- Email: [email protected]
Pirfenidone for idiopathic pulmonary fibrosis
Comment
of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail, or both. Indeed, the number of treatment lines used are clearly relevant for overall outcome (especially survival), which might be very likely also in an elderly and frail population.7 Therefore a further trial that uses all available treatment options sequentially would be helpful to further define the best standard for this elderly and frail population. Despite these limitations of FOCUS2, the approach towards a separate trial design and outcome measures that investigate treatment options for a very specific population of patients is highly relevant, not only for colorectal cancer but also for the other most frequent tumour types. Many, probably most, patients with cancer in the near future will belong to this group of elderly and frail patients.
Hans-Joachim Schmoll Department of Internal Medicine IV, Oncology/Haematology, and Centre for Cell and Gene Therapy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany [email protected] I have received consulting fees, support for travel costs, fees for participation in review activities, and speakers’ fees from Merck and Roche. 1
Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005; 55: 10–30. Seymour MT, Thompson LC, Wasan HS, et al, on behalf of the FOCUS2 Investigators and the National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet 2011; 377: 1749–59. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24: 4085–91. Rafterty L, Sanoff HK, Goldberg R. Colon cancer in elderly patients. Semin Oncol 2008: 35: 561–68. Schmoll HJ, Sargent D. Single agent fluorouracil for first-line treatment of advanced colorectal cancer as standard? Lancet 2007; 370: 105–07. Tebbutt NC, Gebski V, Wilson K, et al. International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): final results of the AGITG MAX trial. J Clin Oncol 2009; 27 (suppl): 4023 (abstr). Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22: 1209–14.
2
3
4 5 6
7
Pirfenidone for idiopathic pulmonary fibrosis In The Lancet today, Paul Noble and colleagues report the results of the CAPACITY programme (Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes).1 Two concurrent phase 3 clinical trials (studies 004 and 006) investigated the role of pirfenidone in patients with mildto-moderate idiopathic pulmonary fibrosis (ie, forced vital capacity [FVC] ≥50% predicted, and diffusing capacity of the lung for carbon monoxide ≥35% predicted). Patients were randomly assigned blinded treatment with oral pirfenidone or placebo for a minimum of 72 weeks. In study 004, 174 patients were assigned a high drug dose (pirfenidone 2403 mg/day), 87 patients a low drug dose (pirfenidone 1197 mg/day), and 174 placebo; in study 006, 171 patients were assigned the same high dose and 173 patients placebo. The primary endpoint was change in percentage predicted FVC at week 72. Secondary endpoints included progression-free survival and 6-min walk-test (6MWT) distance. In study 004, high-dose pirfenidone significantly reduced the decline in percentage predicted FVC with an effect size of 4·4% at week 72; but in study 006, there was no difference between the groups in the primary www.thelancet.com Vol 377 May 21, 2011
endpoint. However, in that study a consistent pirfenidone treatment effect was found up to week 48 (p=0·005) and in the repeated-measures analysis of all study time-points (p=0·007). In study 004, high-dose pirfenidone improved progression-free survival (hazard ratio 0·64, 95% CI 0·44–0·95, p=0·023). In study 006, a significant reduction
Published Online May 14, 2011 DOI:10.1016/S01406736(11)60546-1 See Articles page 1760
Panel: Pathogenic mechanisms in idiopathic pulmonary fibrosis • • • • • • • • • • • • • •
Epithelial-mesenchymal transformation Fibroblast-myofibroblast transformation Circulating fibrocytes Abnormal angiogenesis and lymphangiogenesis Activated alveolar-bronchiolar epithelial cells Gene–environment interactions Fibrogenic cytokines Fibrogenic chemokines Growth factors Epithelial cell apoptosis Immunoderegulation (Th1, Th2, Th17, regulatory T cells) Imbalance in matrix metalloproteinases Oxidant/antioxidant imbalance Coagulation cascade activation
Th=T helper.
