role in

analyzing progression and preventing worsening in these cases. Importantly these cases have documented post covid lung

fibrosis than those with normal follow up titers [22-25, 30-32, 38-40, 48-50, 58-61, 70-72].

Inflammatory markers during follow-up in recovered COVID-19 cases presenting with Long COVID

manifestations:

Rheumatological syndrome is known to occur after COVID pneumonia and now data is available its association

with illness irrespective of diseases severity and hospitalization. Inflammatory markers patterns during initial COVID-19

pneumonia have direct correlation with rheumatological symptoms and can be suspected during hospitalization in indoor

patients by analysing titers of these markers during evolution of pneumonia [73-76]. Inflammatory markers analysis such

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

as IL-6, Ferritin, D-Dimer, CRP and LDH at discharge has helped in majority of cases. Higher the titer of these markers,

there will be more chances of long COVID in these cases. Inflammatory markers such as CRP, Uric acid and LDH are

‗best laboratory clues‘ during follow up to pick up rheumatological symptoms early [77-79]. Cases with history of

antigenic mimicry and antigenic cross reactivity such as positive dengue serology were laboratory clue during

hospitalization that these patients may develop rheumatological or autoimmune features in follow-up.

Although Rheumatological syndrome that occurs with COVID-19 pneumonia is showing reversible nature over

duration of time and few cases are showing persistent nature. All cases with rheumatological symptoms need prompt

workup due to Immunological nature of disease. All cases should undergo analysis of rheumatoid factor, anti CCP, ANA

and other tests to confirm exact type of disease-causing symptoms. Although ANA test is not confirmatory and specific

to rule out Rheumatological syndrome, its high titre signifies towards immune nature of disease. ANA blot panel is more

specific to label in exact nature of autoimmune disease. Steroids are cornerstone of treatment of Rheumatological

syndrome with or without lung involvement and shown excellent response to steroids with hydroxychloroquine.

Echocardiography is must in all cases to rule out cardiac dysfunction before initiation of treatment. Rheumatological

syndrome which is rare vaccine related adverse event, and importantly it is reversible and managed with routinely

available medicines and is having excellent prognosis. Vaccines has shown positive impact on controlling chances of

rheumatological symptoms and now data is available regarding protective role of vaccine in preventing rheumatological

symptoms [80-87].

Long covid is more prevalent chronic health care issue in post covid care settings. We are in great piece of relief

due to nearly end of this deadly pandemic which has caused significant change in routine of entire globe. Long covid is

an unpredicted sequel of COVID-19 disease documented nearly in half cases globally. Long covid is multisystem

syndrome with nonspecific symptoms and organic signs of unidentified pathology occurs after COVID-19 disease. Long

covid symptoms has been documented in ‗selected‘ cases irrespective of disease severity or hospitalization and possible

link remains unknown. Long covid symptoms has significant impact on quality of life in those cases suffered from

disease in recent past and lingering to almost two years since infection. Importantly, not all cases of COVID-19 were

shown long covid symptoms. Most common long covid symptoms as joint pain, fatigability, chest discomfort, shortness

of breath, hair loss, chest pain, weight gain, anxiety/depression & memory impairment. Pathophysiology resulting into

long covid manifestations is still not completely validated. Researchers have reported ‗immune dysregulation‘,

‗autoimmunity‘, ‗antigenic mimicry‘ & ‗coagulation abnormalities‘ are probable pathophysiological mechanism for long

covid. Some of the long covid effects shown complete reversibility including post covid lung fibrosis. Reboot system to

restore immune dysregulation and recovery in long covid is real concern. Long covid symptoms cases are more health

conscious and usually follows pattern of doctor shopping due to underestimation by family physicians either due to lack

of suspicion or lack of knowledge regarding treatment protocol. Still, we are not having right answer for exact duration

of long covid symptoms and when it will show complete reversibility. Further, it needs ‗birds eye vision‘ to pick up and

manage cases with long covid manifestations during routine care in rehabilitation unit [80-87].

COVID-19 pneumonia is heterogeneous disease with variable effect on lung parenchyma, airways and

vasculature leading to long term effects on lung functions. Spirometry is cost effective, non-invasive, easily available,

sensitive tool for assessment lung function in post covid care setting and it will help management of these cases by

assessing response to treatment. Pulmonary functions abnormality in post-COVID-19 pneumonia cases has been

documented and should be assessed cautiously to have successful treatment outcome. Restrictive lung disease is the

predominant lung function impairment in post-COVID 19 recovered lung pneumonia cases. Age above 50 years, male

gender, Diabetes mellitus, High CT severity, longer duration of illness, proper timing of initiation of BIPAP/NIV

therapy, has documented significant impact on post covid lung functions at 12 weeks assessment. All post covid cases

needs lung functions assessment by spirometry to predict course of underlying lung pathology and targeting interventions

accordingly [88, 89].

Inflammatory markers after COVID vaccination:

However, as vaccination programmes are being rolled out globally, many COVID-19 vaccine-related side-

effects have been recently reported [90, 91], ranging from mild local symptoms (e.g. pain at the injection site) to systemic

symptoms (e.g. fever and/or headache) [92]. Localized pain, fatigue, headache and muscle ache are the most prevalent

adverse effects in patients with autoimmune and inflammatory rheumatic diseases following six COVID-19 vaccines

[93]. Previous studies indicated that human papillomavirus, hepatitis B and influenza vaccines may trigger the onset or

exacerbations of autoimmune diseases by molecular mimicry inducing autoimmunity [94, 95]. Authors have reported

reversible autoimmune features which has reported for short period and reverted with medical management [96, 97].

Rheumatological syndrome is known to occur after COVID pneumonia and now data is available its association

with COVID Vaccination [98-100]. Although Rheumatological syndrome that occurs with COVID-19 pneumonia is not

totally reversible or many cases showing persistent nature, authors [94, 95] have documented reversible nature as its

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

association with COVID Vaccination in our case. Rheumatological syndrome which is rare vaccine related adverse event,

and importantly it is reversible and managed with routinely available medicines and is having excellent prognosis.

Minimal systemic adverse events known to occur with all viral vector vaccines, but its occurrence is rare and it should

not impact on routine vaccinations; as vaccination is key step in this pandemic to protect mankind.

Inflammatory markers as a ‘double edge sword’ if not considered with clinical and radiological markers as a

‘Composite Index’:

Since the beginning of COVID-19 outbreak, the capacity of hematological, biochemical, inflammatory, and

immunological factors to predict patients with severe or fatal forms of COVID-19 has been of great scientific

importance. To predict the severity of the disease in the early stages, it is critical to obtain a full profile of the laboratory

analysis. According to the published literature, hematological, inflammatory, and biochemical parameters are associated

with severe prognosis in COVID-19 cases and can thus be used as predictive factors [22-25, 30-32, 38-40, 48-50, 58-61].

