Differential Diagnosis of COVID-19

Amjad Islam Aqib^{1, *}, Iqra Muzammil², Qaisar Tanveer³, Sana Muzammal⁴, Amna Ahmad⁵, Firasat Hussain⁶, Kashif Rahim⁶

¹ Department of Medicine, Faculty of Veterinary Science, Cholistan University of Veterinary and Animal Sciences, Bahawalpur-63100, Pakistan

² Department of Clinical Medicine and Surgery, University of Agriculture, Faisalabad-38000, Pakistan

³ Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad- 38000, Pakistan

⁴ Department of Mathematics, National College of Business Administration and Economics, Sub-Campus Bahawalpur, Pakistan

⁵ Faculty of Veterinary Science, University of Agriculture, Faisalabad-38000, Pakistan

⁶ Department of Microbiology, Faculty of Veterinary Science, Cholistan University of Veterinary and Animal Sciences, Bahawalpur-63100, Pakistan

Abstract

Differential diagnosis is a key step to treat and prevent any disease at current. Differential identification becomes more inevitable in diseases that become pandemic while their signs and symptoms overlap with many diseases. Coronavirus disease-19 shows resemblance in its pneumonic presentation with related coronaviruses (SARS virus, and MERS virus), adenovirus, influenza virus, human Metapneumovirus, parainfluenza, Respiratory Syncytial Virus, rhinovirus, bacterial pneumonia (Streptococcus pneumonia, Haemophilus influenza pneumonia, Moraxella catarrhalis pneumonia, and Chlamydia pneumonia), and Mycoplasma pneumonia. Contrary to the discussion of only diagnostic findings, a comprehensive approach of differences in aetiologies, transmission/epidemiology, pathogeneses, clinical signs, and response therapy is necessary to resolve pandemic corona infection. Additionally, mathematical predictive models calculate the reproductive number (R₀) to show the epidemic nature of the disease in comparison to other conditions, thus aids therapeutic and prevention measures. The current chapter differentiates minor and major differences of COVID-19 compared to viral and bacterial diseases that show similar signs and symptoms.

Keywords: Aetiologies, Clinical signs, Coronavirus disease-19, Diagnosis, Differential, Pathogenesis, Response therapy, Transmission/epidemiology.

^* Corresponding author Dr. Amjad Islam Aqib: Department of Medicine, Faculty of Veterinary Science, Cholistan University of Veterinary and Animal Sciences, Bahawalpur-63100, Pakistan. Tel.: +92 343 7474 583; E-mail: amjadwaseer@cuvas.edu.pk

INTRODUCTION

Common human coronaviruses are Alphacoronaviruses (HCoV-229E, and HCoV-NL63) and Betacoronaviruses (HCoV-OC43, and HCoV-HKU1). They are a source of the Common cold and some upper respiratory tract infections in humans. Severe acute respiratory syndrome-coronavirus disease (SARS-CoV), Middle East respiratory syndrome-coronavirus disease (MERS-CoV), and coronavirus disease-19 (COVID-19) belong to the genus Betacoronavirus. They are a source of major epidemics and cause severe respiratory and other systemic infections [1]. Differential diagnosis must include the probability of various widespread respiratory diseases. Patients remain asymptomatic while the symptomatic may be categorized as mild, moderate, and severe, seasonal flu symptoms. Few people show more severe symptoms of pneumonia and sometimes acute respiratory distress syndrome (ARDS) and septic shock to be hospitalized immediately [2]. Detection of COVID-19 at the earliest is a necessary step to treat patients on accurate guidelines. For suspected cases, rapid antigen detection and other examinations should be done to evaluate common respiratory pathogens and non-infectious disorders. A COVID-19 diagnostic testing kit has been developed and is available in clinical testing labs.

Reverse Transcription-Polymerase Chain Reaction (RT-PCR) is used as a gold standard for testing COVID-19 [3]. A computed tomography (CT) scan has a greater value in initial detection and differential diagnosis of COVID-19 [1]. There are various imaging expressions in COVID-19 at distinct stages primarily associated with pathogenesis. At the initial stages of COVID-19, inflammation of lungs penetrated to the subpleural areas of one or both lungs showing irregular or segmented pure ground-glass opacities (GGOs) along with dilation of vessels. A short number of cases are also noticed with negative CT findings at the initial stages. But in the advanced stage, CT shows chiefly an enhanced amount of pure ground-glass opacities in lungs, consolidations of particular lesions, and GGOs surrounding consolidated lesions, which are the prominent characters of advanced stage COVID-19 infection [4]. Imaging diagnosis for COVID-19 is considered difficult to differentiate for viral pneumonia, including influenza viruses, adenovirus, Respiratory Syncytial Virus, SARS-CoV, MERS-CoV, and bacterial pneumonia [5]. Viral pneumonia, except COVID-19, is chiefly associated with interstitial inflammation of peribronchial and perivascular regions, spreading toward the inner part of the pulmonary interstitium. Their CT expressions are manifold interweaved due to infiltration of the interlobular septa [6].

COVID 2019 must also be differentiated from bacterial pneumonia and Mycoplasma pneumonia (M. pneumonia) (separated from bacterial pneumonia) is the smallest and atypical bacteria that causes mild respiratory symptoms) [7]. Bacterial pneumonia occurs in the lung parenchyma, and there is bronchial or lobar pneumonia and numerous inflammatory secretions. Its CT expressions exhibit widespread irregular consolidations of the lung parenchyma, while GGOs are rare [8]. M. pneumonia usually occurs in children and young people but seldom occurs in adults. The chest CT manifestations of M. pneumonia in adults are commonly bronchial wall thickening, an indicator of lobar pneumonia, and centrilobular nodules, which are small airway lesions. In contrast, the CT scan of COVID-19 shows mostly pure GGOs at the initial stage and observable consolidations in the center of the lesions at the advanced stage [9]. The current chapter will describe in detail about pathogenicity, clinical signs, diagnostic procedures, and treatment of COVID-19 as differential indications keeping relevant viral and bacterial diseases of the respiratory system in an intact discussion (Fig. 1).

Fig. (1))

Differential diagnosis of SARS-CoV-2 with different diseases based on different factors/characteristics.

Differential Diagnosis of COVID-19

Differential diagnosis involves confirmation of a disease condition whose signs and symptoms somehow show similarities with other diseases or disease conditions. To treat or prevent any disease at current and to avoid another illness with similar signs and symptoms, it is imperative to have sound knowledge of the differential diagnosis. Complete knowledge of differences in etiology, transmission/epidemiology, pathogenesis, clinical findings, diagnostic tests, and treatment protocols should be considered to achieve this. The differential diagnosis in this chapter covers differences concerning etiology, epidemiology & transmission, pathogenesis, clinical signs & symptoms, diagnostic outcomes, and response therapies.

COVID-19 will be differentiated with the following diseases in this book chapter:

· Other Coronaviruses (SARS, MERS)

· Adenovirus

· Influenza Virus

· Human Metapneumovirus (HMPV)

· Parainfluenza Virus

· Respiratory Syncytial Virus (RSV)

· Rhinovirus (Common cold)

· Bacterial pneumonia (Streptococcus pneumonia, Haemophilus influenza pneumonia, Moraxella catarrhalis pneumonia, and Chlamydia pneumonia) and

· M. pneumonia

Differential Etiology

COVID-19 and other Coronaviruses

Coronavirus belongs to genus Betacoronavirus, subfamily Orthocoronaviridae, family Coronaviridae and order Nidovirales. Phylogenetic analysis reveals SARS-CoV-2 belonging to Clad I and Clad IIa. The reservoir host of these viruses are bats, while the intermediate host is yet not known. Some studies suspect pangolin as an intermediate host while authenticity is yet questionable [10]. The virus is 50–200 nanometres in diameter, having positive-sense single-stranded RNA (+ssRNA) with a single linear RNA segment that accounts for approximately a genome size of 29,903 bases (2.9kb) and 11 open reading frames (ORFs). SARS-CoV (belonging to Clad I and Clad IIb; bats are animal reservoirs; the intermediate host is palm civets) is single-stranded positive-sense viral RNA having 13–15 ORFs while consists of a total of nearly 3kb (30,000 nucleotides) [11]. Both SARS-CoV and SARS-CoV-2 bind to ACE 2 of the host to get into the human body. Genomic comparison between SARS-CoV and SARS-CoV-2 presents a difference of only 380 amino acid substitutions, which are concentrated mainly in the non-structural protein genes. Viral spike protein, S protein, responsible for binding to the ACE receptor, shows 27 mutations in genes that encode it.

On the other hand, MERS-CoV belongs to Clad II; bats are animal reservoirs; camels are intermediate hosts. The virus binds to the host cellular receptor dipeptidyl peptidase 4 (DPP4) to enter the host cells. The virus is also a positive-sense single-stranded consisting of 301-31kb genome with the versatility of adopting a new environment and transmission across species.

Adenovirus

Adenoviruses result in upper and lower respiratory tract infections, keratoconjunctivitis, pharyngitis, pneumonia, and many other infections in humans. Adenoviruses are named so because they were isolated from human adenoids. They belong to the family Adenoviridae and genus Mastadenovirus. They are non-enveloped, having non-segmented double-stranded DNA. They have icosahedral nucleocapsid, formed by 252 capsomeres: 240 haxons form the face, and 12 forms the vertices. A fiber protrudes from each vertex of the capsid, and it is the organ of attachment and hemagglutinin. More than 100 different serotypes of adenoviruses have been identified. Of which about half infects the human host. Human adenoviruses serotypes are classified into seven sub-genera or species [12]. A: 12, 18, and 31, B: B₁ (3, 7, 16, 21, and 51); B₂ (11, 14, 34, and 35); C: 1, 2, 5, and 6; D: 8, 9, 10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36-39, 42-49, and 50; E: 4; F: 40, 41; G: 52.

Influenza Virus

Influenza viruses are considered significant due to several epidemics and pandemics. They belong to the family Orthomyxoviridae. They have enveloped RNA viruses with segmented genomes, helical nucleocapsid, and lipoprotein envelopes and are small (about 110nm in diameter). Hemagglutinin and neuraminidase protein spikes are present on their surface.

Human Metapneumovirus (HMPV)

Human Metapneumovirus (HMPV), a ubiquitous infection present in all age groups, has similarities to avian metapneumovirus. HMPV is a negative-strand RNA virus known to cause lower respiratory tract infection [13]. It belongs to the family Paramyxoviridae sub-family Pneumovirinae and genus Metapneumovirus. The virus was first isolated from children in 2001 in Netherland, showing symptoms identical to human Respiratory Syncytial Virus (hRSV) infections. The mechanism of the virus recognizing host cell and target receptor is not widely known. However, an experiment showed that the cell lines that cannot synthesize glycosaminoglycans (GAGs), especially heparan sulfate proteoglycans (HSPGs), were resistant to binding and infection HMPV.

