RTIs; Causes, Symptoms, Diagnosis, Treatment

RTI








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RTI (Respiratory tract infections) are illnesses caused by an acute infection which involves the upper respiratory tract including the nose, sinuses, pharynx or larynx. This commonly includes nasal obstruction, sore throat, tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold. Most infections are viral in nature and in other instances the cause is bacterial.[rx] Upper respiratory tract infections can also be fungal or helminth in origin, but these are far less common.[rx]

Upper respiratory tract infection (URTI) or the common cold is a symptom complex usually caused by several families of the virus; these are the rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, and influenza. Occasionally the enterovirus is implicated in summer. Recently, the newly discovered bocavirus (related to the parvovirus) has also been linked to URTI. The term “URTI” is probably a misnomer as it incorrectly implies an absence of lower respiratory tract symptoms. URTI occurs commonly in both children and adults and is a major cause of mild morbidity. URTIs have a high cost to society, being responsible for missed work and unnecessary medical care. Occasionally they have serious sequelae. Often regarded as trivial, URTIs do not receive serious attention in medical school curricula.

Types of RTIs

  • Upper respiratory tract infections: Symptoms occur mainly in the nose and throat. Viral upper respiratory tract infections may occur at any age and include the common cold and influenza.

  • Lower respiratory tract infections: Symptoms occur in the windpipe, airways, and lungs. Viral lower respiratory tract infections are more common among children and include croup, bronchiolitis, and pneumonia.

There are several different types. They’re usually grouped into upper and lower RTIs.

Upper RTIs (sinuses and throat)Lower RTIs (airways and lungs)
Common coldBronchitis
Sinusitis (sinus infection)Bronchiolitis
TonsillitisChest infection
LaryngitisPneumonia (lung infection)
  • A URI may be classified by the area inflamed. Rhinitis affects the nasal mucosa, while rhinosinusitis or sinusitis affects the nose and paranasal sinuses, including frontal, ethmoid, maxillary, and sphenoid sinuses.
  • Nasopharyngitis (rhinopharyngitis or the common cold) affects the nares, pharynx, hypopharynx, uvula, and tonsils generally.
  • Without involving the nose, pharyngitis inflames the pharynx, hypopharynx, uvula, and tonsils. Similarly, epiglottitis (supraglottitis) inflames the superior portion of the larynx and supraglottic area; laryngitis is in the larynx; laryngotracheitis is in the larynx, trachea, and subglottic area; and tracheitis is in the trachea and subglottic area.

Causes of Respiratory Tract Infection

  • Acute pharyngitis
  • Acute ear infection
  • Common cold
  • Bronchitis
  • Pneumonia
  • Bronchiolitis

Flu can be an upper or lower RTI

  • Common cold
  • Sinusitis – Inflammation of the sinuses
  • Epiglottitis – Inflammation of the epiglottis, the upper part of the trachea that helps protect the airways from foreign particles – Swelling here is dangerous because it can block air flow
  • Laryngitis – Inflammation of the larynx (voice box)
  • Bronchitis – Inflammation of the bronchial tubes

Causes and Risk Factors

Lower Respiratory Tract Infections in Children and Important Etiologic Agents

SyndromeEtiologic agents
  • Bronchiolitis
RSV, hMPV, PIV, adenovirus, coronaviruses, influenza viruses, Chlamydophila pneumoniae, Mycoplasma pneumoniae, rhinovirus, bocavirus,
  • Exacerbations of Wheezing/Asthma
RSV, hMPV, rhinovirus, adenovirus, PIV, coronaviruses, influenza viruses, Chlamydophila pneumoniae, Mycoplasma pneumoniae, bocavirus
CroupPIV, Influenza, adenovirus,
  • Pneumonia
Influenza, Streptococcus pneumoniae, Mycoplasma pneumoniae, PIV, adenovirus, RSV,hMPV, Streptococcus pyogenes, Staphylococcus aureus
  • Pneumonitis in Transplant Recipients
RSV, PIV, influenza, hMPV, adenovirus, rhinovirus

NOTE. Pathogens in bold are thought to be the most common etiologies. hMPV, human metapneumovirus; PIV, parainfluenza virus 1, 2, 3; RSV, respiratory syncytial virus.

