Articles on Medical Diseases and Conditions

Tag: Diagnosis

  • Cryptosporidium

    Cryptosporidium is another sporozoan organism with some similarities to Toxoplasma. It was originally found in cattle with diarrhea, where it caused diarrhea in calves (predominantly 7-14 days old but sometimes up to 30 days old). Other animals and some birds (including turkeys and chickens) also can become infected. Cryptosporidium was next reported to cause diarrhea in humans who were immunocompromised, particularly those with AIDS. Then, it was discovered that Cryptosporidium-associated diarrhea occurred in nonimmunocompromised persons, most often children, with a frequency in Western countries of 0.6%-7.3% and in developing countries of 5%-30% of patients with diarrhea. This incidence is similar to that of Giardia and the major bacterial GI pathogens. Cryptosporidium infection is also found in nonimmunocompromised persons in the cattle industry, male homosexuals, travelers in various parts of the world, and in day-care centers. The organism is rarely found in humans without diarrhea. The type found in cattle and humans (C. parvum) lives predominantly in the small intestine from which oocysts pass in the feces to act as sources of infection. Transmission is most frequently through contaminated water, although person-to-person spread has been reported in families, hospital personnel, and care centers. Cryptosporidium cysts (oocysts) are environmentally resistant and also resistant to standard water chlorination. The average incubation period is said to be about 7 days (range, 1-12 days). In nonimmunocompromised persons, illness and oocyst shedding are nearly always finished by 31 days after exposure. The most severe and persistent infections occur in human immunodeficiency virus 1 infections, particularly in AIDS and AIDS-related illnesses (about 6% of patients; range, 3%-28%). These patients have long-standing watery diarrhea, anorexia, abdominal pain, weight loss, and low-grade fever.

    Diagnosis. Diagnosis is most commonly made through stool examination. Although the organisms can be seen in standard concentrated stool preparations, they are hard to identify, are about the same size as yeast cells (4-6 µm), and are most often overlooked. Also, cyst shedding varies from day to day, and there is some correlation between the number of fecal cysts and the presence and severity of diarrhea. Permanent stained slide preparations stained with a special modification of the mycobacterial acid-fast stain has been the most common reasonably effective approach. In two large proficiency test studies, detection rates varied between 75%-96% (in specimens where the participants were instructed to look for cryptosporidia). One study using a standard stool concentration method found that detection needed 5 times as many cysts in formed stools than in liquid stools. Also, various noncryptosporidial objects or organisms in stool specimens may appear acid-fast, requiring observer experience for accurate results. Fluorescent auramine-rhodamine staining has been reported by some (but not others) to be superior to acid-fast slide stain for screening patients. One commercial company markets a kit based on fluorescent monoclonal antibody against Cryptosporidium cyst antigen contained in smears of concentrated fecal specimens on glass slides. In three evaluations to date, this method detected 91% (range, 83%-100%) of cases while Ziehl-Neelsen acid-fast stain detected 85% (range, 76%-93%) of the same cases. Specimens cannot be fixed in PVA or microimmunofluorescent (MF or MIF) stool fixatives. Two companies have recently marketed very similar ELISA kits for combined Giardia and cryptosporidia that use small wells in plastic slides and is read by visual color change. PVA stool fixative cannot be used. In the only two evaluations to date, 93%-97% of cases were detected (in the study with 93% detection, the specimens were not concentrated). One additional company has a somewhat similar kit for cryptosporidia alone; the only published full evaluation to date reported 97% sensitivity.

  • Giardia Lamblia

    This protozoan lives in the duodenum and proximal jejunum and is said to be the most frequent intestinal parasite in the United States. An estimated 3%-7% of U.S. adults may have the disease. The organism is usually transmitted through fecal (sewage) contamination of water. Chloridation will not kill Giardia lamblia, but iodine will. Some reports suggest a high incidence in male homosexuals. G. lamblia can also be transmitted by fecal-oral contact, especially in day-care centers, where it has been estimated that 5%-15% of young children of diaper age become infected. Acute infection typically shows foul-smelling watery diarrhea, usually accompanied by greasy floating stools, considerable intestinal gas, and epigastric pain. The symptoms may last 3-4 days or 1-3 weeks or may become chronic. In severe cases, steatorrhea and intestinal malabsorption have been reported.

