100 - TUBERCULOSIS ( TB )

Background:

As with other scourges of the preantibiotic era, tuberculosis (TB) until recently was considered of passing historical significance to emergency physicians practicing in the developed world. In 1985, due primarily to the newly recognized HIV epidemic and to a growing indigent population, TB resurfaced in inner-city emergency departments. In 1991, highly virulent multi–drug-resistant (MDR) strains of Mycobacterium tuberculosis were reported by the Centers for Disease Control and Prevention (CDC). These strains not only produced fulminant and fatal disease among patients infected with HIV (TB exposure to death in 2-7 mo) but also proved highly infectious (conversion rates of up to 50% in exposed healthcare workers) (CDC MMWR, 1994). Recent recognition of the potential for catastrophic outbreaks resulting from MDR TB has led to national efforts for both surveillance and control.
Because of the prevalence of MDR strains, recommendations for pharmacologic management as well as exposure prophylaxis have evolved over the past decade. To avoid selecting drug-resistant organisms, treatment should begin with at least 4 medications until drug susceptibilities are known. (One in 106 tuberculous bacilli mutate and become isoniazid [INH] resistant.) In 1996, the CDC also provided recommendations for potential use of bacille Calmette-Guérin (BCG) vaccine in healthcare workers (see Special Concerns).
By virtue of the association between TB and poverty, the emergency physician may be a patient's only opportunity for recognition of mycobacterial infection. Note that drug treatment can and should be initiated in the emergency department (ED) for anyone suspected of having active TB infection and that these patients should be isolated and hospitalized.

Pathophysiology:

A single cough can generate 3000 infective droplets. Fewer than 10 mycobacterial bacilli may initiate a pulmonary infection (Sherris, 1990). TB inoculation can result in latent infection or active disease. Depending on the population, 10-30% of inoculated individuals progress directly to active primary disease. More commonly, however, TB inoculation results in an asymptomatic latent infection. Skin test conversion and identification of a Ghon complex on chest radiography are the only means of identifying such cases.
Patients often remain healthy for years; however, some experience reactivation of their disease due to subsequent immunologic stressors. Such reactivation occurs at a rate of approximately 1% percent per year in immunocompetent hosts. The conversion rate is 10% in patients who are immunocompromised. While asymptomatic, patients with latent infection are not contagious. Most qualify for INH prophylaxis, which significantly decreases the risk of future reactivation of disease.
Roughly 80% of TB cases involve pulmonary disease, though TB can involve any organ system. In patients who are severely immunocompromised, extrapulmonary disease and atypical presentations are common.
Treatment markedly reduces infectivity. The first dose of medication reduces the bacillary load 10-fold. Therapy for 2 weeks reduces the bacillary load by a 100-fold factor (CDC, 1997). Patients require 3 negative sputum samples to be considered noninfectious, which usually necessitates treatment for 4 weeks.

Frequency:

• In the US: In 2004, the national active TB case rate was 4.9 cases per 100,000 persons, representing 14,511 reported cases and a decline of 3% from 2003. The majority of cases reported (60%) came from 7 states: California, Florida, Illinois, New York, New Jersey, Georgia, and Texas (CDC MMWR, 2004). In 1997, the CDC estimated that 1 in 17 persons has latent infection.
Active TB cases decreased by about 6% per year from 1953-1979. From 1979-1981, immigration by Indochinese refugees caused a slight increase, but incidence again declined from 1982-1984. From 1985-1992, due to HIV infection and a sharp rise in homelessness, incidence increased by some 20%. From 1993-2004, due to national TB control measures, the rate of new cases fell from 9.8 to 4.9 per 100,000 persons, a relative decline of 50%.

• Internationally:

TB still is on the top 10 list for all-cause, all-age worldwide mortality. It bears emphasis that 95% of all TB cases occur in developing countries. In 1988, TB was the ninth leading cause of death worldwide (Walsh, 1988).
Worldwide, TB prevalence is about 2 billion persons. New cases number about 8 million yearly, and annual mortality worldwide is estimated at 3 million, accounting for 7% of total worldwide mortality.
A 1998 international survey revealed that approximately 1 in 10 new cases of TB is a resistant strain, and 1 in 100 is MDR (Pablos-Mendez, 1998).
Mortality/Morbidity: Active TB was fatal for up to 50% of untreated patients, based on data collected prior to the advent of antibiotic therapy (Lindhardt, 1939). The US mortality rate from TB is currently 0.3 deaths per 100,000 persons—approximately 800 deaths per year. (The mortality rate in 1953 was 12.4 deaths per 100,000 persons.) This represents an annual mortality rate of approximately 6% of newly identified cases (CDC, 2004). MDR TB cases have a reported fatality rate of more than 70% (CDC MMWR, 1996).
Race: In the United States, two thirds of TB cases occur among minorities. The risk to people who are indigent is 300 times higher than the national risk (Slutkin, 1986); the risk for persons with HIV is 200-400 times greater. Other high-risk populations include hospital employees, inner-city residents, nursing home residents, persons with alcoholism, persons who use illicit drugs, and prisoners.

Sex:

In the United States, overall incidence rates are twice as high for men as for women (CDC, 1994).

Age:

Most TB cases are found in the 25- to 44-year-old age group. Two thirds of cases occur in minority populations, in which the median age at onset is 39 years. In nonminorities, the median age of onset is 62 years (Cantwell, 1994).



CLINICAL

History:

Inquire about historical features (eg, indigent, use of shelters, incarceration, HIV, travel to endemic area) that would increase a patient's risk of acquiring TB.
• Classic symptoms are often absent, particularly in patients who are immunocompromised or elderly. Up to 20% of patients with active TB may be asymptomatic.

Classic features associated with active TB are as follows:

o Productive cough
o Hemoptysis
o Fever
o Night sweats
o Anorexia
o Weight loss

• Symptoms of extrapulmonary tuberculosis may be nonspecific.

Physical:

• Fever
• Cachexia
• Hypoxia
• Tachycardia
• Lymphadenopathy
• Abnormal lung sounds
• The absence of any significant physical findings does not exclude active disease. In the high-risk patient, respiratory isolation and sputum sampling are essential.
Causes: TB is caused primarily by direct inhalation of infective droplet nuclei. Transdermal and gastrointestinal (GI) transmission also have been reported. Infected patients living in crowded or closed environments pose a particular risk for noninfected persons.

DIFFERENTIALS

Alcohol and Substance Abuse Evaluation
Asthma
Back Pain, Mechanical
Encephalitis
HIV Infection and AIDS
Meningitis
Neoplasms, Lung
Osteomyelitis
Panic Disorders
Pediatrics, Bacteremia and Sepsis
Pediatrics, Meningitis and Encephalitis
Pediatrics, Pneumonia
Pediatrics, Respiratory Distress Syndrome
Pericarditis and Cardiac Tamponade
Pleural Effusion
Pneumonia, Aspiration
Pneumonia, Bacterial
Pneumonia, Immunocompromised
Pneumonia, Mycoplasma
Pneumothorax, Iatrogenic, Spontaneous and Pneumomediastinum
Pneumothorax, Tension and Traumatic
Respiratory Distress Syndrome, Adult
Shock, Septic
Tuberculosis

WORKUP

Lab Studies:

• In the ED setting, the two most important diagnostic tests are random sample sputum staining for acid-fast bacilli and chest radiography.
o Accept the diagnosis and initiate treatment if either of these tests indicates active disease.
o Ziehl-Neelsen staining of sputum is a simple 5-step process that takes approximately 10 minutes to accomplish (WHO, 1980).
o Do not delay the diagnosis until the following day for patients at high risk for active disease.
• Attempt several sputum collections or induce sputum production by respiratory physiotherapy.
o The absence of a positive smear result does not exclude active TB infection.
o Approximately 35% of culture-positive specimens are associated with a negative smear result.
• Blood cultures using mycobacteria-specific, radioisotope-labeled systems help establish the diagnosis of active TB and are recommended in all patients infected with HIV (Bouza, 1993). Mycobacterial bacteremia (bacillemia) is detectable using blood cultures but only if specialized systems are used because the bacilli have specific nutrient growth requirements not met by routine culture systems. Such blood cultures should be used for all patients with HIV who are suspected of having TB, as bacillemia is particularly prevalent in this population. If available, such cultures may be used on any patient with a high suspicion for active TB.
o One study found an incidence of 88% mycobacterial infection (66% TB, 22% Mycobacterium avium complex [MAC]) detected by blood culture in stage IV HIV disease).
o Most patients had insidious and atypical symptoms (Grinsztejn, 1997).
• All patients who are diagnosed with active TB and who are not known to be HIV positive should be considered for HIV testing. This testing is not usually initiated in the ED.


