key: cord-0917877-9p0dr7rl authors: Fedson, David S title: Confronting an influenza pandemic with inexpensive generic agents: can it be done? date: 2008-04-15 journal: Lancet Infect Dis DOI: 10.1016/s1473-3099(08)70070-7 sha: f6d147027c445a49427507168a019c8b4def0b27 doc_id: 917877 cord_uid: 9p0dr7rl Avian influenza A H5N1 presents a serious and possibly imminent pandemic threat. In such an event, adequate supplies of affordable vaccines and antiviral agents will be unavailable to most people in the world. In view of the overwhelming need for effective alternatives, generic agents that target the host immune response or the pandemic virus should be considered. Many scientists doubt the effectiveness of these agents. Nonetheless, several studies suggest that statins improve outcomes in patients with bacteraemia and pneumonia and might be similarly effective against influenza. An experimental study has shown that the fibrate gemfibrozil, a peroxisome proliferator-activated receptor (PPAR) α agonist, reduces mortality in H2N2 influenza virus-infected mice. There is substantial molecular cross-talk between statins and PPAR agonists, and their clinical effects are additive in patients with cardiovascular diseases. Chloroquine increases endosomal pH, impairing influenza virus release into the cytosol. Statins, fibrates, and chloroquine are produced as generic medications in developing countries. They are inexpensive, could be stockpiled, and would be available on the first pandemic day. With a lack of realistic alternatives for confronting the next pandemic, research is urgently needed to determine whether these and other generic agents could mitigate the effects of what might otherwise become an unprecedented global public-health crisis. It is now clear to health offi cials around the world that another infl uenza pandemic is inevitable. If it is imminent, adequate supplies of aff ordable vaccines will be unavailable to most people in the world. [1] [2] [3] Supplies of antiviral agents will be even more limited and growing concern about antiviral resistance will discourage further pandemic stockpiling. 4 New types of antiviral agents will not be introduced into clinical practice for many years. 5 In view of the overwhelming need for an eff ective alternative to vaccines and antiviral agents, it has been suggested that anti-infl ammatory and immunomodulatory agents might benefi t people when the next pandemic arrives. 6 This suggestion is based in part on observations that severe infections caused by infl uenza A H5N1, the 1918 Spanish infl uenza H1N1, and seasonal infl uenza A viruses are characterised by increased levels of several proinfl ammatory cytokines and chemokines. [7] [8] [9] [10] This response has sometimes been called a "cytokine storm". In an important clinical report, de Jong and colleagues 8 presented detailed virological and immunological fi ndings on 18 patients with infl uenza A H5N1 and compared them with fi ndings from eight individuals who had seasonal infl uenza. The H5N1-infected individuals had higher serum cytokine and chemokine levels, especially the 13 (72%) who died. They also had high viral loads in pharyngeal secretions. The investigators concluded: "although immunomodulatory treatment has potential benefi ts at this stage, the focus of clinical management should be on preventing the intense cytokine response by early diagnosis and eff ective treatment". 8 Unfortunately, all 18 patients sought medical care an average of 6 days after the onset of symptoms, and all but one were treated with a neuraminidase inhibitor. Reports by Szretter 11 and Salomon 12 and their colleagues have cast doubt on the potential effi cacy of treating H5N1 infl uenza virus infections with immunomodulatory agents. Both groups of investigators studied experimental infections in small groups of knockout mice in which the genes for individual proinfl ammatory cytokines and chemokines had been deleted. Szretter and co-workers 11 found that deleting interleukin 6 or macrophage inhibitory protein (MIP) 1α had no eff ect on highly pathogenic H5N1 disease or virus replication, whereas lack of interleukin-1-receptor signalling enhanced disease and delayed virus clearance. Lack of tumour necrosis factor (TNF) α also increased disease severity but had no eff ect on virus replication or outcome. The investigators commented that because of the functional redundancy of many cytokines and chemokines, deleting more than one of these genes might have had a greater (presumably more adverse) eff ect on the course of disease, and concluded that mice are suitable for evaluating agents that "modulate the infl ammatory response induced by H5N1 viruses, either alone or in combination with antiviral therapy". 11 Salomon and colleagues 12 also studied H5N1 infections in groups of mice in which diff erent genes had been deleted-TNFα, TNF receptor 1, both TNF receptor 1 and TNF receptor 2, interleukin 6, and CC chemokine ligand (CCL) 2. 12 Each of these deletions failed to protect mice from death caused by a highly pathogenic H5N1 virus. The researchers concluded that their results "refute the popular paradigm that cytokine storm is the cause of death during H5N1 infection". 