Sick Child Evaluation

Evaluation of the Sick Child in the Office and Clinic

from Paul L. McCarthy, Kliegman: Nelson Textbook of Pediatrics, 18th ed.

There are many reasons for a sick child visit, but most are due to acute self-limited intercurrent infections; often the child is febrile. When evaluating an acutely ill, febrile child, the pediatrician must be aware of categorical statistics about the probable occurrence of serious illness, because one of the major goals of the sick child visit is to identify the seriously ill child who requires specific therapeutic intervention. The risk for and the cause of serious illness in the acutely febrile child vary, depending on age. The infant in the 1st 3 mo of life is more susceptible to sepsis and meningitis caused by group B streptococci and gram-negative organisms. Infants in the 1st mo of life are at highest risk. Urinary tract infections are more frequent in males; infants in this age group more often have an underlying anatomic abnormality of the urinary tract than do older children with urinary tract infections. As the infant matures beyond 3 mo, the bacterial pathogens that usually cause bacteremia, sepsis, and meningitis are Streptococcus pneumoniae, Haemophilus influenzae type b (if the child is unimmunized or only partially immunized), and Neisseria meningitidis. Immunization against some serotypes of S. pneumoniae may reduce the occurrence of occult bacteremia and serious infections caused by that organism, as has immunization against H. influenzae type b. After infancy, urinary tract infections are seen more often in females. Immunity develops rapidly to the common bacterial pathogens during the first 3–4 yr of life. N. meningitidis is the leading cause of bacterial meningitis. In children older than 36 mo, pharyngitis caused by group A streptococci is a common bacterial infection. Mycoplasma pneumoniae assumes increasing importance as a cause of pulmonary infiltrates in children older than 5 yr of age. Table 1 shows serious illnesses documented in children in the 1st 3 yr of life who presented with fever and acute illness at a university hospital and private practice. In many studies, urinary tract infections are the most common serious bacterial infections. Soft tissue infections due to streptococcus or staphylococcus may include cellulitis, fasciitis, osteomyelitis, and septic arthritis. Noninfectious, but serious disease should also be considered and include trauma (abuse), midgut volvulus, appendicitis, intussusception, poisoning (salicylates), metabolic disorders (hypoglycemia, hyperammonemia), neurologic disorders (seizures, infant botulism), or inflammatory diseases (Kawasaki disease, juvenile rheumatoid arthritis, Henoch-Schünlein purpura).

The acutely ill child with a serious illness is identified by careful observation, history taking, physical examination, appreciation of age and body temperature as risk factors, and the judicious use of screening laboratory tests. The physician can use the data to make informed decisions about the need for more definitive laboratory tests (urine culture), therapy, and the advisability of hospital admission. Observation, history, and physical examination are integrated when the sick child evaluation is being done; that is, as the child is being observed, historical data are gathered. History taking and observational assessment often continue as the physical examination is performed. If abdominal tenderness is found on examination, additional history about blood in the stool, cramping abdominal pain, and vomiting may be sought.

TABLE 1 -- Diagnosis of Serious Illnesses During 996 Episodes of Acute Infectious Illness in Febrile Children Younger Than 36 Mo^[*]

	CASES
DIAGNOSIS	NO.	%
Bacterial meningitis	9	0.9
Aseptic meningitis	12	1.2
Pneumonia	30	3.0
Bacteremia	10	1.0
Focal soft tissue infection[†]	10	1.0
Urinary tract infection	8	0.8
Bacterial diarrhea	1	0.1
Abnormal electrolytes or blood gases	9	0.9
Total	89	8.9

From McCarthy PL: Acute infectious illness in children. Compr Ther 1988;14:51.

Includes cellulitis, osteomyelitis, and septic arthritis.

*
†	Includes cellulitis, osteomyelitis, and septic arthritis.

OBSERVATION

Observation is important in the evaluation of the acutely ill child. The child should be observed for specific evidence of a serious illness, such as grunting, which might indicate pneumonia or sepsis, or a bulging fontanel, which might indicate bacterial meningitis or head trauma. Most observational data that the pediatrician gathers during an acute illness should focus, however, on assessing the child's response to stimuli. How does the crying child respond to the parents' comforting? How quickly does the sleeping child awaken with a stimulus? Does the child smile when the examiner interacts with him or her? Assessing responses to stimuli, while often providing those stimuli, requires knowledge of normal responses for different age groups, the manner in which those normal responses are elicited, and to what degree a response might be impaired.

Sometimes the manner in which the child responds to stimuli is readily apparent. For example, the child may vocalize and smile as the examiner enters the room. At other times, more effort and more stimuli are needed to cause the child to act in a normal manner. Often the fussing, irritable child begins to look around and focus on the examiner when held and walked by the parent. This normal visual behavior is an important indicator of well-being. Thus, during observation, the pediatrician must be both clinically and developmentally oriented.

Six observation items and their scales (Acute Illness Observation Scales) that have reliably and validly identified serious illness in febrile children are shown in Figure 1 . A normal finding is scored as 1, moderate impairment as 3, and severe impairment as 5. The best possible score is 6 items × 1 = 6; the worst score is 6 items × 5 = 30. The chance of serious illness is 1–2% if the total score is 10 or less; if the score is >10, the risk of serious illness increases by at least 10-fold. It is not clear whether these scales can be used in the first 1–3 mo of life because infants may not have developed the skills required to score some of these items.