Imaging Studies:

• Chest radiography consistent with TB indicates active disease in the symptomatic patient even in the absence of a diagnostic sputum smear result. Similarly, normal chest radiography in the symptomatic patient does not exclude TB, particularly in a patient who is immunosuppressed.
o In classic reactivation TB, pulmonary lesions are located in the posterior segment of the right upper lobe, apicoposterior segment of the left upper lobe, and apical segments of the lower lobes. In the presence of HIV or other immunosuppressant disease, lesions are often atypical (Korzeniewska-Kosela, 1992). Up to 20% of patients who are HIV positive with active disease have normal chest x-ray findings.
o Radiographic findings consistent with active primary TB are similar to those of lobar pneumonia with ipsilateral hilar adenopathy, often accompanied by atelectasis.
Other Tests:
• Tuberculin skin testing using 5 units (0.1 mL) of purified protein derivative (PPD) injected intradermally may be used for screening or to supplement other diagnostic testing.
o Positive criteria are population dependent, but any induration of 5 mm or more is now suspect.
o Induration, not erythema, is measured 48-72 hours following injection, although positive test results can be declared up to a week after placement.
o Approximately 20% of patients with active TB, particularly those with advanced disease, may have normal PPD test results.
o Testing is also unreliable in infants, patients with immunosuppressive conditions, and patients with serious illnesses (Canadian Thoracic Society, 1994).
• Population-based criteria for PPD positivity
o Patients who are HIV positive, have abnormal chest radiography, or have recent contact with active TB cases - 5-mm induration or more
o Patients who are IV drug users, residents of nursing homes, prisoners, impoverished, or members of minority groups - 10-mm induration or more
o Patients who are young and in good health - 15-mm induration or more
o Reactions in patients who have received the BCG vaccine are often difficult to interpret.
 In adults who received BCG vaccination at birth, consider a 10-mm induration or more a positive result.
 In persons receiving BCG vaccination as adults, consider a 30-mm induration (or larger) a positive result (King, 1990).


TREATMENT

Prehospital Care:

• Prehospital providers should be equipped with respiratory masks meeting standards for prevention of TB transmission and should receive annual tuberculin skin testing.
• For high-risk cases, prehospital workers can assist in identifying household contacts who also may be infected or who may be at high risk of becoming infected. Prehospital workers should be aware that any case of active TB in a child indicates disease in 1 or more adults within the same household (CDC MMWR, 1996).
• A special regimen exists for patients with TB who are actively seizing or who have overdosed on antimycobacterial medication.
o In these patients, overdose with INH should be suspected.
o Diazepam can be attempted to control seizure activity, but IV pyridoxine is the drug of choice, in a gram-for-INH-ingested-gram dose. (If the ingested dose is unknown, 5 g of pyridoxine can be used empirically.)
o For patients who are awake and alert, an oral dose of activated charcoal (1 g/kg) with sorbitol can be administered.

Emergency Department Care:

Isolate any patient with suspected TB infection in a private room (not cohorted, as in the past), ideally with negative pressure. Anyone entering should wear high-efficiency disposable masks sufficient to filter the TB bacillus. Continue isolation until sputum smears return negative results 3 consecutive times. Such sterilization usually requires 2-4 weeks of treatment and must be accompanied by clinical improvement (CDC MMWR, 1994).
• Initial 4-drug therapy is recommended in most areas. Intermittent treatment is as effective as daily treatment (~2% relapses) with the advantage of increased compliance (see below).
o Six-month course, daily therapy - The compliance rate is 61%.
 Initial 2 months (all PO doses) - INH 300 mg qd (pediatric dose: 10-20 mg/kg/d, not to exceed 300 mg/d); rifampin (RIF) 600 mg qd (pediatric: 10 mg/kg/d, not to exceed 600 mg/d); pyrazinamide (PZA) 2 g qd (pediatric: 25 mg/kg/d, not to exceed 2 g/d); and ethambutol (ETB) 2 g qd (pediatric dose: 25 mg/kg/d, not to exceed 2 g/d)
 ETB may be dropped if TB culture drug sensitivities return favorable results.
 Final 4 months (if initial 2 months are successful by smear conversion and resolving symptoms) - INH 300 mg qd and RIF 600 mg qd or, alternatively, INH 900 mg and RIF 600 mg twice weekly.
o Six-month course, directly observed intermittent therapy (Denver protocol) - The compliance rate is 91%.
 Initial 2 weeks (all PO doses except for streptomycin, which is administered IM) - INH 300 mg qd, RIF 600 mg qd, PZA 2 g qd, and streptomycin 1 g qd (pediatric dose: 20 mg/kg/d, not to exceed 1000 mg/d)
 Next 6 weeks - Same drugs twice weekly
 Final 18 weeks - INH and RIF only, twice weekly
 Relapse rate - Comparable to daily 6-month protocol (1.6%) (CDC, 1997)

• Special cases

o Patients who are HIV positive - Extend the treatment protocol to a minimum of 9 months (final stage, 7 mo) with at least 6 months' culture-negative sputum.
o Patients who are pregnant - A 9-month daily course of INH, RIF, and ETB is recommended in the doses above.
 Breastfeeding is permitted.
 PZA is contraindicated due to inadequate teratogenicity data.
 Streptomycin is discouraged unless other drugs are contraindicated (16% fetal ototoxicity).
o Patients who have meningitis - Dexamethasone added to routine 4-drug therapy reduces complications.

• Multi–drug-resistant tuberculosis

o Administer all of the following - An injectable anti-TB aminoglycoside (eg, amikacin, capreomycin, kanamycin), a fluoroquinolone (eg, ciprofloxacin, ofloxacin), ETB, PZA, INH, RIF, and cycloserine, ethionamide, or amino salicylic acid.
o Consider rifabutin substitution for RIF, as approximately 30% of RIF-resistant strains are rifabutin sensitive.
o Do not use intermittent therapy.
o Clusters of MDR TB with 7-drug resistance have been reported and have a high infectivity rate.
o The healthcare worker PPD conversion rate is 18-50% with exposure to MDR TB.
Consultations: Due to changing recommendations, particularly with regard to the treatment of drug-resistant TB, expert consultation for TB management is available from several national centers.
• For information on current national policies and recommendations, call the CDC Division of Tuberculosis Elimination at (404) 639-8140. The CDC Voice and Fax Information System is also available at 1-888-232-3228.
• For expert consultation on the management of drug-resistant TB, call one of the following national Model TB Centers:
o San Francisco Model TB Center - (415) 502-4700
o New York City Model TB Center - (212) 939-8254

MEDICATION

Treatment of TB has 3 basic therapeutic principles. First, any regimen must use multiple drugs to which M tuberculosis is susceptible. Second, the therapy must be taken regularly. Third, the therapy must continue for a period sufficient to resolve the illness.
In the United States, anti-TB therapy is available to all patients at no cost through the Department of Health (see Emergency Department Care).
Drug Category: Anti-TB agents -- Patients thought to have pulmonary TB whose sputum smear returns positive for acid-fast bacillus can be presumptively diagnosed and treated with anti-TB therapy. TB therapy also may be appropriate in patients with a negative sputum smear who have clinical and radiographic findings consistent with pulmonary TB. Immediately treat severely ill patients with presumed TB because a few days on anti-TB agents does not interfere with bacteriologic diagnosis.

