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Identifying and testing for RTIs.

Respiratory tract infections (RTI) or infections in the respiratory tract are divided into upper respiratory tract infections (URI/URTI) and lower respiratory tract infections (LRI/ LRU). Though some disagreement exists regarding the exact boundary between the upper and lower respiratory tracts, URTIs occur in the respiratory tract above the lungs including throat (pharyngitis), nasopharynx (nasopharyngitis), sinus (sinusitis), larynx (laryngitis), epiglottis (epiglottitis) or trachea (trachealis). LRUs affect the lungs and tend to be more serious than URTIs.

Respiratory tract infections can be caused by viruses or bacteria. Most of the time the infections caused by viruses do not require any treatment and resolve on their own; however, bacterial infections require appropriate antibiotic therapy. Hence, early detection of the causative organism is essential for proper patient management.

URTI--mostly viral in nature

UTRIs are the most common reasons for patients to consult a healthcare professional in the outpatient setting. (1) URTIs can be mild, self-limited infections like the common cold, or can escalate to a life-threatening illness such as epiglottitis.

UTRIs are caused by viruses in approximately 90 to 98 percent of cases. (2) Some of the viruses that cause UTRIs are also capable of causing LRTIs. The different viruses and the RTIs they can cause are discussed below.

Common cold and rhinovirus

Around 50 percent of the time, a common cold is caused by rhinoviruses that exist as three genotypes--A, B, and C. The common cold is the most frequently occurring URTI. Each year in the United States there are millions of cases of the common cold. Colds are the main reason that children miss school and adults miss work. Adults have an average of two to three colds per year. (1) A preschool-aged child has an average of six to 10 episodes per year, and 10 to 15 percent of school-aged children have at least 12 infections per year. (3)

The common cold is self-limited and does not cause serious health issues. Symptoms of common cold include: sore throat, runny nose, coughing, sneezing, headache, and body ache. (1)

Most individuals recover within seven to 10 days. Individuals with weakened immune systems, asthma, or other respiratory conditions may develop serious complications such as bronchitis or pneumonia. Other types of viruses that may cause the common cold are: coronaviruses (10 to 15 percent); influenza viruses (five to 15 percent); respiratory syncytial viruses (RSV, -10 percent); parainfluenza viruses (PIV, ~ five percent); enteroviruses (< five percent); and human metapneumovirus (hMPV). (4)

Medicine cannot cure the common cold. Nonsteroidal anti-inflammatories (NSAIDS), analgesics, antihistamines, cough medicines, and decongestants are commonly used. Tylenol may be given to children. Adults can take Tylenol, aspirin, or Naproxen over-the-counter (OTC) to get relief from head and body aches. (5)

Influenza-like illness <1 LI) and influenza virus

The next common URTI with symptoms similar to the common cold is the flu. Influenza (flu) is a contagious respiratory illness commonly caused by influenza viruses A or B--and rarely by type C.

Influenza A viruses are divided into subtypes based on their two surface proteins: the hemagglutinin (H) and the neuraminidase (N). There are 18 different hemagglutinin subtypes (H1 through H18), and 11 different neuraminidase subtypes (N1 through Nil). Currently influenza A (H1N1) and influenza A (H3N2) subtypes are found in infected individuals. Influenza B viruses are not divided into subtypes, but various strains/lineages are found. Vaccines are available for influenza virus A and B.

The flu can cause mild to severe illness. Serious outcomes of flu infection can result in hospitalization or death. Some people, such as the elderly, young children, people with certain chronic health conditions (asthma, diabetes, or heart disease), and pregnant women are at high risk of serious flu complications. Even though the impact of the flu varies based on the virulence of the circulating flu virus and the effectiveness of flu vaccines of that season, it places a substantial burden on the health of people in the U.S. each year. Center for Disease Control (CDC) estimates that influenza causes between 9.2 and 35.6 million illnesses, between 140,000 and 710,000 hospitalizations, and between 12,000 and 56,000 deaths annually since 2010. (6)

Symptoms of flu include: fever or feeling feverish/ chills, cough, sore throat, runny or stuffy nose, muscle or body ache, headache, fatigue, and vomiting and diarrhea, (7) which is common in young children.

