Respiratory disease

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14 Respiratory disease

Questions

As a third-year medical student in Russia I am researching ‘the role of proteolytic enzymes and their inhibitors in lung pathology’. Can you explain how proteolytic enzymes function in the normal lung?

Bronchiectasis is given as one of the causes of bronchial breath sounds. This is difficult to comprehend. Could you explain the mechanism of bronchial breath sounds more clearly?

I have been taught to examine vocal resonance by asking the patient to say ‘ninety-nine’ while auscultating. I listen for a louder ‘ninety-nine’ over an area of consolidation and more quiet sounds with effusion. Is this right?

What role does bupropion play in giving up smoking?

The clinical signs and symptoms of rhinitis are very similar to those of the common cold (influenza). How do I differentiate between the two?

What is the advantage of the drugs des-loratidine and levo-cetirizine over their parent compounds? Are they safe in pregnancy and lactation?

What are the differences between acute bronchitis and pneumonia? Are both diseases caused by infection?

1. If a patient with chronic bronchitis develops obstructive jaundice and Escherichia coli biliary sepsis, should the routine administration of oral steroids (e.g. prednisolone) be suspended until liver function improves?

2. Are there any adverse reactions that preclude the concurrent use of steroids while the patient is treated with IV ciprofloxacin, gentamicin, metronidazole and cefuroxime?

Robbins Basic Pathology mentions that in patients with chronic obstructive pulmonary disease (COPD), the forced ventilation capacity (FVC) is either normal or slightly increased! I just can’t justify that. I mean it should decrease. And this is exactly what is mentioned in your book. I couldn’t contact the authors of that book so I decided to ask you whether there is actually a situation in which the FVC in COPD patients might increase?

Is there any obstructive pulmonary condition in which there might be an increase in FVC? If so by what mechanism?

I am confused whether clubbing is a feature of chronic obstructive pulmonary disease (COPD) or not – you have mentioned that it is not a feature of COPD but some books do say that clubbing is a clinical feature of COPD.

A 70-year-old man with chronic obstructive pulmonary disease (COPD) and a past history of myocardial infarction with a left ventricular ejection fraction (LVEF) of 25% is dyspnoeic on slight exertion such as walking, bathing. He is not orthopnoeic and claims to have no paroxysmal nocturnal dyspnoea (PND). He has no wheezing or productive cough and his blood pressure is normal. He has had three episodes of ventricular tachycardia (VT) and has been on amiodarone for the past year. What is the best way to determine the exact cause of dyspnoea in this case?

In bronchiectasis, what is the reason for using a bronchodilator if the airways are already dilated?

Why is it that asthmatics having a severe attack can be seen clawing their hands?

Practical use of steroids:

• Which form of regimen is better (alternate-day, daily or in pulse form)?

• What should be the dose (once daily or three times daily or {2/3} in the morning)?

• For how long, especially when to give short courses as in asthmatics, when we don’t need to taper it down?

In pregnancy, what is the recommended treatment for bronchial asthma? Is the use of the long-acting beta-adrenergic agonist Seretide, the corticosteroid Symbicort and leucotriene receptor antagonists (LTRAs) recommended?

In asthma patients, which is the safest analgesic to use?

Is the use of nebulized heparin in the treatment of asthmatic attacks recommended?

I would like to ask you about pneumonia and its classifications in particular; what are they?

What are the pathological differences in typical and atypical pneumonia?

Why, sometimes in cases of aspiration pneumonia, would the level of lymphocytes drop below normal range while the level of white blood cells (WBC) and neutrophils are above normal range?

Should steroids be used in the treatment of a standard case of pneumonia in a young child?

I want to know more about the epidemiology and pathophysiology of this severe acute respiratory syndrome (SARS) scare and what advances have been made in its therapy.

What symptoms will confirm, without doubt, a diagnosis of tuberculosis?

Please could you tell me the skin-prick test result for non-infected and non-immune tuberculosis carriers?

Please can you help me find the answer to whether the purified protein derivative (PPD) in the tuberculin skin test develops memory T lymphocytes? If so, would it not be confusing with the way BCG vaccine works?

In diseases that have night sweats as a symptom (e.g. tuberculosis, infective endocarditis), what causes the sweats to occur only at night and not consistently during the day as well?

An asymptomatic patient, whose tuberculous pleural effusion has subsided after a year’s treatment of anti-TB, is left with a small loculated effusion, apparent on ultrasound and chest X-ray. Should this be aspirated?

