Frederick (Freddy) Hargreave, MD, MB, FRCPC, FRCP
Professor, Department of Medicine, McMaster University Professor Emeritus, McMaster University
(The following appeared in the Can Respir J Vol 18 No 4 July/August 2011, written by Dr. Paul O'Byrne and Dr. Parameswaran Nair)
Frederick (Freddy) E Hargreave died unexpectedly on June 15, 2011. He was born in Hong Kong and completed his medical school training at the University of Leeds (Leeds, United Kingdom). After completing his initial clinical training, Freddy moved to London in 1964 to work as a house officer in respiratory medicine with Dr Ej Moran Campbell at the Hammersmith Hospital. Shortly afterward, he began his research training with Professor Jack Pepys at the Brompton Hospital. During this time, Freddy described a new clinical entity, 'Bird fancier's lung disease' - a type of allergic alveolitis caused by the inhalation of bird antigens.
Freddy Hargreave joined the Department of Medicine at McMaster University (Hamilton, Ontario) in 1969, at the behest of Moran Campbell (who had become the first Chair of the Department of Medicine at McMaster University) and Norman Jones (who was the first Division Director for Respiratory Medicine). He was based at the Firestone Institute for Respiratory Health (Hamilton), where he spent his entire career. Shortly after arriving in Hamilton, he started what was to become a lifelong collaboration and close friendship with Dr Jerry Dolovich, and their focus turned to understanding the mechanisms of, and the treatment of asthma. Within 10 years, the studies led by Freddy Hargreave had changed the way that asthma was diagnosed, and had paved the way to future studies that have revolutionized its treatment. In particular, Dr Don Cockcroft (who was Freddy's first clinical fellow) described the methodology for the measurement of airway hyper-responsiveness in asthma. Together, they demonstrated that this was a crucial component of the disease and present in all patients who had current symptoms. They also showed that the degree of airway hyper-responsiveness was related to the amount of treatment needed to manage asthma. The article describing this methodology is a citation classic, having been cited almost 1800 times.
In the early 1980s, the importance of persistent airway inflammation in the pathogenesis of asthma became apparent. The type of inflammatory response differed from patient to patient, and was difficult to measure because it required fiberoptic bronchoscopy and could not be performed routinely. The brilliance of Freddy Hargreave's research was that it was always focused at directly solving patientrelated issues, and he recognized that the noninvasive measurement of airway inflammation was a critical step in the evaluation and treatment of patients with difficult-to-treat asthma. In 1989, this resulted in the development of the methodology for Sputum induction and measurement of inflammatory cells in sputum. Almost immediately, this resulted in the identification of a new syndrome - persistent eosinophilic airway inflammation in the absence of asthma which accounts for approximately 20% of patient referrals with chronic persistent cough to respiratory clinics.
The methods that the Hargreave laboratory developed for sputum induction and processing are now considered the gold standard, and used as research tools in all laboratories that conduct clinical research in asthma. Moreover, based on extensive experience measuring sputum inflammatory cells in the clinical setting, Freddy became convinced of its added value in the everyday management of difficult-to-control asthma. Clinical trials comparing standard guidelinedirected management of asthma with a management scheme that added the routine measurement of induced sputum showed a dramatic advantage of adding the sputum analysis in reducing the risks of severe asthma exacerbations, and also in determining the appropriate doses of inhaled and/or oral corticosteroids to manage these patients. In addition, using induced sputum allowed the identification of a group of patients (about 50% of those with difficult-to-treat asthma), who greatly benefit from the use of a monoclonal antibody directed against interleukin-5. Some, but not all, tertiary level asthma clinics worldwide have embraced this methodology based on this evidence.
Freddy's driving ambition, until his untimely death, was to extend the use of this method to benefit patients. His contribution to asthma care worldwide has been recognized by several honorary lectureships and an honorary degree from the University of Modena (Modena, Italy) in 2010.
Freddy Hargreave's brilliance as a clinical scientist was only eclipsed by his skills as a mentor. Almost all of the research leaders in asthma in Canada have trained at his laboratory at the Firestone Institute, and his previous fellows are research leaders in more than 20 countries. His honesty, integrity and precision in research were legendary, and he tried to impart these qualities to all of the trainees who flocked to train with him from all parts of the world. In addition to making landmark advancements in the diagnosis and treatment of asthma and other obstructive airway diseases, he mentored his trainees to be caring physicians first, and researchers and scientists secondarily. His research was entirely driven by the clinical needs of his patients and epitomized translational research. All of his many important discoveries led directly to the improved health of his patients. He rejoiced, not from his more than 300 publications in high-impact journals, but from the recognition of his grateful patients and the successes of his trainees.
