abstract: The "Spanish" influenza pandemic of 1918–1919, which caused ≈50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.
author: Jeffery K. Taubenberger; David M. MorensJeffery K. Taubenberger, Department of Molecular Pathology, Armed Forces Institute of Pathology, 1413 Research Blvd, Bldg 101, Rm 1057, Rockville, MD 20850-3125, USA; fax. 301-295-9507; email: <firstname.lastname@example.com>
date: 2006-01
references:
title: 1918 Influenza: the Mother of All Pandemics

> "Curiouser and curiouser!" cried Alice
>
> Lewis Carroll, Alice's Adventures in Wonderland, 1865

An estimated one third of the world's population (or ≈500 million persons) were infected and had clinically apparent illnesses (*1**,**2*) during the 1918–1919 influenza pandemic. The disease was exceptionally severe. Case-fatality rates were \>2.5%, compared to \<0.1% in other influenza pandemics (*3**,**4*). Total deaths were estimated at ≈50 million (*5**–**7*) and were arguably as high as 100 million (*7*).

The impact of this pandemic was not limited to 1918–1919. All influenza A pandemics since that time, and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including "drifted" H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the "mother" of all pandemics.

In 1918, the cause of human influenza and its links to avian and swine influenza were unknown. Despite clinical and epidemiologic similarities to influenza pandemics of 1889, 1847, and even earlier, many questioned whether such an explosively fatal disease could be influenza at all. That question did not begin to be resolved until the 1930s, when closely related influenza viruses (now known to be H1N1 viruses) were isolated, first from pigs and shortly thereafter from humans. Seroepidemiologic studies soon linked both of these viruses to the 1918 pandemic (*8*). Subsequent research indicates that descendants of the 1918 virus still persists enzootically in pigs. They probably also circulated continuously in humans, undergoing gradual antigenic drift and causing annual epidemics, until the 1950s. With the appearance of a new H2N2 pandemic strain in 1957 ("Asian flu"), the direct H1N1 viral descendants of the 1918 pandemic strain disappeared from human circulation entirely, although the related lineage persisted enzootically in pigs. But in 1977, human H1N1 viruses suddenly "reemerged" from a laboratory freezer (*9*). They continue to circulate endemically and epidemically.

Thus in 2006, 2 major descendant lineages of the 1918 H1N1 virus, as well as 2 additional reassortant lineages, persist naturally: a human epidemic/endemic H1N1 lineage, a porcine enzootic H1N1 lineage (so-called classic swine flu), and the reassorted human H3N2 virus lineage, which like the human H1N1 virus, has led to a porcine H3N2 lineage. None of these viral descendants, however, approaches the pathogenicity of the 1918 parent virus. Apparently, the porcine H1N1 and H3N2 lineages uncommonly infect humans, and the human H1N1 and H3N2 lineages have both been associated with substantially lower rates of illness and death than the virus of 1918. In fact, current H1N1 death rates are even lower than those for H3N2 lineage strains (prevalent from 1968 until the present). H1N1 viruses descended from the 1918 strain, as well as H3N2 viruses, have now been cocirculating worldwide for 29 years and show little evidence of imminent extinction.

# Trying To Understand What Happened

By the early 1990s, 75 years of research had failed to answer a most basic question about the 1918 pandemic: why was it so fatal? No virus from 1918 had been isolated, but all of its apparent descendants caused substantially milder human disease. Moreover, examination of mortality data from the 1920s suggests that within a few years after 1918, influenza epidemics had settled into a pattern of annual epidemicity associated with strain drifting and substantially lowered death rates. Did some critical viral genetic event produce a 1918 virus of remarkable pathogenicity and then other critical genetic event occur soon after the 1918 pandemic to produce an attenuated H1N1 virus?

In 1995, a scientific team identified archival influenza autopsy materials collected in the autumn of 1918 and began the slow process of sequencing small viral RNA fragments to determine the genomic structure of the causative influenza virus (*10*). These efforts have now determined the complete genomic sequence of 1 virus and partial sequences from 4 others. The primary data from the above studies (*11**–**17*) and a number of reviews covering different aspects of the 1918 pandemic have recently been published (*18**–**20*) and confirm that the 1918 virus is the likely ancestor of all 4 of the human and swine H1N1 and H3N2 lineages, as well as the "extinct" H2N2 lineage. No known mutations correlated with high pathogenicity in other human or animal influenza viruses have been found in the 1918 genome, but ongoing studies to map virulence factors are yielding interesting results. The 1918 sequence data, however, leave unanswered questions about the origin of the virus (*19*) and about the epidemiology of the pandemic.

# When and Where Did the 1918 Influenza Pandemic Arise?

Before and after 1918, most influenza pandemics developed in Asia and spread from there to the rest of the world. Confounding definite assignment of a geographic point of origin, the 1918 pandemic spread more or less simultaneously in 3 distinct waves during an ≈12-month period in 1918–1919, in Europe, Asia, and North America (the first wave was best described in the United States in March 1918). Historical and epidemiologic data are inadequate to identify the geographic origin of the virus (*21*), and recent phylogenetic analysis of the 1918 viral genome does not place the virus in any geographic context (*19*).

Although in 1918 influenza was not a nationally reportable disease and diagnostic criteria for influenza and pneumonia were vague, death rates from influenza and pneumonia in the United States had risen sharply in 1915 and 1916 because of a major respiratory disease epidemic beginning in December 1915 (*22*). Death rates then dipped slightly in 1917. The first pandemic influenza wave appeared in the spring of 1918, followed in rapid succession by much more fatal second and third waves in the fall and winter of 1918–1919, respectively (Figure 1). Is it possible that a poorly-adapted H1N1 virus was already beginning to spread in 1915, causing some serious illnesses but not yet sufficiently fit to initiate a pandemic? Data consistent with this possibility were reported at the time from European military camps (*23*), but a counter argument is that if a strain with a new hemagglutinin (HA) was causing enough illness to affect the US national death rates from pneumonia and influenza, it should have caused a pandemic sooner, and when it eventually did, in 1918, many people should have been immune or at least partially immunoprotected. "Herald" events in 1915, 1916, and possibly even in early 1918, if they occurred, would be difficult to identify.

The 1918 influenza pandemic had another unique feature, the simultaneous (or nearly simultaneous) infection of humans and swine. The virus of the 1918 pandemic likely expressed an antigenically novel subtype to which most humans and swine were immunologically naive in 1918 (*12**,**20*). Recently published sequence and phylogenetic analyses suggest that the genes encoding the HA and neuraminidase (NA) surface proteins of the 1918 virus were derived from an avianlike influenza virus shortly before the start of the pandemic and that the precursor virus had not circulated widely in humans or swine in the few decades before (*12**,**15**,**24*). More recent analyses of the other gene segments of the virus also support this conclusion. Regression analyses of human and swine influenza sequences obtained from 1930 to the present place the initial circulation of the 1918 precursor virus in humans at approximately 1915–1918 (*20*). Thus, the precursor was probably not circulating widely in humans until shortly before 1918, nor did it appear to have jumped directly from any species of bird studied to date (*19*). In summary, its origin remains puzzling.

# Were the 3 Waves in 1918–1919 Caused by the Same Virus? If So, How and Why?

Historical records since the 16th century suggest that new influenza pandemics may appear at any time of year, not necessarily in the familiar annual winter patterns of interpandemic years, presumably because newly shifted influenza viruses behave differently when they find a universal or highly susceptible human population. Thereafter, confronted by the selection pressures of population immunity, these pandemic viruses begin to drift genetically and eventually settle into a pattern of annual epidemic recurrences caused by the drifted virus variants.

In the 1918–1919 pandemic, a first or spring wave began in March 1918 and spread unevenly through the United States, Europe, and possibly Asia over the next 6 months (Figure 1). Illness rates were high, but death rates in most locales were not appreciably above normal. A second or fall wave spread globally from September to November 1918 and was highly fatal. In many nations, a third wave occurred in early 1919 (*21*). Clinical similarities led contemporary observers to conclude initially that they were observing the same disease in the successive waves. The milder forms of illness in all 3 waves were identical and typical of influenza seen in the 1889 pandemic and in prior interpandemic years. In retrospect, even the rapid progressions from uncomplicated influenza infections to fatal pneumonia, a hallmark of the 1918–1919 fall and winter waves, had been noted in the relatively few severe spring wave cases. The differences between the waves thus seemed to be primarily in the much higher frequency of complicated, severe, and fatal cases in the last 2 waves.

But 3 extensive pandemic waves of influenza within 1 year, occurring in rapid succession, with only the briefest of quiescent intervals between them, was unprecedented. The occurrence, and to some extent the severity, of recurrent annual outbreaks, are driven by viral antigenic drift, with an antigenic variant virus emerging to become dominant approximately every 2 to 3 years. Without such drift, circulating human influenza viruses would presumably disappear once herd immunity had reached a critical threshold at which further virus spread was sufficiently limited. The timing and spacing of influenza epidemics in interpandemic years have been subjects of speculation for decades. Factors believed to be responsible include partial herd immunity limiting virus spread in all but the most favorable circumstances, which include lower environmental temperatures and human nasal temperatures (beneficial to thermolabile viruses such as influenza), optimal humidity, increased crowding indoors, and imperfect ventilation due to closed windows and suboptimal airflow.