I want to know what are the exact indications for using steroids in patients with tuberculous pleural effusions/ascites?

Should prednisolone be added to the anti-tuberculosis therapy in all cases of massive tuberculous effusion? Does the quick absorption help prevent fibrosis?

In the case of antituberculous treatment toxicity, how high should the serum glutamic pyruvate transaminase (SGPT) rise before we should stop treatment?

After starting antituberculous treatment, when is the fever expected to subside and the erythrocyte sedimentation rate (ESR) to return to normal?

What are the indications of steroids in the treatment of tuberculosis?

I am a final-year medical student in India, where tuberculosis in all forms is one of the most common diseases with which we deal. I read that you feel there is no indication for steroids in tuberculosis. Is it not reasonable to give steroids with antitubercular therapy (ATT) in a patient with tuberculous pericarditis, meningitis, peritonitis and ocular manifestations due to tuberculosis, in order to reduce the damage caused by inflammation and fibrosis? If not, what suitable alternatives, other than steroids, would you recommend to reduce damage from postinflammatory fibrosis?

What dosage of steroids and duration of treatment should be given to patients with idiopathic pulmonary fibrosis? What are the new drugs, their recommended dosage and duration of treatment?

What is the poor prognostic factor in cryptogenic fibrosis: fibrosis or concomitant connective tissue disorder?

Are wheezes present in extrinsic allergic alveolitis?

Is the measurement of chest expansion with a tape a useful physical examination to indicate the severity of emphysema?

In asbestos-related pleural disease (pleural plaques and mesothelioma), how do asbestos fibres get to the pleural space?

How do you differentiate clinically between thickened pleura and pleural effusion?

What is the difference between transudate and exudate?

I wish to ask about Meigs’ syndrome. I know that it is an association of pleural effusion, ascites and benign ovarian tumours or fibromas. Is the effusion transudate or exudate?

I have read that patients with cystic fibrosis should not meet each other socially. Why is this?

I have a young patient with bilateral hilar lymphadenopathy but no other manifestations of sarcoidosis. How can I make a diagnosis?

We have read in your book that continuous oxygen therapy at home reduces mortality in chronic obstructive pulmonary disease (COPD). I am concerned that my patient might develop acute respiratory failure.

I have a patient with asthma who is on long-term inhaled corticosteroids. She is very concerned about long-term steroid therapy. Could I replace the steroids with a long-acting beta₂ agonist?

What is the role of leukotriene-modifying agents in asthma?

Is it true that the Mantoux test is no longer used?

Is there a screening test that is useful for the diagnosis of lung cancer?

For how long should treatment be continued for cervical lymphadenopathy and abdominal tuberculosis? What role, if any, do steroids play in the treatment of these conditions?

What is the recommended treatment for pleural mesothelioma?

• Why is there an increase in vocal fremitus and vocal resonance in consolidation?

• How are consolidation and pneumonia defined and are they the same thing?

Can hiccough be an early sign of coning due to increased intracranial tension?

What is the recommended maintenance dose of steroids in recurrent facial palsy due to sarcoidosis?

Why is serum angiotensin-converting enzyme (ACE) high in sarcoidosis? And is there a difference between pulmonary and extrapulmonary sarcoidosis regarding the high serum ACE level in that disease?

In the British Thoracic Society’s CURB-65 scale to assess the severity of pneumonia, U stands for Urea of greater than 7 mmol/L. What are the reasons for the raised urea that make it an important indicator of the disease’s severity?

Alpha₁-antitrypsin inhibits neutrophil elastase, a proteolytic enzyme capable of destroying alveolar wall connective tissue. Alpha₁-antitrypsin deficiency allows damage to occur to distal lung tissue with the development of emphysema. Neutrophil elastase is the most abundant antiprotease in the lung and as smoking stimulates elastase release, lung tissue damage occurs leading to worsening emphysema.

In bronchial breathing, the expiratory sound of breathing is louder on auscultation. In bronchiectasis due to collapse, dilatation and sometimes consolidation, the sounds are transmitted more directly through to the chest wall with little lung tissue to filter out the higher frequencies which are also characteristic of bronchial breathing.

Consolidation allows the transmission of higher frequencies, which makes sounds like ‘ninety-nine’ clearer and often louder. Different countries have words of similar frequency to demonstrate this.