Often the common cold and the flu are confused. Table 1 differentiates between the two. The incidence of flu shows seasonality--it tends to start in October, reach a peak between December and February, and declines around May. (8)

Treatment for flu includes common antiviral drugs like oseltamivir (available as a generic version or under the trade name Tamiflu), zanamivir (trade name Relenza), and peramivir (trade name Rapivab). Nonsteroidal anti-inflammatories, analgesics, antihistamines, cough medicines, and decongestants are also commonly used. (9)

Infections by human adenovirus

Human adenovirus (HAdV) is another virus that causes URTI-influenza like infection. Some HAdV serotypes cause conjunctivitis, gastrointestinal, and urinary infections, while some can cause Acute Respiratory Disease (ARD) which can be fatal. Table 2 illustrates the subgroups and serotypes of adenovirus and the infections they are associated with.

During the period of October 2013 to July 2014, Oregon state health authorities identified 198 persons with respiratory symptoms and an HAdV-positive respiratory tract specimen. Among the 136 (69 percent) hospitalized persons, 31 percent were admitted to the intensive care unit, and 18 percent required mechanical ventilation; five patients died. (10)

Some additional viruses include HAdV-B14, which has been associated with outbreaks of acute respiratory illness among U.S. military recruits and the general public since 2007. It is often termed as killer cold. (11) HAdV-E4 was identified in adults with ARD in the northeastern U.S. during 2011-2015, (12,14) and HAdV-B7, which can cause severe respiratory disease, is reemerging in Asia.


Most infections by adenovirus are cleared by the immune system and do not require any medication. However in immunocompromised patients, drugs such as cidofovir, ribavirin, ganciclovir, and vidarabine have been used. (13)

Viruses causing both URTI and LTRI

There are many viruses that are capable of causing infections in both the upper and lower respiratory tract. The following are a few examples of such viruses:

Human Respiratory Syncytial Virus (RSV) is one of the most common viruses to infect children worldwide and is increasingly being recognized as an important pathogen in adults, especially the elderly. It causes mild URIs but severe LRIs. (15) RSV has been implicated in severe acute respiratory illness (SARI). RSV consists of two subtypes--A and B. Subtype A is more virulent and predominate during outbreaks. Subtype B is generally asymptomatic. (15) Medication used in severe high-risk cases include the antiviral drug ribavirin. (16)

Human Parainfluenza Virus (HPIV) can cause both upper and lower respiratory infections. It causes infections in infants and young children. Common symptoms are fever, runny nose, and cough. (17)

HPIV are classified as types 1, 2, 3, and 4. They cause disease of different severity. Type 4 has antigenic cross-reactivity with the mumps virus and very rarely causes respiratory infection that requires medical attention. Types 1 and 2 tend to cause epidemics in the fall, with each serotype occurring in alternate years. Type 3 is endemic and infects most children < 1 year; incidence is increased in the spring. Parainfluenza viruses can cause repeated infections, but reinfection generally causes milder illness. The most common illness in children is an URI with no or low-grade fever. (17) Medication used in severe high-risk cases include the antiviral drug ribavirin. (18,19)

Human coronavirus (HCoV) cause URTI which can lead to LTRI. There are four common types: 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), and HKU1 (beta coronavirus). NL63 has been associated with croup (laryngotracheobronchitis) (20) while HKU1 has been associated with febrile convulsion. (21) OC43 is associated with necrotizing enterocolitis, gastroenteritis (22-24) with typical URTI symptoms such as runny nose, cough, sore throat, and sometimes, fever. (22) 229E is also associated with URTI symptoms like common cold in immunocompetent patients and LTRI symptoms like pneumonia in immunocompromised patients.

Clinically, it is difficult to differentiate common cold by coronavirus from that by rhinovirus. There also exists rarer, more dangerous types such as MERS-CoV, which causes Middle East Respiratory Syndrome (MERS), and SARS-CoV which can cause severe acute respiratory syndrome (SARS). (25,26) Coronavirus infections are treated like a cold. (27)

Human metapneumo virus (HMPV) can cause upper and lower respiratory tract infections. HMPV is commonly found in the pediatric population, with high susceptibility rates in children less than two years. HMPV infection in adults normally shows mild flu-like symptoms. However, in some adult cases (especially elderly adults), severe complications such as chronic obstructive pulmonary disease can occur. HMPV infections have also been reported in several immunocompromised patients, such as lung transplant recipients, patients with hematological malignancies, and hematopoietic stem cell transplant recipients. HMPV exists as two genotypes: A and B. (28) Medication used in severe high-risk cases include the antiviral drug ribavirin. (29)

Human enterovirus (HEV) are ubiquitous in nature. They can cause respiratory, gastrointestinal, and diseases of the central nervous system. The respiratory enteroviruses usually cause no symptom or mild symptoms. At times they can cause severe infection. HEV are found to have 4 genotypes: A, B, C, and D.

