LO Tropmed week 1

1. Respiratory distress (tipe, dll)

Respiratory failure occurs when the respiratory system fails to maintain gas exchange, in which
PaO2 is lower than 60 mmHg and/or PaCO2 is higher than 50 mmHg, resulting in hypoxia or
hypercapnia. It is classified according to blood gases values:
 Type 1 Respiratory Failure (hypoxemic): is associated with damage to lung tissue
which prevents adequate oxygenation of the blood.  However, the remaining normal lung
is still sufficient to excrete carbon dioxide. This results in low oxygen, and normal or low
carbon dioxide levels. Arterial oxygen pressure (PaO2) is <8 kPa (60 mm Hg) with
normal or low arterial carbon dioxide pressure (PaCO2). In this type, the gas exchange is
impaired at the level of alveolar-capillary membrane. Examples of this are carcinogenic
or non-cardiogenic pulmo edema and severe pneumonia.
 Type 2 Respiratory Failure (hypercapnic): occurs when alveolar ventilation is
insufficient to excrete the carbon dioxide being produced. Inadequate ventilation is due to
reduced ventilatory effort or inability to overcome increased resistance to ventilation 
respiratory pump failure. It affects the lung as a whole, and therefore carbon dioxide
accumulates, presenting with PaO2 of <8 kPa (60 mm Hg) or normal, with hypercapnia
PaCO2 >6.0kPa (> 50 mm Hg).
Etiology
Respiratory failure may be due to pulmonary or extra-pulmonary causes which include:
CNS causes due to depression of the neural drive to breath as in cases of overdose of a narcotic
and sedative.
Disorders of the peripheral nervous system: Respiratory muscle and chest wall weakness as in
cases of Guillian-Barre syndrome and myasthenia gravis.
Upper and lower airways obstruction: due to various causes as in cases of exacerbation of
COPD and acute severe bronchial asthma 
Abnormities of the alveoli that result in type 1 (hypoxemic) respiratory failure as in cases of
pulmonary edema and severe pneumonia.
Causes of type 1 respiratory failure include: pulmonary oedema, pneumonia, COPD, asthma,
acute respiratory distress syndrome, chronic pulmonary fibrosis, pneumothorax, pulmonary
embolism, pulmonary hypertension.
Type 2 respiratory failure is commonly caused by COPD but may also be caused by chest-wall
deformities, respiratory muscle weakness and CNS depression. CNS depression is associated
with reduced respiratory drive and is often a side effect of sedatives and strong opioids. It may
also be caused by severe asthma, myasthenia gravis, muscle disorders, obesity, hypothyroidism
and adult respiratory syndrome.
DETECTING TYPE 1 AND TYPE 2 RESPIRATORY FAILURE
 Blood gas analysis: helps professionals identify the type of respiratory failure, which is
crucial to indicate what respiratory support may be needed. Type 1 respiratory failure
may require only supplementary oxygen, but type 2 failure may require additional
support such as continuous positive airway pressure (CPAP) or biphasic positive airway
pressure (BiPAP) to increase exchange of both gases and, where possible, reverse any
causes for low tidal volumes or low respiratory rates. Blood gas analysis will also be
useful in monitoring the clinical condition throughout treatment and recovery.
 Chest radiography: detect chest wall, pleural, and lung parenchymal Lesions.
 Investigations for detecting underlying cause of the respiratory failure may include:
o Complete blood count (CBC)
o Sputum, blood, and urine culture
o Blood electrolytes and thyroid function tests
o Pulmonary function tests
o Electrocardiography (ECG)
o Echocardiography
o Bronchoscopy
 Capnography: provides a continuous reading of respiratory function and end tidal CO2.
 Pulse oximetry: gives a continuous measure of blood oxygen saturation.
 ECG: to monitor cardiac function as tachycardia and cardiac arrhythmias may result
from hypoxaemia and acidosis.
Patients may also present other signs and symptoms of respiratory failure:

SYMPTOMS AND SIGNS OF SYMPTOMS AND SIGNS OF

HYPOXEMIA HYPERCAPNIA
 Dyspnoea, irritability Headache

Confusion, somnolence, fits Change of behaviour

Tachycardia, arrhythmia Coma

Tachypnoea Papilledema

Cyanosis Warm extremities

Symptoms and signs of the underlying disease

Examples:
Fever, cough, sputum production, chest pain in cases of pneumonia.
History of sepsis, polytrauma, burn, or blood transfusions before the onset of acute respiratory
failure may point to acute respiratory distress syndrome.
INTERVENTIONS FOR TYPE 1 AND TYPE 2 RESPIRATORY FAILURE
Intervening in cases of respiratory failure includes not only supportive measures as well as
treatment of the underlying cause. Depending on presentation, interventions aim to correct
hypoxemia or hypercapnia and respiratory acidosis.
 Correction of hypoxemia: aim to maintain adequate tissue oxygenation, achieved with
an arterial oxygen pressure (PaO2) of 60 mm Hg or arterial oxygen saturation (SaO2)
about 90%. Un-controlled oxygen supplementation can result in oxygen toxicity and CO2
(carbon dioxide) narcosis. So the inspired oxygen concentration should be adjusted at the
lowest level, which is sufficient for tissue oxygenation. Oxygen can be delivered via
nasal canula, simple face mask, nonrebreathing mask or high flow nasal canula. In severe
cases, patient may require invasive ventilatory support. Extracorporeal membrane
oxygenation may be needed in refractory cases.
 Correction of hypercapnia and respiratory acidosis: this is achieved by treating the
underlying cause or providing ventilatory support.
Ventilatory support for the patient with respiratory failure
The goals of ventilatory support in respiratory failure are:
 Correct hypoxemia
 Correct acute respiratory acidosis
 Resting of ventilatory muscles 
Common indications for mechanical ventilation include the following:
 Apnea with respiratory arrest 
 Tachypnea with respiratory rate >30 breaths per minute
 Disturbed conscious level or coma
 Respiratory muscle fatigue
 Hemodynamic instability
 Failure of supplemental oxygen to increase PaO2 to 55-60 mm Hg
 Hypercapnea with arterial pH less than 7.25
The choice of invasive or noninvasive ventilatory support depends on the clinical situation,
whether the condition is acute or chronic, and how severe it is. It also depends on the underlying
cause. If there are no absolute indications for invasive mechanical ventilation or intubations and
if there are no contraindications for noninvasive ventilation, non-invasive ventilation is preferred
particularly in cases of COPD exacerbation, Cardiogenic pulmonary edema and obesity
hypoventilation syndrome.
Type 1 and type 2 respiratory failure is a serious medical condition. Mortality associated with
respiratory failure depends on the underlying cause as well as the speed of diagnosis and efficacy
of management. Being able to prevent, detect and intervene adequately is crucial for improved
patient outcomes.
Complications
Complications from respiratory failure may be a result of blood gases disturbances or from the
therapeutic approach itself. Examples of these complications:
Lung complications: for example, pulmonary embolism, irreversible scarring of the
lungs, pneumothorax, and dependence on a ventilator.
Cardiac complications: for example, heart failure, arrhythmias, cardiac arrest, and
acute myocardial infarction.
Neurological complications: a prolonged period of brain hypoxia can lead to irreversible brain
damage and brain death.
Renal:  acute renal failure may occur due to hypoperfusion and/or nephrotoxic drugs.
Gastro-intestinal: stress ulcer, ileus, and hemorrhage
Nutritional: malnutrition, diarrhea hypoglycemia, electrolyte disturbances
Infectious: sepsis is the most common cause of death in patients with acute respiratory failure
Mortality is often due to multiorgan failure.