Drug Name Isoniazid (Laniazid, Nydrazid) -- Best combination of effectiveness, low cost, and minor adverse effects. First-line drug unless known resistance or another contraindication exists. Therapeutic regimens of <6>13 years: Administer as in adults
Contraindications Documented hypersensitivity; optic neuritis (unless clinically indicated)
Interactions Aluminum salts may delay and reduce absorption (administer several hours before or after ETB dose)
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Reduce dose in impaired renal function; may have reversible visual adverse effects if promptly discontinued
Drug Name Streptomycin sulfate -- For treatment of susceptible mycobacterial infections. Use in combination with other anti-TB drugs (eg, INH, ETB, RIF). Total period of treatment for TB is a minimum of 1 y; however, indications for terminating streptomycin therapy may occur at any time. Recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.
Adult Dose 1 g IM qd
Pediatric Dose 20-40 mg/kg/d IM; not to exceed 1 g/d
Contraindications Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Narrow therapeutic index; not intended for long-term therapy; caution in renal failure not on dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Drug Name Capreomycin (Capastat) -- Obtained from Streptomyces capreolus for coadministration with other anti-TB agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. For use only when first-line agents (eg, INH, RIF) have been ineffective or cannot be used because of toxicity or presence of resistant tubercle bacilli.
Adult Dose 1 g IM qd for 60-120 d; followed by 1 g IM 2-3 times weekly; not to exceed 20 mg/kg/d
Pediatric Dose 15 mg/kg/d IM; not to exceed 1 g/d
Contraindications Documented hypersensitivity
Interactions Coadministration with aminoglycosides may increase risk of respiratory paralysis and renal dysfunction; with nondepolarizing neuromuscular blocking agents has synergistic effects on myoneural function
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Assess vestibular auditory function prior to therapy and regularly while treating; monitor renal function throughout treatment (reduce dose in renal impairment); monitor serum potassium levels

Drug Name Clofazimine (Lamprene) -- Inhibits mycobacterial growth, binds preferentially to mycobacterial DNA. Has antimicrobial properties, but mechanism of action is unknown. Always use with other anti-TB agents.
Adult Dose 100 mg/d PO
Pediatric Dose 1 mg/kg/d PO
Contraindications Documented hypersensitivity
Interactions Dapsone may inhibit anti-inflammatory activity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Severe abdominal symptoms may require exploratory laparotomies; caution in patients with GI problems (eg, abdominal pain, diarrhea); skin discoloration due to drug may result in depression or suicide; apply oil to skin for dryness and ichthyosis.

Drug Name Cycloserine (Seromycin) -- Inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. Structural analogue of D-alanine, which antagonizes role of D-alanine in bacterial cell wall synthesis, thus inhibiting their growth.
Adult Dose 500 mg to 1 g PO qd in divided doses monitored by blood levels
Alternatively, 250-500 mg PO bid for first 2 wk; not to exceed 1 g/d
Pyridoxine administered at 200-300 mg/d may prevent neurotoxic effects
Pediatric Dose 10-20 mg/kg/d PO; not to exceed 0.75-1 g/d
Contraindications Documented hypersensitivity; severe anxiety or psychosis, epilepsy, depression; severe renal insufficiency; alcoholism; patients with severe neurological impairments should not receive the drug
Interactions Incompatible with alcohol consumption because may increase possibility and risk of epileptic episodes; INH in combination with cycloserine may result in increased CNS adverse effects such as dizziness
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Discontinue drug or reduce dosage if allergic dermatitis or symptoms of CNS toxicity, such as convulsions, headache, tremor, depression, confusion, psychosis, somnolence, hyperreflexia, vertigo, paresis or dysarthria, develop; risk of convulsions is increased in persons with chronic alcoholism; administration has been associated with vitamin B-12 and folic acid deficiency, megaloblastic anemia, and sideroblastic anemia; monitor blood levels weekly in reduced renal function, patients receiving more than 500 mg/d, and those with symptoms of toxicity.

Drug Name Ethionamide (Trecator) -- Bacteriostatic against M tuberculosis. Recommended when treatment with first-line drugs (INH, RIF) has failed. Treats any form of active TB. Use only with other effective anti-TB agents
Adult Dose 0.5-1 g/d PO divided qid; concomitant administration of pyridoxine recommended
Pediatric Dose 15-20 mg/kg/d PO divided tid/qid; not to exceed 1 g/d; concomitant administration of pyridoxine recommended
Contraindications Documented hypersensitivity; severe hepatic damage
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Make determinations of serum transaminase (AST, ALT) prior to therapy and q2-4wk thereafter; perform in vitro susceptibility tests of recent cultures of M tuberculosis from patient with ethionamide and usual first-line anti-TB drugs; management of diabetes mellitus may be more difficult, and hepatitis may occur more frequently.

Drug Name Dapsone (Avlosulfon) -- Bactericidal as well as bacteriostatic against Mycobacterium strains. The mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent the formation of folic acid, causing bacterial growth inhibition. Use in the treatment of TB is largely experimental.
Adult Dose 50-300 mg/d PO
Pediatric Dose 1-2 mg/kg/d PO; not to exceed 100 mg/d
Contraindications Documented hypersensitivity; known G-6-PD deficiency
Interactions May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during the second and third months of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; due to increased in renal clearance, dapsone levels may significantly decrease when administered concurrently with RIF
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Perform weekly blood counts (first month); then perform WBC counts monthly (6 mo); then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is seen; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M due to high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light.

Drug Name Ciprofloxacin (Cipro) -- Useful in the treatment TB in combination with RIF and other anti-TB agents.
Adult Dose 750 mg PO bid
Pediatric Dose <18>18 years: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy.

Drug Name Levofloxacin (Levaquin) -- Inhibit growth of susceptible organisms by inhibiting DNA gyrase and promoting breakage of DNA strands.
Adult Dose 750 mg PO q24h for 7-14 d
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy.

FOLLOW-UP

Further Inpatient Care:

• Arrange for identification and prophylactic treatment of all contacts.
• Baseline labs for patients undergoing treatment for active TB include liver transaminases, bilirubin, blood count, platelet count, urea nitrogen, creatinine, and, if therapy includes PZA, uric acid. On discharge, conduct monthly follow-up appointments with sputum mycobacterial culture and sensitivity.
• Directly observed therapy (DOT) has proved successful in ensuring ongoing compliance with TB therapy, particularly in areas with high rates of multidrug resistance.
• Consider HIV testing.

Complications:

• Cavitary lesions
• Spread to susceptible persons
• Drug resistance
Prognosis:
• Generally, few complications ensue, and full resolution is expected if the drug regimen is completed.
Patient Education:
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Tuberculosis.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Patients with active TB who are persistently nonadherent with treatment present a public health hazard. Accordingly, legal measures have been initiated in several states allowing for civil or criminal detention of such patients for DOT (Oscherwitz, 1997).
o At this writing, such measures have been enacted in the following locations:
 New York City (New York City Health Code 1994;11.47 and 11.55)
 Louisiana
 California (Calif Health and Safety Code 1996;120175-121400)
 Massachusetts (Mass Gen Laws 1996;94(A)-94(H))
 Florida (Fla Pub Health Code 1996;309.02-392.69)
o In 1997, federal legislation established a cooperative agreement between Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont on the legal detention of patients with TB who refuse treatment (Senate Bill S97-0388, passed Senate and House June 11, 1997).

Special Concerns:

• Among immunocompetent adults who have latent TB, the risk of reactivation is approximately 0.5-1% per year or 15% during the course of a lifetime (Stead, 1987).
o The risk of reactivation is greatest in the first 2 years following initial infection.
o In patients with HIV and TB infection, the risk of reactivation is 10% per year.
o Patients who have HIV without latent disease have a 5% per year risk of developing active primary disease (Hyman, 1995).
o Consider INH prophylaxis in anyone (regardless of age) who has a positive PPD test result in the last 2 years due to the significant likelihood of reactivation disease later in life.
 In addition, prophylaxis is recommended for those patients (regardless of age) who have distant conversions (>2 y prior), who are HIV positive, who use IV drugs, or who have comorbid medical conditions. Prophylaxis also is recommended for known contacts of patients with active TB.
 Additionally, prophylaxis is recommended for patients younger than 35 years with distant conversions who are foreign-born, impoverished, employed as healthcare workers, or living in long-term institutions.
 Pregnant women with recent skin conversions can begin INH following the first trimester. Those with distant conversions can wait until after delivery.
o Protocols vary as follows:
 Three common protocols include INH 300 mg PO qd for 12 months (75% risk reduction), INH 300 mg PO qd for 6 months (65% risk reduction), and INH 900 mg PO twice weekly for 12 months (unknown risk reduction but likely efficacious).
 The dose for children is INH 10-20 mg/kg/d. Recently, INH 300 mg PO qd and RIF 600 PO qd for 3 months was demonstrated to provide a 60% risk reduction in patients who are HIV positive.
 Alternatives currently being studied include RIF 600 mg PO qd for 4 months and RIF 600 mg PO qd plus PZA 1 g PO qd for 2 months. The latter course recently was demonstrated to provide identical risk reduction when compared to 12 months of daily INH (Gordin, 2000).
o A common concern relating to INH prophylaxis is the rate of INH-associated hepatitis. Such rates are age-dependent and are greatly increased with significant ethanol consumption.
 Instruct patients on INH prophylaxis to refrain from ethanol use.
 For patients younger than 35 years, the relative risk of death from reactivation TB (>6%) outweighs the risk of death from INH-related hepatitis (<1%).>
 Halt INH therapy if liver transaminase levels rise to 3 times or more above pretreatment levels.
o The rate of INH toxicity is probably much lower than has been reported. Recent analysis of data from a longitudinal survey of 11,141 consecutive patients treated with preventive INH therapy yielded a total rate for hepatotoxic reactions of 0.10% (n=11) and no mortality. This compares to previously reported rates of 0.5-2.0%. Such data should give clinicians greater confidence in the safety of INH preventive therapy.
• In 1996, due to increased rates of MDR TB, the CDC released updated recommendations for use of the BCG vaccine within the United States.
o Published data evaluating the efficacy of BCG vaccination in preventing pulmonary TB, particularly when used in adulthood, has been disappointing.
o BCG vaccination's greatest utility appears to be in the prevention of meningeal and miliary TB in children, for whom it has demonstrated efficacy rates of 65-95%.
• The CDC recommends BCG vaccination for the following 2 populations (CDC MMWR, 1996).
o Healthcare workers employed in settings with a high likelihood of transmission of TB resistant to both INH and RIF, provided other TB control precautions have failed to prevent transmission
o Children or infants living in settings where the risk of TB (drug resistant or not) transmission is high, when removal of such children from such settings is not possible