In 2014, an uncommon form of enterovirus, called EV-D68, was found circulating in Missouri and Illinois. Unlike the majority of enteroviruses that cause disease--mild upper respiratory illness, rash illness with fever, or neurologic illness (such as aseptic meningitis and encephalitis)--EV-D68 has been associated almost exclusively with respiratory disease, which can range from mild to severe, requiring hospitalization in an intensive care unit. Symptoms have included fever, difficulty breathing, and wheezing or asthma exacerbation. (30) There is no medication for enterovirus. OTC medications like aspirin or Tylenol are given to relieve the symptoms. (30)

Human boca virus (HBoV) has been implicated in both upper and lower respiratory infections. The common clinical diagnoses associated with respiratory HBoV infection include URTIs, bronchiolitis, pneumonia, bronchitis, and asthma exacerbation. (31) There is no medication for bocavirus. Supportive therapy is the mainstay of treatment. (31) Often patients show concomitant presence of different types of viruses.

Upper and lower RTIs caused by bacteria

The human upper respiratory tract harbors several commensal bacteria which can occasionally turn pathogenic. (32) Table 3 lists the bacteria, infection site, the URTIs they cause, and medications of choice. (33) Table 4 lists the bacteria known to cause LRTIs (ie: pneumonia), both typical and atypical, as well as medications of choice.

Diagnostic methods for RTI

Viral infections often resolve on their own and unfortunately, antibiotics have no effect. Clinical manifestation is often not specific enough. Hence, proper diagnosis to determine the causative organism is very important for proper patient management. The various diagnostic tests, along with their pros and cons are listed, below.

Virus tests

* Viral culture: considered the gold standard but difficult to grow and is time consuming.

* Rapid antigen: often have low sensitivity and/or specificity.

* Direct fluorescent antibody (DFA): provides detection of multiple viruses with high specificity. Sensitivity suboptimal for some viruses and requires expertise.

* Molecular method: direct identification of viral RNA or DNA by PCR, Multiplex PCR or Real-Time PCR. Very sensitive and specific. More expensive compared to other methods.

Bacteria tests

* Gram staining: easy and rapid; however not specific.

* Bacterial culture and drug sensitivity: highly specific, sensitivity varies.

* Rapid antigen: often have low sensitivity and/or specificity.

* DFA: provides multiple bacteria detection with high specificity; suboptimal for some bacteria and requires expertise.

* Molecular method: direct identification of viral RNA or DNA by PCR, Multiplex PCR or Real-Time PCR; very sensitive, specific; more expensive compared to other methods.

Commercial RTI tests that identify multiple viruses and/or bacteria using multiplex PCR technology offer convenient method of detection and are highly sensitive and specific.

Please visit for references.

Rajasri Chandra, MS, MBA, heads Product Management for molecular diagnostics provider AutoGenomics, Inc., based in Carlsbad, CA.

Earning CEUs

See test on page 14 or online at under the CE Tests tab.


Upon completion of this article, the reader will be able to:

1. Discuss the URTIs and LRTIs in terms of location, signs, symptoms, and etiologies.

2. Describe URTIs and LRTIs caused by both viruses and bacteria.

3. Recall various characteristics of all RTIs including serotypes and treatments.

4. Recall the various diagnostic tests for viruses and bacteria, including their pros and cons.


Identifying and testing for RTIs--November 2018 [This form may be photocopied. It is no longer valid for CEUs after May 31, 2019.)

1. Respiratory tract infections (RTI) are divided into the

() a. upper respiratory tract and middle respiratory tract.

() b. lower respiratory tract and middle respiratory tract.

() c. upper respiratory tract and lower respiratory tract.

