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HISTORY

Assess menstrual history (including oral contraceptive use), fracture history, and symptoms of depression. Assess dietary practices, eating behaviors, and history of weight changes. Dietary intake logs and a nutritional assessment by a sports dietitian can help. Assess body image, fear of weight gain, fluctuations in weight, history of DE, and use of laxatives, diet pills, or enemas.

PHYSICALEXAM

Height, weight, body mass index (BMI) <17.5% kg/m2 or <85% of expected body weight in adolescents (1)[A]

Common findings include bradycardia, orthostatic hypotension, hypothermia, cold or cyanotic extremities, lanugo, parotid gland enlargement or tenderness, epigastric tenderness, eroded tooth enamel, and knuckle or hand calluses (Russell sign).

Patients with amenorrhea should undergo a pelvic exam to verify the presence of a uterus and evaluate for outflow tract abnormalities. Vaginal atrophy may be present if the patient is hypoestrogenic.

DIFFERENTIALDIAGNOSIS

Screen for anorexia nervosa, bulimia nervosa, avoidant/restrictive food intake disorder, and rumination disorder using the DSM-5 criteria. Rule out the following in amenorrheic patients:

Pregnancy

Endocrine abnormalities: thyroid dysfunction, Cushing syndrome

Hypothalamic dysfunction: psychological stress-induced amenorrhea, medication-induced amenorrhea, Kallmann syndrome

Pituitary dysfunction: prolactinoma, Sheehan syndrome, sarcoidosis, empty sella syndrome

Ovarian dysfunction: polycystic ovarian syndrome, premature ovarian failure, menopause, gonadal dysgenesis, Turner syndrome, ovarian neoplasm, autoimmune disease

Uterine dysfunction: Asherman syndrome, absence of uterus

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Basic metabolic panel, magnesium, phosphorus, albumin, CBC with differential, ESR, thyroid-stimulating hormone (TSH), calcium, 25-OH

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vitamin D, and urinalysis (1,5)

Evaluation for secondary amenorrhea includes urine hCG, FSH, LH, prolactin, and TSH.

Pelvic ultrasound in patients with hyperandrogenism to exclude polycystic ovaries or virilizing ovarian tumors

ECG to rule out prolonged QT interval

Follow-Up Tests & Special Considerations

BMD testing by DEXAis based on a risk stratification model (1). Risk factors include DE, eating disorders >6 months, hypoestrogenism, amenorrhea, oligomenorrhea, and/or in patients with a history of stress fractures or fractures from minimal impact.

In components of the triad persist, ISCD 2013 guidelines suggest reevaluation by the same DEXAmachine every 1 to 2 years.

TREATMENT

The goal is to optimize nutritional status and treat maladaptive behavioral disorders (1,3)[A].

Amultidisciplinary team includes a physician, registered dietitian, and behavioral health provider. Build open lines of communication with coaches, trainers, and family.

Apositive EAof >30 kcal/kg of fat-free muscle mass per day is sufficient to restore menses (5)[A].

Physically active females should strive for an EAof >45 kcal/kg of fat-free muscle mass per day (1)[A].

MEDICATION

First Line

Increasing EAthrough appropriate nutrition is the best strategy for normalizing gonadotropin pulsatility and release. The use of combination oral contraceptive pills (cOCPs), hormone replacement therapy (HRT), and/or bisphosphonates has not been clearly shown to increase BMD or aid in the restoration of normal menstrual cycling. cOCPs or transdermal estradiol with cyclic progesterone can be considered in patients with particularly low BMD Z-scores and fracture histories who do not respond to 1 year of nonpharmacologic management.

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cOCP or transdermal estradiol can also be given to minimize further bone loss in patients >16 years and <21 years who, despite adequate nutrition and body weight gain, continue to have decreasing BMD and functional hypothalamic amenorrhea.

cOCPs do have potential to mask signs of RED-S and do not correct underlying energy deficiency. They can also suppress androgen release, potentially causing a decrease in BMD. Therefore, their use should be reserved for above scenarios (2).