URIs can be caused by both viruses and bacteria. There are several sub-types within each of these categories. For viruses, these include:

  • Rhinovirus
  • Adenovirus
  • Coxsackie virus
  • Parainfluenza virus
  • Respiratory syncytial virus
  • Hyman metapneumovirus

For bacteria, these include

  • Group A beta-hemolytic streptococci (GABHS)
  • Corynebacterium diphtheriae (diphtheria)
  • Neisseria gonorrhoeae (gonorrhea)
  • Chlamydia pneumoniae (chlamydia)
  • Group C beta-hemolytic streptococci

Other Causes

Typical Bacterial Infections

  • Haemophilus influenzae
  • Staphylococcus aureus
  • Klebsiella pneumonia

Atypical Bacterial Infections

  • Legionella pneumophila
  • Mycoplasma pneumoniae
  • Chlamydophila pneumoniae
  • Chlamydia psittaci

Parasitic infections

  • Respiratory cryptosporidiosis

Viral infections

  • Adenovirus
  • Influenza A virus
  • Influenza B virus
  • Human parainfluenza viruses
  • Human respiratory syncytial virus
  • SARS coronavirus
  • Middle East respiratory syndrome coronavirus
  • Aspiration pneumonia

Several actions, events or conditions can increase the risk of a URI, including

  • When someone sick sneezes or coughs without covering their nose and mouth. This causes droplets containing viruses to be sprayed into the air.
  • Closed areas or crowded conditions, such as hospitals, institutions, schools and daycare centers.
  • When you touch your nose or your eyes—infection occurs when secretion touches the nose or eyes.
  • During fall and winter (September to March) while people are more likely to be inside.
  • When humidity is low—indoor heating promotes the survival of many viruses that lead to URIs.
  • If you have a weakened immune system.
  • Chronic respiratory disease
  • Chronic renal disease
  • Chronic liver disease
  • Diabetes
  • Serious central nervous system diseases (cerebral vascular accident, transient ischaemic attack, Parkinson’s disease, dementia, and multiple sclerosis)
  • Rheumatoid arthritis
  • Cancer
  • Osteoporosis

Increased age (>60 years), especially in the presence of:

  • use of benzodiazepines or antidepressants
  • heart failure
  • male sex

Risk factors for poor prognosis

Diabetes, especially in the presence of

  • Exacerbation of COPD
  • Antibiotics within the previous month
  • Pneumonia
  • Heart failure
  • Hospitalisation
  • Current use of glucocorticoids or diabetic medication

Age >80 years, and

  • Diabetes (especially insulin dependent diabetes)
  • Exacerbation of COPD,
  • ≥2 courses oral steroids in previous year
  • Recent antibiotic use
  • Housebound (Socioeconomic factors had little additive influence on outcomes)
  • Smoking
  • Male sex
  • Aged 21–40 years

Modified CRB-65 score

1 point for each of the following

  • Age >65 years
  • Presence of new onset pneumonia-associated mental confusion
  • Hypotension with systolic blood pressure <90 mmHg
  • Respiratory rate >30/minute

Symptoms of RTIs

Symptoms of a URI may include

  • Runny nose, nasal congestion, sneezing, cough and sputum production (these are considered the most common symptoms)
  • Fever
  • Fatigue
  • A headache
  • Pain during swallowing
  • Wheezing
  • congestion, either in the nasal sinuses or lungs
  • a runny nose
  • a cough
  • a sore throat
  • body aches
  • fatigue
  • a fever over 103˚ F (39˚ C) and chills
  • difficulty breathing
  • dizziness
  • loss of consciousness

Acute upper respiratory tract infections include rhinitis, pharyngitis, tonsillitis, and laryngitis. Symptoms of URTIs commonly include

  • Cough
  • Sore throat
  • Runny nose
  • Nasal congestion
  • Headache
  • Low-grade fever
  • Facial pressure
  • Sneezing
  • Malaise
  • Myalgias

The onset of symptoms usually begins one to three days after exposure and lasts 7–10 days, and can persist up to 3 weeks.

Diagnosis of RTIs

If your child has a complicated respiratory infection, the doctor may perform one or more of these tests:

  • Blood tests. These tests are performed to see if bacteria are in the blood.
  • Imaging tests. A chest X-ray or computed tomography (CT) scan may be performed to check for infections in the chest, lungs, orbits or sinuses.
  • Throat or nasal swab. This test takes a sample of cells and mucus from the nose, throat or tonsils to find the cause of the infection.