Parainfluenza Virus

Parainfluenza virus causes laryngitis, bronchiolitis, laryngotracheobronchitis (croup), and pneumonia in children and adults. The virus belongs to the Paramyxoviridae family and has a negative sense of single-stranded enveloped RNA. Hemagglutinin (H), neuraminidase (N), and fusion (F) protein are present as spikes on the surface of the virus. Parainfluenza viruses also infect animals, but strains that cause diseases cannot infect humans [14].

Respiratory Syncytial Virus (RSV)

Respiratory Syncytial Virus (RSV) belongs to the Paramyxoviridae family and is known to cause pneumonia, otitis media, and bronchiolitis in infants and old people [15]. Its nucleocapsid is helical, and the outer envelope consists of lipoprotein molecules covered with spikes of the fusion protein. Fusion proteins present on the surface fuse to form multinucleated giant cells (syncytia), so the virus is named a syncytial virus. The virus has two serotypes named A and B.

Rhinovirus (Common Cold)

Rhinovirus is an important cause of the Common cold, a recurrent but otherwise comparatively insignificant and self-limited disease. It can cause infection of the lower respiratory tract and activate asthma exacerbations in both adults and children. The virus belongs to the family Picornaviridae and genus Enterovirus while appears to be positive-sense, single-stranded-RNA (ssRNA) of about 7,200 bp. The single gene-based whole viral genome is cleaved to translate and produce 11 proteins [16]. These viruses gain entry into the host cell by three major types of cellular membrane glycoproteins, including low-density lipoprotein receptor (LDLR) family members (12 RV-A types), intercellular adhesion molecule-1 (ICAM-1), and cadherin-related family member 3 (CDHR3).

Bacterial Pneumonia

Streptococcus Pneumoniae

Streptococcus pneumoniae (S. pneumoniae), also termed pneumococcus, is a Gram-positive and catalase-negative organism resulting in pneumococcal infections. This bacterium is a leading candidate for community-acquired pneumonia, bacterial meningitis, otitis media, septic arthritis, sinusitis, endocarditis, osteomyelitis, and peritonitis [17].

Haemophilus Influenza

This is a gram-negative coccobacillus facultative anaerobe bacterium. This bacterium inhabits the respiratory tract leads to infection of various body systems for producing bacteremia, meningitis, epiglottitis, endocarditis, septic arthritis, or cellulitis [18].

Moraxella Catarrhalis Pneumonia

Moraxella catarrhalis is responsible for causing chronic bronchitis leading to pneumonia. Moraxella organisms are small, Gram-negative diplococci or bacilli. It is the most significant pathogen of the Moraxella genus [19].

Chlamydial Pneumonia

The causative pathogen is Chlamydial pneumonia, a Gram-negative, small, and obligate intracellular bacterium that leads to community-acquired pneumonia or lung infections [20].

M. Pneumonia

M. pneumonia is a microscopic pathogen that belongs to the class Mollicutes. It damages the lining of the respiratory system (throat, lungs, and windpipe), and sometimes it is referred to as “walking pneumonia” because it causes milder pneumonia than other bacterial pneumonia. It was first isolated in cattle species with pleuropneumonia in 1898 [21].

The differential etiology of COVID-19 with other bacterial and viral respiratory diseases is summarized in Table 1.

Table 1 Differential aetiologies of COVID-19 with viral and bacterial diseases.

Virus/bacteria	Disease Name	Order, Family, Genus	Size and Nature of Nucleic Acid	Animal Reservoir	Intermediate Host	Host Receptor
SARS-CoV2	COVID-19	Order: Nidovirales Clad I and Clad IIa Genus: Betacoronavirus Subfamily: Orthocoronaviridae Family: Coronaviridae	Positive-sense single-stranded RNA (+ssRNA) 29,903 bases (2.9kb)	Bats	Not known yet	ACE-2
SARS-CoV	SARS (Severe acute respiratory syndrome)	Clad I and Clad IIb	Single-stranded positive-sense viral RNA 30,000 nucleotides (3kb)	Bats	Palm civets	ACE-2
MERS	Middle East respiratory syndrome	Clad II	Positive-sense single-stranded RNA 301-31kb	Bats	Camel	Cellular receptor dipeptidyl peptidase 4 (DPP4
Adenovirus	Pharyngitis, pneumonia	Genus: Mastadenovirus Family: Adenoviridae	Non-enveloped non-segmented double-stranded DNA 34-36kb	-	-	Coxsackie virus and adenovirus receptor (CAR)
Influenza virus	Influenza	Family Orthomyxoviridae	Negative-sense single-stranded enveloped RNA 13kb	-	-	Neuraminic acid. sialic acid
human Metapneumovirus (HMPV)	HMPV infection	Genus: Metapneumovirus Family: Paramyxoviridae Sub-family: Pneumovirinae	Negative-sense single-strand RNA 13.3kb	-	-	Heparan sulfate
Parainfluenza virus	Croup	Family: Paramyxoviridae	Negative-sense single-stranded enveloped RNA 15kb	-	-	Sialyl (2-3) GAL receptor
Respiratory Syncytial Virus (RSV)	Bronchiolitis	Genus: Pneumovirus Family: Paramyxoviridae	Negative-sense single-stranded RNA 15kb	-	-	CX3CR1
Rhinovirus (Common cold)	Common cold	Family Picornavirida and genus Enterovirus	Positive-sense, single-stranded RNA (ssRNA) 7.2 kb	-	-	LDLR, ICAM-1, CDHR3
Bacterial Pneumonia	Bacterial pneumonia	1- Genus: Streptococcus Family: Streptococcaceae. 2- Genus‎: ‎Haemophilus Family‎: ‎Pasteurellaceae 3- Genus: Moraxella Family: Moraxellaceae 4- Order: Chlamydiae Family: Chlamydiaceae Genus: Chlamydia	1- Gram-positive bacterium 2.1 Mb 2- Gram-negative, facultative anaerobe 1.8 Mb 3- Gram-negative commensal 1.89 Mb 4- Gram-negative DNA 1234 kb	-	-	-
M. pneumonia	Atypical pneumonia	Class: Mollicutes Order: Mycoplasma tales	816kb	-	-	-

Comparative Modes of Transmission and Epidemiology

COVID-19 and other Coronaviruses (SARS, MERS)

SARS-CoV-2 is contagious and spread by aerosol droplets from infected people and fomites. Human-to-human transmission causes its pandemic. Incubation ranges from 2-14 days. Basic case reproduction rate (BCR)–the number of people infected from a single patient- in the case of COVID-19 is 2-6.47 [22]. It was 2 and 1.3 in the case of SARS and influenza H₁N_1, respectively. Coronavirus infections are limited to cells of mucosa in the respiratory tract. Sometimes, in about 50% of cases, the infection can be asymptomatic yet spread the virus. Reinfection can occur after recovery due to low-cut immunity. SARS disease is spread by the SARS-CoV virus, which is transmitted by respiratory aerosol droplets. Human to human transmission is the major source of disease spread and outbreak. The incubation period for SARS is 2-10 days, in which 5 days are considered to be the average. The death rate is 3-4% and primarily due to respiratory failure. MERS-CoV's transmission of MERS caused by MERS-CoV, also named human coronavirus-EMC (HCoV-EMC), occurs through camel-to- human as the virus is shed in body fluids, mainly respiratory and rectal discharge; and human-to-human [2]. The mortality rate of SARS, MERS, and COVID-19 is 11%, 34%, and 2-3% respectively.

Adenovirus

Adenovirus may have direct transmission from person to person or indirect transmission from the environment. Transmission of adenovirus occurs by aerosol droplet, feco-oral route, and direct inoculation by fingers or contact with fomites [23]. The incubation period is 5-7 days, with fever starts from 2-3 days. The virus continues to excrete for several months from an initial infection. That’s why the feco-oral route is thought to be a major route of viral transmission. Feco-oral route of transmission is common among young children and their families. Usually, adenovirus infections are endemic, but outbreaks occur in the military probably because of close living conditions. Adenovirus infections are ubiquitous and generally common in children and cause 2-5% of total respiratory tract infections to occur in them. Severe complications seldom occur. More specifically, Ad3 and Ad7 from species B, Ad1, Ad2, and Ad5 from species C are common agents associated with respiratory tract infections that may persist in children without causing symptoms for years. Ad8, Ad19, and Ad37 from species D cause conjunctivitis. Ad4 from species E causes both respiratory and ocular infections. Ad40 and Ad41 from species F and Ad52 from species G cause severe gastroenteritis [12].

Influenza Virus

Influenza virus is contagious, and transmission occurs through airborne respiratory droplets. The morbidity rate of influenza is very high, especially in children and elders. Outbreaks occur every year, especially in winters. The incubation period is usually 24-48 hours. Immunocompromised patients, pregnant women, children >2 years of age, and elders are more prone to infection. Influenza A virus is the most virulent human pathogen can cause severe disease and the source of most pandemics. They are capable of infecting both humans and animals. These viruses are categorized into different serotypes keeping in view response to the antibody against the virus. They have 16 antigenically distinct types of hemagglutinin and 9 antigenically distinct types of neuraminidase. Changes in antigenicity occur due to hemagglutinin and neuraminidase proteins. Also, the non-existence of pre-existing antibodies in humans against them causes pandemics of Influenza type A. Influenza B virus is present only in humans. It mutates less than influenza type A virus and causes several outbreaks but not pandemic. Influenza C virus can infect humans, dogs, and pigs. It is a less common type of Influenza virus and causes mild respiratory tract infections.

Human Metapneumovirus (HMPV)

HMPV cases have been reported worldwide. It is prevalent in the winter season and followed by the Respiratory Syncytial Virus (RSV). They show two genotypes named A and B as defined by genomic sequence and phylogenetic analysis [24]. Infection with HMPV is common in childhood. It can cause severe lower respiratory infections such as pneumonitis and bronchospasm in very young children, premature born, people with underlying heart and lung disease, immune-compromised patients, and elders [13].

Parainfluenza Virus

The virus was first isolated in 1955 from children having croup. The disease is present worldwide and mostly occurs during the winter months. Transmission occurs through respiratory droplets [25].

Respiratory Syncytial Virus (RSV)

Transmission of RSV occurs through respiratory droplets and direct contact of contaminated hands with the face. Transmission of the disease is worldwide, and everyone is thought to be infected by 3 years. Children, hospitalized infants, the elderly, and patients with chronic cardiopulmonary diseases are at greater risk. The disease is more prevalent during winters [15].

Rhinovirus (Common cold)

Rhinovirus is responsible for 1/3 to 1/2 of cases in adults per annum. More than 100 serotypes have been recognized. Normally two to three colds per year occur in adults and 8 to 12 colds per year in children because they serve as a chief reservoir for rhinovirus [26]. Aerosols, fomites, and direct contact with infected nasal secretions are common sources of spread. However, the main route has not been identified yet. However, this virus can persist in the environment >8 hours and infect people's hands and consequently transfer to their eyes or nose to develop infection [27].