2. Viral pneumonia apa saja, RF, klinis, etiology, patof

Pneumonia has been defined as an infection of the lung parenchyma. Rather than looking at it as
a single disease, we must remember that pneumonia is an umbrella term for a group  of
syndromes caused by a variety of organisms resulting in varied manifestations and sequelae.
There have been many attempts to classify pneumonia based on the etiology, clinical setting in
which the patent acquired the infection, and the pattern of involvement of lung parenchyma,
among other classifications.
Community-Acquired Pneumonia (CAP)
Any pneumonia acquired outside of a hospital in a community setting.
Hospital-Acquired Pneumonia (HAP)
Any pneumonia acquired 48 hours after being admitted in an inpatient setting such as a hospital
and not incubating at the time of admission is considered as HAP. This classification helps clear
the confusion surrounding the terms healthcare-associated and hospital-acquired pneumonia.
Now all pneumonia acquired in the setting of assisted-living facilities, rehabilitation facilities,
and other healthcare facilities have been included under community-acquired pneumonia, and a
hospital setting is necessary for classifying pneumonia as HAP.
Ventilator Associated Pneumonia (VAP)
Any pneumonia acquired 48 hours after endotracheal intubation is considered as VAP.
These categories have helped establish the common organisms responsible for each type of
pneumonia and helped to formulate treatment guidelines for the efficient management in both in-
patient and out-patient setting.
Depending on the pattern of involvement, pneumonia has historically also been studied as:
 Focal non-segmental or lobar pneumonia: involvement of a single lobe of the lung. 
 Multifocal bronchopneumonia or lobular pneumonia
 Focal or diffuse interstitial pneumonia
Etiology
While identifying an etiologic agent for pneumonia is essential for effective treatment as well as
epidemiological record keeping, this is seldom seen in clinical practice. Widespread reviews
have shown that a single cause of pneumonia has often been identified in less than 10% of
patients presenting to the emergency department. Nonetheless, the most common organisms
causing pneumonia can be studied under the headings mentioned earlier.
Community-Acquired Pneumonia
Bacterial causes
They have been classically studied under the subheadings "typical" and "atypical" organisms in
terms of ease of culture positivity. Common typical organisms
include Pneumococcus, Haemophilus influenzae, Moraxella catarrhalis, Group A Streptococcus,
and other aerobic and anaerobic gram-negative organisms. Atypical organisms commonly seen
in clinical practice include Legionella, Mycoplasma, Chlamydia, among others. In the United
States, the most common bacterial causes of CAP include Streptococcus
pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, and gram-negative enteric
bacilli.
Viral causes
It is often observed that viral species colonize nasopharynx of patients with CAP. Whether they
are the primary cause or contribute to the pathogenesis by secondary bacterial causes is still
being investigated. However, some of the most frequent viral agents implicated in CAP in the
United States include influenza virus followed by respiratory syncytial virus, parainfluenza virus,
and adenoviruses. 
Fungal causes
Fungal infections are usually implicated in patients with certain predisposing
immunocompromised states like HIV and organ transplant recipients, among others. However,
often overlooked, some fungal species can cause pneumonia in immunocompetent individuals
which results in a delay in diagnosis and leads to unfavorable outcomes. The 3 commonest ones
in North America include Histoplasma, Blastomyces, and Coccidioides.
Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia
There is considerable overlap in the etiologic agents in non-ventilated hospitalized patients and
ventilated patients with pneumonia, and it is, therefore, appropriate to consider them together.
These include:
 Gram-negative bacilli like Escherichia coli, Pseudomonas Aerugenosa, Acinetobacter,
and Enterobacter among others
 Gram-positive cocci like Staphylococcus aureus;  both Methicillin-sensitive and resistant,
although the latter is more prevalent
 Other viruses and fungi that are more prevalent in immunocompromised and severely ill
patients
Viral pneumonia is defined as a disease entity wherein there is the viral causation of oxygen
and carbon dioxide gas exchange abnormalities at the level of the alveoli, secondary to viral-
mediated and/or immune response-mediated inflammation. The traditional role of viral
pneumonia was as a disease found predominantly in the very young, the elderly, and those
exposed to influenza. In the past, the diagnosis of viral pneumonia was predicated on it being
somewhat a diagnosis of exclusion. History, physical exam, chest radiography, and available lab
work (until recently) lacked sensitivity and specificity. Once bacterial pneumonia has been
excluded, then viral pneumonia diagnosis was entertained.
Traditionally, the treatment of viral pneumonia revolved around supportive care:
 Supplemental oxygen when indicated
 Airway augmentation as appropriate
 Monitoring of and replacement of any fluid deficits
 Symptomatic control of temperature and cough
 Rest to reduce oxygen demand
 Treatment of any comorbidities and/or concomitant bacterial pneumonia
The concepts of diagnosis, prevalence, clinical role, and treatment of viral pneumonia are in flux
for several reasons.
1. There is a growing population at increased risk of viral pneumonia:
 The increases in life span and early infant survivability have created an additional
population at greater risk of viral pneumonia.
 The increased number of those receiving immune-impairing therapy (radiation and/or
chemotherapy) for cancer.
  The increased use of disease-modifying hematological/immunological agents in chronic
illness, resulting in secondary impaired immunity.
 The advent of HIV
 The increase in the number of patients with inborn immune impairment serving bacterial
infection secondary to antibiotic therapy.
 The increased incidence of organ transplantation and immunosuppressive therapy.
2. The availability of sensitive, specific, real-time-result-available testing for viral entities:
 Polymerase chain reaction (PCR) technology is replacing viral cultures and serial viral
antigen titers. Both viral culture results and serial antigen testing were problematic
because test results were not available until weeks after the acute illness, and viral
culturing for pneumonia could involve invasive sampling techniques to acquire.
 The availability of PCR testing has resulted in increased testing in general.
 The mechanism of PCR itself is more sensitive and specific because many viruses are
notoriously difficult to grow in culture and are very sample dependent.
3. The positive feedback loop that results from improved viral pneumonia testing modalities:
 The test availability results in an increased number of diagnoses.
 The increased number of diagnosis raises the clinical index of suspicion for the entity.
 The increased clinical index of suspicion raises the number of tests ordered.
4. The availability of safe, tolerable, and somewhat specific antiviral therapies:
 Prior viral pneumonia treatment was essentially supportive measures only.
 Initial efforts at antiviral therapy were not well tolerated.
 The availability of some specific and effective treatments now spur earlier testing and a
greater appreciation of the role of viral infection in pneumonia.
 Disease-modifying therapy for HIV is now available.
5. The increasing role of viral pathogens in pneumonia and the increased realization of the role
of bacterial and viral co-infection necessitate a higher clinical index of suspicion and early
identification of viral pulmonary pathogens. Counterbalance seeing this new clinical burden is
the availability of the following:
 Enhanced laboratory detection via ELISA and PCR testing modalities
 Enhanced radiographic detection for a high thin section CAT scan
 An increasing number of safe and efficacious antiviral drugs
  Increased recognition of the role of prevention in viral infectious disease.
Etiology
As pneumonia can be considered somewhat a final common pathway of infection, especially for
those who are immune-compromised, a great number of viruses can cause pneumonia. In
general, these viruses can be divided into those containing DNA or RNA as their nucleic acid. As
this is a bit of an artificial division, a more meaningful approach to etiology is to define by
clinical syndromes produced and demographics affected.
Etiologies of Viral Influenza
Respiratory syncytial virus (RSV)
 RNA virus
 RSV is the most common cause of viral pneumonia in small children and infants.
Rhinovirus
 RNA
 Rhinovirus is the most common cause of upper respiratory tract infection across all age
groups, although it is not as commonly represented as a cause of viral pneumonia.
Influenza A, B and C viruses
 RNA
 Influenza A is the greatest cause of mortality and morbidity among the viral types
of pneumonia.
 There are multiple subtypes of Influenza A.  Two particularly concerning subtypes to be
aware of are the avian flu (H5N1)and swine flu (H1N1).
Human  metapneumovirus
 RNA
 Human Metapneumovirus is a novel viral pathogen that is increasingly recognized as a
cause of viral pneumonia and is implicated as the cause of the SARS outbreak.
Parainfluenza viruses type 1, 2, 3, and 4
 RNA
 Parainfluenza virus has multiple serotypes and is most commonly associated with
pneumonia-like illness in young children seasonally. Spring and fall predominate.
Human bocavirus  Coronavirus
 RNA
  Coronal viruses are already viruses that cause pneumonia, typically in immune
incompetent people.
 However, one subtype of coronavirus is the virus causing Middle Eastern respiratory
syndrome, and another has been implicated in severe acute respiratory syndrome.
Adenovirus
 DNA
 Adenovirus most commonly causes pneumonia in people with solid organ transplantation
or hematological transplantation
Enteroviruses
 RNA
 Enteroviruses, although common causes of polio, gastrointestinal, and upper respiratory
tract syndromes, are less common causes of viral pneumonia.
Varicella-zoster virus
 DNA
 Varicella-zoster virus is associated with both chickenpox and shingles (herpes zoster) and
may cause severe types of pneumonia, particularly in non-immune pregnant women, non-
gravid-adults with chickenpox. It is a fairly common cause of pneumonia in people with
HIV post-shingles outbreak
Hantavirus
 RNA
 Hantavirus is a zoonotic viral pathogen that emerged in the American Southwest and is
associated with rodent feces exposure.
 Hantavirus pneumonia is associated with frequent rapid respiratory failure and
cardiovascular collapse.
Parechoviruses  Epstein-Barr virus (EBV)
 DNA
 Epstein-Barr virus, although commonly implicated in mono-like syndromes, can be rarely
associated with viral pneumonia. The majority of which occur in people with
hematological dyscrasias.
Human herpesvirus 6 and 7
 DNA
Herpes simplex virus
 DNA
 HSV I and II are both associated with viral pneumonia in immune-compromised patients,
including those with HIV, solid organ transplantation, and hematopoietic transplantation.
Minimi virus Cytomegalovirus (CMV)
 DNA
 CMV is a significant cause of pneumonia in HIV-infected patients with a CD4 count less
than 100 cells per millimeter squared.
 CMV is also frequently implicated in pneumonia in recipients of solid organ transplant
and hematopoietic transplant.
Measles
 RNA
 A childhood exanthemata’s illness that, although less common in the industrialized world
secondary to vaccination, remains a major contributor to worldwide childhood mortality
secondary to viral pneumonia as a sequela.
Middle East Respiratory Syndrome (Coronavirus)
 RNA
 A subset of the coronavirus associated with severe pneumonia. This was first observed in
the Middle East and had an initial mortality rate of 30%.
Severe Acute Respiratory Syndrome (Metapneumovirus)
 RNA
 A subset of Coronavirus causing life-threatening pneumonia
Pathophysiology
There is an intricate balance between the organisms residing in the lower respiratory tract and the
local and systemic defense mechanisms (both innate and acquired) which when disturbed gives
rise to inflammation of the lung parenchyma, i.e., pneumonia. Common defense mechanisms that
are compromised in the pathogenesis of pneumonia include:
 Systemic defense mechanisms like humoral and complement-mediated immunity that is
compromised in diseases like common variable immunodeficiency (CVID), X-linked
agammaglobulinemia (inherited), and functional asplenia (acquired). Impaired cell-
mediated immunity predisposes individuals to infection by intracellular organisms like
 viruses and organisms of low virulence like Pneumocystis pneumonia (PJP), fungal
causes, among others
 The mucociliary clearance that is often impaired in cigarette smokers, post-viral state,
Kartergerner syndrome, and other related conditions
 Impaired cough reflex seen in comatose patients, certain substances of abuse
 Accumulation of secretions as seen in cystic fibrosis or bronchial obstruction
The resident macrophages serve to protect the lung from foreign pathogens. Ironically, the
inflammatory reaction triggered by these very macrophages is what is responsible for the
histopathological and clinical findings seen in pneumonia. The macrophages engulf these
pathogens and trigger signal molecules or cytokines like TNF-a, IL-8, and IL-1 that recruit
inflammatory cells like neutrophils to the site of infection. They also serve to present these
antigens to the T cells that trigger both cellular and humoral defense mechanisms, activate
complement and form antibodies against these organisms. This, in turn, causes inflammation of
the lung parenchyma and makes the lining capillaries "leaky," which leads to exudative
congestion and underlines the pathogenesis of pneumonia.
On a macroscopic level, viral pneumonia can occur through one of three mechanisms:
1. Direct inoculation of viral particle into the lung (e.g., RSV or influenza)
2. Spread in a contiguous fashion from viral infections near the upper respiratory tract (e.g.,
measles)
3. Hematogenous spread from a distant viral infection (e.g., CMV) 
On a microscopic level, the general pattern of viral pneumonia pathogenesis is as follows.
 The target cell is the pneumocyte with resultant alveolar damage.
 The submucosa of the alveoli is targeted, causing inflammation and secondary edema,
microhemorrhage, and cellular immune reaction.
 The cellular reaction consists of mononuclear lymphocytes and progresses to PMNs
recruitment.
 Fibrin is released.
 Both CD4 and CD8 cells are involved, beginning a cascade of immune product secretion
that can end in increased vascular permeability and resultant edema.
 This process may lead to intra-alveolar organization and an obliterans clinical picture.
  The far end of the spectrum of the process includes interstitial pneumonia, pulmonary
edema, and cardiogenic shock.
History and Physical
Historically, the chief complaints in case of pneumonia include systemic signs like fever with
chills, malaise, loss of appetite, and myalgias. These findings are more common in viral
pneumonia as compared to bacterial pneumonia. A small fraction of patients may have an altered
mental status, abdominal pain, chest pain, and other systemic findings.  Pulmonary findings
include cough with or without sputum production. Bacterial pneumonia is associated with
purulent or rarely blood-tinged sputum. Viral pneumonia is associated with watery or
occasionally mucopurulent sputum production. There may be an associated pleuritic chest pain
with the concomitant involvement of the pleura. Dyspnea and a diffuse heaviness of the chest are
also seen occasionally.
 Common findings on physical examination include:
 Tachypnea
 Tachycardia
 Fever with or without chills
 Decreased or bronchial breath sounds
 Egophony and tactile fremitus, both suggestive of a consolidative process
 Crackles on auscultation of the affected regions of the lung
 Dullness on percussion
There are no pathognomonic history cues for the diagnosis of viral pneumonia as opposed to
bacterial pneumonia. However, cues are suggestive in differential diagnosis of viral pneumonia:
 Gradual onset as opposed to the sudden onset of symptoms.
 Lower temperature
 Lack of purulent sputum
 History of immunosuppression
 Prodromal viral upper respiratory tract illness
 History of HIV
 History of solid organ transplantation or hematopoietic transplantation
 History of neoplasm
 Concomitant flu symptoms
  Concomitant gastrointestinal symptoms
There are no pathognomonic physical examination findings for the diagnosis of viral pneumonia
as opposed to bacterial pneumonia. However, physical findings are suggestive in the differential
diagnosis of viral pneumonia:
 Tachycardia or tachypnea out of proportion to the temperature
 Temperature elevation disproportionately low to the level of debility
 Concomitant upper respiratory tract infection
 Rash
 The paucity of physical findings on pulmonary exam disproportionate to the level of
debility
 Bilateral positive lung findings 
Evaluation of CAP and HAP involves:
Clinical Evaluation
Involves performing a thorough history and physical examination as summarized in section
above.
Radiological Evaluation
According to the Infectious Diseases Society of America (IDSA) and American Thoracic Society
(ATS) guidelines, a demonstratable infiltrate by chest x-ray is necessary and is considered the
best method (with supportive clinical findings) for the diagnosis of pneumonia. Findings may
vary from lobar to interstitial infiltrate, to occasionally  cavitary lesions with air-fluid levels
suggestive of a more severe disease process.
Laboratory Evaluation
These include a series of tests like blood culture, sputum culture and microscopy, routine blood
counts, and lymphocyte count. Special tests such as urinary antigen testing, bronchial aspirate, or
induced sputum may be used for certain pathogens. Two tests, procalcitonin and C-reactive
protein help differentiate viral from bacterial causes when clinical and radiological findings may
not be obvious. It is also noteworthy that empiric antibiotic treatment may be initiated in all
typical cases of pneumonia, and the entire battery of tests is seldom needed.
Evaluation of VAP, on the other hand, is a bit  different from that of CAP. It requires radiological
and microbiological evidence prior to initiation of antimicrobial therapy. VAP should be
suspected in ventilated patients who have new onset dyspnea, fall in oxygen saturation on the
same ventilator settings, fevers with chills or new onset lung infiltrates. All suspected patients
require a chest x-ray (or a CT scan if x-ray findings are inconclusive). This must be followed by
invasive sampling techniques like mini broncho-alveolar lavage (BAL) or bronchoscopic BAL or
even protected specimen brush (PSB) to identify causal organisms. Once the diagnosis is
confirmed, the appropriate antimicrobial therapy can be initiated.

