The beginning of Osler’s fatal illness in 1919

Osler suffered from recurrent respiratory tract infections from a young age.3 4 These infections became more severe and debilitating as he aged see figure 1, causing his colleagues and family significant concern.3

In September 1919, Osler travelled from Oxford to Glasgow and Edinburgh.4 5 His travel home from this journey was delayed secondary to the British railway strike.4 5 It took him almost 48 hours to arrive home and he had to spend a night in an old inn.4 5 He arrived home unwell, took to bed and later developed a fever and cough.5 6 Osler kept detailed notes on his illness. He noted that he had ‘a little impairment of resonance at the bases, but no rales or tubular breathing’ and his sputum at the time grew ‘No. 3 pneumococcus and Moraxella catarrhalis’.5 6 His main form of treatment for this infection was opium as this was prior to the antibiotic era.6 While the documentation of his illness was sparse and sometimes conflicting, Osler appeared to improve initially before deteriorating again in early November.

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Figure 1

Osler in his garden. Credit: Osler Library of the History of Medicine, McGill University. William Osler Photo Collection/NLM/NIH.

Osler had likely fallen victim to influenza during the deadly Spanish influenza epidemic (1918–1920) when between 10% and 20% of the world’s population are estimated to have been infected and between 3% and 6% perished.3 7 Pneumonia complicating the influenza was the major cause of mortality in that epidemic and Haemophilus influenzae, Streptococcus pneumoniae, S. pyogenes and Staphylococcus aureus were the pathogens commonly isolated.8 Empyema was a deadly consequence of bacterial pneumonia in the preantibiotic era. In the state of Utah, where medical records of empyema death were kept over the past century, the mortality of empyema peaked between 1910 and 1919, likely directly attributable to the Spanish influenza epidemic.9

If Osler lived in 2019, he would receive annual influenza vaccines, which would significantly reduce his risk of infection, and more importantly decrease the risk of secondary pneumonia and associated mortality.10 His postmortem suggested he had underlying bronchiectasis. An earlier definitive diagnosis of bronchiectasis, perhaps supported by a computed tomography (CT) chest scan, would likely have led to more aggressive treatment, such as a low threshold for antibiotic use, chest clearance and perhaps consideration of use of long-term macrolide therapy.11

Onset of Olser’s pleural problems

‘ Pneumonia coming on pleurisy is bad ’ Hippocrat e s

Osler described his clinical course as ‘atypical’.5 6 In early November 1919, his fever returned and he developed new-onset pleuritic chest pain and a repeat sputum sample grew H. influenzae.5 He described this chest pain in a letter as ‘a stab and then fireworks, pain on coughing and deep breath’.6 However, before the end of November, his fever and breathing improved and the pleuritic pain subsided.5

He deteriorated again came December which necessitated a second nurse and Malloch joining the Osler household.6 His fever returned with an associated rise in his white cell count.5 12 Osler was concerned that he may have developed a loculated pleural collection.5 12 A thoracentesis was performed which produced ‘clearish fluid containing polymorphs and Pfeiffer, no strep or pneumo’.5 12 There was no clinical improvement afterwards, and he suffered from ongoing tachycardia, tachypnoea and temperature spikes.5 12

The clinical picture suggested a high likelihood of ongoing pleuropulmonary infection. Risk factors for developing pleural infection are diabetes mellitus, alcohol abuse, the presence of chest pain and elevated inflammatory markers such as a high peripheral blood leucocyte count or C reactive protein.13 14 Osler, as outlined, had both chest pain and an elevated white cell count.

Most pleural infections result from the direct invasion of bacteria from the lung parenchyma to the pleura. Bacteria, such as S. pneumoniae, potently kill mesothelial cells in vitro which may facilitate their entry into the pleural cavity.15 Bacterial invasion of the pleural cavity elicits proinflammatory cytokines release and influx of inflammatory cells, resulting in a neutrophilic exudative ‘parapneumonic’ effusion. About 20% of these effusions eventually exhibit a low pleural fluid pH and high lactate dehydrogenase levels, and are termed ‘complicated parapneumonic effusions’. The current belief is that these changes reflect subclinical infection of the fluid and the patient requires drainage for clinical improvement. Empyema traditionally refers only to cases with frank pleural pus but nowadays is often expanded to incorporate those with bacteria on staining or culture of the fluid.