() d. none of the above

2. Upper respiratory tract infections (URTIs) occur in all but the following

() a. lungs

() b. throat

() c. sinuses

() d. trachea

3. What type of RTIs typically resolve on their own?

() a. fungal

() b. bacterial

() c. viral

() d. all of the above

4. What percentage of UTRI cases are caused by viruses?

() a. five to 10

() b. 20 to 58

() c. 60 to 75

() d. 90 to 98

5. Which illness is the most frequently occurring URTI?

() a. influenza

() b. influenza-like virus

() c. common cold

() d. bronchitis

6. All but the following are viruses that can cause the common cold

() a. influenza virus.

() b. human adenovirus

() c. coronavirus

() d. respiratory syncytial virus

7. There are many types of medications that cure the common cold.

() 8 a. True

() b. False

8. The two current influenza subtypes that are found in infected individuals are

() a. H2N2 and H3N2.

() b. H3N6 and H5N9.

() c. H1N1 and H4N2.

() d. H1N1 and H3N2.

9. The common cold is often confused with

() a. adenovirus.

() b. influenza virus.

() c. boca virus.

() d. all of the above.

10. All of the following are symptoms of flu except

() a. fever of 102-104[degrees] F.

() b. prominent headache at onset.

() c. often severe aches and pains.

() d. mild to moderate chest discomfort and cough.

11. Which infection is sometimes referred to as a "killer cold?"

() a. HAdV-B14

() b. HAdV-E4

() c. HCoV

() d. HEV

12. Human Adenovirus (HAdV) can cause

() a. conjunctivitis.

() b. gastrointestinal infections.

() c. urinary infections.

() d. all of the above.

13. There are many viruses that are capable of causing infections in both the upper and lower respiratory tract.

() a. True

() b. False

14. Which virus is most common to infect children worldwide?

() a. influenza

() b. RSV

() c. HAdV

() d.HEV

15. Which virus contains the rare and dangerous MERS and SARS types?

() a. HMPV

() b. HBoV

() c. HPIV

() d. HCoV

16. Human Enterovirus EV-D68 was found to cause respiratory disease, along with rash, fever and neurologic illness.

() a. True

() b. False

17. The antiviral drug ribavirin is used in high-risks cases in all the following viruses but

() a. RSV.

() b. HEV.

() c. HMPV.

() d. HPIV.

18. Bacterial illness in the upper respiratory tract usually cause--and bacterial illness in the lower respiratory tract usually cause--.

() a. respiratory infections of the upper respiratory tract; pneumonia

() b. pneumonia; respiratory infections of the upper respiratory tract

() c. respiratory infections of the lower respiratory tract; sepsis

() d. sepsis; pneumonia

19. This bacteria can cause pneumonia, however isn't known to cause URTI's.

() a. Neisseria meningitis

() b. Mycoplasma pneumoniae

() c. Chlamydophila pneumoniae

() d. Klebsiella pneumonia

20. Although one of the most expensive tests, this test for viral and/or bacterial identification gives the highest sensitivity and specificity.

() a. direct fluorescent antibody

() b. viral culture

() c. PCR methods

() d. rapid antigen tests
Table 1. Common cold vs flu symptoms

SYMPTOM                   COMMON COLD

Fever                     Rare, usually <101[degrees] F
Clear, runny nose         Prominent at outset
Headache                  Rare
General aches, pains      Slight
Fatigue, weakness         Quite mild
Extreme exhaustion        Never
Chest discomfort, cough   Mild to moderate
Complications             Sinusitis, ear infections
                          (otitis media)

SYMPTOM                   FLU

Fever                     Characteristic 102-104[degrees] F
Clear, runny nose         Can be present
Headache                  Prominent at outset
General aches, pains      Usual, often severe
Fatigue, weakness         Can last up to 2-3 weeks
Extreme exhaustion        Early and prominent
Chest discomfort, cough   Common, often severe
Complications             Bronchitis, pneumonia

Table 2. Adenovirus subgroups and serotypes


A          12,18,31            Gastrointestinal, respiratory,
B Type 1   3,7,16,21           Keratoconjunctivitis,
                               gastrointestinal, respiratory,
B Type 2   11,14,34,35         Gastrointestinal, respiratory,
C          1,2,5,6             Respiratory, gastrointestinal
                               including hepatitis, urinary
D          8-10,13,15,17,19,   Keratoconjunctivitis,
           20,22-30,32,33,     gastrointestinal
E          4                   Keratoconjunctivitis, respiratory
F          40,41               Gastrointestinal
G          52                  Gastrointestinal

