Open access, freely available online

12. Ampel NM, Mosely DG, England B, Vertz PD, Komatsu K, et al. (1998) 20. Gonzalez-Benavides J (1991) The panorama of coccidioidomycosis in Nuevo Coccidioidomycosis in Arizona: Increase in incidence from 1990 to 1995. Leon from 1978 to 1988. Gac Med Mex 127: 427–432. Clin Infect Dis 27: 1528–1530. 21. Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL (2000) 13. Smith CE (1951) Diagnosis of pulmonary coccidioidal infections. Calif Med Comparison of oral fl uconazole and itraconazole for progressive, 75: 385–391. nonmeningeal coccidioidomycosis. Ann Intern Med 133: 676–686. 14. López-Márquez A, Hernández-Avendaño V, Durán-Padilla MA, 22. Holley K, Muldoon M, Tasker S (2002) Coccidioides immitis osteomyelitis: Navidad-Cervera F, Chávez-Macías L, et al. (2004) Coccidioidomicosis A case series review. Orthopedics 25: 827–831, 831–832. diseminada con infección pulmonar, ganglionar y meníngea. 23. Wiant JR, Smith JW (1973) Coccidioidin skin reactivity in pulmonary Caso con hallazgos postmortem. Rev Med Hosp Gen (Mex) coccidioidomycosis. Chest 63: 100–102. 67: 88–93. 24. Cox RA (1993) Coccidioidomycosis. In: Murphy JW, Friedman H, 15. Smith CE, Beard RR, Whiting EG, Rosenberger HG (1946) Varieties of Bendinelli M, editors. Fungal infections and immune responses. New York: coccidioidal infection in relation to the epidemiology and control of the Plenum Press. pp. 173–211. diseases. Am J Public Health 36: 1394–1402. 25. Pappagianis D, Lindsay S, Beall S, Williams P (1979) Ethnic background 16. Cortez KJ, Walsh TJ, Bennett JE (2003) Successful treatment of coccidioidal and the clinical course of coccidioidomycosis. Am Rev Respir Dis 120: meningitis with voriconazole. Clin Infect Dis 36: 1619–1622. 959–961. 17. Castañeda-Godoy R, Laniado-Laborín R (2002) Coexistencia de tuberculosis 26. Ampel NM, Dols CL, Galgiani JN (1993) Coccidioidomycosis during human y coccidioidomicosis. Presentación de dos casos clínicos. Rev Inst Nal Enf immunodefi ciency virus infection; Results of a prospective study in a Resp Mex 15: 98–101. coccidioidal endemic area. Am J Med 94: 235–240. 18. Galgiani JN, Ampel NM, Catanzaro A, Johnson RH, Stevens DA, et al. 27. Cole GT, Xue JM, Okeke CN, Tarcha EJ, Basrur V, et al. (2004) A vaccine (2000) Practice guidelines for the treatment of coccidioidomycosis. Clin against coccidioidomycosis is justifi ed and attainable. Med Mycol 42: 189– Infect Dis 30: 658–661. 216. 19. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, et al. 28. Kuberski TJ, Servi RJ, Rubin PJ (2004) Successful treatment of a critically ill (2002) Voriconazole versus amphotericin B for primary therapy of invasive patient with disseminated coccidioidomycosis, using adjunctive interferon-g. aspergillosis. N Engl J Med 347: 408–415. Clin Infect Dis 38: 910–912.

Perspectives Seasonal Patterns of Infectious Diseases Mercedes Pascual*, Andy Dobson