Composite index: Clinical, radiological and laboratory markers joint assessment of COVID-19 cases with inclusion of

appropriate methods is called as composite index.

1. Clinical criteria are vital parameters assessment which includes oxygen saturation, heart rate, respiratory rate,

blood pressure, and sensorium. Oxygen saturation less than 93% at room air is highly significant and have

impact on overall outcome. Saturation at room air is predictor of hospitalization and outcome. Respiratory rate

and heart rate are good predictors of aggressive interventions in indoor units.

2. Laboratory assessment criteria includes inflammatory markers such as ferritin, CRP, LDH, IL-6, D-Dimer.

Surprisingly, these markers are having very unpredicted course in few cases and unable to predict course during

hospitalization. Authors have also documented that proportionate number of cases with duration of illness < 7

days and many cases with duration of illness >15 days were having normal inflammatory markers titer, while

pneumonia cases between 7-14 days of illness were having abnormal or raised CRP titer. Rational for this

observation is not known, may be inflammatory response pattern is different, and we have correlated

inflammatory markers pattern with other inflammatory markers like IL-6 and D-dimer and documented that

these two markers raised parallel to CRP [22-25, 30-32, 38-40, 48-50, 58-61].

3. Radiological assessment criteria include anatomical involvement of lung parenchyma by means of CT severity

score. Authors have documented CT severity as best visual marker of COVID-19 Pneumonia severity, which

can be correlated with inflammatory markers. Various authors have documented similar observation in their

study [101-103]. Best ‗visual marker‘ of severity of illness is CT thorax and authors have documented

inflammatory markers as stronger inflammatory marker associated with it [22-25, 30-32, 38-40, 48-50, 58-61].

Authors have documented usefulness of inflammatory markers and CT severity in Triaging the cases at entry

point and proper use of interventions in indoor setting according to ‗clinical, radiological and inflammatory

marker panel‘ in their institute [22-25, 30-32, 38-40, 48-50, 58-61].

Importance of composite index as ‘Point of care test’:

Limitations of individual makers has been documented (Clinical, radiological and laboratory markers) when

assessed independently. All these parameters of composite index should be assessed in parallel to avoid overestimation

or underestimation of severity and to analyse exact nature of COVID-19 pneumonia. Discordance with Clinical,

radiological and laboratory markers is possible, and more frequently reported during second and third wave of COVID-

19 pneumonia with delta and omicron variant and less frequently reported in Wuhan variant of corona virus.

In first wave with ‗Wuhan variant‘ caused corona virus related COVID-19 pandemic, many cases were having

concordance and synchronous abnormalities in Clinical, radiological and laboratory markers. Risk stratification, triaging

of cases, targeting interventions and overall planning of COVID-19 cases were quantified well due to proper correlation

of these markers of composite index. Rational is clear virus-related pathophysiological like immune activation,

inflammatory, thrombogenic and direct viral affection to lungs and extrapulmonary tissues presenting with pulmonary

and extrapulmonary manifestations. During first wave, a greater number of cases were having balanced pulmonary and

extrapulmonary manifestations. Cardio-vascular involvement were seen more often in first wave as compared to second

wave, rational for same was not known, may be ‗Wuhan variant virus has more thrombogenic activation syndrome‘ as

compared to Delta variant corona virus. In first wave pseudo-acute coronary syndrome, pulmonary thromboembolism

and stroke were documented in a greater number of cases as compared to second wave. Pulmonary and extrapulmonary

manifestation of pandemic virus were balanced and mortality was minimal with first wave of COVID-19 [77-90].

In second wave with ‗Delta‘ variant caused corona virus related COVID-19 pandemic, many cases were having

discordance and asynchronous abnormalities in Clinical, radiological and laboratory markers. Risk stratification, triaging

of cases, targeting interventions and overall planning of COVID-19 cases were observed difficult to quantify due to

improper correlation of these markers of composite index. In second wave many patients were in advanced stage till they

access treatment and required intensive care unit treatment including ventilatory support. Overall mortality is ‗no

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

significantly different‘ in first and second wave or slightly more in second wave, as we are dealing with Wuhan variant

virus in first wave and mutant Delta variant corona virus in second wave. Shortage of oxygen and shortage of ventilators

was big concern in second wave as compared to first wave in spite of increase in oxygen beds and increase in ventilator

beds across the country, this might be faced because of ‗exuberant case load‘ because of rapidly spreading nature of

Delta variant corona virus as compared to less mutant first wave Wuhan variant corona virus. Although health system has

prepared to tackle a greater number of covid cases till evolution of second wave, rapid resurgence of cases and rapidly

evolving ARDS were determining factor for relatively more mortality in second wave as compared to first wave.

Rational is similar i.e., virus-related pathophysiological like immune activation, inflammatory, thrombogenic and direct

viral affection to lungs and extrapulmonary tissues presenting with pulmonary and extrapulmonary manifestations.

Pulmonary and extrapulmonary manifestation of pandemic virus were balanced and mortality was minimal with first

wave of COVID-19. Rapidly evolving pneumonia or ‗accelerated acute respiratory distress syndrome‘ (a-ARDS) was

more commonly documented in second wave and more number of patients were presenting with similar syndrome in

second wave with time interval of less than a week, with rapidly deteriorating radiological and clinical-laboratory

parameters like increased CT severity score, worsened oxygenation, increased inflammatory markers like CRP, IL-6,

Ferritin, LDH, D-dimer, decreased leucocyte and platelet counts. Cytokine storm were documented very commonly with

first and second wave, but duration of manifestation of cytokine storm was delayed till second week in first wave as

compared to second wave in which cytokine storm presented too early i.e., documented in first 3 days to end of first

week of illness may be due to delayed presentation to hospital admission. Clinical assessment may either overestimate or

underestimate the exact severity of COVID-19 pneumonia in the absence of radiological and laboratory assessment

inflammatory parameters. Clinical scenario where overestimation is possible are the cases with minimal radiological

disease with raised inflammatory markers underestimation is possible with minimal disease with mild symptoms but high

titers of laboratory markers. Underestimation was more frequently reported due to minimal lung involvement and mild

symptoms on first few days of disease and these cases were rapidly evolved and developed advanced disease in short

time and these were picked up with composite index. and advanced disease with Predominant Pulmonary involvement

with minimal extrapulmonary involvement was ‗typical and most common‘ presentation of second wave due to delta

variant. Rational for these localised disease with minimal extrapulmonary disease is not known and requires further

research. Composite index has documented very crucial role in second wave of COVID-19 pandemic [77-90].