12 They added: "inhibiting the host cytokine response is not suffi cient to reduce morbidity and lethality of the viral infection…early inhibition of viral replication is more promising than inhibition of the cytokine response in promoting host survival of H5N1 infl uenza virus infection". 12 Experts writing on behalf of WHO have concluded that "knowledge of the mechanisms of hypercytokinaemia is insuffi cient to guide safe, rational immunomodulatory treatment at present". 13 The host defence against infection involves both an infl ammatory response and subsequent active resolution of infl ammation. 14 Safe targeting of the host response must acknowledge its extraordinary complexity and the many positive and negative cell signalling pathways that keep its individual components in balance. 15 The reports of Szretter and Salomon and colleagues notwithstanding, 11, 12 experiments done in small numbers of knockout mice are unlikely to provide an adequate basis for concluding that broadly acting anti-infl ammatory and immunomodulatory agents will be of no benefi t in treating H5N1 infections in mice or pandemic infl uenza in human beings. Moreover, several earlier studies in knockout mice suggest a diff erent conclusion. The acute infl ammatory response to infl uenza virus infection is generated by interleukin 1α/β, which binds to the type 1 interleukin-1 receptor. 16 This response is counterbalanced by the interleukin-1-receptor antagonist, a naturally occurring anti-infl ammatory cytokine. In studies comparing responses to infl uenza virus infection in interleukin-1-receptor antagonist knockout mice and normal mice, Schmitz and co-workers 16 showed that weight loss in the two groups was similar and lung virus titres in knockout mice increased only moderately, but mortality in knockout mice increased substantially. Thus, interleukin-1α/β-mediated pulmonary infl ammatory changes had little eff ect on virus replication but enhanced survival. An earlier study of the eff ects of the macrophage chemokine receptors CCR5 and CCR2 showed that in infl uenza virus-infected CCR5 knockout mice, lung virus titres were low yet pulmonary infl ammation and mortality were increased compared with virus-infected CCR2 knockout mice. 17 By contrast, in CCR2 knockout mice, lung virus titres were greater, but pulmonary infl ammation was less and mortality was lower. In another study, host responses to infl uenza virus infection were studied in mice defi cient in either cyclooxygenase (COX) 1 or COX2. 18 COX1-defi cient mice had lower infl ammatory cytokine levels, less pulmonary infl ammation, and higher lung viral titres, but better rates of survival than COX2-defi cient mice. 18 More recently, a study of acute infl uenza pneumonia showed that compared with normal mice, Toll-like receptor (TLR) 3 knockout mice had reduced levels of several proinfl ammatory cytokines and chemokines and high pulmonary virus titres, yet mortality was unexpectedly low. 19 An extensive review of the immunopathology of infl uenza virus infection concluded: "Infl uenza mortality is not necessarily a direct function of virus burden, highlighting the role of immune-mediated pathology in this disease". 20 Extrapolating the results of studies of individual cytokine responses in mice to human beings must be done with great caution. In patients with pneumonia, higher serum levels of several infl ammatory cytokines were generally associated with greater severity of illness, but cytokine profi les among individual patients varied and could not be used to predict outcomes. 21 Interest in agents that might control the host immune response to pandemic infl uenza virus infection was initially focused on the group of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins. 6 Laboratory and clinical studies by cardiovascular investigators have shown that statins have pronounced anti-infl ammatory and immunomodulatory (pleiotropic) eff ects. Several clinical studies have shown that statins decrease mortality in patients with bacterial sepsis. 6, 22, 23 These benefi ts are thought to be caused by a multiplicity of molecular eff ects that refl ect statin modifi cation of intracellular signalling cascades, a process that has been likened to "reducing the heat under a boiling kettle". 24 Four observational studies of statins and pneumonia have been published (table) . [25] [26] [27] [28] In a case-control study, van de Garde and colleagues 25 reported that recent prescriptions for statins were associated with a 50% reduction in pneumonia hospital admissions in diabetic patients. In another case-control study, Schlienger and co-workers 26 showed that current prescriptions for statins (within 30 days) were associated with a 53% reduction in 30-day pneumonia mortality. In a retrospective cohort study by Mortensen and colleagues, 27 current statin use was associated with a 46% reduction in 30-day pneumonia mortality. However, Majumdar and colleagues 28 reached a diff erent conclusion; their prospective cohort study failed to demonstrate a benefi cial eff ect of statins and they ascribed the apparent benefi ts of statin treatment seen in other studies to a "healthy user eff ect". Although the healthy user eff ect does exist and can be important, many "healthy users" in the study by Schlienger and colleagues 26 had been given statins in the past (more than 30 days before hospital admission) but were not taking them currently, yet only current users were protected. None of these investigations was able to show whether statins given after pneumonia hospitalisation were associated with protection, unlike an earlier report showing a remarkable reduction in bacteraemiaattributable mortality with in-hospital statin treatment. 