Differential Diagnosis

  • Common Cold
  • Allergic rhinitis
  • Sinusitis
  • Tracheobronchitis
  • Pneumonia
  • Atypical Pneumonia
  • Pertussis
  • Epiglottitis
  • Streptococcal Pharyngitis/Tonsillitis
  • Infectious Mononucleosis

Treatment of RTIs

In most cases, people with URIs know what they have and are visiting the doctor to find symptom relief. Most diagnoses can be made using a medical history and a physical exam. If needed, tests like throat swabs, X-rays or CT scans might be used for diagnosis.

URI treatments include:

  • Cough suppressants
  • Expectorants
  • Vitamin C or zinc
  • Nasal decongestants
  • Steam inhalation and gargling with salt water
  • Analgesics like acetaminophen and NSAIDs can help with fever, aches and pains
  • Treatment of the symptoms of upper respiratory infection is usually continued until the infection has resolved.

The 2008 National Institute for Clinical Excellence (NICE) guidelines recommend no antibiotics or delayed antibiotics for most patients with RTI .

NICE guidance on antibiotic prescribing for self-limiting respiratory tract infections in primary care

Prescribe antibiotics for immediate use and/or arrange further appropriate investigation and management for the following patients:

  • Those who are systemically very unwell
  • Those with symptoms and signs suggesting serious illness and/or complications (particularly pneumonia, mastoiditis, peritonsillar abscess, peritonsillar cellulitis, intraorbital and intracranial complications)
  • Those at high risk of serious complications because of pre-existing comorbidity (including patients with heart, lung, renal, liver, or neuromuscular disease, immunosuppression, or cystic fibrosis, and young children who were born prematurely)
Those who are
  • >65 years with acute cough and two or more of the following criteria, or
  • >80 years with one or more of the following criteria
    • Admission to the hospital in the previous year
    • Diabetes (type 1 or type 2)
    • History of congestive heart failure
    • Current use of glucocorticoids

Consider prescribing antibiotics for immediate use in the following situations

  • Bilateral acute otitis media in children under 2 years
  • Acute otitis media in children with otorrhoea
  • An acute sore throat or acute tonsillitis when ≥3 Centor criteria are present
  • For all others adults and children (over 3 months) with acute otitis media, acute sore throat (or tonsillitis), common cold, acute rhinosinusitis, acute cough, or acute bronchitis, a non-prescribing or delayed-prescribing approach should be adopted.
  • Explore the patient’s concerns and expectations, and consider these when discussing management options.
  • Advise on the usual course of the illness and the average total illness duration.
  • Advise patients how to manage symptoms, including fever.
  • Provide advice and when to re-consult and /or use a delayed prescription.

Treatment

  • Amoxicillin 500 mg (children: 15mg/kg; maximum 500mg) orally every 8 hours for 5 days

or

  • doxycycline 100 mg (children >8 years: 2mg/kg; maximum 100 mg) orally every 12 hours for 5 days (contraindicated during pregnancy)

or

  • sulfamethoxazole 800mg + trimethoprim 160mg (children: 20mg/kg + 4mg/kg; maximum 800mg + 160 mg) orally every 12 hours for 5 days.
  • Cefalosporins and fluoroquinolones are not recommended for bronchitis.

Acute exacerbations of chronic bronchitis

  • Acute exacerbations of chronic bronchitis are often due to viral infection and do not require treatment with antimicrobials. Antimicrobial treatment should, however, be considered in patients with increasing cough, dyspnoea and increased production and purulence of sputum. The most common causative organisms are H. influenzae, Moraxella catarrhalis and S. pneumoniae.

Doses refer to adults, as this condition is rarely found in children.

  • Amoxicillin 500 mg orally every 8 hours for 5 days

or

  • amoxicillin 500mg + clavulanic acid orally every 8 hours for 5 days

or

  • sulfamethoxazole 800mg + trimethoprim 160 mg orally every 12 – 24 hours for 5 days.
  • Chronic purulent bronchial infection and chronic airway disease are predominantly diseases of adults. Chronic suppurative lung disease in children (e.g. bronchiectasis) may occasionally require treatment with amoxicillin (30mg/kg (maximum 1g) orally every 8 hours for 5 days) or chloramphenicol (25mg/kg (maximum 1g) i.v. or i.m. every 6 hours for 5 days). Cystic fibrosis infections require specialist clinical management and laboratory services.