As noted above, both history and physical examination may provide few diagnostic cues as to the
etiology of pneumonia (bacterial versus virus). With the existence of specific effective treatment
modalities, diagnoses of and identification of viruses causing pneumonia is of increased
importance. Fortunately, the diagnostic acuity of laboratory examination in combination with
radiography and history and physical examination has progressed. Laboratory
Examination CBC with differential - There are no absolute diagnostic findings as viral
pneumonia may result in elevated, normal, or decreased WBC counts. However, viral etiology is
less commonly associated with elevated WBC and "left shifts" of the differential than bacterial
types of pneumonia.  Chemistry panel - Useful for gauging the degree of dehydration, relative
renal dysfunction, and dosing of renal excreted medications C-reactive protein  - As a reactive
phase reactant, the CRP level may be elevated with viral pneumonia, although this is not a
specific or sensitive finding. ELISA - rapid antigen tests  - ELISA tests allow real-time data for
a number of viral pneumonia pathogens. Commonly available ELISA tests include the following:
 Herpes simplex virus (HSV)
 Respiratory syncytial virus (RSV)
 Influenza A and B
 Cytomegalovirus (CMV)
A caveat is that many viruses may be detected via ELISA in the presence of other known
bacterial pathogens, and in some cases, the detection of a viral pathogen does not always indicate
active disease. Gene amplification - First and second-generation PCR testing exists and may
allow viral pneumonia etiology diagnosis within clinically relevant timing.  Clinically available
tests using PCR methodology include the following:
 CMV
 RSV
 HPV
  Coronal viruses
Cytological  evaluation - No single cytological evaluation of patient tissue cells is entirely
diagnostic for viral pneumonia. However, the generalization can be made that DNA viruses
typically produce intra-nuclear inclusions, and RNA viruses typically produce cytoplasmic
inclusions. Viral culture - Although viral cultures are the gold standard for the final diagnosis of
viral pneumonia, there are limitations such as the following:
1. Viral cultures are routinely not available for 10 to 15 days, which limits them for acute
clinical care decisions.
2. The cultures are very dependent on obtaining a valid specimen.
3. The success of delivering a viable specimen to the lab varies as many of the viruses have
very specific transport requirements.
4. The fastidious nature of some viral pathogens limits the validity of a negative culture
result.
Viral antigens serology - The great majority of the viral entities involved in viral pneumonia
have serological markers that can be obtained in the tract. Diagnostic problems include positive
serology obtained for people with chronic viral infections that are not a factor in the presence of
pneumonia and the limited use in acute treatment and decision making of viral pneumonia. Chest
x-ray - As there is a tremendous overlap in findings on chest x-ray with both bacterial
pneumonia and viral pneumonia, no one finding or set of findings is pathognomonic.
Features that are suggestive of bacterial pneumonia include the following:
 Alveolar infiltrates
 Lobar consolidation
 Nodular densities 
 Pleural effusion
Features that are more suggestive of viral pneumonia include the following:
 Interstitial infiltrates
 Patchy distribution of interstitial infiltrates
 Bilateral infiltrates
 Pneumonia-like syndrome with an unremarkable chest x-ray
Chest CT scan - The advent of thin-section CT scan has revolutionized the radiographic
diagnosis of viral pneumonia. It has been observed, particularly in cases of viral pneumonia-like
clinical presentation and normal chest radiography, thin-section CT scan will be positive for
parenchymal defects and aid in diagnosis.
RF pneumonia: riwayat opname di RS (terutama yang pakai ventilator/VAP atau HAP/hospital-
acquired pneumonia), orang yang riwayat pergi ke daerah endemic kasus pneumonia tsb.,
merokok (karena defense mechanism silia dll.-nya turun – bisa jadi COPD), punya penyakit
kronis seperti kanker, HT tidak terkontrol, asthma, DM, CHF (bisa jadi pulmo edema);
Treatment / Management
The cornerstone of treatment of viral pneumonia consists of the following: Supportive Care
 The first priority of supportive care is to maintain oxygenation as needed. This may entail
nasal cannula, noninvasive airway, or mechanical ventilation.
 The second priority of supportive care is to maintain hydration either via supervised oral
intake or intravenous fluids.
 The third priority of supportive care is to maintain rest and decrease oxygen demand.
 A final priority of supportive care is to meet the increased calorie needs of the patient,
secondary to the increased respiratory effort.
Management of Comorbid Illnesses Appropriate treatment of Coexisting Bacterial Types
of Pneumonia
Most current evidence indicates the frequent existence of concomitant bacterial types of
pneumonia. The prototypical example is the observation that the majority of mortality during the
1917-1918 influenza pandemic was secondary to bacterial pneumonia, superimposed on the
initial influenza pneumonia.
Specific antiviral therapy for a number of viral pneumonia exists as does preventative or
prophylactic therapies for those at high risk would have been exposed:
Influenza virus
 Treatment: Oseltamivir or peramivir or zanamivir     
 Prophylaxis: Influenza vaccine and/or chemoprophylaxis with zanamivir or oseltamivir
Respiratory syncytial virus (RSV)
 Treatment: Ribavirin                                               
 Prophylaxis: RSV immunoglobulin and/or palivizumab
Parainfluenza virus
 Treatment: Ribavirin
  Prophylaxis: Not available
Herpes simplex virus (HSV)
 Treatment: Acyclovir
 Prophylaxis: Not available
Adenovirus
 Treatment: Ribavirin
 Prophylaxis: Not available
Measles virus
 Treatment: Ribavirin                                               
 Prophylaxis: intravenous immunoglobulin
Cytomegalovirus (CMV)
 Treatment: Ganciclovir or foscarnet                         
 Prophylaxis: intravenous immunoglobulin
Varicella-zoster virus (VZ)
 Treatment: Acyclovir                                              
 Prophylaxis: Varicella-zoster immunoglobulin (VZIG)
Complications
Complications of viral pneumonia include the following:
 Concomitant bacterial infection, resulting in an abscess, empyema, and or pleural
effusion
 Sepsis with secondary multiple organ failure
 Acute respiratory failure
 Cardiovascular collapse
 Acute respiratory distress syndrome
Complications of untreated or under-treated pneumonia include respiratory failure, sepsis,
metastatic infections, empyema, lung abscess, and multi-organ dysfunction.