1727
Comment
in the decline from baseline to week 72 in 6MWT distance was observed in patients assigned pirfenidone (absolute difference 31·8 m, 95% CI 3·2 to 60·4). These large randomised trials provide evidencebased information about the role of pirfenidone in the treatment of this devastating disease. Although there is much discussion about the selection of the primary endpoint in patients with idiopathic pulmonary fibrosis,2 an FVC change of 10% or more is clinically significant and predictive of survival.3 Furthermore, the prognostic value of the observed improvement in 6MWT distance is clinically important and its value has been investigated in idiopathic pulmonary fibrosis.4 However, the trials were not powered to assess survival; no survival benefit was established for all-cause on-treatment mortality, and cause of death was not adjudicated.2,5 Both trials showed a relatively safe profile, especially for gastrointestinal adverse events, abnormalities in laboratory indicators of liver function, photosensitivity, and rash. Although these specific adverse events occurred more frequently in the pirfenidone groups than in the placebo groups, they arose only in a minority of patients, the severity grade was low, and only 6% more patients on pirfenidone than on placebo discontinued treatment because of adverse events. Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults. It is characterised by progressive worsening of dyspnoea and lung function and has a poor prognosis; the estimated survival is 20% after 5 years, which makes the disease more lethal than many cancers.5,6 Prevalence estimates vary from two to 29 cases per 100 000 in the general population.6,7 More than 100 000 people in Europe have idiopathic pulmonary fibrosis. To date, no management approach has proven to be efficacious;5 the disease is largely unresponsive to corticosteroid and immunosuppressive therapy.8,9 Idiopathic pulmonary fibrosis is the most common form of idiopathic interstitial pneumonia, with the pathological and imaging pattern of usual interstitial pneumonia, and is considered as an epithelial–fibroblastic disorder, characterised by abnormal wound healing with excessive fibrosis and little inflammation.9 These emerging data on pathogenesis have focused attention on antifibrotic drugs. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is an orally bioavailable synthetic compound. Although its mechanism of action has not been fully established, 1728
existing data suggest that it has anti-inflammatory, antifibrotic, and antioxidant properties, with antagonism of activities mediated by transforming growth factor β1 and tumour necrosis factor α.10–12 Previously, two small randomised studies10,11 suggested benefit from this drug. However, these trials had substantial limitations, including highly selective enrolment of patients and change of the primary endpoint before unmasking.12 Although pirfenidone has been marketed in Japan since 2008, no drug for the treatment of idiopathic pulmonary fibrosis is approved by the Food and Drug Administration in the USA. The committee that produced the new evidence-based guidelines for diagnosis and management of idiopathic pulmonary fibrosis made a weak recommendation against its use in a collaborative statement on behalf of the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association.5 This recommendation places a high value on side-effects and cost, and a lower value on the possible small reduction in pulmonary function decline. Pirfenidone could be appropriate in patients who are willing to accept possible adverse consequences even if expected benefits are small.5 However, the methodology used by the committee in making recommendations differs from that used by regulatory agencies.5 Recently, the European Commission granted marketing authorisation for pirfenidone, after a positive recommendation from the Committee for Medicinal Products for Human Use “for the treatment of adults with mild to moderate idiopathic pulmonary fibrosis”. Although the successful treatment of idiopathic pulmonary fibrosis is likely to require a combination of therapies targeting several pathways involved in fibroproliferation (panel), pirfenidone is so far the only approved drug that will be commercially available in Europe, raising hopes for many patients with this lifethreatening lung disease. Demosthenes Bouros Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100 Greece [email protected] I declare that I have no conflicts of interest. 1
Noble PW, Albera C, Bradford WZ, et al, for the CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; published online May 14. DOI:10.1016/ S0140-6736(11)60405-4.