    Diagnosis. Diagnosis is made through the same type of stool examinations discussed under amebiasis. Overall detection rate of stool microscopy (direct examination plus stained slide) is usually considered to be 50%-70%. Cathartics do not increase detection rates. Permanent stain techniques detect about one-third more cases than wet mounts. Cyst excretion in the stool may be irregular; Giardia cysts may be passed at 1, 2-3, or even 7-8 day intervals. Although three specimens (one specimen collected every 2 days) are usually sufficient, more may be necessary. The first specimen detects about 75% of cases diagnosed through multiple specimens. Duodenal aspiration has been found to detect more infections (about 80% of cases) than repeated stool specimens. A commercial company has a string apparatus (Entero-Test) that can be swallowed instead of resorting to duodenal aspiration.

    Serologic tests. ELISA tests for antibody have not been widely used, as current tests do not differentiate between past or currently active infection. A commercial test (Pro Spec T Giardia) for antigen detection in stool is commercially available and in several evaluations was found to have a sensitivity of 92%-100% compared to the total positive patients by ELISA plus standard O& P examinations. A commercial indirect immunofluorescent test is also available, and the manufacturer claims 97% sensitivity. To date, I have not seen any independent evaluations.

  • Toxoplasmosis

    Toxoplasmosis is caused by a protozoan organism, Toxoplasma gondii. About 30%-50% (range, 3%-70%) of the U.S. population is reported to have serologic evidence of past infection. The disease is transmitted in some cases via raw or poorly cooked meat but in many cases by oocysts in feces of infected cats. The cats shed oocysts for 7-20 days after infection. The oocysts may remain infective in soil for over a year. There is also a possibility of infection from contact with cat litter box contents while the cat is shedding oocysts. Once ingested, the organisms encyst in various tissues, particularly in muscle, and remain dormant for many years or for the life of the host. Initial infection in children or adults produces clinical disease in about 10% (range, 10%-20%) of cases, usually in the form of lymphadenopathy of varying extent. There is a congenital form of clinical disease and an acquired form. The congenital form of toxoplasmosis occurs when T. gondii organisms are transmitted to the fetus through the placenta when the mother acquires active Toxoplasma infection near the time of conception or during pregnancy (infection several weeks or more before conception will not injure the fetus). Maternal acute infection during the first trimester infects 14% of fetuses; during the second trimester, 29%; and during the third trimester, 59%. One report found the highest incidence of severe fetal infections resulted from first trimester maternal infection and the least in third trimester infection. About 90% of mothers acutely infected during pregnancy are asymptomatic. Congenital toxoplasmosis is manifested most often by chorioretinitis (usually bilateral), which sometimes does not become manifest until teenage or young adulthood. Other frequent findings include brain damage (mental retardation, microcephalus or hydrocephalus, and convulsions) and intracerebral calcifications on x-ray film. Cerebrospinal fluid (CSF) is abnormal in about two thirds of patients, showing xanthochromia, mononuclear pleocytosis, and elevated protein levels (i.e., the findings usually associated with aseptic meningitis). Less frequently there is an acute neonatal disease with fever, hepatosplenomegaly, and cerebral symptoms that are clinically similar to bacterial septicemia. The more severe acute and chronic clinical disorders are more common when the mother is infected early in pregnancy, whereas infection later in pregnancy is more likely to result in symptoms (e.g., mental retardation) that are not manifest until after the neonatal period. Acquired toxoplasmosis is usually seen in older children or adults. The most common manifestations are either asymptomatic lymphadenopathy or a viral type of illness with lymphadenopathy, low-grade fever, malaise, and possibly other symptoms.

    There may (or may not) be some atypical lymphocytes, and the clinical picture may suggest “heterophil-negative” infectious mononucleosis, cytomegalovirus infection, other viral infections or even malignant lymphoma. Another type of acquired infection is associated with deficient immunologic defense mechanisms, due to either immunologic suppression therapy or a disease such as leukemia or acquired immunodeficiency syndrome (AIDS). This is actually a reactivation of previous latent Toxoplasma infestation. Cerebral infection occasionally is the first manifestation of AIDS. Overall, Toxoplasma infects the central nervous system (CNS) in 12%-31% of patients with AIDS and comprises 25%-80% of CNS infections in AIDS.