However, such factors cannot explain the 3 pandemic waves of 1918–1919, which occurred in the spring-summer, summer-fall, and winter (of the Northern Hemisphere), respectively. The first 2 waves occurred at a time of year normally unfavorable to influenza virus spread. The second wave caused simultaneous outbreaks in the Northern and Southern Hemispheres from September to November. Furthermore, the interwave periods were so brief as to be almost undetectable in some locales. Reconciling epidemiologically the steep drop in cases in the first and second waves with the sharp rises in cases of the second and third waves is difficult. Assuming even transient postinfection immunity, how could susceptible persons be too few to sustain transmission at 1 point and yet enough to start a new explosive pandemic wave a few weeks later? Could the virus have mutated profoundly and almost simultaneously around the world, in the short periods between the successive waves? Acquiring viral drift sufficient to produce new influenza strains capable of escaping population immunity is believed to take years of global circulation, not weeks of local circulation. And having occurred, such mutated viruses normally take months to spread around the world.

At the beginning of other "off season" influenza pandemics, successive distinct waves within a year have not been reported. The 1889 pandemic, for example, began in the late spring of 1889 and took several months to spread throughout the world, peaking in northern Europe and the United States late in 1889 or early in 1890. The second recurrence peaked in late spring 1891 (more than a year after the first pandemic appearance) and the third in early 1892 (*21*). As was true for the 1918 pandemic, the second 1891 recurrence produced of the most deaths. The 3 recurrences in 1889–1892, however, were spread over \>3 years, in contrast to 1918–1919, when the sequential waves seen in individual countries were typically compressed into ≈8–9 months.

What gave the 1918 virus the unprecedented ability to generate rapidly successive pandemic waves is unclear. Because the only 1918 pandemic virus samples we have yet identified are from second-wave patients (*16*), nothing can yet be said about whether the first (spring) wave, or for that matter, the third wave, represented circulation of the same virus or variants of it. Data from 1918 suggest that persons infected in the second wave may have been protected from influenza in the third wave. But the few data bearing on protection during the second and third waves after infection in the first wave are inconclusive and do little to resolve the question of whether the first wave was caused by the same virus or whether major genetic evolutionary events were occurring even as the pandemic exploded and progressed. Only influenza RNA–positive human samples from before 1918, and from all 3 waves, can answer this question.

# What Was the Animal Host Origin of the Pandemic Virus?

Viral sequence data now suggest that the entire 1918 virus was novel to humans in, or shortly before, 1918, and that it thus was not a reassortant virus produced from old existing strains that acquired 1 or more new genes, such as those causing the 1957 and 1968 pandemics. On the contrary, the 1918 virus appears to be an avianlike influenza virus derived in toto from an unknown source (*17**,**19*), as its 8 genome segments are substantially different from contemporary avian influenza genes. Influenza virus gene sequences from a number of fixed specimens of wild birds collected circa 1918 show little difference from avian viruses isolated today, indicating that avian viruses likely undergo little antigenic change in their natural hosts even over long periods (*24**,**25*).

For example, the 1918 nucleoprotein (NP) gene sequence is similar to that of viruses found in wild birds at the amino acid level but very divergent at the nucleotide level, which suggests considerable evolutionary distance between the sources of the 1918 NP and of currently sequenced NP genes in wild bird strains (*13**,**19*). One way of looking at the evolutionary distance of genes is to compare ratios of synonymous to nonsynonymous nucleotide substitutions. A synonymous substitution represents a silent change, a nucleotide change in a codon that does not result in an amino acid replacement. A nonsynonymous substitution is a nucleotide change in a codon that results in an amino acid replacement. Generally, a viral gene subjected to immunologic drift pressure or adapting to a new host exhibits a greater percentage of nonsynonymous mutations, while a virus under little selective pressure accumulates mainly synonymous changes. Since little or no selection pressure is exerted on synonymous changes, they are thought to reflect evolutionary distance.

Because the 1918 gene segments have more synonymous changes from known sequences of wild bird strains than expected, they are unlikely to have emerged directly from an avian influenza virus similar to those that have been sequenced so far. This is especially apparent when one examines the differences at 4-fold degenerate codons, the subset of synonymous changes in which, at the third codon position, any of the 4 possible nucleotides can be substituted without changing the resulting amino acid. At the same time, the 1918 sequences have too few amino acid differences from those of wild-bird strains to have spent many years adapting only in a human or swine intermediate host. One possible explanation is that these unusual gene segments were acquired from a reservoir of influenza virus that has not yet been identified or sampled. All of these findings beg the question: where did the 1918 virus come from?

In contrast to the genetic makeup of the 1918 pandemic virus, the novel gene segments of the reassorted 1957 and 1968 pandemic viruses all originated in Eurasian avian viruses (*26*); both human viruses arose by the same mechanism—reassortment of a Eurasian wild waterfowl strain with the previously circulating human H1N1 strain. Proving the hypothesis that the virus responsible for the 1918 pandemic had a markedly different origin requires samples of human influenza strains circulating before 1918 and samples of influenza strains in the wild that more closely resemble the 1918 sequences.

# What Was the Biological Basis for 1918 Pandemic Virus Pathogenicity?

Sequence analysis alone does not offer clues to the pathogenicity of the 1918 virus. A series of experiments are under way to model virulence in vitro and in animal models by using viral constructs containing 1918 genes produced by reverse genetics.

Influenza virus infection requires binding of the HA protein to sialic acid receptors on host cell surface. The HA receptor-binding site configuration is different for those influenza viruses adapted to infect birds and those adapted to infect humans. Influenza virus strains adapted to birds preferentially bind sialic acid receptors with α (2–3) linked sugars (*27**–**29*). Human-adapted influenza viruses are thought to preferentially bind receptors with α (2–6) linkages. The switch from this avian receptor configuration requires of the virus only 1 amino acid change (*30*), and the HAs of all 5 sequenced 1918 viruses have this change, which suggests that it could be a critical step in human host adaptation. A second change that greatly augments virus binding to the human receptor may also occur, but only 3 of 5 1918 HA sequences have it (*16*).

This means that at least 2 H1N1 receptor-binding variants cocirculated in 1918: 1 with high-affinity binding to the human receptor and 1 with mixed-affinity binding to both avian and human receptors. No geographic or chronologic indication exists to suggest that one of these variants was the precursor of the other, nor are there consistent differences between the case histories or histopathologic features of the 5 patients infected with them. Whether the viruses were equally transmissible in 1918, whether they had identical patterns of replication in the respiratory tree, and whether one or both also circulated in the first and third pandemic waves, are unknown.

In a series of in vivo experiments, recombinant influenza viruses containing between 1 and 5 gene segments of the 1918 virus have been produced. Those constructs bearing the 1918 HA and NA are all highly pathogenic in mice (*31*). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (*32*). These findings are unexpected because the viruses with the 1918 genes had not been adapted to mice; control experiments in which mice were infected with modern human viruses showed little disease and limited viral replication. The lungs of animals infected with the 1918 HA/NA construct showed bronchial and alveolar epithelial necrosis and a marked inflammatory infiltrate, which suggests that the 1918 HA (and possibly the NA) contain virulence factors for mice. The viral genotypic basis of this pathogenicity is not yet mapped. Whether pathogenicity in mice effectively models pathogenicity in humans is unclear. The potential role of the other 1918 proteins, singularly and in combination, is also unknown. Experiments to map further the genetic basis of virulence of the 1918 virus in various animal models are planned. These experiments may help define the viral component to the unusual pathogenicity of the 1918 virus but cannot address whether specific host factors in 1918 accounted for unique influenza mortality patterns.

# Why Did the 1918 Virus Kill So Many Healthy Young Adults?

The curve of influenza deaths by age at death has historically, for at least 150 years, been U-shaped (Figure 2), exhibiting mortality peaks in the very young and the very old, with a comparatively low frequency of deaths at all ages in between. In contrast, age-specific death rates in the 1918 pandemic exhibited a distinct pattern that has not been documented before or since: a "W-shaped" curve, similar to the familiar U-shaped curve but with the addition of a third (middle) distinct peak of deaths in young adults ≈20–40 years of age. Influenza and pneumonia death rates for those 15–34 years of age in 1918–1919, for example, were \>20 times higher than in previous years (*35*). Overall, nearly half of the influenza-related deaths in the 1918 pandemic were in young adults 20–40 years of age, a phenomenon unique to that pandemic year. The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza death was higher in those \<65 years of age than in those \>65; persons \<65 years of age accounted for \>99% of all excess influenza-related deaths in 1918–1919. In comparison, the \<65-year age group accounted for 36% of all excess influenza-related deaths in the 1957 H2N2 pandemic and 48% in the 1968 H3N2 pandemic (*33*).