McMaster University, the city of Hamilton, the Canadian respiratory community and the international scientific community have lost an extraordinary physician, humanitarian and clinician scientist. His untimely demise has deprived physicians and scientists across the world of a trusted colleague, friend and mentor. His wife, Alix, his children Clare, Erica and Peter, and his grandchildren have lost a devoted husband, a loving and caring father and an affectionate grandfather. Despite his world class accomplishments, he did not care for titles, accolades or his own advancement. To his patients, he was not Dr Hargreave, but Freddy - the doctor and friend who wore shorts, sandals and knee high socks, even in the depth of winter. There never has been - and probably never will be - a physician whose telephone line and home were always open to anyone in need. He cared genuinely and, in everything he did, he brought a level of decency that so many overlook.
Albert Einstein's tribute to Gandhi,
"Generations to come will scarce believe that such a one as this ever in flesh and blood walked upon this earth" could easily describe the life and contributions of Professor Freddy Hargreave.
Research Contributions
Dr. Hargreave was truly one of the giants of respiratory medicine over the last 40 years and helped change our thinking about the treatment of serious diseases like asthma, chest infections and COPD. In doing so he hugely improved the care of patients throughout the world and his work improved many lives. He taught many students and fellows from many different countries - many of whom returned home and became internationally recognized in their own right. He made St. Joseph's Healthcare Hamilton world famous – but more importantly, he cared for individual patients in an exemplary manner with unfailing courtesy, dedication, humility, kindness and, most particularly, in bringing the challenges they faced each day to the research community to find better ways of relieving their suffering.
Dr. F. E. Hargreave, in his training as clinical researcher with Jack Pepys and his subsequent collaboration with Jerry Dolovich, was a pioneer in the improved understanding and treatment of asthma and its association with chronic cough and COPD. This has been achieved by the use of objective measurements of airway inflammation, airway responsiveness and airflow limitation.With allergen inhalation tests, he validated the occurrence of late asthmatic responses, showed that they were common, that they could result from the combination of allergen with IgE antibodies, that they were associated with allergen-induced increases in airway responsiveness to non-allergic stimuli and with airway inflammation and that they could be (and were subsequently) used to study the anti-inflammatory effect of new drugs. He also standardized and evaluated measurements of non-allergic airway responsiveness to histamine and methacholine. He showed that these are the most sensitive measurements to identify the presence of current asthma when symptoms are present but spirometry is normal and that they are important determinants of the degree of variable airflow limitation. They are now widely used in research and clinical practice.
He also refined the induction processing of sputum to measure airway inflammation relatively non-invasively. He evaluated the measurement qualities and applied them to study the pathogenesis, pathophysiology and treatment of asthma, chronic cough and COPD. The observations emphasize the occurrence of different types of airway inflammation which vary over time, their different causes and different response to treatment.
Sputum inflammatory markers are now being increasingly used in research and clinical trials of anti-inflammatory drugs. They have been available in clinical practice at the Firestone Institute for many years. They are needed by specialists to diagnose and personalize treatment of the bronchitic component of severe, difficult to control or complicated airway diseases.
Research Interests
Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: A method and clinical survey. Clin Allergy 1977; 7:235-43. [A”CITATION CLASSIC”, Current Contents (Clinical Medicine) 1991; 19 (No. 32):10].
Cockcroft DW, Ruffin RE, Dolovich J, Hargreave FE. Allergen-induced increase in non-allergic bronchial reactivity. Clin Allergy 1977; 7:503-13. [A”CITATION CLASSIC”, Current Contents (Clinical Medicine) 1993; 21 (No. 8):8].
O’Byrne PM, Dolovich J, Hargreave FE. Late asthmatic responses. Am Rev Respir Dis 1987; 136:740-51.
Pizzichini E, Pizzichini MMM, Efthimiadis A, Evans S, Morris MM, Squillace D, Gleich G, Dolovich J, Hargreave FE. Indices or airway inflammation in induced sputum: reproducibility and validity of cell and fluid phase measurements. Am J Respir Crit Care Med 1996; 154:308-17.
Jayaram L, Parameswaran K, Sears MR, Hargreave FE. Induced sputum cell counts: their usefulness in clinical practice. Eur Respir J 2000: 16:150-8.
Leigh R, Pizzichini MMM, Morris MM, Maltais F, Hargreave FE, Pizzichini E. Stable COPD: predicting benefit from high-dose corticosteroid treatment. Eur Respir J 2006; 27: 964-71.
Nair PK, Hargreave FE. Airway diseases, inflammometry and individualized therapy. In Polosa R, Holgate ST (eds), Therapeutic Strategies in Asthma: Current Treatments. Clinical Publishing, Oxford, 2007, 155-64.
Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360: 985-93.
Hargreave FE, Nair P. The definition and diagnosis of asthma. Clin Exp Allergy 2009; 39: 1652-8.