A pleural effusion decreases transmission of all breath sounds of whatever frequency and therefore little or no sound is heard.

National Institute of Health and Clinical Excellence (NICE) UK guidelines state that nicotine replacement therapy or bupropion should only be used for the smoker who ‘commits’ to a stop date. Advice and encouragement to stop smoking should be offered. Both treatments are effective aids to stopping smoking; there is no evidence for their combined use. How bupriopion actually works here is unclear.

Colds clear up within 1 week; rhinitis persists, being either seasonal or perennial.

Influenza is different from a cold. With a real episode of influenza the systemic effects of a temperature and muscle aches usually confine the patient to bed.

Des-loratidine and levo-cetirizine are not available in the UK. Loratidine and cetirizine themselves are not teratogenic but loratidine is excreted in breast milk. To be on the safe side, no drugs should be used in pregnancy if possible.

Acute bronchitis is literally inflammation of the bronchi; it is usually viral in origin. Pneumonia is inflammation of the lung substance and is most commonly due to bacteria; over 50% being due to Streptococcus pneumoniae.

1. No, in such a sick patient steroid therapy should be continued, otherwise he or she will develop acute adrenal insufficiency, assuming that the patient has been on steroids for a long time.

2. No, there are no adverse reactions precluding the concurrent use of steroids.

In COPD there is a reduction in the forced vital capacity (FVC) with a relatively greater reduction in forced expiratory volume (FEV₁).

No; an obstructive pattern always reduces FVC.

Clubbing does not occur in COPD. In a patient with COPD and clubbing, one would wonder whether a carcinoma of the bronchus, or bronchiectasis for example, were also present.

Examination of the patient is helpful. Tachycardia, raised venous pressure, third and fourth heart sounds and basal crackles indicate cardiac failure. Chest wheezes suggest bronchospasm, and cough with sputum is more often seen in COPD. Exercise tests are helpful, as is the measurement of serum brain natriuretic peptide (BNP). A normal plasma level of BNP excludes heart failure. Response to therapy is often the best guide.

There is a small element of bronchospasm, but the effect is small.

There is no good reason for this but patients are very often anxious and this is the probable reason for them clawing their hands.

No regimen of steroid usage is the best. Alternate-day administration has not been successful in asthma because patients can deteriorate during the second 24 hours. There is certainly no need to give therapeutic steroids more than once daily except when initiating steroids for acute severe asthma. As with all drugs, it is best to get to know how to use the drug by seeing many patients. The stepwise management of asthma is shown in Table 14.1.

Table 14.1 The stepwise management of asthma

Step	Peak expiratory flow rate	Treatment
1. Occasional symptoms, less frequent than once a day	100% predicted	As-required bronchodilators If used more than once daily, move to step 2
2. Daily symptoms	≤ 80% predicted	Anti-inflammatory drugs: Sodium cromoglicate or lowdose inhaled corticosteroids up to 800 μg If not controlled, move to step 3
3. Severe symptoms	50-80% predicted	High-dose inhaled corticosteroids up to 2000 μg daily
4. Severe symptoms uncontrolled with high-dose inhaled corticosteroids	50-80% predicted	Add regular long-acting beta₂ agonist (e.g. salmeterol)
5. Severe symptoms deteriorating	≤ 50% predicted	Add prednisolone 40 mg daily
6. Severe symptoms deteriorating in spite of prednisolone	≤ 30% predicted	Hospital admission

Short-acting bronchodilator treatment can be taken at any step on an as-required basis.

Asthma must be well controlled during pregnancy and drugs should be given by inhalation to minimize exposure to the fetus. All drugs appear safe by inhalation. In acute attacks, parenteral steroids are safe and you should always keep the mother’s oxygen saturation above 95% to prevent fetal hypoxia.

The classical description of typical pneumonia due to pneumococcus is:

• red hepatization

• grey hepatization

• resolution.

The details of these are available in many books of pathology.

We dislike the term ‘atypical’ because it accounts for 20% of all pneumonias. The pathology in this group is not well described because very few patients die. The best description is by Parker et al. (1947).

Parker F, Jolliffe LS, Finland M (1947) Primary atypical pneumonia: report of 8 cases with autopsies. Archives of Pathology44: 581-608.

It is unusual for the level of lymphocytes to drop below the normal range in aspiration pneumonia but obviously the total number of WBC and neutrophils do increase as a result of infection.