eningococcal meningitis from year to year so important? Isn’t In other words, there are only in western Africa shows it more important for us to instead weak correlations between seasonal Mrecurrent seasonal patterns understand the effects of long-term variations and climate variables at small every year. Epidemics typically start climate change on human health? scales because of the multiple other at the beginning of February and last At fi rst sight, understanding seasonal factors that play a local role and act as until May. We can try to explain the patterns seems disconnected from noise. observed patterns on the basis of some understanding the impact of long-term But we should be cautious about seasonally varying environmental factor climate change. However, seasonal the suggestion that appropriate larger that favors disease transmission. Air patterns are one major pathway for scales will always resolve the problem dryness produced by strong dust winds the subtle but potentially drastic of local variability and present strong is the most likely candidate. effects of climate change on disease linear associations between climate and But while there are qualitative dynamics. Long-term climate change disease. Public health measures might “stories” of this kind in the literature affects seasonal patterns through the require predictions not only at national for many seasonal phenomena, lengthening of the transmission season and regional scales, but also at a variety convincing quantitative evidence and the crossing of environmental of smaller scales. to support them remains largely and demographic thresholds that Moreover, one important source of elusive. Instead, we tend to see weak underlie seasonal outbreaks [2]. variation in how infectious diseases associations between environmental Thus, identifying the specifi c and transmission variables when environmental factors underlying Citation: Pascual M, Dobson A (2004) Seasonal measured by simple, linear correlations. seasonal transmission is a critical step patterns of infectious diseases. PLoS Med 2(1): e63. The study of meningococcal meningitis towards predicting and understanding in Mali by Sultan and colleagues in this how long-term environmental trends in Copyright: © 2005 Pascual and Dobson. This is an open-access article distributed under the terms issue of PLoS Medicine is a remarkable mean climate and their variability will of the Creative Commons Attribution License, exception [1]. The study reports a impact human health. which permits unrestricted use, distribution, and reproduction in any medium, provided the original strong association between the yearly work is properly cited. onset of epidemics and a large-scale The Problem of Scale regional index for atmospheric One important diffi culty in uncovering Mercedes Pascual is an associate professor in the Department of Ecology and Evolutionary Biology, circulation related to the Harmattan seasonal drivers of infectious diseases University of Michigan, Ann Arbor, Michigan, United winds in Sahelo-Sudanian Africa. is to identify the appropriate scale of States of America. Andy Dobson is a professor in the analysis. The relationship between Department of Ecology and Evolutionary Biology, The Importance of Seasonality Princeton University, Princeton, New Jersey, United disease and climate described by States of America. Why is a focus on the seasonality of Sultan and colleagues only becomes Competing Interests: The authors declare that no infectious diseases and its variation apparent at large spatial scales. The competing interests exist. authors argue that these large scales are The Perspectives section is for experts to discuss the necessary to eliminate “idiosyncratic” *To whom correspondence should be addressed. E-mail: [email protected] clinical practice or public health implications of a variability in the relationship between published study that is freely available online. cases and climate at the local level. DOI: 10.1371/journal.pmed.0020005

