Articles on Medical Diseases and Conditions

Tag: Differential Diagnosis

  • Rheumatoid Arthritis (RA)

    Rheumatoid arthritis (RA) is a chronic systemic disease whose most prominent symptom is inflammation of joints. The small joints of the hands and feet, especially the proximal interphalangeal joints, are most frequently affected; involvement of larger joints of the extremities is somewhat less frequent, and occasionally nonextremity joints may be affected. Polyarticular involvement is much more common than monoarticular disease. Articular disease activity may or may not be preceded or accompanied by systemic symptoms such as low-grade fever, myalgias, malaise, and fatigue. Rheumatoid arthritis tends to be a slow, intermittently active, migratory process that is frequently symmetric. Onset is gradual in 75%-80% of affected adults and more severe and abrupt in 20%-25%. Subcutaneous nodules with distinctive microscopic appearance occur in 15%-20% of patients, most frequently distal to (but not far from) the elbows. Inflammatory involvement of nonarticular organs or tissues such as the heart or lungs may sometimes occur. Patients with RA have increased frequency of the antigen HLA-DR4.

    Laboratory findings. In active adult-onset RA, anemia is present in about 40% of men and 60% of women. The anemia usually appears within 2 months after onset of clinical disease, usually does not become more severe, and is usually of mild or moderate degree, with a hemoglobin value less than 10 gm/100 ml (100 g/L) in fewer than 10% of cases. There is said to be some correlation between the degree of anemia and the initial severity of illness. The anemia of RA is usually included with the anemia of chronic disease, which typically is normocytic and normochromic. However, anemia in RA is more likely to be hypochromic (reported in 50%-100% of cases), although microcytosis is found in less than 10% of cases.

    White blood cell (WBC) counts are most often normal or only minimally elevated. About 25% of RA patients are said to have leukocytosis, usually not exceeding 15,000/mm3 (15 Ч 109/L), which is more apt to be present when onset of disease is severe and abrupt. Leukopenia is found in about 3% of cases, usually as part of Felty’s syndrome (RA plus splenomegaly and leukopenia).

    Anemia and leukocytosis are more common in juvenile-onset RA than adult-onset RA.

    In active RA, nonspecific indicators of acute inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein level, are elevated in most (but not all) patients. The serum uric acid level is normal in most patients. The serum iron level is generally low-normal or decreased, and iron-binding capacity is also low-normal or decreased.

    Rheumatoid factor. RA and related diseases are associated with production of a group of immunoglobulins called rheumatoid factors (RFs) that include IgG, IgM, and IgA varieties. These immunoglobulins (antibodies) have specificity for IgG that has been altered in certain ways. It is still not certain whether the altered IgG is the cause of the inflammatory abnormalities in RA or is a body response against the inflammatory process. From the laboratory standpoint, the most important of the is the one that is an IgM macroglobulin. RF combines with its altered IgG antigen in vivo, accompanied by complement fixation. IgM RF, like other antibodies, is produced by lymphocytes and plasma cells of B-cell origin. In some persons, especially in infants, IgM antibody production against some infectious organism not associated with rheumatoid disease may result in concurrent production of varying amounts of IgM RF. Outside the body, IgM RF can combine with normal gamma globulin without complement fixation (in fact, some patient serum contains excess C1q component of complement, which may cause a nonspecific RF test reaction that can be avoided by heat inactivation of complement before the test).

    Serologic tests. Serologic tests are the usual method of laboratory diagnosis in adult-onset RA. Various types of serologic tests may be set up utilizing reaction of IgM RF with IgG gamma globulin, differing mainly in the type of indicator system used to visually demonstrate results. The original method was known as the “Rose-Waaler test,” or “sheep cell agglutination test.” Anti-sheep red blood cell (RBC) antibodies were reacted with tannic acid-treated sheep RBCs, then the RF in the patient’s serum was allowed to combine with the antibody gamma globulin coating the sheep cells. Clumping of RBCs indicated a positive test result. It was found subsequently that synthetic particles such as latex could be coated with gamma globulin and the coated particles could be clumped by RF, thus giving a flocculation test. Just as happened with the serologic test for syphilis, many combinations of ingredients have been tried, with resulting variations in sensitivity and specificity. These tests are too numerous to discuss individually, but a distinction must be made between tube tests and rapid slide tests. The slide tests in general have a slightly greater sensitivity than tube tests but also produce more false positive results. Therefore, slide tests should be used mainly for screening purposes. As noted previously, some patient serum contains a nonspecific C1q agglutinator that can be eliminated by inactivating patient serum by heating at 56°C for 30 minutes.

