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InternalMed_Harrison. clinical laboratories. The epsilometer test (E-test), a novel method for determination of the MIC, uses a plastic strip with a known gradient of antibiotic concentrations along its length. When the strip is placed on the surface of an agar plate seeded with the bacterial strain to be tested, antibiotic diffuses into the medium, and bacterial growth is inhibited. For some organisms, such as obligate anaerobes and some β-hemolytic streptococci, routine susceptibility testing generally is not performed because of the difficulty of growing the organisms or the predictable sensitivity of most isolates to specific antibiotics.


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InternalMed_Harrison. With the advent of many new agents for treating yeasts and systemic fungal agents, the need for testing of individual isolates for susceptibility to specific antifungal agents has increased. In the past, few laboratories participated in such testing because of a lack of standard methods like those available for testing bacterial agents. However, several systems have been approved for antifungal susceptibility testing. These methods, which determine the minimal fungicidal concentration (MFC), are similar to the broth microdilution methods used to determine the MIC for bacteria. The E-test method is approved for testing the susceptibility of yeasts to fluconazole, itraconazole, and flucytosine, and disk diffusion can be used to test the susceptibility of Candida species to fluconazole and voriconazole. Methods for determining the MFC of a drug against fungal agents such as Aspergillus species are technically difficult, and most clinical laboratories refer requests for such testing to


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InternalMed_Harrison. voriconazole. Methods for determining the MFC of a drug against fungal agents such as Aspergillus species are technically difficult, and most clinical laboratories refer requests for such testing to reference laboratories.


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InternalMed_Harrison. See Chaps. 214e and 215e. Climate Change and Infectious Disease Aaron S. Bernstein The release of greenhouse gases—principally carbon dioxide—into Earth’s atmosphere since the late nineteenth century has contributed 151e unprecedented in the last 50 million years. Climate science, although 151e-1 still a relatively new discipline, has provided an ever-clearer picture of how the changing chemistry of the atmosphere has influenced, and will continue to influence, the global climate.


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InternalMed_Harrison. Greenhouse gases (Table 151e-1 and Fig. 151e-2) are a group of gases in Earth’s atmosphere that absorb infrared radiation and thus retain heat inside the atmosphere. In the absence of these gases, the earth’s to a climate unfamiliar to our species, Homo sapiens. This new climate has already altered the epidemiology of some infectious diseases. average temperature would be about 33°C colder. Carbon dioxide, released into the atmosphere primarily from fossil fuel combustionContinued accumulation of greenhouse gases in the atmosphere will and deforestation, has had the greatest effect on climate since thefurther alter the planet’s climate. In some cases climate change may establish conditions favoring the emergence of infectious diseases, Industrial Revolution. Of note, the Swedish scientist Svante Arrhenius first suggested in the late nineteenth century that the addition ofwhile in others it may render areas that are presently suitable for carbon dioxide to the earth’s atmosphere would


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InternalMed_Harrison. Svante Arrhenius first suggested in the late nineteenth century that the addition ofwhile in others it may render areas that are presently suitable for carbon dioxide to the earth’s atmosphere would increase the planet’s certain diseases unsuitable. This chapter presents the current state of surface temperature. Water vapor is the most abundant and a highly knowledge regarding the known and prospective infectious-disease potent greenhouse gas but, given its short atmospheric life span and consequences of climate change.


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InternalMed_Harrison. The term climate change refers to long-term alterations in tempera- sensitivity to temperature, is not a major factor in recently observed climate change. The atmosphere, some of the aerosols suspended in it, and clouds reflect a portion of incoming solar radiation back toward space. The ture, precipitation, wind, humidity, and other components of weather. Over the past 2.5 million years, the earth has warmed and cooled, cycling between glacial and interglacial periods during which average global temperatures moved up and down by 4–7°C. During the last glacial period, which ended roughly 12,000 years ago, global temperatures were, on average, 5°C cooler than in the mid-twentieth century (Fig. 151e-1).


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InternalMed_Harrison. The present climate period, known as the Holocene, is remarkable for its stability: temperatures have largely remained within a range of 2–3°C. This stability has enabled the successful population and cultivation of much of the earth’s landmass by humanity. Current climate change differs from that in the past not only because its primary cause is human activities but also because its pace is faster. The 5°C of warming that occurred at the end of the last ice age took roughly 5000 years, whereas such a temperature increment may occur within the next 150 years unless the release of greenhouse gases is substantially reduced in coming decades. The current rate of warming on Earth is remainder reaches Earth’s surface, where it is absorbed and some is then emitted back at the atmosphere. The earth emits energy absorbed from the sun at longer wavelengths, primarily infrared, that greenhouse gases are able to absorb. The change in wavelength that occurs as solar radiation is absorbed and


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InternalMed_Harrison. earth emits energy absorbed from the sun at longer wavelengths, primarily infrared, that greenhouse gases are able to absorb. The change in wavelength that occurs as solar radiation is absorbed and re-emitted from the earth’s surface is fundamental to the greenhouse effect (Fig. 151e-3).


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InternalMed_Harrison. Climate change has become nearly synonymous with global warming, as a clear signal from rising greenhouse gas concentrations has been an increase in the mean global surface temperature of ~0.85°C since 1880. However, this mean warming belies warming that is occurring much faster in certain regions. The Arctic has warmed twice as fast overall, and winters are warming faster than summers. Nighttime minimum temperatures are also rising faster than daytime high temperatures. Each of these nuances bears upon the incidence of infectious diseases in general and vector-borne disease specifically. 600 500 400 300 200 Time (before 2005), in thousands of years 2.8 3.2 3.6 4.0 4.4 4.8 5.2


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InternalMed_Harrison. FIGURE 151e-1 Overview of the earth’s temperature and primary greenhouse gases over the last 600,000 years. Variations of deuterium (δD; black) serve as a proxy for temperature. Atmospheric concentrations of greenhouse gases—CO2 (red), CH4 (blue), and nitrous oxide (N2O; green)—were derived from air trapped within Antarctic ice cores and from recent atmospheric measurements. Shaded areas indicate interglacial periods. Benthic δ18O marine records (dark gray) are a proxy for global ice-volume fluctuations and can be compared to the ice core data. Downward trends in the benthic δ18O curve reflect increasing ice volumes on land. The stars and labels indicate atmospheric concentrations as of the year 2000. CO2 levels surpassed 400 ppm as of 2013 and are rising at a rate of 2–2.5 ppm per year. (From Intergovernmental Panel on Climate Change Fourth Assessment Report. Working Group I, Chapter 6, Figure 6.3. Cambridge University Press, 2007.)


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InternalMed_Harrison. TABLE 151e-1 GREEnHousE GAsEs: souRCEs, sInks, AnD FoRCInGs aIn this table, a sink refers to the place where greenhouse gases are naturally stored or the mechanism through which they are destroyed. bRadiative forcing, measured in watts per meter squared, refers to how much an entity can alter the balance of incoming and outgoing radiation to and from Earth’s atmosphere. It is measured relative to a preindustrial (i.e., 1750) baseline. Greenhouse gases have a positive “forcing”; that is, on balance, they increase the amount of radiation (and specifically infrared radiation) that is retained in Earth’s atmosphere. (Sources: Intergovernmental Panel on Climate Change Fifth Assessment Report, Working Group 1, Chapter 8; American Chemical Society “Greenhouse gas sources and sinks,” available at www.acs .org/content/acs/en/climatescience/greenhousegases/sourcesandsinks.html.) 0.04 0.03 0.02 0.01 0.00


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InternalMed_Harrison. A moderate projection based on the best available scientific evidence suggests that average global temperatures will warm an additional 1.4–3.1°C by 2100 as compared to the period 1986–2005. Because of climate change, extreme heat waves have already become more common and are expected to be even more frequent later in this century. Besides contributing directly to morbidity and mortality in human populations, heat waves wilt crops and are expected to contribute substantially to predicted agricultural losses. For example, the 2010 heat wave in Russia, which was unprecedented in its severity, contributed to hundreds of forest fires that generated enough air pollution to kill an estimated 56,000 people and that burned 300,000 acres of crops, including roughly 25% of the nation’s wheat fields. Nutritional deficiencies underlie a substantial portion of the global burden of


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InternalMed_Harrison. FIGURE 151e-2 Acceleration of radiative forcing (RF) from release many infectious diseases. of major greenhouse gases, 1850–2011. For definition of radiative forcing, see footnote b to Table 151e-1. (From Intergovernmental Panel PRECIPITATION on Climate Change Fifth Assessment Report, Working Group 1, Chapter 8, In addition to changing temperature, the emission of greenhouse gases Figure 8.6, p. 677.) and the consequent increase in energy in Earth’s atmosphere have influenced the planet’s water cycle. Since 1950, substantial increases in the heaviest precipitation events (i.e., those above the 95th percentile) have been observed in Europe and North America. While trends over the surface transpiration radiation the surface


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InternalMed_Harrison. FIGURE 151e-3 Earth’s energy balance. (Courtesy of NASA CERES project. Data from Trenberth KE et al: Earth’s global energy budget. Bull Am Meteor Soc 90:311, 2009.) that same interval are less clear in other regions because of limited data, regions of Southeast Asia and southern South America have likely experienced increases in heavy precipitation as well. Other areas have seen greater drought, notably southern Australia and the southwestern United States. A warmer atmosphere holds more water vapor; specifically, there is 6–7.5% more water vapor per degree (Celsius) of warming in the lower atmosphere. For areas that have traditionally had more precipitation on average, warming tends to promote heavier precipitation events. In contrast, in regions prone to drought, warming tends to result in greater periods between rainfalls and in the risk of drought.


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InternalMed_Harrison. The world’s oceans have absorbed 90% of the excess heat that greenhouse gases have kept in Earth’s atmosphere since the 1960s. Ocean heat provides energy for hurricanes, and warmer years tend to have greater hurricane activity. Atlantic hurricanes are the best studied and have the most data available. An analysis of satellite observations from 1983 to 2005 has shown a trend toward increasing severity—albeit decreasing frequency—of Atlantic hurricanes. Modeling of future tropical cyclones suggests that their intensity may increase 2–11% by 2100 and that the average storm will bring 20% more rainfall.