A sharper perspective emerges when 1918 age-specific influenza morbidity rates (*21*) are used to adjust the W-shaped mortality curve (Figure 3, panels, A, B, and C \[35,37\]). Persons \<35 years of age in 1918 had a disproportionately high influenza incidence (Figure 3, panel A). But even after adjusting age-specific deaths by age-specific clinical attack rates (Figure 3, panel B), a W-shaped curve with a case-fatality peak in young adults remains and is significantly different from U-shaped age-specific case-fatality curves typically seen in other influenza years, e.g., 1928–1929 (Figure 3, panel C). Also, in 1918 those 5 to 14 years of age accounted for a disproportionate number of influenza cases, but had a much lower death rate from influenza and pneumonia than other age groups. To explain this pattern, we must look beyond properties of the virus to host and environmental factors, possibly including immunopathology (e.g., antibody-dependent infection enhancement associated with prior virus exposures \[38\]) and exposure to risk cofactors such as coinfecting agents, medications, and environmental agents.

One theory that may partially explain these findings is that the 1918 virus had an intrinsically high virulence, tempered only in those patients who had been born before 1889, e.g., because of exposure to a then-circulating virus capable of providing partial immunoprotection against the 1918 virus strain only in persons old enough (\>35 years) to have been infected during that prior era (*35*). But this theory would present an additional paradox: an obscure precursor virus that left no detectable trace today would have had to have appeared and disappeared before 1889 and then reappeared more than 3 decades later.

Epidemiologic data on rates of clinical influenza by age, collected between 1900 and 1918, provide good evidence for the emergence of an antigenically novel influenza virus in 1918 (*21*). Jordan showed that from 1900 to 1917, the 5- to 15-year age group accounted for 11% of total influenza cases, while the \>65-year age group accounted for 6% of influenza cases. But in 1918, cases in the 5- to 15-year-old group jumped to 25% of influenza cases (compatible with exposure to an antigenically novel virus strain), while the \>65 age group only accounted for 0.6% of the influenza cases, findings consistent with previously acquired protective immunity caused by an identical or closely related viral protein to which older persons had once been exposed. Mortality data are in accord. In 1918, persons \>75 years had lower influenza and pneumonia case-fatality rates than they had during the prepandemic period of 1911–1917. At the other end of the age spectrum (Figure 2), a high proportion of deaths in infancy and early childhood in 1918 mimics the age pattern, if not the mortality rate, of other influenza pandemics.

# Could a 1918-like Pandemic Appear Again? If So, What Could We Do About It?

In its disease course and pathologic features, the 1918 pandemic was different in degree, but not in kind, from previous and subsequent pandemics. Despite the extraordinary number of global deaths, most influenza cases in 1918 (\>95% in most locales in industrialized nations) were mild and essentially indistinguishable from influenza cases today. Furthermore, laboratory experiments with recombinant influenza viruses containing genes from the 1918 virus suggest that the 1918 and 1918-like viruses would be as sensitive as other typical virus strains to the Food and Drug Administration–approved antiinfluenza drugs rimantadine and oseltamivir.

However, some characteristics of the 1918 pandemic appear unique: most notably, death rates were 5–20 times higher than expected. Clinically and pathologically, these high death rates appear to be the result of several factors, including a higher proportion of severe and complicated infections of the respiratory tract, rather than involvement of organ systems outside the normal range of the influenza virus. Also, the deaths were concentrated in an unusually young age group. Finally, in 1918, 3 separate recurrences of influenza followed each other with unusual rapidity, resulting in 3 explosive pandemic waves within a year's time (Figure 1). Each of these unique characteristics may reflect genetic features of the 1918 virus, but understanding them will also require examination of host and environmental factors.

Until we can ascertain which of these factors gave rise to the mortality patterns observed and learn more about the formation of the pandemic, predictions are only educated guesses. We can only conclude that since it happened once, analogous conditions could lead to an equally devastating pandemic.

Like the 1918 virus, H5N1 is an avian virus (*39*), though a distantly related one. The evolutionary path that led to pandemic emergence in 1918 is entirely unknown, but it appears to be different in many respects from the current situation with H5N1. There are no historical data, either in 1918 or in any other pandemic, for establishing that a pandemic "precursor" virus caused a highly pathogenic outbreak in domestic poultry, and no highly pathogenic avian influenza (HPAI) virus, including H5N1 and a number of others, has ever been known to cause a major human epidemic, let alone a pandemic. While data bearing on influenza virus human cell adaptation (e.g., receptor binding) are beginning to be understood at the molecular level, the basis for viral adaptation to efficient human-to-human spread, the chief prerequisite for pandemic emergence, is unknown for any influenza virus. The 1918 virus acquired this trait, but we do not know how, and we currently have no way of knowing whether H5N1 viruses are now in a parallel process of acquiring human-to-human transmissibility. Despite an explosion of data on the 1918 virus during the past decade, we are not much closer to understanding pandemic emergence in 2006 than we were in understanding the risk of H1N1 "swine flu" emergence in 1976.

Even with modern antiviral and antibacterial drugs, vaccines, and prevention knowledge, the return of a pandemic virus equivalent in pathogenicity to the virus of 1918 would likely kill \>100 million people worldwide. A pandemic virus with the (alleged) pathogenic potential of some recent H5N1 outbreaks could cause substantially more deaths.

Whether because of viral, host or environmental factors, the 1918 virus causing the first or 'spring' wave was not associated with the exceptional pathogenicity of the second (fall) and third (winter) waves. Identification of an influenza RNA-positive case from the first wave could point to a genetic basis for virulence by allowing differences in viral sequences to be highlighted. Identification of pre-1918 human influenza RNA samples would help us understand the timing of emergence of the 1918 virus. Surveillance and genomic sequencing of large numbers of animal influenza viruses will help us understand the genetic basis of host adaptation and the extent of the natural reservoir of influenza viruses. Understanding influenza pandemics in general requires understanding the 1918 pandemic in all its historical, epidemiologic, and biologic aspects.

Dr Taubenberger is chair of the Department of Molecular Pathology at the Armed Forces Institute of Pathology, Rockville, Maryland. His research interests include the molecular pathophysiology and evolution of influenza viruses.

Dr Morens is an epidemiologist with a long-standing interest in emerging infectious diseases, virology, tropical medicine, and medical history. Since 1999, he has worked at the National Institute of Allergy and Infectious Diseases.

# References


abstract: # Objective
  .
  To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout.
  .
  # Methods
  .
  This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy.
  .
  # Results
  .
  Patients (n=149) received a mean±SD of 28±18 pegloticase infusions and were followed for a mean of 25±11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained \<6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence.
  .
  # Conclusions
  .
  The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.
author: Michael A Becker; Herbert S B Baraf; Robert A Yood; Aileen Dillon; Janitzia Vázquez-Mellado; Faith D Ottery; Dinesh Khanna; John S Sundy[^1]Correspondence to Dr Michael A Becker, 237 East Delaware Pl, Chicago, IL 60611-1713, USA; <email@example.com>
date: 2013-09
institute: 1Rheumatology Section, The University of Chicago, Chicago, Illinois, USA; 2Center for Rheumatology and Bone Research, Wheaton, Maryland, USA; 3Reliant Medical Group, Worcester, Massachusetts, USA; 4Rheumatology Section, Kaiser Permanente Medical Center, San Francisco, California, USA; 5Department of Rheumatology, Hospital General de Mexico, Mexico City, Mexico; 6Savient Pharmaceuticals, Inc., East Brunswick, New Jersey, USA; 7Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA; 8Duke Clinical Research Unit, Duke University Medical Center, Durham, North Carolina, USA
references:
title: Long-term safety of pegloticase in chronic gout refractory to conventional treatment

# Introduction

Urate-lowering therapy is the mainstay of chronic gout management and aims at achieving and maintaining sub-saturating serum uric acid (SUA) concentrations, most often recommended as ≤0.36 mmol/l (≤6 mg/dl).1 2 Long-term maintenance of goal range SUA is associated with depletion of urate crystals in synovial fluid3 4 and reductions in tophus size and flare frequency.5–7 Because the rates of achieving these improvements are related to the degree of urate-lowering,4 6 8 the optimal therapeutic target may be substantially lower than 6 mg/dl in patients with severe manifestations of chronic gout,5 prompting one recommendation for a target SUA of \<5 mg/dl.9

Up to 3% of the estimated eight million patients with gout in the USA10 fail urate-lowering management with standard-of-care therapies (oral xanthine oxidase inhibitors) because of drug intolerance/contraindication or treatment refractoriness.11–13 Such patients are at risk of progression to increasing flare recurrences, gouty arthropathy, destructive and deforming tophi and chronic pain, frequently accompanied by impaired physical function and poor health-related quality of life. Until recently these patients had few or no effective urate-lowering options to prevent or reverse gout progression. Pegloticase, a mammalian recombinant uricase conjugated to monomethoxypoly(ethylene glycol) (mPEG), was developed as an enzymatic alternative for the treatment of patients with gout refractory to conventional oral therapies and was approved in the USA in 2010.14–16 When administered intravenously, pegloticase reduces the urate concentration in the intravascular space to below the limit of solubility (6.8 mg/dl). The resulting reduction in extracellular soluble urate concentration is hypothesised to favour dissolution of deposited urate crystals, resulting in progressive normalisation of body urate pools and improvements in clinical signs and symptoms of gout.17 18

The tolerability and efficacy of pegloticase treatment in patients with refractory chronic gout were demonstrated in replicate 6-month randomised double-blind placebo-controlled trials (RCTs).17 Pegloticase administered every 2 weeks (biweekly) or every 4 weeks (monthly) produced treatment responses (plasma uric acid (PUA)\<6 mg/dl for ≥80% of the time during months 3 and 6) in 42% and 35% of patients, respectively, compared with 0% for patients receiving placebo. PUA normalised within 24 h of the first pegloticase infusion in all patients, but in non-responders the urate-lowering response was lost over time. Infusion-related reactions (IRs) were the most common reason for discontinuations in the RCTs (10% of biweekly treated patients and 13% of monthly treated patients).17 This report focuses on the long-term open-label extension (OLE) of the RCTs which provided an additional 2.5 years of safety data.

