Corticosteroids in Community-acquired Pneumonia: Analysis

Introduction:

Due to minimal development of new treatments since antibiotics in 1950s. There have neither been any new drugs developed targeting Community-Acquired Pneumonia. Therefore, the purpose of the topic for this diploma thesis is to find the significance of corticosteroid treatment applied to community-acquired pneumonia, after new studies has emerged providing scientific evidence of potential positive effects of corticosteroid treatment. The goal is to compare this treatment with the treatment we use today and see if there are any significant improvements. Compare the studies with both positive and negative outcomes, and weigh if the results overweigh the side effects. In the first part of my thesis, we will be introduced and educated about Community-Acquired pneumonia and corticosteroids. On the second part I will focus on a review provided by the research based on the results of corticosteroid treatment on individuals with community-acquired pneumonia.

Method:

A review based on available open access internet sources, books, and articles.

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Conclusion:

Some newly published randomized clinical studies have shown some potentially positive effect of short use of corticosteroids in Community-acquired pneumonia with fast clinical and radiological improvement in addition to one day’s shorter hospitalization. (Stern et al., 2017) (Blum et al., 2015) On the other hand, it is not observed any secure effect in accordance to mortality, and corticosteroid treatment increase the risk of hyperglycemia. Also, other studies have shown no significant effect in this kind of supplementary treatment. (Snijders, Daniels, de Graaff, van der Werf, & Boersma, 2010) Too summarize, its most likely a subgroup of pneumonia patients that can have benefits of corticosteroid treatment, but there is no international consensus. (Wan et al., 2016)

Preface

I choose to write about the topic “Role of corticosteroids in treatment of community-acquired pneumonia” because it is a very important subject in modern medicine, which in a way has stood still in evolving specific and targeted treatment for several decades. It’s a disease where mortality rates are high, and more attention should be shed to find an adequate solution. It’s a very interesting topic that I wanted to learn more about a topic that for sure will follow me after the studies.

My goal is to learn more about community-acquired pneumonia, incidences, todays treatments, the effect corticosteroids has and together gather this information to try to find a solution. It is a big threat for in care patients and thus attracted my attention to write about this topic for my diploma thesis.

I would like to thank my tutor and advisor doc. MD. Robert Vyšehradský, PhD for assigning this topic for my diploma thesis. It has been very interesting and educational.

Also, it is important for me to thank all my family and friends for supporting me though the medical studies in Martin, Slovakia

1 Literary review

1.1 Community-Acquired Pneumonia

1.1.1 Pneumonia

Pneumonia is a lower respiratory tract infection associated with respiratory symptoms and signs of acute infection, most often presenting with lower general condition and fever >38C. Pneumonia affects the lung parenchyma, most commonly with exudation of alveoli’s, but can also involve the bronchi’s, bronchioles, pleura, and interstitial.

Pneumonia is one of the most common causes of hospitalization and still a leading consequence of morbidity and death. Pneumococci used to be one of the most leading causes of pneumonia. Epidemiologic studies in the 19’ hundreds have shown a gradual reduction of pneumococci as a result for pneumonia, and introduction of the pneumococci vaccine in the western world from 2006 has shown an obvious reduction in occurrence in systemic pneumococci disease.

Gene technological methods has the last year been introduced as a routine microbiological diagnostic, as well as culture from airways and blood. Some hospitals also use antigen-based analysis in urine for detecting antigen from pneumococci and legionella bacteria. On the other side, we can see that serologic analysis is in less use due to being in less benefit in acute situations.

Pneumonia can be divided based after its pathological path into Broncho-, lobar- and interstitial/atypical pneumonia. Or based on where it is acquired: Community or Hospital-acquired pneumonia. Community-acquired pneumonia is pneumonia in patients that has not been admitted to the hospital or any other kind of health-related institution last 14 days. Suspicion of this should be present in newly onset of radiological infiltrative and at least 2 of these: Fever, productive cough, or increased inflammation parameters. In addition, we also have aspiration pneumonia which is due to aspiration of food, gastric content to the airways. A common cause is vomiting of someone unconscious. Leading to pneumonia from both the infection and chemic reaction followed by HCl from the stomach.