In third wave with ‗omicron variant‘ caused corona virus related COVID-19 pandemic, many cases were having

discordance and asynchronous abnormalities in Clinical, radiological and laboratory markers. Risk stratification, triaging

of cases, targeting interventions and overall planning of COVID-19 cases were observed difficult to quantify due to

improper correlation of these markers of composite index. Rational is similar which is documented in previous two wave

of COVID-19 i.e., virus-related pathophysiology‘s such as immune activation, inflammatory, thrombogenic and direct

viral affection to lungs and extrapulmonary tissues presenting with pulmonary and extrapulmonary manifestations.

During third wave, a greater number of cases were having extrapulmonary manifestations or involvement due to covid-19

as compared to pulmonary as compared to predominant pulmonary in second wave and balanced pulmonary-

extrapulmonary in first wave. Rational for these localised and systemic disease is not known and requires further global

research. Extrapulmonary manifestations such as Cardio-vascular and neurological involvement were seen more often in

third wave as compared to first and second wave, rational for same was not known, may be ‗omicron variant virus has

more thrombogenic activation syndrome along with inflammatory pathway activation‘ as compared to Wuhan and Delta

variant corona virus. As observed in first wave with Wuhan variant, in third wave with omicron variant associated

pseudo-acute coronary syndrome, pulmonary thromboembolism and stroke were documented in a greater number of

cases. Predominant extrapulmonary with minimal pulmonary manifestation is ‗typical and most common ‗in omicron

variant associated disease in third wave and mortality was minimal with first and second wave of COVID-19 [77-90].

Rational for same virus-related disease with heterogeneous presentation needs more global data and further research.

Importance of composite index as ‘point of care test’ during course of COVID-19 pneumonia in outdoor and

indoor settings:

Composite index has documented in assessment of COVID-19 cases during entry point setting in outdoor units

and guided further in triaging & decision making of these cases before hospitalization. Thus, composite index has guided

for treatment planning and decision to hospitalise were independently assessed by composite index rather than to depend

on only clinical, laboratory or radiological markers. Still, data is available that many cases were underestimated during

second wave due to ‗Delta variant‘ in presence of discordance in individual Clinical, radiological and laboratory markers

and observed crucial role of composite index. Thus, a greater number of cases were presented late due to individual

parameters assessment and received treatment in advanced stage. Thus, composite index is best assessment tool for

assessment of severity of COVID-19 pneumonia. Data is also available stating that many covid cases were overestimated

if analysed individual Clinical, radiological and laboratory markers which was observed in first and third wave due to

‗Wuhan and omicron‘ variant respectively. Composite index is sensitive and effective tool to assess COVID-19 cases at

entry point and to analyse exact status of illness which will have successful treatment outcome and thus considered as

‗point of care test‘ in this COVID-19 pandemic.

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

CONCLUSION

COVID-19 infection involves a complex interplay of the immunological and inflammatory responses.

Inflammatory parameters are closely linked to the COVID-19 severity and mortality. Inflammatory parameters could be

used to predict the transition from mild to severe/critical infection in patients of COVID-19. Low blood-oxygen levels

have been a hallmark in COVID-19 patients. The lung tissue damage infiltered by the viral-mediated inflammation

decreases oxygen saturation to cause silent hypoxia and cell death. Inflammatory markers could effectively discriminate

the risk of mortality in severe COVID-19 patients. As CRP, LDH, and ferritin levels determine the tissue oxygen

availability, they seem to be valuable biomarkers in the prognosis of COVID-19.

CRP should be considered as basic, bed side test, sensitive, cost-effective inflammatory marker which is widely

used and subsequent titer has documented crucial role in analysing inflammatory status. Ferritin is most sensitive marker

of inflammation in correlation with CRP and IL-6 and important marker of predictor of cytokine storm. LDH is best to

assess oxygenation status and follow-up titer will guide chances of post covid lung sequel and high titer during

hospitalisation helps in predicting ongoing severe necrotic lung disease. D-dimer has documented role in predicting

microvascular and microvascular complications of COVOID-19 and subsequent titers has documented role in predicting

post covid complications. IL-6 hs documented very specific role in predicting inflammatory surge and best predictor of

cytokine storm independently.

Composite index will play a crucial role in early suspicion, diagnosis, monitoring, and recognition of

complications, management and disposition of patients. Each of these components in turn can have crucial implications

on the healthcare system and the administrative machinery, directly impacting patient care. Needless to say, clinical

evaluation will be paramount at every step and Composite index will need to be meaningfully integrated into bedside

decision making. Composite index panels rather than single biomarkers may provide more reliable information which

will prevent overestimation and undervaluation to prevent detrimental outcomes. Availability and cost issues cannot be

ignored. It would be impossible for clinicians to consolidate and critically analyse the enormous data that is continuously

added to the COVID-19 literature to extract practically useful information for the benefit of patients. Composite index

should be considered as ‗point of care test‘ to honour successful treatment outcome and prevent mortality and morbidity

due to this ‗Dragon Pandemic‘.

Conflicts of Interest: Nil

Research Funding: Nil

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Jiangsu Province: a multicenter descriptive study. Clin Infect Dis. 2020;71(15):706-712.

58. Patil S, Gondhali G, Acharya A. Role of ferritin as ―Core Marker‖ in the assessment of severity, response to therapy

and predicting outcome in COVID-19 pneumonia: A large, two-center, prospective, observational study of 1000

cases in tertiary care setting in India. Indian J Respir Care 2022; 11:253-60.

59. Patil S, Toshniwal S, Acharya A, Narwade G. Role of ―Ferritin‖ in COVID-19 pneumonia: Sensitive marker of

inflammation, predictor of mechanical ventilation, and early marker of post COVID-lung fibrosis – A prospective,

observational, and interventional study in a tertiary care setting in India. Muller J Med Sci Res 2022; 13:28-34

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60. Patil, S., Gondhali, G. & Acharya, A. ―Serial ferritin titer‖ monitoring in COVID-19 pneumonia: valuable

inflammatory marker in assessment of severity and predicting early lung fibrosis — prospective, multicentric,

observational, and interventional study in tertiary care setting in India. Egypt J Intern Med 34, 75 (2022).

61. Patil S, Dhumal U, Acharya A. Correlation of ferritin with the duration of illness, disease severity, oxygenation

status, ventilatory requirement, and lung fibrosis in COVID-19 pneumonia: A single-center experience of 1000 cases

in tertiary care setting in India. Adesh Univ J Med Sci Res 2022; 4:86-93.