99 - systemic lupus erythematosus ( SLE )

Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that can be fatal, though with recent medical advances, fatalities are becoming increasingly rare. As with other autoimmune diseases, the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage. SLE can affect any part of the body, but most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system. The course of the disease is unpredictable, with periods of illness (called flares) alternating with remission. Lupus can occur at any age, and is most common in women, particularly of non-European descent.^[1] Lupus is treatable symptomatically, mainly with corticosteroids and immunosuppressants, though there is currently no cure. Survival in patients with SLE in the United States, Canada, Europe, and China is approximately 95% at 5 years, 90% at 10 years, and 78% at 20 years.^[2]

Classification

Lupus is a chronic autoimmune disease. Clinically, it can affect multiple organ systems including the heart, skin, joints, kidneys and nervous system. There are several types of lupus; generally when the word 'lupus' alone is used, it refers to the systemic lupus erythematosus or SLE as discussed in this article. Other types include:

• Drug-induced lupus erythematosus, a drug-induced form of SLE; this type of lupus can occur equally for either gender
• Lupus nephritis, an inflammation of the kidneys caused by SLE
• Discoid lupus erythematosus, a skin disorder which causes a red, raised rash on the face, scalp or rest of the body, which occasionally (1-5%) develops into SLE^[3]
• Subacute cutaneous lupus erythematosus, which causes non-scarring skin lesions on patches of skin exposed to sunlight^[4]
• Neonatal lupus, a rare disease affecting babies born to women with SLE, Sjögren's syndrome or sometimes no autoimmune disorder. It is theorized that maternal antibodies attack the fetus, causing skin rash, liver problems, low blood counts (which gradually fade) and heart block leading to bradycardia.^[4]

Signs and symptoms

SLE is one of several diseases known as "the great imitators" ^[5] because its symptoms vary so widely it often mimics or is mistaken for other illnesses, and because the symptoms come and go unpredictably. Diagnosis can be elusive, with patients sometimes suffering unexplained symptoms and untreated SLE for years. Common initial and chronic complaints are fever, malaise, joint pains, myalgias and fatigue. Because they are so often seen with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms (below), however, they are considered suggestive.

Common symptoms explained

Dermatological manifestations

As many as 30% of patients present with some dermatological symptoms (and 65% suffer such symptoms at some point), with 30% to 50% suffering from the classic malar rash (or butterfly rash) associated with the disease. Patients may present with discoid lupus (thick, red scaly patches on the skin). Alopecia, mouth, nasal, and vaginal ulcers, and lesions on the skin are also possible manifestations.

Musculoskeletal manifestations

Patients most often seek medical attention for joint pain, with small joints of the hand and wrist usually affected, although any joint is at risk. The Lupus Foundation of America "estimates more than 90 percent will experience joint and/or muscle pain at some time during the course of their illness".^[6] Unlike rheumatoid arthritis, lupus arthritis is less disabling and it usually does not cause severe destruction of the joints. Fewer than 10 percent of people with lupus arthritis will develop deformities of the hands and feet.^[6]

Hematological manifestations

Anemia and iron deficiency may develop in as many as half of patients. Low platelet and white blood cell counts may be due to the disease or a side-effect of pharmacological treatment. Patients may have an association with antiphospholipid antibody syndrome (a thrombotic disorder) where autoantibodies to phospholipids are present in the patient's serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged PTT (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies; the combination of such findings have earned the term "lupus anticoagulant positive". Another autoantibody finding in lupus is the anticardiolipin antibody which can cause a false positive test for syphilis.

Cardiac manifestations

Patients may present with inflammation of various parts of the heart, such as pericarditis, myocarditis, and endocarditis. The endocarditis of SLE is characteristically non-infective (Libman-Sacks endocarditis) and involves either the mitral valve or the tricuspid valve. Atherosclerosis also tends to occur more often and advance more rapidly in SLE patients than in the general population.^[7][8][9]

Pulmonary manifestations

Lung and pleura inflammation can cause pleuritis, pleural effusion, lupus pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage.

Hepatic involvement

See autoimmune hepatitis

Renal involvement

Painless hematuria or proteinuria may often be the only presenting renal symptom. Acute or chronic renal impairment may develop with lupus nephritis, leading to acute or end stage renal failure. Because of early recognition and management of SLE, end stage renal failure occurs in less than 5% of patients.

Histologically, a hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities.^[10] This finding is due to immune complex deposition along the glomerular basement membrane leading to a typical granular appearance in immunofluorescence testing.

Neurological manifestations

About 10% of patients may present with seizures or psychosis. A third may test positive for abnormalities in the cerebrospinal fluid.

T-cell abnormalities

Abnormalities in T cell signaling are associated with SLE, including deficiency in CD45 phosphatase and increased expression of CD40 ligand.

Other rarer manifestations

lupus gastroenteritis, lupus pancreatitis, lupus cystitis, autoimmune inner ear disease, parasympathetic dysfunction, retinal vasculitis, and systemic vasculitis.

Other abnormalities include:

• Increased expression of FcεRIγ, which replaces the sometimes deficient TCR ζ chain
• Increased and sustained calcium levels in T cells
• Moderate increase of inositol triphosphate
• Reduction in PKC phosphorylation
• Reduction in Ras-MAP kinase signaling
• Deficiencies in protein kinase A I activity

Causes

In SLE, the body's immune system produces antibodies against itself, particularly against proteins in the cell nucleus. SLE is triggered by environmental factors which are unknown (but probably include viruses), in people with certain combinations of genes in their immune system.

"All the key components of the immune system are involved in the underlying mechanisms" of SLE, according to Rahman, and SLE is the prototypical autoimmune disease. The immune system must have a balance (homeostasis) between being sensitive enough to protect against infection, and being too sensitive and attacking the body's own proteins (autoimmunity). From an evolutionary perspective, according to Crow, the population must have enough genetic diversity to protect itself against a wide range of possible infection, and some genetic combinations result in autoimmunity. The likely environmental triggers include ultraviolet light, drugs, and viruses. These stimuli cause the destruction of cells, and expose their DNA, histones, and other proteins, particularly parts of the cell nucleus. Because of genetic variations in different components of the immune system, in some people the immune system attacks these nuclear-related proteins and produces antibodies against them. Ultimately, these antibody complexes damage blood vessels, in critical areas of the body such as the glomeruli of the kidney. These antibody attacks are the cause of SLE. Researchers are now identifying the individual genes, the proteins they produce, and their role in the immune system. Each protein is a link on the autoimmune chain, and researchers are trying to find drugs to break each of those links.

SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement,

Genetics

The first mechanism may arise genetically. Research indicates that SLE may have a genetic link. Lupus does run in families, but no single "lupus gene" has yet been identified. Instead, multiple genes appear to influence a person's chance of lupus developing when triggered by environmental factors. The most important genes are located on chromosome 6, where mutations may occur randomly (de novo) or be inherited. Additionally, people with SLE have an altered RUNX-1 binding site, which may be either cause or contributor (or both) to the condition. Altered binding sites for RUNX-1 have also been found in people with psoriasis and rheumatoid arthritis.