# Methods

## Study design and patients

The OLE (NCT01356498) enrolled patients at 46 centres in the USA, Canada and Mexico who had completed either of the two RCTs (NCT01356498, NCT00325195).17 The OLE was conducted from December 2006 to July 2009; compliance and permission information is provided in the online supplementary material. Protocol amendments extended the OLE from 12 months to a maximum of 30 months. Figure 1 summarises the OLE study design, inclusion criteria (exclusion criteria are presented in the online supplementary material), end points and evaluations. Delays in treatment between the randomised trials and the OLE resulted from administrative requirements, such as time for Institutional Review Board approvals and site implementation. Except where specifically indicated, patients were categorised for analysis purposes according to the first dosing regimen administered during the OLE study.

Details of safety evaluations and prophylaxis regimens for IRs and flares are provided in the online supplementary material. As IRs were one of the events of interest, physical examinations and monitoring of vital signs were performed at the time of all IRs and medical intervention was provided as appropriate. For IRs occurring during infusions, the infusion could be discontinued, slowed by half, or interrupted and later restarted at a slower rate.

Immunogenicity was assessed from serum collected every 12 weeks using a validated ELISA to detect IgG and IgM pegloticase antibody. Antibody titres were categorised as low (≤1 : 2430) or high (\>1 : 2430), consistent with the RCTs.17 Tophus complete response was defined as 100% reduction in the measured area of at least one tophus of baseline diameter ≥5 mm without growth of any other baseline tophus or appearance of any new tophus.

## Statistical analysis

Safety and efficacy end points were evaluated using descriptive statistics in the intent-to-treat population, which included all patients who received at least one dose of pegloticase during the OLE study and had follow-up data. Demographic and baseline clinical values are described in the online supplementary material.

# Results

## Patient disposition

A total of 225 patients were enrolled in the two RCTs and 212 patients were included in the primary efficacy analysis. Of these, 157 patients (74%) completed the RCTs and 151 (96% of completers) entered the OLE study, including 57 (97%) patients from the biweekly pegloticase group, 55 (93%) from the monthly pegloticase group and all 39 patients from the placebo group (figure 2). All patients received pegloticase in the OLE study, except for two patients who chose observation only after receiving monthly pegloticase in the RCTs. For patients treated with pegloticase in the RCTs, a higher proportion of those defined as responders than those defined as non-responders completed the OLE study, as did a higher proportion of patients allocated to placebo in the RCTs who then received biweekly pegloticase compared with those who received monthly pegloticase (figure 2). The most common reasons for discontinuing treatment during the OLE study were adverse events (AEs) in 18% (27/149) of patients and loss of urate-lowering response in 9% (13/149).

## Patients

The OLE study population had a mean age of 56.8 years (range 30–89) and 79% were men. Most patients were white (69%), African-American (13%) or Hispanic/Latino (11%). Risk factors were common; the most common were cardiovascular (94% of patients had at least one cardiovascular risk factor, most commonly hypertension, 72%), obesity (body mass index (BMI) ≥30 kg/m^2^, 65%) and dyslipidaemia (52%). Chronic kidney disease (creatinine clearance \<1.0 ml/s) was present in 26% of patients. Less commonly occurring risk factors and concomitant medications are described in the online supplementary material.

## Exposure to pegloticase

Patients received a mean of 28 pegloticase infusions (median 26; range 1–59) during the OLE study, with RCT responders receiving more infusions than non-responders (mean 35 vs 26). When exposure to pegloticase was pooled from the RCT and OLE studies, patients received a mean of 35 infusions (range 1–70). Thirty of 67 patients (45%) who started on monthly pegloticase switched to biweekly treatment at some point during the OLE study; only 12% (10/82) switched from biweekly to monthly treatment. Overall, patients remained in the OLE study for a mean of 25 months (median 29 months; range 0−37 months, including a mandated end-of-study observation period (no treatment) for a maximum of 6 months).

## Safety

### Adverse events (AEs)

Nearly all patients (98%) had at least one AE during the OLE study (table 1). The overall incidence of AEs did not differ between responders and non-responders from the RCTs or for patients initially on placebo who started pegloticase biweekly versus monthly. Both gout flares and IRs occurred at a lower rate with the biweekly regimen during the OLE study (2.7 per patient per year vs 4.7 with the monthly regimen and 1.3 per patient per year vs 2.1, respectively).

Summary of AEs during the OLE study

|  | All treated patients (N=149) |
|:---|----|
| AEs in the OLE study | N (%) |
| Subjects with any AE | 146 (98) |
| Subjects with any serious AE | 51 (34) |
| Subjects with serious AEs considered related to pegloticase | 13 (9) |
| Discontinuations due to AE | 11 (7) |
| Most common AEs (incidence \>10%) |  |
|  Gout flare | 106 (71) |
|  Infusion-related reaction | 65 (44) |
|  Arthralgia | 29 (20) |
|  Upper respiratory tract infection | 27 (18) |
|  Pain in extremity | 26 (17) |
|  Back pain | 25 (17) |
|  Diarrhoea | 22 (15) |
|  Peripheral oedema | 21 (14) |
|  Urinary tract infection | 20 (13) |
|  Nausea | 17 (11) |
|  Headache | 16 (11) |
|  Fatigue | 15 (10) |
|  Sinusitis | 15 (10) |
|  Nasopharyngitis | 15 (10) |

AE, adverse event; OLE, open-label extension.

The incidence of gout flares during the OLE study was lowest for responders who had received biweekly pegloticase in the RCTs and highest for RCT non-responders to monthly pegloticase and patients treated with placebo in the RCTs. The incidence of IRs in the OLE study was lowest for RCT responders regardless of pegloticase schedule and highest for RCT non-responders to monthly pegloticase and RCT placebo patients starting monthly pegloticase. Eleven patients (7%) discontinued pegloticase due to AEs, including seven patients with IRs; six of these seven patients were RCT pegloticase non-responders or RCT placebo-treated patients. Among all patients with AEs judged as treatment-related by the investigators (66%, 99/149), only gout flares and IRs were reported in \>5% of patients.

Most AEs (53% of patients) were investigator-rated as moderate in intensity. Overall, 36% (54/149) of patients had severe AEs, of which 17% were treatment-related, most commonly IRs (7%) or gout flares (7%). Of note, no RCT pegloticase responder had a severe treatment-related IR or a severe gout flare. The highest rates of severe IRs and flares (26% for both; 6/23) were reported in patients treated with biweekly pegloticase during the OLE study who had received placebo in the RCTs. Assessments of haematology, clinical chemistry and urinalysis identified no significant change from baseline (except for UA) in any of the subgroups defined by response to pegloticase or pegloticase administration schedule.

Twenty-four adjudicated cardiovascular events in 21 patients were identified in the OLE study by the independent expert committee. These events occurred in responders and non-responders with no apparent relationship to the duration of treatment or time since the last pegloticase infusion. Eight of these events occurred in patients who were being observed and had not received pegloticase for \>30 days.

### Serious AEs and deaths

Approximately one-third of patients (34%, 51/149) experienced a total of 106 serious AEs during the OLE study. Thirteen patients who reported serious AEs discontinued treatment. Among the 13 serious AEs considered possibly related to study drug, there were 11 IRs (one serious AE of IR was judged unlikely to be related to the study drug), one skin necrosis (severe) and one nephrolithiasis (moderate). Among the 11 serious AEs of IR, all but one occurred when the UA values exceeded 6 mg/dl. Four deaths occurred during the OLE study, all of which were judged as unlikely to be related to the study drug by the investigator (see online supplementary material).

### IRs

During the RCTs, IRs were the second most common AE and were reported in 26% of patients receiving biweekly pegloticase and 42% of patients receiving monthly pegloticase. In the OLE, IRs were reported in 44% (60/149) of patients. The rate of IRs was lower in RCT responders (17%, 10/60) than in non-responders (52%, 26/50) and highest among patients who received placebo in the RCT (62%, 24/39). IRs were rated mild in 27% (16/60) of patients, moderate in 55% (33/60) and severe in 18% (11/60). IRs rated as severe in the OLE occurred in four patients, none of whom sustained goal range urate lowering, and in seven patients who received placebo in the RCT. IRs were the reason cited for withdrawal from the study for 6% (9/149) of patients.