Provide calcium (1,500 mg/day) and vitamin D supplementation to maintain serum levels within 32 to 50 mg/mL (1)[A].

In male athletes, with RED-S, testosterone replacement therapy can be helpful in patients with hypogonadism and osteoporosis (2).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

Evaluate patients with eating disorders for potentially life-threatening conditions requiring hospital admission, including bradycardia, severe orthostatic hypotension, significant electrolyte imbalances, hypothermia, arrhythmias, or prolonged QT interval.

ONGOING CARE

Patients should have regular follow-up with a multidisciplinary treatment team (6)[A].

Cognitive-behavioral therapy (CBT) is effective for exercising women with ED and may be more beneficial than nutritional counseling alone in women with DE behavior.

“Clearance and Return to Play (RTP) Guidelines by Medical Risk Stratification” help determine when to allow an athlete to return to competition. More research is needed to validate this model (1)[A].

To continue training and competing, athletes with eating disorders must agree to the following stipulations as part of a behavioral contract: to comply with all treatment strategies; to be closely monitored by health care providers; to place treatment goals over training goals; and to modify the type, duration, and intensity of training or competition as necessary.

The RED-S Risk Assessment Model can be used to aide decision to clear athletes to return to play (2).

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PATIENTEDUCATION

All young female patients should be counseled on the importance of proper nutrition, calcium and vitamin D intake, and the benefits of regular weightbearing exercise. Patients presenting with ≥1 components of the triad should be educated about the shortand long-term effects of low BMD (1,3)[A].

RED-S effects on performance: decrease endurance, increased injury risk, decreased training response, impaired judgment, decreased coordination, decreased concentration, irritability, depression, decreased glycogen stores, decreased muscle strength (2)

PROGNOSIS

The shortand long-term prognosis for patients with female athlete triad depends on time to diagnosis and response to treatment.

It is estimated that amenorrheic women will lose 2–3% of bone mass per year without intervention.

With early diagnosis and treatment using a multidisciplinary team, the prognosis for patients with the female athlete triad is good. Patients regain normal menstrual cycling and increase BMD.

Because the triad often occurs within the age window of optimal bone strengthening, patients with a prolonged disease course may suffer from complications of decreased BMD throughout their adolescent and adult life.

Patients with DE behaviors often require long-term therapy to manage their disease.

REFERENCES

1.De Souza MJ, Nattiv A, Joy E, et al. 2014 Female Athlete Triad Coalition consensus statement on treatment and return to play of the female athlete triad: 1st International Conference held in San Francisco, CA, May 2012, and 2nd International Conference held in Indianapolis, IN, May 2013. Clin J Sport Med. 2014;24(2):96–119.

2.Mountjoy M, Sundgot-Borgen J, Burke L, et al. The IOC consensus statement: beyond the Female Athlete Triad—Relative Energy Deficiency in Sport (RED-S). Br J Sports Med. 2014;48(7):491–497.

3.Barrack MT, Ackerman KE, Gibbs JC. Update on the female athlete triad.

Curr Rev Musculoskeletal Med. 2013;6(2):195–204.

4.Lanser EM, Zach KN, Hoch AZ. The female athlete triad and endothelial dysfunction. PM R. 2011;3(5):458–465.

5.Temme KE, Hoch AZ. Recognition and rehabilitation of the female athlete

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triad/tetrad: a multidisciplinary approach. Curr Sports Med Rep.

2013;12(3):190–199.

6.Deimel JF, Dunlap BJ. The female athlete triad. Clin Sports Med. 2012;31(2):247–254.

ADDITIONALREADING

Nattiv A, Loucks AB, Manore MM, et al. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39(10):1867–1882.