Figure 1 Acute illness observational scales for use in clinical evaluation of the well and sick child. (From McCarthy PL, Sharpe MR, Spiesel SZ, et al: Observation scales to identify serious illness in febrile children. Pediatrics 1982;70:802, with permission.)

HISTORY

History taking is complex. Parents must transmit how a younger child has been “feeling.” Parents should also provide information on a specific symptom, such as bloody diarrhea or cyanosis when coughing. The older child's perception of symptoms may reflect a developmentally immature understanding of causation. The examiner pursues the historical information provided by the parents or child to define the symptoms precisely. If the complaint is blood in the stool, additional questions can be asked about other evidence of bowel inflammation, such as watery stools, mucus in the stools, or increased frequency of stooling. If the historical information indicates crying with defecation and streaks of blood on the outer portion of a hard stool, without other changes in the character or frequency of the stool, a diagnosis of a rectal fissure is tenable.

Questions should focus on those entities that are seen most commonly in acute febrile childhood illnesses. The more serious diagnoses are outlined in Table 1 . Organ-specific questions are helpful, such as those concerning fast breathing, cyanosis, retraction, and wheezing with pneumonia, or pain, swelling, and pseudoparalysis with septic arthritis. Because most acute illnesses in children are caused by minor viral infections, specific questions about the epidemiology of the illness can offer important insights. Are there other children in the family with similar symptoms? Has the child had other illness exposures? Finally, it is important to be aware of any underlying chronic problems that might predispose the child to recurring infections or a serious acute illness; for example, the child with sickle cell anemia or AIDS is at increased risk for recurrent episodes of bacteremia. Benign viral illnesses may produce serious secondary consequences, such as dehydration or severe respiratory syncytial virus pneumonia in infants who had bronchopulmonary dysplasia as neonates. Additional questions to assess hydration, such as questions about wet diapers, tears, or awakeness, should be used to assess secondary complications.

PHYSICAL EXAM

During physical examination, the pediatrician seeks evidence of illnesses, especially serious illnesses (see Table 1 ), that are causes of acute febrile episodes in children. The portions of the physical examination that require the child to be optimally cooperative are completed first. Initially, it is best to seat the child on the parent's lap; the older child may be seated on the examination table. Vital signs are often overlooked, but are valuable in assessing ill children. The degree of fever, the presence of tachycardia out of proportion to the fever, and the presence of tachypnea and hypotension all suggest a serious infection. In addition to the general level of interaction, color, and hydration, as assessed by the Acute Illness Observation Scales (see Fig. 1 ), the child's respiratory status is evaluated. This evaluation includes determining respiratory rate and noting any evidence of inspiratory stridor, expiratory wheezing, grunting, or coughing. Evidence of increased work of breathing—retraction, nasal flaring, and the use of abdominal musculature—is sought. Because acute infections in children are most often caused by viral infections, the presence of nasal discharge is noted. It is possible at this time to assess the skin for rashes. Frequently, viral infections cause an exanthematous eruption, and many of these eruptions are diagnostic (the reticulated rash and “slapped-cheek” appearance caused by parvovirus infections or the typical appearance of hand-foot-and-mouth disease caused by coxsackieviruses). The skin examination may also yield evidence of more serious infections (bacterial cellulitis or petechiae associated with bacteremia). Cutaneous perfusion should be assessed by warmth and capillary refill time. When the child is seated and is least perturbed, an assessment of fontanel tension can be completed; it can be determined if the fontanel is depressed, flat, or bulging. It is also important to assess the child's willingness to move and ease of movement. Usually, the child with meningitis will hold the neck stiffly and will often cry when any attempt is made to flex the neck, even during cuddling by the parent. This is termed paradoxic irritability. The child with cellulitis, osteomyelitis, or septic arthritis in an extremity will resist movement of that limb. The child with peritoneal inflammation will sit quietly and become irritable during movement. It is reassuring to see the child moving about on the parent's lap with ease and without discomfort.

During this initial portion of the physical examination, when the child is most comfortable, the heart and lungs are auscultated. In the acutely febrile child, because of the relatively frequent occurrence of respiratory illnesses, it is important to assess adequacy of air entry into the lungs, equality of breath sounds, and evidence of adventitial breath sounds, especially wheezes, rales, and rhonchi. The coarse sound of air moving through a congested nasal passage is frequently transmitted to the lungs. The examiner can become attuned to these coarse sounds by placing the stethoscope near the child's nose and then compensating for this sound as the chest is auscultated. The cardiac examination is completed next; findings such as pericardial friction rub, loud murmurs, or distant heart sounds may indicate an infectious process involving the heart. The eyes are examined to identify features that might indicate an infectious process. Often, viral infections result in a watery discharge or redness of the bulbar conjunctivae. Bacterial infection, if superficial, results in purulent drainage; if the infection is more deep-seated, tenderness, swelling, and redness of the tissues surrounding the eye are present, as well as proptosis, reduced visual acuity, and altered extraocular movement. The extremities may then be evaluated not only for ease of movement, but also for the possibility of swelling, heat, or tenderness; such abnormalities may indicate focal infections.