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InternalMed_Harrison. El Niño events drive alterations in weather worldwide (Fig. 151e-4) 151e-3 and are associated with extreme events and consequently higher rates of morbidity and mortality. Hurricane Mitch, one of the most powerful hurricanes ever observed, with winds reaching 290 km/h, dropped 1–1.8 m (3–6 feet) of rain over 72 h on parts of Honduras and Nicaragua. As a result of this storm, 11,000 people died and 2.7 million were displaced. Outbreaks of cholera, leptospirosis, and dengue occurred in the storm’s aftermath.


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InternalMed_Harrison. The final common outcome of all climate change effects is population migration. Sea level rise, extreme heat and precipitation, droughts, and salinization of water supplies all conspire to make regions (including some inhabited by humans for millennia) uninhabitable. Among climate change migrants in the near future may be the inhabitants of low-lying South Pacific islands that are vulnerable to sea level rise and residents of the Alaskan archipelago, where melting of permafrost has rendered traditional means of cold food storage difficult. Climate change may also be contributing to humanitarian crises and conflicts. A severe 2011 drought in East Africa may have incited the Somali famine that resulted in 1 million refugees; mortality rates reached 7.4/10,000 in some refugee camps. Crop losses associated with the 2010


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InternalMed_Harrison. Between 1901 and 2010, the global sea level rose ~200 mm, or ~1.7 mm per year on average. From 1993 to 2010, the rate of rise nearly doubled—i.e., to 3.2 mm annually. Most of this sea level rise has resulted from the thermal expansion of water. Glacial ice melt is the second greatest factor, and its contribution is accelerating. By 2100, global sea level may rise by ≥500 mm from 1986–2005 levels, with an annual rate of rise of 8–16 mm at the century’s end. A large section of the West Antarctic ice sheet has begun to fall apart, and its melting alone may cause sea level to rise by ≥3 m in coming centuries.


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InternalMed_Harrison. Sea level rise is not uniform. The rate of rise on the eastern seaboard of North America has been roughly double the global rate. Compounding sea level rise is the subsidence of coastal areas due to human settlement. In the absence of levee upgrades, an estimated 170 million people living near coasts worldwide will be at risk of flooding in 2100 because of the combined effects of subsidence, erosion, and sea level rise. Along with extreme storms and overuse of coastal aquifers, rising seas also contribute to salinization of coastal groundwater. About 1 billion people rely on coastal aquifers for potable water.


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InternalMed_Harrison. Along with extreme storms and overuse of coastal aquifers, rising seas also contribute to salinization of coastal groundwater. About 1 billion people rely on coastal aquifers for potable water. The El Niño Southern Oscillation (ENSO) refers to periodic changes in water temperature in the eastern Pacific Ocean that occur roughly every 5 years. ENSO cycles have dramatic effects on weather around the globe. Warmer-than-average water temperatures in the eastern Pacific define El Niño events (see below), whereas cooler-than-average water temperatures define La Niña periods. Evidence is accruing that climate change may be increasing the frequency and severity of FIGURE 151e-4 Characteristic weather anomalies, by season, during El Ni events. (Source: El Niño events. www.cpc.ncep.noaa.gov/products/precip/CWlink/ENSO/ENSO-Global-Impacts/High-Resolution/.) Russian heat wave led Russia to halt grain exports, causing higher grain prices on the world market and food riots in developing nations.


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InternalMed_Harrison. Russian heat wave led Russia to halt grain exports, causing higher grain prices on the world market and food riots in developing nations. The incidence of most, if not all, infectious diseases depends on climate. For any given infection, however, climate change is but one of many factors that determine disease epidemiology, and often it is not the most influential factor. Even in instances in which climate change creates conditions favorable to the spread of infections, diseases may be kept in check through interventions such as vector control or antibiotic treatment.


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InternalMed_Harrison. Detecting climate-change influence on an emerging human disease can be challenging. Research with animal pathogens, which in most instances is less well monitored and intervened upon than that with their human counterparts, has suggested how climate change may influence disease spread. For example, the life cycle of nematode parasites of caribou and musk oxen shortens as temperatures rise. As the Arctic has warmed, higher nematode burdens and consequently higher rates of morbidity and mortality have been observed. Other examples from animals, such as the spread of the protozoan parasite Perkinsus marinus in oysters, demonstrate how warming can enable range expansion of pathogens previously held in check by colder temperatures. As these and other examples from studies of animals make clear, the influence of climate change on infectious diseases can be pronounced. The following sections deal with the infectious diseases for which research has explored the influence of climate change.


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InternalMed_Harrison. Because insects are cold-blooded, ambient temperature dictates their geographic distribution. With increases in temperatures (in particular, nighttime minimum temperatures), insects are freed to move poleward and up mountainsides. At the same time, as new areas become climatically suitable, current mosquito habitats may become unsuitable as a result of heat extremes. In addition, insects tend to be sensitive to water availability. Mosquitoes that transmit malaria, dengue, and other infections may breed in pools of water created by heavy downpours. As has been observed in the Amazon, breeding pools can also appear during periods of drought when rivers recede and leave behind stagnant pools of water for Anopheles mosquitoes. These circumstances have raised interest in the potentially favorable impact of water-cycle intensification on the spread of mosquito-borne disease.


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InternalMed_Harrison. Malaria • TEMPERATURE Higher temperatures promote higher mosquito-biting rates, shorter parasite reproductive cycles, and the potential for the survival of mosquito vectors of Plasmodium infection in locations previously too cold to sustain them. Recent modeling experiments identify highland areas of East Africa and South America as perhaps most vulnerable to increased malarial incidence as a result of rising temperatures. In addition, a recent analysis of interannual malaria in Ecuador and Colombia has documented a greater incidence of malaria at higher altitudes in warmer years. Highland populations may be more vulnerable to malaria epidemics because they lack immunity.


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InternalMed_Harrison. Although rising temperature has the potential to expand the viable range of disease, malaria incidence is not associated with temperature in a strictly linear fashion. While mosquitoes and parasites may adapt to a warming climate, the present optimal temperature for malaria transmission is ~25°C, with a range of transmission temperatures between 16°C and 34°C. Rising temperatures also can have differential effects on parasite development during external incubation and on the mosquitoes’ gonotrophic cycle. Asynchrony between these two temperature-sensitive processes has been shown to decrease the vectorial capacity of mosquitoes.1 1rVc is the vectorial capacity relative to the vector-to-human population ratio and is defined by the equation rVc = a2bhbme–μmn/μm where a is the vector biting rate; bh is the probability of vector-to-human transmission per bite; bm is the probability of human-to-vector infection per bite; n is the duration of the extrinsic incubation period; and μm is the


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InternalMed_Harrison. rate; bh is the probability of vector-to-human transmission per bite; bm is the probability of human-to-vector infection per bite; n is the duration of the extrinsic incubation period; and μm is the vector mortality rate.


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InternalMed_Harrison. PRECIPITATION The abundance of Anopheles mosquitoes is strongly correlated with the availability of surface water pools for mosquito breeding, and biting rates have been linked to soil moisture (a surrogate for breeding pools). Research in the East African highlands has documented that increased variance in rainfall over time has strengthened the association between precipitation and disease incidence. These disease-promoting effects of precipitation may be countered by the potential for extreme rainfall to flush mosquito larvae from breeding sites.


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InternalMed_Harrison. PROJECTIONS Climate models have begun to deliver output on regional scales, permitting projections of climate-suitable regions to assist national and local health authorities. Climate models speak to the temperature and precipitation ranges necessary for malaria transmission but do not—and cannot—account for the capacity of malaria control programs to halt the spread of disease. The global reduction in malaria distribution over the past century makes it clear that, even with climate change, malaria occurs in far fewer places today because of public health interventions.


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InternalMed_Harrison. Despite intensive efforts, malaria remains the single greatest vector-borne disease cause of morbidity and death in the world. Particularly in regions that are most affected by malaria and where the public health infrastructure is inadequate to contain it, climate modeling may provide a useful tool in determining where the disease may spread. Recent modeling studies in sub-Saharan Africa have suggested that, although East African nations may encompass regions that will become more climatically suitable for malaria over this century, West African nations may not. By 2100, temperatures in West Africa may largely exceed those optimal for malaria transmission, and the climate may become drier; in contrast, higher temperatures and changes in precipitation may allow malaria to move up the mountainsides of East African countries. Climate change may create conditions favorable to malaria in subtropical and temperate regions of the Americas, Europe, and Asia as well.


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InternalMed_Harrison. Dengue Like malaria epidemics, dengue fever epidemics depend on temperature (Fig. 151e-5). Higher temperatures increase the rate of larval development and accelerate the emergence of adult Aedes mosquitoes. The daily temperature range may also influence dengue virus transmission, with a smaller range corresponding to a higher transmission potential. Temperatures <15°C or >36°C also substantially reduce mosquito feeding. In a Rhesus model of dengue, viral replication can occur in as little as 7 days with temperatures of >32–35°C; at 30°C, replication takes ≥12 days; and replication does not reliably occur at 26°C. Research on dengue in New Caledonia has shown peak transmission at ~32°C, reflecting combined effects of a shorter extrinsic incubation period, a higher feeding frequency, and more rapid development of mosquitoes. Along with temperature, peak relative humidity is a strong predictor of dengue outbreaks.


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InternalMed_Harrison. The association between dengue epidemics and precipitation is less consistent in the peer-reviewed literature, possibly because of the mosquito vector’s greater reliance on domestic breeding sites than on natural pools of water. For instance, in some studies, increased access to a piped water supply has been linked to dengue epidemics, presumably because of associated increased domestic water storage. Nonetheless, several studies have established rainfall as a predictor of the seasonal timing of dengue epidemics.


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InternalMed_Harrison. The current global distribution of dengue largely overlaps the geographic spread of Aedes mosquitoes (Fig. 151e-6). The presence of Aedes without dengue endemicity in large regions of North and South America and Africa illustrates the relevance of variables other than climate to disease incidence. Nevertheless, coupled climatic– epidemiologic modeling suggests dramatic shifts in the relative vectorial capacity for dengue by the end of this century should little or no mitigation of greenhouse gas emissions occur (Fig. 151e-7). Other Arbovirus Infections Climate change may favor increased geographic spread of other arboviral diseases, including Chikungunya virus disease, West Nile virus disease, and eastern equine encephalitis. Chikungunya virus disease emerged in Italy in 2007, having previously Days (EIP length and development to adult)


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InternalMed_Harrison. Days (EIP length and development to adult) FIGURE 151e-5 Effects of temperature on variables associated with dengue transmission. Shown are the number of days required for development of immature Aedes aegypti mosquitoes to adults, the length of the dengue virus type 2 extrinsic incubation period (EIP), the percentage of A. aegypti mosquitoes that complete a blood meal within 30 min after a blood source is made available, and the percentage of hatched A. aegypti larvae surviving to adulthood. (Reproduced from CW Morin et al: Climate and dengue transmission: evidence and implications.