22 An observational study of hospitalised pneumonia patients is now underway to address this important question. Recently, investigators in South Korea reported preliminary results from a randomised controlled trial of statin treatment in 67 pneumonia patients admitted to intensive care units (ICUs). 29 Treatment with atorvastatin (10 mg daily) was associated with a 45·4% reduction in ICU mortality (p=0·08) and a 51·2% reduction in hospital mortality (p=0·026). Although these studies suggest that statins are associated with reductions in mortality in patients with infections known to be associated with cytokine dysregulation, 2,3,6,22-27,29 no published reports have yet appeared that document their benefi ts in any experimental or human infl uenza virus infection. Another approach to modifying the host response to infl uenza comes from a recent experimental study. 30 Mice were infected with an infl uenza A H2N2 virus and treatment began 4 days later with gemfi brozil, a fi brate that is a peroxisome proliferator-activated receptor (PPAR) α agonist. Mortality was signifi cantly reduced in treated mice: 52% of control mice died compared with only 26% of those treated with gemfi brozil (hazard ratio 0·46, 95% CI 0·26-0·76; log rank test p=0·0026). The investigators did not study the eff ects of treatment on virus replication or dissemination. In their study, simvastatin was reported not to have been eff ective. It has been known for many years that both PPARα and PPARγ agonists have anti-infl ammatory and immunomodulatory activities, and several investigators have suggested that they might be used to treat acute lung injury. [31] [32] [33] One study showed that glitazones (PPARγ agonists) inhibit respiratory syncytial virus infection in human lung epithelial cells, probably by inhibiting viral gene expression and not earlier adhesion or fusion processes. 34 No studies have reported the direct antiviral eff ects of PPARα agonists, yet both PPARα and PPARγ agonists aff ect several intracellular signalling pathways that are crucial for infl uenza virus replication. 35, 36 Moreover, statins and fi brates act synergistically to aff ect some of these pathways, 37, 38 and many of the pleiotropic eff ects of statins are mediated by their eff ects on PPARs. 39 When statins are given in combination with PPARα or PPARγ agonists to patients with cardiovascular diseases and diabetes mellitus, their benefi cial eff ects on important biomarkers of disease are additive. 40, 41 Studies of fi ve commonly used statins and two fi brates (gemfi brozil and fenofi brate) have shown that the potential for important adverse pharmacokinetic interactions is lower for fenofi brate/statin combinations. 42 Prolonged combination therapy with fi brates in adults is safe and well tolerated, suggesting that short-term prophylaxis or acute treatment for infl uenza, if clinically eff ective, would also be acceptable. Thus far, clinical and epidemiological studies of pneumonia patients suggest only that statins might benefi t infl uenza patients. 2, 3, 6, [25] [26] [27] 29 In the study by Schlienger and colleagues, 26 fi brates taken at any time had no eff ect on pneumonia outcomes. Moreover, none of the general changes in cell signalling induced by statins and fi brates has been documented for these agents in experimental infl uenza. However, it is worth noting that the severity of experimental endotoxin-induced acute lung injury is directly proportional to the duration and intensity of nuclear factor (NF) κB activity and that downregulating NFκB even after the onset of pulmonary infl ammation is benefi cial. 43 NFκB is known to suppress the antiviral and immunomodulatory eff ects of interferon in infl uenza virus-infected cells. 44 Both statins 24 and PPAR agonists [31] [32] [33] 38 downregulate NFκB activity. Investigators have yet to show that treating experimental H5N1 or 1918 infl uenza H1N1 virus infections with an anti-infl ammatory or immunomodulatory agent is benefi cial. Nonetheless, the fi nding that gemfi brozil alone signifi cantly reduced mortality in infl uenza H2N2infected mice is of great importance. 30 This result shows that the outcome of a severe infl uenza virus infection can be improved by modifying key steps in cell signalling with an agent that has no known antiviral activity. It provides "proof of principle" that targeting the host response without attacking the virus could be benefi cial, contradicting the views of those who think it would not be useful. 8, 12 An available and aff ordable antiviral agent to complement statins and fi brates Until now, infl uenza virologists have emphasised pandemic treatment strategies that target the virus. 