Treatment  Continue

  • Acetaminophen – Do not take more than one drug that contains acetaminophen. Taking too much acetaminophen can damage your liver. Acetaminophen doses should not exceed 4 grams per day. Individuals with liver damage or liver problems should not exceed 2 grams of acetaminophen per day.
  • Antibiotics – are sometimes used to treat upper respiratory infections if a bacterial infection is suspected or diagnosed. These conditions may include strep throat, bacterial sinusitis, or epiglottitis. Antivirals may occasionally be recommended by doctors in patients who are immunocompromised (poor immune system). The treating doctor can determine which antibiotic would be the best option for a particular infection.
  • Nonsteroidal anti-inflammatory drugs  – such as ibuprofen (Motrin, Advil) can be used for body aches and fever.
  • Antihistamines –  such as diphenhydramine (Benadryl) are helpful in decreasing nasal secretions and congestions.
  • Nasal ipratropium  – (topical) can be used to diminish nasal secretions.
  • Cough medications – (antitussives) can be used to reduce cough. Many cough medications are commercially available such as dextromethorphan, guaifenesin (Robitussin), and codeine all have shown benefits in reducing cough in upper respiratory infections.
  • Target likely organisms with first-line drugs – Amoxicillin, Amoxicillin/Clavulanate
  • Use shortest effective course – Should see improvement in 2–3 days. Continue treatment for 7 days after symptoms improve or resolve (usually a 10–14-day course).
  • Honey – can be used in reducing cough.
  • Steroids  – such as dexamethasone and prednisone orally are sometimes used to reduce inflammation of the airway passage and decrease swelling and congestion.
  • Decongestants – such as pseudoephedrine oral, phenylephrine can be used to reduce nasal congestion (generally not recommended in children less than 2 years of age and not recommended for individuals with high blood pressure).
  • Oxymetazoline –  nasal solution is a decongestant, but should only be used for short-term.
  • To reduce fever and pain — analgesics- Acetaminophen is generally preferred. Ibuprofen or naproxen is also commonly used. Aspirin should be avoided due to its risk of developing Reye’s syndrome. (Reye’s syndrome is a condition that affects all body organs and is most harmful to the brain and liver.)
  • To dry out the nose — antihistamines –  Try an antihistamine, such as diphenhydramine. Because these products can make you sleepy, avoid driving and other complex tasks while taking these medicines. Loratadine available is a non-drowsy alternative, but may not be as effective as other antihistamines for reducing cold and flu symptoms.
  • To relieve a stuffy, clogged nose — decongestants  – Try an oral decongestant, such as pseudoephedrine. However, insomnia, nervousness, and irritability can occur when taking these drugs. Those who are pregnant or have uncontrolled high blood pressure should avoid pseudoephedrine products. Often decongestants are combined with other drugs (especially antihistamines) in OTC medicines. A “-D” at the end of a medicine’s name means it includes an oral decongestant.
  • To relieve a runny nose or sinus pressure — nasal steroids- Medications like fluticasone available without a prescription) or mometasone; prescription needed) can relieve symptoms. These medicines are also used for seasonal allergies. These are not the same as or other OTC nasal preparations. Antihistamines will also help.
  • To make blowing your nose easier or loosening cough/mucus production — expectorants: Try guaifenesin. These products help thin the thick, discolored drainage coming out of the nose and mouth.
  • To reduce coughing — antitussives –  Dextromethorphan can help suppress a cough.
  • To relieve a sore throat – Try throat lozenges or gargle with warm salt water a few times a day. Analgesics are also helpful.
  • Oral zinc supplementation – has been used in recent years to shorten the duration and reduce the severity of symptoms of upper respiratory infection and the common cold. This therapy has been studied in children with an upper respiratory infection and the results are mixed. The FDA has not approved the use of oral zinc to treat the common cold or upper respiratory infections. There are reports of nausea and unpleasant taste caused by oral zinc.
  • Topical nasal zinc products  – has been also used to attenuate the symptoms of upper respiratory infection. Some studies suggest a loss of the sense of smell associated with the use of this over the counter product.
  • The use of oral vitamin C – is thought to shorten the duration of upper respiratory infection symptoms, but research data are inconclusive regarding the benefits of vitamin C.