The components of the physical examination that are more bothersome to the child are completed last. This is best done with the patient on the examination table. Initially, the neck is examined to assess for areas of swelling, redness, or tenderness, as may be seen in cervical adenitis. The neck is then flexed to evaluate suppleness; resistance to flexion is indicative of meningeal irritation. The Kernig and Brudzinski signs may be sought at this time. In children younger than 18 mo, meningeal signs may not always be present with meningitis; however, if they are present, the diagnostic implications are the same as for the child older than 18 mo. During examination of the abdomen, the diaper is removed. The abdomen is inspected for distention. Auscultation is performed to assess adequacy of bowel sounds, followed by palpation. The child often fusses as the abdomen is auscultated and palpated. Every attempt should be made to quiet the child; if this is not possible, increased fussing as the abdomen is palpated may indicate tenderness, especially if this finding is reproducible. In addition to focal tenderness, palpation may elicit involuntary guarding or rebound tenderness; these findings indicate peritoneal irritation, as is seen in appendicitis. The inguinal area and genitals are then sequentially examined. In the febrile child, inguinal adenitis or a strangulated hernia may be the cause of fever. The child is then placed in the prone position, and abnormalities of the back are sought. The spine and costovertebral angle areas are percussed to elicit any tenderness; such findings may be indicative of osteomyelitis or diskitis and pyelonephritis, respectively.

Examining the ears and throat completes the physical examination. These are usually the most bothersome parts of the examination for the child, and parents frequently can be helpful in minimizing head movement. During the oropharyngeal examination, it is important to document the presence of enanthemas; these may be seen in many infectious processes, such as hand-foot-and-mouth disease caused by coxsackievirus. This portion of the examination is also important in documenting inflammation or exudates on the tonsils, which may be viral or bacterial.

At times, repeating portions of the assessment is indicated. If the child cried continuously during the initial clinical evaluation, the examiner may not be certain if the crying was caused by the high fever, stranger anxiety, or pain, or is indicative of a serious illness. Continual crying also makes portions of the physical examination, such as auscultation of the chest, more difficult. Before a repeat assessment is performed, efforts to make the child as comfortable as possible are indicated. Such efforts include reducing the fever with antipyretics and offering the child a bottle. Because most children with fever do not have serious illnesses, repeated assessments are more likely to document normal findings. If, on the other hand, the child is persistently irritable, the possibility of serious illness increases.

RISK FACTORS

The sensitivity of the carefully performed clinical assessment, observation, history, and physical examination for the presence of serious illness is approximately 90%. Careful data gathering is necessary in the observation, history, and physical examination, because each component of the evaluation is as effective as the others in identifying serious illness. Other data, however, should be sought to improve this sensitivity level. In the child with an acute febrile illness, important supplemental data are age, body temperature, and the results of screening laboratory tests. Febrile children in the first 3 mo of life have yet to achieve immunologic maturity and therefore are more susceptible to severe infections and to infections by unusual organisms. Thus, the febrile infant is at greater risk for serious bacterial infection than the child beyond 3 mo of age. In febrile children, the higher the fever, the greater the risk of serious illness. The risk of bacteremia in infants increases as the degree of fever increases. The limit of physiologic thermoregulation is 41.1°C (106°F); fevers in this range and higher indicate bacteremia, but also possible central nervous system infection, pneumonia, or pathologic hyperthermia.

Screening laboratory tests may be helpful in identifying the febrile child at increased risk for selected serious illnesses. S. pneumoniae is currently the most common cause of occult bacteremia not associated with a focal soft tissue infection. A total white blood cell count of ≥15,000/mm³ and/or an absolute neutrophil count of ≥10,000/mm³, in addition to age 3–36 mo, higher grades of fever, and a more ill appearance, are indicators of increased risk for occult bacteremia caused by S. pneumoniae. The incidence of occult pneumococcal bacteremia in febrile children may be declining because of the introduction of conjugated pneumococcal vaccine. Urinalysis and urine culture must be considered when the source of fever is not apparent, especially in the highest-risk groups: females and uncircumcised males younger than 2 yr of age and all boys younger than 1 yr of age. The presence of leukocyte esterase, >5 white blood cells/high-power field on a spun urine specimen, or bacteria by Gram stain on an unspun urine specimen suggests urinary tract infection, but the sensitivity of these indicators is, on average, only 75–85% and urine culture is the definitive test. An elevated C-reactive protein value may also distinguish bacterial from viral infection.

MANAGEMENT

If the febrile child is older than 3 mo and appears well, if the history or physical examination does not suggest a serious illness, and if no age or temperature risk factors are present, the child may be followed expectantly. If otitis media is present, it should be treated. This profile applies to most children with acute infectious illnesses. If, on the other hand, the child appears ill or the history or physical examination suggests a serious illness, definitive laboratory tests appropriate for those findings are indicated (e.g., chest radiograph for a child with grunting). The area of greatest controversy is whether laboratory studies are needed in a febrile child who appears well and has no abnormalities on history and physical examination, but who is younger than 3 mo of age or whose temperature is high. Many would agree that a sepsis work-up is indicated in the febrile child younger than 1 mo and possibly younger than age 3 mo. Obtaining blood cultures in children older than 3 mo with higher grades of fever has gained increased acceptance.