5 No one would seriously argue against using eff ective antiviral agents, but for the foreseeable future these agents (mainly neuraminidase inhibitors) will remain expensive and in short supply. Thus, in addition to identifying one or more eff ective anti-infl ammatory and immunomodulatory agents, identifying an eff ective, inexpensive, and universally available antiviral agent must be a high priority. Chloroquine has been suggested as one such agent. This drug has well-established anti-infl ammatory activity and is sometimes used to treat immune-mediated diseases such as rheumatoid arthritis. 45 Chloroquine's antiviral activity against infl uenza viruses was fi rst demonstrated in the early 1980s and within the past few years it has also been Personal View shown to possess in-vitro antiviral activity against other viruses, including HIV-1 and severe acute respiratory syndrome coronavirus. [45] [46] [47] [48] Chloroquine accumulates in the endosome where it interferes with acidifi cation and thereby impairs viral fusion and release into the cytosol. Diff erent infl uenza virus subtypes respond diff erently to chloroquine, with H3N2 and H1N1 viruses being more susceptible than certain H5 viruses. 48 Structural determinants on subunit 2 of the haem agglutinin molecule seem to determine the antiviral response. The in-vitro antiviral eff ects of chloroquine and the neuraminidase inhibitor oseltamivir have been shown to be additive. 48 The in-vivo effi cacy of chloroquine was recently tested in models of infl uenza A H1N1 virus infection in mice and H3N2 infection in ferrets. 49 Chloroquine treatment was not associated with clinical improvement, but virus titres in lung tissue (mice) and nasal wash specimens (ferrets) obtained later in the course of illness were reported to be lower in treated animals compared with controls. This fi nding suggests that an antiviral eff ect might have occurred but that it failed to bring about clinical improvement because cytokine dysregulation was able to proceed regardless of whether virus replication continued or was suppressed. If this is what happened, it is conceivable that limiting virus replication with chloroquine while at the same time treating the immune response with a fi brate, statin, or other promising agents might have led to clinical recovery. Support for this interpretation comes from another report on the proinfl ammatory and antiinfl ammatory responses of infl uenza virus-infected mice with secondary pneumococcal pneumonia. 50 In this model, there were no diff erences in the outcomes of mice with or without bacteraemia or with high or low levels of bacterial growth in their lungs; all mice in all groups developed rapidly fatal illness. When mice were dually infected with infl uenza virus and Streptococcus pneumoniae and then treated with either ampicillin or clindamycin, ampicillin was more eff ective in clearing pneumococci from the lung, but survival was improved with clindamycin. 51 It seems that factors determining survival involved something more than killing the infecting pneumococci. In other studies of mice infected with infl uenza viruses alone, other macrolides have been shown to inhibit nitric oxide production, increase interleukin 12 in broncho alveolar fl uid, reduce both virus replication and pulmonary infl ammation, and improve survival. 52, 53 Other inexpensive and widely distributed agents should also be considered for their potential as antivirals against infl uenza. 4 For example, resveratrol, a polyphenol with antioxidant properties that is found in red wine, has been shown to inhibit replication of infl uenza viruses in vitro and reduce mortality and virus titres in the lungs of infected mice. 54 Its antiviral activity does not depend on its antioxidant properties; instead, resveratrol blocks the translocation of viral ribonucleoprotein complexes from the nucleus to the cytoplasm during the late stage of infection, probably by interfering with the activity of several protein kinases. Resveratrol also targets TLR cell signalling pathways and interferes with the related upregulation of several proinfl ammatory cytokines and chemokines that contribute to the infl ammatory host response. 55 These important fi ndings appear to have attracted no attention from infl uenza scientists. There are many examples of virus infections in which the virus replicates to similar levels in related species, killing one but causing no disease in the other-for example, infection with simian immunodefi ciency virus is fatal to macaques, but in sooty mangabeys infection causes no disease, despite high levels of virus replication. 56 In the two species, it is the host immune response that determines outcome. 