Even though the vaccination has led to a significant decrease in pneumococci, it is still the highest detected microbe in pneumonia. A new combination of traditional and modern gene techonological microbiologic methods gives new knowledge of causes of pneumonia. Newer studies has shown that viral- and mixed infections are more commen (20-30%) and this is knowledge for how pneumonia should be understood and treated.

Etiology

Risk factors:

1. Congenital disease: Primary ciliary dyskinesia and Cystic fibrosis
2. Impared local imunity: Smoking (inhibits cilia and macrophage activity), impared coughing reflex ( Alcoholism, increased age..), Viral respiratory infections, COPD, Lung malignancies, and Bronchiectasis
3. Immunodeficiencies: Primary: CVID (hypogammaglobulinemia and recurrent infection) and Secondary: HIV
4. From other organs systems: Nevrologic defect in swallowing and cough reflex after stroke, urami and reduced function of spleen.

1.2 Pathogen

Pneumonia is the one of the most infectious causes of hospitalization and death, especially in elderly and immunocompromised.

Bronchopneumonia/Lobar pneumonia: The lungs are constantly exposed to particles. The lower airways is able to stay sterilized due to defense mechanisms, but due to an defect in the defense mechanism or exposure to an virulent microorganism that travels to the lungs due to micro-, macro aspiration or hematogenous route can cause pneumonia. The pathogen microorganism attaches to the respiratory epithelium, causes necrosis, interstitial inflammation, and exudation in the alveoli.

Atypical pneumonia: The reason of dyspnea is so severe in atypical pneumonia is because the gas exchange between the alveoli’s and capillaries is blocked due to interstitial inflammation. With viral pneumonia, a secondary bacterial infection might occur due to the epithelium being damaged from the virus of inhibition of mucocillary transport. Often hard to identify etiologic agent.

Aspiration pneumonia: Gastric acid causes chemical pneumonia which again leads to Acute respiratory distress syndrome. The factors leading to hypoxemia is edema, decreased activity of surfactant, alveolar bleeding, and production of hyaline membrane.

Community-acquired pneumonia is mostly caused from (the 3 first accounts for 80%):

• S.pneumoniae (50%)
• H.influenzae (w/ COPD)
• M.catarrhalis
• C.pneumoniae
• Respiratory viruses

Atypical Pneumonia:

• Virus
• Mycoplasma pneumoniae
• Chlamydophilia Pneumoniae
• Pneumocysties jerovecii (fungi)
• Legionella

In a population-based study from January 2010 to July 2012, was all hospitalized patients over 18 years old admitted with pneumonia in 5 hospitals registered within Chicago and Nashville. Nosocomial pneumonia and immunocompromised patients were excluded from the study. Patients from a general practitioner in Nashville, without symptoms of respiratory tract infections, worked as a control group to find out the prevalence of respiratory pathogens in the healthy population.

Of the 2500 patients in the study, 90% of them had radiologic findings indicating pneumonia. Of these 90%, there was done bacterial and virologic testing. Pathogens was only detected in 38%. The most abundant was Rhinovirus (9%), followed by influensa (6%). Pneumococci was detected in 5%. The yearly admission of pneumonia was 25 cases per 10000 adults. The incidents increased by age, and for the patiants admitted over 80 years old it was 165 incidents per 10000.

The low incidents of Pneumococci can be explained by vaccination the last decade.

• Jain S, Self WH, Wunderink RG, et al. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med 2015. E-publisert 14.7. 2015.
• https://tidsskriftet.no/2015/10/fra-andre-tidsskrifter/hva-er-arsakene-til-pneumoni#reference-1
• https://oslo-universitetssykehus.no/Documents/Medisinsk%20klinikk/Bj%C3%B8rn%20Skrede%20-%20Pneumoni.pdf

1.2.1 Bacteria

As we know, pneumonia is caused by both virus and bacteria. Bacterial infection occurs less frequently then virus infections but are the most serious kind of infection. Bacterial pneumonia is one of the most common serious infections in children but are usually easily treated with antibiotics.