Except for three patients with IRs manifesting in the 2 h period after infusion, all IRs occurred during infusion. The most common signs and symptoms associated with IRs were musculoskeletal pain/discomfort, flushing, erythema, nausea/vomiting, dyspnoea, sweating, headache, blood pressure changes, urticaria and pruritus. All IRs resolved with supportive measures and no patient required intubation, mechanical ventilatory support, pressors or hospitalisation. Three patients were found to have anaphylaxis based on a retrospective analysis. Symptoms included red, itching or swollen eyes, throat irritation, musculoskeletal symptoms, skin flushing, hypotension, dizziness and vomiting.

### Immunogenicity

A total of 31% (52/169) of patients treated with pegloticase had high pegloticase antibody titres (\>1 : 2430) during the RCTs. High-titre antibodies were identified in 53% (67/127) of patients at the week 13 assessment of the OLE; this number increased by the end of the study (antibody titres \>1 : 2430 in 60%; 90/149). Only one patient had evidence of in vitro neutralising antibodies against uricase activity; this was measurable at only one time point. Consistent with findings from the RCTs,17 low titres (≤1 : 2430) of anti-pegloticase antibodies were less likely to be associated with loss of SUA response (see online supplementary material for supporting data).

## Efficacy

### Serum uric acid response

The concordance of PUA and SUA (collected for all patients at the same time points) for values above and below the target of 6 mg/dl was 95% in samples collected during the OLE study. The efficacy data reported here focus on SUA because of its ready accessibility in clinical settings. The overall mean±SD SUA at baseline was 10.1±1.4 mg/dl. Most responders to biweekly and monthly pegloticase in the RCTs maintained SUA\<6 mg/dl throughout the OLE study (figure 3A). Among patients randomised to placebo in the RCTs, biweekly pegloticase administration in the OLE study produced greater reductions in mean SUA and a greater proportion of patients maintaining SUA\<6 mg/dl than monthly pegloticase (figure 3B).

### Tophus response

Tophus burden continued to decrease during ongoing pegloticase therapy. At the end of the RCTs, a complete response in at least one tophus was reported for 40% (21/52) of patients with tophi treated with biweekly pegloticase, 21% (11/52) of those treated with monthly pegloticase and 7% (2/27) of those treated with placebo. By OLE week 13 a complete response in at least one tophus was reported for 45% (36/80) of patients with tophi at RCT inception. At the final OLE visit (week 125), 60% (56/94) of patients with evaluable tophi had a complete response. Patients with a sustained urate-lowering response to treatment were more likely to experience complete tophus resolution. A complete response was seen in 87% (32/37) of patients in the responder group and in 31% (11/36) designated non-responders on the basis of SUA measurements in the RCTs.

As prespecified in the protocol, each patient could have up to five measurable (and two additional) target or index tophi. Responses based on the total number of tophi were assessed to complement information on the proportion of patients with tophus complete response. After 1 year of pegloticase treatment in the OLE study, 61% (185/302) of all target tophi had completely resolved. Among patients who qualified as responders in the RCTs, a complete response of 70% (102/145) of all target tophi was achieved after 1 year of open-label treatment.

### Gout flares

Gout flares occurred in 71% of patients (106/149) during the OLE study; the mean number of flares per patient per 3-month period was 0.5 over the duration of the trial. The highest flare rates occurred in 52% of patients (78/149; 1.1 flares/patient) during the first 3-month period. Flare rates diminished with continued treatment in the OLE among patients who were urate-lowering responders during the RCT compared with patients who were RCT non-responders (figure 4A,B). For example, in the cohort of patients sustaining goal urate-lowering on the biweekly pegloticase OLE dose schedule, flares diminished substantially (occurring in 26% (9/35) during months 1–3 of the OLE study, 9% (3/32) during months 10–12 and 3% (1/29) during months 22–24).

# Discussion

Pegloticase is a PEGylated mammalian recombinant uricase that was developed to control hyperuricaemia and its clinical manifestations in patients with refractory chronic gout and no other urate-lowering options. In the present OLE of two RCTs,17 long-term treatment with pegloticase was safe and generally well tolerated, especially in patients who had experienced sustained goal range urate-lowering responses during blinded treatment. In addition to maintaining markedly sub-saturating urate levels, these patients showed progressive clinical benefit in gout flares and tophus reduction during pegloticase treatment for an average of 2 years in the OLE study.

Target range SUA was achieved for 55% of all patients at week 25 of the OLE study. This is consistent with findings from the RCTs in which 42% of patients treated with biweekly pegloticase showed sustained urate lowering for 6 months.17 Conversely, patients losing urate-lowering efficacy did so within the first few months of treatment in the RCTs, and urate levels for this cohort remained above target for the duration of the OLE study. About one-third of patients who did not sustain SUA\<6 mg/dl in the RCTs retained clinical benefit during the OLE study with at least one tophus remaining resolved. However, this finding could be explained by an initial response followed by a protracted period needed for sufficient reaccumulation of crystal deposits to become clinically detectable.

A post hoc analysis of the RCTs revealed relationships between loss of urate-lowering efficacy, risk of IRs and development of high-titre pegloticase antibodies.17 Because of blinding of urate levels during the RCTs, the relationship between loss of urate-lowering efficacy and the risk of pegloticase infusion reactions was not appreciated until several months after initiation of the OLE study. As a result, some patients who were RCT pegloticase non-responders continued receiving pegloticase during the OLE study, providing additional information with regard to these relationships. Among patients entering the OLE study, 71 had at least one IR during the randomised trials or the OLE study; 85% of these patients (60/71) experienced their first IR when SUA was \>6 mg/dl. Overall, these data support the view that the great majority of IRs can be avoided if patients discontinue treatment when, with routine preinfusion monitoring of SUA, levels in excess of 6 mg/dl indicate a sustained loss of pegloticase urate-lowering efficacy.

There are limitations to this study. First, the open-label study design carries both well-documented value and some bias as a result of being uncontrolled.19 Second, the RCT protocol called for stratification of patients based on treatment response and dosing schedule. Although this provided the opportunity to follow safety and efficacy outcomes during the OLE study for patients with specific treatment histories, it also resulted in six distinct cohorts, each containing small numbers of patients. Nevertheless, the analyses of OLE study data indicate that patients who achieve treatment success throughout the first 6 months of treatment are likely to benefit from sustained long-term urate-lowering by pegloticase with favourable clinical responses. Conversely, patients not sustaining urate-lowering treatment responses to pegloticase infusions should not be expected to have treatment benefits (extending substantially beyond the period of urate-lowering initially achieved) and incur an increased risk of IRs. We recommend discontinuation of pegloticase therapy in such patients.

A final limitation is that patients were identified by their initial allocation to biweekly or monthly treatment in the RCTs but were allowed to change dosing frequency at two time points upon entering the OLE study. A higher proportion of patients switched from monthly to biweekly treatment than vice versa, however, indicating that most patients were receiving the US FDA-approved pegloticase biweekly regimen**.**

In summary, the safety profile of pegloticase in the OLE study was consistent with that observed in the RCTs17 with no evidence of new safety concerns related to long-term exposure. Efficacy findings further demonstrated that clinical improvements were durable and probably progressive during long-term therapy in patients with persistent goal range urate-lowering responses to pegloticase.

# Supplementary Material

###### Web supplement

The authors thank all the investigators and patients who participated in the pegloticase trials. Members of the Cardiovascular Event Adjudication Committee were William B White (chair), Glen E Cooke and Philip Gorelick who were compensated for their participation. The authors wish to acknowledge writing and editorial support from the fm*P* group of Fallon Medica LLC, funded by Savient Pharmaceuticals, in the preparation of this manuscript.

# References

[^1]: **Handling editor** Tore K Kvien


date: 2020-05
title: GLOBAL LEADERS UNITE TO ENSURE EVERYONE EVERYWHERE CAN ACCESS NEW VACCINES, TESTS AND TREATMENTS FOR COVID-19: Unprecedented gathering of heads of government, institutions and industry cements commitment to accelerate development and delivery for all populations

**24 April 2020** - Heads of state and global health leaders today made an unprecedented commitment to work together to accelerate the development and production of new vaccines, tests and treatments for COVID-19 and assure equitable access worldwide.

The COVID-19 pandemic has already affected more than 2.4 million people, killing over 160,000. It is taking a huge toll on families, societies, health systems and economies around the world, and for as long as this virus threatens any country, the entire world is at risk.

There is an urgent need, therefore, while following existing measures to keep people physically distanced and to test and track all contacts of people who test positive, for innovative COVID-19 vaccines, diagnostics and treatments.

"We will only halt COVID-19 through solidarity," said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. "Countries, health partners, manufacturers, and the private sector must act together and ensure that the fruits of science and research can benefit everybody."