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different viral genotypic diseases? Prospective, observational study in tertiary care setting in India. Electron J Gen

Med. 2022;19(6): em400

68. Patil S, Khule S, Gondhali G. Dengue Fever with Corona Virus Disease 2019: Is it a "Double Trouble" with

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69. Patil S, Bhadake M, Gondhali G, Acharya A. Does Clinical-Laboratory Workup in COVID-19 Cases Misdiagnosed

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in India. American Journal of Respiratory and Critical Care Medicine; 203(9), 2021.

72. Shital Vishnu Patil, Rajesh Patil, Gajanan Gondhali. Effect of hyperglycemia on post-Covid-19 lung fibrosis: Study

of 600 cases in tertiary care setting in India. European Respiratory Journal 2021 58: PA3777

73. Baimukhamedov, C. (2023), How long is long COVID. Int J Rheum Dis, 26: 190-192.

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arthritis or virally mediated arthritis?. Infection (2022). https://doi.org/10.1007/s15010-022-01936-2

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syndrome. Scientific and practical rheumatology . 2022;60(3):276-279.

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Lancet Rheumatology Volume 3, Issue 5, E324-E325. DOI:10.1016/S2665-9913(21)00067-9

77. Patil S, Patil R, Gondhali G. Long Covid in Post-Covid-19 Care Setting: Prospective, Observational, and

Interventional Study Of 6,000 Cases in Tertiary Care Setting in India. Chest. 2022 Jun;161(6): A538.

78. S V Patil, G Narwade, G Gondhali, R Patil, A Acharya, U Dhumal ‗Long covid‘ is more common, underestimated,

and ‗core‘ health issue in post covid care setting: study of 6000 cases in tertiary care setting in India. European

Respiratory Journal 2022 60: 576

79. S V Patil, S Patil, S Toshniwal, G Gondhali, R Patil, A Acharya, D Patil. ―Clinical and immunological phenotypes‖

in ‗Long COVID‘: The tsunami of multisystem syndrome of this decade! ERJ Open Research 2023 9: 1; DOI:

10.1183/23120541.LSC-2023.1

80. SV Patil, Neel Tandel, Gajanan Gondhali. Long COVID: An unpredicted multisystem syndrome of COVID-19

disease. World Journal of Advanced Pharmaceutical and Life Sciences, 2023, 04(01), 005–012

81. S Patil, Neel Tandel, Sham Toshniwal, Gajanan Gondhali. Rheumatological symptoms after COVID-19 pneumonia

presenting as long COVID: What we need to know? World Journal of Advanced Pharmaceutical and Life Sciences,

2023, 04(01), 013–022.

82. Shital Patil, Neel Tandel, Omprakash Bhangdia, Gajanan Gondhali (2023). Nintedanib as an Antifibrotic in Post

Covid Lung Fibrosis: Are we Really Overestimating? SAR J Med, 4(2), 16-26.

83. Shital Patil, Vipul Raka, Sanika Narkar, Jayashree Dahiphale, Shubham Choudhari, Gajanan Gondhali. Post COVID

lung fibrosis (PCLF) or post COVID lung sequelae (PCLS): Which one is the right choice? World Journal of

Advanced Pharmaceutical and Life Sciences, 2023, 04(01), 023–033.

84. Shital Patil, Jayashree Dahiphale, Shubham Choudhari, Sanika Narkar, Vipul Raka, Gajanan Gondhali. Long

COVID symptoms: Basic aspects of cardio-pulmonary and neurological pathways! World Journal of Advanced

Pharmaceutical and Life Sciences, 2023, 04(01), 034–047.

85. Shital Patil, Neel Tandel, Omprakash Bhangdia. Post covid lung fibrosis (PCLF) or post covid lung sequelae (PCLS)

in treated case of severe COVID-19 Pneumonia case in Intensive care unit with ventilatory support and home

Shital Patil & Gajanan Gondhali; South Asian Res J Med Sci; Vol-5, Iss-3 (May-Jun, 2023): 63-77

oxygen therapy for twelve weeks. World Journal of Advanced Pharmaceutical and Medical Research, 2023, 04(01),

030–041.

86. Shital Patil, Shubham Choudhari, Vipul Raka, Sanika Narkar, Jayashri Dahiphale, Gajanan Gondhali. Neurological

and systemic manifestations in Long covid: Underestimated sequel of covid‘s pandora! World Journal of Advanced

Pharmaceutical and Medical Research, 2023, 04(01), 042–052.

87. Shital Patil, Sanika Narkar, Jayashree Dahiphale, Vipul Raka, Shubham Choudhari, Gajanan Gondhali. Long

COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning! World Journal of Advanced

Pharmaceutical and Medical Research, 2023, 04(01), 053–065.

88. Patil S, Patil R, Gondhali G. Pulmonary functions assessment in post-COVID-19 pneumonia cases by spirometry:

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2021;70:1053–8

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diseases: a cross-sectional study. Rheumatol Int. 2021;41:2105–8

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disease with rheumatological feature and pulmonary infiltrates. J Adv Lung Health 2022; 2:105-11

97. Patil, S., Narwade, G., & Acharya, A. (2022). Reversible rheumatological syndrome with acute febrile respiratory

illness secondary to COVID vaccination. J Assoc Pulmonologist, 5, 25-30.

98. Baimukhamedov, C. (2021), Arthritis of the left elbow joint after vaccination against SARS-CoV-2 infection. Int J

Rheum Dis, 24, 1218-1220. https://doi.org/10.1111/1756-185X.14202

99. Baimukhamedov, C., Makhmudov, S., & Botabekova, A. (2021), Seropositive rheumatoid arthritis after vaccination

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101. Patil, S., Gondhali, G., & Patil, R. (2022). Radiological Phenotypes' in Covid-19 Pneumonia: Retrospective,

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L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!