A bacterial pneumonia can occur rather spontaneously but is most commonly seen after a cold lasting a few days with fever, rhinorrhea, and cough. The common cold impairs the immune system and injures the muco-cillary transport making it easier for the bacteria to travel down to the lungs causing an infection. There are several bacteria’s causing pneumonia but the most common especially with children is Pneumococci. In 2006 the pneumococcal vaccine was introduced to the vaccination program that protects against some of these pneumococci, but not all. Older children and adolescent are more likely to get pneumonia caused by mycoplasma and chlamydia. Mycoplasma and Chlamydia are contagious.

1.2.1.1 Streptococcus Pneumoniae

Is a Gram-positive cocci in diplo or chains. It gives upper respiratory tract infections, pneumonia, Meningitis, and Sepsis. It’s a polysaccharide capsule and pneumolysin are the most important virulent factors.

The infection occurs normally in the upper respiratory. It’s a frequent cause of opportunistic infections disease of the airways. The highest carrier effect is found in 2-year-old children. Highest incidens in the winter and early spring. The disease normally occurs when normal functions has changed such as during a viral infection, chemical irritation or absent cough reflex. People with low spleen function or has underwent a splenectomy has a high risk of a serious pneumococci infection. It is together with N.menigitidis the most common cause of meningitis.

The infection occurs after the airway virus has damaged the mucosa. The most common cause of disease strains from the capsule. The capsule inhibits phagocytosis of the bacteria and is therefore an important virulent factor. The cell wall of the bacteria contains adhesions that bind to the epithelial cells. The pneumolysin which resembles streptolysin in S.pyogenes, gives cell lysis thru pore production. It destroys ciliated epithelial cells and phagocytes. Activation of the complement system with migration of innflamatory cells and release of cytokines leads to fever and tissue damage. IgA secration causes the bacteria to bind and get captured in the mucus of the airways, then getting transported away via cilia activity. The IgA protease inhibits this interaction. Phorphorylcholine binds platelets, leucocytes, endothelial cells and tissue cells making it accessible for the bacteria to invade the cells. This gives the bacteria protection against detection and phagocytosis. The bacteria can also be transported intracellularly to other areas such as into the blood and central nervous system. This facilitates spread of the infection.

Diagnostics

• Nasal swab is important to prove pneumococci in the airways.
• Blood culture Grows with alpha hemolysis on blood agar.
• Optochin Sensitivity Test is the most used test to identify pneumococci.
• Treatment and prevention

See 1.2.22 and 1.2.2.3

1.2.1.2 H.influenzae

Is a gram negative rod bacteria. The bacteria act in a acapsular and capsular form. The capsule form has several serotypes (a-f). The most important serotype is type b (Hib). People with chronic lung diseases such as COPD is exposed to Hu-infections with worsening of their lung disease. With such non systemic infections it is often caused without a capsule. Systemic (invasive) Hi infections are cause by the capsular variant. Hib was a important cause of systemic disease in small children before the introduction of the vaccine. Which has caused a strong reduction of incidents of Hib infection. The transmission of the infection occurs thru close droplet transmission. The incubation time is 2-4 days (Hib).

Diagnostics

1. Nasal and throat swab
2. Agenspåvisning i blod eller spinalvæske ved dyrkning, antigen- eller ved nukleinsyreamplifiseringstest. Bærertilstand kan eventuelt påvises ved hals- eller neseprøve.
3. Ampicilin treatment.

• https://www.fhi.no/nettpub/smittevernveilederen/sykdommer-a-a/haemophilus-influenzae-invasiv-sykd/

1.2.2 Virus

1.2.2.1 Influenza virus

Is a single-stranded RNA virus with serotypes A, B, and C. It gives the classis influenza disease. It’s important virulent factors are Hemagglutinin-antigen and Neuraminidase-antigen.