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InternalMed_Harrison. Environ Health Perspect 121:1264, 2013.) been mostly a disease of African nations. Climate models predict that, should competent vectors be present, conditions will be suitable for Chikungunya virus to gain a foothold in Western Europe, especially France, in the first half of the twenty-first century. In North America, areas favorable to West Nile virus outbreaks are expected to shift northward in this century. Current hotspots in North America are the California Central Valley, southwestern Arizona, southern Texas, and Louisiana, which have both compatible climates and avian reservoirs for the disease. By mid-century, the upper Midwest and New England will be more climatically suited to West Nile virus; by the end of the century, the area of risk may shift even further north to southern Canada. Whether the disease will ultimately move northward will depend on reservoir availability and mosquito control programs, among other factors.


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InternalMed_Harrison. Whether the disease will ultimately move northward will depend on reservoir availability and mosquito control programs, among other factors. Lyme Disease In the past few decades, Ixodes scapularis, the primary tick vector for Lyme disease as well as for anaplasmosis and babesiosis in New England, has become established in Canada because of warming temperatures. With climate change, the range of the tick is expected to expand further (Fig. 151e-8). Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most commonly reported vector-borne disease in North America, with ~30,000 cases per year. The model used in Fig. 151e-8 showed 95% FIGURE 151e-6 Distribution of Aedes aegypti mosquitoes (turquoise) and dengue fever epidemics (red). (Map produced by the Agricultural Research Service of the U.S. Department of Agriculture.) 0.21 0.12 0.06 0.03 –0.03 –0.06 0.52 0.41 0.26 0.12 0.06 0.03 –0.03 –0.06 –0.12 –0.26 –0.41 –0.52


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InternalMed_Harrison. FIGURE 151e-7 Trend of annually averaged global dengue epidemic potential (rVc). Differences in rVc are based on 30-year averages of temperature and daily temperature range. A. Differences between 1980–2009 and 1901–1930. B. Differences between 2070–2099 and 1980–2009. The mean value of rVc was averaged from five global climate models under RCP8.5, a scenario of high greenhouse-gas emission. The color bar describes the values of the rVc. (From J Liu-Helmersson et al: Vectorial capacity of Aedes aegypti: effects of temperature and implications for global dengue epidemic potential. PLoS ONE 9:e89783, 2014 [doi:10.1371/journal.pone.0089783].) accuracy in predicting current I. scapularis distribution and suggests substantial expansion of tick habitat and consequently of populations at risk for the diseases this tick transmits, particularly in Quebec, Iowa, and Arkansas, by 2080. Of note, some areas on the Gulf Coast may become less suitable for ticks by the end of the century.


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InternalMed_Harrison. Outbreaks of waterborne disease are associated with heavy rainfall events. A review of 548 waterborne disease outbreaks in the United States found that 51% were preceded by precipitation levels above the 90th percentile. Since 1900, most regions of the United States except the Southwest and Hawaii have experienced an increase in heavy downpours (Fig. 151e-9), with the greatest intensification of the water cycle in New England and Alaska. Climate models suggest that by 2100 daily heavy-precipitation events, which are defined as a cumulative daily amount that now occurs once every 20 years, will increase nationwide (Fig. 151e-10). This scenario may be from two to as much as five times more likely, depending on the extent of greenhouse gas emission reductions achieved early in the twenty-first century.


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InternalMed_Harrison. FIGURE 151e-8 Present and projected probability of establishment of Ixodes scapularis. (From U.S. National Climate Assessment 2014, adapted from JS Brownstein et al: Effect of climate change on Lyme disease risk in North America. Ecohealth 2:38, 2005.) U.S. average 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Northeast 1900s20s 40s60s 80s00s Change (%) –50 0 50 DecadeMidwest 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Great Plains, north 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Great Plains, south 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Southeast 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Southwest 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Northwest 1900s20s 40s60s 80s00s Change (%)–50 0 50 Decade Hawaii 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Alaska 1900s20s 40s60s 80s00s Change (%) –50 0 50 Decade Observed change in very heavy precipitation


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InternalMed_Harrison. FIGURE 151e-9 Percentage changes in the annual amount of precipitation falling in very heavy events, defined as the heaviest 1% of all daily events from 1901 to 2012 for each region. Changes are relative to a 1901–1960 average for all regions except values for Alaska and Hawaii, which are relative to the 1951–1980 average. (From U.S. National Climate Assessment 2014, NOAA National Climate Data Center/Cooperative Climate Change and Infectious Disease Institute for Climate and Satellites, North Carolina.) Projected change in heavy precipitation events Rapid emissions reductions (RCP 2.6) Continued emissions increases (RCP 8.5)


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InternalMed_Harrison. FIGURE 151e-10 Increased frequency of extreme daily precipitation events (defined as a daily amount that now occurs once in 20 years) by the latter part of the twenty-first century (2081–2100) compared to the frequency in the latter part of the twentieth century (1981–2000). A representative concentration pathway (RCP) describes a plausible climate future based on a net radiative forcing (e.g., 2.6 or 8.5) in 2100. (From U.S. National Climate Assessment 2014, NOAA National Climate Data Center/Cooperative Institute for Climate and Satellites, North Carolina.) 151e-8 Most disease outbreaks after heavy precipitation occur through contamination of drinking-water supplies. While outbreaks related to surface-water contamination generally occur within a month of the precipitation event, disease outbreaks from groundwater contamination tend to occur ≥2 months later. According to a review of published reports of waterborne disease outbreaks, Vibrio and Leptospira species are the pathogens most


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InternalMed_Harrison. from groundwater contamination tend to occur ≥2 months later. According to a review of published reports of waterborne disease outbreaks, Vibrio and Leptospira species are the pathogens most commonly involved in the wake of heavy precipitation.


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InternalMed_Harrison. Combined Sewer Systems Roughly 40 million people in the United States and millions more around the world rely on combined sewer systems in which storm water and sanitary wastewater are conveyed in the same pipe to treatment facilities. These systems were designed on the basis of the nineteenth-century climate, in which heavy downpours were less frequent than they are today. The frequency of combined sewer overflows resulting in untreated sewage discharge, usually into freshwater bodies, has been increasing in cities worldwide. Overflows are associated with discharges of heavy metals and other chemical pollutants as well as a variety of pathogens. Outbreaks of hepatitis A, Escherichia coli O157:H7 infection, and cryptosporidial disease have been associated with sewer overflows in the United States.


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InternalMed_Harrison. Rising Temperatures and Vibrio Species Warmer temperatures favor proliferation of Vibrio species and disease outbreaks, as has been demonstrated in countries surrounding the Baltic Sea, Chile, Israel, northwestern Spain, and the U.S. Pacific Northwest. Around the Baltic Sea, outbreaks of Vibrio infection may be particularly likely because of faster warming near the poles and the sea’s relatively low salt content. In 2004, a Vibrio parahaemolyticus outbreak occurred from consumption of Alaskan oysters. This pathogen was unknown in Alaskan oysters prior to this event and extended the known geographic range of the disease 1000 km northward.


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InternalMed_Harrison. In the past, El Niño events were used as a model to investigate the potential for extreme weather–related infectious disease epidemics occurring in association with climate change. Recent evidence has indicated that climate change itself may be strengthening El Niño events. These events tend to promote epidemic infections in certain regions (Fig. 151e-11). Associations of El Niño with outbreaks of Rift Valley fever in east ern and southern Africa have been known since the 1950s. El Niño favors wet conditions suitable for the insect vectors of the disease in these regions. Given the strong association between El Niño conditions and disease incidence, models have successfully predicted Rift Valley fever epidemics in humans and animals. In the 2006–2007 El Niño season, for example, outbreaks of Rift Valley fever were accurately predicted 2–6 weeks prior to epidemics in Somalia, Kenya, and Tanzania.


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InternalMed_Harrison. El Niño has had inconsistent associations with malaria incidence in African countries. Some of the strongest associations between El Niño and malaria have been identified in South Africa and Swaziland, where available data on incidence are relatively robust; however, even in these instances, the observed increased risk did not reach statistical significance. A stronger link to El Niño has been found in several studies done in South America. Research on malaria incidence in Colombia between 1960 and 2006 found that a 1°C temperature rise contributed to a 20% increase in incidence. El Niño years are often associated with an increased incidence of dengue. Research on dengue outbreaks in Thailand from 1996 to 2005 revealed that 15–22% of the variance in monthly dengue disease incidence was attributable to El Niño. In South America, data on dengue outbreaks between 1995 and 2010 showed an increased incidence during the El Niño events of 1997–1998 and 2006–2007.


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InternalMed_Harrison. CLIMATE CHANGE, POPULATION DISPLACEMENT, AND INFECTIOUS DISEASE EPIDEMICS For many reasons, including freshwater shortages, flooding, food shortages, and climate change–driven conflicts, climate change has and will continue to put pressure on human populations to move. Human migrations have long been associated with epidemic disease in the migrating populations themselves and in the communities in which they settle. The specific pathogens and patterns of disease that may appear after population migration relate to endemic diseases present in the migrant populations.


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InternalMed_Harrison. Large-scale migrations are common after extreme precipitation events. Hurricane Katrina, for instance, displaced about 1 million people from the U.S. Gulf Coast. Among Katrina refugees, outbreaks of respiratory, diarrheal, and skin diseases were most common. While attribution of a single weather event to increased greenhouse gas emissions is difficult, research can provide information on the likelihood of such events. It is expected, for example, that warming by 1°C increases the odds of a storm as strong as or stronger than Katrina by twoto sevenfold. In the developing world, infectious disease outbreaks associated with population displacement due to extreme weather events may be


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InternalMed_Harrison. In the developing world, infectious disease outbreaks associated with population displacement due to extreme weather events may be FIGURE 151e-11 Characteristic patterns of disease outbreaks associated with El Ni events, determined on the basis of 2006–2007 conditions. (From A Anyamba et al: Developing global climate anomalies suggest potential disease risks for 2006–2007. Int J Health Geogr 5:60, 2006.) especially hard to detect and respond to. Mitigation of disease risk requires overlaying of climate-related migration risk with foci of disease epidemics.