Article

Full-text available

Aug 2023

COVID-19 pandemic is over now and we are in great peace of relief after three years. This pandemic has observed significant impact on quality of life globally and the put unforgettable imprints on history of mankind. Reason for more havoc in this pandemic was less studied virus by medical scientists regarding its pathophysiology, available treatment options and lack of effective vaccine to tackle this dragon. COVID-19 is the first observed and reported pandemic of corona virus related global disease apart from its previous SARS and MERS. Fast track developments in medical treatment options due to this ultrafast digital and artificial intelligence techniques have curtailed mortality on large scale globally. Although mortality is significantly reduced, morbidity is documented on a large scale worldwide in this pandemic. Morbidity due to COVID-19 now called as ‘Long COVID’, which is underreported & half-heartedly evaluated globally. Long COVID is related to persistent immune dysregulation occurs during evolution of COVID-19 as natural trend of disease. Immune dysregulation has documented during course of active viremia, during recovery of viral illness and after post viral phase. Immune dysregulation occurs in ‘selected group’ of cases irrespective of disease severity and vaccination status and observed in cases with negligible illness to advanced one mandates further research. Thus, Immune dysregulation in COVID-19 is predominant cause for long covid and leading to brainstorming effect on medical scientists and researchers as of today. Globally, one third of recovered or affected cases of COVID-19 are facing long covid and needs prompt treatment options to tackle this dragon related long term effect on body. ‘Immunomodulatory’ or immunity modifying agents are the primary targets to curtail immune dysregulation and long covid. Some experts recommend ‘disease modifying agents’ to treat long covid cases. Still, many miles to go to reach to effective treatment options for long covid and we don’t have effective options for this ‘health issue of global concern’. L-Arginine is amino acid with multiple beneficial effects such as immunomodulatory effects which will regulates immunological response in inhibit dysregulated immune system additional to its universally known antioxidant, vasodilatory and regenerative and cellular proliferation effects on immune cells. These Immunomodulatory and or diseases modifying effects of L-Arginine makes it the future candidate with ‘game changer’ role for management of Long covid resulting from immune dysregulation as a core pathophysiologic pathway of this Dragon Pandemic.

Residual lung abnormalities in recovered COVID-19 cases at 1-year follow-up: A single-center final radiological outcome phenotype study in India

Article

Full-text available

May 2024

Abstract INTRODUCTION: The radiological phenotype represents the radiological characteristics of coronavirus disease 2019 (COVID-19) pneumonia. Radiological outcomes initially interpreted as post-COVID-19 lung fibrosis have been detected in short-term follow-up of recovered COVID-19 cases, but long-term radiological evaluation suggests that these abnormalities should be defined as post-COVID-19 sequelae. The present study aimed to evaluate the radiological phenotypes of post-COVID-19 residual radiological lung abnormalities (RLAs) in recovered COVID-19 cases. METHODS: This prospective, observational study included 3000 patients with polymerase chain reaction-confirmed COVID-19, with documented lung involvement and radiological severity categorized as mild, moderate, or severe by high-resolution computed tomography (HRCT) at admission. Final radiological outcomes were based on radiological assessments at 6 months and 1 year after hospital discharge. Final radiological phenotypes were defined as RLAs and categorized as resolving, persistent, or progressive, based on HRCT imaging at 1 year of follow-up. A total of 622 cases with RLAs were finally included. The final outcome phenotypes were evaluated in relation to age, sex, comorbidities, laboratory parameters, and interventions, including oxygen and ventilator-support requirements during hospitalization. The data were analyzed using Chi-square tests. RESULTS: RLAs were documented in 622 of the 3000 COVID-19 pneumonia cases (20.73%). The final radiological outcomes were defined as resolving in 77.17% (480/622), persistent in 15.43% (96/622), and progressive in 7.39% (46/622). Radiological outcome phenotypes and RLAs were significantly associated with the duration of illness at admission (P < 0.00001), laboratory parameters (D-dimer, C-reactive protein, and interleukin-6) at admission (P < 0.00001), radiological severity on computed tomography (P < 0.00001), and inpatient interventions (P < 0.00001). Radiological outcome phenotypes and RLAs were also significantly associated with age, sex, diabetes mellitus, ischemic heart disease, hypertension, chronic obstructive pulmonary disease, obesity, and lung functions assessed by spirometry at 1-year follow-up (P < 0.00001). CONCLUSIONS: Radiological outcome phenotypes have a crucial role in assigning final radiological outcomes in patients with COVID-19 pneumonia and differentiating between post-COVID-19 lung fibrosis and post-COVID-19 lung sequelae. RLAs, categorized as resolving, persistent, and progressive, provide a novel radiological classification of post-COVID-19 lung sequelae. Final phenotypic classification may play an important role in further workups and treatment planning for RLAs; some patients with progressive phenotypes may have underlying rheumatological predispositions and many cases may have resolving phenotypes requiring no further treatment, whereas cases with persistent RLAs require further follow-up.

Pidotimod as an Immunomodulator: An Unsung Warrior to Restore Immune Dysregulation in Acute and Chronic Lung Disease

Article

Full-text available

Feb 2024

Immune dysregulation has been observed in the majority of the infective and non-infectious respiratory illnesses with impact on the natural course of illness in pediatric to geriatric age groups. Immune regulation between Th1 and Th2 is altered and reversal of proportion between these two differential cells and ultimately homeostasis, with predominance Th2 cells will increase susceptibility for recurrent illnesses; is typically documented in pediatric age groups with first respiratory infection during early neonatal period with respiratory viral etiologies. Apart from recurrent childhood infections, pediatric cases with immune dysregulation will have recurrent wheezing in childhood and are prone for development of childhood asthma in adolescent age groups; if immune dysregulation does not restore in time. In adults, respiratory illnesses due acute viral infective etiology will cause immune dysregulation as documented after coronavirus, influenza and respiratory syncytial virus infections. Immune dysregulation has also been documented in chronic respiratory illnesses such bronchial asthma, chronic bronchitis and COPD. Immune dysregulation will cause recurrent exacerbations in these inflammatory conditions. Pidotimod is an immunomodulator which will work as an immunostimulant molecule due to its unique pharmacological actions on antigen presenting cells, and have novel action on immune cell proliferation and differentiation. In spite of three decades of research of this novel drug Pidotimod, still; it is less used as of today for respiratory ailments in spite of need of a molecule with an immunomodulatory effect for prevention and or cure of illnesses; and modification of natural course of recurrent or relapsing course of chronic illnesses. COVID-19 pandemic has taught us many pathways of immune dysregulation which evolved during natural course of disease and now documented with respiratory viral illnesses such as RSV; and its long-term impact as long covid presenting due to immune dysregulation occurred as a natural course in recovered cases. It's unclear whether long covid is reversible as of now, but the majority of symptoms have been resolved and shown response to versatile molecules such as steroid, multivitamins, L-arginine, Paxlovid, beta blockers with variable results and long-term outcomes. Pidotimod can be used in acute COVID-19 illness without pneumonia and comorbidities in stable cases in outdoor settings, and also; considered as potential option in long covid cases with recurrent respiratory infections. In this review we have discussed basic aspects of Pidotimod, and its role in immunomodulatory effects in acute and chronic respiratory illness which have shown positive outcomes.