Bacterial Pneumonia

Streptococcus pneumonia: S. pneumoniae is the source of a wider range of clinical symptoms. It causes disease in surrounding anatomic structures by extending from either direct extension from the nasopharynx and vascular invasion via hematogenous spread. Children with age <5 years and adults aged>55-65 years are considered high-risk patients. Comorbidities like HIV infection, diabetes, and malignancy normally impair the immune system hence infection caused by S. pneumonia is aggravated. Similarly, the synergistic effect of the appearance of clinical symptoms lies with asthma, chronic bronchitis, or chronic obstructive pulmonary disease [17].

Haemophilus influenzae pneumonia: Accurate prevalence and incidence are yet not known. This bacterium can live in the nasopharynx of both children and adults. Almost 3 to 5% of newborns have Haemophilus influenze (H. influenzae) type b in their nasopharynx before vaccination. Children who have been vaccinated against H. influenzae type b have fewer chances to get infected with this organism. But the risk for getting an infection is almost 600 times higher in non-vaccinated persons than the risk in the age-adjusted general population. Transmission is executed due to direct contact with nasopharyngeal respiratory droplets excreted by the carrier or patient. Aspiration of amniotic fluid or contact with contaminated genital tract secretions causes infection in newborns. The disease maximally spread due to lack of vaccination in children <5 years of age and adults with >65. Household contacts, day-care fellows having influenza b infection are salient risk factors. Comorbidities like sickle cell disease, immunoglobulin & complement component deficiencies, HIV, and malignant cancers are situations that are synergistic to strengthen clinical signs [28].

Moraxella catarrhalis pneumonia: M. catarrhalis is a commensal organism generally that transmits from person to person, mostly in hospitals. This infection is more prevalently reported in individuals with respiratory complications like COPD or infants having underdeveloped immune systems [29].

Chlamydial pneumonia: This infection follows the same transmission routes as other respiratory infections, like as it spreads through sneezing or coughing and by touching the surfaces having droplets containing the bacteria [30].

Mycoplasma pneumonia

This type of bacteria spreads through coughing or sneezing from person to person, which produces small respiratory droplets in the air containing bacteria. People surrounding infected people breathe in the bacteria. Asymptomatic individuals may carry bacteria in their nose or throat at one time or another. Most people who spend a very short time with C. pneumoniae infected individuals do not get the disease. The incubation period of C. pneumoniae infection is very long, varying from 1 to 4 weeks [31].

The summary of comparative modes of transmission and epidemiology of COVID-19 to other bacterial and viral respiratory diseases is discussed in Table 2.

Table 2 Characteristic features of viral and bacterial diseases.

Disease	Transmission	Incubation Period	Risk Factors
COVID-19	Aerosol droplets and fomites	2-14 days	Comorbidities like the cardiac and respiratory problems, Immune compromised patients at higher risk
SARS	Aerosol droplets	2-10 days
MERS	Aerosol droplets	2-14 days
Adenovirus	Aerosol droplets, feco-oral and direct inoculation	5-7 days
Influenza virus	Aerosol droplets	24-48 hour
human Metapneumovirus (HMPV)	Aerosol droplets	5-21 days	Young children, premature born, people with underlying heart and lung disease, elders, and immunocompromised patients
Parainfluenza virus	Respiratory droplets	2-6 days	Immunocompromised patients, people after hematopoietic stem cell transplantation (HCT) are at high risk
Respiratory Syncytial Virus (RSV)	Respiratory droplets and direct contact of contaminated hands with face	4-6 days	Children, hospitalized infants, the elderly, and patients with chronic cardiopulmonary diseases are at higher risk
Rhinovirus (Common cold)	Aerosols, fomites, and direct contact with infected nasal secretions	12-72 hr	Chronic medical condition, cancer, smoking
Bacterial Pneumonia	Direct extension from the nasopharynx, coughing, sneezing, or touching the surfaces infected with bacteria while vascular invasion via blood spread	Streptococcus pneumonia: 1-3 days Haemophilus influenzae pneumonia: 7 days Moraxella catarrhalis pneumonia: Unknown Chlamydial pneumonia: 3-4 weeks	Age <5 years and adults of age >55-65 years, presence of other diseases like asthma, chronic bronchitis, diabetes, and malignancy, non-vaccinated people are at higher risk, nosocomial infection
M. pneumonia	Spread through coughing or sneezing droplets in the air containing bacteria	Very long, varying from 1 to 4 weeks	People working at crowded places are at higher risk

Comparative Pathogenesis

COVID-19 and Other Coronaviruses (SARS, MERS)

Coronaviruses enter the host by inhaling the infected person's aerosol droplets and then get attached to their specific receptors. These viruses release their RNA after binding to its receptor and initiate infection development [32]. SARS-CoV-2 may enter the host through the respiratory tract or mucosal surfaces such as the conjunctiva. The inhaled SARS-CoV-2 virus binds to nasal cavity epithelial cells, while the upper respiratory tract is found to be an efficient replication site for this novel coronavirus. This can also replicate in the lower respiratory tract and causes radiological evidence of lower respiratory tract involvement in patients with no clinical pneumonia [33]. In a fluorescent trial, the evidence indicates that the SARS-CoV-2 uses angiotensin-converting enzyme 2, the same entrance receptor as SARS-CoV [2]. Bronchoalveolar lavage fluid from a positive COVID-19 patient reported SARS-CoV-2 use of ACE2 as an entrance receptor [34]. Angiotensin-converting enzyme protein is notable on alveolar epithelial cells and causes regulation and transmission of both human-to-human and cross-species [35].

The S-glycoprotein present on the surface of SARS-CoV-2 that has S1 and S2 subunits binds to ACE2. S1 is responsible for RNA binding domain (RBD), supporting the attachment for both virus-host and cell tropism, while S2 causes the fusion of virus-cell membrane [36]. The critical residue of lysine 31 present on the human receptor ACE2 recognizes the 394-glutamine residue located in the SARS-CoV-2’s RBD region. The viral RNA is released into the host’s cell cytoplasm after membrane fusion, followed by the translation of two viral replicase polyproteins, pp-1a and pp-1ab, which encode the NSPs, ultimately forming a double-membrane vesicle that is replication-transcription complex (RTC). RTC continuously replicates and synthesizes nests of sub-genomic RNAs, which finally encodes structural proteins and accessory relevant proteins. Subsequently, genomic RNA, glycoproteins envelope, and nucleocapsid proteins assemble into the endoplasmic reticulum’s virion, followed by Golgi. Finally, the newly formed vesicles that contain virion are fused with the plasma membrane of the host to release new viruses [37]. SARS’s pathogenesis is highly complex, with several factors leading to severe lung injury and the virus transmitted to several other organs [38]. Like SARS-CoV-2, the proteins and RNA of the specific virus are synthesized after binding with ACE2 receptor and fusion of plasma membrane, probably entirely within the cytoplasm. The expression of the virus begins with the translation of polyproteins including ppla and pplb, which undergo proteolytic co-translational manufacturing of proteins. Newly synthesized virions are accumulated into the intracellular membranes by budding and released through vesicles by cell secretory mechanisms [39]. While in comparison to SARS-CoV-2 and SARS-CoV, MERS-CoV interacts with cellular receptor DPP4 (dipeptidyl peptidase 4) to enter permissive host cells [40]. After entry, MERS-CoV follows the same steps as other CoVs.

Adenovirus

Adenoviruses infect the epithelial layer of different organs particularly the respiratory tract, conjunctiva, and gastrointestinal tract. Type-specific and life-long immunity is based on neutralizing antibodies being produced. Destruction of bronchial epithelium and bronchial glands is observed in severe cases. Tissues involved show cellular infiltrates. Tissue necrosis, cellular infiltrates, and basophilic inclusions are observed in the liver affected by adenovirus. The persistence of the antigen-antibody complex present in the body instigates an inflammatory response that causes damage to the cornea. Adenoviruses cause acute infection and latent infection. In the case of latent infection, their predilection sites are adenoid and tonsillar tissues in the throat. The adenoviruses become less infective when exposed to 56°C or above for 10 minutes. They are insensitive to lipid solvents and stable when exposed to mild acids [41].

Influenza Virus

After the inhalation of the virus, neuraminidase present on its surface degrades the protective mucus layer and helps the virus penetrate the virus to upper and lower respiratory tract cells. The influenza virus is limited to the respiratory tract due to the presence of proteases that cleave hemagglutinin. A virus causes inflammation of the respiratory tract (nose, pharynx, larynx, trachea, bronchi). Necrosis of superficial respiratory tract epithelium can occur. Pneumonia may also be occurred due to circulating cytokines and myalgia. Influenza rarely leads to viremia. Immunity depends on IgA and cytotoxic T-cells' presence.

Human Metapneumovirus (HMPV)

An experimental study was performed on BALB/c mice and cotton rats to understand the pathogenesis of HMPV. After the intranasal administration of virus culture, its replication occurs in the lungs leading to lung inflammation, weight loss, and respiratory distress. Virus titer was recorded at peak at day 5 post-infection, and on day 21 no viruses were recovered. Peak pulmonary inflammation was observed on day 5 and then started to decline and was not observed on day 21. Inflammatory changes include interstitial inflammation, alveolitis, and peri bronchiolitis. Inflammatory cells (neutrophils and macrophages) increased from day 1 post-infection and then gradually slow down. Cytokines level, e.g., interferon-gamma (IFN-γ), macrophage inflammatory protein-1 alpha (MIP-1α), and interleukin-4 (IL-4) increased immediately post-infection at day 1 [42].

Parainfluenza Virus

Based on pathogenicity, parainfluenza viruses are divided into 4 types. Most of the infections are subclinical. However, the clinical disease involves upper and lowers respiratory disease depending on the type of virus that causes it. Type 1 and 2 causes laryngotracheobronchitis or croup. Type 3 virus causes lower respiratory tract infection and is more prevalent in infants. Type 4 causes a Common cold [43].

Respiratory Syncytial Virus (RSV)

RSV does not cause viremia and is localized in the respiratory tract. The disease is more adverse in babies than in elders and older children and involves the lower respiratory tract. Immunity in the recovered patients is incomplete, and infection can be recurring. An IgA antibody lowers the frequency of infection as a personage.

Rhinovirus (Common Cold)

Rhinovirus (RV) infection uses nasal epithelium as a primary site. About 90% of well-known RV stereotypes, HRV-A, and HRV-B families use ICAM-1 as the receptor for cell entry. In contrast, the other 10 serotypes use small group receptors, which is low-density lipoprotein [44]. ICAM-1 uses as a binding site for HRV. After binding, the virus loses its capsid of protein. Virus uptake occurs through micropinocytosis, independent endocytosis, and clathrin-dependent [45]. The virions consequently go through some structural alterations for producing hydrophobic subviral particles. In endosomes, this process is started via ICAM-1 and/or the low-pH environment. Negative strand RNA is replicated and undergoes translation to form structural and non-structural proteins. The virion is accumulated before cellular export and packed via cell lysis [16]. The cold symptoms begin one day after entry of the virus and highest on the third or fourth day. It is unknown whether rhinitis is caused by the direct cytocidal effect of virus replication or mediator release. Symptoms of RV infection are generally confined to the upper respiratory tract in non-asthmatic individuals. The most prominent rhinorrhoea and nasal obstruction symptoms are linked with an inflammatory neutrophilic response associated with enlarged permeability of vessels and activation of increased secretion of mucous [46].