Complications of a Respiratory Infection may include

  • Empyema – Empyema is a collection of pus beside the lungs, caused by a bacterial infection that can lead to life-threatening problems such as sepsis (bacteria in the blood) and shock. Symptoms include fever, cough, shortness of breath and chest pain.
  • Lung abscess – A lung abscess is a pus-filled cavity in the lung surrounded by inflamed tissue. It is usually caused by a severe infection such as pneumonia or tuberculosis or from inhaling material into the lungs from the mouth.
  • Potts puffy tumor – This is an uncommon complication of sinusitis (a type of upper respiratory tract infection that causes inflammation of the sinus cavities in the skull). It is an abscess of the forehead area with frontal swelling. Potts puffy tumor is usually seen in late childhood or adolescence. Symptoms include red, tender swelling in the mid-forehead, headache, and fever.
  • Orbital cellulitis – Orbital cellulitis is another possible complication of sinusitis. This is an infection of the tissue within the eye socket and around the eye. Symptoms include pain, swelling, red eye, fever, a bulging eye, impaired vision, and impaired eye movements.
  • Orbital abscess  – Also a further complication of sinusitis causing orbital cellulitis, an orbital abscess is a collection of bacteria and pus behind the eye. Symptoms include eye pain, bulging of the eye, redness of the eye, changes in vision and fever.
  • Mastoiditis – Mastoiditis is a complication of otitis (a type of upper respiratory tract infection that causes inflammation and possible infection of the middle ear). This is a serious bacterial infection that affects the mastoid bone behind the ear. Symptoms may include ear pain, fever, headache, drainage from the infected ear, redness, swelling and tenderness in the affected ear.dentifying patients at risk of poor prognosis for developing pneumonia

Non-antibiotic management of RTIs

  • Beta-2 agonists for acute bronchitis (mainly oral agents) –  little evidence for routine use in acute bronchitis in primary care, but if there is evidence of airflow obstruction with the symptoms, some adults may derive some symptomatic benefit. Only two included studies were in children, and there was no evidence of benefit.
  • Over-the-counter (OTC) medications for acute cough – review of antitussives, expectorants, mucolytics, antihistamine/decongestant combinations, other drug combinations and antihistamines concluded there was no good evidence for or against the effectiveness of OTC medications in children or adults, but that the few studies were mostly of poor design, with small sample sizes and that interventions and outcomes were so diverse that is was difficult to generalise the findings. In 2008, the Commission on Human Medicines (CHM) advised about the unfavorable risk/benefit ratio of these medicines in children. The Medicines and Healthcare Regulatory Authority (MHRA) subsequently amended the product license for cough medications for children due to safety concerns. They should not be used by children under 6 years of age, and can only be purchased for children aged 6–12 years in a pharmacy. The MHRA has also recommended that certain combinations should be phased out (the combination of cough suppressant and expectorant).
  • Corticosteroids for sore throats – a systematic review and meta-analysis of eight trials involving 369 children and 374 adults found that despite heterogeneity, corticosteroids significantly reduced sore throat pain in addition to antibiotic therapy mainly in patients with a severe or an exudative sore throat.
  • Vitamin C for preventing and treating pneumonia – review of five trials carried out in extraordinary conditions suggested there may be a benefit at both preventing and treating pneumonia, but possibly only in those with low plasma vitamin C levels.
  • Vitamin C for preventing and treating the common cold – no benefit in the general population, but six trials which showed some evidence may reduce the risk of catching the common cold by half in individuals undergoing short periods of acute physical or cold stress or both (for example, marathon runners and soldiers training at sub-arctic conditions); poor study designs showed inconsistent results on effect of duration or severity of a cold.
  • Vitamin A for preventing acute LRTIs in children up to 7 years of age – some evidence for benefit if poor nutritional status, but some studies actually found increased chances of infection or worsened symptoms.
  • Echinacea for preventing and treating the common cold – some preparations based on Echinacea purpura might be effective, but no clear evidence of other preparation effectiveness or effectiveness in children.
  • Garlic for the common cold – only one study was eligible for inclusion and showed that people taking garlic every day for 3 months had fewer colds than those taking placebo, but the duration of a cold was similar in both groups; there have been no trials examining whether taking garlic at the time of a cold reduces severity or duration.
  • Chinese medicines for bronchitis, influenza, sore throats, and the common cold –  no conclusion due to study design limitations and concerns over lack of safety data.
  • Increased fluids – no evidence for or against, although some evidence from some observational studies that may be harmful.
  • Heated or humidified air for the common cold – in some studies this helped, in others it did not; no studies included children.
  • Humidified air inhalation for treating croup – three small studies in emergency settings in a total of 135 patients with moderate to severe croup showed there did not appear to be any benefit, but there have been no studies in primary care.
  • Non-steroidal anti-inflammatory drugs for the common cold – nine studies with 1064 patients showed improvement in most analgesia-related symptoms, but no clear evidence of improvement in runny noses or cough.
  • Reviews of zinc and the homeopathic remedy, Oscillococcinum, have been withdrawn from the Cochrane database.