Current knowledge suggests that bacteriology of empyema differs among countries and regions, between children and adults and between community-acquired or hospital-acquired cases. Streptococci (especially S. milleri and S. pneumoniae) and S. aureus account for many of the community-acquired empyema.16 Pneumococci are the predominant cause in paediatric empyema; however, following the introduction of pneumococcal vaccines, the previously common serotypes of empyema are now replaced by other serotypes as well as by S. pyogenes.17

Even with modern day laboratory techniques, at least 50% of patients with pleural infection do not have any organism cultured from their effusion, as in Osler’s case, which can create diagnostic dilemmas. Old photographs have often captured Osler smoking socially3 and led to published concerns (proved erroneous) that his persistent pleural effusion was due to lung cancer rather than infection.3 This was of course disproved by his clinical course and eventual autopsy.

The troublesome recurrent pleural effusions

There were differing versions of the number of thoracentesis/pleural procedures performed during Osler’s final month of life. In A Narrative of Osler’s Last Illness in the Osler Library Newsletter, Blackman and Teigen reported two further thoracentesis were performed prior to surgical intervention.12 The second thoracentesis was performed secondary to progressive dullness at the right base up to the axilla with associated friction and harsh breath sounds.12 This repeat aspiration drew one pint of clear fluid.12 Despite the repeat aspiration, fevers, tachycardia and tachypnoea persisted as well as intermittent nausea and vomiting.5 12

Hippocrates observed that ‘if empyema does not rupture, death follows’ and laid the principle that empyema should be drained, a practice which has stood the test of time. We recently found that S. pneumoniae consistently proliferate in pleural fluid at a strikingly high rate (median ~4000-fold increase within 24 hours),18 supporting the need for evacuation of the pleural fluid. The recently published Advanced Ultrasound in Pleural Infection (AUDIO) study provided interesting pilot data that bacteria were present also in the pleural tissue, even in many patients already receiving antibiotics.19

The desperate search for pus

Lord Horder was clinically astute to suggest there must be other undrained infected collections and with Osler’s agreement further exploration took place.20 It is intriguing that ‘ultralong’ needles had to be specially procured for a third aspirate which eventually found a small collection (<5 mL) of turbid brown pus associated with foul odour.4 12 Osler was excited by this finding of pus and shouted out at the time ‘You’ve got it, my boy’.20

In our opinion, it is likely that the doctors had aspirated a lung abscess rather than pus in the interlobar fissure as there is a very low probability of successfully targeting the interlobar fissure without imaging guidance.

In Hippocrates’ time, he had to shake the patient and listen to the sound of fluid with his ears on their chest to identify the presence of pleural effusions! Clinical examination (percussion, etc) is very unreliable for locating effusions.21 Advances in imaging since Osler’s days have allowed us to identify pneumonia on radiographs. Bedside ultrasonography is now routine practice in most developed countries and significantly enhanced safety by minimising ‘blind’ pleural interventions.22 CT can help separate consolidated lung, abscesses and (often loculated) pleural effusions. In patients like Osler, CT can help locate remaining collections and lung abscesses, and allows their aspiration under direct imaging guidance.