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InternalMed_Harrison. Climate change has far-reaching implications for the distribution and spread of infectious diseases worldwide. However, the greatest disease burdens related to climate change may not be due to infections. Because climate change disrupts the foundations of health, such as access to safe drinking water and food, it has the potential to undermine progress against major existing health problems such as malnutrition. In addition, resource scarcity and climate instability are increasingly associated with conflicts. Scholars have argued that events related to climate change were a factor in the revolutions of the Arab Spring and the Syrian civil war.


InternalMed_Harrison

InternalMed_Harrison. The public health response to climate change entails both mitigation 151e-9 and adaptation measures. Mitigation represents primary prevention and involves the reduction of greenhouse gas emissions into the atmosphere. Although no clear safety threshold of greenhouse gas emissions has been agreed upon, national governments from the major industrialized countries have agreed to set a warming target of <2°C above preindustrial levels by 2050; the attainment of this goal will require reducing greenhouse gas emissions by 40–70% below 2010 levels. To date, no international agreement exists to facilitate this reduction. Adaptation represents secondary prevention and is aimed at reducing the harms associated with sea level rise, heat waves, floods, droughts, wildfires, and other greenhouse gas–driven events. The efficacy of adaptation is constrained by the challenges inherent in predicting the precise location, duration, and severity of extreme weather events and flooding related to sea level


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InternalMed_Harrison. events. The efficacy of adaptation is constrained by the challenges inherent in predicting the precise location, duration, and severity of extreme weather events and flooding related to sea level rise, among other considerations.


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InternalMed_Harrison. Infections in Veterans Returning from Foreign Wars Andrew W. Artenstein Wars are an unfortunate but apparently inescapable consequence of human socialization. In the past quarter-century alone, there have 152e been dozens of major armed conflicts worldwide. Several of these wars have been multinational in scope and have involved the deployment of large numbers of ground forces from their home countries to distinct areas of conflict in developing portions of the world, such as southwest and central Asia (e.g., Iraq, Afghanistan) and Africa.


InternalMed_Harrison

InternalMed_Harrison. Troops who are deployed as combatants or in other military capacities on foreign soil are at risk of acquiring infectious diseases endemic to that region on the basis of intimate human and environmental exposures and their immunologic naiveté with regard to local endemic or enzootic pathogens. This risk is magnified by the crowded social conditions engendered by mass troop deployments, infrastructure destruction, and population displacement; it is further amplified by vulnerabilities in public health, such as the lapses in hygiene and sanitation that invariably accompany armed conflicts. The clinical spectrum of infectious illness acquired in this setting includes acute infections in the combat theater, acute infections with delayed symptoms, and chronic or relapsing infections. The latter two scenarios have the potential to cause illness in veterans returning from foreign wars.


InternalMed_Harrison

InternalMed_Harrison. The impact of acute infectious diseases of war, which were once a major cause of noncombat mortality, has significantly lessened in modern conflicts, largely because of the use of preventive vaccines and the early institution of antimicrobial therapy. Nonetheless, these acute diseases remain an important cause of morbidity in deployed military personnel (Table 152e-1). Many acute infectious diseases, such as influenza, meningococcal meningitis, hepatitis A, and adenoviral respiratory disease, can largely be prevented by routine vaccination of troops. Others, such as bacterial gastroenteritis and viral respiratory tract infections, continue to represent common causes of minor morbidity among deployed forces. The incidence of several other acute infections, such as malaria and dengue, can be favorably impacted— although not completely abrogated—by the use of chemoprophylaxis, personal protective measures, and vector control. Uncommonly, infections that have short incubation periods and


InternalMed_Harrison

InternalMed_Harrison. favorably impacted— although not completely abrogated—by the use of chemoprophylaxis, personal protective measures, and vector control. Uncommonly, infections that have short incubation periods and are acquired just days before leaving a combat theater may become clinically manifest only upon the return of troops to their countries of origin. Such was the case in a cluster of African tick typhus that occurred during short-term


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InternalMed_Harrison. U.S. troop deployments to Somalia and Botswana in the early 1990s. However, because most acute infections with brief clinical incubation periods are self-limited or responsive to treatment, they are not typically seen in returning war veterans and will not be addressed further in this chapter. A number of infectious diseases acquired in a theater of military operations may become apparent in veterans only after they have returned to their home countries. Although their incidences have not been precisely defined, these complications of military service—manifesting clinically with either acute or chronic signs and symptoms— may cause significant morbidity in affected veterans and in some settings may endanger public health through secondary transmission or contamination of the blood supply. Of a sample of nearly 53,000 U.S.


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InternalMed_Harrison. U.S. veterans of the Persian Gulf War (1990–1991), 7% were diagnosed with an infectious disease in the aftermath of the war; no excess risk of mortality was observed over a 6-year follow-up comparison with nondeployed veterans. This chapter focuses on infectious diseases that have occurred or have been a source of concern in returning veterans of foreign wars over the past quarter-century. During this period, several pathogens have been associated with disease in this population, as discussed below. Some pathogens have been associated with only rare case reports in war veterans, and some, given their epidemiology, may pose Gastroenteritis (enterotoxigenic or enteroinvasive Escherichia coli, Shigella, Salmonella, Campylobacter) Typhus (epidemic, murine, scrub) Sexually transmitted diseases (gonorrhea, chlamydial infection, genital her pes, genital warts, chancroid, syphilis) Combat wound infections Q fever


InternalMed_Harrison

InternalMed_Harrison. Typhus (epidemic, murine, scrub) Sexually transmitted diseases (gonorrhea, chlamydial infection, genital her pes, genital warts, chancroid, syphilis) Combat wound infections Q fever Norovirus gastroenteritis West Nile virus infection Crimean-Congo hemorrhagic fever Influenza Adenoviral respiratory disease Viral upper respiratory tract infections Dengue Alphavirus infections (e.g., Chikungunya, O'nyong-nyong, or Sindbis virus) Tickborne encephalitis Sandfly fever Hantavirus syndromes


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InternalMed_Harrison. Gastroenteritis (cryptosporidiosis, giardiasis, amebiasis) a risk in future conflicts. In general, it is practical to classify infections with delayed signs and symptoms related to prolonged incubation periods or significant clinical latency in terms of their potential to manifest clinically as acute illnesses or chronic/relapsing diseases. Table 152e-2 provides details regarding the epidemiology, clinical characteristics, diagnosis, therapy, and prevention of infectious diseases of concern in returning war veterans. Figure 152e-1 illustrates a differential diagnostic approach—based on prominent signs or symptoms—to suspected infections in this population.


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InternalMed_Harrison. ACUTE INFECTIOUS DISEASES WITH DELAYED CLINICAL PRESENTATIONS Malaria (See Chap. 248) Malaria, which is due to infection with Plasmodium species of protozoa, has historically caused significant battlefield morbidity and lost duty time among armed forces; these phenomena have been affirmed by recent U.S. military experiences in Africa and central Asia. Because of its worldwide prevalence and its pathophysiology, malaria remains an important cause of infection both during military operations and in returning war veterans.


InternalMed_Harrison

InternalMed_Harrison. The risk of malaria is exacerbated by several factors inherent to war: inadequate shelter promoting increased troop exposure to vectors; abeyance of governmental programs for vector control; and ecologic changes leading to an increased vector presence in the contested environment. Because of the complex life cycle of the parasite and the predilection of P. vivax and P. ovale to remain latent in their liver stages of development for prolonged periods, malaria in foreign-stationed troops may become clinically apparent only after their return home. In the aftermath of the Vietnam War, more than 13,000 cases of malaria—the vast majority due to P. vivax—were imported into the United States. Of the 7683 Soviet troops diagnosed with P. vivax InFECTIous DIsEAsEs AssoCIATED WITH DElAyED ClInICAl mAnIFEsTATIons THAT mAy PREsEnT WITH ACuTE, CHRonIC, oR RElAPsIng CouRsEs In VETERAns RETuRnIng FRom RECEnT FoREIgn WARs


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InternalMed_Harrison. InFECTIous DIsEAsEs AssoCIATED WITH DElAyED ClInICAl mAnIFEsTATIons THAT mAy PREsEnT WITH ACuTE, CHRonIC, oR RElAPsIng CouRsEs In VETERAns RETuRnIng FRom RECEnT FoREIgn WARs InFECTIous DIsEAsEs AssoCIATED WITH DElAyED ClInICAl mAnIFEsTATIons THAT mAy PREsEnT WITH ACuTE, CHRonIC, oR RElAPsIng CouRsEs In VETERAns RETuRnIng FRom RECEnT FoREIgn WARs (CONTINUED) Cryptosporidiosis Cryptosporidium Worldwide Fecal-oral 3–6 days Symptoms as above; Fecal microscopy or No specific anti-Food and water hygiene 254 spp. chronic watery diarrhea, intestinal biopsy; stool parasitic therapy for with or without fever, antigen assay postinfectious syn-abdominal pain, nausea


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InternalMed_Harrison. chronic watery diarrhea, intestinal biopsy; stool parasitic therapy for with or without fever, antigen assay postinfectious syn-abdominal pain, nausea Strongyloidiasis Strongyloides Tropical and subtropi-Fecal-oral as 11–28 days Abdominal pain, persis-Stool antigen detec-Ivermectin; thiaben-Personal protective 257 stercoralis cal climates initial route; per- tent diarrhea, urticaria; tion assay; serology dazole or albendazole measures, includsistent infection cause wasting, pulmonary symptoms, eosinophilia Sandfly fever Phleboviruses Africa, Asia, South and Vector Weeks to Depression, fatigue, gener-Serology No specific therapy Personal protective 233 (convalescence) Central America (Phlebotomus spp. months for alized weakness


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InternalMed_Harrison. Central America (Phlebotomus spp. months for alized weakness Relapsing fever Borrelia recurren-Worldwide Vector (body 4–18 days Recurrent episodes of fever, Spirochetes on stained Tetracycline or eryth-Personal protective 209 tis (louse-borne, louse; soft tick) initially, with rigors, diaphoresis, head-peripheral-blood romycin; antibiotic measures; vector epidemic), Borrelia relapses after ache, myalgias, arthralgias, smear during febrile treatment may lead control spp. (tick-borne, 7to 10-day asthenia lasting 3–6 days episodes to Jarisch-Herxheimer endemic) intervals and alternating with symp reaction with fever, tom-free periods rigor, hypotension within 2 h of initiation Brill-Zinsser Rickettsia prowazekii Worldwide Vector (body Recrudescent Mild febrile illness with Serology Doxycycline or Vector control; personal 211 disease appropriate treatment episode of epi