If the physician feels comfortable in following as an outpatient the child in whom no specific diagnosis has been established, a follow-up examination often yields a diagnosis. During the initial visit, or from one visit to the next during the acute illness, the change in symptoms or in the findings on physical examination over time may provide important diagnostic clues. For the child in whom a diagnosis has already been established and who does not require hospitalization, follow-up by telephone or an office visit should be used to monitor the course of the illness and to further educate and support the parents.

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Women's Health

Women's Health

From Harrison's Principles of Internal Medicine 17th Ed.

INTRODUCTION

The study of biologic differences between sexes has emerged as a distinct scientific discipline. A report from the Institute of Medicine (IOM) found that sex has a broad impact on biologic and disease processes and succinctly concluded: sex matters. The National Institutes of Health established the Office of Research on Women's Health in 1990 to develop an agenda for future research in the field. In parallel, women's health has become a distinct clinical discipline with a focus on disorders that are disproportionately represented in women. The integration of women's health into internal medicine and other specialties has been accompanied by novel approaches to health care delivery, including greater attention to patient education and involvement in disease prevention and medical decision-making.

The IOM report recommended the term sex difference to describe biologic processes that differ between males and females and gender difference for features related to social influences.
DISEASE RISK : REALITY AND PERCEPTION

The leading causes of death are the same in women and men: (1) heart disease, (2) cancer, and (3) cerebrovascular disease (Table 1; Fig. 1). The leading cause of cancer death, lung cancer, is the same in both sexes, with higher mortality rates than breast, colon, and prostate cancer combined. Breast cancer is the second leading cause of cancer death in women, but it causes about 60% fewer deaths than lung cancer. Men are substantially more likely to die from suicide, homicide, and accidents than women.

Table 1 Deaths and Percent of Total Deaths for the 15 Leading Causes of Death by Sex in the United States, 2003

Women Men Cause of Death Rank Deaths Total Deaths, % Rank Deaths Total Deaths, % Diseases of heart 1 348,994 28.0 1 336,095 28.0 Malignant neoplasms 2 268,912 21.6 2 287,990 24.0 Cerebrovascular diseases 3 96,263 7.7 4 61,426 5.1 Chronic lower respiratory diseases 4 65,668 5.3 5 60,714 5.1 Alzheimer's disease 5 45,122 3.6 10 18,335 1.5 Diabetes mellitus 6 38,781 3.1 6 35,438 2.9 Accidents 7 38,745 3.1 3 70,532 5.9 Influenza, pneumonia 8 36,385 2.9 7 28,778 2.4 Nephritis, nephrotic syndrome, nephrosis 9 21,972 1.8 9 20,481 1.7 Septicemia 10 19,082 1.5 12 14,987 1.2 Essential (primary) hypertension, hypertensive renal disease 11 13,727 1.1 15 8,213 0.7 Chronic liver disease, cirrhosis 12 9,591 0.8 11 17,912 1.5 Parkinson's disease 13 7,817 0.6 14 10,180 0.8 Intentional self-harm (suicide) 14 6,281 0.5 8 25,203 2.1 Assault (homicide) 15 3,850 0.3 13 13,882 1.2

Source: Data from Centers for Disease Control and Prevention: National Vital Statistics Reports, Vol. 54, No. 13, April 19, 2006, Table 12, http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_13.pdf.

Figure 1. Death rates per 100,000 population for 2003 by 5-year age groups in U.S. women. Note that the scale of the y-axis is increased by tenfold in the graph on the right compared to that on the left. Accidents and HIV/AIDS are the leading causes of death in young women 20–34 years of age. Accidents, breast cancer, and ischemic heart disease (IHD) are the leading causes of death in women 35–44 years of age. Breast cancer is the leading cause of death in women 45–49 years of age, and IHD becomes the leading cause of death in women beginning at 50 years of age. In older women, IHD remains the leading cause of death, cerebrovascular disease becomes the second leading cause of death, and lung cancer is the leading cause of cancer-related deaths. AD, Alzheimer's disease; Ca, cancer; CLRD, chronic lower respiratory disease; DM, diabetes mellitus. (Data adapted from Centers for Disease Control and Prevention,www.cdc.gov/nchs/data/statab/Mortfinal2003_worktable210r.pdf.)

Women's risk for many diseases increases at menopause, which occurs at a median age of 51.4 years. In the industrialized world, women spend one-third of their lives in the postmenopausal period. Estrogen levels fall abruptly at menopause, inducing a variety of physiologic and metabolic responses. Rates of cardiovascular disease increase and bone density begins to decrease rapidly after menopause. In the United States, women live on average about 5 years longer than men, with a life expectancy at birth in 2004 of 80.4 years, compared to 75.2 years in men. Elderly women outnumber elderly men, so that age-related conditions, such as hypertension, have a female preponderance. However, the difference in life expectancy between men and women has decreased an average of 0.1 year every year since 1980, and, if this convergence in mortality figures continues, it is projected that mortality rates will be similar by 2054.