4. Pathogenesis covid-19
(struktur virus, bentuk virus, pathogenesis, reseptor di dalam tubuh, etiology, bagaimana
seseorang terinfeksi, diagnosis dan patof COVID-19)
Coronaviruses comprise a vast family of viruses, seven of which are known to cause disease in
humans. Some coronaviruses that typically infect animals have evolved to infect humans. SARS-
CoV-2 is likely one such virus, postulated to have originated in a large animal and seafood
market.
Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) also
are caused by coronaviruses that “jumped” from animals to humans. More than 8000 individuals
developed SARS, nearly 800 of whom died of the illness (mortality rate, approximately 10%),
before it was controlled in 2003. MERS continues to resurface in sporadic cases. A total of 2465
laboratory-confirmed cases of MERS have been reported since 2012, resulting in 850 deaths
(mortality rate, 34.5%).
Route of Transmission
The principal mode by which people are infected with SARS-CoV-2 is through exposure to
respiratory droplets carrying infectious virus (generally within a space of 6 feet). Additional
methods include contact transmission (eg, shaking hands) and airborne transmission of droplets
that linger in the air over long distances (usually greater than 6 feet). Virus released in respiratory
secretions (eg, during coughing, sneezing, talking) can infect other individuals via contact with
mucous membranes.
On July 9, 2020, the WHO issued an update stating that airborne transmission may play a role in
the spread of COVID-19, particularly involving “super spreader” events in confined spaces such
as bars, although they stressed a lack of such evidence in medical settings. Thus, they
emphasized the importance of social distancing and masks in prevention. 
The virus can also persist on surfaces to varying durations and degrees of infectivity, although
this is not believed to be the main route of transmission.  One study found that SARS-CoV-2
remained detectable for up to 72 hours on some surfaces despite decreasing infectivity over time.
Notably, the study reported that no viable SARS-CoV-2 was measured after 4 hours on copper or
after 24 hours on cardboard. 
In a separate study, Chin and colleagues found the virus was very susceptible to high heat
(70°C). At room temperature and moderate (65%) humidity, no infectious virus could be
recovered from printing and tissue papers after a 3-hour incubation period or from wood and
cloth by day 2. On treated smooth surfaces, infectious virus became undetectable from glass by
day 4 and from stainless steel and plastic by day 7. “Strikingly, a detectable level of infectious
virus could still be present on the outer layer of a surgical mask on day 7 (~0.1% of the original
inoculum).” Contact with fomites is thought to be less significant than person-to-person spread as
a means of transmission. 
Viral shedding
The duration of viral shedding varies significantly and may depend on severity. Among 137
survivors of COVID-19, viral shedding based on testing of oropharyngeal samples ranged from 8
to 37 days, with a median of 20 days. [37] A different study found that repeated viral RNA tests
using nasopharyngeal swabs were negative in 90% of cases among 21 patients with mild illness,
whereas results were positive for longer durations in patients with severe COVID-19.  [38] In an
evaluation of patients recovering from severe COVID-19, Zhou and colleagues found a median
shedding duration of 31 days (range, 18-48 days). [39]  These studies have all used PCR detection
as a proxy for viral shedding. The Korean CDC, investigating a cohort of patients who had
prolonged PCR positivity, determined that infectious virus was not present.  [40] These findings
were incorporated into the CDC guidance on the duration of isolation following COVID-19
infection. 
Additionally, patients with profound immunosuppression (eg, following hematopoietic stem-cell
transplantation, receiving cellular therapies) may shed viable SARS-CoV-2 for at least 2
months.  
SARS-CoV-2 has been found in the semen of men with acute infection, as well as in some male
patients who have recovered. 
Asymptomatic/presymptomatic SARS-CoV-2 infection and its role in transmission
Oran and Topol published a narrative review of multiple studies on asymptomatic SARS-CoV-2
infection. Such studies and news articles reported rates of asymptomatic infection in several
worldwide cohorts, including resident populations from Iceland and Italy, passengers and crew
aboard the cruise ship Diamond Princess, homeless persons in Boston and Los Angeles, obstetric
patients in New York City, and crew aboard the USS Theodore Roosevelt and Charles de Gaulle
aircraft carriers, among several others. Almost half (40-45%) of SARS-CoV-2 infections were
asymptomatic. [44]  
Utilizing a decision analytical model, Johansson et al from the CDC assessed transmission from
presymptomatic, never symptomatic, and symptomatic individuals across various scenarios to
determine the infectious period of transmitting SARS-CoV-2. Results from their base case
determined 59% of all transmission came from asymptomatic transmission, 35% from
presymptomatic individuals and 24% from individuals who never developed symptoms. They
estimate at least 50% of new SARSCoV-2 infections originated from exposure to individuals
with infection, but without symptoms. [45]  
Zou and colleagues followed viral expression through infection via nasal and throat swabs in a
small cohort of patients. They found increases in viral loads at the time that the patients became
symptomatic. One patient never developed symptoms but was shedding virus beginning at day 7
after presumed infection.
Virology
The full genome of SARS-CoV-2 was first posted by Chinese health authorities soon after the
initial detection, facilitating viral characterization and diagnosis. The CDC analyzed the genome
from the first US patient who developed the infection on January 24, 2020, concluding that the
sequence is nearly identical to the sequences reported by China. SARS-CoV-2 is a group 2b beta-
coronavirus that has at least 70% similarity in genetic sequence to SARS-CoV.  Like MERS-
CoV and SARS-CoV, SARS-CoV-2 originated in bats. 
Viral variants emerge when the virus develops one or more mutations that differentiate it from
the predominant virus variants circulating in a population. The CDC surveillance of SARS-CoV-
2 variants includes US COVID-19 cases caused by variants. The site also includes which
mutations are associated with particular variants. The CDC has launched a genomic surveillance
dashboard and a website tracking US COVID-19 case trends caused by variants. Researchers are
studying how variants may or may not alter the extent of protection by available vaccines. 
Variants of Concern in the United States
As mentioned, viruses such as SARS-CoV-2 are constantly changing. Among the hundreds of
variants detected in the first year of the pandemic, the ones that are most concerning are the so-
called variants of concern (VOCs). Researchers are continually studying how variants may or
may not alter the extent of protection by available vaccines and antibody-directed therapies.  
Omicron
The omicron variant (B.1.1.529), initially identified in South Africa, was declared a variant of
concern in the United States by the CDC November 30, 2021. This VOC contains several dozen
mutations, including a large number in the spike gene, more than previous VOCs.   These
mutations include several associated with increased transmission. The omicron variant has
quickly become dominant in the United States. As of January 8, 2022 it accounts for over 98% of
circulating virus, compared with less than 8% on December 11, 2021. 
Antiviral agent effectiveness
An in vitro study published in December 2021 indicate that remdesivir, nirmatrelvir,
molnupiravir, EIDD-1931, and GS-441524 (oral prodrug of remdesivir) retain their activity
against the VOCs alpha, beta, gamma, delta, and omicron. 
Monoclonal antibody effectiveness
Data analyzed by the FDA and NIH in mid-December 2021 found tixagevimab plus cilgavimab
(Evusheld) and sotrovimab retain their neutralizing activity against the omicron variant.
However, casirivimab plus imdevimab (REGN-COV) and bamlanivimab plus etesevimab lose
most of their effectiveness when exposed in laboratory tests to omicron. [82, 83, 84]   
Vaccine effectiveness
A preprinted, nonpeer reviewed article of routine surveillance data from South Africa suggests
the Omicron variant may evade immunity from prior infection. Among 2,796,982 individuals
with laboratory-confirmed SARS-CoV-2 who had a positive test result for SARS-CoV-2 at least
90 days before November 27, 2021, there were 35,670 suspected reinfections identified. [85]  
In another preprinted article, neutralization performed with sera from double or triple
BNT162b2-vaccinated individuals (6, 0.5 or 3 months after last vaccination/booster) revealed an
11.4-, 37.0- and 24.5-fold reduction, respectively. Sera from double mRNA-1273-vaccinated and
additionally BNT162b2-vaccinated individuals (sampled 6 or 0.5 months after last
vaccination/booster) showed a 20- and 22.7-fold reduction in the neutralization capacity. [84]  
Delta
The delta variant (B.1.617.2) that was first identified in India became the dominant variant in the
United States in mid-July 2021. This variant increases ACE binding and transmissibility. An
approximate 6.8-fold decreased neutralization for mRNA vaccines and convalescent plasma was
observed with the delta variant. [86, 87]  However, a study completed by Public Health England
found the BNT162b2 vaccine was only slightly reduced from 93.7% with the B.1.1.7 variant to
88% for the delta variant 2 weeks after the second dose. [88]  As the omicron variant transmission
increased rapidly in December 2021, the delta variant now accounts for less than 2% of cases in
the United States. 
Mutations
Viral mutations may naturally occur anywhere in the SARS-CoV-2 genome. Unlike the human
DNA genome, which is slow to mutate, RNA viruses can readily, and quickly, mutate. A
mutation may alter the viral function (eg, enhance receptor binding), or may have no discernable
function. 
Mutations have been identified for the receptor-binding domain (RBD) on the spike protein of
SARS-CoV-2. Several of these mutations display higher binding affinity to human ACE2, likely
owing to enhanced structural stabilization of the RBD. Whether a mutation enhances viral
transmission is a question to explore. Possible mechanisms of increased transmissibility include
increased viral shedding, longer contagious interval, increased infectivity, or increased
environmental stability. 
Table 1. Examples of mutations and resulting actions

Mutation Actions Variants with Mutation

N501Y Increased viral load Alpha UK (B.1.117)

Del69-
Increased ACE binding Alpha UK (B.1.117); Omicron (B.1.1.529)
70

Increased transmission and

virulence; decreased
neutralization by vaccines Beta South Africa (B.1.351), Gamma
E484K and monoclonal antibodies Brazil (P1), and Iota NYC (B.1.526 and
When combined with other B.1.526.1)
mutations, may result in an
escape mutation