Bacterial Pneumonia

Streptococcus pneumoniae: The pneumococcus is the traditional extracellular bacterial, Gram-positive pathogen. A wide range of pneumococcal virulence factors tailored effectively to specific host niches. The nasopharynx is the ecological niche that pneumococcus employs. When bacteria enter the lower respiratory tract, the mucous defense must be escaped, and bacteria must reach the alveoli [47]. Bacteria strongly attaches to the alveolar epithelium, followed by replication and beginning of host damage leading to classic lobar pneumonia. This process is driven by the collaboration of secretions and attached bacterial constituents of the cell surface with the alveolar epithelium and innate immune defenses. The pore-forming toxin pneumolysin and hydrogen peroxide produced by the bacteria in large amounts interferes with the alveolar epithelium and accumulates edema fluid in the alveolar space [48]. This infection can become severe due to other invasive diseases like pneumonia, meningitis, and septicemia [49].

Haemophilus influenzae pneumonia: The bacterium H. influenzae lives in the human nasopharynx and conjunctiva may spread to cause pneumonia, otitis media, or meningitis. The H. Influenzae is classified into encapsulated and non-encapsulated strains. Infections caused by encapsulated strains invade the bloodstream to cause hematogenic spread. A capsular polysaccharide is a crucial factor that facilitates invasion by virulence [18]. The initial stage in the pathogenesis of non-typeable H. Influenzae is an invasion of the upper respiratory tract. Multiple virulence factors mediate colonization and infection, including adhesives, nutrient absorption systems, host-resistant molecules, and others [18].

Moraxella catarrhalis pneumonia: M. catarrhalis is found mainly in the respiratory tract of humans. This organism sticks to mucosal cells with the help of pili. It spreads from colonization to the infection site due to more infectious strains to which the host does not possess immunity. M. catarrhalis can occur in respiratory secretions along with H. influenza because the outer membrane vesicles of M. catarrhalis deactivate complement to increase the latter's existence. M. catarrhalis is linked to various infections, including upper and lower respiratory tract infections, bacteraemia, septic complications, endocarditis, meningitis, and brain abscess in addition to wound infections [50].

Chlamydia pneumoniae: C. pneumoniae has been shown to replicate and thrive within the vascular walls (macrophages, smooth muscle cells, endothelial cells, and epithelial cells) and the airway of most cell types. These types of cells can lead to both acute infection and chronic respiratory disease progression. The pathogenesis of C. pneumoniae is a complicated process that relies on the population of an invaded cell, initiation of a genetic state of replicative and non-replicative pathogens, and the effector molecules of host cells [51]. In adolescents and young adults, C. pneumoniae causes sinusitis, pharyngitis, bronchitis, and pneumonia. Older adults can experience more severe illnesses and recurrent infections. An increased risk of vascular lesions, asthma, and COPD was associated with frequent or recurrent infections [52].

Mycoplasma pneumonia

M. pneumonia attachment to the respiratory epithelium (Cytadherence) is a precondition for subsequent changes resulting in the development of diseases. The P1 adhesin is a concentrated 170-kDa protein at the tip of the attachment responsible for attachment of M. pneumonia with host cells [53]. Extrapulmonary complications that involve the systems of all the major organs may happen in association with M. pneumoniae infection by an autoimmune response or direct invasion. Sometimes the extra-pulmonary occurrences are more lethal and clinically important than the primary infection of the respiratory system [54]. In association with M. pneumoniae infection, pro-inflammatory cytokines release has been involved as a possible mechanism for underlying chronic pulmonary diseases such as asthma. Evidence of the contributory role of mechanism in the chronic condition of lungs such as asthma is gradually building [53]. The differential pathogenesis of COVID-19 with viral and bacterial respiratory diseases is summarized in Table 3.

Table 3 Differential pathogenesis of COVID-19 with viral and bacterial diseases.

Disease	Pathogenesis
COVID-19
SARS
MERS
Adenovirus
Influenza virus
Human Metapneumovirus (HMPV)
Parainfluenza
Respiratory Syncytial Virus (RSV)
Bacterial Pneumonia
M. pneumonia

Differential Signs and Symptoms

COVID-19 and other Coronaviruses (SARS, MERS)

COVID-19 may involve multiple body systems such as respiratory, gastrointestinal, musculoskeletal, and nervous systems. High-grade fever, shortness of breath, cough, body aches, fatigue, headache, the new loss of taste or smell, sore throat, congestion, vomiting, and diarrhea are salient symptoms of COVID-19. They progressively lead to acute respiratory distress syndrome (ARDS) and multiple organ failure. The disease is also remaining asymptomatic in most patients. The common cold caused by coronavirus is identified as coryza (rhinorrhoea, and runny nose), sore throat, bronchitis, and low-grade fever. The illness continues for several days. Clinical finding for SARS and MERS is similar. They cause severe but atypical pneumonia characterized by fever (38^◦C), dyspnoea, non-productive cough, and hypoxia. Chills, rigors, malaise, and headaches are commonly seen. Sore throat and rhinorrhoea are generally not observed.

Adenovirus

About half of the adenovirus infections are asymptomatic. And from the remaining symptomatic infections, most of them settle spontaneously. Severe infections occur only in children or immunocompromised patients such as AIDS, organ, or stem cell transplant in which patients already intake immune-suppressing drugs. Adenoviruses in the upper respiratory tract cause pharyngitis and pharyngoconjunctival fever (PCF), an acute respiratory disease characterized by fever, nonproductive cough, headache, and sore throat, coryza, and conjunctivitis. In the lower respiratory tract, they cause bronchitis and atypical pneumonia with dyspnoea, ulceration, and scarring of bronchial epithelium, and destruction of bronchial glands. Post-infection bronchiectasis is also observed in patients, especially children recovering from pneumonia [55].

Influenza Virus

Influenza is characterized by severe myalgia with respiratory signs (sore throat, cough), fever, and headache. Vomiting and diarrhea are uncommon. If no secondary bacterial infection is involved, symptoms usually limit to 4-7 days. The involvement of bacterial infection (generally Staphylococcus aureus or Streptococcus pneumoniae) can worsen the condition by developing pneumonia. Reye’s syndrome is a life-threatening condition, categorized by encephalopathy and liver degeneration, usually occurring in children as sequelae of some viral infections.

Human Metapneumovirus (HMPV)

Cough and wheezing, dyspnoea, sputum production, bronchitis, and pneumonia are also present. Fever is uncommon: a differential feature from influenza infection. Unlike human Respiratory Syncytial Virus (hRSV), young adults generally have asymptomatic infection [15]. HMPV is more likely to cause bronchiolitis and less likely to cause pneumonia than influenza and RSV. Mostly lower respiratory tract infection, but upper respiratory tract infection can also be present uncommonly. Patients with HMPV upper respiratory infection show otitis media (OM) because inflammatory response against virus causes blockage of the

Eustachian tube, bacteria get entry and cause osteomyelitis. Disease by HMPV is not severe unless it coincides with other infections [42].

Parainfluenza Virus

Parainfluenza virus infection is characterized as croup in children <5 years of age. Croup is indicated by hoarseness and harsh cough. Other clinical findings include respiratory conditions such as Common cold, pharyngitis, laryngitis, bronchitis, pneumonia, and osteomyelitis [14].

Respiratory Syncytial Virus (RSV)

The severity of the infection varies depending on the age group. RSV is one of the major causes of pneumonia and bronchiolitis in infants. Young children develop otitis media due to RSV, while older children, young and healthy adults develop respiratory tract infections like Common cold and bronchitis. In old age and patients with cardiopulmonary diseases, RSV can cause severe diseases such as severe lower respiratory tract infections and pneumonia [56].

Rhinovirus (Common cold)

Characteristic signs of cold are cough, runny nose, sneezing, nasal congestion, sore throat, muscle ache, fatigue, headache, and loss of appetite. There are 40% of cases suffering from sore throat while 50% are presented with cough. Fever usually does not occur in adults but common in newborns and young children. In the case of rhinovirus, mild cough is present as compared to influenza. Mostly Common cold viruses exhibit asymptomatic infections [57].

Bacterial Pneumonia

Streptococcus pneumonia: Conjunctivitis, otitis media, sinusitis, acute exacerbations of chronic bronchitis, pneumonia, meningitis, bacteremia, osteomyelitis, septic arthritis, myositis, periorbital cellulitis, abscess, peritonitis, and endocarditis [17].

Haemophilus influenzae pneumonia: Clinical signs of H. influenzae include fever, cough, and lobar consolidation in the radiographic examination. Sometimes parapneumonic effusions or empyema may also occur [18].

Moraxella catarrhalis pneumonia: M. catarrhalis causes chronic bronchitis, pneumonia, chronic obstructive pulmonary disease, and comorbidities like diabetes mellitus. Additionally, M. catarrhalis can cause nosocomial pneumonia due to the person-to-person spread of the organism [58].

Chlamydial pneumonia: General signs are runny nose, tiredness, low-grade fever, harshness or loss of voice, sore throat, slowly increasing cough, and headache. Lower respiratory tract infections include bronchitis and pneumonia, which can take 3 to 4 weeks for symptoms to appear after the invasion of bacteria [59].

Mycoplasma pneumonia

Signs of M. pneumoniae infections are very similar to cold pneumonia in children. Generally, M. pneumoniae causes mild disease symptoms that appear and worsen within 1 to 4 weeks. This bacterium can cause tracheobronchitis (chest cold) in children, including sore throat symptoms, fatigue, fever, slowly worsening cough that can last for weeks or months, and headache. It is estimated that 1/10 people develop pneumonia due to an M. pneumoniae infection. General symptoms of pneumonia include productive cough, fever and chills, shortness of breath, chest pain, and fatigue [21]. Table 4 summarizes the differential clinical signs of COVID-19 with other viral and bacterial respiratory diseases.

Table 4 Differential clinical signs of COVID-19 with other viral and bacterial diseases.