Women's perception of disease risk is often inaccurate. Public awareness campaigns have resulted in almost 50% of U.S. women knowing that cardiovascular disease is the leading cause of death in women. Nevertheless, the condition they fear most is breast cancer, despite the fact that death rates from breast cancer have been falling since the 1990s. In any given decade of life, a woman's risk for breast cancer never exceeds 1 in 34. Although a woman's lifetime risk of developing breast cancer if she lives past 85 years is about 1 in 9, it is much more likely that she will die from cardiovascular disease than from breast cancer. In other words, many elderly women have breast cancer but die from other causes. Similarly, a minority of women are aware that lung cancer is the leading cause of cancer death in women. These misconceptions are unfortunate as they perpetuate inadequate attention to modifiable risk factors, such as dyslipidemia, hypertension, and cigarette smoking.

Physicians are also less likely to recognize women's risk for cardiovascular disease. A survey of physicians in 2004 found that women with intermediate risk for cardiovascular disease, according to Framingham risk score, were significantly more likely to be assigned to a lower risk category than men with similar risk profiles. Moreover, when presented with actors portraying patients with chest pain, physicians' estimates for probability of coronary heart disease (CHD) were significantly lower for women than for men and lower for black women than for white women. These perceptions on the part of both the patient and her physician lead to important differences in cardiac care.

Alzheimer's Disease

Alzheimer's disease (AD) affects approximately twice as many women as men. Because the risk for AD increases with age, part of this sex difference is accounted for by the fact that women live longer than men. However, additional factors likely contribute to the increased risk for AD in women, including sex differences in brain size, structure, and functional organization. There is emerging evidence for sex-specific differences in gene expression, not only for genes on the X and Y chromosomes but also for some autosomal genes. Estrogens have pleiotropic genomic and nongenomic effects on the central nervous system, including neurotrophic actions in key areas involved in cognition and memory. Women with AD have lower endogenous estrogen levels compared to women without AD. These observations have led to the hypothesis that estrogen is neuroprotective.

Some studies have suggested that estrogen administration improves cognitive function in nondemented postmenopausal women as well as in women with AD, and several observational studies have suggested that postmenopausal hormone therapy (PHT) may decrease the risk of AD. However, recent placebo-controlled trials have found no improvement in disease progression or cognitive function after up to 15 months of PHT in women with AD. Further, the Women's Health Initiative Memory Study (WHIMS), an ancillary study in the Women's Health Initiative (WHI), found no benefit compared to placebo of estrogen alone [combined continuous equine estrogen (CEE), 0.625 mg qd] or estrogen with progestin [CEE, 0.625 mg qd, and medroxyprogesterone acetate (MPA), 2.5 mg qd] on cognitive function or the development of dementia in women 65 years and older. Indeed, there was a significantly increased risk for both dementia and mild cognitive impairment in women receiving hormone therapy. The possible explanations for the discrepant results between the observational studies and the randomized clinical trials remain unclear.

Coronary Heart Disease

There are major sex differences in CHD, the leading cause of death in men and women in developed countries. CHD death rates have been falling in men over the past 30 years, but they have been increasing in women. Since 1984, more women than men have died of cardiovascular disease. Gonadal steroids have major effects on the cardiovascular system and lipid metabolism. Estrogen increases high-density lipoprotein (HDL) and lowers low-density lipoprotein (LDL), whereas androgens have the opposite effect. Estrogen has direct vasodilatory effects on the vascular endothelium, enhances insulin sensitivity, and has antioxidant properties. There is a striking increase in CHD after both natural and surgical menopause suggesting that endogenous estrogens are cardioprotective. Women also have longer QT intervals on electrocardiograms, which increases their susceptibility to certain arrhythmias. Animal studies suggest that the sex difference in QT interval duration is caused by sex steroid effects on cardiac repolarization, in part related to their effects on cardiac voltage-gated potassium channels; there is a lower density of the rapid component (I_Kr) of the delayed rectifier potassium current (I_K) in females.

CHD presents differently in women, who are usually 10–15 years older than their male counterparts and are more likely to have comorbidities such as hypertension, congestive heart failure, and diabetes mellitus (DM). In the Framingham study, angina was the most frequent initial symptom of CHD in women, whereas myocardial infarction was the most frequent initial presentation in men. Women more often have atypical symptoms, such as nausea, vomiting, indigestion, and upper back pain.

Women with myocardial infarction are more likely to present with cardiac arrest or cardiogenic shock, whereas men are more likely to present with ventricular tachycardia. Further, younger women with myocardial infarction are more likely to die than men of similar age, with women under 50 experiencing twice the mortality rate of men, even after adjustment for differences in disease severity and management. Indeed, the younger the woman, the greater the risk of death from myocardial infarction compared to men (Fig. 2).

Fig.2 Rates of death during hospitalization for myocardial infarction among women and men according to age. The overall mortality rate during hospitalization was 16.7% among women and 11.5% among men but was twice the rate in women <50>p(From V Vaccarino et al: N Engl J Med 341:217, 1999; with permission.) <.001).

Physicians are less likely to suspect heart disease in women with chest pain and less likely to perform diagnostic and therapeutic cardiac procedures in women. In addition, there are sex differences in the accuracy of certain diagnostic procedures. The exercise electrocardiogram has substantial false-positive as well as false-negative rates in women compared to men. Women are less likely to receive therapies such as angioplasty, thrombolytic therapy, coronary artery bypass grafts (CABGs), beta blockers, or aspirin. There are also sex differences in outcomes when women with CHD do receive therapeutic interventions. Women undergoing CABG surgery have more advanced disease, a higher perioperative mortality rate, less relief of angina, and less graft patency; however, 5- and 10-year survival rates are similar. Women undergoing percutaneous transluminal coronary angioplasty have lower rates of initial angiographic and clinical success than men, but they also have a lower rate of restenosis and a better long-term outcome. Women may benefit less and have more frequent serious bleeding complications from thrombolytic therapy than do men. Factors such as older age, more comorbid conditions, and more severe CHD in women at the time of events or procedures appear to account in part for the observed sex differences.