    Diagnosis

    Diagnosis requires isolation of the organisms or serologic tests for antibody formation. Culture has proved to be very difficult, and most laboratories are not equipped to do it. Tissue culture is positive in about 40% of cases. In one study, culture sensitivity was only 25%. Mouse inoculation is a form of culture method and is positive in up to 70% of cases. Lymph node biopsy frequently can suggest the diagnosis by showing small groups of histiocytes that involve germinal centers, although the pattern is not specific enough for definitive diagnosis. Histologic slides rarely show organisms in lymph nodes.

    Serologic tests form the backbone of diagnosis. The indirect fluorescent antibody (IFA) procedure is the most commonly used present-day serologic procedure. The IFA test detects the same antibody as the Sabin-Feldman methylene blue dye test, which was the original standard test for toxoplasmosis. The dye test, however, required working with live Toxoplasma organisms. The IFA procedure can be used to detect either IgM or IgG antibody. It is somewhat better in detection of IgG than IgM.

    The IFA-IgM antibody titer begins to rise about 7-10 days after infection, reaches a peak at about 8 weeks (range, 4-10 weeks) and usually becomes nondetectable 6-12 months after infection. In one study, 20% were still detectable at 12 months. High titers of IgG antibody may cause false negative IgM results. If the IgG can be separated from the IgM, the false negative reaction can be avoided. The presence of rheumatoid factor or antinuclear antibody may produce false positive results. False positive results may also be found on tests of some newborns with other congenital infections. If the IgG can be separated from the IgM, the false positive reaction can be eliminated.

    The IFA-IgG antibody titer begins to rise about 4-7 days after the IgM antibody; reaches a peak in about 8 weeks (range, 4-10 weeks), and begins to fall slowly in about 6 months. Low titers usually persist for many years. Antinuclear antibody may produce false positive results.

    Rise in titer of either IgM or IgG antibody to Toxoplasma is rapid, with considerable elevation occurring by the end of 1 week. Therefore, a low titer of IgM or IgG usually means old rather than recent infection in patients with maternal or congenital infection. However, when ocular infection is seen as an isolated finding in older children or adults, titers frequently are not high because the initial infection was congenital. Therefore, it may be difficult to tell whether the ocular disease is due to toxoplasmosis or to something else. This is made more difficult because exposure to Toxoplasma infection is very common.

    An indirect hemagglutination (IHA) test that detects only IgG antibody is used in some laboratories. It is used mainly to see if a newly pregnant woman has antibody against Toxoplasma, thus suggesting immunity to infection.

    Enzyme-linked immunosorbent assay (ELISA) methods detecting IgM, IgG, or both, as well as other methods such as latex agglutination (LA), are commercially available. Evaluations in general show 85%-100% sensitivity compared to IFA in older children and adults and 30%-77% in newborns. However, there is significant variation in different kits. Nucleic acid probes with polymerase chain reaction (PCR) amplification have also been reported.

    In immunosuppressed patients with serious toxoplasma infection, the infection often is reactivated from previous but dormant infection. In these cases, unfortunately, antibody does not increase in response to the reactivation.

    Interpretation of toxoplasma serologic results

    If a woman is pregnant and it is desirable to know if she is immune to Toxoplasma infection, a negative titer means that she is susceptible to infection. A low titer of IgG (<1:1000) or the presence of IHA antibodies usually means that she had the disease at some time in the past and is immune. Since there is a small chance that a very early infection could be present and the titer is just beginning to rise, an IFA-IgM test can then be done. If the IFA-IgM antibody titer is greatly elevated but the IFA-IgG antibody titer is still low, this indicates early acute infection with the IgG antibody just starting to rise. Alternatively, an additional specimen may be drawn 7-10 days later and retested for IFA-IgG antibody. A fourfold rising titer indicates acute infection. A stable low titer means no recent infection. If the original specimen contains a high titer of IFA-IgG or IHA antibodies, the problem is difficult. The infection could be either acute or recent (within 1-2 years) but not acute. Only the acute infection is dangerous to the fetus. A high IgM titer is suggestive of recent infection, but in some cases it may persist for several weeks or months, falsely suggesting a more recent infection. On the other hand, it may fall rapidly and thus can be negative in association with a high IFA-IgG titer, even though acute infection began only a few weeks before.