Symptoms	COVID-19	SARS	MERS	Adenovirus	Influenza Virus	human Metapneumovirus (HMPV)	Para Influenza Virus	Respiratory Syncytial Virus (RSV)	Rhinovirus (Common cold)	Bacterial Pneumonia	M. pneumonia
Cough	Present	Present	Present	Present	Present	Present	Absent	Present	Present	Absent	Present
Fever	Present	Present	Present	Present	Present	Occasional	Absent	Occasional	Absent	Occasional	Present
Dsypnoea	Present	Present	Present	Present	Present	Present	Absent	Absent	Absent	Absent	Absent
Flu	Absent	Present	Present	Present	Present	Present	Present	Absent	Present	Present	Occasional
Pneumonia	Present	Present	Present	Present	Present	Present	Present	Present	Absent	Present	Present
Headache	Present	Present	Present	Present	Present	Occasional	Absent	Absent	Absent	Absent	Present
Sore throat	Present	Present	Present	Present	Present	Absent	Present	Absent	Absent	Present	Present
Others	Loss of taste or smell, nasal congestion, vomiting, diarrhea	Not specific	Chills, rigors, malaise	coryza and conjunctivitis	Severe myalgia	Sputum production, bronchitis	Croup, pharyngitis, laryngitis, bronchitis	Otitis media, bronchitis	Mostly asymptomatic infections occur	Conjunctivitis, otitis media, sinusitis, meningitis, bacteremia	Fatigue

Differential Diagnostic Approaches

COVID-19 and other Coronaviruses (SARS, MERS)

Chest radiograph shows multifocal alveolar opacities leading to complete pleural opacity in severe cases. At the initial stages of infection, no significant alveolar changes can be depicted in a chest radiograph. It is not a sensitive means in disease diagnosis, although it can help in the diagnostic process or follow-up events of disease [60]. Chest computed tomography scan (CT-scan) is abnormal even in asymptomatic patients and shows infiltrates, sub-segmental consolidation, and ground-glass opacities. Diagnosis with CT-scan can be made even in the patients with the negative molecular tests. In reported cases, abnormal CT-scan with negative molecular test showed positive molecular test on repeat testing [61]. Cavitations, calcifications, pleural effusion, and lymphadenopathies are also found during the chest CT-scan. None of them has specifically been associated with the novel coronavirus disease. These findings are equally present in other respiratory tract infections that cause pneumonia-like SARS, MERS, influenza, CMV, and bacterial infections Mycoplasma, Chlamydia, and Streptococcus [62]. Lung ultrasonography shows a focal interstitial pattern (“White lung”) with subpleural consolidations or nodules [63]. Laboratory findings: Leucopenia, lymphopenia, high neutrophil-to-lymphocyte, and platelet to lymphocyte count ratio. Raised levels of liver enzymes like lactate dehydrogenase (LDH), muscle enzymes, and C-reactive protein. Elevated D-dimer, particularly in severe cases [64]. A serological assay, commonly called an antibody test is conducted to detect the presence or absence of the level of antibodies present in an individual against a specific disease. Each antibody present in a testing individual is against a specific disease. The presence of antibodies does not always indicate the ongoing infection as it is also used to detect the previous infection and immunity against that infection. Serological testing can be used to detect the previous or ongoing infection and the level of antibodies detected depends upon the timing of the infection started and test performed. However, it is not specific or sensitive to diagnose COVID-19. The molecular assay is the recommended test by WHO for the diagnosis of COVID-19. It is also named a viral test or test for current infection by CDC. A cotton swab collects the sample for the test from an oropharyngeal or nasopharyngeal site. Other samples such as bronchoalveolar lavage (BAL), expectorated sputum, or endotracheal aspirates can also be used for patients on ventilators. The sample is then processed for the presence or absence of a viral pathogen by RT-PCR. The mechanism of the molecular assay is the first conversion of single-stranded viral RNA into double-stranded DNA by reverse transcriptase enzyme. It amplifies the genomic material up to the extent that it’s sufficient to detect the specific genetic code of the virus that is already conserved by gene sequencing of the specific virus. Typical commercially available primers are used for this purpose. It is the only confirmatory test available and should be repeated to check the viral clearance in the recovered patients [3]. Other coronaviruses are primarily diagnosed on a clinical basis. If suspected, SARS and MERS can be confirmed by RT-PCR and antibody-based tests [11]. Seroconversion of SARS-CoV was observed when grown on Vero cells for virus isolation. Viral RNA was also detected in plasma during the acute phase of infection and feces during the late convalescent phase. Still, concentration was low, and high concentration was seen in sputum.

Adenovirus

Clinical diagnosis can be made on characteristic clinical signs: ARD and conjunctivitis. Throat, nasal, anal, or conjunctival scraping samples are used for isolation of virus on cell culture, and detection of the antibody titer (4-fold or greater rise) is the frequently used method of diagnosis. ELISA is an improved and quicker technique to detect antibodies. However, some serologic tests can be used as confirmatory tests, such as fluorescence microscopy, complement fixation test (CFT), and hemagglutination-inhibition (HI). Electron microscopic image shows a procrystalline array of adenovirus particles [65].

Influenza Virus

Generally, diagnosis is made on clinical findings. However, some tests can be used for this purpose, like ELISA for detecting viral antigen using nasal or throat swab/washing or sputum sample. Some rapid clinic tests involved FLU OIA and QuickVue Influenza Test to detect viral antigen by monoclonal antibodies, ZSTATFLU for detection of viral neuraminidase by using the color-changing substrate. Diagnosis can be made by evaluating the increase in antibody titer up to fourfold early in the illness and 10 days after. For this purpose, HI or CFT can be used. Other tests used are fluorescent antibody and polymerase chain reaction (PCR).

Human Metapneumovirus (HMPV)

Chest radiograph shows patchy densities in the lower lobes due to infiltration, peribronchial cuffing, and hyperinflation [24]. This virus grows poorly on cell culture as it requires trypsin for its propagation. Immunofluorescence is a quick method to detect respiratory virus antibodies but not as sensitive as RT-PCR. RT-PCR can detect viruses from subgroups of both genotypes of HMPV using different primers [42].

Parainfluenza Virus

Most infections are diagnosed based on clinical signs. Other diagnostic tools like virus isolation and detection of increased antibody titer can also be used. PCR is available for confirmatory diagnosis [14].

Respiratory Syncytial Virus (RSV)

Antigen detection by isolation in cell culture, Rapid antigen test, or immunofluorescence can be performed to diagnose the disease. A four-fold or more significant rise in antibody titer can also be used as a diagnostic tool. However, RT-PCR is also available [56].

Rhinovirus (Common cold)

The difference between viral upper respiratory tract infections is made based on visible signs like rhinitis, pharyngitis, and bronchitis. Sometimes an infection may occur in more than one area. The Common cold is generally well-defined as nasal inflammation along with throat inflammation. Self-diagnosis is common. Mostly virus isolation is not done, and sometimes it is not possible to recognize the virus type through symptoms [66].

Bacterial Pneumonia

Streptococcus pneumonia: Potential specimens may be taken from blood, cerebrospinal fluid, sputum, pleural, Joint fluid, bone, and other abscess or tissue specimens to perform PCR. Imaging studies include chest radiography, ultrasonography, and CT-scans of the chest, sinuses, face, bones or joints, and magnetic resonance imaging (MRI) of the brain, bones, and joints [67].

Haemophilus influenzae pneumonia: The most common testing method uses blood or spinal fluid sample to diagnose H. influenzae infection. Gram-negative, small, pleomorphic coccobacilli with polymorphonuclear cells are the strongest indication of infection that is usually obtained by the test results on the body fluids from different sites of infection. Detection of organisms in blood culture or any other body fluid is the most valid diagnostic method [18].

Moraxella catarrhalis pneumoniae: M. catarrhalis may be differentiated from other bacteria by reducing nitrates, loss of colony pigmentation, and production of deoxyribonuclease [50]. Hydrolysis of DNA (detected using DNAse test agar with methyl green) and tributyrin are valuable differentiating tests for M. catarrhalis. Valuable methods like polymerase chain reaction are under the development phase to identify M. catarrhalis and other bacterial pathogens of respiratory secretions [19].

Chlamydial pneumoniae: Diagnosis of Chlamydia pneumoniae infection can be done using culture, serology, or molecular methods by taking a sample of sputum (phlegm) or a swab from the nose or throat or blood test. Culture is particular, but it is technically expensive, requires more time and transport. Direct fluorescent antibody assay and immunoassay enzymes are the detection tests that may provide a quick diagnosis without the need for rigid transport conditions. RT-PCR is the desired method for diagnosing acute testing of C. Pneumoniae infection, assum-ing an appropriate type of specimen is available [51]. For recurrent and acute diagnosis of C. Pneumoniae infection, the kinetics of antibody expression must consider. After 2-3 weeks of infection in a patient, and remain detectable and elevated for up to 2 to 6 months [52]. So far, there has been no proper reference test to validate persistent and chronic infection via serological testing. Persistent elevation of IgA and IgG antibodies has been used as a serological indicator. Numerous studies have recommended that IgA titers can be a good indicator of chronic infection than IgG [51].

Mycoplasma Pneumonia

Diagnosis of M. pneumonia is difficult due to its fastidious nature and the possibility of transitory asymptomatic carriage [68]. Diagnosis is made clinically; PCR of the nasopharyngeal swab, aspirate or sputum, or cultures can confirm the diagnosis. A serological method like CFT is most used. PCR is now used as a method of choice to detect pathogens directly, which provides greater sensitivity than ELISA [69]. The entire summary of differential diagnostic approaches of COVID-19 with other viral and bacterial respiratory diseases is discussed in Table 5.

Table 5 Differential diagnostic approaches of COVID-19 with other viral and bacterial diseases.

Diagnostic Technique	COVID-19	SARS	MERS	Adenovirus	Influenza Virus	Human Metapneumovirus (HMPV)	Parainfluenza Virus	Respiratory Syncytial Virus (RSV)	Rhinovirus (Common cold)	Bacterial Pneumonia	M. pneumonia
Chest Radiograph	Bilateral peripheral consolidation	Focal opacity	Lung consolidation	Multifocal or diffuse opacity	Basal and axial alveolar consolidation	Parahilar opacities	Bilateral perihilar peribronchial thickening and interstitial infiltrates	Central pneumonia or peribronchitis	Bilateral perihilar peribronchial thickening	Focal segmental or lobar opacities in lungs	Bilateral lesions, pleural effusion, and hilar lymphadenopathy
Chest CT scan	Sub pleural, posterior consolidations, bilateral ground-glass opacities	Multifocal opacity, ground-glass opacities	Ground glass opacity, fibrosis of lungs	Bilateral GGO and consolidation with or without pleural effusion	Unilateral or bilateral multifocal ground-glass opacities	Hyperinflation, atelectasis, and consolidation of lungs	Multiple small peribronchial nodules, ground-glass opacities, and airspace consolidation	Multiple small peribronchial nodules and ground-glass opacities	Interlobular septal thickening, nodules, and consolidation of lungs	Abscesses or pleural effusions and enlarged lymph nodes	Combination of bronchial wall thickening and centrilobular nodules
ELISA	COVID-19 Nucleocapsid (NP) IgG/IgM anibodies	rN-type IgM and IgG antibodies	IgG antibodies detection	IgM antibody detection	Anti-Influenza virus A IgG antibodies	detection of hMPV antigens	IgG antibodies detection	IgG antibodies detection	Specific antibody IgA detection in serum and nasal secretion	C-polysaccharide (PnC) antigen detection	IgM antibodies detection
PCR	Qualitative detection of nucleic acid from SARS-CoV-2	Identification of SARS CoV genome	Target MERS- CoV nucleocapsid (N) gene	Detect DNA of adenovirus	Detect RNA from respiratory samples	89.6% sensitivity	Viral genome detection	Detect RNA of RSV	Detect HRV RNA from respiratory samples	Detect bacterial genome	A highly sensitive method for detection of mycoplasma

Differential Response Therapy

COVID-19 and other Coronaviruses (SARS, MERS)

There is currently no recommended drug by the U.S. Food and Drug Administration (FDA) against COVID-19.