SEE ALSO

Algorithms: Amenorrhea, Primary (Absence of Menarche by Age 16); Amenorrhea, Secondary; Weight Loss, Unintentional

CODES

ICD10

F50.9 Eating disorder, unspecified

N91.2 Amenorrhea, unspecified

R53.83 Other fatigue

CLINICALPEARLS

The female athlete triad consists of low EA(with or without DE), MD, and low BMD. Athletes may exhibit varying degrees of dysfunction in any of these three areas.

Screen at-risk women to allow for early diagnosis and intervention.

Early intervention by a multidisciplinary team, including physicians, registered dietitians, mental health professionals, coaches, trainers, and parents, is the most successful strategy to minimize further bone loss, recover BMD, and regain normal menstrual function.

Current guidelines recommend screening for abnormal BMD using DEXA studies for patients with DE, eating disorders >6 months, hypoestrogenism, amenorrhea, oligomenorrhea, and/or in patients with a history of stress fractures or fractures from minimal impact.

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FEVER OF UNKNOWN ORIGIN (FUO)

Scott T. Henderson, MD

BASICS

DESCRIPTION

Classic definition

–Repeated fever >38.3°C

–Fever duration at least 3 weeks

–Uncertain diagnosis after 1 week of study in the hospital

The definition of fever of unknown origin (FUO) has evolved and is based on patient characteristics and presentation. The need for in-hospital evaluation has been eliminated in previously healthy people.

Some expand the definition to include nosocomial, neutropenic (immunodeficient), and HIV-associated fevers.

EPIDEMIOLOGY

Incidence

Incidence unclear

ETIOLOGYAND PATHOPHYSIOLOGY

>200 causes; each with prevalence of ≤5%

Most commonly, FUO is an atypical presentation of a common condition. Spectrum of causes varies geographically and temporally.

–Noninfectious inflammatory diseases are the most frequent causes in highincome countries. Common causes include temporal arteritis, polymyalgia rheumatica, or rheumatoid arthritis.

Infection

–Abdominal or pelvic abscesses

–Amebic hepatitis

–Catheter infections

–Cytomegalovirus

–Dental abscesses

–Endocarditis/pericarditis

–HIV (advanced stage)

–Mycobacterial infection (often with advanced HIV)

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–Osteomyelitis

–Pyelonephritis or renal abscess

–Sinusitis

–Wound infections

–Other miscellaneous infections

Neoplasms

–Atrial myxoma

–Colorectal cancer and other GI malignancies

–Hepatoma

–Lymphoma

–Leukemia

–Solid tumors (renal cell carcinoma)

Noninfectious inflammatory disease

–Connective tissue diseases Adult Still disease

Rheumatoid arthritis

Systemic lupus erythematosus

–Granulomatous disease Crohn disease

Sarcoidosis

–Vasculitis syndromes Giant cell arteritis

Polymyalgia rheumatica

Other causes

–Alcoholic hepatitis

–Cerebrovascular accident

–Cirrhosis

–Medications

Allopurinol, captopril, carbamazepine, cephalosporins, cimetidine, clofibrate, erythromycin, heparin, hydralazine, hydrochlorothiazide, isoniazid, meperidine, methyldopa, nifedipine, nitrofurantoin, penicillin, phenytoin, procainamide, quinidine, sulfonamides

–Endocrine disease

–Factitious/fraudulent fever

–Occupational causes

–Periodic fever

–Pulmonary emboli/deep vein thrombosis

–Thermoregulatory disorders

In up to 20–30% of cases, the cause of the fever is never identified despite a

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thorough workup.

RISK FACTORS

Recent travel (malaria, enteric fevers)

Exposure to biologic or chemical agents

HIV infection (particularly in acute infection and advanced stages)

Elderly

Drug abuse

Immigrants

Young female health care workers (consider factitious fever)

Geriatric Considerations

Common causes of geriatric infections include intra-abdominal abscess, urinary tract infection, tuberculosis, and endocarditis. Other common causes of FUO in patients >65 years include malignancies (particularly hematologic cancers) and drug-induced fever.