PLoS Medicine | www.plosmedicine.org 0018 January 2005 | Volume 2 | Issue 1 | e2 | e5 understand the interaction between only simple seasonal forcing functions susceptibility levels and climate (mathematical functions that are variation [3,4,5]. periodic in time and therefore describe The problem of scale also arises in a generic way the seasonal variation when we need to identify the in the transmission rate or some other appropriate timing (the temporal seasonal parameter—a sine wave is an window) to detect strong associations example). There are some important between disease outbreaks and exceptions to this—some models environmental covariates. This is do incorporate more complicated particularly important when strong seasonal forcing functions that describe couplings between environment and the actual processes underlying the transmission occur only transiently. seasonal drivers of transmission. This seems to be the case for cholera Examples are models of childhood in Bangladesh, where couplings diseases that describe the regular are strong during El Niños, but stopping and starting of school terms considerably weaker the rest of the [9,10,11], and recent malaria models time [6]. Intermittent couplings that include the seasonal dynamics provide insight into how the system of mosquito births and pathogen might behave if pushed into specifi c incubation as functions of temperature dynamic regions by a change in and rainfall [12]. DOI: 10.1371/journal.pmed.0020005.g001 climate. Intermittent couplings also The explicit way in which models Figure 1. The Role of Rainfall in Driving the suggest the existence of thresholds treat seasonal environmental drivers Seasonal Nature of Cholera Is Unclear in the response to climate, an area may be critical in addressing the links This photograph was taken during a of research that remains in need of between within-year seasonal cycles cholera and nutrition survey during fl ooding in Bangladesh in 1974. In quantitative approaches. and those of longer period that are Bangladesh, monsoon rains appear observed in many infectious diseases. to have a seasonal “dilution” effect on Seasonal Drivers May Be Elusive For meningococcal meningitis, we transmission, producing a decrease in Besides scale, specifi c seasonal still need to examine the connection cholera cases during that season. We don’t know whether extreme rains also drivers are often elusive because of between the seasonal association produce a lagged increase in cases later the simpler reason that in nature described by Sultan and colleagues on in the cycle. In other parts of the seasonality is ubiquitous. Multiple and the previously proposed role of world, cases typically peak during the and covarying drivers have been humidity in inter-annual cycles [13]. rainy season. (Photo: Jack Weissman, proposed for the seasonal nature Centers for Disease Control and The Complexity of Infectious Prevention) of cholera, including temperature, rainfall, and plankton blooms [7]. Yet Disease Dynamics the specifi c roles of these drivers in Sultan and colleagues’ study is respond to climate is the fraction the bimodal seasonal cycle of cholera, exceptional in that it illustrates of susceptible individuals in the and particularly in the second peak in a clear relationship between an population. This fraction varies endemic regions in south Asia, have external environmental variable and over time as the result of immunity not been convincingly shown (Figure the initiation of disease outbreaks. acquired by previous infection, and by 1) [8]. We still don’t have predictive In contrast, many studies seeking the input of births and migrants into explanations of the geographic environmental drivers are plagued the pool of susceptible people. The variation in seasonal patterns. We won’t by the many confounding factors, constant waxing and waning of this fi nd such explanations by considering particularly the impact that other pool of hosts underlies the intrinsic the average seasonal pattern; instead, components of global change have potential of the population dynamics we must consider the anomalies in on the transmission dynamics of of infectious diseases to oscillate amplitude and onset of the peaks that infectious diseases. Thus, when we and create epidemic outbreaks. The occur in different years. examine datasets for malaria, we tendency of these intrinsic cycles to go Ecologists have considered must also consider the evolution of up and down in synchrony at different seasonality in mathematical models of drug resistance and a growing human locations in space will determine the population dynamics of infectious population that is increasingly forced whether susceptibility levels act as noise diseases. Models of populations with to live in areas that are marginal for at small scales or, alternatively, whether seasonally forced, dynamic interactions agricultural production but optimal for their effect must be considered in (births, deaths, aggregation, or malaria transmission. conjunction with climate at larger disease transmission) reveal an array Given this complexity, a serious scales. Because the number of of possible responses, from simple limiting factor to quantitative analyses susceptible individuals is a hidden yearly cycles, through cycles that and predictive models of ecological variable in most epidemiological repeat with longer periods, to irregular and disease patterns is the lack of analyses, recently proposed methods chaotic fl uctuations. Some models also long-term disease records with similar for its reconstruction from data on predict intermittent switching between data collected over a network of spatial cases must be combined with studies different dynamic infectious disease locations. The handful of extremely on climate variation if we are to behaviors. But typical models consider valuable records that have allowed

PLoS Medicine | www.plosmedicine.org 0019 January 2005 | Volume 2 | Issue 1 | e5 Open access, freely available online progress in understanding long-term References 7. Colwell R (1996) Global climate and infectious patterns in disease dynamics pale in 1. Sultan B, Labadi K, Guégan JF, Janicot S disease: The cholera paradigm. Science 274: (2005) Climate drives the meningitis epidemics 2025–2031. comparison to the spatiotemporal onset in West Africa. PLoS Med 1: e57. 8. Pascual M, Bouma MJ, Dobson AP (2002) coverage available for climate studies 2. Harvell CD, Mitchell CE, Ward JR, Alitzer S, Cholera and climate: Revisiting the quantitative Dobson AP, et al. (2002) Climate warming and evidence. Microbes Infect 4: 237–245. and modeling. The need to resolve disease risks for terrestrial and marine biota. 9. Grenfell BT, Bolker BM, Kleczkowski A (1993) these issues of scale and confounding Science 296: 2158–2162. Seasonality, demography, and the dynamics of variability only underscores the urgency 3. Ellner SP, Bailey BA, Bobashev GV, Gallant measles in developed countries. In: Mollison AR, Grenfell BT, et al. (1998) Noise and D, editor. Epidemic models: Their structure and importance of maintaining and nonlinearity in measles epidemics: Combining and relation to data. Cambridge: Cambridge developing systematic surveillance mechanistic and statistical approaches to University Press. pp. 248–270. programs for infectious diseases around population modeling. Am Nat 151: 425–440. 10. Grenfell BT, Bolker BM, Kleczkowski A 4. Finkenstädt BF, Grenfell BT (2000) Time series (1995) Seasonality and extinction in chaotic the world. modelling of childhood diseases: A dynamical metapopulations. Proc R Soc Lond B Biol Sci systems approach. Appl Stat 49: 187–205. 259: 97–103. Acknowledgments 5. Koelle K, Pascual M (2004) Disentangling 11. Earn DJ, Rohani P, Bolker BM, Grenfell BT extrinsic from intrinsic factors in disease (2000) A simple model for complex dynamical We thank the participants of the working dynamics: A nonlinear time series approach transitions in epidemics. Science 287: 667–670. group on “Seasonality and the population with an application to cholera. Am Nat. 163: 12. Hoshen MB, Morse AP (2004) A weather-driven dynamics of infectious diseases” at the 901–913. model of malaria transmission. Malar J 3: 32. 6. Rodó X, Pascual M, Fuchs G, Faruque ASG 13. Besancenot JP, Boko M, Oke PC (1997) National Center of Ecological Analysis (2002) ENSO and cholera: A nonstationary Weather conditions and cerebrospinal and Synthesis (NCEAS, Santa Barbara, link related to climate change. Proc Natl Acad meningitis in Benin (Gulf of Guinea, west California). Sci U S A 99: 12901–12907. Africa). Eur J Epidemiol 13: 807–815.