Antiviral drugs: Chloroquine/hydroxychloroquine acts as an immunomodulant by lowering the viral load. They show a synergistic effect when used with macrolides (Azithromycin) with anti-inflammatory and immunomodulatory effects [2]. It should be used in low doses as higher doses cause toxicity and QT-prolongation, and cardiac arrhythmia. Remdesivir- a potent RNA polymerase inhibitor that obstructs viral RNA multiplication [70]. Unselective antibiotic intake should not be practiced. Immunotherapy: Anti-Interleukin 6 (Tocilizumab) is a monoclonal antibody directed against interleukin-6 receptors, reduces mortality in COVID-19 patients by improving respiratory function and reducing inflammatory storm-pathogenic T-cells and inflammatory monocytes with an increased level of interleukin-6 due to host immune response [2]. Antithrombotic therapy: Patients infected with COVID-19 show an increase in fibrin, fibrin degradation products, fibrinogen, and D-dimers that results in increased chances of thromboembolic diseases (like venous thromboembolism VTE). Antithrombotic agents (e.g., Enoxaparin) are directed to reduce the chances [71]. Systemic corticosteroids (e.g., methylprednisolone) should not be used except in critically ventilated patients. Oxygen therapy: Oxygen fast challenge, non-invasive ventilation, intubation, and protective mechanical ventilation, extracorporeal membrane oxygenation (ECMO) should be used in patients with multiple organ dysfunctions (MOD) to support organ function with respiratory support. There is no specific antiviral therapy and vaccine available. However, combined therapy of antiviral drugs (ribavirin) and glucocorticosteroids is helpful, but their efficacy is uncertain [64].

Adenovirus

Epidemic keratoconjunctivitis (EKC) is an iatrogenic disease and can be prevented by strict asepsis [12]. There is not any specific antiviral therapy for it. The treatment used is symptomatic and supportive. Infection can be prevented by using vaccines. Live non-attenuated, monovalent vaccines against AdV4, 7, and 21 are available in the form of enteric-coated capsules. But these vaccines are used only by the military.

Influenza Virus

Commonly used drugs for the treatment of Influenza are Oseltamivir (Tamiflu) taken orally and zanamivir (Relenza) inhaled into the nose. Treatment is effective when taken within 48 hours from the onset of symptoms and helps to reduce the duration of symptoms by 1 to 2 days.

Human Metapneumovirus (HMPV)

Peramivir (Rapivab) is administered intravenously and became available in 2015. They are neuraminidase inhibitors that inhibit the release of the virus from infected cells and limit the infection by reducing the spread of the virus. They are effective against both influenza A and B viruses. Rimantadine (Flumadine), a derivative of amantadine, is used instead of amantadine to treat and prevent influenza A because of its higher efficacy and lower side effects than amantadine. The best way to control the influenza infection is by preventing it from using vaccines. About every year, influenza vaccines are formulated using new prevalent strains to get better immunity. Killed (flu shot), live attenuated vaccine (nasal spray), and recombinant vaccines are available having hemagglutinin as a major antigen. Vaccination is not always effective due to a wide variety of antigens.

Parainfluenza Virus

No specific treatment and vaccine are available for treatment and as a prophylaxis measure [14].

Respiratory Syncytial Virus (RSV)

The use of aerosolized ribavirin is recommended in critically ill infants. However, it is more useful due to its uncertain effectiveness, a combination of hyperimmune antibodies and ribavirin. There is no vaccine available to prevent the disease. However, passive immunization with monoclonal antibodies and hyperimmune globulins is available for prophylaxis in premature or immunocompromised infants and chronic pulmonary disease children. Hand wash and gloves should be used to prevent nosocomial transmission [72].

Rhinovirus (Common cold)

Till now, no effective antiviral drugs for the Common cold, even though some initial research has shown benefits [65].

Bacterial pneumonia

Streptococcus pneumonia: Empirical antibiotics including β-lactams, Macrolides, and Fluoroquinolones are used, but bacteria develop resistance against these agents, specifically multidrug resistance, which causes treatment failure [73]. However, penicillin and β-lactam compounds can be selected to treat invasive pneumococcal diseases [74].

Haemophilus influenzae pneumonia: Third-generation cephalosporins are used to treat H. influenzae infections like meningitis or epiglottitis. Treatment with ceftriaxone or cefotaxime should be given to patients with confirmed or suspected H. influenzae infection. It must be continued till complete susceptibility data are available [28].

Moraxella catarrhalis pneumonia: Oral antibiotics like β-lactamase stable antibiotics such as amoxicillin-clavulanate are used to treat M. catarrhalis infections because of the presence of induced β-lactamases in many isolates. Besides, cephalosporin (cefaclor), or a non–β-lactam antibiotic such as trimethoprim-sulfamethoxazole should be introduced awaiting susceptibility test results [19].

Chlamydial pneumonia: Most clinicians prescribe macrolides (azithromycin) as first-line therapy, tetracyclines (tetracycline and doxycycline), and fluoroquinolones [59]. Tetracyclines and erythromycin show good activity in vitro and have been the most frequently used drugs in treating C. pneumonia infection. The most active macrolide is clarithromycin. The fluoroquinolones demonstrate good activity. Levofloxacin is much more active than ofloxacin and ciprofloxacin [75].

Mycoplasma pneumonia

M. pneumoniae infections are mostly mild, and they do not require any medicine, but some patients may need to become hospitalized if they develop pneumonia due to M. pneumoniae. In the case of hospitalization, azithromycin is commonly recommended [76]. Table 6 summarizes the differential response therapy of COVID-19 with other viral and bacterial respiratory diseases.

Table 6 Differential response therapy of COVID-19 with other viral and bacterial diseases.

Disease	Antiviral	Antibacterial	Steroids	NSAIDS	Others
COVID-19	Chloroquine/ hydroxychloroquine	Macrolides (Azithromycin)	Methylprednisolone	Ibuprofen, Aspirin	Anti-Interleukin 6 (Tocilizumab)
SARS
MERS
Adenovirus	Cidofovir	-	-	Paracetamol, Ibuprofen	-
Influenza virus	Oseltamivir (Tamiflu), zanamivir (Relenza)	-	Dexamethasone	Naproxen	-
Human Metapneumovirus (HMPV)	Peramivir (Rapivab)	-	Prednisone	Ibuprofen, Naproxen	-
Parainfluenza	Ribavirin (Virazole)	-	Dexamethasone, Prednisone	Paracetamol, Ibuprofen	Adrenalin
Respiratory Syncytial Virus (RSV)	Ribavirin	-	Glucocorticoids	Acetaminophen	-
Rhinovirus (Common cold)	-	-	-	Paracetamol, Ibuprofen	Pseudoephedrine
Bacterial Pneumonia	-	β-lactams, Macrolides, and Fluoroquinolones	Corticosteroids	-	-
M. pneumonia	-	Azithromycin, Tetracycline	Prednisolone	Ibuprofen, Naproxen	-

Mathematical Modelling in the Prediction of COVID-19

Simulations and modeling are proven predictive diagnostic tools that are helpful to control the human and animal diseases. Each disease exhibits typical biological properties; hence models are adapted accordingly to tackle the malaise in actual situations [77]. An accurate model for COVID-19 demands its ability of estimation, consideration of varying scenarios, many positive cases, death tolls & hospitalized patients, and COVID-19 territories in health-compromising areas. Several other models may be developed to help the control of the disease. Such models give rise to a product number of diseases which indicates the trend of the disease. A comparison of reproductive number R₀ of SARS-CoV-2 (2-2.5) compared to MERS (<1) and SARS (1.7-1.9) suggesting the higher pandemic potential of novel infection.

Salient and Latest Models Applied

Some short forecast phenomenological models that are real-time forecast models have already been used in various outbreaks of infectious diseases, e.g., SARS, Ebola, dengue, and pandemic influenza in the past. These three phenomenological models include the generalized logistic growth model, Richard model, and sub-epidemic wave model [78]. Generalized logistic growth models accommodate sub-exponential growth dynamics using p-value, but the process extends a simple logistic growth model. Richard model uses scaling model to permit deviation from asymmetric logistic curve. The latter model helps in complex epidemics having multiple peaks, e.g., SARS cases in Singapore. The resultant curve of this model is assumed as an aggregation of multiple primary sub-epidemics.

Mathematical equations can describe details about the spread rate of COVID-19 in a time-dependent analytical function with units of days [79]. For a country or region having population , it claimed that the time rate of change (spread rate) of H (Number of individuals contracting the disease) is proportional to the multiplication of no. of people who are infected with the disease and those did not infect. It is stated that “the time-dependent change (Spreading) rate of the H; the number of individuals who have caught a contagious disease is proportional to the multiplication of the numbers of those who have caught the disease and those who have not” [80]. Here only one equation is given while there are a series of equations that are kept on the resolution to reach the final equation., Further reading and explanation may be obtained from Cakir and Savas [79], keeping in view the domain of the book chapter.

dH / dt = µH(P-H)

H (0) = H₀

H(t₁) = t₁

where

t denotes unit days as an independent time variable

(t) represent dependent variable showing no. of the patient at “t” time

dH / dt represents derivatives corresponding to “t” dependent variation rat of disease

µ is a parameter covering the sum of factors that affect the spreading rate. Supposition to these equations include initially t = 0, no. of the patient (0) = H0, no. of patients at time t = t1 provided as additional information (t1) = H1 , and no. of people open at risk to the diseases be P .

The currently applicable model for SARS-CoV2 is the θ-SEIHRD model, a novel model that has passed previous experiments over the Ebola virus outbreak from 2014-2016 and 2018-2020 in Congo with successful forecasts. This model is now applied in an adapted form on COVID-19, and an example was taken from China where corona outbreak occurr. It relates disease fatality percentage and percentage detected over real infected to find out the importance of outcome on the impact of the disease. The model utilizes assumptions inclusive of which are a) Susceptible (S) which are not infected by pathogen; b) Exposed (E) which are going through incubation period with no clinical signs but have ability to infect other with low probability however they may shift to next infectious category once show signs; c) Infectious (I) which are now showing clinical signs that in turn may be hospitalized or may keep spreading if SOPs are not adopted; d) Infectious but undetected (I u) are the group of people with clinical signs which are not severe enough to be considered for hospitalization or authorities may have overlooked, and are source of spread of pathogen in the absence of SOPs; e) Hospitalized or in quarantine at home (denoted by H_R) are group of people who are identified by authorities, shifted to hospital or quarantine at home, but may spread disease in the absence of observation of SOPs, f) Hospitalized that will die (H_D) are the group of people who are hospitalized in life threatening condition, and are still able to infect people, g) Dead by COVID-19 (D) are the group of people who did not survive, f) Recovered (R_d) are the group of people who recovered after being hospitalized, and have developed immunity but are not source of spread of infection to others, NB: days a person spend in hospital for convalescent period are “C” days, g) Recovered from infectious but stayed undetected (R_u) is the group of people who got infected previously but stayed undetected and have recovered with no threat to spread disease to others. Explanation of further variables and details to use this model can be studied from Ivorra et al. [77].