SARS is due to a novel coronavirus, which is spread between humans by droplet infection. It is a zoonosis spread from small mammals, e.g. civet cats, raccoons. After initial non-specific symptoms, bronchopneumonia develops.

Further reading

Guan Y et al. (2004) Molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome. Lancet363: 99-104.

Ten separate articles on SARS appear in the New England Journal of Medicine349 (2003).

No symptoms will confirm the diagnosis of tuberculosis. A firm diagnosis can only be made by finding the tubercle bacillus in a specimen taken from the patient. Other features are only suggestive.

Following infection with Mycobacterium tuberculosis the patient will develop cellular immunity to the organism. An intradermal injection of purified protein derivative (PPD) of Mycobacterium tuberculosis, usually in the forearm, will produce induration and inflammation at the site of the infection in such a patient. This reaction persists despite successful treatment of the disease. The reaction may not occur if the patient is very ill or develops AIDS, when the immune system is impaired.

Following intradermal tuberculin challenge in a sensitized individual, antigen-specific memory T cells are activated to secrete interferon gamma (IFN-γ), which activates macrophages to produce more cytokines. BCG induces cellular immunity to the TB bacillus, which is an intracellular organism, in an unsensitized individual (Box 14.1).

Box 14.1 Tuberculin testing

Mainly used for:

• Contact tracing

• BCG vaccination programmes

It is rarely of any value in the diagnosis of tuberculosis. Patients are tested with purified protein derivative (PPD) of Myocobacterium tuberculosis.

The test is based on cell-mediated immunity with the development of induration and inflammation at the site of infection due to infiltration with mainly T lymphocytes. The test can be falsely negative in patients with AIDS because of impairment of delayed hypersensitivity.

The Mantoux test

• 0.1 mL of a 1:1000 strength PPD (equivalent to 10 tuberculin units) is injected intradermally.

• The induration (not the erythema) is measured after 72 hours. The test is positive if the induration is 10mm or more in diameter.

Whole blood interferon-gamma assay

Can be used in all circumstances:

• In-vitro T cell basal assay

• T cells of individuals who have previously been sensitized to TB antigens will produce IFN-gamma when they are incubated with TB antigens (e.g. PPD)

• ELISA test or an enzyme-linked monospot assay

• Advantages:

• no return visit to look at test

• variable sensitivity and specificity

Sweats do mainly occur at night but patients often have a fever during the daytime but sweating is not prominent. Remember the commonest cause of night sweats is anxiety not an infective cause.

Aspiration under ultrasound guidance should be performed, although 1 year’s treatment is usually adequate.

Steroids are usually not recommended in these situations as there is insufficient evidence to know about their efficacy (Cochrane review).

It is suggested that steroids might be beneficial here.

Rifampicin should be stopped if the serum transferases, that is, the SGPT or alanine transferase (ALT) are raised more than three times normal. This is a rare situation.

Fever should settle within 2 weeks. The ESR is usually normal within the month.

The use of steroids is still controversial. In TB pericarditis, the European Society of Cardiology gives it a class II b recommendation (usefulness of efficacy less well established by evidence). The American Thoracic Society recommends steroids in the first 11 weeks. There is a growing base of clinical data for the use of steroids in meningitis; in one study it improved mortality.

It is always tempting to use steroids in the conditions mentioned but the evidence is not convincing. They are said to reduce inflammation and tissue damage in pericarditis and meningitis (see above) but it is not currently recommended in pericarditis. For TB of the retina, systemic steroids are usually added to the ATT. Remember, you must not do harm with the use of drugs.

Prednisolone dosage is variable. Prednisolone 30mg daily often combined with azathioprine is a common regimen. Some clinicians use high doses, e.g. 1mg/kg daily for 8-12 weeks but there is no good evidence that steroid therapy with or without azathioprine is beneficial. Methotrexate has also been used in place of azathioprine. A trial of both interferon-beta and interferon-gamma showed no benefit. Drugs that are being used include Bosentan (endothelin receptor antagonist), etanercept (a tumour necrosis factor-α receptor blocker) and imatinib [a platelet-derived growth factor (PDGF) inhibitor].

Further reading

Dempsey OJ et al. (2006) Idiopathic pulmonary fibrosis: an update. Quarterly Journal of Medicine99: 643-654.

Concomitant connective tissue disorder usually with renal complications.

Yes. Any disease that produces airflow limitation produces some wheeze on auscultation.