Elevated cholesterol levels, hypertension, smoking, obesity, low HDL cholesterol levels, DM, and lack of physical activity are important risk factors for CHD in both men and women. Total triglyceride levels are an independent risk factor for CHD in women but not in men. Low HDL cholesterol and DM are more important risk factors for CHD in women than in men. Smoking is an important risk factor for CHD in women—it accelerates atherosclerosis, exerts direct negative effects on cardiac function, and is associated with an earlier age of menopause. Cholesterol-lowering drugs are equally effective in men and women for primary and secondary prevention of CHD. However, because of perceptions that women are at lower risk for CHD, they receive fewer interventions for modifiable risk factors than do men. In contrast to men, randomized trials have shown that aspirin was not effective in the primary prevention of CHD in women; it did significantly reduce the risk of ischemic stroke. Secondary prevention in women with known CHD is also suboptimal. At baseline, only about 30% of women enrolled in the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention trial in women with established CHD, were taking beta blockers, and only 45% received lipid-lowering medications.

The sex differences in CHD prevalence, beneficial biologic effects of estradiol on the cardiovascular system, and reduced risk for CHD in observational studies of women receiving PHT led to the widespread use of PHT for the prevention of CHD. However, the WHI, which studied more than 16,000 women on CEE plus MPA or placebo and more than 10,000 women with hysterectomy on CEE alone or placebo, did not demonstrate a benefit of PHT for the primary or secondary prevention of CHD. In addition, CEE plus MPA was associated with an increased risk for CHD, particularly in the first year of therapy, whereas CEE alone neither increased nor decreased CHD risk. There was no evidence for cardioprotective effects of estrogens in smaller randomized trials that used either oral or transdermal estradiol, arguing against the hypothesis that the type of estrogen or its route of administration accounted for the lack of CHD risk reduction. In the WHI, there was a suggestion of a reduction in CHD risk in women ages 50–59 at baseline who received CEE alone. This finding suggests that the time at which PHT is initiated is critical for cardioprotection and is consistent with the "timing hypothesis." According to this hypothesis, PHT has differential effects depending on the stage of atherosclerosis; adverse effects are seen with advanced, unstable lesions. This hypothesis is currently under investigation in randomized clinical trials.

Diabetes Mellitus

Women are more sensitive to insulin than men. Despite this, the prevalence of type 2 DM is similar in men and women. There is a sex difference in the relationship between endogenous androgen levels and DM risk: higher bioavailable testosterone levels are associated with increased risk in women, whereas lower bioavailable testosterone levels are associated with increased risk in men. Polycystic ovary syndrome and gestational DM—common conditions in premenopausal women—are associated with a significantly increased risk for type 2 DM. Premenopausal women with DM lose the cardioprotective effect of female sex and have identical rates of CHD to those in males. These women have impaired endothelial function and reduced coronary vasodilatory responses, which may predispose to cardiovascular complications. In individuals with DM, women have a greater risk for myocardial infarction than men. Women with DM are more likely to have left ventricular hypertrophy. In the WHI, CEE plus MPA significantly reduced the incidence of DM, whereas with CEE alone there was a trend only toward decreased DM incidence.

Hypertension

After age 60, hypertension is more common in U.S. women than in men, largely because of the high prevalence of hypertension in older age groups and the longer survival of women. Isolated systolic hypertension is present in 30% of women >60 years. Sex hormones affect blood pressure. Both normotensive and hypertensive women have higher blood pressure levels during the follicular phase than during the luteal phase. In the Nurses Health Study, the relative risk of hypertension was 1.8 in current users of oral contraceptives, but this risk is lower with the newer low-dose contraceptive preparations. PHT is not associated with hypertension. Among secondary causes of hypertension, there is a female preponderance of renal artery fibromuscular dysplasia.

The benefits of treatment for hypertension have been dramatic in both women and men. In a meta-analysis of the effects of hypertension treatment, the Individual Data Analysis of Antihypertensive Intervention Trial found a reduction of risk for stroke and for major cardiovascular events in women. The effectiveness of various antihypertensive drugs appears to be comparable in women and men; however, women may experience more side effects. For example, women are more likely to develop cough with angiotensin-converting enzyme inhibitors.

Autoimmune Disorders

Most autoimmune disorders occur more commonly in women than in men; these include autoimmune thyroid and liver diseases, lupus, rheumatoid arthritis (RA), scleroderma, multiple sclerosis (MS), and idiopathic thrombocytopenic purpura. However, there is no sex difference in the incidence of type 1 DM, and ankylosing spondylitis occurs more commonly in men. There are relatively few differences in bacterial disease infection rates in men and women. In general, sex differences in viral diseases can be accounted for by differences in behaviors, such as exposures or rates of immunization. Sex differences in both immune responses and adverse reactions to vaccines have been reported. For example, there is a female preponderance of postvaccination arthritis.