Covid-19 Pneumonia Presenting as a ‘Typical Radiological Bronchopneumonia’ Pattern in Clinical-Radiological-Pathological Phenotype with Transient Hyperglycemia

Article

Full-text available

Jan 2024

Radiological phenotypes are radiological patterns or observable characteristics of COVID19 pneumonia. Various phenotypic classifications have been reported in literature. CT severity radiological phenotypes are widely used and universally accepted radiological phenotypic methods. Radiological CT severity phenotypic differentiation has documented very crucial role in initial assessment and during triaging of these cases in indoor and outdoor setting. Typical COVID-19 lung parenchymal involvement described as predominant ground glass opacities (GGOs) and consolidations in peripheral and subpleural portion of any lobe, predominantly involving lower lobes. Atypical Radiological patterns in COVID-19 has been documented as bronchopneumonia, multifocal consolidations, necrotizing pneumonia, cavitations with GGOs with or without consolidations. In present case report, 43-year male, presented with acute febrile respiratory illness with acute hypoxic respiratory failure documented as oxygen saturation of 80% at room air with tachypnea and respiratory distress. HRCT thorax was showing Pleural based, peripheral, central, multifocal patchy, confluent & ill-defined GGOs and consolidations in bilateral lung fields in upper, middle and lower lobes. These typical radiological features suggestive of bronchopneumonia like radiological pattern which was very unusual for typical COVID-19 radiology. His laboratory parameters have shown abnormally raised inflammatory markers like CRP, Ferritin, LDH, D-Dimer and IL-6. Importantly, his random blood sugars were raised with abnormally raised HbA1c levels to label as diabetes mellitus. He was diagnosed with diabetes mellitus this time with COVID-19 illness without use of steroids. He was treated with standardized COVID-19 management institutional protocol with combination of low molecular weight heparin, methylprednisolone, remdesivir, meropenem and teicoplanin. Patient required BIPAP support with higher oxygen requirement with nasals canula for one week due to advanced radiological disease with more anatomical involvement. We have documented successful treatment outcome with use of rational treatment in timely by predicting disease severity with use of composite analysis of clinical, laboratory and radiological markers of illness. Transient hyperglycemia is known to occur and reported after COVID-19 illness due to virus induced inflammatory response and pancreatopathy with beta cell dysfunction. Transient hyperglycemia can be easily managed with insulin during hospitalization and oral anti-diabetic agents after discharge for few weeks. Dietary and lifestyle modification will help in majority with complete reversal of abnormally high sugar levels with restoration of normal HbA1c levels to non-diabetic range.

Unilateral Lung Parenchymal Infiltrates with GGO & Evolving Consolidation as Presenting Feature of Sporadic COVID-19 Pneumonia in Post Pandemic Era in a Patient with Acute Febrile Respiratory Illness

Article

Full-text available

Jan 2024

Sporadic COVID-19 cases will be predicted to occur in coming few years ahead as observed in previously known influenza virus related pandemics. Herd immunity due to natural infection and hybrid immunity after COVID-19 vaccination has played crucial role in waning of this pandemic. COVID-19 pneumonia has a very 'typical' radiological presentations, observed globally; classified as GGO and consolidations involving peripheral parts of lung, bilateral disease, predominantly pleural based areas initially and involves central portions as disease process advances. Such radiological presentations are never documented in history before this pandemic, which has helped in suspecting COVID-19 illness in cases with negative microbiological results initially and such illness were classified as SARI (severe acute respiratory illness). Cases with typical radiological features for COVID-19 with RT PCR positive results were defined as case of COVID-19 illness. Both the clinical scenarios were managed with similar protocol during hospitalization. COVID-19 case burden has significantly decreased in last one year since declaration of end of pandemic by WHO and now we are in post pandemic phase. Since beginnings of pandemic, many corona virus variants were emerged with variable infectivity, virulence, pathogenesis, mortality and morbidity. As pandemic is over, cases are rarely observed with lung involvement, COVID RT PCR testing, HRCT reporting's in line with pandemic protocol and requirement of resources to treat these cases are less required and utilized today. In present case report, 32-year male, presented in outdoor unit with history of acute febrile respiratory illness with dry cough, high grade fever and chest tightness and chest discomfort of acute onset. HRCT thorax documented Pleural based, peripheral, unifocal or solitary opacity with predominant GGOs in right lower lobe with normal left lung. He is treated in indoor unit in line with community acquired pneumonia protocol and observed clinical worsening with four-fold raised in inflammatory markers. Oxygenation is worsened and raised IL-6, CRP and LDH has given clue to think towards COVID-19 etiology. Thorat swab for COVID-19 RT PCR is positive and managed according to protocol for COVID-19 illness. This is the only observed COVID-19 pneumonia case in last six months, in which; clinical-radiological patters were typical of pandemic illness of second wave of COVID-19 illness due to delta variant. Our case is the sporadic case reported with all clinical features of pandemic illness. We have suspected COVID-19 etiology in spite of 'atypical unilateral lung involvement' due to worsened clinical features and abnormally raised inflammatory markers with poor response to standard treatment protocol for community acquired pneumonia. High index of suspicion is must, and; timely interventions with use of rational treatment including remdesivir, heparin & steroids combination during hospitalization has documented successful outcome. We recommend COVID-19 RT PCR testing in all community acquired cases nonresponding to standard guidelines to have timely diagnosis and treatment. Sporadic cases rare to occur, and they do occur for few years ahead of this end of pandemic due to virus variant, and we must quote 'rare things are not rare to happen'.

Persistent Residual Lung Abnormalities (PRLAs) as Post COVID Lung Sequel in Recovered Severe Pneumonia Case with Lung Function Abnormality at Two Year Follow Up

Article

Full-text available

Jun 2024

Shital Patil

Coronavirus related (SARS-CoV-2) global pandemic has caused significant mortality and morbidity globally in the last three years. Although, pandemic has waned since last year, we are not in great peace of relief due to lingering effects of COVID-19 persisted even after two years of illness. Radiological phenotypes are radiological patterns or observable characteristics of COVID-19 pneumonia. Radiological outcomes are initially interpreted as post covid lung fibrosis in short term follow-up of recovered COVID-19 cases in post covid care settings and during long term evaluation these abnormalities are defined as post covid sequalae’s. In present case report, 38-year male, presented in outdoor unit for shortness of breath on exertion with history of severe COVID-19 Pneumonia resulted into acute respiratory distress syndrome with hospitalization in intensive care unit one year back and required high flow nasal cannula (HFNC) with Noninvasive ventilatory support (NIV) for two weeks. He was offered oxygen supplementation at home with antibiotics for three months and no requirement of oxygen and some respiratory symptoms even after one year. His HRCT thorax documented at one year of discharge from hospital revealed typical interstitial opacities labelled as Persistent Residual lung abnormalities (RLAs) which are predominantly reticular and linear opacities in peripheral parts of lungs without honeycombing within typical pleural based areas with parenchymal bands and minimally altered lung architecture and preserved lung volume

Infodemic-A new rapidly evolving virtual communicable pandemic with global threat! Hypothetical or real?