www.thelancet.com Vol 377 May 21, 2011
Comment
2
3
4
5
6
Seymour S. Division Summary: Overview of the FDA background materials for New Drug Application (NDA) 22-535, Esbriet (pirfenidone) for the treatment of patients with idiopathic pulmonary fibrosis (IPF) to reduce the decline in lung function. Feb 12, 2010. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PulmonaryAllergyDrugsAdvisoryCommittee/UCM203081.pdf (accessed May 10, 2010). Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003; 168: 531–37. du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med 2010; 183: 1231–37. Raghu G, Collard HR, Egan JJ, et al, on behalf of the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. Idiopathic pulmonary fibrosis: evidence based guidelines for diagnosis and management. A joint ATS/ERS/ JRS/ALAT Statement. Am J Respir Crit Care Med 2011; 183: 788–824. Karakatsani A, Papakosta D, Rapti A, et al, for the Hellenic Interstitial Lung Diseases Group. Epidemiology of interstitial lung diseases in Greece. Respir Med 2009; 103: 1122–29.
7
8 9 10
11
12
Martinez FJ, Safrin S, Weycker D, et al, for the IPF study group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142: 963–67. Bouros D, Antoniou KM. Current and future therapeutic approaches in idiopathic pulmonary fibrosis. Eur Respir J 2005; 26: 693–702. Bouros D. Interferon gamma for idiopathic pulmonary fibrosis. Lancet 2009; 374: 180–82. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med 1999; 159: 1061–69. Taniguchi H, Ebina M, Kondoh Y, et al, for the Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: 821–29. Collard HR. Idiopathic pulmonary fibrosis and pirfenidone. Eur Respir J 2010; 35: 728–29.
The mysteries of immunity to malaria
www.thelancet.com Vol 377 May 21, 2011
In 2009, Meta Roestenberg and colleagues5 reported use of this approach to prevent malaria. Ten Dutch volunteers were infected three times with monthly intervals by bites of mosquitoes infected with a chloroquine-sensitive strain of Plasmodium falciparum (NF54) while receiving chloroquine prophylaxis. All participants were protected when challenged with the same parasite strain 1 month after stopping chloroquine; no blood-stage parasites were detected by microscopy or PCR. By contrast, positive PCR tests were obtained during the immunising infections, so that immunity to either liver or blood stages of the infection, or both, might have contributed to the protection seen in the participants. Low-density blood-stage infections can induce protection.6 Blood concentrations of chloroquine had dropped to a very low level before challenge and had no measurable parasiticidal
Published Online April 25, 2011 DOI:10.1016/S01406736(11)60515-1 See Articles page 1770
Science Photo Library
Residents of malaria-endemic areas eventually develop some immunity to the infection, but the process is drawn out and inefficient. Why it is so difficult to develop immunity to malaria, and the mechanism by which partial protection is finally achieved, remains a mystery. Two main hypotheses have been put forward to explain why development of partial immunity takes so long. The first suggests that the problem is one of strain specificity. The second postulates that repeated exposure to malaria antigens is needed to drive an effective immune response, perhaps accompanied by a maturation of the immune system with increasing age. Study of patients infected with malaria parasites as a treatment for syphilis showed that a single infection induced some protective immunity, shown by a reduction in symptoms and parasite density. The effect was most notable when the same strain was used for initial and subsequent infections, which supports an important role for strain-specific immunity, although there was some cross-strain protection.1 A logical extension to these findings was the attempt to induce protection with an attenuated parasite that did not induce the severe febrile response required for malaria therapy, but which was still able to induce immunity. This was duly accomplished with irradiated sporozoites2 and, more recently, by genetic manipulation3—approaches to vaccine development that are being explored at present.4 An alternative approach to attenuation is administration of a potentially virulent organism with a subtherapeutic dose of an antimicrobial drug, which contains the growth of the pathogen sufficiently to prevent symptoms while allowing induction of a protective immune response.