Pediatric Considerations

~50% of FUO in pediatric cases are infectious. Collagen vascular disease, malignancy are common.

Inflammatory bowel disease is a common cause of FUO in older children and adolescents.

DIAGNOSIS

HISTORY

Onset and pattern of fever

Constitutional symptoms:

–Chills, night sweats, myalgias, weight loss with an intact appetite (infectious etiology)

–Arthralgias, myalgias, fatigue (inflammatory etiology)

–Fatigue, night sweats, weight loss with loss of appetite (neoplastic etiology)

Past medical history: chronic infections, abdominal diseases, transfusion history, malignancy, psychiatric illness, and recent hospitalization

Past surgical history: type of surgery performed, postoperative complications, and any indwelling foreign material

Comprehensive medication history, including over-the-counter and herbal

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products

Family history, such as periodic fever syndromes and recent febrile illnesses in close contacts

Social history: travel, exposures, living environment, sexual activity, recreational drug use

ALERT

Obtain a thorough travel, psychosocial, occupational, sexual, and drug use history.

PHYSICALEXAM

Physical findings with high diagnostic yield

–Funduscopic exam for choroid tubercles or Roth spots

–Temporal artery tenderness

–Oral-mucosal lesions

–Cardiac auscultation for bruits and murmurs

–Pulmonary exam: consolidation or effusion

–Abdominal palpation for organomegaly and tenderness or peritoneal signs

–Rectal examination for blood, fluctuance and/or tenderness

–Testicular examination

–Lymph node examination

–Skin and nail bed exam for clubbing, nodules, lesions, and erosions

–Focal neurologic signs

–Musculoskeletal exam for tenderness or effusion

–Serial exams help identify evolving physical signs (e.g., findings associated with endocarditis).

DIFFERENTIALDIAGNOSIS

See “Etiology and Pathophysiology.”

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

CBC; C-reactive protein; ESR

Peripheral blood smear

Electrolytes, BUN and creatinine; LFT; calcium

Lactate dehydrogenase

HIV testing

Blood cultures (not to exceed six sets)

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Urinalysis and urine culture

Chest x-ray

CT or MRI of abdomen and pelvis (with directed biopsy, if indicated) (1)[C]

Follow-Up Tests & Special Considerations

Rheumatoid factor and antinuclear antibody test

Serologies: Epstein-Barr, hepatitis, syphilis, Lyme disease, Q fever, cytomegalovirus, brucellosis, amebiasis, coccidioidomycosis

Serum ferritin

Serum procalcitonin

Serum protein electrophoresis

Sputum and urine cultures for TB Tuberculin skin test

–May not be helpful if anergic or acute infection

–If test negative, repeat in 2 weeks.

–If indicated, consider an interferon gamma release assay (IGRA) test.

Thyroid function tests

Technetium-based scan (infection tumor) (1)[B]

FDG-PET/CT scan if infectious process, inflammatory process, or tumor suspected; PET scans have a high negative predictive value and good sensitivity (but may have false positives) (2)[A].

Ultrasound of abdomen and pelvis (with directed biopsy, if indicated) if renal obstruction or biliary pathology suspected

Echocardiogram if endocarditis, atrial myxomas, or pericardial effusion is suspected

Lower extremity Doppler if deep vein thrombosis/pulmonary embolism suspected

CT scan of chest if pulmonary embolism suspected

Indium-labeled leukocyte scanning if inflammatory process or occult abscess suspected

Bone scan if osteomyelitis or metastatic disease suspected

Diagnostic Procedures/Other

Liver biopsy if granulomatous disease suspected (1)[C]

Temporal artery biopsy, particularly in the elderly

Lymph node, muscle, or skin biopsy, if clinically indicated

Bone marrow aspiration biopsy with smear, culture, histologic examination, and flow cytometry

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