    The latex fixation tube test for RA, known also as the “Plotz-Singer latex test,” currently is considered the standard diagnostic method. The average sensitivity in well-established clinical cases of adult RA is about 76% (range, 50%-95%). Clinically normal controls have about 1%-2% positive results (range, 0.2%-4%). Latex slide tests offer an average sensitivity of approximately 85% (literature range, 78%-98%), with positive results seen in approximately 5%-8% of normal control persons (range, 0.2%-15%). It may take several weeks or months after onset of clinical symptoms, even as long as 6 months, before RA serologic test results become abnormal.

    False positive results. Certain diseases, especially those associated with increased gamma globulin (“hyperglobulinemia”), produce a significantly high number of positive reactions analogous to the “biologic false positive” reactions of syphilis serology. These include collagen diseases, sarcoidosis, syphilis, viral hepatitis and cirrhosis, bacterial infections (especially subacute bacterial endocarditis[SBE]), and even old age (as many as 10%-25% positive over age 70). The incidence of reactive RA tests is higher with the slide than the tube tests. The percentage of positive reactions in the diseases listed ranges from 5%-40%. Sjцgren’s syndrome (75%-96%) and SBE (50%) are most likely to produce false positive results.

    Differential diagnosis. RA is usually part of the differential diagnosis of joint pain. However, other causes must be considered, especially if symptoms, location of joint involvement, laboratory test results, or other features are atypical. Even a positive test result is not conclusive evidence for RA. Other diseases that frequently enter the differential diagnosis are the so-called seronegative spondyloarthropathies, septic (infectious) arthritis, systemic lupus erythematosus (SLE) and other collagen-vascular diseases, crystal-deposition arthritis, and acute rheumatic fever (ARF). These conditions will be discussed later in this chapter.

  • Infectious Diarrhea due to Bacterial Agents

    Diarrhea caused by Clostridium difficile related to antibiotic therapy was discussed previously. Many cases of diarrhea produced by bacterial infection are also part of the spectrum of “food poisoning.” Clostridium botulinum generates a preformed neurotoxin and in adults is associated with improperly canned food. Usually there is no diarrhea. The organism was discussed earlier with the clostridia. Staphylococcus aureus also generates a preformed toxin after it is allowed to grow in certain foods (typically custards, creams, potato salad, and ham, usually when allowed to remain warm). Symptoms most often occur less than 7 hours after ingestion of the food (average, 3 hours) and consist of nausea, vomiting, abdominal cramps, and diarrhea.

    Clostridium perfringens occasionally may contaminate food, typically meat or gravy, that has been cooked and then allowed to cool slowly. Symptoms are due to exotoxin formed within the intestine, occur about 12 hours after eating, and consist of simultaneous abdominal cramps and diarrhea without fever or vomiting. Bacillus cereus uncommonly causes food poisoning, usually in fried rice that is kept warm. Bacillus cereus forms an endotoxin that can either be preformed (such as C. botulinum or S. aureus) or produced as the bacteria multiply after being ingested by the patient (such as C. perfringens). Diarrhea without vomiting is the major symptom. Vibrio parahaemolyticus is ingested with raw or poorly cooked fish or shellfish. The organism may invade tissue or may produce an exotoxin. Average onset of symptoms is 12-24 hours after ingestion. Symptoms are vomiting, nausea, cramps, diarrhea, chill, and fever.

    Other bacteria associated with diarrhea. Several bacterial species cause infectious diarrhea but are not ordinarily considered to be agents of food poisoning because of their relatively long incubation periods. These include Salmonella, Shigella, Yersinia enterocolitica, Campylobacter fetus ssp. jejuni, E. coli, Vibrio cholerae, and possibly V. parahaemolyticus. Other bacteria less often involved that should be mentioned are Aeromonas hydrophila and Plesiomonas shigelloides. Recent reports suggest the possibility that Bacteroides fragilis may cause diarrhea. Most of the bacteria listed are associated with contaminated water. Several of them, such as E. coli, may be transmitted via contaminated food or water. E. coli may invade tissue or may produce an exotoxin. Symptoms occur 10-12 hours after contact and consist of vomiting, nausea, cramps, diarrhea, chills, and fever. Salmonella or Shigella gastroenteritis is due to tissue infection by the organisms, although Shigella is capable of toxin production. Shigella dysentery symptoms ordinarily occur 36-48 hours after infection, but the time is variable. Salmonella gastroenteritis (due to species other than Salmonella typhi) is most frequently associated with ingestion of poultry, eggs and egg products, powdered milk, and fresh pork. Symptoms most often manifest in 8-48 hours, with an average onset at 24 hours. Symptoms of both Shigella and Salmonella gastroenteritis are similar to those of E. coli. Salmonella dysentery should be differentiated from typhoid and paratyphoid fever, which have considerably longer incubations and different emphasis in symptoms.