The mechanisms for these sex differences remain obscure. Adaptive immune responses are more robust in women than in men, which may be explained by the stimulatory actions of estrogens and the inhibitory actions of androgens on the cellular mediators of immunity. Consistent with an important role for gonadal hormones, there is variation in immune responses during the menstrual cycle, and the activity of certain autoimmune disorders is altered by castration or pregnancy (e.g., RA and MS may remit during pregnancy). Nevertheless, the majority of studies show that exogenous estrogens and progestins in the form of PHT or oral contraceptives do not alter autoimmune disease incidence or activity. Exposure to fetal antigens, including circulating fetal cells that persist in certain tissues, has been speculated to increase the risk of autoimmune responses. There is clearly an important genetic component to autoimmunity, as indicated by the familial clustering and HLA association of many such disorders. However, HLA types are not sexually dimorphic.

HIV Infection

Women account for almost 50% of the 40 million persons infected with HIV-1 worldwide. AIDS is an important cause of death in younger women (Fig. 1). Heterosexual contact with an at-risk partner is the fastest-growing transmission category, and women are more susceptible to HIV infection than men. This increased susceptibility is in part accounted for by an increased prevalence of sexually transmitted diseases in women. Some studies have suggested that hormonal contraceptives may increase the risk of HIV transmission. Progesterone has been shown to increase susceptibility to infection in nonhuman primate models of HIV. Women are also more likely to be infected by multiple variants of the virus than men. Women with HIV have more rapid decreases in their CD4 cell counts than men. Compared with men, HIV-infected women more frequently develop candidiasis, but Kaposi's sarcoma is less common than in men.

Other sexually transmitted diseases, such as chlamydial infection and gonorrhea, are important causes of infertility in women, and papilloma virus infection predisposes to cervical cancer.

Obesity

The prevalence of obesity is higher in women than in men. However, according to a recent study by the Agency for Healthcare Research and Quality, >80% of patients undergoing bariatric surgery are women. Pregnancy and menopause are risk factors for obesity. There are major sex differences in body fat distribution. Women characteristically have gluteal and femoral or gynoid pattern of fat distribution, whereas men typically have a central or android pattern. Gonadal steroids appear to be the major regulators of fat distribution through a number of direct effects on adipose tissue. Studies in humans also suggest that gonadal steroids play a role in modulating food intake and energy expenditure.

In men and women, upper-body obesity characterized by increased visceral fat is associated with an increased risk for cardiovascular disease and DM. In women, endogenous androgen levels are positively associated with upper-body obesity, and androgen administration increases visceral fat. In contrast, there is an inverse relationship between endogenous androgen levels and central obesity in men. Further, androgen administration decreases visceral fat in centrally obese men. The reasons for these sex differences in the relationship between visceral fat and androgens are unknown. Obesity increases a woman's risk for certain cancers, in particular postmenopausal breast and endometrial cancer, in part because adipose tissue provides an extragonadal source of estrogen through aromatization of circulating adrenal and ovarian androgens, especially the conversion of androstenedione to estrone. Obesity increases the risk of infertility, miscarriage, and complications of pregnancy.

Osteoporosis

Osteoporosis is about five times more common in postmenopausal women than in age-matched men, and osteoporotic hip fractures are a major cause of morbidity in elderly women. Men accumulate more bone mass and lose bone more slowly than women. Sex differences in bone mass are found as early as infancy. Calcium intake, vitamin D, and estrogen all play important roles in bone formation and bone loss. Particularly during adolescence, calcium intake is an important determinant of peak bone mass. Vitamin D deficiency is surprisingly common in elderly women, occurring in >40% of women living in northern latitudes. Receptors for estrogens and androgens have been identified in bone. Estrogen deficiency is associated with increased osteoclast activity and a decreased number of bone-forming units, leading to net bone loss. The aromatase enzyme, which converts androgens to estrogens, is also present in bone. Recent studies show that estrogen is an important determinant of bone mass in men (derived from the aromatization of androgens) as well as in women.

Pharmacology

On average, women have lower body weights, smaller organs, higher percent body fat, and lower total-body water than men. There are also important sex differences in drug action and metabolism that are not accounted for by these differences in body size and composition. Gonadal steroids alter the binding and metabolism of a number of drugs. Further, menstrual cycle phase and pregnancy can alter drug action. Two-thirds of cases of drug-induced torsades des pointes, a rare, life-threatening ventricular arrhythmia, occur in women because they have a longer, more vulnerable QT interval. These drugs, which include certain antihistamines, antibiotics, antiarrhythmics, and antipsychotics, can prolong cardiac repolarization by blocking cardiac voltage-gated potassium channels, particularly I_Kr. Women require lower doses of neuroleptics to control schizophrenia. Women awaken from anesthesia faster than men given the same doses of anesthetics. Women also take more medications than men, including over-the-counter formulations and supplements. The greater use of medications combined with these biologic differences may account for the reported higher frequency of adverse drug reactions in women than in men.