B.1.526.1, Epsilon California (B.1.427 and

Monoclonal antibodies may
L452R B.1.429), and Delta India (B.1.617 linages
be less effective
and sub-lineages)
 One of the first documented mutations in
the United States after initially circulating
D614G Increased transmission in Europe. Included in nearly all variants of
interest and variants of concern, including
Delta and Omicron

Older Variants Monitored in the United States 

Alpha 
The CDC tracks variant proportions circulating in the United States and estimates the B.1.1.7
variant (Alpha) that was first detected in the United Kingdom accounted for over 44% of cases
from January 2 to March 27, 2021. On April 7, 2021, the CDC announced B.1.1.7 was the
dominant strain circulating in the United States. It was the dominant strain until mid-July 2021,
when the Delta variant became the dominant strain. 
A novel spike mutation with deletions of (delta)69/delta(70) has been shown to occur de novo on
multiple occasions and to be maintained through sustained transmission in association with other
mutations. [89]  This is the source of intense scrutiny in Europe, especially in the United Kingdom.
A recent VOC – 202012/01 (201/501Y.V1) contains the deletion 69-70 as well as several other
mutations including: N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. The variant is
being investigated as a cause of rapid increase in case numbers, possibly due to increased viral
loads and transmissibility. The N501Y mutation seems to increase viral loads 0.5 log. [90]   
Additionally, VOC-202012/01 has mutations that appear to account for its enhanced
transmission. The N501Y replacement on the spike protein has been shown to increase ACE2
binding and cell infectivity in animal models. The deletion at positions 69 and 70 of the spike
protein (delta69-70) has been associated with diagnostic test failure for the ThermoFisher
TaqPath probe targeting the spike protein. Therefore, British labs are using this test failure to
identify the variant. [91]   
Surveillance data from the UK national community testing (“Pillar 2”) showed a rapid increase
in S-gene target failures (SGTF) in PCR testing for SARS-CoV-2 in November and December
2020. The R0 of this variant seems higher. At the same time that the transmission of the wild
type virus was dropping, the variant increased, suggesting that the same recommendations (eg,
masks, social distancing) may not be enough. The UK variant is also infecting more children
(aged 19 years and younger) than the wild type, indicating that it may be more transmissible in
children. This has raised concerns because a relative sparing of children has been observed to
date. This variant is hypothesized to have a stronger ACE binding than the original variant,
which was felt to have trouble infecting younger individuals as they express ACE to a lesser
degree. [91]    
Beta
The E484K mutation was found initially in the South Africa VOC (B.1.351 [Beta]) and also with
the Brazil variants in late 2020, and was observed in the UK variant in early February 2021.
Position 484 and 501 mutations that are both present in the South African variant, and the
combination is a concern that immune escape may occur. These mutations, among others, have
combined to create the VOC B.1.351. The mutation at the 501 position changes the shape of the
RBD by rotating it by 20 degrees to allow deeper binding. The mutation at the 484 position
changes the RBD to a positive charge, and allows a higher affinity to the ACE2 receptor. [92]    
Gamma
The Brazil VOC P.1 (Gamma) was responsible for an enormous second surge of
infections. Sabino et al describe resurgence of COVID-19 in Manaus, Brazil in January 2021,
despite a high seroprevalence. A study of blood donors indicated that 76% of the population had
been infected with SARS-CoV-2 by October 2020. Hospitalizations for COVID-19 in Manaus
numbered 3431 in January 1 to 19, 2021 compared with 552 for December 1 to 19, 2020.
Hospitalizations had remained stable and low for 7 months prior to December 2020. Several
postulated variables regarding this resurgence include waning titers to the original viral lineage
and the high prevalence of the P.1 variant, which was first discovered in Manaus. [93] In addition,
researchers are monitoring emergence of a second variant in Brazil, P.2, identified in Rio de
Janeiro. As of September 21, 2021, the CDC lists P.2 as a variant being monitored. 
Epsilon 
VOCs B.1.427 (Epsilon) and B.1.429 (Epsilon) emerged in California. These variants accounted
for 2.9% and 6.9% of variants circulating in the United States between January 2 to March 27,
2021. An approximate 20% increase in transmission has been observed with this variant. 
Pathogenesis of COVID-19
The pathogenic phases of COVID-19 remain incompletely understood. Previous studies have
proposed SARS may consist of three phases: Viral replication, immune hyperactivity and
pulmonary destruction. The clinical phases of COVID-19 have been recently proposed: Viremia
phase, acute phase and recovery phase. It is generally hypothesized that the course of infection
goes through the following stages: Viral invasion and replication, dysregulated immune
response, multiple organ damage and recovery. Firstly, the virus enters the host cells, where it
replicates, assembles and is released extracellularly to target cells, and this directly causes the
damage and destruction of parenchymal cells such as alveolar epithelial cells. At the same time,
a large number of pathogen associated molecular pattern (PAMP) and damage associated
molecular pattern (DAMP) molecules are released to stimulate the innate immune response,
induce inflammatory cell infiltration, release large quantities of cytokines, chemokines, proteases
and free radicals, causing ARDS, sepsis and MODS. It has been observed that the pathological
findings of COVID-19-induced pneumonia appear to resemble those seen in SARS-CoV and
MERS-CoV infection including bilateral acute changes with diffuse alveolar damage and
vascular congestion, patchy inflammatory cellular infiltration, intra-alveolar edema, hemorrhage,
proteinaceous exudate, denudation and reactive hyperplasia of pneumocytes, as well as the
presence of multinucleated giant cells, but hyaline membrane formation was is not prominent
observed. After the initial critical stage, the inflammatory response is gradually resolved, the
damaged organ gradually recovers, and some of the damaged organs enter fibrosis and chronic
stage, such as chronic critical illness, persistent inflammation, immunosuppression and
catabolism syndrome.
It is speculated that the major pathological alterations that take place in the vital organs during
COVID-19 may be caused directly by the cytopathic effect mediated by SARS-CoV-2, and
indirectly as a result of the harmful immune responses induced by SARS-CoV-2, but the relative
importance of each of these requires further study. There is some evidence supporting the more
important role of an abnormal immune response (rather than a direct viral cytopathic effect) in
the effects of COVID-19. It has been observed that patients with COVID-19 had the highest viral
load during the early stage (43). The timeline of COVID-19 infection showed that the median
time from onset of symptoms to first hospital admission was 7 days, 9 days till ARDS, and 10.5
days till ICU (24). The association of worsening clinical progression with declining viral loads
(42) and the onset of an immunological response, plus the presence of significantly elevated
cytokines levels suggested that severe lung damage was largely immunopathological in nature.
Receptor use and pathogenesis
SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2).
Besides human ACE2 (hACE2), SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus
monkey, civet, cat, pangolin, rabbit and dog. The broad receptor usage of SARS-CoV-2 implies
that it may have a wide host range, and the varied efficiency of ACE2 usage in different animals
may indicate their different susceptibilities to SARS-CoV-2 infection. The S1 subunit of a
coronavirus is further divided into two functional domains, an N-terminal domain and a C-
terminal domain. Structural and biochemical analyses identified a 211 amino acid region (amino
acids 319–529) at the S1 C-terminal domain of SARS-CoV-2 as the RBD, which has a key role
in virus entry and is the target of neutralizing antibodies. The RBM mediates contact with the
ACE2 receptor (amino acids 437–507 of SARS-CoV-2 S protein), and this region in SARS-
CoV-2 differs from that in SARS-CoV in the five residues critical for ACE2 binding, namely
Y455L, L486F, N493Q, D494S and T501N52 (Fig. 3b,c). Owing to these residue changes,
interaction of SARS-CoV-2 with its receptor stabilizes the two virus-binding hotspots on the
surface of hACE2 (ref.50) (Fig. 3d). Moreover, a four-residue motif in the RBM of SARS-CoV-
2 (amino acids 482–485: G-V-E-G) results in a more compact conformation of its hACE2-
binding ridge than in SARS-CoV and enables better contact with the N-terminal helix of hACE2
(ref.50). Biochemical data confirmed that the structural features of the SARS-CoV-2 RBD has
strengthened its hACE2 binding affinity compared with that of SARS-CoV.
Similarly to other coronaviruses, SARS-CoV-2 needs proteolytic processing of the S protein to
activate the endocytic route. It has been shown that host proteases participate in the cleavage of
the S protein and activate the entry of SARS-CoV-2, including transmembrane protease serine
protease 2 (TMPRSS2), cathepsin L and furin. Single-cell RNA sequencing data showed that
TMPRSS2 is highly expressed in several tissues and body sites and is co-expressed with ACE2
in nasal epithelial cells, lungs and bronchial branches, which explains some of the tissue tropism
of SARS-CoV-2. SARS-CoV-2 pseudovirus entry assays revealed that TMPRSS2 and cathepsin
L have cumulative effects with furin on activating virus entry55. Analysis of the cryo-electron
microscopy structure of SARS-CoV-2 S protein revealed that its RBD is mostly in the lying-
down state, whereas the SARS-CoV S protein assumes equally standing-up and lying-down
conformational states. A lying-down conformation of the SARS-CoV-2 S protein may not be in
favour of receptor binding but is helpful for immune evasion.
The pathogenesis of SARS-CoV-2 infection in humans manifests itself as mild symptoms to
severe respiratory failure. On binding to epithelial cells in the respiratory tract, SARS-CoV-2
starts replicating and migrating down to the airways and enters alveolar epithelial cells in the
lungs. The rapid replication of SARS-CoV-2 in the lungs may trigger a strong immune response.
Cytokine storm syndrome causes acute respiratory distress syndrome and respiratory failure,
which is considered the main cause of death in patients with COVID-19. Patients of older age
(>60 years) and with serious pre-existing diseases have a greater risk of developing acute
respiratory distress syndrome and death. Multiple organ failure has also been reported in some
COVID-19 cases
Histopathological changes in patients with COVID-19 occur mainly in the lungs. Histopathology
analyses showed bilateral diffused alveolar damage, hyaline membrane formation, desquamation
of pneumocytes and fibrin deposits in lungs of patients with severe COVID-19. Exudative
inflammation was also shown in some cases. Immunohistochemistry assays detected SARS-
CoV-2 antigen in the upper airway, bronchiolar epithelium and submucosal gland epithelium, as
well as in type I and type II pneumocytes, alveolar macrophages and hyaline membranes in the