False-colour transmission electron micrograph of two merozoites of Plasmodium falciparum (blue/pink) inside red blood cell
1729
of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail, or both. Indeed, the number of treatment lines used are clearly relevant for overall outcome (especially survival), which might be very likely also in an elderly and frail population.7 Therefore a further trial that uses all available treatment options sequentially would be helpful to further define the best standard for this elderly and frail population. Despite these limitations of FOCUS2, the approach towards a separate trial design and outcome measures that investigate treatment options for a very specific population of patients is highly relevant, not only for colorectal cancer but also for the other most frequent tumour types. Many, probably most, patients with cancer in the near future will belong to this group of elderly and frail patients.
Hans-Joachim Schmoll Department of Internal Medicine IV, Oncology/Haematology, and Centre for Cell and Gene Therapy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany [email protected] I have received consulting fees, support for travel costs, fees for participation in review activities, and speakers’ fees from Merck and Roche. 1
Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005; 55: 10–30. Seymour MT, Thompson LC, Wasan HS, et al, on behalf of the FOCUS2 Investigators and the National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet 2011; 377: 1749–59. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24: 4085–91. Rafterty L, Sanoff HK, Goldberg R. Colon cancer in elderly patients. Semin Oncol 2008: 35: 561–68. Schmoll HJ, Sargent D. Single agent fluorouracil for first-line treatment of advanced colorectal cancer as standard? Lancet 2007; 370: 105–07. Tebbutt NC, Gebski V, Wilson K, et al. International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): final results of the AGITG MAX trial. J Clin Oncol 2009; 27 (suppl): 4023 (abstr). Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22: 1209–14.
2
3
4 5 6
7
Pirfenidone for idiopathic pulmonary fibrosis In The Lancet today, Paul Noble and colleagues report the results of the CAPACITY programme (Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes).1 Two concurrent phase 3 clinical trials (studies 004 and 006) investigated the role of pirfenidone in patients with mildto-moderate idiopathic pulmonary fibrosis (ie, forced vital capacity [FVC] ≥50% predicted, and diffusing capacity of the lung for carbon monoxide ≥35% predicted). Patients were randomly assigned blinded treatment with oral pirfenidone or placebo for a minimum of 72 weeks. In study 004, 174 patients were assigned a high drug dose (pirfenidone 2403 mg/day), 87 patients a low drug dose (pirfenidone 1197 mg/day), and 174 placebo; in study 006, 171 patients were assigned the same high dose and 173 patients placebo. The primary endpoint was change in percentage predicted FVC at week 72. Secondary endpoints included progression-free survival and 6-min walk-test (6MWT) distance. In study 004, high-dose pirfenidone significantly reduced the decline in percentage predicted FVC with an effect size of 4·4% at week 72; but in study 006, there was no difference between the groups in the primary www.thelancet.com Vol 377 May 21, 2011
endpoint. However, in that study a consistent pirfenidone treatment effect was found up to week 48 (p=0·005) and in the repeated-measures analysis of all study time-points (p=0·007). In study 004, high-dose pirfenidone improved progression-free survival (hazard ratio 0·64, 95% CI 0·44–0·95, p=0·023). In study 006, a significant reduction
Published Online May 14, 2011 DOI:10.1016/S01406736(11)60546-1 See Articles page 1760
Panel: Pathogenic mechanisms in idiopathic pulmonary fibrosis • • • • • • • • • • • • • •
Epithelial-mesenchymal transformation Fibroblast-myofibroblast transformation Circulating fibrocytes Abnormal angiogenesis and lymphangiogenesis Activated alveolar-bronchiolar epithelial cells Gene–environment interactions Fibrogenic cytokines Fibrogenic chemokines Growth factors Epithelial cell apoptosis Immunoderegulation (Th1, Th2, Th17, regulatory T cells) Imbalance in matrix metalloproteinases Oxidant/antioxidant imbalance Coagulation cascade activation
Th=T helper.