    In a newborn with possible congenital toxoplasmosis, most investigators believe that an elevated IgM level would support the diagnosis (although other infections can also produce IgM response). The IFA-IgG titer may be considerably elevated, but IgG antibody can cross the placenta; thus, maternal IgG antibody can appear in the fetal circulation if the mother has an elevated titer from either old or recent infestation. Therefore, to make a diagnosis of congenital toxoplasmosis, it is necessary to demonstrate a rising IgG titer in the infant. If no active infant infection is present and antibody is only passively acquired from the mother, the infant IgG titer, instead of rising, should fall by the sixth week as the maternally acquired antibody is gradually eliminated.

  • Rabies

    Human disease from rabies virus infection is very uncommon in the United States. The number of human cases in the United States is usually less than five per year, and only nine were reported from 1980 to 1987. However, there are always questions about the disease, and several thousand cases of animal rabies are confirmed each year (6975 in 1991). Until 1990, wildlife rabies was most common in skunks; beginning in 1990, raccoon cases have been most frequent, followed by skunks, bats, and foxes in order of decreasing numbers. Actually most animal bites are from caged rodent pets such as rabbits, gerbils, or mice. This is not a problem since rodents (including squirrels) very rarely are infected by the rabies virus even when wild. Interestingly, of the nine human rabies cases mentioned above, six did not give a history of bat or other animal contact when they were hospitalized. Non-bite transmission of rabies from human to human (e.g., contact with saliva or CSF) has not been proven in the United States to date.

    The standard procedure for suspected rabies in domestic dogs or cats is to quarantine the animal under observation of a veterinarian for 10 days. The incubation period in humans is 1-3 months (although inoculation through facial bites may have an incubation as short as 10 days), which provides enough time for diagnosis of the animal before beginning treatment in the person who was bitten. Animal rabies will produce symptoms in the animal within 10 days in nearly all cases.

    For wild animals, if the animal was defending itself normally, it might be captured and quarantined. If it was thought to be exhibiting abnormal behavior, the animal is usually killed and the head is sent for rabies examination of the brain. The head (or brain) should be kept at refrigerator temperature (not frozen) and sent to a reference laboratory (usually a public health laboratory) as soon as possible. If the specimen will be received within 1 day, it should be sent refrigerated with ordinary ice; it if is to be stored longer than 1 day, dry ice should be used.

    Diagnosis. Laboratory diagnosis consists of stained impression smears of the brain, mouse inoculation, and serologic tests. Impression smears from Ammon’s horn of the hippocampal area in the temporal lobe stained with Seller’s stain is the traditional method for diagnosis. The smears are examined microscopically for Negri body inclusions in neurons. Use of Seller’s stain has approximately 65% sensitivity, with sensitivity reported to be somewhat greater than this in dogs (75%-80%) and somewhat less in skunks and bats. Fluorescent antibody stains on the smears have more than 95% sensitivity and currently are the standard method for diagnosis. Mouse inoculation with fresh brain extracts also has more than 95% sensitivity but may eventually be replaced by tissue culture. Saliva from animals or humans can be used for mouse inoculation, but the sensitivity is not as great as brain testing. All specimens should be taken with sterile instruments, which should be immediately decontaminated by autoclaving after use. Serologic tests (ELISA method) for rabies antibody in serum or CSF can be done if the patient has not been immunized against rabies. For serum, this requires two specimens drawn at least 1 week apart. For CSF, a single specimen positive result is diagnostic.

  • Diagnosis of Viral Diseases

    Culture. Until the 1980s, except in a relatively few cases the only available laboratory methods were culture and serologic tests for antibodies. There have been significant advances in culture techniques in the past few years, but most virus culture still is difficult and expensive. Culture is performed using living cell preparations or in living tissues. This fact in itself rules out mass production testing. Partly for this reason, facilities for culture are limited and are available mainly at sizable medical centers, regional reference laboratories, or large public health laboratories. In addition, culture and identification of the virus takes several days. Finally, cultural isolation of certain viruses does not absolutely prove that the virus is causing actual patient disease, since many viruses are quite prevalent in the general clinically healthy population. In these instances, confirmation of recent infection is helpful, such as presence of IgM antibodies or a fourfold rising titer of antibodies.