Work has already started. Since January, WHO has been working with researchers from hundreds of institutions to develop and test vaccines, standardize assays and standardize regulatory approaches on innovative trial designs and define criteria to prioritize vaccine candidates. The Organization has prequalified diagnostics that are being used all over the world, and more are in the pipeline. And it is coordinating a global trial to assess the safety and efficacy of four therapeutics against COVID-19.

The challenge is to speed up and harmonize processes to ensure that once products are deemed safe and effective, they can be brought to the billions of people in the world who need them. Past experience, in the early days of HIV treatment, for example, and in the deployment of vaccines against the H1N1 outbreak in 2009, shows that even when tools are available, they have not been equally available to all.

So today leaders came together at a virtual event, co-hosted by the World Health Organization, the President of France, the President of the European Commission, and the Bill & Melinda Gates Foundation. The event was joined by the UN Secretary General, the AU Commission Chairperson, the G20 President, heads of state of France, South Africa, Germany, Vietnam, Costa Rica, Italy, Rwanda, Norway, Spain, Malaysia and the UK (represented by the First Secretary of State).

Health leaders from the Coalition for Epidemic Preparedness Innovations (CEPI), GAVI-the Vaccine Alliance, the Global Fund, UNITAID, the Wellcome Trust, the International Red Cross and Red Crescent Movement (IFRC), the International Federation of Pharmaceutical Manufacturers (IFPMA), the Developing Countries Vaccine Manufacturers' Network (DCVMN), and the International Generic and Biosimilar Medicines Association (IGBA) committed to come together, guided by a common vision of a planet protected from human suffering and the devastating social and economic consequences of COVID-19, to launch this groundbreaking collaboration. They are joined by two Special Envoys: Ngozi Okonjo-Iweala, Gavi Board Chair and Sir Andrew Witty, former CEO of GlaxoSmithKline.

They pledged to work towards equitable global access based on an unprecedented level of partnership. They agreed to create a strong unified voice, to build on past experience and to be accountable to the world, to communities and to one another.

"Our shared commitment is to ensure all people have access to all the tools to prevent, detect, treat and defeat COVID-19," said Dr Tedros. "No country and no organization can do this alone. The Access to COVID-19 Tools Accelerator brings together the combined power of several organizations to work with speed and scale."

Health leaders called on the global community and political leaders to support this landmark collaboration and for donors to provide the necessary resources to accelerate achievement of its objectives, capitalizing on the opportunity provided by a forthcoming pledging initiative that starts on 4 May 2020. This initiative, spearheaded by the European Union, aims to mobilize the significant resources needed to accelerate the work towards protecting the world from COVID-19.

Available from: <https://www.who.int/news-room/detail/24-04-2020-global-leaders-unite-to-ensure-everyone-everywhere-can-access-new-vaccines-tests-and-treatments-for-covid-19>


author: J Yazdany; C Feldman; J Liu; MM Ward; MA Fischer; KH Costenbader
date: 2012
institute: 1University of California, San Francisco, CA, USA; 2Brigham and Women's Hospital, Boston, MA, USA; 3National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA
title: Usual source of care and geographic region are largest predictors of healthcare quality for incident lupus nephritis in US Medicaid recipients

# Background

Little is known about the quality of healthcare delivered to patients with lupus nephritis in the United States and the major determinants of quality remain unknown. We aimed to examine the sociodemographic, geographic, and healthcare system factors associated with performance on a healthcare quality measure in a nationwide cohort of Medicaid recipients with incident lupus nephritis.

# Methods

We used US Medicaid analytic extract (MAX) data from 2000 to 2004 containing person-level files on Medicaid eligibility, utilization and payments. We identified patients meeting a validated administrative data definition of incident lupus nephritis, and used this group as the denominator population for the quality metric (QM). The QM numerator assessed receipt of **i**nduction therapy with glucocorticoids and another immunosuppressant (azathioprine, mycophenolate mofetil, mycophenolic acid, cyclophosphamide, cyclosporine A, or tacrolimus) within 90 days of lupus nephritis onset. Patients with end-stage renal disease were excluded. We used multivariable logistic regression models to examine sociodemographic (age, sex, race/ethnicity), geographic (US region), and healthcare (health professional shortage areas, HPSAs, from the Area Resource File) predictors of higher performance. We also examined the restrictiveness of Medicaid benefits in each state, defined by less generous medication coverage policies (mandatory generic substitution, requirements for prior authorization and drug co-payments), and whether the patient's usual source of care was the emergency department or the ambulatory setting (\>50% visits).

# Results

A total of 974 Medicaid recipients met the definition of incident lupus nephritis. The mean age was 39 years (SD 12), 93% were female, and most were African American (African American 48%, White 27%, Hispanic 13%, Asian 6%). Individuals were geographically dispersed (20% Midwest, 22% Northeast, 34% South, 24% West), and 95% resided in partial or complete HPSAs. One hundred and sixty-four individuals resided in states with more restrictive Medicaid benefits. At 90 days, only 16% of patients met all numerator components of QM1; 45% of individuals received only steroids (mean prednisone dose 28 mg/day), and 3% received an immunosuppressant alone. Among those treated with an immunosuppressant, 31% received azathioprine, 47% received mycophenolate, 14% received cyclophosphamide, and 11% received a calcineurin inhibitor. For 20% (*n* = 192) of patients, the usual source of care was in the emergency setting. In multivariable logistic regression models, younger individuals were more likely to receive optimal treatment (OR for 18 to 34 years vs. 51 to 64 years = 3.5, CI = 1.6 to 7.6), while those living in the South and Midwest were less likely (OR = 0.49, CI = 0.24 to 0.67 and OR = 0.30 CI = 0.15 to 0.61, respectively). Those whose usual source of care was the emergency department were less likely to receive optimal treatment (OR = 0.47, CI = 0.28 to 0.81). In this adjusted analysis, we did not find significant associations for race/ethnicity, HPSA or Medicaid restrictiveness with QM performance.

# Conclusion

Most US Medicaid recipients with incident lupus nephritis in our study did not receive timely induction therapy, and many were treated with high-dose steroids alone. We found significant geographic variation in performance, with the South and Midwest having lower performance than other regions. A substantial number of Medicaid patients with lupus nephritis used the emergency department as a usual source of care and performance on the QM is lower in this setting. These data suggest a need for targeted quality improvement interventions, including increasing access to appropriate ambulatory care for Medicaid recipients with lupus nephritis.


author: Linda S. Birnbaum[^1]
date: 2012-08-01
references:
title: NIEHS's New Strategic Plan

I am pleased to present "our" new strategic plan for the National Institute of Environmental Health Sciences (NIEHS 2012). I say that it's "our" plan because the entire document reflects tremendous thought, discussion, and sharing of ideas by hundreds of scientists and community stakeholders, and it speaks to the entire field of environmental health research. This plan is about what we will strive to accomplish together as we devote ourselves to research that, in my opinion, has the greatest chance for preventing disease and for improving health throughout the world.

As reflected in the new strategic plan (NIEHS 2012), the NIEHS has a fresh vision, not because our values have changed but because our research has been so successful—and many of you have made a huge contribution to that progress.

New technologies and increasing knowledge bring exciting new opportunities each and every year. The NIEHS's new strategic plan builds upon the accomplishments and vision that came before.

The NIEHS has come a long way in making environmental health research responsive to the needs and concerns of the American people—
to make environmental health part of the public health debate. This continues to be a source of motivation and purpose for NIEHS staff and our research partners. Environmental justice is an everlasting core value for NIEHS research.

In the past few years, we at the NIEHS have made some important progress in exposure science, supporting new technologies for sensor devices and bioinformatics. We have been embracing new science such as epigenetics and exposure phenotyping, focusing on interdisciplinary research and translational research. In addition, our clinical research unit is now up and running.

As the NIEHS moves forward, our overall goal is to make the institute, including the National Toxicology Program (NTP), the foremost trusted source of environmental health knowledge, leading the field in innovation and the application of research to solve health problems.

Our new vision statement (NIEHS 2012) captures our collective dreams and aspirations, and reflects our strong commitment to making a real difference:

> The vision of the National Institute of Environmental Health Sciences is to provide global leadership for innovative research that improves public health by preventing disease and disability from our environment.

What this means in practical terms is that we are pursuing some of the "big influences" that have been understudied, all of which interact with traditional environmental exposures: the microbiome, for example, and inflammation pathways, immunological pathways, nutrition, and epigenetic processes. We also want to lead the process of defining the "exposome," which is the totality of exposure encountered by humans.

We have elevated the NTP to the divisional level within the NIEHS. And we will continue to integrate our toxicology research with our excellent basic and translational science programs, not because I am a toxicologist but because the NTP is a problem-solving program—a truly translational component of the NIEHS. For example, the NTP is part of our consortium on bisphenol A, contributing to the scientific deliberations, right along with our intramural scientists and our grantees.

