- Email: [email protected]
Corticosteroid therapy for pneumonia
Correspondence
We declare no competing interests.
*Pedro Póvoa, Jorge I F Salluh [email protected] Polyvalent Intensive Care Unit, Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal (PP); NOVA Medical School, New University of Lisbon, Lisbon, Portugal (PP); D’Or Institute for Research and Education, Rio de Janeiro, Brazil (JIFS); and Postgraduation Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil (JIFS) 1
2
3
4
Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511–18. Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 2023–30. Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC. The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C? Crit Care Med 2014; 42: 1714–21. Rubenfeld GD, Angus DC, Pinsky MR, Curtis JR, Connors AF Jr, Bernard GR. Outcomes research in critical care: results of the American Thoracic Society Critical Care Assembly Workshop on Outcomes Research. The Members of the Outcomes Research Workshop. Am J Respir Crit Care Med 1999; 160: 358–67.
Respiratory tract infections (RTIs) cause millions of deaths worldwide each year.1 Despite the availability of appropriate antibiotic therapy, treatment of all forms of RTIs is associated with major long-term morbidity and mortality. This outcome could be attributable to excessive, sustained inflammatory responses with consequential pulmonary damage, dampening of effective immune responses, and pulmonary dysfunction, all of which retard recovery and cure. Adjunct, host-directed therapies that modulate destructive inflammatory responses could improve morbidity and mortality www.thelancet.com Vol 386 September 5, 2015
rates and prevent serious long-term sequelae. In their multicentre, double-blind, randomised, placebo-controlled trial, Claudine Blum and colleagues2 show that adjunct treatment with prednisone in inpatients with community-acquired pneumonia shortens time to clinical stability, and slightly reduces length of hospital stay and duration of intravenous antibiotic treatment. These data offer support to calls for more investment into development and evaluation of adjunct host-directed therapies for a range of other RTIs associated with excess inflammatory and immune responses, and poor treatment outcomes despite the availability of optimum antibiotic therapy. Worldwide in 2014, there were an estimated 500 000 cases of patients with pulmonary infections due to multi-drug resistant (MDR) tuberculosis, and extensively drug-resistant (XDR) tuberculosis, many of whom had concomitant co-infection with human immunodeficiency virus (HIV). Bacterial sepsis is an important cause of morbidity and mortality in patients with MDR tuberculosis who are co-infected with HIV because of HIV-induced immunological abberations. 3 The mortality rates of patients with MDR tuberculosis and XDR tuberculosis with or without HIV co-infection remains unacceptably high (up to 50% mortality) despite the use of optimum WHO-recommended anti-tuberculosis drug treatment regimens. Many innate and adaptive immune and inflammatory responses have been reported in patients with MDR tuberculosis and XDR tuberculosis. These responses could be amenable to modulation and evaluation of a spectrum of host-directed therapies (eg, cellular therapy, immune-based therapies, and repurposed drugs with immune-modulatory effects).4 Placebo-controlled clinical trials evaluating immunogenicity, effect on mortality, and reduction of duration of therapy are urgently required.5
Autologous bone-marrow-derived mesenchymal stromal cells (MSCs) could modulate innate and adaptive immune responses, have trophic activity on damaged tissues, anti-scarring and angiogenesis effects through stem cell growth and differentiation, and might be useful as adjunct therapy for treatment of MDR tuberculosis and XDR tuberculosis in both HIV-infected and HIV-uninfected individuals. The adjunct use of autologous bone-marrow-derived MSCs has been found to be safe in a phase 1 trial in patients with MDR tuberculosis,6 and further phase 2 and 3 evaluations are required to assess the potential for improving the current dismal treatment outcomes. Host-directed therapies could fulfil a critical clinical need in view of the growing global problem of antibiotic-resistant RTIs, and require urgent evaluation.1
Molekuul/Science Photo Library
must highlight the fact that clinical trials should have patient-centred, meaningful outcomes.3,4 Outcomes should be clinically relevant (mortality, duration of hospitalisation), multidimensional (ie, quality of life), and have clear association with patients’ and relatives’ perceptions of value rather than physiological or biological surrogates that are not necessarily linked to clinical benefits.
We declare no competing interests.
*Alimuddin Zumla, Matthew Bates, Markus Maeurer [email protected] Division of Infection and Immunity, University College London, and NIHR BRC at University College Hospital, London, UK (AZ, MB); UNZA-UCLMS Project, University Teaching Hospital, Lusaka, Zambia (AZ, MB, MM); and Therapeutic Immunology, Departments of Laboratory Medicine and Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden (MM) 1
2
3
4
5
6
Zumla A, Memish ZA, Maeurer M, et al. Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options. Lancet Infect Dis 2014; 14: 1136–49. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511–18. Huson MA, Grobusch MP, van der Poll T. The effect of HIV infection on the host response to bacterial sepsis. Lancet Infect Dis 2015; 15: 95–108. Zumla A, Chakaya J, Hoelscher M, et al. Towards host-directed therapies for tuberculosis. Nat Rev Drugs Discov 2015; 14: 511–12. Kaufmann SH, Lange C, Rao M, et al. Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir Med 2014; 2: 301–20. Skrahin A, Ahmed RK, Ferrara G, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med 2014; 2: 108–22.