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InternalMed_Harrison. Brill-Zinsser Rickettsia prowazekii Worldwide Vector (body Recrudescent Mild febrile illness with Serology Doxycycline or Vector control; personal 211 disease appropriate treatment episode of epi Chronic wound Acinetobacter Worldwide Inoculation via Weeks to Chronic pain, swelling, ± Culture of tissue Guided by results of Adequate initial wound Miscellaneous infection spp., other gram- and penetrating gression of lent drainage of infected antibiotic susceptibil-treatment of acute soft- injury acute infection site with or without consti ity testing; carbape-tissue infection; removal aureus, including nem ± amikacin as of foreign bodies; strict MRSA; invasive empirical therapy for adherence to infection molds (Aspergillus, multidrug-resistant control precautions to Fusarium, Mucor, Acinetobacter; colistin prevent nosocomial Absidia spp.); atypi (M. chelonei, M. abscessus) associated with draining sinuses


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InternalMed_Harrison. Acinetobacter; colistin prevent nosocomial Absidia spp.); atypi (M. chelonei, M. abscessus) associated with draining sinuses InFECTIous DIsEAsEs AssoCIATED WITH DElAyED ClInICAl mAnIFEsTATIons THAT mAy PREsEnT WITH ACuTE, CHRonIC, oR RElAPsIng CouRsEs In VETERAns RETuRnIng FRom RECEnT FoREIgn WARs (CONTINUED) • Schistosomiasis, including Katayama fever • Strongyloidiasis • Visceral larva migrans • Filariasis • Echinococcal disease FIGURE 152e-1 Syndromic approach to the differential diagnosis of suspected infection in a veteran who has returned from a foreign war in southwest Asia, central Asia, or Africa at least 2 weeks prior to clinical presentation. HBV, hepatitis B virus. malaria acquired during the U.S.S.R.’s war in Afghanistan in the 1980s, 76% developed clinical manifestations >1 month after their return to the U.S.S.R., with some cases developing as long as 3 years later.


InternalMed_Harrison

InternalMed_Harrison. Imported malaria with prolonged clinical latency periods remains a problem among veterans returning from wars in endemic areas. In a cluster of 112 cases of imported disease in U.S. Marines returning to the United States from deployment to Somalia in 1993, falciparum malaria was diagnosed as late as 12 weeks after return; some cases due to P. vivax were diagnosed after an additional 2 months. In an outbreak of imported P. vivax malaria among U.S. Army Rangers deployed to Afghanistan in 2002, the median time to diagnosis was nearly 8 months after return.


InternalMed_Harrison

InternalMed_Harrison. Although malaria is largely preventable through the combined use of vector control, personal protective measures (e.g., bed nets, insect repellent, long sleeves, permethrin-treated clothing), and chemoprophylaxis, nonadherence to these measures and/or to chemotherapy (including terminal primaquine prophylaxis to eradicate the liver stage of P. vivax) appears to be responsible for the majority of cases in recent U.S. military experiences. However, there is also evidence to support chemoprophylaxis failures in a small subgroup of cases of P. falciparum and P. vivax malaria acquired during U.S. deployments to Somalia. Thus, imported malaria in returning war veterans remains possible despite appropriate adherence to chemoprophylaxis.


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InternalMed_Harrison. Viral Hepatitis (See Chap. 360) The incidence of viral hepatitis, once a major scourge of military campaigns and their aftermath, has declined considerably over the past half-century of military engagements. Although more than 115,000 cases of viral hepatitis, most due to hepatitis A virus, were reported among Soviet troops serving in Afghanistan in the 1980s, only rare reports of hepatitis A and B were noted during the massive, short-term deployment of U.S. troops to the Persian Gulf in the early 1990s. Hepatitis A and E, endemic in many parts of the developing world, present clinically as acute infections transmitted by the fecal-oral route and can be largely controlled with interventions practiced widely among military forces from industrialized countries: appropriate food and water hygiene and pre-deployment vaccination against hepatitis A. Hepatitis B contamination of serum-stabilized yellow fever vaccine caused a large outbreak of the disease among


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InternalMed_Harrison. U.S. forces during World War II; such events are currently unlikely, given the use of modern virus-inactivation techniques in vaccine manufacturing. Despite their potential—as a consequence of their long clinical incubation and latency periods—to cause disease in returning veterans, hepatitis B and hepatitis C have been acquired relatively rarely in theater because of risk factor mitigation: routine drug testing of modern armies and screening of the blood supply to exclude viral contamination.


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InternalMed_Harrison. Rabies (See Chap. 232) Deployed soldiers are often in close contact with feral dogs and other potentially rabid animals in both urban and remote combat environments. In the period 2001–2010, 643 animal bites were documented during medical encounters among U.S. forces in the combat theaters of southwest and central Asia; the majority of these potential exposures were dog bites. Of bitten personnel, 18% received rabies postexposure prophylaxis. Recently, a U.S. soldier developed rapidly progressive signs and symptoms of rabies 8 months after a dog bite in Afghanistan and died within 17 days of illness onset. This case, which represents the first rabies death in nearly 40 years in a member of the U.S. military who acquired the infection overseas, reinforces both the lethality of the disease and the need to practice vigilant exposure precautions among deployed military personnel and to administer postexposure prophylaxis to troops who are bitten by animals in high-risk areas.


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InternalMed_Harrison. CHRONIC OR RELAPSING INFECTIOUS DISEASES ACQUIRED IN THE THEATER OF WAR Leishmaniasis (See Chap. 251) Various forms of leishmaniasis may be acquired during military deployment and may present with myriad chronic clinical manifestations in war veterans. Because the protozoal pathogens (Leishmania species) are endemic throughout much of southwest and central Asia, their associated diseases have occurred in veterans returning from several recent conflicts there. The widespread distribution of various species of Leishmania elsewhere throughout the developing world suggests that leishmaniasis may complicate future conflicts as well.


InternalMed_Harrison

InternalMed_Harrison. Leishmaniasis may present clinically as cutaneous, mucocutaneous, or visceral disease; all forms are transmitted to humans by the bite of infected phlebotomine sandflies via zoonotic (small mammal) reservoirs. In rare circumstances, infection may be transmitted through blood transfusion. Transmission to humans is enhanced by factors that bring them into close proximity to animal reservoirs, such as life in dense, mobile populations; disruption of ecologic niches; and infrastructural breakdown. All these factors are common sequelae of war. At least 1300 cases of cutaneous leishmaniasis caused by L. major or


InternalMed_Harrison

InternalMed_Harrison. At least 1300 cases of cutaneous leishmaniasis caused by L. major or L. tropica have been diagnosed in American soldiers deployed to Iraq and Afghanistan over the past decade; however, the actual burden of infection may be higher due to underreporting, as lesions spontaneously resolve in many cases. The infection manifests clinically as one or more chronic, painless skin ulcers or nodules that may persist for 6–12 months. Rarely, lesions of cutaneous leishmaniasis may disseminate locally or diffusely.


InternalMed_Harrison

InternalMed_Harrison. Visceral disease (kala-azar) is typically caused by L. donovani and may be life-threatening. There have been at least five confirmed reports of U.S. veterans returning from recent deployments with classic visceral leishmaniasis associated with chronic fever, weight loss, pancytopenia, hypergammaglobulinemia, and organomegaly. As systemic leishmanial infection is known to manifest clinically years after exposure and may recrudesce if host immunity wanes due to unrelated causes, it remains possible that additional cases may yet surface.


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InternalMed_Harrison. Chronic Diarrhea Although acute bacterial gastroenteritis remains a major noncombat cause of morbidity and duty days lost during troop deployments, chronic illness is unusual. However, selected bacterial and parasitic enteric pathogens may cause chronic infections or illnesses in returning veterans. Although such infections have been uncommonly noted in recent deployments, they pose potential threats in future wars because of their worldwide prevalence.


InternalMed_Harrison

InternalMed_Harrison. Giardiasis (Chap. 254), amebiasis (Chap. 247), and cryptosporidiosis (Chap. 254), which usually cause self-limited protozoal gastroenteritis in immunocompetent hosts, may result in persistent symptoms in immunocompromised populations or when complicated by secondary illness. Giardia infection has been associated with chronic diarrhea due to postinfectious irritable bowel syndrome and with chronic signs and symptoms of systemic illness in association with postinfection fatigue or protein-losing enteropathy. Cryptosporidiosis also may cause chronic diarrhea or malabsorptive syndromes in immunocompromised individuals. Amebic infection of the colon may be associated with several serious complications, including perforation, fistulae, and obstruction; extraintestinal spread of amebiasis may result in hepatic invasion leading to abscess formation.


InternalMed_Harrison

InternalMed_Harrison. Systemic Illness Due to Enteric Pathogens Certain helminthic infections are endemic in many parts of the developing world and may pose continuing risks to infected military personnel after their return. Larvae of the intestinal nematode Strongyloides stercoralis (Chap. 257) either may be passed in the feces and develop into the infective stage in the external environment or may persist in the human small intestine and initiate new infective cycles in a process known as autoinfection. Autoinfection with Strongyloides may result in chronic clinical manifestations such as pruritus, rash, abdominal pain, weight loss, diarrhea, and eosinophilia. In immunocompromised hosts, chronic strongyloidiasis may cause a life-threatening hyperinfection syndrome, likely triggered by high parasite burdens and resulting in a multiorgan, systemic illness consistent with severe inflammatory response syndrome. In some cases, Strongyloides hyperinfection syndrome may be complicated by gram-negative sepsis or


InternalMed_Harrison

InternalMed_Harrison. resulting in a multiorgan, systemic illness consistent with severe inflammatory response syndrome. In some cases, Strongyloides hyperinfection syndrome may be complicated by gram-negative sepsis or meningitis related to bacterial seeding from parasitic involvement of the lungs or gastrointestinal tract. Although not described in association with recent wars, chronic strongyloidiasis was an uncommon phenomenon affecting a small number of World War II and Vietnam War veterans; one study estimated that there were up to 400 affected individuals still living in Great Britain. The pathogen may pose a risk to troops deployed in the future to tropical and subtropical regions of the world where the parasite is endemic.