The virus is transmitted thru droplets and contact. Low infectious dose is enough. It takes approximately 3-5 days from transmission till symptoms first starts. The season for influenza starts normally between December and lasts for 3 months. The Influenza A-epidemy occurs every 1-3 years because new variants of influenza type 1 shows up which causes most people to lose their immunity. The influenza A-pandemic occurs every 10-40 years because it has a new virus type that large parts of the world don’t have immunity to. Incubation period is 1-4 days dependent on the inoculums size.

Human influenza virus is divided into 3 serotypes A, B and C. The division is based on the antigenic properties of the nucleoprotein. The virus is round shaped. The genome is single stranded RNA which I put together by 8 parts in influenza A- and B-virus. The virus is membrane encoded, with an inner protein heath and a other lipid membrane. The surface of the virus has 2 types of protein particles:

• Hemagglutinin which binds the virus to receptors on host cell membranes. After binding to the host cell, it’s taken up to the endocytosis. Red blood cells also has receptors for the influenza virus, so the virus can agglutinate the RBC (this is used in diagnostics).
• Neuraminidase an enzyme which causes destruction of receptors. Its enzymatic activity cleaves syaline acid from glycoporteins in mucus and from glycoproetins that are receptors for host cell. It cleaves bindings of hemagglutinin in syaline acid containing receptors.

Replication of the virus RNA undergoes in the nucleus of the host cell, while the virus protein I produced in the cytoplasm.

When the virus reaches the airways thru droplet infection, there is a primary replication of the virus in the mucus of the pharynx and trachea. Ciliary epithelium with receptors for H id invaded at first by the virus. Mucus producing cells is also attacked which leads to cassation in mucus production in affected areas. Leucocytes infiltrate the area and causes edema and bronchospasm. Alveolar macrophages are recruited which leads to reduction of phagocytose of secondary infection of bacteria. Under the infection large amount of interferon is produced. This induces production f protein MxA which administrates antiviral activity. The virus quantity in the airways is reduced with increased interferon quantity. When the infection goes down the lower airways it will lead to primary influenza pneumonia. This can lead to necrosis of alveolar cells, capillary thrombosis and interstitial edema. Immunity against influenza arises from IgG antibody against H- and N-antigen. Local IgA antibody against the virus hemagglutinin is also produced. IgA antibodies last some monthes while IgG stays for years to prevent infection from same disease.

The infection can be asymptomatic or arise as a mild airway infection. More serious causes can lead to more life-threatening pneumonia. The disease last around 7 till 10 days and its incubation period is 1-2 days. Typical symptoms are shivers, fever, myalgia, dry cough, dysphagia, tiredness and reduced general condition.

Complications from this infection may be primary acute influenza pneumonia or secondary bacterial superinfection with yellow staphylococcus, S.pyogenes or H.influenzae which can present as pneumonia and other diseases. Death may occur especially in elderly and patients with reduced immunity. Reyes syndrome, which is a rare, acute encephalitis with liver failure, seen in children with influenza type B infection.

Diagnostics

1. A swab from the nasopharynx can be used. The virus can be detected thru cell culture, under fluoroscopic microscopy or PCR.
2. Treatment
3. Antiviral treatment shortens the disease time and has healing effects if started within 2 days of the first symptoms. Oseltamivir and Zanamivir is used.