    Nonbacterial causes of diarrhea. There are other causes for food poisoning that do not involve bacterial agents. Some of these are ingestion of toxins from certain fish (e.g., ciguatera or scombroid fishes) or shellfish, and the Chinese restaurant syndrome (due to excess monosodium glutamate seasoning; however, at least one report disputes this etiology). Other causes for nonbacterial infectious diarrhea include viral infection (especially by rotavirus) and infection by the parasite Giardia lamblia. Ulcerative colitis and other conditions may also have to be considered.

    Differential diagnosis. Some differential points include incubation time and presence of fever, vomiting, or diarrhea. Incubation time less than 7 hours without fever suggests S. aureus or ingestion of the preformed toxin of B. cereus. Both of these usually are associated with vomiting, but S. aureus is more likely to cause diarrhea (about 75% of cases) than B. cereus (<40% of cases). Incubation of about 12 hours favors C. perfringens and B. cereus without preformed toxin; in both disorders toxin is formed after the organism is ingested rather than before. Symptoms of both are predominantly abdominal cramps and diarrhea, usually without fever or vomiting. Presence of neurologic symptoms suggests C. botulinum or chemical poisoning (mushrooms or fish toxins).

    Laboratory diagnosis. Includes stool culture and culture of possibly contaminated food or water. Diagnosis of C. botulinum or C. difficile infections usually requires demonstration of toxin, which was discussed earlier in the section on clostridia. Gram stain of the stool may be helpful in some patients. Patients with infection by bacteria that invade the mucosa of the GI tract tend to have WBCs in the stools, whereas those whose effect is produced by toxin usually do not. However, this is only a general rule. Many WBCs in the stool are typical of Shigella, Campylobacter, or C. difficile infection, although it also frequently occurs with Salmonella gastroenteritis, E. coli, Y. enterocolitica, or V. parahaemolyticus. Grossly visible blood in the stools is frequently found with Campylobacter, but gross blood may occasionally appear with severe infection by the other enteroinvasive bacteria, and microscopic blood is fairly frequent. Diagnosis of S. aureus or C. perfringens contamination usually necessitates culture of the affected food, since these organisms are considered normal stool flora.

    Traveler’s diarrhea. Diarrhea is common among visitors to many third-world countries; although it should be remembered that diarrhea may occur in persons who never leave the United States, and one half or more of the visitors to these countries (especially those on guided tours) do not get diarrhea. Several studies have shown that the most common cause for so-called traveler’s diarrhea in the majority of these countries is a subgroup of E. coli bacteria known as toxigenic E. coli. A much smaller number of persons develop diarrhea because of infection by other bacteria such as Salmonella, Shigella, and cholera vibrios; and by parasites such as Amoeba histolytica and Giardia lamblia. Infection by traveler’s diarrhea bacteria or by parasites most often is caused by use of water containing the organisms or food contaminated by the water.

    At present, there are three ways to control diarrhea: take precautions to avoid infection; take medicine to prevent infection (so-called prophylactic medication); or take medicine after diarrhea starts in order to quickly end the diarrhea.

    The best way to prevent traveler’s diarrhea is to avoid getting infected. This means avoiding local water unless there is no doubt that the water is safe. It is not advisable to take the word of the local people that the water is safe—it may be safe for them but not for visitors. Travelers must remember that local water may be present in ways they do not suspect; they should avoid ice, cocktails, drinks that need water or ice added, juice made from concentrate, and fresh salads with lettuce or ingredients that could have been washed. When tourists order orange juice they often cannot be certain it is 100% freshly squeezed from the fruit (even if a waiter says it is), so it is better to eat freshly cut fruit than to take a chance with the juice. It is also wise not to eat the outside skin of fruit (such as apples or pears) that could have been washed with local water. Alcohol—even 86 proof—may not sufficiently sterilize contaminated ice or water.