    Antigen detection. In the 1980s, several other diagnostic techniques that can detect viral antigen have appeared. These include electron microscopy, fluorescent antibody (FA or IFA) methods, enzymelinked immunoassay (ELISA), latex agglutination (LA) methods, and, even more recently, nucleic acid (DNA) probes (Chapter 14). These methods can provide same-day results. However, many of them are relatively expensive, especially the DNA probes, particularly when only one patient specimen is tested at a time. Except in large-volume reference laboratories, most institutions do not receive a large number of orders for virus tests in general; and with the possible exception of rubella, hepatitis B virus (HBV), human immunodeficiency virus type 1 (HIV-1), Epstein-Barr virus (EBV), and possibly rotavirus, laboratories usually receive very few requests for diagnosis of any one particular virus. This makes it difficult for the average laboratory to keep reagents for testing many different viruses; and without having the advantage of testing many specimens at the same time, costs (and therefore, prices) are much higher.

    Antibody detection. In addition to culture and tests for viral antigen, serologic tests for antibody are available for most viruses. There are many techniques, including complement fixation (CF), hemagglutination (HA or HAI), radioimmunoassay (RIA), ELISA, FA, and LA. Some of these methods can be adapted to detect either antigen or antibody and either IgM or IgG antibody. Although they are considerably less exacting than culture, most techniques other than LA and ELISA monoclonal spot test modifications are still somewhat tedious and time-consuming. Therefore, these tests are not immediately available except at reference laboratories. Serologic tests have the additional disadvantage that antibodies usually take 1-2 weeks to develop after onset of illness, and unless a significantly (fourfold or two-tube) rising titer is demonstrated, they do not differentiate past from recent infection by the viral agent in question. One serum specimen is obtained as early in the disease as possible (“acute” stage) and a second sample is obtained 2-3 weeks later (“convalescent” stage). Blood should be collected in sterile tubes or Vacutainer tubes and serum processed aseptically to avoid bacterial contamination. Hemolyzed serum is not acceptable. To help prevent hemolysis, serum should be separated from blood clot as soon as possible. The serum should be frozen as soon as possible after collection to minimize bacterial growth and sent still frozen (packed in dry ice) to the virus laboratory. Here a variety of serologic tests can be done to demonstrate specific antibodies to the various organisms. A fourfold rise in titer from acute to convalescent stage of the disease is considered diagnostic. If only a single specimen is taken, an elevated titer could be due to previous infection rather than to currently active disease. A single negative test result is likewise difficult to interpret, since the specimen might have been obtained too early (before antibody rise occurred) or in the case of short-lived antibodies such as IgM, a previously elevated antibody value may have decreased to nondetectable levels.

    There is one notable exception to the rule of acute and convalescent serologic specimens. In some circumstances, it is desirable to learn whether a person has an antibody titer to a particular virus that is sufficient to prevent onset of the disease. This is especially true for a woman in early pregnancy who might be exposed to rubella. A single significant antibody titer to rubella suggests immunity to the virus.

    Two types of antibodies are produced in most, but not all, bacterial or viral infections. A macroglobulin (IgM) type appears first, usually shortly before or just after onset of clinical illness; reaches a peak titer about 1-2 weeks after clinical symptoms begin; and then falls to normal levels within a few weeks (usually in less than 6 months). A gamma-globulin (IgG) type appears 1 or more weeks after detection of IgM antibody. The IgG antibody reaches a peak 1-3 weeks (sometimes longer) after the peak of the IgM antibody. The IgG antibody typically persists much longer than the IgM antibody (several years or even for life). Therefore, presence of the IgM antibody usually indicates recent acute infection. Presence of the IgG antibody usually requires that a rising titer be obtained to diagnose acute infection (although in some diseases there are circumstances that alter this requirement), since without a rising titer one does not know whether the IgG antibody elevation is due to recent or to old infection.

    Special stains. The Tzanck test is sometimes requested in certain skin diseases associated with vesicles or bullae. One of the vesicles is carefully unroofed, and the base and undersurface of the vesicle membrane is scraped; the scrapings are gently smeared on glass slides. The smear can be stained with Wright’s stain or Giemsa stain; if so, the slide can either be methanol-fixed or air-dried. Papanicolaou (Pap) stain can also be used, in which case the slide must be immediately fixed in a cytology fixative. The slide is then examined microscopically for multinucleated giant cells or characteristic large abnormal rounded epithelial cells. If found, these are suggestive of herpes simplex or varicella-zoster infection.

    Viral test specimens

    The type of specimen needed for viral culture depends on the type of illness. In aseptic meningitis, a CSF specimen should be obtained. In addition, stool culture for virus should be done, since enteroviruses are frequent causes of meningitis. In enterovirus meningitis, stool culture is 2-3 times more effective than CSF culture.