InternalMed_Harrison

InternalMed_Harrison. Chronic schistosomiasis (Chap. 259) results from intravascular infection by trematode parasites whose larval forms penetrate the skin of humans through contact with freshwater inhabited by the snail intermediate host. The pathogens are widely distributed throughout large portions of the developing world. A chronic inflammatory response in the portal circulation to the eggs of S. mansoni and S. japonicum leads to fibrosing disease in the liver and eventually to cirrhosis. Similar pathophysiologic events occur in the vascular plexus of the human genitourinary tract in response to chronic S. haematobium infection, leading to fibrosing changes in the human bladder and ureters—a precursor to bladder cancer. Rarely, individuals with chronic schistosomiasis develop a syndrome of persistent or relapsing bacteremia with Salmonella typhi, which is the etiologic agent of typhoid fever and is not otherwise a typical infectious cause of chronic disease in veterans.


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InternalMed_Harrison. Other Chronic Infections/Syndromes Awareness of the potential threat of troop exposure to agents of biological warfare (Chap. 261e) has been heightened over the past two decades by revelations regarding Iraq’s state-sponsored chemical weapons program in the 1990s, the known broad availability of such technology, and escalations of global and geopolitical conflicts as well as of international acts of terrorism. Most of the high-risk pathogens posing a threat of bioterrorism cause acute clinical manifestations; however, selected agents, such as those causing Q fever and brucellosis, may result in chronic diseases, whether exposure is natural or intentional. Isolated cases of naturally acquired Q fever and brucellosis have been reported in recent U.S. veterans of the wars in Iraq and Afghanistan. To date, there has been no confirmed evidence of infections related to exposure to biological weapons in returning war veterans.


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InternalMed_Harrison. HIV-1 infection (Chap. 226), ubiquitous throughout the world, continues to pose a potential bloodborne and sexually transmitted risk to soldiers engaged in armed conflict in high-prevalence areas. Several reports describe war veterans returning to their countries of origin harboring HIV-1; in some of these cases, novel viral genotypes have been imported into the population. Tuberculosis (Chap. 202) also is endemic throughout much of the developing world and is prevalent in several areas of recent multinational conflicts. Although there is no evidence that active, chronic tuberculosis has affected veterans of recent wars, the rate of tuberculin skin test conversion, which indicates new infections, was noted to be 2.5% among U.S. military personnel deployed to southwest Asia in the early 2000s.


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InternalMed_Harrison. Several chronic infections that pose a risk to war veterans tend to recur or become clinically active in immunocompromised individuals and may be particularly aggressive in this population. Latent infections such as leishmaniasis, tuberculosis, histoplasmosis, brucellosis, Q fever, and strongyloidiasis in otherwise healthy veterans returning from war may become clinically expressed only much later in the setting of chronic glucocorticoid use, monoclonal antibody therapy, organ transplantation, cytotoxic chemotherapy, advanced HIV-1 disease, hematologic malignancy, or other immunosuppressive conditions. Thus, physicians should remain vigilant regarding the potential development of symptomatic disease due to such latent microbes in immunologically compromised veterans who may have initially acquired an infection years previously while serving in the military.


InternalMed_Harrison

InternalMed_Harrison. A number of syndromes of possible infectious etiology, some of which may present with chronic clinical manifestations, have been noted in veterans returning from recent wars. After the Gulf War in 1990–1991, numerous veterans from several countries experienced constellations of various common, nonspecific symptoms, including fatigue, musculoskeletal pain, sleep disturbances, and difficulty concentrating. Despite exhaustive investigations and several hypotheses regarding potential etiologies of this chronic multisystemic illness, including infectious agents, no unifying or single cause has been identified. In a randomized, placebo-controlled trial, a prolonged course of doxycycline failed to alleviate such symptoms at 1 year. In 2003, a small outbreak of acute idiopathic eosinophilic pneumonia was reported among U.S. troops serving in southwest Asia. Although a thorough investigation failed to elucidate an infectious etiology, it is noteworthy that symptoms developed up to 11 months


InternalMed_Harrison

InternalMed_Harrison. was reported among U.S. troops serving in southwest Asia. Although a thorough investigation failed to elucidate an infectious etiology, it is noteworthy that symptoms developed up to 11 months after arrival in the theater of combat; this time frame suggests that such cases may become clinically manifest after return to the home front.


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InternalMed_Harrison. Chronic Wound Infections and Osteomyelitis War wounds, an important cause of morbidity in all armed conflicts, are at high risk of infection due to contamination with environmental bacteria and the presence of retained foreign bodies. In recent conflicts, improved survival rates due to enhanced and expedited care of combat casualties have had the unintended consequence of increasing the potential for infectious complications, a situation exacerbated by repeated and at times prolonged exposure to health care environments and their associated pathogens. Many wounds sustained in recent wars have resulted from penetrating soft-tissue trauma and open fractures of the extremities— injuries attributable to improvised explosive devices used as antipersonnel weapons and to body armor that leaves the limbs unprotected. Cultures of samples taken at the time of injury at a combat support hospital in Iraq revealed that most contaminated wounds harbored gram-positive commensal skin bacteria; other


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InternalMed_Harrison. limbs unprotected. Cultures of samples taken at the time of injury at a combat support hospital in Iraq revealed that most contaminated wounds harbored gram-positive commensal skin bacteria; other investigators, however, have noted an early predominance of gram-negative bacteria, including multidrug-resistant (MDR) pathogens.


InternalMed_Harrison

InternalMed_Harrison. Approximately 3% of nearly 17,000 combat injuries sustained between 2003 and 2009 in U.S. military operations in Iraq and Afghanistan involved soft tissue infections. Although it is not clear how many of these infections became chronic or progressed to involve deeper tissue structures, a significant number were managed in tertiary care facilities, many on the home front. The bacteriology of infected combat wounds comprises predominantly gram-negative bacilli and MDR organisms. Broad-spectrum antimicrobial prophylaxis administered at the time of injury appears to be a risk factor for subsequent infection; nosocomial acquisition of health care–associated MDR pathogens likely contributes as well. Invasive fungal infections have recently emerged as a significant cause of morbidity and death in the context of combat wounds.


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InternalMed_Harrison. During the past decade of wars in Iraq and Afghanistan, MDR strains of Acinetobacter baumannii (Chap. 187) have emerged as important pathogens in both wound and bloodstream infections 152e-9 among returning veterans treated at U.S. health care facilities. The majority of isolates display in vitro susceptibility to amikacin and variable susceptibility to carbapenems but are largely resistant to other commonly used antimicrobial agents. Antimicrobial treatment should be guided by in vitro susceptibility data; patients who are critically ill, are immunocompromised, or have significant medical co-morbidities may benefit from combination therapy. Colistin (polymyxin E) has been shown to be clinically effective against Acinetobacter infections caused by isolates resistant to both aminoglycosides and carbapenems. Mortality rates have been low among immunocompetent hosts receiving appropriate antimicrobial treatment and undergoing debridement; however, Acinetobacter infections in


InternalMed_Harrison

InternalMed_Harrison. and carbapenems. Mortality rates have been low among immunocompetent hosts receiving appropriate antimicrobial treatment and undergoing debridement; however, Acinetobacter infections in immunocompromised individuals are associated with higher mortality risk. Strict adherence to hand-washing and other infection control procedures is important to limit the nosocomial spread of MDR organisms.


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InternalMed_Harrison. Chronic osteomyelitis related to either extension of a contiguous soft tissue infection or an infected prosthesis also represents a burgeoning problem for wounded veterans of recent wars. Limited micro-biologic data have shown a predominance of gram-negative etiologic agents—most often Acinetobacter and Pseudomonas aeruginosa—in the initial episodes of osteomyelitis but a shift to staphylococcal isolates in the majority of recurrent cases—a change that may perhaps be related to nosocomial acquisition. Relapses have been noted to occur 1 month to 1 year after treatment of the initial infection.


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InternalMed_Harrison. Veterans with traumatic brain injury, who have accounted for 22% of American casualties in recent wars in Iraq and Afghanistan, are at risk for infectious complications due to several factors: the presence of foreign bodies or prosthetic material related to their traumatic wounds; acquisition of a wide range of nosocomial infections during repeated interactions with the health care system; and injury-induced cognitive changes that may increase impulsivity and risk-taking behaviors. In line with the last-mentioned factor, this subgroup of veterans may be at heightened risk for substance abuse and other practices that expose them to various bloodborne and sexually transmitted infections. Moreover, they may be at risk for post-neurosurgical complications, such as pyogenic meningitis due to multidrug-resistant Acinetobacter species.


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InternalMed_Harrison. Pneumonia Lionel A. Mandell, Richard G. Wunderink DEFINITION Pneumonia is an infection of the pulmonary parenchyma. Despite being the cause of significant morbidity and mortality, pneumonia 153 SECTIon 2 Pseudomonas Acinetobacter MDR Condition MRSA aeruginosa spp. Enterobacteriaceae √ Chronic dialysis √ Home infusion therapy √ Home wound care √ Family member with MDR infection √ √ Abbreviations: MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus.


InternalMed_Harrison

InternalMed_Harrison. is often misdiagnosed, mistreated, and underestimated. In the past, pneumonia was typically classified as community-acquired (CAP), hospital-acquired (HAP), or ventilator-associated (VAP). Over the past two decades, however, some persons presenting with onset of pneumonia as outpatients have been found to be infected with the multidrug-resistant (MDR) pathogens previously associated with HAP. Factors responsible for this phenomenon include the development and widespread use of potent oral antibiotics, earlier transfer of patients out of acute-care hospitals to their homes or various lower-acuity facilities, increased use of outpatient IV antibiotic therapy, general aging of the population, and more extensive immunomodulatory therapies. The potential involvement of these MDR pathogens has led to a designation for a new category of pneumonia—health care–associated pneumonia (HCAP)—that is distinct from CAP. Conditions associated with HCAP and the likely pathogens are listed in Table


InternalMed_Harrison

InternalMed_Harrison. led to a designation for a new category of pneumonia—health care–associated pneumonia (HCAP)—that is distinct from CAP. Conditions associated with HCAP and the likely pathogens are listed in Table 153-1.