CONCLUSION

COVID-19, pandemic disease, differentially attaches to ACE-2 with substitution of 380 amino acids in non-structural kinds of proteins while 27 mutations in spike protein compared to that of SARS disease virus. High fever, shortness of breathing, dry cough, body aches are typical differential signs of this disease. CT-scan shows infiltrate sub-segmental consolidation and ground-glass opacities even in patients with false-negative molecular tests. RT-PCR is a gold standard test to quarantine/admission the patient to the hospital, while the coupling of this molecular test with other diagnostic approaches paves the road to treat the malaise. Azithromycin and chloroquine as immunomodulant and plasma therapy are used as response treatment and symptomatic treatment of the patient. The mathematical predictive model identifies 2-2.5 as the reproductive number (R₀) of this disease as differentially higher than related coronaviruses. The chapter thus acknowledges all aspects of disease before reaching confirmatory diagnosis to help effective treatment, control, and prevent pandemic coronavirus infection.

CONSENT FOR PUBLICATION

Not Applicable.

CONFLICT OF INTEREST

The author confirms that this chapter contents have no conflict of interest.

ACKNOWLEDGEMENT

Declared none.

REFERENCES

[1]	Chung M, Zeng X, Jacobi A. CT Imaging Features of 2019 Novel Coronavirus 2020.
[2]	Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res 2020; 7(1): 11.[http://dx.doi.org/10.1186/s40779-020-00240-0] [PMID: 32169119]
[3]	Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill 2020; 25(3): 1-8.[http://dx.doi.org/10.2807/1560-7917.ES.2020.25.3.2000045] [PMID: 31992387]
[4]	Bassetti M, Vena A, Giacobbe DR. The novel Chinese coronavirus (2019-nCoV) infections: Challenges for fighting the storm. Eur J Clin Invest 2020; 50(3): e13209.[http://dx.doi.org/10.1111/eci.13209] [PMID: 32003000]
[5]	Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill 2020; 25(3). [http://dx.doi.org/10.2807/1560-7917.ES.2020.25.3.2000045] [PMID: 31992387]
[6]	Kishaba T. Community-acquired pneumonia caused by Mycoplasma pneumoniae: How physical and radiological examination contribute to successful diagnosis. Front Med (Lausanne) 2016; 3: 28.[http://dx.doi.org/10.3389/fmed.2016.00028] [PMID: 27379238]
[7]	Ishiguro T, Kobayashi Y, Uozumi R, et al. Viral pneumonia requiring differentiation from acute and progressive diffuse interstitial lung diseases. Intern Med 2019; 58(24): 3509-19.[http://dx.doi.org/10.2169/internalmedicine.2696-19] [PMID: 31839671]
[8]	Dai H, Zhang X, Xia J, Zhang T, Shang Y, Huang R. High-resolution chest CT features and clinical characteristics of patients infected with COVID-19 in Jiangsu, China. International Journal of Infectious Diseases 2020; 95: 106-2.[http://dx.doi.org/10.1016/j.ijid.2020.04.003]
[9]	Dai WC, Zhang HW, Yu J, et al. CT imaging and differential diagnosis of COVID-19. Can Assoc Radiol J 2020; 71(2): 195-200.[http://dx.doi.org/10.1177/0846537120913033] [PMID: 32129670]
[10]	Ji W, Wang W, Zhao X, Zai J, Li X. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol 2020; 92(4): 433-40.[http://dx.doi.org/10.1002/jmv.25682] [PMID: 31967321]
[11]	Ksiazek TG, Erdman D, Goldsmith CS, et al. SARS Working GroupA novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1953-66.[http://dx.doi.org/10.1056/NEJMoa030781] [PMID: 12690092]
[12]	Ebner K, Suda M, Watzinger F, Lion T. Molecular detection and quantitative analysis of the entire spectrum of human adenoviruses by a two-reaction real-time PCR assay. J Clin Microbiol 2005; 43(7): 3049-53.[http://dx.doi.org/10.1128/JCM.43.7.3049-3053.2005] [PMID: 16000414]
[13]	Stockton J, Stephenson I, Fleming D, Zambon M. human metapneumovirus as a cause of community-acquired respiratory illness. Emerg Infect Dis 2002; 8(9): 897-901.[http://dx.doi.org/10.3201/eid0809.020084] [PMID: 12194763]
[14]	Karron RA, Collins PL. Parainfluenza viruses. In Fields Virology: Sixth Edition 2013; 1[http://dx.doi.org/10.1159/000393651]
[15]	Hall CB. Respiratory Syncitial Virus and Parainflueza Virus1. Hall CB. Respiratory Syncitial Virus and Parainflueza Virus. English J. 2011;344(25):1917-1928. N Engl J Med 2001; 344: 1917-28.[http://dx.doi.org/10.1056/NEJM200106213442507] [PMID: 11419430]
[16]	Palmenberg AC, Rathe JA, Liggett SB. Analysis of the complete genome sequences of human rhinovirus. J Allergy Clin Immunol 2010; 125(6): 1190-9.[http://dx.doi.org/10.1016/j.jaci.2010.04.010] [PMID: 20471068]
[17]	Østergaard C, Konradsen HB, Samuelsson S. Clinical presentation and prognostic factors of Streptococcus pneumoniae meningitis according to the focus of infection. BMC Infect Dis 2005; 5: 93.[http://dx.doi.org/10.1186/1471-2334-5-93] [PMID: 16253143]
[18]	Agrawal A, Murphy TF. Haemophilus influenzae infections in the H. influenzae type b conjugate vaccine era. J Clin Microbiol 2011; 49(11): 3728-32.[http://dx.doi.org/10.1128/JCM.05476-11] [PMID: 21900515]
[19]	Murphy TF, Parameswaran GI. Moraxella catarrhalis, a human respiratory tract pathogen. Clin Infect Dis 2009; 49(1): 124-31.[http://dx.doi.org/10.1086/599375] [PMID: 19480579]
[20]	Megran David, Peeling Rosanna W, Marrie Thomas J. Chlamydia Pneumoniae Pneumonia: An Evolving Clinical Spectrum. Canadian J Infectious Diseases 1995; 6: 191-5.
[21]	Kashyap S, Sarkar M. Mycoplasma pneumonia: Clinical features and management. Lung India 2010; 27(2): 75-85.[http://dx.doi.org/10.4103/0970-2113.63611] [PMID: 20616940]
[22]	Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet 2020; 395(10223): 470-3.[http://dx.doi.org/10.1016/S0140-6736(20)30185-9] [PMID: 31986257]
[23]	Ramanathan K, Antognini D, Combes A, Paden M, Zakhary B, Ogino M. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID research that is available on the COVID-19 resource centre - including this for unrestricted research re-use 202019-21.
[24]	Biacchesi S, Skiadopoulos MH, Boivin G, et al. Genetic diversity between human Metapneumovirus subgroups. Virology 2003; 315(1): 1-9.[http://dx.doi.org/10.1016/S0042-6822(03)00528-2] [PMID: 14592754]
[25]	Ansari SA, Springthorpe VS, Sattar SA, Rivard S, Rahman M. Potential role of hands in the spread of respiratory viral infections: studies with human parainfluenza virus 3 and rhinovirus 14. J Clin Microbiol 1991; 29(10): 2115-9.[http://dx.doi.org/10.1128/jcm.29.10.2115-2119.1991] [PMID: 1658033]
[26]	Peltola V, Waris M, Österback R, Susi P, Ruuskanen O, Hyypiä T. Rhinovirus transmission within families with children: incidence of symptomatic and asymptomatic infections. J Infect Dis 2008; 197(3): 382-9.[http://dx.doi.org/10.1086/525542] [PMID: 18248302]
[27]	Saraya T, Kurai D, Ishii H, et al. Epidemiology of virus-induced asthma exacerbations: with special reference to the role of human rhinovirus. Front Microbiol 2014; 5: 226.[http://dx.doi.org/10.3389/fmicb.2014.00226] [PMID: 24904541]
[28]	MacNeil JR, Cohn AC, Farley M, et al. Current epidemiology and trends in invasive Haemophilus influenzae disease--United States, 1989-2008. Clin Infect Dis 2011; 53(12): 1230-6.[http://dx.doi.org/10.1093/cid/cir735] [PMID: 22080119]
[29]	Richards SJ, Greening AP, Enright MC, Morgan MG, McKenzie H. Outbreak of Moraxella catarrhalis in a respiratory unit. Thorax 1993; 48(1): 91-2.[http://dx.doi.org/10.1136/thx.48.1.91] [PMID: 8434362]
[30]	Porritt RA, Crother TR. Chlamydia pneumoniae infection and inflammatory diseases. For Immunopathol Dis Therap 2016; 7(3-4): 237-54.[http://dx.doi.org/10.1615/ForumImmunDisTher.2017020161] [PMID: 30687565]
[31]	Dawood FS, Ambrose JF, Russell BP, et al. Outbreak of pneumonia in the setting of fatal pneumococcal meningitis among US Army trainees: potential role of Chlamydia pneumoniae infection. BMC Infect Dis 2011; 11: 157.[http://dx.doi.org/10.1186/1471-2334-11-157] [PMID: 21635754]
[32]	Perlman S, Netland J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 2009; 7(6): 439-50.[http://dx.doi.org/10.1038/nrmicro2147] [PMID: 19430490]
[33]	Chan JF-W, Yip CC-Y, To KK-W, Tang TH-C, Wong SC-Y, Leung K-H. Improved molecular diagnosis of COVID-19 by the novel, highly sensitive and specific COVID-19-RdRp/Hel real-time reverse transcription-PCR assay validated in vitro and with clinical specimen. J Clin Microbiol 2020; 23;58(5): e00310-20.[http://dx.doi.org/10.1128/JCM.00310-20]
[34]	Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-280.e8.[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[35]	Chu DKW, Pan Y, Cheng SMS, et al. Molecular diagnosis of a novel coronavirus (2019-nCoV) causing an outbreak of pneumonia. Clin Chem 2020; 66(4): 549-55.[http://dx.doi.org/10.1093/clinchem/hvaa029] [PMID: 32031583]
[36]	Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG. Author correction: A new coronavirus associated with human respiratory disease in China. Nature 2020; 580(7803): E7.[http://dx.doi.org/10.1038/s41586-020-2008-3]
[37]	Zhao S, Ge X, Wang X, Liu A, Guo X, Zhou L. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19.The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information 2020.