Psychological Disorders

Depression, anxiety, and affective and eating disorders (bulimia and anorexia nervosa) are more common in women than in men. Epidemiologic studies from both developed and developing nations consistently find major depression to be twice as common in women as in men, with the sex difference becoming evident in early adolescence. Depression occurs in 10% of women during pregnancy and in 10–15% of women during the postpartum period. There is a high likelihood of recurrence of postpartum depression with subsequent pregnancies. The incidence of major depression diminishes after age 45 years and does not increase with the onset of menopause. Depression in women appears to have a worse prognosis than in men; episodes last longer, and there is a lower rate of spontaneous remission. Schizophrenia and bipolar disorders occur at equal rates in men and women, although there may be sex differences in symptoms.

Both biologic and social factors account for the greater prevalence of depressive disorders in women. Men have higher levels of the neurotransmitter serotonin. Gonadal steroids also affect mood, and fluctuations during the menstrual cycle have been linked to symptoms of premenstrual syndrome. Sex hormones differentially affect the hypothalamic-pituitary-adrenal responses to stress. Testosterone appears to blunt cortisol responses to corticotropin-releasing hormone. Both low and high levels of estrogen can activate the hypothalamic-pituitary-adrenal axis.

Sleep Disorders

There are striking sex differences in sleep and its disorders. During sleep, women have an increased amount of slow-wave activity, differences in timing of delta activity, and an increase in the number of sleep spindles. Testosterone modulates neural control of breathing and upper airway mechanics. Men have a higher prevalence of sleep apnea. Testosterone administration to hypogonadal men as well as to women increases apneic episodes during sleep. Women with the hyperandrogenic disorder polycystic ovary syndrome have an increased prevalence of obstructive sleep apnea, and apneic episodes are positively correlated with their circulating testosterone levels. In contrast, progesterone accelerates breathing, and, in the past, progestins were used for treatment of sleep apnea.

Substance Abuse and Tobacco

Substance abuse is more common in men than in women. However, one-third of Americans who suffer from alcoholism are women. Women alcoholics are less likely to be diagnosed than men. A greater proportion of men than women seek help for alcohol and drug abuse. Men are more likely to go to an alcohol or drug treatment facility, while women tend to approach a primary care physician or mental health professional for help under the guise of a psychosocial problem. Late-life alcoholism is more common in women than men. On average, alcoholic women drink less than alcoholic men but exhibit the same degree of impairment. Blood alcohol levels are higher in women than in men after drinking equivalent amounts of alcohol, adjusted for body weight. This greater bioavailability of alcohol in women is due to both the smaller volume of distribution and the slower gastric metabolism of alcohol secondary to lower activity of gastric alcohol dehydrogenase than is the case in men. In addition, alcoholic women are more likely to abuse tranquilizers, sedatives, and amphetamines. Women alcoholics have a higher mortality rate than do nonalcoholic women and alcoholic men. Women also appear to develop alcoholic liver disease and other alcohol-related diseases with shorter drinking histories and lower levels of alcohol consumption. Alcohol abuse also poses special risks to a woman, adversely affecting fertility and the health of the baby (fetal alcohol syndrome). Even moderate alcohol use increases the risk of breast cancer, hypertension, and stroke in women.

More men than women smoke tobacco, but the prevalence of smoking is declining faster in men than in women. Smoking markedly increases the risk of cardiovascular disease in premenopausal women and is also associated with a decrease in the age of menopause. Women who smoke are more likely to develop chronic obstructive pulmonary disease and lung cancer than men and at lower levels of tobacco exposure.

Violence Against Women

Domestic violence is the most common cause of physical injury in women, exceeding the combined incidence of all other types of injury (such as from rape, mugging, and auto accidents). Sexual assault is one of the most common crimes against women. One in five adult women in the United States reports having experienced sexual assault during her lifetime. Adult women are much more likely to be raped by a spouse, ex-spouse, or acquaintance than by a stranger. Domestic violence may be an unrecognized feature of certain clinical presentations such as chronic abdominal pain, headaches, substance abuse, and eating disorders, in addition to more obvious manifestations such as trauma.

SUMMARY

Women's health is now a mature discipline, and the importance of sex differences in biologic processes is well-recognized. It is clear that understanding the mechanisms of these differences will have an impact on both women's and men's health. For example, estrogen is now recognized as an important regulator of bone density in men as well as in women. Elucidating the biology of sex hormone action has resulted in the design of drugs with tissue-specific hormone agonist and antagonist effects. These discoveries will make it feasible to selectively modulate the actions of sex hormones in both women and men to prevent and treat disease.

FURTHER READINGS Hsia J et al: Conjugated equine estrogens and coronary heart disease: The Women's Health Initiative. Arch Intern Med 166:357, 2006 [PMID: 16476878] Mendelsohn ME, Karas RH: Molecular and cellular basis of cardiovascular gender differences. Science 308:1583, 2005 [PMID: 15947175] Mosca L et al: National Study of Physician Awareness and Adherence to Cardiovascular Disease Prevention Guidelines. Circulation 111:499, 2005 [PMID: 15687140] Ridker PM et al: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 352:1293, 2005 [PMID: 15753114] Special Section Women's Health. Science 308:1569, 2005 Turgeon JL et al: Hormone therapy: Physiological complexity belies therapeutic simplicity. Science 304:1269, 2004 [PMID: 15166356] Wizemann TM, Pardue M-L (eds): Exploring the Biological Contributions to Human Health: Does Sex Matter? Washington, DC, National Academy of Sciences, 2001

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