lungs.
SARS-CoV-2 invades host cells
It is widely accepted that human CoV transmissibility and pathogenesis primarily depends on the
interactions between the virus and specific host cells. Receptor recognition and entry is the first
step of viral infection and is the key determinant of tissue tropism. Enhanced binding affinity
between SARS-CoV-2 and ACE2 has been proposed to correlate with elevated virus
transmissibility and disease severity in humans. CoV entry into host cells is a multi-step process
involving several distinct domains in the S protein that mediates viral attachment to the target
cell surface, receptor engagement, protease processing and membrane fusion. Subsequently, the
viral genome is released into the cytoplasm, and the virus replicates within the host cells (53).
Notably, three CoV (human CoV-NL63, SARS-CoV and SARS-CoV-2) that bind to the same
receptor (ACE2) cause diseases of varying severity, indicating that there may be other
pathogenic factors underlying the differences between these three coronaviruses (54). It has been
demonstrated that the overall ACE2-binding mode of the SARS-CoV-2 S receptor-binding
domain (RBD) is nearly identical to that of the SARS-CoV RBD, but SARS-CoV-2 RBD takes a
more compact conformation, which enhances its ACE2-binding affinity (8,9). Walls et al (7)
showed that the RBD of SARS-CoV-2 S protein and SARS-CoV S protein bind with similar
affinities to human ACE2 to enter cells. However, another study observed that SARS-CoV-2 and
ACE2 have an affinity that is 10-20 times that of SARS-CoV, which may be related to the higher
transmissibility seen in SARS-CoV-2(55).
The characteristic distribution of SARS-CoV-2 and ACE2 may contribute to revealing the
pathogenic mechanisms of COVID-19. SARS-CoV-2 viral RNA can be detected in respiratory
secretions, peripheral blood, urine and stool specimens of some patients with COVID-19, which
coincides with various transmission pathways in SARS-CoV-2 infection (56). Virions in the
blood that are released from the primary target (for example the lung) may circulate and infect
host cells in the remote secondary organs and tissues.
On the other hand, ACE2 is expressed in the lungs, heart, renal system and gastrointestinal tract,
of which it is abundantly present in the epithelia of the human lungs and small intestines (57-59).
These observations may indicate that ACE2 serves an important role in extrapulmonary
manifestations of COVID-19, such as gastrointestinal symptoms (57,60,61). It is noteworthy that
gut-lung crosstalk may be involved in the pathogenesis of COVID-19; however, the potential
efficacy of probiotics as one of the novel therapeutic approaches of COVID-19 requires further
exploration (62). In addition, ACE2 is widely expressed in the vascular endothelial cells and
smooth muscle cells in all organs, which may cause extensive vascular endothelial cell injury
and this may be the molecular basis by which multiple organ lesions are formed in COVID-19-
infected patients. Cardiac injury has been reported in 7-23% of patients with COVID-19, which
is associated with a higher mortality. A more recent study showed that patients with basic heart
failure disease showed increased ACE2 expression, suggesting that cardiac cells with high
expression of ACE2 may act as the target cells of SARS-CoV-2(65).
Direct cytopathic effect of SARS-CoV-2
After entering the host cells, the virus can replicate and survive within the target cells. It is
speculated that the life cycle of SARS-CoV-2 may be similar to other single positive-strand RNA
coronaviruses to a certain extent. After replication is complete, new virus particles are assembled
in the endoplasmic reticulum, after which they are released outside of the cell. At the same time,
target cells lyse or form syncytia and other lesions occur. SARS-CoV-2 may induce a substantial
cytopathic effect on host cells, thus early effective antiviral treatment may reduce the risk of
progression, and thereby mortality (68). It is unclear whether SARS-CoV-2 interferes with target
cells in other ways to cause host cell damage or apoptosis, including mitochondrial damage,
endoplasmic reticulum stress, intracellular environment alterations (such as pH changes) or
enzyme dysfunction.
In view of the expression of ACE2 in immune cells, including monocytes/macrophages and
lymphocytes (59), it is unclear whether SARS-CoV-2 can directly infect certain immune cells to
cause immune cell damage. More importantly, immune cells may migrate within the body.
Therefore, the SARS-CoV-2-infected immune cells may allow the virus to disseminate
systemically. Pathological studies using COVID-19 models have shown that the common type of
damage caused by SARS-CoV-2 infection also occurs in the immune system, and spleen and
lymphoid atrophy have been shown to be associated with marked cytokine activation, suggesting
that SARS-CoV-2 might directly damage immune cells.
Initiation of the innate immune response
The innate immune response, which uses various pattern recognition receptors (PRRs) to
recognize and respond to viruses, is an important barrier to viral infection. The intensity of the
host immune and inflammatory responses are closely related to the type of invading virus, the
viral load, and the age and immune status of the host. In general, host innate immune cells are
stimulated to produce antiviral and proinflammatory cytokines and chemokines to eliminate the
invading viruses.
PAMP-PRR pathway
The viral RNA that is present within the infected cells is detected by various PRRs in the
immune cells, which leads to the secretion of type I interferons (IFNs), proinflammatory
cytokines and chemokines (70,73). Previous studies have demonstrated that key components of
the innate immune signaling pathways serve important roles as protective factors against SARS-
CoV disease, including STAT1 and myeloid differentiation primary response protein
MyD88(74). Gralinski et al (75) identified an adaptor protein (TIR domain-containing adapter
molecule 2) in the toll-like receptor signaling pathway that may be involved in the development
of SARS. The IFN response, a key component of antiviral innate immunity, is initiated by
retinoic acid-inducible gene-I-like receptor-mediated recognition of viral replicative
intermediates in the cytosol (73). However, Channappanavar et al (76) showed that robust
SARS-CoV replication and delayed IFN-I signaling promotes severe SARS, as IFN-I could
promote the accumulation of pathogenic macrophages, thus causing lung immunopathology and
vascular leakage. In this regard, the specific pathogenic PAMPs of SARS-CoV-2 and the
corresponding PRRs and signaling pathways remain to be systemically identified.
Macrophages are crucial components of innate immunity and potential mediators of
immunopathology (77). Moreover, macrophages are the main target cells for SARS-CoV
replication (78). MERS-CoV and SARS-CoV can easily infect and robustly replicate in human
macrophages and dendritic cells, inducing the aberrant production of proinflammatory cytokines
and chemokines (77,79,80). In SARS-CoV infection, viroporin 3a has also been shown to induce
the activation of nucleotide oligomerization domain-like receptor protein 3 inflammasome and
the secretion of IL-1β in macrophages, suggesting that PAMP-PRR signaling in macrophages
may result in the release of proinflammatory cytokines in COVID-19(15).
DAMP-PRR pathway
Following cellular injury and necrosis, endogenous DAMPs can be released, such as DNA,
RNA, ATP, heat shock proteins, high mobility group protein B1 and the extracellular matrix,
which could be recognized and activated by corresponding PRRs, and promote the release of
cytokines and chemokines, and this may further aggravate the inflammatory response and tissue
damage, forming a vicious cycle (81). It is speculated that both DAMPs and PAMPs may also
contribute to the systemic dysregulation of the innate immune response and may be involved in
the development of MODS in COVID-19. After SARS-CoV-2 activates PRRs, it may induce the
antiviral innate immune response, and also lead to cell damage and organ dysfunction.
Adaptive immune response
Antigen-presenting cells present antigen peptides to T and B cells for recognition, thereby
inducing cellular and humoral immunity. Ni et al (82) characterized SARS-CoV-2-specific
humoral and cellular immunity in recovered patients with Covid-19. Both T cells and B cells
were detected in newly discharged patients (82). In addition, Spearmen's correlation showed that
the neutralizing antibody titers were significantly positively correlated with the numbers of NP-
specific T cells (82). These findings suggested both B and T cells participate in immune-
mediated protection to viral infection.
Cellular immune response
The role of T cells and its subsets in resisting COVID-19 remains unclear. Previous studies have
confirmed that the S protein of SARS-CoV is the primary antigen protein that induces the host
immune response, and serves an important role in activating cytotoxic T cell responses and
causing humoral immune responses. Xu et al (23) found that the proportions of circulating
CD4+ and CD8+ T cells were substantially decreased in patients infected with COVID-19, but
their status was hyperactivated. In addition, there is an increased percentage of highly
proinflammatory T helper 17 (Th17) cells and high numbers of cytotoxic CD8 + T cells,
indicating that the overactivation of T cells may partly account for the severe inflammatory
response (23). However, the disease is more severe when lymphocytopenia is present in COVID-
19, suggesting that the T cell response may be necessary for SARS-CoV-2 clearance. Diao et
al (83) observed that in addition to a reduction in the number of T cells, surviving T cells are
functionally exhausted in COVID-19. In addition, T cell subpopulation differentiation and
functional imbalance are key factors in the development of some inflammatory diseases.
Therefore, an imbalance in the ratio of Th1/Th2 and Th17/regulatory T cells in COVID-19 may
be a research topic that requires further study.
Humoral immune response
The host humoral response against SARS-CoV-2 comprises specific IgA, IgM and IgG
responses. Most patients with COVID-19 have a specific Ab response ≥10 days following the
onset of symptoms. In a recent study of 82 confirmed and 58 probable COVID-19 cases, the
specific IgM and IgA Abs were detected on day 5 (IQR 3-6), while IgG was detected on day 14
(IQR 10-18) after symptom onset (84). However, the persistence of neutralizing Abs for SARS-
CoV-2 requires further study.
Antiviral neutralizing Abs play a pivotal role in viral clearance. The S protein RBD is specific
for SARS-CoV-2 and may be the direct target for neutralizing Abs (43). Tian et al (17) assessed
the cross-reactivity of anti-SARS-CoV Abs with SARS-CoV-2 S protein. This previous study
revealed that the epitope of CR3022, a SARS-CoV-specific human monoclonal Ab, which does
not overlap with the ACE2 binding site, could bind potently with SARS-CoV-2 RBD. Most
recently, the neutralizing Ab from three convalescent SARS patients was reported to reduce
SARS-CoV-2-driven cell entry, although with lower efficiency compared with SARS-CoV,
suggesting that Ab responses raised against SARS-CoV S protein during infection or vaccination
could at least partially protect against SARS-CoV-2 infection (22). It has also been suggested
that convalescent plasma in patients with COVID-19 might be useful as a potential therapy (85).