The NTP is leading the Tox21 initiative along with the National Institute of Health's National Center for Comparative Genomics, the U.S. Environmental Protection Agency, and the Food and Drug Administration. This high throughput testing program shows great promise not only as a new and faster method but also for moving toxicology into a predictive science.

The NTP is moving beyond the traditional approaches of testing one chemical at a time and are taking on the significant challenge of evaluating mixtures. We are also looking at the effects of exposures throughout the life span, expanding our research and testing to include prenatal exposures and how they may link to adult disease. It is clear that there are multiple windows of susceptibility and that exposures early in life may have long-lasting consequences to both health and disease.

Finally, the antiquated idea that the dose makes the poison is overly simplistic. The newest research clearly shows that biology is affected by low doses of chemicals, often within the range of general population exposure, and that these biological changes can be harmful, especially during periods of development. Therefore, low-dose research must go hand in hand with our life-span approach.

The NIEHS's job doesn't stop with the publication of scientific results. We also have an obligation to help translate the nation's research investment into public health intervention, new policy, and preventive clinical practice.

To be successful, we at the NIEHS need to conduct and support the best science, whether it is led by an individual researcher or a multidisiplinary team, and this means working together with all of our partners. We thank everyone who joined us in our strategic planning process. We appreciate your commitment and support.

# Reference

[^1]: Linda S. Birnbaum, director of the NIEHS and the NTP, oversees a budget that funds multidisciplinary biomedical research programs and prevention and intervention efforts that encompass training, education, technology transfer, and community outreach. She recently received an honorary Doctor of Science from the University of Rochester, the distinguished alumna award from the University of Illinois, and was elected to the Institute of Medicine. She is the author of \> 900 peer-reviewed publications, book chapters, abstracts, and reports. Birnbaum received her M.S. and Ph.D. in microbiology from the University of Illinois, Urbana. A board-certified toxicologist, she has served as a federal scientist for \> 32 years, 19 with the U.S. EPA Office of Research and Development, preceded by 10 years at the NIEHS as a senior staff fellow, a principal investigator, a research microbiologist, and a group leader for the institute's Chemical Disposition Group.


abstract: # Background
  .
  We have previously shown that irregular lifestyle of young Japanese female students are significantly related to their desire to be thinner. In the present study, we examined the nutritional knowledge and food habits of Chinese university students and compared them with those of other Asian populations.
  .
  # Methods
  .
  A self-reported questionnaire was administered to 540 students, ranging in age from 19-24 years. Medical students from Beijing University (135 men and 150 women) in Northern China and Kunming Medical College in southern China (95 men and 160 women) participated in this study. The parametric variables were analyzed using the Student's *t*-test. Chi-square analyses were conducted for non-parametric variables
  .
  # Results
  .
  Our results showed that 80.5% of students had a normal BMI and 16.6 % of students were underweight with the prevalence of BMI\>30 obesity being very low in this study sample. Young Chinese female students had a greater desire to be thinner (62.0%) than males (47.4%). Habits involving regular eating patterns and vegetable intake were reported and represent practices that ought to be encouraged.
  .
  # Conclusions
  .
  The university and college arenas represent the final opportunity for the health and nutritional education of a large number of students from the educator's perspective. Our findings suggest the need for strategies designed to improve competence in the area of nutrition.
author: Ruka Sakamaki; Kenji Toyama; Rie Amamoto; Chuan-Jun Liu; Naotaka Shinfuku
date: 2005
institute: 1International Center for Medical Research. Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan; 2Seinan Jo Gakuin University Faculty of Health and Welfare, Department of Nutritional Sciences, Kitakyusyu, 803-0835, Japan; 3Department of Plastic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
references:
title: Nutritional knowledge, food habits and health attitude of Chinese university students –a cross sectional study–

# Background

The increasing problem of obesity has been observed in many lower-income countries during the last decades. China has adopted an open-market policy and experienced explosive economic growth, which has led to less food scarcity at the national level and to a remarkable transition in the structure of the diet of Chinese \[1\]. The composition of the Chinese diet has been shifting towards a diet higher in fat and meat, and lower in carbohydrates and fiber \[2\]. Additionally, decreased levels of physical activity and leisure are linked to increases in the prevalence of an overweight condition, obesity and diet-related non-communicable diseases \[3\].

In previous reports, we examined eating habits and dietary knowledge of female students in Japan. Our results showed that irregular lifestyle was significantly related to indefinite complaint, with the majority of students having a desire to be thinner although the prevalence of students who were overweight was very low in this study sample \[4\]. Universities and colleges are potentially important targets for the promotion of healthy lifestyles of the adult population. However, little is known concerning the body mass index (BMI) distribution and nutritional and health-related behavior of Chinese university students. The purpose of this study was to obtain a preliminary understanding of the relative level of BMI distribution of Chinese university students and to determine the nutritional knowledge and body-shape perceptions.

# Material and Methods

This study was carried out between February 2001 and April 2002. Medical students from Beijing University (135 men and 150 women) in Northern China and Kunming Medical College in southern China (95 men and 160 women) participated in this study. A sample of 540 students aged 19 – 24 years were administered a self-reported questionnaire. The questionnaire consisted of 21 questions regarding eating, drinking and smoking habits (19 questions), with 2 questions related to dieting (trying to lose weight). Self-reported height and weight were used to calculate BMI (kg/m^2^). The questionnaire was designed by the authors and based on a national dietary survey held by the Health and Labor Ministry of Japan. Some of the authors also traveled to China to investigate the dietary life of Chinese to facilitate questionnaire design. The questionnaire was first written in Japanese and then translated to Chinese utilizing fluent bilingual linguistic services. The translated Chinese version was back-translated to insure the original meaning was not lost. Informed consent was obtained from all participants of this study according to the Declaration of Helsinki. The statistical software package SPSS 10.0 was used for the analysis of data \[5\]. In this study, parametric variables were analyzed using the Student's *t*-test. Chi-square analyses were conducted for non-parametric variables. All analyses were two-tailed, and a 'p' value less than 0.05 was considered statistically significant.

# Results

## Characteristics of the sample and BMI categories

The response rate was 96% (512 / 540). The characteristics of the subjects are shown in Table 1. A total of 212 men and 300 women, with a mean age of 20 ± 1.9 years, participated in this study. The average height was 165.8 ± 7.8 cm, while the average weight was 56.9 ± 9.2 kg. Mean BMI was 20.6 ± 2.2. To analyze the distribution of BMI and health-related behavior, BMI was categorized into 4 groups according to mean BMI of ± 1 standard deviation (SD) (Figure 1). The average BMI for male students was 21.4 ± 2.5 and was highest in the categories 18.9≤BMI\<21.4 (37.7%) and 21.4≤BMI\<23.9 (32.5%). The average BMI for female students was 20.0 ± 1.8, with the categories 18.2≤BMI\<20.0 (37.5%) and 20.0≤BMI\<21.8 (31.4%) displaying high values. According to WHO BMI classifications \[6\], 97.1% of students were classified into the underweight or normal weight categories. 2.5% (13/512) students were overweight (BMI\>25) and 0.4% (2/512) of students were obese (BMI\>30). BMI values of deviations from the average sample show the presence of few extreme values.

## Eating habit

The life style practices were compared by gender (see additional file 1). The majority of students (83.6 %) reported taking meals regularly, with 79.0% eating meals 3 times per day; there were no gender differences. However, a significant gender difference was found in the response relating to breakfast intake, with 66.8% of males and 82.3% of females reporting eating breakfast regularly (p \< 0.0006). The frequency of snacking rate was significantly higher in females (31.1%) than in males (11.5%; p \< 0.0001). The present sample demonstrated high consumption of vegetable and fruits. A total of 47.9% of students reported the consumption of colored vegetables such as spinach and carrots, and 32.5% of subjects reported eating fruit daily. Female students tend to eat more fruit than males (p \< 0.0001). In addition, female students tend to eat with friends and family more frequently than males (p \< 0.01). Few subjects smoke or drink alcohol. When the students eat out, female students are more likely to consider the calorie content of the menu than males (data not shown). Although 85.6% of students are aware of the concept of nutritionally balanced food, only a small number of students (7%) apply this concept when selecting food from a menu. Moreover, only 51% of students showed a desire to learn about healthy diets.

## Body image and health consciousness

When subjects were asked about their history of dieting, 22.7% of respondents reported that they had dieted (see additional file 2). The proportion of female students having a dieting experience (29.8%) was more than twice as great as that of male subjects (12.7%; p \< 0.0006). In total, 56% of the students selected 'thin or slim is beautiful'. The percentage by gender was, 47.4% for male and 62.0% for female students. Female students have a significantly greater desire to be thinner than males (p \< 0.001). More than half of the respondents reported a desire to adopt healthier dietary habits. Moreover, a question regarding the degree of consciousness pertaining to health and diet was asked; 45.2% of male students and 48.3% of female students wish to learn about health and diet. Among female subjects, BMI\<18.2 strongly showed their consciousness of health and diet (p \< 0.03).