The decision for surgery

E mpyema needs three inches of cold steel instead of the fool of a physician… William Osler

Osler was known to be cheerful and continued to uphold his bright demeanour throughout his illness.5 He remained engaged in management of his disease and wrote notes on his signs and symptoms as well as letters to close friends which provided insight into his final months.5 6

By this time, it was approaching Christmas and the decision was made to progress to surgical drainage to evaluate whether there was a further pocket of pus. Three inches of the right ninth rib was resected in turn opening a large cavity containing thick, malodorous, blood stained fluid and surgical drains were placed.5

Management of empyema has advanced since Osler’s time. Antibiotics and evacuation of the infected pleural material are important current principles of care. Surgical techniques have also evolved. Minimally invasive approaches, such as video-assisted thoracoscopic surgery (VATS), are now usually used. Open thoracotomy is still used but open drainage, as Osler had, is rare. Two randomised controlled trials (RCT) comparing VATS with chest tube drainage reported reduced hospital length of stay with VATS but were of insufficient size to reliably estimate differences in other important outcomes such as mortality.23 24

The advent of intrapleural therapy has revolutionised empyema management and negate the need of surgery in many (>90%) patients. Rahman et al from Oxford led the MIST-2 multicentre RCT which showed that intrapleural instillation of tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) provide synergistic benefits in clearing pleural fluid, reducing hospitalisation and need for surgery.25 The fibrinolytics help break loculations but also stimulate fluid formation (via monocyte chemotactic protein-1-mediated mechanisms) that may also provide a lavage effect.26 Ongoing research focuses on optimising the drug delivery regime, their dosages and their long-term safety.27

The final events

Unfortunately, Osler’s weakness continued to progress after the operation and he passed away secondary to haemorrhage from his surgical wound, on 29 December 1919.

On the morning of his death, Osler appeared bright.12 He reported a good night’s sleep and felt his outlook was more favourable.12 Around lunch time, Osler suddenly deteriorated. He was found pale, vomiting and almost pulseless.12 His dressings were covered in blood and, when removed, ‘handful of clots came out of pleura’.12 Osler passed away later that afternoon. An autopsy revealed ‘bronchiectasis of the right lower lobe with unresolved pneumonia, multiple lung abscesses and an empyema’.3 5

The famous French surgeon Guillaume Dupuytren (1777–1835) consulted five doctors for his empyema, and concluded: ‘I prefer to die by the hand of God than with the help of a surgeon’.1 Osler chose to have surgery out of desperation and died postoperatively from a massive haemorrhage. Surgery for empyema has a risk of severe complications and death, particularly in older adults or those with comorbid conditions. The decision to use surgery or continued more conservative management is difficult. An RCT is currently underway to compare VATS with use of intrapleural tPA and DNase therapy.

Pleural infection: future research directions

Osler would have received the best care possible 100 years ago in Oxford. Had he been managed with the diagnostic and treatment tools we have in 2019, there is a good chance he would have made a full recovery.

Advances in the last century such as antibiotics and less invasive techniques for evacuation of infected pleural fluid have likely contributed to improved mortality for the illness that affected Osler. However, reported mortality rates for patients with pleural infection are still high. This may be due to factors such as older patients with comorbid conditions leading to relatively poorer prognosis, and research is ongoing to establish causal factors for high mortality.

An important topic for research is the cause and prevention of pleural infection and effusion formation. Although the use of antibiotics plays an important role, the pleural penetration of commonly used antibiotics, or what the optimal choice of antibiotic should be, are both unclear. If the use of antibiotics can be optimised, then this could result in early eradication of pleural bacteria and may reduce the need for subsequent drainage.

Recent data suggest that parapneumonic effusion could develop as a result of overexaggerated pleural inflammatory response to pneumonia. In a study of 3612 patients with community-acquired pneumonia, the incidence of parapneumonic effusion was significantly lower in patients receiving inhaled corticosteroids (ICS): OR 0.40, 95% CI 0.23 to 0.69; p=0.001, and their parapneumonic fluid had significantly lower inflammatory indices than those from patients who had no prior ICS treatment.28 A randomised placebo controlled trial showed that children with parapneumonic effusions recovered faster when treated with intravenous dexamethasone.29 An exploratory randomised study of dexamethasone (vs placebo) in adult pneumonia patients with a pleural effusion is underway.

It is hoped that with continued research efforts complete eradication of pleural infection can be achieved before the next centenary series of Osler’s death.