Article

Full-text available

Apr 2023

‘Infodemic’ is a pandemic of misinformation spread in a pandemic manner regarding health issues of global concern. Globally, Infodemic is rapidly rising and more adverse outcomes are observed in social, economic and family lives. Infodemic is reported first time during SARS in 2003 & now during evolution of COVID-19 pandemic in 2020. Infodemic is more rapidly spreading pandemic than any communicable disease due to its ultrafast method of transmission by means of electronic & social media in the form of print or digital platform. Here, in Infodemic, the culprit is ‘misinformation’ spread without any scientific evidence regarding health issues of global concern. During COVID-19 pandemic infodemic evolved parallel with actual natural viral disaster and documented comparable effects on mankind globally. Infodemic is considered a global issue of concern for this decade. Infodemic in COVID-19 pandemic was documented as source of agent to cause & its evolution globally, available treatment options such as Remdesivir and its safety with efficacy& lastly, COVID-19 vaccines and its role in preventing and protecting COVID-19 disease with adverse events. Infodemic needs more stringent steps to control before its evolution, which includes active involvement of health experts, medical scientists, government agencies and trust organizations working worldwide. Timely shared right and scientifically evidenced proof information is a key step in controlling misinformation and ‘infodemic’.

Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning!

Article

Full-text available

Mar 2023

Long COVID is an unpredicted sequel of COVID-19 disease documented nearly in half cases globally. Long COVID is multisystem syndrome with nonspecific symptoms and organic signs of unidentified pathology occurs after COVID-19 disease. Long COVID symptoms has been documented in some cases irrespective of disease severity or hospitalization. Long COVID symptoms has significant impact on quality of life in those cases suffered from disease in recent past and lingering to almost two years since infection. Importantly, not all cases of COVID-19 were shown long COVID symptoms. Most common long COVID symptoms (ten in number) as joint pain, fatigability, chest discomfort, shortness of breath, hair loss, chest pain, weight gain, anxiety/depression & memory impairment. Pathophysiology resulting into long COVID manifestations is still not completely validated. Researchers have reported 'immune dysregulation' and 'coagulation abnormalities' are probable pathophysiological mechanism for long COVID. Some of the long COVID effects shown complete reversibility including post COVID lung fibrosis. Reboot system to restore immune dysregulation and recovery in long COVID is real concern. Long COVID symptoms cases are more health conscious and usually follows pattern of doctor shopping due to underestimation by family physicians either due to lack of suspicion or lack of knowledge regarding treatment protocol.

Post COVID lung fibrosis (PCLF) or post COVID lung sequelae (PCLS): Which one is the right choice?

Article

Full-text available

Mar 2023

Lung is the primary target organ in COVID-19 disease with diverse clinical and radiological presentations and outcome. It has caused minimal to moderate lung disease in some patients and in some cases caused deadly acute respiratory distress syndrome (ARDS). COVID-19 disease caused lung damage by direct virus induced alveolar damage, cytokine induced alveolar and vascular damage and microvascular thrombosis resulting into acute hypoxic respiratory failure. COVID-19 pneumonia evolved over period of three weeks in cases with ARDS as natural course of illness. Usually, ARDS resolves by fibrosis or resolution as final outcome. Similarly, in COVID-19 recovered cases of advanced disease or those suffering from ARDS are having post COVID lung disease. Lung fibrosis is final radiological outcome of COVID-19 pneumonia documented in proportionately majority of cases. Post COVID lung fibrosis is considered as worrisome radiological complication observed during early phase of pandemic. Time trends of final radiological outcome has evolved over months with or without treatment with antifibrotics and steroids. Importantly, Post COVID lung fibrosis resolved more than fifty percent cases in six months and nearly in all cases after one year. Post COVID lung fibrosis is considered as ‘health issue of great concern’ initially in post pandemic phase of first wave, and due to its resolving nature over time period; now considered as ‘sigh with relief’ due to its reversible pathophysiology. Post COVID sequel is minimal residual effects of COVID-19 lung disease irrespective of disease severity in past. We recommend to use term post COVID sequel over post COVID lung fibrosis.

Role of Initial and Follow-up LDH Titer in COVID-19 Pneumonia: A Single Center Experience of 2000 Cases in Tertiary Care Setting in India

Article

Full-text available

Mar 2023

Introduction: Robust data of LDH (Lactate dehydrogenase) is available in bacterial infection, and it can be utilized in this COVID-19 Pneumonia pandemic for initial assessment, planning of treatment in indoor setting in association with HRCT severity. Methods: Prospective, observational, 12 weeks follow up study, included 2000 COVID-19cases confirmed with RT PCR. All cases were assessed with lung involvement documented and categorized on HRCT thorax, oxygen saturation, LDH at entry point and follow up. Age, gender, comorbidity and BIPAP/NIV use and outcome as with or without lung fibrosis as per CT severity. Statistical analysis is done by Chi square test. Results: HRCT severity score at entry point has significant correlation with LDH titer [p<0.00001] LDH titer has significant association with duration of illness (Doi) [p<0.00001] Comorbidities has significant association with LDH titer. [p<0.00001] LDH titer has significant association with oxygen saturation [p<0.00001] BIPAP/NIV requirement during hospitalization has significant association with LDH titer. [p<0.00001] Timing of BIPAP/NIV requirement has significant association with LDH titer. [p<0.00001] Follow-up LDH titer during hospitalization as compared to entry point (initial) normal and abnormal LDH has significant association in post-covid lung fibrosis [p<0.00001] Conclusion: LDH is easily available, and universally acceptable inflammatory marker in COVID-19 pandemic and documented very crucial role in covid-19 pneumonia in predicting severity of illness, assessing response to treatment and analyzing outcome during hospitalization. J MEDICINE 2023; 24: 10-17

Neurological and systemic manifestations in Long covid: Underestimated sequel of covid's pandora!

Article

Full-text available

Mar 2023

COVID-19 pandemic is phase of decline worldwide and in short time declared as pandemic is over. Globally, more than half cases are now facing either one vague or nonspecific and or organic symptoms in post covid phase. Long covid symptoms has significant impact on quality of life in those cases suffered from disease in recent past and lingering to almost two years since infection. Importantly, not all cases of COVID-19 were shown long covid symptoms. Most common long covid symptoms as joint pain, fatigability, chest discomfort, shortness of breath, hair loss, chest pain, weight gain, anxiety/depression & memory impairment. Neurological, gastrointestinal, renal, endocrine & rheumatological systems were badly affected in long covid. Brain fog, renal dysfunction, and diabetes mellitus were frequently documented as systemic manifestations of long covid. Pathophysiology resulting into long covid manifestations is still not completely validated. Researchers have reported 'immune dysregulation', 'autoimmunity', 'antigenic mimicry' & 'coagulation abnormalities' are probable pathophysiological mechanism for long covid. Some of the long covid effects shown complete reversibility including post covid lung fibrosis. Reboot system to restore immune dysregulation and recovery in long covid is real concern. Protocolised approach is required for timely workup of cases with long covid symptoms. Effect of vaccination in preventing long covid is not known and impact of evolution of new strains COVID-19 in future on ongoing long covid is real concern.