Environmental triggers

The second mechanism may be due to environmental factors. These factors may not only exacerbate existing lupus conditions, but also trigger the initial onset. They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections. Some researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease. UV radiation has been shown to trigger the photosensitive lupus rash, but some evidence also suggests that UV light is capable of altering the structure of the DNA, leading to the creation of autoantibodies. Some researchers have found that women with silicone gel-filled breast implants have produced antibodies to their own collagen, but it is not known how often these antibodies occur in the general population and there is no data that show these antibodies cause connective tissue diseases such as lupus.

Drug reactions

Drug-induced lupus erythematosus is a reversible condition that usually occurs in patients being treated for a long-term illness. Drug-induced lupus mimics systemic lupus. However, symptoms of drug-induced lupus generally disappear once a patient is taken off the medication which triggered the episode. There are about 400 medications currently in use that can cause this condition, though the most common drugs are procainamide, hydralazine and quinidine.

Non-SLE forms of lupus

Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed via biopsy of skin rash on the face, neck or scalp. Often an anti-nuclear antibody (ANA) test for discoid patients is negative or a low-titre positive. About 1-5% of discoid lupus patients eventually develop SLE.

Clearance deficiency

Clearance deficiency

The exact mechanisms for the development of systemic lupus erythematosus (SLE) are still unclear since the pathogenesis is a multifactorial event. Beside discussed causations, impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. This includes deficient phagocytic activity, scant serum components in addition to increased apoptosis.

Monocytes isolated from whole blood of SLE patients show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBM), which are found in the germinal centres of lymph nodes, even show a definitely different morphology in patients with SLE. They are smaller or scarce and die earlier. Serum components like complement factors, CRP and some glycoproteins are furthermore decisively important for an efficiently operating phagocytosis. In patients these components are often missing, diminished or inefficient.

The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondary necrosis of the cells, if this ability is disturbed. Necrotic cells release nuclear fragments as potential autoantigens as well as internal danger signals, inducing maturation of dendritic cells (DC), since they have lost their membranes integrity. Increased appearance of apoptotic cells also is simulating inefficient clearance. That leads to maturation of DC and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules. Autoimmunity possibly results by the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in patients with cutaneous lupus erythematosus (CLE).

germinal centres

Accumulation in germinal centres (GC)

In healthy conditions apoptotic lymphocytes are removed in germinal centres by specialised phagocytes, the tingible body macrophages (TBM); that’s why no free apoptotic and potential autoantigenic material can be seen. In some patients with SLE accumulation of apoptotic debris can be observed in GC, because of an ineffective clearance of apoptotic cells. In close proximity to TBM, follicular dendritic cells (FDC) are localised in GC, which attach antigen material to their surface and in contrast to bone marrow-derived DC, neither take it up nor present it via MHC molecules. Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the GC light zone. Autoreactive B cells, maturated coincidently, normally don’t receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis. In the case of clearance deficiency apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal for autoreactive B-cells. After migration into the mantle zone autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody producing plasma cells and B memory cells. In the presence of autoreactive T cells a chronic autoimmune disease may be the consequence.

Pathophysiology

One manifestation of lupus is abnormalities in apoptosis, a type of programmed cell death in which aging or damaged cells are neatly disposed of as a part of normal growth or functioning.

Abnormalities in apoptosis

• Apoptosis is increased in monocytes and keratinocytes
• Expression of Fas by B cells and T cells is increased
• There are correlations between the apoptotic rates of lymphocytes and disease activity

Tingible body macrophages (TBMs) are large phagocytic cells in the germinal centers of secondary lymph nodes. They express CD68 protein. These cells normally engulf B cells which have undergone apoptosis after somatic hypermutation. In some patients with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells which may have randomly acquired self-specificity through somatic hypermutation.^[15]

Diagnosis

Microphotograph of a histological section of human skin prepared for direct immunofluorescence using an anti-IgG antibody. The skin is from a patient with systemic lupus erythematosus and shows IgG deposit at two different places : the first is a band-like deposit along the epidermal basement membrane ("lupus band test" is positive), the second is within the nuclei of the epidermal cells (anti-nuclear antibodies are present).

Some physicians make a diagnosis on the basis of the ACR classification criteria (see below). The criteria, however, were established mainly for use in scientific research (i.e. inclusion in randomized controlled trials), and patients may have lupus but never meet the full criteria.

Anti-nuclear antibody testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for lupus. Antiphospholipid antibodies occur more often in SLE, and can predispose for thrombosis. More specific are the anti-smith and anti-dsDNA antibodies. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and renal function (disturbed if the kidney is involved), liver enzymes and a complete blood count.

Formerly, the lupus erythematosus (LE) cell test was used for diagnosis, however those LE cells are only found in 50-75% of SLE patients, and are also found in some patients with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance.^[16]

Diagnostic criteria

The American College of Rheumatology (ACR) has established eleven criteria in 1982,^[17] which were revised in 1997^[18] as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individual patients and do not do well in that capacity. For inclusion in clinical trials, patients must meet the following three criteria to be classified as having SLE: (i) patient must present with four of the below eleven symptoms (ii) either simultaneously or serially (iii) during a given period of observation.

1. Serositis: Pleuritis (inflammation of the membrane around the lungs) or pericarditis (inflammation of the membrane around the heart)sensitivity = 56%; specificity = 86% (pleural is more sensitive; cardiac is more specific)^[19]
2. Oral ulcers: include oral or nasopharyngeal ulcers
3. Arthritis: nonerosive arthritis of two or more peripheral joints, with tenderness, swelling or effusionsensitivity = 86%; specificity = 37%^[19]
4. Photosensitivity (exposure to ultraviolet light causes rash). sensitivity = 43%; specificity = 96%^[19]
5. Hematologic disorder: Hemolytic anemia (low red blood cell count) or leukopenia (white blood cell count<4000/ul), sensitivity =" 59%;" specificity =" 89%[19] Hypocomplementemia is also seen, due to either consumption of C3 and C4 by immune complex-induced inflammation, or to congenitally complement deficiency, which may predispose to SLE.
6. Renal disorder: More than 0.5 g per day protein in urine, or cellular casts seen in urine under a microscope.sensitivity = 51%; specificity = 94%^[19]
7. Anti-nuclear antibody test positive. sensitivity = 99%; specificity = 49%^[19]
8. Immunologic disorder: Positive anti-Sm, anti-ds DNA, anti-phospholipid antibody and/or false positive serological test for syphilis. sensitivity = 85%; specificity = 93%^[19]. Presence of anti-ss DNA in 70% of patients (though also positive in patients with rheumatic disease and healthy persons^[20])
9. Neurologic disorder: Seizures or psychosis. sensitivity = 20%; specificity = 98%^[19]
10. Malar rash (rash on cheeks). sensitivity = 57%; specificity = 96%^[19]
11. Discoid lupus (red, scaly patches on skin which cause scarring) sensitivity = 18%; specificity = 99%^[19]

A useful mnemonic for these 11 criteria is SOAP BRAIN MD: Serositis (8), Oral ulcers (4), Arthritis (5), Photosensitivity (3), Blood Changes (9), Renal involvement (proteinuria or casts) (6), ANA (10), Immunological changes (11), Neurological signs (seizures, frank psychosis) (7), Malar Rash (1), Discoid Rash (2).

Some patients, especially those with antiphospholipid syndrome, may have SLE without four criteria and SLE is associated with manifestations other than those listed in the criteria.^[21][22][23]

Alternative criteria

Recursive partitioning has been used to identify more parsimonious criteria.^[19] This analysis presented two diagnostic classification trees:

1. Simplest classification tree: LSE is diagnosed if the patient has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) or malar rash.

• sensitivity = 92%
• specificity = 92%

2. Full classification tree: Uses 6 criteria.

• sensitivity = 97%
• specificity = 95%

Other alternative criteria have been suggested.^[24]

Common misdiagnoses

Porphyria

Porphyrias are complex genetic disorders that share many symptoms with lupus, but impact the enzymes responsible for building heme, a component needed in heme proteins. Porphyrias are ecogenic disorders requiring both environmental and genetic backgrounds to manifest with a variety of symptoms and medical complications. They are noted for photosensitivity and have been associated with transient and permanent production of autoantibodies. The five major forms of dominantly inherited porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been detected in systemic lupus erythematosus and discoid lupus patients over the past 50 years. Physicians should have a high degree of suspicion of porphyrias in all lupus cases and act accordingly when patients are in a medical crisis that may be due to an underlying acute hepatic porphyria. Drug-induced lupus and photosensitivity warrant an investigation for an underlying porphyria since multiple drug reactions are a hallmark complication of porphyrias. Patients with both lupus and porphyrias should avoid porphyrinogenic drugs and hormone preparations.