    Raw fish or shellfish (such as oysters or clams) can be contaminated by the bacteria that cause cholera. Raw or poorly cooked (“rare”) meat may be contaminated by different or even more dangerous organisms. Nonpasteurized milk is also dangerous, and it is usually hard to be certain whether local milk is pasteurized or not, especially if it is served already poured.

    There are ways to find safe water:

    1. Canned or bottled juices or colas are usually safe, as are drinks made with hot water (hot coffee, hot tea).
    2. Travelers can buy safe bottled water. The easiest and safest to find is mineral water. Mineral water with carbonation is available everywhere and is safe, because the carbonation does not permit bacteria to grow. However, some persons do not like the taste. Mineral water without carbonation (in Spanish, called “sin gas”) can be purchased in most places. This is generally safe if it comes from a sealed bottle, but it is harder to make certain whether the source of the water is pure. In many countries it is possible to purchase mineral water without gas in liter (quart) bottles in supermarkets (in Mexico, it is sold in pharmacies).
    3. Travelers can bring water purification tablets with them. There is a choice of chlorine or iodide; iodide is preferred because it will kill the parasite Giardia lamblia, whereas chlorine may not, if the amount of chlorine is not up to full strength. Both will kill bacteria. (Note: City water supplies in some cities of some countries may be chlorinated but not in sufficient strength.)
    4. Travelers may bring water purification filter equipment with them. The equipment should have a filter 0.45 microns or smaller hole size in order to be effective against E. coli. One easily portable, easily usable, and relatively inexpensive filtration system I have personally used is called “First Need Water Purifier.” It has a filter life of 800 pints, the filter can be replaced, and the apparatus including filter costs about $45.00. It can be obtained from REI Inc., P.O. Box C-88125, Seattle, WA 98188-0125, or from the manufacturer: General Ecology, Inc., 151 Sheree Blvd, Lionville, PA 19353.
    5. Travelers can boil local water. Three minutes boiling time (3 minutes starting from the time vigorous boiling and many large bubbles appear) is safe against bacteria. For locations at high altitudes, 5 minutes boiling time (or even longer at very high altitudes) is necessary.

    Travelers can take certain medicines to prevent infection, or before they get diarrhea (“prophylactic medication”). However, most experts do not recommend prophylactic medication, especially antibiotics, because the medicines may produce side effects in a small number of people.

    Travelers can take certain medications to stop diarrhea after it starts. Most cases of diarrhea are not life-threatening and will stop without medication in 2-3 days; therefore, some experts do not advise any treatment of mild or moderate diarrhea for the first 48 hours. However, it is not always possible to predict which cases will stop and which will become worse. The most commonly used medications are antidiarrheal preparations and antibiotics. These should not be used simultaneously. Some experts feel that antibiotics should not be used in cases of nausea and vomiting without diarrhea.

    Antidiarrheal medications include the following:

    1. Bismuth subsalicylate (trade name “Pepto-Bismol”). The dose is 1 ounce (30 ml) every 30 minutes until the diarrhea stops, but no more than 8 doses (8 ounces) within each 24-hour period. Take for 1-2 days.
    2. Loperamide (trade name “Imodium”). More experts prefer this medication than bismuth subsalicylate. Loperamide comes in 2-mg capsules. The usual dose is 2 capsules to begin with, then 1 capsule after each additional loose stool, up to a maximum of 8 capsules within each 24-hour period. At present, this is probably the best overall antidiarrheal medication.

    Travelers can take antibiotics to stop diarrhea caused by bacterial infection. Antibiotics would help E. coli infections, but would not cure Giardia infections. The most commonly recommended antibiotics are the following:

    1. Doxycycline. It is ordered in 100-mg capsules. The dose is one capsule twice a day for a total of 3-5 days. Doxycycline is a tetracycline antibiotic, and children under age 12 years may get very undesirable side effects.
    2. Trimethoprim-sulfamethoxazole (trade names “Bactrim” or “Septra”). It is ordered in double-strength tablets containing 160 mg of trimethoprim. The usual dose is one double-strength tablet twice a day for a total of 3-5 days. A few persons are allergic to the sulfa part of this antibiotic combination.
    3. Trimethoprim (without sulfa; trade name “Trimpex”). It is ordered in 100 mg tablets. The usual dose is 2 tablets twice each day for a total of 3-5 days. For persons with poor kidney function the dose is less; a physician should be consulted (the same warning is true for Trimethoprim-sulfa).
    4. Ciprofloxacin (trade name “Cipro”). This is ordered in 500 mg capsules. The dose is one capsule twice daily for 5 days. Results are reported to be as good as or better than results of Trimethoprim. Do not use in children or in pregnant or nursing women.