    In any kind of meningitis with negative spinal fluid cultures or severe respiratory tract infection of unknown etiology it is a good idea to freeze a specimen of serum as early in the disease as possible. Later on, if desired, another specimen can be drawn and the two sent for virus studies. As noted, serum specimens are generally drawn 2 weeks apart.

    In suspected cases of (nonbacterial) encephalitis, whole blood should be collected for virus culture during the first 2 days of illness. During this short time there is a chance of demonstrating arbovirus viremia. This procedure is not useful in aseptic meningitis. Spinal fluid should also be sent for virus culture. Although the yield is relatively small in arbovirus infections, the specimen results sometimes are positive, and culture also helps to rule out other organisms, such as enterovirus. In upper respiratory tract illness, throat or nasopharyngeal swabs are preferred. These should be placed in trypticase broth (standard bacterial medium). Swabs not preserved in some type of medium such as trypticase or Hank’s solution are usually not satisfactory, since they dry out quickly, and most viruses are killed by drying. Throat washings or gargle material can be used but are difficult to obtain properly. In viral pneumonia, sputum or throat swabs are needed. If throat swabs are used, they should be placed in acceptable transport solutions. Whether throat swab or sputum is used, the specimen must be frozen immediately and sent to the virus laboratory packed in dry ice. In addition, a sputum specimen (or throat swab) should be obtained for Mycoplasma culture (Chapter 14).

    In possible viral gastroenteritis, the most logical specimen is stool. At present, rotavirus and Norwalk viruses cannot be cultured from stool, but stool can be examined for Norwalk virus by immune electron microscopy and for rotavirus antigen by RIA, ELISA, or slide LA. Serologic tests on serum can be used for diagnosis of rotavirus infection, but only a few laboratories are able to do this. Whenever a stool culture for virus is needed, actual stool specimens are preferred to rectal swabs, since there is a better chance of isolating an organism from the larger sample. Stool samples should be collected as soon as possible—according to the U.S. Centers for Disease Control (CDC), no later than 48 hours after onset of symptoms (to ensure the best chance of success). The stool specimen should be refrigerated, not frozen; and if sent to an outside laboratory, the specimen should be shipped the day of collection (if possible), and kept cool with dry ice. However, it is better to mail any virus specimens early in the week to avoid arrival on weekends. An insulated container helps prolong effects of the dry ice.

    An adequate clinical history with pertinent physical and laboratory findings should accompany any virus specimen, whether for culture or serologic studies. As a minimum, the date of clinical illness onset, collection date of each specimen, and clinical diagnosis must be included. The most likely organism should be indicated. This information helps the virus laboratory to decide what initial procedures to use. For example, some tissue culture cell types are better adapted than others for certain viruses. Considerable time and effort can be saved and a meaningful interpretation of results can be provided.

    Certain viruses deserve individual discussion. The method of diagnosis or type of specimen required for some of these organisms is different from the usual procedure, whereas in other cases it is desirable to emphasize certain aspects of the clinical illness that suggest the diagnosis.

  • Septicemia and Bacteremia

    The concept of septicemia should probably be separated from that of bacteremia, although in many studies the two are not clearly separated. In bacteremia, a few bacteria from a focal area of infection escape from time to time into the peripheral blood. However, the main focus remains localized, and symptoms are primarily those that are caused by infection in the particular organ or tissues involved. Bacteremia may occur without infection following certain procedures, such as dental extraction (18%-85%), periodontal surgery (32%-88%), tooth brushing (0%-26%), bronchoscopy (15%), tonsillectomy (28%-38%), upper GI endoscopy (8%-12%), sigmoidoscopy (0%-10%), urethral dilatation (18%-33%), cystoscopy (0%-17%), and prostate transurethral resection (12%-46%). In one representative series, E. coli was isolated in about 20% of patients with bacteremia; S. aureus, 10%; and Klebsiella, pneumococcus, Streptococcus viridans, Bacteroides, and Pseudomonas, about 6% each. The percentage of S. epidermidis isolated varies greatly (3%-34%), probably depending on how many were considered contaminants. Polymicrobial bacteremia is reported in about 7% of cases (range, 0.7%-17%). In septicemia there is widespread and relatively continuous peripheral blood involvement. The characteristic symptoms are systemic, such as marked weakness and shock or near shock. Shock has been reported in 16%-44% of patients with gramegative bacteremia. These symptoms are usually accompanied by high fever and leukocytosis. However, septic patients may be afebrile in 10% (range, 4%-18%) of cases. Leukocytosis occurs in 60%-65% of patients (range, 42%-76%), leukopenia in 10% (range, 7%–17%), bands increased in 70%-75% (range, 62%-84%), and total neutrophils are increased in about 75% (range, 66%-92%). Any bacteria may cause septicemia. More than 50% of cases are due to gramegative rod organisms, with E. coli being the most frequent. Staphylococcus aureus probably is next most common. (In one literature review of seven studies of sepsis published in 1990 and 1991, four studies had predominance of gramegative organisms and three had predominance of gram-positive. In four of the seven studies, the percentage of gramegative and gram-positive organisms was within 10% of each other). The portal of entry of the gramegative organisms is usually from previous urinary tract infection. Many cases of septicemia follow surgery or instrumentation. The source of Staphylococcus septicemia is often very difficult to trace, even at autopsy. However, pneumonia and skin infections (sometimes very small) are the most frequent findings.