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We declare no competing interests.
*Pedro Póvoa, Jorge I F Salluh [email protected] Polyvalent Intensive Care Unit, Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal (PP); NOVA Medical School, New University of Lisbon, Lisbon, Portugal (PP); D’Or Institute for Research and Education, Rio de Janeiro, Brazil (JIFS); and Postgraduation Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil (JIFS) 1
2
3
4
Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511–18. Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 2023–30. Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC. The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C? Crit Care Med 2014; 42: 1714–21. Rubenfeld GD, Angus DC, Pinsky MR, Curtis JR, Connors AF Jr, Bernard GR. Outcomes research in critical care: results of the American Thoracic Society Critical Care Assembly Workshop on Outcomes Research. The Members of the Outcomes Research Workshop. Am J Respir Crit Care Med 1999; 160: 358–67.
Respiratory tract infections (RTIs) cause millions of deaths worldwide each year.1 Despite the availability of appropriate antibiotic therapy, treatment of all forms of RTIs is associated with major long-term morbidity and mortality. This outcome could be attributable to excessive, sustained inflammatory responses with consequential pulmonary damage, dampening of effective immune responses, and pulmonary dysfunction, all of which retard recovery and cure. Adjunct, host-directed therapies that modulate destructive inflammatory responses could improve morbidity and mortality www.thelancet.com Vol 386 September 5, 2015
rates and prevent serious long-term sequelae. In their multicentre, double-blind, randomised, placebo-controlled trial, Claudine Blum and colleagues2 show that adjunct treatment with prednisone in inpatients with community-acquired pneumonia shortens time to clinical stability, and slightly reduces length of hospital stay and duration of intravenous antibiotic treatment. These data offer support to calls for more investment into development and evaluation of adjunct host-directed therapies for a range of other RTIs associated with excess inflammatory and immune responses, and poor treatment outcomes despite the availability of optimum antibiotic therapy. Worldwide in 2014, there were an estimated 500 000 cases of patients with pulmonary infections due to multi-drug resistant (MDR) tuberculosis, and extensively drug-resistant (XDR) tuberculosis, many of whom had concomitant co-infection with human immunodeficiency virus (HIV). Bacterial sepsis is an important cause of morbidity and mortality in patients with MDR tuberculosis who are co-infected with HIV because of HIV-induced immunological abberations. 3 The mortality rates of patients with MDR tuberculosis and XDR tuberculosis with or without HIV co-infection remains unacceptably high (up to 50% mortality) despite the use of optimum WHO-recommended anti-tuberculosis drug treatment regimens. Many innate and adaptive immune and inflammatory responses have been reported in patients with MDR tuberculosis and XDR tuberculosis. These responses could be amenable to modulation and evaluation of a spectrum of host-directed therapies (eg, cellular therapy, immune-based therapies, and repurposed drugs with immune-modulatory effects).4 Placebo-controlled clinical trials evaluating immunogenicity, effect on mortality, and reduction of duration of therapy are urgently required.5
Autologous bone-marrow-derived mesenchymal stromal cells (MSCs) could modulate innate and adaptive immune responses, have trophic activity on damaged tissues, anti-scarring and angiogenesis effects through stem cell growth and differentiation, and might be useful as adjunct therapy for treatment of MDR tuberculosis and XDR tuberculosis in both HIV-infected and HIV-uninfected individuals. The adjunct use of autologous bone-marrow-derived MSCs has been found to be safe in a phase 1 trial in patients with MDR tuberculosis,6 and further phase 2 and 3 evaluations are required to assess the potential for improving the current dismal treatment outcomes. Host-directed therapies could fulfil a critical clinical need in view of the growing global problem of antibiotic-resistant RTIs, and require urgent evaluation.1
Molekuul/Science Photo Library
must highlight the fact that clinical trials should have patient-centred, meaningful outcomes.3,4 Outcomes should be clinically relevant (mortality, duration of hospitalisation), multidimensional (ie, quality of life), and have clear association with patients’ and relatives’ perceptions of value rather than physiological or biological surrogates that are not necessarily linked to clinical benefits.
We declare no competing interests.
*Alimuddin Zumla, Matthew Bates, Markus Maeurer [email protected] Division of Infection and Immunity, University College London, and NIHR BRC at University College Hospital, London, UK (AZ, MB); UNZA-UCLMS Project, University Teaching Hospital, Lusaka, Zambia (AZ, MB, MM); and Therapeutic Immunology, Departments of Laboratory Medicine and Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden (MM) 1
2
3
4
5
6
Zumla A, Memish ZA, Maeurer M, et al. Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options. Lancet Infect Dis 2014; 14: 1136–49. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511–18. Huson MA, Grobusch MP, van der Poll T. The effect of HIV infection on the host response to bacterial sepsis. Lancet Infect Dis 2015; 15: 95–108. Zumla A, Chakaya J, Hoelscher M, et al. Towards host-directed therapies for tuberculosis. Nat Rev Drugs Discov 2015; 14: 511–12. Kaufmann SH, Lange C, Rao M, et al. Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir Med 2014; 2: 301–20. Skrahin A, Ahmed RK, Ferrara G, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med 2014; 2: 108–22.
955