# Discussion

This study aimed to determine the health, nutritional knowledge and dietary behavior of university students in China. As a result, we recorded the distribution of BMI among Chinese students and found a low prevalence of obesity, a finding that is consistent with a study of Japanese female students (BMI≥25 overweight was 5.8%, BMI\>30 of obesity was 0%) \[4\]. In the United States, 35% of the college students are reported to be overweight or obese (BMI≥25) \[7\]. According to the WHO definition of obesity, BMI\>30 is the cut-off point \[6\]. The definition is based on research of Caucasian populations. Asian populations are reported to have a higher body fat (%) at a lower BMI compared to Caucasians \[8\]. The WHO expert consultation reported that BMI in Asian populations is related to disease at a lower level \[9\]. In order to compare obesity prevalence between ethnic groups, BMI cut-off points for Asians need to be considered by well constructed and standardized body composition studies. It is notable that in China, the prevalence of overweight individuals increased from 1991 to 1997, with the increasing rate changing from 6.4 to 7.7 \[10\]. The proportion of energy derived from the fat of both vegetable and animal sources increased each year. A recent study revealed that energy derived from dietary fat accounted for more than 30% of the total energy \[11\]. Changes in dietary composition, which correspond to socioeconomic growth, may accelerate the prevalence of obesity in China.

The results of our study show that the majority of students regularly eat three times per day, and almost 80% of students eat vegetables and fruit twice per day. These eating habits ought to be encouraged. The traditional Chinese diet contains plenty of vegetables and is rice-based. The present study reported a high proportion of Chinese students eat breakfast daily. In contrast, a dietary survey of young Japanese subjects revealed a low rate of individuals engaged in regular eating patterns \[12\]. The skipping of breakfast has been associated with lower nutritional status and the risk of cardiovascular diseases \[13\]. It has also been reported that less adequate breakfast habits may contribute to the appearance and further development of obesity \[14\]. Therefore the importance of regular eating patterns cannot be overemphasized in nutritional education.

Our results showed that body figure perception was significantly different between female and male students. A number of researchers have investigated the relationship of body image and gender role. Women tend to desire a thinner figure, express more anxiety about becoming fat, and are more likely to diet than men \[15,16\]. In contrast, men have reported a desire for a heavier physique and muscularity \[17\]. In recent years, eating disorders have been increasing dramatically among young women. The results of our study did not confirm this suggestion to the level of statistical significance; however, it is worth pointing out that 65.0% of female students with BMI\<20, which is under to normal weight range, indicated a desire to be thin. Dissatisfaction with body figure and eating disorders are closely related \[18-20\]. Being young, female, and dieting are identified risk factors that have been reliably linked to the development of eating disorders \[21\]. It was speculated that some of the students who were preoccupied with a thin body may develop eating disturbances. Thus, the promotion of healthy weight management practices should be considered when developing health education programs.

# Conclusions

In conclusion, our findings reveal that the majority of students were classified into the normal BMI group, with the prevalence of BMI \>30 obesity being very low in this study sample. Young female students had a greater desire to be thinner than male students. Habits involving regular eating patterns and vegetable intake were found and represent practices that ought to be encouraged. The meal and snack patterns in Chinese students were very similar to the traditional eating pattern model, although diets are changing rapidly in China and other low-income countries. The university and college arenas represent the final opportunity for nutritional education of a large number of students from the educator's perspective. Our findings suggest the need for strategies designed to improve competence in the area of nutrition, especially with respect to information relating to sources of nutrition and healthy weight management. Furthermore, public demand for health and nutritional information should be taken into consideration when implementing strategies aimed at improving the nutritional well-being of individuals.

# Authors' contributions

R.S carried out questionnaire design, manuscript drafting and total coordination of the study. K.T has been involved in drafting and revision of the article. R.A contributed to the data entry and its analysis. L.CJ contributed to the questionnaire design, data collection and language translations. N.S contributed to final approval of the manuscript.

# Supplementary Material

###### Additional File 1

Table 2 containing the results of questions related to lifestyle practices with special reference to food habit. The meal patterns, consumption of fruits and vegetables, consumption of fried foods, consumption of alcohol were assessed in male and female students. The Chi-square analyses were employed to compare the behavioral differences by gender. The evaluations of statistical significance were made at the p \< 0.05.

Click here for file

###### Additional File 2

Table 3 contains the results of body shape perception and health consciousness of male and female students. Male and female respondents were categorized in to 4 groups respectively, according to mean BMI of ± 1 standard deviation (SD). Analyses were made between BMI groups using Chi-square analysis. The evaluations of statistical significance were made at the p \< 0.05.

Click here for file

### Acknowledgements

The authors express their appreciation for the invaluable partnership and support of Dr. Wang of Beijing University, Dr Zhao of Kunming Medical College and all the study participants of both institutes. We also thank Dr. Shigeki Minakami for valuable comments on the manuscript.

## Figures and Tables

Characteristics of Participants

|                   | **Total**   | **Male**    | **Female**  |
|-------------------|-------------|-------------|-------------|
| **Variable**      | n = 512     | n = 212     | n = 300     |
| **Age (y)**       | 20.4 ± 1.9  | 20.3 ± 1.7  | 20.4 ± 2.0  |
| **weight (kg)**   | 56.9 ± 9.2  | 63.7 ± 8.8  | 52.1 ± 5.9  |
| **height (cm)**   | 165.8 ± 7.8 | 172.3 ± 5.5 | 161.2 ± 5.6 |
| **BMI (kg/m^2^)** | 20.6 ± 2.2  | 21.4 ± 2.5  | 20.0 ± 1.8  |

Gender distribution in the sampled population. BMI is based on self-reported height and weight. BMI = weight \[kg\] / height \[m\]^2^


date: 2016-12
title: OVER 1 MILLION TREATED WITH HIGHLY EFFECTIVE HEPATITIS C MEDICINES

2 SEPTEMBER 2016 \| GENEVA - 27 OCTOBER 2016 \| GENEVA - Over one million people in low- and middle-income countries have been treated with a revolutionary new cure for hepatitis C since its introduction two years ago.

When Direct Acting Antivirals (DAAs) were first approved for hepatitis C treatment in 2013, there were widespread fears that their high price would put them out of reach for the more than 80 million people with chronic hepatitis C infections worldwide.

The new medicines have a cure rate of over 95%, fewer side effects than previously available therapies, and can completely cure the disease within three months. But at an initial estimated price of some US\$85 000 they were unaffordable even in high-income countries.

Countries show hepatitis C treatment is achievable

Thanks to a series of access strategies supported by the World Health Organization (WHO) and other partners, a range of low- and middle-income countries, including Argentina, Brazil, Egypt, Georgia, Indonesia, Morocco, Nigeria, Pakistan, Philippines, Romania, Rwanda, Thailand and Ukraine – are beginning to succeed in getting drugs to people who need them. Strategies include competition from generic medicines through licensing agreements, local production and price negotiations.

"Maximizing access to lifesaving hepatitis C treatment is a priority for WHO," says Dr Gottfried Hirnschall, Director of WHO's Department of HIV and Global Hepatitis Programme. "It is encouraging to see countries starting to make important progress. However, access still remains beyond the reach for most people."

A new WHO report, Global Report on Access to Hepatitis C Treatment: Focus on Overcoming Barriers, released today shows how political will, civil society advocacy and pricing negotiations are helping address hepatitis C, a disease which kills almost 700 000 people annually and places a heavy burden on health systems' capacities and resources.

"Licensing agreements and local production in some countries have gone a long way to make these treatments more affordable," says Dr Suzanne Hill, WHO Director for Essential Medicines and Health Products. For example, the price of a three-month treatment in Egypt dropped from US\$900 in 2014 to less than US\$200 in 2016.

"But there are still huge differences between what countries are paying. Some middle-income countries, which bear the largest burden of hepatitis C, are still paying very high prices. WHO is working on new pricing models for these, and other expensive medicines, in order to increase access to all essential medicines in all countries," says Dr Hill.

80% of people in need still face challenges

Among middle-income countries, the price for a three-month treatment of sofosbuvir and daclatasvir varies greatly. Costs range from US\$9 400 in Brazil to US\$79 900 in Romania.

High costs have led to treatment rationing in some countries, including in the European Union, where price agreements have not accounted for the full cost of treating the whole affected population.

"Today's report on access, prices, patents and registration of hepatitis C medicines will help create the much needed market transparency which should support country efforts to increase access to DAAs," said Dr Hirnschall. "We hope countries will update their hepatitis treatment guidelines, work to remove barriers to access, and make these medicines available promptly for everyone in need."

In May 2016, at the World Health Assembly, 194 countries adopted the first-ever Global Health Sector Strategy on Viral Hepatitis, agreeing to eliminate hepatitis as a public health threat by 2030. The strategy includes a target to treat 80% of people in need by this date.

WHO issued guidelines recommending the use of DAAs in 2014 and 2016 and included DAAs on its Essential Medicines List – which is compiled to address the priority healthcare needs of populations; to make needed essential medicines available at all times in adequate amounts, at a price the health system and community can afford.

Available from: <http://www.who.int/mediacentre/news/releases/2016/hepatitis-c-medicines/en/>