[38]	Lam CWK, Chan MHM, Wong CK. Severe acute respiratory syndrome: clinical and laboratory manifestations. Clin Biochem Rev 2004; 25(2): 121-32.[PMID: 18458712]
[39]	Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581(7807): 215-20.[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[40]	Kukla M, Skonieczna-Żydecka K, Kotfis K, et al. COVID-19, MERS and SARS with Concomitant Liver Injury-Systematic Review of the Existing Literature. J Clin Med 2020; 9(5): 1420.[http://dx.doi.org/10.3390/jcm9051420] [PMID: 32403255]
[41]	Lefkowitz EJ, Dempsey DM, Hendrickson RC, Orton RJ, Siddell SG, Smith DB. Virus taxonomy: the database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Res 2018; 46(D1): D708-17.[http://dx.doi.org/10.1093/nar/gkx932] [PMID: 29040670]
[42]	Hamelin M-È, Yim K, Kuhn KH, et al. Pathogenesis of human Metapneumovirus lung infection in BALB/c mice and cotton rats. J Virol 2005; 79(14): 8894-903.[http://dx.doi.org/10.1128/JVI.79.14.8894-8903.2005] [PMID: 15994783]
[43]	Schomacker H, Schaap-Nutt A, Collins PL, Schmidt AC. Pathogenesis of acute respiratory illness caused by human parainfluenza viruses. Curr Opin Virol 2012; 2(3): 294-9.[http://dx.doi.org/10.1016/j.coviro.2012.02.001] [PMID: 22709516]
[44]	Sonja A. Rasmussen, MD, MS JCS. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-. Ann Oncol 2020; 19–21[http://dx.doi.org/10.1007/s00134-020-05991-x.Bizzarro]
[45]	Vlasak M, Roivainen M, Reithmayer M, et al. The minor receptor group of human rhinovirus (HRV) includes HRV23 and HRV25, but the presence of a lysine in the VP1 HI loop is not sufficient for receptor binding. J Virol 2005; 79(12): 7389-95.[http://dx.doi.org/10.1128/JVI.79.12.7389-7395.2005] [PMID: 15919894]
[46]	Kennedy JL, Turner RB, Braciale T, Heymann PW, Borish L. Pathogenesis of rhinovirus infection. Curr Opin Virol 2012; 2(3): 287-93.[http://dx.doi.org/10.1016/j.coviro.2012.03.008] [PMID: 22542099]
[47]	Henriques-Normark B, Tuomanen EI. The pneumococcus: epidemiology, microbiology, and pathogenesis. Cold Spring Harb Perspect Med 2013; 3(7): 1-16.[http://dx.doi.org/10.1101/cshperspect.a010215] [PMID: 23818515]
[48]	Subramanian K, Henriques-Normark B, Normark S. Emerging concepts in the pathogenesis of the Streptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen. Cell Microbiol 2019; 21(11): e13077.[http://dx.doi.org/10.1111/cmi.13077] [PMID: 31251447]
[49]	Hammerschmidt S, Bergmann S, Paterson GK, Mitchell TJ. Pathogenesis of Streptococcus pneumoniae infections:adaptive immunity, innate immunity, cell biology, virulence factors 2007139-81.[http://dx.doi.org/10.1007/978-3-7643-7563-8_8]
[50]	Al-Anazi K, Al-Fraih F, Chaudhri N, Al-Mohareb F. Pneumonia caused by Moraxella catarrhalis in haematopoietic stem cell transplant patients. Report of two cases and review of the literature. Libyan J Med 2007; 2(3): 144-7.[http://dx.doi.org/10.3402/ljm.v2i3.4716] [PMID: 21503215]
[51]	Krüll M, Suttorp N. Pathogenesis of Chlamydophila pneumoniae infections — epidemiology, immunity, cell biology, virulence factors 200783-110.[http://dx.doi.org/10.1007/978-3-7643-7563-8_6]
[52]	Kern JM, Maass V, Maass M. Molecular pathogenesis of chronic Chlamydia pneumoniae infection: a brief overview. Clin Microbiol Infect 2009; 15(1): 36-41.[http://dx.doi.org/10.1111/j.1469-0691.2008.02631.x] [PMID: 19220338]
[53]	Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004; 17(4): 697-728.[http://dx.doi.org/10.1128/CMR.17.4.697-728.2004] [PMID: 15489344]
[54]	Atkinson TP, Balish MF, Waites KB. Epidemiology, clinical manifestations, pathogenesis and laboratory detection of Mycoplasma pneumoniae infections. FEMS Microbiol Rev 2008; 32(6): 956-73.[http://dx.doi.org/10.1111/j.1574-6976.2008.00129.x] [PMID: 18754792]
[55]	Ellis1 BRADTB. The enigma of yellow fever in East Africa. Rev Med Virol 2009; 19: 57-64.[http://dx.doi.org/10.1002/rmv]
[56]	Falsey AR, McElhaney JE, Beran J, et al. Respiratory Syncytial Virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness. J Infect Dis 2014; 209(12): 1873-81.[http://dx.doi.org/10.1093/infdis/jit839] [PMID: 24482398]
[57]	Heymann PW, Platts-Mills TAE, Johnston SL. Discussion. Pediatr Infect Dis J 2005; 24: 217-22.[http://dx.doi.org/10.1097/01.inf.0000188164.33856.f9] [PMID: 16378049]
[58]	Pappas DE, Hendley JO, Hayden FG, Winther B. Symptom profile of Common colds in school-aged children. Pediatr Infect Dis J 2008; 27(1): 8-11.[http://dx.doi.org/10.1097/INF.0b013e31814847d9] [PMID: 18162930]
[59]	Fajardo KA, Zorich SC, Voss JD, Thervil JW. Pneumonia outbreak caused by chlamydophila pneumoniae among US air force academy cadets, Colorado, USA. Emerg Infect Dis 2015; 21(6): 1049-51.[http://dx.doi.org/10.3201/eid2106.141394] [PMID: 25988545]
[60]	Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology 2020; 296(2): E32-40.[http://dx.doi.org/10.1148/radiol.2020200642] [PMID: 32101510]
[61]	Bernheim A, Mei X, Huang M, et al. Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection. Radiology 2020; 295(3): 200463.[http://dx.doi.org/10.1148/radiol.2020200463] [PMID: 32077789]
[62]	Yang Y, Yang M, Shen C, Wang F, Yuan J, Li J. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. MedRxiv 2020.[http://dx.doi.org/10.1101/2020.02.11.20021493]
[63]	Wen Z, Chi Y, Zhang L, et al. Coronavirus disease 2019: initial detection on chest ct in a retrospective multicenter study of 103 chinese patients. Radiol Cardiothorac Imaging 2020; 2(2): e200092.[http://dx.doi.org/10.1148/ryct.2020200092] [PMID: 33778564]
[64]	Petrosillo N, Viceconte G, Ergonul O, Ippolito G, Petersen E. COVID-19, SARS and MERS: are they closely related? Clin Microbiol Infect 2020; 26(6): 729-34.[http://dx.doi.org/10.1016/j.cmi.2020.03.026] [PMID: 32234451]
[65]	Moore HC, Jacoby P, Taylor A, et al. Kalgoorlie Otitis Media Research Project TeamThe interaction between respiratory viruses and pathogenic bacteria in the upper respiratory tract of asymptomatic Aboriginal and non-Aboriginal children. Pediatr Infect Dis J 2010; 29(6): 540-5.[http://dx.doi.org/10.1097/INF.0b013e3181d067cb] [PMID: 20134359]
[66]	Royston L, Tapparel C. Rhinoviruses and respiratory enteroviruses: Not as simple as ABC. Viruses 2016; 8(1): E16.[http://dx.doi.org/10.3390/v8010016] [PMID: 26761027]
[67]	Khan SS, Smith MS, Reda D, Suffredini AF, McCoy JP, Jr. Multiplex bead array assays for detection of soluble cytokines: comparisons of sensitivity and quantitative values among kits from multiple manufacturers. Cytometry B Clin Cytom 2004; 61(1): 35-9.[http://dx.doi.org/10.1002/cyto.b.20021] [PMID: 15351980]
[68]	Daxboeck F, Krause R, Wenisch C. Laboratory diagnosis of Mycoplasma pneumoniae infection. Clin Microbiol Infect 2003; 9(4): 263-73.[http://dx.doi.org/10.1046/j.1469-0691.2003.00590.x] [PMID: 12667235]
[69]	Montagnani F, Rossetti B, Vannoni A, Cusi MG, De Luca A. Laboratory diagnosis of Mycoplasma pneumoniae infections: data analysis from clinical practice. New Microbiol 2018; 41(3): 203-7.[PMID: 29874388]
[70]	Lee N-Y, Li C-W, Tsai H-P, Chen P-L, Syue L-S, Li M-C. A case of COVID-19 and pneumonia returning from Macau in Taiwan: Clinical course and anti-SARS-CoV-2 IgG dynamic. J Microbiol Immunol Infect 2020; 53(3): 485-7.[http://dx.doi.org/10.1016/j.jmii.2020.03.003]
[71]	Woelfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Mueller MA. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. MedRxiv 2020.[http://dx.doi.org/10.1101/2020.03.05.20030502]
[72]	Hall CB. Respiratory Syncytial Virus (6th ed.) 6th ed.2009441-61.[http://dx.doi.org/10.1002/9780470741405.ch18]
[73]	Ramirez JA, Anzueto AR. Changing needs of community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (Suppl. 3): iii3-9.[http://dx.doi.org/10.1093/jac/dkr094] [PMID: 21482567]
[74]	Wang CY, Chen YH, Fang C, et al. Antibiotic resistance profiles and multidrug resistance patterns of Streptococcus pneumoniae in pediatrics: A multicenter retrospective study in mainland China. Medicine (Baltimore) 2019; 98(24): e15942.[http://dx.doi.org/10.1097/MD.0000000000015942] [PMID: 31192930]
[75]	Apan TZ, Alpay D, Alpay Y. The possible association of Chlamydia pneumoniae infection with nasal polyps. Eur Arch Otorhinolaryngol 2007; 264(1): 27-31.[http://dx.doi.org/10.1007/s00405-006-0140-9] [PMID: 16902779]
[76]	Zhang W, Zhang S, Wang Q, Li Y, Jing H, Hu G. Outbreak of macrolide-resistant mycoplasma pneumoniae in a primary school in Beijing China 20184-10.
[77]	Ivorra B, Ferrández MR, Vela-pérez M, Ramos AM. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information 2020.
[78]	Roosa K, Lee Y, Luo R, et al. Real-time forecasts of the COVID-19 epidemic in China from February 5th to February 24th, 2020. Infect Dis Model 2020; 5: 256-63.[http://dx.doi.org/10.1016/j.idm.2020.02.002] [PMID: 32110742]
[79]	Cakir Z, Savas HB. A mathematical modelling approach in the spread of the novel 2019 coronavirus SARS-COV-2 (COVID-19) pandemic. Electron J Gen Med 2020; 17: 1-3.[http://dx.doi.org/10.29333/ejgm/7861]
[80]	Edwards CH, Penney DE. Differential equations : computing and modeling 1996; 1(various pagings)