Table 3. URTIs caused by bacteria


Group A             Throat, pharynx   Sore throat,
([beta]-hemolytic                     pharyngitis
Group C             Throat, pharynx   Severe acute
[beta]-hemolytic                      pharyngitis
Corynebacterium     Throat, pharynx   Diptheria
Neisseria           Oropharynx        Tonsillitis,
gonorrhoea                            pharyngitis

Neisseria           Larynx            Epiglottitis
Arcano-             Pharynx           Pharyngitis

Chlamydophilia      Throat, pharynx   Sore throat, phar-
pneumoniae                            yngitis, sinusitis,
                                      otitis media
Mycoplasma          Throat, pharynx   Sore throat phar-
pneumoniae                            yngitis, sinusitis,
                                      otitis media
Haemophilus         Nasopharynx       URTI, meningitis,
influenza                             epiglottitis

Moraxella           Nasopharynx       Otitis media,
catarrhalis                           sinusitis

Bordetella          Human respira-    Whooping cough
pertussis           tory mucosa

Bordetella          Human respira-    Whooping cough
parapertussis       tory mucosa       (milder)


Group A             Penicillin or Erythromycin
([beta]-hemolytic   for penicillin allergic
streptococcus       patients (34)
Group C             Penicillin34
Corynebacterium     Antitoxin; Penicillin or
diphtheria          Erythromycin (35)
Neisseria           Intramuscular
gonorrhoea          Ceftriaxone and oral
                    Azithromycin (36)
Neisseria           Penicillin, Ampicillin
meningitis          and Ceftriaxone (37)
Arcano-             Erythromycin,
bacterium           Azithromycin,
haemolyticum        Gentamicin, or
                    Clindamycin (38)
Chlamydophilia      Azithromycin or
pneumoniae          Tetracycline (39)

Mycoplasma          Tetracycline and
pneumoniae          Erythromycin (40)

Haemophilus         Ceftriaxone, Cefotaxime,
influenza           or Cefuroxime.
                    Fluoroquinolones, and
                    Clarithromycin (41)
Moraxella           Amoxicillin-clavulanate,
catarrhalis         second- and third-
                    generation oral
                    and Trimethoprim-
                    Sulfamethoxazole (42)
Bordetella          Azithromycin,
pertussis           Clarithromycin, and
                    Erythromycin (43)
Bordetella          Erythromycin (44)

Table 4. LRTIs caused by bacteria

                 Typical bacterial infections

Streptococcus    Ceftriaxone (Rocephin) for cases with reduced
  pneumonia      susceptibility to penicillin (45)
Haemophilus      Amoxicillin-clavulanate, Azithromycin,
  influenza      Cephalosporins, Fluoroquinolones, Clarithromycin (46)
Klebsiella       Imipenem, third-generation Cephalosporins,
  pneumonia      Quinolones, or Aminoglycosides may be used alone or
                 in combination (47)
Staphyloccus     Linezolid, Vancomycin, Clindamycin or Telavancin (48)

                 Atypical bacterial infections
Legionella       Azithromycin, Levofloxacin, Moxifloxacin,
  pneumophila    Doxycycline or Trimethoprim and Sulfamethoxazole (49)
Mycoplasma       Macrolides (e.g., azithromycin): Children and adults
  pneumonae      Flouroquinolones: Adults
                 Tetracylines (e.g., doxycycline): Older children
                 and adults (50)
Chlamydophila    Macrolides (e.g., azithromycin): Children and adults
 pneumoniae      Tetracylines (e.g., doxycycline): Older children
                 and adults (51)
Chlamydia        Macrolides (e.g., azithromycin): Children and adults
  psittaci       Tetracylines (e.g., doxycycline): Older children
                 and adults (52)
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Title Annotation:CONTINUING EDUCATION :: FLU/RESPIRATORY; respiratory tract infections
Author:Chandra, Rajasri
Publication:Medical Laboratory Observer
Article Type:Disease/Disorder overview
Date:Nov 1, 2018
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