No. The so-called ‘barrel-shaped’ chest is usually associated with kyphosis and old age rather than emphysema. N.B. This condition has been renamed hypersensitivity pneumonitis.

Crocidolite fibres are long and thin and easily impact in the small airways where they are engulfed by macrophages. How exactly they get into the pleura is unclear, but they do because they can be found in pathological specimens.

A pleural effusion produces stony dullness on percussion with reduced tactile vocal fremitus and vocal resonance over a wide area. Occasionally, it can be difficult to detect and then ultrasound is helpful.

A transudate is a fluid with protein content less than 30g/L; an exudate has greater than 30g/L. Other ways of expressing this are pleural fluid protein:serum protein ratio > 0.5 in exudates; a pleural fluid lactate dehydrogenase (LDH) > 200; or pleural fluid:serum LDH of > 0.6.

In Meigs’ syndrome, there is indeed some confusion. In Crofton and Douglas’s Respiratory Disease, it is described as a transudate. It is likely that the pleural effusion has been formed by tracking of fluid through the diaphragm into the pleural space.

Meigs JV (1954) Fibroma of the ovary with ascites and hydrothorax; Meigs’ syndrome. American Journal of Obstetrics and Gynecology67: 962.

A major problem in cystic fibrosis is sputum infection with Burkholderia cepacia, a plant pathogen which was previously thought to be a harmless commensal. It’s acquisition, however, can be associated with accelerated disease and rapid death. Sadly, this means that CF sufferers should not intermingle.

Further reading

Rowe S.M. et al. (2005) Mechanisms of disease: cystic fibrosis. New England Journal of Medicine252: 1992-2001.

We assume you have done a serum angiotensin-converting enzyme level, which is elevated (75% of cases) of sarcoidosis. If this is not elevated, then biopsy confirmation is required. In your patient’s case, this will be an endobronchial biopsy.

You imply that your patient has hypercapnia. If this is the case you will have to give the oxygen via a 28% ventimask. If this is tolerated and blood gases show no rise in PCO₂, then you can increase the amount of inspiratory O₂ via a 34% mask.

No! Fatalities have occurred in this situation. It would be reasonable to add a long-acting beta₂-agonist so that the inhaled steroids can be reduced. Patients should be warned about the possible exacerbation of their asthma that can occur with the addition of long-term beta₂-agonists.

The clear indication for leukotriene modifying agents is in asthma due to aspirin sensitivity as these drugs inhibit lipoxygenase. A2-week trial of one of these agents can be used to assess their effect on asthma control. If there is no improvement, the drug should be stopped.

No. Tuberculin skin tests are still used but there is sometimes difficulty in interpreting the results. Whole-blood interferon gamma assays are being used. Their advantage is that they eliminate the error in interpreting the skin tests and only require a single visit.

Yes, a recent study has shown that repeated annual spiral computerized tomography (CT) in smokers can detect lung cancer that is curable.

Further reading

Unger M (2006) A pause, progress and reassessment in lung cancer screening. New England Journal of Medicine355: 1763.

For 6-9 months for extrapulmonary tuberculosis in a patient with organisms sensitive to the first-line drugs. Steroids have no part to play.

Treatment of mesothelioma does not usually effect the median survival time of 6-12 months after presentation. Surgery (pleurectomy/decortication) and even more radical surgery with pre-and postoperative radiation and chemotherapy have all been tried without great success, good palliative care is essential.

In consolidation, the lung is ‘solid’. A solid lung conducts high-frequency sound better than air, which tends to dampen the high-frequency sound. As a result, vocal fremitus and vocal resonance are increased in consolidation with bronchial breathing being heard, which is a high-frequency sound. Pneumonia is defined as an inflammation of the substance of the lungs. The pathological process that occurs in the lungs as a result of the infection is called consolidation.

Hiccough lasting greater than 48 hours certainly occurs with brainstem lesions with raised intracranial pressure. It is not, however, an early sign of raised pressure.

The maintenance dose is 20 mg of prednisolone daily. However, if long-term steroids are necessary, you should probably use a steroid-sparing agent, e.g. azathioprine, with a lower dose of steroids, although the data on efficacy of this regimen are sparse.

The granuloma cells produce angiotensin-converting enzyme. There is no useful difference between lung and extrapulmonary disease ACE serum levels.

The raised urea indicates dehydration which indicates severe illness lasting a few days.

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