Perspectives Gene Mutations in Lung Cancer: Promising Predictive Factors for the Success of Molecular Therapy Akira Inoue*, Toshihiro Nukiwa

ung cancer is the leading overexpressed in non-small-cell were not correlated with the response; cause of cancer death in lung cancer (NSCLC), especially in high response rates were seen in Lmany countries. To date, squamous cell carcinoma, and its women, patients with adenocarcinoma, chemotherapy with cytotoxic agents expression is related to the cancer’s nonsmokers, and Japanese patients. has been the mainstay of treatment for proliferation. Initial clinical trials of Recent studies have now shed light on advanced lung cancer. However, the gefi tinib showed its modest clinical why certain patients are more likely to activity of these agents is quite limited, activity in patients who had failed respond than others—the key lies in and they have severe adverse effects. previous standard chemotherapy. the presence of gene mutations. Recent, rapid advances in molecular But subsequent randomized trials in biology have led to the development patients with previously untreated, Citation: Inoue A, Nukiwa T (2005) Gene mutations of many new agents that inhibit the advanced NSCLC have not shown in lung cancer: Promising predictive factors for the activities of specifi c molecules related a clinical advantage of gefi tinib success of molecular therapy. PLoS Med 2(1): e13. to tumor growth, invasion, or metastasis combined with standard chemotherapy Copyright: © 2005 Inoue and Nukiwa. This is an [1], and these agents have the potential over chemotherapy alone [2,3,4,5]. open-access article distributed under the terms to improve the outcome of lung Erlotinib, another EGFR tyrosine of the Creative Commons Attribution License, which permits unrestricted use, distribution, and cancer treatment. But we have not yet kinase inhibitor for treating NSCLC, reproduction in any medium, provided the original managed to successfully deliver these which was approved by the United work is properly cited. agents from the bench to the bedside. States Food and Drug Administration Abbreviations: EGFR, epidermal growth factor in November 2004, has a therapeutic receptor; NSCLC, non-small-cell lung cancer Molecular Therapy for Lung Cancer profi le similar to that of gefi tinib. Akira Inoue is a research assistant and Toshihiro Gefi tinib is the fi rst “molecular-target Erlotinib has shown a survival benefi t Nukiwa is a professor in the Department of agent” for lung cancer that inhibits in a phase III trial for chemo-refractory Respiratory Oncology and Molecular Medicine, the tyrosine kinase of the epidermal NSCLC that compared erlotinib to Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan. growth factor receptor (EGFR; also best supportive care [6]. (To date, known as ERBB1). EGFR is frequently there have been no trials showing a Competing Interests: The authors declare that they survival benefi t of EGFR inhibitors over have no competing interests. The Perspectives section is for experts to discuss the standard chemotherapy.) Interestingly, *To whom correspondence should be addressed. clinical practice or public health implications of a in these trials of EGFR inhibitors, E-mail: [email protected] published study that is freely available online. EGFR expression levels in the tumors DOI: 10.1371/journal.pmed.0020013

PLoS Medicine | www.plosmedicine.org 0020 January 2005 | Volume 2 | Issue 1 | e5 | e13