• https://legeforeningen.no/PageFiles/26765/Foreldreinformasjon%20Lungebetennelse.pdf
• http://meddev.uio.no/elaring/lcms/indremedisin/infeksjonsmedisin/nl-streptococcus-pneumonia.xml?menuItemIndex=17
• http://meddev.uio.no/elaring/lcms/indremedisin/infeksjonsmedisin/nl-influensavirus.xml?menuItemIndex=11

1.2.2.2 Respiratory Syncytial virus

Respiratory Syncytial virus is a infection from the paramyxoviridae. RSV is divided into two groups (A and B), but its uncertain if this has any clinical difference. Clinically it’s difficult to differentiate between infection with asthma. RSV is the main cause of bronchopulmonary obstruction in children under 2 years. In older children and adults, the infection is a cold. RSV causes outbreak every winter. Like influenza there is a variation between the time and size of the outbreaks. The RSV seaseon is normally from November till May. Most likely the spread of the virus in older children, often with sibling that are not sick themselves. Numbers from US shows that 1,7% of childran under 6 monthes gets hospitalized due to RSV. 60-70% of all children har within their first year gone thru a RSV infection with a high between 2 till 5 monthes old. The disease is a important cause of death in underdeveloped countries.

The infection is transmited thru direct contact thru infectiousus material such as snot and droplets. The person is the most infectious in the early stages of the disease, but children can spread the disease within 1-2 weeks after the symptoms. Reinfections are common. The incubation period is 3-6 days.

Normally only symptomatic treatment is needed, with obstruction an inhalationtreatment is recired. To prevent spread good hand hygene is the most important preventive measure against RSV infection at home or the hospital. Childran that wants to be protected agains the RSV-infection has to keep away from possible carriers. Palivizumab is available as a prophylaxis to vaurnable children. In these children palivizumab is show to prevent RSv infections causing hospitalization, but has noe documented affect against death. Its given before season start. Its given to children under 2 years with congential diseases, immundeficency, serious pulmonary-heart diseases and extremely premature children.

Diagnostics

1. Nasopharynx swab with immunoflourecent tecnic or PCR-test.

• https://www.fhi.no/nettpub/smittevernveilederen/sykdommer-a-a/rs-virusinfeksjon---veileder-for-he/

1.4 Symptoms

(Bacterial pneumonia: Fever, reduced general condition and very often, but not always; cough and dyspnea. Sometimes also abdominal pain. Young children show unspecific symptoms such as fatigue, anorexia and sometimes vomiting. – These are symptoms usually seen in acute viral infections such as cold. If the symptoms get stronger over time with rising fever and tachypnoea and dyspnea, bacterial infection might be suspected.)

People with Pneumonia often present symptoms of sickness, reduced appetite, sweating, shivers, muscle/joint pain and headache (many has previously had an upper respiratory tract infection. Following its typical with cough, fever and in many dyspnea. With bacterial etiology it is often seen purulent exporant. The frequency of respiration is an important indicator of the seriousness of the infection. Elderly often present with little or diffuse symptoms. Cough and fever can be absent. Sometimes reduced general condition or delirium can be the only clinical signs.

1.5 Diagnosis

Clinical findings

The frequency of respiration is increased but can also be normal. Reduced respiratory sound above the affected section of the lung in pleural effusion. Gliding sound if presents of pleuritis. Attenuation in lobar pneumonia. Peripheral cyanosis as a consequence of type 2 respiratory failure. The oxygen saturation is usually normal.

In children to differ pneumonia from bronchitis, you look if tachypnea is present, then its most likely pneumonia. Tachypnea is defined as a respiratory rate over 60 in 2 months old children, over 50 in children between 2-12m, over 40 in 1 year old’s. High fever and tachycardia can give tachypnea. In children, COPD patients and in respiratory failure we can see localized intercostal retraction.

To score the severity of pneumonia we use CURB65

1. C: Confusion
2. U: Urea >7 mmol/l
3. R: Respiratory rate >30/min
4. B: Blood pressure 100 (S.Pneumoniae often >300), in atypical pneumonia 20-40 in pneumonia lasting over >1 week.

• Arterial bloodgas
• Nasal swab, PCR – Used to identify Mycoplasma pneumoniae, Clamydophila pneumoniae and viruses.
• Cultivation
• Pneumococci antigen test (urine, quick test) – Sensitivity 70%, Spesifisity 96%
• Blood Culture

In patient with poor therapy response and clinical worsening after 2-3 days, you have to think about the possibilities of infection from Legionella, resistant pathogens or metastasis. Always have TB in mind.