1727
Comment
in the decline from baseline to week 72 in 6MWT distance was observed in patients assigned pirfenidone (absolute difference 31·8 m, 95% CI 3·2 to 60·4). These large randomised trials provide evidencebased information about the role of pirfenidone in the treatment of this devastating disease. Although there is much discussion about the selection of the primary endpoint in patients with idiopathic pulmonary fibrosis,2 an FVC change of 10% or more is clinically significant and predictive of survival.3 Furthermore, the prognostic value of the observed improvement in 6MWT distance is clinically important and its value has been investigated in idiopathic pulmonary fibrosis.4 However, the trials were not powered to assess survival; no survival benefit was established for all-cause on-treatment mortality, and cause of death was not adjudicated.2,5 Both trials showed a relatively safe profile, especially for gastrointestinal adverse events, abnormalities in laboratory indicators of liver function, photosensitivity, and rash. Although these specific adverse events occurred more frequently in the pirfenidone groups than in the placebo groups, they arose only in a minority of patients, the severity grade was low, and only 6% more patients on pirfenidone than on placebo discontinued treatment because of adverse events. Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults. It is characterised by progressive worsening of dyspnoea and lung function and has a poor prognosis; the estimated survival is 20% after 5 years, which makes the disease more lethal than many cancers.5,6 Prevalence estimates vary from two to 29 cases per 100 000 in the general population.6,7 More than 100 000 people in Europe have idiopathic pulmonary fibrosis. To date, no management approach has proven to be efficacious;5 the disease is largely unresponsive to corticosteroid and immunosuppressive therapy.8,9 Idiopathic pulmonary fibrosis is the most common form of idiopathic interstitial pneumonia, with the pathological and imaging pattern of usual interstitial pneumonia, and is considered as an epithelial–fibroblastic disorder, characterised by abnormal wound healing with excessive fibrosis and little inflammation.9 These emerging data on pathogenesis have focused attention on antifibrotic drugs. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is an orally bioavailable synthetic compound. Although its mechanism of action has not been fully established, 1728
existing data suggest that it has anti-inflammatory, antifibrotic, and antioxidant properties, with antagonism of activities mediated by transforming growth factor β1 and tumour necrosis factor α.10–12 Previously, two small randomised studies10,11 suggested benefit from this drug. However, these trials had substantial limitations, including highly selective enrolment of patients and change of the primary endpoint before unmasking.12 Although pirfenidone has been marketed in Japan since 2008, no drug for the treatment of idiopathic pulmonary fibrosis is approved by the Food and Drug Administration in the USA. The committee that produced the new evidence-based guidelines for diagnosis and management of idiopathic pulmonary fibrosis made a weak recommendation against its use in a collaborative statement on behalf of the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association.5 This recommendation places a high value on side-effects and cost, and a lower value on the possible small reduction in pulmonary function decline. Pirfenidone could be appropriate in patients who are willing to accept possible adverse consequences even if expected benefits are small.5 However, the methodology used by the committee in making recommendations differs from that used by regulatory agencies.5 Recently, the European Commission granted marketing authorisation for pirfenidone, after a positive recommendation from the Committee for Medicinal Products for Human Use “for the treatment of adults with mild to moderate idiopathic pulmonary fibrosis”. Although the successful treatment of idiopathic pulmonary fibrosis is likely to require a combination of therapies targeting several pathways involved in fibroproliferation (panel), pirfenidone is so far the only approved drug that will be commercially available in Europe, raising hopes for many patients with this lifethreatening lung disease. Demosthenes Bouros Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100 Greece [email protected] I declare that I have no conflicts of interest. 1
Noble PW, Albera C, Bradford WZ, et al, for the CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; published online May 14. DOI:10.1016/ S0140-6736(11)60405-4.