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InternalMed_Harrison. Although the new classification system has been helpful in designing empirical antibiotic strategies, it is not without its disadvantages. Not all MDR pathogens are associated with all risk factors (Table 153-1). Moreover, HCAP is a distillation of multiple risk factors, and each patient must be considered individually. For example, the risk of infection with MDR pathogens for a nursing home resident who has dementia but can independently dress, ambulate, and eat is quite different from the risk for a patient who is in a chronic vegetative state with a tracheostomy and a percutaneous feeding tube in place. In addition, risk factors for MDR infection do not preclude the development of pneumonia caused by the usual CAP pathogens.


InternalMed_Harrison

InternalMed_Harrison. This chapter deals with pneumonia in patients who are not considered to be immunocompromised. Pneumonia in severely immunocompromised patients, some of whom overlap with the groups 804 of patients considered in this chapter, warrants separate discussion (see Chaps. 104, 169, and 226). Pneumonia results from the proliferation of microbial pathogens at the alveolar level and the host’s response to those pathogens. Microorganisms gain access to the lower respiratory tract in several ways. The most common is by aspiration from the oropharynx. Small-volume aspiration occurs frequently during sleep (especially in the elderly) and in patients with decreased levels of consciousness. Many pathogens are inhaled as contaminated droplets. Rarely, pneumonia occurs via hematogenous spread (e.g., from tricuspid endocarditis) or by contiguous extension from an infected pleural or mediastinal space.


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InternalMed_Harrison. Mechanical factors are critically important in host defense. The hairs and turbinates of the nares capture larger inhaled particles before they reach the lower respiratory tract. The branching architecture of the tracheobronchial tree traps microbes on the airway lining, where mucociliary clearance and local antibacterial factors either clear or kill the potential pathogen. The gag reflex and the cough mechanism offer critical protection from aspiration. In addition, the normal flora adhering to mucosal cells of the oropharynx, whose components are remarkably constant, prevents pathogenic bacteria from binding and thereby decreases the risk of pneumonia caused by these more virulent bacteria.


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InternalMed_Harrison. When these barriers are overcome or when microorganisms are small enough to be inhaled to the alveolar level, resident alveolar macrophages are extremely efficient at clearing and killing pathogens. Macrophages are assisted by proteins that are produced by the alveolar epithelial cells (e.g., surfactant proteins A and D) and that have intrinsic opsonizing properties or antibacterial or antiviral activity. Once engulfed by the macrophage, the pathogens—even if they are not killed—are eliminated via either the mucociliary elevator or the lymphatics and no longer represent an infectious challenge. Only when the capacity of the alveolar macrophages to ingest or kill the microorganisms is exceeded does clinical pneumonia become manifest. In that situation, the alveolar macrophages initiate the inflammatory response to bolster lower respiratory tract defenses. The host inflammatory response, rather than proliferation of microorganisms, triggers the clinical syndrome of pneumonia. The


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InternalMed_Harrison. the inflammatory response to bolster lower respiratory tract defenses. The host inflammatory response, rather than proliferation of microorganisms, triggers the clinical syndrome of pneumonia. The release of inflammatory mediators, such as interleukin 1 and tumor necrosis factor, results in fever. Chemokines, such as interleukin 8 and granulocyte colony-stimulating factor, stimulate the release of neutrophils and their attraction to the lung, producing both peripheral leukocytosis and increased purulent secretions. Inflammatory mediators released by macrophages and the newly recruited neutrophils create an alveolar capillary leak equivalent to that seen in the acute respiratory distress syndrome, although in pneumonia this leak is localized (at least initially). Even erythrocytes can cross the alveolar-capillary membrane, with consequent hemoptysis. The capillary leak results in a radiographic infiltrate and rales detectable on auscultation, and hypoxemia results from alveolar


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InternalMed_Harrison. cross the alveolar-capillary membrane, with consequent hemoptysis. The capillary leak results in a radiographic infiltrate and rales detectable on auscultation, and hypoxemia results from alveolar filling. Moreover, some bacterial pathogens appear to interfere with the hypoxemic vasoconstriction that would normally occur with fluid-filled alveoli, and this interference can result in severe hypoxemia. Increased respiratory drive in the systemic inflammatory response syndrome (Chap. 325) leads to respiratory alkalosis. Decreased compliance due to capillary leak, hypoxemia, increased respiratory drive, increased secretions, and occasionally infection-related bronchospasm all lead to dyspnea. If severe enough, the changes in lung mechanics secondary to reductions in lung volume and compliance and the intrapulmonary shunting of blood may cause respiratory failure and the patient’s death.


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InternalMed_Harrison. Classic pneumonia evolves through a series of pathologic changes. The initial phase is one of edema, with the presence of a proteinaceous exudate—and often of bacteria—in the alveoli. This phase is rarely evident in clinical or autopsy specimens because of the rapid transition to the red hepatization phase. The presence of erythrocytes in the cellular intraalveolar exudate gives this second stage its name, but neutrophil influx is more important with regard to host defense. Bacteria are occasionally seen in pathologic specimens collected during this phase. In the third phase, gray hepatization, no new erythrocytes are extravasating, and those already present have been lysed and degraded. The neutrophil is the predominant cell, fibrin deposition is abundant, and bacteria have disappeared. This phase corresponds with successful containment of the infection and improvement in gas exchange. In the final phase, resolution, the macrophage reappears as the dominant cell type in the alveolar


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InternalMed_Harrison. This phase corresponds with successful containment of the infection and improvement in gas exchange. In the final phase, resolution, the macrophage reappears as the dominant cell type in the alveolar space, and the debris of neutrophils, bacteria, and fibrin has been cleared, as has the inflammatory response.


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InternalMed_Harrison. This pattern has been described best for lobar pneumococcal pneumonia and may not apply to pneumonia of all etiologies, especially viral or Pneumocystis pneumonia. In VAP, respiratory bronchiolitis may precede the development of a radiologically apparent infiltrate. Because of the microaspiration mechanism, a bronchopneumonia pattern is most common in nosocomial pneumonias, whereas a lobar pattern is more common in bacterial CAP. Despite the radiographic appearance, viral and Pneumocystis pneumonias represent alveolar rather than interstitial processes.


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InternalMed_Harrison. The extensive list of potential etiologic agents in CAP includes bacteria, fungi, viruses, and protozoa. Newly identified pathogens include metapneumoviruses, the coronaviruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, and community-acquired strains of methicillin-resistant Staphylococcus aureus (MRSA). Most cases of CAP, however, are caused by relatively few pathogens (Table 153-2). Although Streptococcus pneumoniae is most common, other organisms also must be considered in light of the patient’s risk factors and severity of illness. Separation of potential agents into either “typical” bacterial pathogens or “atypical” organisms may be helpful. The former category includes S. pneumoniae, Haemophilus influenzae, and (in selected patients) S. aureus and gram-negative bacilli such as Klebsiella pneumoniae and Pseudomonas aeruginosa. The “atypical” organisms include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species


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InternalMed_Harrison. S. aureus and gram-negative bacilli such as Klebsiella pneumoniae and Pseudomonas aeruginosa. The “atypical” organisms include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species (in inpatients) as well as respiratory viruses such as influenza viruses, adenoviruses, human metapneumovirus, and respiratory syncytial viruses. Viruses may be responsible for a large proportion of CAP cases that require hospital admission, even in adults. Atypical organisms cannot be cultured on standard media or seen on Gram’s stain. The frequency and importance of atypical pathogens have significant implications for therapy. These organisms are intrinsically resistant to all β-lactam agents and must be treated with a macrolide, a fluoroquinolone, or a tetracycline. In the ∼10–15% of CAP cases that are polymicrobial, the etiology usually includes a combination of typical and atypical pathogens.


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InternalMed_Harrison. Anaerobes play a significant role only when an episode of aspiration has occurred days to weeks before presentation of pneumonia. The TABLE 153-2 MICRoBIAL CAuSES of CoMMunITy-ACquIRED PnEuMonIA, By SITE of CARE aInfluenza A and B viruses, human metapneumovirus, adenoviruses, respiratory syncytial viruses, parainfluenza viruses. Note: Pathogens are listed in descending order of frequency. ICU, intensive care unit. combination of an unprotected airway (e.g., in patients with alcohol or drug overdose or a seizure disorder) and significant gingivitis constitutes the major risk factor. Anaerobic pneumonias are often complicated by abscess formation and by significant empyemas or parapneumonic effusions.


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InternalMed_Harrison. S. aureus pneumonia is well known to complicate influenza infection. However, MRSA has been reported as the primary etiologic agent of CAP. While this entity is still relatively uncommon, clinicians must be aware of its potentially serious consequences, such as necrotizing pneumonia. Two important developments have led to this problem: the spread of MRSA from the hospital setting to the community and the emergence of genetically distinct strains of MRSA in the community. The former circumstance is more likely to result in HCAP, whereas the novel community-acquired MRSA (CA-MRSA) strains may infect healthy individuals with no association with health care.


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InternalMed_Harrison. Unfortunately, despite a careful history and physical examination as well as routine radiographic studies, the causative pathogen in a case of CAP is difficult to predict with any degree of certainty; in more than one-half of cases, a specific etiology is never determined. Nevertheless, epidemiologic and risk factors may suggest the involvement of certain pathogens (Table 153-3).


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InternalMed_Harrison. More than 5 million CAP cases occur annually in the United States; usually, 80% of the affected patients are treated as outpatients and 20% as inpatients. The mortality rate among outpatients is usually ≤1%, whereas among hospitalized patients the rate can range from ∼12% to 40%, depending on whether treatment is provided in or outside of the intensive care unit (ICU). CAP results in more than 1.2 million hospitalizations and more than 55,000 deaths annually. The overall yearly cost associated with CAP is estimated at $12 billion. The incidence rates are highest at the extremes of age. The overall annual rate in the United States is 12 cases/1000 persons, but the figure increases to 12–18/1000 among children <4 years of age and to 20/1000 among persons >60 years of age. Structural lung disease (e.g., bronchiectasis) Dementia, stroke, decreased level of consciousness Travel to Ohio or St. Lawrence river valleys Travel to southwestern United States Travel to Southeast Asia


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InternalMed_Harrison. Dementia, stroke, decreased level of consciousness Travel to Ohio or St. Lawrence river valleys Travel to southwestern United States Travel to Southeast Asia Stay in hotel or on cruise ship in previous 2 weeks Local influenza activity Exposure to bats or birds Exposure to birds Exposure to rabbits Exposure to sheep, goats, parturient cats Streptococcus pneumoniae, oral anaerobes, Klebsiella pneumoniae, Acinetobacter spp., Mycobacterium tuberculosis Haemophilus influenzae, Pseudomonas aeruginosa, Legionella spp., S. pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae P. aeruginosa, Burkholderia cepacia, Staphylococcus aureus Oral anaerobes, gram-negative enteric bacteria CA-MRSA, oral anaerobes, endemic fungi, M. tuberculosis, atypical mycobacteria Histoplasma capsulatum Hantavirus, Coccidioides spp. Burkholderia pseudomallei, avian influenza virus Legionella spp. Influenza virus, S. pneumoniae, S. aureus


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InternalMed_Harrison. Hantavirus, Coccidioides spp. Burkholderia pseudomallei, avian influenza virus Legionella spp. Influenza virus, S. pneumoniae, S. aureus H. capsulatum Chlamydia psittaci Francisella tularensis Coxiella burnetii Abbreviations: CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; COPD, chronic obstructive pulmonary disease.