Patients with acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been detected in lupus patients with severe life-threatening "lupus" complications known as neurolupus. Symptoms are identical to acute hepatic porphyria attacks and include seizures, psychosis, peripheral neuropathy and syndrome of inappropriate antidiuretic hormone (SIADH) associated with dangerously low sodium levels (hyponatremia). Porphyria attacks require intervention with intravenous glucose, heme preparations and the discontinuation of dangerous porphyrinogenic drugs including antiseizure drugs. Several other lupus complications have been associated with porphyrias including pancreatitis and pericarditis. Porphyrin testing should be performed on urine, stool/bile and blood to detect all types of porphyrias, and repeat testing should be performed in suspicious cases. Appropriate enzyme tests or DNA testing should also be pursued to obtain a complete diagnosis which could include a dual porphyria.

Common dual diagnoses

SLE is sometimes diagnosed in conjunction with other conditions, including Rheumatoid Arthritis, Scurvy and Fibromyalgia...

Treatment

As lupus erythematosus is a chronic disease with no known cure, treatment is restricted to dealing with the symptoms; essentially this involves preventing flares and reducing their severity and duration when they occur. There are several means of preventing and dealing with flares, including drugs, alternative medicine and lifestyle changes.

Drug therapy

Due to the variety of symptoms and organ system involvement with Lupus patients, the severity of the SLE in a particular patient must be assessed in order to successfully treat SLE. Mild or remittent disease can sometimes be safely left untreated. If required, non-steroidal anti-inflammatory drug and anti-malarials may be used.

Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce incidence of flares, the process of the disease, and lower the need for steroid use; when flares occur, they are treated with corticosteroids. DMARDs commonly in use are anti-malarials and immunosuppressants (e.g. methotrexate and azathioprine). Hydroxychloroquine (trade name Plaquenil) is an FDA approved anti-malarial used for constitutional, cutaneous, and articular manifestations, while Cyclophosphamide (trade names Cytoxan and Neosar) is used for severe glomerulonephritis or other organ-damaging complications, and in 2005, mycophenolic acid (trade name CellCept) became accepted for treatment of lupus nephritis.

In more severe cases, medications that modulate the immune system (primarily corticosteroids and Immunosuppresive drug immunosuppressants) are used to control the disease and prevent recurrence of symptoms (known as flares). Patients who require steroids frequently may develop obesity, diabetes mellitus diabetes and osteoporosis. Depending on the dosage, corticosteroids can cause other side effects such as a puffy face, an unusually large appetite and difficulty sleeping. Those side effects can subside if and when the large initial dosage is reduced, but long term use of even low doses can cause elevated blood pressure and cataracts. Due to these side effects, steroids are avoided if possible.

Since a large percentage of Lupus patients suffer from varying amounts of chronic pain, stronger prescription analgesics may be used if over-the-counter drugs, mainly non-steroidal anti-inflammatory drug do not provide effective relief. Moderate pain in Lupus patients if typically treated with mild prescription opiates such as Dextropropoxyphene (trade name Darvocet), and Co-codamol (trade name Tylenol #3). Moderate to severe chronic pain is treated with stronger opioids such as Hydrocodone (trade names Lorcet, Lortab, Norco, Vicodin, Vicoprofen) or longer-acting continuous release opioids such as Oxycodone (trade names OxyContin), MS Contin, or Methadone. The Fentanyl Duragesic Transdermal patch is also a widely-used treatment option for chronic pain due to Lupus complications because of its long-acting timed release and easy usage. When opioids are used for prolonged periods drug tolerance, chemical dependency and (rarely) addiction may occur. Opiate addiction is not typically a concern for Lupus patients, since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common in Lupus patients that exhibit chronic pain symptoms; accompanied by periodic titration that is typical of any long-term opioid regimen.

UVA1 phototherapy

In 1987, Tina Lomardi, MD first reported that long-wave ultraviolet radiation (UVA1) had a favorable effect on disease activity in SLE model mice. Several clinicals trials investigating this new, counter-intuitive therapeutic approach, conducted by both McGrath and independent Dutch searchers, have confirmed these findings in SLE patients. ^[25] Devices for administering therapeutic doses of UVA1 are available in Europe but not in the U.S. However, the U.S. Food and Drug Administration Office of Science and Technology conducted UVA1 phototherapy studies in an SLE mouse model in 1997 "to prepare for future reviews of UVA-emitting tanning devices for such clinical applications".

Lifestyle changes

Other measures such as avoiding sunlight or covering up with sun protective clothing can also be effective in preventing problems due to photosensitivity. Weight loss is also recommended in overweight and obese patients to alleviate some of the effects of the disease, especially where joint involvement is significant.

Treatment research

Other immunosuppressants (drugs that lower the body's normal immune response) and bone marrow transplant autologous stem cell transplants are under investigation as a possible cure. Recently, treatments that are more specific in modifying the particular subset of the immune cells (e.g. B- or T- cells) or cytokine proteins they secrete have been gaining attention. Research into new treatments has recently been accelerated by genetic discoveries, especially mapping of the human genome. According to a June 2006 market analysis report by Datamonitor, treatment for SLE could be on the verge of a breakthrough as there are numerous late-Phase trials currently being carried out. There have been promising advances in the area of stem cell research implicating a treatment with adult stem cells being harvested from the patients themselves.

Prevention

Lupus is not understood well enough to be prevented, but when the disease develops, quality of life can be improved through flare prevention. The warning signs of an impending flare include increased fatigue, pain, rash, fever, abdominal discomfort, headache and dizziness. Early recognition of warning signs and good communication with a doctor can help individuals with lupus remain active, experience less pain and reduce medical visits.

Prevention of complications during pregnancy

While most infants born to mothers with lupus are healthy, pregnant mothers with SLE should remain under a doctor's care until delivery. Neonatal lupus is rare, but identification of mothers at highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare during pregnancy and proper treatment can maintain the health of the mother for longer. Women pregnant and known to have the antibodies for anti-Ro (SSA) or anti-La (SSB) should have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature.^[4]

Prognosis

In the 1950s, most patients diagnosed with SLE lived fewer than five years. Advances in diagnosis and treatment have improved survival to the point where over 90% of patients now survive for more than ten years and many can live relatively asymptomatically. The most common cause of death is infection due to immunosuppression as a result of medications used to manage the disease. Prognosis is normally worse for men and children than for women. Fortunately, if symptoms are present after age 60, the disease tends to run a more benign course. The ANA is the most sensitive screening test while Anti-Sm (Anti Smith) is the most specific. The ds-DNA (double-stranded DNA) antibody is also fairly specific and often fluctuates with disease activity. The ds-DNA titer is therefore sometimes useful to diagnose or monitor acute flares or response to treatment.

Epidemiology

Previously believed to be a rare disease, Lupus has seen an increase in awareness and education since the 1960s. This has helped many more patients get an accurate diagnosis making it possible to estimate the number of people with lupus. In the United States alone, it is estimated that between 270,000 and 1.5 million people have lupus, making it more common than cystic fibrosis or cerebral palsy. The disease affects both females and males, though young women are diagnosed nine times more often than men. SLE occurs with much greater severity among African-American women, who suffer more severe symptoms as well as a higher mortality rate.^[31] Worldwide, a conservative estimate states that over 5 million people have lupus.

Although SLE can occur in anyone at any age, it is most common in women of childbearing age. It affects 1 in 4000 people in the United States, with women becoming afflicted far more often than men. The disease appears to be more prevalent in women of African, Asian, Hispanic and Native American origin but this may be due to socioeconomic factors. People with relatives who suffer from SLE, rheumatoid arthritis or thrombotic thrombocytopenic purpura are at a slightly higher risk than the general population.

History

Medical historians have theorized people with porphyrias (a disease that shares many symptoms with Lupus) generated folklore stories of vampires and werewolves due to the photosensitivity, scarring, hair growth and porphyrin brownish-red stained teeth in severe recessive forms of porphyria or combinations of the disorders known as dual, homozygous or compound heterozygous porphyrias.