    Diagnosis. Blood cultures are the mainstay of bacteremia or septicemia diagnosis. Strict aseptic technique must be used when cultures are obtained, since contamination from skin bacteria may give false or confusing results. In cases of bacteremia or in septicemia with spiking fever, the best time to draw blood cultures is just before or at the rise in temperature. Three culture sets, one drawn every 3 hours, are a reasonable compromise among the widely diverging recommendations in the literature.

    Antibiotics and blood cultures. Blood should be drawn for culture before antibiotic therapy is begun, although a substantial number of cultures are positive despite antibiotics. Certain antibiotic removal devices are commercially available that can be of considerable help in these patients. It is essential that the culture request contain the information that antibiotics have been given, unless they have been stopped for more than 1 week. If penicillin has been used, some laboratories add the antipenicillin enzyme penicillinase to the culture medium. However, others believe that penicillinase is of little value and might actually be a potential source of contamination.

  • Diagnosis of Chronic Iron Deficiency

    The usual signals of iron deficiency are a decreased MCV (or anemia with a low-normal MCV) or elevated RDW. Hypochromia with or without microcytosis on peripheral blood smear is also suspicious. Conditions frequently associated with chronic iron deficiency (e.g., malabsorption, megaloblastic anemia, pregnancy, infants on prolonged milk feeding) should also prompt further investigation. The major conditions to be considered are chronic iron deficiency, thalassemia minor, and anemia of chronic disease. The most frequently used differential tests are the serum iron plus TIBC (considered as one test) and the serum ferritin. Although the serum ferritin test alone may be diagnostic, the test combination is frequently ordered together to save time (since the results of the serum ferritin test may not be conclusive), to help interpret the values obtained, and to provide additional information. Low serum iron levels plus low TIBC suggests chronic disease effect (Table 3-2 and Table 37-2). Low serum iron levels with high-normal or elevated TIBC suggest possible iron deficiency. If the serum iron level and %TS are both low, it is strong evidence against thalassemia minor. Laboratory tests for thalassemia minor are discussed elsewhere in more detail. If the serum ferritin level is low, this is diagnostic of chronic iron deficiency and excludes both thalassemia and anemia of chronic disease, unless they are coexisting with iron deficiency or the ferritin result was a lab error. If iron deficiency is superimposed on another condition, the iron deficiency can be treated first and the other condition diagnosed later. In some cases there may be a question whether chronic iron deficiency is being obscured by chronic disease elevation of the serum ferritin value. In some of these instances there may be indication for a bone marrow aspiration or a therapeutic trial of oral iron.

    Since RBC indices and peripheral blood smear may appear to be normal in some patients with chronic iron deficiency, it may be rational and justifiable to perform a biochemical screening test for iron deficiency (serum iron or serum ferritin) in patients with normocytic-normochromic anemia. In fact, no single biochemical test, not even serum ferritin determination, will rule out iron deficiency simply because the test result is normal. In 42 of our patients with chronic iron deficiency anemia, 9% had an MCV of 90-100 fL and 45% overall had a normal MCV. Fifteen percent had normal serum iron levels and 65% had normal TIBC. Ten percent had a serum iron level and TIBC pattern suggestive of anemia of chronic disease (presumably coexistent with the iron deficiency). Thirty percent had a serum ferritin level greater than 15 ng/100 ml (although all but one were less than 25 ng).