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InternalMed_Harrison. The risk factors for CAP in general and for pneumococcal pneu-805 monia in particular have implications for treatment regimens. Risk factors for CAP include alcoholism, asthma, immunosuppression, institutionalization, and an age of ≥70 years. In the elderly, factors such as decreased cough and gag reflexes as well as reduced antibody and Toll-like receptor responses increase the likelihood of pneumonia. Risk factors for pneumococcal pneumonia include dementia, seizure disorders, heart failure, cerebrovascular disease, alcoholism, tobacco smoking, chronic obstructive pulmonary disease, and HIV infection. CA-MRSA pneumonia is more likely in patients with skin colonization or infection with CA-MRSA. Enterobacteriaceae tend to infect patients who have recently been hospitalized and/or received antibiotic therapy or who have comorbidities such as alcoholism, heart failure, or renal failure. P. aeruginosa is a particular problem in patients with severe structural lung disease, such as


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InternalMed_Harrison. antibiotic therapy or who have comorbidities such as alcoholism, heart failure, or renal failure. P. aeruginosa is a particular problem in patients with severe structural lung disease, such as bronchiectasis, cystic fibrosis, or severe chronic obstructive pulmonary disease. Risk factors for Legionella infection include diabetes, hematologic malignancy, cancer, severe renal disease, HIV infection, smoking, male gender, and a recent hotel stay or ship cruise. (Many of these risk factors would now reclassify as HCAP some cases that were previously designated CAP.)


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InternalMed_Harrison. CAP can vary from indolent to fulminant in presentation and from mild to fatal in severity. Manifestations of progression and severity include both constitutional findings and those limited to the lung and associated structures. In light of the pathobiology of the disease, many of the findings are to be expected. The patient is frequently febrile with tachycardia or may have a history of chills and/or sweats. Cough may be either nonproductive or productive of mucoid, purulent, or blood-tinged sputum. Gross hemoptysis is suggestive of CA-MRSA pneumonia. Depending on severity, the patient may be able to speak in full sentences or may be very short of breath. If the pleura is involved, the patient may experience pleuritic chest pain. Up to 20% of patients may have gastrointestinal symptoms such as nausea, vomiting, and/or diarrhea. Other symptoms may include fatigue, headache, myalgias, and arthralgias.


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InternalMed_Harrison. Findings on physical examination vary with the degree of pulmonary consolidation and the presence or absence of a significant pleural effusion. An increased respiratory rate and use of accessory muscles of respiration are common. Palpation may reveal increased or decreased tactile fremitus, and the percussion note can vary from dull to flat, reflecting underlying consolidated lung and pleural fluid, respectively. Crackles, bronchial breath sounds, and possibly a pleural friction rub may be heard on auscultation. The clinical presentation may not be so obvious in the elderly, who may initially display new-onset or worsening confusion and few other manifestations. Severely ill patients may have septic shock and evidence of organ failure.


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InternalMed_Harrison. When confronted with possible CAP, the physician must ask two questions: Is this pneumonia, and, if so, what is the likely etiology? The former question is typically answered by clinical and radiographic methods, whereas the latter requires the aid of laboratory techniques. Clinical Diagnosis The differential diagnosis includes both infectious and noninfectious entities such as acute bronchitis, acute exacerbations of chronic bronchitis, heart failure, pulmonary embolism, hypersensitivity pneumonitis, and radiation pneumonitis. The importance of a careful history cannot be overemphasized. For example, known cardiac disease may suggest worsening pulmonary edema, while underlying carcinoma may suggest lung injury secondary to irradiation.


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InternalMed_Harrison. Unfortunately, the sensitivity and specificity of the findings on physical examination are less than ideal, averaging 58% and 67%, respectively. Therefore, chest radiography is often necessary to differentiate CAP from other conditions. Radiographic findings may include risk factors for increased severity (e.g., cavitation or multilobar involvement). Occasionally, radiographic results suggest an etiologic diagnosis. For example, pneumatoceles suggest infection with S. aureus, and an upper-lobe cavitating lesion suggests tuberculosis. CT may be of value in a patient with suspected postobstructive 806 pneumonia caused by a tumor or foreign body or suspected cavitary disease. For outpatients, the clinical and radiologic assessments are usually all that is done before treatment for CAP is started since most laboratory results are not available soon enough to influence initial management significantly. In certain cases, the availability of rapid point-of-care outpatient diagnostic tests


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InternalMed_Harrison. since most laboratory results are not available soon enough to influence initial management significantly. In certain cases, the availability of rapid point-of-care outpatient diagnostic tests can be very important; for example, rapid diagnosis of influenza virus infection can prompt specific anti-influenza drug treatment and secondary prevention.


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InternalMed_Harrison. Etiologic Diagnosis The etiology of pneumonia usually cannot be determined solely on the basis of clinical presentation. Except for CAP patients admitted to the ICU, no data exist to show that treatment directed at a specific pathogen is statistically superior to empirical therapy. The benefit of establishing a microbial etiology can therefore be questioned, particularly in light of the cost of diagnostic testing. However, a number of reasons can be advanced for attempting an etiologic diagnosis. Identification of an unexpected pathogen allows narrowing of the initial empirical regimen, thereby decreasing antibiotic selection pressure and lessening the risk of resistance. Pathogens with important public safety implications, such as Mycobacterium tuberculosis and influenza virus, may be found in some cases. Finally, without culture and susceptibility data, trends in resistance cannot be followed accurately, and appropriate empirical therapeutic regimens are harder to devise.


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InternalMed_Harrison. GRAM’S STAIN AND CULTURE OF SPUTUM The main purpose of the sputum Gram’s stain is to ensure that a sample is suitable for culture. However, Gram’s staining may also identify certain pathogens (e.g., S. pneumoniae, S. aureus, and gram-negative bacteria) by their characteristic appearance. To be adequate for culture, a sputum sample must have >25 neutrophils and <10 squamous epithelial cells per low-power field. The sensitivity and specificity of the sputum Gram’s stain and culture are highly variable. Even in cases of proven bacteremic pneumococcal pneumonia, the yield of positive cultures from sputum samples is ≤50%.


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InternalMed_Harrison. Some patients, particularly elderly individuals, may not be able to produce an appropriate expectorated sputum sample. Others may already have started a course of antibiotics that can interfere with culture results at the time a sample is obtained. Inability to produce sputum can be a consequence of dehydration, and the correction of this condition may result in increased sputum production and a more obvious infiltrate on chest radiography. For patients admitted to the ICU and intubated, a deep-suction aspirate or bronchoalveolar lavage sample (obtained either via bronchoscopy or non-bronchoscopically) has a high yield on culture when sent to the microbiology laboratory as soon as possible. Since the etiologies in severe CAP are somewhat different from those in milder disease (Table 153-2), the greatest benefit of staining and culturing respiratory secretions is to alert the physician of unsuspected and/or resistant pathogens and to permit appropriate modification of therapy. Other


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InternalMed_Harrison. the greatest benefit of staining and culturing respiratory secretions is to alert the physician of unsuspected and/or resistant pathogens and to permit appropriate modification of therapy. Other stains and cultures (e.g., specific stains for M. tuberculosis or fungi) may be useful as well.


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InternalMed_Harrison. BLOOD CULTURES The yield from blood cultures, even when samples are collected before antibiotic therapy, is disappointingly low. Only 5–14% of cultures of blood from patients hospitalized with CAP are positive, and the most frequently isolated pathogen is S. pneumoniae. Since recommended empirical regimens all provide pneumococcal coverage, a blood culture positive for this pathogen has little, if any, effect on clinical outcome. However, susceptibility data may allow narrowing of antibiotic therapy in appropriate cases. Because of the low yield and the lack of significant impact on outcome, blood cultures are no longer considered de rigueur for all hospitalized CAP patients. Certain high-risk patients—including those with neutropenia secondary to pneumonia, asplenia, complement deficiencies, chronic liver disease, or severe CAP—should have blood cultured.


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InternalMed_Harrison. URINARY ANTIGEN TESTS Two commercially available tests detect pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects only serogroup 1, but this serogroup accounts for most community-acquired cases of Legionnaires’ disease in the United States. The sensitivity and specificity of the Legionella urine antigen test are as high as 90% and 99%, respectively. The pneumococcal urine antigen test also is quite sensitive and specific (80% and >90%, respectively). Although false-positive results can be obtained with samples from pneumococcus-colonized children, the test is generally reliable. Both tests can detect antigen even after the initiation of appropriate antibiotic therapy.


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InternalMed_Harrison. POLYMERASE CHAIN REACTION Polymerase chain reaction (PCR) tests, which amplify a microorganism’s DNA or RNA, are available for a number of pathogens. PCR of nasopharyngeal swabs has become the standard for diagnosis of respiratory viral infection. In addition, PCR can detect the nucleic acid of Legionella species, M. pneumoniae, C. pneumoniae, and mycobacteria. In patients with pneumococcal pneumonia, an increased bacterial load in whole blood documented by PCR is associated with an increased risk of septic shock, the need for mechanical ventilation, and death. Clinical availability of such a test could conceivably help identify patients suitable for ICU admission.


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InternalMed_Harrison. SEROLOGY A fourfold rise in specific IgM antibody titer between acuteand convalescent-phase serum samples is generally considered diagnostic of infection with the pathogen in question. In the past, serologic tests were used to help identify atypical pathogens as well as selected unusual organisms such as Coxiella burnetii. Recently, however, they have fallen out of favor because of the time required to obtain a final result for the convalescent-phase sample.