Nintedanib as an Antifibrotic in Post Covid Lung Fibrosis: Are we Really Overestimating?

Article

Full-text available

Mar 2023

Antifibrotics were exuberantly used to treat post covid lung complications.

Rheumatological symptoms after COVID-19 pneumonia presenting as long COVID: What we need to know?

Article

Full-text available

Mar 2023

COVID-19 pandemic is in verge of over and evolved over last three years in different waves across the globe with various genetic mutants or strains. As of now, many COVID-19 recovered patients are lingering with residual symptoms of illness irrespective of disease severity called as long COVID. Nonspecific or vague and organic or topographical organ specific symptoms are very well described in literature in COVID-19 survived cases. Rheumatological symptoms are most documented in published data as sequel after COVID-19 illness. Clinical presentations of rheumatological symptoms are joint or musculoskeletal pain, chronic fatigue with minimal exertion and weakness or impaired quality of life. Pathophysiology involving in rheumatological manifestations would be persistent or dysregulated inflammatory response, immune activation or thrombogenic pathway abnormality after acute COVID-19 illness. Diagnosis is little difficult and needs prompt workup to rule out underlying rheumatological illness. Inflammatory markers and autoantibody analysis has documented role in work up and confirming the diagnosis in majority of cases. Management of these cases is still evolving and showed response to lifestyle modification, physiotherapy, and short course of steroids and multivitamins in various published studies.

Post covid lung fibrosis (PCLF) or post covid lung sequelae (PCLS) in treated case of severe COVID-19 Pneumonia case in Intensive care unit with ventilatory support and home oxygen therapy for twelve weeks

Article

Full-text available

Mar 2023

Lung fibrosis is final radiological outcome of COVID-19 pneumonia documented in proportionately majority of cases. Post COVID lung fibrosis is considered as worrisome radiological complication observed during early phase of pandemic. Time trends of final radiological outcome has evolved over months with or without treatment with antifibrotics and steroids. Importantly, Post covid lung fibrosis resolved more than fifty percent cases in six months and nearly in all cases after one year. In this case report we have documented PCLF in 32-year male hospitalized for severe COVID-19 illness with acute hypoxic respiratory failure secondary to ARDS (acute respiratory distress syndrome). He required high flow nasal canula oxygen supplementation with noninvasive ventilatory support for three weeks. He responded to medical treatment such as injection remdesivir, methylprednisolone and low molecular weight heparin injection. He was discharged to home with advice for home oxygen therapy and medicines such as steroids and antifibrotics Nintedanib. He required oxygen for twelve weeks. His chest imaging done at one year shown residual post covid sequel without any cardiopulmonary and exercise performance impact.

Role of CRP in COVID-19 pneumonia: A single-center experience of 1000 cases in a tertiary care setting in India

Article

Full-text available

Mar 2023

Introduction Robust data are available for C-reactive protein (CRP) in bacterial infection, and it can be used in this coronavirus disease 2019 (COVID-19) pneumonia pandemic for initial assessment before planning of treatment in indoor settings in comparison with other inflammatory markers and computed tomography (CT) severity. Materials and methods A prospective, observational, follow up study was conducted that included 1000 COVID 19 cases confirmed with RT PCR. All cases were assessed with lung involvement documented and categorized based on high resolution computed tomography (HRCT) thorax, oxygen saturation, and inflammatory markers such as CRP at the entry point and follow up. Age, sex, comorbidities, use of BIPAP/NIV (Bi-level positive airway pressure/Non-invasive ventilation), and outcomes such as with or without lung fibrosis as per HRCT severity were key observations. Statistical analysis was done using χ2 test. Results Age (50 years) and sex (male versus female) had a significant association with CRP in predicting severity (P < 0.00001 and P < 0.010, respectively). CT severity score at the entry point with CRP level had a significant correlation (P < 0.00001). CRP level had a significant association with duration of illness (P < 0.00001). Comorbidities had a significant association with CRP level (P < 0.00001). CRP level had a significant association with oxygen saturation (P < 0.00001). BIPAP/NIV requirement during hospitalization had a significant association with CRP level (P < 0.00001). Timing of BIPAP/NIV requirement had a significant association with CRP level. (P < 0.00001). Follow-up CRP titer during hospitalization as compared with the entry point normal and abnormal CRP levels showed a significant association in post-COVID lung fibrosis (P < 0.00001). Conclusion CRP is an easily available and universally acceptable inflammatory marker and documented to play a very crucial role in predicting timings of interventions and post-COVID lung fibrosis.

Iron Storage in Women is Positively Correlated with Aging and BMI Values

Article

Apr 2016

Iron deficiency occurs commonly in vulnerable groups of women at reproductive age. But many studies have shown that the situation of iron overload in the elderly becomes an increasingly serious issue. In the present study, we aimed to investigate the association of serum ferritin levels with age and body mass index (BMI) and the iron status in middle‐aged women. This cross‐sectional study was carried out on 4625 healthy women in Qingdao who were at the age of 40–70 and had informed consent to participate in the study. Serum ferritin concentrations of all participants were measured by an automated radioimmunoassay analyzer. For female adults, normal serum ferritin is defined by the World Health Organization as 15~150 μg/L, and anemia as <15 μg/L, iron overload as ≥150 μg/L. Among all the participants, 76.25% had a normal iron storage, 19.10% had iron deficiency, and 4.65% had iron overload. The median of serum ferritin concentration in 65–70 years old was nearly two‐fold higher than that in 45–50 yeas old. And in obese people, the median of serum ferritin concentration was significantly higher than that in lean people. Furthermore, serum ferritin was positively correlated with age and BMI, with the correlation coefficient values at 0.376 and 0.156 (both p<0.05), respectively. In conclusion, our results suggest an increasing prevalence of iron overload with age and BMI. Support or Funding Information Supported by the National Natural Science fund (No. 81373000)

Inflammatory Markers or ‘Composite Index’ in COVID-19 as ‘Point Of Care Test’: Which One is the Best Choice to Tackle Dragon!

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