www.thelancet.com Vol 377 May 21, 2011
Comment
2
3
4
5
6
Seymour S. Division Summary: Overview of the FDA background materials for New Drug Application (NDA) 22-535, Esbriet (pirfenidone) for the treatment of patients with idiopathic pulmonary fibrosis (IPF) to reduce the decline in lung function. Feb 12, 2010. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PulmonaryAllergyDrugsAdvisoryCommittee/UCM203081.pdf (accessed May 10, 2010). Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003; 168: 531–37. du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med 2010; 183: 1231–37. Raghu G, Collard HR, Egan JJ, et al, on behalf of the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. Idiopathic pulmonary fibrosis: evidence based guidelines for diagnosis and management. A joint ATS/ERS/ JRS/ALAT Statement. Am J Respir Crit Care Med 2011; 183: 788–824. Karakatsani A, Papakosta D, Rapti A, et al, for the Hellenic Interstitial Lung Diseases Group. Epidemiology of interstitial lung diseases in Greece. Respir Med 2009; 103: 1122–29.
7
8 9 10
11
12
Martinez FJ, Safrin S, Weycker D, et al, for the IPF study group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142: 963–67. Bouros D, Antoniou KM. Current and future therapeutic approaches in idiopathic pulmonary fibrosis. Eur Respir J 2005; 26: 693–702. Bouros D. Interferon gamma for idiopathic pulmonary fibrosis. Lancet 2009; 374: 180–82. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med 1999; 159: 1061–69. Taniguchi H, Ebina M, Kondoh Y, et al, for the Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: 821–29. Collard HR. Idiopathic pulmonary fibrosis and pirfenidone. Eur Respir J 2010; 35: 728–29.
The mysteries of immunity to malaria
www.thelancet.com Vol 377 May 21, 2011
In 2009, Meta Roestenberg and colleagues5 reported use of this approach to prevent malaria. Ten Dutch volunteers were infected three times with monthly intervals by bites of mosquitoes infected with a chloroquine-sensitive strain of Plasmodium falciparum (NF54) while receiving chloroquine prophylaxis. All participants were protected when challenged with the same parasite strain 1 month after stopping chloroquine; no blood-stage parasites were detected by microscopy or PCR. By contrast, positive PCR tests were obtained during the immunising infections, so that immunity to either liver or blood stages of the infection, or both, might have contributed to the protection seen in the participants. Low-density blood-stage infections can induce protection.6 Blood concentrations of chloroquine had dropped to a very low level before challenge and had no measurable parasiticidal
Published Online April 25, 2011 DOI:10.1016/S01406736(11)60515-1 See Articles page 1770
Science Photo Library
Residents of malaria-endemic areas eventually develop some immunity to the infection, but the process is drawn out and inefficient. Why it is so difficult to develop immunity to malaria, and the mechanism by which partial protection is finally achieved, remains a mystery. Two main hypotheses have been put forward to explain why development of partial immunity takes so long. The first suggests that the problem is one of strain specificity. The second postulates that repeated exposure to malaria antigens is needed to drive an effective immune response, perhaps accompanied by a maturation of the immune system with increasing age. Study of patients infected with malaria parasites as a treatment for syphilis showed that a single infection induced some protective immunity, shown by a reduction in symptoms and parasite density. The effect was most notable when the same strain was used for initial and subsequent infections, which supports an important role for strain-specific immunity, although there was some cross-strain protection.1 A logical extension to these findings was the attempt to induce protection with an attenuated parasite that did not induce the severe febrile response required for malaria therapy, but which was still able to induce immunity. This was duly accomplished with irradiated sporozoites2 and, more recently, by genetic manipulation3—approaches to vaccine development that are being explored at present.4 An alternative approach to attenuation is administration of a potentially virulent organism with a subtherapeutic dose of an antimicrobial drug, which contains the growth of the pathogen sufficiently to prevent symptoms while allowing induction of a protective immune response.
False-colour transmission electron micrograph of two merozoites of Plasmodium falciparum (blue/pink) inside red blood cell
1729