Microbiological diagnostics

Two set of bloodculture is reccomende in patients which are hospitalized due to pneumonia. Exporants/sputumtest from the airways is also very beneficial.

Bronchoscopy with bronchoalveolar lavage is costly but most beneficial in critically ill or difficult infections. One nasopharynx test is enough for both PCR and culture. Antigen in urine is beneficial for pneumococci and legionella.

Blood culture: two sets of blood culture is recommended in patients that is hospitalized for CAP. A positive finding of a typical airway bacteria can be in significant clinical importance. On the other side, there are a majority of negative results and atypical bacteria cannot grow the normal way.

Airway test

Exporant/sputum: Microbiological analysis of exporatory induced sputum is in the routine testing, low cost efficant with good microbiological results.

Bronchoscopy w bronchoalveolar lavage: This diagnostic method is costly but Is used in crityclly ill or immunocompirmized patients.

Transthoracale airway sample: Is a costly method with radiological guided fine needle aspiration of contaminated lung parenchyma. Pneumothorax is a complication. But this method is of strong clinical beneficial.

Infection serology: serological analysis has in the western world been replaced with PCR, but can still be benefical in epidemiological studies(5,6) or in suspicion of more chronic path in atypical microbes such as bordella pertussis(11,12)

Urine antigen: Urin-antigen analysis is used to detect pneumococci and legionella pneumophila serotype 1 are fast and easy analysis with high spesifisity (>95%), but with low sensitivity for both microbes (50-80%). Another problem is that pneumococci antigen can still be in the urine several weeks after an infecition and a postitive finding can be misleading.

Biomarkers

C-reactive protein is a polypeptide produced in the liver. CRP is increased during inflammation such as pneumonia. Excpecially an high increase in this marker can be seen in bacterial pneumonia(14), while infections from viral microbes and atypical bacteria gives less of an increase. Many studies has shown that CRP has a limited benefit in providing information of the inflammation being of bacterial or viral etiology.(15,16). But what is know is that the CRP is of correlation in the size of the infiltration of the lung(17) and that limited fall in CRP after some days of treatment is correlated to a bad prognosis(18,19).

Procalcitonin is a precursor of the thyroid hormone calcitonin and is produced in the tissues of the thyroid gland. Secration of the this precursor is correspondant to the innflamatory process of pneumonia. Procalcitonin is primarily increased in bacterial infections. High value of procalcitonin is also correlated to a bad prognosis.

Leukocytes' increase of neutrophilic granulucytes and low value of lymphocytes can indicate bacterial pneumonia. Therfor an ration of 10-20 between this two can draw us towards an bacterial pneumonia (22).

1.7 Vaccination

Pneumococci infection

The introduction of Hib vaccine in the vaccination program in children I many countries has caused a significant reduction in Hib infections. In 2016 the EU/EØS-area rapported of 3379 causes of systemic Hi infection. Most cases per 100 000 of the population was reported in the Nordic countries, Irland, Great Britain, and the Netherlands. Hib-vaccine is from 2017 introduced in 191 countries, and the global vaccination coverage with 3 doses vaccine is from WHO calculated to be 72%.

1.8 Complications

1. Sepsis (expecioally people with splenectomy)
2. Sterile pleural effusion
3. Emphysema
4. Lung abscess
5. Risk factors for complicated course of disease is elderly, preexisting lung disease, immunodeficiency/AIDS, and nosocomial infection.

1.9 Differential diagnosis

• Acute Bronchitis: Better general condition, faster fall in temperature and CRP
• Bronchiolitis: Generally, within first year of living. Tachypnea and retraction.
• Asthma: Obstruction dominates
• COPD: Obstructive, excarbation can develop to pneumonia
• Heart failure: Dyspnea is the main symptom, afebrile, CRP is normal or slightly increased.
• Lung cancer: Afebril, can be impossible to devide from pneumonia in acute state.