The history of lupus erythematosus can be divided into three periods: the classical, neoclassical, and modern. The classical period began when the disease was first recognized in the Middle Ages and saw the description of the dermatological manifestation of the disorder. The term lupus is attributed to the 12th century physician Rogerius, who used it to describe the classic malar rash. The neoclassical period was heralded by Móric Kaposi's recognition in 1872 of the systemic manifestations of the disease. The modern period began in 1948 with the discovery of the LE cell (the Lupus Erythematosus cell, a misnomer as it occurs with other diseases as well) and is characterised by advances in our knowledge of the pathophysiology and clinical-laboratory features of the disease, as well as advances in treatment.

Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment to patients until the middle of the twentieth century, when Hench discovered the efficacy of corticosteroids in the treatment of SLE.

Origins of "Lupus Erythematosus"

There are several explanations ventured for the term lupus erythematosus. Lupus is Latin for wolf, and 'erythro' is derived from ερυθρός, Greek for "red". All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks.

1. In various accounts, some doctors thought the rash resembled the pattern of fur on a wolf's face.
2. In other accounts doctors thought that the rash, which was often more severe in earlier centuries, created lesions that resembled wolf bites or scratches.
3. Another account claims that the term "Lupus" did not come from Latin at all, but from the term for a French style of mask which women reportedly wore to conceal the rash on their faces. The mask is called a "loup", French for "Wolf"
4. Another common explanation for the term is that the disease's course involves repeated attacks like those of a voracious predator, leaving behind the red blotches.

98 - test yourself - mcqs in medicine with answers and explanations - 901 to 1000

901 – the highest concentration of potassium is in ?

a- plasma

b- isotonic saline

c- ringer lactate

d- darrow’s solution .

answer is d . darrow’s solution . Darrow's solution - a mixture of potassium chloride, sodium chloride and sodium lactate; used in fluid therapy to repair a potassium deficit. also called lactated potassium saline injection.

902 – highest concentration of potassium is seen in ?

a- duodenum

b- jejunum

c- ileum

d- colon

answer : d . colon .

903 - colonic pseudo-obstruction occurs in all except ?

a- diabetes mellitus

b- dermatomyositis

c- scleroderma

d- hyperthyroidism

answer is d . hyperthyroidism . pseudo-obstruction occurs in hypothyroidism not hyperthyroidism .

904 - the commonest cause of intestinal obstructions in a 30 year old indian female ?

answer : post operative adhesions .

905 - commonest site of ischemic colitis ?

a- hepatic flexure

b- splenic flexure

c- transverse colon

d- sigmoid colon

answer is b. splenic flexure .

906 - the surgery of choice for biliary atresia ?

answer : kasai's operation .

907 - the most common facial abnormality in gardener's syndrome ?

answer : multiple osteomas .

908 - turcot's syndrome is associated with ?

a- duodenal polyps

b- familial adenomatous polyposis

c- brain tumors

d- villous adenoma

e- hyperplastic polyps

answer is b and c . familial adenomatous polyposis and brain tumors .

909 - ramu is a 60 year male with carcinoma of descending colon presents with acute intestinal obstruction . in emergency department treatment of choice is ?

answer : hartman's procedure . ( for right side colon obstructive lesion - resection with ileotransverse colostomy is done ) .

910 - the most common neoplasm of the kidney ?

answer : renal cell carcinoma .

911 - colopotomy is done to treat ?

a- ischeorectal abscess

b- pelvic abscess

c- appendicular abscess

d- perianal abscess

answer is b . pelvic abscess .

912 - ursodeoxycholic acid is a ?

a- urinary stone dissolving drug

b- thrombolytic drug

c- gallstone dissolving drug

d- antifibrinolytic

answer is c . gallstone dissolving drug .

913 - aspirin sensitive asthma is associated with ?

a- extrinsic asthma

b- urticaria

c- nasal polyps

d- obesity

answer is c . nasal polyps .

914 – most common signof aspiration pneumonitis ?

a- tachypnoea

b- bronchospasm

c- cyanosis

d- crepitations

answer : a . tachypnoea .

915 – most common clinical sign of pulmonary embolism ?

answer : tachypnoea .

916 – a 60 year old man presented to the emergency with breathlessness ,facial swelling and dilated veins on the chest wall . the most common cause is ?

a- thymoma

b- lung cancer

c- hodgkin’s lymphoma

d- superior venacaval obstruction

answer : d . superior venacaval obstruction .

917 – most common cause of superior venacaval obstruction ?

a- thrombosis

b- extrinsic compression

c- mediastinal lymphoma

d- teratoma

answer is b . extrinsic compression .

918 – sleep apnoea is defined as a temporary pause in breathing during sleep lasting at least how many seconds ?

answer : 10 seconds .

919 – the following are located in the anterior mediastinum except ?

a- thymoma .

b- neurofibroma

c- neurogenic parasitic cyst

d- teratoma

answer is b. neurofibroma .

920 – X – bodies called birbeck granules are characteristically seen in ?

answer : langerhan’s cell granulomatosis .

921 – in kartagener’s syndrome all are seen except ?

a- cystic fibrosis

b- dextrocardia

c- sinusitis

d- absence of cilia

answer is a .

922 – electrical alterans is seen in ?

a- cardiac tamponade

b- restrictive cardiomyopathy

c- left atrial myxoma

d- COPD

answer is a .

923 – live vaccines should not be given with in 3 months of giving IV immunoglobulin . exception to this rule is ?

answer : OPV .

924 – vaccines with good herd immunity ?

answer : tetanus and BCG .

925 – vaccines with no herd immunity ?

answer : OPV and measles .

926 – the metabolic derangement in congenital hypertrophic pyloric stenosis ?

answer - hypochloremic alkalosis .

927 - early hematogenous seedling to tuberculous bacilli in the apex of the lungs is called?

answer : simon’s focus .

928 – crawling of an infant is at ?

answer : 9 to 10 months .

929 – the international agency supporting the no-scalpel vasectomy in India is ?

answer : UNFPA .

930 – which one of the following is not an combined injectable contraceptive ?

a- cyclofem

b- cycloprovera

c- depot provera

d- mesigyna

answer is c . depot provera .

931 – the MTP act allows the termination of pregnancy till how many weeks ?

answer : 20 weeks .

932 – the minimum number of three antenatal visits recommended by RCH programme is at ?

answer : 20 weeks , 32 weeks , 36 weeks .

933 – preterm babies are born before how many weeks of gestation ?

answer : before 37 weeks of gestation .

934 – mini pill or micro pill contains ?

a- progesterone

b- oestrogen

c- both progesterone and oestrogen

d- gossypol

e- non-steroidal and non-estrogenic components

answer is a . progesterone .

935 – the failure rate of male condom is ?

answer : 2-20 / 100 women years .

936 – the failure rate of IUCD ?

answer : 2-3 / 100 women years .

937 – the faiure rate of female condom?

Answer : 5-21 / 100 women years . ( combined type of OCPs are 100 % effective in preventing pregnancy )

938 – which one of the following is an example of a second generation IUCD ?

a- NOVA T

b- condom

c- lippes loop

d- LNG 20

e- progestasert

answer is Nova T . d and e belong to third generation IUCDs.

939 – isochromosomes – structurally abnormal chromosomes arising because of misdivision .

940 – the ESI act covers manual , supervisory , clerical and technical employees upto how many rupees per month ?

answer : 1000 per month .

941 – what is the minimum cubic feet of space for each worker prescribed under factories act ?

answer : 500 cubic feet .

942 – which one of the following method of communication is not a method of mass approach ?

a- internet

b- poster

c- role play

d- exhibition

answer is c . role play .

943 – nosocomial pneumonia is most commonly caused by ?

a- gram negative bacilli

b- gram positive bacilli

c- gram negative cocci

d- mycoplasma

answer is a . gram negative bacilli .

944 – bronchiectasis is most common in which lobe ?

answer : left lower - bronchiectasis - lobe .

945 – a drug is to be delivered by a nebuliser . the size of a droplet for its humidification is ?

answer : less than 5 microns .

946 – feature of torsades de pointes is ?

answer : prolonged QT c interval ( marked QT prolongation ) .

947 – radiofrequency ablation is done for ?

a- ventricular tachycardia

b- PSVT

c- WPW

d- atrial tachycardia

answer is c . wolf Parkinson white syndrome – radiofrequency ablation .

948 – low doses of aspirin therapy is essentially advised for all of the following conditions except ?

a- SLE

b- post myocardial infarction

c- pre eclampsia

d- IUGR

answer is a . though NSAIDs are useful no rationale , so here it is the single best answer of exclusion .

949 – a 30 year old catherine zeta jones presents with light brown lesions involving both her cheeks . the lesions had never been erythematous . which of the following is the most probable diagnosis ?

answer : chloasma .