    Persons who already have severe disease (lung, heart, kidney, etc.) or who get severe diarrhea should see a physician rather than try to treat themselves.

  • Differential Diagnosis of Chronic Myelogenous Leukemia, Agnogenic Myeloid Metaplasia, and Leukemoid Reaction

    When CML has the typical picture of a WBC count more than 100,000/mm3 (100 x 109/L) with myelocytic predominance, increased platelets, and basophilia, the diagnosis is reasonably safe. Otherwise, the two conditions that most frequently enter the differential diagnosis are agnogenic myeloid metaplasia and leukemoid reaction. CML tends to have a greater degree of leukocytosis than AMM or leukemoid reactions, so that WBC counts more than 100,000/mm3 are more likely to be CML. An increased basophil count is more likely to occur in CML than in AMM and is not expected in leukemoid reactions. More than an occasional teardrop cell is more often seen in AMM than in CML, whereas teardrop cells are not expected in leukemoid reactions.

    Bone marrow examination is a valuable differentiating procedure for CML, AMM, and leukemoid or leukoerythroblastic reactions. CML has a hypercellular marrow with a moderate degree of immaturity; AMM most often has a marrow with varying degrees of fibrosis (although a hypercellular marrow may occur); and bone marrow in leukoerythroblastic reactions due to metastatic tumor frequently contains tumor cells. Clot sections as well as smears are desirable to increase diagnostic accuracy. In some patients with AMM and occasionally in patients with bone marrow tumor metastasis, no marrow can be obtained by aspiration, and a bone biopsy is necessary to be certain that the problem was not due to technical factors but to actual absence of marrow.

    Although these distinguishing features suggest that differentiation between CML and AMM should be easy, the differences may be slight and the differentiating elements may at times appear in either disease. In fact, CML and AMM have been classified together under the term “myeloproliferative syndrome.” Some workers include the whole spectrum of leukemic-type proliferations of granulocytes, RBCs, and platelets within this term.

    Leukocyte alkaline phosphatase (LAP) stain is the second useful test for differentiating leukemoid reaction, CML, and AMM. A fresh peripheral blood smear is stained with a reagent that colors the alkaline phosphatase granules normally found in the cytoplasm of mature and moderately immature neutrophils. One hundred neutrophils are counted, each neutrophil is graded 0 to 4+, depending on the amount of alkaline phosphatase it possesses, and the total count (score) for the 100 cells is added up. In most patients with leukemoid reaction or simple leukocytosis due to infection, or leukocytosis of pregnancy or estrogen therapy (birth control pills), and in 80%-90% of patients with polycythemia vera, the score is higher than reference range. About two thirds of patients with AMM have elevated values, about 25% have values within normal limits, and about 10% have low values. In CML, about 90% of patients have below-normal values, but 5%-10% reportedly have normal values. Values may be normal in CML during remission, blast crisis, or superimposed infection. In acute leukemia, each cell type differs in percentage of LAP values that are low, normal, or high, but results are not sufficiently clear cut to provide adequate cell type diagnosis. Overlap and borderline cases limit the usefulness of LAP in establishing a definitive diagnosis; however, values that are elevated are substantial evidence against CML, whereas values that are definitely low suggest CML rather than AMM. An experienced technician is needed to make the test reliable because the test reagents often give trouble, and the reading of the results is subjective and sometimes is not easy. Therefore, diagnosis should not be based on this test alone. In obvious cases, there is no need to do this test.

    The LAP value is elevated in many patients with “active” Hodgkin’s disease. Infectious mononucleosis in early stages is associated with low or normal values in 95% of cases. In sickle cell anemia, LAP values are decreased even though WBCs are increased; however, if infection is superimposed, there may be an LAP increase (although a normal LAP value does not rule out infection). Low values are found in paroxysmal nocturnal hemoglobinuria.

    A cytogenetic or DNA probe study for the Philadelphia chromosome is a third test that may be helpful in occasional diagnostic problems. Presence of the Philadelphia chromosome in a clinical and laboratory setting suspicious for chronic leukemia would be strong evidence in favor of CML.