On the other hand, Ab-dependent cell-mediated cytotoxicity may also be involved in cellular
damage and organ injury (15). The Fc receptor-mediated Ab-dependent enhancement of SARS-
CoV-2 infection may additionally lead to inflammatory responses (15).
Hypercytokinemia and organ damage
COVID-19 can cause both pulmonary and systemic inflammation, leading to MODS in high risk
patients (86). Organ dysfunction is the key diagnostic criterion for severe or critical SARS-CoV-
2 pneumonia. The most frequent organ dysfunction in patients with severe and critical COVID-
19 includes ARDS, shock, acute myocardial injury, liver injury, kidney injury and MODS. The
most frequent type of organ dysfunction in patients with severe and critical COVID-19 admitted
to the ICU includes ARDS (61.1%), arrhythmia (44.4%), shock (30.6%), myocardial injury
(22.2%) and acute kidney injury (8.3%) (82). Another clinical trial indicated that the majority of
critically ill patients with COVID-19 had organ function injury, including ARDS (67%), acute
kidney injury (29%), liver dysfunction (29%) and cardiac injury (23%), and 71% of these
patients required mechanical ventilation (2). It is generally assumed that the fundamental
pathophysiology of critical COVID-19 is severe ARDS (2).
The involvement of multiple organs may be related to the direct damage of target cells by SARS-
CoV-2 and improper host responses, such as the immune-inflammatory response. The effects of
the host immune response are a double-edged sword, both protecting the host (immunity) by
clearing the infection, and harming the host by inducing tissue and cell damage, resulting in
immunopathology and worse clinical outcomes (91). In other words, cytokines and chemokines
released from activated immune cells not only participate in the antiviral immune response, but
can also cause cell damage and organ dysfunction. The optimal objective is to achieve a careful
balance in the immune response, which could eliminate the virus, whilst avoiding inflammatory-
mediated organ injury.
Hypercytokinemia is an uncontrolled host inflammatory state that is characterized by fulminant
MOD and elevated proinflammatory cytokine responses. Hypercytokinemia serves a key role in
pathogenic inflammation both in severe SARS and COVID-19. The cytokines and chemokines
found in MERS-CoV-infected cells share a similar expression profile to SARS-CoV-infected
cells. Several studies from humans who succumbed to highly pathogenic human CoV infections,
such as SARS and MERS, have also suggested that a dysregulated immune response and
immunopathology occurred, resulting in excessive inflammation and lethal consequences during
human CoV infections (92,95). Macrophages in the lung tissue are proposed to be the primary
inducer of hypercytokinemiaand underlie the pathogenesis of MERS and SARS (54). In serum
from patients with COVID-19 with a poor outcome, there was a significant increase in CRP, IL-
2, IL-7, IL-10, G-CSF, IP10, MCP-1, MIP-1A and TNF-α, characterized as hypercytokinemia
(24). Chen et al (6) also demonstrated elevated cytokine levels (IL-6, IL-10 and TNF-α) in
severe COVID-19. A recent study reported that COVID-19 is associated with an elevated
cytokine profile that is similar to that observed in secondary hemophagocytic
lymphohistiocytosis (97). Findings from autopsies and serum of patients with COVID-19 suggest
a crucial immune-inflammatory implication in the progression to ARDS and MODS (23). ARDS
caused by SARS-CoV-2 infection seems to primarily result from exaggerated and uncontrollable
inflammation initiated by viral replication. High levels of proinflammatory cytokines may lead to
tissue damage in the heart, liver, kidney and the central nervous system, causing sepsis, shock or
multiple organ failure (92). The detailed expression profile of the cytokine and chemokine
responses in COVID-19 requires further investigation and comparison with that in MERS and
SARS.
Acquired immune-induced proinflammatory reactions (including Th17 and cytotoxic T
lymphocyte accumulation) may also serve an important role in tissue damage caused by
hypercytokinemia (23). This exacerbated detrimental inflammatory response towards invading
viruses is termed sepsis (98). It is suggested that appropriate immunomodulatory treatments
according to the changes of patients' immune status may be the key breakthrough in treatment.
Most recently, preliminary data have shown that dexamethasone resulted in lower 28-day
mortality amongst patients hospitalized with COVID-19 who were receiving respiratory support
(99). In addition, proteolytic enzymes (such as elastase, collagenase, cathepsin and matrix
metalloproteinase) released at the site of inflammation may also mediate tissue and organ
damage (100). Oxidative stress (such as increased reactive oxygen species and reactive nitrogen
species) is an important pathway that contributes to numerous inflammatory pathological
processes, including in patients infected with COVID-19. The oxidative damage imposed on host
tissues via polymorphonuclear cells and macrophage activation may lead to tissue damage and
organ dysfunction (101-103). Considering the harmful effects of oxidative stress in COVID-19,
antioxidant therapies using bioactive compounds, as well as encouraging healthy lifestyles as a
potential treatment is an attractive and practical strategy that warrants further study in the
treatment of COVID-19 (103-106).
Immunosuppression
It has been observed that lymphopenia (defective acquired immunity) is a common feature in
patients with COVID-19, and it is related to disease severity and mortality. Immunosuppression
may lead to difficulty in removing the virus or secondary infections. Hospital-acquired
secondary infection is frequent in patients with severe COVID-19 (5-15.5%). A recent meta-
analysis (109), including 3,448 patients from 28 studies, showed that secondary bacterial
infection was identified in 14.3% of patients with COVID-19. Moreover, it has been suggested
that immunocompromised patients may have a higher viral load of SARS-CoV-2, prolonged
viral shedding and impaired Ab responses (10,43). Liang et al (110) found that patients with
cancer may be more susceptible to infection with SARS-CoV-2 than healthy individuals, and had
a worse prognosis, as their immune systems were suppressed by the effects of the tumors and
anticancer treatment.
The reason for significant lymphopenia in patients with severe COVID-19 remains unclear. It is
speculated that the underlying mechanisms of lymphopenia may include hemopoietic tissue
depression, as well as direct invasion by viral particles, which damages the lymphocytes and
results in its destruction (2). It has been postulated that SARS-CoV-2 may directly infect T cells
and lead to T cell depletion (79). Pathological studies on biopsy tissues from patients with
COVID-19 have revealed that the cell damage caused by SARS-CoV-2 infection often occurs in
the immune system (50). Furthermore, it is hypothesized that the underlying mechanism includes
increased apoptosis or necrosis of immune cells (2), and lymphocyte recruitment and
sequestration in the infection sites or lymphoid tissues (lymphocyte redistribution). However,
these speculations require experimental confirmation. In addition, several other factors may also
contribute to the development of immune suppression, such as a reduction in the number or
function of antigen presenting cells, increased anti-inflammatory cytokines (such as IL-10 and
TGF-β), neuroendocrine responses (such as glucocorticoids), elevated regulatory T cells and
myeloid-derived suppressor cells (111). Of note, lymphopenia and hypercytokinemia were
observed in patients with critical SARS-CoV in 2003, Swine flu in 2009, and COVID-19 in
2019, which may indicate that there is a particular dysregulated immunological phenotype
associated with significantly elevated severity (25).
Renin-angiotensin system in COVID-19
ACE2 is an important component of the renin-angiotensin-aldosterone system, which converts
angiotensin II into angiotensin 1-7 and angiotensin I into angiotensin 1-9(112). Notably, in
addition to mediating viral entry, the SARS-CoV S protein also has effects on the downregulated
expression of ACE2, leading to aggravated lung injury (33). These results have led to the
hypothesis that the binding of SARS-CoV-2 S protein is a virulence factor for COVID-19
outside of its role in viral attachment and entry.
Our studies have demonstrated that angiotensin II is involved in the pathophysiological processes
of pulmonary inflammation, pulmonary edema, pulmonary fibrosis and parenchymal cell
apoptosis in a lipopolysaccharide-induced ARDS animal model. Blocking the angiotensin II
receptor may inhibit the function of mature lung dendritic cells, reducing lipopolysaccharide-
induced ARDS, and thus guide the development of potentially beneficial drugs.
Recovery of immune homeostasis and repair of organ damage
There are distinct long-term outcomes observed in patients with COVID-19, including recovery,
organ fibrosis and dysfunction, chronic critical illness or persistent inflammation,
immunosuppression and catabolism syndrome, and possibly even death. A retrospective study of
1,591 consecutive patients with COVID-19 referred to ICU for admission in Italy revealed that
58% of patients were still in the ICU, 16% patients were discharged, and 26% succumbed to the
disease whilst in ICU. The long-term prognosis of patients with COVID-19 depends on a variety
of factors, including whether the virus is cleared in time, and whether the inflammatory response
subsides and inflammatory cells and cytokines are cleared. During the recovery of COVID-19,
the number of CD4+ T cells, CD8+ T cells, B cells and NK cells, and the markers of CD8 + T cell
exhaustion may gradually normalize. Additionally, SARS-CoV-2-specific Abs can be identified.
Long-term prognosis also depends on the regeneration and repair of parenchymal cells in
damaged organ tissues. Pulmonary fibrosis appears frequently in COVID-19, including in
patients who survived the infection. However, at present it is unknown whether patients with
COVID-19 will develop chronic critical illnesses or persistent inflammation-immunosuppression
and catabolism syndrome. There are a number of problems that require solving even after the
patient clears the acute phase. For example, how can chronic critical illness, persistent
inflammation, immunosuppression and catabolism syndrome be avoided? What are the roles and
mechanisms of specialized pro-resolving mediators in COVID-19?
Of note, patients with COVID-19 can relapse or become reinfected. Relapse in patients with
COVID-19 refers to the reappearance of symptoms in survivors due to the persistence of the
SARS-CoV-2 at immunologically segregated body sites. Reinfection refers to survivors being
susceptible to acquiring new infections after recovery. Patients reinfected with a strain
determined to be of a different genotype or subtype than the previous strain they were originally
infected with can easily be identified using genotyping assays. Elsayed et al reported that there
were 11 cases of relapse for COVID-19 at the time of study. The reason for this is currently
unknown, but it may involve factors such as age and immune status of the host, the presence of
underlying lung disease, and the severity of SARS-CoV2 infection, all of which could affect the
elimination of the virus. It is noteworthy to speculate that an inflammatory rebound triggered by
an inappropriate immune response could constitute a probable explanation of the recurrence of
clinical symptoms 