950 – a female developed brown macule on the cheek , forehead and nose after exposure to light following delivery of the baby , the diagnosis is ?

answer : chloasma .

951 – which one of the following is not used as a tumor marker in testicular tumors ?

a- HCG

b- AFP

c- LDH

d- CEA

answer is d . CEA .

952 – hepar lobatum is due to ?

answer : syphilis . The liver in syphilitic cirrhosis, having a nodular lobulated appearance. a fissured liver, from the scars of healed syphilitic gummas.

953 – match virus with the disease ?

a- EBV - nasopharyngeal carcinoma

b- HTLV 1 - leukemia

c- HCV - Hepatocellular carcinoma

d- HPV - cervical carcinoma

answer : all are correctly matched .

954 – what is choristoma ?

answer : normal tissue in abnormal site .

955 – which of the following is not associated with malignancy ?

a- fragile x syndrome

b- fanconi’s syndrome

c- down’s syndrome

d- bloom syndrome

answer is a . fragile x syndrome is not associated with malignancy .

956 - a 2 cms firm mass is palpable beneath the skin of the left forearm in a 27 year old female. She is in excellent health . the mass is most suggestive of ?

a- metastatic carcinoma

b- mycobacterial granuloma

c- sarcoma

d- lipoma

e- staphylococcal abscess

answer is d . lipoma .

957 – cell division in malignant neoplasms , but not in normal cells , is aided by the presence of an enzyme which repairs progressive chromosomal shortening .this enzyme is known as ?

answer : topoisomerase .

958 – the most abundant glycoprotein present in the basement membrane ?

answer : laminin .

959 – triple helix structure is seen in ?

answer : collagen .

960 – of the following substances , the one that functions intracellularly in cells involved in wound healing is ?

a- fibronectin

b- laminin

c- tyrosine kinase

d- hyaluronic acid

e- collagen

answer is c . tyrosine kinase .

961 – keloid scars are made up of ?

answer : dense collagen .

962 – the appearance of red, swollen nasal mucosa from allergy to ragweed pollen has been mediated by ?

a- complement c3b

b- PAF

c- TNF

d- Histamine

e- Immunoglobulin G

Answer is d . histamine .

963 – A 50 year old male presented with epigastric pain . endoscopic biopsy reveals a tumor made up of spindle shaped cells . this is likely to be associated with ?

a- t ( 11 = 18 ) translocation

b- c KIT mutations

c- E – cadherin expression

d- ECL cell hyperplasia

Answer is a . t ( 11 = 18 ) translocation – gastric lymphoma .

Option b – c KIT mutations & PDGFR mutations – gastrointestinal stromal cell tumor .

Option c – E – cadherin expression – gastric adenocarcinoma .

Option d – ECL ( enterochromaffin like cell ) hyperplasia – gastric carcionoids .

964 – the most common outcome of pulmonary thromboembolism is ?

a- sudden death

b- corpulmonale

c- hemoptysis

d- dyspnea

e- no symptoms

answer is e . surprised ? even I am too .

965 – over several decades , which of the following inhaled pollutants is most likely to produce extensive pulmonary fibrosis ?

a- silica

b- tobacco smoke

c- ozone

d- wood dust

e- carbondioxide

answer is a . silica .

966 – in alcoholic liver disease , the following keratin filaments are seen ?

answer : Mallory bodies .

967 – the most common lysosomal storage disorder is ?

a- gaucher’s disease

b- taysach’s disease

c- wolman disease

d- niemann pick’s disease

answer is a . gaucher’s disease .

968 – C-X-C is an example of ?

answer : lipoxin .

969 – major opsonins include ?

a- Ig G antibodies

b- C3b

c- MBL – mannose binding lectin

d- All the above

Answer is d . all the above .

970 – the following are tumor suppressor genes ?

a- RB

b- BRCA 1

c- NF1

d- All the above

Answer is d . all the above .

971 – fatty change in the liver is due to the accumulation of ?

a- cholesterol

b- VLDL

c- LDL

d- Triglycerides

Answer is d . triglycerides .

972 – colonic bacteria , on digestion of dietary fibres would give ?

a- free radicals

b- glycerol

c- butyrate

d- sucrose

answer is c . butyrates .

973 – when NaCl is injected in the internal carotid artery , it causes release of ADH by acting on ?

answer : supraoptic nucleus .

974 – the dose of which of the following anti-tubercular drugs need not be adjusted in renal failure ?

a- rifampicin

b- INH

c- Ethambutol

d- Pyrazinamide

Answer is a . rifampicin . other drugs which need not be adjusted in renal failure are rifabutin and rifapentine .

975 – anti-tubercular drugs which need not be adjusted in hepatic failure ?

Answer : SREE – streptomycin , rifabutin and ethambutol .

976 – in a population of pregnant female , Hb is estimated on 100 women with standard deviation of 1 gm % . the standard error is ?

answer : standard error = standard deviation / root of number of observations . so it is 1 / root 100 = 1/10 = 0.1 . so the standard error is 0.1 .

977 – the median of values 2, 5, 7 , 10, 10, 13, 25 ?

answer is 10 . all the values are arranged in either the ascending or descending order and the centre or middle value is taken .

978 – burden of the disease is best detected by ?

answer : DALY ( disability adjusted life years ) .

979 – in ICDS the requirement in pregnant females is ?

answer : 500 cal and 25 gm protein . children less than one year – 200 cal and 8 – 10 gm protein . children ( 1 – 6 years ) – 300 cal and 15 gm protein .

980 – according to WHO criteria , anemia in infants of 6 months age is defined as Hb less than ?

answer : 110 gm/litre .

6 m to 6 years - 11 gm / dl .

6 yrs to 14 years – 12 gm/dl .

adult male – 13 gm / dl .

adult female – 12 gm/dl

adult female pregnant – 11 gm/dl .

981 – on complete hydrolysis of DNA , we will get all of the following except ?

a- adenosine

b- purine bases

c- phosphoric acid

d- deoxy pentose sugar

answer is a . adenosine will also be hydrolysed to adenine and ribose .

982 – greisinger sign is seen in ?

a- bezold abscess

b- lateral sinus thrombosis

c- acute mastoiditis

d- citelli’s abscess

answer is b . lateral sinus thrombosis .

983 – tobey ayer test Is positive in ?

answer : lateral sinus thrombosis .

984 – acoustic neuroma arises usually from ?

answer : superior vestibular nerve .

985 – McEwans triangle corresponds to ?

a- mastoid tip

b- cochlea

c- mastoid antrum

d- all the above

answer is c . mastoid antrum .

986 – dark blue tympanic membrane is seen in ?

a- cholesteatoma

b- granulation tissue

c- cholesterol granuloma

d- all the above

answer is cholesterol granuloma .

987 – common operation for meniere’s disease ?

answer : decompression of endolymphatic sac .

988 – myringoplasty is plastic repair of ?

answer : tympanic membrane .

989 – positive fistula test in the presence of intact tympanic membrane ( henneberl’s sign ) is seen in ?

answer : congenital syphilis .

990 – butterfly chart helps in finding anamolies of ?

answer : vestibular dysfunction .

991 – ototoxic drug is ?

a- gentamicin

b- kanamycin

c- metronidazole

d- pencillin

answer is b . kanamycin .

992 – otomycosis is commonly caused by ?

answer : aspergillus .

993 – earliest symptom of acoustic neuroma ?

answer : deafness .

994 – dangerous type of ear refers to ?

a- attic granulation

b- central perforation

c- marginal perforation

d- multiple perforation

answer is a . attic granulation .

995 – grommet tube is used in ?

answer : glue ear .

996 – genetic disorder of deafness developing after birth are all except ?

a- alport syndrome

b- refsum’s disease

c- cogan’s syndrome

d- usher’s syndrome

answer is d . usher’s syndrome – autosomal dominant retinitis pigmentosa with progressive sensorineural loss . congenital deafness . then how can usher’s syndrome be the answer . have to think again .

997 – structure not visualized in posterior rhinoscopy ?

a- superior turbinate

b- middle turbinate

c- inferior turbinate

d- Eustachian tube

Answer : a . superior turbinate .

998 – a 12 year old child with recurrent antrochoanal polyp . the treatment of choice is ?

answer : endoscopic nasal polypectomy .

999 – the commonest presentation of carcinoma nasopharynx ?

answer : posterior triangle lymph nodal metastasis .

1000 – Eustachian tube opens into the nasopharynx approximately 1 cm behind the ?

answer : posterior end of the inferior turbinate .