Modifying Antibiotic Prescribing

  • Antibiotics are more likely to be prescribed when patients expect them.However, patients frequently consult when antibiotics are not their main expectation, and clinicians are not able to discriminate well between those patients who expect and those who do not expect antibiotics. Perception of patient pressure is a strong independent predictor of antibiotic prescribing., It is a major driver in prescribing antibiotics when faced with normal chest auscultation.
  • Consultations about RTIs are sometimes seen as an opportunity ‘catch-up’ and information-sharing can be inadequate. Sharing information about the likely natural history of RTIs helps set realistic expectations about illness duration, which may reduce expectations (or perceived expectations) for antibiotics and reduce future consulting.
  • RCTs of interventions incorporating shared decision making during consultations, including the use of an interactive booklet in the consultation, demonstrated reductions in antibiotic prescribing without adversely effecting recovery or satisfaction with care.

Delayed Prescriptions

  • A Cochrane review that included nine trials found that delayed prescribing can reduce antibiotic use for acute respiratory infections without harming patients. Delayed prescribing compared to immediate antibiotics was associated with reduced patient satisfaction in three trials, and no difference in two.
  • However, delayed antibiotics may have little advantage over not prescribing them at all where it appears safe to do so. Nevertheless some clinicians find delayed antibiotics are easier to implement than refusing antibiotics altogether, and a time trend analysis of UK data suggested that delayed prescribing was responsible for a 10–15% reduction in antibiotic use by children between 1998 and 2003.

Prevention and Treatment of Seasonal Influenza

Vaccination

  • Systematic reviews of the efficacy (ability of the vaccine to prevent confirmed influenza cases), effectiveness (ability of the vaccine to prevent influenza–like illness) and safety of vaccines are limited by lack of current, well-designed RCTs.
  • A systematic review on the use of influenza vaccination for healthy children found evidence of efficacy in children older than 2 years but little evidence for children under 2, no comparisons of safety, and a marked difference between vaccine efficacy and effectiveness.
  • If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required. A similar review on the use of influenza vaccination for healthy adults found little support for use as a routine public health measure. Even in older people, the effectiveness of influenza vaccination is modest in long-term care settings and less so in community- residing residents.
  • Wash your hands regularly with soap and water to reduce exposure to secretions.
  • Avoid being in close contact with sick people.
  • Sanitize commonly-touched objects like remote controls, phones and doorknobs when anyone in the house may have a URI.
  • Cover your mouth and nose if you are sick.
  • Stay home if you are sick.

Anti-Virals Neuraminidase Inhibitors

  • The recent H1N1 influenza pandemic increased interest in neuraminadase inhibitors in preventing and treating influenza. It is unclear whether data from use in seasonal influenza is applicable to pandemic situations. Two recent systematic reviews, based on evidence from prophylaxis (four trials), treatment (12 trials), and post-exposure prophylaxis (four trials), both concluded that these drugs did not result in meaningful symptomatic improvement in seasonal influenza.,
  • Whether oseltamivir reduces influenza-related LRTI complications remains unclear. The 2005 Cochrane systematic review concluded that it did. However, the most recent Cochrane review withdrew this conclusion on the basis that none of the original studies had been powered to detect differences in severe adverse events, and the authors had been unable to obtain trial data on complications from eight of 10 trials from an originally included meta-analysis

References

RTI

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