History
Presentations of COVID-19 range from asymptomatic/mild symptoms to severe illness and
mortality. Common symptoms include fever, cough, and shortness of breath. Other symptoms,
such as malaise and respiratory distress, have also been described. 
Symptoms may develop 2 days to 2 weeks after exposure to the virus. A pooled analysis of 181
confirmed cases of COVID-19 outside Wuhan, China, found the mean incubation period was 5.1
days, and that 97.5% of individuals who developed symptoms did so within 11.5 days of
infection. 
The following symptoms may indicate COVID-19:
 Fever or chills
 Cough
 Shortness of breath or difficulty breathing
 Fatigue
 Muscle or body aches
 Headache
 New loss of taste or smell
 Sore throat
 Congestion or runny nose
  Nausea or vomiting
 Diarrhea
Other reported symptomsinclude the following:
 Sputum production
 Malaise
 Respiratory distress
 Neurologic (eg, headache, altered mentality) 
Wu and McGoogan reported that, among 72,314 COVID-19 cases reported to the CCDC, 81%
were mild (absent or mild pneumonia), 14% were severe (hypoxia, dyspnea, >50% lung
involvement within 24-48 hours), 5% were critical (shock, respiratory failure, multiorgan
dysfunction), and 2.3% were fatal.  [17] These general symptom distributions have been
reconfirmed across multiple observations. [94, 95]
Clinicians evaluating patients with fever and acute respiratory illness should obtain information
regarding travel history or exposure to an individual who recently returned from a country or US
state experiencing active local transmission. [96]
Williamson and colleagues, in an analysis of 17 million patients, reaffirmed that severe COVID-
19 and mortality was more common in males, older individuals, individuals in poverty, Black
persons, and patients with medical conditions such as diabetes and severe asthma, among
others. [97]
A multicenter observational cohort study conducted in Europe found frailty was a greater
predictor of mortality than age or comorbidities. [98]
Type A blood has been suggested as a potential factor that predisposes to severe COVID-19,
specifically in terms of increasing the risk for respiratory failure. Blood type O appears to confer
a protective effect. [99, 100]
Patients with suspected COVID-19 should be reported immediately to infection-control
personnel at their healthcare facility and the local or state health department. CDC guidance calls
for the patient to be cared for with airborne and contact precautions (including eye shield) in
place. [20] Patient candidates for such reporting include those with fever and symptoms of lower
respiratory illness who have travelled from Wuhan City, China, within the preceding 14 days or
who have been in contact with an individual under investigation for COVID-19 or a patient with
laboratory-confirmed COVID-19 in the preceding 14 days. [96]
A complete or partial loss of the sense of smell (anosmia) has been reported as a potential history
finding in patients eventually diagnosed with COVID-19. [18] A phone survey of outpatients with
mildly symptomatic COVID-19 found that 64.4% (130 of 202) reported any altered sense of
smell or taste. [19] In a European study of 72 patients with PCR results positive for COVID-19, 53
patients (74%) reported reduced olfaction, while 50 patients (69%) reported a reduced sense of
taste. Forty-nine patients (68%) reported both symptoms.
Physical Examination
Patients who are under investigation for COVID-19 should be evaluated in a private room with
the door closed (an airborne infection isolation room is ideal) and asked to wear a surgical mask.
All other standard contact and airborne precautions should be observed, and treating healthcare
personnel should wear eye protection. [20]
The most common serious manifestation of COVID-19 upon initial presentation is pneumonia.
Fever, cough, dyspnea, and abnormalities on chest imaging are common in these
cases. [102, 103, 104, 105]
Huang and colleagues found that, among patients with pneumonia, 99% had fever, 70% reported
fatigue, 59% had dry cough, 40% had anorexia, 35% experienced myalgias, 31% had dyspnea,
and 27% had sputum production.
Approach Considerations
Diagnostic testing for SARS-CoV-2 infection can be conducted by the CDC, state public health
laboratories, hospitals using their own developed and validated tests, and some commercial
reference laboratories. [124]
State health departments with a patient under investigation (PUI) should contact CDC’s
Emergency Operations Center (EOC) at 770-488-7100 for assistance with collection, storage,
and shipment of clinical specimens for diagnostic testing. Specimens from the upper respiratory
tract, lower respiratory tract, and serum should be collected to optimize the likelihood of
detection. [96]
The FDA now recommends that nasal swabs that access just the front of the nose be used in
symptomatic patients, allowing for (1) a more comfortable and simplified collection method and
(2) self-collection at collection sites. [125]
Various organizations, including the CDC, have published guidelines on COVID-19. 
Laboratory Studies
Signs and symptoms of coronavirus disease 2019 (COVID-19) may overlap with those of other
respiratory infections; therefore, it is important to perform laboratory testing to specifically
identify symptomatic individuals infected with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). 
Three types of tests may be utilized to determine if an individual has been infected with SARS-
CoV-2: 
 Viral nucleic acid (RNA) detection 
 Viral antigen detection 
 Detection of antibodies to the virus  
Viral tests (nucleic acid or antigen detection tests) are used to assess acute infection, whereas
antibody tests provide evidence of prior infection with SARS-CoV-2. Home sample collection
kits for COVID-19 testing have been available by prescription; in December 2020, the LabCorp
Pixel COVID-19 Test Home Collection Kit became the first to receive an FDA EUA for
nonprescription use. 
The FDA has advised against the use of antibody tests to ascertain immunity or protection from
COVID-19, particularly in patients who have been vaccinated against the disease. According to
the agency, differences between antibodies that arise from prior SARS-CoV-2 infection and
those induced by vaccination leave the tests unable to determine whether an individual has
achieved protection through a vaccine.
Laboratory findings in patients with COVID-19
Leukopenia, leukocytosis, and lymphopenia were common among early cases. [31, 102]  
Lactate dehydrogenase and ferritin levels are commonly elevated. [102]
Wu and colleagues [126] reported that, among 200 patients with COVID-19 who were hospitalized,
older age, neutrophilia, and elevated lactate dehydrogenase and D-dimer levels increased the
risks for ARDS and death.
CT Scanning
Chest computed tomography (CT) scanning in patients with COVID-19–associated pneumonia
usually shows ground-glass opacification, possibly with consolidation. Some studies have
reported that abnormalities on chest CT scans are usually bilateral, involve the lower lobes, and
have a peripheral distribution. Pleural effusion, pleural thickening, and lymphadenopathy have
also been reported, although with less frequency. [102, 127, 128]
Bai and colleagues reported the following common chest CT scanning features among 201
patients with CT abnormalities and positive RT-PCR results for COVID-19 [129] :
 Peripheral distribution (80%)
 Ground-glass opacity (91%)
 Fine reticular opacity (56%)
 Vascular thickening (59%)
Less-common features on chest CT scanning included the following [129] :
 Central and peripheral distribution (14%)
 Pleural effusion (4.1%)
 Lymphadenopathy (2.7%)
The American College of Radiology (ACR) recommends against using CT scanning for
screening or diagnosis but instead reserving it for management in hospitalized patients. [130]
At least two studies have reported on manifestations of infection in apparently asymptomatic
individuals. Hu and colleagues reported on 24 asymptomatic infected persons in whom chest CT
scanning revealed ground-glass opacities/patchy shadowing in 50% of cases.  [131]  Wang and
colleagues reported on 55 patients with asymptomatic infection, two thirds of whom had
evidence of pneumonia as revealed by CT scanning. [132]
Progression of CT abnormalities
Li and colleagues recommend high-resolution CT scanning and reported the following CT
changes over time in patients with COVID-19 among three Chinese hospitals:
 Early phase: Multiple small patchy shadows and interstitial changes begin to emerge in a
distribution beginning near the pleura or bronchi rather than the pulmonary parenchyma.
 Progressive phase: The lesions enlarge and increase, evolving to multiple ground-glass
opacities and infiltrating consolidation in both lungs.
 Severe phase: Massive pulmonary consolidations occur, while pleural effusion is rare.
 Dissipative phase: Ground-glass opacities and pulmonary consolidations are absorbed
completely. The lesions begin evolving into fibrosis. [133]
 Axial chest CT
demonstrates patchy ground-glass opacities with peripheral distribution.
View Media Gallery
 Coronal
reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
View Media Gallery
 Axial chest CT
shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity.
Findings are in peripheral and subpleural distribution.
Chest Radiography
In a retrospective study of patients in Hong Kong with COVID-19, common abnormalities on
chest radiography, when present, included consolidation (30 of 64 patients; 47%) and ground-
glass opacities (33%). Consolidation was commonly bilateral and of lower zone distribution.
Pleural effusion was an uncommon finding. Severity on chest radiography peaked 10 to 12 days
after symptom onset. [134]
Chest radiography may reveal pulmonary infiltrates. [135]
 The heart is normal in
size. There are diffuse, patchy opacities throughout both lungs, which may represent multifocal
viral/bacterial pneumonia versus pulmonary edema. These opacities are particularly confluent
along the periphery of the right lung. There is left midlung platelike atelectasis. Obscuration of
the left costophrenic angle may represent consolidation versus a pleural effusion with atelectasis.
There is no pneumothorax.
View Media Gallery
 The heart is normal in size.
There are bilateral hazy opacities, with lower lobe predominance. These findings are consistent
with multifocal/viral pneumonia. No pleural effusion or pneumothorax are seen.
View Media Gallery
 The heart is
normal in size. Patchy opacities are seen throughout the lung fields. Patchy areas of
consolidation at the right lung base partially silhouettes the right diaphragm. There is no effusion
or pneumothorax. Degenerative changes of the thoracic spine are noted.
View Media Gallery
 The same patient
as above 10 days later.
View Media Gallery
 The trachea is in midline.
The cardiomediastinal silhouette is normal in size. There are diffuse hazy reticulonodular
opacities in both lungs. Differential diagnoses include viral pneumonia, multifocal bacterial
pneumonia or ARDS. There is no pleural effusion or pneumothorax.