56 Moreover, infectious diseases such as tuberculosis and bacterial sepsis respond better to treatment with two or more agents than to only one, with some agents targeting the pathogen while others treat the host. Can the same approach be used for pandemic treatment and prophylaxis? Is an eff ective "bottom up" approach using one or more widely available generic agents a realistic possibility? [2] [3] 6 The global public-health importance of generic agents One of the avian infl uenza A H5N1 viruses currently causing sporadic human disease might become effi ciently transmissible between human beings and lead to a pandemic. Although the probability that this will occur is unknown, 7,13 health offi cials and infl uenza experts, whether through unwillingness or inability to "envision the worst", 2,57 have remained silent on the potential enormity of an H5N1 pandemic: it could conceivably cause the deaths of hundreds of millions of people worldwide. The theoretical possibility that this could happen was shown experimentally more than 30 years ago. 58 Thus, the implications of being able to successfully confront the next pandemic with one or more widely available generic antiviral and immunomodulatory agents are immense. A major reason for the initial interest in using statins for pandemic treatment and prophylaxis is the universal aff ordability and accessibility of one of these agents. Generic simvastatin is now produced by almost 100 companies, over half of which are located in China and India. 3 In developing countries, a 5-day course of treatment would probably cost US$0·50. Gemfi brozil and fenofi brate (a clinically more acceptable PPARα agonist) are also produced as generic agents by at least 20 companies, many of them located in developing countries. In Canada and the USA, a 5-day treatment course with a fi brate would cost less than $2·00 and in developing countries probably much less. Equally important, chloroquine and hydroxychloroquine are generically produced, very inexpensive, and could be made available worldwide. For reasons of global public health it is crucially important for investigators to undertake experimental studies to determine whether these or other generic agents (or several of them in combination) could be eff ective in treating H5N1 and other potentially pandemic infl uenza virus infections. Individual agents might act directly on the virus itself or stabilise the cardiopulmonary response of the host to infection, or both. 6 The primary goal of the research, however, should be to identify specifi c agents that can be used to manage a pandemic rather than to simply explain the molecular mechanisms by which they work. The research must include the human pharmacokinetics of each agent, potential dosing regimens for acute treatment and prophylaxis, important drug-drug interactions, and safety, especially in children and pregnant women. Any agent found to be eff ective could be stockpiled and would be available and aff ordable to people in developing countries on the fi rst pandemic day (fi gure). The same will never be said for pandemic vaccines and current antiviral agents. Moreover, no matter when the next pandemic virus emerges and no matter how severe the pandemic might be, this research will directly inform the prevention and control of seasonal infl uenza. There is no guarantee that generic agents will be useful for pandemic treatment and prophylaxis. Nonetheless, if we believe the next pandemic could be imminent, we have two alternatives: we can either do this research before the pandemic arrives and perhaps show that generic agents will not be useful or we can do it after the pandemic has passed and perhaps discover that millions of people could have been saved. We can no longer avoid this choice. More than 85% of the world's population will not have meaningful access to pandemic vaccines or antiviral agents. [1] [2] [3] Consequently, health offi cials, especially those in countries without these treatments, must consider entirely new approaches to confronting a pandemic. They must support investigators willing to study any existing agent that has promising antiviral or anti-infl ammatory and immunomodulatory activities. These agents must be identifi ed from among the large number that are already licensed, 59 produced as generics by companies in developing countries, and sold at prices that are aff ordable to people everywhere. The reports reviewed here deserve the attention of all investigators who are working on ways to confront the next pandemic. They emphasise once again that "given their low cost, safety, and worldwide availability, generic (agents) could become crucially important for confronting the next pandemic. They could greatly reduce the disparity that will otherwise separate developed and developing countries". 6 Generic agents could become the only measures to alter the course of what otherwise might become an unprecedented global health crisis. For this reason, the research agenda suggested by these reports demands the immediate attention of laboratory and clinical investigators, health offi cials, and political leaders throughout the world. We simply cannot aff ord not to undertake this work. I have received speaker's fees from Sanofi Pasteur and consultation fees from Crucell, Dynavax, Merck, and Sanofi Pasteur. Vaccine development for an imminent pandemic. 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IV. Selection and transmission of "new" infl uenza viruses in vivo New uses for old drugs I thank Peter Dunnill for his contributions to discussions that preceded the writing of this article.